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Yale University is a private Ivy League research university in New Haven, Connecticut. Founded in 1701 as the "Collegiate School" by a group of Congregationalist ministers and chartered by the Colony of Connecticut, the university is the third-oldest institution of higher education in the United States. In 1718, the school was renamed "Yale College" in recognition of a gift from Elihu Yale, a governor of the British East India Company. Established to train Connecticut ministers in theology and sacred languages, by 1777 the school's curriculum began to incorporate humanities and science. During the 19th century Yale gradually incorporated graduate and professional instruction, awarding the first Ph.D. in the United States in 1861 and organizing as a university in 1887.Yale is organized into twelve constituent schools: the original undergraduate college, the Graduate School of Arts & science, and ten professional schools. While the university is governed by the Yale Corporation, each school's faculty oversees its curriculum and degree programs. In addition to a central campus in downtown New Haven, the University owns athletic facilities in Western New Haven, including the Yale Bowl, a campus in West Haven, Connecticut, and forest and nature preserves throughout New England. The University's assets include an endowment valued at $23.9 billion as of September 27, 2014.Yale College undergraduates follow a liberal arts curriculum with departmental majors and are organized into a system of residential colleges. The Yale University Library, serving all twelve schools, holds more than 15 million volumes and is the third-largest academic library in the United States. Almost all faculty teach undergraduate courses, more than 2,000 of which are offered annually. Students compete intercollegiately as the Yale Bulldogs in the NCAA Division I Ivy League.Yale has graduated many notable alumni, including five U.S. Presidents, 19 U.S. Supreme Court Justices, 13 living billionaires, and many foreign heads of state. In addition, Yale has graduated hundreds of members of Congress and many high-level U.S. diplomats, including former U.S. Secretary of State Hillary Clinton and current Secretary of State John Kerry. Fifty-two Nobel laureates have been affiliated with the University as students, faculty, or staff, and 230 Rhodes Scholars graduated from the University. Wikipedia.


The rheological properties of the mantle of super-Earths have important influences on their orbital and thermal evolution. Mineral physics observations are reviewed to obtain some insights into the rheological properties of deep mantles of these planets where pressure can be as high as ∼1TPa. It is shown that, in contrast to a conventional view that the viscosity of a solid increases with pressure (at a fixed temperature), viscosity will decrease with pressure (and depth) when pressure exceeds ∼0.1TPa. The causes for pressure-weakening include: (i) the transition in diffusion mechanisms from vacancy to interstitial mechanism (at ∼0.1TPa), (ii) the phase transition in MgO from B1 to B2 structure (at ∼0.5TPa), (iii) the dissociation of MgSiO 3 into MgO and SiO 2 (at ∼1TPa), and (iv) the transition to the metallic state (at ∼1TPa). Some (or all) of them individually or in combination reduce the effective viscosity of constituent materials in the deep interior of super-Earths. Taken together, super-Earths are likely to have low viscosity deep mantle by at least 2-3 orders of magnitude less than the maximum viscosity in the lower mantle of Earth. Because viscosity likely decreases with pressure above ∼0.1TPa (in addition to higher temperatures for larger planets), deep mantle viscosity of super-Earths will decrease with increasing planetary mass. The inferred low viscosity of the deep mantle results in high tidal dissipation and resultant rapid orbital evolution, and affects thermal history and hence generation of the magnetic field and the style of mantle convection. © 2010 Elsevier Inc. Source


Perazella M.A.,Yale University
Clinical Journal of the American Society of Nephrology | Year: 2012

Despite dramatic improvements in patient survival and drug tolerability, nephrotoxicity remains an important complication of chemotherapy. Adverse renal effects occur because of innate drug toxicity and a number of patient- and drug-related factors. To provide cutting edge care for these patients, nephrologists and oncologists must be familiar with the nephrotoxicity of these drugs, particularly their associated clinical and laboratory manifestations. Rapid diagnosis, targeted treatment, and supportive care are critical to improving care for these patients. Unfortunately, some patients who develop nephrotoxicity will be left with long-term complications such as chronic tubulopathies and CKD. Onco-Nephrology is a new area that is rapidly expanding and requires a close working relationship between oncologists and nephrologists. © 2012 by the American Society of Nephrology. Source


Mehal W.Z.,Yale University
Nature Reviews Gastroenterology and Hepatology | Year: 2013

The development of obesity and NAFLD is known to be determined by host genetics, diet and lack of exercise. In addition, the gut microbiota has been identified to influence the development of both obesity and NAFLD. Evidence for the role of the gut microbiota has been shown by preclinical studies of transfer of gut microbiota from lean and obese individuals, with the recipient developing the metabolic features of the donor. Many bidirectional interactions of the gut microbiota, including with food, bile and the intestinal epithelium, have been identified. These interactions might contribute to the distinct steps in the progression from lean to obese states, and to steatosis, steatohepatitis and eventually fibrosis. The predominant steps are efficient caloric extraction from the diet, intestinal epithelial damage and greater entry of bacterial components into the portal circulation. These steps result in activation of the innate immune system, liver inflammation and fibrosis. Fortunately, therapeutic interventions might not require a full understanding of these complex interactions. Although antibiotics are too unselective in their action, probiotics have shown efficacy in reversing obesity and NASH in experimental systems, and are under investigation in humans. © 2013 Macmillan Publishers Limited. All rights reserved. Source


Forget B.G.,Yale University
Cold Spring Harbor perspectives in medicine | Year: 2013

Over the years, study of the disorders of hemoglobin has served as a paradigm for gaining insights into the cellular and molecular biology, as well as the pathophysiology, of inherited genetic disorders. To date, more than 1000 disorders of hemoglobin synthesis and/or structure have been identified and characterized. Study of these disorders has established the principle of how a mutant genotype can alter the function of the encoded protein, which in turn can lead to a distinct clinical phenotype. Genotype/phenotype correlations have provided important understanding of pathophysiological mechanisms of disease. Before presenting a brief overview of these disorders, we provide a summary of the structure and function of hemoglobin, along with the mechanism of assembly of its subunits, as background for the rationale and basis of the different categories of disorders in the classification. Source


Bell M.L.,Yale University
Research report (Health Effects Institute) | Year: 2012

While numerous studies have demonstrated that shortterm exposure to particulate matter (PM*) is associated with adverse health effects, the characteristics of PM that cause harm are not well understood, and PM toxicity may vary by its chemical composition. This study investigates whether spatial and temporal patterns in PM health effect estimates based on total mass can be explained by spatial and temporal heterogeneity in the chemical composition of the particles. A database of 52 chemical components of PM with an aerodynamic diameter < or = 2.5 pm (PM2.5) was constructed for 187 U.S. counties, for 2000 through 2005, based on data from U.S. Environmental Protection Agency (U.S. EPA) monitoring networks. Components that covary with PM2.5 total mass and/or are large contributors to PM2.5, total mass were identified using actual and seasonally detrended data. Using Bayesian hierarchical modeling, seasonal and temporal variation in PM2.5 and the risk of total, cardiovascular, and respiratory hospital admissions were investigated for persons > or = 65 years in 202 U.S. counties for 1999 through 2005. Seasonal variation was investigated using three model structures with different underlying assumptions about the relationship between PM2.5 and hospitalizations. The findings of this study indicate higher effects in winter for both causes of hospitalization, and higher effects in the Northeast for cardiovascular admissions, although 53% of the counties were in this region. Higher PM2.5 effect estimates for cardiovascular or respiratory hospitalizations were observed in seasons and counties with a higher PM2.5 content of nickel (Ni), vanadium (V), or EC. Mortality effect estimates for PM with an aerodynamic diameter < or = 10 pm (PM10) were higher in seasons and counties with higher PM2.5 Ni content. The association between the Ni content of PM2.5 and effect estimates for cardiovascular hospitalization was robust to adjustment by EC, V, or both EC and V. An interquartile range (IQR) increase in the fraction of PM2.5 that is Ni was associated with a 14.9% (PI, 3.4-26.4) increase in the relative rates of cardiovascular hospital admissions associated with PM2.5 total mass adjusted for EC and V. No associations were observed between PM total mass health effect estimates and community-level variables for socioeconomic status, racial composition, or urbanicity. Communities with a higher prevalence of central AC had lower PM2.5 effect estimates for cardiovascular hospital admissions. The findings of this study indicate strong spatial and temporal variation in the chemical composition of the particle mixture and in the regional and seasonal variation in health effect estimates for PM2.5 total mass. The chemical composition of particles partially explained the heterogeneity of effect estimates. Observed associations could be related to the components themselves, to other components, or to a combination of components that share similar sources. The findings do not exclude the possibility that other components or characteristics of PM are harmful. The limitations of this study include the use of community-level aggregated data for exposure and for the variables used to investigate alternate hypotheses. Also, particle components and chemical forms (e.g., ammonium sulfate) not measured in the U.S. EPA database were not included. PM10 results in particular should be viewed with caution as the time frame of measurement and PM size fraction are different for the chemical composition and health effects data. A better understanding of the particular chemical components or sources that are most harmful to health can help decision-makers develop more targeted air pollution regulations and can aid in understanding the biological mechanisms by which air pollution-related health effects occur, thereby informing future research. Source


Ghazal S.,Yale University
Current Opinion in Obstetrics and Gynecology | Year: 2013

PURPOSE OF REVIEW: Germline stem cell research over the last decade has brought into question one of the basic tenets of reproductive biology that women are born with a finite number of oocytes without the potential for renewal. Evidence for the existence of oogonial stem cells in the postnatal ovary has gained momentum, but skepticism remains. RECENT FINDINGS: Several research studies claimed that they have identified functional oogonial stem cells in the postnatal ovary of several different species including humans. The scientific community has questioned both the methods and significance of these studies. SUMMARY: Many speculate that germline stem cells could make a significant impact on the treatment of female infertility. However, this field of research is still in its infancy. There is still much to learn about the biology of oogonial stem cells and their potential clinical application. More research is needed before oogonial stem cells can become a viable treatment modality for women with infertility. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source


Rothman J.E.,Yale University | Schekman R.,University of California at Berkeley
Cell | Year: 2011

F.-Ulrich Hartl and Arthur Horwich will share this year's Lasker Basic Medical Science Award for the discovery of the cell's protein-folding machinery, exemplified by cage-like structures that convert newly synthesized proteins into their biologically active forms. Their fundamental findings reveal mechanisms that operate in normal physiologic processes and help to explain the problems that arise in diseases of protein folding. © 2011 Elsevier Inc. Source


Karato S.-I.,Yale University
Physics of the Earth and Planetary Interiors | Year: 2010

The influence of anisotropic diffusion coefficients on diffusion-controlled high-temperature creep is examined. Anisotropic diffusion affects anisotropy of diffusion-controlled deformation of a single crystal. The shape change of a single crystal by diffusional mass flux is controlled directly by the anisotropy in diffusion coefficients. The rate of shape change of a single crystal by diffusion-controlled dislocation glide is controlled by the anisotropy of diffusion coefficients on the plane normal to the dislocation line. Consequently, if a polycrystalline aggregate is deformed uniformly by diffusion creep, then the rate of deformation is controlled by that of diffusion (of the slowest diffusion species) along the slowest direction. In contrast, when a polycrystalline aggregate is deformed by climb-controlled dislocation creep, the rate of deformation is controlled by the diffusion (of the slowest diffusion species) along the direction where the diffusion coefficient has the intermediate value. The results are applied to olivine and post-perovskite. For olivine, the observed large plastic anisotropy and small anisotropy in diffusion suggests that high-temperature power-law creep is controlled not only by diffusion but also by some other factors such as jog density. For post-perovskite, the results of numerical calculations on the mobility of vacancies would suggest that the viscosity of post-perovskite aggregates is higher than or comparable to that of the perovskite aggregates if the defect concentrations were the same among these minerals. However, currently nothing is known about the defect concentrations in post-perovskite and other coexisting phases, and therefore it is impossible to compare the creep strength among coexisting phases from these results. © 2010 Elsevier B.V. Source


Korenaga J.,Yale University
Astrophysical Journal Letters | Year: 2010

The operation of plate tectonics on Earth is essential to modulate its atmospheric composition over geological time and is thus commonly believed to be vital for planetary habitability at large. It has been suggested that plate tectonics is very likely for super-Earths, with or without surface water, because a planet with a larger mass tends to have sufficient convective stress to escape from the mode of stagnant-lid convection. Here, this suggestion is revisited on the basis of the recently developed scaling laws of plate-tectonic convection, which indicate that the planetary size plays a rather minor role and that the likelihood of plate tectonics is controlled largely by the presence of surface water. © 2010. The American Astronomical Society. All rights reserved. Source


Unger N.,Yale University
Geophysical Research Letters | Year: 2011

Aircraft emissions can affect climate change through increasing carbon dioxide (CO2) but also via a host of other short-lived non-CO 2 effects that are complex, involve impacts that are both warming and cooling and are unique to this sector. Previous assessments of aviation climate impacts have used a segmented approach whereby each effect was calculated separately and the effects summed. Integrated approaches using newly available Earth System models that allow simulation of more realistic interactions between effects are now possible. The NASA GISS Earth System Model (ModelE) is applied to reassess the net climate impact of civil aviation emissions based on a new inventory for year 2006 developed using the Federal Aviation Administration's (FAA) Aviation Environmental Design Tool (AEDT). The model simulates all known non-CO2 aviation climate impacts except linear contrails and contrail-cirrus for which a recent estimate is assumed. For standard jet fuel, the net global climate impact for sustained constant year 2006 aviation emissions is +44 ± 10 mWm-2 (2/3 due to non-CO2 effects) on a 20-year timescale and +73 ± 10 mWm-2 (over 1/3 due to non-CO2 effects) on a 100-year timescale. For desulfurized jet fuel, the net climate impact is +40 ± 10 mWm-2 on the 20-year timescale, slightly less warming than the standard fuel case due to the complex interplay between sulfate and nitrate and the competition for ammonia. Ozone (O3) greenhouse efficiency (W per g O3 change) is 20-60% larger for aviation than surface transportation emissions. Copyright 2011 by the American Geophysical Union. Source


Objective. Our objective was to determine the effectiveness of cervical collars and cervicothoracic orthoses for stabilizing clinically relevant, experimentally produced cervical spine injuries. Summary of Background Data. Most previous in vitro studies of cervical orthoses used a simplified injury model with all ligaments transected at a single spinal level, which differs from real-life neck injuries. Human volunteer studies are limited to measuring only sagittal motions or 3-dimensional motions only of the head or 1 or 2 spinal levels. Methods. Three-plane flexibility tests were performed to evaluate 2 cervical collars (Vista Collar and Vista Multipost Collar) and 2 cervicothoracic orthoses (Vista TS and Vista TS4) using a skull-neckthorax model with 8 injured cervical spine specimens (manufacturer of orthoses: Aspen Medical Products Inc, Irvine, CA). The injuries consisted of flexion-compression at the lower cervical spine and extension-compression at superior spinal levels. Pair-wise repeated measures analysis of variance (P < 0.05) and Bonferroni post hoc tests determined significant differences in average range of motions of the head relative to the base, C7 or T1, among experimental conditions. Results. All orthoses significantly reduced unrestricted head/base flexion and extension. The orthoses allowed between 8.4% and 25.8% of unrestricted head/base motion in flexion/extension, 57.8% to 75.5% in axial rotation, and 53.8% to 73.7% in lateral bending. The average percentages of unrestricted motion allowed by the Vista Collar, Vista Multipost Collar, Vista TS, and Vista TS4 were: 14.0, 9.7, 6.1, and 4.7, respectively, for middle cervical spine extension and 13.2, 11.8, 3.3, and 0.4, respectively, for lower cervical spine flexion. Conclusion. Successive increases in immobilization were observed from Vista Collar to Vista Multipost Collar, Vista TS, and Vista TS4 in extension at the injured middle cervical spine and in flexion at the injured lower cervical spine. Our results may assist clinicians in selecting the most appropriate orthosis based upon patient-specific cervical spine injuries. Copyright © 2013 Lippincott Williams & Wilkins. Source


Zou W.,University of Michigan | Wolchok J.D.,Sloan Kettering Cancer Center | Chen L.,Yale University
Science Translational Medicine | Year: 2016

PD-L1 and PD-1 (PD) pathway blockade is a highly promising therapy and has elicited durable antitumor responses and long-term remissions in a subset of patients with a broad spectrum of cancers. How to improve, widen, and predict the clinical response to anti-PD therapy is a central theme in the field of cancer immunology and immunotherapy. Oncologic, immunologic, genetic, and biological studies focused on the human cancer microenvironment have yielded substantial insight into this issue. Here, we focus on tumor microenvironment and evaluate several potential therapeutic response markers including the PD-L1 and PD-1 expression pattern, genetic mutations within cancer cells and neoantigens, cancer epigenetics and effector T cell landscape, and microbiota. We further clarify the mechanisms of action of these markers and their roles in shaping, being shaped, and/or predicting therapeutic responses. We also discuss a variety of combinations with PD pathway blockade and their scientific rationales for cancer treatment. © 2016 by the American Association for the Advancement of Science; all rights reserved. Source


Redlich C.A.,Yale University
Proceedings of the American Thoracic Society | Year: 2010

Numerous occupational and environmental exposures that increase asthma risk have been identified. Research and prevention have focused primarily on the respiratory tract. However, recent studies suggest that the skinmayalso be an important route of exposureand site of sensitization that contributes to asthmadevelopment. Factors that impair skin barrier function, such as filaggrin gene mutations or skin trauma, may facilitate allergen entry and promote Th2-like sensitization and subsequent asthma. Animal studies demonstrate that skin exposure to chemical and protein allergens is highly effective at inducing sensitization, with subsequent inhalation challenge eliciting asthmatic responses. A similar role for human skin exposure to certain sensitizing agents, such as isocyanates, is likely. Skin exposure methodologies are being developed to incorporate skin exposure assessment into epidemiology studies investigating asthma risk factors. Source


Higley M.J.,Yale University | Sabatini B.L.,Howard Hughes Medical Institute
Cold Spring Harbor Perspectives in Biology | Year: 2012

Calcium (Ca2+) is a ubiquitous signaling molecule that accumulates in the cytoplasm in response to diverse classes of stimuli and, in turn, regulates many aspects of cell function. In neurons, Ca2+ influx in response to action potentials or synaptic stimulation triggers neurotransmitter release, modulates ion channels, induces synaptic plasticity, and activates transcription. In this article, we discuss the factors that regulate Ca2+ signaling in mammalian neurons with a particular focus on Ca2+ signaling within dendritic spines. This includes consideration of the routes of entry and exit of Ca2+, the cellular mechanisms that establish the temporal and spatial profile of Ca2+ signaling, and the biophysical criteria that determine which downstream signals are activated when Ca2+ accumulates in a spine. Furthermore, we also briefly discuss the technical advances that made possible the quantitative study of Ca2+ signaling in dendritic spines. © 2012 Cold Spring Harbor Laboratory Press; all rights reserved. Source


Landskroner-Eiger S.,Yale University
Cold Spring Harbor perspectives in medicine | Year: 2013

MicroRNAs are highly expressed in endothelial cells, and recent data suggest that they regulate aspects of vascular development and angiogenesis. This study highlights the state of the art in this field and potential therapeutic opportunities. MicroRNAs (miRNAs) represent a family of conserved short (≈22 nt) noncoding single-stranded RNAs that have been identified in plants and animals. They are generated by the sequential processing of the RNA template by the enzymes Drosha and Dicer, and mature miRNAs can regulate the levels of gene expression at the posttranscriptional level. miRNAs participate in a diverse range of regulatory events via regulation of genes involved in the control of processes such as development, differentiation, homeostasis, metabolism, growth, proliferation, and apoptosis. However, rather than functioning as regulatory on-off switches, miRNAs often function to modulate or fine-tune cellular phenotypes. So far, more than 1000 mammalian miRNAs have been identified since the discovery of the first two miRNAs (lin-4 and let-7), and bioinformatics predictions indicate that mammalian miRNAs can regulate ∼30% of all protein-coding genes. Source


Justice A.C.,Yale University
Current HIV/AIDS Reports | Year: 2010

The population of patients with HIV infection achieving viral suppression on combination antiretroviral therapy is growing, aging, and experiencing a widening spectrum of non-AIDS diseases. Concurrently, AIDSdefining conditions are becoming less common and are variably associated with outcome. Nonetheless, the spectrum of disease experienced by those aging with HIV remains strongly influenced by HIV, its treatment, and the behaviors, conditions, and demographics associated with HIV infection. Our focus must shift from a narrow interest in CD4 counts, HIV-RNA, and AIDS-defining illnesses to determining the optimal management of HIV infection as a complex chronic disease in which the causes of morbidity and mortality are multiple and overlapping. We need a new paradigm of care with which to maximize functional status, minimize frailty, and prolong life expectancy. A composite index that summarizes a patient's risk of morbidity and mortality could facilitate this work and help chart its progress. © Springer Science+Business Media, LLC 2010. Source


Ko C.J.,Yale University
Clinics in Dermatology | Year: 2010

The keratoacanthoma and its variants are clinically and histologically heterogenous. Some consider the keratoacanthoma to be benign, whereas others classify it as a subtype of squamous cell carcinoma. The keratoacanthoma is generally treated rather than observed for spontaneous resolution. This hampers evaluation of the true natural history of lesions diagnosed as keratoacanthoma. In addition, studies have not found a reliable marker to differentiate keratoacanthoma from squamous cell carcinoma. It currently remains unclear how the keratoacanthoma relates to squamous cell carcinoma, and continued investigation is necessary. © 2010 Elsevier Inc. Source


Dhodapkar M.V.,Yale University
Current Opinion in Immunology | Year: 2010

A growing body of data points to not only intraclonal heterogeneity and hierarchy of growth potential, but also plasticity of cellular differentiation within human tumors. Recent studies have also identified surprising overlap between pathways that regulate pluripotency in embryonal stem (ES) cells and oncogenesis. While there is a long history of targeting embryonal tissues toward cancer vaccines, recent identification of crucial stemness pathways in ES cells as well as putative cancer stem cells (CSCs) provides novel opportunities for antigen-specific targeted therapy. Here we discuss recent insights into the capacity of the immune system to target these pathways. Immunologic targeting of pathways associated with stemness has implications for both immune regulation of tumor growth as well as regenerative therapies with embryonal stem cells. © 2010 Elsevier Ltd. Source


Brash D.E.,Yale University
Photochemistry and Photobiology | Year: 2015

Sequencing complete tumor genomes and exomes has sparked the cancer field's interest in mutation signatures for identifying the tumor's carcinogen. This review and meta-analysis discusses signatures and their proper use. We first distinguish between a mutagen's canonical mutations - deviations from a random distribution of base changes to create a pattern typical of that mutagen - and the subset of signature mutations, which are unique to that mutagen and permit inference backward from mutations to mutagen. To verify UV signature mutations, we assembled literature datasets on cells exposed to UVC, UVB, UVA, or solar simulator light (SSL) and tested canonical UV mutation features as criteria for clustering datasets. A confirmed UV signature was: ≥60% of mutations are C→T at a dipyrimidine site, with ≥5% CC→TT. Other canonical features such as a bias for mutations on the nontranscribed strand or at the 3 pyrimidine had limited application. The most robust classifier combined these features with criteria for the rarity of non-UV canonical mutations. In addition, several signatures proposed for specific UV wavelengths were limited to specific genes or species; UV's nonsignature mutations may cause melanoma BRAF mutations; and the mutagen for sunlight-related skin neoplasms may vary between continents. Inverse relationship of canonical mutation patterns and mutation signatures for inferring the mutagen from mutations. Two mutagens are illustrated. A mutagen's canonical mutations deviate from random base changes, establishing a pattern typical for that mutagen. Different mutagens can produce the same canonical mutations (non-informative mutations). Signature mutations are the subset of canonical mutations that, in addition, are unique to that mutagen and permit inference backward from mutations to mutagen. A mutagen therefore produces signature mutations plus non-informative mutations. The latter are real and are produced by the mutagen, but are not useful for identifying that mutagen or carcinogen. © 2014 The American Society of Photobiology. Source


The REDUCE MRSA Trial (Randomized Evaluation of Decolonization vs Universal Clearance to Eliminate Methicillin-Resistant Staphylococcus aureus), a large multicenter, randomized controlled trial in adult intensive care units (ICUs), found universal decolonization to be more effective than surveillance and isolation procedures with or without targeted decolonization for reducing rates of MRSA-positive clinical cultures. The Agency for Healthcare Research and Quality and the Centers for Disease Control and Prevention subsequently published protocols for implementing universal decolonization in ICUs based on the trial's methods. Caution should be exercised before widely adopting these procedures in neonatal intensive care units (NICUs), particularly strategies that involve bathing with chlorhexidine and mupirocin application due to the potential for adverse events in their unique patient population, especially preterm infants. Large multicenter trials in the NICUs are needed to evaluate the efficacy, short- and long-term safety, and cost effectiveness of these strategies prior to their widespread implementation.Journal of Perinatology advance online publication, 10 July 2014; doi:10.1038/jp.2014.125. Source


Pomeranz J.L.,Yale University
American Journal of Public Health | Year: 2011

The United States has 51 state health departments and thousands of local health agencies. Their size, structure, and authority differ, but they all possess unique abilities to address obesity. Because they are responsible for public health, they can take various steps themselves and can coordinate efforts with other agencies to further health in all policy domains. I describe the value of health agencies' rule-making authority and clarify this process through 2 case studies involving menu-labeling regulations. I detail rule-making procedures and examine the legal and practical limitations on agency activity. Health departments have many options to effect change in the incidence of obesity but need the support of other government entities and officials. Source


The study objective was to assess the feasibility of a computerized alcohol-screening interview (CASI) program to identify at-risk alcohol users among adult emergency department (ED) patients. The study aimed to evaluate the feasibility of implementing a computerized screening, brief intervention, and referral to treatment (SBIRT) program within a busy urban ED setting, to report on accurate deployment of alcohol screening results, and to assess comprehension and satisfaction with CASI from both patient and research staff perspectives. Research assistants (RAs) screened a convenience sample of medically stable ED patients. The RAs brought CASI to patients' bedsides, and patients entered their own alcohol consumption data. The CASI intervention consisted of an alcohol use screening identification test, a personalized normative feedback profile, NIAAA low-risk drinking educational materials, and treatment referrals (when indicated). Five hundred seventeen patients were enrolled. The median age of participants was 37 years (range, 21-85 years); 37% were men, 62% were Hispanic, 7% were Caucasian, 30% were African American, and 2% were multiracial. Eighty percent reported regular use of computers at home. Eighty percent of patients approached consented to participate, and 99% of those who started CASI were able to complete it. Two percent of interviews were interrupted for medical tests and procedures, however, no patients required breaks from using CASI for not feeling well. The CASI program accurately provided alcohol risk education to patients 100% of the time. Thirty-two percent of patients in the sample screened positive for at-risk drinking. Sixty percent of patients reported that CASI increased their knowledge of safe drinking limits, 39% reported some likeliness to change their alcohol use, and 28% reported some intention to consult a health care professional about their alcohol use as a result of their screening results. Ninety-three percent reported CASI was easy to use, 93% felt comfortable receiving alcohol education via computer, and 89% liked using CASI. Ninety percent of patients correctly identified their alcohol risk level after participating in CASI. With regard to research staff experience, RAs needed to provide standby assistance to patients during <1% of CASI administrations and needed to troubleshoot computer issues in 4% of interviews. The RAs distributed the correct alcohol risk normative profiles to patients 97% of the time and provided patients with treatment referrals when indicated 81% of the time. The RAs rated patients as "not bothered at all" by using CASI 94% of the time. This study demonstrates that an ED-based computerized alcohol screening program is both acceptable to patients and effective in educating patients about their alcohol risk level. Additionally, this study demonstrates that few logistical problems related to using computers for these interventions were experienced by research staff: in most cases, staff accurately deployed alcohol risk education to patients, and in all cases, the computer provided accurate education to patients. Computer-assisted SBIRT may represent a significant time-saving measure, allowing EDs to reach larger numbers of patients for alcohol intervention without causing undue clinical burden or interruptions to clinical care. Future studies with follow-up are needed to replicate these results and assess drinking reductions post-intervention. Source


The aggregation and deposition of the neuronal protein α-synuclein in the substantia nigra region of the brain is a key pathological feature of Parkinson's disease. α-Synuclein assembles from a monomeric state in solution, which lacks stable secondary and tertiary contacts, into highly structured fibrillar aggregates through a pathway which involves the population of multiple oligomeric species over a range of time scales. These features make α-synuclein well suited for study with single-molecule techniques, which are particularly useful for characterizing dynamic, heterogeneous samples. Here, we review the current literature featuring single-molecule fluorescence studies of α-synuclein and discuss how these studies have contributed to our understanding of both its function and its role in disease. Source


In this paper, I use a social interactions framework to detect whether individual smoking decisions are influenced by classmate smoking decisions. There are several large challenges in addressing this question, including the endogeneity of school (and thus classmates) through residential location choices, 'third factors' such as school-level unobservables that influence individual and classmate choices simultaneously, and the difficulty of the identification of parameters in empirical models of social interactions. In order to address these issues, I use an instrumental variables/fixed effects methodology that compares students in different grades within the same high school who face a different set of classmates and classmates' decisions. Preferred specifications suggest that increasing the proportion of classmates who smoke by 10% will increase the likelihood an individual smokes by approximately 3 percentage points. I compare these results with previous findings that are unable to use school fixed effects and/or use potentially invalid instruments and find that the current results suggest smaller social interactions in adolescent smoking decisions than some previous work. Copyright © 2009 John Wiley & Sons, Ltd. Source


Nygaard H.B.,Yale University
Clinical Therapeutics | Year: 2013

Alzheimer's disease (AD) is a devastating neurodegenerative disorder, with a rapidly increasing worldwide prevalence. Although no cure for AD has yet been found, substantial progress has been made in our understanding of AD pathogenesis. This progress has led to the development of numerous promising compounds in various stages of clinical testing. In this review, the current pharmacologic treatments for AD are discussed in detail, followed by an overview of the main experimental strategies that will shape AD therapeutics over the next decade. © 2013 Elsevier HS Journals, Inc. Source


