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Madison, WI, United States

The University of Wisconsin–Madison is a selective public research university located in Madison, Wisconsin, United States. Founded when Wisconsin achieved statehood in 1848, UW–Madison is the official state university of Wisconsin, and the flagship campus of the University of Wisconsin System. It was the first public university established in Wisconsin and remains the oldest and largest public university in the state. It became a land-grant institution in 1866. The 933-acre main campus includes four National Historic Landmarks.UW–Madison is organized into 20 schools and colleges, which enrolled 29,504 undergraduate, 9,430 graduate, and 2,526 professional students and granted 6,494 bachelor's, 3,560 graduate and professional degrees in 2012-2013. The University employs over 21,727 faculty and staff. Its comprehensive academic program offers 132 undergraduate majors, along with 149 master's degree programs and 120 doctoral programs.The UW is categorized as an RU/VH Research University in the Carnegie Classification of Institutions of Higher Education. In 2012, it had research expenditures of more than $1.1 billion, the third highest among universities in the country. Wisconsin is a founding member of the Association of American Universities.The Wisconsin Badgers compete in 25 intercollegiate sports in the NCAA's Division I Big Ten Conference and have won 28 national championships. Wikipedia.


Ziegler T.E.,University of Wisconsin - Madison
American Journal of Primatology | Year: 2013

Most primates are social species whose reproduction is influenced by their social relationships. The cotton-top tamarin, Saguinus oedipus, and the common marmoset, Callithrix jacchus, are cooperative breeding species where the family structure alters reproductive function in many ways. While primates receive social effects on reproduction via all sensory stimuli, the marmosets and tamarins are particularly influenced by olfactory/chemosensory stimuli. The olfactory sensory processing is the "social glue" that keeps the family together. This review describes a number of studies using the marmosets and tamarins at the University of Wisconsin to demonstrate how odor cues are used for altering reproductive function and dysfunction. Several key studies will be discussed to show the role of odor signaling of the female reproductive state. The suppressive effects of odors are mediated by priming odors and can cause a suppressive influence on ovulation in young females via their mother's scents. Additionally, odor cues from the infant function as priming odors to ensure that fathers and mothers are present and receptive to their parental care duties. Neural pathways occur via the processing of priming odors that consequently stimulate alterations in the behavioral and endocrine response to the stimuli. The dynamics of the cooperative breeding system ensure that offspring have essential needs met and that they develop in a family environment. Olfactory communication plays a key role in maintenance of the social system of Callitrichid monkeys. © 2012 Wiley Periodicals, Inc. Source


Tononi G.,University of Wisconsin - Madison
Archives Italiennes de Biologie | Year: 2012

This article presents an updated account of integrated information theory of consciousness (IIT) and some of its implications. IIT stems from thought experiments that lead to phenomenological axioms and ontological postulates. The information axiom asserts that every experience is specific - it is what it is by differing in its particular way from a large repertoire of alternatives. The integration axiom asserts that each experience is unified - it cannot be reduced to independent components. The exclusion axiom asserts that every experience is definite - it is limited to particular things and not others and flows at a particular speed and resolution. IIT formalizes these intuitions with three postulates. The information postulate states that only "differences that make a difference" from the intrinsic perspective of a system matter: a mechanism generates cause-effect information if its present state has specific past causes and specific future effects within a system. The integration postulate states that only information that is irreducible matters: mechanisms generate integrated information only to the extent that the information they generate cannot be partitioned into that generated within independent components. The exclusion postulate states that only maxima of integrated information matter: a mechanism specifies only one maximally irreducible set of past causes and future effects - a concept. A complex is a set of elements specifying a maximally irreducible constellation of concepts, where the maximum is evaluated over elements and at the optimal spatio-temporal scale. Its concepts specify a maximally integrated conceptual information structure or quale, which is identical with an experience. Finally, changes in information integration upon exposure to the environment reflect a system's ability to match the causal structure of the world. After introducing an updated definition of information integration and related quantities, the article presents some theoretical considerations about the relationship between information and causation and about the relational structure of concepts within a quale. It also explores the relationship between the temporal grain size of information integration and the dynamic of metastable states in the corticothalamic complex. Finally, it summarizes how IIT accounts for empirical findings about the neural substrate of consciousness, and how various aspects of phenomenology may in principle be addressed in terms of the geometry of information integration. Source


Gilliland A.L.,University of Wisconsin - Madison
Midwifery | Year: 2011

Objective: to describe in detail the emotional support techniques employed by birth doulas during labour. Design: grounded theory methodology was utilised in collecting and analysing interviews given by doulas and mothers who had doula care. By using both informants, a clearer picture of what constitutes emotional support by doulas emerged. Participants: 10 mothers from three different states in the Midwestern USA and 30 doulas from 10 different states and two Canadian provinces were interviewed. Two doulas worked in hospital-based programmes whereas the others had independent practices. Doulas usually attended births in hospitals where medical attendants spent little focused time with the mother. Findings: nine different strategies were distinguished. Four strategies (reassurance, encouragement, praise, explaining) were similar to those attributed to nurses in published research. Five were original and described as only being used by doulas (mirroring, acceptance, reinforcing, reframing, debriefing). Conclusions: emotional support by professional birth doulas is more complex and sophisticated than previously surmised. Mothers experienced these strategies as extremely meaningful and significant with their ability to cope and influencing the course of their labour. Implications for practice: the doula's role in providing emotional support is distinct from the obstetric nurse and midwife. Professional doulas utilise intricate and complex emotional support skills when providing continuous support for women in labour. Application of these skills may provide an explanation for the positive 'doula effect' on obstetric and neonatal outcomes in certain settings. © 2010 Elsevier Ltd. Source


Johnson E.A.,University of Wisconsin - Madison
Applied Microbiology and Biotechnology | Year: 2013

Saccharomyces cerevisiae and several other yeast species are among the most important groups of biotechnological organisms. S. cerevisiae and closely related ascomycetous yeasts are the major producer of biotechnology products worldwide, exceeding other groups of industrial microorganisms in productivity and economic revenues. Traditional industrial attributes of the S. cerevisiae group include their primary roles in food fermentations such as beers, cider, wines, sake, distilled spirits, bakery products, cheese, sausages, and other fermented foods. Other long-standing industrial processes involving S. cerevisae yeasts are production of fuel ethanol, single-cell protein (SCP), feeds and fodder, industrial enzymes, and small molecular weight metabolites. More recently, non-Saccharomyces yeasts (non-conventional yeasts) have been utilized as industrial organisms for a variety of biotechnological roles. Non-Saccharomyces yeasts are increasingly being used as hosts for expression of proteins, biocatalysts and multi-enzyme pathways for the synthesis of fine chemicals and small molecular weight compounds of medicinal and nutritional importance. Non-Saccharomyces yeasts also have important roles in agriculture as agents of biocontrol, bioremediation, and as indicators of environmental quality. Several of these products and processes have reached commercial utility, while others are in advanced development. The objective of this mini-review is to describe processes currently used by industry and those in developmental stages and close to commercialization primarily from non-Saccharomyces yeasts with an emphasis on new opportunities. The utility of S. cerevisiae in heterologous production of selected products is also described. © 2012 Springer-Verlag Berlin Heidelberg. Source


Hollister S.J.,University of Michigan | Murphy W.L.,University of Wisconsin - Madison
Tissue Engineering - Part B: Reviews | Year: 2011

Translation of scaffold-based bone tissue engineering (BTE) therapies to clinical use remains, bluntly, a failure. This dearth of translated tissue engineering therapies (including scaffolds) remains despite 25 years of research, research funding totaling hundreds of millions of dollars, over 12,000 papers on BTE and over 2000 papers on BTE scaffolds alone in the past 10 years (PubMed search). Enabling scaffold translation requires first an understanding of the challenges, and second, addressing the complete range of these challenges. There are the obvious technical challenges of designing, manufacturing, and functionalizing scaffolds to fill the Form, Fixation, Function, and Formation needs of bone defect repair. However, these technical solutions should be targeted to specific clinical indications (e.g., mandibular defects, spine fusion, long bone defects, etc.). Further, technical solutions should also address business challenges, including the need to obtain regulatory approval, meet specific market needs, and obtain private investment to develop products, again for specific clinical indications. Finally, these business and technical challenges present a much different model than the typical research paradigm, presenting the field with philosophical challenges in terms of publishing and funding priorities that should be addressed as well. In this article, we review in detail the technical, business, and philosophical barriers of translating scaffolds from Concept to Clinic. We argue that envisioning and engineering scaffolds as modular systems with a sliding scale of complexity offers the best path to addressing these translational challenges. © 2011, Mary Ann Liebert, Inc. Source


Burdick J.A.,University of Pennsylvania | Murphy W.L.,University of Wisconsin - Madison
Nature Communications | Year: 2012

Hydrogels are water-swollen polymer networks that have found a range of applications from biological scaffolds to contact lenses. Historically, their design has consisted primarily of static systems and those that exhibit simple degradation. However, advances in polymer synthesis and processing have led to a new generation of dynamic systems that are capable of responding to artificial triggers and biological signals with spatial precision. These systems will open up new possibilities for the use of hydrogels as model biological structures and in tissue regeneration. © 2012 Macmillan Publishers Limited. All rights reserved. Source


Keller N.P.,University of Wisconsin - Madison
Nature Chemical Biology | Year: 2015

Filamentous fungi are renowned for the production of a diverse array of secondary metabolites (SMs) where the genetic material required for synthesis of a SM is typically arrayed in a biosynthetic gene cluster (BGC). These natural products are valued for their bioactive properties stemming from their functions in fungal biology, key among those protection from abiotic and biotic stress and establishment of a secure niche. The producing fungus must not only avoid self-harm from endogenous SMs but also deliver specific SMs at the right time to the right tissue requiring biochemical aid. This review highlights functions of BGCs beyond the enzymatic assembly of SMs, considering the timing and location of SM production and other proteins in the clusters that control SM activity. Specifically, self-protection is provided by both BGC-encoded mechanisms and non-BGC subcellular containment of toxic SM precursors; delivery and timing is orchestrated through cellular trafficking patterns and stress- and developmental-responsive transcriptional programs. © 2015 Nature America, Inc. All rights reserved. Source


Weimer P.J.,U.S. Department of Agriculture | Weimer P.J.,University of Wisconsin - Madison
Frontiers in Microbiology | Year: 2015

The ruminal microbial community is remarkably diverse, containing 100s of different bacterial and archaeal species, plus many species of fungi and protozoa. Molecular studies have identified a "core microbiome" dominated by phyla Firmicutes and Bacteroidetes, but also containing many other taxa. The rumen provides an ideal laboratory for studies on microbial ecology and the demonstration of ecological principles. In particular, the microbial community demonstrates both redundancy (overlap of function among multiple species) and resilience (resistance to, and capacity to recover from, perturbation). These twin properties provide remarkable stability that maintains digestive function for the host across a range of feeding and management conditions, but they also provide a challenge to engineering the rumen for improved function (e.g., improved fiber utilization or decreased methane production). Direct ruminal dosing or feeding of probiotic strains often fails to establish the added strains, due to intensive competition and amensalism from the indigenous residents that are well-adapted to the historical conditions within each rumen. Known exceptions include introduced strains that can fill otherwise unoccupied niches, as in the case of specialist bacteria that degrade phytotoxins such as mimosine or fluoroacetate. An additional complicating factor in manipulating the ruminal fermentation is the individuality or host specificity of the microbiota, in which individual animals contain a particular community whose species composition is capable of reconstituting itself, even following a near-total exchange of ruminal contents from another herd mate maintained on the same diet. Elucidation of the interactions between the microbial community and the individual host that establish and maintain this specificity may provide insights into why individual hosts vary in production metrics (e.g., feed efficiency or milk fat synthesis), and how to improve herd performance. © 2015 Weimer. Source


Westmark C.J.,University of Wisconsin - Madison
Molecular Psychiatry | Year: 2013

Accumulating evidence suggests that dysregulated levels of amyloid β-protein precursor (APP) and its catabolites contribute to the impaired synaptic plasticity and seizure incidence observed in several neurological disorders, including Alzheimer's disease, fragile X syndrome, Down's syndrome, autism, epilepsy and Parkinson's disease as well as in brain injury. This review article summarizes what is known regarding the synaptic synthesis, processing and function of APP and amyloid-beta (Aβ), as well as discusses how these proteins could contribute to the altered synaptic plasticity and pathology of the aforementioned disorders. In addition, APP and its proteolytic fragments are emerging as biomarkers for neurological health, and pharmacological interventions that modulate their levels, such as secretase inhibitors, passive immunotherapy against Aβ and mGluR 5 antagonists, are reviewed. © 2013 Macmillan Publishers Limited. Source


Serrano-Ruiz J.C.,University of Alicante | Dumesic J.A.,University of Wisconsin - Madison
Energy and Environmental Science | Year: 2011

Concerns about diminishing fossil fuel reserves along with global warming effects caused by increasing levels of CO2 in the atmosphere are driving society toward the search for new renewable sources of energy that can substitute for coal, natural gas and petroleum in the current energy system. Lignocellulosic biomass is abundant, and it has the potential to significantly displace petroleum in the production of fuels for the transportation sector. Ethanol, the main biomass-derived fuel used today, has benefited from production by a well-established technology and by partial compatibility with the current transportation infrastructure, leading to the domination of the world biofuel market. However, ethanol suffers from important limitations as a fuel (e.g., low energy density, high solubility in water) than can be overcome by designing strategies to convert non-edible lignocellulosic biomass into liquid hydrocarbon fuels (LHF) chemically similar to those currently used in internal combustion engines. The present review describes the main routes available to carry out such deep chemical transformation (e.g., gasification, pyrolysis, and aqueous-phase catalytic processing), with particular emphasis on those pathways involving aqueous-phase catalytic reactions. These latter catalytic routes achieve the required transformations in biomass-derived molecules with controlled chemistry and high yields, but require pretreatment/hydrolysis steps to overcome the recalcitrance of lignocellulose. To be economically viable, these aqueous-phase routes should be carried out with a small number of reactors and with minimum utilization of external fossil fuel-based hydrogen sources, as illustrated in the examples presented here. © 2011 The Royal Society of Chemistry. Source


Lalley P.M.,University of Wisconsin - Madison
Respiratory Physiology and Neurobiology | Year: 2013

Pulmonary structure and function change significantly between young adulthood and old age. Elastic elements of the lung degenerate, parenchymal tissue is lost, alveolar ducts and bronchioles dilate, chest wall compliance decreases, intercostal muscle mass and force are reduced and gas exchange surface lessens. Disturbances of innate immunity predispose the elderly to pulmonary inflammation. These changes affect pulmonary function tests and gas exchange, but adaptive changes in breathing frequency and tidal volume serve to maintain adequate ventilation. Aging depresses cough reflexes and ventilatory responsiveness to hypoxia and hypercapnia. Sleep-associated apnea and periodic breathing occur more frequently in the elderly, implying that neural feed back and feed-forward control (loop gain) are impaired. Low loop gain may contribute to sleep apnea but not to periodic breathing. A likely cause of age related pulmonary tissue degeneration and a future therapeutic target is defective protein folding in the endoplasmic reticulum. Nervous system adaptations that accompany structural and functional changes in the elderly are poorly understood. © 2013 Elsevier B.V. Source


Said A.,University of Wisconsin - Madison
World Journal of Gastroenterology | Year: 2013

Non-alcoholic fatty liver disease (NAFLD) is one of the most prevalent causes of chronic liver disease worldwide. In the last decade it has become the third most common indication for liver transplantation in the United States. Increasing prevalence of NAFLD in the general population also poses a risk to organ donation, as allograft steatosis can be associated with non-function of the graft. Post-transplant survival is comparable between NAFLD and non-NAFLD causes of liver disease, although long term outcomes beyond 10 year are lacking. NAFLD can recur in the allograft frequently although thus far post transplant survival has not been impacted. De novo NAFLD can also occur in the allograft of patients transplanted for non-NAFLD liver disease. Predictors for NAFLD post-transplant recurrence include obesity, hyperlipidemia and diabetes as well as steroid dose after liver transplantation. A polymorphism in PNPLA3 that mediates triglyceride hydrolysis and is linked to pre-transplant risk of obesity and NAFLD has also been linked to post transplant NAFLD risk. Although immunosuppression side effects potentiate obesity and the metabolic syndrome, studies of immunosuppression modulation and trials of specific immunosuppression regimens post-transplant are lacking in this patient population. Based on pre-transplant data, sustained weight loss through diet and exercise is the most effective therapy for NAFLD. Other agents occasionally utilized in NAFLD prior to transplantation include vitamin E and insulin-sensitizing agents. Studies of these therapies are lacking in the post-transplant population. A multimodality and multidisciplinary approach to treatment should be utilized in management of post-transplant NAFLD. © 2013 Baishideng Publishing Group Co., Limited. All rights reserved. Source


Stafstrom C.E.,University of Wisconsin - Madison
Current Opinion in Neurology | Year: 2010

Purpose of Review: The aim is to review rational polytherapy of antiepileptic drugs in terms of conventional and novel mechanisms of action, consider combinations that might be beneficial when used as polytherapy, and discuss whether animal models can predict clinical efficacy. Recent Findings: Many patients with epilepsy require concurrent treatment with more than one antiepileptic drug (rational polytherapy), but there is little information available as to which drugs might work best in combination. Conventional antiepileptic drugs act by blocking sodium channels or enhancing γ-aminobutyric acid function. Some newer antiepileptic drugs have novel mechanisms of action, including impairment of the slow inactivation of sodium channels, binding to the presynaptic vesicle protein SV2A, binding to the calcium channel α2δ subunit, and opening select potassium channels. Several antiepileptic drugs have multiple or uncertain mechanisms of action. Quantitative techniques such as isobolography can be used to compare the efficacy and side effects of antiepileptic drug combinations in animals. However, neither such methods nor antiepileptic drug mechanisms of action have yet proven useful in predicting clinical benefit in patients. Summary: Animal models can be used to help predict drug combinations that might be effective clinically, based on novel mechanisms of action. However, at this point, antiepileptic drug choice in patients with epilepsy remains empirical. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source


Ohler U.,Duke University | Wassarman D.A.,University of Wisconsin - Madison
Development | Year: 2010

Animal growth and development depend on the precise control of gene expression at the level of transcription. A central role in the regulation of developmental transcription is attributed to transcription factors that bind DNA enhancer elements, which are often located far from gene transcription start sites. Here, we review recent studies that have uncovered significant regulatory functions in developmental transcription for the TFIID basal transcription factors and for the DNA core promoter elements that are located close to transcription start sites. Source


Fredrickson D.C.,University of Wisconsin - Madison
Journal of the American Chemical Society | Year: 2012

Atomic size effects have long played a role in our empirical understanding of inorganic crystal structures. At the level of electronic structure calculations, however, the contribution of atomic size remains difficult to analyze, both alone and relative to other influences. In this paper, we extend the concepts outlined in a recent communication to develop a theoretical method for revealing the impact of the space requirements of atoms: the density functional theory-chemical pressure (DFT-CP) analysis. The influence of atomic size is most pronounced when the optimization of bonding contacts is impeded by steric repulsion at other contacts, resulting in nonideal interatomic distances. Such contacts are associated with chemical pressures (CPs) acting upon the atoms involved. The DFT-CP analysis allows for the calculation and interpretation of the CP distributions within crystal structures using DFT results. The method is demonstrated using the stability of the Ca 2Ag 7 structure over the simpler CaCu 5-type alternative adopted by its Sr-analogue, SrAg 5. A hypothetical CaCu 5-type CaAg 5 phase is found to exhibit large negative pressures on each Ca atom, which are concentrated in two symmetry-related interstitial spaces on opposite sides of the Ca nucleus. In moving to the Ca 2Ag 7 structure, relief comes to each Ca atom as a defect plane is introduced into one of these two negative-pressure regions, breaking the symmetry equivalence of the two sides and yielding a more compact Ca coordination environment. These results illustrate how the DFT-CP analysis can visually and intuitively portray how atomic size interacts with electronics in determining structure, and bridge theoretical and experimental approaches toward understanding the structural chemistry of inorganic materials. © 2012 American Chemical Society. Source


Hein P.P.,University of Wisconsin - Madison
Nature Structural and Molecular Biology | Year: 2014

The rates of RNA synthesis and the folding of nascent RNA into biologically active structures are linked via pausing by RNA polymerase (RNAP). Structures that form within the RNA-exit channel can either increase pausing by interacting with RNAP or decrease pausing by preventing backtracking. Conversely, pausing is required for proper folding of some RNAs. Opening of the RNAP clamp domain has been proposed to mediate some effects of nascent-RNA structures. However, the connections among RNA structure formation and RNAP clamp movement and catalytic activity remain uncertain. Here, we assayed exit-channel structure formation in Escherichia coli RNAP with disulfide cross-links that favor closed- or open-clamp conformations and found that clamp position directly influences RNA structure formation and RNAP catalytic activity. We report that exit-channel RNA structures slow pause escape by favoring clamp opening through interactions with the flap that slow translocation. Source


Veasey S.C.,University of Pennsylvania | Morgan B.J.,University of Wisconsin - Madison | O'Donnell C.P.,University of Pittsburgh
Physiological Reviews | Year: 2010

Sleep-induced apnea and disordered breathing refers to intermittent, cyclical cessations or reductions of airflow, with or without obstructions of the upper airway (OSA). In the presence of an anatomically compromised, collapsible airway, the sleep-induced loss of compensatory tonic input to the upper airway dilator muscle motor neurons leads to collapse of the pharyngeal airway. In turn, the ability of the sleeping subject to compensate for this airway obstruction will determine the degree of cycling of these events. Several of the classic neurotransmitters and a growing list of neuromodulators have now been identified that contribute to neurochemical regulation of pharyngeal motor neuron activity and airway patency. Limited progress has been made in developing pharmacotherapies with acceptable specificity for the treatment of sleep-induced airway obstruction. We review three types of major long-term sequelae to severe OSA that have been assessed in humans through use of continuous positive airway pressure (CPAP) treatment and in animal models via long-term intermittent hypoxemia (IH): 1) cardiovascular. The evidence is strongest to support daytime systemic hypertension as a consequence of severe OSA, with less conclusive effects on pulmonary hypertension, stroke, coronary artery disease, and cardiac arrhythmias. The underlying mechanisms mediating hypertension include enhanced chemoreceptor sensitivity causing excessive daytime sympathetic vasoconstrictor activity, combined with overproduction of superoxide ion and inflammatory effects on resistance vessels. 2) Insulin sensitivity and homeostasis of glucose regulation are negatively impacted by both intermittent hypoxemia and sleep disruption, but whether these influences of OSA are sufficient, independent of obesity, to contribute significantly to the "metabolic syndrome" remains unsettled. 3) Neurocognitive effects include daytime sleepiness and impaired memory and concentration. These effects reflect hypoxic-induced "neural injury." We discuss future research into understanding the pathophysiology of sleep apnea as a basis for uncovering newer forms of treatment of both the ventilatory disorder and its multiple sequelae. Copyright © 2010 the American Physiological Society. Source


Rivera-Rodriguez A.J.,University of Wisconsin - Madison
Quality & safety in health care | Year: 2010

To systematically review the peer-reviewed literature on interruptions in healthcare settings to determine the state of the science and to identify the gaps in research. Inclusion criteria were determined, and the online databases PubMed and Web of Knowledge-CrossSearch were searched. Thirty-three papers were reviewed. Several important findings were identified: (1) interruptions occur frequently in all healthcare settings, (2) an important gap exists: only seven studies examined outcomes related to interruptions, (3) interruptions in healthcare have only been studied from the viewpoint of the person being interrupted and (4) few studies explicitly or implicitly examined the cognitive implications of interruptions. The high frequency of interruptions coupled with information content may simply be indicative of the high need for constant communication and coordination in healthcare. Many interruptions may be necessary for safe, high-quality care; thus, trying to eliminate all interruptions is unwise. That said, there may be situations, such as during high-risk procedures, when limiting interruptions may be warranted. Taking a complex sociotechnical systems approach will help researchers view interruptions more holistically and will result in more comprehensive studies that take into account the complexity of interruptions and the many variables in healthcare settings. Source


Wright S.J.,University of Wisconsin - Madison
SIAM Journal on Optimization | Year: 2012

We discuss minimization of a smooth function to which is added a separable regularization function that induces structure in the solution. A block-coordinate relaxation approach with proximal linearized subproblems yields convergence to critical points, while identification of the optimal manifold (under a nondegeneracy condition) allows acceleration techniques to be applied on a reduced space. The work is motivated by experience with an algorithm for regularized logistic regression, and computational results for the algorithm on problems of this type are presented. © 2012 Society for Industrial and Applied Mathematics. Source


Gern J.E.,University of Wisconsin - Madison
Journal of Allergy and Clinical Immunology | Year: 2015

Recent advances in understanding environmental risk factors for allergic diseases in children have led to renewed efforts aimed at prevention. Factors that modify the probability of developing allergies include prenatal exposures, mode of delivery, diet, patterns of medication use, and exposure to pets and farm animals. Recent advances in microbial detection techniques demonstrate that exposure to diverse microbial communities in early life is associated with a reduction in allergic disease. In fact, microbes and their metabolic products might be essential for normal immune development. Identification of these risk factors has provided new targets for prevention of allergic diseases, and possibilities of altering microbial exposure and colonization to reduce the incidence of allergies is a promising approach. This review examines the rationale, feasibility, and potential effect for the prevention of childhood allergic diseases and explores possible strategies for enhancing exposure to beneficial microbes. © 2015 American Academy of Allergy, Asthma & Immunology. Source


Fairbairn M.,University of Wisconsin - Madison
Agriculture and Human Values | Year: 2012

Originally created by the international peasant movement La Vía Campesina, the concept of "food sovereignty" is being used with increasing frequency by agrifood activists and others in the Global North. Using the analytical lens of framing, I explore the effects of this diffusion on the transformative potential of food sovereignty. US agrifood initiatives have recently been the subject of criticism for their lack of transformative potential, whether because they offer market-based solutions rather than demanding political ones or because they fail to adequately address existing social injustice. In this paper, I consider how food sovereignty measures up to this critique both as it was originally framed by Vía Campesina and as it is being reframed for the US context. First I briefly compare food sovereignty to community food security (CFS), which was developed more explicitly for the North American context and has been criticized for its lack of transformative potential. I then explore how the potential of food sovereignty has been affected as it is reframed to resonate with US audiences through an examination of its use on the web sites of US-based organizations. I find that, while some reframing of the concept to highlight consumer choice does seem to be occurring, it remains a primarily political concept. It may not, however, be fulfilling its potential for addressing social injustice in the US agrifood system because it tends to be used either in reference to international issues or, when applied to the US context, treated as a rough synonym for local control. I conclude that, if advocates can successfully guide the reframing process, food sovereignty could serve as a valuable counter-hegemonic vision to complement the more pragmatic and locally-grounded work of CFS advocates. © 2011 Springer Science+Business Media B.V. Source


Chiu S.Y.,University of Wisconsin - Madison
Neuroscientist | Year: 2011

Myelinated axons conduct nerve impulses at high speed using a unique mode of excitation, referred to as saltatory conduction, which is enabled structurally by the narrowing of the site of action potentials to a tiny gap in the axon called the node of Ranvier. With this structural specialization comes an interesting metabolic matching problem. How do mitochondria find and supply energy to these tiny nodes of Ranvier distributed sparsely along a myelinated axon? Does the intense Na+ influx at the node, which is produced by the highest known sodium channel density in all excitable membranes, help guide where mitochondria stop? Evidence suggests that during excitation in the peripheral nervous system, Na+ influx recruits mitochondria to the node by triggering Ca2+ elevation and activating Na+ pumps. Intriguingly, indirect evidence suggests that in the central nervous system, activity recruits mitochondria to the internode (myelin-covered portion of the axon). Metabolic dysfunction thus might produce spatially distinct lesions in PNS and CNS myelinated fibers. Future dissection of regional variation in mitochondrial biology in myelinated axons using live imaging will likely yield surprises about sites of vulnerability in demyelinating diseases and clues for therapeutic intervention strategy. © The Author(s) 2011. Source


Meyers S.R.,University of Wisconsin - Madison | Hinnov L.A.,Johns Hopkins University
Paleoceanography | Year: 2010

Deterministic orbital controls on climate variability are commonly inferred to dominate across timescales of 104-106 years, although some studies have suggested that stochastic processes may be of equal or greater importance. Here we explicitly quantify changes in deterministic orbital processes (forcing and/or pacing) versus stochastic climate processes during the Plio-Pleistocene, via time-frequency analysis of two prominent foraminifera oxygen isotopic stacks. Our results indicate that development of the Northern Hemisphere ice sheet is paralleled by an overall amplification of both deterministic and stochastic climate energy, but their relative dominance is variable. The progression from a more stochastic early Pliocene to a strongly deterministic late Pleistocene is primarily accommodated during two transitory phases of Northern Hemisphere ice sheet growth. This long-term trend is punctuated by "stochastic events," which we interpret as evidence for abrupt reorganization of the climate system at the initiation and termination of the mid-Pleistocene transition and at the onset of Northern Hemisphere glaciation. In addition to highlighting a complex interplay between deterministic and stochastic climate change during the Plio-Pleistocene, our results support an early onset for Northern Hemisphere glaciation (between 3.5 and 3.7 Ma) and reveal some new characteristics of the orbital signal response, such as the puzzling emergence of 100 ka and 400 ka cyclic climate variability during theoretical eccentricity nodes. Copyright 2010 by the American Geophysical Union. Source


Shakun J.D.,Oregon State University | Carlson A.E.,University of Wisconsin - Madison
Quaternary Science Reviews | Year: 2010

While the abrupt climate events of the last deglaciation are well defined in ice core records from the polar regions of both hemispheres, their manifestation elsewhere is less well constrained. Here we compile 104 high-resolution paleoclimate records to characterize the timing and spatial pattern of climate change during the last deglaciation. This compilation indicates relatively concurrent timing of the Last Glacial Maximum (LGM; peak glacial conditions) and the Altithermal (peak interglacial conditions) in the Northern (22.1 ± 4.3. ka and 8.0 ± 3.2. ka) and Southern (22.3 ± 3.6. ka and 7.4 ± 3.7. ka) Hemispheres, suggesting the hemispheres were synchronized by greenhouse gases, local insolation, and/or Northern Hemisphere induced ocean circulation changes. The magnitude of the glacial-interglacial temperature change increases with latitude, reflecting the polar amplification of climate change, with a likely minimum global mean cooling of ∼-4.9 °C during the LGM relative to the Altithermal.Empirical orthogonal function (EOF) analysis of 71 records spanning 19-11ka indicates that two modes explain 72% of deglacial climate variability. EOF1 (61% of variance) shows a globally near-uniform pattern, with its principal component (PC1) strongly correlated with changes in atmospheric CO2. EOF2 (11% of variance) exhibits a bipolar seesaw pattern between the hemispheres, with its principal component (PC2) resembling changes in Atlantic meridional overturning circulation strength. EOF analysis of 90 records from 15 to 11ka indicates that northern and southern modes of climate variability characterize the Younger Dryas-Bølling/Allerød interval. These modes dominate at the higher latitudes of each hemisphere and exhibit a complex interaction in the tropics. The magnitude of the Younger Dryas climate anomaly (cooler/drier) increases with latitude in the Northern Hemisphere, with an opposite pattern (warmer/wetter) in the Southern Hemisphere reflecting a general bipolar seesaw climate response. Global mean temperature decreased by ∼0.6°C during the Younger Dryas. Therefore, our analysis supports the paradigm that while the Younger Dryas was a period of global climate change, it was not a major global cooling event but rather a manifestation of the bipolar seesaw driven by a reduction in Atlantic meridional overturning circulation strength. © 2010 Elsevier Ltd. Source


Yang J.,University of Wisconsin - Madison | Ozel O.,University of Maryland University College | Ulukus S.,University of Maryland University College
IEEE Transactions on Wireless Communications | Year: 2012

In this paper, we investigate the transmission completion time minimization problem in an additive white Gaussian noise (AWGN) broadcast channel, where the transmitter is able to harvest energy from the nature, using a rechargeable battery. The harvested energy is modeled to arrive at the transmitter during the course of transmissions. The transmitter has a fixed number of packets to be delivered to each receiver. The objective is to minimize the time by which all of the packets are delivered to their respective destinations. To this end, we optimize the transmit powers and transmission rates in a deterministic setting. We first analyze the structural properties of the optimal transmission policy in a two-user broadcast channel via the dual problem of maximizing the departure region by a fixed time T. We prove that the optimal total transmit power sequence has the same structure as the optimal single-user transmit power sequence in. In addition, the total power is split optimally based on a cut-off power level; if the total transmit power is lower than this cut-off level, all transmit power is allocated to the stronger user; otherwise, all transmit power above this level is allocated to the weaker user. We then extend our analysis to an M-user broadcast channel. We show that the optimal total power sequence has the same structure as the two-user case and optimally splitting the total power among M users involves M-1 cut-off power levels. Using this structure, we propose an algorithm that finds the globally optimal policy. Our algorithm is based on reducing the broadcast channel problem to a single-user problem as much as possible. Finally, we illustrate the optimal policy and compare its performance with several suboptimal policies under different settings. © 2012 IEEE. Source


