Charlottesville, VA, United States
Charlottesville, VA, United States

The University of Virginia , often referred to as simply Virginia, is a public research university in Charlottesville, Virginia. UVA is known for its historic foundations, student-run honor code, and secret societies.Its initial Board of Visitors included U.S. Presidents Thomas Jefferson, James Madison, and James Monroe. President Monroe was the sitting President of the United States at the time of the founding; Jefferson and Madison were the first two rectors. UVA was established in 1819, with its Academical Village and original courses of study conceived and designed entirely by Jefferson. UNESCO designated it a World Heritage Site in 1987, an honor shared with nearby Monticello.The first university of the American South elected to the Association of American Universities in 1904, UVA is classified as Very High Research Activity in the Carnegie Classification. The university is affiliated with 7 Nobel Laureates, and has produced 7 NASA astronauts, 7 Marshall Scholars, 4 Churchill Scholars, 29 Truman Scholars, and 50 Rhodes Scholars, the most of any state-affiliated institution in the U.S. Supported in part by the Commonwealth, it receives far more funding from private sources than public, and its students come from all 50 states and 147 countries. It also operates a small liberal arts branch campus in the far southwestern corner of the state.Since 1953, Virginia's athletic teams have competed in the Atlantic Coast Conference of Division I of the NCAA and are known as the Virginia Cavaliers. Virginia won its 7th men's soccer national title in December 2014, bringing its collective total to 24 National Championships, and 63 ACC Championships since 2002 , the most of any conference member during that time. Wikipedia.


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Grant
Agency: NSF | Branch: Standard Grant | Program: | Phase: COMPUTER SYSTEMS | Award Amount: 270.00K | Year: 2011

Over the past decade or more, microprocessors have faced increasing challenges in achieving high-performance for current and emerging software applications while abiding by severe power and thermal limits. In response, industry has turned to approaches that use specialized graphics and computational hardware and complex memory organizations. The end result is that computer systems have become more heterogeneous and complex, in ways that make it difficult for programmers to write efficient and high-performance software. Software tuned to run on one implementation will often not run at all or will perform poorly or unpredictably when ported to even a different implementation in the same chip family. The objective of this research effort is to design and evaluate system and hardware support that tailors memory and data access/movements to improve performance and power efficiency, while also easing the issues of programmability and of tuning software for individual chip characteristics.
The two key themes of this work are ShapeShifting and PubSub data abstractions. ShapeShifting refers to optimizations and hardware support structures that allow data to be transformed in layout, in order to support faster access, more efficient use of memory, and other attributes that improve power and performance. In some preliminary experiments, even a software-only implementation of ShapeShifting improves performance by 15%-2.8X. PubSub data abstractions offer methods for individual processors to indicate interest (or disinterest) in updates regarding other program variables. These abstractions form the underpinning for memory optimizations that are tailored to the application?s memory usage patterns. By mitigating false sharing, encouraging coarse-grained fetches, and reducing coherence broadcasts to uninterested cores, PubSub has the potential to improve the power and performance efficiency of multi-core implementations by a factor of 2X or more.
The research program is targeting several types of broad impact. First, the simulators and tools developed by this project will be released as free, open-source software. Second, the results can enhance performance and energy efficiency of future parallel hardware. Energy-efficiency is of particular concern from a national economic and strategic standpoint, given the growing electricity consumption of computer systems and the important role of the memory hierarchy in influencing computer power consumption.


Patent
University of Virginia and Beth Israel Deaconess Medical Center | Date: 2016-08-03

Methods, systems, and computer-readable media for rapid 3D dynamic arterial spin labeling with a sparse model-based image reconstruction are disclosed. In one embodiment, a method includes acquiring magnetic resonance data associated with an area of interest of a subject. The magnetic resonance data includes associated with arterial spin labeling (ASL) of the area of interest. The method also includes performing image reconstruction on the acquired resonance data. The image reconstruction includes compressed sensing enforcing a model-based sparsity constraint, where the model-based sparsity constraint is based on an ASL signal prototype dictionary.


Patent
University of Virginia | Date: 2016-10-17

Systems and methods for epicardial electrophysiology and other procedures are provided in which the location of an access needle may be inferred according to the detection of different pressure frequencies in separate organs, or different locations, in the body of a subject. Methods may include inserting a needle including a first sensor into a body of a subject, and receiving pressure frequency information from the first sensor. A second sensor may be used to provide cardiac waveform information of the subject. A current location of the needle may be distinguished from another location based on an algorithm including the pressure frequency information and the cardiac waveform information.


A gait device and method for rehabilitating or developing a subjects lower extremity. The device may include a movable belt configured for the subject to ambulate thereon; a track provided above the movable belt that is generally aligned with the movable belt; and a coupler that is configured to travel along the track and attach to the distal portion of the lower extremity of the subject while the subject is ambulating on the movable belt.


Patent
Technion Research And Development Foundation Ltd. and University of Virginia | Date: 2016-10-17

There are provided methods and compositions useful in cell-cell fusion using Fusion Family (FF) proteins of nematode origin. There are further provided antinematodal methods and compositions, utilizing fusogenic proteins of the nematode Fusion Family.


Patent
University of Virginia | Date: 2015-03-17

The present invention encompasses the use of adipose tissue derived cells, or conditioned medium of such cells, to treat and prevent vascular related injuries, diseases, disorders, and conditions such as diabetic retinopathy, where, in one aspect, pericytes such as retinal pericytes have been lost or damaged. The present application further discloses compositions and methods useful for enhancing the function and activity of the adipose tissue derived cells in the treatment and prevention of injuries, diseases, disorders, and conditions including the use of TGF to condition the cells to enhance their activity.


A technique for treating diabetes that recognizes patient insulin sensitivity is a time-varying physiological parameter. The described techniques for treating diabetes include measuring interstitial fluid glucose concentration, reading insulin delivery data, determining patient insulin sensitivity based on the interstitial fluid glucose concentration and insulin delivery data, and a time-varying physiological parameter, and dispensing an insulin dose from an insulin delivery device based on the determined patient insulin sensitivity.


Patent
University of Virginia | Date: 2015-04-15

Provided are isolated TCRs, TCR-like molecules, and portions thereof that bind to phosphopeptide-HLA-A2 complexes. The isolated TCRs, TCR-like molecules, or portions are optionally soluble TCRs, TCR-like molecules, or portions. Also provided are isolated nucleic acids encoding the disclosed TCRs, TCR-like molecules, or portions; host cells that contain the disclosed TCRs, TCR-like molecules, or portions; pharmaceutical compositions that include the disclosed TCRs, TCR-like molecules, portions, nucleic acids, and/or T cells; kits; and methods of using the same.


A graphene composite, and method of making and using the graphene composite.


Patent
University of Iowa and University of Virginia | Date: 2016-09-16

A method for treating intractable pain via electrical stimulation of the spinal cord. Remote, non-contact stimulation of a selected region of spinal cord is achieved by placement of a transceiver patch directly on the surface of that region of spinal cord, with said patch optionally being inductively coupled to a transmitter patch of similar size on either the outer or inner wall of the dura surrounding that region of the spinal cord. By inductively exchanging electrical power and signals between said transmitter and transceiver patches, and by carrying out the necessary electronic and stimulus signal distribution functions on the transceiver patch, the targeted dorsal column axons can be stimulated without the unintended stray stimulation of nearby dorsal rootlets. Novel configurations of a pliable surface-sheath and clamp or dentate ligament attachment features which realize undamaging attachment of the patch to the spinal cord are described.


A low voltage crystal oscillator (XTAL) driver with feedback controlled duty cycling for ultra low power biases an amplifier for an XTAL in the sub-threshold operating regime. A feedback control scheme can be used to bias the amplifier for an XTAL biased in the sub-threshold operating regime. The amplifier of a XTAL oscillator can be duty cycled to save power, e.g., the XTAL driver can be turned off to save power when the amplitude of the XTAL oscillation reaches a maximum value in range; but be turned back on when the amplitude of the XTAL oscillation starts to decay, to maintain the oscillation before it stops. In addition or alternatively, a feedback control scheme to duty cycle the amplifier of a XTAL oscillator can be used to monitor the amplitude of the oscillation.


Patent
University of Virginia | Date: 2016-09-01

A pulse train comprising chirped pulses can be used to excite a sample, such as for spectroscopic analysis. The respective chirped pulses can include a frequency sweep to establish a first frequency-domain comb. A width of frequency-domain comb peaks can be established at least in part by a total duration of the pulse train, and a bandwidth of the first frequency-domain comb can be determined at least in part by a bandwidth of the frequency sweep of the respective chirped pulses. A free-space or enclosed sample interaction region can be used.


Patent
The Regents Of The University Of Colorado and University of Virginia | Date: 2016-11-14

Disclosed are biomarkers, methods and assay systems for the identification of cancer patients who are predicted to respond, or not respond to the therapeutic administration of radiation therapy to treat cancer. Thus, the invention provides a diagnostic paradigm to select cancer patients who will benefit from radiation therapy. In particular, the invention provides a novel 41-gene biomarker model associated with clinical outcome following radiotherapy across multiple histological tumor types, including the biomarker Cyclophilin B (PPIB).


Patent
University of Virginia | Date: 2016-11-18

The invention provides methods to assess protein stability and to obtain sizing information. In one aspect, the screen comprises a 94 detergent panel and a series of MWCO filtered microplates. A protein of interest is bound to an affinity matrix and aliquoted into a 96-well microplate. Wells containing the immobilized protein are washed in the new detergent and then eluted in the new detergent into a collection plate. Protein not stable in the new detergent is precipitated on the resin and not present in the elutions. Half of the elution is passed through a high (i.e., 300 kDa) MWCO microplate and the other half through a low (i.e., 100 kDa) MWCO microplate. Elutions from the microplates are spotted on a nitrocellulose membrane, visualized by Western analysis (or by some other method), and quantified. The high MWCO provides stability readout and the ratio of low/high kDa provides sizing information.


Patent
University of Virginia | Date: 2015-04-14

Cellular materials and methods of making and using the cellular materials.


Patent
University of Virginia | Date: 2016-09-23

A flexible electrode comprises an activated cotton textile composite comprising activated carbon fibers, nickel sulfide nanoparticles and graphene and a process for making the flexible electrode. The process may comprise preparing a cotton textile containing Ni(NO_(3))_(2). Then, the cotton textile containing Ni(NO_(3))_(2 )may be heated at a first temperature to produce an activated cotton textile composite comprising activated carbon fibers, nickel nanoparticles and graphene. The activated cotton textile composite may be then treated with sulfur to produce an activated cotton textile composite comprising activated carbon fibers, nickel sulfide nanoparticles and graphene. The nickel sulfide particles may be NiS_(2 )nanoparticles in a form of nanobowls, and distributed on a surface and inside the activated carbon fibers. The activated carbon fibers and the nickel sulfide nanoparticles may be coated with graphene. Banana peels may be activated and treated with the similar processes to form electrodes for both supercapacitor and battery applications.


Patent
University of Virginia | Date: 2015-09-30

The present invention discloses a heterogeneous computation framework, of Association. Rule Mining (ARM) using Microns Autotmata Processor (AP). This framework is based on the Apriori algorithm. Two Automaton designs are proposed to match and count the individual itemset. Several performance improvement strategies are proposed including minimizing the number of reporting vectors and reduce reconfiguration delays. The experiment results show up to 94 speed ups of the proposed AP-accelerated Apriori on six synthetic and real-world datasets, when compared with the Apriori single-core CPU implementation. The proposed AP-accelerated Apriori solution also outperforms the state-of-the-art multicore and GPU implementations of Equivalence Class Transformation (Eclat) algorithm on big datasets.


Patent
University of Virginia | Date: 2016-09-16

In one aspect, the disclosed technology relates to a method which, in one example embodiment, includes acquiring magnetic resonance imaging data for a plurality of images of the heart of a subject during free breathing of the subject. The method also includes generating an additional plurality of images with high tissue-blood contrast over the region of interest, and selecting a subset of images from the plurality of images, based upon a pre-determined quality metric of image similarity, to be used for non-rigid image registration. The method also includes aligning the subset of images by non-rigid image registration using a combination of the plurality of images and the additional plurality of images, and creating a parametric map from the aligned images.


Saucerman J.J.,University of Virginia | Bers D.M.,University of California at Davis
Journal of Molecular and Cellular Cardiology | Year: 2012

Calmodulin (CaM) acts as a common Ca 2+ sensor for many signaling pathways, transducing local Ca 2+ signals into specific cellular outcomes. Many of CaM's signaling functions can be explained by its unique biochemical properties, including high and low affinity Ca 2+-binding sites with slow and fast kinetics, respectively. CaM is expected to have a limited spatial range of action, emphasizing its role in local Ca 2+ signaling. Interactions with target proteins further fine-tune CaM signal transduction. Here, we focus on only three specific cellular targets for CaM signaling in cardiac myocytes: the L-type Ca 2+ channel, the ryanodine receptor, and the IP 3 receptor. We elaborate a working hypothesis that each channel is regulated by two distinct functional populations of CaM: dedicated CaM and promiscuous CaM. Dedicated CaM is typically tethered to each channel and directly regulates channel activity. In addition, a local pool of promiscuous CaM appears poised to sense local Ca 2+ signals and trigger downstream pathways such as Ca 2+/CaM dependent-protein kinase II and calcineurin. Understanding how promiscuous CaM coordinates multiple distinct signaling pathways remains a challenge, but is aided by the use of mathematical modeling and a new generation of fluorescent biosensors. This article is part of a special issue entitled "Local Signaling in Myocytes.". © 2011 Elsevier Ltd.


Ioannidis J.P.A.,Stanford University | Munafo M.R.,University of Bristol | Fusar-Poli P.,King's College London | Nosek B.A.,University of Virginia | David S.P.,Stanford University
Trends in Cognitive Sciences | Year: 2014

Recent systematic reviews and empirical evaluations of the cognitive sciences literature suggest that publication and other reporting biases are prevalent across diverse domains of cognitive science. In this review, we summarize the various forms of publication and reporting biases and other questionable research practices, and overview the available methods for probing into their existence. We discuss the available empirical evidence for the presence of such biases across the neuroimaging, animal, other preclinical, psychological, clinical trials, and genetics literature in the cognitive sciences. We also highlight emerging solutions (from study design to data analyses and reporting) to prevent bias and improve the fidelity in the field of cognitive science research. © 2014 Elsevier Ltd.


Wu X.,Shanghai JiaoTong University | Lin Z.,University of Virginia
IEEE Transactions on Automatic Control | Year: 2012

This technical note examines the immediate, delayed and anticipatory activation of anti-windup mechanism. Traditional anti-windup compensators are designed for immediate activation. A recent innovation is to delay the activation of the anti-windup mechanism until the degree of saturation reaches to a certain level. By allowing the nominal controller to function undisturbed in the face of modest actuator saturation, delayed activation of the anti-windup mechanism has been shown to lead to improvement in the closed-loop performance. In this technical note, we propose to activate the static anti-windup compensation in anticipation of actuator saturation and show that such a "precautionary" approach has the potential of leading to further improvement in the closed-loop performance, in terms of both the transient quality in reference tracking and the region of stability. © 2011 IEEE.


Grant
Agency: National Science Foundation | Branch: | Program: STTR | Phase: Phase I | Award Amount: 225.00K | Year: 2015

The broader impact/commercial potential of this project is bringing numerous economic and social benefits to the public: advance the security of information and communication, decrease public health risk, and overall increase the quality of life all around the world. VLC has the potential to significantly increase the speed of Internet connection in multiuser indoor environments due to the broad bandwidth of the visible light. Commercializing the VLC technology will not only be a big step toward energy saving and provide stronger justification and desire for implementing economical LED systems, but also will increase the speed and security of wireless data communications. It will offer a huge energy saving for the nation since energy is already used for lighting, and thus does not require separate expenditure for communications. It will also increase the quality of life for those who are concerned about the impacts of Wi-Fi on their health, and any group of people including children and pregnant women can use it for Internet connection without any concern about the effect of electromagnetic waves. VLC can replace the controversial Wi-Fi technology in schools, hospitals, kindergartens and any other place that health issues are of major concerns. This Small Business Technology Transfer Research (STTR) Phase I project is to develop the technology for visible light communication (VLC) system that achieves high data-rates using low-cost commercial light emitting diodes (LED). VLC is a potential alternative data communication technique for wireless applications that uses optical energy to provide simultaneously lighting needs and data transmission. The idea in this technology is to transmit the data using the lighting systems that are already used for the illumination of indoor environments. Spectrally efficient coding and modulation techniques with dimming feature support will be developed based on combinatorial designs to modulate LEDs. Multi-input multi-output (MIMO) will be explored to increase the transmission speeds since each user receives signals from multiple LEDs. Solutions to address technical problems of using LEDs intended for lighting in commercial VLC systems, such as LED heating, LED nonlinearity and controlling large LED-arrays with low-cost small circuits will be explored. The techniques developed in the Phase I of this proposal can also be employed along with faster but more expensive LEDs and photo-detectors to achieve Gbps streaming in VLC systems. Furthermore, tri-chromatic LEDs can be used to achieve a three-fold increase in the data-rate by modulating each color independently.


Oishi S.,University of Virginia | Diener E.,University of Illinois at Urbana - Champaign
Psychological Science | Year: 2014

Using Gallup World Poll data, we examined the role of societal wealth for meaning in life across 132 nations. Although life satisfaction was substantially higher in wealthy nations than in poor nations, meaning in life was higher in poor nations than in wealthy nations. In part, meaning in life was higher in poor nations because people in those nations were more religious. The mediating role of religiosity remained significant after we controlled for potential third variables, such as education, fertility rate, and individualism. As Frankl (1963) stated in Man's Search for Meaning, it appears that meaning can be attained even under objectively dire living conditions, and religiosity plays an important role in this search. © The Author(s) 2013.


Agnew S.R.,University of Virginia | Nie J.F.,Monash University
Scripta Materialia | Year: 2010

Research papers, which will guide future research aimed in magnesium alloys at improving the properties and broadening the structural applications of the metal, are discussed. Three papers in the viewpoint set are devoted to creep mechanisms and development of creep-resistant alloys. The paper by Saddock and co-researchers demonstrate that there is no significant contribution of grain boundary sliding to creep in alloys based on the Mg-Al-Ca system, at least when tested at 175°C. Spigarelli and El Mehtedi make a comparison of the constitutive response in creep and hot torsion of both cast and wrought magnesium alloys, obtained in the temperature range 100-150°C. The potential to develop high-strength low-cost magnesium wrought alloys through precipitation hardening is discussed in the paper by Hono and co-researchers, with emphasis on microalloying additions to Mg-Zn and Mg-Sn alloys. The paper by Kim and researchers predicts that even twinroll cast material is not free from the concerns associated with strong basal texture that have plagued traditional direct-chill cast and hot-rolled materials.


Rulli M.C.,Polytechnic of Milan | Saviori A.,Polytechnic of Milan | D'Odorico P.,University of Virginia
Proceedings of the National Academy of Sciences of the United States of America | Year: 2013

Societal pressure on the global land and freshwater resources is increasing as a result of the rising food demand by the growing human population, dietary changes, and the enhancement of biofuel production induced by the rising oil prices and recent changes in United States and European Union bioethanol policies. Many countries and corporations have started to acquire relatively inexpensive and productive agricultural land located in foreign countries, as evidenced by the dramatic increase in the number of transnational land deals between 2005 and 2009.Often known as "land grabbing," this phenomenon is associated with an appropriation of freshwater resources that has never been assessed before. Herewe gather landgrabbing data frommultiple sources and use a hydrological model to determine the associated rates of freshwater grabbing. We find that land and water grabbing are occurring at alarming rates in all continents except Antarctica. The per capita volume of grabbed water often exceeds the water requirements for a balanced diet andwould be sufficient to improve food security and abate malnourishment in the grabbed countries. It is found that about 0.31 × 1012 m3·y -1 of green water (i.e., rainwater) and up to 0.14 × 10 12 m3·y-1 of blue water (i.e., irrigation water) are appropriated globally for crop and livestock production in 47 × 106 ha of grabbed landworldwide (i.e., in 90% of the reported global grabbed land).


Ungewitter E.,Kogod Center on Aging | Ungewitter E.,University of Virginia | Scrable H.,Kogod Center on Aging
Genes and Development | Year: 2010

Δ40p53 is a transactivation-deficient isoform of the tumor suppressor p53. We discovered that Δ40p53, in addition to being highly expressed in embryonic stem cells (ESCs), is the major p53 isoform during early stages of embryogenesis in the mouse. By altering the dose of Δ40p53 in ESCs, we identified a critical role for this isoform in maintaining the ESC state. Haploinsufficiency for Δ40p53 causes a loss of pluripotency in ESCs and acquisition of a somatic cell cycle, while increased dosage of Δ40p53 prolongs pluripotency and inhibits progression to a more differentiated state. Δ40p53 controls the switch from pluripotent ESCs to differentiated somatic cells by controlling the activity of full-length p53 at critical targets such as Nanog and the IGF-1 receptor (IGF-1R). The IGF axis plays a central role in the switch between pluripotency and differentiation in ESCs - and Δ40p53, by controlling the level of the IGF-1R, acts as a master regulator of this switch. We propose that this is the primary function of Δ40p53 in cells of the early embryo and stem cells, which are the only normal cells in which this isoform is expressed. © 2010 by Cold Spring Harbor Laboratory Press.


Gwathmey K.G.,University of Virginia | Burns T.M.,University of Virginia | Collins M.P.,Medical College of Wisconsin | Dyck P.J.B.,Mayo Medical School
The Lancet Neurology | Year: 2014

The vasculitic neuropathies are a diverse group of disorders characterised by the acute-to-subacute onset of painful sensory and motor deficits that result from inflammatory destruction of nerve blood vessels and subsequent ischaemic injury. They are common in patients with primary systemic vasculitis and are seen in vasculitis secondary to disorders such as rheumatoid arthritis, viral infections, and diabetic inflammatory neuropathies. It is imperative that neurologists recognise these disorders to initiate treatment promptly and thereby prevent morbidity and mortality. To simplify the approach to patients with vasculitis of the peripheral nerves, a straightforward, dichotomous classification scheme can be used in which the vasculitic neuropathies are divided into two groups-nerve large arteriole vasculitis and nerve microvasculitis-on the basis of the size of the involved vessels. The size of the affected blood vessels correlates with the clinical course and prognosis in patients with vasculitic neuropathy. © 2014 Elsevier Ltd.


Grant
Agency: Department of Defense | Branch: Navy | Program: STTR | Phase: Phase I | Award Amount: 80.00K | Year: 2015

Cyber physical systems are ubiquitous in the modern world; they control transportation, energy, military, medical, and manufacturing infrastructures. Cyber resiliency remains a problem in these systems that rely on both functional and real-time specifications to meet physical, and often safety-critical, goals. We propose a system that integrates existing software strengthening tools (e.g., automated program repair and software hardening) with practical static real-time specification checking to enhance the functional robustness of the target systems while ensuring continued schedulability and real-time specification adherence. The underlying techniques will benefit in a dual fashion: we propose enhancements to the scalability and extensibility of static runtime calculation and consequently will improve upon state-of-the-art software strengthening techniques (in terms of program validation and performance), thus expanding their applicability to operate on the targeted cyber physical systems. The resulting framework will help to guard against both known and unknown vulnerabilities in these critical systems while accounting for schedulability, thus enhancing their cyber resiliency in practice.


Grant
Agency: Department of Defense | Branch: Air Force | Program: STTR | Phase: Phase I | Award Amount: 98.59K | Year: 2011

ABSTRACT: Military and other software systems often face the need to accept untrusted software components into the system. The proposed research will enable secure integration of untrusted software components by (1) isolating these components using application-level (per-process) virtualization; (2) assisting the customer in constructing a security policy tailored to each untrusted component; (3) enforcing that security policy in the field using the virtualization technology; and (4) detecting, where possible, likely sources of security policy violation prior to deployment of the software so that vulnerabilities and malware can be detected early. The security policies will be specified with an interactive tool and will focus on the locations (both local disk and network locations) to which the untrusted component is allowed communication privileges. BENEFIT: Military and other uses of the product will be able to accept untrusted software components into trusted systems and tailor security policies specifically to those software components. Violations of the security policies will be detected and prevented.


Grant
Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: SEC-2012.6.1-3 | Award Amount: 5.44M | Year: 2013

The ATHENA project brings together major user communities with world leading experts in crisis management and experts and technology developers of mobile and social media use and development. The goal of the ATHENA project is to deliver two major outputs that will enable and encourage users of new media to contribute to the security of citizens in crisis situations and for search and rescue actions: First, a set of best practice guidelines for LEAs, police, first responders and citizens for the use of new media, supporting tools and technologies in crisis situations Second, a suite of prototype software tools to enhance the ability of LEAs, police, first responders and citizens in their use of mobile and smart devices in crisis situations This project will explore how the huge popularity of new communication media, particularly web-based social media such as Twitter and Facebook, and the prolific use of high-tech mobile devices, can be harnessed to provide efficient and effective communication and enhanced situational awareness during a crisis. The ATHENA system is a crisis communication and management system that encourages and enables the public to participate, in an ethical way, in the process of emergency communication to contribute to the security of the citizen in crisis situations and for search and rescue actions. ATHENA makes use of new social media and high tech mobile devices to efficiently and effectively acquire, analyse and disseminate crisis information and intelligence that is appropriate and useful to LEAs/police/first responders and the public.


Klibanov A.L.,University of Virginia
Journal of Cardiovascular Translational Research | Year: 2013

Ultrasound imaging is widely used in cardiovascular diagnostics. Contrast agents expand the range of tasks that ultrasound can perform. In the clinic in the USA, endocardial border delineation and left ventricle opacification have been an approved indication for more than a decade. However, myocardial perfusion contrast ultrasound studies are still at the clinical trials stage. Blood pool contrast and perfusion in other tissues might be an easier indication to achieve: general blood pool ultrasound contrast is in wider use in Europe, Canada, Japan, and China. Targeted (molecular) contrast microbubbles will be the next generation of ultrasound imaging probes, capable of specific delineation of the areas of disease by adherence to molecular targets. The shell of targeted microbubbles (currently in the preclinical research and early stage clinical trials) is decorated with the ligands (antibodies, peptides or mimetics, hormones, and carbohydrates) that ensure firm binding to the molecular markers of disease. © 2013 Springer Science+Business Media New York.


Ruiz-Perez F.,University of Virginia | Nataro J.P.,University of Virginia
Cellular and Molecular Life Sciences | Year: 2014

Serine proteases exist in eukaryotic and prokaryotic organisms and have emerged during evolution as the most abundant and functionally diverse group. In Gramnegative bacteria, there is a growing family of high molecular weight serine proteases secreted to the external milieu by a fascinating and widely employed bacterial secretion mechanism, known as the autotransporter pathway. They were initially found in Neisseria, Shigella, and pathogenic Escherichia coli, but have now also been identified in Citrobacter rodentium, Salmonella, and Edwardsiella species. Here, we focus on proteins belonging to the serine protease autotransporter of Enterobacteriaceae (SPATEs) family. Recent findings regarding the predilection of serine proteases to host intracellular or extracellular proteinsubstrates involved in numerous biological functions, such as those implicated in cytoskeleton stability, autophagy or innate and adaptive immunity, have helped provide a better understanding of SPATEs' contributions in pathogenesis. Here, we discuss their classification, substrate specificity, and potential roles in pathogenesis. © Springer Basel 2013.


Curran J.C.,University of Virginia
Geomorphology | Year: 2010

Mobility of large woody debris (LWD) in low gradient channels is an important but often overlooked transport process. The majority of studies on LWD have focused on its role in geomorphic and ecologic river processes. When jams extend across the width of the channel, they have the potential to retain sediment and alter the channel profile. When jams obstruct only a portion of the channel, they can re-direct flow, altering patterns of scour and deposition. The boundary complexity created by LWD has a recognized role in riverine ecosystems which has led to programs of replacing LWD in-channel corridors where it was previously removed. Although LWD jams are common in rivers around the world, they have been studied most intensely in steep, forested channel reaches where they are often found to be stable channel features. It is not fully known how much of the information on LWD from steep forested channels will transfer to other channel types. Whereas it may be reasonable to assume that the ecological benefits of LWD are similar in low gradient channels, research has shown that a much higher rate of LWD transport occurs in low gradient channels, with jams mobilized on timescales of 100-102 years. This study evaluates the distribution and mobility of LWD over 72 km of the San Antonio River, a low gradient channel in southeast Texas. LWD jam locations were identified for 2003 and 2007 using a combination of aerial photography and field mapping. Each jam was cataloged according to its location in the channel cross-section and the amount of channel area blocked. During the four-year period, all the LWD jams were mobilized, including those jams extending across the channel width. Although easily mobilized, 34 jams re-form in the same locations, creating 34 channel locations with persistent LWD jams. Data from the San Antonio River are applied to two models developed to predict LWD mobility and transport distances to assess the applicability of each model to a low gradient channel. The locations of stable (or recurring) LWD jams were matched to model results where predicted LWD transport distances were equal to measured LWD jam spacing. Model results showed good agreement with the mean and median spacing of LWD jams when given input parameters specific to the channel and wood species. The ability to predict where LWD jams will persist over time in a low gradient channel has application in watershed management. Persistent LWD jams can exert a greater influence on channel morphology and may require active management. © 2009 Elsevier B.V. All rights reserved.


Egelman E.H.,University of Virginia
Archives of Biochemistry and Biophysics | Year: 2015

The field of three-dimensional electron microscopy began more than 45 years ago with a reconstruction of a helical phage tail, and helical polymers continue to be important objects for three-dimensional reconstruction due to the centrality of helical protein and nucleoprotein polymers in all aspects of biology. We are now witnessing a fundamental revolution in this area, made possible by direct electron detectors, which has led to near-atomic resolution for a number of important helical structures. Most importantly, the possibility of achieving such resolution routinely for a vast number of helical samples is within our reach. One of the main problems in helical reconstruction, ambiguities in assigning the helical symmetry, is overcome when one reaches a resolution where secondary structure is clearly visible. However, obstacles still exist due to the intrinsic variability within many helical filaments. © 2015 Elsevier Inc. All rights reserved.


Santos W.L.,Virginia Polytechnic Institute and State University | Lynch K.R.,University of Virginia
ACS Chemical Biology | Year: 2015

The transfer of the gamma phosphate from ATP to sphingosine (Sph) to generate a small signaling molecule, sphingosine 1-phosphate (S1P), is catalyzed by sphingosine kinases (SphK), which exist as two isoforms, SphK1 and SphK2. SphK is a key regulator of S1P and the S1P:Sph/ceramide ratio. Increases in S1P levels have been linked to diseases including sickle cell disease, cancer, and fibrosis. Therefore, SphKs are potential targets for drug discovery. However, the current chemical biology toolkit needed to validate these enzymes as drug targets is inadequate. With this review, we survey in vivo active SphK inhibitors and highlight the need for developing more potent and selective inhibitors. © 2014 American Chemical Society.


Columbus L.,University of Virginia
Current Opinion in Structural Biology | Year: 2015

Currently, membrane proteins only comprise 1.5% of the protein data bank and, thus, still remain a challenge for structural biologists. Expression, stabilization in membrane mimics (e.g. detergent), heterogeneity (conformational and chemical), and crystallization in the presence of a membrane mimic are four major bottlenecks encountered. In response, several post-expression protein modifications have been utilized to facilitate structure determination of membrane proteins. This review highlights four approaches: limited proteolysis, deglycosylation, cysteine alkylation, and lysine methylation. Combined these approaches have facilitated the structure determination of more than 40 membrane proteins and, therefore, are a useful addition to the membrane protein structural biologist's toolkit. © 2015 Elsevier Ltd.


Rychak J.J.,Targeson Inc. | Klibanov A.L.,University of Virginia
Advanced Drug Delivery Reviews | Year: 2014

Nucleic acid-based therapy is a growing field of drug delivery research. Although ultrasound has been suggested to enhance transfection decades ago, it took a combination of ultrasound with nucleic acid carrier systems (microbubbles, liposomes, polyplexes, and viral carriers) to achieve reasonable nucleic acid delivery efficacy. Microbubbles serve as foci for local deposition of ultrasound energy near the target cell, and greatly enhance sonoporation. The major advantage of this approach is in the minimal transfection in the non-insonated non-target tissues. Microbubbles can be simply co-administered with the nucleic acid carrier or can be modified to carry nucleic acid themselves. Liposomes with embedded gas or gas precursor particles can also be used to carry nucleic acid, release and deliver it by the ultrasound trigger. Successful testing in a wide variety of animal models (myocardium, solid tumors, skeletal muscle, and pancreas) proves the potential usefulness of this technique for nucleic acid drug delivery. © 2014 Elsevier B.V.


Larsson P.,University of Virginia | Kasson P.M.,University of Virginia
PLoS Computational Biology | Year: 2013

Fusion peptides from influenza hemagglutinin act on membranes to promote membrane fusion, but the mechanism by which they do so remains unknown. Recent theoretical work has suggested that contact of protruding lipid tails may be an important feature of the transition state for membrane fusion. If this is so, then influenza fusion peptides would be expected to promote tail protrusion in proportion to the ability of the corresponding full-length hemagglutinin to drive lipid mixing in fusion assays. We have performed molecular dynamics simulations of influenza fusion peptides in lipid bilayers, comparing the X-31 influenza strain against a series of N-terminal mutants. As hypothesized, the probability of lipid tail protrusion correlates well with the lipid mixing rate induced by each mutant. This supports the conclusion that tail protrusion is important to the transition state for fusion. Furthermore, it suggests that tail protrusion can be used to examine how fusion peptides might interact with membranes to promote fusion. Previous models for native influenza fusion peptide structure in membranes include a kinked helix, a straight helix, and a helical hairpin. Our simulations visit each of these conformations. Thus, the free energy differences between each are likely low enough that specifics of the membrane environment and peptide construct may be sufficient to modulate the equilibrium between them. However, the kinked helix promotes lipid tail protrusion in our simulations much more strongly than the other two structures. We therefore predict that the kinked helix is the most fusogenic of these three conformations. © 2013 Larsson, Kasson.