Sinard J.H.,Yale University
Archives of Pathology and Laboratory Medicine | Year: 2013

Context. - With an increasing trend toward fee-code- based methods of measuring the clinical professional productivity of pathologists, those pathologists whose clinical activities include the performance of autopsies have been disadvantaged by the lack of generally accepted workload equivalents for autopsy performance and supervision. Objective. - To develop recommended benchmarks to account for this important and often overlooked professional activity. Design. - Based on the professional experience of members of the Autopsy Committee of the College of American Pathologists, a survey of autopsy pathologists, and the limited additional material available in the literature, we developed recommended workload equivalents for the professional work associated with performing an autopsy, which we elected to express as multiples of established Current Procedural Terminology codes. Results. - As represented in Table 3, we recommend that the professional work associated with a full adult autopsy be equivalent to 5.5 3 88309-26. Additional professional credit of 1.5 3 88309-26 should be added for evaluation of the brain and for a detailed clinical-pathologic discussion. The corresponding value for a fetal/neonatal autopsy is 4.0 3 88309-26. Conclusion. - Although we recognize that autopsy practices vary significantly from institution to institution, it is hoped that our proposed guidelines will be a valuable starting point that individual practices can then adapt, taking into account the specifics of their practice environment. Source


Objective To assess the treatment recommendations from a nationally representative sample of radiation oncologists and urologists on adjuvant radiotherapy for patients with pathologically advanced prostate cancer after radical prostatectomy. Methods From a random sample of 1422 physicians (n = 711 radiation oncologists; n = 711 urologists) in the American Medical Association Masterfile, a mail survey queried treatment recommendations for adjuvant radiotherapy that varied by the following pathologic features: extraprostatic extension (pT3a) vs seminal vesicle invasion (pT3b), Gleason 7 vs Gleason 8-10, and margin negative (MN) vs margin positive (MP). Pearson chi-square and multivariable logistic regression were used to test for differences in treatment recommendations by physician specialty. Results Response rates for radiation oncologists and urologists were similar (44% vs 46%; P =.42). Radiation oncologists were more likely to recommend adjuvant radiotherapy than urologists for all the varying pathologic scenarios from pT3a, Gleason 7, and MN (42.5% vs 9.7%; adjusted odds ratio [OR]: 7.82, P <.001) to pT3b, Gleason 8-10, and MP disease (94.5% vs 89.1%, adjusted OR: 2.46, P <.001). Compared with radiation oncologists, urologists were more likely to recommend salvage radiotherapy pT3a, Gleason 7, and MN (90.3% vs 57.7%; adjusted OR: 7.72, P <.001) to pT3b, Gleason 8-10, and MP disease (10.9% vs 5.5%; adjusted OR: 2.22, P <.001). Conclusion In this national survey, radiation oncologists and urologists have markedly different treatment recommendations for adjuvant and salvage radiotherapy. Patients with adverse pathologic features after radical prostatectomy should consult with both a urologist and radiation oncologist to hear a diversity of opinions to make the most informed decision possible. © 2013 Elsevier Inc. All Rights Reserved. Source


Bruce R.D.,Yale University
International Journal of Drug Policy | Year: 2010

The link between injection drug use and HIV has been extensively described. Despite worldwide prevention efforts, injection drug use continues to be a risk factor for HIV transmission and both HIV and injection drug use continues to spread across the globe. Although methadone has demonstrated multiple health benefits including the reduction in injection drug use and HIV acquisition, the utilisation of methadone in many areas of the world remains one of secondary, rather than primary, HIV prevention. As a result, many who finally begin methadone enter treatment having accumulated medical and mental health problems as a result of delayed treatment. Rapid access to treatment and a more aggressive policy that realizes that methadone can help reduce opioid drug use is necessary if methadone is effectively going to act as primary HIV prevention. To delay access to methadone only increases the probability that the individual will acquire an infectious disease that is more costly to the individual in terms of morbidity and mortality and more costly to society as a whole. © 2009 Elsevier B.V. All rights reserved. Source


Lampert R.,Yale University
Progress in Cardiovascular Diseases | Year: 2012

Athletes may present with palpitations, syncope, or arrest resulting in the diagnosis of arrhythmia, or screening may result in diagnosis of conditions with predisposition to arrhythmia. This chapter focuses on 3 common arrhythmic conditions in athletes-atrial fibrillation, premature ventricular contractions (PVCs), and the athlete with an implanted device.(1) Atrial fibrillation: most studies show that atrial fibrillation is more common in competitive athletes, particularly those participating in long-term endurance sports. Postulated mechanisms include morphologic changes such as atrial dilatation, autonomic changes such as increased vagal tone, or inflammatory changes due to sports participation. Treatment options include long-term antiarrhythmic agents, "pill in the pocket" medications, or radiofrequency ablation, a highly successful procedure in athletes.(2) Premature ventricular contractions: data conflict on whether the incidence of PVCs is increased in highly trained individuals. Very frequent PVCs in athletes, however, can be a manifestation of underlying heart disease, and athletes presenting with PVCs should undergo evaluation. In the absence of underlying heart disease, PVCs do not carry a poor prognosis, and US guidelines do not recommend restriction from sports.(3) Implanted devices: the safety of sports for the athlete with an implanted device is unknown, and current guidelines recommend against participation in vigorous competitive sports, based on postulated risks including failure to defibrillate and risk of injury. Many athletes with defibrillators and pacemakers do participate in sports. Ongoing research will better delineate the risks of sports for the athlete with an implanted device. © 2012 Elsevier Inc.. Source


Smooke M.D.,Yale University
Proceedings of the Combustion Institute | Year: 2013

Hydrocarbon fuels will remain a major source of energy well into the second half of the 21st century and, despite dire warnings about their limited supply, known resources have actually increased over the past decade. Nevertheless, finite supplies and increasing demand will exert pressure on the efficient use of these fuels, especially if their price continues to climb. Specifically, electricity generation and propulsion will continue to rely heavily upon the burning of hydrocarbon fuels for many years to come. Although an understanding of combustion in practical combustors is essential to the goals of reducing pollution and increasing energy efficiency, three-dimensional models of these systems with detailed transportation fuel chemistry and complex transport are beyond our current computational capabilities. Instead, one can study flames with complex chemistry in simpler laminar configurations to provide insight into the chemical and physical processes occurring in many engineered systems. In this paper, we trace the development of mathematical models and computational methods for laminar flame problems, with a particular emphasis on numerical algorithms that enable their coupled solution. While most of the focus is on steady systems, we also discuss issues related to time-dependent flames. © 2012 The Combustion Institute. Published by Elsevier Inc. All rights reserved. Source


Picciotto M.R.,Yale University
Cold Spring Harbor perspectives in medicine | Year: 2013

Tobacco smoking results in more than 5 million deaths each year and accounts for almost 90% of all deaths from lung cancer. Nicotine, the major reinforcing component of tobacco smoke, acts in the brain through the neuronal nicotinic acetylcholine receptors (nAChRs). The nAChRs are allosterically regulated, ligand-gated ion channels consisting of five membrane-spanning subunits. Twelve mammalian α subunits (α2-α10) and β subunits (β2-β4) have been cloned. The predominant nAChR subtypes in mammalian brain are those containing α4 and β2 subunits (denoted as α4β2* nAChRs). The α4β2* nAChRs mediate many behaviors related to nicotine addiction and are the primary targets for currently approved smoking cessation agents. Considering the large number of nAChR subunits in the brain, it is likely that nAChRs containing subunits in addition to α4 and β2 also play a role in tobacco smoking. Indeed, genetic variation in the CHRNA5-CHRNA3-CHRNB4 gene cluster, encoding the α5, α3, and β4 nAChR subunits, respectively, has been shown to increase vulnerability to tobacco dependence and smoking-associated diseases including lung cancer. Moreover, mice in which expression of α5 or β4 subunits has been genetically modified have profoundly altered patterns of nicotine consumption. In addition to the reinforcing properties of nicotine, the effects of nicotine on appetite, attention, and mood are also thought to contribute to establishment and maintenance of the tobacco smoking habit. Here we review recent insights into the behavioral actions of nicotine and the nAChRs subtypes involved, which likely contribute to the development of tobacco dependence in smokers. Source


Vasudevan A.,Yale University
Arthritis and rheumatism | Year: 2012

To examine whether patients with rheumatoid arthritis (RA) demonstrate patterns of prosthetic wear or cellular responses to implant wear debris different from those demonstrated by patients without inflammatory joint disease. Thirty-eight patients who had undergone a primary revision of a total elbow arthroplasty for aseptic loosening between 1996 and 2008 were identified. Twenty-five of these patients had RA, and 13 did not have inflammatory arthritis. Clinical data, gross wear patterns of the removed prostheses, and histopathologic analyses of peri-implant tissue were compared between the patients with RA and those without RA. Evaluation of the retrieved prostheses showed that conformational change of the humeral polyethylene bushing was associated with the generation of polyethylene and metal particles. The amount and type of wear debris in periprosthetic tissues were similar in patients with and those without RA. Patients with RA who were not receiving anti-tumor necrosis factor (anti-TNF) therapy exhibited a histologic pattern of interstitial and sheet-like lymphocytic infiltrates associated with a high plasma cell composition, which was different from the predominantly perivascular infiltrates with few plasma cells seen in non-RA patients (P = 0.04). Patients with RA who were receiving anti-TNF therapy showed a mixed perivascular and interstitial pattern of infiltrates with variable cell composition. Patients with RA exhibited a distinct cellular response to implant wear debris compared with patients without RA. This reaction was unrelated to differences in the type or amount of wear debris and was mitigated by anti-TNF therapy. These results suggest an intrinsic alteration in immunoregulation in RA and have implications for potential immunologic treatment of osteolysis in these patients. Copyright © 2012 by the American College of Rheumatology. Source


Bakar K.S.,Yale University | Sahu S.K.,University of Southampton
Journal of Statistical Software | Year: 2015

Hierarchical Bayesian modeling of large point-referenced space-time data is increas- ingly becoming feasible in many environmental applications due to the recent advances in both statistical methodology and computation power. Implementation of these meth- ods using the Markov chain Monte Carlo (MCMC) computational techniques, however, requires development of problem-specific and user-written computer code, possibly in a low-level language. This programming requirement is hindering the widespread use of the Bayesian model-based methods among practitioners and, hence there is an urgent need to develop high-level software that can analyze large data sets rich in both space and time. This paper develops the package spTimer for hierarchical Bayesian modeling of stylized environmental space-time monitoring data as a contributed software package in the R language that is fast becoming a very popular statistical computing platform. The package is able to fit, spatially and temporally predict large amounts of space-time data using three recently developed Bayesian models. The user is given control over many options regarding covariance function selection, distance calculation, prior selection and tuning of the implemented MCMC algorithms, although suitable defaults are provided. The package has many other attractive features such as on the y transformations and an ability to spatially predict temporally aggregated summaries on the original scale, which saves the problem of storage when using MCMC methods for large datasets. A simulation example, with more than a million observations, and a real life data example are used to validate the underlying code and to illustrate the software capabilities. Source


Waldron-Lynch F.,Yale University
Science translational medicine | Year: 2012

The development and optimization of immune therapies in patients has been hampered by the lack of preclinical models in which their effects on human immune cells can be studied. As a result, observations that have been made in preclinical studies have suggested mechanisms of drug action in murine models that have not been confirmed in clinical studies. Here, we used a humanized mouse reconstituted with human hematopoietic stem cells to study the mechanism of action of teplizumab, an Fc receptor nonbinding humanized monoclonal antibody to CD3 being tested in clinical trials for the treatment of patients with type 1 diabetes mellitus. In this model, human gut-tropic CCR6(+) T cells exited the circulation and secondary lymph organs and migrated to the small intestine. These cells then produced interleukin-10 (IL-10), a regulatory cytokine, in quantities that could be detected in the peripheral circulation. Blocking T cell migration to the small intestine with natalizumab, which prevents cellular adhesion by inhibiting α(4) integrin binding, abolished the treatment effects of teplizumab. Moreover, IL-10 expression by CD4(+)CD25(high)CCR6(+)FoxP3 cells returning to the peripheral circulation was increased in patients with type 1 diabetes treated with teplizumab. These findings demonstrate that humanized mice may be used to identify novel immunologic mechanisms that occur in patients treated with immunomodulators. Source


Weigelt P.,University of Gottingen | Jetz W.,Yale University | Kreft H.,University of Gottingen
Proceedings of the National Academy of Sciences of the United States of America | Year: 2013

The Earth's islands harbor a distinct, yet highly threatened, biological and cultural diversity that has been shaped by geographic isolation and unique environments. Island systems are key natural laboratories for testing theory in ecology and evolution. However, despite their potential usefulness for research, a quantitative description of island environments and an environmental classification are still lacking. Here, we prepare a standardized dataset and perform a comprehensive global environmental characterization for 17,883 of the world's marine islands >1 km2 (∼98% of total island area). We consider area, temperature, precipitation, seasonality in temperature and precipitation, past climate change velocity, elevation, isolation, and past connectivity-key island characteristics and drivers of ecosystem processes. We find that islands are significantly cooler, wetter, and less seasonal than mainlands. Constrained by their limited area, they show less elevational heterogeneity. Wet temperate climates are more prevalent on islands, whereas desert climates are comparatively rare. We use ordination and clustering to characterize islands in multidimensional environmental space and to delimit island ecoregions, which provides unique insights into the environmental configuration and diversity of the world's islands. Combining ordination and classification together with global environmental data in a common framework opens up avenues for a more integrative use of islands in biogeography, macroecology, and conservation. To showcase possible applications of the presented data, we predict vascular plant species richness for all 17,883 islands based on statistically derived environment-richness relationships. Source


Unger N.,Yale University
Journal of Geophysical Research: Atmospheres | Year: 2013

A biochemical model of isoprene emission embedded within a global chemistry-climate simulation framework is applied to investigate the transient response to environmental change over the past century. In the model, the isoprene production is directly coupled to photosynthesis and depends on intercellular carbon dioxide concentration (CO2), atmospheric CO 2, and canopy temperature. Sensitivity runs are performed to isolate the relative roles of individual global change drivers: CO2, physical climate, and anthropogenic land cover change (ALCC). Between 1880 and 2000, atmospheric CO2 increased by ~30% from 291 to 370 ppmv, global average surface air temperature increased by 0.7°C, and the crop cover fraction of vegetated land area more than doubled from 15 to 37%. Over the past century, isoprene emission has decreased globally by 20% from 534 to 449 Tg C/yr, while gross primary productivity has increased by 15% from 107 to 124 Pg C/yr mostly due to CO2 fertilization. In terms of individual drivers, the global isoprene source increased by 7% due to the atmospheric CO 2 concentration rise (including the opposing effects of CO 2 fertilization and CO2 inhibition), decreased by 22% due to ALCC, and increased by only 3% due to physical climate change. Thus, ALCC is the dominant driver of isoprene emission change. Modeled global isoprene emissions were higher in the preindustrial than in the present day. In the industrial era, isoprene emission change represents a human-induced climate forcing, analogous to land use-driven CO2 emission, not a climate feedback because temperature-driven increase was a relatively weak driver of isoprene emission change from 1880 to 2000. Key Points Isoprene emission was 20% higher in 1880 than in 2000 Human land use is dominant driver of twentieth century isoprene change Twentieth century isoprene emission change is a climate forcing not a feedback ©2013. American Geophysical Union. All Rights Reserved. Source


Li J.,Yale University
Nature Genetics | Year: 2015

Gliomas represent approximately 30% of all central nervous system tumors and 80% of malignant brain tumors. To understand the molecular mechanisms underlying the malignant progression of low-grade gliomas with mutations in IDH1 (encoding isocitrate dehydrogenase 1), we studied paired tumor samples from 41 patients, comparing higher-grade, progressed samples to their lower-grade counterparts. Integrated genomic analyses, including whole-exome sequencing and copy number, gene expression and DNA methylation profiling, demonstrated nonlinear clonal expansion of the original tumors and identified oncogenic pathways driving progression. These include activation of the MYC and RTK-RAS-PI3K pathways and upregulation of the FOXM1- and E2F2-mediated cell cycle transitions, as well as epigenetic silencing of developmental transcription factor genes bound by Polycomb repressive complex 2 in human embryonic stem cells. Our results not only provide mechanistic insight into the genetic and epigenetic mechanisms driving glioma progression but also identify inhibition of the bromodomain and extraterminal (BET) family as a potential therapeutic approach. © 2015 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. Source


Mizuno-Yamasaki E.,Gunma University | Rivera-Molina F.,Yale University | Novick P.,University of California at San Diego
Annual Review of Biochemistry | Year: 2012

Members of the Rab or ARFSar branches of the Ras GTPase superfamily regulate almost every step of intracellular membrane traffic. A rapidly growing body of evidence indicates that these GTPases do not act as lone agents but are networked to one another through a variety of mechanisms to coordinate the individual events of one stage of transport and to link together the different stages of an entire transport pathway. These mechanisms include guanine nucleotide exchange factor (GEF) cascades, GTPase-activating protein (GAP) cascades, effectors that bind to multiple GTPases, and positive-feedback loops generated by exchange factor-effector interactions. Together these mechanisms can lead to an ordered series of transitions from one GTPase to the next. As each GTPase recruits a unique set of effectors, these transitions help to define changes in the functionality of the membrane compartments with which they are associated. © 2012 by Annual Reviews. All rights reserved. Source


Voight B.F.,University of Pennsylvania | Cotsapas C.,Yale University
Current Opinion in Immunology | Year: 2012

In genetic studies of autoimmune and inflammatory diseases, one clear finding that has emerged from genome-wide association studies is that a substantial fraction of variation modifying risk in one disease also contributes mediate risk to multiple, additional autoimmune and inflammatory diseases. The unexpected magnitude of this overlap presents the unique opportunity to dissect the pathogenic mechanisms underlying multiple disease states in the expectation that this may lead to both more sensitive diagnostics and novel therapies. Here, we review the current evidence for this shared genetic architecture and, based on these data, outline models for shared pathways, the underlying hypotheses for them, how these models can be tested and validated. © 2012 Elsevier Ltd. Source


Picciotto M.R.,Yale University | Kenny P.J.,Scripps Research Institute
Cold Spring Harbor Perspectives in Medicine | Year: 2013

Tobacco smoking results in more than 5 million deaths each year and accounts for almost 90% of all deaths from lung cancer. Nicotine, the major reinforcing component of tobacco smoke, acts in the brain through the neuronal nicotinic acetylcholine receptors (nAChRs). The nAChRs are allosterically regulated, ligand-gated ion channels consisting of five membrane-spanning subunits. Twelve mammalian α subunits (α2-α10) and β subunits (β2-β4) have been cloned. The predominant nAChR subtypes in mammalian brain are those containing α4 and β2 subunits (denoted as α4β2* nAChRs). The α4β2* nAChRs mediate many behaviors related to nicotine addiction and are the primary targets for currently approved smoking cessation agents. Considering the large number of nAChR subunits in the brain, it is likely that nAChRs containing subunits in addition to α4 and β2 also play a role in tobacco smoking. Indeed, genetic variation in the CHRNA5-CHRNA3-CHRNB4 gene cluster, encoding the α5, α3, and β4 nAChR subunits, respectively, has been shown to increase vulnerability to tobacco dependence and smoking-associated diseases including lung cancer. Moreover, mice in which expression of α5 or β4 subunits has been genetically modified have profoundly altered patterns of nicotine consumption. In addition to the reinforcing properties of nicotine, the effects of nicotine on appetite, attention, and mood are also thought to contribute to establishment and maintenance of the tobacco smoking habit. Here we review recent insights into the behavioral actions of nicotine and the nAChRs subtypes involved, which likely contribute to the development of tobacco dependence in smokers. © 2013 Cold Spring Harbor Laboratory Press; all rights reserved. Source


Wang J.,Yale University
Biology of reproduction | Year: 2012

Mammalian spermatogenesis is a complex process that involves spatiotemporal regulation of gene expression and meiotic recombination, both of which require the modulation of chromatin structure. Proteins important for chromatin regulation during spermatogenesis remain poorly understood. Here we addressed the role of BRG1, the catalytic subunit of the mammalian Swi/Snf-like BAF chromatin-remodeling complex, during spermatogenesis in mice. BRG1 expression is dynamically regulated in the male germline, being weakly detectable in spermatogonia, highly expressed in pachytene spermatocytes, and turned off in maturing round spermatids. This expression pattern overlaps that of Brm, the Brg1 homolog. While Brm knockout males are known to be fertile, germline-specific Brg1 deletion completely arrests spermatogenesis at the midpachytene stage, which is associated with spermatocyte apoptosis and apparently also with impaired homologous recombination and meiotic sex chromosome inactivation. However, Brg1 is dispensable for gammaH2AX formation during meiotic recombination, contrary to its reported role in DNA repair in somatic cells. Our study reveals the essential role of Brg1 in meiosis and underscores the differences in the mechanisms of DNA repair between germ cells and somatic cells. Source


Pomeranz J.L.,Yale University
Journal of Public Health Policy | Year: 2012

Consumption of sugar-sweetened beverages (SSBs) has increased worldwide. As public health studies expose the detrimental impact of SSBs, consumer protection and public health advocates have called for increased government control. A major focus has been on restricting marketing of SSBs to children, but many innovative policy options - legally defensible ways to regulate SSBs and support public health - are largely unexplored. We describe the public health, economic, and retail marketing research related to SSBs (including energy drinks). We review policy options available to governments, including mandatory factual disclosures, earmarked taxation, and regulating sales, including placement within retail and food service establishments, and schools. Our review describes recent international initiatives and classifies options available in the United States by jurisdiction (federal, state, and local) based on legal viability. © 2012 Macmillan Publishers Ltd. Source


Background: Quality improvement collaboratives are an increasingly common strategy for implementing evidence-based practices in health care. However, research shows that many participating organizations do not achieve the level of performance improvement desired. Purpose: This study examined the use of interorganizational learning activities (inter-OLAs) as an explanation for mixed performance improvement among collaborative participants. We tested the hypotheses that inter-OLA use is positively associated with participants' performance improvement and that this relationship is moderated by the use of intraorganizational learning activities (intra-OLAs) and quality-focused human resource (Q-HR) practices. Methodology: We conducted a survey of organizational teams participating in 4 Institute for Healthcare Improvement Breakthrough Series collaboratives. Survey responses from 52 teams, regarding the use of inter-OLAs, intra-OLAs and Q-HR practices, were linked to performance improvement data obtained from the Institute for Healthcare Improvement and demographic data obtained from secondary sources. Findings: The more collaborative teams used inter-OLAs, the more their organizations' performance improved. Contrary to our hypothesis, the use of intra-OLAs did not moderate this relationship; teams' use of intra-OLAs added to, but did not multiply, the effect of inter-OLA use. In contrast, an organization's use of Q-HR practices multiplied the performance benefit of inter-OLA use. Practice Implications: Our findings suggest that organizations that participate in collaboratives are more likely to improve their performance if they use the inter-OLAs offered by the collaborative. Our results also suggest that complementing high use of inter-OLAs with intra-OLA use and Q-HR practices enhances performance improvement. For collaborative sponsors, our findings imply that including activities that facilitate interorganizational and intraorganizational learning are worthwhile. Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source


Iwakiri Y.,Yale University
Liver International | Year: 2012

Portal hypertension is caused by an increased intrahepatic resistance, a major consequence of cirrhosis. Endothelial dysfunction in liver sinusoidal endothelial cells (LSECs) decreases the production of vasodilators, such as nitric oxide, and favours vasoconstriction. This contributes to an increased vascular resistance in the intrahepatic/sinusoidal microcirculation and develops portal hypertension. Portal hypertension, in turn, causes endothelial dysfunction in the extrahepatic, i.e. splanchnic and systemic, circulation. Unlike dysfunction in LSECs, endothelial dysfunction in the splanchnic and systemic circulation causes overproduction of vasodilator molecules, leading to arterial vasodilation. In addition, portal hypertension leads to the formation of portosystemic collateral vessels. Both arterial vasodilation and portosystemic collateral vessel formation exacerbate portal hypertension by increasing the blood flow through the portal vein. Pathological consequences, such as oesophageal varices and ascites, result. While the sequence of pathological vascular events in cirrhosis and portal hypertension has been elucidated, the underlying cellular and molecular mechanisms causing endothelial dysfunctions are not yet fully understood. This review article summarizes the current cellular and molecular studies on endothelial dysfunctions found during the development of cirrhosis and portal hypertension with a focus on the intra- and extrahepatic circulations. The article ends by discussing the future directions of the study for endothelial dysfunction. © 2011 John Wiley & Sons A/S. Source


White M.A.,Yale University
Comprehensive Psychiatry | Year: 2012

Objective: This study examined interrelationships between cigarette smoking for weight control and eating disorder symptoms in a community sample of adult female smokers. Method: Participants were 107 female smokers who completed a battery of questionnaires, including the Eating Disorder Examination- Questionnaire (EDE-Q). Key items measured weight-control smoking, including smoking to prevent overeating, smoking to undo the effects of overeating, and smoking to feel less hungry. Smokers who endorsed smoking in an attempt to control weight were compared with those who denied such behaviors on EDE-Q scores and frequency of binge eating and purging. Results: A substantial proportion of participants reported weight-control smoking. Participants who endorsed weight-control smoking reported elevations on eating disorder symptoms as measured by the EDE-Q. Compensatory smoking was related to the frequency of binge eating. Discussion: The findings have implications for clinicians working with eating disorder patients; for some individuals, cigarette smoking may be used as an attempt to compensate for overeating. © 2012 Elsevier Inc. Source


Stanley J.,Yale University | Krakauer J.W.,Johns Hopkins University
Frontiers in Human Neuroscience | Year: 2013

Those in 20th century philosophy, psychology, and neuroscience who have discussed the nature of skilled action have, for the most part, accepted the view that being skilled at an activity is independent of knowing facts about that activity, i.e., that skill is independent of knowledge of facts. In this paper we question this view of motor skill. We begin by situating the notion of skill in historical and philosophical context. We use the discussion to explain and motivate the view that motor skill depends upon knowledge of facts. This conclusion seemingly contradicts well-known results in cognitive science. It is natural, on the face of it, to take the case of H.M., the seminal case in cognitive neuroscience that led to the discovery of different memory systems, as providing powerful evidence for the independence of knowledge and skill acquisition. After all, H.M. seems to show that motor learning is retained even when previous knowledge about the activity has been lost. Improvements in skill generally require increased precision of selected actions, which we call motor acuity. Motor acuity may indeed not require propositional knowledge and has direct parallels with perceptual acuity. We argue, however, that reflection on the specifics of H.M.'s case, as well as other research on the nature of skill, indicates that learning to become skilled at a motor task, for example tennis, depends also on knowledge-based selection of the right actions. Thus skilled activity requires both acuity and knowledge, with both increasing with practice. The moral of our discussion ranges beyond debates about motor skill; we argue that it undermines any attempt to draw a distinction between practical and theoretical activities. While we will reject the independence of skill and knowledge, our discussion leaves open several different possible relations between knowledge and skill. Deciding between them is a task to be resolved by future research. © 2013 Stanley and Krakauer. Source


Detterbeck F.C.,Yale University
JNCCN Journal of the National Comprehensive Cancer Network | Year: 2013

Thymic tumors are considered an orphan disease, and therefore treatment recommendations have been largely empiric, based on small, retrospective, often poorly characterized series of patients. The International Thymic Malignancy Interest Group (ITMIG) has organized individual efforts, making collation of individual experiences and global collaboration possible. This article summarizes the development of ITMIG and accomplishments achieved since its inception in 2010. A great deal of infrastructure has been built, paving the way for scientifically robust progress in the future. Guidelines such as the NCCN Clinical Practice Guidelines in Oncology are of significant clinical value despite being, of necessity, largely consensus-based. The ITMIG provides the foundation for development of more evidence-based guidelines in the future. Copyright © 2013 by the National Comprehensive Cancer Network. All rights reserved. Source


Roux F.J.,Yale University
Respirology | Year: 2013

Restless legs syndrome (RLS) is a common chronic sensory-motor neurological disorder that remains a clinical diagnosis. Most RLS patients present with sleep complaints in the form of initiation and/or maintenance insomnia as RLS has a circadian rhythmicity. An increased number of periodic leg movements during sleep (PLMS) is a supportive criterion in the diagnosis of RLS. Abnormalities in the central dopaminergic and iron systems are involved in the physiopathology of RLS. There is a higher prevalence of RLS and PLMS in sleep-disordered breathing patients, particularly those with obstructive sleep apnoea (OSA), the most common sleep disorder in western societies. The complex mechanisms underlying the association between OSA, RLS and PLMS remain unclear. Untreated OSA can lead to adverse cardiovascular consequences due to cardio-metabolic dysfunction. It remains controversial whether RLS could further adversely impact the cardiovascular consequences of OSA. The PLMS do not have an additive effect on the hypersomnia experienced by some sleep-disordered breathing patients. Continuous positive airway pressure (CPAP) therapy is the most effective therapy for OSA. The presence of PLMS during CPAP treatment could be a marker of an incomplete resolution of sleep-disordered breathing in the form of increased upper airway resistance syndrome, despite treatment. Dopaminergic agonists are the preferred agent for the treatment of RLS, and are indicated when RLS symptoms are frequent and affect quality of life. PLMS and RLS do not seem to contribute to the residual hypersomnia that can be observed in some sleep-disordered breathing patients despite adequate compliance and effective CPAP therapy. © 2012 Asian Pacific Society of Respirology. Source


Mishara A.L.,Yale University
Schizophrenia bulletin | Year: 2010

Klaus Conrad's major contribution to the phenomenology of psychosis focused on the patient's experiences during the prodromal and early psychotic phases of schizophrenia. The literature in English concerning his work is sparse, in part because Conrad's work contains complex concepts that lose much in translation. This communication attempts to clarify Conrad's thought, especially as it pertains to the role of mood and delusions in beginning psychosis and its underlying neurobiology. Source