Tononi G.,University of Wisconsin - Madison
Archives italiennes de biologie | Year: 2012

This article presents an updated account of integrated information theory of consciousness (liT) and some of its implications. /IT stems from thought experiments that lead to phenomenological axioms (existence, compositionality, information, integration, exclusion) and corresponding ontological postulates. The information axiom asserts that every experience is spec~fic - it is what it is by differing in its particular way from a large repertoire of alternatives. The integration axiom asserts that each experience is unified- it cannot be reduced to independent components. The exclusion axiom asserts that every experience is definite - it is limited to particular things and not others and flows at a particular speed and resolution. /IT formalizes these intuitions with postulates. The information postulate states that only "differences that make a difference" from the intrinsic perpective of a system matter: a mechanism generates cause-effect information if its present state has selective past causes and selective future effects within a system. The integration postulate states that only information that is irreducible matters: mechanisms generate integrated information only to the extent that the information they generate cannot be partitioned into that generated within independent components. The exclusion postulate states that only maxima of integrated information matter: a mechanism specifies only one maximally irreducible set of past causes and future effects - a concept. A complex is a set of elements specifying a maximally irreducible constellation of concepts, where the maximum is evaluated over elements and at the optimal spatiatemporal scale. Its concepts specify a maximally integrated conceptual information structure or quale, which is identical with an experience. Finally, changes in information integration upon exposure to the environment reflect a system's ability to match the causal structure of the world. After introducing an updated definition of information integration and related quantities, the article presents some theoretical considerations about the relationship between information and causation and about the relational structure of concepts within a qua/e. It also explores the relationship between the temporal grain size of information integration and the dynamic of metastable states in the corticothalamic complex. Finally, it summarizes how liT accounts for empirical findings about the neural substrate of consciousness, and how various aspects of phenomenology may in principle be addressed in terms of the geometry of information integration. Source


Pickhardt P.J.,University of Wisconsin - Madison
Current Opinion in Gastroenterology | Year: 2013

PURPOSE OF REVIEW: Computed tomography colonography (CTC) continues to mature and evolve as a noninvasive imaging test of the large intestine. The aim of this review is to provide an update on the recent and emerging data that further supports the clinical effectiveness of CTC. RECENT FINDINGS: The diagnostic performance of CTC for detecting colorectal polyps and masses is well established, but its precise clinical role is yet to be determined. Recent data on test performance, patient acceptance, and study technique may help to clarify the role of CTC and accelerate its clinical implementation. SUMMARY: Recent advances and refinements in CTC should help to clarify and expand its clinical role, both as a screening and diagnostic test. High patient acceptance for CTC could lead to increased adherence rates. Ultimately, the complementary nature of CTC and optical colonoscopy should result in improved patient care. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source


Vimont D.J.,University of Wisconsin - Madison
Journal of Climate | Year: 2010

The dynamics of thermodynamically coupled disturbances in the tropics that bear a strong resemblance to observed meridional mode variations are investigated using two simple linear coupled models. Both models involve an ocean equation coupled to the atmosphere via the linearized effect of zonal wind variations on the surface bulk latent heat flux. The two models differ in their atmospheric components, which consist of (i) a Gill-Matsuno style model of the free troposphere in which atmospheric heating is parameterized to be linearly proportional to sea surface temperature and (ii) a reduced-gravity model of the tropical boundary layer in which SST anomalies are associated with hydrostatic pressure perturbations throughout the boundary layer. Both atmospheric models follow the standard shallow-water equations on an equatorial beta plane. Growth rates and propagation of coupled disturbances are calculated and diagnosed via eigenanalysis of the linear models and singular value decomposition of the Green's function for each model. It is found that the eigenvectors of either model are all damped, not orthogonal, and not particularly meaningful in understanding observed tropical coupled variability. The nonnormality of the system, however, leads to transient growth over a time period of about 100 days (based on the choice of parameters in this study). The idealized initial and final conditions that experience this transient growth resemble observed tropical meridional mode variations and tend to propagate equatorward and westward in accord with findings from previous theoretical and modeling studies. Instantaneous growth rates and propagation characteristics of idealized transient disturbances are diagnosed via the linearized atmospheric potential vorticity equation and via propagation characteristics of atmospheric equatorial Rossby waves. Constraints on the poleward extent of initial conditions or imposed steady forcing that can lead to tropical meridional mode variations are identified through analysis of the steady coupled equations. Three constraints limit the poleward extent of forcing that can generate tropical meridional mode variations: (i) a dynamical constraint imposed by the damping rate of the temperature equation as well as the propagation speed of the mode along its wave characteristic; (ii) a constraint imposed by the effectiveness of zonal wind variations in generating surface latent heat flux anomalies; and (iii) the surface moisture convergence, which limits the poleward extent and strength of ocean to atmosphere coupling. © 2010 American Meteorological Society. Source


Wald A.,University of Wisconsin - Madison
Clinical Gastroenterology and Hepatology | Year: 2014

Fecal incontinence is one of the most emotionally devastating of all nonfatal conditions. Many patients do not respond satisfactorily to conservative measures, and there is a need for new and effective strategies when medical therapy fails. The development of sacral nerve stimulation and other forms of neuromodulation and the injection of biologically compatible substances into the anal sphincter complex have brought renewed enthusiasm for using these novel treatments in this underserved population. Because injectable bulking agents such as dextranomer in stabilized hyaluronic acid can be administered in an outpatient setting, this procedure is being marketed to both gastroenterologists and surgeons. This article reviews both sacral nerve stimulation and dextranomer bulking agents and compares their strengths and potential limitations in patients with fecal incontinence. © 2014 AGA Institute. Source


Bockheim J.G.,University of Wisconsin - Madison
Geomorphology | Year: 2010

Compared to mid-latitude deserts, the properties, formation and evolution of desert pavements and the underlying vesicular layer in Antarctica are poorly understood. This study examines the desert pavements and the vesicular layer from seven soil chronosequences in the Transantarctic Mountains that have developed on two contrasting parent materials: sandstone-dolerite and granite-gneiss. The pavement density commonly ranges from 63 to 92% with a median value of 80% and does not vary significantly with time of exposure or parent material composition. The dominant size range of clasts decreases with time of exposure, ranging from 16-64. mm on Holocene and late Quaternary surfaces to 8-16. mm on surfaces of middle Quaternary and older age. The proportion of clasts with ventifaction increases progressively through time from 20% on drifts of Holocene and late Quaternary age to 35% on Miocene-aged drifts. Desert varnish forms rapidly, especially on dolerite clasts, with nearly 100% cover on surfaces of early Quaternary and older age. Macropitting occurs only on clasts that have been exposed since the Miocene. A pavement development index, based on predominant clast-size class, pavement density, and the proportion of clasts with ventifaction, varnish, and pits, readily differentiated pavements according to relative age. From these findings we judge that desert pavements initially form from a surficial concentration of boulders during till deposition followed by a short period of deflation and a longer period of progressive chemical and physical weathering of surface clasts. The vesicular layer that underlies the desert pavement averages 4. cm in thickness and is enriched in silt, which is contributed primarily by weathering rather than eolian deposition. A comparison is made between desert pavement properties in mid-latitude deserts and Antarctic deserts. © 2010 Elsevier B.V. Source


Desai A.R.,University of Wisconsin - Madison
Journal of Geophysical Research: Biogeosciences | Year: 2010

The climate sensitivity of plant seasonal life cycles, or phenology, may impart significant carbon cycle feedbacks on climatic change. Analysis of interannual ecosystem carbon exchange provides one way to assess this climate sensitivity. Multiyear eddy covariance carbon dioxide flux observations from five different ecosystems (deciduous forest, northern hardwood mixed forest, old-growth forest, shrub wetland, and mixed wetland-forest) in the Upper Great Lakes, United States, located within 400 km of each other and exhibiting coherent interannual variability, were used to parameterize a simple ecosystem model. The model, when properly constrained with an interannual sensitive cost function, was able to explain a significant proportion of the interannual variation of carbon fluxes in all ecosystems except the old-growth forest. The results reveal that spring or autumn climate thresholds impact annual carbon uptake, though the magnitude and strength varied by site. When the model was forced to maintain the same climate-phenology relationship across the five sites, most of the interannual variability could still be explained except at the old-growth forest and the forest farthest in distance from the others. These results suggest that at least for this region, coarse spatial resolution carbon-climate models could likely specify general climate-phenological relationships at grid scales on order of 100 km without appreciably sacrificing ability to model interannual carbon cycling. Copyright 2010 by the American Geophysical Union. Source


Wang X.,University of Wisconsin - Madison
Nature Materials | Year: 2015

Topological defects in liquid crystals (LCs) have been widely used to organize colloidal dispersions and template polymerization, leading to a range of assemblies, elastomers and gels. However, little is understood about molecular-level assembly processes within defects. Here, we report that nanoscopic environments defined by LC topological defects can selectively trigger processes of molecular self-assembly. By using fluorescence microscopy, cryogenic transmission electron microscopy and super-resolution optical microscopy, we observed signatures of molecular self-assembly of amphiphilic molecules in topological defects, including cooperativity, reversibility and controlled growth. We also show that nanoscopic o-rings synthesized from Saturn-ring disclinations and other molecular assemblies templated by defects can be preserved by using photocrosslinkable amphiphiles. Our results reveal that, in analogy to other classes of macromolecular templates such as polymer–surfactant complexes, topological defects in LCs are a versatile class of three-dimensional, dynamic and reconfigurable templates that can direct processes of molecular self-assembly. © 2015 Nature Publishing Group Source


Vakil N.,University of Wisconsin - Madison
Drugs | Year: 2012

Proton pump inhibitors (PPIs) are among the most widely used agents in the world. The prevalence of reflux disease is increasing, as is the incidence of oesophageal adenocarcinoma, a complication that is strongly correlated with chronic reflux disease. Although these agents are generally safe, a number of potential side effects have been described and a careful assessment of the risks and benefits of PPI therapy is required in all patients being prescribed long-term therapy.Overutilization of PPIs is a problem in clinical practice and needs further attention. PPI use has been associated with osteoporosis and bone fracture, hypomagnesaemia, the development of gastric polyps, enteric infections, interstitial nephritis and pneumonia. Patients on long-term therapy should be periodically evaluated for the indications for continued therapy. Despite widespread publicity in the lay press, and regulatory guidance regarding a number of associations, the evidence for serious side effects is poor and the risk of confounding remains a real possibility for many associations. Patients are more concerned about the absolute risk of developing a complication than a relative risk. The absolute risk of all the complications attributed to PPIs is low and patients who need long-term PPI therapy need a clear discussion of the available data on the risk of therapy and also a discussion of the risk of continued reflux. © 2012 Adis Data Information BV. All rights reserved. Source


Barrett B.,University of Wisconsin - Madison
Journal of General Internal Medicine | Year: 2012

Medical decision-making involves choices, which can lead to benefits or to harms. Most benefits and harms may or may not occur, and can be minor or major when they do. Medical research, especially randomized controlled trials, provides estimates of chance of occurrence and magnitude of event. Because there is no universally accepted method for weighing harms against benefits, and because the ethical principle of autonomy mandates informed choice by patient, medical decision-making is inherently an individualized process. It follows that the practice of aiming for universal implementation of standardized guidelines is irrational and unethical. Irrational because the possibility of benefits is implicitly valued more than the possibility of comparable harms, and unethical because guidelines remove decision making from the patient and give it instead to a physician, committee or health care system. This essay considers the cases of cancer screening and diabetes management, where guidelines often advocate universal implementation, without regard to informed choice and individual decision-making. © 2011 Society of General Internal Medicine. Source


Pellett S.,University of Wisconsin - Madison
Current Opinion in Microbiology | Year: 2012

Botulinum neurotoxins are the most poisonous substances known to humankind, but also are the bacterial toxins most frequently used as pharmaceuticals to benefit humans. The discovery of botulinum toxins and development into a useful drug is unique and fascinating, dating back to the early 19th century, when Justinus Kerner first recognized that botulism was caused by a biological toxin and suggested its use for medicinal purposes. This was translated into reality in 1980, when Alan Scott for the first time used the toxins to successfully treat strabismus. Now a subset of botulinum toxins are widely used for cosmetic applications, treatment of various movement disorders, pain and many other syndromes, and further developments using other botulinum toxins or recombinant molecules engineered from subdomains are promising. © 2012 Elsevier Ltd. Source


Christens B.D.,University of Wisconsin - Madison
American Journal of Community Psychology | Year: 2012

Psychological empowerment has been theorized as a construct with emotional, behavioral and cognitive components. Yet, many studies have stressed that empowerment processes are contingent on interpersonal relationships. Moreover, theory suggests that power is developed and exercised through relationships. This article makes the case that expanding our conceptions of psychological empowerment through the addition of a relational component can enhance our understanding of psychological empowerment and the effectiveness of empowerment-oriented community practice. Previous research on empowerment is reviewed for relational content, and additional insights into the relational context of empowerment processes are marshaled from other concepts in community research including social capital, sense of community, social networks, social support, and citizen participation. A new iteration of the nomological network for psychological empowerment is presented, including the elements of a relational component. © 2011 Society for Community Research and Action. Source


Wald A.,University of Wisconsin - Madison
JAMA - Journal of the American Medical Association | Year: 2016

Importance Chronic constipation accounts for at least 8 million annual visits to health care providers in the United States and is associated with large expenditures for diagnostic testing and prescription and nonprescription laxatives. OBSERVATIONS Strong evidence for efficacy has been established for stimulant and osmotic laxatives, new intestinal secretogogues, and peripherally restricted ì-opiate receptor antagonists, the latter a major advance in the treatment of opioid-induced constipation (OIC). An algorithm provided to evaluate chronic idiopathic constipation (CIC) that is refractory to available laxatives focuses on the importance of defecation disorders and biofeedback therapies. When used appropriately, available stimulant laxatives such as senna and bisacodyl are both safe and effective when used long-term. There is a paucity of (and a strong desire for) studies that compare inexpensive laxatives with newer agents that work by other mechanisms. Conclusions and Relevance The choice of treatment for CIC and OIC should be based on cost as well as efficacy. The small subgroup of patients who do not respond to currently available laxatives requires further evaluation at experienced centers that are capable of performing studies of defecation and colonic transit. © 2016 American Medical Association. All rights reserved. Source


Miller A.H.,Emory University | Raison C.L.,University of Wisconsin - Madison
Nature Reviews Immunology | Year: 2016

Crosstalk between inflammatory pathways and neurocircuits in the brain can lead to behavioural responses, such as avoidance and alarm, that are likely to have provided early humans with an evolutionary advantage in their interactions with pathogens and predators. However, in modern times, such interactions between inflammation and the brain appear to drive the development of depression and may contribute to non-responsiveness to current antidepressant therapies. Recent data have elucidated the mechanisms by which the innate and adaptive immune systems interact with neurotransmitters and neurocircuits to influence the risk for depression. Here, we detail our current understanding of these pathways and discuss the therapeutic potential of targeting the immune system to treat depression. © 2015 Macmillan Publishers Limited. Source


Wiegmann D.A.,University of Wisconsin - Madison
Annals of Surgery | Year: 2016

Efforts to implement quality improvements in surgery are notoriously problematic.1,2 One needs to look no farther than recent attempts to implement checklists, team training, and surgical briefings. These interventions have been empirically shown to improve team communication and performance.3,4 Yet numerous barriers to implementation have limited their broad adoption and use. Apparently, knowing the remedy (intervention) does not translate into knowing how to administer (implement) it.5 Or in surgical terms, knowing "what" procedure needs to be performed does not necessarily mean that one knows "how" to perform it. Surgeons serve a vital leadership role in driving quality and patient safety initiatives in the operating room. Achieving success requires both an in-depth understanding of the intervention and the complex dynamics of the elements involved in the implementation process. To aid in this endeavor, the present article describes a Model for Understanding System Transitions Associated with the Implementation of New Goals (MUSTAING). The model highlights important variables associated with implementation success. It also provides a tool for diagnosing why certain interventions may not have worked as intended so that improvements in the implementation process can be made. Finally, the model offers a general framework for guiding future implementation or "how to" research. © Copyright 2015 Wolters Kluwer Health, Inc. All rights reserved. Source


Shah P.,University of Wisconsin - Madison | Parrilo P.A.,Massachusetts Institute of Technology
IEEE Transactions on Automatic Control | Year: 2013

We develop a complete state-space solution to ℋ2-optimal decentralized control of poset-causal systems with state-feedback. Our solution is based on the exploitation of a key separability property of the problem that enables an efficient computation of the optimal controller by solving a small number of uncoupled standard Riccati equations. Our approach gives important insight into the structure of optimal controllers, such as controller degree bounds that depend on the structure of the poset. A novel element in our state-space characterization of the controller is an intuitive description of the controller as an aggregation of local control laws. © 1963-2013 IEEE. Source


Michaelsen K.F.,Copenhagen University | Greer F.R.,University of Wisconsin - Madison
American Journal of Clinical Nutrition | Year: 2014

The objective of this review was to summarize selected health aspects of protein intake during the first 2 y of life. During this period there is a marked increase in protein intake from an intake of ∼5% of energy from protein (PE%) in an exclusively breastfed infant to ∼15 PE% when complementary foods have been introduced. At this age, mean protein intake is ∼3 times as high as the physiologic requirement, but some children receive 4-5 times their physiologic requirement. Protein from cow milk constitutes a main part of protein intake in toddlers and seems to have a specific effect on insulin-like growth factor I concentrations and growth. Meat has a high protein content, but the small amounts of meat needed to ensure good iron status have less impact on total protein intake. The difference in protein intake between breastfed and formula-fed infants is likely to play a role in the difference between breastfed and formula-fed infants. There is emerging evidence that high protein intake during the first 2 y of life is a risk factor for later development of overweight and obesity. It therefore seems prudent to avoid a high protein intake during the first 2 y of life. This could be accomplished by decreasing the upper allowable limit of the protein content of infant formulas for the first year of life and limiting the intake of cow milk in the second year of life. © 2014 American Society for Nutrition. Source


Dell H.,Humboldt University of Berlin | Van Melkebeek D.,University of Wisconsin - Madison
Proceedings of the Annual ACM Symposium on Theory of Computing | Year: 2010

Consider the following two-player communication process to decide a language L: The first player holds the entire input x but is polynomially bounded; the second player is computationally unbounded but does not know any part of x; their goal is to cooperatively decide whether x belongs to L at small cost, where the cost measure is the number of bits of communication from the first player to the second player. For any integer d ≥ 3 and positive real ∈ we show that if satisfiability for n-variable d-CNF formulas has a protocol of cost O(nd-∈) then coNP is in NP/poly, which implies that the polynomial-time hierarchy collapses to its third level. The result even holds when the first player is conondeterministic, and is tight as there exists a trivial protocol for ∈ = 0. Under the hypothesis that coNP is not in NP/poly, our result implies tight lower bounds for parameters of interest in several areas, namely sparsification, kernelization in parameterized complexity, lossy compression, and probabilistically checkable proofs. By reduction, similar results hold for other NP-complete problems. For the vertex cover problem on n-vertex d-uniform hypergraphs, the above statement holds for any integer d ≥ 2. The case d=2 implies that no NP-hard vertex deletion problem based on a graph property that is inherited by subgraphs can have kernels consisting of O(k2-∈) edges unless coNP is in NP/poly, where k denotes the size of the deletion set. Kernels consisting of O(k2) edges are known for several problems in the class, including vertex cover, feedback vertex set, and bounded-degree deletion. © 2010 ACM. Source


Marin-Spiotta E.,University of Wisconsin - Madison | Sharma S.,York University
Global Ecology and Biogeography | Year: 2013

Aim: To analyse global patterns in soil carbon (C) in tropical successional and plantation forests based on climate, forest age, former land use and soil type to determine factors driving below-ground C storage. Location: Pantropical. Methods: We conducted a synthesis of 81 studies reporting soil C stocks in more than 400 reforested and tree plantation sites. We used regression models and regression tree analyses to determine the importance of multiple predictor variables on soil C stocks standardized to three common depth ranges: 0-10, 0-30 and 0-100cm. Results: Mean annual temperature (MAT) was the most important predictor of soil C. Forest age explained little to no variability in soil C, in contrast with above-ground studies. Data on long-term trends in soil C are limited, as median time since forest growth was 15 years. Soil C stocks were similar between tropical secondary forests, tree plantations and reference forests. Differences between plantation and successional forests only appeared below 10cm on sites with MAT < 21.3°C. Former pastures and cultivated sites differed from each other only to depths of 30 or 100cm. Climatic variables appeared multiple times across all layers of the regression trees, consistent with strong interactions between MAT and precipitation on soil C stocks. Main conclusions: Climate explained greater variability in soil C in successional and plantation forests than former land use or forest age, despite the tropical location of all sites. Human management factors were more important for predicting soil C stocks in cooler and drier sites, while environmental variables were more important in hotter and wetter sites. The relative importance and interactions between soil type, previous land use and forest cover type differed with soil depth, highlighting the importance of comparing C across consistent depths. © 2012 Blackwell Publishing Ltd. Source


Lavis L.D.,Howard Hughes Medical Institute | Raines R.T.,University of Wisconsin - Madison
ACS Chemical Biology | Year: 2014

Small-molecule fluorophores manifest the ability of chemistry to solve problems in biology. As we noted in a previous review (Lavis, L. D.; Raines, R. T. ACS Chem. Biol. 2008, 3, 142-155), the extant collection of fluorescent probes is built on a modest set of "core" scaffolds that evolved during a century of academic and industrial research. Here, we survey traditional and modern synthetic routes to small-molecule fluorophores and highlight recent biological insights attained with customized fluorescent probes. Our intent is to inspire the design and creation of new high-precision tools that empower chemical biologists. © 2014 American Chemical Society. Source


Eide D.J.,University of Wisconsin - Madison
Metallomics | Year: 2011

Zinc is an essential catalytic and structural cofactor for many enzymes and other proteins. While Zn2+ is not redox active under physiological conditions, it has been known for many years that zinc deficiency causes increased oxidative stress and, consequently, increased oxidative damage to DNA, proteins, and lipids. These results have indicated that zinc plays an indirect antioxidant role and that dietary inadequacy may contribute to human diseases such as cancer. Recent studies are helping to identify the primary sources of oxidative stress in low zinc. In addition, through studies of the model eukaryotic cell, Saccharomyces cerevisiae, we are now beginning to understand the strategies cells use to limit this stress and reduce its damage. © 2011 The Royal Society of Chemistry. Source


Halzen F.,University of Wisconsin - Madison
Nature Physics | Year: 2016

The chargeless, weakly interacting neutrinos are ideal astronomical messengers as they travel through space without scattering, absorption or deflection. But this weak interaction also makes them notoriously difficult to detect, leading to neutrino observatories requiring large-scale detectors. A few years ago, the IceCube experiment discovered neutrinos originating beyond the Sun with energies bracketed by those of the highest energy gamma rays and cosmic rays. I discuss how these high-energy neutrinos can be detected and what they can tell us about the origins of cosmic rays and about dark matter. © 2016 Nature Publishing Group Source


Fredrickson D.C.,University of Wisconsin - Madison
Journal of the American Chemical Society | Year: 2011

The assignment of distinct roles to electronics and sterics has a long history in our rationalization of chemical phenomena. Exploratory synthesis in the field of intermetallic compounds challenges this dichotomy with a growing list of phases whose structural chemis ry points to an interplay between atomic size effects and orbital interactions. In this paper, we begin with a simple model for how this interdependence may arise in the dense atomic packing of intermetallics: correlations between interatomic distances lead to the inability of a phase to optimize bonds without simultaneously shortening electronically under-supported contacts, a conflict we term electronic packing frustration (EPF). An anticipated consequence of this frustration is the emergence of chemical pressures (CPs) acting on the affected atoms. We develop a theoretical method based on DFT-calibrated μ2-Hückel calculations for probing these CP effects. Applying this method to the Ca2Ag 7 structure, a variant of the CaCu5 type with defect planes, reveals its formation is EPF-driven. The defect planes resolve severe CPs surrounding the Ca atoms in a hypothetical CaCu5-type CaAg 5 phase. CP analysis also points to a rationale for these results in terms of a CP analogue of the pressure-distance paradox and predicts that the impetus for defect plane insertion is tunable via variations in the electron count. © 2011 American Chemical Society. Source


Eide D.J.,University of Wisconsin - Madison
Science signaling | Year: 2012

An often-asked question is, Why are there so many different transporters in a cell to take up a particular substrate? At least part of the answer comes from work on the possible competitive advantage of dual-transporter systems. In such systems, low-affinity transporters function when a nutrient is plentiful in the environment, and the abundance of high-affinity transporters is increased when that nutrient becomes scarce. A dual-transporter system enabled a long "preparation phase" to occur during which cells induce gene expression as they become increasingly starved. Surprisingly, the preparation phase is important not for growth under low-nutrient conditions but rather for fluctuating nutrient amounts as commonly occurs in nature. Thus, this creative study provides a previously unconsidered explanation for the abundance of dual-transporter systems in biology. Source


Johnson R.A.,University of Wisconsin - Madison
Veterinary Anaesthesia and Analgesia | Year: 2014

Objective: To evaluate the efficacy of maropitant for prevention of vomiting and gastroesophageal reflux (GER) in dogs following acepromazine-hydromorphone premedication and inhalation anesthesia. Study design: Randomized, blinded, prospective clinical study. Animals: Twenty-six dogs admitted for elective soft tissue or orthopedic procedures that were 3.1 ±3.1 years of age and weighed 20.5 ± 11.4 kg. Methods: Dogs were randomly assigned to one of two groups: Group M received maropitant (1.0 mg kg-1) and Group S received 0.9% saline (0.1 mL kg-1) intravenously 45-60 minutes before premedication with hydromorphone (0.1 mg kg-1) and acepromazine (0.03 mg kg-1) intramuscularly. An observer blinded to treatment documented any retching or vomiting for 20 minutes before induction with propofol (2-6 mg kg-1) and inhalation anesthesia. A pH probe inserted into the distal esophagus was used to detect GER. Results: None of the dogs in Group M retched or vomited (0/13), 6/13 (46%) in Group S were observed to retch or vomit, and the difference between groups was significant (p = 0.015). There were no differences between groups in the number of dogs with GER (Group M: 4/13, Group S: 6/13 dogs) or the number of reflux events. Esophageal pH at the end of anesthesia was significantly lower in both M and S groups in dogs with GER versus dogs without GER (p = 0.004 and 0.011, respectively). Only dogs with GER in Group S had significantly lower pH at the end compared to the beginning of anesthesia (p = 0.004). Conclusions and clinical relevance: Intravenous maropitant prevented retching and vomiting associated with acepromazine-hydromorphone premedication. Maropitant did not prevent the occurrence of GER. Fewer dogs in Group M developed GER but further study with a larger number of dogs is necessary to determine if there is a significant difference. © 2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia. Source


Thein-Nissenbaum J.,University of Wisconsin - Madison
Maturitas | Year: 2013

In the past 40 years, female sports participation, particularly at the high school level, has significantly increased. Physical activity in females has numerous positive benefits, including improved body image and overall health. Unfortunately, a select population of exercising females may experience symptoms related to the female athlete triad, which refers to the interrelatedness of energy availability, menstrual function, and bone mineral density. Clinically, these conditions can manifest as disordered eating behaviors, menstrual irregularity, and stress fractures. Triad symptoms are distributed along a spectrum between optimal health and disease; all of the components of the triad may not be affected simultaneously. The female athlete triad was first identified in 1992. Since that time, a vast amount of research related to the identification, management and prevention of this condition has been published. More recently, research related to the long term effects of triad components has come into light. Women who were diagnosed with female athlete triad syndrome as adolescents and young adults in the 1990s are now in their 30s and 40s; negative long term effects of the female athlete triad, such as low bone mineral density, are now starting to manifest. Women of all ages should be assessed for triad components during routine annual physical examinations; appropriate measures to treat any current triad components should be implemented. In addition, women in their 30s, 40s and early 50s should be screened for a history of the female athlete triad. Multidisciplinary management of these conditions is strongly recommended. © 2013 Elsevier Ireland Ltd. Source


Blankenbaker D.G.,University of Wisconsin - Madison
Seminars in musculoskeletal radiology | Year: 2010

Muscle injuries are common and often occur during sport or training. The sonographic and magnetic resonance (MR) imaging appearance of muscle injures help to categorize the degree of muscle injury and when the athlete can return to play. The recent advances in ultrasound technology producing images of exquisite detail allow diagnosis of muscle injury with similar accuracy as MR imaging. Muscle injury may be divided into acute and chronic pathology, with muscle strain injury the most common clinical problem presenting to sports physicians. This article reviews the MR Imaging and ultrasound appearance of muscle injuries ranging from acute to chronic injuries, as well as the appearance of normal healing and the complications that can occur from muscle strain injuries. Source


Chu C.,University of Wisconsin - Madison
PloS one | Year: 2012

The influenza virus RNA polymerase complex is a heterotrimer composed of the PB1, PB2, and PA subunits. PB1, the catalytic core and structural backbone of the polymerase, possesses four highly conserved amino acid motifs that are present among all viral RNA-dependent RNA polymerases. A previous study demonstrated the importance of several of these conserved amino acids in PB1 for influenza polymerase activity through mutational analysis. However, a small number of viruses isolated in nature possesses non-consensus amino acids in one of the four motifs, most of which have not been tested for their replicative ability. Here, we assessed the transcription/replication activities of 25 selected PB1 mutations found in natural isolates by using minireplicon assays in human and avian cells. Most of the mutations tested significantly reduced polymerase activity. One exception was mutation K480R, observed in several pandemic (H1N1) 2009 viruses, which slightly increased polymerase activity relative to wild-type. However, in the background of the pandemic A/California/04/2009 (H1N1) virus, this mutation did not affect virus titers in cell culture. Our results further demonstrate the functional importance of the four conserved PB1 motifs in influenza virus transcription/replication. The finding of natural isolates with non-consensus PB1 motifs that are nonfunctional in minireplicon assays suggests compensatory mutations and/or mixed infections which may have 'rescued' the inactive PB1 protein. Source


Terasawa E.,University of Wisconsin - Madison
Advances in experimental medicine and biology | Year: 2013

Since the discovery of the G-protein coupled receptor 54 (kisspeptin receptor) and its ligand, kisspeptin, our understanding of the neurobiological mechanisms that govern the pituitary-gonadal axis has evolved dramatically. In this chapter, we have reviewed progress regarding the relationship between kisspeptin and puberty, and have proposed a novel hypothesis for the role of kisspeptin signaling in the onset of this crucial developmental event. According to this hypothesis, although kisspeptin neurons in the arcuate nucleus (ARC) are critical for puberty, this is simply because these cells are an integral component of the hypothalamic GnRH pulse generating mechanism that drives intermittent release of the decapeptide, as an increase in GnRH is obligatory for the onset of puberty. In our model, ARC kisspeptin neurons play no "regulatory" role in controlling the timing of puberty. Rather, as a component of the neural network responsible for GnRH pulse generation, they subserve upstream regulatory mechanisms that are responsible for the timing of puberty. Source


Chemical signaling mediates nearly all aspects of species interactions. Our knowledge of these signals has progressed dramatically, and now includes good characterizations of the bioactivities, modes of action, biosynthesis, and genetic programming of numerous compounds affecting a wide range of species. A major challenge now is to integrate this information so as to better understand actual selective pressures under natural conditions, make meaningful predictions about how organisms and ecosystems will respond to a changing environment, and provide useful guidance to managers who must contend with difficult trade-offs among competing socioeconomic values. One approach is to place stronger emphasis on cross-scale interactions, an understanding of which can help us better connect pattern with process, and improve our ability to make mechanistically grounded predictions over large areas and time frames. The opportunity to achieve such progress has been heightened by the rapid development of new scientific and technological tools. There are significant difficulties, however: Attempts to extend arrays of lower-scale processes into higher scale functioning can generate overly diffuse patterns. Conversely, attempts to infer process from pattern can miss critically important lower-scale drivers in systems where their biological and statistical significance is negated after critical thresholds are breached. Chemical signaling in bark beetle - conifer interactions has been explored for several decades, including by the two pioneers after whom this award is named. The strong knowledge base developed by many researchers, the importance of bark beetles in ecosystem functioning, and the socioeconomic challenges they pose, establish these insects as an ideal model for studying chemical signaling within a cross-scale context. This report describes our recent work at three levels of scale: interactions of bacteria with host plant compounds and symbiotic fungi (tree level, biochemical time), relationships among inducible and constitutive defenses, population dynamics, and plastic host-selection behavior (stand level, ecological time), and climate-driven range expansion of a native eruptive species into semi-naïve and potentially naïve habitats (geographical level, evolutionary time). I approach this problem by focusing primarily on one chemical group, terpenes, by emphasizing the curvilinear and threshold-structured basis of most underlying relationships, and by focusing on the system's feedback structure, which can either buffer or amplify relationships across scales. © 2013 Springer Science+Business Media New York. Source