Community-associated (CA) methicillin-resistant Staphylococcus aureus (MRSA) strains have emerged as major human pathogens. CA-MRSA virulence appears to be distinct from healthcare-associated (HA) MRSA with several factors [α-hemolysin (Hla), Panton-Valentine leukocidin (PVL), α-type phenol soluble modulins (PSMα) and SCCmec IV] postulated to enhance virulence or fitness. Using the Caenorhabditis elegans infection model, we compared the virulence of clinical and laboratory isolates of CA-MRSA and HA-MRSA and explored the contribution of CA-MRSA associated virulence factors to nematode killing. All CA-MRSA strains were highly pathogenic to nematodes, while HA-MRSA strains demonstrated variable nematode killing. Nematode killing by isogenic mutants of hla or the loci for PVL, PSMα, PSMβ, PSMδ or SCCmec IV was not different than the parental strains. These results demonstrate that CA-MRSA is highly virulent, shows some strains of HA-MRSA are equally virulent toward nematodes and suggests CA-MRSA virulence in C. elegans is not linked to a single virulence factor.


Thisse B.,University of Virginia | Thisse C.,University of Virginia
Seminars in Cell and Developmental Biology | Year: 2015

During the course of their classic experiments, Hilde Mangold and Hans Spemann discovered that the dorsal blastopore lip of an amphibian gastrula was able to induce formation of a complete embryonic axis when transplanted into the ventral side of a host gastrula embryo. Since then, the inducing activity of the dorsal lip has been known as the Spemann or dorsal organizer. During the past 25 years, studies performed in a variety of species have led to the identification of molecular factors associated with the properties of this tissue. However, none of them is, by itself, able to induce formation of the main body axis from a population of naive pluripotent embryonic cells. Recently, experiments performed using the zebrafish (Danio rerio) revealed that the organizing activities present in the embryo are not restricted to the Spemann organizer but are distributed along the entire blastula/gastrula margin. These organizing activities result from the interaction between two opposing gradients of morphogens, BMP and Nodal, that are the primary signals that trigger the cascade of developmental events leading to the organization of the embryo. These studies mark the end of the era during which developmental biologists saw the Spemann organizer as the core element for the organization of the vertebrate embryonic axis and, instead, provides opportunities for the experimental control of morphogenesis starting with a population of embryonic pluripotent cells that will be instructed using those two morphogen gradients. © 2015 Elsevier Ltd.


Volkov A.N.,University of Virginia | Zhigilei L.V.,University of Virginia
Physical Review Letters | Year: 2010

The scaling laws describing the thermal conductivity in random networks of straight conducting nanofibers are derived analytically and verified in numerical simulations. The applicability of the scaling laws to more complex structures of interconnected networks of bundles in carbon nanotube (CNT) films and mats is investigated in mesoscopic simulations. The heat transfer in CNT materials is found to be strongly enhanced by self-organization of CNTs into continuous networks of bundles. The thermal conductivity of CNT films varies by orders of magnitude depending on the length of the nanotubes and their structural arrangement in the material. © 2010 The American Physical Society.


Cano J.,University of Virginia | Fendley P.,University of Virginia
Physical Review Letters | Year: 2010

Quantum dimer models exhibit quantum critical points and liquid states when the ground state is the resonating-valence bond (RVB) state. We construct SU(2)-invariant spin-1/2 Hamiltonians with the same RVB ground state. The main technical obstacle overcome is the fact that different dimer configurations in the spin model are not orthogonal. We show that the physics depends on how dimers are related to the spins, and find a Hamiltonian that is likely to be quantum critical. © 2010 The American Physical Society.


Janes K.A.,University of Virginia
Cell | Year: 2015

How stochastic is gene expression in mammalian cells? Not very, according to Battich et al., who report that single-cell variability in cytoplasmic mRNAs is remarkably predictable given measurements of a cell's phenotypic state and microenvironment. The noise from transcriptional bursts is buffered by a hallmark of eukaryotes - the nucleus. © 2015 Elsevier Inc. All rights reserved.


Salerno M.,University of Virginia | Kramer C.M.,University of Virginia
JACC: Cardiovascular Imaging | Year: 2013

Cardiac magnetic resonance imaging (CMR) is well established and considered the gold standard for assessing myocardial volumes and function, and for quantifying myocardial fibrosis in both ischemic and nonischemic heart disease. Recent developments in CMR imaging techniques are enabling clinically-feasible rapid parametric mapping of myocardial perfusion and magnetic relaxation properties (T1, T2, and T2* relaxation times) that are further expanding the range of unique tissue parameters that can be assessed using CMR. To generate a parametric map of perfusion or relaxation times, multiple images of the same region of the myocardium are acquired with different sensitivity to the parameter of interest, and the signal intensities of these images are fit to a model which describes the underlying physiology or relaxation parameters. The parametric map is an image of the fitted perfusion parameters or relaxation times. Parametric mapping requires acquisition of multiple images typically within a breath-hold and thus requires specialized rapid acquisition techniques. Quantitative perfusion imaging techniques can more accurately determine the extent of myocardial ischemia in coronary artery disease and provide the opportunity to evaluate microvascular disease with CMR. T1 mapping techniques performed both with and without contrast are enabling quantification of diffuse myocardial fibrosis and myocardial infiltration. Myocardial edema and inflammation can be evaluated using T 2 mapping techniques. T2* mapping provides an assessment of myocardial iron-overload and myocardial hemorrhage. There is a growing body of evidence for the clinical utility of quantitative assessment of perfusion and relaxation times, although current techniques still have some important limitations. This article will review the current imaging technologies for parametric mapping, emerging applications, current limitations, and potential of CMR parametric mapping of the myocardium. The specific focus will be the assessment and quantification of myocardial perfusion and magnetic relaxation times. © 2013 by The American College of Cardiology Foundation.


Cafiso D.S.,University of Virginia
Accounts of Chemical Research | Year: 2014

ConspectusProtein structures are not static but sample different conformations over a range of amplitudes and time scales. These fluctuations may involve relatively small changes in bond angles or quite large rearrangements in secondary structure and tertiary fold. The equilibrium between discrete structural substates on the microsecond to millisecond time scale is sometimes termed conformational exchange. Protein dynamics and conformational exchange are believed to provide the basis for many important activities, such as protein-protein and protein-ligand interactions, enzymatic activity and protein allostery; however, for many proteins, the dynamics and conformational exchange that lead to function are poorly defined.Spectroscopic methods, such as NMR, are among the most important methods to explore protein dynamics and conformational exchange; however, they are difficult to implement in some systems and with some types of exchange events. Site-directed spin labeling (SDSL) is an EPR based approach that is particularly well-suited to high molecular-weight systems such as membrane proteins. Because of the relatively fast time scale for EPR spectroscopy, it is an excellent method to examine exchange. Conformations that are in exchange are captured as distinct populations in the EPR spectrum, and this feature when combined with the use of methods that can shift the free energy of conformational substates allows one to identify regions of proteins that are in dynamic exchange. In addition, modern pulse EPR methods have the ability to examine conformational heterogeneity, resolve discrete protein states, and identify the substates in exchange.Protein crystallography has provided high-resolution models for a number of membrane proteins; but because of conformational exchange, these models do not always reflect the structures that are present when the protein is in a native bilayer environment. In the case of the Escherichia coli vitamin B12 transporter, BtuB, the energy coupling segment of this protein undergoes a substrate-dependent unfolding, which acts to couple this outer-membrane protein to the inner-membrane protein TonB. EPR spectroscopy demonstrates that the energy coupling segment is in equilibrium between ordered and disordered states, and that substrate binding shifts this equilibrium to favor an unfolded state. However, in crystal structures of BtuB, this segment is resolved and folded within the protein, and neither the presence of this equilibrium nor the substrate-induced change is revealed. This is a result of the solute environment and the crystal lattice, both of which act to stabilize one conformational substate of the transporter.Using SDSL, it can be shown that conformational exchange is present in other regions of BtuB and in other members of this transporter family. Conformational exchange has also been examined in systems such as the plasma membrane SNARE protein, syntaxin 1A, where dynamics are controlled by regulatory proteins such as munc18. Regulating the microsecond to millisecond time scale dynamics in the neuronal SNAREs is likely to be a key feature that regulates assembly of the SNAREs and neurotransmitter release. © 2014 American Chemical Society.


Blair J.,University of Virginia | Iwasaki T.,University of California at Los Angeles
IEEE Transactions on Automatic Control | Year: 2011

The essential mechanism underlying animal locomotion can be viewed as mechanical rectification that converts periodic body movements to thrust force through interactions with the environment. This paper defines a general class of mechanical rectifiers as multi-body systems equipped with such thrust generation mechanisms. A simple model is developed from the EulerLagrange equation by assuming small body oscillations around a given nominal posture. The model reveals that the rectifying dynamics can be captured by a bilinear, but not linear, term of body shape variables. An optimal gait problem is formulated for the bilinear rectifier model as a minimization of a quadratic cost function over the set of periodic functions subject to a constraint on the average locomotion velocity. We prove that a globally optimal solution is given by a harmonic gait that can be found by generalized eigenvalue computation with a line search over cycle frequencies. We provide case studies of a chain of links for which snake-like undulations and jellyfish-like flapping gaits are found to be optimal. © 2010 IEEE.


Annex B.H.,University of Virginia
Nature Reviews Cardiology | Year: 2013

Peripheral arterial disease (PAD) is caused by occlusive atherosclerosis in a vascular bed other than the heart. The lower extremity is the most-common location for PAD. Critical limb ischaemia (CLI) is the most-severe clinical manifestation of PAD. Despite improvements in medical care and revascularization, patients with CLI continue to have a high risk of major amputation (below the knee or higher) and cardiovascular death. The primary goal of therapy in CLI is to achieve blood flow to the distal limb vessels with angioplasty or bypass surgery. However, many patients with CLI are unsuitable for revascularization, or the procedure is unsuccessful. Angiogenesis is the growth and proliferation of blood vessels from an existing vascular structure. In therapeutic angiogenesis, attempts are made to utilize blood vessel growth to augment perfusion. In this Review, data from phase II and III clinical trials of therapeutic angiogenesis in patients with PAD will be presented and discussed. Potential explanations for the limited success of therapeutic angiogenesis in humans will be viewed in the context of advances in our understanding of the complex mechanisms underlying angiogenesis and vascular remodelling. This Review will also cover how advances in systems biology, genetics, and gene therapy might still allow the development of new approaches to therapeutic angiogenesis and achieve the goal of restoring perfusion. © 2013 Macmillan Publishers Limited.


Borek H.A.,University of Virginia | Holstege C.P.,University of Virginia
Annals of Emergency Medicine | Year: 2012

"Bath salts" are being increasingly used as drugs of abuse. These products have been found to contain a variety of compounds, including 3,4-methylenedioxypyrovalerone (MDPV). We present a case of a 25-year-old man who injected bath salts and acutely developed severe agitation, hyperthermia, and tachycardia. Despite aggressive early medical management, including dialysis, he progressed to multiorgan system failure, although he ultimately recovered after a prolonged hospital course. The only chemical substance detected on comprehensive toxicologic testing was MDPV, a synthetic cathinone analogue. According to our case, MDPV abuse may result in adverse multisystem organ effects, including rhabdomyolysis, cardiac injury, hepatic injury, and renal failure. It is unknown whether these end-organ effects were due to direct cellular toxicity induced by MDPV or a result of the patient's marked agitation and hyperthermia. Acute management should focus on the rapid identification of organ injury and appropriate supportive care. Copyright © 2012 by the American College of Emergency Physicians.


Liedtka J.,University of Virginia
Journal of Product Innovation Management | Year: 2014

"Design thinking" has generated significant attention in the business press and has been heralded as a novel problem-solving methodology well suited to the often-cited challenges business organizations face in encouraging innovation and growth. Yet the specific mechanisms through which the use of design, approached as a thought process, might improve innovation outcomes have not received significant attention from business scholars. In particular, its utility has only rarely been linked to the academic literature on individual cognition and decision-making. This perspective piece advocates addressing this omission by examining "design thinking" as a practice potentially valuable for improving innovation outcomes by helping decision-makers reduce their individual level cognitive biases. In this essay, I first review the assumptions, principles, and key process tools associated with design thinking. I then establish its foundation in the decision-making literature, drawing on an extensive body of research on cognitive biases and their impact. The essay concludes by advancing a set of propositions and research implications, aiming to demonstrate one particular path that future research might take in assessing the utility of design thinking as a method for improving organizational outcomes related to innovation. In doing so, it seeks to address the challenge of conducting academic research on a practice that is obviously popular in management circles but appears resistant to rigorous empirical inquiry because of the multifaceted nature of its "basket" of tools and processes and the complexity of measuring the outcomes it produces. © 2014 Product Development & Management Association.


Yu S.,University of Virginia | Pu L.,University of Virginia
Journal of the American Chemical Society | Year: 2010

Two enantioselective fluorescent sensors, namely, the 1,1′-binaphthol (BINOL)-amino alcohol (S)-1 and the H8BINOL-amino alcohol (R)-2, have been prepared as a pseudoenantiomeric pair. These two compounds have the opposite chiral configuration at both the axially chiral biaryl centers and the amino alcohol units. In methylene chloride solution, (R)-mandelic acid greatly enhances the emission of (S)-1 at λ1 = 374 nm and (S)-mandelic acid greatly enhances the emission of (R)-2 at λ2 = 330 nm. A 1:1 mixture of (S)-1 and (R)-2 was used to interact with mandelic acid at a variety of concentrations with various enantiomeric compositions. It was found that both the concentration of mandelic acid and its enantiomeric composition can be directly determined by measuring the sum and difference of the fluorescence intensities at λ1 and λ2. © 2010 American Chemical Society.


Pu L.,University of Virginia
Accounts of Chemical Research | Year: 2014

ConspectusChiral alcohols are ubiquitous in organic structures. One efficient method to generate chiral alcohols is the catalytic asymmetric addition of a carbon nucleophile to a carbonyl compound since this process produces a C-C bond and a chiral center simultaneously. In comparison with the carbon nucleophiles such as an organolithium or a Grignard reagent, an organozinc reagent possesses the advantages of functional group tolerance and more mild reaction conditions. Catalytic asymmetric reactions of aldehydes with arylzincs, vinylzincs, and alkynylzincs to generate functional chiral alcohols are discussed in this Account.Our laboratory has developed a series of 1,1′-bi-2-naphthol (BINOL)-based chiral catalysts for the asymmetric organozinc addition to aldehydes. It is found that the 3,3′-dianisyl- substituted BINOLs are not only highly enantioselective for the alkylzinc addition to aldehydes, but also highly enantioselective for the diphenylzinc addition to aldehydes. A one-step synthesis has been achieved to incorporate Lewis basic amine groups into the 3,3′-positions of the partially hydrogenated H8BINOL. These H8BINOL-amine compounds have become more generally enantioselective and efficient catalysts for the diphenylzinc addition to aldehydes to produce various types of chiral benzylic alcohols. The application of the H8BINOL-amine catalysts is expanded by using in situ generated diarylzinc reagents from the reaction of aryl iodides with ZnEt2, which still gives high enantioselectivity and good catalytic activity. Such a H8BINOL-amine compound is further found to catalyze the highly enantioselective addition of vinylzincs, in situ generated from the treatment of vinyl iodides with ZnEt2, to aldehydes to give the synthetically very useful chiral allylic alcohols.We have discovered that the unfunctionalized BINOL in combination with ZnEt2 and Ti(O iPr)4 can catalyze the terminal alkyne addition to aldehydes to produce chiral propargylic alcohols of high synthetic utility. The reaction was conducted by first heating an alkyne with ZnEt2 in refluxing toluene to generate an alkynylzinc reagent, which can then add to a broad range of aldehydes at room temperature in the presence of BINOL and Ti(OiPr)4 with high enantioselectivity. It was then found that the addition of a catalytic amount of dicyclohexylamine (Cy2NH) allows the entire process to be conducted at room temperature without the need to generate the alkynylzincs at elevated temperature. This BINOL-ZnEt 2-Ti(OiPr)4-Cy2NH catalyst system can be used to catalyze the reaction of structurally diverse alkynes with a broad range of aldehydes at room temperature with high enantioselectivity and good catalytic activity.The work described in this Account demonstrates that BINOL and its derivatives can be used to develop highly enantioselective catalysts for the asymmetric organozinc addition to aldehydes. These processes have allowed the efficient synthesis of many functional chiral alcohols that are useful in organic synthesis. © 2014 American Chemical Society.


Ide M.S.,University of Virginia | Davis R.J.,University of Virginia
Accounts of Chemical Research | Year: 2014

Although gold is generally considered to be a relatively inert metal, supported gold nanoparticles have demonstrated exceptionally high catalytic activity for the oxidation of carbon monoxide and alcohols at modest temperatures. In both cases, the presence of hydroxyl groups substantially promotes the reaction rate, presumably by participating in the reaction.Direct comparisons of CO oxidation to alcohol oxidation over gold catalysts have been difficult for scientists to explain. The former reaction is usually performed with gas phase reagents, whereas the latter reaction is often performed in the condensed phase. In this Account, we discuss the important role of hydroxyl for these two oxidation reactions catalyzed by gold, in terms of its influence on the turnover frequency.During CO oxidation over gold, a hydroxyl can directly react with CO to form COOH, which eventually decomposes to CO2. The gas phase CO oxidation reaction likely occurs at the gold-support interface, where adsorbed hydroxyl groups can be found after the addition of water to the feed. When we perform CO oxidation in liquid water, increasing the pH substantially promotes the reaction rate by providing an external source of hydroxyl. Likewise, we can also promote alcohol oxidations over gold catalysts in aqueous media by increasing the pH of the system. Since the hydroxyl groups are supplied through the reaction medium instead of on the support surface, the gold-support interface is much less important in the aqueous phase reactions. Even bulk gold powder becomes an active oxidation catalyst in alkaline water.The role of O2 in both CO and alcohol oxidation in aqueous media is to remove electrons from the gold surface that are deposited during oxidation, maintaining electroneutrality. Thus, the oxidation of CO and alcohols in water at high pH is analogous to the electrochemical oxidation reactions performed on gold electrodes. As the field of chemistry continues to encourage the development of sustainable chemical processes utilizing environmentally benign reaction conditions, the use of water as a "green" solvent becomes an attractive choice. In general, however, heterogeneous catalysts that scientists have developed over the last century for the petrochemical industry have not been optimized for use in aqueous media. Given the active role of water in oxidation reactions catalyzed by gold, additional research is needed to understand how water affects other catalytic transformations on traditional transition metal catalysts. © 2013 American Chemical Society.


Cardiovascular disease (CVD) and type 2 diabetes mellitus have their roots in childhood, particularly in obese children and adolescents, raising important opportunities for early lifestyle intervention in at-risk individuals. However, not all obese individuals are at the same risk for disease progression. Accurate screening of obese adolescents may identify those in greatest need for intensive intervention to prevent or delay future disease. One potential screening target is obesity-related inflammation, which contributes to insulin resistance, metabolic syndrome, and CVD. In adults, the inflammatory marker high-sensitivity C-reactive protein (hsCRP) has utility for risk stratification and treatment initiation in individuals of intermediate CVD risk. In adolescents, hsCRP shares many of the associations of hsCRP in adults regarding the degree of insulin resistance, metabolic syndrome, and carotid artery media thickness. However, long-term data linking increased hsCRP levels-and increased insulin or decreased adiponectin-in childhood to adult disease outcomes are lacking at this time. Future efforts continue to be needed to identify childhood clinical and laboratory characteristics that could be used as screening tests to predict adult disease progression. Such tests may have utility in motivating physicians and patients' families toward lifestyle changes, ultimately improving prevention efforts. © 2013 Elsevier Inc.


Fairchild K.D.,University of Virginia
Current Opinion in Pediatrics | Year: 2013

PURPOSE OF REVIEW: Predictive monitoring is an exciting new field involving analysis of physiologic data to detect abnormal patterns associated with critical illness. The first example of predictive monitoring being taken from inception (proof of concept) to reality (demonstration of improved outcomes) is the use of heart rate characteristics (HRC) monitoring to detect sepsis in infants in the neonatal ICU. The commercially available 'HeRO' monitor analyzes electrocardiogram data from existing bedside monitors for decreased HR variability and transient decelerations associated with sepsis, and converts these changes into a score (the HRC index or HeRO score). This score is the fold increase in probability that a patient will have a clinical deterioration from sepsis within 24h. This review focuses on HRC monitoring and discusses future directions in predictive monitoring of ICU patients. RECENT FINDINGS: In a randomized trial of 3003 very low birthweight infants, display of the HeRO score reduced mortality more than 20%. Ongoing research aims to combine respiratory and HR analysis to optimize care of ICU patients. SUMMARY: Predictive monitoring has recently been shown to save lives. Harnessing and analyzing the vast amounts of physiologic data constantly displayed in ICU patients will lead to improved algorithms for early detection, prognosis, and therapy of critical illnesses. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Zhou B.,Harbin Institute of Technology | Lin Z.,University of Virginia
Automatica | Year: 2014

We study in this paper the consensus problem for multi-agent systems with agents characterized by high-order linear systems with time delays in both the communication network and inputs. Provided that the open-loop dynamics of the agents is not exponentially unstable, but may be polynomially unstable, and the communication topology contains a directed spanning tree, a truncated predictor feedback approach is established to solve the consensus problem. It is shown that, if the delays are constant and exactly known, the consensus problems can be solved by both full state feedback and observer based output feedback protocols for arbitrarily large yet bounded delays. If it is further assumed that the open-loop dynamics of the agents only contains zero eigenvalues, the delays are allowed to be time-varying and unknown. Numerical examples are worked out to illustrate the effectiveness of the proposed approaches. © 2013 Elsevier Ltd. All rights reserved.


Herbst E.,University of Virginia
Physical Chemistry Chemical Physics | Year: 2014

The interdisciplinary science of astrochemistry is 45 years of age, if we pinpoint its origin to have occurred when the first polyatomic molecules were detected in the interstellar gas. Since that time, the field has grown remarkably from an esoteric area of research to one that unites scientists around the globe. Almost 200 different molecules have been detected in the gas-phase of interstellar clouds, mainly by rotational spectroscopy, while dust particles and their icy mantles in colder regions can be probed by vibrational spectroscopy. Astrochemistry is exciting to scientists in a number of different fields. Astronomers are interested in molecular spectra from the heavens because such spectra are excellent probes of the physical conditions where molecules exist, while chemists are interested in the exotic molecules, their spectra, and the unusual chemical processes that produce and destroy them under conditions often very different from those on our home planet. Chemical simulations involving thousands of reactions are now used to calculate concentrations and spectra of interstellar molecules as functions of time. Even biologists share an interest in the subject, because the interstellar clouds of gas and dust, portions of which collapse to form stars and planetary systems, contain organic molecules that may become part of the initial inventory of new planets and may indeed be the precursors of life. An irresistible subject to its practitioners, astrochemistry is proving to be exciting to a much wider audience. In this perspective article, the field is first introduced, and the emphasis is then placed on the three environments in which chemistry occurs in the interstellar medium: the gas phase, the surfaces of bare dust particles, and the ice mantles that cover bare grains in cold dense interstellar clouds. What we do know and what we do not know is distinguished. The status of chemical simulations for a variety of interstellar sources having to do with stellar and planetary evolution is surveyed. An optimistic view of the future of astrochemistry ends the article. © 2014 the Owner Societies.


Reynolds P.P.,University of Virginia
Academic Medicine | Year: 2012

The community health center (CHC), or neighborhood health center as it was originally known, was an innovation developed under President Lyndon Johnson's War on Poverty to address the needs of poor urban and rural Americans. The ranks of CHCs have grown from 8 pilot health centers in 1965 to more than 1,100 health centers serving over 19 million Americans in 2012. The capacity of CHCs is limited by the availability of primary care clinicians (physicians, nurse practitioners, and physician assistants) who are trained to work in these settings. Primary care residency program faculties have long recognized the value and importance of educating physicians in CHCs, but productivity pressures over the past decade forced the dissolution of many CHC-medical school and residency program partnerships. Advocacy and research conducted in the 1990s and 2000s laid the groundwork for the Teaching Health Center Graduate Medical Education (THCGME) program, funded under the 2010 Patient Protection and Affordable Care Act, which enables funding for residency training to flow directly to CHCs. This new federal initiative aligns the graduate medical education (GME) mission of preparing competent professionals with the CHC mission of providing quality and comprehensive care; it also helps address health care reform and the need for more primary care clinicians. Of the first 21 THCGME grants, 15 (71%) were awarded for family medicine residency training. As Chen and colleagues suggest in this issue of Academic Medicine, the THCGME program is an important step in reform of GME financing and training.


Clayton A.H.,University of Virginia
International Journal of Gynecology and Obstetrics | Year: 2010

Hypoactive sexual desire disorder (HSDD) is defined as a deficiency or absence of sexual fantasies and desire for sexual activity that causes marked distress or interpersonal difficulty. The dysfunction cannot be better accounted for by another psychiatric disorder (except another sexual dysfunction) and must not be due exclusively to the physiological effects of a substance or a general medical condition. HSDD occurs in approximately 1 in 10 adult women in the USA and its prevalence appears to be similar in Europe. A number of potential causative and contributory factors to low sexual desire have been identified, reflecting the interplay among hormonal, neurobiological, and psychosocial factors. One theory is that sexual desire is controlled in the brain by a balance between inhibitory and excitatory factors. In general, dopamine, estrogen, progesterone, and testosterone play an excitatory role in sexual desire, whereas serotonin, prolactin, and opioids play an inhibitory role. It is hypothesized that decreased sexual desire may be due to a reduced level of excitatory activity, an increased level of inhibitory activity, or both. A greater understanding of the complex pathophysiology of HSDD would improve the identification and management of women for whom low sexual desire is a concern. © 2010 International Federation of Gynecology and Obstetrics.


Triant D.A.,University of Virginia | Pearson W.R.,University of Virginia
Genome Biology | Year: 2015

Background: Protein domains are commonly used to assess the functional roles and evolutionary relationships of proteins and protein families. Here, we use the Pfam protein family database to examine a set of candidate partial domains. Pfam protein domains are often thought of as evolutionarily indivisible, structurally compact, units from which larger functional proteins are assembled; however, almost 4% of Pfam27 PfamA domains are shorter than 50% of their family model length, suggesting that more than half of the domain is missing at those locations. To better understand the structural nature of partial domains in proteins, we examined 30,961 partial domain regions from 136 domain families contained in a representative subset of PfamA domains (RefProtDom2 or RPD2). Results: We characterized three types of apparent partial domains: split domains, bounded partials, and unbounded partials. We find that bounded partial domains are over-represented in eukaryotes and in lower quality protein predictions, suggesting that they often result from inaccurate genome assemblies or gene models. We also find that a large percentage of unbounded partial domains produce long alignments, which suggests that their annotation as a partial is an alignment artifact; yet some can be found as partials in other sequence contexts. Conclusions: Partial domains are largely the result of alignment and annotation artifacts and should be viewed with caution. The presence of partial domain annotations in proteins should raise the concern that the prediction of the protein's gene may be incomplete. In general, protein domains can be considered the structural building blocks of proteins. © 2015 Triant and Pearson; licensee BioMed Central.


Steinke J.W.,University of Virginia | Platts-Mills T.A.E.,University of Virginia | Commins S.P.,University of Virginia
Journal of Allergy and Clinical Immunology | Year: 2015

Anaphylaxis is a severe allergic reaction that can be rapidly progressing and fatal, and therefore establishing its cause is pivotal to long-term risk management. Our recent work has identified a novel IgE antibody response to a mammalian oligosaccharide epitope, galactose-alpha-1,3-galactose (alpha-gal). IgE to alpha-gal has been associated with 2 distinct forms of anaphylaxis: (1) immediate-onset anaphylaxis during first exposure to intravenous cetuximab and (2) delayed-onset anaphylaxis 3 to 6 hours after ingestion of mammalian food products (eg, beef and pork). Results of our studies and those of others strongly suggest that tick bites are a cause, if not the only significant cause, of IgE antibody responses to alpha-gal in the southern, eastern, and central United States; Europe; Australia; and parts of Asia. Typical immune responses to carbohydrates are considered to be T-cell independent, whereas IgE antibody production is thought to involve sequential class-switching that requires input from T cells. Therefore, establishing the mechanism of the specific IgE antibody response to alpha-gal will be an important aspect to address as this area of research continues. © 2015 American Academy of Allergy, Asthma & Immunology.


Mugler J.P.,University of Virginia
Journal of Magnetic Resonance Imaging | Year: 2014

Spin-echo-based acquisitions are the workhorse of clinical MRI because they provide a variety of useful image contrasts and are resistant to image artifacts from radio-frequency or static field inhomogeneity. Three-dimensional (3D) acquisitions provide datasets that can be retrospectively reformatted for viewing in freely selectable orientations, and are thus advantageous for evaluating the complex anatomy associated with many clinical applications of MRI. Historically, however, 3D spin-echo-based acquisitions have not played a significant role in clinical MRI due to unacceptably long acquisition times or image artifacts associated with details of the acquisition method. Recently, optimized forms of 3D fast/turbo spin-echo imaging have become available from several MR-equipment manufacturers (for example, CUBE [GE], SPACE [Siemens], and VISTA [Philips]). Through specific design strategies and optimization, including short non-spatially selective radio-frequency pulses to significantly shorten the echo spacing and variable flip angles for the refocusing radio-frequency pulses to suppress blurring or considerably lengthen the useable duration of the spin-echo train, these techniques permit single-slab 3D imaging of sizeable volumes in clinically acceptable acquisition times. These optimized fast/turbo spin-echo pulse sequences provide a robust and flexible approach for 3D spin-echo-based imaging with a broad range of clinical applications. © 2014 Wiley Periodicals, Inc.


Clines G.A.,University of Virginia
Current Opinion in Organ Transplantation | Year: 2010

Purpose of review: Bone regeneration and fracture repair are the complex processes of mesenchymal stem cell invasion, chondrogenesis, osteogenesis and angiogenesis. The coordinated actions of these principal processes result in the reconstruction of a normal bone and restoration of a structural unit. However, these normal bone regenerative mechanisms breakdown during fracture repair failure and postmenopausal osteoporosis. Recent findings: Recent discoveries of circulating multipotent stem cells with mixed characteristics of endothelial cell and osteogenic capacity have raised interest in new and potentially breakthrough therapies for fracture and pathologic bone loss. The cooperative actions of other mesenchymal stem cell lineage such as adipocytes and processes such as angiogenesis in bone repair could also serve as novel therapeutic targets. Recent data suggest that anabolic parathyroid hormone therapy, already approved for the treatment of osteoporosis, may recruit osteoprogenitor cells and also have a role in fracture repair. Summary: The present review will highlight recent information on stem cells and bone repair and examine potential avenues for future research. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Platts-Mills T.A.E.,University of Virginia | Commins S.P.,University of Virginia
Current Opinion in Immunology | Year: 2013

New allergic diseases can 'emerge' because of exposure to a novel antigen, because the immune responsiveness of the subject changes, or because of a change in the behavior of the population. Novel antigens have entered the environment as new pests in the home (e.g., Asian lady beetle or stink bugs), in the diet (e.g., prebiotics or wheat isolates), or because of the spread of a biting arthropod (e.g., ticks). Over the last few years, a significant new disease has been identified, which has changed the paradigm for food allergy. Bites of the tick, Amblyomma americanum, are capable of inducing IgE antibodies to galactose-alpha-1,3-galactose, which is associated with two novel forms of anaphylaxis. In a large area of the southeastern United States, the disease of delayed anaphylaxis to mammalian meat is now common. This disease challenges many previous rules about food allergy and provides a striking model of an emerging allergic disease. © 2013 Elsevier Ltd.


Sun Y.,University of Virginia | Day R.N.,Indiana University | Periasamy A.,University of Virginia
Nature Protocols | Year: 2011

Fluorescence lifetime imaging microscopy (FLIM) is now routinely used for dynamic measurements of signaling events inside living cells, including detection of protein-protein interactions. An understanding of the basic physics of fluorescence lifetime measurements is required to use this technique. In this protocol, we describe both the time-correlated single photon counting and the frequency-domain methods for FLIM data acquisition and analysis. We describe calibration of both FLIM systems, and demonstrate how they are used to measure the quenched donor fluorescence lifetime that results from FÃ ¶rster resonance energy transfer (FRET). We then show how the FLIM-FRET methods are used to detect the dimerization of the transcription factor CCAAT/enhancer binding protein-Î ± in live mouse pituitary cell nuclei. Notably, the factors required for accurate determination and reproducibility of lifetime measurements are described. With either method, the entire protocol including specimen preparation, imaging and data analysis takes ∼2 d. © 2011 Nature America, Inc. All rights reserved.


Prevention of invasive Candida infections (ICI) is an achievable goal for every NICU and supported by A-1 evidence. Due to the incidence of ICI, high infection-associated mortality and neurodevelopmental impairment, antifungal prophylaxis should be targeted to infants <1000 g or ≤27 weeks gestation. There is A-1 evidence for both fluconazole and nystatin prophylaxis for the prevention of ICI. Evidence currently would favour fluconazole prophylaxis in high-risk preterm infants since intravenous fluconazole prophylaxis has greater efficacy compared to enteral nystatin prophylaxis, efficacy in the most immature patients in whom mortality is the highest, requires less dosing, and can be given to infants with gastrointestinal disease or haemodynamic instability. All NICUs caring for extremely preterm infants should use antifungal prophylaxis. Even in NICUs with low rates of ICI, antifungal prophylaxis is crucial to improving survival and neurodevelopmental outcomes for this vulnerable population. For infants 1000-1500 g if there is concern for ICI in the NICU, either drug could be chosen for prophylaxis. Fluconazole prophylaxis administered at 3 mg/kg twice a week, while intravenous access is required, appears to be the safest and most effective schedule in preventing ICI while attenuating the emergence of fungal resistance. Invasive Candida infections are one group of infections we can prevent. © 2012 Elsevier Ireland Ltd.