Bhandari V.,Yale University
Seminars in Perinatology | Year: 2013

Bronchopulmonary dysplasia (BPD), the most common chronic lung disease in infancy, has serious long-term pulmonary and neurodevelopmental consequences right up to adulthood, and is associated with significant healthcare costs. BPD is a multifactorial disease, with genetic and environmental factors interacting to culminate in the characteristic clinical and pathological phenotype. Among the environmental factors, invasive endotracheal tube ventilation is considered a critical contributing factor to the pathogenesis of BPD. Since BPD currently has no specific preventive or effective therapy, considerable interest has focused on the use of non-invasive ventilation as a means to potentially decrease the incidence of BPD. This article reviews the progress made in the last 5 years in the use of nasal continuous positive airways pressure (NCPAP) and nasal intermittent positive pressure ventilation (NIPPV) as it pertains to impacting on BPD rates. Research efforts are summarized, and some guidelines are suggested for clinical use of these techniques in neonates. © 2013 Elsevier Inc. Source


De La Mora J.F.,Yale University
Journal of the American Society for Mass Spectrometry | Year: 2012

The reasons for the existence of two gas phase conformers for electrosprayed ions of the large tetradecameric protein complex GroEL are considered. Key features are that: (1) both conformers extrapolate to very similar cross sections in the limit of zero charge; (2) both conformers supercharge above the maximum value permitted by the Rayleigh criterion; and (3) one of the conformers supercharges substantially more than the other. We hypothesize that the supercharging observed is associated to the approximately cylindrical shape of GroEL in aqueous solution, enabling accumulation of extra charge on either one or two of its bases when they intersect the evaporating drop surface. The two conformers would then correspond to cases when either one or the two bases of the cylinder carry extra charge. Apparently, the conformer symmetrically (doubly) supercharged on both ends is Coulombically stretched, therefore exhibiting a mobility different from the conformer asymmetrically supercharged only on one end. Several general consequences follow. First, non-spherical proteins may generally be charged above the usual Rayleigh limit. Second, we confirm the previously advanced but contentious notion that gas phase protein ions are readily compacted or stretched away from their crystal structure by capillary and Coulombic forces during the electrospraying process. © 2012 American Society for Mass Spectrometry. Source


Cheianov V.,Lancaster University | Glazman L.I.,Yale University
Physical Review Letters | Year: 2013

Elastic backscattering of electrons moving along the helical edge is prohibited by time-reversal symmetry. We demonstrate, however, that an ensemble of magnetic impurities may cause time-reversal symmetry-preserving quasielastic backscattering, resulting in interference effects in the conductance. The characteristic energy transferred in a backscattering event is suppressed due to the Ruderman-Kittel-Kasuya-Yosida interaction of localized spins (the suppression is exponential in the total number of magnetic impurities). We predict the statistics of conductance fluctuations to differ from those in the conventional case of a one-dimensional system with quenched disorder. © 2013 American Physical Society. Source


Lemmon M.A.,University of Pennsylvania | Schlessinger J.,Yale University | Ferguson K.M.,University of Pennsylvania
Cold Spring Harbor Perspectives in Biology | Year: 2014

The epidermal growth factor receptor (EGFR) was among the first receptor tyrosine kinases (RTKs) for which ligand binding was studied and for which the importance of ligand-induced dimerization was established. As a result, EGFR and its relatives have frequently been termed “prototypical” RTKs. Many years of mechanistic studies, however, have revealed that—far from being prototypical—the EGFR family is quite unique. As we discuss in this review, the EGFR family uses a distinctive “receptor-mediated” dimerization mechanism, with ligand binding inducing a dramatic conformational change that exposes a dimerization arm. Intracellular kinase domain regulation in this family is also unique, being driven byallosteric changes induced by asymmetric dimer formation rather than the more typical activation-loop phosphorylation. EGFR family members also distinguish themselves from other RTKs in having an intracellular juxtamembrane (JM) domain that activates (rather than autoinhibits) the receptor and a very large carboxy-terminal tail that contains autophosphorylation sites and serves an autoregulatory function. We discuss recent advances in mechanistic aspects of all of these components of EGFR family members, attempting tointegrate them intoaview of how RTKs in this important class are regulated at the cell surface. © 2014 Cold Spring Harbor Laboratory Press; all rights reserved. Source


Walsh M.R.,Yale University
Trends in Ecology and Evolution | Year: 2013

Indirect effects occur when the effect of one species on another is mediated by a third species or through other links in the ecosystem. Indirect interactions are widespread in nature with effects on the properties of populations, communities, and ecosystems. Despite their far-reaching ecological relevance, the evolutionary importance of indirect effects has only recently garnered attention. Here I highlight recent research illustrating significant evolutionary consequences of indirect effects. These studies span field and laboratory studies as well as terrestrial and aquatic ecosystems. I argue that these results provide a blueprint that future research can utilize to evaluate the link between the ecological community and evolution and, thereby, improve the predictive power of evolution in a natural setting. © 2012 Elsevier Ltd. Source


Longrich N.R.,Yale University
Cretaceous Research | Year: 2011

At the end of the Cretaceous, 65.5 million years ago, the giant ceratopsids Triceratops and Torosaurus dominated North America's dinosaur fauna. The origins of these giant ceratopsids, the Triceratopsini, are poorly understood. This paper describes Titanoceratops ouranos, a giant ceratopsid from the late Campanian (73-74 Ma) of New Mexico, and the earliest known triceratopsin. The holotype was previously interpreted as an aberrant and exceptionally large specimen of Pentaceratops sternbergi, but the animal does not show the diagnostic features of Pentaceratops. Instead, cladistic analysis shows that Titanoceratops is the sister taxon of a clade formed by Eotriceratops, Triceratops, and Torosaurus. With an estimated mass of 6.5 tons, Titanoceratops is among the largest dinosaurs known from the Campanian of North America, and rivaled Triceratops in size. The recognition of Titanoceratops suggests that giant chasmosaurines evolved once, among the Triceratopsini, and that the group evolved large size five million years earlier than previously thought. The giant horned dinosaurs probably originated in the southern part of the North American continent during the Campanian but only became widespread during the Maastrichtian. © 2010. Source


Saif M.W.,Yale University
Expert Opinion on Investigational Drugs | Year: 2010

Importance of the field: The overexpression of EGFR has been documented in 30-90% of cases of advanced colorectal cancer (CRC). An increased understanding of the EGFR pathway in CRC has paved the way for the development of other targeted agents to augment therapeutic efficacy as well as for efforts to circumvent tumor resistance to therapy. Areas covered in this review: Our aim is to discuss the recent progress in the role of the EGFR pathway, the status of anti-EGFR therapeutic agents currently in use and the rationale for the development of novel agents that work along the pathway for the treatment of CRC. What the reader will gain: The readers will learn about the development and evolution of mAbs directed against EGFR as well as tyrosine kinase inhibitors in the management of CRC patients. In the same vein, determination of optimal dosing and better methods of defining those subsets of patients most likely to benefit will be discussed. Take home message: All these data must encourage clinicians and basic researches to continue in their efforts to untangle the network behind EGFR and try to focus all that effort towards improving patient's quality of life as well as survival. © 2010 Informa UK Ltd. Source


Quintero I.,Yale University | Wiens J.J.,University of Arizona
Ecology Letters | Year: 2013

A key question in predicting responses to anthropogenic climate change is: how quickly can species adapt to different climatic conditions? Here, we take a phylogenetic approach to this question. We use 17 time-calibrated phylogenies representing the major tetrapod clades (amphibians, birds, crocodilians, mammals, squamates, turtles) and climatic data from distributions of > 500 extant species. We estimate rates of change based on differences in climatic variables between sister species and estimated times of their splitting. We compare these rates to predicted rates of climate change from 2000 to 2100. Our results are striking: matching projected changes for 2100 would require rates of niche evolution that are > 10 000 times faster than rates typically observed among species, for most variables and clades. Despite many caveats, our results suggest that adaptation to projected changes in the next 100 years would require rates that are largely unprecedented based on observed rates among vertebrate species. © 2013 John Wiley & Sons Ltd/CNRS. Source


Boyce J.M.,Yale University
Infection Control and Hospital Epidemiology | Year: 2011

Monitoring hand hygiene compliance and providing healthcare workers with feedback regarding their performance are considered integral parts of multidisciplinary hand hygiene improvement programs. Observational surveys conducted by trained personnel are currently considered the ''gold standard'' method for establishing compliance rates, but they are time-consuming and have a number of shortcomings. Monitoring hand hygiene product consumption is less time-consuming and can provide useful information regarding the frequency of hand hygiene that can be used to give caregivers feedback. Electronic counting devices placed in hand hygiene product dispensers provide detailed information about hand hygiene frequency over time, by unit and during interventions. Electronic hand hygiene monitoring systems that utilize wireless systems to monitor room entry and exit of healthcare workers and their use of hand hygiene product dispensers can provide individual and unit-based data on compliance with the most common hand hygiene indications. Some systems include badges (tags) that can provide healthcare workers with real-time reminders to clean their hands upon entering and exiting patient rooms. Preliminary studies suggest that use of electronic monitoring systems is associated with increased hand hygiene compliance rates and that such systems may be acceptable to care givers. Although there are many questions remaining about the practicality, accuracy, cost, and long-term impact of electronic monitoring systems on compliance rates, they appear to have considerable promise for improving our efforts to monitor and improve hand hygiene practices among healthcare workers. © 2011 by The Society for Healthcare Epidemiology of America. All rights reserved. Source


Background: In descriptive epidemiological studies, investigators must screen large numbers of individuals. How one best screens populations for essential tremor (ET); however, remains an open question. The collection of a standardized writing sample (e.g., a hand-drawn spiral) is a method with many practical advantages, yet there are virtually no data on the validity of this particular method. Methods: Four hand-drawn spirals (2 right, 2 left) were collected from 831 ET cases across four distinct study settings (population-based study, family study, environmental epidemiological study, brain repository) and, in two of these studies, from 697 controls. Spirals were rated (range 0-3) by a senior movement disorder neurologist. These 1,528 participants also underwent a detailed neurological examination, and total tremor scores (range 0-36) and ET diagnoses were assigned by the neurologist. Results: The proportion of cases with hand-drawn spiral ratings ≥1.5 in either arm ranged from 78.8-97.0%; only 4.7% of controls had spirals with tremor of that severity. The hand-drawn spiral rating was highly correlated with the total tremor score (r = 0.65-0.73, p < 0.001). Conclusions: The hand-drawn spiral is a sensitive and specific method of screening for ET. Furthermore, it serves as a valid measure of overall tremor severity. © 2015 S. Karger AG, Basel. Source


Alonzo S.H.,Yale University
Proceedings of the Royal Society B: Biological Sciences | Year: 2012

Explaining the evolution ofmale care has proved difficult. Recent theory predicts that female promiscuity and sexual selection on males inherently disfavour male care. In sharp contrast to these expectations, male-only care is often found in species with high extra-pair paternity and striking variation in mating success, where current theory predicts female-only care. Using a model that examines the coevolution of male care, female care and female choice; I show that inter-sexual selection can drive the evolution of male care when females are able to bias mating or paternity towards parental males. Surprisingly, female choice for parental males allows male care to evolve despite low relatedness between the male and the offspring in his care. These results imply that predicting how sexual selection affects parental care evolution will require further understanding of why females, in many species, either do not prefer or cannot favour males that provide care. © 2012 The Royal Society. Source


Luo X.,Northwestern University | Herold K.C.,Yale University | Miller S.D.,Northwestern University
Immunity | Year: 2010

Type 1 diabetes (T1D) is a chronic autoimmune disorder characterized by destruction of insulin-producing pancreatic β cells. Many broad-based immunosuppressive and antigen-specific immunoregulatory therapies have been and are currently being evaluated for their utility in the prevention and treatment of T1D. Looking forward, this review discusses the potential therapeutic use of antigen-specific tolerance strategies, including tolerance induced by " tolerogenic" antigen-presenting cells pulsed with diabetogenic antigens and transfer of induced or expanded regulatory T cells, which have demonstrated efficacy in nonobese diabetic (NOD) mice. Depending on the time of therapeutic intervention in the T1D disease process, antigen-specific immunoregulatory strategies may be employed as monotherapies, or in combination with short-term tolerance-promoting immunoregulatory drugs and/or drugs promoting differentiation of insulin-producing β cells from endogenous progenitors. © 2010 Elsevier Inc. Source


Sofuoglu M.,Yale University
Addiction | Year: 2010

Background No medications have been proven to be effective for cocaine and methamphetamine addiction. Attenuation of drug reward has been the main strategy for medications development, but this approach has not led to effective treatments. Thus, there is a need to identify novel treatment targets in addition to the brain reward system. Aim To propose a novel treatment strategy for stimulant addiction that will focus on medications enhancing cognitive function and attenuating drug reward. Methods Pre-clinical and clinical literature on potential use of cognitive enhancers for stimulant addiction pharmacotherapy was reviewed. Results and conclusions Cocaine and methamphetamine users show significant cognitive impairments, especially in attention, working memory and response inhibition functions. The cognitive impairments seem to be predictive of poor treatment retention and outcome. Medications targeting acetylcholine and norepinephrine are particularly well suited for enhancing cognitive function in stimulant users. Many cholinergic and noradrenergic medications are on the market and have a good safety profile and low abuse potential. These include galantamine, donepezil and rivastigmine (cholinesterase inhibitors), varenicline (partial nicotine agonist), guanfacine (alpha2-adrenergic agonist) and atomoxetine (norepinephrine transporter inhibitor). Future clinical studies designed optimally to measure cognitive function as well as drug use behavior would be needed to test the efficacy of these cognitive enhancers for stimulant addiction. © 2010 Society for the Study of Addiction. Source


Moore P.B.,Yale University
Annual Review of Biophysics | Year: 2012

In a few years we are likely to have structures for the ribosome in all the conformations it assumes during protein synthesis. The golden age of ribosome structure determination is thus drawing to a close, and as it does the focus in the field will shift from structure determination to understanding why the ribosome's structure changes the way it does as it performs its function. Thus in the future, kinetic and thermodynamic experiments will become increasingly important, and as they do, the field will have to start thinking about the dynamics of the ribosome far more carefully than it has in the past. The reasoning that underlies these assertions will be explained, and a more general issue explored, namely what can be said today about the modus operandi of the ribosome. What kind of a device is it? © 2012 by Annual Reviews. All rights reserved. Source


Polikanov Y.S.,Howard Hughes Medical Institute | Steitz T.A.,Howard Hughes Medical Institute | Innis C.A.,Yale University
Nature Structural and Molecular Biology | Year: 2014

During peptide-bond formation on the ribosome, the α-amine of an aminoacyl-tRNA attacks the ester carbonyl carbon of a peptidyl-tRNA to yield a peptide lengthened by one amino acid. Although the ribosome's contribution to catalysis is predominantly entropic, the lack of high-resolution structural data for the complete active site in complex with full-length ligands has made it difficult to assess how the ribosome might influence the pathway of the reaction. Here, we present crystal structures of preattack and postcatalysis complexes of the Thermus thermophilus 70S ribosome at ~2.6-Å resolution. These structures reveal a network of hydrogen bonds along which proton transfer could take place to ensure the concerted, rate-limiting formation of a tetrahedral intermediate. We propose that, unlike earlier models, the ribosome and the A-site tRNA facilitate the deprotonation of the nucleophile through the activation of a water molecule. Source


Wang X.-J.,Yale University
Physiological Reviews | Year: 2010

Synchronous rhythms represent a core mechanism for sculpting temporal coordination of neural activity in the brain-wide network. This review focuses on oscillations in the cerebral cortex that occur during cognition, in alert behaving conditions. Over the last two decades, experimental and modeling work has made great strides in elucidating the detailed cellular and circuit basis of these rhythms, particularly gamma and theta rhythms. The underlying physiological mechanisms are diverse (ranging from resonance and pacemaker properties of single cells to multiple scenarios for population synchronization and wave propagation), but also exhibit unifying principles. A major conceptual advance was the realization that synaptic inhibition plays a fundamental role in rhythmogenesis, either in an interneuronal network or in a reciprocal excitatory-inhibitory loop. Computational functions of synchronous oscillations in cognition are still a matter of debate among systems neuroscientists, in part because the notion of regular oscillation seems to contradict the common observation that spiking discharges of individual neurons in the cortex are highly stochastic and far from being clocklike. However, recent findings have led to a framework that goes beyond the conventional theory of coupled oscillators and reconciles the apparent dichotomy between irregular single neuron activity and field potential oscillations. From this perspective, a plethora of studies will be reviewed on the involvement of long-distance neuronal coherence in cognitive functions such as multisensory integration, working memory, and selective attention. Finally, implications of abnormal neural synchronization are discussed as they relate to mental disorders like schizophrenia and autism. Copyright © 2010 the American Physiological Society. Source


Moran M.S.,Yale University
The Lancet Oncology | Year: 2015

This Review assesses the relevant data and controversies regarding the use of radiotherapy for, and locoregional management of, women with triple-negative breast cancer (TNBC). In view of the strong association between BRCA1 and TNBC, knowledge of baseline mutation status can be useful to guide locoregional treatment decisions. TNBC is not a contraindication for breast conservation therapy because data suggest increased locoregional recurrence risks (relative to luminal subtypes) with breast conservation therapy or mastectomy. Although a boost to the tumour bed should routinely be considered after whole breast radiation therapy, TNBC should not be the sole indication for post-mastectomy radiation, and accelerated delivery methods for TNBC should be offered on clinical trials. Preliminary data implying a relative radioresistance for TNBC do not imply radiation omission because radiation provides an absolute locoregional risk reduction. At present, the integration of subtypes in locoregional management decisions is still in its infancy. Until level 1 data supporting treatment decisions based on subtypes are available, standard locoregional management principles should be adhered to. © 2015 Elsevier Ltd. Source


Carroll K.M.,Yale University
Annals of the New York Academy of Sciences | Year: 2014

In the treatment of addictions, the gap between the availability of evidence-based therapies and their limited implementation in practice has not yet been bridged. Two empirically validated behavioral therapies, contingency management (CM) and cognitive behavioral therapy (CBT), exemplify this challenge. Both have a relatively strong level of empirical support but each has weak and uneven adoption in clinical practice. This review highlights examples of how barriers to their implementation in practice have been addressed systematically, using the Stage Model of Behavioral Therapies Development as an organizing framework. For CM, barriers such as cost and ideology have been addressed through the development of lower-cost and other adaptations to make it more community friendly. For CBT, barriers such as relative complexity, lack of trained providers, and need for supervision have been addressed via conversion to standardized computer-assisted versions that can serve as clinician extenders. Although these and other modifications have rendered both interventions more disseminable, diffusion of innovation remains a complex, often unpredictable process. The existing specialty addiction-treatment system may require significant reforms to fully implement CBT and CM, particularly greater focus on definable treatment goals and performance-based outcomes. © 2014 New York Academy of Sciences. Source


Pollard T.D.,Yale University
Molecular Biology of the Cell | Year: 2010

The aim of binding assays is to measure interactions between two molecules, such as a protein binding another protein, a small molecule, or a nucleic acid. Hard work is required to prepare reagents, but flaws in the design of many binding experiments limit the information obtained. In particular many experiments fail to measure the affinity of the reactants for each other. This essay describes simple methods to get the most out of valuable reagents in binding experiments. © 2010 T. D. Pollard. Source


Receptor tyrosine kinases (RTKs) play important roles in the control of many cellular processes including cell proliferation, cell adhesion, angiogenesis, and apoptosis. Ligand-induced dimerization of RTKs leads to autophosphorylation and activation of RTKs. Structural studies have shown that while isolated ectodomains of several RTKs form symmetric dimers the isolated cytoplasmic kinase domains of epidermal growth factor receptor (EGFR) and fibroblast growth factor receptor (FGFR) form asymmetric dimers during their activation. Binding of one kinase molecule of EGFR to a second kinase molecule asymmetrically leads to stimulation of kinase activity and enhanced autophosphorylation. Furthermore, the structures of the kinase domain of FGFR1 and FGFR2 reveal the formation of asymmetric interfaces in the processes of autophosphorylation at their specific phosphotyrosine (pY) sites. Disruption of asymmetric dimer interface of EGFR leads to reduction in enzymatic activity and drastic reduction of autophosphorylation of FGFRs in ligand-stimulated live cells. These studies demonstrate that asymmetric dimer formation is as a common phenomenon critical for activation and autophosphorylation of RTKs. Source


Yang X.,Yale University
Genes and Development | Year: 2010

It is a long-standing view that the circadian clock functions to proactively align internal physiology with the 24-h rotation of the earth. Recent studies, including one by Schmutz and colleagues (pp. 345-357) in the February 15, 2010, issue of Genes & Development, delineate strikingly complex connections between molecular clocks and nuclear receptor signaling pathways, implying the existence of a large-scale circadian regulatory network coordinating a diverse array of physiological processes to maintain dynamic homeostasis. © 2010 by Cold Spring Harbor Laboratory Press. Source


Shan G.,Yale University
International Journal of Biochemistry and Cell Biology | Year: 2010

Not many scientific breakthroughs bring significant advances simultaneously in both basic research and translational applications like the discovery of RNA interference. Along with the elucidation of the RNA interference pathway and the discovery of its participation in crucial biological events, a branch of science has grown to utilize the RNA interference pathway as a biotechnology for both basic and applied research. Small interference RNA, plasmid-, and virus-encoded short-hairpin RNA are now regular reagents in the tool box of biologists to knockdown the expression of specific genes posttranscriptionally. Efforts have also been made to develop RNA interference based therapeutics into reality. Many concerns about the RNA interference technique have now been answered through research and development, although hurdles are still present. In this review, the RNA interference/microRNA pathway is briefly introduced followed with a detailed summary about the design and application of the RNA interference experiments, along with examples of the utilization of the RNA interference technology in animal cells and model organisms. Recent progresses and current concerns are also highlighted. Two techniques, namely morpholino and external guide sequence, are discussed as complementary gene knockdown technology. RNA interference technology, along with several other alternative gene knockdown techniques, is now indispensable to modern biological and medical research. © 2009 Elsevier Ltd. Source


Tomita S.,Yale University
Physiology | Year: 2010

Glutamate receptors are major excitatory receptors in the brain. Recent findings have established auxiliary subunits of glutamate receptors as critical modulators of synaptic transmission, synaptic plasticity, and neurological disorder. The elucidation of the molecular rules governing glutamate receptors and subunits will improve our understanding of synapses and of neural-circuit regulation in the brain. ©2010 Int. Union Physiol. Sci./Am. Physiol. Soc. Source


Lipkind H.S.,Yale University
Obstetrics and Gynecology | Year: 2010

Objective: To evaluate the effects of the September 11, 2001, World Trade Center attacks on birth outcomes. Methods: Live singleton births between September 11, 2001, and October 31, 2002, to women enrolled in a World Trade Center Health Registry (the Registry, n=446) were compared with births to women residing more than 5 miles from the World Trade Center (n=49,616). Birth weight, gestational age, low birth weight, and preterm delivery were evaluated using linear and logistic regression. Births before September 11, 2001, were analyzed to assess possible seasonal biases of associations with pregnancy trimester on September 11. Associations of birth outcomes with September 11-related psychologic stress and physical exposures were assessed among births to women within the Registry (n=499). Results: Birth weight and gestational age distributions were similar for births to women enrolled in the Registry and comparison births. Although mean gestational age and birth weight varied with trimester on September 11, a similar association was found among births in previous years, consistent with a seasonal effect not related to exposure. Registry-linked births to mothers with probable posttraumatic stress disorder (n=61) had a higher odds of low birth weight (adjusted odds ratio [OR] 2.49, 95% confidence interval [CI] 1.02-6.08) and preterm delivery (adjusted OR 2.48, 95% CI 1.05-5.84) compared with births to women without posttraumatic stress disorder. Conclusion: Women who lived, worked, or were near the World Trade Center on or soon after September 11 had pregnancy outcomes similar to women residing more than 5 miles away. However, among exposed women, probable posttraumatic stress disorder was associated with low birth weight and preterm delivery. © 2010 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams and Wilkins. Source


Among older persons, disability in activities of daily living is common and highly morbid. The Precipitating Events Project (PEP Study), an ongoing longitudinal study of 754 initially nondisabled, community-living persons, aged 70 or older, was designed to further elucidate the epidemiology of disability, with the goal of informing the development of effective interventions to maintain and restore independent function. Over the past 16 years, participants have completed comprehensive, home-based assessments at 18-month intervals and have been interviewed monthly to reassess their functional status and ascertain intervening events, other health care utilization, and deaths. Findings from the PEP Study have demonstrated that the disabling process for many older persons is characterized by multiple and possibly interrelated disability episodes, even over relatively short periods of time, and that disability often results when an intervening event is superimposed upon a vulnerable host. Given the frequency of assessments, long duration of follow-up, and recent linkage to Medicare data, the PEP Study will continue to be an outstanding platform for disability research in older persons. In addition, as the number of decedents accrues, the PEP Study will increasingly become a valuable resource for investigating symptoms, function, and health care utilization at the end of life. © 2014 The Author 2014. Source


Goldsmith T.H.,Yale University
Visual Neuroscience | Year: 2013

Eyes have evolved many times, and arthropods and vertebrates share transcription factors for early development. Moreover, the photochemistry of vision in all eyes employs an opsin and the isomerization of a retinoid from the 11-cis to the all-trans configuration. The opsins, however, have associated with several different G proteins, initiating hyperpolarizing and depolarizing conductance changes at the photoreceptor membrane. Beyond these obvious instances of homology, much of the evolutionary story is one of tinkering, producing a great variety of morphological forms and variation within functional themes. This outcome poses a central issue in the convergence of evolutionary and developmental biology: what are the heritable features in the later stages of development that give natural selection traction in altering phenotypic outcomes? This paper discusses some results of evolutionary tinkering where this question arises and, in some cases, where the reasons for particular outcomes and the role of adaptation may not be understood. Phenotypic features include: the exploitation of microvilli in rhabdomeric photoreceptors for detecting the plane of polarized light; different instances of retinoid in the visual pigment; examples of the many uses of accessory pigments in tuning the spectral sensitivity of photoreceptors; selection of opsins in tuning sensitivity in aquatic environments; employing either reflection or refraction in the optics of compound eyes; the multiple ways of constructing images in compound eyes; and the various ways of regenerating 11-cis retinals to maintain visual sensitivity. Evolution is an irreversible process, but tinkering may recover some lost functions, albeit by new mutational routes. There is both elegance and intellectual coherence to the natural processes that produce such variety and functional complexity. But marginalizing the teaching of evolution in public education is a continuing social and political problem that contributes to the reckless capacity of humans to alter the planet without trying to understand how nature works. Copyright © Cambridge University Press 2012. Source


Romberg N.,Yale University
Nature Genetics | Year: 2014

Upon detection of pathogen-associated molecular patterns, innate immune receptors initiate inflammatory responses. These receptors include cytoplasmic NOD-like receptors (NLRs) whose stimulation recruits and proteolytically activates caspase-1 within the inflammasome, a multiprotein complex. Caspase-1 mediates the production of interleukin-1 family cytokines (IL1FCs), leading to fever and inflammatory cell death (pyroptosis). Mutations that constitutively activate these pathways underlie several autoinflammatory diseases with diverse clinical features. We describe a family with a previously unreported syndrome featuring neonatal-onset enterocolitis, periodic fever, and fatal or near-fatal episodes of autoinflammation. We show that the disease is caused by a de novo gain-of-function mutation in NLRC4 encoding a p.Val341Ala substitution in the HD1 domain of the protein that cosegregates with disease. Mutant NLRC4 causes constitutive IL1FC production and macrophage cell death. Infected macrophages from affected individuals are polarized toward pyroptosis and exhibit abnormal staining for inflammasome components. These findings identify and describe the cause of a life-threatening but treatable autoinflammatory disease that underscores the divergent roles of the NLRC4 inflammasome. © 2014 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. Source


Sessa W.C.,Yale University
Cell Metabolism | Year: 2010

Activation of TRPV1 channels in sensory nerves by capsaicin promotes neuropeptide release, leading to the perception of pain and inflammation. In this issue, Yang et al. (2010) demonstrate that vascular TRPV1 mediates a beneficial effect of capsaicin in the cardiovascular system, promoting nitric oxide release and lowering blood pressure. © 2010 Elsevier Inc. Source


The longevity of deep continental roots depends critically on the rheological properties of upper mantle minerals under deep upper mantle conditions. Geodynamic studies suggest that the rheological contrast between the deep continental and oceanic upper mantle is a key factor that controls the longevity of the continental roots. Current understanding of rheological properties of deep upper mantle is reviewed to examine how a large enough rheological contrast between the continental and oceanic upper mantle develops that leads to the longevity of the deep continental roots. Based on the microstructures of naturally deformed deep continental rocks as well as on the observations of seismic anisotropy, it is concluded that power-law dislocation creep dominates in most of the deep upper mantle. Deformation by power-law creep is sensitive to water content and therefore the removal of water by partial melting to form depleted continental roots is a likely mechanism to establish a large rheological contrast. The results of experimental studies on the influence of temperature, pressure and water content on plastic flow by power-law dislocation creep are reviewed. The degree of rheological contrast depends critically on the dependence of effective viscosity on water content under "wet" (water-rich) conditions but it is also sensitive to the effective viscosity under "dry" (water-free) conditions that depends critically on the influence of pressure on deformation. Based on the analysis of thermodynamics of defects and high-temperature creep, it is shown that a robust estimate of the influence of water and pressure can be made only by the combination of low-pressure (< 0.5 GPa) and high-pressure (> 5 GPa) studies. A wide range of flow laws has been reported, leading to nearly 10 orders of magnitude differences in estimated viscosities under the deep upper mantle conditions. However, based on the examination of several criteria, it is concluded that relatively robust experimental data are now available for power-law dislocation creep in olivine both under "dry" (water-free) and "wet" (water-saturated) conditions. These data show that the influence of water is large (a change in viscosity up to ∼ 4 orders of magnitude for a constant stress) at the depth of ∼ 200-400 km. I conclude that the conditions for survival of a deep root for a few billions of years can be satisfied when "dry" olivine rheology with a relatively large activation volume (> (10-15) × 10- 6 m3/mol)) is used and the substantial water removal occurs to these depths. High degree of water removal requires a large degree of melting in the deep upper mantle that could have occurred in the Archean where geotherm was likely hotter than the current one by ∼ 200 K presumably with the help of water. © 2009 Elsevier B.V. All rights reserved. Source