Kent K.C.,University of Wisconsin - Madison
New England Journal of Medicine | Year: 2014

A 76-year-old woman presents with a 2-day history of left-lower-quadrant pain. A computed tomographic (CT) scan reveals diverticulitis and an incidental 5.6-cm infrarenal abdominal aortic aneurysm. Her medical history is notable for hypertension, hypercholesterolemia, and obesity. She is a current smoker, with an 80 pack-year history. How should her case be managed? Copyright © 2014 Massachusetts Medical Society. Source


Cabrera V.E.,University of Wisconsin - Madison
Animal | Year: 2014

The objective of this review paper was to summarise the latest findings in dairy cattle reproductive economics with an emphasis on high yielding, confined total mixed ration systems. The economic gain increases as the reproductive efficiency improves. These increments follow the law of diminishing returns, but are still positive even at high reproductive performance. Reproductive improvement results in higher milk productivity and, therefore, higher milk income over feed cost, more calf sales and lower culling and breeding expenses. Most high-yielding herds in the United States use a combination of timed artificial insemination (TAI) and oestrous detection (OD) reproductive programme. The ratio of achievable pregnancies between OD and TAI determines the economic value difference between both and their combinations. Nonetheless, complex interactions between reproductive programme, herd relative milk yield, and type of reproductive programme are reported. For example, higher herd relative milk yield would favour programme relying more on TAI. In addition, improved reproductive efficiency produces extra replacements. The availability of additional replacements could allow more aggressive culling policies (e.g. less services for non-pregnant cows) to balance on-farm supply and demand of replacements. Balancing heifer replacement availability in an efficient reproductive programme brings additional economic benefits. New technologies such as the use of earlier chemical tests for pregnancy diagnosis could be economically effective depending on the goals and characteristics of the farm. Opportunities for individual cow reproductive management within defined reproductive programme exist. These decisions would be based on economic metrics derived from the value of a cow such as the value of a new pregnancy, the cost of a pregnancy loss, or the cost of an extra day open. © 2014 The Animal Consortium. Source


Houle J.N.,University of Wisconsin - Madison
Psychosomatic Medicine | Year: 2013

OBJECTIVE: To examine the relationship between depressive symptoms and all-cause mortality in a longitudinal study with a nationally representative sample. Research has shown that depressive symptoms increase mortality risk, but results have been inconclusive regarding the role of physical health conditions in the relationship. This study asks whether the association between depressive symptoms and mortality exists independent of contemporaneous physical health conditions, is spurious because of prior physical health conditions, or is mediated by later physical health conditions. METHODS: Data are drawn from the Americans' Changing Lives Study, a sample of 3617 noninstitutionalized Americans aged 25 years or older. Respondents were interviewed in 1986, 1989, 1994, and 2002. Depressive symptoms (Center for Epidemiologic Studies Depression Scale [CES-D]), physical health, and confounders were measured at each wave. Mortality status was ascertained yearly through 2007. Discrete time hazard models with time-varying covariates were used to estimate the association between CES-D scores and mortality. RESULTS: Between 1986 and 2007, 1411 survey respondents died. Depressive symptoms were associated with mortality after adjusting for stress, coping characteristics, social support, and health behaviors (odds ratio [OR] = 1.23, 95% confidence interval [CI] = 1.11-1.36, p < .001). However, the association became nonsignificant after accounting for contemporaneous physical health conditions (OR = 1.06, 95% CI = 0.95-1.17, p = .31). Prior physical health conditions did not explain the association (OR = 1.24, 95% CI = 1.11-1.39, p < .001). The association between lagged depressive symptoms and mortality was mediated by later physical health conditions (p = .94). CONCLUSIONS: Study findings support the mediation hypothesis. The effect of depressive symptoms on mortality is mediated by later physical health. Copyright © 2013 by the American Psychosomatic Society. Source


Lee C.E.,University of Wisconsin - Madison
Evolutionary Applications | Year: 2016

The study of the copepod Eurytemora affinis has provided unprecedented insights into mechanisms of invasive success. In this invited review, I summarize a subset of work from my laboratory to highlight key insights gained from studying E. affinis as a model system. Invasive species with brackish origins are overrepresented in freshwater habitats. The copepod E. affinis is an example of such a brackish invader, and has invaded freshwater habitats multiple times independently in recent years. These invasions were accompanied by the evolution of physiological tolerance and plasticity, increased body fluid regulation, and evolutionary shifts in ion transporter (V-type H+ ATPase, Na+, K+-ATPase) activity and expression. These evolutionary changes occurred in parallel across independent invasions in nature and in laboratory selection experiments. Selection appears to act on standing genetic variation during invasions, and maintenance of this variation is likely facilitated through 'beneficial reversal of dominance' in salinity tolerance across habitats. Expression of critical ion transporters is localized in newly discovered Crusalis leg organs. Increased freshwater tolerance is accompanied by costs to development time and greater requirements for food. High-food concentration increases low-salinity tolerance, allowing saline populations to invade freshwater habitats. Mechanisms observed here likely have relevance for other taxa undergoing fundamental niche expansions. © 2016 John Wiley & Sons Ltd. Source


Burns M.E.,University of Wisconsin - Madison
Psychiatric Services | Year: 2015

Approximately one-third of adults who enroll in Medicaid because of a disability have a serious mental illness. Arguably, this population stands to bene fi t from insurance coverage that complies with the Mental Health Parity and Addiction Equity Act (MHPAEA). The MHPAEA and the Affordable Care Act (ACA) do not guarantee such coverage for this bene fi ciary group; however, they provide a variety of mechanisms by which statesmay provide parity-compliant coverage for mental health and substance use disorder treatment. This column explains key interactions between the MHPAEA, the ACA, and the Medicaid program that permit states to determine whether and how to provide parity-consistent coverage to bene ficiaries with disabilities. © 2015, American Psychiatric Association. All rights reserved. Source


Brace C.L.,University of Wisconsin - Madison
Medical Physics | Year: 2011

Purpose: Design and validate an efficient dual-slot coaxial microwave ablation antenna that produces an approximately spherical heating pattern to match the shape of most abdominal and pulmonary tumor targets.Methods: A dual-slot antenna geometry was utilized for this study. Permutations of the antenna geometry using proximal and distal slot widths from 1 to 10 mm separated by 1-20 mm were analyzed using finite-element electromagnetic simulations. From this series, the most optimal antenna geometry was selected using a two-term sigmoidal objective function to minimize antenna reflection coefficient and maximize the diameter-to-length aspect ratio of heat generation. Sensitivities to variations in tissue properties and insertion depth were also evaluated in numerical models. The most optimal dual-slot geometry of the parametric analysis was then fabricated from semirigid coaxial cable. Antenna reflection coefficients at various insertion depths were recorded in ex vivo bovine livers and compared to numerical results. Ablation zones were then created by applying 50 W for 2-10 min in simulations and ex vivo livers. Mean zone diameter, length, aspect ratio, and reflection coefficients before and after heating were then compared to a conventional monopole antenna using ANOVA with post-hoc t-tests. Statistical significance was indicated for P < 0.05.Results: Antenna performance was highly sensitive to dual-slot geometry. The best-performing designs utilized a proximal slot width of 1 mm, distal slot width of 4 mm ± 1 mm and separation of 8 mm ± 1 mm. These designs were characterized by an active choking mechanism that focused heating to the distal tip of the antenna. A dual-band resonance was observed in the most optimal design, with a minimum reflection coefficient of -20.9 dB at 2.45 and 1.25 GHz. Total operating bandwidth was greater than 1 GHz, but the desired heating pattern was achieved only near 2.45 GHz. As a result, antenna performance was robust to changes in insertion depth and variations in relative permittivity of the surrounding tissue medium. In both simulations and ex vivo liver, the dual-slot antenna created ablations greater in diameter than a coaxial monopole (35 mm ± 2 mm versus 31 mm ± 2 mm; P < 0.05), while also shorter in length (49 mm ± 2 mm versus 60 mm ± 6 mm; P < 0.001) after 10 min. Similar results were obtained after 2 and 5 min as well.Conclusions: Dual-slot antennas can produce more spherical ablation zones while retaining low reflection coefficients. These benefits are obtained without adding to the antenna diameter. Further evaluation for clinical microwave ablation appears warranted. © 2011 American Association of Physicists in Medicine. Source


Backonja M.,University of Wisconsin - Madison
The oncologist | Year: 2010

In the majority of patients, existing therapies for neuropathic pain are far from effective. Furthermore, all current treatments are symptomatic rather than disease-modifying or curative. A range of therapeutic modalities is emerging, targeting a variety of mechanisms, but choosing the best target and evaluating the resulting therapies against the many types of neuropathic pain disorders is not an easy task. In this article, we suggest a shift in emphasis of the drug discovery paradigm toward unbiased evaluation of the particular neurobiological mechanisms contributing to neuropathic pain in individual patients. Genomewide association studies and other discovery science approaches to identify significant novel targets should be given priority as should the development of increasingly sophisticated tools for measuring and categorizing neuropathic pain. Source


Skinner J.L.,University of Wisconsin - Madison
Theoretical Chemistry Accounts | Year: 2011

A theoretical/computational framework for determining vibrational energy relaxation rates, pathways, and mechanisms, for small molecules and ions in liquids, is presented. The framework is based on the system-bath coupling approach, Fermi's golden rule, classical time-correlation functions, and quantum correction factors. We provide results for three specific problems: relaxation of the oxygen stretch in neat liquid oxygen at 77 K, relaxation of the water bend in chloroform at room temperature, and relaxation of the azide ion anti-symmetric stretch in water at room temperature. In each case, our calculated lifetimes are in reasonable agreement with experiment. In the latter two cases, theory for the observed solvent isotope effects illuminates the relaxation pathways and mechanisms. Our results suggest several propensity rules for both pathways and mechanisms. © 2010 Springer-Verlag. Source


Gregoire V.,Catholic University of Louvain | Jeraj R.,University of Wisconsin - Madison | Lee J.A.,Catholic University of Louvain | O'Sullivan B.,University of Toronto
The Lancet Oncology | Year: 2012

Intensity-modulated radiation therapy (IMRT) is a conformal irradiation technique that enables steep dose gradients. In head and neck tumours this approach spares parotid-gland function without compromise to treatment efficacy. Anatomical and molecular imaging modalities may be used to tailor treatment by enabling proper selection and delineation of target volumes and organs at risk, which in turn lead to dose prescriptions that take into account the underlying tumour biology (eg, human papillomavirus status). Therefore, adaptations can be made throughout the course of radiotherapy, as required. Planned dose increases to parts of the target volumes may also be used to match the radiosensitivity of tumours (so-called dose-painting), assessed by molecular imaging. For swift implementation of tailored and adaptive IMRT, tools and procedures, such as accurate image acquisition and reconstruction, automatic segmentation of target volumes and organs at risk, non-rigid image and dose registration, and dose summation methods, need to be developed and properly validated. © 2012 Elsevier Ltd. Source


De Smet A.A.,University of Wisconsin - Madison
American Journal of Roentgenology | Year: 2012

OBJECTIVE. The goal of this article is to summarize the literature about the diagnosis of meniscal tears on MRI including the normal appearance of the meniscus and the appearance of the various types of meniscal tears. In addition, I discuss my experience with the causes of errors in the MR diagnosis of meniscal abnormalities and the nuances of meniscal abnormalities that can mimic a meniscal tear. CONCLUSION. MRI is a highly accurate imaging method for diagnosing meniscal tears. To avoid errors in diagnosing meniscal tears, those interpreting MR examinations of the knee need to be aware of the attachments of the menisci and the normal variations in meniscal anatomy that may resemble a meniscal tear. In addition, by being aware of the patterns of meniscal tears, it is easier to diagnose the less common tears. © American Roentgen Ray Society. Source


Storz G.,Eunice Kennedy Shriver National Institute of Child Health and Human Development | Vogel J.,University of Wurzburg | Wassarman K.,University of Wisconsin - Madison
Molecular Cell | Year: 2011

Research on the discovery and characterization of small, regulatory RNAs in bacteria has exploded in recent years. These sRNAs act by base pairing with target mRNAs with which they share limited or extended complementarity, or by modulating protein activity, in some cases by mimicking other nucleic acids. Mechanistic insights into how sRNAs bind mRNAs and proteins, how they compete with each other, and how they interface with ribonucleases are active areas of discovery. Current work also has begun to illuminate how sRNAs modulate expression of distinct regulons and key transcription factors, thus integrating sRNA activity into extensive regulatory networks. In addition, the application of RNA deep sequencing has led to reports of hundreds of additional sRNA candidates in a wide swath of bacterial species. Most importantly, recent studies have served to clarify the abundance of remaining questions about how, when, and why sRNA-mediated regulation is of such importance to bacterial lifestyles. © 2011 Elsevier Inc. Source


Bacharier L.B.,University of Washington | Guilbert T.W.,University of Wisconsin - Madison
Journal of Allergy and Clinical Immunology | Year: 2012

Asthma is a common disease in young children and is associated with significant morbidity and an increasing prevalence over time. Early childhood wheezing and asthma are heterogeneous disorders; thus identifying phenotypes of asthma remains a goal to identify high-risk children who might benefit from specific therapies or secondary prevention interventions. The typical pattern of illness in preschool-aged children consists of short but recurrent exacerbations of cough and wheeze usually triggered by viral respiratory tract infections. Documenting reversible airflow obstruction on lung function, allergen sensitization, increased IgE levels, or blood eosinophilia is helpful in establishing a diagnosis of asthma in preschool-aged children, if present; however, the diagnosis is most often based on symptom patterns, presence of risk factors, and therapeutic responses. The preschool-aged asthmatic population tends to be characterized as exacerbation prone with relatively limited impairment, unlike older children and adolescents who have more impairment-dominant disease. However, management of persistent disease is based largely on expert opinion and extrapolation from studies in older children given the relative lack of data in this age group. Strategies used to manage intermittent disease include daily and intermittent controller therapy. Management strategies for persistent asthma include daily inhaled corticosteroids, daily leukotriene receptor antagonists, and combination therapies. Finally, regular monitoring of symptom control and medication side effects is important along with titrating controllers to the minimally effective dose. © 2012 American Academy of Allergy, Asthma & Immunology. Source


Ryff C.D.,University of Wisconsin - Madison
Psychotherapy and Psychosomatics | Year: 2013

This article reviews research and interventions that have grown up around a model of psychological well-being generated more than two decades ago to address neglected aspects of positive functioning such as purposeful engagement in life, realization of personal talents and capacities, and enlightened self-knowledge. The conceptual origins of this formulation are revisited and scientific products emerging from 6 thematic areas are examined: (1) how well-being changes across adult development and later life; (2) what are the personality correlates of well-being; (3) how well-being is linked with experiences in family life; (4) how well-being relates to work and other community activities; (5) what are the connections between well-being and health, including biological risk factors, and (6) via clinical and intervention studies, how psychological well-being can be promoted for ever-greater segments of society. Together, these topics illustrate flourishing interest across diverse scientific disciplines in understanding adults as striving, meaning-making, proactive organisms who are actively negotiating the challenges of life. A take-home message is that increasing evidence supports the health protective features of psychological well-being in reducing risk for disease and promoting length of life. A recurrent and increasingly important theme is resilience - the capacity to maintain or regain well-being in the face of adversity. Implications for future research and practice are considered. © 2013 S. Karger AG, Basel. Source


Vakil N.,University of Wisconsin - Madison
Best Practice and Research: Clinical Gastroenterology | Year: 2010

Gastro-esophageal reflux disease is a global problem and affects children, adolescents and adults. The incidence of the disease appears to be increasing particularly in Asia where reflux disease has not traditionally been a major health problem in the past. Recent consensus efforts to define and classify the disease in both adults and children make it possible to obtain epidemiologic and natural history data using a universally acceptable definition and classification. © 2010 Elsevier Ltd. All rights reserved. Source


Davis K.W.,University of Wisconsin - Madison
Radiologic Clinics of North America | Year: 2010

Injuries to pediatric athletes, which are becoming increasingly common, take the form of acute injuries and chronic overuse injuries. Acute injuries of the lower extremity include avulsions of the pelvic apophyses, muscle-tendon injuries, transient dislocation of the patella, ankle sprains, and acute tears of the anterior cruciate ligament and menisci. Magnetic resonance (MR) imaging of the latter 2 injuries should approach the accuracy of MR imaging of the adult knee. Chronic overuse injuries of the lower extremity in this age group include stress fractures, which are most common in the tibia; ankle impingement syndromes; osteochondritis dissecans of the knee and osteochondral lesions of the talus; and traction apophysitis, most commonly presenting as Osgood-Schlatter disease and Sinding-Larsen-Johannson disease, affecting the patellar tendon. Imaging findings of all these lesions are characteristic, and allow radiologists to assist their clinical colleagues in diagnosing and treating pediatric athletic injuries. © 2010 Elsevier Inc. Source


Davis K.W.,University of Wisconsin - Madison
Radiologic Clinics of North America | Year: 2010

With increasing youth participation in organized sports, more injuries in this age group are being treated by primary care and sports medicine physicians. Overuse injuries are much more common now than in past decades, with Little League shoulder, Little League elbow, and gymnast wrist being particular concerns. Rotator cuff tears and glenoid labral injuries, once thought to be rare in this age group, are also more common now. Osteochondritis dissecans of the elbow is relatively common and typically fares poorly without surgery. Wrist abnormalities that occur nowadays include triangular fibrocartilage tears. Tendonitis, which is now observed frequently in clinical practice in this age group, rarely requires imaging. © 2010 Elsevier Inc. Source


Ozdogan M.,University of Wisconsin - Madison
Hydrology and Earth System Sciences | Year: 2011

This study investigates the effects of projected climate change on snow water availability in the Euphrates-Tigris basin using the Variable Infiltration Capacity (VIC) macro scale hydrologic model and a set of regional climate-change outputs from 13 global circulation models (GCMs) forced with two greenhouse gas emission scenarios for two time periods in the 21st century (2050 and 2090). The hydrologic model produces a reasonable simulation of seasonal and spatial variation in snow cover and associated snow water equivalent (SWE) in the mountainous areas of the basin, although its performance is poorer at marginal snow cover sites. While there is great variation across GCM outputs influencing snow water availability, the majority of models and scenarios suggest a significant decline (between 10 and 60 percent) in available snow water, particularly under the high-impact A2 climate change scenario and later in the 21st century. The changes in SWE are more stable when multi-model ensemble GCM outputs are used to minimize inter-model variability, suggesting a consistent and significant decrease in snow-covered areas and associated water availability in the headwaters of the Euphrates-Tigris basin. Detailed analysis of future climatic conditions point to the combined effects of reduced precipitation and increased temperatures as primary drivers of reduced snowpack. Results also indicate a more rapid decline in snow cover in the lower elevation zones than the higher areas in a changing climate but these findings also contain a larger uncertainty. The simulated changes in snow water availability have important implications for the future of water resources and associated hydropower generation and land-use management and planning in a region already ripe for interstate water conflict. While the changes in the frequency and intensity of snow-bearing circulation systems or the interannual variability related to climate were not considered, the simulated changes in snow water availability presented here are likely to be indicative of climate change impacts on the water resources of the Euphrates-Tigris basin. © 2011 Author(s). Source


Halzen F.,University of Wisconsin - Madison
Rivista del Nuovo Cimento | Year: 2013

Detecting neutrinos associated with the still enigmatic sources of cosmic rays has reached a new watershed with the completion of IceCube, the first detector with sensitivity to the anticipated fluxes. In this review, we will briefly revisit the rationale for constructing kilometer-scale neutrino detectors and summarize the status of the field. © Società Italiana di Fisica. Source


Svaren J.,University of Wisconsin - Madison
Neurochemistry International | Year: 2014

Several recent studies have addressed the important role of microRNA in regulation of differentiation of myelinating glia. While Schwann cells and oligodendrocytes in the peripheral and central nervous systems, respectively, exhibit significant morphological and regulatory differences, some aspects of transcriptional and microRNA regulation are shared between these two cell types. This review focuses on the intersection of microRNAs with transcriptional regulation in Schwann cell and oligodendrocyte differentiation. In particular, several microRNAs have been shown to modulate expression of critical transcription factors, and in turn, the regulation of microRNA expression is enmeshed within transcriptional networks that coordinate both coding gene and noncoding RNA profiles of myelinating cells. These hubs of regulation control both myelin gene expression as well as the cell cycle transitions of Schwann cells and oligodendrocytes as they terminally differentiate. In addition, some studies have begin to highlight the combinatorial effects of different microRNAs that establish the narrow range of gene regulation required for efficient and stable myelin formation. Overall, the integration of microRNA and transcriptional aspects will help elucidate mechanistic control of the myelination process. © 2014 Elsevier Ltd. All rights reserved. Source


Saltzman W.,University of California at Riverside | Ziegler T.E.,University of Wisconsin - Madison
Journal of Neuroendocrinology | Year: 2014

In the 5-10% of mammals in which both parents routinely provide infant care, fathers as well as mothers undergo systematic endocrine changes as they transition into parenthood. Although fatherhood-associated changes in such hormones and neuropeptides as prolactin, testosterone, glucocorticoids, vasopressin and oxytocin have been characterised in only a small number of biparental rodents and primates, they appear to be more variable than corresponding changes in mothers, and experimental studies typically have not provided strong or consistent evidence that these endocrine shifts play causal roles in the activation of paternal care. Consequently, their functional significance remains unclear. We propose that endocrine changes in mammalian fathers may enable males to meet the species-specific demands of fatherhood by influencing diverse aspects of their behaviour and physiology, similar to many effects of hormones and neuropeptides in mothers. We review the evidence for such effects, focusing on recent studies investigating whether mammalian fathers in biparental species undergo systematic changes in (i) energetics and body composition; (ii) neural plasticity, cognition and sensory physiology; and (iii) stress responsiveness and emotionality, all of which may be mediated by endocrine changes. The few published studies, based on a small number of rodent and primate species, suggest that hormonal and neuropeptide alterations in mammalian fathers might mediate shifts in paternal energy balance, body composition and neural plasticity, although they do not appear to have major effects on stress responsiveness or emotionality. Further research is needed on a wider variety of biparental mammals, under more naturalistic conditions, to more fully determine the functional significance of hormone and neuropeptide profiles of mammalian fatherhood and to clarify how fatherhood may trade off with (or perhaps enhance) aspects of organismal function in biparental mammals. © 2014 British Society for Neuroendocrinology. Source


Wolk A.B.,Yale University | Leavitt C.M.,Yale University | Garand E.,University of Wisconsin - Madison | Johnson M.A.,Yale University
Accounts of Chemical Research | Year: 2014

The use of mass spectrometry in macromolecular analysis is an incredibly important technique and has allowed efficient identification of secondary and tertiary protein structures. Over 20 years ago, Chemistry Nobelist John Fenn and co-workers revolutionized mass spectrometry by developing ways to non-destructively extract large molecules directly from solution into the gas phase. This advance, in turn, enabled rapid sequencing of biopolymers through tandem mass spectrometry at the heart of the burgeoning field of proteomics. In this Account, we discuss how cryogenic cooling, mass selection, and reactive processing together provide a powerful way to characterize ion structures as well as rationally synthesize labile reaction intermediates. This is accomplished by first cooling the ions close to 10 K and condensing onto them weakly bound, chemically inert small molecules or rare gas atoms. This assembly can then be used as a medium in which to quench reactive encounters by rapid evaporation of the adducts, as well as provide a universal means for acquiring highly resolved vibrational action spectra of the embedded species by photoinduced mass loss. Moreover, the spectroscopic measurements can be obtained with readily available, broadly tunable pulsed infrared lasers because absorption of a single photon is sufficient to induce evaporation. We discuss the implementation of these methods with a new type of hybrid photofragmentation mass spectrometer involving two stages of mass selection with two laser excitation regions interfaced to the cryogenic ion source.We illustrate several capabilities of the cryogenic ion spectrometer by presenting recent applications to peptides, a biomimetic catalyst, a large antibiotic molecule (vancomycin), and reaction intermediates pertinent to the chemistry of the ionosphere. First, we demonstrate how site-specific isotopic substitution can be used to identify bands due to local functional groups in a protonated tripeptide designed to stereoselectively catalyze bromination of biaryl substrates. This procedure directly reveals the particular H-bond donor and acceptor groups that enforce the folded structure of the bare ion as well as provide contact points for noncovalent interaction with substrates. We then show how photochemical hole-burning involving only vibrational excitations can be used in a double-resonance mode to systematically disentangle overlapping spectra that arise when several conformers of a dipeptide are prepared in the ion source. Finally, we highlight our ability to systematically capture reaction intermediates and spectroscopically characterize their structures. Through this method, we can identify the pathway for water-network-mediated, proton-coupled transformation of nitrosonium, NO+ to HONO, a key reaction controlling the cations present in the ionosphere. Through this work, we reveal the critical role played by water molecules occupying the second solvation shell around the ion, where they stabilize the emergent product ion in a fashion reminiscent of the solvent coordinate responsible for the barrier to charge transfer in solution. Looking to the future, we predict that the capture and characterization of fleeting intermediate complexes in the homogeneous catalytic activation of small molecules like water, alkanes, and CO2 is a likely avenue rich with opportunity. © 2013 American Chemical Society. Source


Frey P.A.,University of Wisconsin - Madison
Accounts of Chemical Research | Year: 2014

As a graduate student under Professor R. H. Abeles, I began my journey with 5′-deoxyadenosine, studying the coenzyme B12 (adenosylcobalamin)-dependent dioldehydrase (DDH). I proved that suicide inactivation of dioldehydrase by glycolaldehyde proceeded with irreversible cleavage of adenosylcobalamin to 5′-deoxyadenosine. I further showed that suicide inactivation by [2-3H]glycolaldehyde produced 5′-deoxy[3H]adenosine, the first demonstration of hydrogen transfer to adenosyl-C5′ of adenosylcobalamin. The tritium kinetic isotope effect Tk was 15, which correlated well with the measurement Dk = 12 for transformation of [1-2H]propane-1,2-diol to [2-2H]propionaldehyde by DDH. After establishing my own research program, I returned to the glycolaldehyde inactivation of DDH, showing by EPR that suicide inactivation produced glycolaldehyde-2-yl. In retrospect, suicide inactivation involved scission of adenosylcobalamin to 5′-deoxyadenosine- 5′-yl, which abstracted a hydrogen from glycolaldehyde. Captodative-stabilized glycolaldehyde-2-yl could not react further, leading to suicide inactivation.In 1986, my colleagues and I took up the problem of the mechanism by which lysine 2,3-aminomutase (LAM) catalyzes S-adenosylmethionine (SAM) and pyridoxal-5′-phosphate (PLP)-dependent interconversion of l-lysine and l-β-lysine. Because the reaction followed the pattern of adenosylcobalamin-dependent rearrangements, I postulated that SAM might be an evolutionary predecessor to adenosylcobalamin. Testing this hypothesis, we traced hydrogen transfer from lysine through the adenosyl-C5′ of SAM to β-lysine. Thus, the 5′-deoxyadenosyl of SAM mediated hydrogen transfer by LAM exactly as in adenosylcobalamin mediated hydrogen transfer in B12-dependent isomerizations. The mechanism postulated that SAM cleaves to form 5′-deoxyadenosine-5′-yl followed by abstraction of C3(H) from PLP-α-lysine aldimine to form PLP-α-lysine-3-yl. PLP-α-lysine-3-yl isomerizes to pyridoxal-β-lysine-2-yl, and a hydrogen abstraction from 5′-deoxyadenosine regenerates 5′-deoxyadenosine-5′-yl and releases β-lysine. Of four radicals in the postulated mechanism, three have been characterized by EPR spectroscopy as kinetically competent intermediates.The analysis of the role of iron allowed researchers to elucidate the mechanism by which SAM is cleaved to 5′-deoxyadenosine-5′-yl. LAM contains one [4Fe-4S] cluster ligated by three cysteine residues. As shown by ENDOR spectroscopy and X-ray crystallography, the fourth ligand to the cluster is SAM, through the methionyl carboxylate and amino groups. Inner sphere electron transfer within the [4Fe-4S]1+-SAM complex leads to [4Fe-4S]2+-Met and 5′-deoxyadenosine-5′-yl.The iron-binding motif in LAM, CxxxCxxC, found by other groups in four other SAM-dependent enzymes, is the founding motif for the radical SAM superfamily. These enzymes number in the tens of thousands and are responsible for highly diverse and chemically difficult transformations in the biosphere. Available information supports the hypothesis that this superfamily provides the chemical context from which the much more structurally complex adenosylcobalamin evolved. © 2013 American Chemical Society. Source


Barger V.,University of Wisconsin - Madison | Ishida M.,Meisei University
Physics Letters, Section B: Nuclear, Elementary Particle and High-Energy Physics | Year: 2012

The radion is expected to be the first signal of the Randall-Sundrum (RS) model. We explore the possibility of finding it in the ongoing Higgs searches at the LHC. The little RS model (LRS), which has a fundamental scale at ~10 3 TeV, is excluded over wide ranges of the radion mass from the latest WW and γγ data by ATLAS and CMS. © 2012 Elsevier B.V. Source


Williams J.C.,University of Wisconsin - Madison | Denison T.,Medtronics
Science Translational Medicine | Year: 2013

The f eld of optogenetics has provided new insight into neuronal communication and complex brain function. Now, scientists eagerly anticipate clinical application of this technology, with the hope that it will help improve treatments for various neurological disorders. However, the translational hurdles are high. In this Perspective, we highlight the technical, practical, and regulatory hurdles that lie ahead along the path towards making optogenetic neuromodulation therapies a reality in the clinic. Source


Masters K.S.,University of Wisconsin - Madison
Macromolecular Bioscience | Year: 2011

Growth factors play a critical role in regulating processes involved in cellular differentiation and tissue regeneration, and are therefore considered essential elements in many tissue engineering strategies. The covalent immobilization of growth factors to biomaterial matrices addresses many of the challenges associated with delivering freely-diffusible growth factors and has thus emerged as a promising method of achieving localized and sustained growth factor delivery. This Feature Article discusses methods that have been used to immobilize growth factors to substrates, followed by an overview of several tissue repair and regeneration applications in which immobilized growth factors have been used. Covalently immobilized growth factors are capable of stimulating cell behaviors that aid in tissue repair and regeneration, often eliciting a more pronounced cellular response than growth factor delivered in a soluble or adsorbed form. This Feature Article discusses strategies for immobilizing growth factors and applications of growth factor-modified materials in regenerative medicine. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Source


Bates D.,University of Wisconsin - Madison | Machler M.,ETH Zurich | Bolker B.M.,McMaster University | Walker S.C.,McMaster University
Journal of Statistical Software | Year: 2015

Maximum likelihood or restricted maximum likelihood (REML) estimates of the parameters in linear mixed-effects models can be determined using the lmer function in the lme4 package for R. As for most model-fitting functions in R, the model is described in an lmer call by a formula, in this case including both fixed- and random-effects terms. The formula and data together determine a numerical representation of the model from which the profiled deviance or the profiled REML criterion can be evaluated as a function of some of the model parameters. The appropriate criterion is optimized, using one of the constrained optimization functions in R, to provide the parameter estimates. We describe the structure of the model, the steps in evaluating the profiled deviance or REML criterion, and the structure of classes or types that represents such a model. Sufficient detail is included to allow specialization of these structures by users who wish to write functions to fit specialized linear mixed models, such as models incorporating pedigrees or smoothing splines, that are not easily expressible in the formula language used by lmer. © 2015, American Statistical Association. All rights reserved. Source


Huang Y.,University of Wisconsin - Madison
Investigative ophthalmology & visual science | Year: 2012

The purpose of this article was to assess signal quality of retinal optical coherence tomography (OCT) images from multiple devices using subjective and quantitative measurements. A total of 120 multiframe OCT images from 4 spectral domain OCT devices (Cirrus, RTVue, Spectralis, and 3D OCT-1000) were evaluated subjectively by trained graders, and measured quantitatively using a derived parameter, maximum tissue contrast index (mTCI). An intensity histogram decomposition model was proposed to separate the foreground and background information of OCT images and to calculate the mTCI. The mTCI results were compared with the manufacturer signal index (MSI) provided by the respective devices, and to the subjective grading scores (SGS). Statistically significant correlations were observed between the paired methods (i.e., SGS and MSI, SGS and mTCI, and mTCI and MSI). Fisher's Z transformation indicated the Pearson correlation coefficient ρ ≥ 0.8 for all devices. Using the Deming regression, correlation parameters between the paired methods were established. This allowed conversion from the proprietary MSI values to SGS and mTCI that are universally applied to each device. The study suggests signal quality of retinal OCT images can be evaluated subjectively and objectively, independent of the devices. Together with the proposed histogram decomposition model, mTCI may be used as a standardization metric for OCT signal quality that would affect measurements. Source