Angle J.F.,University of Virginia
Techniques in Vascular and Interventional Radiology | Year: 2013

Cone-beam computed tomography (CBCT) provides three-dimensional rendering of opacified vascular structures that are very useful for catheter guidance and anatomical correlation in many arterial and venous procedures. CBCT has been shown to improve the technical success of transarterial chemoembolization (TACE), which may lead to better outcomes. Similarly, it is useful in planning for selective internal radiation therapy of the liver by defining the treatment volume and preventing misembolization. There is emerging application of CBCT fusion with magnetic resonance angiography (MRA) or computed tomographic angiography (CTA) for use in catheterization or needle puncture of otherwise difficult to opacify vascular structures. CBCT also has a role in needle guidance for type II endoleak embolization, translumbar venous catheter placement, and embolization of vascular malformations. © 2013.


Garson A.,University of Virginia
Academic Medicine | Year: 2013

Improving access to appropriate health care, currently inadequate for many Americans, is more complex than merely increasing the projected number of physicians and nurses. Any attainable increase in their numbers will not solve the problem. To bring supply and demand closer, new systems of care are required, leveraging every member of the health care workforce, permitting professionals to provide their unique contributions.To increase supply: Redefine the roles of physicians and nurse practitioners (NPs), assess how much primary care must be delivered by a physician, and provide support from other team members to let the physician deal with complex patients. NPs can deliver much primary care and some specialty care. Care must be delivered in integrated systems permitting new payment models (e.g., salary with bonus) and team-based care as well as maximum use of electronic health records. Teams must make better use of nonprofessionals, such as Grand-Aides, using telephone protocols and portable telemedicine with home visits and online direct reporting of every encounter. The goals are to improve health and reduce unnecessary clinic and emergency department visits, admissions, and readmissions.To decrease demand: Physician payment must foster quality and appropriate patient volume (if accompanied by high patient satisfaction). Patients must be part of the team, work to remain healthy, and reduce inappropriate demand.The nation may not need as many physicians and nurses if the systems can be changed to promote integration, leveraging every member of the workforce to perform at his or her maximum competency.


Erdbrugger U.,University of Virginia | Le T.H.,University of Virginia
Journal of the American Society of Nephrology | Year: 2016

Extracellular vesicles from the urine and circulation have gained significant interest as potential diagnostic biomarkers in renal diseases. Urinary extracellular vesicles contain proteins from all sections of the nephron, whereas most studied circulating extracellular vesicles are derived fromplatelets, immune cells, and the endothelium. In addition to their diagnostic role as markers of kidney and vascular damage, extracellular vesicles may have functional significance in renal health and disease by facilitating communication between cells and protecting against kidney injury and bacterial infection in the urinary tract. However, the current understanding of extracellular vesicles has derived mostly from studies with very small numbers of patients or in vitro data.Moreover, accurate assessment of these vesicles remains a challenge, in part because of a lack of consensus in the methodologies to measure extracellular vesicles and the inability of most techniques to capture the entire size range of these vesicles. However, newer techniques and standardized protocols to improve the detection of extracellular vesicles are in development. A clearer understanding of the composition and biology of extracellular vesicles will provide insights into their pathophysiologic, diagnostic, and therapeutic roles. © 2016 by the American Society of Nephrology.


Kooyers N.J.,University of Virginia
Plant Science | Year: 2015

While the functional genetics and physiological mechanisms controlling drought resistance in crop plants have been intensely studied, less research has examined the genetic basis of adaptation to drought stress in natural populations. Drought resistance adaptations in nature reflect natural rather than human-mediated selection and may identify novel mechanisms for stress tolerance. Adaptations conferring drought resistance have historically been divided into alternative strategies including drought escape (rapid development to complete a life cycle before drought) and drought avoidance (reducing water loss to prevent dehydration). Recent studies in genetic model systems such as Arabidopsis, Mimulus, and Panicum have begun to elucidate the genes, expression profiles, and physiological changes responsible for ecologically important variation in drought resistance. Similar to most crop plants, variation in drought escape and avoidance is complex, underlain by many QTL of small effect, and pervasive gene by environment interactions. Recently identified major-effect alleles point to a significant role for genetic constraints in limiting the concurrent evolution of both drought escape and avoidance strategies, although these constraints are not universally found. This progress suggests that understanding the mechanistic basic and fitness consequences of gene by environment interactions will be critical for crop improvement and forecasting population persistence in unpredictable environments. © 2015.


Wallace K.L.,University of Virginia | Linden J.,La Jolla Institute for Allergy and Immunology
Blood | Year: 2010

We showed previously that pulmonary function and arterial oxygen saturation in NY1DD mice with sickle cell disease (SCD) are improved by depletion of invariant natural killer T (iNKT) cells or blockade of their activation. Here we demonstrate that SCD causes a 9- and 6-fold induction of adenosine A 2A receptor (A2AR) mRNA in mouse pulmonary iNKT and natural killer (NK) cells, respectively. Treating SCD mice with the A 2AR agonist ATL146e produced a dose-dependent reversal of pulmonary dysfunction with maximal efficacy at 10 ng/kg/minute that peaked within 3 days and persisted throughout 7 days of continuous infusion. Crossing NY1DD mice with Rag1-/- mice reduced pulmonary injury that was restored by adoptive transfer of 106 purified iNKT cells. Reconstituted injury was reversed by ATL146e unless the adoptively transferred iNKT cells were pretreated with the A2AR alkylating antagonist, FSPTP (5-amino-7-[2-(4- fluorosulfonyl)phenylethyl]-2-(2-furyl)-pryazolo[4,3-∈]-1,2,4-triazolo[1, 5-c]pyrimidine), which completely prevented protection. In NY1DD mice exposed to hypoxia-reoxygenation, treatment with ATL146e at the start of reoxygenation prevented further lung injury. Together, these data indicate that activation of induced A2ARs on iNKT and NK cells in SCD mice is sufficient to improve baseline pulmonary function and prevent hypoxia-reoxygenation-induced exacerbation of pulmonary injury. A2A agonists have promise for treating diseases associated with iNKT or NK cell activation. © 2010 by The American Society of Hematology.


Dunn S.P.,University of Virginia
Journal of the American Heart Association | Year: 2013

Proton pump inhibitors (PPIs) may interfere with the metabolic activation of clopidogrel via inhibition of cytochrome P450 2C19, but the clinical implications remain unclear. The impact of PPI use on the 1-year primary end point (ischemic stroke, myocardial infarction [MI], or vascular death) in the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial and the 28-day (all-cause death, MI, or urgent target vessel revascularization) and 1-year (all-cause death, MI, or stroke) primary end points in the Clopidogrel for Reduction of Events During Observation (CREDO) trial were examined. Clopidogrel appeared to elevate risk for the primary end point in CAPRIE among PPI users (estimated hazard ratio [EHR] 2.66, 95% CI 0.94 to 7.50) while lowering it for non-PPI users (EHR 0.90, 95% CI 0.83 to 0.99, interaction P=0.047). Moreover, PPI use was associated with worse outcomes in patients receiving clopidogrel (EHR 2.39, 95% CI 1.74 to 3.28) but not aspirin (EHR 1.04, 95% CI 0.70 to 1.57, interaction P=0.001). Clopidogrel did not significantly alter risk for the 1-year primary end point in CREDO among PPI users (EHR 0.82, 95% CI 0.48 to 1.40) while lowering it for non-PPI users (EHR 0.71, 95% CI 0.52 to 0.98, interaction P=0.682). Also, PPI use was associated with worse outcomes in both patients receiving clopidogrel (EHR 1.67, 95% CI 1.06 to 2.64) and those receiving placebo (EHR 1.56, 95% CI 1.06 to 2.30, interaction P=0.811). In CREDO, the efficacy of clopidogrel was not significantly affected by PPI use. However, in CAPRIE, clopidogrel was beneficial to non-PPI users while apparently harmful to PPI users. Whether this negative interaction is clinically important for patients receiving clopidogrel without aspirin needs further study.


Salthouse T.A.,University of Virginia
Journal of Experimental Psychology: General | Year: 2014

Although there has been considerable interest in identifying potential correlates of cognitive change, results of past studies have been inconsistent. The present study incorporated a number of methodological features intended to maximize sensitivity to detect characteristics of individuals with different amounts of cognitive change. Cognitive change in 5 cognitive abilities was analyzed with 2nd-order latent growth curve models applied to data from a moderately large sample of healthy adults ranging from 18 to 99 years of age (Ns of 4,802 with 1 occasion, 2,265 with 2 occasions, and 1,128 with 3 occasions). There was significant individual difference variance in the longitudinal changes in several cognitive abilities, even in separate analyses of individuals between 18 years of age and 39, between 40 and 64, and 65 and over. Potential correlates of change included measures of self-rated health, vision, mood, personality, and lifestyle. Most of the potential correlates of change had high reliability, and several analyses were based on even more reliable factors determined by the variance common to multiple measures. Despite favorable conditions for detecting correlates of change, there was little evidence that cognitive change was moderated by any of the variables examined. Possible reasons for the inconsistent results regarding correlates of cognitive change are discussed. © 2013 American Psychological Association.


Northup P.G.,University of Virginia | Caldwell S.H.,University of Virginia
Clinical Gastroenterology and Hepatology | Year: 2013

The human hemostasis system is complex and poorly understood after decades of intense scientific study. Despite multiple defects in routine coagulation laboratory studies in patients with chronic liver disease, there is growing evidence that these patients are effectively "rebalanced" with regard to procoagulant and anticoagulant activity and that most of these patients remain in a tenuous but balanced state of hemostasis. A major difficulty in the assessment of these patients is that there are no established laboratory tests that accurately reflect the changes in both the procoagulant and anticoagulant systems; therefore, routine laboratory testing is misleading to the clinician and may prompt inappropriate or risky therapies with little real benefit to the patient. The international normalized ratio is an example of this type of misleading test. Although the international normalized ratio is inextricably linked to prognosis and severity of protein synthetic dysfunction in acute and chronic liver disease, it is a very poor marker for bleeding risk and should not be used in isolation for this purpose. Coagulation disorders are critical in the management of frequent clinical scenarios such as esophageal variceal bleeding, invasive and percutaneous procedures, portal vein thrombosis, venous thromboembolism, and acute liver failure. This article summarizes the pathophysiology of hemostasis in liver disease, describes the strengths and weaknesses of various laboratory tests in assessment of these patients, and outlines the optimal management of hemostasis for some common clinical scenarios. Further research is needed for proper understanding of hemostasis in liver disease to optimally and safely manage these complex patients. © 2013 AGA Institute.


Carroll T.J.,Southwestern Medical Center | Yu J.,University of Virginia
Current Topics in Developmental Biology | Year: 2012

Planar cell polarity (PCP) or tissue polarity describes a coordinated polarity at the plane of the tissue where most or all cells within a tissue are polarized in one direction. It is perpendicular to the apical-basal polarity of the cell. PCP is manifested readily in the Drosophila wing and cuticle bristles, Drosophila eye ommatidia, and mammalian hair and inner ear hair bundles, and less evidently, in cellular processes such as in the coordinated, directional cell movements, and oriented cell divisions that are important for tissue morphogenesis. Several distinct molecular and cellular processes have been implicated in the regulation of PCP. Here, we review potential roles for PCP during mouse kidney development and maintenance, including ureteric bud branching morphogenesis, renal medulla elongation, tubule diameter establishment/maintenance, glomerulogenesis, and response to injury. The potential mechanisms underlying these processes, including oriented cell division and coordinated cell migration/cell intercalation, are discussed. In addition, we discuss some unaddressed research topics related to PCP in the kidney that we hope will spur further discussion and investigation. © 2012 Elsevier Inc.


Under the Affordable Care Act, the new Center for Medicare and Medicaid Innovation will guide a number of experimental programs in health care payment and delivery. Among the most ambitious of the reform models is the accountable care organization (ACO), which will offer providers economic rewards if they can reduce Medicare's cost growth in their communities. However, the dismal history of provider-led attempts to manage costs suggests that this program is unlikely to accomplish its objectives. What's more, if ACOs foster more market concentration among providers, they have the potential to shift costs onto private insurers. This paper proposes a more flexible payment model for providers and private insurers that would divide health care services into three categories: long-term, low-intensity primary care; unscheduled care, including unscheduled emergency services; and major clinical interventions that usually involve hospitalization or organized outpatient care. Each category of care would be paid for differently, with each containing different elements of financial risk for the providers. Health plans would then be encouraged to provide logistical and analytic support to providers in managing health costs in these categories. ©2011 Project HOPE - The People-to-People Health Foundation, Inc.


Karnani N.,University of Virginia | Dutta A.,University of Virginia
Genes and Development | Year: 2011

Although many chemotherapy drugs activate the intra-S-phase checkpoint pathway to block S-phase progression, not much is known about how and where the intra-S-phase checkpoint regulates origins of replication in human chromosomes. A genomic analysis of replication in human cells in the presence of hydroxyurea (HU) revealed that only the earliest origins fire, but the forks stall within 2 kb and neighboring clusters of dormant origins are activated. The initiation events are located near expressed genes with a preference for transcription start and end sites, and when they are located in intergenic regions they are located near regulatory factor-binding regions (RFBR). The activation of clustered neo-origins by HU suggests that there are many potential replication initiation sites in permissive parts of the genome, most of which are not used in a normal S phase. Consistent with this redundancy, we see multiple sites bound to MCM3 (representative of the helicase) in the region flanking three out of three origins studied in detail. Bypass of the intra-S-phase checkpoint by caffeine activates many new origins in mid- and late-replicating parts of the genome. The intra-S-phase checkpoint suppresses origin firing after the loading of Mcm10, but before the recruitment of Cdc45 and AND-1/CTF4; i.e., after helicase loading but before helicase activation and polymerase loading. Interestingly, Cdc45 recruitment upon checkpoint bypass was accompanied by the restoration of global Cdk2 kinase activity and decrease in both global and origin-bound histone H3 Lys 4 trimethylation (H3K4me3), consistent with the suggestion that both of these factors are important for Cdc45 recruitment. © 2011 by Cold Spring Harbor Laboratory Press.


Glanowska K.M.,University of Virginia | Burger L.L.,University of Michigan | Moenter S.M.,University of Michigan
Journal of Neuroscience | Year: 2014

Acquisition of a mature pattern of gonadotropin-releasing hormone (GnRH) secretion from theCNSis a hallmark of the pubertal process. Little is known about GnRH release during sexual maturation, but it is assumed to be minimal before later stages of puberty. We studied spontaneous GnRH secretion in brain slices from male mice during perinatal and postnatal development using fast-scan cyclic voltammetry (FSCV) to detect directly the oxidation of secreted GnRH. There was good correspondence between the frequency of GnRH release detected by FSCV in the median eminence of slices from adults with previous reports of in vivo luteinizing hormone (LH) pulse frequency. The frequency of GnRH release in the late embryonic stage was surprisingly high, reaching a maximum in newborns and remaining elevated in 1-week-old animals despite low LH levels. Early high-frequency GnRH release was similar in wild-type and kisspeptin knock-out mice indicating that this release is independent of kisspeptin-mediated excitation. In vivo treatment with testosterone or in vitro treatment with gonadotropin-inhibitory hormone (GnIH) reduced GnRH release frequency in slices from 1-week-old mice. RF9, a putative GnIH antagonist, restoredGnRHrelease in slices from testosterone-treated mice, suggesting that testosterone inhibition may be GnIH-dependent. At 2-3 weeks, GnRH release is suppressed before attaining adult patterns. Reduction in early life spontaneous GnRH release frequency coincides with the onset of the ability of exogenous GnRH to induce pituitary LH secretion. These findings suggest that lack of pituitary secretory response, not lack of GnRH release, initially blocks downstream activation of the reproductive system. © 2014 the authors.


Penberthy K.K.,University of Virginia | Ravichandran K.S.,University of Virginia
Immunological Reviews | Year: 2016

Phosphatidylserine recognition receptors are a highly diverse set of receptors grouped by their ability to recognize the 'eat-me' signal phosphatidylserine on apoptotic cells. Most of the phosphatidylserine recognition receptors dampen inflammation by inducing the production of anti-inflammatory mediators during the phagocytosis of apoptotic corpses. However, many phosphatidylserine receptors are also capable of recognizing other ligands, with some receptors being categorized as scavenger receptors. It is now appreciated that these receptors can elicit different downstream events for particular ligands. Therefore, how phosphatidylserine recognition receptors mediate specific signals during recognition of apoptotic cells versus other ligands, and how this might help regulate the inflammatory state of a tissue is an important question that is not fully understood. Here, we revisit the work on signaling downstream of the phosphatidylserine recognition receptor BAI1, and evaluate how these and other signaling modules mediate signaling downstream from other receptors, including Stabilin-2, MerTK, and αvβ5. We also propose the concept that phosphatidylserine recognition receptors could be viewed as a subset of scavenger receptors that are capable of eliciting anti-inflammatory responses to apoptotic cells. © 2016 John Wiley & Sons A/S.


Myers N.L.,University of Virginia
Current Psychiatry Reports | Year: 2011

The incidence of schizophrenia, as well as the symptoms, course, and outcomes for people so diagnosed seem to vary across some cultural contexts. The mechanisms by which cultural variations may protect one from or increase one's risk of developing schizophrenia remain unclear. Recent findings from transdisciplinary cross-cultural research, indicate ways that we may better understand how socioenvironmental and cultural variables interact with physiologic pathways relating psychosocial stress and psychotic symptoms, epigenetic changes, and people's use of culturally available tools to mitigate stress, in ways that may inform relevant, effective interventions for people diagnosed with psychotic disorders worldwide. © 2011 Springer Science+Business Media, LLC.


Wang L.,University of Virginia | Janes K.A.,University of Virginia
Nature Protocols | Year: 2013

Single-cell variations in gene and protein expression are important during development and disease. Such cell-to-cell heterogeneities can be directly inspected one cell at a time, but global methods are usually not sensitive enough to work with the starting material of a single cell. Here we provide a detailed protocol for stochastic profiling, a method that infers single-cell regulatory heterogeneities by repeatedly sampling small collections of cells selected at random. Repeated stochastic sampling is performed by laser-capture microdissection or limiting dilution, followed by careful exponential cDNA amplification, hybridization to microarrays and statistical analysis. Stochastic profiling surveys the transcriptome for programs that are heterogeneously regulated among cellular subpopulations in their native tissue context. The protocol is readily optimized for specific biological applications and takes about 1 week to complete. © 2013 Nature America, Inc. All rights reserved.


Al-Shawi M.K.,University of Virginia
Essays in Biochemistry | Year: 2011

ABC (ATP-binding cassette) transporters are arguably the most important family of ATP-driven transporters in biology. Despite considerable effort and advances in determining the structures and physiology of these transporters, their fundamental molecular mechanisms remain elusive and highly controversial. How does ATP hydrolysis by ABC transporters drive their transport function? Part of the problem in answering this question appears to be a perceived need to formulate a universal mechanism. Although it has been generally hoped and assumed that the whole superfamily of ABC transporters would exhibit similar conserved mechanisms, this is proving not to be the case. Structural considerations alone suggest that there are three overall types of coupling mechanisms related to ABC exporters, small ABC importers and large ABC importers. Biochemical and biophysical characterization leads us to the conclusion that, even within these three classes, the catalytic and transport mechanisms are not fully conserved, but continue to evolve. ABC transporters also exhibit unusual characteristics not observed in other primary transporters, such as uncoupled basal ATPase activity, that severely complicate mechanistic studies by established methods. In this chapter, I review these issues as related to ABC exporters in particular. A consensus view has emerged that ABC exporters follow alternating-access switch transport mechanisms. However, some biochemical data suggest that alternating catalytic site transport mechanisms are more appropriate for fully symmetrical ABC exporters. Heterodimeric and asymmetrical ABC exporters appear to conform to simple alternating-access-type mechanisms. © 2011 Biochemical Society.


Chevalier R.A.,University of Virginia | Irwin C.M.,University of Virginia
Astrophysical Journal Letters | Year: 2011

We examine the case where a circumstellar medium around a supernova is sufficiently opaque that a radiation-dominated shock propagates in the circumstellar region. The initial propagation of the shock front into the circumstellar region can be approximated by a self-similar solution that determines the radiative energy in a shocked shell; the eventual escape of this energy gives the maximum luminosity of the supernova. If the circumstellar density is described by ρ = Dr -2 out to a radius Rw , where D is a constant, the properties of the shock breakout radiation depend on Rw and Rd ≡ κDv sh/c, where κ is the opacity and v sh is the shock velocity. If R w >Rd , the rise to maximum light begins at R d /v sh; the duration of the rise is also Rd /v sh; the outer parts of the opaque medium are extended and at low velocity at the time of peak luminosity; and a dense shell forms whose continued interaction with the dense mass loss gives a characteristic flatter portion of the declining light curve. If Rw < Rd , the rise to maximum light begins at Rw /v sh; the duration of the rise is R 2 w/v sh Rd ; the outer parts of the opaque medium are not extended and are accelerated to high velocity by radiation pressure at the time of maximum luminosity; and a dense shell forms but does not affect the light curve near maximum. We argue that SN 2006gy is an example of the first kind of event, while SN 2010gx and related supernovae are examples of the second. © 2011. The American Astronomical Society. All rights reserved.


Xiao N.,University of Virginia | Venton B.J.,University of Virginia
Analytical Chemistry | Year: 2012

Carbon nanotube (CNT) modification of microelectrodes can result in increased sensitivity without compromising time response. However, dip coating CNTs is not very reproducible and the CNTs tend to lay flat on the electrode surface which limits access to the electroactive sites on the ends. In this study, aligned CNT forests were formed using a chemical self-assembly method, which resulted in more exposed CNT ends to the analyte. Shortened, carboxylic acid functionalized single-walled CNTs were assembled from a dimethylformamide (DMF) suspension onto a carbon-fiber disk microelectrode modified with a thin iron hydroxide-decorated Nafion film. The modified electrodes were highly sensitive, with 36-fold higher oxidation currents for dopamine using fast-scan cyclic voltammetry than bare electrodes and 34-fold more current than electrodes dipped in CNTs. The limit of detection (LOD) for dopamine was 17 ± 3 nM at a 10 Hz repetition rate and 65 ± 7 nM at 90 Hz. The LOD at 90 Hz was the same as a bare electrode at 10 Hz, allowing a 9-fold increase in temporal resolution without a decrease in sensitivity. Similar increases were observed for other cationic catecholamine neurotransmitters, and the increases in current were greater than for anionic interferents such as ascorbic acid and 3,4-dihydroxyphenylacetic acid (DOPAC). The CNT forest electrodes had high sensitivity at 90 Hz repetition rate when stimulated dopamine release was measured in Drosophila. The sensitivity, temporal resolution, and spatial resolution of these CNT forest modified disk electrodes facilitate enhanced electrochemical measurements of neurotransmitter release in vivo. © 2012 American Chemical Society.


Chevalier R.A.,University of Virginia | Soderberg A.M.,Harvard - Smithsonian Center for Astrophysics
Astrophysical Journal Letters | Year: 2010

The classic example of a Type IIb supernova is SN 1993J, which had a cool extended progenitor surrounded by a dense wind. There is evidence for another category of Type IIb supernova that has a more compact progenitor with a lower density, probably fast, wind. Distinguishing features of the compact category are weak optical emission from the shock heated envelope at early times, nonexistent or very weak H emission in the late nebular phase, rapidly evolving radio emission, rapid expansion of the radio shell, and expected nonthermal as opposed to thermal X-ray emission. Type IIb supernovae that have one or more of these features include SNe 1996cb, 2001ig, 2003bg, 2008ax, and 2008bo. All of these with sufficient radio data (the last four) show evidence for presupernova wind variability. We estimate a progenitor envelope radius ∼1 × 1011 cm for SN 2008ax, a value consistent with a compact Wolf-Rayet progenitor. Supernovae in the SN 1993J extended category include SN 2001gd and probably the Cas A supernova. We suggest that the compact Type IIb events be designated Type cIIb and the extended ones Type eIIb. The H envelope mass dividing these categories is ∼0.1 M⊙. © 2010. The American Astronomical Society. All rights reserved.


Izotov Y.I.,Ukrainian Academy of Sciences | Thuan T.X.,University of Virginia
Astrophysical Journal Letters | Year: 2010

We present a new determination of the primordial helium mass fraction Yp , based on 93 spectra of 86 low-metallicity extragalactic H II regions, and taking into account the latest developments concerning systematic effects. These include collisional and fluorescent enhancements of He I recombination lines, underlying He I stellar absorption lines, collisional and fluorescent excitation of hydrogen lines, and temperature and ionization structure of the H II region. Using Monte Carlo methods to solve simultaneously for the above systematic effects, we find the best value to be Yp = 0.2565 ± 0.0010 (stat.) ± 0.0050 (syst.). This value is higher at the 2σ level than the value given by standard big bang nucleosynthesis, implying deviations from it. The effective number of light neutrino species N ν is equal to 3.68+0.80 -0.70 (2σ) and 3.80+0.80 -0.70 (2σ) for a neutron lifetime τn equal to 885.4 ± 0.9 s and 878.5 ± 0.8 s, respectively, i.e., it is larger than the experimental value of 2.993 ± 0.011. © 2010. The American Astronomical Society. All rights reserved.


A previous report described lipid mixing of reconstituted proteoliposomes made using lipid mixtures that mimic the composition of yeast vacuoles. This lipid mixing required SNARE {SNAP [soluble NSF (N-ethylmaleimide-sensitive factor)-attachment protein] receptor} proteins, Sec18p and Sec17p (yeast NSF and α-SNAP) and the HOPS (homotypic fusion and protein sorting)-Class C Vps (vacuole protein sorting) complex, but not the vacuolar Rab GTPase Ypt7p. The present study investigates the activity of Ypt7p in proteoliposome lipid mixing. Ypt7p is required for the lipid mixing of proteoliposomes lacking cardiolipin [1,3-bis-(sn-3′-phosphatidyl)-sn-glycerol]. Omission of other lipids with negatively charged and/or small head groups does not cause Ypt7p dependence for lipid mixing.Yeast vacuoles made from strains disrupted for CRD1 (cardiolipin synthase) fuse to the same extent as vacuoles from strains with functional CRD1. Disruption of CRD1 does not alter dependence on Rab GTPases for vacuole fusion. It has been proposed that the recruitment of the HOPS complex to membranes is the main function of Ypt7p. However, Ypt7p is still required for lipid mixing even when the concentration of HOPS complex in lipid-mixing reactions is adjusted such that cardiolipin-free proteoliposomes with or without Ypt7p bind to equal amounts of HOPS. Ypt7p therefore must stimulate membrane fusion by a mechanism that is in addition to recruitment of HOPS to the membrane. This is the first demonstration of such a stimulatory activity - that is, beyond bulk effector recruitment - for a Rab GTPase. © The Authors Journal compilation © 2012 Biochemical Society.


McCaffrey L.M.,McGill University | Montalbano J.,University of Virginia | Mihai C.,McGill University | Macara I.G.,Vanderbilt University
Cancer Cell | Year: 2012

Loss of epithelial organization is a hallmark of carcinomas, but whether polarity regulates tumor growth and metastasis is poorly understood. To address this issue, we depleted the Par3 polarity gene by RNAi in combination with oncogenic Notch or Ras61L expression in the murine mammary gland. Par3 silencing dramatically reduced tumor latency in both models and produced invasive and metastatic tumors that retained epithelial marker expression. Par3 depletion was associated with induction of MMP9, destruction of the extracellular matrix, and invasion, all mediated by atypical PKC-dependant JAK/Stat3 activation. Importantly, Par3 expression is significantly reduced in human breast cancers, which correlates with active aPKC and Stat3. These data identify Par3 as a regulator of signaling pathways relevant to invasive breast cancer. © 2012 Elsevier Inc.


Walpole J.,University of Virginia | Papin J.A.,University of Virginia | Peirce S.M.,University of Virginia
Annual Review of Biomedical Engineering | Year: 2013

Integration of data across spatial, temporal, and functional scales is a primary focus of biomedical engineering efforts. The advent of powerful computing platforms, coupled with quantitative data from high-throughput experimental methodologies, has allowed multiscale modeling to expand as a means to more comprehensively investigate biological phenomena in experimentally relevant ways. This review aims to highlight recently published multiscale models of biological systems, using their successes to propose the best practices for future model development. We demonstrate that coupling continuous and discrete systems best captures biological ormation across spatial scales by selecting modeling techniques that are suited to the task. Further, we suggest how to leverage these multiscale models to gain insight into biological systems using quantitative biomedical engineering methods to analyze data in nonintuitive ways. These topics are discussed with a focus on the future of the field, current challenges encountered, and opportunities yet to be realized. Copyright © 2013 by Annual Reviews.


Janes K.A.,University of Virginia | Lauffenburger D.A.,Massachusetts Institute of Technology
Journal of Cell Science | Year: 2013

Computational models of cell signalling are perceived by many biologists to be prohibitively complicated. Why do math when you can simply do another experiment? Here, we explain how conceptual models, which have been formulated mathematically, have provided insights that directly advance experimental cell biology. In the past several years, models have influenced the way we talk about signalling networks, how we monitor them, and what we conclude when we perturb them. These insights required wet-lab experiments but would not have arisen without explicit computational modelling and quantitative analysis. Today, the best modellers are crosstrained investigators in experimental biology who work closely with collaborators but also undertake experimental work in their own laboratories. Biologists would benefit by becoming conversant in core principles of modelling in order to identify when a computational model could be a useful complement to their experiments. Although the mathematical foundations of a model are useful to appreciate its strengths and weaknesses, they are not required to test or generate a worthwhile biological hypothesis computationally. © 2013. Published by The Company of Biologists Ltd.


Egelman E.H.,University of Virginia
Current Opinion in Cell Biology | Year: 2010

The bacterial flagellar system is an intricate assembly (containing ∼40 different proteins) that is involved in both protein secretion and bacterial motility. It has also become the icon of the neo-creationist movement in the United States, with the argument that it shows 'irreducible complexity' and could not have been the product of evolution. Recent studies provide new insights into the evolution of the flagellar system and lead to the suggestion that the divergence of quaternary structure in protein assemblies may be an underappreciated mechanism for rapid evolutionary divergence. Work on the enzyme FucU, involved in fucose metabolism, may suggest similar conclusions. © 2009 Elsevier Ltd. All rights reserved.


Loman N.J.,University of Birmingham | Quinlan A.R.,University of Virginia
Bioinformatics | Year: 2014

Motivation: Nanopore sequencing may be the next disruptive technology in genomics, owing to its ability to detect single DNA molecules without prior amplification, lack of reliance on expensive optical components, and the ability to sequence long fragments. The MinION™ from Oxford Nanopore Technologies (ONT) is the first nanopore sequencer to be commercialized and is now available to early-access users. The MinION™ is a USB-connected, portable nanopore sequencer that permits real-time analysis of streaming event data. Currently, the research community lacks a standardized toolkit for the analysis of nanopore datasets. Results: We introduce poretools, a flexible toolkit for exploring datasets generated by nanopore sequencing devices from MinION™ for the purposes of quality control and downstream analysis. Poretools operates directly on the native FAST5 (an application of the HDF5 standard) file format produced by ONT and provides a wealth of format conversion utilities and data exploration and visualization tools. © The Author 2014. Published by Oxford University Press.


Hypertension is characterized by endothelial dysfunction and increased risk for adverse cardiovascular outcomes. In addition to lowering blood pressure, the calcium-channel blocker amlodipine and blockers of the renin-angiotensin- aldosterone system (angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers) may further reduce cardiovascular risk by improving endothelial function when used alone or in combination. In fact, the beneficial effects of the combination of amlodipine and a renin-angiotensin-aldosterone system blocker on endothelial function have been found to be greater than the effect of either drug alone, likely due to additive effects on nitric oxide activity. This review summarizes the observed effects of these agents on endothelial function and the complementary mechanisms by which they act, thus providing rationale (beyond blood pressure benefits) for their use in combination. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Rosner M.H.,University of Virginia
Kidney International | Year: 2012

Hyponatremia, the most common electrolyte disorder encountered in clinical practice, is associated with significant morbidity and mortality. The introduction of medications that specifically antagonize the vasopressin V2 receptor (vaptans) has provided a safe and effective means of therapy. Lixivaptan is the newest of these agents that reliably increase serum sodium levels in patients with euvolemic hyponatremia. However, significant questions remain regarding the specific indications for vaptans, and their potential impact on morbidity and mortality associated with hyponatremia. © 2012 International Society of Nephrology.


Korpe P.S.,University of Virginia | Petri W.A.,University of Virginia
Trends in Molecular Medicine | Year: 2012

Environmental enteropathy (also called tropical enteropathy) is a subclinical condition caused by constant fecal-oral contamination and resulting in blunting of intestinal villi and intestinal inflammation. Although these histological changes were discovered decades ago, the clinical impact of environmental enteropathy is just starting to be recognized. The failure of nutritional interventions and oral vaccines in the developing world may be attributed to environmental enteropathy, as the intestinal absorptive and immunologic functions are significantly deranged. Here we review the existing literature and examine potential mechanisms of pathogenesis for this poorly understood condition. © 2012 Elsevier Ltd.