Korenaga J.,Yale University
Journal of Geophysical Research: Solid Earth | Year: 2010

The scaling of plate tectonic convection is investigated by simulating thermal convection with pseudoplastic rheology and strongly temperature- dependent viscosity. The effect of mantle melting is also explored with additional depth-dependent viscosity. Heat flow scaling can be constructed with only two parameters, the internal Rayleigh number and the lithospheric viscosity contrast, the latter of which is determined entirely by rheological properties. The critical viscosity contrast for the transition between plate tectonic and stagnant lid convection is found to be proportional to the square root of the internal Rayleigh number. The relation between mantle temperature and surface heat flux on Earth is discussed on the basis of these scaling laws, and the inverse relationship between them, as previously suggested from the consideration of global energy balance, is confirmed by this fully dynamic approach. In the presence of surface water to reduce the effective friction coefficient, the operation of plate tectonics is suggested to be plausible throughout the Earth history. Copyright 2010 by the American Geophysical Union. Source


Brownell K.D.,Yale University
Behaviour Research and Therapy | Year: 2010

Obesity has humbled one research group after another. Some of the field's brightest scientists have attempted to subdue obesity by treating it, but now, after decades of work, treatment gains remain small, maintenance is poor, and the field produces effects far below what patients want or expect. This can be explained by strong biological and environmental forces that oppose weight loss and foster regain. Attempts to improve treatment must continue, but with recognition that treatment is a clinical measure and will not affect prevalence (because treatments are too expensive to be used broadly). Policy change and prevention will be necessary to improve public health. © 2010. Source


Sindelar C.V.,Yale University
Biophysical Reviews | Year: 2011

Recent structural observations of kinesin-1, the founding member of the kinesin group of motor proteins, have led to substantial gains in our understanding of this molecular machine. Kinesin-1, similar to many kinesin family members, assembles to form homodimers that use alternating ATPase cycles of the catalytic motor domains, or "heads", to proceed unidirectionally along its partner filament (the microtubule) via a hand-over-hand mechanism. Cryo-electron microscopy has now revealed 8-Å resolution, 3D reconstructions of kinesin-1•microtubule complexes for all three of this motor's principal nucleotide-state intermediates (ADP-bound, no-nucleotide, and ATP analog), the first time filament co-complexes of any cytoskeletal motor have been visualized at this level of detail. These reconstructions comprehensively describe nucleotide-dependent changes in a monomeric head domain at the secondary structure level, and this information has been combined with atomic-resolution crystallography data to synthesize an atomic-level "seesaw" mechanism describing how microtubules activate kinesin's ATP-sensing machinery. The new structural information revises or replaces key details of earlier models of kinesin's ATPase cycle that were based principally on crystal structures of free kinesin, and demonstrates that high-resolution characterization of the kinesin-microtubule complex is essential for understanding the structural basis of the cycle. I discuss the broader implications of the seesaw mechanism within the cycle of a fully functional kinesin dimer and show how the seesaw can account for two types of "gating" that keep the ATPase cycles of the two heads out of sync during processive movement. © 2011 The Author(s). Source


Horsley V.,Yale University
EMBO Journal | Year: 2011

Recent data suggest that heterogeneous compartments of the bulge display differential gene expression, and supply cells to different lineages within the pilosebaceous unit (Jaks et al, 2008; Jensen et al, 2009; Snippert et al, 2010). In particular, Lgr6 and Lrig1 are expressed above the CD34\+ bulge region and Lgr6 expressing cells contribute primarily to the sebaceous gland (Figure 1). Thus, if and how the multipotent bulge cells give rise to cells to the sebaceous gland is not well understood. In this issue of The EMBO Journal, Petersson et al (2011) investigate how bulge cells contribute to the sebaceous gland in vivo using careful lineage tracing experiments and live bulge cell imaging in intact organ cultures. © 2011 European Molecular Biology Organization. Source


The alignment of self-assembled structures in block copolymer (BCP) films by using solvent vapor permeation method was discussed. The polymer was triblock copolymer prepared by slow solvent casting of a 10 wt % toluene solution at room temperature. The samples were exposed to toluene vapor permeation at two temperatures, 65 and 140 °C. The alignment produced in the samples was due to the pressure driven flow of the solvent vapor through the polymer film. The glass-transition temperature of poly(styrene) in the absence of the permeating solvent was ~ 105°C and that of the ethylene/butylene midblock was about 35°C. The solvent vapor annealing utilizes a reservoir of solvent vapor, particularly at atmospheric pressure, to provide moderate swelling of a polymer film by condensed solvent molecules over a particular period of time. The alignment of microstructure by solvent vapor is based on directional evaporation of the solvent from a swollen film. Source


Humphrey J.D.,Yale University
Nature Reviews Molecular Cell Biology | Year: 2014

Soft connective tissues at steady state are dynamic; resident cells continually read environmental cues and respond to them to promote homeostasis, including maintenance of the mechanical properties of the extracellular matrix (ECM) that are fundamental to cellular and tissue health. The mechanosensing process involves assessment of the mechanics of the ECM by the cells through integrins and the actomyosin cytoskeleton, and is followed by a mechanoregulation process, which includes the deposition, rearrangement or removal of the ECM to maintain overall form and function. Progress towards understanding the molecular, cellular and tissue-level effects that promote mechanical homeostasis has helped to identify key questions for future research. © 2014 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. Source


Upon analysis of 636 primary breast carcinoma patient samples, we have found that programmed cell death ligand 1 (PD-L1) mRNA expression is associated with tumor-infiltrating lymphocytes (TI Ls). Furthermore, PD-L1 expression and elevated TI Ls were associated with longer recurrence-free survival. Thus, our findings indicate that PD-L1 is prognostic in breast cancer and suggests a functional link between TI Ls and tumor PD-L1 upregulation. © 2014 Landes Bioscience. Source


Karato S.-i.,Yale University
Gondwana Research | Year: 2010

Historical development of our understanding of rheological properties of the Earth's mantle is reviewed. Rheological properties of the Earth's mantle control most of the important geological processes such as the style of mantle convection (e.g., stagnant lid versus plate tectonics) and the nature of thermal evolution. However, inferring the rheological properties of the Earth's mantle is challenging because of the presence of multiple mechanisms of deformation that have different dependence on time-scale (strain-rate), stress levels and other parameters. Through the integration of a broad range of observations including the elastic stiffness from tidal deformation and the viscosity from the concept of isostasy, a gross picture of rheological stratification of the Earth's mantle (a strong lithosphere, a weak asthenosphere and a strong layer below) was proposed in the mid-19th century. However, not only the physical basis for such a model was weak due to the lack of proper understanding of some materials science issues such as the interplay between elastic and viscous deformation but also the lack of understanding of temperature-depth relation associated with convection prevented our understanding of the rheological structure of the Earth's interior. Major progress occurred in the first half of the 20th century in our understanding of the atomistic mechanisms of plastic deformation in solids, and much of the theoretical framework on the plastic deformation of solids was established by late 1960s. Those developments provided a basis for scaling analyses that are critical to the applications of laboratory results to the Earth's interior. Major progress in laboratory studies on rheological properties occurred in the mid-1960s to the early 1970s in Griggs' lab using a new type of solid-medium high-pressure deformation apparatus to pressure ∼ 2 GPa and temperature ∼ 1600 K. The basic concepts such as the water weakening, non-linear rheology and deformation-induced lattice-preferred orientation were identified by their studies. However, large uncertainties in the stress measurements with this type of apparatus were recognized in the late 1970s and high-resolution experimental studies using synthetic samples were initiated in Paterson's lab in the mid-1980s using a high-resolution gas-medium deformation apparatus. However, experimental studies with such a gas-medium deformation apparatus can be conducted only at low pressures (< 0.5 GPa) and it is difficult to apply these low-pressure data to the Earth's interior deeper than ∼ 20 km. New experimental techniques to study rheological properties in Earth's deep interior have been developed during the last a few years. These techniques allow us to quantitatively study the rheological properties of Earth materials down to the lower mantle condition (∼ 24 GPa, ∼ 2000 K). Some geodynamic issues related to rheological properties are discussed including (i) the strength of the lithosphere and the origin of plate tectonics, (ii) the origin of the asthenosphere, and (iii) the deep mantle rheology and its influence on thermal history of Earth. Existing models on these topics are reviewed and new alternative models are discussed. © 2010 International Association for Gondwana Research. Source


Li et al. (Reports, 30 January, p. 555) reported on a crystal structure for a translocator protein (TSPO) from Rhodobacter sphaeroides in which some of the electron density is modeled as a porphyrin. The analysis of the x-ray data discussed here suggests that this assignment is incorrect. Source


Beales P.A.,University of Leeds | Vanderlick T.K.,Yale University
Advances in Colloid and Interface Science | Year: 2014

We present a critical review of recent work related to the assembly of multicompartment liposome clusters using nucleic acids as a specific recognition unit to link liposomal modules. The asymmetry in nucleic acid binding to its non-self complementary strand allows the controlled association of different compartmental modules into composite systems. These biomimetic multicompartment architectures could have future applications in chemical process control, drug delivery and synthetic biology. We assess the different methods of anchoring DNA to lipid membrane surfaces and discuss how lipid and DNA properties can be tuned to control the morphology and properties of liposome superstructures. We consider different methods for chemical communication between the contents of liposomal compartments within these clusters and assess the progress towards making this chemical mixing efficient, switchable and chemically specific. Finally, given the current state of the art, we assess the outlook for future developments towards functional modular networks of liposomes. © 2014 Elsevier B.V. Source


Richardson J.L.,University of Connecticut | Urban M.C.,University of Connecticut | Bolnick D.I.,Howard Hughes Medical Institute | Skelly D.K.,Yale University
Trends in Ecology and Evolution | Year: 2014

Local adaptation has been a major focus of evolutionary ecologists working across diverse systems for decades. However, little of this research has explored variation at microgeographic scales because it has often been assumed that high rates of gene flow will prevent adaptive divergence at fine spatial scales. Here, we establish a quantitative definition of microgeographic adaptation based on Wright's dispersal neighborhood that standardizes dispersal abilities, enabling this measure to be compared across species. We use this definition to evaluate growing evidence of evolutionary divergence at fine spatial scales. We identify the main mechanisms known to facilitate this adaptation and highlight illustrative examples of microgeographic evolution in nature. Collectively, this evidence requires that we revisit our understanding of the spatial scale of adaptation and consider how microgeographic adaptation and its driving mechanisms can fundamentally alter ecological and evolutionary dynamics in nature. © 2014 Elsevier Ltd. Source


Huang Y.,Yale University
Wiley Interdisciplinary Reviews: RNA | Year: 2012

Lin28 is an evolutionarily conserved RNA-binding protein that plays important roles in development, pluripotency, tumorigenesis, and metabolism. Emerging evidence suggests that the pleiotropic roles of Lin28 in the diverse physiological and pathological processes are mechanistically linked to its ability to modulate not only the biogenesis of miRNAs, particularly the let-7 family miRNAs, but also the translation of mRNAs important for cell growth and metabolism. Let-7 negatively regulates the translation of oncogenes, cell cycle regulators, and metabolic pathway components. Lin28 relieves this repression by blocking the production of mature let-7. Lin28 binds to the terminal loops of let-7 precursors, leading to inhibition of processing and the induction of uridylation and precursor degradation. Lin28 also is a direct translational regulator: it selectively binds to a cohort of mRNAs and stimulates their translation. Recent advances in our understanding of Lin28-mediated mechanisms of posttranscriptional regulation of gene expression reveal important roles of this protein in the fields of development, stem cells, metabolic diseases, and cancer. © 2012 John Wiley & Sons, Ltd. Source


Prolactin and GH form reversible aggregates in the trans-Golgi lumen that become the dense cores of secretory granules. Aggregation is an economical means of sorting, because self-association removes the hormones from other possible pathways. Secretory granules containing different aggregates show different behavior, such as the reduction in stimulated release of granules containingR183H-GHcompared with release of those containing wild-type hormone. Aggregates may facilitate localization of membrane proteins necessary for transport and exocytosis of secretory granules, and therefore understanding their properties is important. Three types of self-association have been characterized: dimers of humanGHthat form with Zn2 +, low-affinity self-association of human prolactin caused by acidic pH and Zn2 + with macromolecular crowding, and amyloid fibers of prolactin. The best candidate for the form in most granules may be low-affinity self-association because it occurs rapidly at Zn2 + concentrations that are likely to be in granules and reverses rapidly in neutral pH. Amyloid may form in older granules. Determining differences between aggregates of wild type and those of R183H-GH should help to understand why granules containing the mutant behave differently from those containing wild-type hormone. If reversible aggregation of other hormones, including those that are proteolytically processed, is the crucial act in forming granules, rather than use of a sorting signal, then prohormones should form reversible aggregates in solution in conditions that resemble those of the trans-Golgi lumen, including macromolecular crowding. © 2012 by The Endocrine Society. Source


Kaplan E.H.,Yale University
Operations Research | Year: 2010

This article presents the first models developed specifically for understanding the infiltration and interdiction of ongoing terror plots by undercover intelligence agents, and does so via novel application of ideas from queueing theory and Markov population processes. The resulting "terror queue" models predict the number of undetected terror threats in an area from agent activity/utilization data, and also estimate the rate with which such threats can be detected and interdicted. The models treat terror plots as customers and intelligence agents as servers. Agents spend all of their time either detecting and infiltrating new terror plots (in which case they are "available"), or interdicting already detected terror plots (in which case they are "busy"). Initially we examine a Markov model assuming that intelligence agents, while unable to detect all plots, never err by falsely detecting fake plots. While this model can be solved numerically, a simpler Ornstein-Uhlenbeck diffusion approximation yields some results in closed form while providing nearly identical numerical performance. The transient behavior of the terror queue model is discussed briefly along with a sample sensitivity analysis to study how model predictions compare to simulated results when using estimated versus known terror plot arrival rates. The diffusion model is then extended to allow for the false detection of fake plots. Such false detection is a real feature of counterterror intelligence given that intelligence agents or informants can make mistakes, as well as the proclivity of terrorists to deliberately broadcast false information. The false detection model is illustrated using suicide bombing data from Israel. © 2010 INFORMS. Source


Saenger C.,Alaska Pacific University | Wang Z.,Yale University
Quaternary Science Reviews | Year: 2014

Geochemical variations in marine biogenic carbonates that are preserved in the geological record serve as proxies of past environmental change. However, interpreting most proxies is complicated by biologically-mediated vital effects, highlighting the need to develop new tools for reconstructing paleoenvironmental change. Recently, magnesium (Mg) isotope variability in carbonates has been explored extensively to determine its utility as a paleoenvironmental proxy. We review the results of these works, which have yielded valuable information on the factors affecting Mg isotope fractionation between carbonates and solution (δ26Mgcarb-sol) in biogenic and abiogenic carbonate minerals. Strong evidence exists for a mineralogical control on δ26Mgcarb-sol, with the negative offset from 0‰ following the sequence aragonite~3mol/mol) and saturation states (Ω >~3) that are similar to seawater suggest that δ26Mgcarb-sol has a temperature dependence of ~0.01‰ °C-1 and is insensitive to precipitation rate. In contrast, a significant precipitation rate dependence is observed in calcites precipitated from solutions with relatively low Mg/Ca ratios (<~3mol/mol) and saturation states (Ω <~3). This difference likely reflects varying mineral growth mechanisms and we discuss the degree to which δ26Mgcarb-sol may be affected by factors such as fluid inclusions, amorphous calcium carbonate precursors, ion attachment/detachment kinetics, surface entrapment and Mg speciation. High-Mg calcite organisms, which likely precipitate from relatively unmodified seawater, also exhibit a temperature dependence of ~0.01‰ °C-1, albeit sometimes with a systematic offset toward smaller fractionations. In contrast, strong vital effects in low-Mg calcite organisms, which exclude Mg from their calcifying fluids, lead to δ26Mgcarb-sol values that exhibit no clear temperature dependence and are offset from abiogenic experiments. The majority of biogenic aragonites have δ26Mgcarb-sol values that are slightly more positive than those in abiogenic experiments, but bivalves and one sclerosponge species can exhibit significantly larger fractionations. Although vital effects and analytical uncertainties will limit δ26Mgcarb-sol paleotemperature reconstructions to anomalies of at least ±10°C, Mg isotope variability in biogenic carbonates may be a useful proxy for the Mg isotope composition of seawater, which reflects continental weathering, dolomitization and hydrothermal activity. © 2014 Elsevier Ltd. Source


Szyf M.,McGill University | Bick J.,Yale University
Child Development | Year: 2013

Although epidemiological data provide evidence that early life experience plays a critical role in human development, the mechanism of how this works remains in question. Recent data from human and animal literature suggest that epigenetic changes, such as DNA methylation, are involved not only in cellular differentiation but also in the modulation of genome function in response to early life experience affecting gene function and the phenotype. Such modulations may serve as a mechanism for life-long genome adaptation. These changes seem to be widely distributed across the genome and to involve central and peripheral systems. Examining the environmental circumstances associated with the onset and reversal of DNA methylation will be critical for understanding risk and resiliency. © 2012 Society for Research in Child Development, Inc. Source


Burd C.,Yale University | Cullen P.J.,University of Bristol
Cold Spring Harbor Perspectives in Biology | Year: 2014

The endosomal network comprises an interconnected network of membranous compartments whose primary function is to receive, dissociate, and sort cargo that originates fromthe plasma membrane and the biosynthetic pathway. A major challenge in cell biology is to achieve a thorough molecular description of howthis network operates, and in so doing, how defects contribute to the etiology and pathology of human disease.We discuss the increasing body of evidence that implicates an ancient evolutionary conserved complex, termed "retromer," as a master conductor in the complex orchestration of multiple cargo-sorting events within the endosomal network. © 2014 Cold Spring Harbor Laboratory Press; all rights reserved. Source


Moore P.B.,Yale University
Biophysical Journal | Year: 2014

The solution-scattering profiles of macromolecules are significantly affected by the thermal motions of their atoms, especially at wide scattering angles, even when only a single conformational state is significantly populated in solution. Here it is shown that the impact thermal motions have on the molecular component of the solution-scattering profile of a single-state macromolecule can be predicted accurately if the variances and covariances of the thermal excursions of its atoms from their average positions are known. © 2014 Biophysical Society. Source


Theoharis C.,Yale University
Current opinion in oncology | Year: 2012

The molecular work-up of thyroid nodules on fine needle aspiration (FNA) cytology samples has given clinicians a new level of diagnostic information. We focus this review on the molecular techniques used in the diagnosis of thyroid cancer, especially BRAF, and the resulting management considerations that are raised. BRAF testing offers both diagnostic and prognostic information; it has been used along with the Bethesda Thyroid FNA Classification System to offer preoperative guidance in the management of thyroid nodules. Various authors have successfully utilized molecular panels on cytologic specimens including mutations and rearrangements such as RAS and RET/PTC. Preoperative mutation detection allows initial management decisions to be made with a greater clinical confidence. BRAF molecular testing holds promise as a possible diagnostic tool for indeterminate FNAs, and as a determinant for planning initial clinical management of thyroid nodules. Further developments in the molecular approach to thyroid cancer are expected to allow greater individualization of patient care. Source


Physical processes that control ENSO are relatively fast. For instance, it takes only several months for a Kelvin wave to cross the Pacific basin (Tk ≈ 2 months), while Rossby waves travel the same distance in about half a year. Compared to such short time scales, the typical periodicity of El Niño is much longer (T ≈ 2-7 yr). Thus, ENSO is fundamentally a low-frequency phenomenon in the context of these faster processes. Here, the author takes advantage of this fact and uses the smallness of the ratio εk 5 Tk/T to expand solutions of the ocean shallow-water equations into power series (the actual parameter of expansion also includes the oceanic damping rate). Using such an expansion, referred to here as the low-frequency approximation, the author relates thermocline depth anomalies to temperature variations in the eastern equatorial Pacific via an explicit integral operator. This allows a simplified formulation of ENSO dynamics based on an integro-differential equation. Within this formulation, the author shows how the interplay between wind stress curl and oceanic damping rates affects 1) the amplitude and periodicity of El Niño and 2) the phase lag between variations in the equatorial warm water volume and SST in the eastern Pacific. A simple analytical expression is derived for the phase lag. Further, applying the low-frequency approximation to the observed variations in SST, the author computes thermocline depth anomalies in the western and eastern equatorial Pacific to show a good agreement with the observed variations in warm water volume. Ultimately, this approach provides a rigorous framework for deriving other simple models of ENSO (the delayed and recharge oscillators), highlights the limitations of such models, and can be easily used for decadal climate variability in the Pacific. © 2010 American Meteorological Society. Source


Long M.D.,Yale University | Becker T.W.,University of Southern California
Earth and Planetary Science Letters | Year: 2010

Observations of seismic anisotropy yield some of the most direct constraints available on both past and present-day deformation in the Earth's mantle. Insight into the character of mantle flow can also be gained from the geodynamical modeling of mantle processes on both global and regional scales. We highlight recent progress toward understanding mantle flow from both observations and modeling and discuss outstanding problems and avenues for progress, particularly in the integration of seismological and geodynamical constraints to understand seismic anisotropy and the deformation that produces it. To first order, the predictions of upper mantle anisotropy made by global mantle circulation models match seismological observations well beneath the ocean basins, but the fit is poorer in regions of greater tectonic complexity, such as beneath continental interiors and within subduction systems. In many regions of the upper mantle, models of anisotropy derived from surface waves are seemingly inconsistent with shear wave splitting observations, which suggests that our understanding of complex anisotropic regions remains incomplete. Observations of anisotropy in the D" layer hold promise for improving our understanding of dynamic processes in the deep Earth but much progress remains to be made in characterizing anisotropic structure and relating it to the geometry of flow, geochemical heterogeneity, or phase transitions. Major outstanding problems related to understanding mantle anisotropy remain, particularly regarding the deformation and evolution of continents, the nature of the asthenosphere, subduction zone geodynamics, and the thermo-chemical state of the lowermost mantle. However, we expect that new seismological deployments and closer integration of observations with geodynamical models will yield rapid progress in these areas. © 2010 Elsevier B.V. Source


Cao H.,Yale University | Wiersig J.,Otto Von Guericke University of Magdeburg
Reviews of Modern Physics | Year: 2015

This is a review on theoretical and experimental studies on dielectric microcavities, which play a significant role in fundamental and applied research. The basic concepts and theories are introduced. Experimental techniques for fabrication of microcavities and optical characterization are described. Starting from undeformed cavities, the review moves on to weak deformation, intermediate deformation with mixed phase space, and then strong deformation with full ray chaos. Non-Hermitian physics such as avoided resonance crossings and exceptional points are covered along with various dynamical tunneling phenomena. Some specific topics such as unidirectional output, beam shifts, wavelength-scale microcavities, and rotating microcavities are discussed. The open microdisk and microsphere cavities are ideal model systems for the studies on wave chaos and non-Hermitian physics. © 2015 American Physical Society. Source


Rothman J.E.,Yale University
Molecular biology of the cell | Year: 2010

This essay looks backward on the past three decades of research toward understanding the mechanism of macromolecular traffic through and within the Golgi apparatus with an eye to the future. I also explain why I feel the Golgi should continue to hold the attention of molecular cell biologists. Source


Yip S.W.,Yale University
Neuropsychopharmacology | Year: 2014

Preclinical research has demonstrated the effects of prenatal cocaine exposure (PCE) on brain regions involved in emotional regulation, motivational control, and addiction vulnerability-eg, the ventral striatum (VS), anterior cingulate (ACC), and prefrontal cortex (PFC). However, little is known about the function of these regions in human adolescents with PCE. Twenty-two adolescents with PCE and 22 age-, gender-, and IQ-matched non-cocaine exposed (NCE) adolescents underwent functional magnetic resonance imaging (fMRI) during exposure to individually personalized neutral/relaxing, stressful, and favorite-food cues. fMRI data were compared using group-level two-tailed t-tests in the BioImage Suite. In comparison with NCE adolescents, PCE adolescents had reduced activity within cortical and subcortical brain regions, including the VS, ACC, and medial and dorslolateral PFC during exposure to favorite-food cues but did not differ in neural responses to stress cues. Subjective food craving was inversely related to dorsolateral PFC activation among PCE adolescents. Among PCE adolescents, subjective anxiety ratings correlated inversely with activations in the orbitofrontal cortex and brainstem during the stress condition and with ACC, dorsolateral PFC, and hippocampus activity during the neutral-relaxing condition. Thus adolescents with PCE display hypoactivation of brain regions involved in appetitive processing, with subjective intensities of craving and anxiety correlating inversely with extent of activation. These findings suggest possible mechanisms by which PCE might predispose to the development of addictions and related disorders, eg, substance-use disorders and binge-eating.Neuropsychopharmacology advance online publication, 16 July 2014; doi:10.1038/npp.2014.133. Source


Landry M.L.,Yale University
Current Opinion in Pediatrics | Year: 2011

Purpose of Review: The 2009 H1N1 pandemic focused attention on the speed and accuracy of influenza diagnostic methods. This review provides an update on current tests and new developments. RECENT FINDINGS: Widely used rapid antigen tests and immunofluorescence tests were generally less sensitive for 2009 H1N1 influenza than for seasonal influenza. In addition, marked variability was reported for the same tests in different settings and patient groups. The advantages of molecular testing gained wide recognition, namely high sensitivity, speed compared with culture, ability to assess viral load and to identify subtype. Although adoption of influenza molecular testing can be expected to accelerate, immunoassays and rapid cultures performed on site retain advantages for many facilities. Falsely negative results were seen with all methods, especially for samples collected very early or late. SUMMARY: Influenza diagnostic test performance can be adversely affected by viral genetic and antigenic changes and should be re-assessed annually. Variability in sensitivity and specificity of the same test in different settings highlights the need for each laboratory to ensure optimal procedures and work with clinicians to improve sample quality. Manufacturers have been motivated to improve immunoassays and develop simpler and faster multiplex molecular tests, hopefully in advance of the next pandemic. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source


STUDY DESIGN:: Retrospective analysis of the National Surgical Quality Improvement Program (NSQIP), a prospectively-collected multicenter surgical outcomes database.OBJECTIVE:: To determine the effect of preoperative nutritional status, as measured by serum albumin concentration, on outcomes following anterior cervical discectomy and fusion (ACDF).SUMMARY OF BACKGROUND DATA:: Nutritional status has been shown to be an important predictor of postoperative recovery and outcomes. Serum albumin concentration is an established marker of overall nutrition and systemic disease, however, its correlation to outcomes following ACDF is unknown.METHODS:: ACDF cases from 2005-2010 were identified in the NSQIP and categorized by preoperative serum albumin: normal (≥3.5 g/dL), hypoalbuminemic (<3.5 g/dL), or not measured. Independent demographic and comorbidity variables were assessed, including American Society of Anesthesiologists (ASA) classification. Risk factors for major postoperative complications were identified, including preoperative hypoalbuminemia, and incorporated into a multivariable logistic regression model to determine the strength of preoperative hypoalbuminemia as an adjusted predictor of major postoperative complications.RESULTS:: There were 3671 ACDF cases, of which 1382 (37.6%) had preoperative albumin measurements. Patients with albumin measurements were older and more likely to have higher ASA class, hypertension, and diabetes. Hypoalbuminemic patients had higher rates of having any major postoperative complication(s), specifically pulmonary complications, cardiac complications, and re-operation, relative to those with normal albumin (all P<0.01). These patients also had longer lengths of stay (5.0 vs. 1.9 d). With multivariable regression, preoperative hypoalbuminemia was a strong independent predictor of major postoperative complications, with an adjusted odds ratio of 3.37 (P=0.003).CONCLUSIONS:: In this analysis of a prospective surgical outcomes database, preoperative serum hypoalbuminemia was an important adjunct predictor of major complications following ACDF. In high risk patients with multiple medical comorbidities, we recommend that clinicians consider nutritional screening and optimization as part of preoperative risk assessment. © 2014 by Lippincott Williams & Wilkins, Inc. Source


Changes in skin blood and sweating are the primary mechanisms for heat loss in humans. A hot, humid environment concomitant with dehydration limits the ability to increase skin blood flow for the purpose of transferring heat from the body core to skin surface and evaporate sweat to maintain core temperature within safe limits during exercise. Adequate hydration improves thermoregulation by maintaining blood volume to support skin blood flow and sweating. Humans rely on fluid intake to maintain total body water and blood volume, and have developed complex mechanisms to sense changes in the amount and composition of fluid in the body. This paper addresses the interrelationship of research in the laboratory and the field to assess hydration status involved in body water and temperature regulation during exercise. In the controlled setting of a research laboratory, investigators are able to investigate the contributions of volume and tonicity of fluid in the plasma to body water and temperature regulation during exercise and recovery. For example, laboratory studies have shown that tonicity in a rehydration beverage maintains the thirst mechanism (and stimulates drinking), and contributes to the ongoing stimulation of renal fluid retention hormones, ultimately leading to a more complete rehydration. Research in the field cannot control the environment precisely, but these studies provide a natural, 'real-life' setting to study fluid and temperature regulation during exercise. The conditions encountered in the field are closest to the environment during competition, and data collected in the field can have an immediate impact on performance and safety during exercise. There is an important synergy between these two methods of collecting data that support performance and protect athletes from harm during training and improve performance during competition. © The Author(s) 2014. Source