We report discoveries of different haplotypes associated with the centromeres of three potato chromosomes, including haplotypes composed of long arrays of satellite repeats and haplotypes lacking the same repeats. These results are in favor of the hypothesis that satellite repeat-based centromeres may originate from neocentromeres that lack repeats. Source


Stein J.H.,University of Wisconsin - Madison
Topics in Antiviral Medicine | Year: 2012

HIV infection and antiretroviral therapy each appear to increase cardiovascular disease risk. Increased risk may be attributable to the inflammatory effects of HIV infection and dyslipidemia associated with some antiretroviral agents. The prevalence of cardiovascular disease is increasing as patients live longer, age, and acquire traditional coronary heart disease (CHD) risk factors. In general, any additional cardiovascular risk posed by HIV infection or antiretroviral therapy is of potential concern for patients who are already at moderate or high risk for CHD. Long-term and well-designed studies are needed to more accurately ascertain to what degree HIV infection and antiretroviral therapy affect long-term cardiovascular disease risk. Management of dyslipidemia to reduce CHD risk in HIV-infected patients is much the same as in the general population, with the cornerstone consisting of statin therapy and lifestyle interventions. Smoking cessation is a major step in reducing CHD risk in those who smoke. © 2012, IAS-USA. Source


Spalding E.P.,University of Wisconsin - Madison
American Journal of Botany | Year: 2013

Polar auxin transport can be likened to water following the path of least resistance as it fl ows downhill. In the case of auxin, the hill is the difference in electrochemical potential of the auxin anion (IAA-). H + -ATPases and H + -IAA symporters at the plasma membrane create the electrical and IAA- concentration gradients that constitute this thermodynamic hill. PIN and ABCB transporters also at the plasma membrane bias the direction and limit the rate of downhill fl ow out of the cell. This article will present the thermodynamic basis for this view and critically examine how well the molecular biological descriptions of the polar auxin transport process fi t the framework. An auxin concentration gradient across an organ has long been recognized as the cause of bending growth during tropisms. Its generation can be viewed as a result of redirected polar auxin transport. This article will examine how molecular regulation of the paths of least resistance to auxin effl ux diverts the downhill fl ow of auxin to steer growth during tropisms. © 2013 Botanical Society of America. Source


Kushner B.J.,University of Wisconsin - Madison
Archives of Ophthalmology | Year: 2010

The paradigm that an "underacting" extraocular muscle is always atrophic or hypoplastic and that an overacting extraocular muscle should always be enlarged leads to inconsistencies with clinical observations. These include findings of "overacting" inferior oblique muscles, superior rectus muscle overaction or contracture syndrome, and normal extraocular muscle diameters in patients with apparent superior oblique muscle palsy, among other clinical entities. These inconsistencies can be reconciled if one accepts the possibility that extraocular muscle contractile activity may reflect a change in neural input to an anatomically normal muscle or that muscle contractile activity may be altered by shifts in fiber type and distribution within a normal-sized muscle. This remodeling may result from vergence adaptation or from any change in neural stimulus to the muscle. There is substantial evidence to suggest that both of these theoretical possibilities may likely occur. ©2010 American Medical Association. All rights reserved. Source


Burton J K.,University of Wisconsin - Madison
Archives of Ophthalmology | Year: 2010

Objective: To determine if ocular torsion is a major cause of A and V patterns and oblique muscle overaction or merely a contributing factor. Methods: Three separate investigations were conducted. (1) The trajectory of eyes with oblique muscle overaction was plotted across the horizontal field of gaze from videographs to determine if it was linear or curvilinear. (2) The effect of successful Harada-Ito surgery to reduce extorsion on overelevation in adduction in patients with fourth cranial nerve palsy was studied. (3) The effect of successful surgery to treat pattern strabismus in the form of vertical transposition of the horizontal rectus muscles on objective torsion was studied. Results: (1) Three eyes with inferior oblique muscle overaction and 2 with superior oblique muscle overaction had a curvilinear rise or fall (respectively) as they moved into adduction. (2) Surgery that successfully decreased extorsion had a negligible effect on overelevation in adduction in 2 patients. (3) Horizontal rectus muscle transposition that was uniformly successful in eliminating A or V patterns consistently caused an increase in objective torsion in all 5 patients studied. Conclusion: Ocular torsion may contribute to A or V patterns and overelevation or overdepression in adduction, but it is probably not the major cause of these phenomena. ©2010 American Medical Association. Source


Meyer K.C.,University of Wisconsin - Madison
Seminars in Respiratory and Critical Care Medicine | Year: 2010

Advancing age is associated with a decline in the integrity of physical barriers and protection against invading pathogens, and age-related changes in the immune system are associated with increased susceptibility to the emergence of autoimmune phenomena, neoplasia, and infections. Respiratory tract infections can occur at any age, but the incidence of lower respiratory tract infections increases significantly with advanced age such that pneumonia is a leading cause of illness and death in the elderly. Changes in lung physiology and immune function coupled with inflammation induced by environmental exposures or endogenous factors such as predisposition to aspiration may, in part, account for the increase in susceptibility to respiratory infections. Additionally, age-associated alterations in immune regulation ("immunosenescence") with dysregulation of lung homeostasis may allow low-grade inflammatory changes that lead to anatomical and physiological changes that characterize the senescent lung. The presence of disease states in elderly populations, such as chronic obstructive pulmonary disease (COPD) or nonpulmonary organ system diseases, may increase the likelihood of developing severe respiratory infections. This article examines age-related changes in immune function that predispose elderly individuals to lung remodeling but focuses especially on lower respiratory tract infections. It will discuss risk factors, identify pathogens that typically lead to respiratory infections in the elderly, and review current approaches to treatment and prevention of respiratory infections in the elderly population. © 2010 by Thieme Medical Publishers, Inc. Source


Maxfield B.A.,University of Wisconsin - Madison
Radiologic Clinics of North America | Year: 2010

Acute spinal injuries are fortunately rare in pediatric sports but can be catastrophic. Imaging is integral to the diagnosis and care of spinal trauma. Plain radiographs and CT are critical for detecting vertebral fracture, and MR imaging is an essential adjunct for evaluating muscular, ligamentous, and spinal cord injury. Back pain is a common complaint among athletes of all ages. The growing spine has unique weaknesses that result in a higher rate of detectable radiologic abnormalities. Disk pathology is less common in children, and is often uniquely associated with fracture of the ring apophyses. Spondylolysis is far more prevalent in youth athletes than in their adult counterparts, requiring a different approach to imaging for assessment of adolescent back pain. © 2010 Elsevier Inc. Source


Hoang T.,University of Toronto | Lazarian A.,University of Wisconsin - Madison
Monthly Notices of the Royal Astronomical Society | Year: 2014

Grain alignment by radiative torques (RATs) has been extensively studied for various environment conditions, including interstellar medium, dense molecular clouds and accretion discs, thanks to significant progress in observational, theoretical and numerical studies. In this paper, we explore the alignment by RATs and provide quantitative predictions of dust polarization for a set of astrophysical environments that can be tested observationally. We first consider the alignment of grains in the local interstellar medium and compare predictions for linear polarization by aligned grains with recent observational data for nearby stars. We then revisit the problem of grain alignment in accretions discs by taking into account the dependence of RAT alignment efficiency on the anisotropic direction of radiation fields relative to magnetic fields. Moreover, we study the grain alignment in interplanetary medium, including diffuse Zodiacal cloud and cometary comae, and calculate the degree of circular polarization (CP) of scattered light arising from single scattering by aligned grains. We also discuss a new type of grain alignment, namely the alignment with respect to the ambient electric field instead of the alignment with the magnetic field. We show that this type of alignment can allow us to reproduce the systematic features of CP observed across a cometary coma. Our findings suggest that polarized Zodiacal dust emission may be an important polarized foreground component, which should be treated carefully in cosmic microwave background experiments. © 2013 The Authors Published by Oxford University Press on behalf of the Royal Astronomical Society. Source


Gleicher M.,University of Wisconsin - Madison
IEEE Transactions on Visualization and Computer Graphics | Year: 2013

This paper introduces an approach to exploration and discovery in high-dimensional data that incorporates a user's knowledge and questions to craft sets of projection functions meaningful to them. Unlike most prior work that defines projections based on their statistical properties, our approach creates projection functions that align with user-specified annotations. Therefore, the resulting derived dimensions represent concepts defined by the user's examples. These especially crafted projection functions, or explainers, can help find and explain relationships between the data variables and user-designated concepts. They can organize the data according to these concepts. Sets of explainers can provide multiple perspectives on the data. Our approach considers tradeoffs in choosing these projection functions, including their simplicity, expressive power, alignment with prior knowledge, and diversity. We provide techniques for creating collections of explainers. The methods, based on machine learning optimization frameworks, allow exploring the tradeoffs. We demonstrate our approach on model problems and applications in text analysis. © 1995-2012 IEEE. Source


Lee J.,University of Wisconsin - Madison
Nature communications | Year: 2013

Studies of natural genetic variation for the vernalization requirement in Arabidopsis have revealed two genes, FRIGIDA and FLOWERING LOCUS C (FLC), that are determinants of the vernalization-requiring, winter-annual habit. In this study, we show that FLOWERING LOCUS C EXPRESSOR-LIKE 4 (FLL4) is essential for upregulation of FLC in winter-annual Arabidopsis accessions and establishment of a vernalization requirement. FLL4 is part of the FLOWERING LOCUS C EXPRESSOR gene family and both are non-redundantly involved in flowering time control. Epistasis analysis among FRIGIDA, FLL4, FLOWERING LOCUS C EXPRESSOR and autonomous-pathway genes reveals that FRIGIDA fve exhibits an extreme delay of flowering compared with fri fve, but mutants in other autonomous-pathway genes do not, indicating that FVE acts most antagonistically to FRIGIDA. FLL4 may represent a new member of a FRI-containing complex that activates FLC. Source


Pickhardt P.J.,University of Wisconsin - Madison
Abdominal Imaging | Year: 2013

Misinterpretation at CT colonography (CTC) can result in either a colorectal lesion being missed (false-negative) or a false-positive diagnosis. This review will largely focus on potential missed lesions - and ways to avoid such misses. The general causes of false-negative interpretation at CTC can be broadly characterized and grouped into discrete categories related to suboptimal study technique, specific lesion characteristics, anatomic location, and imaging artifacts. Overlapping causes further increase the likelihood of missing a clinically relevant lesion. In the end, if the technical factors of bowel preparation, colonic distention, and robust CTC software are adequately addressed on a consistent basis, and the reader is aware of all the potential pitfalls at CTC, important lesions will seldom be missed. © 2012 Springer Science+Business Media, LLC. Source


Perouansky M.,University of Wisconsin - Madison
Anesthesiology | Year: 2012

An accepted truism among clinicians and researchers attributes the persistence of the quest for a unitary mechanism of anesthetic action to the lasting influence of Hans Meyer and Ernest Overton. This article presents a different view: the experiments that led to the Meyer-Overton rule were the consequence-not the source-of a unitary paradigm that was formulated by Claude Bernard a quarter of a century earlier. Bernard firmly believed that the sensitivity to anesthesia was a fundamental criterion that separated 'true life' from 'mere chemistry.' Bernard's scientific authority in the context of 19 century natural philosophy is responsible for establishing a unified (i.e., unitary mechanism and universality across life forms) paradigm of anesthetic action. Meyer and Overton's work was targeted at systematizing and solidifying existing knowledge within this paradigm, not at discovering novelty, and its publication did not substantially affect contemporary research. Claude Bernard's paradigm, by contrast, still influences investigations of mechanisms of anesthetic action. Copyright © 2012, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins. Source


Pike J.W.,University of Wisconsin - Madison
Journal of Bone and Mineral Research | Year: 2011

The regulation of gene expression represents one of the most fundamental of biologic processes that controls cellular proliferation, differentiation, and function. Recent technological advances in genome-wide annotation together with bioinformatic/computational analyses have contributed significantly to our understanding of transcriptional regulation at the epigenomic and regulomic levels. This perspective outlines the techniques that are being utilized and summarizes a few of the outcomes. © 2011 American Society for Bone and Mineral Research. Copyright © 2011 American Society for Bone and Mineral Research. Source


Halzen F.,University of Wisconsin - Madison
Astroparticle Physics | Year: 2013

Identifying the accelerators that produce the Galactic and extragalactic cosmic rays has been a priority mission of several generations of high energy gamma ray and neutrino telescopes; success has been elusive so far. Detecting the gamma-ray and neutrino fluxes associated with cosmic rays reaches a new watershed with the completion of IceCube, the first neutrino detector with sensitivity to the anticipated fluxes, and the construction of CTA, a ground-based gamma ray detector that will map and study candidate sources with unprecedented precision. In this paper, we revisit the prospects for revealing the sources of the cosmic rays by a multiwavelength approach; after reviewing the methods, we discuss supernova remnants, gamma ray bursts, active galaxies and GZK neutrinos in some detail. © 2011 Elsevier B.V. All rights reserved. Source


Dent E.W.,University of Wisconsin - Madison | Baas P.W.,Drexel University
Journal of Neurochemistry | Year: 2014

Microtubules in neurons consist of highly dynamic regions as well as stable regions, some of which persist after bouts of severing as short mobile polymers. Concentrated at the plus ends of the highly dynamic regions are microtubule plus end tracking proteins called +TIPs that can interact with an array of other proteins and structures relevant to the plasticity of the neuron. It is also provocative to ponder that short mobile microtubules might similarly convey information with them as they transit within the neuron. Thus, beyond their known conventional functions in supporting neuronal architecture and organelle transport, microtubules may act as 'information carriers' in the neuron. © 2013 International Society for Neurochemistry. Source


Ives A.R.,University of Wisconsin - Madison | Helmus M.R.,CAS Xishuangbanna Tropical Botanical Garden
Ecological Monographs | Year: 2011

There is growing appreciation that ecological communities are phylogenetically structured, with phylogenetically closely related species either more or less likely to co-occur at the same site. Here, we present phylogenetic generalized linear mixed models (PGLMMs) that can statistically test a wide variety of phylogenetic patterns in community structure. In contrast to most current statistical approaches that rely on community metrics and randomization tests, PGLMMs are model-based statistics that fit observed presence/absence data to underlying hypotheses about the distributions of species among communities. We built four PGLMMs to address (1) phylogenetic patterns in community composition, (2) phylogenetic variation in species sensitivities to environmental gradients among communities, (3) phylogenetic repulsion in which closely related species are less likely to co-occur, and (4) trait-based variation in species sensitivities to environmental gradients. We also built a fifth PGLMM to test a key underlying assumption of phylogenetic community structure: that phylogenetic information serves as a surrogate for trait information about species; this model tests whether the introduction of trait information can explain all variation in species occurrences among communities, leaving no phylogenetic residual variation. We assessed the performance of these PGLMMs using community simulation models and show that PGLMMs have equal or greater statistical power than alternative approaches currently in the literature. Finally, we illustrate the PGLMM advantage of fitting a model to data by showing how variation in species occurrences among communities can be partitioned into phylogenetic and site-specific components, and how fitted models can be used to predict the co-occurrence of phylogenetically related species. © 2011 by the Ecological Society of America. Source


Francis J.A.,Rutgers University | Vavrus S.J.,University of Wisconsin - Madison
Geophysical Research Letters | Year: 2012

Arctic amplification (AA)-the observed enhanced warming in high northern latitudes relative to the northern hemisphere-is evident in lower-tropospheric temperatures and in 1000-to-500hPa thicknesses. Daily fields of 500hPa heights from the National Centers for Environmental Prediction Reanalysis are analyzed over N. America and the N. Atlantic to assess changes in north-south (Rossby) wave characteristics associated with AA and the relaxation of poleward thickness gradients. Two effects are identified that each contribute to a slower eastward progression of Rossby waves in the upper-level flow: 1) weakened zonal winds, and 2) increased wave amplitude. These effects are particularly evident in autumn and winter consistent with sea-ice loss, but are also apparent in summer, possibly related to earlier snow melt on high-latitude land. Slower progression of upper-level waves would cause associated weather patterns in mid-latitudes to be more persistent, which may lead to an increased probability of extreme weather events that result from prolonged conditions, such as drought, flooding, cold spells, and heat waves. copyright 2012 by the American Geophysical Union. Source


Jackson M.B.,University of Wisconsin - Madison
Journal of Membrane Biology | Year: 2010

The assembly of SNARE proteins into a tight complex has been hypothesized to drive membrane fusion. A model of the initial fusion pore as a proteinaceous channel formed by SNARE proteins places their membrane anchors in separate membranes. This leaves the possibility of a final assembly step that brings the membrane anchors together and drives fusion pore expansion. The present study develops a model for expansion in which the final SNARE complex zipping step drives a transition from a proteinaceous fusion pore to a lipidic fusion pore. An estimate of the energy released upon merger of the helical segments of the SNARE motifs with the helical segments of the membrane anchors indicates that completing the assembly of a few SNARE complexes can overcome the elastic energy that opposes lipid bilayer deformation into a narrow fusion pore. The angle between the helical axes of the membrane anchor and SNARE motif serves as a useful reaction coordinate for this transition. Energy was calculated as a function of this angle, incorporating contributions from membrane bending, SNARE complex assembly, membrane anchor flexing and hydrophobic interactions. The rate of this transition was evaluated as a process of diffusion over the barrier imposed by these combined energies, and the rates estimated were consistent with experimental measurements. © 2010 Springer Science+Business Media, LLC. Source


Chern G.-W.,University of Wisconsin - Madison
Physical Review Letters | Year: 2010

Exchange interaction tends to favor collinear or coplanar magnetic orders in rotationally invariant spin systems. Indeed, such magnetic structures are usually selected by thermal or quantum fluctuations in highly frustrated magnets. Here we show that a complex noncoplanar magnetic order with a quadrupled unit cell is stabilized by itinerant electrons on the pyrochlore lattice. Specifically, we consider a Kondo-lattice model with classical localized moments at quarter filling. The electron Fermi "surface" at this filling factor is topologically equivalent to three intersecting Fermi circles. Perfect nesting of the Fermi lines leads to magnetic ordering with multiple wave vectors and a definite handedness. The chiral order might persist without magnetic order in a chiral spin liquid at finite temperatures. © 2010 The American Physical Society. Source


Smith J.A.,University of Wisconsin - Madison
Frontiers in Microbiology | Year: 2014

The immune system depends upon combinations of signals to mount appropriate responses: pathogen specific signals in the context of co-stimulatory "danger" signals drive immune strength and accuracy. Viral infections trigger anti-viral type I interferon (IFN) responses by stimulating endosomal and cytosolic pattern recognition receptors (PRRs). However, viruses have also evolved many strategies to counteract IFN responses. Are there intracellular danger signals that enhance immune responses to viruses? During infection, viruses place a heavy demand on the protein folding machinery of the host endoplasmic reticulum (ER). To survive ER stress, host cells mount an unfolded protein response (UPR) to decrease ER protein load and enhance protein-folding capacity. Viruses also directly elicit the UPR to enhance their replication. Increasing evidence supports an intersection between the host UPR and inflammation, in particular the production of pro-inflammatory cytokines and type I IFN. The UPR directly activates pro-inflammatory cytokine transcription factors and dramatically enhances cytokine production in response to viral PRR engagement. Additionally, viral PRR engagement may stimulate specific pathways within the UPR to enhance cytokine production. Through these mechanisms, viral detection via the UPR and inflammatory cytokine production are intertwined. Consequently, the UPR response is perfectly poised to act as an infection-triggered "danger" signal. The UPR may serve as an internal "co-stimulatory" signal that (1) provides specificity and (2) critically augments responses to overcome viral subterfuge. Further work is needed to test this hypothesis during viral infections. © 2014 Smith. Source


McManus P.S.,University of Wisconsin - Madison
Current Opinion in Microbiology | Year: 2014

Antibiotics are applied to plants to prevent bacterial diseases, although the diversity of antibiotics and total amounts used are dwarfed by antibiotic use in animal agriculture. Nevertheless, the release of antibiotics into the open environment during crop treatment draws scrutiny for its potential impact on the global pool of resistance genes. The main use of antibiotics on plants is application of streptomycin to prevent fire blight, a serious disease of apple and pear trees. A series of recent studies identified and quantified antibiotic resistance genes and profiled bacterial communities in apple orchard plots that were or were not sprayed with streptomycin. While the specific objectives and methods varied, the results of these studies suggest that streptomycin application for fire blight control does not influence bacterial community structure or increase the abundance of resistance genes in orchards. © 2014 Elsevier Ltd. Source


Hornberger T.A.,University of Wisconsin - Madison
International Journal of Biochemistry and Cell Biology | Year: 2011

Mechanical stimuli play a major role in the regulation of skeletal muscle mass, and the maintenance of muscle mass contributes significantly to disease prevention and issues associated with the quality of life. Although the link between mechanical signals and the regulation of muscle mass has been recognized for decades, the mechanisms involved in converting mechanical information into the molecular events that control this process remain poorly defined. Nevertheless, our knowledge of these mechanisms is advancing and recent studies have revealed that signaling through a protein kinase called the mammalian target of rapamycin (mTOR) plays a central role in this event. In this review we will, (1) discuss the evidence which implicates mTOR in the mechanical regulation of skeletal muscle mass, (2) provide an overview of the mechanisms through which signaling by mTOR can be regulated, and (3) summarize our current knowledge of the potential mechanisms involved in the mechanical activation of mTOR signaling. © 2011 Elsevier Ltd. All rights reserved. Source


Kratochwill T.R.,University of Wisconsin - Madison | Levin J.R.,University of Arizona
Psychological Methods | Year: 2010

In recent years, single-case designs have increasingly been used to establish an empirical basis for evidence-based interventions and techniques in a variety of disciplines, including psychology and education. Although traditional single-case designs have typically not met the criteria for a randomized controlled trial relative to conventional multiple-participant experimental designs, there are procedures that can be adopted to create a randomized experiment in this class of experimental design. Our two major purposes in writing this article were (a) to review the various types of single-case design that have been and can be used in psychological and educational intervention research and (b) to incorporate randomized experimental schemes into these designs, thereby improving them so that investigators can draw more valid conclusions from their research. For each traditional single-case design type reviewed, we provide illustrations of how various forms of randomization can be introduced into the basic design structure. We conclude by recommending that traditional single-case intervention designs be transformed into more scientifically credible randomized single-case intervention designs whenever the research conditions under consideration permit. © 2010 American Psychological Association. Source


Sutherland E.R.,University of Colorado at Denver | Busse W.W.,University of Wisconsin - Madison
Journal of Allergy and Clinical Immunology | Year: 2014

In 2008, the National Heart, Lung, and Blood Institute announced its intent to support a new asthma network known as AsthmaNet. This clinical trials consortium, now in its fifth year, has been charged with developing and executing clinical trials to address the most important asthma management questions and identify new treatment approaches in pediatric and adult patients. This review will discuss the organization of AsthmaNet and the scientific context in which the network was developed and began its work, report the results of an internal priority-setting exercise designed to guide the network's scientific strategy, and highlight the portfolio of clinical trials, proof-of-concept studies, and mechanistic studies planned for the 7-year period of the network to update the global asthma community regarding the progress and processes of the network. © 2013 American Academy of Allergy, Asthma & Immunology. Source


Halpin M.,University of Wisconsin - Madison
Omega (United States) | Year: 2012

Health professionals, researchers, and philosophers have debated extensively about suicide. Some believe suicides result from mental pathology, whereas others argue that individuals are capable of rational suicide. This debate is particularly poignant within illness communities, where individuals may be suffering from chronic and incurable conditions. This article engages with these issues by presenting the accounts of 20 individuals with Huntington disease (HD), a fatal degenerative condition, and 10 informal caregivers (e.g., spouses). Suicide is a leading cause of death amongst people with HD, with an incidence rate many times higher than the general population. In contrast to the majority of the academic literature on HD suicidality, study participants did not connect suicide with mental pathology. Instead, they perceived suicide as a response to the realities of living with HD, such as prolonged physiological degeneration and the need for long-term intensive health care. These findings are subsequently discussed in relation to the rational-pathological suicide binary. © 2012, Baywood Publishing Co., Inc. Source


Seeds are studied to understand dispersal and establishment of the next generation, as units of agricultural yield, and for other important reasons. Thus, elucidating the genetic architecture of seed size and shape traits will benefit basic and applied plant biology research. This study sought quantitative trait loci (QTL) controlling the size and shape of Arabidopsis thaliana seeds by computational analysis of seed phenotypes in recombinant inbred lines derived from the small-seeded Landsberg erecta × large-seeded Cape Verde Islands accessions. On the order of 10(3) seeds from each recombinant inbred line were automatically measured with flatbed photo scanners and custom image analysis software. The eight significant QTL affecting seed area explained 63% of the variation, and overlapped with five of the six major-axis (length) QTL and three of the five minor-axis (width) QTL, which accounted for 57% and 38% of the variation in those traits, respectively. Because the Arabidopsis seed is exalbuminous, lacking an endosperm at maturity, the results are relatable to embryo length and width. The Cvi allele generally had a positive effect of 2.6-4.0%. Analysis of variance showed heritability of the three traits ranged between 60% and 73%. Repeating the experiment with 2.2 million seeds from a separate harvest of the RIL population and approximately 0.5 million seeds from 92 near-isogenic lines confirmed the aforementioned results. Structured for download are files containing phenotype measurements, all sets of seed images, and the seed trait measuring tool. Source


Andes D.,University of Wisconsin - Madison
Current Medical Research and Opinion | Year: 2013

Background: The antifungal armamentarium includes a number of drug classes and agents within each class. Successful IFI management depends on optimal matching of drug choice with the individual patient and causative pathogen, and maximizing effectiveness of the selected drug through appropriate dosing and toxicity management. Objective: This review is intended to provide a brief overview of key factors involved in optimizing antifungal choice and administration for patients with invasive fungal infections (IFIs). Findings: Antifungals differ in spectrum of activity, and these differences are critical when selecting the antifungal most likely to provide success for a patient with an IFI. When the species has not yet been identified, an analysis of regional epidemiology and risk factors can provide clues as to the most likely pathogen. For severely immunocompromised patients, a fungicidal agent may be preferred over a fungistatic agent, although more research is needed in this area. Triazoles, particularly itraconazole and posaconazole, exhibit great interpatient pharmacokinetic variability related to absorption. Steps can be taken to maximize absorption when using these agents. Voriconazole concentration is affected by polymorphisms in the major metabolic enzyme, cytochrome P450 2C19. Triazoles, and to a lesser extent other antifungals, are also subject to drug-drug interactions, which needs to be considered when selecting a particular antifungal agent for use in a severely ill patient on polypharmacy. Therapeutic drug monitoring may be a useful adjunct for patients receiving itraconazole, voriconazole, or posaconazole. When the IFI involves a pharmacologically protected site, such as the central nervous system (CNS) or eye, 5-fluorocytosine, fluconazole, or voriconazole are generally preferred. Echinocandin penetration is typically inadequate for IFIs of the CNS or eye. Antifungal agents also differ in their toxicity profiles, and these issues also need to be considered and managed when making an antifungal choice. Conclusion: Successful management of IFIs relies in part on the accurate selection of an antifungal agent for the infection. Drug characteristics can help in the selection of drug therapy. These characteristics include the drug's spectrum of activity, pharmacokinetics, pharmacodynamics, toxicity profile, and distribution to the infection site. Matching the drug profile to the patient and fungal species contribute to optimal management of infection. © 2013 Informa UK Ltd. Source


Litovsky R.Y.,University of Wisconsin - Madison
Cochlear implants international | Year: 2011

Review of recent studies on spatial-hearing abilities in children who use bilateral cochlear implants (BiCIs); compare performance of children who use BiCIs with children who have normal hearing. Results from recent studies are reviewed in two categories. First, studies measured spatial hearing by using sound localization or identification methods, thereby focusing on localization accuracy. Second, studies that measured the ability of children to discriminate between sound source positions in the horizontal plane, thereby focusing on localization acuity where performance was quantified using the minimum audible angle (MAA). Children with BiCIs have localization errors that vary widely. There is evidence that for many children errors are smaller when using two vs. one implant. In the bilateral condition, some children's performance falls within the range of errors seen in children with normal hearing (less than 30° root mean square), but most children have errors that are significantly greater than those of children with normal hearing. On MAA tasks, performance is generally significantly better (lower MAAs) when children are tested in the bilateral listening mode than in the unilateral listening mode. However, MAAs are generally higher than those measured in children with normal hearing. Results are discussed in the context of auditory experience, and also with regard to the lack of availability of binaural cues presented through the CI speech processors when the children are using their processors in everyday listening situations. The potential roles of interaural timing vs. level cues are discussed. Source


Hoekman D.,University of Notre Dame | Hoekman D.,University of Wisconsin - Madison
Ecology | Year: 2010

Understanding how communities respond to changes in temperature is a major challenge for community ecology. Temperature influences the relative degree to which top-down and bottom-up forces structure ecological communities. In greenhouse experiments using the aquatic community found in pitcher plants (Sarracenia purpurea), I tested how temperature affected the relative importance of top-down (mosquito predation) and bottom-up (ant carcasses) forces on protozoa and bacteria populations. While bottom-up effects did not vary consistently with temperature, the top-down effects of predators on protozoa increased at higher temperatures. These results suggest that temperature could change the relative importance of top-down and bottom-up effects in ecological communities. Specifically, higher temperature may increase the strength of top-down effects by raising predator metabolic rate and concomitant processes (e.g., activity, foraging, digestion, growth) relative to cooler temperatures. These findings apply broadly to an understanding of trophic interactions in a variable environment and are especially relevant in the context of ongoing climate change. © 2010 by the Ecological Society of America. Source


Several ionic and nonionic additives are known to affect structural stability of proteins in aqueous solutions. At a fundamental level, the mechanism of stabilization or destabilization of proteins by cosolvents must be related to three-body interactions between the protein, additive, and the water medium. In this study, the role of the Lifshitz-van der Waals electrodynamic interaction between various additives (sucrose, glycerol, urea, poly(ethylene glycol)-200, betaine, taurine, proline, and valine) and bovine serum albumin (BSA) in water medium was examined. The electrodynamic interaction energy was attractive for all of the additives studied here when both far ultraviolet and infrared relaxations of the additives were included in their dielectric susceptibility representations. However, when only the infrared contribution was included for structure stabilizers and both far ultraviolet and infrared contributions for the structure destabilizers, the resulting electrodynamic interaction energy (E/kT) followed the structure stabilizing and/or destabilizing behavior of the additives; that is, the interaction was attractive for urea and PEG200 (structure destabilizers), whereas it was repulsive for sucrose, glycerol, betaine, taurine, alanine, valine, and proline (structure stabilizers). The electrodynamic interaction energy E/kT at any given surface-to-surface separation distance between the additives and BSA was positively correlated (r 2 = 0.92) with the experimental thermal denaturation temperature (T d) of BSA in 1 M solutions of the additives. These analyses provided a mechanistic basis for the experimental observations of exclusion of the structure-stabilizing additives from the protein-water interface and binding of the structure-destabilizing additives to the protein surface. The role of water structure in the three-body electrodynamic interaction is discussed. It is hypothesized that in the case of additives that enhance water structure the hydration shells formed around the additives effectively dampen the contribution of ultraviolet frequencies to the dielectric susceptibility of the additives and thus impart repulsive electrodyanamic interaction between the additive and the protein, whereas the opposite occurs in the case of additives that breakdown the hydrogen-bonded structure of water. © 2012 American Chemical Society. Source


Lasseter R.H.,University of Wisconsin - Madison
Proceedings of the IEEE | Year: 2011

The distribution system provides major opportunities for smart grid concepts. One way to approach distribution system problems is to rethinking our distribution system to include the integration of high levels of distributed energy resources, using microgrid concepts. Basic objectives are improved reliability, promote high penetration of renewable sources, dynamic islanding, and improved generation efficiencies through the use of waste heat. Managing significant levels of distributed energy resources (DERs) with a wide and dynamic set of resources and control points can become overwhelming. The best way to manage such a system is to break the distribution system down into small clusters or microgrids, with distributed optimizing controls coordinating multimicrogrids. The Consortium for Electric Reliability Technology Solutions (CERTSs) concept views clustered generation and associated loads as a grid resource or a microgrid. The clustered sources and loads can operate in parallel to the grid or as an island. This grid resource can disconnect from the utility during events (i.e., faults, voltage collapses), but may also intentionally disconnect when the quality of power from the grid falls below certain standards. This paper focuses on DER-based distribution, the basics of microgrids, possibility of smart distribution systems using coupled microgrid and the current state of autonomous microgrid technology. © 2011 IEEE. Source


Heino J.,Finnish Environment Institute | Peckarsky B.L.,University of Wisconsin - Madison
Current Opinion in Insect Science | Year: 2014