Shin J.,University of Virginia
Annals of biomedical engineering | Year: 2012

A finite element (FE) model of the foot and leg was developed to improve understanding of injury mechanisms of the ankle and subtalar joints during vehicle collisions and to aid in the design of injury countermeasures. The FE model was developed based on the reconstructed geometry of a male volunteer close to the anthropometry of a 50th percentile male and a commercial anatomical database. While the forefoot bones were defined as rigid bodies connected by ligament models, the surrounding bones of the ankle and subtalar joints and the leg bones were modeled as deformable structures. The material and structural properties were selected based on a synthesis of current knowledge of the constitutive models for each tissue. The whole foot and leg model was validated in different loading conditions including forefoot impact, axial rotation, dorsiflexion, and combined loadings. Overall results obtained in the model validation indicated improved biofidelity relative to previous FE models. The developed model was used to investigate the injury tolerance of the ankle joint under brake pedal loading for internally and externally rotated feet. Ligament failures were predicted as the main source of injury in this loading condition. A 12% variation of failure moment was observed in the range of axial foot rotations (±15°). The most vulnerable position was the internally rotated (15°) posture among three different foot positions. Furthermore, the present foot and ankle model will be coupled together with other body region FE models into the state-of-art human FE model to be used in the field of automotive safety.


Hamre B.K.,University of Virginia
Child Development Perspectives | Year: 2014

To ensure that investments in expanding early childhood programs are effective in supporting children's school readiness, early childhood settings must include responsive and cognitively stimulating daily interactions between teachers and children. Few young children are exposed to the types of teacher-child interactions needed to help ensure that they are prepared to start kindergarten. In this article, I review studies identifying teacher-child interactions that promote children's development and documenting how systematic professional development enhances these areas of teachers' practice. I also address the limits to research and the policy implications of this work. © 2014 The Society for Research in Child Development.


Gioeli D.,University of Virginia | Paschal B.M.,University of Virginia
Molecular and Cellular Endocrinology | Year: 2012

Regulation of the androgen receptor (AR) by its cognate ligand is well established, but how post-translational modification modulates AR activity is only emerging. The AR is subject to modification by phosphorylation, acetylation, methylation, SUMOylation, and ubiquitination. As several of the enzymes that modify the AR are altered in prostate cancer, defining the context and physiological effects of these modifications could provide insight into mechanisms that underpin human disease. Here, we review how post-translational modification contributes to AR function as a transcription factor with particular emphasis on phosphorylation and dephosphorylation mechanisms. © 2011.


Ruhm C.J.,University of Virginia
Journal of Health Economics | Year: 2015

Over the 1976-2010 period, total mortality shifted from strongly procyclical to being weakly or unrelated to macroeconomic conditions. The association is likely to be poorly measured when using short (less than 15 year) analysis periods. Deaths from cardiovascular disease and transport accidents continue to be procyclical; however, countercyclical patterns have emerged for fatalities from cancer mortality and external causes. Among the latter, non-transport accidents, particularly accidental poisonings, play an important role. © 2015 Elsevier B.V.


Horwitz A.R.,University of Virginia
Nature Reviews Molecular Cell Biology | Year: 2012

Recognition of the importance of cell adhesion grew steadily during the twentieth century as it promised answers to fundamental questions in diverse fields that included cell biology, developmental biology, tumorigenesis, immunology and neurobiology. However, the route towards a better understanding of its molecular basis was long and difficult, with many false starts. Major progress was made in the late 1970s to late 1980s with the identification of the major families of adhesion molecules, including integrins and cadherins. This in turn set the stage for the explosive growth in adhesion research over the past 25 years. © 2012 Macmillan Publishers Limited. All rights reserved.


Dey B.K.,University of Virginia | Gagan J.,University of Virginia | Yan Z.,University of Virginia | Dutta A.,University of Virginia
Genes and Development | Year: 2012

Multiple microRNAs are known to be induced during the differentiation of myoblasts to myotubes. Yet, experiments in animals have not provided clear evidence for the requirement of most of these microRNAs in myogenic differentiation in vivo. miR-26a is induced during skeletal muscle differentiation and is predicted to target a well-known inhibitor of differentiation, the transforming growth factor β/bone morphogenetic protein (TGF-β/BMP) signaling pathway. Here we show that exogenous miR-26a promotes differentiation of myoblasts, while inhibition of miR-26a by antisense oligonucleotides or by Tough-Decoys delays differentiation. miR-26a targets the transcription factors Smad1 and Smad4, critical for the TGF-β/BMP pathway, and expression of microRNA-resistant forms of these transcription factors inhibits differentiation. Injection of antagomirs specific to miR-26a into neonatal mice derepressed both Smad expression and activity and consequently inhibited skeletal muscle differentiation. In addition, miR-26a is induced during skeletal muscle regeneration after injury. Inhibiting miR-26a in the tibialis anterior muscles through the injection of adeno-associated virus expressing a Tough-Decoy targeting miR-26a prevents Smad down-regulation and delays regeneration. These findings provide evidence for the requirement of miR-26a for skeletal muscle differentiation and regeneration in vivo. © 2012 by Cold Spring Harbor Laboratory Press.


Miyake T.,University of Virginia | Parsons S.J.,University of Virginia
Oncogene | Year: 2012

Epidermal growth factor receptor (EGFR) family members and c-Src are co-overexpressed in many cancers. The synergistic effect of EGFR and c-Src has been shown in the tumorigenesis of breast and other cancers. Reported mechanisms of synergy include transcriptional regulation by STAT5b and the regulation of cellular ATP production by mitochondrial protein COX II. Here, we report a new mechanism of EGFR-c-Src synergy through choline kinase α (CHKA). The first enzyme of the phosphatidyl choline production pathway, CHKA, is overexpressed in many cancers, and the product of the enzyme, phosphocholine, is also increased in tumor cells. In this report, we find that CHKA forms a complex with EGFR in a c-Src-dependent manner. Endogenous CHKA and EGFR co- immunoprecipitated from a variety of breast cancer cell lines and immortalized mammary epithelial cells. CHKA interacted with the EGFR kinase domain upon c-Src co-overexpression and was phosphorylated in a c-Src-dependent manner on Y197 and Y333. Overexpression of EGFR and c-Src increased total cellular activity and protein levels of CHKA. Mutation of CHKA Y197 and Y333 reduced complex formation, EGFR-dependent activation of CHKA enzyme activity and epidermal growth factor (EGF)-dependent DNA synthesis. Furthermore, small interfering RNA-mediated knockdown of CHKA in MCF-7 and MCF-10A cells reduced EGF-dependent cell proliferation. Together, these results strongly implicate a new c-Src-dependent link between CHKA and EGFR, which contributes to the regulation of cell proliferation and tumorigenesis. © 2012 Macmillan Publishers Limited All rights reserved.


Lillard A.S.,University of Virginia | Peterson J.,University of Virginia
Pediatrics | Year: 2011

OBJECTIVE: The goal of this research was to study whether a fast-paced television show immediately influences preschool-aged children's executive function (eg, self-regulation, working memory). METHODS: Sixty 4-year-olds were randomly assigned to watch a fast-paced television cartoon or an educational cartoon or draw for 9 minutes. They were then given 4 tasks tapping executive function, including the classic delay-of-gratification and Tower of Hanoi tasks. Parents completed surveys regarding television viewing and child's attention. RESULTS: Children who watched the fast-paced television cartoon performed significantly worse on the executive function tasks than children in the other 2 groups when controlling for child attention, age, and television exposure. CONCLUSIONS: Just 9 minutes of viewing a fast-paced television cartoon had immediate negative effects on 4-year-olds' executive function. Parents should be aware that fast-paced television shows could at least temporarily impair young children's executive function. Copyright © 2011 by the American Academy of Pediatrics.


Klich I.,University of Virginia
Physical Review Letters | Year: 2012

In this Letter we study the entanglement of a quantum radiation field interacting with a dielectric medium. In particular, we describe the quantum mixed state of a field interacting with a dielectric through plasma and Drude models and show that these generate very different entanglement behavior, as manifested in the entanglement entropy of the field. We also present a formula for a "Casimir" entanglement entropy, i.e., the distance dependence of the field entropy. Finally, we study a toy model of the interaction between two plates. In this model, the field entanglement entropy is divergent; however, as in the Casimir effect, its distance-dependent part is finite, and the field matter entanglement is reduced when the objects are far. © 2012 American Physical Society.


Shirts M.R.,University of Virginia
Journal of Chemical Theory and Computation | Year: 2013

It is often difficult to quantitatively determine if a new molecular simulation algorithm or software properly implements sampling of the desired thermodynamic ensemble. We present some simple statistical analysis procedures to allow sensitive determination of whether the desired thermodynamic ensemble is properly sampled. These procedures use paired simulations to cancel out system dependent densities of state and directly test the extent to which the Boltzmann distribution associated with the ensemble (usually canonical, isobaric-isothermal, or grand canonical) is satisfied. We demonstrate the utility of these tests for model systems and for molecular dynamics simulations in a range of situations and describe an implementation of the tests designed for end users. © 2012 American Chemical Society.


Basconi J.E.,University of Virginia | Shirts M.R.,University of Virginia
Journal of Chemical Theory and Computation | Year: 2013

Temperature control algorithms in molecular dynamics (MD) simulations are necessary to study isothermal systems. However, these thermostatting algorithms alter the velocities of the particles and thus modify the dynamics of the system with respect to the microcanonical ensemble, which could potentially lead to thermostat-dependent dynamical artifacts. In this study, we investigate how six well-established thermostat algorithms applied with different coupling strengths and to different degrees of freedom affect the dynamics of various molecular systems. We consider dynamic processes occurring on different times scales by measuring translational and rotational self-diffusion as well as the shear viscosity of water, diffusion of a small molecule solvated in water, and diffusion and the dynamic structure factor of a polymer chain in water. All of these properties are significantly dampened by thermostat algorithms which randomize particle velocities, such as the Andersen thermostat and Langevin dynamics, when strong coupling is used. For the solvated small molecule and polymer, these dampening effects are reduced somewhat if the thermostats are applied to the solvent alone, such that the solute's temperature is maintained only through thermal contact with solvent particles. Algorithms which operate by scaling the velocities, such as the Berendsen thermostat, the stochastic velocity rescaling approach of Bussi and co-workers, and the Nosé-Hoover thermostat, yield transport properties that are statistically indistinguishable from those of the microcanonical ensemble, provided they are applied globally, i.e. coupled to the system's kinetic energy. When coupled to local kinetic energies, a velocity scaling thermostat can have dampening effects comparable to a velocity randomizing method, as we observe when a massive Nose-Hoover coupling scheme is used to simulate water. Correct dynamical properties, at least those studied in this paper, are obtained with the Berendsen thermostat applied globally, despite the fact that it yields the wrong kinetic energy distribution. © 2013 American Chemical Society.


Sabol T.J.,University of Virginia | Pianta R.C.,University of Virginia
Child Development | Year: 2012

A person-oriented approach examined patterns of functioning in social and executive function domains at 54months and in turn forecasted 5th-grade socioemotional and achievement outcomes for 944 children. Six distinct profiles of 54-month school readiness patterns predicted outcomes in 5th grade with indications of cross-domain association between 54-month performance and later functioning. A group of children at 54months characterized by low working memory exhibited elevated levels of socioemotional problems and low achievement in 5th grade. Patterns in which high social competence or high working memory were prominent predicted high 5th-grade achievement. Unexpectedly, a group distinguished by attention problems performed well on later achievement outcomes. After controlling for children's early demographics, readiness profiles accounted for math achievement in 5th grade. © 2011 The Authors. Child Development © 2011 Society for Research in Child Development, Inc.


Salthouse T.A.,University of Virginia
Journal of the International Neuropsychological Society | Year: 2012

Two major challenges facing researchers interested in cognitive change are that measures of change are often not very reliable, and they may reflect effects of prior test experience in addition to the factors of primary interest. One approach to dealing with these problems is to obtain multiple measures of change on parallel versions of the same tests in a measurement burst design. A total of 783 adults performed three parallel versions of cognitive tests on two occasions separated by an average of 2.6 years. Performance increased substantially across the three sessions within each occasion, and for all but vocabulary ability these within-occasion improvements were considerably larger than the between-occasion changes. Reliabilities of the changes in composite scores were low, but averages of the three changes had larger, albeit still quite modest, reliabilities. In some cognitive abilities individual differences were evident in the relation of prior test experience and the magnitude of longitudinal change. Although multiple assessments are more time consuming than traditional measurement procedures, the resulting estimates of change are more robust than those from conventional methods, and also allow the influence of practice on change to be systematically investigated. © 2012 INS. Published by Cambridge University Press.


Okusa M.D.,University of Virginia | Davenport A.,University College London
Kidney International | Year: 2014

The KDIGO guidelines for acute kidney injury (AKI) are designed to assist health-care providers around the world in managing patients with AKI. Clinical guidelines are intended to help the clinician make an informed decision based on review of the currently available evidence. Due to the generic nature of guidelines, it is sometimes difficult to translate a guideline for a particular individual patient who may have specific clinical circumstances. To illustrate this point, we have discussed the interpretation of the KDIGO guideline in patients who have subtleties in their clinical presentation, which may make treatment decisions less than straightforward © 2013 International Society of Nephrology.


Chevalier R.A.,University of Virginia | Irwin C.M.,University of Virginia
Astrophysical Journal Letters | Year: 2012

Type IIn and related supernovae show evidence for an interaction with a dense circumstellar medium that produces most of the supernova luminosity. X-ray emission from shock heated gas is crucial for the energetics of the interaction and can provide diagnostics on the shock interaction. Provided that the shock is at an optical depth τw ≲ c/vs in the wind, where c is the speed of light and vs is the shock velocity, a viscous shock is expected that heats the gas to a high temperature. For τw ≳ 1, the shock wave is in the cooling regime; inverse Compton cooling dominates bremsstrahlung at higher densities and shock velocities. Although τw ≳ 1, the optical depth through the emission zone is ≲ 1 so that inverse Compton effects do not give rise to significant X-ray emission. The electrons may not reach energy equipartition with the protons at higher shock velocities. As X-rays move out through the cool wind, the higher energy photons are lost to Compton degradation. If bremsstrahlung dominates the cooling and Compton losses are small, the energetic radiation can completely photoionize the preshock gas. However, inverse Compton cooling in the hot region and Compton degradation in the wind reduce the ionizing flux, so that complete photoionization is not obtained and photoabsorption by the wind further reduces the escaping X-ray flux. We conjecture that the combination of these effects led to the low observed X-ray flux from the optically luminous SN 2006gy. © 2012. The American Astronomical Society. All rights reserved.


Chevalier R.A.,University of Virginia
Astrophysical Journal Letters | Year: 2012

A variety of supernova events, including TypeIIn supernovae and ultraluminous supernovae, appear to have lost up to solar masses of their envelopes in tens to hundreds of years leading up to the explosion. In order to explain the close timing of the mass loss and supernova events, we explore the possibility that the mass loss is driven by common envelope evolution of a compact object (neutron star or black hole) in the envelope of a massive star and the supernova is triggered by the inspiral of the compact object to the central core of the companion star. The expected rate of such events is smaller than the observed rate of TypeIIn supernovae but the rates may agree within the uncertainties. The mass loss velocity is related to the escape velocity from the common envelope system and is comparable to the observed velocity of hundreds of kilometers per second in TypeIIn events. The mass loss is expected to be denser near the equatorial plane of the binary system and there is good evidence that the circumstellar media in TypeIIn supernovae are asymmetric. Some of these supernova types show evidence for energies in excess of the canonical 1051 erg, which might be the result of explosions from rapid accretion onto a compact object through a disk. © 2012. The American Astronomical Society. All rights reserved.


BACKGROUND: Axon degeneration is a characteristic feature of multiple neuropathologic states and is also a mechanism of physiological neurodevelopmental pruning. The vast majority of in vivo studies looking at axon degeneration have relied on the use of classical silver degeneration stains, which have many limitations including lack of molecular specificity and incompatibility with immunolabeling methods. Because Wallerian degeneration is well known to involve cytoskeletal disassembly and because caspases are recently implicated in aspects of this process, we asked whether antibodies directed at caspase-generated neoepitopes of beta-actin and alpha-tubulin would be useful immunohistochemical markers of pathological and developmental axon degeneration.RESULTS: Here we demonstrate that several forms of axon degeneration involve caspase-mediated cleavage of these cytoskeletal elements and are well-visualized using this approach. We demonstrate the generation of caspase-induced neoepitopes in a) an in vitro neuronal culture model using nerve growth factor-deprivation-induced degeneration and b) an in vivo model using ethanol-induced neuronal apoptosis, and c) during normal developmental pruning and physiological turnover of neurons.CONCLUSIONS: Our findings support recent experimental data that suggests caspase-3 and caspase-6 have specific non-redundant roles in developmental pruning. Finally, these findings may have clinical utility, as these markers highlight degenerating neurites in human hypoxic-ischemic injury. Our work not only confirms a common downstream mechanism involved in axon degeneration, but also illuminates the potential utility of caspase-cleavage-neoepitope antibodies as markers of neurodegeneration.


Rosner M.H.,University of Virginia
Clinics in Geriatric Medicine | Year: 2013

Most patients who develop acute kidney injury (AKI) are older than 65 years. Specific structural and functional changes that occur in the aging kidney predispose the elderly patient to AKI. This risk is further compounded by comorbid conditions, polypharmacy, and the need for invasive procedures. When AKI does occur, it is associated with significant morbidity and mortality. Although morbidity and mortality increases with advancing age, many elderly patients can survive AKI and do well. Thus, decision making should be thoughtful and individualized, and not dependent on age. Whenever possible, preventive approaches should be pursued to lessen the burden of AKI. © 2013 Elsevier Inc.


Sandilos J.K.,University of Virginia | Bayliss D.A.,University of Virginia
Journal of Physiology | Year: 2012

It is widely recognized that ATP, along with other nucleotides, subserves important intercellular signalling processes. Among various nucleotide release mechanisms, the relatively recently identified pannexin 1 (Panx1) channel is gaining prominence by virtue of its ability to support nucleotide permeation and release in a variety of different tissues. Here, we review recent advances in our understanding of the factors that control Panx1 channel activity. By using electrophysiological and biochemical approaches, diverse mechanisms that dynamically regulate Panx1 channel function have been identified in various settings; these include, among others, activation by caspase-mediated channel cleavage in apoptotic immune cells, by G protein-coupled receptors in vascular smooth muscle, by low oxygen tension in erythrocytes and neurons, by high extracellular K+ in various cell types and by stretch/strain in airway epithelia. Delineating the distinct mechanisms of Panx1 modulation that prevail in different physiological contexts provides the possibility that these channels, and ATP release, could ultimately be targeted in a context-dependent manner. © 2012 The Physiological Society.


Horgan C.O.,University of Virginia
International Journal of Non-Linear Mechanics | Year: 2015

In 1996, Alan Gent published a short paper that proposed the use of a very simple two parameter phenomenological constitutive model for hyperelastic isotropic incompressible materials. The model is empirical but has the advantages of mathematical simplicity, reflects the severe strain-stiffening at large strains observed experimentally, reduces to the classic neo-Hookean model for small strains and involves just two material parameters namely the shear modulus for infinitesimal deformations and a parameter that measures a maximum allowable value of strain. The model reflects the limiting chain extensibility characteristic of non-Gaussian molecular models for rubber. Here we review some of the numerous developments, extensions and widespread applications that have resulted from that groundbreaking paper not only in rubber elasticity but also in the area of biomechanics of soft biomaterials. The Gent model is remarkably robust: its mathematical simplicity combined with physical basis has ensured that it has reached status as a fundamental canonical phenomenological constitutive model for hyperelastic materials. © 2014 Elsevier Ltd. All rights reserved.


Moskaluk C.A.,University of Virginia
Head and Neck Pathology | Year: 2013

The clinical features and common molecular alterations of adenoid cystic carcinoma (ACC) are reviewed in this paper. ACC is an uncommon neoplasm that most frequently arises in salivary glands and related tissue in the head and neck region. ACC has distinct histologic features, with cribriform and tubular growth patterns of basaloid cells displaying a predominantly myoepithelial cellular phenotype. This neoplasm also has uncommon clinical features of rare regional lymph node metastasis and a prolonged but relentlessly progressive clinical course. Clinical outcome in ACC is correlated to histologic grade, which is correlated to the degree of aneuploidy and genetic alterations present in the tumor genomes. Recent studies have identified that the majority of ACC contain alterations of the MYB gene, usually resulting in a fusion gene product with the NFIB gene by a t(6;9) translocation event. The molecular consequences of this alteration are incompletely understood, as are secondary molecular alterations that contribute to the neoplastic phenotype of ACC. © 2013 Springer Science+Business Media New York.


Derewenda Z.S.,University of Virginia
Acta Crystallographica Section D: Biological Crystallography | Year: 2010

Until recently, protein crystallization has mostly been regarded as a stochastic event over which the investigator has little or no control. With the dramatic technological advances in synchrotron-radiation sources and detectors and the equally impressive progress in crystallographic software, including automated model building and validation, crystallization has increasingly become the rate-limiting step in X-ray diffraction studies of macromolecules. However, with the advent of recombinant methods it has also become possible to engineer target proteins and their complexes for higher propensity to form crystals with desirable X-ray diffraction qualities. As most proteins that are under investigation today are obtained by heterologous overexpression, these tech-niques hold the promise of becoming routine tools with the potential to transform classical crystallization screening into a more rational high-success-rate approach. This article presents an overview of protein-engineering methods designed to enhance crystallizability and discusses a number of examples of their successful application. © 2010 International Union of Crystallography. Printed in Singapore-all rights reserved.


Gadani S.P.,University of Virginia | Walsh J.T.,University of Virginia | Lukens J.R.,University of Virginia | Kipnis J.,University of Virginia
Neuron | Year: 2015

Fighting pathogens and maintaining tissue homeostasis are prerequisites for survival. Both of these functions are upheld by the immune system, though the latter is often overlooked in the context of the CNS. The mere presence of immune cells in the CNS was long considered a hallmark of pathology, but this view has been recently challenged by studies demonstrating that immunological signaling can confer pivotal neuroprotective effects on the injured CNS. In this review, we describe the temporal sequence of immunological events that follow CNS injury. Beginning with immediate changes at the injury site, including death of neural cells and release of damage-associated molecular patterns (DAMPs), and progressing through innate and adaptive immune responses, we describe the cascade of inflammatory mediators and the implications of their post-injury effects. We conclude by proposing a revised interpretation of immune privilege in the brain, which takes beneficial neuro-immune communications into account. © 2015 Elsevier Inc.


Taylor R.P.,University of Virginia
Blood | Year: 2013

In this issue of Blood, Rossi et al provide convincing evidence that extends and generalizes the importance of trogocytosis, a process in which effector cells use Fcγ receptors to remove Immunoglobulin G (IgG)-chelated antigens from donor cells. Their work suggests that the process may be beneficial in the context of epratuzumab treatment of autoimmune diseases.


Burns T.M.,University of Virginia
Annals of the New York Academy of Sciences | Year: 2012

The myasthenia gravis composite (MGC) was constructed by selecting the best performing items from three commonly used, MG-specific scales. The response categories of the items were subsequently weighted for importance. The MGC, which takes less than five minutes to complete, is made up of three ocular, three bulbar, one respiratory, one neck, and two limb items. After its construction, the MGC was validated in an 11-center scale validity study. During the validation study, which included test-retest analysis, it was determined that a 3-point improvement in MGC score reliably indicates clinical improvement. A 3-point improvement in MGC also appears to be meaningful to the patient. Rasch analysis of the MGC confirmed that all 10 items belong and can be summed to provide a total score, and that the weights given to the response categories of the items are appropriate. © 2012 New York Academy of Sciences.


McCaffrey L.M.,McGill University | Macara I.G.,University of Virginia
Trends in Cell Biology | Year: 2011

Epithelial cells comprise the foundation for the majority of organs in the mammalian body, and are the source of approximately 90% of all human cancers. Characteristically, epithelial cells form intercellular adhesions, exhibit apical/basal polarity, and orient their mitotic spindles in the plane of the epithelial sheet. Defects in these attributes result in the tissue disorganization associated with cancer. Epithelia undergo self-renewal from stem cells, which might in some cases be the cell of origin for cancers. The PAR polarity proteins are master regulators of epithelial organization, and are closely linked to signaling pathways such as Hippo, which orchestrate proliferation and apoptosis to control organ size. 3D ex vivo culture systems can now faithfully recapitulate epithelial organ morphogenesis, providing a powerful approach to study both normal development and the initiating events in carcinogenesis. © 2011 Elsevier Ltd.


Mozdzer T.J.,University of Virginia | Zieman J.C.,University of Virginia
Journal of Ecology | Year: 2010

Over the last century, native Phragmites australis lineages have been almost completely replaced along the North American Atlantic coast by an aggressive lineage originating from Eurasia. Understanding the mechanisms that facilitate biological invasions is critical to better understand what makes an invasive species successful. Our objective was to determine what makes the introduced lineage so successful in the study area by specifically investigating if morphological and ecophysiological differences exist between native and introduced genetic lineages of P. australis. We hypothesized a priori that due to phenotypic differences and differences in plant nitrogen (N) content between lineages, the introduced lineage would have a greater photosynthetic potential. In situ ecophysiological and morphological data were collected for 2 years in a mid-Atlantic tidal marsh and in a glasshouse experiment. We measured photosynthetic parameters (Amax, water use efficiency, stomatal conductance) using infrared gas analysis, in conjunction with ecophysiological and morphological parameters [specific leaf area (SLA), leaf area, chlorophyll content, N content]. Introduced P. australis maintained 51% greater rates of photosynthesis and up to 100% greater rates of stomatal conductance which are magnified by its 38-83% greater photosynthetic canopy compared to the native type. The introduced lineage also had a significantly greater SLA and N content. Glasshouse-grown plants and naturally occurring populations demonstrated similar trends in ecophysiological characteristics, verifying the heritability of these differences. These ecophysiological differences, when combined with an extended growing season, provide the mechanism to explain the success of introduced P. australis in North America. Our findings suggest the native type is a low-nutrient specialist, with a more efficient photosynthetic mechanisms and lower N demand, whereas the introduced type requires nearly four times more N than the native type to be an effective competitor. Synthesis. Our study is the first to combine field and laboratory data to explain a biological invasion attributed to ecophysiological differences between genetic lineages. Our data corroborates earlier work suggesting anthropogenic modification of wetland environments has provided the state change necessary for the success of introduced P. australis. Finally, our results suggest that genotypic differences within species merit further investigations, especially when related to biological invasions. © 2010 The Authors. Journal compilation © 2010 British Ecological Society.


Saha M.V.,University of Virginia
American Journal of Epidemiology | Year: 2014

Mortality rates increase immediately after periods of high air temperature. In the days and weeks after heat events, time series may exhibit mortality displacement - periods of lower than expected mortality. We examined all-cause mortality and meteorological data from 1980 to 2009 in the cities of Atlanta, Georgia; Boston, Massachusetts; Minneapolis-St. Paul, Minnesota; Philadelphia, Pennsylvania; Phoenix, Arizona; Seattle, Washington; and St. Louis, Missouri. We modeled baseline mortality using a generalized additive model. Heat waves were defined as periods of 3 or more consecutive days in which the apparent temperature exceeded a variable percentile. For each heat wave, we calculated the sum of excess and deficit mortality. Mortality displacement, which is the ratio of grand sum deficit to grand sum excess mortality, decreased as a function of event strength in all cities. Displacement was close to 1.00 for the weakest events. At the highest temperatures, displacement varied from 0.35 (95% confidence interval: 0.21, 0.55) to 0.75 (95% confidence interval: 0.54, 0.97). We found strong evidence of acclimatization across cities. Without consideration of displacement effects, the net impacts of heat-wave mortality are likely to be significant overestimations. A statistically significant positive relationship between the onset temperature of nondisplaced heat mortality and mean warm-season temperature (R2 = 0.78, P < 0.01) suggests that heat mortality thresholds may be predictable across cities. © The Author 2013.


Williams M.E.,University of Virginia
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program | Year: 2013

Mantle cell lymphoma (MCL) is a unique subtype of non-Hodgkin lymphoma that is both biologically and clinically heterogeneous. A variety of biomarkers, the achievement of minimal residual disease negativity after initial therapy, and the MCL International Prognostic Index (MIPI) are associated with patient outcome, although none has as yet been used for routine treatment stratification. Given the lack of widely accepted and standardized treatment approaches, clinical trial enrollment should always be considered for the initial therapy of MCL. Outside of the trial setting, younger and transplantation-eligible patients with newly diagnosed MCL who require treatment should first be considered for a rituximab+a high-dose cytarabine-containing regimen, followed by autologous stem cell transplantation consolidation in first remission. Symptomatic elderly and nontransplantation-eligible individuals typically receive rituximab+bendamustine, or R-CHOP (rituximab+cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone/prednisolone) followed by maintenance rituximab, the latter a treatment plan that has demonstrated extended response duration and survival. Promising early results for consolidation approaches with proteasome inhibitors and immunomodulatory drugs are now being tested in randomized clinical trials. The availability of highly active BCR signaling pathway inhibitors and cell death pathway modulation via BH3 mimetics, among other novel agents, promise to rapidly expand treatment options, change existing treatment paradigms, and further improve outcomes for MCL patients.


Platts-Mills T.A.E.,University of Virginia
Journal of Allergy and Clinical Immunology | Year: 2015

Before the first description of hay fever in 1870, there was very little awareness of allergic disease, which is actually similar to the situation in prehygiene villages in Africa today. The best explanation for the appearance and subsequent increase in hay fever at that time is the combination of hygiene and increased pollen secondary to changes in agriculture. However, it is important to remember that the major changes in hygiene in Northern Europe and the United States were complete by 1920. Asthma in children did not start to increase until 1960, but by 1990, it had clearly increased to epidemic numbers in all countries where children had adopted an indoor lifestyle. There are many features of the move indoors that could have played a role; these include increased sensitization to indoor allergens, diet, and decreased physical activity, as well as the effects of prolonged periods of shallow breathing. Since 1990, there has been a remarkable increase in food allergy, which has now reached epidemic numbers. Peanut has played a major role in the food epidemic, and there is increasing evidence that sensitization to peanut can occur through the skin. This suggests the possibility that changes in lifestyle in the last 20 years could have influenced the permeability of the skin. Overall, the important conclusion is that sequential changes in lifestyle have led to increases in different forms of allergic disease. Equally, it is clear that the consequences of hygiene, indoor entertainment, and changes in diet or physical activity have never been predicted. © 2015 American Academy of Allergy, Asthma & Immunology.


Carey R.M.,University of Virginia
Current Opinion in Endocrinology, Diabetes and Obesity | Year: 2010

Purpose of Review: The renin-angiotensin-aldosterone system is a co-ordinated hormonal cascade of major importance in the control of fluid and electrolyte homeostasis and blood pressure. During the past decade, the scientific community has realized that this system is also of paramount importance in pathophysiology of cardiovascular and renal target organ damage. In particular, inappropriately elevated aldosterone levels in the face of body sodium expansion have been incriminated in cardiac and vascular inflammation and fibrosis leading to remodeling and disease. Substantial advances on the role and mechanisms of aldosterone-induced tissue damage and novel findings on the genetic control of aldosterone secretion have been reported during the past year, and these are the subjects of this brief review. Recent Findings: A novel control mechanism for aldosterone secretion may be circadian clock genes, disruption of which leads to increased aldosterone secretion and hypertension. Animal models for human idiopathic hyperaldosteronism have been reported for the first time. Glucocorticoids have now been found to activate cardiac mineralocorticoid receptors during certain cardiovascular disease states. Crosstalk between mineralocorticoid and angiotensin AT1 receptors contributes to target organ damage. Endogenous cardiotonic steroids may explain at least some of the tissue damage during sodium loading previously attributed to aldosterone. Summary: Insights on aldosterone and cardiovascular disease gained during the past year provide new avenues for research and applications for treatment in the future. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Parsons J.T.,University of Virginia | Horwitz A.R.,University of Virginia | Schwartz M.A.,University of Virginia
Nature Reviews Molecular Cell Biology | Year: 2010

Cell migration affects all morphogenetic processes and contributes to numerous diseases, including cancer and cardiovascular disease. For most cells in most environments, movement begins with protrusion of the cell membrane followed by the formation of new adhesions at the cell front that link the actin cytoskeleton to the substratum, generation of traction forces that move the cell forwards and disassembly of adhesions at the cell rear. Adhesion formation and disassembly drive the migration cycle by activating Rho GTPases, which in turn regulate actin polymerization and myosin II activity, and therefore adhesion dynamics. © 2010 Macmillan Publishers Limited. All rights reserved.


Christian C.A.,University of Virginia | Moenter S.M.,University of Virginia
Endocrine Reviews | Year: 2010

Ovarian steroids normally exert homeostatic negative feedback on GnRH release. During sustained exposure to elevated estradiol in the late follicular phase of the reproductive cycle, however, the feedback action of estradiol switches to positive, inducing a surge of GnRH release from the brain, which signals the pituitary LH surge that triggers ovulation. In rodents, this switch appears dependent on a circadian signal that times the surge to a specific time of day (e.g., late afternoon in nocturnal species). Although the precise nature of this daily signal and the mechanism of the switch from negative to positive feedback have remained elusive, work in the past decade has provided much insight into the role of circadian/diurnal and estradiol-dependent signals in GnRH/LH surge regulation and timing. Here we review the current knowledge of the neurobiology of the GnRH surge, in particular the actions of estradiol on GnRH neurons and their synaptic afferents, the regulation of GnRH neurons by fast synaptic transmission mediated by the neurotransmitters γ-aminobutyric acid and glutamate, and the host of excitatory and inhibitory neuromodulators including kisspeptin, vasoactive intestinal polypeptide, catecholamines, neurokinin B, and RFamide-related peptides, that appear essential for GnRH surge regulation, and ultimately ovulation and fertility. Copyright © 2010 by The Endocrine Society.