Little is known about the pathophysiology of myxomatous degeneration of the mitral valve, the pathological hallmark of mitral valve prolapse, associated with symptomatic mitral regurgitation, heart failure, and death. Excess transforming growth factor (TGF)-β signaling is known to cause mitral valve degeneration and regurgitation in a mouse model of Marfan syndrome. We examined if TGF-β signaling is dysregulated in clinical specimens of sporadic mitral valve prolapse compared with explanted nondiseased mitral valves and we tested the effects of angiotensin II receptor blockers on TGF-β signaling in cultured human mitral valve cells. Operative specimens, cultured valve tissues, and cultured valvular interstitial cells were obtained from patients with mitral valve prolapse undergoing mitral valve repair or from organ donors without mitral valve disease. Increased extracellular matrix in diseased valve tissue correlated with an upregulation of TGF-β expression and signaling as evidenced by SMAD2/3 phosphorylation. Both TGF-β ligand and signaling mediators colocalized primarily to valvular interstitial cells suggesting autocrine/paracrine activation. In cultured valve tissue, exogenous TGF-β increased basal extracellular matrix production, whereas serological neutralization of TGF-β inhibited disease-driven extracellular matrix overproduction. TGF-β-induced extracellular matrix production in cultured valvular interstitial cells was dependent on SMAD2/3 and p38 signaling and was inhibited by angiotensin II receptor blockers. TGF-β has a profibrotic role in the pathogenesis of sporadic mitral valve prolapse. Attenuation of TGF-β signaling by angiotensin II receptor blockers may represent a mechanistically based strategy to modulate the pathological progression of mitral valve prolapse in patients. Source


Finkelstein F.O.,Yale University
Clinical Journal of the American Society of Nephrology | Year: 2015

As the care of patients gets more focused and directed by predetermined standards of care, physicians must not lose sight of the primary focus of their treatment goal—maximizing the quality of life of each patient. Physicians must recognize the uniqueness of each individual’s experience and make every effort to understand the domains that are of concern to each patient. In addition, physicians must make sure that this focus is not obscured by the setting of arbitrary standards and targets that lend themselves to easy assessments and reporting by simple laboratory measures or computer-generated data. Finally, physicians must focus on modifying and tailoring treatment to maximize each patient’s health-related quality of life. © 2015 by the American Society of Nephrology. Source


Albert V.V.,Yale University
Physical Review Letters | Year: 2012

A tractable N-state Rabi Hamiltonian is introduced by extending the parity symmetry of the two-state model. The single-mode case provides a few-parameter description of a novel class of periodic systems, predicting that the ground state of certain four-state atom-cavity systems will undergo parity change at strong-coupling. A group-theoretical treatment provides physical insight into dynamics and a modified rotating wave approximation obtains accurate analytical energies. The dissipative case can be applied to study excitation energy transfer in molecular rings or chains. © 2012 American Physical Society. Source


Kazmierczak B.I.,Yale University | Hendrixson D.R.,University of Texas Southwestern Medical Center
Molecular Microbiology | Year: 2013

Summary: Control of surface organelle number and placement is a crucial aspect of the cell biology of many Gram-positive and Gram-negative bacteria, yet mechanistic insights into how bacteria spatially and numerically organize organelles are lacking. Many surface structures and internal complexes are spatially restricted in the bacterial cell (e.g. type IV pili, holdfasts, chemoreceptors), but perhaps none show so many distinct patterns in terms of number and localization as the flagellum. In this review, we discuss two proteins, FlhF and FlhG (also annotated FleN/YlxH), which control aspects of flagellar assembly, placement and number in polar flagellates, and may influence flagellation in some bacteria that produce peritrichous flagella. Experimental data obtained in a number of bacterial species suggest that these proteins may have acquired distinct attributes influencing flagellar assembly that reflect the diversity of flagellation patterns seen in different polar flagellates. Recent findings also suggest FlhF and FlhG are involved in other processes, such as influencing the rotation of flagella and proper cell division. Continued examination of these proteins in polar flagellates is expected to reveal how different bacteria have adapted FlhF or FlhG with specific activities to tailor flagellar biosynthesis and motility to fit the needs of each species. Copyright © 2013 John Wiley & Sons Ltd. Source


Crabtree R.H.,Yale University
Topics in Organometallic Chemistry | Year: 2011

Iridium had shown no special advantage in heterogeneous catalysis and this situation seemed to carry over into the early work in homogeneous catalysis. In particular, the failure of IrCl(PPh 3) 3, the Ir analog of Wilkinson's catalyst, to give catalytic hydrogenation strongly influenced thinking at the time. The developments that changed the situation were Shrock and Osborn's work on [(cod)RhL 2] + complexes that showed how lowering the L:M ratio from 3 to 2 gave improved catalysts, followed by our own finding that [(cod)IrL 2] + and especially [(cod)IrLL′] + complexes are even more highly active, particularly for highly substituted alkenes. This performance is absent in the classical coordinating solvents then standard in the field but only appears in weakly coordinating solvents like dichloromethane. A special property of the Ir complexes is a pronounced directing effect caused by catalyst binding to substrate functionality, leading to very high diastereoselectivity of the reduction. Asymmetric hydrogenations consistently gave lower ee values for iridium over rhodium, however, so academic work still strongly emphasized Rh. The exceedingly rapid rates of hydrogenation with Ir attracted industrial attention, because rate is such an important factor in that case, and Novartis' catalytic asymmetric route to the pesticide (S)-Metolachlor employs iridium, even though the ee value is only ca 80%. Leading applications of these and other Ir catalysts up to about 1,990 are also discussed. Work by Pfaltz, Burgess, and Andersson showed how efficient asymmetric Ir catalysts could be made by judicious choice of ligand. Alkane dehydrogenation by reverse hydrogenation also proved possible with Ir catalysts. © 2011 Springer Berlin Heidelberg. Source


Long M.D.,Yale University
Reviews of Geophysics | Year: 2013

Much progress has been made over the past several decades in delineating the structure of subducting slabs, but several key aspects of their dynamics remain poorly constrained. Major unsolved problems in subduction geodynamics include those related to mantle wedge viscosity and rheology, slab hydration and dehydration, mechanical coupling between slabs and the ambient mantle, the geometry of mantle flow above and beneath slabs, and the interactions between slabs and deep discontinuities such as the core-mantle boundary. Observations of seismic anisotropy can provide relatively direct constraints on mantle dynamics because of the link between deformation and the resulting anisotropy: when mantle rocks are deformed, a preferred orientation of individual mineral crystals or materials such as partial melt often develops, resulting in the directional dependence of seismic wave speeds. Measurements of seismic anisotropy thus represent a powerful tool for probing mantle dynamics in subduction systems. Here I review the observational constraints on seismic anisotropy in subduction zones and discuss how seismic data can place constraints on wedge, slab, and sub-slab anisotropy. I also discuss constraints from mineral physics investigations and geodynamical modeling studies and how they inform our interpretation of observations. I evaluate different models in light of constraints from seismology, geodynamics, and mineral physics. Finally, I discuss some of the major unsolved problems related to the dynamics of subduction systems and how ongoing and future work on the characterization and interpretation of seismic anisotropy can lead to progress, particularly in frontier areas such as understanding slab dynamics in the deep mantle. Key PointsSeismic anisotropy in subduction systems reflects complex processes.Different models for anisotropy in subduction systems are evaluated.Major unsolved problems can be addressed with anisotropy observations. ©2013. American Geophysical Union. All Rights Reserved. Source


Waxman S.G.,Yale University | Waxman S.G.,Rehabilitation Research Center
Trends in Molecular Medicine | Year: 2013

The universe of painful Na-channelopathies - human disorders caused by mutations in voltage-gated sodium channels - has recently expanded in three dimensions. We now know that mutations of sodium channels cause not only rare genetic 'model disorders' such as inherited erythromelalgia and channelopathy-associated insensitivity to pain but also common painful neuropathies. We have learned that mutations of NaV1.8, as well as mutations of NaV1.7, can cause painful Na-channelopathies. Moreover, recent studies combining atomic level structural models and pharmacogenomics suggest that the goal of genomically guided pain therapy may not be unrealistic. © 2013 Elsevier Ltd. Source


Riley K.J.,Rollins College | Steitz J.A.,Yale University | Steitz J.A.,Howard Hughes Medical Institute
Molecular Cell | Year: 2013

Recent technological advances have spurred genome-wide studies that afford insights into ribonucleoprotein biology and transcript regulation on an unprecedented scale. Here we review techniques currently used to obtain genome-wide profiles of RNA-protein interactions in living cells. We highlight recent studies of the mRNA-bound proteome and address pitfalls inherent in such investigations. © 2013 Elsevier Inc. Source


Garate I.,Yale University
Physical Review Letters | Year: 2013

We show that electron-phonon interactions can alter the topological properties of Dirac insulators and semimetals, at both zero and nonzero temperature. Contrary to the common belief that increasing temperature always destabilizes topological phases, our results highlight instances in which phonons may lead to the appearance of topological surface states above a crossover temperature in a material that has a topologically trivial ground state. © 2013 American Physical Society. Source


Craiglow B.G.,Yale University
Seminars in Perinatology | Year: 2013

The ichthyoses encompass a variety of genetic disorders marked by abnormal epidermal differentiation. The neonatal period is critical for patients with ichthyosis because of the risk for significant associated morbidity and mortality, with the majority of complications arising as a result of impaired barrier function. This article reviews presentations of ichthyosis in the neonate, outlines risks and complications, and provides strategies for management. © 2013 Elsevier Inc. Source


Niemann C.,University of Cologne | Horsley V.,Yale University
Seminars in Cell and Developmental Biology | Year: 2012

The important role of epidermal appendages especially the sebaceous gland has only recently been recognized. In particular, it has been convincingly shown that normal development and maintenance of the sebaceous gland are required for skin homeostasis since atrophic sebaceous glands and disturbances in sebaceous lipid composition result in major defects of the physiological barrier and maintenance of the skin. Consequently, it is important to unravel the signaling network controlling proper sebaceous lineage differentiation in mammalian skin and to understand the underlying mechanisms leading to severe skin diseases, including abnormal proliferation and differentiation of the gland, defects of the lipid metabolism and barrier, as well as sebaceous tumor formation. Over the last years, results from transgenic and knock out mouse models manipulating distinct signaling pathways in the skin as well as the detailed analysis of human sebaceous gland-derived cell lines provided new insights into crucial mediators balancing proliferation and differentiation of the sebaceous gland. Here, we discuss our current knowledge of in vivo mechanisms of sebaceous gland development, maintenance and disorders and highlight recent contributions to the field of sebaceous gland biology. © 2012 Elsevier Ltd. Source


Spudich S.S.,Yale University
Topics in Antiviral Medicine | Year: 2014

A shift in focus in the field of neuroHIV was clearly manifest at the 2014 Conference on Retroviruses and Opportunistic Infections (CROI), where a major emphasis was on the milder forms of neurologic morbidity, including cognitive impairment, seen in well-treated patients. Mechanisms of this persistent abnormality were investigated, including extensive analysis of the prevalence and associations of persistent HIV detection in cerebrospinal fluid (CSF) and characterization of persistent CNS immune activation. Another key emphasis was the early establishment of HIV replication and inflammation within the central nervous system (CNS) and the potentially salutary effect of very early HIV diagnosis and treatment in protecting the CNS from HIV-related injury. Mitochondrial function was identified as a potential mediator of a number of aspects of HIV-associated CNS dysfunction, including neurotoxicity associated with efavirenz, host genetic determinants of HIV-associated neurocognitive disorders (HAND), associations with direct measures of mitochondria in CSF, and metabolomic screening of CSF in HIV-infected subjects and those with HAND. Many studies employed laboratory rather than neuropsychologic end points, with a major focus on CSF biomarkers. Overall, neuroHIV presentations at CROI 2014 provided new insights into pathogenesis and treatment of the CNS, raising new challenges for researchers and practitioners aiming to optimize the status of the brain in people living with HIV infection. © 2014, IAS-USA. All rights reserved. Source


Korenaga J.,Yale University
Journal of Geophysical Research: Solid Earth | Year: 2011

The net influx of water into the deep mantle by plate tectonics has been poorly constrained because it is difficult to quantify how efficiently subducting slabs are devolatilized on a global scale. The significance of deep water cycle in the Earth history is similarly ambiguous because it depends critically on when plate tectonics started and how it evolved through time. Here I show that, using the new scaling of plate-tectonic convection based on fully dynamic calculations, the thermal evolution of Earth consistent with geochemical, petrological, and geological data requires continuous mantle hydration since the early Earth, with the net water influx of ∼2-3 × 1014 g yr-1. A drier mantle in the Hadean and Archean is suggested to help the initiation of plate tectonics by reducing the viscosity contrast between lithosphere and asthenosphere. As an increase in the vigor of plate tectonics with time would encourage global marine inundation, the slow intake of surface water by the convecting mantle is essential to maintain the continental freeboard. Copyright 2011 by the American Geophysical Union. Source


Jorgensen W.L.,Yale University
Cell | Year: 2013

The 2013 Nobel Prize in Chemistry has been awarded to Martin Karplus, Michael Levitt, and Arieh Warshel for "development of multiscale models for complex chemical systems." The honored work from the 1970s has provided a foundation for the widespread activities today in modeling organic and biomolecular systems. © 2013 Elsevier Inc. Source


Graedel T.E.,Yale University
Annual Review of Materials Research | Year: 2011

The routine availability of metals, long assumed by materials scientists to be unworthy of concern, is now a topic of wide interest but one with little clear guidance. This review discusses availability issues from the perspective of the metals utilized in the energy industry. Although the availability of metals is a dynamic characteristic, availability of the widely used base metals appears assured in the immediate future. The same cannot be said for by-product (daughter) metals, which are increasingly vital for many carbon-free energy technologies but are produced only if recovered as part of parent metal processing. Additionally, the direct substitution of one metal for another in short supply is often difficult because the best substitutes tend to have the same availability constraints as did the original metal. Gallium, indium, and neodymium are singled out as elements of particular concern from a long-term-supply standpoint. © 2011 by Annual Reviews. All rights reserved. Source


Hirsch L.J.,Yale University
Epilepsia | Year: 2011

There is significant variability and controversy regarding the interpretation, nomenclature, and clinical implications of many EEG patterns seen in encephalopathic patients. The American Clinical Neurophysiology Society has attempted to create well-defined, objective rules for naming these patterns in order to allow scientific investigation into their significance. After many revisions, clarifications in definitions, and Web-based training modules, interrater reliability has improved. A perfect system for describing complex wave forms with words will never be perfect; scalp EEG itself has substantial limitations, as intracranial recordings in neurocritical care patients have shown. The latest version of the nomenclature is available at. © Wiley Periodicals, Inc. © 2011 International League Against Epilepsy. Source


Karato S.-I.,Yale University
Earth and Planetary Science Letters | Year: 2011

Various methods for inferring the water distribution in Earth's mantle are reviewed including geochemical and geophysical methods. The geochemical approach using the water contents of basalts shows that the water content in the source regions of ocean island basalt is generally larger than that of the source region of mid-ocean ridge basalt, but the location of the source regions of ocean island basalts is poorly constrained. Geophysical approaches have potential of providing constraints on the spatial distribution of water but their usefulness depends critically on the sensitivity of geophysical observations to water content relative to other factors, in addition to the resolution of geophysical observations. Existing experimental data on the influence of water on seismologically observable properties and on electrical conductivity are reviewed. Frequently used seismological observations such as the anomalies in seismic wave velocities and of the topography on the mantle discontinuities are only weakly sensitive to water content but more sensitive to other factors such as the major element chemistry and temperature for a typical range of water contents. In contrast, electrical conductivity is highly sensitive to water content and only modestly sensitive to other factors such as temperature, oxygen fugacity and major element chemistry. Models of electrical conductivity-depth profiles are constructed where the influence of hydrogen and iron partitioning among coexisting minerals and of the depth variation in oxygen fugacity are incorporated. It is shown (i) that the electrical conductivity varies more than two orders of magnitude for a plausible range of water content in the mantle (~ 10 ppm wt to ~ 1 wt.%) and (ii) that if water content is constant with depth, there will be a drop in electrical conductivity at ~ 410-km. Although the resolution is not as high as seismological observations, geophysically inferred electrical conductivity distributions generally show higher conductivity in the mantle transition zone than the upper mantle, suggesting that the water content in the transition zone is higher than that in the upper mantle with some lateral variations. Implications of inferred water distribution are discussed including the possible partial melting near 410-km and its role in global water circulation. © 2010 Elsevier B.V. Source


Wysolmerski J.J.,Yale University
Bone | Year: 2013

Lactation is associated with an increased demand for calcium and is accompanied by a remarkable cycle of bone loss and recovery that helps to supply calcium and phosphorus for milk production. Bone loss is the result of increased bone resorption that is due, in part, to increased levels of PTHrP and decreased levels of estrogen. However, the regulation of bone turnover during this time is not fully understood. In the 1960s and 1970s many observations were made to suggest that osteocytes could resorb bone and increase the size of their lacunae. This concept became known as osteocytic osteolysis and studies suggested that it occurred in response to parathyroid hormone and/or an increased systemic demand for calcium. However, this concept fell out of favor in the late 1970s when it was established that osteoclasts were the principal bone-resorbing cells. Given that lactation is associated with increased PTHrP levels and negative calcium balance, we recently examined whether osteocytes contribute to bone loss during this time. Our findings suggest that osteocytes can remodel their perilacunar and pericanalicular matrix and that they participate in the liberation of skeletal calcium stores during reproductive cycles. These findings raise new questions about the role of osteocytes in coordinating bone and mineral metabolism during lactation as well as the recovery of bone mass after weaning. It is also interesting to consider whether osteocyte lacunar and canalicular remodeling contribute more broadly to the maintenance of skeletal and mineral homeostasis. This article is part of a Special Issue entitled "The Osteocyte". © 2013 Elsevier Inc. Source


Wang J.,Yale University | Wing R.A.,Rockefeller University
Acta Crystallographica Section D: Biological Crystallography | Year: 2014

Overwhelming evidence exists to show that the inclusion of weak-intensity, high-resolution X-ray diffraction data helps improve the refinement of atomic models by imposing strong constraints on individual and overall temperature B factors and thus the quality of crystal structures. Some researchers consider these data to be of little value and opt to discard them during data processing, particularly at medium and low resolution, at which individual B factors of atomic models cannot be refined. Here, new evidence is provided to show that the inclusion of these data helps to improve the quality of experimental phases by imposing proper constraints on electron-density models during noncrystallographic symmetry (NCS) averaging. Using electron-density correlation coefficients as criteria, the resolution of data has successfully been extended from 3.1 to 2.5Å resolution with redundancy-independent merging R factors from below 100% to about 310%. It is further demonstrated that phase information can be fully extracted from observed amplitudes through de novo NCS averaging. Averaging starts with uniform density inside double-shelled spherical masks and NCS matrices that are derived from bound heavy-atom clusters at the vertices of cuboctahedrally symmetric protein particles. © 2014 International Union Of Crystallography. Source


Barash P.,Yale University
British journal of anaesthesia | Year: 2010

Patients with coronary stents undergoing non-cardiac surgery are at increased risk of major adverse cardiovascular events perioperatively. Impeccable patient care and communication between all members of the healthcare team will minimize this risk. The dominant risk factor for stent thrombosis and major adverse cardiovascular events is the interruption of dual antiplatelet therapy (e.g. aspirin and clopidogrel). If clopidogrel therapy has to be interrupted due to increased risk of bleeding, continuation of aspirin is strongly recommended to reduce the risk of stent thrombosis. The interval between percutaneous coronary interventions and operation is the next major risk factor for stent thrombosis. The incidence of major adverse cardiovascular events is inversely related to this interval, with the highest mortality rate occurring <30 days after stent implantation. Ideally, for patients with drug-eluting stents, elective surgery should be delayed for at least 1 yr and for patients with bare-metal stents, the recommended minimum period is 6 weeks. The use of a neuraxial anaesthetic technique must be carefully considered due to the risk of an epidural haematoma. Perioperative monitoring should focus on early recognition of myocardial ischaemia, infarction, or both. If stent thrombosis is present, rapid triage to an interventional catheterization laboratory is essential for restoration of coronary blood flow. Source


Loren L.,Yale University
New England Journal of Medicine | Year: 2016

A 55-year-old woman presents to the emergency department at 11:30 p.m. with hematemesis. She is otherwise healthy and has no risk factors for liver disease. Her only medication is aspirin (at a dose of 81 mg daily), which she started to take 6 months ago after reading that it reduces the risk of heart disease. The blood pressure is 94/60 mm Hg, and the heart rate is 108 beats per minute; the physical examination is otherwise normal. The hemoglobin level is 11.0 g per deciliter, platelet count 220,000 per cubic millimeter, international normalized ratio 1.0, and blood urea nitrogen level 20 mg per deciliter (7.1 mmol per liter). How should this case be further evaluated and managed? Copyright © 2016 Massachusetts Medical Society. Source


The honey bee, Apis mellifera, harbors a characteristic gut microbiota composed of only a few species which seem to be specific to social bees. The maintenance of this stable and distinct microbial community depends on the social lifestyle of these insects. As in other animals, the bacteria in the gut of honey bees probably govern important functions critical to host health. We recently sequenced a metagenome of the gut microbiota of A. mellifera, assigned gene contents to bins corresponding to the major species present in the honey bee gut, and compared functional gene categories between these species, and between the complete metagenome and those of other animals. Gene contents could be linked to different symbiotic functions with the host. Further, we found a high degree of genetic diversity within each of these species. In the case of the gammaproteobacterial species Gilliamella apicola, we experimentally showed a link between genetic variation of isolates and functional differences suggesting that niche partitioning within this species has emerged during evolution with its bee hosts. The consistent presence of only a few species, combined with strain variation within each of these species, makes the gut microbiota of social bees an ideal model for studying functional, structural, and evolutionary aspects of host-associated microbial communities: many characteristics resemble the gut microbiota of humans and other mammals, but the complexity is considerably reduced. In this addendum, we summarize and discuss our major findings and provide a detailed perspective on future research. Source


Wysolmerski J.J.,Yale University
Annals of the New York Academy of Sciences | Year: 2010

Mammalian reproduction requires that nursing mothers transfer large amounts of calcium to their offspring through milk. As a result, lactation is associated with dramatic alterations in bone and mineral metabolism, including reversible bone loss. One theme that has emerged from recent studies examining these adaptations is that the lactating breast actively participates in regulating bone and mineral metabolism. This review will detail our current knowledge of interactions between the breast, skeleton, and hypothalamus during lactation and will consider implications that this reproductive physiology has for the pathophysiology of osteoporosis and breast cancer. © 2010 New York Academy of Sciences. Source


Sanacora G.,Yale University | Schatzberg A.F.,Stanford University
Neuropsychopharmacology | Year: 2015

Large 'real world' studies demonstrating the limited effectiveness and slow onset of clinical response associated with our existing antidepressant medications has highlighted the need for the development of new therapeutic strategies for major depression and other mood disorders. Yet, despite intense research efforts, the field has had little success in developing antidepressant treatments with fundamentally novel mechanisms of action over the past six decades, leaving the field wary and skeptical about any new developments. However, a series of relatively small proof-of-concept studies conducted over the last 15 years has gradually gained great interest by providing strong evidence that a unique, rapid onset of sustained, but still temporally limited, antidepressant effects can be achieved with a single administration of ketamine. We are now left with several questions regarding the true clinical meaningfulness of the findings and the mechanisms underlying the antidepressant action. In this Circumspectives piece, Dr Sanacora and Dr Schatzberg share their opinions on these issues and discuss paths to move the field forward. Source


Carroll K.M.,Yale University
Addiction | Year: 2016

Commentary to: After 30 years of dissemination, have we achieved sustained practice change in motivational interviewing? © 2016 Society for the Study of Addiction. Source


Jetz W.,Yale University | McPherson J.M.,Center for Conservation Research | McPherson J.M.,Simon Fraser University | Guralnick R.P.,University of Colorado at Boulder
Trends in Ecology and Evolution | Year: 2012

Global knowledge about the spatial distribution of species is orders of magnitude coarser in resolution than other geographically-structured environmental datasets such as topography or land cover. Yet such knowledge is crucial in deciphering ecological and evolutionary processes and in managing global change. In this review, we propose a conceptual and cyber-infrastructure framework for refining species distributional knowledge that is novel in its ability to mobilize and integrate diverse types of data such that their collective strengths overcome individual weaknesses. The ultimate aim is a public, online, quality-vetted 'Map of Life' that for every species integrates and visualizes available distributional knowledge, while also facilitating user feedback and dynamic biodiversity analyses. First milestones toward such an infrastructure have now been implemented. © 2011 Elsevier Ltd. Source


Tufro A.,Yale University
Pediatric Nephrology | Year: 2014

Semaphorin3a (sema3a), a member of class 3 semaphorins, is a guidance protein that regulates angiogenesis, branching morphogenesis, axon growth, and cell migration, and has pleiotropic roles on organogenesis, immune response, and cancer. Sema3a is secreted by podocytes and is required for normal kidney patterning and glomerular filtration barrier development. We recently discovered that after completion of kidney development, Sema3a gain-of-function in podocytes leads to proteinuric glomerular disease in mice. Excess sema3a causes foot process effacement, glomerular basement lamination, and endothelial damage in vivo, and disrupts cell autonomously podocyte shape by down-regulating nephrin and inhibiting αvβ3 integrin. We identified a novel direct interaction between nephrin and plexinA1, the sema3a signaling receptor. Nephrin-plexinA1 interaction links the slit-diaphragm signaling complex to extracellular sema3a signals. Hence, sema3a functions as an extracellular negative regulator of the structure and function of the glomerular filtration barrier. © 2014 IPNA. Source


Collins S.C.,Yale University
Current Opinion in Obstetrics and Gynecology | Year: 2013

PURPOSE OF REVIEW: To review the foundations, recent technical advances, and increasing number of applications for in-vitro fertilization with preimplantation genetic diagnosis (PGD). RECENT FINDINGS: PGD is an important technique for reducing the burden of genetic disease. Studies have shown that the diagnostic accuracy and subsequent live-birth rate after PGD are impacted by the developmental stage at the time of biopsy, as well as the biopsy protocol used. Also essential for accurate diagnosis are refined mutation detection protocols which avoid the common problem of allele drop-out. As the technique has improved, there has been a concomitant increase in the popularity and breadth of application of PGD. A recently published 10-year dataset of worldwide PGD reveals the increasing frequency of its use and the growing number of indications for which PGD is offered. SUMMARY: Technical advances from biopsy to detection of mutations have led to improved diagnostic accuracy and an increased frequency and breadth of use for PGD. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source


Camarena L.,Yale University
PLoS pathogens | Year: 2010

Acinetobacter baumannii is a common pathogen whose recent resistance to drugs has emerged as a major health problem. Ethanol has been found to increase the virulence of A. baumannii in Dictyostelium discoideum and Caenorhabditis elegans models of infection. To better understand the causes of this effect, we examined the transcriptional profile of A. baumannii grown in the presence or absence of ethanol using RNA-Seq. Using the Illumina/Solexa platform, a total of 43,453,960 reads (35 nt) were obtained, of which 3,596,474 mapped uniquely to the genome. Our analysis revealed that ethanol induces the expression of 49 genes that belong to different functional categories. A strong induction was observed for genes encoding metabolic enzymes, indicating that ethanol is efficiently assimilated. In addition, we detected the induction of genes encoding stress proteins, including upsA, hsp90, groEL and lon as well as permeases, efflux pumps and a secreted phospholipase C. In stationary phase, ethanol strongly induced several genes involved with iron assimilation and a high-affinity phosphate transport system, indicating that A. baumannii makes a better use of the iron and phosphate resources in the medium when ethanol is used as a carbon source. To evaluate the role of phospholipase C (Plc1) in virulence, we generated and analyzed a deletion mutant for plc1. This strain exhibits a modest, but reproducible, reduction in the cytotoxic effect caused by A. baumannii on epithelial cells, suggesting that phospholipase C is important for virulence. Overall, our results indicate the power of applying RNA-Seq to identify key modulators of bacterial pathogenesis. We suggest that the effect of ethanol on the virulence of A. baumannii is multifactorial and includes a general stress response and other specific components such as phospholipase C. Source


Mora C.,Ecole Normale Superieure de Paris | Le Hur K.,Yale University
Nature Physics | Year: 2010

Mesoscopic circuits cooled down to low temperatures witness marked non-local effects in their transport properties because of electron coherenceĝ€"electron wavefunctions spread over the sample and correlate its different parts. One of the consequences is that, in one dimension, the maximum d.c. conductance is quantized in steps of e 2/h. Here we extend the concept of e2/huniversal quantized resistance'to the a.c. regime. We analyse the coherent quantum resistanc-capacitance circuit comprising a cavity capacitively coupled to a gate and connected by means of a single spin-polarized channel to a reservoir lead. We show that, as a result of the Coulomb interaction and global phase coherence, the charge relaxation resistance Rq is identical for weak and large transmissions and that it smoothly changes from h/2e2 to h/e 2 when the frequency exceeds the level spacing of the cavity. For large cavities, we relate the resistance h/e2 to the Korring-Shiba relation of the Kondo model. Finally, we introduce a larger class of models with a universal charge relaxation resistance. © 2010 Macmillan Publishers Limited. All rights reserved. Source


Bradley E.H.,Yale University
PloS one | Year: 2012

Multiple interventions have been launched to improve the quality, access, and utilization of primary health care in rural, low-income settings; however, the success of these interventions varies substantially, even within single studies where the measured impact of interventions differs across sites, centers, and regions. Accordingly, we sought to examine the variation in impact of a health systems strengthening intervention and understand factors that might explain the variation in impact across primary health care units. We conducted a mixed methods positive deviance study of 20 Primary Health Care Units (PHCUs) in rural Ethiopia. Using longitudinal data from the Ethiopia Millennium Rural Initiative (EMRI), we identified PHCUs with consistently higher performance (n = 2), most improved performance (n = 3), or consistently lower performance (n = 2) in the provision of antenatal care, HIV testing in antenatal care, and skilled birth attendance rates. Using data from site visits and in-depth interviews (n = 51), we applied the constant comparative method of qualitative data analysis to identify key themes that distinguished PHCUs with different performance trajectories. Key themes that distinguished PHCUs were 1) managerial problem solving capacity, 2) relationship with the woreda (district) health office, and 3) community engagement. In higher performing PHCUs and those with the greatest improvement after the EMRI intervention, health center and health post staff were more able to solve day-to-day problems, staff had better relationships with the woreda health official, and PHCU communities' leadership, particularly religious leadership, were strongly engaged with the health improvement effort. Distance from the nearest city, quality of roads and transportation, and cultural norms did not differ substantially among PHCUs. Effective health strengthening efforts may require intensive development of managerial problem solving skills, strong relationships with government offices that oversee front-line providers, and committed community leadership to succeed. Source