Stream insects are ubiquitous in running waters, show high diversity in terms of species numbers, form and function, have key roles in ecosystem processes, and are thereby important components of ecological research. Here, we emphasize that the integration of behavior, population-level processes and large-scale constraints, such as the history of the regional species pool, drainage basin morphology and environmental conditions, may be key to increasing our understanding of how stream insect communities are assembled. We argue that as an alternative to analyzing the species composition of whole insect communities, focusing on variation in the composition of behavioral trait groups is likely to provide increased understanding of how stream insect communities are assembled, thereby linking behavioral, population and community ecology. © 2014 Elsevier Inc. Source


Ordonez A.,University of Wisconsin - Madison
American Journal of Botany | Year: 2013

Premise of the study: Predicting species responses to climate change has become a dynamic field in global change research. A crucial question in this debate is whether-or-not species have been and will be able to respond quickly enough to keep up with changing climatic conditions. Methods: Focusing on fossil pollen records and paleoclimatic simulations, this work assesses the change in realized climatic niches (climatic temporal trajectories) of 20 plant taxa over the last 16 000 yr, and whether this tracking has been the same for different climatic niche dimensions. Key results: Climatic factors showed a consistent trend toward warmer temperatures and higher precipitation. Although the response types varied across taxa, species' realized climatic niches lagged in response to changes in climatic conditions. Temperature niches responded to late Pleistocene (16 000-11 000 yr ago) climate change, but did so at slower rates than changes in climatic conditions during the same period. In contrast, precipitation niches were relatively stable from 16 000 to 11 000 yr ago, but still lagged behind changes in climatic conditions. Changes in temperature and precipitation niches eventually stabilized during the Holocene (11 000-1000 yr ago). Conclusions: These results underscore how the climatic niche realized at any one moment represents a subset of the climate conditions in which a taxon can persist, particularly during times of fast climatic change. Variability in the rates of temporal trajectories across evaluated climatic variables showed taxa specific responses to changes in climatic conditions over time and emphasizes the need to incorporate variation, intensity, and duration of lag effects in assessments of the possible effects of climatic change. © 2013 Botanical Society of America. Source


Xi L.,Massachusetts Institute of Technology | Graham M.D.,University of Wisconsin - Madison
Physical Review Letters | Year: 2012

Dynamical trajectories on the boundary in state space between laminar and turbulent plane channel flow-edge states-are computed for Newtonian and viscoelastic fluids. Viscoelasticity has a negligible effect on the properties of these solutions, and, at least at a low Reynolds number, their mean velocity profiles correspond closely to experimental observations for polymer solutions in the maximum drag reduction regime. These results confirm the existence of weak turbulence states that cannot be suppressed by polymer additives, explaining the fact that there is an upper limit for polymer-induced drag reduction. © 2012 American Physical Society. Source


Haasl R.J.,University of Wisconsin - Platteville | Payseur B.A.,University of Wisconsin - Madison
Molecular Ecology | Year: 2016

Genomewide scans for natural selection (GWSS) have become increasingly common over the last 15 years due to increased availability of genome-scale genetic data. Here, we report a representative survey of GWSS from 1999 to present and find that (i) between 1999 and 2009, 35 of 49 (71%) GWSS focused on human, while from 2010 to present, only 38 of 83 (46%) of GWSS focused on human, indicating increased focus on nonmodel organisms; (ii) the large majority of GWSS incorporate interpopulation or interspecific comparisons using, for example FST, cross-population extended haplotype homozygosity or the ratio of nonsynonymous to synonymous substitutions; (III) most GWSS focus on detection of directional selection rather than other modes such as balancing selection; and (iv) in human GWSS, there is a clear shift after 2004 from microsatellite markers to dense SNP data. A survey of GWSS meant to identify loci positively selected in response to severe hypoxic conditions support an approach to GWSS in which a list of a priori candidate genes based on potential selective pressures are used to filter the list of significant hits a posteriori. We also discuss four frequently ignored determinants of genomic heterogeneity that complicate GWSS: mutation, recombination, selection and the genetic architecture of adaptive traits. We recommend that GWSS methodology should better incorporate aspects of genomewide heterogeneity using empirical estimates of relevant parameters and/or realistic, whole-chromosome simulations to improve interpretation of GWSS results. Finally, we argue that knowledge of potential selective agents improves interpretation of GWSS results and that new methods focused on correlations between environmental variables and genetic variation can help automate this approach. © 2015 John Wiley & Sons Ltd. Source


Khodas M.,University of Iowa | Chubukov A.V.,University of Wisconsin - Madison
Physical Review Letters | Year: 2012

We analyze the pairing symmetry in Fe-based superconductors AFe 2Se 2 (A=K, Rb, Cs) which contain only electron pockets. We argue that the pairing condensate in such systems contains not only intrapocket component but also interpocket component, made of fermions belonging to different electron pockets. We analyze the interplay between intrapocket and interpocket pairing, depending on the ellipticity of electron pockets and the strength of their hybridization. We show that with increasing hybridization, the system undergoes a transition from a d-wave state to an s + - state, in which the gap changes sign between hybridized pockets. This s +- state has the full gap and at the same time supports spin resonance, in agreement with the data. Near the boundary between d and s +- states, we found a long-sought s+id state which breaks time-reversal symmetry. © 2012 American Physical Society. Source


Hardin J.,University of Wisconsin - Madison
Methods in Cell Biology | Year: 2011

The Caenorhabditis elegans embryo is well suited to morphogenetic analysis via modern microscopy, due to its short generation time, transparency, invariant lineage, and the ability to generate transgenic embryos expressing various fluorescent proteins. This chapter provides an overview of microscopy techniques for imaging embryonic morphogenesis, including making agar mounts, capturing four-dimensional (4D) data using Nomarski microscopy, imaging of actin in embryos, factors important for optimizing 4D fluorescence microscopy, and recent techniques that leverage fluorescence microscopy for intracellular imaging of cellular components during morphogenesis. © 2011 Elsevier Inc. Source


Ives A.R.,University of Wisconsin - Madison | Garland T.,University of California at Riverside
Systematic Biology | Year: 2010

We develop statistical methods for phylogenetic logistic regression in which the dependent variable is binary (0 or 1) and values are nonindependent among species, with phylogenetically related species tending to have the same value of the dependent variable. The methods are based on an evolutionary model of binary traits in which trait values switch between 0 and 1 as species evolve up a phylogenetic tree. The more frequently the trait values switch (i.e., the higher the rate of evolution), the more rapidly correlations between trait values for phylogenetically related species break down. Therefore, the statistical methods also give a way to estimate the phylogenetic signal of binary traits. More generally, the methods can be applied with continuous-and/or discrete-valued independent variables. Using simulations, we assess the statistical properties of the methods, including bias in the estimates of the logistic regression coefficients and the parameter that estimates the strength of phylogenetic signal in the dependent variable. These analyses show that, as with the case for continuous-valued dependent variables, phylogenetic logistic regression should be used rather than standard logistic regression when there is the possibility of phylogenetic correlations among species. Standard logistic regression does not properly account for the loss of information caused by resemblance of relatives and as a result is likely to give inflated type I error rates, incorrectly identifying regression parameters as statistically significantly different from zero when they are not. Source


Kreeger P.K.,University of Wisconsin - Madison
Science Signaling | Year: 2013

This Teaching Resource provides lecture notes, slides, and a problem set for a lecture introducing the mathematical concepts and interpretation of partial least squares regression (PLSR) that were part of a course entitled "Systems Biology: Mammalian Signaling Networks." PLSR is a multivariate regression technique commonly applied to analyze relationships between signaling or transcriptional data and cellular behavior. Copyright © 2008 by the American Association for the Advancement of Science; all rights reserved. Source


The purpose of the present study was to identify abnormal areas of regional synchronization in patients with mesial temporal lobe epilepsy and hippocampus sclerosis (mTLE-HS) compared to healthy controls, by applying a relatively novel method, the Regional Homogeneity (ReHo) method to resting state fMRI (RS-fMRI) data. Eyes closed RS-fMRI data were acquired from 10 mTLE-HS patients (four right-side, six left-side) and 15 age- and gender-matched healthy subjects, and were analyzed by using ReHo. For group analysis, four right-side MTLE-HS patients' functional images were flipped, in order to make a homogeneous left MTLE-HS group (10 cases) and increase the sample size. Compared to the healthy control group, patients showed significantly increased ReHo in ipsilateral parahippocampal gyrus, midbrain, insula, corpus callosum, bilateral sensorimotor cortex, and frontoparietal subcortical structures, whereas decreased ReHo was observed mainly in default mode network (DMN) (including precuneus and posterior cingulate gyrus, bilateral inferior lateral parietal, and mesial prefrontal cortex) and cerebellum in patients relative to the control group. This study identified that ReHo pattern in mTLE-HS patients was altered compared to healthy controls. We consider decreased ReHo in DMN to be responsible for wide functional impairments in cognitive processes. We propose that the increased ReHo in specific regions may form a network that might be responsible for seizure genesis and propagation. Wiley Periodicals, Inc. © 2013 International League Against Epilepsy. Source


Hastenrath S.,University of Wisconsin - Madison
International Journal of Climatology | Year: 2010

Equatorial glaciers are particularly climate sensitive components of the environment and their area shrinkage is spectacular, but the quantitative appraisal of climatic forcing requires information on net balance and changing ice thickness. Unique in the tropical belt, observations of mass budget and surface topography have been gathered by decades- long monitoring on Mount Kenya, particularly its largest, the Lewis Glacier. More limited information on ice thickness change is available for the summit of Kilimanjaro. Sensitivity analyses with constant precipitation, net allwave radiation and relative humidity serve to explore the sensible and latent heat transfer processes; humidity change riding on that of temperature providing the more substantial energy contribution to ablation. For Lewis Glacier it is found that with air some 0.7 °C cooler the mass budget could reach equilibrium. Observations on the secular evolution of air temperature and humidity in the areas of Mount Kenya and Rwenzori show compatible magnitudes, although contribution by radiative forcing cannot be excluded. For the summit of Kilimanjaro, above the mean freezing level, where ablation is limited to sublimation, turbulent heat transfer processes associated with temperature differences cannot account for the imbalance of the mass budget, and solar radiation forcing continues to be important for both the ice thinning and the lateral retreat of ice cliffs. © 2009 Royal Meteorological Society. Source


Guzei I.A.,University of Wisconsin - Madison
Journal of Applied Crystallography | Year: 2014

An idealized molecular geometry library with 40 geometries of molecules and ions optimized by density functional theory methods has been created. All geometries are accessible through a web site. The library entries are tailored for constrained (also known as rigid body) refinements of problematic small-molecule structures with the OLEX2 and SHELXL software packages. The library application is demonstrated with the refinement of a Pd complex, trans-Pd(dimethyl sulfoxide)(OH2)(trifluoroacetate)2, that co-crystallizes in a 2:1 ratio with a solvent molecule of ethyl acetate disordered over an inversion center. Alternative approaches to constrained refinements are discussed. © 2014. Source


Garbarski D.,University of Wisconsin - Madison
Journal of Health and Social Behavior | Year: 2014

While many studies use parental socioeconomic status and health to predict children's health, this study examines the interplay over time between child and maternal health across childhood and adolescence. Using data from women in the National Longitudinal Study of Youth 1979 cohort and their children (N = 2,225), autoregressive cross-lagged models demonstrate a reciprocal relationship between child activity limitations and maternal health limitations in direct effects of child activity limitations on maternal health limitations two years later and vice versa-net of a range of health-relevant time-varying and time-invariant covariates. Furthermore, there are indirect effects of child activity limitations on subsequent maternal health limitations and indirect effects of maternal health limitations on subsequent child activity limitations via intervening health statuses. This study examines how the interplay between child and maternal health unfolds over time and describes how these interdependent statuses jointly experience health disadvantages. © American Sociological Association 2014. Source


Pagliarini D.J.,University of Wisconsin - Madison | Rutter J.,University of Utah
Genes and Development | Year: 2013

Stemming from the pioneering studies of bioenergetics in the 1950s, 1960s, and 1970s, mitochondria have become ingrained in the collective psyche of scientists as the "powerhouses" of the cell. While this remains a worthy moniker, more recent efforts have revealed that these organelles are home to a vast array of metabolic and signaling processes and possess a proteomic landscape that is both highly varied and largely uncharted. As mitochondrial dysfunction is increasingly being implicated in a spectrum of human diseases, it is imperative that we construct a more complete framework of these organelles by systematically defining the functions of their component parts. Powerful new approaches in biochemistry and systems biology are helping to fill in the gaps. © 2013 Pagliarini and Rutter. Source


Dent E.W.,University of Wisconsin - Madison | Gupton S.L.,Massachusetts Institute of Technology | Gupton S.L.,University of North Carolina at Chapel Hill | Gertler F.B.,Massachusetts Institute of Technology
Cold Spring Harbor Perspectives in Biology | Year: 2011

Axon outgrowth and guidance to the proper target requires the coordination of filamentous (F)-actin and microtubules (MTs), the dynamic cytoskeletal polymers that promote shape change and locomotion. Over the past two decades, our knowledge of the many guidance cues, receptors, and downstream signaling cascades involved in neuronal outgrowth and guidance has increased dramatically. Less is known, however, about how those cascades of information converge and direct appropriate remodeling and interaction of cytoskeletal polymers, the ultimate effectors of movement and guidance. During development, much of the communication that occurs between environmental guidance cues and the cytoskeleton takes place at the growing tip of the axon, the neuronal growth cone. Several articles on this topic focus on the "input" to the growth cone, themyriad of receptor types, and their corresponding cognate ligands. Others investigate the signaling cascades initiated by receptors and propagated by second messenger pathways (i.e., kinases, phosphatases, GTPases). Ultimately, this plethora of information converges on proteins that associate directly with the actin and microtubule cytoskeletons. The role of these cytoskeletal-associated proteins, aswell as the cytoskeleton itself in axon outgrowth and guidance, is the subject of this article. © 2011 Cold Spring Harbor Laboratory Press. Source


Chirkin D.,University of Wisconsin - Madison
Nuclear Instruments and Methods in Physics Research, Section A: Accelerators, Spectrometers, Detectors and Associated Equipment | Year: 2013

GPUs (graphics processing units) have become increasingly popular in the recent years for scientific calculations involving large numbers of similar steps. Photon propagation is a necessary part of simulating detector response to passing charged particles in IceCube that is an ideal application for use with GPUs. We discuss the principle ideas and practical issues of running such an application within the simulation chain used within our collaboration. Source


Ahlers M.,University of Wisconsin - Madison
Physical Review Letters | Year: 2014

The propagation of cosmic rays (CRs) in turbulent interstellar magnetic fields is typically described as a spatial diffusion process. This formalism predicts only a small deviation from an isotropic CR distribution in the form of a dipole in the direction of the CR density gradient or relative background flow. We show that the existence of a global CR dipole moment necessarily generates a spectrum of higher multipole moments in the local CR distribution. These anomalous anisotropies are a direct consequence of Liouville's theorem in the presence of a local turbulent magnetic field. We show that the predictions of this model are in excellent agreement with the observed power spectrum of multi-TeV CRs. © 2014 American Physical Society. Source


Roden E.E.,University of Wisconsin - Madison
Biochemical Society Transactions | Year: 2012

In addition to its central role in mediating electron-transfer reactions within all living cells, iron undergoes extracellular redox transformations linked to microbial energy generation through utilization of Fe(II) as a source of chemical energy or Fe(III) as an electron acceptor for anaerobic respiration. These processes permit microbial populations and communities to engage in cyclic coupled iron oxidation and reduction within redox transition zones in subsurface environments. In the present paper, I review and synthesize a few case studies of iron-redox cycling in subsurface environments, highlighting key biochemical aspects of the extracellular iron-redox metabolisms involved. Of specific interest are the coupling of iron oxidation and reduction in field and experimental systems that model redox gradients and fluctuations in the subsurface, and novel pathways and organisms involved in the redox cycling of insoluble iron-bearing minerals. These findings set the stage for rapid expansion in our knowledge of the range of extracellular electron-transfer mechanisms utilized by subsurface micro-organisms. The observation that closely coupled oxidation and reduction of iron can take place under conditions common to the subsurface motivates this expansion in pursuit of molecular tools for studying iron-redox cycling communities in situ. ©The Authors Journal compilation ©2012 Biochemical Society. Source


Vogelius I.R.,Copenhagen University | Bentzen S.M.,University of Wisconsin - Madison
International Journal of Radiation Oncology Biology Physics | Year: 2013

Purpose: To present a novel method for meta-analysis of the fractionation sensitivity of tumors as applied to prostate cancer in the presence of an overall time factor. Methods and Materials: A systematic search for radiation dose-fractionation trials in prostate cancer was performed using PubMed and by manual search. Published trials comparing standard fractionated external beam radiation therapy with alternative fractionation were eligible. For each trial the α/β ratio and its 95% confidence interval (CI) were extracted, and the data were synthesized with each study weighted by the inverse variance. An overall time factor was included in the analysis, and its influence on α/β was investigated. Results: Five studies involving 1965 patients were included in the meta-analysis of α/β. The synthesized α/β assuming no effect of overall treatment time was -0.07 Gy (95% CI -0.73-0.59), which was increased to 0.47 Gy (95% CI -0.55-1.50) if a single highly weighted study was excluded. In a separate analysis, 2 studies based on 10,808 patients in total allowed extraction of a synthesized estimate of a time factor of 0.31 Gy/d (95% CI 0.20-0.42). The time factor increased the α/β estimate to 0.58 Gy (95% CI -0.53-1.69)/1.93 Gy (95% CI -0.27-4.14) with/without the heavily weighted study. An analysis of the uncertainty of the α/β estimate showed a loss of information when the hypofractionated arm was underdosed compared with the normo-fractionated arm. Conclusions: The current external beam fractionation studies are consistent with a very low α/β ratio for prostate cancer, although the CIs include α/β ratios up to 4.14 Gy in the presence of a time factor. Details of the dose fractionation in the 2 trial arms have critical influence on the information that can be extracted from a study. Studies with unfortunate designs will supply little or no information about α/β regardless of the number of subjects enrolled. © 2013 Elsevier Inc. Source


Jackson D.J.,University of Wisconsin - Madison
Current Opinion in Allergy and Clinical Immunology | Year: 2010

PURPOSE OF REVIEW: To discuss the role of human rhinoviruses (HRVs) in early childhood wheezing illnesses and how HRVs contribute to the development of childhood asthma. RECENT FINDINGS: Advanced molecular diagnostics have identified HRVs as pathogens frequently causing wheezing illnesses in infants and young children. Wheezing during HRV infection in early life identifies children at particularly high-risk of asthma development. Plausible mechanisms by which HRV could cause airway damage, promote airway remodeling, and lead to asthma development have recently been identified. SUMMARY: HRV is a significant source of morbidity in infants and young children. The present review identifies mechanisms by which HRV lower respiratory tract infection, particularly in a susceptible host, could promote the development of childhood asthma. Further studies are needed to elucidate the mechanisms underlying the link between HRV wheezing in early childhood and subsequent asthma development, with the critical goal of identifying novel therapeutic and prevention strategies for both early childhood wheezing and asthma. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source


Flook L.,University of Wisconsin - Madison
Child Development | Year: 2011

This study examined daily interpersonal events with parents and friends and daily well-being among 589 ninth-grade students (mean age=14.9years) from Mexican, Chinese, and European backgrounds. Associations were examined using a daily diary methodology whereby adolescents reported on positive and negative interpersonal experiences and mood each day for 2weeks. Analyses using hierarchical linear modeling revealed bidirectional associations between adolescents' daily social interactions and mood. Findings indicated gender differences in adolescents' reactivity to daily interpersonal events as well as in the strength of daily mood as a predictor of interpersonal events. Furthermore, the ratio of positive to negative events experienced daily was consequential for adolescents' daily mood. Findings have practical implications for adolescents' everyday functioning and potential long-term adjustment. © 2011 The Author. Child Development © 2011 Society for Research in Child Development, Inc.. Source


Fernandes R.M.,University of Minnesota | Chubukov A.V.,University of Wisconsin - Madison | Schmalian J.,Karlsruhe Institute of Technology
Nature Physics | Year: 2014

Although the existence of nematic order in iron-based superconductors is now a well-established experimental fact, its origin remains controversial. Nematic order breaks the discrete lattice rotational symmetry by making the x and y directions in the iron plane non-equivalent. This can happen because of a regular structural transition or as the result of an electronically driven instability-in particular, orbital order or spin-driven Ising-nematic order. The latter is a magnetic state that breaks rotational symmetry but preserves time-reversal symmetry. Symmetry dictates that the development of one of these orders immediately induces the other two, making the origin of nematicity a physics realization of the 'chicken and egg problem'. In this Review, we argue that the evidence strongly points to an electronic mechanism of nematicity, placing nematic order in the class of correlation-driven electronic instabilities, like superconductivity and density-wave transitions. We discuss different microscopic models for nematicity and link them to the properties of the magnetic and superconducting states, providing a unified perspective on the phase diagram of the iron pnictides. © 2014 Macmillan Publishers Limited. Source


Luedtke J.,University of Wisconsin - Madison
Mathematical Programming | Year: 2014

We present a new approach for exactly solving chance-constrained mathematical programs having discrete distributions with finite support and random polyhedral constraints. Such problems have been notoriously difficult to solve due to nonconvexity of the feasible region, and most available methods are only able to find provably good solutions in certain very special cases. Our approach uses both decomposition, to enable processing subproblems corresponding to one possible outcome at a time, and integer programming techniques, to combine the results of these subproblems to yield strong valid inequalities. Computational results on a chance-constrained formulation of a resource planning problem inspired by a call center staffing application indicate the approach works significantly better than both an existing mixed-integer programming formulation and a simple decomposition approach that does not use strong valid inequalities. We also demonstrate how the approach can be used to efficiently solve for a sequence of risk levels, as would be done when solving for the efficient frontier of risk and cost. © 2013 Springer-Verlag Berlin Heidelberg and Mathematical Optimization Society. Source


Hill J.C.,Purdue University | Choi K.-S.,University of Wisconsin - Madison
Journal of Materials Chemistry A | Year: 2013

Two n-type W-containing ternary oxides, CuWO4 and Bi 2WO6, were prepared as high surface area electrodes and characterized for use as photoanodes in a water-splitting photoelectrochemical cell. The synthesis involved electrochemical preparation of porous WO 3 electrodes and annealing them with Cu2+- or Bi 3+-containing solutions on their surfaces to form the respective electrodes. The resulting CuWO4 electrode had a bandgap of 2.3 eV, and showed excellent photostability and photocurrent-to-O2 conversion efficiency (ca. 100%) in 0.1 M borate buffer solution (pH 9). Bi 2WO6 had a bandgap of 2.8 eV but, regardless of its higher bandgap energy, Bi2WO6 showed an earlier photocurrent onset and much higher photocurrent than CuWO4 due to its more favorable CB edge and flatband potential position for water splitting. Bi 2WO6 also showed chemical stability over a wide pH range (-0.26 ≤ pH ≤ 9.0). The photocurrent-to-O2 conversion efficiency of Bi2WO6 was in the range of 50-75% and its photocurrent decayed over time, indicating photocorrosion. However, stable photocurrent was obtained when H2O2, which has faster oxidation kinetics than water, was introduced into the electrolyte as a hole scavenger. This suggests that the photocorrosion of Bi2WO6 can be suppressed when an oxygen evolution catalyst is placed on its surface to improve interfacial hole transfer kinetics. With proper oxygen evolution catalysts and improved charge transport properties, both CuWO4 and Bi2WO6 have the possibility of achieving better photoelectrochemical performances than WO3. © The Royal Society of Chemistry 2013. Source


Kelsic E.D.,Harvard University | Zhao J.,Harvard University | Vetsigian K.,University of Wisconsin - Madison | Kishony R.,Harvard University | Kishony R.,Technion - Israel Institute of Technology
Nature | Year: 2015

A major challenge in theoretical ecology is understanding how natural microbial communities support species diversity, and in particular how antibiotic-producing, -sensitive and -resistant species coexist. While cyclic rock-paper-scissors interactions can stabilize communities in spatial environments, coexistence in unstructured environments remains unexplained. Here, using simulations and analytical models, we show that the opposing actions of antibiotic production and degradation enable coexistence even in well-mixed environments. Coexistence depends on three-way interactions in which an antibiotic-degrading species attenuates the inhibitory interactions between two other species. These interactions enable coexistence that is robust to substantial differences in inherent species growth rates and to invasion by cheating species that cease to produce or degrade antibiotics. At least two antibiotics are required for stability, with greater numbers of antibiotics enabling more complex communities and diverse dynamic behaviours ranging from stable fixed points to limit cycles and chaos. Together, these results show how multi-species antibiotic interactions can generate ecological stability in both spatially structured and mixed microbial communities, suggesting strategies for engineering synthetic ecosystems and highlighting the importance of toxin production and degradation for microbial biodiversity. © 2015 Macmillan Publishers Limited. All rights reserved. Source


Keely P.J.,University of Wisconsin - Madison
Journal of Mammary Gland Biology and Neoplasia | Year: 2011

Cell adhesion to the extracellular matrix (ECM) is necessary for development of the mammary gland, and to maintain the normal architecture and function of the gland. Cells adhere to the ECM via the integrin family of transmembrane receptors, which signal to control mammaryspecific gene expression and regulate cell proliferation and survival. During tumor formation, the ECM is extensively remodeled and signaling through integrins is altered such that cells become proliferative and invasive. A key regulator of whether integrin-mediated adhesion will promote tumor suppression or tumor formation is the stiffness of the stromal ECM. The normal mammary gland is typically surrounded by a loose collagenous stroma. An increase in the deposition of collagen and other stromal components is associated with mammographic density, which is one of the greatest risk factors for developing breast carcinoma. Several groups have demonstrated that increased stromal ECM density results in a matrix that is stiffer. Cells sense the stiffness of their surrounding ECM by Rho-mediated contraction of the actin-myosin cytoskeleton. If the surrounding ECM is stiffer than the cell's ability to contract it, then the tensile forces that result are able to drive the clustering of integrins and assemble adhesion signaling complexes. The result is subsequent activation of signaling pathways including FAK, ERK, and PI3K that drive cell proliferation and survival. In contrast, focal complexes are not formed in a compliant matrix, and activation of FAK and pERK is diminished, resulting in control of proliferation. Signaling from FAK moreover regulates p53 and miR-200 members, which control apoptosis and epithelial phenotype, such that a compliant matrix is predicted to promote normal mammary gland architecture and suppress tumor formation. © Springer Science+Business Media, LLC 2011. Source


Hammerschmidt W.,Helmholtz Center for Environmental Research | Sugden B.,University of Wisconsin - Madison
Cold Spring Harbor Perspectives in Biology | Year: 2013

Epstein-Barr virus (EBV) is a paradigm for human tumor viruses: it is the first virus recognized to cause cancer in people; it causes both lymphomas and carcinomas; yet these tumors arise infrequently given that most people in theworld are infected with the virus. EBVis maintained extrachromosomally in infected normal and tumor cells. Eighty-four percent of these viral plasmids replicate each S phase, are licensed, require a single viral protein for their synthesis, and can use two functionally distinct origins of DNA replication, oriP, and Raji ori. Eightyeight percent of newly synthesized plasmids are segregated faithfully to the daughter cells. Infectious viral particles are not synthesized under these conditions of latent infection. This plasmid replication is consistent with survival of EBV's host cells. Rare cells in an infected population either spontaneously or following exogenous induction support EBV's lytic cycle, which is lethal for the cell. In this case, the viralDNA replicates 100-fold or more, uses a third kind of viral origin ofDNAreplication, oriLyt, and manyviral proteins. Herewe shall describe the three modes of EBV's replication as a function of the viral origins used and the viral and cellular proteins that mediate theDNAsynthesis fromthese origins focusing,where practical, on recent advances in our understanding. © 2013 Cold Spring Harbor Laboratory Press; all rights reserved. Source


Jonker M.A.,University of Wisconsin - Madison
Annals of Surgery | Year: 2015

OBJECTIVE:: To define gut-associated lymphoid tissue (GALT) phenotype changes with parenteral nutrition (PN) and PN with bombesin (BBS).BACKGROUND:: PN reduces respiratory tract (RT) and GALT Peyer patch and lamina propria lymphocytes, lowers gut and RT immunoglobulin A (IgA) levels, and destroys established RT antiviral and antibacterial immunity. BBS, an enteric nervous system neuropeptide, reverses PN-induced IgA and RT immune defects.METHODS:: Experiment 1: Intravenously cannulated ICR mice received chow, PN, or PN + BBS injections for 5 days. LSR-II flow cytometer analyzed Peyer patches and lamina propria isolated lymphocytes for homing phenotypes (L-selectin and LPAM-1) and state of activation (CD25, CD44) in T (CD3)-cell subsets (CD4 and CD8) along with homing phenotype (L-selectin and LPAM-1) in naive B (IgD) and antigen-activated (IgD or IgM) B (CD45R/B220) cells. Experiment 2: Following the initial experiment 1 protocol, lamina propria T regulatory cell phenotype was evaluated by Foxp3 expression.RESULTS:: Experiment 1: PN significantly reduced lamina propria (1) CD4CD25 (activated) and (2) CD4CD25LPAM-1 (activated cells homed to the lamina propria) T cells, whereas PN-BBS assimilated chow levels. PN significantly reduced lamina propria (1) IgD (naive), (2) IgDLPAM (antigen-activated homed to the lamina propria) and CD44 memory B cells, whereas PN-BBS assimilated chow levels. Experiment 2: PN significantly reduced lamina propria CD4CD25Foxp3 T regulatory cells compared with chow-fed mice, whereas PN + BBS assimilated chow levels.CONCLUSIONS:: PN reduces lamina propria activated and T regulatory cells and also naive and memory B cells. BBS addition to PN maintains these cell phenotypes, demonstrating the intimate involvement of the enteric nervous system in mucosal immunity. © 2015 by Lippincott Williams & Wilkins. Source


Lucey M.R.,University of Wisconsin - Madison
Nature Reviews Gastroenterology and Hepatology | Year: 2014

Alcoholic liver disease (ALD) is the major cause of life-threatening liver disease in Western countries. Abstinence from alcohol is the foundation of all treatment programmes for patients with ALD. Liver transplantation is a valuable option for patients with life-threatening ALD. Although the role of liver transplantation in the treatment of alcoholic hepatitis that is unresponsive to medical therapy is controversial, the latest prospective studies support this approach. No single measure gives a reliable estimate of the risk of drinking relapses before or after liver transplantation, but careful evaluation by an addiction specialist with a particular interest in transplant medicine is the best available approach. Survival, both on the waiting list and after the operation, is better in patients with ALD than in patients with HCV infection. Alcohol relapse may lead to liver damage and increased mortality, albeit usually after many years of renewed drinking. After liver transplantation, patients with ALD have increased rates of mortality and morbidity that are attributable to cardiovascular disease and new-onset cancers of the aerodigestive tract. The latter are probably linked to the high prevalence of smoking in this population. Cessation of smoking is thus an important goal in the care of patients with ALD after they have undergone liver transplantation. © 2014 Macmillan Publishers Limited. All rights reserved. Source


Gaisser T.,University of Delaware | Halzen F.,University of Wisconsin - Madison
Annual Review of Nuclear and Particle Science | Year: 2014

IceCube is the first kilometer-scale neutrino detector. Built primarily for neutrino astronomy, it has recently discovered events with energies above 100 TeV that are likely to be from distant sources beyond the solar system. Among the events are three with deposited energies of more than 1 PeV, the highest-energy neutrinos ever detected. We review the astrophysical arguments that motivate such a large detector, and we describe how it works and how the high-energy events are reconstructed and identified above the background of atmospheric neutrinos. We also describe the broad range of neutrino physics and particle astrophysics topics addressed by IceCube, as well as its potential for the future. Copyright © 2014 by Annual Reviews. All rights reserved. Source


Vogelsang E.M.,University of Wisconsin - Madison
Journals of Gerontology - Series B Psychological Sciences and Social Sciences | Year: 2014

Objectives. This study explores how 2 measures of self-rated health (SRH) change are related to mortality among oldest-old adults. In doing so, it also considers how associations between SRH and mortality may depend on prior SRH. Method. Data come from the Asset and Health Dynamics survey-the oldest-old portion of the Health and Retirement Study-and follow 6,233 individuals across 13 years. I use parametric hazard models to examine relationships between death and 2 measures of short-term SRH change-a computed measure comparing SRH at time t-1 and t, and a respondent-provided retrospectively reported change. Results. Respondents who demonstrate or report any SRH change between survey waves died at a greater rate than those with consistent SRH. After controlling for morbidity, individual characteristics, and SRH, those who changed SRH categories between survey waves and those who retrospectively reported an improvement in health continue to have a greater risk of death, when compared with those with no change. Discussion. These findings suggest that the well-established associations between SRH status and mortality may understate the risk of death for oldest-old individuals with recent subjective health improvements. © 2014 The Author. Source


Spalding E.P.,University of Wisconsin - Madison | Harper J.F.,University of Nevada, Reno
Current Opinion in Plant Biology | Year: 2011