Zhang H.,University of Virginia | Li L.,University of Virginia
Plant Journal | Year: 2013

MicroRNAs (miRNAs) are endogenous small RNAs repressing target gene expression post-transcriptionally and are critically involved in various development processes and responses to environmental stresses. MiR408 is highly conserved in land plants and targets several transcripts encoding copper proteins. Although it has been well documented that expression level of miR408 is strongly influenced by a variety of environmental conditions including copper availability, the biological function of this miRNA is still unknown. Here we show that constitutive expression of miR408 results in enhanced growth of seedling and adult plant while knocking down miR408 level by T-DNA insertions or the artificial miRNA technique causes impaired growth. Further, we found that constitutively activated miR408 is able to complement the growth defects of the T-DNA lines. Regarding the molecular mechanism governing miR408 expression, we found that the transcription factors SQUAMOSA PROMOTER BINDING PROTEIN-LIKE7 (SPL7) binds to the GTAC motifs in the MIR408 promoter in response to copper deficiency. Interestingly, constitutive activation of miR408 in the spl7 background could partially rescue the severe growth defects of the mutant. Together these results demonstrate that miR408 is a powerful modulator of vegetative growth. Our finding thus reveals a novel control mechanism for vegetative development based on calculated miR408 expression in response to environmental cues. © 2013 The Authors The Plant Journal © 2013 Blackwell Publishing Ltd.


Cherepanova O.A.,University of Virginia
Nature Medicine | Year: 2016

Although somatic cell activation of the embryonic stem cell (ESC) pluripotency factor OCT4 has been reported, this previous work has been controversial and has not demonstrated a functional role for OCT4 in somatic cells. Here we demonstrate that smooth muscle cell (SMC)-specific conditional knockout of Oct4 in Apoe-/- mice resulted in increased lesion size and changes in lesion composition that are consistent with decreased plaque stability, including a thinner fibrous cap, increased necrotic core area, and increased intraplaque hemorrhage. Results of SMC-lineage-tracing studies showed that these effects were probably the result of marked reductions in SMC numbers within lesions and SMC investment within the fibrous cap, which may result from impaired SMC migration. The reactivation of Oct4 within SMCs was associated with hydroxymethylation of the Oct4 promoter and was hypoxia inducible factor-1α (HIF-1α, encoded by HIF1A) and Krüppel-like factor-4 (KLF4)-dependent. These results provide the first direct evidence that OCT4 has a functional role in somatic cells, and they highlight the potential role of OCT4 in normal and diseased somatic cells. © 2016 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.


The pathologic anatomy and hemodynamics of the left-sided portal circulation that is associated with gastric varices (GVs) are complex and highly variable. Understanding the pathologic anatomy and hemodynamics associated with GVs is important for clinical management decisions and for the technical descriptive details of the balloon-occluded retrograde transvenous obliteration (BRTO) and balloon-occluded antegrade transvenous obliteration procedures. A reflection of the considerable variability in anatomy, pathology, and hemodynamics is the numerous descriptive and categorical classifications that have been described in the past 2 decades. This article reviews the detailed descriptive gross anatomy, radiographic anatomy, and portosystemic venous hemodynamics that are associated with GVs and that can be encountered during the BRTO or balloon-occluded antegrade transvenous obliteration procedure(s) or both. Definitions are also set to clarify this detailed anatomy that received limited description in the prior literature. Moreover, all the classifications that have been described (to the best of the author's knowledge) that are relevant to the BRTO procedure are detailed in the article. © 2013 Elsevier Inc.


Tolan P.H.,University of Virginia
Journal of Abnormal Child Psychology | Year: 2014

The set of studies in this special section bring into relief the importance of due attention to maintenance effects and use of boosters as critical components of intervention planning and evaluation, requiring theoretical and analytic forethought and direction. While some trends can be identified across these included reports and the other few studies of boosters in child psychopathology intervention, the main implication of work to date is to highlight the need to consider maintenance and booster effects analyses as more than afterthoughts of technical interest primarily. In addition, this collection of studies includes treatment and prevention efforts focused on a shared topic, which is rare in child psychopathology topical collections. This juxtaposition helps illuminate some of the many considerations that could influence how maintenance effects and booster contributions might be tested. It is hoped that further work will occur that builds on these exemplary efforts. © 2014 Springer Science+Business Media New York.


Platts-Mills T.A.E.,University of Virginia | Woodfolk J.A.,University of Virginia
Immunological Reviews | Year: 2011

Allergens are recognized as the proteins that induce immunoglobulin E (IgE) responses in humans. The proteins come from a range of sources and, not surprisingly, have many different biological functions. However, the delivery of allergens to the nose is exclusively on particles, which carry a range of molecules in addition to the protein allergens. These molecules include pathogen-associated molecular patterns (PAMPs) that can alter the response. Although the response to allergens is characterized by IgE antibodies, it also includes other isotypes (IgG, IgA, and IgG4), as well as T cells. The challenge is to identify the characteristics of these exposures that favor the production of this form of response. The primary features of the exposure appear to be the delivery in particles, such as pollen grains or mite feces, containing both proteins and PAMPs, but with overall low dose. Within this model, there is a simple direct relationship between the dose of exposure to mite or grass pollen and the prevalence of IgE responses. By contrast, the highest levels of exposure to cat allergen are associated with a lower prevalence of IgE responses. Although the detailed mechanisms for this phenomenon are not clear, it appears that enhanced production of interleukin-10 in response to specific Fel d 1 peptides could influence the response. However, it is striking that the animal sources that are most clearly associated with decreased responses at high allergen dose are derived from animals from which humans evolved more recently (∼65 million years ago). Although the nose is still recognized as the primary route for sensitization to inhalant allergens, there is increasing evidence that the skin is also an important site for the generation of IgE antibody responses. By contrast, it is now evident that delivery of foreign proteins by the oral route or sublingually will favor the generation of tolerance. © 2011 John Wiley & Sons A/S.


Sang Q.,University of Virginia | Tao G.,University of Virginia
IEEE Transactions on Automatic Control | Year: 2012

Nonlinear controlled systems at multiple operating points are modeled as piecewise linear systems, where changes in operating points are modeled as switches between constituent linearized systems. This note studies the adaptive state feedback for state tracking control problem for such systems. Piecewise linear reference model systems are used for generating desired state trajectories and their stability properties are studied. Adaptive state feedback control schemes are developed, and their stability and tracking performance are analyzed and evaluated by simulation examples. It is shown that exponential tracking performance can be achieved if the reference input is sufficiently rich and the switches are sufficiently slow. © 2011 IEEE.


Fountain N.B.,University of Virginia
Current Opinion in Neurology | Year: 2013

Purpose of Review: The science of quality of care in medicine has been emerging for the past decade, but it has only recently addressed epilepsy care. Quality of care in this sense refers to implementation of policies in large populations to improve care. This can have a large impact on epilepsy patients, as much of their care is delivered by generalists who can improve their care through the explicit direct requirements of quality measures. Purpose of Review: Eight epilepsy quality performance measures were recently approved by national organizations, but only three were adopted by Medicare and only one by the National Quality Forum. The main reason for not adopting them is the lack of high-level evidence. However, there is high-level evidence for the efficacy of epilepsy surgery and use of newer antiepileptic drugs for the treatment of intractable epilepsy. Other problems are the lack of information about gaps in care and the imprecision in epilepsy diagnosis coding. Summary: Quality measurement will continue in epilepsy care, so a working knowledge of the topic is required by healthcare providers. Implementation of standardized quality measures can improve the care of people with epilepsy if the measures have demonstrated efficacy and can address gaps in care, and implementation is feasible. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Durbin Jr. C.G.,University of Virginia
Respiratory Care | Year: 2010

Tracheostomy is one of the most frequent procedures performed in intensive care unit (ICU) patients. Of the many purported advantages of tracheostomy, only patient comfort, early movement from the ICU, and shorter ICU and hospital stay have significant supporting data. Even the belief of increased safety with tracheostomy may not be correct. Various techniques for tracheostomy have been developed; however, use of percutaneous dilation techniques with bronchoscopic control continue to expand in popularity throughout the world. Tracheostomy should occur as soon as the need for prolonged intubation (longer than 14 d) is identified. Accurate prediction of this duration by day 3 remains elusive. Mortality is not worse with tracheotomy and may be improved with earlier provision, especially in head-injured and critically ill medical patients. The timing of when to perform a tracheostomy continues to be individualized, should include daily weaning assessment, and can generally be made within 7 days of intubation. Bedside techniques are safe and efficient, allowing timely tracheostomy with low morbidity. © 2010 Daedalus Enterprises.


Santen R.J.,University of Virginia
Journal of Clinical Endocrinology and Metabolism | Year: 2011

Context: Two common strategies are used to treat estrogen receptor-positive breast cancer in women: tamoxifen to inhibit estrogen action, and aromatase inhibitors (AIs) to block estrogen biosynthesis. Recent data suggest that AIs are more effective than tamoxifen in the adjuvant and advanced disease settings and are now being more commonly used. Tamoxifen, as a selective estrogen receptor modulator, exerts estrogenic effects to preserve bone, whereas the AIs profoundly lower estrogen levels and cause bone loss. Recent comparative studies of these agents provide extensive data on fracture rates, bone mineral density, and markers of bone formation and resorption. Objective: The aim of the study was to review the mechanistic effects of estrogen on bone and clinical data regarding bone density, bone turnover markers, and fracture rates in women with breast cancer taking tamoxifen or AIs. Evidence Acquisition and Synthesis: Data presented reflect a review of the literature and data integration from the perspective of the author's knowledge of the field. Results: Tamoxifen increases bone density and reduces fractures in postmenopausal women with breast cancer, whereas AIs increase rate of fracture, accelerate loss of bone mineral density, and enhance levels of markers of bone formation and resorption. Bisphosphonates and denosumab counteract the effects of the AIs on bone. Guidelines for management of AI-induced bone loss are available from several sources, but a simple algorithm guides decision making most effectively. Conclusions: Endocrine therapy for postmenopausal women with breast cancer exerts substantial effects on bone, and guidelines are available to assist in the management of bone-related problems. Copyright © 2011 by The Endocrine Society.


Schwarzbauer J.E.,Princeton University | DeSimone D.W.,University of Virginia
Cold Spring Harbor Perspectives in Biology | Year: 2011

Fibronectin (FN) is a multidomain protein with the ability to bind simultaneously to cell surface receptors, collagen, proteoglycans, and other FN molecules. Many of these domains and interactions are also involved in the assembly of FN dimers into a multimeric fibrillar matrix. When, where, and how FN binds to its various partners must be controlled and coordinated during fibrillogenesis. Steps in the process of FN fibrillogenesis including FN self-association, receptor activities, and intracellular pathways have been under intense investigation for years. In this review, the domain organization of FN including the extra domains and variable region that are controlled by alternative splicing are described. We discuss how FN-FN and cell-FN interactions play essential roles in the initiation and progression of matrix assembly using complementary results from cell culture and embryonic model systems that have enhanced our understanding of this process. © 2011 Cold Spring Harbor Laboratory Press.


Mikami A.Y.,University of Virginia
Clinical Child and Family Psychology Review | Year: 2010

It is well-established that youth with attention-deficit/hyperactivity disorder (ADHD) are often peer-rejected and rated by parents, teachers, and observers to have poor social skills, when compared to typically developing peers. Significantly less research, however, has been devoted to the experiences youth with ADHD have in their close friendships. The aim of this article is to draw attention to friendship as a distinct construct from peer rejection and social skills and to summarize what is known about youth with ADHD in their friendships. The potential for stable, high-quality friendships to buffer the negative outcomes typically conferred by peer rejection in this population is discussed. This article concludes with recommendations for interventions that specifically target improving the close friendships of youth with ADHD as a treatment strategy. © 2010 Springer Science+Business Media, LLC.


Keeley E.C.,University of Virginia
Advances in cancer research | Year: 2010

The tumor microenvironment is extremely complex that depends on tumor cell interaction with the responding host cells. Angiogenesis, or new blood vessel growth from preexisting vasculature, is a preeminent feature of successful tumor growth of all solid tumors. While a number of factors produced by both the tumor cells and host responding cells have been discovered that regulate angiogenesis, increasing evidence is growing to support the important role of CXC chemokines in this process. As a family of cytokines, the CXC chemokines are pleiotropic in their ability to regulate tumor-associated angiogenesis, as well as cancer cell metastases. In this chapter, we will discuss the disparate activity that CXC chemokines play in regulating cancer-associated angiogenesis and metastases. Copyright 2010 Elsevier Inc. All rights reserved.


Neuroendocrine mechanisms underlying the progression of sleep-wake gonadotrophin-releasing hormone (GnRH) pulse secretion across puberty have remained enigmatic. Here, the changes of sleep-wake luteinising hormone (LH) (and, by inference, GnRH) pulse secretion across puberty in normal girls are reviewed, primarily focusing on available human data. It is suggested that the primary control of GnRH pulse frequency changes across puberty, with sex steroid feedback exerting minimal control during childhood, but primary control during adulthood. A working model is proposed regarding how such a transfer of GnRH pulse frequency control may partly account for the prominent day-night differences of GnRH pulse frequency characteristic of puberty. How this model may be relevant to the genesis of abnormal GnRH secretion in peripubertal girls with hyperandrogenaemia is then described. © 2010 The Author. Journal Compilation © 2010 Blackwell Publishing Ltd.


Boyd J.C.,University of Virginia | Bruns D.E.,University of Virginia
Clinical Chemistry | Year: 2014

BACKGROUND: Total error allowances have been proposed for glucose meters used in tight-glucose-control (TGC) protocols. It is unclear whether these proposed quality specifications are appropriate for continuous glucose monitoring (CGM). METHODS: We performed Monte Carlo simulations of patients on TGC protocols. To simulate use of glucose meters, measurements were made hourly. To simulate CGM, glucose measurements were made every 5 min. Glucose was measured with defined bias (varied from -20% to 20%) and imprecision (0% to 20% CV). The measured glucose concentrations were used to alter insulin infusion rates according to established treatment protocols. Changes in true glucose were calculated hourly on the basis of the insulin infusion rate, the modeled patient's insulin sensitivity, and a model of glucose homeostasis. Wemodeled 18 000 patients, equally divided between the hourly and every-5-min measurement schemas and distributed among 45 combinations of bias and imprecision and 2 treatment protocols. RESULTS: With both treatment protocols and both measurement frequencies, higher measurement imprecision increased the rates of hypoglycemia and hyperglycemia and increased glycemic variability (SD). These adverse effects of measurement imprecision were lower at the higher measurement frequency. The rate of hypoglycemia at an imprecision (CV) of 5% with hourly measurements was similar to the rate of hypoglycemia at 10% CV when measurements were made every 5 min. With measurements every 5 min, imprecision up to 10% had minimal effects on hyperglycemia or glycemic variability. Effects of simulated analytical bias on glycemia were unaffected by measurement frequency. CONCLUSIONS: Quality specifications for imprecision of glucose meters are not transferable to CGM. © 2013 American Association for Clinical Chemistry.


Ruhm C.J.,University of Virginia
Journal of Health Economics | Year: 2012

The combination of economic and biological factors is likely to result in overeating in the current environment of cheap and readily available food. This propensity is shown using a "dual decision" approach where choices reflect the interaction of a "deliberative" system, operating as in standard economic models, and an "affective" system that responds rapidly to stimuli without considering long-term consequences. This framework is characterized by excess food consumption and body weight, in that individuals prefer both ex-ante and ex-post to eat and weigh less than they actually do, with weight loss attempts being common but often unsuccessful or only partially successful. As in the standard model, weight is related to prices. However, another potentially important reason for rising obesity is that food producers have incentives to engineer products to stimulate the affective system so as to encourage overeating. Data from several sources are used to investigate predictions of the dual decision model, with the evidence providing broad support for at least some irrationality in food consumption. Most importantly, there is little indication that the large secular increases in body mass index have been accompanied by corresponding growth in utility-maximizing weight. One result is that efforts to reduce weight have become more common as obesity has increased. © 2012 Elsevier B.V.


Hart J.M.,University of Virginia
Journal of athletic training | Year: 2010

Arthrogenic muscle inhibition is an important underlying factor in persistent quadriceps muscle weakness after knee injury or surgery. To determine the magnitude and prevalence of volitional quadriceps activation deficits after knee injury. Web of Science database. Eligible studies involved human participants and measured quadriceps activation using either twitch interpolation or burst superimposition on patients with knee injuries or surgeries such as anterior cruciate ligament deficiency (ACLd), anterior cruciate ligament reconstruction (ACLr), and anterior knee pain (AKP). Means, measures of variability, and prevalence of quadriceps activation (QA) failure (<95%) were recorded for experiments involving ACLd (10), ACLr (5), and AKP (3). A total of 21 data sets from 18 studies were initially identified. Data from 3 studies (1 paper reporting data for both ACLd and ACLr, 1 on AKP, and the postarthroscopy paper) were excluded from the primary analyses because only graphical data were reported. Of the remaining 17 data sets (from 15 studies), weighted mean QA in 352 ACLd patients was 87.3% on the involved side, 89.1% on the uninvolved side, and 91% in control participants. The QA failure prevalence ranged from 0% to 100%. Weighted mean QA in 99 total ACLr patients was 89.2% on the involved side, 84% on the uninvolved side, and 98.5% for the control group, with prevalence ranging from 0% to 71%. Thirty-eight patients with AKP averaged 78.6% on the involved side and 77.7% on the contralateral side. Bilateral QA failure was commonly reported in patients. Quadriceps activation failure is common in patients with ACLd, ACLr, and AKP and is often observed bilaterally.


Purow B.,University of Virginia
Advances in Experimental Medicine and Biology | Year: 2012

The Notch pathway powerfully influences stem cell maintenance, development and cell fate and is increasingly recognized for the key roles it plays in cancer. Notch promotes cell survival, angiogenesis and treatment resistance in numerous cancers, making it a promising target for cancer therapy. It also crosstalks with other critical oncogenes, providing a means to affect numerous signaling pathways with one intervention. While the gamma-secretase inhibitors are the only form of Notch inhibitors in clinical trials, other forms of Notch inhibition have been developed or are theoretically feasible. In this chapter we review the rationales for Notch inhibition in cancer and then discuss in detail the various modalities for Notch inhibition, both current and speculative. © 2012 Landes Bioscience and Springer Science+Business Media.


Carr D.E.,University of Virginia | Eubanks M.D.,Texas A&M University
Annual Review of Entomology | Year: 2014

Self-pollination is common in plants, and limited seed and pollen dispersal can create localized inbreeding even within outcrossing plants. Consequently, insects regularly encounter inbred plants in nature. Because inbreeding results in elevated homozygosity, greater expression of recessive alleles, and subsequent phenotypic changes in inbred plants, inbreeding may alter plant-insect interactions. Recent research has found that plant inbreeding alters resistance and tolerance to herbivores, alters the attraction and susceptibility of plants to insects that vector plant pathogens, and alters visitation rates of insect pollinators. These results suggest that interactions with insects can increase or decrease inbreeding depression (the loss of fitness due to self-fertilization) and subsequently alter the evolution of selfing within plant populations. Future work needs to focus on the mechanisms underlying genetic variation in the effects of inbreeding on plant-insect interactions and the consequences of altered plant-insect interactions on the evolution of plant defense and plant mating systems. © Copyright ©2014 by Annual Reviews. All rights reserved.


Blackhall L.J.,University of Virginia
Muscle and Nerve | Year: 2012

Patients with amyotrophic lateral sclerosis (ALS) have high symptom burdens, including pain, fatigue, dyspnea, and sialorrhea, and they must make difficult decisions about the use of life-prolonging therapies, such as long-term mechanical ventilation. The impact of ALS is also felt by family caregivers who often struggle to meet the heavy physical, financial, and emotional demands associated with the illness. Expert multidisciplinary care may improve both quality and length of life of patients with ALS. However, although advances have been made in the treatment of some symptoms, others, including pain management, remain poorly studied. Involvement of palliative care specialists as part of the ALS multidisciplinary team is recommended, as we continue to work toward improving the quality of life for patients and their families. © 2011 Wiley Periodicals, Inc.


Wu M.,University of Virginia | Scott A.J.,University of Virginia
Bioinformatics | Year: 2012

With the explosive growth of bacterial and archaeal sequence data, large-scale phylogenetic analyses present both opportunities and challenges. Here we describe AMPHORA2, an automated phylogenomic inference tool that can be used for high-throughput, high-quality genome tree reconstruction and metagenomic phylotyping. Compared with its predecessor, AMPHORA2 has several major enhancements and new functions: it has a greatly expanded phylogenetic marker database and can analyze both bacterial and archaeal sequences; it incorporates probability-based sequence alignment masks that improve the phylogenetic accuracy; it can analyze DNA as well as protein sequences and is more sensitive in marker identification; finally, it is over 100× faster in metagenomic phylotyping. © The Author 2012. Published by Oxford University Press. All rights reserved.


Egodapitiya K.N.,University of Virginia | Li S.,University of Virginia | Jones R.R.,University of Virginia
Physical Review Letters | Year: 2014

We have used picosecond THz pulses to induce transient field-free orientation of OCS molecules. Coherent optical Raman excitation prepares the molecules in rotational superposition states prior to THz irradiation, substantially enhancing the degree of orientation. The time-dependent alignment and orientation are characterized via Coulomb explosion in an intense probe laser. The degree of OCS orientation is an order of magnitude larger than previously observed following THz irradiation and is achieved with a significantly smaller THz field.The field-free orientation level is comparable to that generated using pulsed, two-color laser fields but is obtained with negligible target ionization. © 2014 American Physical Society.


Chevalier R.L.,University of Virginia
Current Medicinal Chemistry | Year: 2012

The renin-angiotensin system is highly conserved through evolutionary history, and has multiple functions in addition to maintaining cardiovascular homeostasis: these include the regulation of renal cell survival and cell death, and development of the kidney. The importance of angiotensin (ANG) in normal kidney development was first recognized in infants with renal maldevelopment born to mothers treated with angiotensin converting enzyme (ACE) inhibitors or with ANG AT1 receptor blockers. The molecular role of ANG in renal development has been elucidated using gene targeting in mice, revealing major effects in branching morphogenesis, vasculogenesis, development of the papilla and renal concentrating mechanism. Although exposure of the fetus to ANG inhibitors is potentially harmful throughout pregnancy, effects are greater in late compared to early gestation. Significant differences between humans and rodents in placental transfer of ANG and timing of renal development contributed to initial delays in recognizing the teratogenic effects of ANG inhibitors. Although administration of ACE or AT1 receptor inhibitors can slow progression of renal disease in older children, ANG inhibition in the neonatal period can aggravate renal injury due to congenital urinary tract obstruction. Neonates are also far more sensitive than older children to the hypotensive actions these agents and doses must be markedly reduced to avoid precipitating oliguria. Understanding the complex interactions of the maturing renin-angiotensin system in the perinatal period is essential in the use of ANG or renin inhibitors in women during childbearing years or in neonates with cardiovascular or renal disease. © 2012 Bentham Science Publishers.


Spotnitz W.D.,University of Virginia
American Surgeon | Year: 2012

Hemostats, sealants, and adhesives are useful adjuncts to modern surgical procedures. To maximize their benefit, a surgeon needs to understand the safety, efficacy, usability, and cost of these agents. To be truly added to a surgeon's own toolbox, the operator must also have knowledge of when and how to best use these materials. This commentary is designed to succinctly facilitate this understanding and knowledge. A nomenclature and classification system based on group, category, and class has been created to help with this process and is provided here. By using this system, materials consisting of similar design and for common indications can be compared. For example, in this system, the three functional groups are hemostats, sealants, and adhesives. The hemostats may be divided into four categories: mechanical, active, flowable, and fibrin sealant. These hemostat categories are further subdivided into generic classes based on the composition of the approved materials. Similarly, categories and classes are provided for sealants and adhesives. In this commentary, the salient points with respect to the characteristics of these agents are presented. A discussion of when these agents can be used in specific indications and how they may be applied to achieve the best results is also provided. Copyright Southeastern Surgical Congress. All rights reserved.


Li S.,University of Virginia | Jones R.R.,University of Virginia
Physical Review Letters | Year: 2014

We have employed intense, single-cycle THz pulses to explore strong-field ionization of low-lying Na Rydberg states in the low-frequency limit. At the largest fields used, F≃430kV/cm, electrons with energies up to 60 eV are created. The field ionization threshold is greater than expected for adiabatic "over-the-barrier" ionization and is found to scale as n-3. In addition, for a given field amplitude, higher energy electrons are produced during the ionization of the most tightly bound states. These observations can be attributed to the suppression of scattering from the nonhydrogenic ion core, the long times required for Rydberg electrons to escape over the barrier in the field-dressed Coulomb potential, and the failure, in the single-cycle limit, of the standard prediction for electron energy transfer in an oscillating field. The latter, in particular, holds important implications for future strong-field experiments involving the interaction of ground-state atoms and molecules with true single-cycle laser fields. © 2014 American Physical Society.


Walsh J.T.,University of Virginia | Kipnis J.,University of Virginia
Trends in Molecular Medicine | Year: 2011

Regulatory CD4 +CD25 +Foxp3 + T cells (Tregs) have been the focus of significant attention for their role in controlling immune responses. Although knowledge of Treg biology has burgeoned, wide gaps remain in our understanding of Treg function under both normal and pathological conditions. Pioneering studies demonstrated roles for Tregs in cancer and autoimmune diseases, including experimental autoimmune encephalitis, and this knowledge is often applied to other pathologies including neurodegenerative conditions. However, differences between immunity in neurodegeneration and in malignancy or autoimmunity are often neglected. Thus, Treg manipulations in central nervous system (CNS) neurodegenerative conditions often yield unexpected outcomes. In this piece, we explore how the immunology of neurodegeneration differs from that of cancer and autoimmunity and how these differences create confusion about the role of Tregs in neurodegenerative conditions. © 2011 Elsevier Ltd.


Morgan J.L.W.,University of Virginia | McNamara J.T.,University of Virginia | Zimmer J.,University of Virginia
Nature Structural and Molecular Biology | Year: 2014

The bacterial signaling molecule cyclic di-GMP (c-di-GMP) stimulates the synthesis of bacterial cellulose, which is frequently found in biofilms. Bacterial cellulose is synthesized and translocated across the inner membrane by a complex of cellulose synthase BcsA and BcsB subunits. Here we present crystal structures of the c-di-GMP-activated BcsA-BcsB complex. The structures reveal that c-di-GMP releases an autoinhibited state of the enzyme by breaking a salt bridge that otherwise tethers a conserved gating loop that controls access to and substrate coordination at the active site. Disrupting the salt bridge by mutagenesis generates a constitutively active cellulose synthase. Additionally, the c-di-GMP-activated BcsA-BcsB complex contains a nascent cellulose polymer whose terminal glucose unit rests at a new location above BcsA's active site and is positioned for catalysis. Our mechanistic insights indicate how c-di-GMP allosterically modulates enzymatic functions. © 2014 Nature America, Inc.


Glanowska K.M.,University of Virginia | Moenter S.M.,University of Michigan
Endocrinology | Year: 2015

GnRH release in the median eminence (ME) is the central output for control of reproduction. GnRH processes in the preoptic area (POA) also release GnRH.Weexamined region-specific regulation of GnRH secretion using fast-scan cyclic voltammetry to detect GnRH release in brain slices from adult male mice. Blocking endoplasmic reticulum calcium reuptake to elevate intracellular calcium evokes GnRH release in both the ME and POA. This release is action potential dependent in the ME but not the POA. Locally applied kisspeptin induced GnRH secretion in both theMEand POA. Local blockade of inositol triphospate-mediated calcium release inhibited kisspeptin-induced GnRH release in the ME, but broad blockade was required in the POA. In contrast, kisspeptin-evoked secretion in the POA was blocked by local gonadotropin-inhibitory hormone, but broad gonadotropin-inhibitory hormone application was required in the ME. Although action potentials are required for GnRH release induced by pharmacologically-increased intracellular calcium in theMEand kisspeptin-evoked release requires nositol triphosphate-mediated calcium release, blocking action potentials did not inhibit kisspeptin-induced GnRH release in the ME. Kisspeptin-induced GnRH release was suppressed after blocking both action potentials and plasma membrane Ca2+ channels. This suggests that kisspeptin action in theMErequiresbothincreased intracellular calciumandinfluxfromthe outside of the cell but not action potentials. Local interactions among kisspeptin and GnRH processes in the ME could thus stimulate GnRH release without involving perisomatic regions of GnRH neurons. Coupling between action potential generation and hormone release in GnRH neurons is thus likely physiologically labile and may vary with region. © 2015 by the Endocrine Society Received April 18, 2014.


Santen R.J.,University of Virginia
The Journal of clinical endocrinology and metabolism | Year: 2010

OBJECTIVE: Our objective was to provide a scholarly review of the published literature on menopausal hormonal therapy (MHT), make scientifically valid assessments of the available data, and grade the level of evidence available for each clinically important endpoint. PARTICIPANTS IN DEVELOPMENT OF SCIENTIFIC STATEMENT: The 12-member Scientific Statement Task Force of The Endocrine Society selected the leader of the statement development group (R.J.S.) and suggested experts with expertise in specific areas. In conjunction with the Task Force, lead authors (n = 25) and peer reviewers (n = 14) for each specific topic were selected. All discussions regarding content and grading of evidence occurred via teleconference or electronic and written correspondence. No funding was provided to any expert or peer reviewer, and all participants volunteered their time to prepare this Scientific Statement. EVIDENCE: Each expert conducted extensive literature searches of case control, cohort, and randomized controlled trials as well as meta-analyses, Cochrane reviews, and Position Statements from other professional societies in order to compile and evaluate available evidence. No unpublished data were used to draw conclusions from the evidence. CONSENSUS PROCESS: A consensus was reached after several iterations. Each topic was considered separately, and a consensus was achieved as to content to be included and conclusions reached between the primary author and the peer reviewer specific to that topic. In a separate iteration, the quality of evidence was judged using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) system in common use by The Endocrine Society for preparing clinical guidelines. The final iteration involved responses to four levels of additional review: 1) general comments offered by each of the 25 authors; 2) comments of the individual Task Force members; 3) critiques by the reviewers of the Journal of Clinical Endocrinology & Metabolism; and 4) suggestions offered by the Council and members of The Endocrine Society. The lead author compiled each individual topic into a coherent document and finalized the content for the final Statement. The writing process was analogous to preparation of a multiauthored textbook with input from individual authors and the textbook editors. CONCLUSIONS: The major conclusions related to the overall benefits and risks of MHT expressed as the number of women per 1000 taking MHT for 5 yr who would experience benefit or harm. Primary areas of benefit included relief of hot flashes and symptoms of urogenital atrophy and prevention of fractures and diabetes. Risks included venothrombotic episodes, stroke, and cholecystitis. In the subgroup of women starting MHT between ages 50 and 59 or less than 10 yr after onset of menopause, congruent trends suggested additional benefit including reduction of overall mortality and coronary artery disease. In this subgroup, estrogen plus some progestogens increased the risk of breast cancer, whereas estrogen alone did not. Beneficial effects on colorectal and endometrial cancer and harmful effects on ovarian cancer occurred but affected only a small number of women. Data from the various Women's Health Initiative studies, which involved women of average age 63, cannot be appropriately applied to calculate risks and benefits of MHT in women starting shortly after menopause. At the present time, assessments of benefit and risk in these younger women are based on lower levels of evidence.


Huang J.,University of Virginia | Siragy H.M.,University of Virginia
Hypertension | Year: 2012

(Pro)renin receptor (PRR) is expressed in renal vasculature, glomeruli, and tubules. The physiological regulation of this receptor is not well established. We hypothesized that sodium depletion increases PRR expression through cGMP-protein kinase G (PKG) signaling pathway. Renal PRR expressions were evaluated in Sprague-Dawley rats on normal sodium or low-sodium diet (LS) and in cultured rat proximal tubular cells and mouse renal inner medullary collecting duct cells exposed to LS concentration. LS augmented PRR expression in renal glomeruli, proximal tubules, distal tubules, and collecting ducts. LS also increased cGMP production and PKG activity. In cells exposed to normal sodium, cGMP analog increased PKG activity and upregulated PRR expression. In cells exposed to LS, blockade of guanylyl cyclase with 1H-(1,2,4)oxadiazolo(4,3-a) quinoxalin-1-one decreased PKG activity and downregulated PRR expression. PKG inhibition decreased phosphatase protein phosphatase 2A activity; suppressed LS-mediated phosphorylation of extracellular signal-regulated kinase, c-Jun N-terminal kinase, c-Jun, and nuclear factor-κB p65; and attenuated LS-mediated PRR upregulation. LS also enhanced DNA binding of cAMP response element binding protein 1 to cAMP response elements, nuclear factor-κB p65 to nuclear factor-κB elements, and c-Jun to activator protein 1 elements in PRR promoter in proximal tubular cells. We conclude that sodium depletion upregulates renal PRR expression via the cGMP-PKG signaling pathway by enhancing binding of cAMP response element binding protein 1, nuclear factor-κB p65, and c-Jun to PRR promotor. © 2011 American Heart Association, Inc.