Sevellec F.,University of Southampton | Fedorov A.V.,Yale University
Journal of Climate | Year: 2013

Variations in the strength of the Atlantic meridional overturning circulation (AMOC) are a major potential source of decadal and longer climate variability in the Atlantic. This study analyzes continuous integrations of tangent linear and adjoint versions of an ocean general circulation model [Océan Paralleélisé (OPA)] and rigorously shows the existence of a weakly damped oscillatory eigenmode of the AMOCcentered in the North Atlantic Ocean and controlled solely by linearized ocean dynamics. In this particular GCM, the mode period is roughly 24 years, its e-folding decay time scale is 40 years, and it is the least-damped oscillatory mode in the system. Its mechanism is related to the westward propagation of large-scale temperature anomalies in the northern Atlantic in the latitudinal band between 30° and 60°N. The westward propagation results froma competition among mean eastward zonal advection, equivalent anomalous westward advection caused by the mean meridional temperature gradient, and westward propagation typical of long baroclinic Rossby waves. The zonal structure of temperature anomalies alternates between a dipole (corresponding to an anomalous AMOC) and anomalies of one sign (yielding no changes in the AMOC). Further, it is shown that the system is nonnormal, which implies that the structure of the least-damped eigenmode of the tangent linear model is different from that of the adjoint model. The "adjoint" mode describes the sensitivity of the system(i.e., it gives the most efficient patterns for exciting the leading eigenmode). An idealized model is formulated to highlight the role of the background meridional temperature gradient in the North Atlantic for the mode mechanism and the system nonnormality. © 2013 American Meteorological Society. Source


Ransohoff R.M.,Biogen Idec | Hafler D.A.,Yale University | Lucchinetti C.F.,Rochester College
Nature Reviews Neurology | Year: 2015

Multiple sclerosis (MS) has been thought to be a complex and indecipherable disease, and poorly understood with regards to aetiology. Here, we suggest an emphatically positive view of progress over several decades in the understanding and treatment of MS, particularly focusing on advances made within the past 20 years. As with virtually all complex disorders, MS is caused by the interaction of genetic and environmental factors. In recent years, formidable biochemical, bioinformatic, epidemiological and neuroimaging tools have been brought to bear on research into the causes of MS. While susceptibility to the disease is now relatively well accounted for, disease course is not and remains a salient challenge. In the therapeutic realm, numerous agents have become available, reflecting the fact that the disease can be attacked successfully at many levels and using varied strategies. Tailoring therapies to individuals, risk mitigation and selection of first-line as compared with second-line medications remain to be completed. In our view, the MS landscape has been comprehensively and irreversibly transformed by this progress. Here we focus on MS therapeutics - the most meaningful outcome of research efforts. Source


Bhandari V.,Yale University
Birth Defects Research Part A - Clinical and Molecular Teratology | Year: 2014

Exposure to hyperoxia, invasive mechanical ventilation, and systemic/local sepsis are important antecedents of postnatal inflammation in the pathogenesis of bronchopulmonary dysplasia (BPD). This review will summarize information obtained from animal (baboon, lamb/sheep, rat and mouse) models that pertain to the specific inflammatory agents and signaling molecules that predispose a premature infant to BPD. © 2014 Wiley Periodicals, Inc. Source


Zhong W.,Yale University
Cold Spring Harbor perspectives in biology | Year: 2011

The Golgi is essential for processing proteins and sorting them, as well as plasma membrane components, to their final destinations. Not surprisingly, this organelle, a major compartment of the secretory pathway, is an important venue for regulating many aspects of development in both invertebrates and vertebrates. Through its role as a site for protein cleavage and glycosylation as well as through changes in its spatial organization and secretory trafficking, the Golgi exerts highly specific effects on cellular differentiation and morphogenesis by spatially and temporally constraining developmental pathways. Source


Natural hybridization is of marked importance from global to local biological diversity. In mangroves, species ranges overlap extensively with one another and species share a long overlap of flowering time. Although hybridization has been suggested, patterns of hybridization and the evolutionary potential of hybrids are not yet fully understood. This study provides molecular evidence for the parental origins and status of hybrids in the dominant mangrove genus Rhizophora based on comparisons of chloroplast and nuclear phylogenies and estimations of genetic relatedness and structure from inter-simple sequence repeat (ISSR) markers. Phylogenetic analyses indicate that almost all species can act as maternal parents to hybrids and that hybridization can be bidirectional. Bayesian analyses indicate that hybrids are simple F1s, and no trace of backcrossing was detected within populations. Hybridization, for the most part, occurs almost only locally and dispersal of hybrid individuals is limited beyond the hybrid sites. © 2010 European Society For Evolutionary Biology. Source


In 1911, a book was published in Europe by Eugen Bleuler describing in detail asylum patients under his care who met clinical criteria for the psychotic disorder named Dementia Praecox by Emil Kraepelin. Bleuler's voluminous publication, now a classic to world psychiatry, validated Kraepelin's observations and extended them in ways that remain familiar to us a full century later in how we describe, diagnose, treat, and understand psychosis. © The Author 2010. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. Source


The relationship between isotope diffusion coefficient and electrical conductivity is examined for a material where a dominant charge-carrying atomic species (e.g., hydrogen) is present as various forms with different diffusion coefficients (e.g., two protons trapped at M-site vacancy, one proton trapped at M-site vacancy etc.). It is shown that the isotopic diffusion occurs keeping the concentration ratio of each species fixed as determined by the thermo-chemical environment. Consequently, the isotope diffusion coefficient is the harmonic average of diffusion coefficients of individual species and is dominated by the slowest diffusing species. In contrast, when electric current is carried by charged species, the concentrations of individual species do not change. Therefore, electrical conductivity is related to the arithmetic average of individual diffusion coefficients dominated by the fastest diffusing species. The difference between these two cases can be large when different species have largely different diffusion coefficients. This model provides an explanation for the observed differences between experimental observations on isotopic diffusion (of H-D) and hydrogen-enhanced electrical conductivity and supports a hybrid model of hydrogen-enhanced electrical conduction where electrical conductivity is dominated by the fast moving hydrogen-related species. The species with the largest mobility may change with temperature leading to a change in anisotropy of conductivity. The degree of enhancement of electrical conductivity by hydrogen is high enough to explain most of the geophysically observed electrical conductivity of Earth's upper mantle. © 2013 Elsevier B.V. Source


Korenaga J.,Yale University
Annual Review of Earth and Planetary Sciences | Year: 2013

The inception of plate tectonics on Earth and its subsequent evolution are discussed on the basis of theoretical considerations and observational constraints. The likelihood of plate tectonics in the past depends on what mechanism is responsible for the relatively constant surface heat flux that is indicated by the likely thermal history of Earth. The continuous operation of plate tectonics throughout Earth's history is possible if, for example, the strength of convective stress in the mantle is affected by the gradual subduction of surface water. Various geological indicators for the emergence of plate tectonics are evaluated from a geodynamical perspective, and they invariably involve certain implicit assumptions about mantle dynamics, which are either demonstrably wrong or yet to be explored. The history of plate tectonics is suggested to be intrinsically connected to the secular evolution of the atmosphere, through sea-level changes caused by ocean-mantle interaction. © Copyright ©2013 by Annual Reviews. All rights reserved. Source


Calderwood D.A.,Yale University | Campbell I.D.,University of Oxford | Critchley D.R.,University of Leicester
Nature Reviews Molecular Cell Biology | Year: 2013

Integrin receptors provide a dynamic, tightly-regulated link between the extracellular matrix (or cellular counter-receptors) and intracellular cytoskeletal and signalling networks, enabling cells to sense and respond to their chemical and physical environment. Talins and kindlins, two families of FERM-domain proteins, bind the cytoplasmic tail of integrins, recruit cytoskeletal and signalling proteins involved in mechanotransduction and synergize to activate integrin binding to extracellular ligands. New data reveal the domain structure of full-length talin, provide insights into talin-mediated integrin activation and show that RIAM recruits talin to the plasma membrane, whereas vinculin stabilizes talin in cell-matrix junctions. How kindlins act is less well-defined, but disease-causing mutations show that kindlins are also essential for integrin activation, adhesion, cell spreading and signalling. © 2013 Macmillan Publishers Limited. All rights reserved. Source


Karato S.-I.,Yale University
Earth and Planetary Science Letters | Year: 2013

Although the Moon was considered to be "dry", recent measurements of hydrogen content in some of the lunar samples showed a substantial amount of water comparable to the water content in the Earth's asthenosphere. However, the interpretation of these observations in terms of the distribution of water in the lunar interior is difficult because the composition of these rocks reflects a complicated history involving melting and crystallization. In this study, I analyze geophysically inferred properties to obtain constraints on the distribution of water (and temperature) in the lunar interior. The electrical conductivity inferred from electromagnetic induction observations and the geodetically or geophysically inferred Q are interpreted in terms of laboratory data and the theoretical models on the influence of water (hydrogen) on these properties. Both electrical conductivity and Q are controlled by defect-related processes that are sensitive to the water (hydrogen) content and temperature but less sensitive to the major element chemistry. After a correction for the influence of the major element chemistry constrained by geophysical observations and geochemical considerations, I estimate the temperature-water content combinations that are consistent with the geophysically inferred electrical conductivity and Q. I conclude that the lunar interior is cooler than Earth (at the same depth) but the water content of the lunar mantle is similar to that of Earth's asthenosphere. A possible model is presented to explain the not-so-dry Moon where a small degree of water loss during the Moon formation is attributed to the role of liquid phases that play an important role in the Moon-forming environment. © 2013 Elsevier B.V. Source


Schmidt T.L.,Yale University
Physical Review Letters | Year: 2011

We consider a four-terminal setup of a two-dimensional topological insulator (quantum spin Hall insulator) with local tunneling between the upper and lower edges. The edge modes are modeled as helical Luttinger liquids and the electron-electron interactions are taken into account exactly. Using perturbation theory in the tunneling, we derive the cumulant generating function for the interedge current. We show that different possible transport channels give rise to different signatures in the current noise and current cross correlations, which could be exploited in experiments to elucidate the interplay between electron-electron interactions and the helical nature of the edge states. © 2011 American Physical Society. Source


Reichow B.,Yale University
Cochrane database of systematic reviews (Online) | Year: 2012

The rising prevalence of autism spectrum disorders (ASD) increases the need for evidence-based behavioral treatments to lessen the impact of symptoms on children's functioning. At present, there are no curative or psychopharmacological therapies to effectively treat all symptoms of the disorder. Early intensive behavioral intervention (EIBI), a treatment based on the principles of applied behavior analysis delivered for multiple years at an intensity of 20 to 40 hours per week, is one of the more well-established treatments for ASD. To systematically review the evidence for the effectiveness of EIBI in increasing the functional behaviors and skills of young children with ASD. We searched the following databases on 22 November 2011: CENTRAL (2011 Issue 4), MEDLINE (1948 to November Week 2, 2011), EMBASE (1980 to Week 46, 2011), PsycINFO (1806 to November Week 3, 2011), CINAHL (1937 to current), ERIC (1966 to current), Sociological Abstracts (1952 to current), Social Science Citation Index (1970 to current), WorldCat, metaRegister of Controlled Trials, and Networked Digital Library of Theses and Dissertations. We also searched the reference lists of published papers. Randomized control trials (RCTs), quasi-randomized control trials, or clinical control trials (CCTs) in which EIBI was compared to a no-treatment or treatment-as-usual control condition. Participants must have been less than six years of age at treatment onset and assigned to their study condition prior to commencing treatment. Two authors independently selected and appraised studies for inclusion and assessed the risk of bias in each included study. All outcome data were continuous, from which standardized mean difference effect sizes with small sample correction were calculated. We conducted random-effects meta-analysis where possible, which means we assumed individual studies would provide different estimates of treatment effects. One RCT and four CCTs with a total of 203 participants were included. Reliance on synthesis from four CCTs limits the evidential base and this should be borne in mind when interpreting the results. All studies used a treatment-as-usual comparison group. We synthesized the results of the four CCTs using a random-effects model of meta-analysis of the standardized mean differences. Positive effects in favor of the EIBI treatment group were found for all outcomes. The mean effect size for adaptive behavior was g = 0.69 (95% CI 0.38 to 1.01; P < 0.0001). The mean effect size for IQ was g = 0.76 (95% CI 0.40 to 1.11; P < 0.0001). Three measures of communication and language skills all showed results in favor of EIBI: expressive language g = 0.50 (95% CI 0.05 to 0.95; P = 0.03), receptive language g = 0.57 (95% CI 0.20 to 0.94; P = .03), and daily communication skills g = 0.74 (95% CI 0.30 to 1.18; P = 0.0009). The mean effect size for socialization was g = 0.42 (95% CI 0.11 to 0.73; P = 0.0008), and for daily living skills was g = 0.55 (95% CI 0.24 to 0.87; P = 0.0005). Additional descriptive analyses of other aspects related to quality of life and psychopathology are presented. However, due to the inclusion of non-randomized studies, there is a high risk of bias and the overall quality of evidence was rated as 'low' using the GRADE system, which rates the quality of evidence from meta-analyses to determine recommendations for practice. There is some evidence that EIBI is an effective behavioral treatment for some children with ASD. However, the current state of the evidence is limited because of the reliance on data from non-randomized studies (CCTs) due to the lack of RCTs. Additional studies using RCT research designs are needed to make stronger conclusions about the effects of EIBI for children with ASD. Source


Leckman J.F.,Yale University
Journal of Child Psychology and Psychiatry and Allied Disciplines | Year: 2014

In the past, we have typically regarded the 'immune system' as a complex set of cellular and molecular processes that protect us against pathogens, from viruses to parasitic worms. It is now clear that the cellular and molecular processes that make up our 'immune system' are also crucial to normal brain development and play a role in the pathoaetiology of many mental and physical disorders. In their Annual Research Review, O'Connor, Moynihan and Caserta (2014) provide a useful introduction to this emerging area of science that is highly relevant to our field and is a natural outgrowth of their earlier and ongoing work in psychoneuroimmunology. However, their review goes well beyond these seminal findings. While work in developmental psychoneuroimmunology engenders a good deal of excitement among academic researchers, the 'promise' of the field clearly remains greater than the 'deliverables', in terms of any direct effect on patient care. This commentary looks at the implication of these findings for clinical practice and where future research efforts should be expended. © 2014 The Author. Journal of Child Psychology and Psychiatry. © 2014 Association for Child and Adolescent Mental Health. Source


Shrock R.,Yale University
Physical Review D - Particles, Fields, Gravitation and Cosmology | Year: 2013

We investigate some higher-loop structural properties of the β function in asymptotically free vectorial gauge theories. Our main focus is on theories with fermion contents that lead to an infrared (IR) zero in β. We present analytic and numerical calculations of the value of the gauge coupling where β reaches a minimum, the value of β at this minimum, and the slope of β at the IR zero, at two-, three-, and four-loop order. The slope of β at the IR zero is relevant for estimates of a dilaton mass in quasiconformal gauge theories. Some inequalities are derived concerning the dependence of the above quantities on loop order. A general inequality is derived concerning the dependence of the shift of the IR zero of β, from the n-loop to the (n+1)-loop order, on the sign of the (n+1)-loop coefficient in β. Some results are also given for gauge theories with N=1 supersymmetry. © 2013 American Physical Society. Source


This article quantifies the frequency of infanticide and abortion in one region of Japan by comparing observed fertility in a sample of 4.9 million person-years (1660–1872) with a Monte Carlo simulation of how many conceptions and births that population should have experienced. The simulation uses empirical values for the determinants of fertility from Eastern Japan itself as well as the best available studies of comparable populations. This procedure reveals that in several decades of the eighteenth century, at least 40 % of pregnancies must have ended in either an induced abortion or an infanticide. In addition, the simulation results imply a rapid decline in the incidence of infanticide and abortion during the nineteenth century, when in a reverse fertility transition, this premodern family-planning regime gave way to a new age of large families. © 2015, Population Association of America. Source


Nath A.,Yale University
Methods in enzymology | Year: 2010

Nanodiscs are a new class of model membranes that are being used to solubilize and study a range of integral membrane proteins and membrane-associated proteins. Unlike other model membranes, the Nanodisc bilayer is bounded by a scaffold protein coat that confers enhanced stability and a narrow particle size distribution. The bilayer diameter can be precisely controlled by changing the diameter of the protein coat. All these properties make Nanodiscs excellent model membranes for single-molecule fluorescence applications. In this chapter, we describe our work using Nanodiscs to apply total internal reflection fluorescence microscopy (TIRFM), fluorescence correlation spectroscopy (FCS), and Förster resonance energy transfer (FRET) to study the integral membrane protein cytochrome P450 3A4 and the peripheral membrane-binding proteins islet amyloid polypeptide (IAPP) and alpha-synuclein, respectively. The monodisperse size distribution of Nanodiscs enhances control over the oligomeric state of the membrane protein of interest, and facilitates accurate solution-based measurements as well. Nanodiscs also comprise an excellent system to stably immobilize integral membrane proteins in a bilayer without covalent modification, enabling a range of surface-based experiments where accurate localization of the protein of interest is required. Copyright 2010 Elsevier Inc. All rights reserved. Source


Shapiro E.D.,Yale University
New England Journal of Medicine | Year: 2014

A 32-year-old pregnant woman from southeastern Connecticut presents to her physician in July at 26 weeks' gestation because of a skin lesion. She reports she has had fatigue, arthralgia, and headache for 2 days and a rash in her left axilla for 1 day. She lives in a wooded area and works in her garden frequently. Six weeks earlier, she had removed a small tick that was attached behind her right knee. On physical examination, she is afebrile. She has an erythematous, oval macular lesion, 7 to 8 cm in diameter, in her left axilla, with enhanced central erythema; no other abnormalities are noted. How should her case be managed? Copyright © 2014 Massachusetts Medical Society. Source


Burke G.R.,University of Arizona | Moran N.A.,Yale University
Genome Biology and Evolution | Year: 2011

All vertically transmitted bacterial symbionts undergo a process of genome reduction over time, resulting in tiny, gene-dense genomes. Comparison of genomes of ancient bacterial symbionts gives only limited information about the early stages in the transition from a free-living to symbiotic lifestyle because many changes become obscured over time. Here, we present the genome sequence for the recently evolved aphid symbiont Serratia symbiotica. The S. symbiotica genome exhibits several of the hallmarks of genome evolution observed in more ancient symbionts, including elevated rates of evolution and reduction in genome size. The genome also shows evidence for massive genomic decay compared with free-living relatives in the same genus of bacteria, including large deletions, many pseudogenes, and a slew of rearrangements, perhaps promoted by mobileDNA. Annotation of pseudogenes allowed examination of the past and current metabolic capabilities of S. symbiotica and revealed a somewhat random process of gene inactivation with respect to function. Analysis of mutational patterns showed that deletions are more common in neutral DNA. The S. symbiotica genome provides a rare opportunity to study genome evolution in a recently derived heritable symbiont. © The Author(s) 2011. Source


A modified semi-classical method is used to construct both ground and excited state solutions to the canonically quantized vacuum Bianchi IX (Mixmaster) cosmological models. Employing a modified form of the semi-classical Ansatz we solve the relevant Wheeler-DeWitt equation asymptotically by integrating a set of linear transport equations along the flow of a suitably chosen solution to the corresponding Euclidean-signature Hamilton-Jacobi equation. For the Moncrief-Ryan (or 'wormhole') Hamilton-Jacobi solution, we compute the ground state quantum correction term associated with operator ordering ambiguities and show how higher order correction terms can be computed. We also determine the explicit, leading order forms of a family of excited states and show how to compute their quantum corrections as smooth, globally defined functions on the Bianchi IX minisuperspace. These excited state solutions are peaked away from the minisuperspace origin and are labeled by a pair of positive integers that can be plausibly interpreted as graviton excitation numbers for the two independent anisotropy degrees of freedom. The Euclidean-signature semi-classical method used here is applicable to more general models, representing a significant progress in the Wheeler-DeWitt approach to quantum gravity. © 2015 IOP Publishing Ltd. Source


Guntuboyina A.,Yale University
IEEE Transactions on Information Theory | Year: 2011

Lower bounds involving f-divergences between the underlying probability measures are proved for the minimax risk in estimation problems. Our proofs just use simple convexity facts. Special cases and straightforward corollaries of our bounds include well known inequalities for establishing minimax lower bounds such as Fano's inequality, Pinsker's inequality and inequalities based on global entropy conditions. Two applications are provided: a new minimax lower bound for the reconstruction of convex bodies from noisy support function measurements and a different proof of a recent minimax lower bound for the estimation of a covariance matrix. © 2011 IEEE. Source


Nordhaus W.D.,Yale University
Energy Journal | Year: 2014

Modeling of technological change has been a major empirical and analytical obstacle for many years. One approach to modeling technology is learning or experience curves, which originated in techniques used to estimate cost functions in manufacturing. These have recently been introduced in policy models of energy and climate-change economics to make the process of technological change endogenous- that is, allow technologies to vary with economic conditions. It is not widely appreciated that using learning in modeling raises major potential problems. The present note has three points. First, it shows that there is a fundamental statistical identification problem in trying to separate learning from exogenous technological change and that the estimated learning coefficient will generally be biased upwards. Second, we present two empirical tests that illustrate the potential bias in practice and show that learning parameters are not robust to alternative specifications. Finally, we show that an overestimate of the learning coefficient will provide incorrect estimates of the total marginal cost of output and will therefore bias optimization models to tilt toward technologies that are incorrectly specified as having high learning coefficients. Copyright © 2014 by the IAEE. All rights reserved. Source


Paintsil E.,Yale University
Current Opinion in Pediatrics | Year: 2013

PURPOSE OF REVIEW: Recent guidelines on the management of urinary tract infections (UTIs) in children have seen a shift from aggressive imaging studies and the use of prophylactic antibiotics to a more restrictive and targeted approach. This review focuses on new additions to the literature on management of UTI from January 2011 to September 2012. RECENT FINDINGS: The causal relationship between UTI-vesicoureteral reflux (VUR) and renal scarring has been challenged by several studies. Concerns about unnecessary exposure to ionizing radiation, invasiveness of some of the procedures, and risk of infection have also been raised. With improved prenatal ultrasound, a 'top-down' approach to investigating febrile UTI in children using renal bladder ultrasound alone as an initial study has become popular. Several studies have reported that prophylactic antibiotics and imaging studies after first UTI can be reduced substantially without affecting the risk of recurrent UTI or renal scarring. SUMMARY: The use of targeted imaging approach in evaluating febrile UTI in children may lead to improved resource use and reduction of potential harmful procedures and interventions, without affecting outcomes of UTI in children. Providers using current guidelines should endeavor to collect practice-based evidence to validate and inform future guidelines. © 2013 Wolters Kluwer Health Lippincott Williams & Wilkins. Source


Anderson G.M.,Yale University
Journal of Autism and Developmental Disorders | Year: 2015

Network perspectives, in their emphasis on components and their interactions, might afford the best approach to the complexities of the ASD realm. Categorical approaches are unlikely to be fruitful as one should not expect to find a single or even predominant underlying cause of autism behavior across individuals. It is possible that the complex, highly interactive, heterogeneous and individualistic nature of the autism realm is intractable in terms of identifying clinically useful biomarker tests. It is hopeful from an emergenic perspective that small corrective changes in a single component of a deleterious network/configuration might have large beneficial consequences on developmental trajectories and in later treatment. It is suggested that the relationship between ASD and intellectual disability might be fundamentally different in single-gene versus nonsyndromic ASD. It is strongly stated that available biomarker “tests” for autism/ASD will do more harm than good. Finally, the serotonin–melatonin-oxidative stress-placental intersection might be an especially fruitful area of biological investigation. © 2014, Springer Science+Business Media New York. Source


Strauss J.,Yale University
Schizophrenia Bulletin | Year: 2011

To have a complete human science in the mental health field it is essential to give adequate attention to both the objective and the subjective data related to people with psychiatric disorders. The tendency in the past has been to ignore or discount one or the other of these data sources. Subjective data are particularly neglected, sometimes considered (only) part of the "art" of medicine since the usual methodologies of the physical sciences in themselves are not adequate to reflect the nature, elusiveness, and complexity of human subjective experience. The complete experience of hallucinated voices, for instance, often includes not only the voices themselves but also terrible anguish and terrifying inability to concentrate. But even such descriptors fall unnecessarily short of reflecting the data of the experience, thus leaving research, theory, and treatment with incomplete information. To represent adequately the subjective data it is essential to recognize that besides the usual discursive knowledge and methods of traditional physical science, a second kind of knowledge and method is required to reflect the depth of human experience. To accomplish this, we must employ approaches to narrative and the arts that are uniquely capable of capturing the nature of these experiences. Only by attending seriously in our research, training, theory, and practice to the unique nature of subjective data is it possible to have a true human science for our field. © 2010 The Author. Source


Moore P.B.,Yale University
Cold Spring Harbor perspectives in biology | Year: 2011

The crystal structures of ribosomes that have been obtained since 2000 have transformed our understanding of protein synthesis. In addition to proving that RNA is responsible for catalyzing peptide bond formation, these structures have provided important insights into the mechanistic details of how the ribosome functions. This review emphasizes what has been learned about the mechanism of peptide bond formation, the antibiotics that inhibit ribosome function, and the fidelity of decoding. Source


Altman S.,Yale University
RNA | Year: 2013

Following the naming of the RNAWorld for the hypothetical biochemical world during very early life forms, the current world was named the Protein World. However, the astonishing high level of transcripts from virtually all chromosomes in an organism now found in eucaryotes, as well as their extensive roles in regulating gene expression, suggests that today's world should be labeled as the RNA-Protein World. Copyright © 2013 RNA Society. Source


Ivancic P.C.,Yale University
European Spine Journal | Year: 2013

Purpose: Our objectives were to develop a skull-neck-thorax model capable of quantifying spinal motions in an intact human cadaver neck with and without cervical orthoses, determine the effect of orthoses on three-dimensional load-displacement properties of all cervical spinal levels, and compare and contrast our results with previously reported in vivo data. Methods: Load input flexibility tests were performed to evaluate two cervical collars (Vista® collar and Vista® Multipost collar) and two cervicothoracic orthoses (CTOs: Vista® TS and Vista® TS4) using the skull-neck-thorax model with 10 intact whole cervical spine specimens. The physiologic range of motion (RoM) limit was the peak obtained from flexibility tests with no orthosis. Pair-wise repeated measures, analysis of variance (p < 0.05), and Bonferroni post hoc tests determined significant differences in average peak RoM at each spinal level among the experimental conditions. Results: Significant reductions below physiologic limits were observed due to all orthoses in: three-dimensional head/T1 RoMs, all sagittal intervertebral RoMs, and lateral bending at C4/5 through C7/T1. Both CTOs significantly reduced C6/7 sagittal RoM as compared to both collars. Intervertebral RoMs with the orthoses could not be differentiated from physiologic limits at the upper cervical spine in lateral bending and throughout the entire cervical spine in axial rotation, with the exception of C1/2. Conclusions: Our results indicate that cervical orthoses effectively immobilized the entire cervical spine in flexion/extension and the lower cervical spine in lateral bending. The CTOs improved immobilization of the lower cervical spine in flexion/extension as compared to the collars. The orthoses were least effective at restricting lateral bending of the upper spinal levels and axial rotation of all spinal levels, except C1/2. Understanding immobilization provided by orthoses will assist clinicians in selecting the most appropriate brace based upon patient-specific immobilization requirements. © 2012 Springer-Verlag Berlin Heidelberg. Source


C 4 photosynthesis relies on spatial and quantitative specializations of common features of leaf anatomy, including venation pattern, bundle sheath cell and chloroplast differentiation, plasmodesmatal abundance, and secondary cell wall enhancement. It has thus far been challenging to dissect the molecular basis for these C4-specific alterations in spatial and quantitative patterns of regulation. The target downstream networks of genes and protein interactions that produce these fundamental anatomical features in both C 4 and C 3 species are poorly understood. The developing leaves of monocot grasses provide a base-to-tip gradient of developmental stages that can provide the platform for comprehensive molecular and anatomical data that can yield a better understanding both of the regulators and the targets that produce C 4 patterns, through a variety of gene discovery and systems analysis strategies. © 2011 The Author. Source


Leeman R.F.,Yale University
Experimental and clinical psychopharmacology | Year: 2013

We developed an alcohol self-administration paradigm to model individual differences in impaired control. The paradigm includes moderate drinking guidelines meant to model limits on alcohol consumption, which are typically exceeded by people with impaired control. Possible payment reductions provided a disincentive for excessive drinking. Alcohol use above the guideline, despite possible pay reductions, was considered to be indicative of impaired control. Heavy-drinking 21- to 25-year-olds (n = 39) were randomized to an experimental condition including the elements of the impaired control paradigm or to a free-drinking condition without these elements. Alcohol self-administration was compared between these two conditions to establish the internal validity of the experimental paradigm. In both conditions, participants self-administered beer and nonalcoholic beverages for 3 hours in a bar setting with 1-3 other participants. Experimental condition participants self-administered significantly fewer beers and drank to lower blood-alcohol concentrations (BACs) on average than those in the free-drinking condition. Experimental condition participants were more likely than free-drinking condition participants to intersperse nonalcoholic beverages with beer and to drink at a slower pace. Although experimental condition participants drank more moderately than those in the free-drinking condition overall, their range of drinking was considerable (BAC range = .024-.097), with several participants drinking excessively. A lower initial subjective response to alcohol and earlier age of alcohol use onset were associated with greater alcohol self-administration in the experimental condition. Given the variability in response, the impaired control laboratory paradigm may have utility for preliminary tests of novel interventions in future studies and for identifying individual differences in problem-drinking risk. PsycINFO Database Record (c) 2013 APA, all rights reserved Source


Zhao C.,Yale University
Nature Structural and Molecular Biology | Year: 2016

Group II introns are self-splicing ribozymes that are essential in many organisms, and they have been hypothesized to share a common evolutionary ancestor with the spliceosome. Although structural similarity of RNA components supports this connection, it is of interest to determine whether associated protein factors also share an evolutionary heritage. Here we present the crystal structures of reverse transcriptase (RT) domains from two group II intron–encoded proteins (maturases) from Roseburia intestinalis and Eubacterium rectale, obtained at 1.2-Å and 2.1-Å resolution, respectively. These domains are more similar in architecture to the spliceosomal Prp8 RT-like domain than to any other RTs, and they share substantial similarity with flaviviral RNA polymerases. The RT domain itself is sufficient for binding intron RNA with high affinity and specificity, and it is contained within an active RT enzyme. These studies provide a foundation for understanding structure–function relationships within group II intron–maturase complexes. © 2016 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. Source