The cytoplasmic Ca 2+ signals that participate in nearly all aspects of plant growth and development encode information as binary switches or information-rich signatures. They are the result of influx (thermodynamically passive) and efflux (thermodynamically active) activities mediated by membrane transport proteins. On the influx side, confirming the molecular identities of Ca 2+-permeable channels is still a major research topic. Cyclic nucleotide-gated channels and glutamate receptor-like channels are candidates well supported by evidence. On the efflux side, CAX antiporters and P-type ATPase pumps are the principal molecular entities. Both of these active transporters load Ca 2+ into specific compartments and have the potential to reduce the magnitude and duration of a Ca 2+ transient. Recent studies indicate calmodulin-activated Ca 2+ pumps in endomembrane systems can dampen the magnitude and duration of a Ca 2+ transient that could otherwise grow into a Ca 2+ cell death signature. An important challenge following molecular characterization of the influx and efflux pathways is to understand how they are coordinately regulated to produce a Ca 2+ switch or encode specific information into a Ca 2+ signature. © 2011. Source


Paolone D.R.,University of Wisconsin - Madison
Clinics in Geriatric Medicine | Year: 2010

This article reviews the epidemiology of benign prostatic hyperplasia (BPH), evaluation of patients with lower urinary tract symptomatology (LUTS), and management of patients with BPH and LUTS. The evaluation includes history and physical examination, laboratory testing, and specialized studies. The management includes medical and surgical options. Medical options include alpha-1-adrenergic receptor blockers, 5alpha-reductase inhibitors, and combinations of these and other medications. Surgical options include endoscopic procedures, open procedures, and laser procedures. © 2010. Source


Huber D.L.,University of Wisconsin - Madison
Journal of Physics Condensed Matter | Year: 2012

Electron spin resonance (ESR) in the Kondo lattice compound Y bRh 2Si 2 has stimulated discussion as to whether the low-field resonance outside the Fermi liquid regime in this material is more appropriately characterized as a local-moment phenomenon or one that requires a Landau quasiparticle interpretation. In earlier work, we outlined a collective mode approach to the ESR that involves only the local 4f moments. In this paper, we extend the collective mode approach to a situation where there are two subsystems of unlike spins: the pseudospins of the ground multiplet of the Yb ions and the spins of the itinerant conduction electrons. We assume a weakly anisotropic exchange interaction between the two subsystems. With suitable approximations our expression for the g-factor also reproduces that found in recent unlike-spin quasiparticle calculations. It is pointed out that the success of the local-moment approach in describing the resonance is due to the fact that the susceptibility of the Yb subsystem dominates that of the conduction electrons with the consequence that the relative shift in the resonance frequency predicted by the unlike-spin models (and absent in the local-moment models) is 1. The connection with theoretical studies of a two-component model with like spins is also discussed. © 2012 IOP Publishing Ltd. Source


Richards M.P.,University of Wisconsin - Madison
Antioxidants and Redox Signaling | Year: 2013

Significance: Failure to maintain myoglobin (Mb) in the reduced state causes the formation of metMb, ferryl Mb species, and cross-linked Mb. Dissociation of ferriprotoporphyrin IX from the globin and release of iron atoms can also occur as oxidized Mb accumulates. These modifications may contribute to various oxidative pathologies in muscle and muscle foods. Recent Advances: The mechanism of ferryl Mb-mediated oxidative damage to nearby structures has been partially elucidated. Dissociation of ferriprotoporphyrin IX from metMb occurs more readily at acidic pH values. The dissociated ferriprotoporphyrin IX (also called hemin) readily decomposes preformed lipid hydroperoxides to reactive oxygen species. Heme oxygenase as well as lipophilic free radicals can degrade the protoporphyrin IX moiety, which results in the formation of free iron. Critical Issues: The multiple pathways by which Mb can incur toxicity create difficulties in determining the major cause of oxidative damage in a particular system. Peroxides and low pH activate each of the oxidative Mb forms, ferriprotoporphyrin IX, and released iron. Determining the relative concentration of these species is technically difficult, but essential to a complete understanding of oxidative pathology in muscle tissue. Future Directions: Improved methods to assess the different pathways of Mb toxicity are needed. Although significant advances have been made in the understanding of Mb interactions with other biomolecules, further investigation is needed to understand the physical and chemical nature of these interactions. Antioxid. Redox Signal. 18, 2342-2351. © 2013, Mary Ann Liebert, Inc. Source


Hittinger C.T.,University of Wisconsin - Madison
Trends in Genetics | Year: 2013

Saccharomyces cerevisiae is one of the best-understood and most powerful genetic model systems. Several disciplines are now converging to turn Saccharomyces into an exciting model genus for evolutionary genetics and genomics. Yeast taxonomists and ecologists have dramatically expanded and clarified Saccharomyces diversity, more than doubling the number of bona fide species since 2000. High-quality genome sequences are available (or soon will be) for all seven known species. Haploid laboratory strains are enabling a deep integration of classic genetic approaches with modern genomic tools. Population genomic surveys and quantitative trait mapping of variation within species are underway across the genus. Finally, several case studies have illuminated general and novel genetic mechanisms of evolution. Expanding strain collections, low-cost genome sequencing, and tools for precise genetic manipulation promise to usher in a golden era for this surprisingly diverse genus as an evolutionary model. © 2013 Elsevier Ltd. Source


Kapur S.K.,University of Wisconsin - Madison | Katz A.J.,University of Florida
Biochimie | Year: 2013

Recent advances in protein detection and analysis have lead to multiple in depth studies that analyze the adipose-derived stem cell (ASC) secretome. These studies differ significantly in their methods of secretome preparation and analysis. Most of them use a pro-differentiation or pro-inflammatory stimulus to observe differential expression of secreted proteins. In spite of the variance in methodologies used, 68 proteins are reported to be commonly expressed in a majority of the studies and may serve as potential candidates for conserved secretome proteins. Multiple recent clinical and basic science studies demonstrate the beneficial role played by secreted proteins in augmenting ASC effects in scenarios involving angiogenesis, wound healing, tissue regeneration and immunomodulation. Furthermore, 3-D formulations of ASCs that preserve the niche environment of cells and their secreted proteins have also shown enhanced clinical effects. In light of the lack of uniformity in prior secretome-analysis studies, and the growing clinical importance of the ASC secretome, more in depth studies that use uniform and standardized means of protein detection and analysis are necessary. © 2013 Elsevier Masson SAS. All rights reserved. Source


Likos W.J.,University of Wisconsin - Madison | Jaafar R.,Fugro
Journal of Geotechnical and Geoenvironmental Engineering | Year: 2013

A model for the water retention behavior of unsaturated granular soil is developed by extending the classic bundled cylindrical capillary representation of pore space to a geometry more closely approximating that of granular porous media. Expressions for pore-scale saturation are derived as functions of matric suction for a three-dimensional unit pore comprising angular pore space bounded by spheres in simple cubic packing order. Water retention curves are modeled byassigning a statistical distribution of pore sizes optimized to best match experimentally determined retention curves. A key model attribute is its capability to capture evolution of fluid partitioning along drainage or wetting paths by differentiating pore water retained as thin films adsorbed to particle surfaces, liquid bridges retained in wedge-shaped pores, and saturated pockets in relatively small pores. Interfacial surface tension, solid-liquid contact angle, wettingdirection, and mineralogy (Hamaker constant) are treated as model variables to examine their influences on water retention. Modeled retention curves compare well with measured curves obtained for glass beads, natural sands, and soils fromthe literature. The model effectively estimates hysteretic wetting-drying response, surfactant-induced surface tension lowering, and air-water interface area as a function of saturation. Capability to model evolution of fluid distributionhas potentially important implications toward more robust understanding of macroscopic hydraulic, electrical, thermal, and mechanical behavior of unsaturated soil. © 2013 American Society of Civil Engineers. Source


Kemnitz J.W.,University of Wisconsin - Madison
ILAR Journal | Year: 2011

In the 75 years since the seminal observation of Clive McCay that restriction of calorie intake extends the lifespan of rats, a great deal has been learned about the effects of calorie restriction (CR; reduced intake of a nutritious diet) on aging in various short-lived animal models. Studies have demonstrated many benefi cial effects of CR on health, the rate of aging, and longevity. Two prospective investigations of the effects of CR on long-lived nonhuman primate (NHP) species began nearly 25 years ago and are still under way. This review presents the design, methods, and main fi ndings of these and other important contributing studies, which have generally revealed benefi cial effects of CR on physiological function and the retardation of disease consistent with studies in other species. Specifi cally, prolonged CR appears to extend the lifespan of rhesus monkeys, which exhibited lower body fat; slower rate of muscle loss with age; lower incidence of neoplasia, cardiovascular disease, type 2 diabetes mellitus, and endometriosis; improved insulin sensitivity and glucose tolerance; and no apparent adverse effect on bone health, as well as a reduction in total energy expenditure. In addition, there are no reports of deleterious effects of CR on reproductive endpoints, and brain morphology is preserved by CR. Adrenal and thyroid hormone profi les are inconsistently affected. More research is needed to delineate the mechanisms of the desirable outcomes of CR and to develop interventions that can produce similar benefi cial outcomes for humans. This research offers tremendous potential for producing novel insights into aging and risk of disease. Source


Demets D.L.,University of Wisconsin - Madison
Statistics in Medicine | Year: 2012

Clinical trials, especially the randomized clinical trial, have been and will remain the gold standard for the evaluation of new interventions, including pharmaceuticals, biologics, medical devices, procedures, or behavioral modifications. Despite more than five decades of experience, there are still challenges in their design, conduct, monitoring, and analyses. Some of these challenges remain and some are emerging, in part due to the progress in genomics and proteomics. These issues may be statistical, logistical, or a combination. Included are follow-up of subjects who withdraw from intervention, the proposed use of recent adaptive designs, implementing noninferiority designs, reliance on surrogate markers, and gene transfer studies. Comparative effectiveness studies are of increasing interest but present major design and analysis issues. Forces external to the trial are also becoming more common. © 2012 John Wiley & Sons, Ltd. Source


Reich H.J.,University of Wisconsin - Madison
Journal of Organic Chemistry | Year: 2012

This Perspective describes a series of research projects that led the author from an interest in lithium reagents as synthetically valuable building blocks to studies aimed at understanding the science behind the empirical art developed by synthetic chemists trying to impose their will on these reactive species. Understanding lithium reagent behavior is not an easy task; since many are mixtures of aggregates, various solvates are present, and frequently new mixed aggregates are formed during their reactions with electrophiles. All of these species are typically in fast exchange at temperatures above -78 °C. Described are multinuclear NMR experiments at very low temperatures aimed at defining solution structures and dynamics and some kinetic studies, both using classic techniques as well as the rapid inject NMR (RINMR) technique, which can in favorable cases operate on multispecies solutions without the masking effect of the Curtin-Hammett principle. © 2012 American Chemical Society. Source


Moses T.,University of Wisconsin - Madison
Journal of Nervous and Mental Disease | Year: 2011

This study explores stigma apprehension (fear of being devalued or rejected) and its correlates among 102 adolescents, interviewed within 7 days of discharge from their first psychiatric hospitalization. Components of the Model of Stigma-Induced Identity Threat by Major and OBrien (Annu Rev Psychol 56:393-421, 2005) comprise the study model, including collective stigma representations and group and domain identification; additional clinical, personal, and contextual characteristics such as social affiliation, interpersonal support, self-identification as having a mental disorder, and perceived need for others approval were added to the model. We found that, on average, the participants reported "a little" stigma apprehension, and 21% reported substantial stigma apprehension. Multivariate analysis demonstrated that higher stigma apprehension was most associated with the female sex, younger age at initiation of mental health treatment, lower self-esteem, greater need for others approval, more experiences with personal stigmatization, and not identifying or affiliating with peers who have mental health or behavior challenges. These factors collectively accounted for 46% of the variance. The studys findings particularly highlight the role of social context and external contingencies of self-worth in determining adolescents perceptions of stigma-related threat. Copyright © 2011 by Lippincott Williams & Wilkins. Source


The 2010 Position Development Conference addressed four questions related to the impact of previous fractures on 10-year fracture risk as calculated by FRAX®.•Does the number of past fractures affect future fracture risk?•Does the severity of past vertebral fractures affect future fracture risk?•Does the site of past fractures affect future fracture risk?•Should the family history of fracture be expanded to include additional sites, additional family members, or account for age at fracture? To address these questions, PubMed was searched on the keywords "fracture, epidemiology, osteoporosis." Titles of retrieved articles were reviewed for an indication that risk for future fracture was discussed. Abstracts of these articles were reviewed for an indication that one or more of the questions listed above was discussed. For those that did, the articles were reviewed in greater detail to extract the findings and to find additional past work and citing works that also bore on the questions. The official positions and the supporting literature review are presented here. FRAX® underestimates fracture probability in persons with a history of multiple fractures (good, A, W). FRAX® may underestimate fracture probability in individuals with prevalent severe vertebral fractures (good, A, W). While there is evidence that hip, vertebral, and humeral fractures appear to confer greater risk of subsequent fracture than fractures at other sites, quantification of this incremental risk in FRAX® is not possible (fair, B, W). FRAX® may underestimate fracture probability in individuals with a parental history of non-hip fragility fracture (fair, B, W). Limitations of the methodology include performance by a single reviewer, preliminary review of the literature being confined to titles, and secondary review being limited to abstracts. Limitations of the evidence base include publication bias, overrepresentation of persons of European descent in the published studies, and technical differences in the methods used to identify prevalent and incident fractures. Emerging topics for future research include fracture epidemiology in non-European populations and men, the impact of fractures in family members other than parents, and the genetic contribution to fracture risk. © 2011 The International Society for Clinical Densitometry. Source


Ewer M.S.,University of Houston | Ewer S.M.,University of Wisconsin - Madison
Nature Reviews Cardiology | Year: 2015

Patients with cancer can experience adverse cardiovascular events secondary to the malignant process itself or its treatment. Patients with cancer might also have underlying cardiovascular illness, the consequences of which are often exacerbated by the stress of the tumour growth or its treatment. With the advent of new treatments and subsequent prolonged survival time, late effects of cancer treatment can become clinically evident decades after completion of therapy. The heart's extensive energy reserve and its ability to compensate for reduced function add to the complexity of diagnosis and timely initiation of therapy. Additionally, modern oncological treatment regimens often incorporate multiple agents whose deleterious cardiac effects might be additive or synergistic. Treatment-related impairment of cardiac contractility can be either transient or irreversible. Furthermore, cancer treatment is associated with life-threatening arrhythmia, ischaemia, infarction, and damage to cardiac valves, the conduction system, or the pericardium. Awareness of these processes has gained prominence with the arrival of strategies to monitor and to prevent or to mitigate the effects of cardiovascular damage. A greater understanding of the mechanisms of injury can prolong the lives of those cured of their malignancy, but left with potentially devastating cardiac sequelae. © 2015 Macmillan Publishers Limited. All rights reserved. Source


Kushner B.J.,University of Wisconsin - Madison
Archives of Ophthalmology | Year: 2011

Insertion slanting recessions or biased resections have been reported to be useful for treating A- and V-pattern strabismus, convergence insufficiency, and convergence excess esotropia. Paradoxically, good results have been reported with methods that are opposite in nature. For example, some researchers would recess the medial rectus muscles and slant the superior pole of each muscle back farther than the inferior pole (Simonsz/von Graefe method) for a V-pattern esotropia, and others would slant the inferior poles back farther (Bietti method). The Simonsz/von Graefe method seems to be based on sound concepts of oculomotor mechanics. The Bietti method has been justified based on a misquoting and misinterpretation of previous work by Alan Scott, MD. Probably neither method contributes substantially to the outcome of strabismus surgery because sarcomere remodeling should rapidly negate the effect of the slanting. Most likely it is the recession or resection itself that affects the outcome. ©2011 American Medical Association. All rights reserved. Source


Jackson D.J.,University of Wisconsin - Madison
Current Opinion in Allergy and Clinical Immunology | Year: 2014

PURPOSE OF REVIEW: To discuss the recent insights into the relationships between viral respiratory infections and asthma inception in the context of a long-term goal of moving toward prevention strategies for childhood asthma. RECENT FINDINGS: There is strong evidence for respiratory syncytial virus and human rhinovirus wheezing illnesses as important risk factors for asthma inception. The mechanisms underlying these relationships have been an intense area of study. Novel approaches for the prevention of virus infections and/or lessening the severity of associated illnesses are at various stages of development, and are important potential tools in efforts aimed at primary and secondary prevention of asthma. SUMMARY: Viral respiratory infections in early life are a major source of morbidity and are critical in the development of asthma. Mechanisms by which these infections lead to asthma inception in susceptible individuals are emerging. Further, there are promising potential interventions currently available that should be tested in clinical trials. The goal of prevention of disease inception is clearly on the horizon. © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source


Larget B.,University of Wisconsin - Madison
Systematic Biology | Year: 2013

In this article I introduce the idea of conditional independence of separated subtrees as a principle by which to estimate the posterior probability of trees using conditional clade probability distributions rather than simple sample relative frequencies. I describe an algorithm for these calculations and software which implements these ideas. I show that these alternative calculations are very similar to simple sample relative frequencies for high probability trees but are substantially more accurate for relatively low probability trees. The method allows the posterior probability of unsampled trees to be calculated when these trees contain only clades that are in other sampled trees. Furthermore, the method can be used to estimate the total probability of the set of sampled trees which provides ameasure of the thoroughness of a posterior sample. [Bayesian phylogenetics; conditional clade distributions; improved accuracy; posterior probabilities of trees.] © The Author(s) 2013. Source


Acher C.,University of Wisconsin - Madison
Journal of Thoracic and Cardiovascular Surgery | Year: 2010

We have surgically treated 771 patients for thoracic and thoracoabdominal aortic aneurysms since 1983. Our primary effort has been to develop experimentally validated strategies to reduce paraplegia, renal failure, and mortality in these high-risk patients. This approach has led to a spinal cord protection protocol that has reduced paraplegia risk by 80% (observed/expected ratio = 0.19) with the use of cerebral spinal fluid drainage, moderate hypothermia (31°C-33°C), endorphin receptor antagonist (naloxone), and thiopental burst suppression while optimizing mean arterial pressure (>90 mm Hg) and cardiac index. The elective mortality rate is 2.80% (17% for acute patients), and with rapid renal cooling for renal protection, only 0.88% required permanent dialysis. These results were achieved without the use of assisted circulation. We have reattached intercostal arteries since 2005 using preoperative magnetic resonance angiographic localization, but it remains unclear whether intercostal reimplantation reduces paraplegia risk, as we had initially proposed. We strongly believe that a consistent anesthetic and postoperative care protocol uniformly built and applied around these principles greatly enhances our surgical outcomes. We also show that improved outcomes with assisted circulation and hypothermic arrest in treatment of thoracoabdominal aortic disease follow similar principles of spinal cord and end-organ protection. Copyright © 2010 by The American Association for Thoracic Surgery. Source


Fleming J.O.,University of Wisconsin - Madison
International Journal for Parasitology | Year: 2013

Multiple sclerosis is a common and frequently disabling neurological disease of young adults. It is characterised by recurrent areas of focal inflammation (plaques) in the CNS which give rise to episodic neurological signs and symptoms. According to the hygiene (microbial deprivation) hypothesis, evolutionarily abnormal high levels of sanitation in the environment of the developed world may contribute to disordered immunoregulation in this and other putative autoimmune disorders. Helminths have been shown to augment immunoregulation. On this basis, the possibility of treating multiple sclerosis with live helminths or helminth products has been explored in animal models, natural human infections and phase 1 clinical trials. To date helminth therapy appears safe and preliminary clinical, magnetic resonance imaging and immunological outcomes have generally been favourable. Nevertheless, serious adverse effects are always possible, particularly with live parasitic administration. Follow up studies with safety monitoring, regulatory oversight and objective outcome measures will be required to definitively assess safety and efficacy for this novel class of potential immunological therapies in multiple sclerosis. © 2013 Australian Society for Parasitology Inc. Source


Smith C.A.,University of Wisconsin - Madison
Journal of medical Internet research | Year: 2011

A basic tenet of consumer health informatics is that understandable health resources empower the public. Text comprehension holds great promise for helping to characterize consumer problems in understanding health texts. The need for efficient ways to assess consumer-oriented health texts and the availability of computationally supported tools led us to explore the effect of various text characteristics on readers' understanding of health texts, as well as to develop novel approaches to assessing these characteristics. The goal of this study was to compare the impact of two different approaches to enhancing readability, and three interventions, on individuals' comprehension of short, complex passages of health text. Participants were 80 university staff, faculty, or students. Each participant was asked to "retell" the content of two health texts: one a clinical trial in the domain of diabetes mellitus, and the other typical Visit Notes. These texts were transformed for the intervention arms of the study. Two interventions provided terminology support via (1) standard dictionary or (2) contextualized vocabulary definitions. The third intervention provided coherence improvement. We assessed participants' comprehension of the clinical texts through propositional analysis, an open-ended questionnaire, and analysis of the number of errors made. For the clinical trial text, the effect of text condition was not significant in any of the comparisons, suggesting no differences in recall, despite the varying levels of support (P=.84). For the Visit Note, however, the difference in the median total propositions recalled between the Coherent and the (Original+Dictionary) conditions was significant (P=.04). This suggests that participants in the Coherent condition recalled more of the original Visit Notes content than did participants in the Original and the Dictionary conditions combined. However, no difference was seen between (Original+Dictionary) and Vocabulary (P=.36) nor Coherent and Vocabulary (P=.62). No statistically significant effect of any document transformation was found either in the open-ended questionnaire (clinical trial: P=.86, Visit Note: P=.20) or in the error rate (clinical trial: P=.47, Visit Note: P=.25). However, post hoc power analysis suggested that increasing the sample size by approximately 6 participants per condition would result in a significant difference for the Visit Note, but not for the clinical trial text. Statistically, the results of this study attest that improving coherence has a small effect on consumer comprehension of clinical text, but the task is extremely labor intensive and not scalable. Further research is needed using texts from more diverse clinical domains and more heterogeneous participants, including actual patients. Since comprehensibility of clinical text appears difficult to automate, informatics support tools may most productively support the health care professionals tasked with making clinical information understandable to patients. Source


Reed J.L.,University of Wisconsin - Madison
PLoS Computational Biology | Year: 2012

Constraint-based models of metabolism have been used in a variety of studies on drug discovery, metabolic engineering, evolution, and multi-species interactions. These genome-scale models can be generated for any sequenced organism since their main parameters (i.e., reaction stoichiometry) are highly conserved. Their relatively low parameter requirement makes these models easy to develop; however, these models often result in a solution space with multiple possible flux distributions, making it difficult to determine the precise flux state in the cell. Recent research efforts in this modeling field have investigated how additional experimental data, including gene expression, protein expression, metabolite concentrations, and kinetic parameters, can be used to reduce the solution space. This mini-review provides a summary of the data-driven computational approaches that are available for reducing the solution space and thereby improve predictions of intracellular fluxes by constraint-based models. © 2012 Jennifer L. Reed. Source


Allen D.B.,University of Wisconsin - Madison | Cuttler L.,Case Western Reserve University
New England Journal of Medicine | Year: 2013

A family seeks evaluation and treatment of short stature in their 11.5-year-old son. He previously was in the 3rd percentile for height, but his growth rate has slowed during the past 2 years, and his height is now just below the 1st percentile (Fig. 1). His mother is 5 ft 0 in. (152 cm), and his father is 5 ft 6 in. (167 cm). The child's size at birth was normal. His medical history and a review of systems are unremarkable. His physical examination is normal and shows prepubertal development. The complete blood count, erythrocyte sedimentation rate, thyrotropin, tissue transglutaminase antibody, and insulin-like growth factor I (IGF-I) levels and growth hormone levels after provocative testing are normal. His skeletal maturation (bone age) is approximately 9 years, and his predicted adult height is 5 ft 5 in. (165 cm) plus or minus 1.3 in. (3.3 cm).1 How should his condition be managed? Copyright © 2013 Massachusetts Medical Society. Source


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. Source


Brucellosis is a common zoonotic disease that remains endemic in many parts of the world. Dissecting the host immune response during this disease provides insight as to why brucellosis is often difficult to resolve. We used a Brucella epitope specific in vivo killing assay to investigate the ability of CD8+ T cells to kill targets treated with purified pathogenic protein. Importantly, we found the pathogenic protein TcpB to be a novel effector of adaptive immune evasion by inhibiting CD8+ T cell killing of Brucella epitope specific target cells in mice. Further, BALB/c mice show active Brucella melitensis infection beyond one year, many with previously unreported focal infection of the urogenital area. A fraction of CD8+ T cells show a CD8+ Tmem phenotype of LFA-1hi, CD127hi, KLRG-1lo during the course of chronic brucellosis, while the CD8+ T cell pool as a whole had a very weak polyfunctional cytokine response with diminished co-expression of IFN-γ with TNFα and/or IL-2, a hallmark of exhaustion. When investigating the expression of these 3 cytokines individually, we observed significant IFN-γ expression at 90 and 180 days post-infection. TNFα expression did not significantly exceed or fall below background levels at any time. IL-2 expression did not significantly exceeded background, but, interestingly, did fall significantly below that of uninfected mice at 180 days post-infection. Brucella melitensis evades and blunts adaptive immunity during acute infection and our findings provide potential mechanisms for the deficit observed in responding CD8+ T cells during chronic brucellosis. Source


Blastomyces dermatitidis belongs to a group of human pathogenic fungi that exhibit thermal dimorphism. At 22 degrees C, these fungi grow as mold that produce conidia or infectious particles, whereas at 37 degrees C they convert to budding yeast. The ability to switch between these forms is essential for virulence in mammals and may enable these organisms to survive in the soil. To identify genes that regulate this phase transition, we used Agrobacterium tumefaciens to mutagenize B. dermatitidis conidia and screened transformants for defects in morphogenesis. We found that the GATA transcription factor SREB governs multiple fates in B. dermatitidis: phase transition from yeast to mold, cell growth at 22 degrees C, and biosynthesis of siderophores under iron-replete conditions. Insertional and null mutants fail to convert to mold, do not accumulate significant biomass at 22 degrees C, and are unable to suppress siderophore biosynthesis under iron-replete conditions. The defect in morphogenesis in the SREB mutant was independent of exogenous iron concentration, suggesting that SREB promotes the phase transition by altering the expression of genes that are unrelated to siderophore biosynthesis. Using bioinformatic and gene expression analyses, we identified candidate genes with upstream GATA sites whose expression is altered in the null mutant that may be direct or indirect targets of SREB and promote the phase transition. We conclude that SREB functions as a transcription factor that promotes morphogenesis and regulates siderophore biosynthesis. To our knowledge, this is the first gene identified that promotes the conversion from yeast to mold in the dimorphic fungi, and may shed light on environmental persistence of these pathogens. Source


Chiles R.M.,University of Wisconsin - Madison
Agriculture and Human Values | Year: 2013

According to recent literature in the sociology of expectations, expectations about the future are "performative" in that they provide guidance for activities, attract attention, mobilize political and economic resources, coordinate between groups, link technical and social concerns, create visions, and enroll supporters. While this framework has blossomed over the past decade in science and technology studies, it has yet to be applied towards a more refined understanding of how the future of the modern agrofood system is being actively contested and understood. I seek to redress this gap by using the sociology of expectations to explain the discursive topography surrounding in vitro meat, a nascent agrofood technology whereby processed meat products are developed from stem cells as opposed to live animals. In discussing the obstacles and challenges which confront the proponents of this technology, I utilize three key concepts from the sociology of expectations: (1) hype, (2) retrospective prospects, and (3) the role of myth, metaphor, and ideology. I find that despite sluggish results and financial setbacks, the controversial legacy of previous agrofood technologies, and persistent cultural skepticism, the core ideological justifications for in vitro meat have proven to be resilient in buoying the technology through rough discursive waters. © 2013 Springer Science+Business Media Dordrecht. Source


Quorum sensing (QS) is often critical in both pathogenic and mutualistic relationships between bacteria and their eukaryotic hosts. Gram-negative bacteria typically use N-acylated l-homoserine lactone (AHL) signals for QS. We have identified a number of synthetic AHL analogues that are able to strongly modulate QS in culture-based, reporter gene assays. While informative, these assays represent idealized systems, and their relevance to QS under native conditions is often unclear. As one of our goals is to utilize synthetic QS modulators to study bacterial communication under native conditions, identifying robust host-bacteria model systems for their evaluation is crucial. We reasoned that the host-pathogen interaction between Solanum tuberosum (potato) and the Gram-negative pathogen Pectobacterium carotovora would be ideal for such studies as we have identified several potent, synthetic QS modulators for this pathogen, and infection assays in potato are facile. Herein, we report on our development of this host-pathogen system, and another in Phaseolus vulgaris (green bean), as a means for monitoring the ability of abiotic AHLs to modulate QS-regulated virulence in host infection assays. Our assays confirmed that QS modulators previously identified through culture-based assays largely retained their activity profiles when introduced into the plant host. However, inhibition of virulence in wild-type infections was highly dependent on the timing of compound dosing. This study is the first to demonstrate that our AHL analogues are active in wild-type bacteria in their native eukaryotic hosts and provides compelling evidence for the application of these molecules as probes to study QS in a range of organisms and environments. Source


Tucker A.C.,University of Wisconsin - Madison | Escalante-Semerena J.C.,University of Georgia
Molecular Microbiology | Year: 2013

GCN5-type N-acetyltransferases (GNATs) are enzymes that catalyse the transfer of the acetyl group from acetyl-CoA to a primary amine. GNATs are conserved in all domains of life. Some members of this family of enzymes acetylate the side-chain of specific lysine residues in proteins of diverse function. In bacteria, GNAT-catalysed protein acetylation regulates carbon metabolism, RNA metabolism and transcriptional regulation. Metabolic regulation in Streptomyces species is of interest due to the role of these organisms in natural product synthesis. Here we identify SlPatA, a GNAT in Streptomyces lividans with unique domain organization, and a new acetylation target, namely acetoacetyl-CoA synthetase (SlAacS). The latter has homologues in all domains of life. In vitro and in vivo evidence show that SlAacS is a bona fide acetoacetyl-CoA synthetase. SlPatA acetylates SlAacS more efficiently than it does acetyl-CoA synthetase, an enzyme known to be under acetylation control. SlPatA acetylates SlAacS at the active-site residue Lys617 and acetylation inactivates SlAacS. Acetylated SlAacS was deacetylated by a sirtuin-type protein deacetylase. SlAacS acetylation/deacetylation may represent a conserved mechanism for regulation of acetoacetyl-CoA synthetase activity in all domains of life. © 2012 Blackwell Publishing Ltd. Source


Suryanarayanan S.,University of Wisconsin - Madison
Current Opinion in Insect Science | Year: 2015

I examine recent policymaking efforts in the United States (US) that seek to improve how risks posed by pesticides to insect pollinators are assessed and managed. Utilizing the case of ongoing honey bee die-offs, I argue for a context-sensitive policy framework. From a scientific perspective, this entails not ignoring the uncertain knowledge emerging from laboratory and field studies regarding the indirect effects of low levels of certain insecticides in combination with other factors. From a social scientific perspective, policy initiatives to build partnerships between growers and beekeepers toward mitigating exposure to pesticides are crucial, and need to acknowledge barriers to the adoption of best management practices as well as a historically-established asymmetry between growers and beekeepers in the pollination industry. © 2015 Elsevier Inc. Source


Singer B.S.,University of Wisconsin - Madison
Quaternary Geochronology | Year: 2014

Reversals and excursions of Earth's geomagnetic field create marker horizons that are readily detected in sedimentary and volcanic rocks worldwide. An accurate and precise chronology of these geomagnetic field instabilities is fundamental to understanding several aspects of Quaternary climate, dynamo processes, and surface processes. For example, stratigraphic correlation between marine sediment and polar ice records of climate change across the cryospheres benefits from a highly resolved record of reversals and excursions. The temporal patterns of dynamo behavior may reflect physical interactions between the molten outer core and the solid inner core or lowermost mantle. These interactions may control reversal frequency and shape the weak magnetic fields that arise during successive dynamo instabilities. Moreover, weakening of the axial dipole during reversals and excursions enhances the production of cosmogenic isotopes that are used in sediment and ice core stratigraphy and surface exposure dating. The Geomagnetic Instability Time Scale (GITS) is based on the direct dating of transitional polarity states in lava flows using the 40Ar/39Ar method, in parallel with astrochronologic age models of marine sediments in which oxygen isotope and magnetic records have been obtained. A review of data from Quaternary lava flows and sediments gives rise to a GITS that comprises 10 polarity reversals and 27 excursions that occurred during the past 2.6 million years. Nine of the ten reversals bounding chrons and subchrons are associated with 40Ar/39Ar ages of transitionally-magnetized lava flows. The tenth, the Gauss-Matuyama chron boundary, is tightly bracketed by 40Ar/39Ar dated ash deposits. Of the 27 well-documented geomagnetic field instabilities manifest as short-lived excursions, 14 occurred during the Matuyama chron and 13 during the Brunhes chron. Nineteen excursions have been dated directly using the 40Ar/39Ar method on transitionally-magnetized volcanic rocks and these form the backbone of the GITS. Excursions are clearly not the rare phenomena once thought. Rather, during the Quaternary period, they occur nearly three times as often as full polarity reversals. © 2013 Elsevier B.V. Source