We showed previously that pulmonary function and arterial oxygen saturation in NY1DD mice with sickle cell disease (SCD) are improved by depletion of invariant natural killer T (iNKT) cells or blockade of their activation. Here we demonstrate that SCD causes a 9- and 6-fold induction of adenosine A(2A) receptor (A(2A)R) mRNA in mouse pulmonary iNKT and natural killer (NK) cells, respectively. Treating SCD mice with the A(2A)R agonist ATL146e produced a dose-dependent reversal of pulmonary dysfunction with maximal efficacy at 10 ng/kg/minute that peaked within 3 days and persisted throughout 7 days of continuous infusion. Crossing NY1DD mice with Rag1(-/-) mice reduced pulmonary injury that was restored by adoptive transfer of 10(6) purified iNKT cells. Reconstituted injury was reversed by ATL146e unless the adoptively transferred iNKT cells were pretreated with the A(2A)R alkylating antagonist, FSPTP (5-amino-7-[2-(4-fluorosulfonyl)phenylethyl]-2-(2-furyl)-pryazolo[4,3-ε]-1,2,4-triazolo[1,5-c]pyrimidine), which completely prevented pro-tection. In NY1DD mice exposed to hypoxia-reoxygenation, treatment with ATL146e at the start of reoxygenation prevented further lung injury. Together, these data indicate that activation of induced A(2A)Rs on iNKT and NK cells in SCD mice is sufficient to improve baseline pulmonary function and prevent hypoxia-reoxygenation-induced exacerbation of pulmonary injury. A(2A) agonists have promise for treating diseases associated with iNKT or NK cell activation.


Kipnis J.,University of Virginia
Science | Year: 2016

Neuroimmunologists seek to understand the interactions between the central nervous system (CNS) and the immune system, both under homeostatic conditions and in diseases. Unanswered questions include those relating to the diversity and specificity of the meningeal T cell repertoire; the routes taken by immune cells that patrol the meninges under healthy conditions and invade the parenchyma during pathology; the opposing effects (beneficial or detrimental) of these cells on CNS function; the role of immune cells after CNS injury; and the evolutionary link between the two systems, resulting in their tight interaction and interdependence. This Review summarizes the current standing of and challenging questions related to interactions between adaptive immunity and the CNS and considers the possible directions in which these aspects of neuroimmunology will be heading over the next decade.


Roulston T.H.,University of Virginia | Goodell K.,Ohio State University
Annual Review of Entomology | Year: 2011

Recent declines of bee species have led to great interest in preserving and promoting bee populations for agricultural and wild plant pollination. Many correlational studies have examined the indirect effects of factors such as landscape context and land management practices and found great variation in bee response. We focus here on the evidence for effects of direct factors (i.e., food resources, nesting resources, and incidental risks) regulating bee populations and then interpret varied responses to indirect factors through their species-specific and habitat-specific effects on direct factors. We find strong evidence for food resource availability regulating bee populations, but little clear evidence that other direct factors are commonly limiting. We recommend manipulative experiments to illuminate the effects of these different factors. We contend that much of the variation in impact from indirect factors, such as grazing, can be explained by the relationships between indirect factors and floral resource availability based on environmental circumstances. © 2011 by Annual Reviews. All rights reserved.


Johnson B.A.,University of Virginia
American Journal of Psychiatry | Year: 2010

Alcoholism remains a serious cause of morbidity and mortality despite progress through neurobiological research in identifying new pharmacological strategies for its treatment. Drugs that affect neural pathways that modulate the activity of the cortico-mesolimbic dopamine system have been shown to alter drinking behavior, presumably because this dopaminergic system is closely associated with rewarding behavior. Ondansetron, naltrexone, topiramate, and baclofen are examples. Subtyping alcoholism in adults into an early-onset type, with chronic symptoms and a strong biological predisposition to the disease, and a late-onset type, typically brought on by psychosocial triggers and associated with mood symptoms, may help in the selection of optimal therapy. Emerging adults with binge drinking patterns also might be aided by selective treatments. Although preliminary work on the pharmacogenetics of alcoholism and its treatment has been promising, the assignment to treatment still depends on clinical assessment. Brief behavioral interventions that encourage the patient to set goals for a reduction in heavy drinking or abstinence also are part of optimal therapy.


Koenig M.A.,University of Minnesota | Jaswal V.K.,University of Virginia
Child Development | Year: 2011

Do children expect an expert in one domain to also be an expert in an unrelated domain? In Study 1, 32 three- and four-year-olds learned that one informant was an expert about dogs relative to another informant. When presented with pictures of new dogs or of artifacts, children who could remember which informant was the dog expert preferred her over the novice as an informant about the names of dogs, but they had no preference when the informants presented artifact labels. In Study 2, 32 children learned that one informant was incompetent about dogs whereas another was neutral. In this case, children preferred the neutral speaker over the incompetent one about both dogs and artifacts. Taken together, these results suggest that for children, expertise is not subject to a "halo effect," but incompetence may be subject to a "pitchfork effect". © 2011 The Authors. Child Development © 2011 Society for Research in Child Development, Inc.


Ruhm C.J.,University of Virginia
Future of Children | Year: 2011

The struggle to balance work responsibilities with family obligations may be most difficult for working parents of the youngest children, those five and under. Any policy changes designed to ease the difficulties for these families are likely to be controversial, requiring a careful effort to weigh both the costs and benefits of possible interventions while respecting diverse and at times conflicting American values. In this article, Christopher Ruhm looks at two potential interventions- parental leave and early childhood education and care (ECEC)-comparing differences in policies in the United States, Canada, and several European nations and assessing their consequences for important parent and child outcomes. By and large, Canadian and European policies are more generous than those in the United States, with most women eligible for paid maternity leave, which in a few countries can last for three years or more. Many of these countries also provide for paid leave that can be used by either the mother or the father. And in many European countries ECEC programs are nearly universal after the child reaches a certain age. In the United States, parental leave, if it is available, is usually short and unpaid, and ECEC is generally regarded as a private responsibility of parents, although some federal programs help defray costs of care and preschool education. Ruhm notes that research on the effects of differences in policies is not completely conclusive, in part because of the difficulty of isolating consequences of leave and ECEC policies from other influences on employment and children's outcomes. But, he says, the comparative evidence does suggest desirable directions for future policy in the United States. Policies establishing rights to short parental leaves increase time at home with infants and slightly improve the job continuity of mothers, with small, but positive, long-run consequences for mothers and children. Therefore, Ruhm indicates that moderate extensions of existing U.S. leave entitlements (up to several months in duration) make sense. He also suggests that some form of paid leave would facilitate its use, particularly among less advantaged parents, and that efforts to improve the quality of ECEC, while maintaining or enhancing affordability, are desirable.


Wang Z.,University of Virginia | Wu M.,University of Virginia
Molecular Biology and Evolution | Year: 2013

Large-scale, genome-level molecular phylogenetic analyses present both opportunities and challenges for bacterial evolutionary and ecological studies. We constructed a phylum-level bacterial phylogenetic marker database by surveying all complete bacterial genomes and identifying single-copy genes that were widely distributed in each of the 20 bacterial phyla. We showed that phylum trees made using these markers were highly resolved and were more robust than the bacterial genome tree based on 31 universal bacterial marker genes. In addition, using the Global Ocean Sampling data set as an example, we demonstrated that the expanded marker database greatly increased the power of metagenomic phylotyping. We incorporated the database into an automated phylogenomic inference application (Phyla-AMPHORA) and made it publicly available. We believe that this centralized resource should have broad applicability in bacterial systematics, phylogenetics, and metagenomic studies. © The Author 2013. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved.


Chang Q.,University of Virginia | Herbst E.,University of Virginia
Astrophysical Journal | Year: 2012

For the first time, we report a unified microscopic-macroscopic Monte Carlo simulation of gas-grain chemistry in cold interstellar clouds in which both the gas-phase and the grain-surface chemistry are simulated by a stochastic technique. The surface chemistry is simulated with a microscopic Monte Carlo method in which the chemistry occurs on an initially flat surface. The surface chemical network consists of 29 reactions initiated by the accreting species H, O, C, and CO. Four different models are run with diverse but homogeneous physical conditions including temperature, gas density, and diffusion-barrier- to-desorption energy ratio. As time increases, icy interstellar mantles begin to grow. Our approach allows us to determine the morphology of the ice, layer by layer, as a function of time, and to ascertain the environment or environments for individual molecules. Our calculated abundances can be compared with observations of ices and gas-phase species, as well as the results of other models. © 2012. The American Astronomical Society. All rights reserved.


Winckler B.,University of Virginia
Cold Spring Harbor perspectives in biology | Year: 2010

Wiring of the brain relies initially on the correct outgrowth of axons to reach the appropriate target area for innervation. A large number of guidance receptors present in the plasma membrane of axonal growth cones and elsewhere on the neuron read and execute directional cues present in the extracellular environment of the navigating growth cone. The exact timing, levels, and localization of expression of the guidance receptors in the plasma membrane therefore determine the outcome of guidance decisions. Many guidance receptors are localized in exquisitely precise spatial and temporal patterns. The cellular mechanisms ensuring these localization patterns include spatially accurate sorting after synthesis in the secretory pathway, retrieval of inappropriately expressed receptors by endocytosis followed by degradation or recycling, and restriction of diffusion. This article will discuss the machinery and regulation underlying the restricted distribution of membrane receptors, focusing on the currently best-studied example, the L1 cell adhesion molecule. In addition to the long-range mechanisms ensuring appropriate localization, the same mechanisms can act locally to adjust levels and localization of receptors. These local mechanisms are regulated by ligand binding and subsequent activation of local signaling cascades. It is likely that the localization of all guidance receptors is regulated by a combination of sorting, retrieval, recycling and retention, similar to the ones we discuss here for L1.


Ransom T.S.,University of Virginia
Oecologia | Year: 2011

Ecosystem engineers create habitat that can be used by other species in multiple ways, such as refuges from predators, places to breed, or areas with increased prey resources. I conducted a series of enclosure experiments to: (1) determine if salamanders use earthworm burrows, and (2) examine the potential influence of earthworm burrow use and indirect effects on salamander intra- and interspecific competition, predator avoidance, and seasonal performance. I found that one species of woodland salamander, Plethodon cinereus, used earthworm burrows 50% of the time when burrows were present. Neither adults nor juveniles of the congeneric P. glutinosus used earthworm burrows. Intraspecific, but not interspecific, competition by P. cinereus affected salamander behavior when earthworms were absent, with P. cinereus found under cover objects >70% of the time when alone or with a P. glutinosus, but only 40% of the time when with another P. cinereus. When earthworms were present, the behavior of P. cinereus was similar across salamander treatments. Earthworms decreased the amount of leaf litter and microinvertebrates, although this did not affect salamander mass. In subsequent experiments using only P. cinereus, the refuge provided by earthworm burrows increased the survival of P. cinereus over the winter and allowed P. cinereus to avoid being consumed by the common garter snake (Thamnophis sirtalis). Because earthworm burrows provide a refuge for P. cinereus during intraspecific encounters, in the presence of a predator and over the winter, they may serve as an important belowground-aboveground linkage in eastern forests where salamanders are common. © 2010 Springer-Verlag.


Gress D.R.,University of Virginia
Journal of the American College of Cardiology | Year: 2012

Cerebral embolic events related to carotid and cardiac disease have been known for decades. Recently, cerebral embolic events have become a focus of clinical importance as complications of vascular procedures. Further, the development of new technologies and procedures has increased the overall clinical significance. Although the relative safety of these procedures is usually defined by acute stroke risk, it is also becoming clear that far more subclinical events are occurring. Recent reports provided substantial evidence of memory loss, cognitive decline, and dementia related to these so-called silent infarcts. Literature reports of magnetic resonance imaging events lead to an estimate of as many as 600,000 patients with new brain injury each year in the United States alone. Given the magnitude of the numbers involved, the impact of accelerated cognitive loss and premature senescence in a vulnerable at-risk population could well be significant. © 2012 American College of Cardiology Foundation.


Gray M.,University of Virginia
American Journal of Clinical Dermatology | Year: 2010

Incontinence-associated dermatitis (IAD), sometimes referred to as perineal dermatitis, is an inflammation of the skin associated with exposure to urine or stool. Elderly adults, and especially those in long-term care facilities, are at risk for urinary or fecal incontinence and IAD. Traditionally, IAD has received little attention as a distinct disorder, and it is sometimes confused with stage I or II pressure ulcers. However, a modest but growing body of research is beginning to provide insights into the epidemiology, etiology, and pathophysiology of IAD. In addition, recent changes in reimbursement policies from the US Center for Medicare and Medicaid Services regarding pressure ulcer prevention has focused attention on the differential diagnosis of IAD versus pressure ulcer, and its influence on pressure ulcer risk. Color, location, depth, and the presence or absence of necrotic tissue are visual indicators used to differentiate IAD from pressure-related skin damage. Prevention is based on avoiding or minimizing exposure to stool or urine combined with a structured skin-care program based on principles of gentle cleansing, moisturization, preferably with an emollient, and application of a skin protectant. Treatment of IAD focuses on three main goals: (i) removal of irritants from the affected skin; (ii) eradication of cutaneous infections such as candidiasis; and (iii) containment or diversion of incontinent urine or stool. © 2010 Adis Data Information BV. All rights reserved.


Lewis G.M.,University of Virginia | Kucenas S.,University of Virginia
Journal of Neuroscience | Year: 2014

Development and maintenance of the peripheral nervous system (PNS) are essential for an organism to survive and reproduce, and damage to the PNS by disease or injury is often debilitating. Remarkably, the nerves of the PNS are capable of regenerating after trauma. However, full functional recovery after nerve injuries remains poor. Peripheral nerve regeneration has been studied extensively, with particular emphasis on elucidating the roles of Schwann cells and macrophages during degeneration and subsequent regeneration. In contrast, the roles of other essential nerve components, including perineurial glia, are poorly understood. Here, we use laser nerve transection and in vivo, time-lapse imaging in zebrafish to investigate the role and requirement of perineurial glia after nerve injury. We show that perineurial glia respond rapidly and dynamically to nerve transections by extending processes into injury sites and phagocytizing debris. Perineurial glia also bridge injury gaps before Schwann cells and axons, and we demonstrate that these bridges are essential for axon regrowth. Additionally, we show that perineurial glia and macrophages spatially coordinate early debris clearance and that perineurial glia require Schwann cells for their attraction to injury sites. This work highlights the complex nature of cellcell interactions after injury and introduces perineurial glia as integral players in the regenerative process. © 2014 the authors.


Beans C.M.,University of Virginia
Ecology and Evolution | Year: 2014

The evidence for character displacement as a widespread response to competition is now building. This progress is largely the result of the establishment of rigorous criteria for demonstrating character displacement in the animal literature. There are, however, relatively few well-supported examples of character displacement in plants. This review explores the potential for character displacement in plants by addressing the following questions: (1) Why aren't examples of character displacement in plants more common? (2) What are the requirements for character displacement to occur and how do plant populations meet those requirements? (3) What are the criteria for testing the pattern and process of character displacement and what methods can and have been used to address these criteria in the plant literature? (4) What are some additional approaches for studying character displacement in plants? While more research is needed, the few plant systems in which character displacement hypotheses have been rigorously tested suggest that character displacement may play a role in shaping plant communities. Plants are especially amenable to character displacement studies because of the experimental ease with which they can be used in common gardens, selection analyses, and breeding designs. A deeper investigation of character displacement in plants is critical for a more complete understanding of the ecological and evolutionary processes that permit the coexistence of plant species. © 2014 The Author. Ecology and Evolution published by John Wiley & Sons Ltd.


Schwartz M.A.,University of Virginia
Cold Spring Harbor perspectives in biology | Year: 2010

Integrins bind extracellular matrix fibrils and associate with intracellular actin filaments through a variety of cytoskeletal linker proteins to mechanically connect intracellular and extracellular structures. Each component of the linkage from the cytoskeleton through the integrin-mediated adhesions to the extracellular matrix therefore transmits forces that may derive from both intracellular, myosin-generated contractile forces and forces from outside the cell. These forces activate a wide range of signaling pathways and genetic programs to control cell survival, fate, and behavior. Additionally, cells sense the physical properties of their surrounding environment through forces exerted on integrin-mediated adhesions. This article first summarizes current knowledge about regulation of cell function by mechanical forces acting through integrin-mediated adhesions and then discusses models for mechanotransduction and sensing of environmental forces.


Porter J.H.,University of Virginia | Hanson P.C.,University of Wisconsin - Madison | Lin C.-C.,Taiwan Forestry Research Institute
Trends in Ecology and Evolution | Year: 2012

Developments in sensor design, electronics, computer technology and networking have converged to provide new ways of collecting environmental data at rates hitherto impossible to achieve. To translate this 'data deluge' into scientific knowledge requires comparable advances in our ability to integrate, process and analyze massive data sets. We review the experience of one large project in ingesting and analyzing sensor data from global lakes and provide a synopsis of innovative approaches being used to confront the information management and analytical challenges posed by massive volumes of data. © 2011 Elsevier Ltd.


Chen M.,University of Virginia | Menicucci N.C.,University of Sydney | Pfister O.,University of Virginia
Physical Review Letters | Year: 2014

We report the experimental realization and characterization of one 60-mode copy and of two 30-mode copies of a dual-rail quantum-wire cluster state in the quantum optical frequency comb of a bimodally pumped optical parametric oscillator. This is the largest entangled system ever created whose subsystems are all available simultaneously. The entanglement proceeds from the coherent concatenation of a multitude of Einstein, Podolsky, and Rosen pairs by a single beam splitter, a procedure which is also a building block for the realization of hypercubic-lattice cluster states for universal quantum computing. © 2014 American Physical Society.


Stankovic J.A.,University of Virginia
IEEE Internet of Things Journal | Year: 2014

Many technical communities are vigorously pursuing research topics that contribute to the Internet of Things (IoT). Nowadays, as sensing, actuation, communication, and control become even more sophisticated and ubiquitous, there is a significant overlap in these communities, sometimes from slightly different perspectives. More cooperation between communities is encouraged. To provide a basis for discussing open research problems in IoT, a vision for how IoT could change the world in the distant future is first presented. Then, eight key research topics are enumerated and research problems within these topics are discussed. © 2014 IEEE.


Pinkerton J.V.,University of Virginia
Menopause | Year: 2014

Unsubstantiated claims, lack of scientific safety and efficacy data, and lack of quality control surround customcompounded bioidentical hormone products. FDA-approved hormone therapy provides tested and regulated therapy without the risks of unregulated and untested custom preparations. © 2014 by The North American Menopause Society.


Adler P.N.,University of Virginia
Current topics in developmental biology | Year: 2012

Drosophila has been the key model system for studies on planar cell polarity (PCP). The rich morphology of the insect exoskeleton contains many structures that display PCP. Among these are the trichomes (cuticular hairs) that cover much of the exoskeleton, sensory bristles, and ommatidia. Many genes have been identified that must function for the development of normal PCP. Among these are the genes that comprise the frizzled/starry night (fz/stan) and dachsous/fat pathways. The mechanisms that underlie the function of the fz/stan pathway are best understood. All of the protein products of these genes accumulate asymmetrically in wing cells and there is good evidence that this involves local intercellular signaling between protein complexes on the distal edge of one cell and the juxtaposed proximal edge of its neighbor. It is thought that a feedback system, directed transport, and stabilizing protein-protein interactions mediate the formation of distal and proximal protein complexes. These complexes appear to recruit downstream proteins that function to spatially restrict the activation of the cytoskeleton in wing cells. This leads to the formation of the array of distally pointing hairs found on wings. Copyright © 2012 Elsevier Inc. All rights reserved.


Roach D.A.,University of Virginia
Experimental Gerontology | Year: 2012

Individuals in a large experimental field population, of the short-lived perennial species Plantago lanceolata, were followed to determine the sources of variation that influence mortality and life span. The design included multiple age groups with initially similar genetic structure, which made it possible to separate age effects from period effects and to identify the genetic component to variation in life span. During a period of stress, individuals of all ages showed parallel increases in mortality but different cohorts experienced this period of high mortality at different ages. This then influenced the distribution of life spans across cohorts. Age and size-age interactions influenced mortality during the period of stress. Smaller individuals died but only if they were old. Additionally, growth and age interacted with stress such that older individuals had negative growth and high mortality whereas younger individuals had positive growth and relatively lower mortality during stress. The results of this study show that it is not simply the environment that can have a major impact on demography in natural populations; rather, age, size and growth can interact with the environment to influence mortality and life span when the environment is stressful. © 2012 Elsevier Inc.


Gerber M.S.,University of Virginia
Decision Support Systems | Year: 2014

Twitter is used extensively in the United States as well as globally, creating many opportunities to augment decision support systems with Twitter-driven predictive analytics. Twitter is an ideal data source for decision support: its users, who number in the millions, publicly discuss events, emotions, and innumerable other topics; its content is authored and distributed in real time at no charge; and individual messages (also known as tweets) are often tagged with precise spatial and temporal coordinates. This article presents research investigating the use of spatiotemporally tagged tweets for crime prediction. We use Twitter-specific linguistic analysis and statistical topic modeling to automatically identify discussion topics across a major city in the United States. We then incorporate these topics into a crime prediction model and show that, for 19 of the 25 crime types we studied, the addition of Twitter data improves crime prediction performance versus a standard approach based on kernel density estimation. We identify a number of performance bottlenecks that could impact the use of Twitter in an actual decision support system. We also point out important areas of future work for this research, including deeper semantic analysis of message content, temporal modeling, and incorporation of auxiliary data sources. This research has implications specifically for criminal justice decision makers in charge of resource allocation for crime prevention. More generally, this research has implications for decision makers concerned with geographic spaces occupied by Twitter-using individuals. ©2014 Elsevier B.V. All rights reserved.


Egelman E.H.,University of Virginia
eLife | Year: 2014

Helical polymers are found throughout biology and account for a substantial fraction of the protein in a cell. These filaments are very attractive for three-dimensional reconstruction from electron micrographs due to the fact that projections of these filaments show many different views of identical subunits in identical environments. However, ambiguities exist in defining the symmetry of a helical filament when one has limited resolution, and mistakes can be made. Until one reaches a near-atomic level of resolution, there are not necessarily reality-checks that can distinguish between correct and incorrect solutions. A recent paper in eLife (Xu et al., 2014) almost certainly imposed an incorrect helical symmetry and this can be seen using filament images posted by Xu et al. A comparison between the atomic model proposed and the published three-dimensional reconstruction should have suggested that an incorrect solution was found.


Quinlan A.R.,University of Virginia
Current Protocols in Bioinformatics | Year: 2014

Technological advances have enabled the use of DNA sequencing as a flexible tool to characterize genetic variation and to measure the activity of diverse cellular phenomena such as gene isoform expression and transcription factor binding. Extracting biological insight from the experiments enabled by these advances demands the analysis of large, multi-dimensional datasets. This unit describes the use of the BEDTools toolkit for the exploration of high-throughput genomics datasets. Several protocols are presented for common genomic analyses, demonstrating how simple BEDTools operations may be combined to create bespoke pipelines addressing complex questions. © 2014 John Wiley & Sons, Inc.


Hayden F.G.,University of Virginia
Influenza and other Respiratory Viruses | Year: 2013

Progress in the development of antivirals for non-influenza respiratory viruses has been slow with the result that many unmet medical needs and few approved agents currently exist. This commentary selectively reviews examples of where specific agents have provided promising clinical benefits in selected target populations and also considers potential therapeutics for emerging threats like the SARS and Middle East respiratory syndrome coronaviruses. Recent studies have provided encouraging results in treating respiratory syncytial virus infections in lung transplant recipients, serious parainfluenza virus and adenovirus infections in immunocompromised hosts, and rhinovirus colds in outpatient asthmatics. While additional studies are needed to confirm the efficacy and safety of the specific agents tested, these observations offer the opportunity to expand therapeutic studies to other patient populations.© 2013 Blackwell Publishing Ltd.


Mathers A.J.,University of Virginia | Peirano G.,University of Calgary | Pitout J.D.D.,University of Calgary | Pitout J.D.D.,University of Pretoria
Clinical Microbiology Reviews | Year: 2015

Escherichia coli sequence type 131 (ST131) and Klebsiella pneumoniae ST258 emerged in the 2000s as important human pathogens, have spread extensively throughout the world, and are responsible for the rapid increase in antimicrobial resistance among E. coli and K. pneumoniae strains, respectively. E. coli ST131 causes extraintestinal infections and is often fluoroquinolone resistant and associated with extended-spectrum β-lactamase production, especially CTX-M-15. K. pneumoniae ST258 causes urinary and respiratory tract infections and is associated with carbapenemases, most often KPC-2 and KPC-3. The most prevalent lineage within ST131 is named fimH30 because it contains the H30 variant of the type 1 fimbrial adhesin gene, and recent molecular studies have demonstrated that this lineage emerged in the early 2000s and was then followed by the rapid expansion of its sublineages H30-R and H30-Rx. K. pneumoniae ST258 comprises 2 distinct lineages, namely clade I and clade II. Moreover, it seems that ST258 is a hybrid clone that was created by a large recombination event between ST11 and ST442. Epidemic plasmids with blaCTX-M and blaKPC belonging to incompatibility group F have contributed significantly to the success of these clones. E. coli ST131 and K. pneumoniae ST258 are the quintessential examples of international multidrug-resistant high-risk clones. © 2015, American Society for Microbiology. All Rights Reserved.


Lamacraft A.,University of Virginia
Physical Review A - Atomic, Molecular, and Optical Physics | Year: 2011

We study a spin-1 Bose-Einstein condensate small enough to be treated as a single magnetic domain: a system that we term a microcondensate. Because all particles occupy a single spatial mode, this quantum many-body system has a well-defined classical limit consisting of three degrees of freedom, corresponding to the three macroscopically occupied spin states. We study both the classical limit and its quantization, finding an integrable system in both cases. Depending on the sign of the ratio of the spin interaction energy and the quadratic Zeeman energy, the classical limit displays either a separatrix in phase space or Hamiltonian monodromy corresponding to nontrivial phase space topology. We discuss the quantum signatures of these classical phenomena using semiclassical quantization as well as an exact solution using the Bethe ansatz. © 2011 American Physical Society.


Pu L.,University of Virginia
Accounts of chemical research | Year: 2012

The development of automated, high-throughput organic synthesis and screening techniques has created an urgent demand for methods that rapidly determine the enantiomeric composition of chiral compounds. Enantioselective fluorescent sensors offer the potential for real-time, high-sensitivity techniques for determining enantiomeric data in high-throughput chiral assays. In this Account, we describe a range of fluorescent sensors derived from 1,1'-bi-2-naphthol (BINOL), a readily available biaryl compound with axial chirality. We show that BINOL can be used to construct structurally diverse, chiral fluorescent sensors to carry out highly enantioselective, sensitive recognition of chiral amino alcohols, α-hydroxycarboxylic acids, and amino acid derivatives. For example, we prepared an (S)-BINOL derivative whose 3,3'-positions are attached to two chiral amino alcohol units, each having two phenyl substituents. This compound shows a fluorescence enhancement of 950-fold in the presence of (S)-mandelic acid but very little change in the presence of (R)-mandelic acid. It also allows the enantiomers of this α-hydroxycarboxylic acid to be visually discriminated by an enantioselective precipitation process. A structurally similar (S)-BINOL-amino alcohol molecule, but with three rather than two phenyl substitutents in each of the two amino alcohol units, was found to exhibit generally enantioselective fluorescence responses toward structurally diverse α-hydroxycarboxylic acids. We further prepared a pseudoenantiomeric analogue of this compound from (R)-H(8)BINOL, which has the opposite chiral configuration at both the biaryl center as well as the pendant amino alcohols. These two compounds have opposite enantioselectivity in the recognition of a chiral substrate, with distinctly different fluorescence emission wavelengths. By mixing them together, we developed a pseudoenantiomeric sensor pair to facilitate chiral assays. Using this pseudoenantiomeric sensor pair allows both the concentration and the enantiomeric composition of a substrate to be determined in a single fluorescence measurement. We synthesized another compound by ligating a terpyridine unit to BINOL and found that coordination of a Cu(II) ion to the terpyridine unit almost completely quenched its fluorescence. Displacement of the Cu(2+) ion from this complex by chiral amino alcohols leads to enantioselective fluorescence enhancement. This BINOL-terpyridine-Cu(II) complex also exhibits enantioselective gel collapsing in the presence of chiral amino alcohols, providing a new visual chiral discrimination method. When a series of light-absorbing conjugated units are attached to the BINOL structure, the resulting multiarmed dendritic molecules show greatly amplified fluorescence responses. Thus, the light harvesting effect of dendrimers can be used to greatly increase the sensitivity of the fluorescent sensors. The progress described here demonstrates that highly enantioselective and sensitive fluorescent sensors can be obtained through a systematic investigation of the structure-property relation between the sensors and the substrates. These sensors show great potential for the development of rapid assays of chiral organic compounds.


Culp S.H.,University of Virginia | Schellhammer P.F.,Eastern Virginia Medical School | Williams M.B.,Eastern Virginia Medical School
European Urology | Year: 2014

Background Few data exist regarding the impact on survival of definitive treatment of the prostate in men diagnosed with metastatic prostate cancer (mPCa). Objective To evaluate the survival of men diagnosed with mPCa based on definitive treatment of the prostate. Design, setting, and participants Men with documented stage IV (M1a-c) PCa at diagnosis identified using Surveillance Epidemiology and End Results (SEER) (2004-2010) and divided based on definitive treatment of the prostate (radical prostatectomy [RP] or brachytherapy [BT]) or no surgery or radiation therapy (NSR). Outcome measurements and statistical analysis Kaplan-Meier methods were used to calculate overall survival (OS). Multivariable competing risks regression analysis was used to calculate disease-specific survival (DSS) probability and identify factors associated with cause-specific mortality (CSM). Results and limitations A total of 8185 patients were identified: NSR (n = 7811), RP (n = 245), and BT (n = 129). The 5-yr OS and predicted DSS were each significantly higher in patients undergoing RP (67.4% and 75.8%, respectively) or BT (52.6 and 61.3%, respectively) compared with NSR patients (22.5% and 48.7%, respectively) (p < 0.001). Undergoing RP or BT was each independently associated with decreased CSM (p < 0.01). Similar results were noted regardless of the American Joint Committee on Cancer (AJCC) M stage. Factors associated with increased CSM in patients undergoing local therapy included AJCC T4 stage, high-grade disease, prostate-specific antigen ≤20 ng/ml, age ≤70 yr, and pelvic lymphadenopathy (p < 0.05). The major limitation of this study was the lack of variables from SEER known to influence survival of patients with mPCa, including treatment with systemic therapy. Conclusions Definitive treatment of the prostate in men diagnosed with mPCa suggests a survival benefit in this large population-based study. These results should serve as a foundation for future prospective trials. Patient summary We used a large population-based cancer database to examine survival in men diagnosed with metastatic prostate cancer (mPCa) undergoing definitive therapy for the prostate. Local therapy (LT) appeared to confer a survival benefit. Therefore, we conclude that prospective trials are needed to further evaluate the role of LT in mPCa. © 2013 European Association of Urology.


Jaswal V.K.,University of Virginia
Cognitive Psychology | Year: 2010

How do children resolve conflicts between a self-generated belief and what they are told? Four studies investigated the circumstances under which toddlers would trust testimony that conflicted with their expectations about the physical world. Thirty-month-olds believed testimony that conflicted with a naive bias (Study 1), and they also repeatedly trusted testimony that conflicted with an event they had just seen (Study 2)-even when they had an incentive to ignore the testimony (Study 3). Children responded more skeptically if they could see that the testimony was wrong as it was being delivered (Study 3), or if they had the opportunity to accumulate evidence confirming their initial belief before hearing someone contradict it (Study 4). Together, these studies demonstrate that toddlers have a robust bias to trust even surprising testimony, but this trust can be influenced by how much confidence they have in their initial belief. © 2010 Elsevier Inc.


Wang L.,University of Virginia | Brautigan D.L.,University of Virginia
Nature Communications | Year: 2013

The AMP-activated protein kinase (AMPK) regulates metabolism in normal and pathological conditions and responds to nutrients, hormones, anti-diabetic drugs and physical exercise. AMPK is activated by the kinase LKB1 and inactivated by phosphatases whose identities remain uncertain. Here we show that AMPK associates with α-SNAP, an adapter that enables disassembly of cis-SNARE complexes formed during membrane fusion. Knockdown of α-SNAP activates AMPK to phosphorylate its endogenous substrates acetyl CoA carboxylase and Raptor, and provokes mitochondrial biogenesis. AMPK phosphorylation is rescued from α-SNAP RNA interference by LKB1 knockdown or expression of wild-type but not mutated α-SNAP. Recombinant wild-type but not mutated α-SNAP dephosphorylates pThr172 in AMPKα in vitro. Overexpression of wild-type but not mutated α-SNAP prevents AMPK activation in cells treated with agents to elevate AMP concentration. The mouse α-SNAP mutant hyh (hydrocephalus with hop gait) shows enhanced binding and inhibition of AMPK. By negatively controlling AMPK, α-SNAP therefore potentially coordinates membrane trafficking and metabolism. © 2013 Macmillan Publishers Limited. All rights reserved.


Chhabra P.,University of Virginia | Brayman K.L.,University of Virginia
Stem Cells Translational Medicine | Year: 2013

Type 1 diabetes mellitus (T1D) is a chronic, multifactorial autoimmune disease that involves the progressive destruction of pancreatic Β-cells, ultimately resulting in the loss of insulin production and secretion. The goal of clinical intervention is to prevent or arrest the onset and progression of autoimmunity, reverse Β-cell destruction, and restore glycometabolic and immune homeostasis. Despite promising outcomes observed with islet transplantation and advancements in immunomodulatory therapies, the need for an effective cell replacement strategy for curing T1D still persists. Stem cell therapy offers a solution to the cited challenges of islet transplantation. While the regenerative potential of stem cells can be harnessed to make available a self-replenishing supply of glucose-responsive insulin-producing cells, their immunomodulatory properties may potentially be used to prevent, arrest, or reverse autoimmunity, ameliorate innate/alloimmune graft rejection, and prevent recurrence of the disease. Herein, we discuss the therapeutic potential of stem cells derived from a variety of sources for the cure of T1D, for example, embryonic stem cells, induced pluripotent stem cells, bone marrow-derived hematopoietic stem cells, and multipotent mesenchymal stromal cells derived from bone marrow, umbilical cord blood, and adipose tissue. The benefits of combinatorial approaches designed to ensure the successful clinical translation of stem cell therapeutic strategies, such as approaches combining effective stem cell strategies with islet transplantation, immunomodulatory drug regimens, and/or novel bioengineering techniques, are also discussed. To conclude, the application of stem cell therapy in the cure for T1D appears extremely promising. © AlphaMed Press 2013.