Samanez-Larkin G.R.,Yale University | Knutson B.,Stanford University
Nature Reviews Neuroscience | Year: 2015

As the global population ages, older decision makers will be required to take greater responsibility for their own physical, psychological and financial well-being. With this in mind, researchers have begun to examine the effects of ageing on decision making and associated neural circuits. A new 'affect-integration-motivation' (AIM) framework may help to clarify how affective and motivational circuits support decision making. Recent research has shed light on whether and how ageing influences these circuits, providing an interdisciplinary account of how ageing can alter decision making. © 2015 Macmillan Publishers Limited. All rights reserved. Source


Detterbeck F.C.,Yale University
Journal of Thoracic Oncology | Year: 2010

Thymomas are relatively uncommon. Nevertheless, an accumulation of studies (mostly retrospective, single-institution series) have made it important to approach this disease in a knowledgeable, evidence-based fashion. This begins with the approach to evaluation of a patient with an anterior mediastinal mass, in whom a reliable clinical diagnosis is usually possible in experienced centers. Surgical resection is the mainstay of treatment, and every effort must be made to achieve a complete resection. © 2010 by the International Association for the Study of Lung Cancer. Source


Fuchs E.,Howard Hughes Medical Institute | Horsley V.,Yale University
Nature Cell Biology | Year: 2011

Over the past decade, it has become increasingly clear that many tissues have regenerative capabilities. The challenge has been to find the stem cells or progenitors that are responsible for tissue renewal and repair. The revolution in technological advances that permit sophisticated spatial, temporal and kinetic analyses of stem cells has allowed stem cell hunters to ferret out where stem cells live, and to monitor when they come and go from these hiding places. © 2011 Macmillan Publishers Limited. All rights reserved. Source


Marchesi V.T.,Yale University
American Journal of Pathology | Year: 2012

Alzheimer's disease threatens to become the scourge of the 21 st century. Hundreds of millions of aging people throughout the world are at risk, but it is clear that the disease encompasses more than just the natural aging process. Deposits of amyloid β peptides in the brains of demented individuals are a defining feature of the disease, yet two decades of intensive investigation, focusing on reducing or removing amyloid deposits, have failed to produce any meaningful therapeutic interventions. Some researchers question whether amyloid is the appropriate target. Others maintain that early, presymptomatic intervention would be a more informative test, and propose large-scale clinical trials in patients who are believed to be in the earliest, and potentially reversible, stages of the disease. This review explores the wisdom of that approach. © 2012 American Society for Investigative Pathology. Source


Ackerman J.M.,Massachusetts Institute of Technology | Nocera C.C.,Harvard University | Bargh J.A.,Yale University
Science | Year: 2010

Touch is both the first sense to develop and a critical means of information acquisition and environmental manipulation. Physical touch experiences may create an ontological scaffold for the development of intrapersonal and interpersonal conceptual and metaphorical knowledge, as well as a springboard for the application of this knowledge. In six experiments, holding heavy or light clipboards, solving rough or smooth puzzles, and touching hard or soft objects nonconsciously influenced impressions and decisions formed about unrelated people and situations. Among other effects, heavy objects made job candidates appear more important, rough objects made social interactions appear more difficult, and hard objects increased rigidity in negotiations. Basic tactile sensations are thus shown to influence higher social cognitive processing in dimension-specific and metaphor-specific ways. Source


Abu-Alfa A.K.,Yale University
Advances in Chronic Kidney Disease | Year: 2011

The strong association between nephrogenic systemic fibrosis (NSF) and exposure to gadolinium-based contrast agents (GBCAs) has greatly affected the care of patients with kidney disease. NSF has been reported in patients with ESRD, CKD, and acute kidney injury (AKI). The majority of cases have occurred in patients with ESRD, but about 20% have been reported in patients with AKI or CKD stages 4 and 5. There is also a risk difference among GBCAs, with the Food and Drug Administration contraindicating 3 linear agents in patients at risk. Given the significant morbidity and mortality of NSF, it is imperative to identify individuals at risk. Although there are no data to support a role for hemodialysis (HD) in reducing the risk for NSF after administration of GBCAs, immediate HD is still recommended within 2 hours. Patients maintained on peritoneal dialysis seem to be at high risk and immediate HD is also recommended. However, this is not the current recommendation for CKD stages 4 and 5, especially with suspected lower risk of noncontraindicated agents. Individualized assessment is important and especially in those patients close to dialysis initiation. Instituting policies is important to address the imaging needs of patients with CKD and AKI while ensuring a balance between benefits and risks. © 2011 National Kidney Foundation, Inc. Source


Crabtree R.H.,Yale University
Chemical Reviews | Year: 2015

Active catalysts typically have labile sites that are in principle much more sensitive to all the species present in the reaction medium as well as to the ambient conditions than is a stable complex in solution. The effects of changing solvents, additives, and conditions may therefore have big effects. Avoiding impurities in the solvent or substrate can also be a help, big or small depending on the case. The relevance of the topic is not limited to catalyst chemists. Many researchers, not themselves specialists in the field, apply a homogeneous catalyst taken from the literature in the hope of obtaining a needed organic product or bringing about some desired transformation. These efforts sometimes go astray from neglect of some unstated assumption in the original work or from a change either in the substrate structure or in the conditions used in the prior reports. Source


Bercovici D.,Yale University | Ricard Y.,University of Lyon
Earth and Planetary Science Letters | Year: 2013

The grain-damage and pinning mechanism of Bercovici and Ricard (2012) for lithospheric shear-localization is employed in two-dimensional flow calculations to test its ability to generate toroidal (strike-slip) motion and influence plate evolution. This mechanism posits that damage to the interface between phases in a polycrystalline material like peridotite (composed primarily of olivine and pyroxene) increases the number of small Zener pinning surfaces, which then constrain mineral grains to ever smaller sizes, regardless of creep mechanism. This effect allows a self-softening feedback in which damage and grain-reduction can co-exist with a grain-size dependent diffusion creep rheology; moreover, grain growth and weak-zone healing are greatly impeded by Zener pinning thereby leading to long-lived relic weak zones. The fluid dynamical calculations employ source-sink driven flow as a proxy for convective poloidal flow (upwelling/downwelling and divergent/convergent motion), and the coupling of this flow with non-linear rheological mechanisms excites toroidal or strike-slip motion. The numerical experiments show that pure dislocation-creep rheology, and grain-damage without Zener pinning (as occurs in a single-phase assemblages) permit only weak localization and toroidal flow; however, the full grain-damage with pinning readily allows focussed localization and intense, plate-like toroidal motion and strike-slip deformation. Rapid plate motion changes are also tested with abrupt rotations of the source-sink field after a plate-like configuration is developed; the post-rotation flow and material property fields retain memory of the original configuration for extensive periods, leading to suboptimally aligned plate boundaries (e.g., strike-slip margins non-parallel to plate motion), oblique subduction, and highly localized, weak and long lived acute plate-boundary junctions such as at what is observed at the Aleutian-Kurile intersection. The grain-damage and pinning theory therefore readily satisfies key plate-tectonic metrics of localized toroidal motion and plate-boundary inheritance, and thus provides a predictive theory for the generation of plate tectonics on Earth and other planets. © 2013 Elsevier B.V. Source


Depression and anxiety are more strongly associated with quality of life (QOL) than seizure frequency in several populations with epilepsy. However, QOL is culturally determined and may be influenced by cultural values and norms as well as local policies and resources. The goal of this study is to investigate the impact of neuropsychiatric symptoms and seizure severity on QOL and employment in people with epilepsy living in Jordan. Seizure severity and complications, antiepileptic drug side effects, social stigma, neuropsychiatric symptoms, and mental health (MH-SF36) and physical health (PH-SF36) domains of QOL were assessed in 45 adult patients with epilepsy in a university neurology clinic. Multivariate regression analysis was used to evaluate the relationship between these variables and the quality of life of Jordanians with epilepsy. Neuropsychiatric symptoms, seizure frequency, and history of injury due to seizure were associated with the MH-SF36. However, earlier age of seizure onset, longer duration of epilepsy, unemployment, and history of chronic disease was associated with lower PH-SF36 scores. Furthermore, there were no differences in QOL, neuropsychiatric symptoms, and seizure frequency in Jordanians who were employed versus unemployed in this study. Neuropsychiatric symptoms were significantly associated with mental health-related QOL measures, but not with physically-related QOL measures, in Jordanians with epilepsy. For studies across populations, it is critical to separate mental health from physical health QOL measures. Furthermore, regional differences in culture and policy may more strongly influence employment status than individuals' experiences of epilepsy, neuropsychiatric symptoms, or QOL in some populations. Copyright © 2013. Published by Elsevier Inc. Source


Goldstein D.R.,Yale University
Journals of Gerontology - Series A Biological Sciences and Medical Sciences | Year: 2012

Older people exhibit increased morbidity and mortality after viral infections than younger people. Additionally, vaccines are less protective in older people than in younger people. As the immune system is critical for host defense to viral infections and for vaccine efficacy, the implications are that aging negatively affects immunity. The immune system is broadly categorized into adaptive and innate systems. The innate immune system acts as a first line of defense to pathogen invasion. In this review, I focus on how aging affects the innate immune response to viral infection. © 2011 The Author. Source


Lampert R.,Yale University
Trends in Cardiovascular Medicine | Year: 2016

Stress can trigger both ventricular and atrial arrhythmias, as evidenced by epidemiological, clinical, and laboratory studies, through its impact on autonomic activity. Chronic stress also increases vulnerability to arrhythmias. Novel therapies aimed at decreasing the psychological and physiological response to stress may decrease arrhythmia frequency and improve quality of life. © 2016 Elsevier Inc. Source


Modis Y.,Yale University
Current Opinion in Virology | Year: 2014

Enveloped viruses must fuse their lipid membrane to a cellular membrane to deliver the viral genome into the cytoplasm for replication. Viral envelope proteins catalyze this critical membrane fusion event. They fall into at least three distinct structural classes. Class II fusion proteins have a conserved three-domain architecture and are found in many important viral pathogens. Until 2013, class II proteins had only been found in flaviviruses and alphaviruses. However, in 2013 a class II fusion protein was discovered in the unrelated phlebovirus genus, and two unexpectedly divergent envelope proteins were identified in families that also contain prototypical class II proteins. The structural relationships of newly identified class II proteins, reviewed herein, shift the paradigm for how these proteins evolved. © 2014 Elsevier B.V. Source


Briggs D.E.G.,Yale University | Summons R.E.,Massachusetts Institute of Technology
BioEssays | Year: 2014

The discovery of traces of a blood meal in the abdomen of a 50-million-year-old mosquito reminds us of the insights that the chemistry of fossils can provide. Ancient DNA is the best known fossil molecule. It is less well known that new fossil targets and a growing database of ancient gene sequences are paralleled by discoveries on other classes of organic molecules. New analytical tools, such as the synchrotron, reveal traces of the original composition of arthropod cuticles that are more than 400 my old. Pigments such as melanin are readily fossilized, surviving virtually unaltered for ~200 my. Other biomarkers provide evidence of microbial processes in ancient sediments, and have been used to reveal the presence of demosponges, for example, more than 635 mya, long before their spicules appear in the fossil record. Ancient biomolecules are a powerful complement to fossil remains in revealing the history of life. Ancient biomolecules range from hundreds of thousand-year-old DNA to lipids and structural macromolecules that survive for billions of years. Extracted from fossils and sedimentary rocks, they reveal organism relationships, past environments, and the origin of fossil fuels. In the oldest rocks they may be the only evidence of particular life forms. © 2014 WILEY Periodicals, Inc. Source


Nolen-Hoeksema S.,Yale University
Annual Review of Clinical Psychology | Year: 2012

This review addresses three questions regarding the relationships among gender, emotion regulation, and psychopathology: (a) are there gender differences in emotion regulation strategies, (b) are emotion regulation strategies similarly related to psychopathology in men and women, and (c) do gender differences in emotion regulation strategies account for gender differences in psychopathology? Women report using most emotion regulation strategies more than men do, and emotion regulation strategies are similarly related to psychopathology in women and men. More rumination in women compared to men partially accounts for greater depression and anxiety in women compared to men, while a greater tendency to use alcohol to cope partially accounts for more alcohol misuse in men compared to women. The literature on emotion regulation is likely missing vital information on how men regulate their emotions. I discuss lessons learned and questions raised about the relationships between gender differences in emotion regulation and gender differences in psychopathology. © Copyright ©2012 by Annual Reviews. All rights reserved. Source


Wells D.G.,Yale University
Current Opinion in Cell Biology | Year: 2012

The regulation of protein synthesis in discrete cellular subdomains, or local protein synthesis, has important roles in development as well as brain function. This review will discuss some recent findings that shed new light on mRNA translation regulation and how these layers of regulation may work together to elicit tissue specific and spatially restricted gene expression. © 2012 Elsevier Ltd. Source


Ivancic P.C.,Yale University
European Spine Journal | Year: 2012

Purpose Chronic radicular symptoms have been documented in whiplash patients, potentially caused by cervical neural tissue compression during an automobile rear crash. Our goals were to determine neural space narrowing of the lower cervical spine during simulated rear crashes with whiplash protection system (WHIPS) and active head restraint (AHR) and to compare these data to those obtained with no head restraint (NHR). We extrapolated our results to determine the potential for cord, ganglion, and nerve root compression. Methods Our model, consisting of a human neck specimen within a BioRID II crash dummy, was subjected to simulated rear crashes in a WHIPS seat (n = 6, peak 12.0 g and DV 11.4 kph) or AHR seat and subsequently with NHR (n = 6, peak 11.0 g and DV 10.2 kph with AHR; peak 11.5 g and DV 10.7 kph with NHR). Cervical canal and foraminal narrowing were computed and average peak values statistically compared (P<0.05) between WHIPS, AHR, and NHR. Results Average peak canal and foramen narrowing could not be statistically differentiated between WHIPS, AHR, or NHR. Peak narrowing with WHIPS or AHR was 2.7 mm for canal diameter and 1.6 mm, 2.7 mm, and 5.9 mm2 for foraminal width, height and area, respectively. Conclusions While lower cervical spine cord compression during a rear crash is unlikely in those with normal canal diameters, our results demonstrated foraminal kinematics sufficient to compress spinal ganglia and nerve roots. Future anti-whiplash systems designed to reduce cervical neural space narrowing may lead to reduced radicular symptoms in whiplash patients. © 2011 Springer-Verlag. Source


Androgen deprivation therapy (ADT) is a common treatment for non-metastatic, low-risk prostate cancer, but a potential side effect of ADT is impaired brain functioning. Previous work with functional magnetic resonance imaging (MRI) demonstrated altered prefrontal cortical activations in cognitive control, with undetectable changes in behavioral performance. Given the utility of brain imaging in identifying the potentially deleterious effects of ADT on brain functions, the current study examined the effects of ADT on cerebral structures using high resolution MRI and voxel-based morphometry (VBM). High resolution T1 weighted image of the whole brain were acquired at baseline and six months after ADT for 12 prostate cancer patients and 12 demographically matched non-exposed control participants imaged at the same time points. Brain images were segmented into gray matter, white matter and cerebral ventricles using the VBM toolbox as implemented in Statistical Parametric Mapping 8. Compared to baseline scan, prostate cancer patients undergoing ADT showed decreased gray matter volume in frontopolar cortex, dorsolateral prefrontal cortex and primary motor cortex, whereas the non-exposed control participants did not show such changes. In addition, the decrease in gray matter volume of the primary motor cortex showed a significant correlation with longer reaction time to target detection in a working memory task. ADT can affect cerebral gray matter volumes in prostate cancer patients. If replicated, these results may facilitate future studies of cognitive function and quality of life in men receiving ADT, and can also help clinicians weigh the benefits and risks of hormonal therapy in the treatment of prostate cancer. Source


Woolford Jr. J.L.,Carnegie Mellon University | Baserga S.J.,Yale University
Genetics | Year: 2013

Ribosomes are highly conserved ribonucleoprotein nanomachines that translate information in the genome to create the proteome in all cells. In yeast these complex particles contain four RNAs (.5400 nucleotides) and 79 different proteins. During the past 25 years, studies in yeast have led the way to understanding how these molecules are assembled into ribosomes in vivo. Assembly begins with transcription of ribosomal RNA in the nucleolus, where the RNA then undergoes complex pathways of folding, coupled with nucleotide modification, removal of spacer sequences, and binding to ribosomal proteins. More than 200 assembly factors and 76 small nucleolar RNAs transiently associate with assembling ribosomes, to enable their accurate and efficient construction. Following export of preribosomes from the nucleus to the cytoplasm, they undergo final stages of maturation before entering the pool of functioning ribosomes. Elaborate mechanisms exist to monitor the formation of correct structural and functional neighborhoods within ribosomes and to destroy preribosomes that fail to assemble properly. Studies of yeast ribosome biogenesis provide useful models for ribosomopathies, diseases in humans that result from failure to properly assemble ribosomes. © 2013 by the Genetics Society of America. Source


Garcia-Tsao G.,Yale University | Bosch J.,University of Barcelona
New England Journal of Medicine | Year: 2010

Gastroesophageal varices are present at diagnosis in almost half of patients with cirrhosis, and variceal hemorrhage continues to be a lethal complication of cirrhosis. This review explains the three main challenges in clinical management: primary prophylaxis to prevent a first episode of hemorrhage, the treatment of acute bleeding episodes, and secondary prophylaxis to prevent recurrence of variceal hemorrhage. Copyright © 2010 Massachusetts Medical Society. Source


Solomon L.R.,Yale University
Diabetes Care | Year: 2011

OBJECTIVE - Functional cobalamin (Cbl) deficiency (i.e., high methylmalonic acid [MMA] values despite normal serum Cbl levels) is common in the elderly and associatedwith neuropathy and anemia. Because diabetes is also common in the elderly and diabetic neuropathy resembles that of Cbl deficiency, the role of diabetes in functional Cbl deficiency was explored. RESEARCH DESIGN AND METHODS - A retrospective review was performed of all ambulatory community-dwelling adults with normal renal function evaluated for Cbl deficiency over a 12-year period in a primary care setting. Functional Cbl deficiency was defined as MMA values >250 nmol/L with Cbl levels >400 pg/mL. RESULTS - In nondiabetic subjects, MMA values varied directly with age and inversely with serum Cbl. In diabetic subjects, MMA values also increased with age but did not fall as Cbl levels increased. Thus, when Cbl levels were >400 pg/mL, mean MMA values and the incidence of functional Cbl deficiency were both significantly greater in elderly diabetic subjects (at least 70 years old) than in elderly nondiabetic subjects. Moreover, neuropathy was present in 62% of diabetic subjects with high MMA values and in only 18% of diabetic subjects with normal MMA values. Finally, pharmacologic doses of Cbl improved MMA values and neuropathy in 88 and 86% of evaluable diabetic subjects, respectively. CONCLUSIONS - These observations suggest that functional Cbl deficiency is common in elderly diabetic individuals, is associated with neuropathy, and is responsive to Cbl therapy. A role for oxidative stress in the pathogenesis of functional Cbl deficiency is proposed. © 2011 by the American Diabetes Association. Source


Stergiou A.,Yale University
Physics Letters, Section B: Nuclear, Elementary Particle and High-Energy Physics | Year: 2015

We consider nontrivial critical models in d= 6. +. ε spacetime dimensions with anticommuting scalars transforming under the symplectic group Sp(N). These models are nonunitary, but the couplings are real and all operator dimensions are positive. At large N we can take ε→1 consistently with the loop expansion and thus provide evidence that these theories may be used to define critical models in d= 7. The relation of these theories to critical Sp(N) theories, defined similarly to the well-known critical O(N) theories, is examined, and some similarities are pointed out. © 2015 The Author. Source


Meffre E.,Yale University
Annals of the New York Academy of Sciences | Year: 2011

Patients with primary immunodeficiency (PID) provide rare opportunities to study the impact of specific gene mutations on the regulation of human B cell tolerance. Alterations in B cell receptor and Toll-like receptor signaling pathways result in a defective central checkpoint and a failure to counterselect developing autoreactive B cells in the bone marrow. In contrast, CD40L- and MHC class II-deficient patients only displayed peripheral B cell tolerance defects, suggesting that decreased numbers of regulatory T cells and increased concentration of B cell activating factor (BAFF) may interfere with the peripheral removal of autoreactive B cells. The pathways regulating B cell tolerance identified in PID patients are likely to be affected in patients with rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes who display defective central and peripheral B cell tolerance checkpoints. Indeed, risk alleles encoding variants altering BCR signaling, such as PTPN22 alleles associated with the development of these diseases, interfere with the removal of developing autoreactive B cells. Hence, insights into B cell selection from PID patients are highly relevant to the understanding of the etiology of autoimmune conditions. © 2011 New York Academy of Sciences. Source


Hamilton K.R.,Yale University
Alcoholism, clinical and experimental research | Year: 2012

Hazardous drinking is characterized by decisions to engage in excessive or risky patterns of alcohol consumption. Levels of impulsivity and behavioral approach and inhibition may differ in hazardous drinkers and nonhazardous drinkers. A comparison of the relative levels of dimensions of impulsivity and behavioral inhibition and approach in adult men and women hazardous and nonhazardous drinkers may inform treatment and prevention efforts. In the present research, 466 men and women from a community sample were administered the Alcohol Use Disorders Identification Test (AUDIT), the Behavioral Inhibition System/Behavioral Approach System (BIS/BAS) scale, and the Barratt Impulsiveness Scale, version 11 (BIS-11). Relations among the dimensions of these constructs were examined using multivariate analysis of covariance (MANCOVA), with age and race as covariates. There were main effects of hazardous drinking on all 3 dimensions of impulsivity, the behavioral inhibition system, and the behavioral activation system Reward Responsiveness, and Fun-Seeking components, with hazardous drinkers scoring higher than nonhazardous drinkers. This research provides a better understanding of the manner in which impulsivity and behavioral inhibition and approach tendencies relate to hazardous alcohol use in men and women. The present results have implications for alcohol-related prevention and treatment strategies for adult men and women. Copyright © 2012 by the Research Society on Alcoholism. Source


The seismic structure of large igneous provinces provides unique constraints on the nature of their parental mantle, allowing us to investigate past mantle dynamics from present crustal structure. To exploit this crust-mantle connection, however, it is prerequisite to quantify the uncertainty of a crustal velocity model, as it could suffer from considerable velocity-depth ambiguity. In this contribution, a practical strategy is suggested to estimate the model uncertainty by explicitly exploring the degree of velocity-depth ambiguity in the model space. In addition, wide-angle seismic data collected over the Ontong Java Plateau are revisited to provide a worked example of the new approach. My analysis indicates that the crustal structure of this gigantic plateau is difficult to reconcile with the melting of a pyrolitic mantle, pointing to the possibility of large-scale compositional heterogeneity in the convecting mantle. © 2011 The Author Geophysical Journal International © 2011 RAS. Source


Fletcher J.M.,Yale University
Health Economics | Year: 2010

This paper contributes to the literature on the relationship between adolescent depression and educational attainment in several ways. First, while cross-sectional data are normally used, this paper uses longitudinal data in order to defend against the potential of reverse causality. Second, this is the first paper in the literature to control for sibling-fixed effects in examining the relationship between adolescent depressive symptoms and human capital accumulation. Importantly, this eliminates omitted factors such as family and neighborhood characteristics common to siblings that affect both depressive symptoms and educational attainments (e.g. neighborhood crime, and family resources). Third, this paper examines the effects of both an indicator and scale of depressive symptoms and finds important associations with these depressive symptoms and human capital accumulation. Though the results cannot be given a causal interpretation, the findings show a negative relationship between depressive symptoms and years of schooling. The relationship appears to be driven primarily through increasing the chances of dropping out but may have small impacts on the likelihood of college attendance (conditional on high school graduation). In particular, preferred estimates suggest that a standard deviation increase in depressive symptoms is associated with a 25-30% increase in the likelihood of dropping out. Copyright © 2009 John Wiley & Sons, Ltd. Source


Bracken M.B.,Yale University
Cochrane database of systematic reviews (Online) | Year: 2012

Acute spinal cord injury is a devastating condition typically affecting young people, mostly males. Steroid treatment in the early hours after the injury is aimed at reducing the extent of permanent paralysis during the rest of the patient's life. To review randomized trials of steroids for human acute spinal cord injury. We searched the Cochrane Injuries Group Specialised Register (searched 02 Aug 2011), The Cochrane Central Register of Controlled Trials 2011, issue 3 (The Cochrane Library), MEDLINE (Ovid) 1948 to July Week 3 2011, EMBASE (Ovid) 1974 to 2011 week 17, ISI Web of Science: Science Citation Index Expanded (SCI-EXPANDED) 1970 to Aug 2011, ISI Web of Science: Conference Proceedings Citation Index- Science (CPCI-S) 1990 to Aug 2011 and PubMed [www.ncbi.nlm.nih.gov/sites/entrez/] (searched 04 Aug 2011) for records added to PubMed in the last 90 days). Files of the National Acute Spinal Cord Injury Study (NASCIS) were reviewed (NASCIS was founded in 1977 and has tracked trials in this area since that date). We also searched the reference lists of relevant studies and previously published reviews. All randomized controlled trials of steroid treatment for acute spinal cord injury in any language. One review author extracted data from trial reports. Japanese and French studies were found through NASCIS and additional data (e.g. SDs) were obtained from the original study authors. Eight trials are included in this review, seven used methylprednisolone. Methylprednisolone sodium succinate has been shown to improve neurologic outcome up to one year post-injury if administered within eight hours of injury and in a dose regimen of: bolus 30mg/kg over 15 minutes, with maintenance infusion of 5.4 mg/kg per hour infused for 23 hours. The initial North American trial results were replicated in a Japanese trial but not in the one from France. Data was obtained from the latter studies to permit appropriate meta-analysis of all three trials. This indicated significant recovery in motor function after methylprednisolone therapy, when administration commenced within eight hours of injury. A more recent trial indicates that, if methylprednisolone therapy is given for an additional 24 hours (a total of 48 hours), additional improvement in motor neurologic function and functional status are observed. This is particularly observed if treatment cannot be started until between three to eight hours after injury. The same methylprednisolone therapy has been found effective in whiplash injuries. A modified regimen was found to improve recovery after surgery for lumbar disc disease. The risk of bias was low in the largest methyprednisolne trials. Overall, there was no evidence of significantly increased complications or mortality from the 23 or 48 hour therapy. High-dose methylprednisolone steroid therapy is the only pharmacologic therapy shown to have efficacy in a phase three randomized trial when administered within eight hours of injury. One trial indicates additional benefit by extending the maintenance dose from 24 to 48 hours, if start of treatment must be delayed to between three and eight hours after injury. There is an urgent need for more randomized trials of pharmacologic therapy for acute spinal cord injury. Source


Jetz W.,Yale University | Rubenstein D.R.,Columbia University
Current Biology | Year: 2011

Understanding why organisms as different as amoebas, ants, and birds cooperate remains an important question in evolutionary biology. Although ecology can influence cooperation and conflict within animal societies and has been implicated in species differences in sociality [1], the environmental predictors of sociality across broad geographic and taxonomic scales remain poorly understood [2]. In particular, the importance of temporal variation in selection pressure has been underestimated in most evolutionary studies [3, 4]. Environmental uncertainty resulting from climatic variation is likely to be an important driver of temporal variation in selection pressure and therefore is expected to impact the evolution of behavioral, morphological, and physiological traits, including cooperation [5]. Using a data set of over 95% of the worlds birds, we examine the global geography and environmental, biotic, and historical biogeographic predictors of avian social behavior. We find dramatic spatial variation in social behavior for which environmental and biotic factors - namely, among-year environmental variability in precipitation - are important predictors. Although the clear global biogeographic structure in avian social behavior carries a strong signal of evolutionary history, environmental uncertainty plays an additional key role in explaining the incidence and distribution of avian cooperative breeding behavior. © 2011 Elsevier Ltd. Source


Ague J.J.,Yale University | Nicolescu S.,Yale Peabody Museum of Natural History
Nature Geoscience | Year: 2014

The balance between the subduction of carbonate mineral-bearing rocks into Earth's mantle and the return of CO2 to the atmosphere by volcanic and metamorphic degassing is critical to the carbon cycle. Carbon is thought to be released from subducted rocks mostly by simple devolatilization reactions. However, these reactions will also retain large amounts of carbon within the subducting slab and have difficulty in accounting for the mass of CO2 emitted from volcanic arcs. Carbon release may therefore occur via fluid-induced dissolution of calcium carbonate. Here we use carbonate δ18O and δ13C systematics, combined with analyses of rock and fluid inclusion mineralogy and geochemistry, to investigate the alteration of the exhumed Eocene Cycladic subduction complex on the Syros and Tinos islands, Greece. We find that in marble rocks adjacent to two fluid conduits that were active during subduction, the abundance of calcium carbonate drastically decreases approaching the conduits, whereas silicate minerals increase. Up to 60-90% of the CO2 was released from the rocks - far greater than expected via simple devolatilization reactions. The δ18O of the carbonate minerals is 5-10‰ lighter than is typical for metamorphosed carbonate rocks, implying that isotopically light oxygen was transported by fluid infiltration from the surroundings. We suggest that fluid-mediated carbonate mineral removal, accompanied by silicate mineral precipitation, provides a mechanism for the release of enormous amounts of CO2 from subduction zones. © 2014 Macmillan Publishers Limited. Source