Johnson E.A.,University of Wisconsin - Madison
Applied Microbiology and Biotechnology | Year: 2013

Yeasts are the major producer of biotechnology products worldwide, exceeding production in capacity and economic revenues of other groups of industrial microorganisms. Yeasts have wide-ranging fundamental and industrial importance in scientific, food, medical, and agricultural disciplines (Fig. 1). Saccharomyces is the most important genus of yeast from fundamental and applied perspectives and has been expansively studied. Non-Saccharomyces yeasts (nonconventional yeasts) including members of the Ascomycetes and Basidiomycetes also have substantial current utility and potential applicability in biotechnology. In an earlier minireview, Biotechnology of non-Saccharomyces yeasts-the ascomycetes (Johnson Appl Microb Biotechnol 97: 503- 517, 2013), the extensive biotechnological utility and potential of ascomycetous yeasts are described. Ascomycetous yeasts are particularly important in food and ethanol formation, production of single-cell protein, feeds and fodder, heterologous production of proteins and enzymes, and as model and fundamental organisms for the delineation of genes and their function in mammalian and human metabolism and disease processes. In contrast, the roles of basidiomycetous yeasts in biotechnology have mainly been evaluated only in the past few decades and compared to the ascomycetous yeasts currently have limited industrial utility. From a biotechnology perspective, the basidiomycetous yeasts are known mainly for the production of enzymes used in pharmaceutical and chemical synthesis, for production of certain classes of primary and secondary metabolites such as terpenoids and carotenoids, for aerobic catabolism of complex carbon sources, and for bioremediation of environmental pollutants and xenotoxicants. Notwithstanding, the basidiomycetous yeasts appear to have considerable potential in biotechnology owing to their catabolic utilities, formation of enzymes acting on recalcitrant substrates, and through the production of unique primary and secondary metabolites. This and the earlier mini-review (Johnson Appl Microb Biotechnol 97:503-517, 2013) were motivated during the preparation and publication of the landmark three-volume set of The yeasts: a taxonomic study, 5th edition (Kurtzman et al. 2011a, b). © Springer-Verlag Berlin Heidelberg 2013. Source


Hegge J.O.,University of Wisconsin - Madison
Human gene therapy | Year: 2010

The administration route is emerging as a critical aspect of nonviral and viral vector delivery to muscle, so as to enable gene therapy for disorders such as muscular dystrophy. Although direct intramuscular routes were used initially, intravascular routes are garnering interest because of their ability to target multiple muscles at once and to increase the efficiency of delivery and expression. For the delivery of naked plasmid DNA, our group has developed a hydrodynamic, limb vein procedure that entails placing a tourniquet over the proximal part of the target limb to block all blood flow and injecting the gene vector rapidly in a large volume so as to enable the gene vector to be extravasated and to access the myofibers. The present study was conducted in part to optimize the procedure in preparation for a human clinical study. Various injection parameters such as the effect of papaverine preinjection, tourniquet inflation pressure and duration, and rate of injection were evaluated in rats and nonhuman primates. In addition, the safety of the procedure was further established by determining the effect of the procedure on the neuromuscular and vascular systems. The results from these studies provide additional evidence that the procedure is well tolerated and they provide a foundation on which to formulate the procedure for a human clinical study. Source


Vlach H.A.,University of Wisconsin - Madison
Child Development Perspectives | Year: 2014

Distributing learning events in time promotes memory to a greater degree than massing learning together in immediate succession, a phenomenon known as the spacing effect. In this article, I review research on the spacing effect in children's acquisition and generalization of conceptual knowledge. For decades, researchers hypothesized that spaced learning should deter generalization because the forgetting that occurs between learning events limits children's ability to retrieve prior learning. However, new research suggests that spaced learning promotes children's generalization and implicates forgetting as the mechanism that supports, rather than deters, children's generalization. This work counters the intuitive assumption that forgetting uniformly constrains children's learning, suggesting instead that forgetting is a domain-general process that promotes cognitive development. © 2014 The Society for Research in Child Development. Source


Carrithers M.D.,University of Wisconsin - Madison
Clinical Therapeutics | Year: 2014

Purpose The purpose of this review is to discuss the selection and use of disease- modifying treatments for patients with relapsing forms of multiple sclerosis (MS).Methods PubMed was searched (1966-2014) using the terms multiple sclerosis, treatment, interferon, glatiramer acetate, dimethyl fumarate, fingolimod, teriflunomide, natalizumab, rituximab, and alemtuzumab.Findings MS is a chronic neurological disorder that can cause a substantial degree of disability. Because of its usual onset in young adults, patients may require treatment for several decades. Currently available agents include platform injectable therapies, newer oral agents, and second-line monoclonal antibody treatments. Treatment decisions have become more complex with the introduction of new approaches, and a major goal is to balance perceived efficacy and tolerability in a specific patient with the relative impact of disease activity and adverse events on quality of life. Here the options for disease-modifying treatments for relapsing forms of MS are reviewed, and current and future challenges are discussed.Implications An evidence-based approach can be used for the selection of disease-modifying treatments based on disease phenotype and severity, adverse events, and perceived efficacy. Source


Kanne J.P.,University of Wisconsin - Madison
American Journal of Roentgenology | Year: 2012

OBJECTIVE. The purpose of this essay is to review the spectrum of high-resolution CT findings of Pneumocystis jiroveci pneumonia in immunocompromised patients with and without HIV infection. CONCLUSION. Pneumocystis jiroveci pneumonia is a common opportunistic infection affecting immunosuppressed patients. High-resolution CT may be indicated for evaluation of immunosuppressed patients with suspected pneumonia and normal chest radiographic findings. The most common high-resolution CT finding of Pneumocystis jiroveci pneumonia is diffuse ground-glass opacity. Consolidation, nodules, cysts, and spontaneous pneumothorax also can develop. © American Roentgen Ray Society. Source


Chern G.-W.,University of Wisconsin - Madison | Mellado P.,Harvard University | Tchernyshyov O.,Johns Hopkins University
Physical Review Letters | Year: 2011

Spin ice, a peculiar thermal state of a frustrated ferromagnet on the pyrochlore lattice, has a finite entropy density and excitations carrying magnetic charge. By combining analytical arguments and Monte Carlo simulations, we show that spin ice on the two-dimensional kagome lattice orders in two stages. The intermediate phase has ordered magnetic charges and is separated from the paramagnetic phase by an Ising transition. The transition to the low-temperature phase is of the three-state Potts or Kosterlitz-Thouless type, depending on the presence of defects in the charge order. © 2011 American Physical Society. Source


Chubukov A.V.,University of Wisconsin - Madison | Starykh O.A.,University of Utah
Physical Review Letters | Year: 2013

We analyze instabilities of the collinear up-up-down state of a two-dimensional quantum spin-S spatially anisotropic triangular lattice antiferromagnet in a magnetic field. We find, within the large-S approximation, that near the end point of the plateau, the collinear state becomes unstable due to the condensation of two-magnon bound pairs rather than single magnons. The two-magnon instability leads to a novel two-dimensional vector chiral phase with alternating spin currents but no magnetic order in the direction transverse to the field. This phase breaks a discrete Z2 symmetry but preserves a continuous U(1) one of rotations about the field axis. It possesses orbital antiferromagnetism and displays a magnetoelectric effect. © 2013 American Physical Society. Source


List J.A.,University of Chicago | Samek A.S.,University of Wisconsin - Madison
Journal of Health Economics | Year: 2015

We leverage behavioral economics to explore new approaches to tackling child food choice and consumption. Using a field experiment with >1500 children, we report several key insights. We find that incentives have large influences: in the control, 17% of children prefer the healthy snack, whereas introduction of small incentives increases take-up of the healthy snack to ~75%. There is some evidence that the effects continue post-treatment, consistent with a model of habit formation. We find little evidence that the framing of incentives (loss vs. gain) matters. Educational messaging alone has little effect, but we observe a combined effect of messaging and incentives: together they provide an important influence on food choice. © 2014 Elsevier B.V. Source


Huttenlocher A.,University of Wisconsin - Madison
Cold Spring Harbor perspectives in biology | Year: 2011

Integrin-based adhesion has served as a model for studying the central role of adhesion in migration. In this article, we outline modes of migration, both integrin-dependent and -independent in vitro and in vivo. We next discuss the roles of adhesion contacts as signaling centers and linkages between the ECM and actin that allows adhesions to serve as traction sites. This includes signaling complexes that regulate migration and the interplay among adhesion, signaling, and pliability of the substratum. Finally, we address mechanisms of adhesion assembly and disassembly and the role of adhesion in cellular polarity. Source


Baum D.,University of Wisconsin - Madison
Plant Cell | Year: 2013

The idea of an endosymbiotic origin of plastids has become incontrovertible, but many important aspects of plastid origins remain obscured in the mists of more than a billion years of evolutionary history. This commentary provides a critical summary of a recent proposal that primary plastid endosymbiosis was facilitated by the secretion into the host cytosol of effector proteins from intracellular Chlamydiales pathogens that allowed the host to utilize carbohydrates exported from the incipient plastid. Although not without flaws, the model provides an explanation for why primary plastids have evolved so rarely and why Archaeplastida, among all phagotrophic eukaryotes, succeeded in establishing primary plastids. © 2013 American Society of Plant Biologists. All rights reserved. Source


Gondi V.,University of Wisconsin - Madison
International journal of radiation oncology, biology, physics | Year: 2013

To prospectively evaluate the association between hippocampal dose and long-term neurocognitive function (NCF) impairment for benign or low-grade adult brain tumors treated with fractionated stereotactic radiotherapy (FSRT). Adult patients with benign or low-grade adult brain tumors were treated with FSRT per institutional practice. No attempt was made to spare the hippocampus. NCF testing was conducted at baseline and 18 months follow-up, on a prospective clinical trial. Regression-based standardized z scores were calculated by using similar healthy control individuals evaluated at the same test-retest interval. NCF impairment was defined as a z score ≤-1.5. After delineation of the bilateral hippocampi according to the Radiation Therapy Oncology Group contouring atlas, dose-volume histograms were generated for the left and right hippocampi and for the composite pair. Biologically equivalent doses in 2-Gy fractions (EQD(2)) assuming an α/β ratio of 2 Gy were computed. Fisher's exact test and binary logistic regression were used for univariate and multivariate analyses, respectively. Dose-response data were fit to a nonlinear model. Of 29 patients enrolled in this trial, 18 completed both baseline and 18-month NCF testing. An EQD(2) to 40% of the bilateral hippocampi >7.3 Gy was associated with impairment in Wechsler Memory Scale-III Word List (WMS-WL) delayed recall (odds ratio [OR] 19.3; p = 0.043). The association between WMS-WL delayed recall and EQD(2) to 100% of the bilateral hippocampi >0.0 Gy trended to significance (OR 14.8; p = 0.068). EQD(2) to 40% of the bilateral hippocampi greater than 7.3 Gy is associated with long-term impairment in list-learning delayed recall after FSRT for benign or low-grade adult brain tumors. Given that modern intensity-modulated radiotherapy techniques can reduce the dose to the bilateral hippocampi below this dosimetric threshold, patients should be enrolled in ongoing prospective trials of hippocampal sparing during cranial irradiation to confirm these preliminary results. Copyright © 2013. Published by Elsevier Inc. Source


Turner M.G.,University of Wisconsin - Madison
Ecology | Year: 2010

Disturbance regimes are changing rapidly, and the consequences of such changes for ecosystems and linked social-ecological systems will be profound. This paper synthesizes current understanding of disturbance with an emphasis on fundamental contributions to contemporary landscape and ecosystem ecology, then identifies future research priorities. Studies of disturbance led to insights about heterogeneity, scale, and thresholds in space and time and catalyzed new paradigms in ecology. Because they create vegetation patterns, disturbances also establish spatial patterns of many ecosystem processes on the landscape. Drivers of global change will produce new spatial patterns, altered disturbance regimes, novel trajectories of change, and surprises. Future disturbances will continue to provide valuable opportunities for studying pattern-process interactions. Changing disturbance regimes will produce acute changes in ecosystems and ecosystem services over the short (years to decades) and long term (centuries and beyond). Future research should address questions related to (1) disturbances as catalysts of rapid ecological change, (2) interactions among disturbances, (3) relationships between disturbance and society, especially the intersection of land use and disturbance, and (4) feedbacks from disturbance to other global drivers. Ecologists should make a renewed and concerted effort to understand and anticipate the causes and consequences of changing disturbance regimes. © 2010 by the Ecological Society of America. Source


Givnish T.J.,University of Wisconsin - Madison
Taxon | Year: 2010

Ecology affects each of the three principal processes leading to speciation: genetic differentiation among populations within species, acquisition of reproductive isolation among populations, and the rise of ecological differentiation among such populations, allowing them to coexist. Until recently, however, the ties between ecology and speciation in plants have received relatively little attention. This paper reviews some exciting new insights into the role of ecology in speciation, focusing on the angiosperms. I consider five main topics, including (1) the determinants of the spatial scale of genetic differentiation within species; (2) the role and limits of adaptive radiation in increasing net rates of plant diversification; (3) the potential role of ecological speciation; (4) the contributions of hybridization to speciation, adaptive radiation, and the ecological breadth of clades; and (5) the ecological determinants of net diversification rate for individual lineages, and of the species richness for regional floras. Limited dispersal, especially of seeds, favors genetic differentiation at small spatial scales and is likely to foster rapid speciation and narrow endemism. Meta-analyses show that the minimum area required for in situ speciation on islands increases with the spatial scale of gene flow in various organisms. In angiosperms, fleshy fruits dispersed by vertebrates often increase the distance over which seeds are dispersed, but can decrease it in forest understories. Nutrient-poor soils should work against the evolution of fleshy fruits and promote speciation and narrow endemism. Selection for adaptation to different conditions drives adaptive radiation, the rise of a diversity of ecological roles and attendant adaptations within a lineage. On islands, adaptive radiation often leads to woodiness, monocarpy, developmental heterophylly, and sexual dimorphism, as well as differences in habitat, growth form, and floral morphology. Adaptive radiation appears to accelerate speciation in only some plant clades. Extensive radiation in some lineages has been ascribed to early colonization, large amounts of heritable genetic variation, "genetic lines of least resistance" upon which selection could act, absence of potential competitors, and possession of "key innovations" that provide access to novel resources. To these should be added large island area, organismal abundance, saturation of ecological space, and the synergism action of limited dispersal and divergent selection producing parallel radiations in isolated regions. Data for Hawaiian lobeliads suggest that within-island species richness of Cyanea-involving divergence in elevation and flower tube length-saturates within 0.6 and 1.5 Ma. Adaptive radiation in pollinators is an important mechanism of ecological speciation: adaptation to different pollinators leads to pollinator partitioning and reproductive isolation. Selection for longer nectar spurs and pollinator mouth parts led to increased speciation in Aquilegia and other groups. A similar process may work once tubular flowers evolve from cup-shaped blossoms. Selection for floral divergence may be limited in forest understories illuminated by dim, greenish light, which may account for the predominance of small, visually inconspicuous flowers in temperate and tropical understory species. Hybridization can stimulate speciation by forming transgressive phenotypes that exceed the range seen in parental taxa, and by introgressing adaptive gene combinations. The likelihood of transgressive phenotypes increases with the genetic divergence between parental taxa, so speciation via transgressive hybridization may be most likely among taxa with intermediate amounts of divergence. Several large adaptive radiations appear to have occurred after hybridization, suggesting a special role for the extensive amount of genetic variation that can be supplied and refreshed by syngameons. Rates of net species diversification are greater in herbs (especially annuals) vs. woody plants; in animal- vs. wind-pollinated species; in plants with poorly dispersed seeds; in families with a greater diversity of growth forms, pollination and seed dispersal mechanisms, and species distributions; in families at lower latitudes; in families with higher rates of genetic evolution; in hermaphroditic or monoecious vs. dioecious clades; in earlier-maturing woody plants; in plants with bilateral vs. radial flowers; in plants with hummingbird-pollinated flowers; in epiphytic vs. terrestrial bromeliads and orchids; in bromeliads differentiating along geographically extensive cordilleras; and in young vs. old clades. Evidence for the last pattern may, however, be an artifact of (auto)regressing (ln N) / t vs. t. High rates of diversification in epiphytic orchids are tied to small effective population sizes, suggesting a role for intermittent genetic drift alternating with strong selection on floral traits. Across angiosperms, a massive increase in diversification rates was preceded by a major increase in leaf vein density and hydraulic conductance between 140 and 110 Ma ago, leading to higher photosynthetic rates than coexisting ferns and gymnosperms. Based on the economic theory of plant defense, this should have led to lower allocation to anti-herbivore defenses, selecting for low-cost qualitative toxins rather than all-purpose but highly expensive qualitative defenses, triggering an arms' race between angiosperm and their herbivores. Finally, regional plant species richness increases with regional area and proxies for latitude, rainfall, topographic heterogeneity, and vegetation stratification. The Cape Floristic Province has roughly twice as many species as expected from its area and environmental conditions, most likely reflecting the predominance of short-distance dispersal associated with poor soils and myrmecochory in the Cape Province, as well as low rates of regeneration and competitive exclusion following fire. Source


Ives A.R.,University of Wisconsin - Madison
Methods in Ecology and Evolution | Year: 2015

The rise in the use of statistical models for non-Gaussian data, such as generalized linear models (GLMs) and generalized linear mixed models (GLMMs), is pushing aside the traditional approach of transforming data and applying least-squares linear models (LMs). Nonetheless, many least-squares statistical tests depend on the variance of the sum of residuals, which by the Central Limit Theorem converge to a Gaussian distribution for large sample sizes. Therefore, least-squares LMs will likely have good performance in assessing the statistical significance of regression coefficients. Using simulations of count data, I compared GLM approaches for testing whether regression coefficients differ from zero with the traditional approach of applying LMs to transformed data. Simulations assumed that variation among sample populations was either (i) negative binomial or (ii) log-normal Poisson (i.e. log-normal variation among populations that were then sampled by a Poisson distribution). I used the simulated data to conduct tests of the hypotheses that regression coefficients differed from zero; I did not investigate statistical properties of the coefficient estimators, such as bias and precision. For negative binomial simulations whose assumptions closely matched the GLMs, the GLMs were nonetheless prone to type I errors (false positives) especially when there was more than one predictor (independent) variable. After correcting for type I errors, however, the GLMs provided slightly better statistical power than LMs. For log-normal-Poisson simulations, both a GLMM and the LMs performed well, but under some simulated conditions the GLMs had high type I error rates, a deadly sin for statistical tests. These results show that, while GLMs have slight advantages in power when they are properly specified, they can lead to badly wrong conclusions about the significance of regression coefficients if they are mis-specified. In contrast, transforming data and applying least-squares linear analyses provide robust statistical tests for significance over a wide range of conditions. Thus, the traditional approach of transforming data and applying LMs is still useful. © 2015 British Ecological Society. Source


This is a speculative review of the role of the lysosome in ischemic cell death in the mammalian brain. In particular, it focuses on the role of the permeabilization of the lysosomal membrane to proteins (LMP) as a major mechanism of cell death in mild, but lethal, ischemic insults. The first section of the review outlines the evidence that this is the case, using the relatively few extant studies of mammalian brain. In the second section of the review, the mechanism by which an ischemic insult might lead to LMP is discussed. A metabolic sequence including NMDA receptor activation, activation of phospholipase A2 and production of free radicals, and also the activation of calpain are shown to be critical. The remainder of the section speculates on the actual agent(s) which may be causing the lysosomal membrane change, based on extensive literature references. There is currently no knowledge of the actual mechanism. The third section considers potential targets of the released lysosomal proteases and other proteins that might mediate the lethal effects of LMP, focusing largely on the mitochondria as the target. Again, this is speculative as the targets are not known. Finally, the fourth section addresses the level of importance that LMP has in the process of ischemic cell death and concludes that it may well play the major role during mild but lethal ischemic insults. This novel, so-called "lysosomocentric," hypothesis is briefly critiqued. The therapeutic potential of this conclusion is then discussed. © 2013 Springer Science+Business Media New York. Source


Goodman C.A.,University of Wisconsin - Madison
Reviews of physiology, biochemistry and pharmacology | Year: 2014

Skeletal muscle plays a fundamental role in mobility, disease prevention, and quality of life. Skeletal muscle mass is, in part, determined by the rates of protein synthesis, and mechanical loading is a major regulator of protein synthesis and skeletal muscle mass. The mammalian/mechanistic target of rapamycin (mTOR), found in the multi-protein complex, mTORC1, is proposed to play an essential role in the regulation of protein synthesis and skeletal muscle mass. The purpose of this review is to examine the function of mTORC1 in relation to protein synthesis and cell growth, the current evidence from rodent and human studies for the activation of mTORC1 signaling by different types of mechanical stimuli, whether mTORC1 signaling is necessary for changes in protein synthesis and skeletal muscle mass that occur in response to different types of mechanical stimuli, and the proposed molecular signaling mechanisms that may be responsible for the mechanical activation of mTORC1 signaling. Source


Cirelli C.,University of Wisconsin - Madison
Gerontology | Year: 2012

The link between sleep and aging is a hot topic of research. On the one hand, much attention has been paid to epidemiological studies showing that both short sleep and long sleep in humans are associated with reduced longevity. I will briefly review this literature and discuss recent experiments in the fruit fly Drosophila melanogaster that may contribute to understanding this complicated association. On the other hand, other experiments have focused on age-related sleep changes. Sleep quantity and quality tend to decrease with age, but the underlying mechanisms remain unclear. In young subjects, converging evidence from human and animal studies shows that the need for sleep is strongly modulated by the amount of brain plasticity during prior wake. In short, the more we learn and adapt our brain to an ever-changing environment, the more we need to sleep. If so, poor sleep in the elderly could be caused by a chronic decrease in sleep need due to reduced opportunity to learn and be exposed to novel experiences, rather than, or in addition to, an intrinsic problem in the neural circuits responsible for sleep regulation. This distinction has obvious practical implications. However, very little research has been done on this topic. Copyright © 2012 S. Karger AG, Basel. Source


Perepezko J.H.,University of Wisconsin - Madison
Annual Review of Materials Research | Year: 2015

The synthesis of robust coatings that provide protection against environmental attack at ultrahigh temperatures is a difficult challenge. To achieve this goal for Mo-base alloys, the fundamental concepts of reactive diffusion pathway analysis and kinetic biasing are used to design a multilayer Mo-Si-B-base coating with a phase sequencing that allows for structural and thermodynamic compatibility and an underlying diffusion barrier to maintain coating integrity. The coating design concepts have a general applicability. The coating structure evolution during high-temperature exposure facilitates a prolonged lifetime as well as self-healing capability. The borosilicide coatings that can be synthesized by a pack cementation process yield superior environmental resistance for Mo-base systems at temperatures up to at least 1,700°C and can be adapted to apply to other refractory metal and ceramic systems. Copyright © 2015 by Annual Reviews. All rights reserved. Source


Grob R.,University of Wisconsin - Madison
Journal of Health Politics, Policy and Law | Year: 2013

This article examines the multiple aspirations and practices subsumed under the rubric "patient-centered care." Clarifying the term's meaning is essential to understanding its impact on policy discourse and health care. © 2013 by Duke University Press. Source


Foster M.J.,University of Wisconsin - Madison | Heidinger A.,The Center for Satellite Applications and Research
Journal of Climate | Year: 2013

Satellite drift is a historical issue affecting the consistency of those few satellite records capable of being used for studies on climate time scales. Here, the authors address this issue for the Pathfinder Atmospheres Extended (PATMOS-x)/Advanced Very High Resolution Radiometer (AVHRR) cloudiness record, which spans three decades and 11 disparatesensors.Atwo-harmonic sinusoidal function is fit to a mean diurnal cycle of cloudiness derived over the course of the entire AVHRRrecord. The authors validate this function against measurements from Geostationary Operational Environmental Satellite (GOES) sensors, finding good agreement, and then test the stability of the diurnal cycle over the course ofthe AVHRR record. It is found that the diurnal cycle is subject to some interannual variability over land but that the differences are somewhat offset when averaged over an entire day. The fit function is used to generate daily averaged time series of ice, water, andtotal cloudiness over the tropics, where it is found that the diurnal correction affects the magnitude and even the sign of long-term cloudiness trends. A statistical method is applied to determine the minimum length of time required to detect significant trends, andthe authors find that only recently have they begun generating satellite records of sufficient length to detect trends in cloudiness. © 2013 American Meteorological Society. Source


Sunde R.A.,University of Wisconsin - Madison
Experimental Biology and Medicine | Year: 2010

Molecular biomarkers are mRNA transcripts that indicate the (nutrient) status of an organism or tissue. Molecular biomarker panels have the potential to readily and more accurately determine nutrient status than individual traditional biomarkers. To study the efficacy of molecular biomarker panels for predicting selenium (Se) status, we examined 30 biomarkers from rats fed graded levels of Se from deficient to eight times the minimum Se requirement, including four liver and four kidney traditional biomarkers, and 13 liver and nine kidney selenoprotein mRNA levels. Multiple regression analysis against liver and kidney Se and glutathione peroxidase-1 (Gpx1) activity, with stepwise single elimination of biomarkers that did not significantly contribute, was used to identify biomarker panels with significant (P < 0.05) regression coefficients. Resulting regression equations were then used to predict Se status, and compared with traditional Se biomarkers panels. Over the full spectrum of Se status from 0 to 0.8 μg Se/g diet, the resulting 4-selenoprotein mRNA biomarker panel predicted liver Se concentration with a correlation of 0.948, which was nominally higher and statistically the same as the correlation of 0.909 for the panel based on Gpx1 activity. The molecular biomarker panels for predicting kidney Se and liver and kidney Gpx1 activity were all comparable to predictions based on traditional biomarkers. These analyses show that molecular biomarker panels can be used to predict accurately two traditional biomarkers of Se status. The resulting analyses also illustrate that additional orthogonal biomarkers reflecting higher Se intakes are needed to better predict supernutritional Se status and further strengthen this approach. Copyright © 2010 by the Society for Experimental Biology and Medicine. Source


Tsvelik A.M.,Brookhaven National Laboratory | Chubukov A.V.,University of Wisconsin - Madison
Physical Review B - Condensed Matter and Materials Physics | Year: 2014

We study the Ginzburg-Landau free energy functional for two coupled U(1) charge order parameters describing two nonequivalent charge orders with wave vector Q detected in x-ray and STM measurements of underdoped cuprates. We do not rely on a mean-field analysis, but rather utilize a field-theoretical technique suitable to study the interplay between vortex physics and discrete symmetry breaking in two-dimensional systems with U(1) symmetry. Our calculations support the idea that in the clean systems there are two transitions: from a high-temperature disordered state into a state with a composite charge order which breaks time-reversal symmetry, but leaves U(1) fields disordered, and then into a state with quasi-long-range order in the U(1) fields. © 2014 American Physical Society. Source


D'Esposito M.,University of California at Berkeley | Postle B.R.,University of Wisconsin - Madison
Annual Review of Psychology | Year: 2015

For more than 50 years, psychologists and neuroscientists have recognized the importance of a working memory to coordinate processing when multiple goals are active and to guide behavior with information that is not present in the immediate environment. In recent years, psychological theory and cognitive neuroscience data have converged on the idea that information is encoded into working memory by allocating attention to internal representations, whether semantic long-term memory (e.g., letters, digits, words), sensory, or motoric. Thus, information-based multivariate analyses of human functional MRI data typically find evidence for the temporary representation of stimuli in regions that also process this information in nonworking memory contexts. The prefrontal cortex (PFC), on the other hand, exerts control over behavior by biasing the salience of mnemonic representations and adjudicating among competing, context-dependent rules. The "control of the controller" emerges from a complex interplay between PFC and striatal circuits and ascending dopaminergic neuromodulatory signals. © 2015 by Annual Reviews. All rights reserved. Source


Background. We report in vitro studies of a commercially available novel antimicrobial Luer-activated connector with the inner surface coated with nanoparticle-silver to prevent contaminants from forming biofilm and causing catheter-related bloodstream infection. Methods. Sterile control nonmedicated connectors and antimicrobial connectors were filled with ∼1 × 10 5 cfu/mL of Staphylococcus epidermidis, methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus, Enterobacter cloacae, Pseudomonas aeruginosa, or Candida albicans; after 24 h of incubation, the numbers of remaining viable microorganisms were quantified and compared with the concentration in control connectors (∼1 × 107 cfu/mL). In trials simulating clinical use, septal membranes of connectors were inoculated with E. cloacae, were allowed to dry, and were then actuated and infused with lactated ringer's solution for 72 h, with sampling for microorganisms in downstream efferent fluid and for biofilm in the connector. Results. Microorganisms suspended in the intraluminal fluid path of antimicrobial connectors were rapidly killed. For 5 species, there was a 5.23-6.80 mean log10 reduction (>99.999%), and with C. albicans, there was a 99.9% reduction. In clinical simulation trials, heavy contamination of downstream fluid was detected at all time points with control connectors, reaching ∼1 × 105 cfu/mL at 72 h, and heavy biofilm was uniformly present; with the antimicrobial connectors, there was complete prevention of downstream fluid contamination and total absence of biofilm formation. Conclusions. These simulation experiments show that needleless connectors readily acquire an internal biofilm when microorganisms gain access to the internal fluid path and that biofilm formation allows an exponential buildup of internal contamination, with shedding back into the fluid path and downstream sufficient to cause bacteremia. Incorporation of nanoparticle silver into the lining surfaces of the novel connector kills microorganisms in the fluid pathway and prevents internal biofilm formation, even with high levels of introduced contamination and continuous fluid flow. This technology deserves to be evaluated in a prospective, randomized clinical trial to determine its capacity to prevent catheter-associated bloodstream infection. © 2010 by the Infectious Diseases Society of America. All rights reserved. Source


Shin J.-H.,University of Wisconsin - Madison
American Journal of Community Psychology | Year: 2014

This study examines the residential experiences of Korean ethnic elders in affordable housing in the greater Chicago area, focusing on how patterns of social relationships that evolved around a geographical location and its urban infrastructure enabled the elders to achieve their desire for residential independence. Based on the theoretical concept of activity settings and social capital, the study suggests an integrated theoretical model where social capital is understood as an embedded asset of an activity setting. Methodologically, this study uses a combined method of qualitative interviews with 138 Korean elders in affordable housing in the greater Chicago area and a geographic analysis of their social relationships in order to present associations among social relationships, urban infrastructures, and the shared value of independence within their residential communities. The study findings indicate that the elders mobilized ethnic businesses, urban infrastructures, and the collective efficacy of groups to achieve the shared goal of maintaining residential independence. In each community, a cultural broker acted as an important bridge between the community of ethnic minorities and the larger social networks coexisting within the community boundary. The relational perspective as a potent ground for understanding and further solving the issues of aging and ethnicity is highlighted. © 2014 Society for Community Research and Action. Source


Barbey A.K.,University of Illinois at Urbana - Champaign | Koenigs M.,University of Wisconsin - Madison | Grafman J.,Traumatic Brain Injury Research Laboratory
Cortex | Year: 2013

Although neuroscience has made remarkable progress in understanding the involvement of prefrontal cortex (PFC) in human memory, the necessity of dorsolateral PFC (dlPFC) for key competencies of working memory remains largely unexplored. We therefore studied human brain lesion patients to determine whether dlPFC is necessary for working memory function, administering subtests of the Wechsler Memory Scale, the Wechsler Adult Intelligence Scale, and the N-Back Task to three participant groups: dlPFC lesions (n = 19), non-dlPFC lesions (n = 152), and no brain lesions (n = 54). DlPFC damage was associated with deficits in the manipulation of verbal and spatial knowledge, with left dlPFC necessary for manipulating information in working memory and right dlPFC critical for manipulating information in a broader range of reasoning contexts. Our findings elucidate the architecture of working memory, providing key neuropsychological evidence for the necessity of dlPFC in the manipulation of verbal and spatial knowledge. © 2012 Elsevier Ltd. Source


Sprott J.C.,University of Wisconsin - Madison
IEEE Transactions on Circuits and Systems II: Express Briefs | Year: 2011

Much recent interest has been given to simple chaotic oscillators based on jerk equations that involve a third-time derivative of a single scalar variable. The simplest such equation has yet to be electronically implemented. This paper describes a particularly elegant circuit whose operation is accurately described by a simple variant of that equation in which the requisite nonlinearity is provided by a single diode and for which the analysis is particularly straightforward. © 2011 IEEE. Source


Tuite M.J.,University of Wisconsin - Madison
Magnetic Resonance Imaging Clinics of North America | Year: 2012