Diabetes mellitus (DM) and hypertension may be associated with complications following fractionated radiotherapy. To date no studies have determined the risk of radiation toxicity in patients with DM or hypertension who have undergone Gamma Knife surgery (GKS) for brain arteriovenous malformations (AVMs). The goal of the present study was to determine associations between DM or hypertension and other factors in the development of radiotoxicity, as measured by radiation-induced changes (RICs) on MR images following radiosurgery for AVM. Using univariate methods and multivariate logistic regression, the authors compared the RIC status in patients 18 years of age and older with these patients' history of, or medication use for, DM or hypertension; tobacco use; patient age and sex; AVM volume; Spetzler-Martin AVM severity scale (Grades I and II vs Grades III-V); AVM surgery, AVM embolization, or hemorrhage prior to radiosurgery; AVM location; number of draining veins; and radiosurgery margin dose. Radiation-induced changes occurred in 38% of 539 adults within a mean (± standard deviation) of 12 ± 10 months after radiosurgery, as observed during a median follow-up time of 55 months. Among patients in whom RICs occurred, 34% had headaches, neurological deficits, or new-onset seizures. Larger RICs were associated with worse symptoms. According to a univariate analysis, DM (3% of patients), larger AVM volume, worse Spetzler-Martin grade, lack of AVM surgery prior to radiosurgery, lack of hemorrhage prior to radiosurgery, and smaller margin dose of radiation had significant associations with the presence of RICs. Hypertension (20%), patient sex, tobacco use, number of draining veins, superficial or deep location of the lesion, and AVM embolization prior to radiosurgery had no association with the presence of RICs. According to a multivariate analysis, larger AVM volume, worse Spetzler-Martin grade, and no AVM surgery prior to radiosurgery predicted the occurrence of an RIC. Diabetes mellitus had borderline significance. Vascular factors such as hypertension, patient sex, and tobacco use did not convey additional risks of radiotoxicity, but DM remained a possible cardiovascular risk factor in the development of RICs.


Bloom G.S.,University of Virginia
JAMA Neurology | Year: 2014

The defining features of Alzheimer disease (AD) include conspicuous changes in both brain histology and behavior. The AD brain is characterized microscopically by the combined presence of 2 classes of abnormal structures, extracellular amyloid plaques and intraneuronal neurofibrillary tangles, both of which comprise highly insoluble, densely packed filaments. The soluble building blocks of these structures are amyloid-β (Aβ) peptides for plaques and tau for tangles. Amyloid-β peptides are proteolytic fragments of the transmembrane amyloid precursor protein, whereas tau is a brain-specific, axon-enriched microtubule-associated protein. The behavioral symptoms of AD correlate with the accumulation of plaques and tangles, and they are a direct consequence of the damage and destruction of synapses that mediate memory and cognition. Synapse loss can be caused by the failure of live neurons to maintain functional axons and dendrites or by neuron death. During the past dozen years, a steadily accumulating body of evidence has indicated that soluble forms of Aβ and tau work together, independently of their accumulation into plaques and tangles, to drive healthy neurons into the diseased state and that hallmark toxic properties of Aβ require tau. For instance, acute neuron death, delayed neuron death following ectopic cell cycle reentry, and synaptic dysfunction are triggered by soluble, extracellular Aβ species and depend on soluble, cytoplasmic tau. Therefore, Aβ is upstream of tau in AD pathogenesis and triggers the conversion of tau from a normal to a toxic state, but there is also evidence that toxic tau enhances Aβ toxicity via a feedback loop. Because soluble toxic aggregates of both Aβ and tau can self-propagate and spread throughout the brain by prionlike mechanisms, successful therapeutic intervention for AD would benefit from detecting these species before plaques, tangles, and cognitive impairment become evident and from interfering with the destructive biochemical pathways that they initiate. Copyright 2014 American Medical Association. All rights reserved.


Kaufman D.A.,University of Virginia
Current medical research and opinion | Year: 2010

In an era of quality improvement and 'getting to zero (infections and/or related mortality),' neonatal candidiasis is ripe for evidence-based initiatives. Knowledge of each institution's invasive Candida infection (ICI) incidence and infection-related mortality is critical to evaluate disease burden and effective interventions. Evidenced-based interventions include: antifungal prophylaxis, starting with appropriate dosing, and prompt removal of central venous catheters (CVC). There is A-I evidence supporting antifungal prophylaxis with fluconazole, and it should be considered in every neonatal intensive care unit (NICU). The literature supports targeting infants <1000 g and/or 1000 g and >or=28 weeks not receiving antifungal prophylaxis. Evaluation of ICI incidence and mortality by gestational age and birth week should be followed in each NICU, to evaluate infection control and prevention.


Gandy S.,Mount Sinai School of Medicine | DeKosky S.T.,University of Virginia
Annual Review of Medicine | Year: 2013

Alzheimer's disease (AD) is the major cause of late-life brain failure. In the past 25 years, autosomal dominant forms of AD were found to be primariy attributable to mutations in one of two presenilins, polytopic proteins that contain the catalytic site of the ?-secretase protease that releases the amyloid beta (Aβ) peptide. Some familial AD is also due to mutations in the amyloid precursor protein (APP), but recently a mutation in APP was discovered that reduces Aβ generation and is protective against AD, further implicating amyloid metabolism. Prion-like seeding of amyloid fibrils and neurofibrillary tangles has been invoked to explain the stereotypical spread of AD within the brain. Treatment trials with anti-Aβ antibodies have shown target engagement, if not significant treatment effects. Attention is increasingly focused on presymptomatic intervention, because Aβ mismetabolism begins up to 25 years before symptoms begin. AD trials deriving from new biological information involve extraordinary international collaboration and may hold the best hope for success in the fight against AD. Copyright © 2013 by Annual Reviews.


Vasyunin A.I.,University of Virginia | Herbst E.,University of Virginia
Astrophysical Journal | Year: 2013

The observed gas-phase molecular inventory of hot cores is believed to be significantly impacted by the products of chemistry in interstellar ices. In this study, we report the construction of a full macroscopic Monte Carlo model of both the gas-phase chemistry and the chemistry occurring in the icy mantles of interstellar grains. Our model treats icy grain mantles in a layer-by-layer manner, which incorporates laboratory data on ice desorption correctly. The ice treatment includes a distinction between a reactive ice surface and an inert bulk. The treatment also distinguishes between zeroth- and first-order desorption, and includes the entrapment of volatile species in more refractory ice mantles. We apply the model to the investigation of the chemistry in hot cores, in which a thick ice mantle built up during the previous cold phase of protostellar evolution undergoes surface reactions and is eventually evaporated. For the first time, the impact of a detailed multilayer approach to grain mantle formation on the warm-up chemistry is explored. The use of a multilayer ice structure has a mixed impact on the abundances of organic species formed during the warm-up phase. For example, the abundance of gaseous HCOOCH 3 is lower in the multilayer model than in previous grain models that do not distinguish between layers (so-called two phase models). Other gaseous organic species formed in the warm-up phase are affected slightly. Finally, we find that the entrapment of volatile species in water ice can explain the two-jump behavior of H2CO previously found in observations of protostars. © 2013. The American Astronomical Society. All rights reserved..


Mueller A.C.,University of Virginia | Sun D.,University of Virginia | Dutta A.,University of Virginia
Oncogene | Year: 2013

Chromatin remodeling factors are becoming known as crucial facilitators of recruitment of repair proteins to sites of DNA damage. Multiple chromatin remodeling protein complexes are now known to be required for efficient double strand break repair. In a screen for microRNAs (miRNAs) that modulate the DNA damage response, we discovered that expression of the miR-99 family of miRNAs correlates with radiation sensitivity. These miRNAs were also transiently induced following radiation. The miRNAs target the SWI/SNF chromatin remodeling factor SNF2H/SMARCA5, a component of the ACF1 complex. We found that by reducing levels of SNF2H, miR-99a and miR-100 reduced BRCA1 localization to sites of DNA damage. Introduction of the miR-99 family of miRNAs into cells reduced the rate and overall efficiency of repair by both homologous recombination and non-homologous end joining. Finally, induction of the miR-99 family following radiation prevents an increase in SNF2H expression and reduces the recruitment of BRCA1 to the sites of DNA damage following a second dose of radiation, reducing the efficiency of repair after multiple rounds of radiation, as used in fractionated radiotherapy. © 2013 Macmillan Publishers Limited All rights reserved.


Lawrence D.,University of Virginia | Vandecar K.,University of Virginia
Nature Climate Change | Year: 2015

Tower, ground-based and satellite observations indicate that tropical deforestation results in warmer, drier conditions at the local scale. Understanding the regional or global impacts of deforestation on climate, and ultimately on agriculture, requires modelling. General circulation models show that completely deforesting the tropics could result in global warming equivalent to that caused by burning of fossil fuels since 1850, with more warming and considerable drying in the tropics. More realistic scenarios of deforestation yield less warming and less drying, suggesting critical thresholds beyond which rainfall is substantially reduced. In regional, mesoscale models that capture topography and vegetation-based discontinuities, small clearings can actually enhance rainfall. At this smaller scale as well, a critical deforestation threshold exists, beyond which rainfall declines. Future agricultural productivity in the tropics is at risk from a deforestation-induced increase in mean temperature and the associated heat extremes and from a decline in mean rainfall or rainfall frequency. Through teleconnections, negative impacts on agriculture could extend well beyond the tropics.


Grimes R.N.,University of Virginia
Dalton Transactions | Year: 2015

Once seldom encountered outside of a few laboratories, carboranes are now everywhere, playing a role in the development of a broad range of technologies encompassing organic synthesis, radionuclide handling, drug design, heat-resistant polymers, cancer therapy, nanomaterials, catalysis, metal-organic frameworks, molecular machines, batteries, electronic devices, and more. This perspective highlights selected examples in which the special attributes of carboranes and metallacarboranes are being exploited for targeted purposes in the laboratory and in the wider world. This journal is © The Royal Society of Chemistry 2015.


Law D.R.,University of California at Los Angeles | Majewski S.R.,University of Virginia
Astrophysical Journal | Year: 2010

Numerical models of the tidal disruption of the Sagittarius (Sgr) dwarf galaxy have recently been developed that for the first time simultaneously satisfy most observational constraints on the angular position, distance, and radial velocity trends of both leading and trailing tidal streams emanating from the dwarf. We use these dynamical models in combination with extant three-dimensional position and velocity data for Galactic globular clusters and dSph galaxies to identify those Milky Way satellites that are likely to have originally formed in the gravitational potential well of the Sgr dwarf, and have been stripped from Sgr during its extended interaction with the Milky Way. We conclude that the globular clusters Arp 2, M 54, NGC 5634, Terzan 8, and Whiting 1 are almost certainly associated with the Sgr dwarf, and that Berkeley 29, NGC 5053, Pal 12, and Terzan 7 are likely to be as well (albeit at lower confidence). The initial Sgr system therefore may have contained five to nine globular clusters, corresponding to a specific frequency SN = 5-9 for an initial Sgr luminosity MV = -15.0. Our result is consistent with the 8 ± 2 genuine Sgr globular clusters expected on the basis of statistical modeling of the Galactic globular cluster distribution and the corresponding falseassociation rate due to chance alignments with the Sgr streams. The globular clusters identified as most likely to be associated with Sgr are consistent with previous reconstructions of the Sgr age-metallicity relation, and show no evidence for a second-parameter effect shaping their horizontal branch morphologies. We find no statistically significant evidence to suggest that any of the recently discovered population of ultrafaint dwarf galaxies are associated with the Sgr tidal streams, but are unable to rule out this possibility conclusively for all systems. © 2010. The American Astronomical Society. All rights reserved.


Ma L.,Malvern Inc. | Danoff T.M.,Malvern Inc. | Borish L.,University of Virginia
Journal of Allergy and Clinical Immunology | Year: 2014

Background Anaphylaxis is a serious allergic reaction that can cause death; however, the actual risk of death is unclear. Objective We sought to estimate the case fatality rate among hospitalizations or emergency department (ED) presentations for anaphylaxis and the mortality rate associated with anaphylaxis for the general population. Methods This was a population-based epidemiologic study using 3 national databases: the Nationwide Inpatient Sample (NIS; 1999-2009), the Nationwide Emergency Department Sample (NEDS; 2006-2009), and Multiple Cause of Death Data (MCDD; 1999-2009). Sources for these databases are hospital and ED discharge records and death certificates, respectively. Results Case fatality rates were between 0.25% and 0.33% among hospitalizations or ED presentations with anaphylaxis as the principal diagnosis (NIS+NEDS, 2006-2009). These rates represent 63 to 99 deaths per year in the United States, approximately 77% of which occurred in hospitalized patients. The rate of anaphylaxis-related hospitalizations increased from 21.0 to 25.1 per million population between 1999 and 2009 (annual percentage change, 2.23%; 95% CI, 1.52% to 2.94%), contrasting with a decreasing case fatality rate among hospitalizations (annual percentage change, -2.35%; 95% CI, -4.98% to 0.34%). Overall mortality rates ranged from 0.63 to 0.76 per million population (186-225 deaths per year, MCDD) and appeared stable in the last decade (annual percentage change, -0.31%; 95% CI, -1.54% to 0.93%). Conclusion From 2006 to 2009, the overwhelming majority of hospitalizations or ED presentations for anaphylaxis did not result in death, with an average case fatality rate of 0.3%. Anaphylaxis-related hospitalizations increased steadily in the last decade (1999-2009), but this increase was offset by the decreasing case fatality rate among those hospitalized; both inpatient and overall mortality rates associated with anaphylaxis appeared stable and were well under 1 per million population. Although anaphylactic reactions are potentially life-threatening, the probability of dying is actually very low. With the prevalence of anaphylaxis on the increase, practitioners need to stay vigilant and follow the treatment guidelines to further reduce anaphylaxis-related deaths. © 2013 American Academy of Allergy, Asthma & Immunology.


Evans E.C.,University of Virginia
Midwifery | Year: 2013

Objective: identify research examining the effect of culture on maternal mortality rates. Design: literature review of CINAHL, Cochrane, PsychInfo, OVID Medline and Web of Science databases. Setting: developing countries with typically higher rates of maternal mortality. Participants: women, birth attendants, family members, nurse midwives, health-care workers, and community members. Measurements and findings: reviews, qualitative and mixed-methods research have identified components of culture that have a direct impact on maternal mortality. Examples of culture are given in the text and categorised according to the way in which they impact maternal mortality. Key conclusions: cultural customs, practices, beliefs and values profoundly influence women's behaviours during the perinatal period and in some cases increase the likelihood of maternal death in childbirth. The four ways in which culture may increase MMR are as follows: directly harmful acts, inaction, use of care and social status. Implications for practice: understanding the specifics of how the culture surrounding childbirth contributes to maternal mortality can assist nurses, midwives and other health-care workers in providing culturally competent care and designing effective programs to help decrease MMR, especially in the developing world. Interventions designed without accounting for these cultural factors are likely to be less effective in reducing maternal mortality. © 2012 Elsevier Ltd.


Egorov S.A.,University of Virginia
Soft Matter | Year: 2012

We present a self-consistent field theoretical study of phase separation in binary polymer brushes physisorbed on cylindrical surfaces under good solvent conditions. In agreement with earlier simulation and experimental work, we find that macrophase separation occurs for two immiscible polymers of the same length, while a chain length mismatch between two polymer types promotes microphase separation, with ring-shaped alternating stripes forming perpendicular to the cylinder axis. We observe that the width of the stripes increases with increasing immiscibility, increasing substrate curvature, decreasing mismatch in the chain length, and decreasing the amount of adsorbed polymer. We rationalize these observations by analyzing entropic and energetic contributions to the Helmholtz free energy of the system. © 2012 The Royal Society of Chemistry.


Santen R.A.V.,TU Eindhoven | Neurock M.,University of Virginia | Shetty S.G.,TU Eindhoven
Chemical Reviews | Year: 2010

A study was conducted to demonstrate the application of the Brønsted-Evans-Polanyi (BEP) relationship in the analysis of surface elementary reaction steps. The BEP equation directly related the change in activation energy of the reaction, δEact to the corresponding change of the reaction energy, δEr for different surfaces through a constant factor α. The activation energy was deduced from the reaction energy, which was a thermodynamic parameter. An analytic derivation of the BEP equation was presented using a Marcus-type analysis to provide a conceptual frame for the discussion. The physical chemistry of the surface reaction was viewed as a potential-energy curve crossing problem. It was found that surface electronic factors required a modification of this simple potential-energy crossing model.


Vasyunin A.I.,University of Virginia | Herbst E.,University of Virginia
Astrophysical Journal | Year: 2013

The recent discovery of terrestrial-type organic species such as methyl formate and dimethyl ether in the cold interstellar gas has proved that the formation of organic matter in the Galaxy begins at a much earlier stage of star formation than was previously thought. This discovery represents a challenge for astrochemical modelers. The abundances of these molecules cannot be explained by the previously developed "warm-up" scenario, in which organic molecules are formed via diffusive chemistry on surfaces of interstellar grains starting at 30 K, and then released to the gas at higher temperatures during later stages of star formation. In this article, we investigate an alternative scenario in which complex organic species are formed via a sequence of gas-phase reactions between precursor species formed on grain surfaces and then ejected into the gas via efficient reactive desorption, a process in which non-thermal desorption occurs as a result of conversion of the exothermicity of chemical reactions into the ejection of products from the surface. The proposed scenario leads to reasonable if somewhat mixed results at temperatures as low as 10 K and may be considered as a step toward the explanation of abundances of terrestrial-like organic species observed during the earliest stages of star formation. © 2013. The American Astronomical Society. All rights reserved.


Gomez D.,University of Virginia | Shankman L.S.,University of Virginia | Nguyen A.T.,University of Virginia | Owens G.K.,University of Virginia
Nature Methods | Year: 2013

Chromatin immunoprecipitation assays have contributed greatly to our understanding of the role of histone modifications in gene regulation. However, they do not permit analysis with single-cell resolution, thus confounding analyses of heterogeneous cell populations. Here we present a method that permits visualization of histone modifications of single genomic loci with single-cell resolution in formaldehyde-fixed paraffin-embedded tissue sections based on combined use of in situ hybridization and proximity ligation assays. We show that dimethylation of lysine 4 of histone H3 (H3K4me2) at the MYH11 locus is restricted to the smooth muscle cell (SMC) lineage in human and mouse tissue sections and that the mark persists even in phenotypically modulated SMC in atherosclerotic lesions that show no detectable expression of SMC marker genes. This methodology has promise for broad applications in the study of epigenetic mechanisms in complex multicellular tissues in development and disease. © 2013 Nature America, Inc. All rights reserved.


Siragy H.M.,University of Virginia
Vascular Health and Risk Management | Year: 2011

The safety of angiotensin II receptor blockers (ARBs) for the treatment of hypertension and cardiovascular and renal diseases has been well documented in numerous randomized clinical trials involving thousands of patients. However, recent concerns have surfaced about possible links between ARBs and increased risks of myocardial infarction and cancer. Less is known about the safety of the direct renin inhibitor aliskiren, which was approved as an antihypertensive in 2007. This article provides a detailed review of the safety of ARBs and aliskiren, with an emphasis on the risks of cancer and myocardial infarction associated with ARBs. Safety data were identified by searching PubMed and Food and Drug Administration (FDA) Web sites through April 2011. ARBs are generally well tolerated, with no known class-specific adverse events. The possibility of an increased risk of myocardial infarction associated with ARBs was suggested predominantly because the Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) trial reported a statistically significant increase in the incidence of myocardial infarction with valsartan compared with amlodipine. However, no large-scale, randomized clinical trials published after the VALUE study have shown a statistically significant increase in the incidence of myocardial infarction associated with ARBs compared with placebo or non-ARBs. Meta-analyses examining the risk of cancer associated with ARBs have produced conflicting results, most likely due to the inherent limitations of analyzing heterogeneous data and a lack of published cancer data. An ongoing safety investigation by the FDA has not concluded that ARBs increase the risk of cancer. Pooled safety results from clinical trials indicate that aliskiren is well tolerated, with a safety profile similar to that of placebo. ARBs and aliskiren are well tolerated in patients with hypertension and certain cardiovascular and renal conditions; their benefits outweigh possible safety concerns. © 2011 Siragy, publisher and licensee Dove Medical Press Ltd.


Ding D.,University of Virginia
Neurosurgical focus | Year: 2011

Intracranial atherosclerosis presents a therapeutic challenge to medical and surgical physicians alike. Despite maximal medical therapy, the stroke rate from this disease is still high, especially when arterial stenosis is severe and patients are symptomatic. Open surgical therapy has yet to be shown to be a more efficacious treatment than medical therapy alone, largely due to the relatively high rates of perioperative complications. Angioplasty has a similar fate, with the risk of periprocedural complications outweighing the overall benefit of treatment. With the advent of stents for use in intracranial vasculature, new hope has arisen for the treatment of intracranial atherosclerosis. The NEUROLINK system, the drug-eluting stents Taxus and Cypher, the flexible Wingspan stent, the Apollo stent, and the Pharos stent have all been used in various prospective and retrospective clinical studies with varying technical and clinical results. The authors' objective is to review and loosely compare the data presented for each of these stenting systems. While the Wingspan stent appears to have somewhat of an advantage with regard to technical success in comparison with the other stenting systems, the clinical follow-up time of its studies is too short to properly compare its complication rates with those of other stents. Before we continue to move forward with stenting for intracranial stenosis, a randomized prospective trial is ultimately needed to directly compare intracranial stenting to medical therapy.


Koeppel A.F.,University of Virginia | Wu M.,University of Virginia
Nucleic Acids Research | Year: 2013

The lack of a consensus bacterial species concept greatly hampers our ability to understand and organize bacterial diversity. Operational taxonomic units (OTUs), which are clustered on the basis of DNA sequence identity alone, are the most commonly used microbial diversity unit. Although it is understood that OTUs can be phylogenetically incoherent, the degree and the extent of the phylogenetic inconsistency have not been explicitly studied. Here, we tested the phylogenetic signal of OTUs in a broad range of bacterial genera from various phyla. Strikingly, we found that very few OTUs were monophyletic, and many showed evidence of multiple independent origins. Using previously established bacterial habitats as benchmarks, we showed that OTUs frequently spanned multiple ecological habitats. We demonstrated that ecological heterogeneity within OTUs is caused by their phylogenetic inconsistency, and not merely due to 'lumping' of taxa resulting from using relaxed identity cut-offs. We argue that ecotypes, as described by the Stable Ecotype Model, are phylogenetically and ecologically more consistent than OTUs and therefore could serve as an alternative unit for bacterial diversity studies. In addition, we introduce QuickES, a new wrapper program for the Ecotype Simulation algorithm, which is capable of demarcating ecotypes in data sets with tens of thousands of sequences. © 2013 The Author(s) 2013.


Pearson W.R.,University of Virginia
Current Protocols in Bioinformatics | Year: 2013

Sequence similarity searching, typically with BLAST, is the most widely used and most reliable strategy for characterizing newly determined sequences. Sequence similarity searches can identify "homologous" proteins or genes by detecting excess similarity- statistically significant similarity that reflects common ancestry. This unit provides an overview of the inference of homology from significant similarity, and introduces other units in this chapter that provide more details on effective strategies for identifying homologs. © 2013 by John Wiley & Sons, Inc.


Oishi S.,University of Virginia | Schimmack U.,University of Toronto
Journal of Personality and Social Psychology | Year: 2010

We tested the relation between residential mobility and well-being in a sample of 7,108 American adults who were followed for 10 years. The more residential moves participants had experienced as children, the lower the levels of well-being as adults. As predicted, however, the negative association between the number of residential moves and well-being was observed among introverts but not among extraverts. We further demonstrated that the negative association between residential mobility and well-being among introverts was explained by the relative lack of close social relationships. Finally, we found that introverts who had moved frequently as children were more likely to have died during the 10-year follow-up. Among extraverts, childhood residential mobility was unrelated to their mortality risk as adults. These findings indicate that residential moves can be a risk factor for introverts and that extraversion can be an interpersonal resource for social relationships and well-being in mobile societies. © 2010 American Psychological Association.


Chevalier R.L.,University of Virginia
Advances in Chronic Kidney Disease | Year: 2015

Maldevelopment of the collecting system resulting in urinary tract obstruction (UTO) is the leading identifiable cause of CKD in children. Specific etiologies are unknown; most cases are suspected by discovering hydronephrosis on prenatal ultrasonography. Congenital UTO can reduce nephron number and cause bladder dysfunction, which contribute to ongoing injury. Severe UTO can impair kidney growth in utero, and animal models of unilateral ureteral obstruction show that ischemia and oxidative stress cause proximal tubular cell death, with later development of interstitial fibrosis. Congenital obstructive nephropathy, therefore, results from combined developmental and obstructive kidney injury. Because of inadequacy of available biomarkers, criteria for surgical correction of upper tract obstruction are poorly established. Lower tract obstruction requires fetal or immediate postnatal intervention, and the rate of progression of CKD is highly variable. New biomarkers based on proteomics and determination of glomerular number by magnetic resonance imaging should improve future care. Angiotensin inhibitors have not been effective in slowing progression, although avoidance of nephrotoxins and timely treatment of hypertension are important. Because congenital UTO begins in fetal life, smooth transfer of care from perinatologist to pediatric and adult urology and nephrology teams should optimize quality of life and ultimate outcomes for these patients. © 2015 National Kidney Foundation, Inc.


Hazen K.C.,University of Virginia
Diagnostic Microbiology and Infectious Disease | Year: 2013

Dimethylsulfoxide (DMSO) binds within the plasma membrane of cells and increases membrane permeability. DMSO is used in antifungal (AF) susceptibility assays for water insoluble agents. DMSO was observed to cause Candida albicans to express enhanced, diminished, or no change in growth compared to control medium, suggesting DMSO could influence the efficacy of water-insoluble AF agents. The activity of 4 water soluble AF agents against 6 yeast species was tested under conditions similar to the CSLI M27-A3 method. Growth response to 0.5% and 1% DMSO was variable. In 15 of 67 AF assays, DMSO resulted in a different MIC-2 (substantial inhibition of growth) value compared to control. Two of these involved differences of two doubling dilutions. The results imply that, in some cases of water-insoluble AF drug-yeast combinations, the MIC-2 may be skewed from the more clinically relevant MIC, providing one reason for possible discordance between MIC results and clinical outcomes. © 2013 Elsevier Inc..


Begley M.R.,University of California at Santa Barbara | Wadley H.N.G.,University of Virginia
Acta Materialia | Year: 2012

Micromechanical models are developed to explore the effect of embedded metal layers upon thermal cycling delamination failure of thermal barrier coatings (TBCs) driven by thickening of a thermally grown oxide (TGO). The effects of reductions in the steady-state (i.e. maximum) energy release rate (ERR) controlling debonding from large interface flaws and decreases in the thickening kinetics of TGO are investigated. The models are used to quantify the dependence of the ERR and delamination lifetime upon the geometry and constitutive properties of metal/TBC/TGO multilayers. Combinations of multilayer properties are identified which maximize the increase in delamination lifetime. It is found that even in the absence of TGO growth rate effects, the delamination lifetime of TBC systems with weak TGO/bond coat interfaces can be more than doubled by replacing 10-20% of the ceramic TBC layer with a metal whose ambient temperature yield stress is in the ∼100-200 MPa range. © 2011 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.


Courtoy A.,University of Liège | Liuti S.,University of Virginia
Physics Letters, Section B: Nuclear, Elementary Particle and High-Energy Physics | Year: 2013

We present an analysis of the role of the running coupling constant at the intersection of perturbative and non-perturbative QCD. Although the approaches that have been considered so far in these two regimes appear to be complementary to each other, a unified description might be derived through the definition of the effective coupling, as they both provide ways of analyzing its freezing at low values of the scale. We extract the effective coupling from all available experimental data on the unpolarized structure function of the proton, F2p, at large values of Bjorken x, including the resonance region. We suggest that parton-hadron duality observed in this region can be explained if non-perturbative effects are included in the coupling constant. The outcome of our analysis is a smooth transition from perturbative to non-perturbative QCD physics, embodied in the running of the coupling constant at intermediate scales. © 2013 Elsevier B.V.


Guyenet P.G.,University of Virginia | Bayliss D.A.,University of Virginia
Neuron | Year: 2015

Recent advances have clarified how the brain detects CO2 to regulate breathing (central respiratory chemoreception). These mechanisms are reviewed and their significance is presented in the general context of CO2/pH homeostasis through breathing. At rest, respiratory chemoreflexes initiated at peripheral and central sites mediate rapid stabilization of arterial PCO2 and pH. Specific brainstem neurons (e.g., retrotrapezoid nucleus, RTN; serotonergic) are activated by PCO2 and stimulate breathing. RTN neurons detect CO2 via intrinsic proton receptors (TASK-2, GPR4), synaptic input from peripheral chemoreceptors and signals from astrocytes. Respiratory chemoreflexes are arousal state dependent whereas chemoreceptor stimulation produces arousal. When abnormal, these interactions lead to sleep-disordered breathing. During exercise, central command and reflexes from exercising muscles produce the breathing stimulation required to maintain arterial PCO2 and pH despite elevated metabolic activity. The neural circuits underlying central command and muscle afferent control of breathing remain elusive and represent a fertile area for future investigation. © 2015 Elsevier Inc.


Hanein D.,Sanford Burnham Institute for Medical Research | Horwitz A.R.,University of Virginia
Current Opinion in Cell Biology | Year: 2012

Adhesions between the cell and the extracellular matrix (ECM) are mechanosensitive multi-protein assemblies that transmit force across the cell membrane and regulate biochemical signals in response to the chemical and mechanical environment. These combined functions in force transduction, signaling and mechanosensing contribute to cellular phenotypes that span development, homeostasis and disease. These adhesions form, mature and disassemble in response to actin organization and physical forces that originate from endogenous myosin activity or external forces by the extracellular matrix. Despite advances in our understanding of the protein composition, interactions and regulation, our understanding of matrix adhesion structure and organization, how forces affect this organization, and how these changes dictate specific signaling events is limited. Insights across multiple structural levels are acutely needed to elucidate adhesion structure and ultimately the molecular basis of signaling and mechanotransduction. Here we describe the challenges and recent advances and prospects for unraveling the structure of cell-matrix adhesions and their response to force. © 2011 Elsevier Ltd.


Arandjelovic S.,University of Virginia | Ravichandran K.S.,University of Virginia
Nature Immunology | Year: 2015

Human bodies collectively turn over about 200 billion to 300 billion cells every day. Such turnover is an integral part of embryonic and postnatal development, as well as routine tissue homeostasis. This process involves the induction of programmed cell death in specific cells within the tissues and the specific recognition and removal of dying cells by a clearance 'crew' composed of professional, non-professional and specialized phagocytes. In the past few years, considerable progress has been made in identifying many features of apoptotic cell clearance. Some of these new observations challenge the way dying cells themselves are viewed, as well as how healthy cells interact with and respond to dying cells. Here we focus on the homeostatic removal of apoptotic cells in tissues. © 2015 Nature America, Inc.


Deboer M.D.,University of Virginia
Current Pharmaceutical Design | Year: 2012

Ghrelin is a stomach-derived hormone that acts at the ghrelin receptor (formerly called the Growth Hormone Secretagogue (GHS)-1a receptor) in multiple tissues throughout the body, exhibiting pleotropic effects potentially beneficial as a treatment in human disease states. Given its properties including increasing appetite, decreasing systemic inflammation, decreasing vascular resistance, increasing cardiac output, and increasing growth hormone and IGF-1 levels, ghrelin has been tested as a treatment in animal models of multiple disease states that produce the deficits in these processes. Thus, the efficacy of ghrelin has been testing in diseases involving anorexia, negative energy balance, cardiovascular compromise, systemic inflammation and gastroparesis. These diseases include cancer cachexia, chronic heart failure, chronic renal failure, chemotherapy, arthritis, gastroparesis and inflammatory bowel disease. Across this wide variety of diseases treatment with ghrelin and ghrelin agonists have produced benefits, though given ghrelin's widespread effects, the exact mechanisms behind ghrelin's action in these settings is frequently difficult to determine. Further investigation using animal models may help to determine mechanisms that are most operative in these disease states and narrow treatment parameters helpful for human application. © 2012 Bentham Science Publishers.


Madan R.,University of Virginia | Petri Jr. W.A.,University of Virginia
Trends in Molecular Medicine | Year: 2012

Clostridium difficile is the causal agent of antibiotic-associated diarrhea and is a leading cause of hospital-acquired infections in the US.. C. difficile has been known to cause severe diarrhea and colitis for more than 30 years, but the emergence of a newer, hypervirulent strain of. C. difficile (BI/NAP1) has further compounded the problem, and recently both the number of cases and mortality associated with. C. difficile-associated diarrhea have been increasing. One of the major drivers of disease pathogenesis is believed to be an excessive host inflammatory response. A better understanding of the host inflammation and immune mechanisms that modulate the course of disease and control host susceptibility to. C. difficile could lead to novel (host-targeted) strategies for combating the challenges posed by this deadly infection. © 2012 Elsevier Ltd.