Magnetic resonance (MR) imaging plays a major role in helping to identify rotator cuff disease and in demonstrating the pathology associated with external impingement. Many surgeons rely on MR imaging to assist in decision making and presurgical planning for patients with rotator cuff pain. This article reviews the etiology of external impingement and rotator cuff tears, and describes the MR imaging appearance of the normal and the pathologic rotator cuffs. It focuses on the supraspinatus tendon because this is the tendon involved in 95% of rotator cuff tears. © 2012 Elsevier Inc. Source


Funato K.,Sloan Kettering Cancer Center | Major T.,Sloan Kettering Cancer Center | Lewis P.W.,University of Wisconsin - Madison | Allis C.D.,Chromatin | Tabar V.,Sloan Kettering Cancer Center
Science | Year: 2014

Over 70% of diffuse intrinsic pediatric gliomas, an aggressive brainstem tumor, harbor heterozygous mutations that create a K27M amino acid substitution (methionine replaces lysine 27) in the tail of histone H3.3. The role of the H3.3K27M mutation in tumorigenesis is not fully understood. Here, we use a human embryonic stem cell system to model this tumor. We show that H3.3K27M expression synergizes with p53 loss and PDGFRA activation in neural progenitor cells derived from human embryonic stem cells, resulting in neoplastic transformation. Genome-wide analyses indicate a resetting of the transformed precursors to a developmentally more primitive stem cell state, with evidence of major modifications of histone marks at several master regulator genes. Drug screening assays identified a compound targeting the protein menin as an inhibitor of tumor cell growth in vitro and in mice. Source


Lupyan G.,University of Wisconsin - Madison | Mirman D.,Moss Rehabilitation Research Institute
Cortex | Year: 2013

In addition to its use in communication, language appears to have a variety of extra-communicative functions; disrupting language disrupts performance in seemingly non-linguistic tasks. Previous work has specifically linked linguistic impairments to categorization impairments. Here, we systematically tested this link by comparing categorization performance in a group of 12 participants with aphasia and 12 age- and education-matched control participants. Participants were asked to choose all of the objects that fit a specified criterion from sets of 20 pictured objects. The criterion was either " high-dimensional" (i.e., the objects shared many features, such as " farm animals") or " low-dimensional" (i.e., the objects shared one or a few features, such as " things that are green" ). Participants with aphasia were selectively impaired on low-dimensional categorization. This selective impairment was correlated with the severity of their naming impairment and not with the overall severity of their aphasia, semantic impairment, lesion size, or lesion location. These results indicate that linguistic impairment impacts categorization specifically when that categorization requires focusing attention and isolating individual features - a task that requires a larger degree of cognitive control than high-dimensional categorization. The results offer some support for the hypothesis that language supports cognitive functioning, particularly the ability to select task-relevant stimulus features. © 2012 Elsevier Ltd. Source


Conservation subdivision design offers an environmentally superior alternative to traditional large-lot, low-density subdivision development but remains far less prevalent. Moreover, when it is implemented, commonly identified goals of protection of lands with conservation value, creation of a regional network of open spaces, and contribution to improved water quality are often not reached. This paper investigates how local land use regulations impact conservation subdivision implementation; specifically whether regulations pose barriers to the development and environmental success of conservation subdivisions. The empirical analysis is based on a review of the zoning ordinances of 19 Waukesha County, WI, U.S.A. communities where 54 conservation subdivisions were built between 1990 and 2005. The ordinance review was supplemented with a review of permitting documents for 22 subdivisions and interviews with 16 developers. The analysis finds that conservation outcomes in a subdivision were seldom significantly different based on the presence and specificity of land use regulations and guidelines. In addition, the study identifies the permitting process and its most important tool, the zoning ordinance, as barriers to the successful implementation of conservation subdivision design. An important implication of this research is that unless conservation subdivisions are permitted by right or encouraged with incentives, rigorous guidelines for natural resource protection are provided, and the design is championed by key decision makers, conservation subdivision design is likely going to remain the less-popular development pattern at the urban fringe, and its environmental goals will continue to be compromised. © 2012 Elsevier B.V. Source


Noel-Miller C.,University of Wisconsin - Madison
Journals of Gerontology - Series B Psychological Sciences and Social Sciences | Year: 2010

Objectives.Informed by a life course perspective, this study investigates the effects of spousal loss and availability of adult children on elderly husbands' and wives' risk of nursing home entry.Methods.Based on longitudinal data from the Health and Retirement Study, we studied 2,116 couples who were community residents in 1998. We estimate proportional hazards models for husbands' and wives' duration to first nursing home admission during 8 years of follow-up.Results.Overall, 438 (20.7%) husbands and 382 (18.1%) wives were institutionalized, and 362 (17.1%) husbands and 701 (33.1%) wives lost their spouse. Accounting for measured covariates, the risk of nursing home entry doubled for men following spousal death, but was unchanged for women. Results indicate that adult children reduced wives' risk of nursing home admission regardless of husbands' vital status, but buffered husbands' risk only after the death of their wives. We uncover suggestive evidence of parent-child gender concordance in children's buffering effect of widowed parents' risk of institutionalization.Discussion.Our findings are consistent with gender variations in spousal caregiving and in husbands' and wives' relative reliance on care from a partner and children. This study provides new evidence on the relationship between institutionalization and family structure among married elderly persons. © The Author 2010. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. Source


Noel-Miller C.,University of Wisconsin - Madison
Gerontologist | Year: 2010

Purpose of the Study:This study contrasts 2-year adjustments in disabled husbands' and wives' amount of received care following both worsening and recovery in personal (activities of daily living [ADLs]) and routine care (instrumental activities of daily living [IADLs]) disability.Design and Methods:Using longitudinal data on 789 husbands and 778 wives from the Health and Retirement Study (2000 and 2002), changes in marital partners' monthly hours of spousal and nonspousal care were jointly modeled using bivariate Tobit models. In addition, asymmetry in the magnitude of responses to worsening and improvement of function was examined.Results:Disabled husbands receive more hours of spousal and nonspousal care following worsening in ADL function than wives. Conversely, disabled wives lose more spousal and nonspousal care hours following improvements in ADL disability than husbands. Moreover, wives recovering in ADL function lose more hours of spousal care than they receive following worsening in personal care disability. There is no evidence of corresponding gender differences in the dynamics of assistance received following changes in IADL function.Implications:Compared with husbands, disabled wives are disadvantaged in the adjustment of their personal care hours. Although disabled married community residents receive more hours of care than their unmarried counterparts, there are important gender differences in the advantages offered by marriage. © 2010 The Author. Source


Plante D.T.,University of Wisconsin - Madison
Sleep Medicine Reviews | Year: 2014

Periodic limb movements of sleep (PLMS) are repetitive, stereotyped movements that can disrupt sleep and result in insomnia, non-restorative sleep, and/or daytime sleepiness. Currently, polysomnography is the gold standard and only clinically acceptable means of quantifying PLMS. Leg-worn actigraphy is an alternative method of measuring PLMS, which may circumvent many of the economic and technical limitations of polysomnography to quantify nocturnal leg movements. However, the use of leg actigraphy as a diagnostic means of assessing PLMS has not been systematically evaluated. In this review, the use of leg-worn actigraphy to measure PLMS is systematically evaluated, using both qualitative and quantitative assessment. Findings demonstrate significant heterogeneity among a limited number of studies in terms of type of actigraph utilized, position of the device on the lower extremity, and methods employed to count PLMS. In general, common accelerometers vary in their sensitivity and specificity to detect PLMS, which is likely related to the technical specifications of a given device. A current limitation in the ability to combine data from actigraphs placed on both legs is also a significant barrier to their use in clinical settings. Further research is required to determine the optimal methods to quantify PLMS using leg actigraphy, as well as specific clinical situations in which these devices may prove most useful. © 2014 Elsevier Ltd. Source


Roch S.,University of Wisconsin - Madison | Warnow T.,University of Illinois at Urbana - Champaign
Systematic Biology | Year: 2015

The estimation of species trees using multiple loci has become increasingly common. Because different loci can have different phylogenetic histories (reflected in different gene tree topologies) for multiple biological causes, new approaches to species tree estimation have been developed that take gene tree heterogeneity into account. Among these multiple causes, incomplete lineage sorting (ILS), modeled by the multi-species coalescent, is potentially the most common cause of gene tree heterogeneity, and much of the focus of the recent literature has been on how to estimate species trees in the presence of ILS. Despite progress in developing statistically consistent techniques for estimating species trees when gene trees can differ due to ILS, there is substantial controversy in the systematics community as to whether to use the new coalescent-based methods or the traditional concatenation methods. One of the key issues that has been raised is understanding the impact of gene tree estimation error on coalescent-based methods that operate by combining gene trees. Here we explore the mathematical guarantees of coalescent-based methods when analyzing estimated rather than true gene trees. Our results provide some insight into the differences between promise of coalescent-based methods in theory and their performance in practice. © 2015 The Author(s) 2015. Published by Oxford University Press, on behalf of the Society of Systematic Biologists. All rights reserved. Source


De Los Campos G.,University of Alabama at Birmingham | Gianola D.,University of Wisconsin - Madison | Allison D.B.,University of Alabama at Birmingham
Nature Reviews Genetics | Year: 2010

Although genome-wide association studies have identified markers that are associated with various human traits and diseases, our ability to predict such phenotypes remains limited. A perhaps overlooked explanation lies in the limitations of the genetic models and statistical techniques commonly used in association studies. We propose that alternative approaches, which are largely borrowed from animal breeding, provide potential for advances. We review selected methods and discuss the challenges and opportunities ahead. © 2010 Macmillan Publishers Limited. All rights reserved. Source


Pauli J.N.,University of Wisconsin - Madison
Proceedings. Biological sciences / The Royal Society | Year: 2014

Arboreal herbivory is rare among mammals. The few species with this lifestyle possess unique adaptions to overcome size-related constraints on nutritional energetics. Sloths are folivores that spend most of their time resting or eating in the forest canopy. A three-toed sloth will, however, descend its tree weekly to defecate, which is risky, energetically costly and, until now, inexplicable. We hypothesized that this behaviour sustains an ecosystem in the fur of sloths, which confers cryptic nutritional benefits to sloths. We found that the more specialized three-toed sloths harboured more phoretic moths, greater concentrations of inorganic nitrogen and higher algal biomass than the generalist two-toed sloths. Moth density was positively related to inorganic nitrogen concentration and algal biomass in the fur. We discovered that sloths consumed algae from their fur, which was highly digestible and lipid-rich. By descending a tree to defecate, sloths transport moths to their oviposition sites in sloth dung, which facilitates moth colonization of sloth fur. Moths are portals for nutrients, increasing nitrogen levels in sloth fur, which fuels algal growth. Sloths consume these algae-gardens, presumably to augment their limited diet. These linked mutualisms between moths, sloths and algae appear to aid the sloth in overcoming a highly constrained lifestyle. Source


Pike J.W.,University of Wisconsin - Madison
Molecular and Cellular Endocrinology | Year: 2011

The vitamin D receptor (VDR) mediates virtually all of the known biological actions of the hormonal ligand 1,25-dihydroxyvitamin D 3 (1,25(OH) 2D 3). These actions are directed toward the nucleus, where the VDR binds to the regulatory regions of target genes and modulates their transcriptional output. Recent technological advances have enabled the study of transcription factor binding on a genome-wide scale in cells and tissues that are major targets of vitamin D action. In this review, the results of several of these studies are discussed wherein overarching principles of gene regulation by the vitamin D hormone are beginning to emerge. In addition, several specific genes that are regulated by 1,25(OH) 2D 3 and which provide new insight into the increasingly complex mechanism whereby the receptor functions to modulate gene expression are considered. These studies suggest that while many of the principles that are now accepted regarding the regulation of gene expression by hormones and other regulatory factors are well grounded, others require extensive modification. © 2011 Elsevier Ireland Ltd. Source


Karasov W.H.,University of Wisconsin - Madison
American Journal of Physiology - Regulatory Integrative and Comparative Physiology | Year: 2011

Digestive physiology links physiology to applications valued by society, such as understanding ecology and ecological toxicology and managing and conserving species. Here I illustrate this applied and integrative perspective with several avian case studies. The match between digestive features and diet provides evidence of tradeoffs that preclude doing well on all possible substrates with a single digestive design, and this influences ecological niche partitioning. But some birds, such as wild house sparrow (Passer domesticus) nestlings, are digestively very flexible. Their intestinal maltase activity and mRNA for intestinal maltase glucoamylase specifically and reversibly change when they switch among foods with different starch content. Houses sparrows and many other birds absorb hydrolyzed water-soluble monomers, such as glucose, mainly passively via tight junctions between enterocytes (i.e., paracellular absorption). Such species might be good models for studying this process, which is important biomedically for absorption of drugs. High paracellular absorption may enhance absorption of low molecular weight, natural water-soluble toxins. Also, reliance of American robins (Turdus migratorius) on passive absorption makes them less sensitive to types of plant toxins that inhibit mediated glucose absorption, such as phlorizin or the flavanoid isoquercetrin. Determining absorption of environmental contaminants is another important ecological application. Common loon (Gavia immer) chicks absorbed 83% of methyl mercury in fish meals, eliminate the mercury slowly, and consequently are predicted in the wild to bioaccumulate mercury to higher concentrations than in their foods. The quantitative details can be used to set regulatory levels for mercury that will protect wildlife. © 2011 the American Physiological Society. Source


Zlatos A.,University of Wisconsin - Madison
Archive for Rational Mechanics and Analysis | Year: 2013

We prove existence, uniqueness, and stability of transition fronts (generalized traveling waves) for reaction-diffusion equations in cylindrical domains with general inhomogeneous ignition reactions. We also show uniform convergence of solutions with exponentially decaying initial data to time translations of the front. In the case of stationary ergodic reactions, the fronts are proved to propagate with a deterministic positive speed. Our results extend to reaction-advection-diffusion equations with periodic advection and diffusion. © 2012 Springer-Verlag Berlin Heidelberg. Source


Suresh K.,University of Wisconsin - Madison
Structural and Multidisciplinary Optimization | Year: 2010

The paper 'A 99-line topology optimization code written in Matlab' by Sigmund (Struct Multidisc Optim 21(2):120-127, 2001) demonstrated that SIMP-based topology optimization can be easily implemented in less than hundred lines of Matlab code. The published method and code has been used even since by numerous researchers to advance the field of topology optimization. Inspired by the above paper, we demonstrate here that, by exploiting the notion of topological-sensitivity (an alternate to SIMP), one can generate Pareto-optimal topologies in about twice the number of lines of Matlab code. In other words, optimal topologies for various volume fractions can be generated in a highly efficient manner, by directly tracing the Pareto-optimal curve. © c Springer-Verlag 2010. Source


Larson M.H.,Stanford University | Landick R.,University of Wisconsin - Madison | Block S.M.,Stanford University
Molecular Cell | Year: 2011

Transcription is the first of many biochemical steps that turn the genetic information found in DNA into the proteins responsible for driving cellular processes. In this review, we highlight certain advantages of single-molecule techniques in the study of prokaryotic and eukaryotic transcription, and the specific ways in which these techniques complement conventional, ensemble-based biochemistry. We focus on recent literature, highlighting examples where single-molecule methods have provided fresh insights into mechanism. We also present recent technological advances and outline future directions in the field. © 2011 Elsevier Inc. Source


Cutter A.D.,University of Toronto | Payseur B.A.,University of Wisconsin - Madison
Nature Reviews Genetics | Year: 2013

Population genetics theory supplies powerful predictions about how natural selection interacts with genetic linkage to sculpt the genomic landscape of nucleotide polymorphism. Both the spread of beneficial mutations and the removal of deleterious mutations act to depress polymorphism levels, especially in low-recombination regions. However, empiricists have documented extreme disparities among species. Here we characterize the dominant features that could drive differences in linked selection among species - including roles for selective sweeps being 'hard' or 'soft' - and the concealing effects of demography and confounding genomic variables. We advocate targeted studies of closely related species to unify our understanding of how selection and linkage interact to shape genome evolution. © 2013 Macmillan Publishers Limited. All rights reserved. Source


Beffa G.M.,University of Wisconsin - Madison
Journal of Nonlinear Science | Year: 2013

In this paper we investigate discretizations of AGD flows whose projective realizations are defined by intersecting different types of subspace in RP m. These maps are natural candidates to generalize the pentagram map, itself defined as the intersection of consecutive shortest diagonals of a convex polygon, and a completely integrable discretization of the Boussinesq equation. We conjecture that the r-AGD flow in m dimensions can be discretized using one (r-1)-dimensional subspace and r-1 different (m-1)-dimensional subspaces of RPm. © 2012 Springer Science+Business Media New York. Source


Busse W.W.,University of Wisconsin - Madison
The Journal of allergy and clinical immunology | Year: 2012

Asthma clinical research will highly benefit from standardization of major outcomes in terms of definition and assessment methodology. This will permit useful comparisons across interventional or observational studies and will allow more effective data sharing. National Institutes of Health (NIH) institutes and the Agency for Healthcare Research and Quality convened a workshop involving 7 expert subcommittees to propose which asthma outcomes should be assessed with standardized methodology in future asthma clinical research studies. Each subcommittee utilized comprehensive literature reviews and expert opinion to compile a list of asthma outcomes and classified them as either core (required in future studies), supplemental (to be used according to study aims and standardized), or emerging (requiring validation and standardization). This work was discussed at an NIH-organized workshop in March 2010 and finalized in September 2011. Outcomes for study participant characterization, as well as for prospective clinical trial intervention and observational studies, were proposed for adults and children, and methodologies for outcome collection and reporting were determined. Furthermore, the workshop identified areas in which new outcomes or instruments for their measurement need to be developed and validated. Standardized outcomes for clinical research in asthma have been proposed. Participating NIH institutes and other federal agencies will consider these recommendations in future clinical research initiatives in asthma. Published by Mosby, Inc. Source


Enantioselective intramolecular oxidative amidation of alkenes has been achieved using a (pyrox)Pd(II)(TFA)(2) catalyst (pyrox = pyridine-oxazoline, TFA = trifluoroacetate) and O(2) as the sole stoichiometric oxidant. The reactions proceed at room temperature in good-to-excellent yields (58-98%) and with high enantioselectivity (ee = 92-98%). Catalyst-controlled stereoselective cyclization reactions are demonstrated for a number of chiral substrates. DFT calculations suggest that the electronic asymmetry of the pyrox ligand synergizes with steric asymmetry to control the stereochemical outcome of the key amidopalladation step. Source


Intracellular trafficking is critical for delivering molecules and organelles to their proper destinations to carry out normal cellular functions. Disruption of intracellular trafficking has been implicated in the pathogenesis of various neurodegenerative disorders. In addition, a number of genes involved in vesicle/organelle trafficking are also essential for pigmentation, and loss of those genes is often associated with mouse coat-color dilution and human hypopigmentary disorders. Hence, we postulated that screening for mouse mutants with both neurological defects and coat-color dilution will help identify additional factors associated with intracellular trafficking in neuronal cells. In this study, we characterized a mouse mutant with a unique N-ethyl-N-nitrosourea (ENU)-induced mutation, named nur17. nur17 mutant mice exhibit both coat-color dilution and ataxia due to Purkinje cell degeneration in the cerebellum. By positional cloning, we identified that the nur17 mouse carries a T-to-C missense mutation in archain 1 (Arcn1) gene which encodes the delta subunit of the coat protein I (COPI) complex required for intracellular trafficking. Consistent with this function, we found that intracellular trafficking is disrupted in nur17 melanocytes. Moreover, the nur17 mutation leads to common characteristics of neurodegenerative disorders such as abnormal protein accumulation, ER stress, and neurofibrillary tangles. Our study documents for the first time the physiological consequences of the impairment of the ARCN1 function in the whole animal and demonstrates a direct association between ARCN1 and neurodegeneration. Source


Berry J.F.,University of Wisconsin - Madison
Dalton Transactions | Year: 2012

Three-center/four-electron (3c/4e) bonds are important bonding motifs that dictate the electronic structure, and thereby the reactivity, of metal-metal bonded carbene and nitrene intermediate complexes that are crucial to the dirhodium-catalyzed functionalization of hydrocarbons. In this Perspective article, general features of the 3c/4e bond are presented and discussed in comparison to two-center/two-electron (2c/2e) bonds. Specifically, 3c/4e bonding interactions lead to longer distances between the atoms involved and measurably weaker bonds. Additionally, excited states derived from the 3c/4e bonding manifold are lower in energy than those derived from a 2c/2e manifold, signifying a greater degree of reactivity in the former case. Three coterminous 3c/4e Ru-Ru-N bonds are present in metal-metal/metal-ligand multiply bonded diruthenium terminal nitrido compounds. This bonding situation results in an unusual superelectrophilic character of the nitride nitrogen atom, exemplified by its insertion into aryl C-H bonds via an electrophilic aromatic substitution mechanism. The key catalytic intermediates in dirhodium-catalyzed C-H functionalization reactions, dirhodium carbene and dirhodium nitrene complexes, may also be described as superelectrophilic by virtue of 3c/4e Rh-Rh-C(or N) σ and π bonds. These 3c/4e bonding interactions set apart dirhodium carbene and nitrene intermediates from other, less electrophilic, carbene or nitrene species. Source


Broman K.W.,University of Wisconsin - Madison
Genetics | Year: 2012

The mouse Collaborative Cross (CC) is a panel of eight-way recombinant inbred lines: eight diverse parental strains are intermated, followed by repeated sibling mating, many times in parallel, to create a new set of inbred lines whose genomes are random mosaics of the genomes of the original eight strains. Many generations are required to reach inbreeding, and so a number of investigators have sought to make use of phenotype and genotype data on mice from intermediate generations during the formation of the CC lines (so-called pre-CC mice). The development of a hidden Markov model for genotype reconstruction in such pre-CC mice, on the basis of incompletely informative genetic markers (such as single-nucleotide polymorphisms), formally requires the two-locus genotype probabilities at an arbitrary generation along the path to inbreeding. In this article, I describe my efforts to calculate such probabilities. While closed-form solutions for the two-locus genotype probabilities could not be derived, I provide a prescription for calculating such probabilities numerically. In addition, I present a number of useful quantities, including single-locus genotype probabilities, two-locus haplotype probabilities, and the fixation probability and map expansion at each generation along the course to inbreeding. © 2012 by the Genetics Society of America. Source


Gelenberg A.J.,University of Wisconsin - Madison
The Journal of clinical psychiatry | Year: 2010

Depression remains underrecognized and undertreated worldwide, although it is a leading cause of disease burden. Many instruments are available to enhance the assessment of major depressive disorder (MDD) at 3 levels: screening, diagnosing, and monitoring treatment. This article reviews a variety of tools that can be used at each level of assessment as part of a measurement-based care approach to MDD. Measurement-based care for MDD is feasible in clinical practice. Patient self-reports can be used instead of clinician-rated scales to save time, whether in paper, computerized, or interactive voice response formats. Assessment tools are available in many languages. Treatment algorithms can rationalize decision making, and collaborative care can speed and enhance treatment results. Source


Clarkson B.D.,University of Wisconsin - Madison
Advances in Experimental Medicine and Biology | Year: 2012

Dendritic cells (DCs) are a heterogeneous group of professional antigen presenting cells that lie in a nexus between innate and adaptive immunity because they recognize and respond to danger signals and subsequently initiate and regulate effector T-cell responses. Initially thought to be absent from the CNS, both plasmacytoid and conventional DCs as well as DC precursors have recently been detected in several CNS compartments where they are seemingly poised for responding to injury and pathogens. Additionally, monocyte-derived DCs rapidly accumulate in the inflamed CNS where they, along with other DC subsets, may function to locally regulate effector T-cells and/or carry antigens to CNS-draining cervical lymph nodes. In this review we highlight recent research showing that (a) distinct inflammatory stimuli differentially recruit DC subsets to the CNS; (b) DC recruitment across the blood-brain barrier (BBB) is regulated by adhesion molecules, growth factors, and chemokines; and (c) DCs positively or negatively regulate immune responses in the CNS. Source


Lin J.J.,University of California at Irvine | Mula M.,University of Piemonte Orientale | Hermann B.P.,University of Wisconsin - Madison
The Lancet | Year: 2012

Epilepsy is a common neurological disorder that is complicated by psychiatric, cognitive, and social comorbidities that have become a major target of concern and investigation in view of their adverse effect on the course and quality of life. In this report we define the specific psychiatric, cognitive, and social comorbidities of paediatric and adult epilepsy, their epidemiology, and real life effects; examine the relation between epilepsy syndromes and the risk of neurobehavioural comorbidities; address the lifespan effect of epilepsy on brain neurodevelopment and brain ageing and the risk of neurobehavioural comorbidities; consider the overarching effect of broader brain disorders on both epilepsy and neurobehavioural comorbidities; examine directions of causality and the contribution of selected epilepsy-related characteristics; and outline clinic-friendly screening approaches for these problems and recommended pharmacological, behavioural, and educational interventions. Source


Johansson M.W.,University of Wisconsin - Madison
Clinical and Experimental Allergy | Year: 2014

Asthma is characterized by airway inflammation rich in eosinophils. Airway eosinophilia is associated with exacerbations and has been suggested to play a role in airway remodelling. Recruitment of eosinophils from the circulation requires that blood eosinophils become activated, leading to their arrest on the endothelium and extravasation. Circulating eosinophils can be envisioned as potentially being in different activation states, including non-activated, pre-activated or 'primed', or fully activated. In addition, the circulation can potentially be deficient of pre-activated or activated eosinophils, because such cells have marginated on activated endothelium or extravasated into the tissue. A number of eosinophil surface proteins, including CD69, L-selectin, intercellular adhesion molecule-1 (ICAM-1, CD54), CD44, P-selectin glycoprotein ligand-1 (PSGL-1, CD162), cytokine receptors, Fc receptors, integrins including αM integrin (CD11b), and activated conformations of Fc receptors and integrins, have been proposed to report cell activation. Variation in eosinophil activation states may be associated with asthma activity. Eosinophil surface proteins proposed to be activation markers, with a particular focus on integrins, and evidence for associations between activation states of blood eosinophils and features of asthma are reviewed here. Partial activation of β1 and β2 integrins on blood eosinophils, reported by monoclonal antibodies (mAbs) N29 and KIM-127, is associated with impaired pulmonary function and airway eosinophilia, respectively, in non-severe asthma. The association with lung function does not occur in severe asthma, presumably due to greater eosinophil extravasation, specifically of activated or pre-activated cells, in severe disease. © 2014 John Wiley & Sons Ltd. Source


Boutonnet B.,Leiden University | Lupyan G.,University of Wisconsin - Madison
Journal of Neuroscience | Year: 2015

People use language to shape each other’s behavior in highly flexible ways. Effects of language are often assumed to be “high-level” in that, whereas language clearly influences reasoning, decision making, and memory, it does not influence low-level visual processes. Here, we test the prediction that words are able to provide top-down guidance at the very earliest stages of visual processing by acting as powerful categorical cues. We investigated whether visual processing of images of familiar animals and artifacts was enhanced after hearing their name (e.g., “dog”) compared with hearing an equally familiar and unambiguous nonverbal sound (e.g., a dog bark) in 14 English monolingual speakers. Because the relationship between words and their referents is categorical, we expected words to deploy more effective categorical templates, allowing for more rapid visual recognition. By recording EEGs, we were able to determine whether this label advantage stemmed from changes to early visual processing or later semantic decision processes. The results showed that hearing a word affected early visual processes and that this modulation was specific to the named category. An analysis of ERPs showed that the P1 was larger when people were cued by labels compared with equally informative nonverbal cues—an enhancement occurring within 100 ms of image onset, which also predicted behavioral responses occurring almost 500 ms later. Hearing labels modulated the P1 such that it distinguished between target and nontarget images, showing that words rapidly guide early visual processing. © 2015 the authors. Source


Busse W.W.,University of Wisconsin - Madison
Chemical Immunology and Allergy | Year: 2012

Stress has been associated as an important contributor to asthma in some patients. The mechanisms, however, which underlie this relationship remain unclear. In this review, the role of stress will be examined in relationship to the development of airway inflammation. As will be discussed, stress may not cause inflammation but enhances its expression when it develops to a second signal. In addition, recent studies using function magnetic resonance imaging (fMRI) have shown that specific circuits in the brain, i.e., anterior cingulate cortex and insula, are activated in relationship and intensity to the development of a late-phase response (LPR) to inhaled antigen, and that these brain signals are predictive and associated with the development of airway inflammation as measured by sputum eosinophils. Finally, in studies with mice, chronic stress enhances airway inflammation to an inhaled antigen, and these effects are associated with the development of corticosteroid unresponsiveness. Collectively, these data suggest that chronic stress enhances asthma severity through a number of novel mechanisms and the resulting increase in severity of asthma may not be responsiveness to standardly used treatments. Copyright © 2012 S. Karger AG, Basel. Source


Caban-Acevedo M.,University of Wisconsin - Madison
Nature Materials | Year: 2015

The scalable and sustainable production of hydrogen fuel through water splitting demands efficient and robust Earth-abundant catalysts for the hydrogen evolution reaction (HER). Building on promising metal compounds with high HER catalytic activity, such as pyrite structure cobalt disulphide (CoS2), and substituting non-metal elements to tune the hydrogen adsorption free energy could lead to further improvements in catalytic activity. Here we present a combined theoretical and experimental study to establish ternary pyrite-type cobalt phosphosulphide (CoPS) as a high-performance Earth-abundant catalyst for electrochemical and photoelectrochemical hydrogen production. Nanostructured CoPS electrodes achieved a geometrical catalytic current density of 10 mA cm-2 at overpotentials as low as 48 mV, with outstanding long-term operational stability. Integrated photocathodes of CoPS on n+–p–p+ silicon micropyramids achieved photocurrents up to 35 mA cm-2 at 0 V versus the reversible hydrogen electrode (RHE), onset photovoltages as high as 450 mV versus RHE, and the most efficient solar-driven hydrogen generation from Earth-abundant systems. © 2015 Nature Publishing Group Source


Savage J.W.,Northwestern University | Anderson P.A.,University of Wisconsin - Madison
Spine Journal | Year: 2013

Background context: Despite an increase in physician and public awareness and advances in infection control practices, surgical site infection (SSI) remains to be one of the most common complications after an operation. Surgical site infections have been shown to decrease health-related quality of life, double the risk of readmission, prolong the length of hospital stay, and increase hospital costs. Purpose: To critically evaluate the literature and identify modifiable factors to reduce the risk of SSI. Study design/setting: Systematic review of the literature. Methods: A critical review of the literature was performed using OVID, Pubmed, and the Cochrane database and focused on eight identifiable factors: preoperative screening and decolonization of methicillin-sensitive Staphylococcus aureus and methicillin-resistant S. aureus protocols, antiseptic showers, antiseptic cloths, perioperative skin preparation, surgeon hand hygiene, antibiotic irrigation and/or use of vancomycin powder, closed suction drains, and antibiotic suture. Results: Screening protocols have shown that 18% to 25% of patients undergoing elective orthopedic surgery are nasal carriers of S. aureus and that carriers are more likely to have a nosocomial infection and SSI. The evidence suggests that an institutionalized prescreening program, followed by an appropriate eradication using mupirocin ointment and chlorhexidine soap/shower, will lower the rate of nosocomial S. aureus infections. Based on the current literature, definitive conclusions cannot be made on whether preoperative antiseptic showers effectively reduce the incidence of postoperative infection. The use of a chlorhexidine bathing cloth before surgery may decrease the risk of SSI. There is no definitive clinical evidence that one skin preparation solution effectively lowers the rate of postoperative infection compared with another. The use of dilute betadine irrigation or vancomycin powder in the wound before closure likely decreases the incidence of SSI. Conclusions: There is strong evidence in the literature that optimizing specific preoperative, intraoperative, and postoperative variables can significantly lower the risk of developing an SSI. © 2013 Elsevier Inc. All rights reserved. Source


Adaptive radiation is the rise of a diversity of ecological roles and role-specific adaptations within a lineage. Recently, some researchers have begun to use 'adaptive radiation' or 'radiation' as synonymous with 'explosive species diversification'. This essay aims to clarify distinctions between these concepts, and the related ideas of geographic speciation, sexual selection, key innovations, key landscapes and ecological keys. Several examples are given to demonstrate that adaptive radiation and explosive diversification are not the same phenomenon, and that focusing on explosive diversification and the analysis of phylogenetic topology ignores much of the rich biology associated with adaptive radiation, and risks generating confusion about the nature of the evolutionary forces driving species diversification. Some 'radiations' involve bursts of geographic speciation or sexual selection, rather than adaptive diversification; some adaptive radiations have little or no effect on speciation, or even a negative effect. Many classic examples of 'adaptive radiation' appear to involve effects driven partly by geographic speciation, species' dispersal abilities, and the nature of extrinsic dispersal barriers; partly by sexual selection; and partly by adaptive radiation in the classical sense, including the origin of traits and invasion of adaptive zones that result in decreased diversification rates but add to overall diversity. © 2015 New Phytologist Trust. Source