Marozkina N.V.,University of Virginia | Gaston B.,University of Virginia
Biochimica et Biophysica Acta - General Subjects | Year: 2012

Background: S-Nitrosothiols are made by nitric oxide synthases and other metalloproteins. Unlike nitric oxide, S-nitrosothiols are involved in localized, covalent signaling reactions in specific cellular compartments. These reactions are enzymatically regulated. Scope: S-Nitrosylation affects interactions involved in virtually every aspect of normal cell biology. This article is part of a Special Issue entitled Regulation of Cellular Processes by S-nitrosylation. Major Conclusions and Significance: S-Nitrosylation is a regulated signaling reaction. © 2011 Elsevier B.V. All rights reserved.


Carey R.M.,University of Virginia
Advances in Chronic Kidney Disease | Year: 2015

The renin-angiotensin system (RAS) is a well-studied hormonal cascade controlling fluid and electrolyte balance and blood pressure through systemic actions. The classical RAS includes renin, an enzyme catalyzing the conversion of angiotensinogen to angiotensin (Ang) I, followed by angiotensin-converting enzyme (ACE) cleavage of Ang I to II, and activation of AT1 receptors, which are responsible for all RAS biologic actions. Recent discoveries have transformed the RAS into a far more complex system with several new pathways: the (des-aspartyl1)-Ang II (Ang III)/AT2 receptor pathway, the ACE-2/Ang (1-7)/Mas receptor pathway, and the prorenin-renin/prorenin receptor/mitogen-activated protein kinase pathway, among others. Although the classical RAS pathway induces Na+ reabsorption and increases blood pressure, several new pathways constitute a natriuretic/vasodilator arm of the system, opposing detrimental actions of Ang II through Ang II type 1 receptors. Instead of a simple circulating RAS, several independently functioning tissue RASs exist, the most important of which is the intrarenal RAS. Several physiological characteristics of the intrarenal RAS differ from those of the circulating RAS, autoamplifying the activity of the intrarenal RAS and leading to hypertension. This review will update current knowledge on the RAS with particular attention to the intrarenal RAS and its role in the pathophysiology of hypertension. © 2015 National Kidney Foundation, Inc.


Damron F.H.,University of Virginia | Goldberg J.B.,University of Virginia
Molecular Microbiology | Year: 2012

Pseudomonas aeruginosa, a Gram-negative bacterium, is a significant opportunistic pathogen associated with skin and soft tissue infections, nosocomial pneumonia and sepsis. In addition, it can chronically colonize the lungs of cystic fibrosis (CF) patients. Overproduction of the exopolysaccharide called alginate provides P.aeruginosa with a selective advantage and facilitates survival in the CF lung. The in vitro phenotype of alginate overproduction observed on solid culture media is referred to as mucoid. Expression of the alginate machinery and biosynthetic enzymes are controlled by the extracytoplasmic sigma factor, σ 22 (AlgU/T). The key negative regulator of both σ 22 activity and the mucoid phenotype is the cognate anti-sigma factor MucA. MucA sequesters σ 22 to the inner membrane inhibiting the sigma factor's transcriptional activity. The well-studied mechanism for transition to the mucoid phenotype is mutation of mucA, leading to loss of MucA function and therefore activation of σ 22. Recently, regulated intramembrane proteolysis (RIP) has been recognized as a mechanism whereby proteolysis of the anti-sigma factor MucA leads to active σ 22 allowing P.aeruginosa to respond to environmental stress conditions by overproduction of alginate. The goal of this review is to illuminate the pathways leading to RIP that have been identified and proposed. © 2012 Blackwell Publishing Ltd.


Miller A.R.,University of Virginia | Tucker C.,Massachusetts Institute of Technology
Information Systems Research | Year: 2013

Given the demand for authentic personal interactions over social media, it is unclear how much firms should actively manage their social media presence. We study this question empirically in a health care setting. We show that active social media management drives more user-generated content. However, we find that this is due to an incremental increase in user postings from an organization's employees rather than from its clients. This result holds when we explore exogenous variation in social media policies, employees, and clients that are explained by medical marketing laws, medical malpractice laws, and distortions in Medicare incentives. Further examination suggests that content being generated mainly by employees can be avoided if a firm's postings are entirely client focused. However, most firm postings seem not to be specifically targeted to clients' interests, instead highlighting more general observations or achievements of the firm itself. We show that untargeted postings like these provoke activity by employees rather than clients. This may not be a bad thing because employee-generated content may help with employee motivation, recruitment, or retention, but it does suggest that social media should not be funded or managed exclusively as a marketing function of the firm. © 2013 INFORMS.


Saulsbury F.T.,University of Virginia
Current Opinion in Rheumatology | Year: 2010

Purpose Of Review: To provide an update on recent advances in the genetic susceptibility, pathogenesis and treatment of Henoch-Schönlein purpura. Recent Findings: Recent work has advanced our understanding of the genetic susceptibility and pathogenesis of Henoch-Schönlein purpura, but there are still significant gaps in our knowledge. Information concerning the most effective treatment of Henoch-Schönlein purpura has begun to emerge. Corticosteroid therapy reduces the duration and severity of abdominal and joint pain, but corticosteroids do not prevent the development of nephritis, or alter the natural history of Henoch-Schönlein purpura. The most effective treatment for severe nephritis remains unclear despite multiple, mostly retrospective reports investigating a variety of drugs. Summary: Despite recent progress, our understanding of the genetic susceptibility, pathogenesis and treatment of Henoch-Schönlein purpura remains incomplete. Further research is necessary in order to clearly define the genetic susceptibility and the pathogenesis of Henoch-Schönlein purpura. Multicenter clinical trials are needed to determine the most effective treatment of Henoch-Schönlein purpura, particularly for patients with severe nephritis. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Carmody J.B.,University of Virginia | Charlton J.R.,University of Virginia
Pediatrics | Year: 2013

Thanks to remarkable advances in neonatal intensive care, infants who once had little chance for survival can now enter adulthood. Yet the consequences of premature birth or low birth weight (LBW) on nephrogenesis, final nephron number, and long-term kidney function are unclear. This review focuses on the theory, experimental evidence, and observational data that suggest an increased risk of chronic kidney disease (CKD) for infants born prematurely. Many premature and LBW infants begin life with an incomplete complement of immature nephrons. They are then exposed to a variety of external stressors that can hinder ongoing kidney development or cause additional nephron loss such as hemodynamic alterations, nephrotoxic medications, infections, and suboptimal nutrition. Acute kidney injury, in particular, may be a significant risk factor for the development of CKD. According to Brenner's hypothesis, patients with decreased nephron number develop hyperfiltration that results in sodium retention, hypertension, nephron loss, and CKD due to secondary focal segmental glomerulosclerosis. Because the risk of CKD in premature and LBW infants has not been accurately determined, there are no evidence-based recommendations for screening or management. Yet with the first generation of infants from the surfactant era only now reaching adulthood, it is possible that there is already an unrecognized epidemic of CKD. We suggest individualized, risk-based assessments of premature and LBW infants due to the increased risk of CKD and call for additional research into the long-term risk for CKD these infants face.


Davies J.M.,University of Queensland | Platts-Mills T.A.,University of Virginia | Aalberse R.C.,University of Amsterdam
Journal of Allergy and Clinical Immunology | Year: 2013

Our understanding of the origin and fate of the IgE-switched B cell has been markedly improved by studies in mouse models. The immediate precursor of the IgE-switched B cell is either a relatively naive nonswitched B cell or a mature IgG-switched B cell. These 2 routes are referred to as the direct and indirect pathways, respectively. IgE responses derived from each pathway differ significantly, largely reflecting the difference in time spent in a germinal center and thus time for clonal expansion, somatic hypermutation, affinity maturation, and acquisition of a memory phenotype. The clinical and therapeutic implications for IgE responses in human subjects are still a matter of debate, largely because the immunization procedures used in the animal models are significantly different from classical atopic sensitization to allergens from pollen and mites. On the basis of the limited information available, it seems likely that these atopic IgE responses are characterized by a relatively low IgG/IgE ratio, low B-cell memory, and modest affinity maturation, which fits well with the direct switching pathway. It is still unresolved how the IgE response evolves to cover a wide epitope repertoire involving many epitopes per allergen, as well as many different allergens from a single allergen source. © 2013 American Academy of Allergy, Asthma & Immunology.


Derecki N.C.,University of Virginia | Cronk J.C.,University of Virginia | Kipnis J.,University of Virginia
Trends in Immunology | Year: 2013

The role of microglia in central nervous system (CNS) pathology has been studied extensively, and more recently, examination of microglia in the healthy brain has yielded important insights into their many functions. It was long assumed that microglia were essentially quiescent cells, unless provoked into activation, which was considered a hallmark of disease. More recently, however, it has become increasingly clear that they are extraordinarily dynamic cells, constantly sampling their environment and adjusting to exquisitely delicate stimuli. Along these lines, our laboratory has identified a new and unexpected role for microglial phagocytosis - or lack thereof - in the pathophysiology of Rett syndrome, a neurodevelopmental disease caused by mutation of the gene encoding methyl-CpG binding protein (MECP)2. We have shown that specific expression of wild type Mecp2 in myeloid cells of Mecp2-null mice is sufficient to arrest major symptoms associated with this devastating disease. This beneficial effect, however, is abolished if phagocytic activity of microglia is inhibited. Here, we discuss microglial origins, the role of microglia in brain development and maintenance, and the phenomenon of microglial augmentation by myeloid progenitor cells in the adult brain. Finally, we address in some detail the beneficial roles of microglia as clinical targets in Rett syndrome and other neurological disorders. © 2012 Elsevier Ltd.


Beam C.R.,University of Virginia | Turkheimer E.,University of Virginia
Development and Psychopathology | Year: 2013

Gene-environment correlation (rGE) exists both within and between families. Between families, accumulating rGE has been used to explain dramatic changes in phenotypic means over time. The Dickens and Flynn model of increases in cognitive ability over generational time, for example, suggests that small changes in phenotype can lead to subsequent reallocation of environmental resources. This process sets up a reciprocal feedback loop between phenotype and environment, producing accumulating rGE that can cause large changes in the mean of ability, even though ability remains highly heritable in cross-sectional data. We report simulations suggesting that similar processes may operate within twin and sibling pairs. Especially in dizygotic twins and siblings, small differences in phenotype can become associated with reallocations of environmental resources within families. We show that phenotype-environment effects can account for age-related increases in rGE, rapid differentiation of siblings raised together, and widely reported increases in the heritability of behavior during childhood and adolescence. © 2013 Cambridge University Press.


Goh C.,University of Virginia | Narayanan S.,University of Virginia | Hahn Y.S.,University of Virginia
Immunological Reviews | Year: 2013

Myeloid derived suppressor cells (MDSCs) are immature cells of myeloid origin, frequently found in tumor microenvironments and in the blood of cancer patients. In recent years, MDSCs have also been found in non-cancer settings, including a number of viral infections. The evasion of host immunity employed by viruses to establish viral persistence strikingly parallels mechanisms of tumor escape, prompting investigations into the generation and function of MDSCs in chronic viral infections. Importantly, analogous to the tumor microenvironment, MDSCs effectively suppress antiviral host immunity by limiting the function of several immune cells including T cells, natural killer cells, and antigen-presenting cells. In this article, we review studies on the mechanisms of MDSC generation, accumulation, and survival in an effort to understand their emergent importance in viral infections. We include a growing list of viral infections in which MDSCs have been reported. Finally, we discuss how MDSCs might play a role in establishing chronic viral infections and identify potential therapeutics that target MDSCs. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.


Rogol A.D.,University of Virginia | Hayden G.F.,University of Virginia
Journal of Pediatrics | Year: 2014

Accurate measurement of height and weight using standardized techniques is a fundamental component of pediatric medical visits. Calculation of height velocity over time enables comparison with standardized growth charts to identify potential deviations from normal. Growth deviations may be expressed as SD from the normal population mean for children of comparable age and sex; children with heights >2 SD below the mean are generally classified as short stature. In a child with suspected impaired growth, a detailed evaluation should be conducted to identify the cause. Such an evaluation may include a combination of personal, family, and social history; physical examination; general and perhaps specialized laboratory evaluations; radiologic examinations; genetic testing; and consultation with a pediatric subspecialist, such as a pediatric endocrinologist. Variants of normal growth include familial short stature, constitutional delay of growth and puberty, and small for gestational age with catch-up growth. Pathological causes of abnormal growth include many systemic diseases and their treatments, growth hormone deficiency, and a series of genetic syndromes, including Noonan syndrome and Turner syndrome. Children with short stature in whom no specific cause is identified may be diagnosed with idiopathic short stature. Early identification of abnormal growth patterns and prompt referral to specialist care offer children with growth failure and/or short stature the greatest chance for appropriate diagnosis, treatment, and improved clinical outcomes.


Mugler III J.P.,University of Virginia | Altes T.A.,University of Virginia
Journal of Magnetic Resonance Imaging | Year: 2013

By permitting direct visualization of the airspaces of the lung, magnetic resonance imaging (MRI) using hyperpolarized gases provides unique strategies for evaluating pulmonary structure and function. Although the vast majority of research in humans has been performed using hyperpolarized 3He, recent contraction in the supply of 3He and consequent increases in price have turned attention to the alternative agent, hyperpolarized 129Xe. Compared to 3He, 129Xe yields reduced signal due to its smaller magnetic moment. Nonetheless, taking advantage of advances in gas-polarization technology, recent studies in humans using techniques for measuring ventilation, diffusion, and partial pressure of oxygen have demonstrated results for hyperpolarized 129Xe comparable to those previously demonstrated using hyperpolarized 3He. In addition, xenon has the advantage of readily dissolving in lung tissue and blood following inhalation, which makes hyperpolarized 129Xe particularly attractive for exploring certain characteristics of lung function, such as gas exchange and uptake, which cannot be accessed using 3He. Preliminary results from methods for imaging 129Xe dissolved in the human lung suggest that these approaches will provide new opportunities for quantifying relationships among gas delivery, exchange, and transport, and thus show substantial potential to broaden our understanding of lung disease. Finally, recent changes in the commercial landscape of the hyperpolarized-gas field now make it possible for this innovative technology to move beyond the research laboratory. © 2012 Wiley Periodicals, Inc.


DeBoer M.D.,University of Virginia
Expert Review of Endocrinology and Metabolism | Year: 2011

Pediatric obesity threatens the future health of a growing number of children worldwide. An added challenge in identifying the patients at greatest need for intervention due to their elevated risk for future disease is that pediatric obesity and the associated metabolic syndrome manifest differently among different ethnic groups. African-Americans and Hispanics are more likely to exhibit obesity and insulin resistance and are at a higher risk for developing Type 2 diabetes. Nevertheless, using current criteria, African-American adolescents are much less likely to be diagnosed with metabolic syndrome, largely owing to lower rates of dyslipidemia. Further development is needed in ethnicity-inclusive means of risk identification among adolescents to accurately target treatment toward children at highest risk for future disease and to motivate adolescent patients and their families towards lifestyle improvement. Effective targeting and intensive treatment efforts may help in avoiding future sequelae of obesity among all ethnicities. © 2011 Expert Reviews Ltd.


Harland R.M.,University of California at Berkeley | Grainger R.M.,University of Virginia
Trends in Genetics | Year: 2011

Research using Xenopus takes advantage of large, abundant eggs and readily manipulated embryos in addition to conserved cellular, developmental and genomic organization with mammals. Research on Xenopus has defined key principles of gene regulation and signal transduction, embryonic induction, morphogenesis and patterning as well as cell cycle regulation. Genomic and genetic advances in this system, including the development of Xenopus tropicalis as a genetically tractable complement to the widely used Xenopus laevis, capitalize on the classical strengths and wealth of achievements. These attributes provide the tools to tackle the complex biological problems of the new century, including cellular reprogramming, organogenesis, regeneration, gene regulatory networks and protein interactions controlling growth and development, all of which provide insights into a multitude of human diseases and their potential treatments. © 2011 Elsevier Ltd.


Yang J.H.,University of Virginia | Saucerman J.J.,University of Virginia
Circulation Research | Year: 2011

Cardiac signaling networks exhibit considerable complexity in size and connectivity. The intrinsic complexity of these networks complicates the interpretation of experimental findings. This motivates new methods for investigating the mechanisms regulating cardiac signaling networks and the consequences these networks have on cardiac physiology and disease. Next-generation experimental techniques are also generating a wealth of genomic and proteomic data that can be difficult to analyze or interpret. Computational models are poised to play a key role in addressing these challenges. Computational models have a long history in contributing to the understanding of cardiac physiology and are useful for identifying biological mechanisms, inferring multiscale consequences to cell signaling activities and reducing the complexity of large data sets. Models also integrate well with experimental studies to explain experimental observations and generate new hypotheses. Here, we review the contributions computational modeling approaches have made to the analysis of cardiac signaling networks and forecast opportunities for computational models to accelerate cardiac signaling research. © 2011 American Heart Association, Inc.


Li M.D.,University of Virginia | Van Der Vaart A.D.,University of Virginia
Molecular Psychiatry | Year: 2011

A central question in addiction is how drug-induced changes in synaptic signaling are converted into long-term neuroadaptations. Emerging evidence reveals that microRNAs (miRNAs) have a distinct role in this process through rapid response to cellular signals and dynamic regulation of local mRNA transcripts. Because each miRNA can target hundreds of mRNAs, relative changes in the expression of miRNAs can greatly impact cellular responsiveness, synaptic plasticity and transcriptional events. These diverse consequences of miRNA action occur through coordination with genes implicated in addictions, the most compelling of these being the neurotrophin BDNF, the transcription factor cAMP-responsive element-binding protein (CREB) and the DNA-binding methyl CpG binding protein 2 (MeCP2). In this study, we review the recent progress in the understanding of miRNAs in general mechanisms of plasticity and neuroadaptation and then focus on specific examples of miRNA regulation in the context of addiction. We conclude that miRNA-mediated gene regulation is a conserved means of converting environmental signals into neuronal response, which holds significant implications for addiction and other psychiatric illnesses. © 2011 Macmillan Publishers Limited All rights reserved.


As a discipline, chronobiology has come of age in the last 25 years. There has been an exponential increase in our understanding of the molecular mechanism underlying circadian rhythms of gene expression, physiology, and behavior. While the mammalian clock mechanism has not yet been fully described, most of the primary gears have probably been identified; however, there remains a large submerged portion of this physiological iceberg. What is the extent of "clock-controlled gene" expression in the myriad cell types in mammals? What are the cell specific physiological processes that depend either directly or indirectly on the clock? These questions remain largely unanswered, but recent advances suggest a substantial link between basic clock function and physiology in several systems. In the reproductive system, there has been a recent surge in research on molecular clock function in neuroendocrine and endocrine tissues. This makes sense a priori, given the established link between the circadian clock, behavior (including reproductive behavior), and endocrine physiology. By understanding the role of the clock in basic mammalian reproductive physiology, we can begin to explore its role in the onset and progression of diseases that negatively affect fertility. Advances in this area will certainly yield novel insights into the etiology of these disorders and may provide new and exciting avenues for clinical research in reproduction and fertility.


Elias W.J.,University of Virginia | Shah B.B.,University of Virginia
JAMA - Journal of the American Medical Association | Year: 2014

Tremor, defined as a rhythmic and involuntary movement of any body part, is the most prevalent-movement disorder, affecting millions of people in the United States. All adults have varying degrees of physiological tremor so it is imperative to distinguish physiological tremor from pathological tremor types. Tremor is not inherently dangerous, but it can cause significant disability at home and in the workplace. Common tremors like essential tremor and Parkinson disease tremor can be recognized by most clinicians at the early stages for the initiation of disease specific medical therapies. Less common tremors, such as those induced by drugs or brain lesions, are also important to recognize because they may be more refractory to medical therapies and may require earlier referral to a neurological specialist. In patients with the most progressive and severe tremors that are resistant to medical therapies, surgical interventions are available and typically target deep brain regions with stimulation or lesioning. This Grand Rounds review describes the evaluation and evidence-based management of the most common tremors, essential tremor and Parkinson disease tremor. Copyright 2014 American Medical Association. All rights reserved.


Ravichandran K.S.,University of Virginia
Journal of Experimental Medicine | Year: 2010

Everyday we turnover billions of cells. The quick, efficient, and immunologically silent disposal of the dying cells requires a coordinated orchestration of multiple steps, through which phagocytes selectively recognize and engulf apoptotic cells. Recent studies have suggested an important role for soluble mediators released by apoptotic cells that attract phagocytes ("find-me" signals). New information has also emerged on multiple receptors that can recognize phosphatidylserine, the key "eat-me" signal exposed on the surface of apoptotic cells. This perspective discusses recent exciting progress, gaps in our understanding, and the conflicting issues that arise from the newly acquired knowledge. © 2010 Ravichandran.


DeBoer M.D.,University of Virginia
Nutrition | Year: 2010

Cachexia is a devastating syndrome of body wasting that is associated with multiple common chronic diseases including cancer, chronic kidney disease, and chronic heart failure. These underlying diseases are associated with increased levels of inflammatory cytokines and result in anorexia, increased resting energy expenditure, and loss of fat and lean body mass. Prior experiments have implicated the central melanocortin system in the hypothalamus with the propagation of these symptoms of cachexia. Pharmacologic blockade of this system using melanocortin antagonists causes attenuation of the signs of cachexia in laboratory models. Recent advances in our knowledge of this disease process have involved further elucidation of the pathophysiology of melanocortin activation and demonstration of the efficacy of melanocortin antagonists in new models of cachexia, including cardiac cachexia. In addition, small molecule antagonists of the melanocortin-4 receptor continue to be introduced, including ones with oral bioavailability. These developments generate optimism that melanocortin antagonism will be used to treat humans with disease-associated cachexia. However, to date, human application has remained elusive and it is unclear when we will know whether humans with cachexia would benefit from treatment with these compounds. © 2010 Elsevier Inc. All rights reserved.


Ruddiman W.F.,University of Virginia
Annual Review of Earth and Planetary Sciences | Year: 2013

The start of the period of large-scale human effects on this planet (the Anthropocene) is debated. The industrial view holds that most significant impacts have occurred since the early industrial era (∼1850), whereas the early-Anthropogenic view recognizes large impacts thousands of years earlier. This review focuses on three indices of global-scale human influence: forest clearance (and related land use), emissions of greenhouse gases (CO2 and CH4), and effects on global temperature. Because reliable, systematic land-use surveys are rare prior to 1950, most reconstructions for early-industrial centuries and prior millennia are hind casts that assume humans have used roughly the same amount of land per person for 7,000 years. But this assumption is incorrect. Historical data and new archeological databases reveal much greater per-capita land use in preindustrial than in recent centuries. This early forest clearance caused much greater preindustrial greenhouse-gas emissions and global temperature changes than those proposed within the industrial paradigm. © Copyright ©2013 by Annual Reviews. All rights reserved.


Joseph K.L.,University of Virginia
Energy Policy | Year: 2010

Ongoing theft, corruption, and an artificially decreased pricing structure have made it nearly impossible for the state utilities in India to improve power service. As a result, industrial consumers across India exit the state-run system and rely on their own on-site power generation in order to ensure a consistent and reliable source of electricity. The 2003 Electricity Act encourages further power production from these captive plants through its open access clause. By encouraging the growth of these captive power plants, politicians in India set up a dual-track economy, whereby state-run and market-run production exist side-by-side. This strategy allows politicians to encourage private sector involvement in the electricity market, without jeopardizing the support of key political constituencies at the state level. © 2009 Elsevier Ltd. All rights reserved.


Schroen A.T.,University of Virginia
The Journal of thoracic and cardiovascular surgery | Year: 2012

To develop a research productivity scoring program within an academic department of surgery that would help realign incentives to encourage and reward research. Although research is highly valued in the academic mission, financial incentives are generally aligned to reward clinical productivity. A formula assigning points for publications and extramural grants was created and used to award a research incentive payment proportional to the research productivity score, beginning July 2007. Publication points reflect journal impact factor, author role, and manuscript type. Grant points reflect total funding and percentage of effort. Publication data were gathered from Web of Science/PubMed/Medline and grants data from the departmental grants office. An annual award is presented to the person with the greatest improvement. The research productivity score data after July 2007 were compared with control data for the 2 preceding years. A 33-question survey to 28 clinical faculty was conducted after the first year to measure satisfaction and solicit constructive feedback. The mean annual point scores increased from the preresearch productivity score to the postresearch productivity score academic years (2180 vs 3389, respectively, P = .08), with a significant change in the grant component score (272 vs 801, P = .03). Since research productivity score implementation, the operative case volumes increased 4.3% from 2006 to 2011. With a response rate of 89%, the survey indicated that 76% of the faculty wished to devote more time to research and 52% believed 1 or more research-related behaviors would change because of the research productivity score program. An objective, transparent research incentive program, through both monetary incentives and recognition, can stimulate productivity and was well-received by faculty. Copyright © 2012 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.


Law D.R.,University of California at Los Angeles | Majewski S.R.,University of Virginia
Astrophysical Journal | Year: 2010

We present a new N-body model for the tidal disruption of the Sagittarius (Sgr) dwarf that is capable of simultaneously satisfying the majority of angular position, distance, and radial velocity constraints imposed by current wide-field surveys of its dynamically young (≲3Gyr) tidal debris streams. In particular, this model resolves the conflicting angular position and radial velocity constraints on the Sgr leading tidal stream that have been highlighted in recent years. While the model does not reproduce the apparent bifurcation observed in the leading debris stream, recent observational data suggest that this bifurcation may represent a constraint on the internal properties of the Sgr dwarf rather than the details of its orbit. The key element in the success of this model is the introduction of a non-axisymmetric component to the Galactic gravitational potential that can be described in terms of a triaxial dark matter halo whose minor/major axis ratio (c/a)Φ = 0.72 and intermediate/major axis ratio (b/a)Φ = 0.99 at radii 20 kpc < r < 60kpc. The minor/intermediate/major axes of this halo lie along the directions (l, b) = (7°, 0°), (0°, 90°), and (97°, 0°) respectively, corresponding to a nearly oblate ellipsoid whose minor axis is contained within the Galactic disk plane. This particular disk/halo orientation is difficult to reconcile within the general context of galactic dynamics (and cold dark matter models in particular), suggesting either that the orientation may have evolved significantly with time or that inclusion of other non-axisymmetric components (such as the gravitational influence of the Magellanic Clouds) in the model may obviate the need for triaxiality in the dark matter halo. The apparent proper motion of Sgr in this model is estimated to be (μlcos b, μb) = (-2.16, 1.73)masyr-1, corresponding to a Galactocentric space velocity (U, V, W) = (230, -35, 195) km s-1 . Based on the velocity dispersion in the stellar tidal streams, we estimate that Sgr has a current bound mass M Sgr = 2.5 +1.3 -1.0 × 108 M. We demonstrate that with simple assumptions about the star formation history of Sgr, tidal stripping models naturally give rise to gradients in the metallicity distribution function (MDF) along the stellar debris streams similar to those observed in recent studies. These models predict a strong evolution in the MDF of the model Sgr dwarf with time, indicating that the chemical abundances of stars in Sgr at the present day may be significantly different than the abundances of those already contributed to the Galactic stellar halo. We conclude by using the new N-body model to re-evaluate previous claims of the association of miscellaneous halo substructure with the Sgr dwarf. © 2010. The American Astronomical Society. All rights reserved.


Weber G.F.,University of Virginia | Bjerke M.A.,University of Virginia | DeSimone D.W.,University of Virginia
Journal of Cell Science | Year: 2011

Cell-cell and cell-extracellular-matrix (cell-ECM) adhesions have much in common, including shared cytoskeletal linkages, signaling molecules and adaptor proteins that serve to regulate multiple cellular functions. The term 'adhesive crosstalk' is widely used to indicate the presumed functional communication between distinct adhesive specializations in the cell. However, this distinction is largely a simplification on the basis of the non-overlapping subcellular distribution of molecules that are involved in adhesion and adhesion-dependent signaling at points of cell-cell and cell-substrate contact. The purpose of this Commentary is to highlight data that demonstrate the coordination and interdependence of cadherin and integrin adhesions. We describe the convergence of adhesive inputs on cell signaling pathways and cytoskeletal assemblies involved in regulating cell polarity, migration, proliferation and survival, differentiation and morphogenesis. Cell-cell and cell-ECM adhesions represent highly integrated networks of protein interactions that are crucial for tissue homeostasis and the responses of individual cells to their adhesive environments. We argue that the machinery of adhesion in multicellular tissues comprises an interdependent network of cell-cell and cell-ECM interactions and signaling responses, and not merely crosstalk between spatially and functionally distinct adhesive specializations within cells. © 2011. Published by The Company of Biologists Ltd.


Lillard A.S.,University of Virginia | Kavanaugh R.D.,Williams College
Child Development | Year: 2014

Theorists have speculated about the symbolic underpinnings of theory of mind (ToM), but no study has examined them across the main developmental span of ToM. Here, the onset of symbolic understandings in three domains (pretend play, language, and understanding representations) and ToM was examined. Fifty-eight children were tested on batteries of tasks four times from ages 2.5 to 5 years. Some significant interrelations among variables were seen at each age level. Canonical correlation analysis found that a subset of the symbolic variables was significantly related to ToM at ages 4 and 5, providing the best evidence to date that ToM is undergirded by a symbolic element that also supports language, pretend play, and representational understanding. © 2014 Society for Research in Child Development, Inc.


Santen R.J.,University of Virginia
Journal of Steroid Biochemistry and Molecular Biology | Year: 2014

Observational and randomized controlled trial data have extensively examined the relationship between menopausal hormone therapy (MHT) and risk of developing breast cancer. A highly influential study from the Women's Health Initiative (WHI) in 2002 reported that a MHT regimen of conjugated equine estrogens and medroxyprogesterone acetate increased the risk of breast cancer by 26%. Later reports from the WHI indicated that a MHT regimen with conjugated equine estrogens alone decreased the risk of breast cancer by 23%. Critical re-examination of the WHI study noted that the average participant age was 63, that few women had symptoms, and that the WHI results might not apply to younger, symptomatic women shortly after menopause. Since the original publications, several post hoc analyses and observational studies have stimulated reconsideration of the WHI findings. Emphasis has been directed toward risks in younger women just entering the menopause, the subgroup who are most likely to be considering MHT use. The goal of this treatise is to integrate available mechanistic and clinical information related to the use of estrogen alone or estrogen plus a progestogen for five years or less. These data suggest that estrogen alone neither decreases nor increases risk in younger women initiating therapy close to the time of menopause but decreases risk in older women. Both younger and older women experience an excess risk with estrogen plus a progestogen. The attributable risk in younger women is less in those with a low underlying Gail Model risk score. Effects of MHT on risk largely reflect actions on pre-existing, occult, undiagnosed breast cancers. Tumor kinetic models suggest that the pro-proliferative effects of estrogen plus a progestogen on occult tumors provide a mechanistic explanation for the increased risk with this therapy. Pro-apoptotic effects of estrogen alone may explain the reduction of breast cancer in women starting this therapy at an average age of 63 as reported in the WHI study. This article is part of a Special Issue entitled 'Menopause'. © 2013 Elsevier Ltd.


Herakovich C.T.,University of Virginia
Mechanics Research Communications | Year: 2012

This review is concerned with mechanics of continuous fiber composites. The earliest and most important advancements in the field are emphasized. No doubt the coverage is limited to some extent by the interests and experiences of the writer as well as time and space considerations. The advancements in mechanics of composites have been influenced to a great extent by the development of advanced composites through materials science. No attempt is made to discuss these developments. This review emphasizes the use of theoretical and applied mechanics in the development of theories, confirmed by experimentation, to predict the response of composite materials and structures. Citations have been given for many published works, but certainly not all. Apologies to those not listed; numerous additional references can be found in the works cited. © 2012 Elsevier Ltd.


Noonan D.,University of Virginia
Public Health Nursing | Year: 2010

Popularity of waterpipe smoking or hookah smoking in the United States has been growing for some time now among youth and young adults. Currently, many cities and states have exemptions that allow hookah bars to remain in operation despite the passage of clean indoor air legislation. From a public health perspective this is concerning for many reasons. One public health concern with the increase in popularity of this type of tobacco use is the associated health effects. Another concern is that hookah smoke produces a sweet smelling aroma making it less obvious that patrons and employees of hookah bars are inhaling noxious fumes from mainstream smoke, as well as the toxins from the charcoal that is used to heat the tobacco. The purpose of this paper is to discuss smoke-free air legislation in relation to hookah use, the public health implications of exempting hookah bars from current smoke-free legislation, and implications for the public health nurse in protecting the public from the dangers of second-hand smoke, and limiting this new form of tobacco use. © 2009 Wiley Periodicals, Inc.


Keith D.S.,University of Virginia
Seminars in Dialysis | Year: 2012

Recurrent idiopathic focal segmental glomerulosclerosis (FSGS) after renal transplantation can lead to a rapid failure of the allograft. A circulating, nonimmunoglobulin factor appears to be important in the pathogenesis of this complication in many cases. Between 30% and 50% of transplant recipients with FSGS develop recurrent disease. Three major risk factors for recurrence have been identified: short duration of native kidney disease, history of recurrence with previous kidney transplant, and pediatric aged recipients. Although no properly controlled trials have been conducted, plasmapheresis has emerged as one of the important treatment modalities for this entity. Retrospective studies prior to the routine use of plasmapheresis showed graft loss rates as high as 80%, a rate much higher than that seen in more recent series managed with plasmapheresis. Duration and intensity of treatment of plasmaphersis have not been studied rigorously, but in most case series, plasmapheresis was continued until a clear diminution of proteinuria was seen. The benefit of other adjuvant therapies for this condition remains unclear, but also may play a role in the treatment of this entity. © 2011 Wiley Periodicals, Inc.

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