Solomon L.R.,Yale University
European Journal of Clinical Nutrition | Year: 2015

Background/Objective:Functional cobalamin (Cbl; vitamin B12) deficiency (that is, high levels of the Cbl-dependent metabolites, methylmalonic acid (MMA) and homocysteine (HCys), despite normal serum Cbl values) is common in the elderly and is associated with neurocognitive abnormalities, but its cause is unknown. As only reduced Cbls are metabolically active, the possibility that functional Cbl deficiency is associated with disorders having biomarkers indicative of increased oxidative stress (oxidant risks) was considered.Subjects/Methods:A retrospective record review of community-dwelling adults evaluated over a 12-year period for Cbl deficiency in a primary care setting who had serum Cbl values ≥400 pg/ml (n=170).Results:When no oxidant risks were present, older subjects (≥70 years) had higher metabolite values than younger individuals (<70 years). MMA values were even higher in the elderly when one oxidant risk was present and in younger subjects when two or more oxidant risks were present. Even at Cbl levels ≥800 pg/ml, MMA values were increased in 73% of elderly subjects with at least one oxidant risk. HCys values were also higher in both age groups when at least two oxidant risks were present. Cyanocobalamin therapy decreased MMA and HCys values in 86 and 76% of subjects, respectively, with nonresponders more likely to have two or more oxidant risks.Conclusion:Functional Cbl deficiency is associated with disorders marked by increased oxidative stress particularly in the elderly; it occurs even when Cbl levels are high and is not consistently corrected with high-dose cyanocobalamin therapy. Thus, current approaches to recognizing and managing this disorder may be inadequate. © 2015 Macmillan Publishers Limited. Source


Wilson F.P.,Yale University
Clinical Journal of the American Society of Nephrology | Year: 2014

Background and objectives Previous studies in chronic disease states have demonstrated an association between lower urinary creatinine excretion (UCr) and increased mortality, a finding presumed to reflect the effect of low muscle mass on clinical outcomes. Little is known about the relationship between UCr and other measures of body composition in terms of the ability to predict outcomes of interest. Design, setting, participants, & measurements Using data from the Chronic Renal Insufficiency Cohort (CRIC), the relationship between UCr, fat free mass (FFM) as estimated by bioelectrical impedance analysis, and (in a subpopulation) whole-body dual-energy x-ray absorptiometry assessment of appendicular lean mass were characterized. The associations of UCr and FFM with mortality and ESRD were compared using Cox proportional hazards models. Results A total of 3604 CRIC participants (91% of the full CRIC cohort) with both a baseline UCr and FFM measurement were included; of these, 232 had contemporaneous dual-energy x-ray absorptiometry measurements. Participants were recruited between July 2003 and March 2007. UCr and FFM were modestly correlated (rho=0.50; P<0.001),while FFM and appendicular lean mass were highly correlated (rho=0.91; P<0.001).Higher urinary urea nitrogen, black race, younger age, and lower serumcystatin C levelwere all significantly associated with higher UCr. Over a median (interquartile range) of 4.2 (3.1–5.0) years of follow-up, 336 (9.3%) participants died and 510 (14.2%) reached ESRD. Lower UCr was associated with death and ESRD even after adjustment for FFM (adjusted hazard ratio for death per 1 SD higher level of UCr, 0.63 [95% confidence interval, 0.56 to 0.72]; adjusted hazard ratio for ESRD per 1 SD higher level of UCr, 0.70 [95% confidence interval, 0.63 to 0.75]). Conclusions Among a cohort of individuals with CKD, lower UCr is associated with death and ESRD independent of FFM as assessed by bioelectrical impedance analysis. © 2014 by the American Society of Nephrology. Source


Reichow B.,Yale University
Cochrane database of systematic reviews (Online) | Year: 2012

Since autism was first described, major difficulties in social interaction have been a defining feature of individuals with autism spectrum disorders (ASD). Social skills groups are a common intervention for individuals with ASD. Although a frequently recommended practice, the few studies that have addressed the efficacy of social skills groups have shown mixed results. To determine the effectiveness of social skills groups for improving social competence, social communication, and quality of life for people with ASD who are six to 21 years of age. We searched the following databases in December 2011: CENTRAL (2011 Issue 4), MEDLINE (1948 to November Week 3, 2011), EMBASE (1980 to Week 50, 2011), PsycINFO (1887 to December Week 2, 2011), CINAHL (1937 to current), ERIC (1966 to current), Sociological Abstracts (1952 to current), OCLC WorldCat (12 December 2011), Social Science Citation Index (1970 to 16 December 2011), and the metaRegister of Controlled Trials (20 December 2011). We also searched the reference lists of published papers. Randomized control trials (RCTs) comparing treatment (social skills groups) with a control group who were not receiving the treatment for participants aged six to 21 years with ASD. The control group could be no intervention, wait list, or treatment as usual. Outcomes sought were standardized measures of social competence, social communication, quality of life, emotion recognition, and any other specific behaviors. Two review authors independently selected and appraised studies for inclusion and assessed the risk of bias in each included study. All outcome data were continuous and standardized mean difference effect sizes (ES) with small sample correction were calculated. We conducted random-effects meta-analysis where possible. We included five RCTs evaluating the effects of social skills groups in 196 participants with ASD aged 6 to 21 years old. The results show there is some evidence that social skills groups improve overall social competence (ES = 0.47, 95% confidence interval (CI) 0.16 to 0.78, P = 0.003) and friendship quality (ES = 0.41, 95% CI 0.02 to 0.81, P = 0.04) for this population. No differences were found between treatment and control groups in relation to emotional recognition (ES = 0.34, 95% CI -0.20 to 0.88, P = 0.21) assessed in two studies or social communication as related to the understanding of idioms (ES = 0.05, 95% CI -0.63 to 0.72, P = 0.89), which was assessed in only one study. Two additional quality of life outcomes were evaluated, with results of single studies suggesting decreases in loneliness (ES = -0.66, 95% CI -1.15 to -0.17) but no effect on child or parental depression. No adverse events were reported.Given the nature of the intervention and the selected outcome measures, the risk of performance and detection bias are high. There is limited generalizability from the studies as they were all conducted in the US; they focused mainly on children aged 7 to 12, and the participants were all of average or above average intelligence. There is some evidence that social skills groups can improve social competence for some children and adolescents with ASD. More research is needed to draw more robust conclusions, especially with respect to improvements in quality of life. Source


Jorgensen W.L.,Yale University
Angewandte Chemie - International Edition | Year: 2012

Modus operandi: There is increased interest and activity in drug discovery at universities and other non-profit organizations. The essay addresses challenges associated with progress in this area. Lead optimization and preclinical testing are identified as key bottlenecks. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Source


Katz D.L.,Yale University
International Journal of Obesity | Year: 2011

Childhood obesity rates have risen alarmingly for decades, and although recent data suggest a possible plateau, obesity is seen in ever younger children, and is increasingly severe. The proximal cause of obesity is energy imbalance; the root cause is modern living. Throughout most of human history, calories were relatively scarce and hard to get, and physical activity unavoidable. We have devised a modern world, in which physical activity is scarce and hard to get and calories are unavoidable. Although both sides of the energy balance equation matter, forced to pick sides, we should prioritize forks over feet for weight control based on both science and sense. The modern world makes it very easy to out-eat exercise, and nearly impossible to out-exercise excessive eating. © 2011 Macmillan Publishers Limited All rights reserved. Source


Neumeister V.M.,Yale University
Clinical Biochemistry | Year: 2014

Biospecimen science has recognized the importance of tissue quality for accurate molecular and biomarker analysis and efforts are made to standardize tissue procurement, processing and storage conditions of tissue samples. At the same time the field has emphasized the lack of standardization of processes between different laboratories, the variability inherent in the analytical phase and the lack of control over the pre-analytical phase of tissue processing. The problem extends back into tissue samples in biorepositories, which are often decades old and where documentation about tissue processing might not be available. This review highlights pre-analytical variations in tissue handling, processing, fixation and storage and emphasizes the effects of these variables on nucleic acids and proteins in harvested tissue. Finally current tools for quality control regarding molecular or biomarker analysis are summarized and discussed. © 2014 The Canadian Society of Clinical Chemists. Source


Broderick N.A.,Yale University
Frontiers in Immunology | Year: 2015

Historically, the digestive and immune systems were viewed and studied as separate entities. However, there are remarkable similarities and shared functions in both nutrient acquisition and host defense. Here, I propose a common origin for both systems. This association provides a new prism for viewing the emergence and evolution of host defense mechanisms. © 2015 Broderick. Source


Lal M.,Karolinska Institutet | Caplan M.,Yale University
Physiology | Year: 2011

Intramembrane cleavage of transmembrane proteins is a fundamental cellular process. Several enzymes capable of releasing domains of integral membrane proteins have been described. Transmembrane protein proteo-lytic cleavage is regulated and involved not only in degrading membrane spanning segments but also in generating messengers that elicit biological responses. This review examines the role of the released functional protein domain in signaling mechanisms regulating an array of cellular and physiological processes. © 2011 Int. Union Physiol. Sci./Am. Physiol. Soc. Source


The lack of quality-oriented organizational climates is partly responsible for deficiencies in patient-centered care and poor quality more broadly. To improve their quality-oriented climates, several organizations have joined quality improvement collaboratives. The effectiveness of this approach is unknown. To evaluate the impact of collaborative membership on organizational climate for quality and service quality. Twenty-one clinics, 4 of which participated in a collaborative sponsored by the Institute for Clinical Systems Improvement. Pre-post design. Preassessments occurred 2 months before the collaborative began in January 2009. Postassessments of service quality and climate occurred about 6 months and 1 year, respectively, after the collaborative ended in January 2010. We surveyed clinic employees (eg, physicians, nurses, receptionists, etc.) about the organizational climate and patients about service quality. Prioritization of quality care, high-quality staff relationships, and open communication as indicators of quality-oriented climate and timeliness of care, staff helpfulness, doctor-patient communication, rating of doctor, and willingness to recommend doctor's office as indicators of service quality. There was no significant effect of collaborative membership on quality-oriented climate and mixed effects on service quality. Doctors' ratings improved significantly more in intervention clinics than in control clinics, staff helpfulness improved less, and timeliness of care declined more. Ratings of doctor-patient communication and willingness to recommend doctor were not significantly different between intervention and comparison clinics. Membership in the collaborative provided no significant advantage for improving quality-oriented climate and had equivocal effects on service quality. Source


Peters E.N.,Yale University
Experimental and clinical psychopharmacology | Year: 2013

Delay discounting is an index of impulsive decision-making and reflects an individual's preference for smaller immediate rewards relative to larger delayed rewards. Multiple studies have indicated comparatively high rates of discounting among tobacco, alcohol, cocaine, and other types of drug users, but few studies have examined discounting among marijuana users. This report is a secondary analysis of data from a clinical trial that randomized adults with marijuana dependence to receive one of four treatments that involved contingency management (CM) and cognitive-behavioral therapy interventions. Delay discounting was assessed with the Experiential Discounting Task (Reynolds & Schiffbauer, 2004) at pretreatment in 93 participants and at 12 weeks posttreatment in 61 participants. Results indicated that higher pretreatment delay discounting (i.e., more impulsive decision-making) significantly correlated with lower readiness to change marijuana use (r = -0.22, p = .03) and greater number of days of cigarette use (r = .21, p = .04). Pretreatment discounting was not associated with any marijuana treatment outcomes. CM treatment significantly interacted with time to predict change in delay discounting from pre- to posttreatment; participants who received CM did not change their discounting over time, whereas those who did not receive CM significantly increased their discounting from pre- to posttreatment. In this sample of court-referred young adults receiving treatment for marijuana dependence, delay discounting was not strongly related to treatment outcomes, but there was some evidence that CM may protect against time-related increases in discounting. (c) 2013 APA, all rights reserved. Source


Hirschi K.K.,Yale University
Blood | Year: 2012

During embryonic development, multilineage HSCs/progenitor cells are derived from specialized endothelial cells, termed hemogenic endothelium, within the yolk sac, placenta, and aorta. Whether hemogenic endothelial cells contribute to blood cell development at other sites of definitive hematopoiesis, such as in the fetal liver and fetal bone marrow, is not known. Also unknown is whether such cells exist within the vasculature of adult bone marrow and generate hematopoietic stem cells after birth. These issues and their clinical relevance are discussed herein. © 2012 by The American Society of Hematology. Source


Gao B.,McMaster University | Gao B.,Yale University | Gupta R.S.,McMaster University
Microbiology and Molecular Biology Reviews | Year: 2012

The phylum Actinobacteria harbors many important human pathogens and also provides one of the richest sources of natural products, including numerous antibiotics and other compounds of biotechnological interest. Thus, a reliable phylogeny of this large phylum and the means to accurately identify its different constituent groups are of much interest. Detailed phylogenetic and comparative analyses of >150 actinobacterial genomes reported here form the basis for achieving these objectives. In phylogenetic trees based upon 35 conserved proteins, most of the main groups of Actinobacteria as well as a number of their superageneric clades are resolved. We also describe large numbers of molecular markers consisting of conserved signature indels in protein sequences and whole proteins that are specific for either all Actinobacteria or their different clades (viz., orders, families, genera, and subgenera) at various taxonomic levels. These signatures independently support the existence of different phylogenetic clades, and based upon them, it is now possible to delimit the phylum Actinobacteria (excluding Coriobacteriia) and most of its major groups in clear molecular terms. The species distribution patterns of these markers also provide important information regarding the interrelationships among different main orders of Actinobacteria. The identified molecular markers, in addition to enabling the development of a stable and reliable phylogenetic framework for this phylum, also provide novel and powerful means for the identification of different groups of Actinobacteria in diverse environments. Genetic and biochemical studies on these Actinobacteria-specific markers should lead to the discovery of novel biochemical and/or other properties that are unique to different groups of Actinobacteria. Copyright © 2012, American Society for Microbiology. All Rights Reserved. Source


Nordhaus W.,Yale University
Energy Economics | Year: 2011

What is the best strategy to encourage research and development on new energy technologies in a market economy? What steps can ensure a rapid and efficient transition to an economy that has much lower net carbon emissions? This paper shows that, under limited conditions, a necessary and sufficient condition for an appropriate innovational environment is a universal, credible, and durable price on carbon emissions. Such a price would balance the marginal damages from carbon emissions against the marginal costs of abating emissions; it should not contain a correction factor for inducing technological change. This result, which the paper calls "price fundamentalism," applies principally to the market-oriented part of research and innovation. It is subject to qualifications regarding the efficacy of intellectual property protection and the proper level of carbon prices, and it applies primarily to market sectors. The role of appropriate prices on emissions is a central part of public policies to encourage technologies to combat global warming. © 2010 Elsevier B.V. Source


Selway K.,University of Adelaide | Selway K.,Yale University
Surveys in Geophysics | Year: 2014

Magnetotelluric (MT) data can image the electrical resistivity of the entire lithospheric column and are therefore one of the most important data sources for understanding the structure, composition and evolution of the lithosphere. However, interpretations of MT data from stable lithosphere are often ambiguous. Recent results from mineral physics studies show that, from the mid-crust to the base of the lithosphere, temperature and the hydrogen content of nominally anhydrous minerals are the two most important controls on electrical conductivity. Graphite films on mineral grain boundaries also enhance conductivity but are stable only to the uppermost mantle. The thermal profile of most stable lithosphere can be well constrained, so the two important unknowns that can affect the conductivity of a lithospheric section are hydrogen content and graphite films. The presence of both of these factors is controlled by the geological history of the lithosphere. Hydrogen in nominally anhydrous minerals behaves as an incompatible element and is preferentially removed during melting or high-temperature tectonothermal events. Grain-boundary graphite films are only stable to ~900 °C so they are also destroyed by high-temperature events. Conversely, tectonic events that enrich the lithosphere in incompatible elements, such as interaction with fluids from a subducting slab or a plume, can introduce both hydrogen and carbon into the lithosphere and therefore increase its electrical conductivity. Case studies of MT results from central Australia and the Slave Craton in Canada suggest that electrical conductivity can act as a proxy for the level of enrichment in incompatible elements of the lithosphere. © 2013 Springer Science+Business Media Dordrecht. Source


Dranoff J.A.,Yale University | Wells R.G.,University of Pennsylvania
Hepatology | Year: 2010

Portal fibroblasts are an important yet often overlooked nonparenchymal cell population in the liver. They are distinct from hepatic stellate cells, yet like stellate cells differentiate in the setting of chronic injury to fibrogenic myofibroblasts, playing an important role in collagen production in the fibrotic liver. Portal fibroblasts (PFs) are located adjacent to bile duct epithelia and thus play a particularly significant role in biliary fibrosis. New data suggest that they may also have key functions independent of fibrogenesis. This review addresses the definition and characteristics of PFs as well as their signaling pathways, interactions with the biliary epithelium, and contributions to liver pathobiology. Conclusion: PFs are an important and multifunctional nonparenchymal cell population in need of further study. Copyright © 2010 by the American Association for the Study of Liver Diseases. Source


Zhang Z.-R.,U.S. National Institutes of Health | Zhang Z.-R.,Yale University | Bonifacino J.S.,U.S. National Institutes of Health | Hegde R.S.,University of Cambridge
Cell | Year: 2013

Newly synthesized membrane proteins are queried by ubiquitin ligase complexes and triaged between degradative and nondegradative fates. The mechanisms that convert modest differences in substrate-ligase interactions into decisive outcomes of ubiquitination are not well understood. Here, we reconstitute membrane protein recognition and ubiquitination in liposomes using purified components from a viral-mediated degradation pathway. We find that substrate-ligase interactions in the membrane directly influence processivity of ubiquitin attachment to modulate polyubiquitination. Unexpectedly, differential processivity alone could not explain the differential fates in cultured cells of degraded and nondegraded clients. Both computational and experimental analyses identified continuous deubiquitination as a prerequisite for maximal substrate discrimination. Deubiquitinases reduce polyubiquitin dwell times preferentially on clients that dissociate more rapidly from the ligase. This explains how small differences in substrate-ligase interaction can be amplified into larger differences in net degradation. These results provide a conceptual framework for substrate discrimination during membrane protein quality control. © 2013 The Authors. Source


Ruger J.P.,Yale University
Journal of Epidemiology and Community Health | Year: 2012

Background: With the exception of key 'proven successes' in global health, the current regime of global health governance can be understood as transnational and national actors pursuing their own interests under a rational actor model of international cooperation, which fails to provide sufficient justification for an obligation to assist in meeting the health needs of others. An ethical commitment to providing all with the ability to be healthy is required. Methods: This article develops select components of an alternative model of shared health governance (SHG), which aims to provide a 'road map,' 'focal points' and 'the glue' among various global health actors to better effectuate cooperation on universal ethical principles for an alternative global health equilibrium. Key features of SHG include public moral norms as shared authoritative standards; ethical commitments, shared goals and role allocation; shared sovereignty and constitutional commitments; legitimacy and accountability; country-level attention to international health relations. Results: A framework of social agreement based on 'overlapping consensus' is contrasted against one based on self-interested political bargaining. A global health constitution delineating duties and obligations of global health actors and a global institute of health and medicine for holding actors responsible are proposed. Indicators for empirical assessment of select SHG principles are described. Conclusion: Global health actors, including states, must work together to correct and avert global health injustices through a framework of SHG based on shared ethical commitments. Source


Rabinowitz P.,Yale University | Conti L.,Global One Health Solutions
Annual Review of Public Health | Year: 2013

In the face of growing world human and animal populations and rapid environmental change, the linkages between human, animal, and environmental health are becoming more evident. Because animals and humans have shared risk to health from changing environments, it seems logical to expand the perspective of public health beyond a single species to detect and manage emerging public health threats. Mitigating the effects of climate change, emerging pathogens, toxicant releases, and changes in the built environment requires a retooling of global public health resources and capabilities across multiple species. Furthermore, human and animal health professionals must overcome specific barriers to interprofessional collaboration to implement needed health strategies. This review outlines the relationships between human, animal, and ecosystem health and the public health challenges and opportunities that these links present. © 2013 by Annual Reviews. All rights reserved. Source


Solomon L.R.,Yale University
Journal of the American Geriatrics Society | Year: 2013

To determine whether high serum folate levels contribute to metabolite changes in elderly subjects with normal cobalamin levels. Case series. Outpatient clinic at a university-based staff model health maintenance organization. Two hundred thirty-three ambulatory individuals without diabetes mellitus with normal renal function and normal cobalamin levels evaluated for cobalamin deficiency. Cobalamin, serum folate, methylmalonic acid (MMA), and homocysteine. Older individuals (≥60) with low-normal cobalamin levels (201-300 pg/mL) had higher MMA and lower homocysteine levels when serum folate levels were high (>20 ng/mL) than when serum folate levels were normal (P < .02), but serum folate levels within the normal range were not a determinant of either metabolite. In younger subjects with low-normal cobalamin levels, high serum folate levels were not associated with significant differences in either metabolite. At mid-normal cobalamin levels (301-600 pg/mL), high serum folate levels were associated with lower homocysteine levels in older adults (P < .001) but not with differences in MMA in either age group. Cobalamin therapy decreased or normalized MMA and homocysteine in 89% or more of participants even at pretherapy cobalamin levels greater than 600 pg/mL. High serum folate levels are associated with higher MMA levels when cobalamin levels are low-normal, and this effect is age dependent, not progressive within the normal serum folate range (suggesting a threshold effect), and reversed by cobalamin therapy. Because MMA may be neurotoxic, these findings suggest caution in the use of folic acid supplements in elderly adults. © 2013, Copyright the Author Journal compilation © 2013, The American Geriatrics Society. Source


Walther T.C.,Yale University | Farese R.V.,University of California at San Francisco
Annual Review of Biochemistry | Year: 2012

Among organelles, lipid droplets (LDs) uniquely constitute a hydrophobic phase in the aqueous environment of the cytosol. Their hydrophobic core of neutral lipids stores metabolic energy and membrane components, making LDs hubs for lipid metabolism. In addition, LDs are implicated in a number of other cellular functions, ranging from protein storage and degradation to viral replication. These processes are functionally linked to many physiological and pathological conditions, including obesity and related metabolic diseases. Despite their important functions and nearly ubiquitous presence in cells, many aspects of LD biology are unknown. In the past few years, the pace of LD investigation has increased, providing new insights. Here, we review the current knowledge of LD cell biology and its translation to physiology. © 2012 by Annual Reviews. All rights reserved. Source


Sinha R.,Yale University
Alcohol Research: Current Reviews | Year: 2012

Empirical findings from human laboratory and brain-imaging studies are consistentwith clinical observations and indicate that chronic alcohol-related dysfunction inemotional and stress responses plays a role in motivation to consume alcohol inpeople with alcohol use disorders. Recent findings on differences in stress responsivityin alcohol-dependent versus nondependent social drinkers demonstrate alterations instress pathways that partially may explain the significant contribution of stress-relatedmechanisms on craving and relapse susceptibility. These findings have significantimplications for clinical practice, including (1) the development of novel brain andstress biologyrelated measures of relapse risk that could serve as biomarkers toidentify those most at risk of alcohol relapse during early recovery from alcoholism; and (2) the development of novel interventions that target stress-related effects on themotivation to drink alcohol and on relapse outcomese. Source


Iwasaki A.,Yale University
Immunity | Year: 2012

In contrast to the extraordinary body of knowledge gained over the past three decades on the virology, pathogenesis, and immunology of HIV-1 infection, innate sensors that detect HIV-1 had remained elusive until recently. By virtue of integration, retroviridae makes up a substantial portion of our genome. Thus, immune strategies that deal with endogenous retroviruses are, by necessity, those of self-preservation and not of virus elimination. Some of the principles of such strategies may also apply for defense against exogenous retroviruses including HIV-1. Here, I highlight several sensors that have recently been revealed to be capable of recognizing distinct features of HIV-1 infection, while taking into account the host-retrovirus relationship that converges on avoiding pathogenic inflammatory consequences. © 2012 Elsevier Inc. Source


Bhandari V.,Yale University
Clinics in Perinatology | Year: 2012

Multiple randomized controlled trials have suggested that nasal intermittent positive pressure ventilation, compared with nasal continuous airway pressure, prevents extubation failure and may decrease bronchopulmonary dysplasia. This article summarizes these studies and suggests strategies for the use of nasal intermittent positive pressure ventilation in neonates. © 2012 Elsevier Inc. Source


Craft J.E.,Yale University
Nature Reviews Rheumatology | Year: 2012

Follicular helper T (T FH) cells are essential for B-cell maturation and immunoglobulin production after immunization with thymus-dependent antigens. Nevertheless, the development and function of T FH cells have been less clearly defined than classic CD4 + effector T-cell subsets, including T-helper-1 (T H 1), T H 2 and T H 17 cells. As such, our understanding of the genesis of T FH cells in humans and their role in the development of autoimmunity remains incomplete. However, evidence from animal models of systemic lupus erythematosus (SLE) and patients with systemic autoimmune diseases suggests that these cells are necessary for pathogenic autoantibody production, in a manner analogous to their role in promotion of B-cell maturation during normal immune responses. In this Review, I discuss the findings that have increased our knowledge of T FH -cell development and function in normal and aberrant immune responses. Such information might improve our understanding of autoimmune diseases, such as SLE, and highlights the potential of T FH cells as therapeutic targets in these diseases. © 2012 Macmillan Publishers Limited. Source


Li F.,Yale University
Journal of the American Chemical Society | Year: 2014

SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins mediate fusion by pulling biological membranes together via a zippering mechanism. Recent biophysical studies have shown that t- and v-SNAREs can assemble in multiple stages from the N-termini toward the C-termini. Here we show that functionally, membrane fusion requires a sequential, two-step folding pathway and assign specific and distinct functions for each step. First, the N-terminal domain (NTD) of the v-SNARE docks to the t-SNARE, which leads to a conformational rearrangement into an activated half-zippered SNARE complex. This partially assembled SNARE complex locks the C-terminal (CTD) portion of the t-SNARE into the same structure as in the postfusion 4-helix bundle, thereby creating the binding site for the CTD of the v-SNARE and enabling fusion. Then zippering of the remaining CTD, the membrane-proximal linker (LD), and transmembrane (TMD) domains is required and sufficient to trigger fusion. This intrinsic property of the SNAREs fits well with the action of physiologically vital regulators such as complexin. We also report that NTD assembly is the rate-limiting step. Our findings provide a refined framework for delineating the molecular mechanism of SNARE-mediated membrane fusion and action of regulatory proteins. Source


Dimaio D.,Yale University
Annual Review of Microbiology | Year: 2014

Many viruses encode short transmembrane proteins that play vital roles in virus replication or virulence. Because many of these proteins are less than 50 amino acids long and not homologous to cellular proteins, their open reading frames were often overlooked during the initial annotation of viral genomes. Some of these proteins oligomerize in membranes and form ion channels. Other miniproteins bind to cellular transmembrane proteins and modulate their activity, whereas still others have an unknown mechanism of action. Based on the underlying principles of transmembrane miniprotein structure, it is possible to build artificial small transmembrane proteins that modulate a variety of biological processes. These findings suggest that short transmembrane proteins provide a versatile mechanism to regulate a wide range of cellular activities, and we speculate that cells also express many similar proteins that have not yet been discovered. Copyright © 2014 by Annual Reviews. All rights reserved. Source


Johnson K.M.,Yale University | Dowe D.A.,Atlantic Medical Imaging
Journal of the American College of Cardiology | Year: 2014

Background Accurate assignment of statin therapy is a major public health issue. Objectives The American Heart Association and the American College of Cardiology released a new guideline on the assessment of cardiovascular risk (GACR) to replace the 2001 National Cholesterol Education Program (NCEP) Adult Treatment Panel III recommendations. The aim of this study was to determine which method more accurately assigns statins to patients with features of coronary imaging known to have predictive value for cardiovascular events and whether more patients would be assigned to statins under the new method. Methods The burden of coronary atherosclerosis on computed tomography angiography was measured in several ways on the basis of a 16-segment model. Whether to assign a given patient to statin therapy was compared between the NCEP and GACR guidelines. Results A total of 3,076 subjects were studied (65.3% men, mean age 55.4 ± 10.3 years, mean age of women 58.9 ± 10.3 years). The probability of prescribing statins rose sharply with increasing plaque burden under the GACR compared with the NCEP guideline. Under the NCEP guideline, 59% of patients with â 50% stenosis of the left main coronary artery and 40% of patients with â 50% stenosis of other branches would not have been treated. The comparable results for the GACR were 19% and 10%. The use of low-density lipoprotein targets seriously degraded the accuracy of the NCEP guideline for statin assignment. The proportion of patients assigned to statin therapy was 15% higher under the GACR. Conclusions The new American Heart Association/American College of Cardiology guideline matches statin assignment to total plaque burden better than the older guidelines, with only a modest increase in the number of patients who were assigned statins. © 2014 by the American College of Cardiology Foundation. Source


Hammarlund M.,Yale University | Jin Y.,Howard Hughes Medical Institute
Current Opinion in Neurobiology | Year: 2014

Single axon transection by laser surgery has made Caenorhabditis elegans a new model for axon regeneration. Multiple conserved molecular signaling modules have been discovered through powerful genetic screening. In vivo imaging with single cell and axon resolution has revealed unprecedented cellular dynamics in regenerating axons. Information from C. elegans has greatly expanded our knowledge of the molecular and cellular mechanisms of axon regeneration. © 2014 Elsevier Ltd. Source


Although health is generally believed to improve with higher wealth, research on HIV in sub-Saharan Africa has shown otherwise. Whereas researchers and advocates have frequently advanced poverty as a social determinant that can help to explain sub-Saharan Africa's disproportionate burden of HIV infection, recent evidence from population surveys suggests that HIV infection is higher among wealthier individuals. Furthermore, wealthier countries in Africa have experienced the fastest growing epidemics. Some researchers have theorized that inequality in wealth may be more important than absolute wealth in explaining why some countries have higher rates of infection and rapidly increasing epidemics. Studies taking a longitudinal approach have further suggested a dynamic process whereby wealth initially increases risk for HIV acquisition and later becomes protective. Prior studies, conducted exclusively at either the individual or the country level, have neither attempted to disentangle the effects of absolute and relative wealth on HIV infection nor to look simultaneously at different levels of analysis within countries at different stages in their epidemics. The current study used micro-, meso- and macro-level data from Demographic and Health Surveys (DHS) across 170 regions within sixteen countries in sub-Saharan Africa to test the hypothesis that socioeconomic inequality, adjusted for absolute wealth, is associated with greater risk of HIV infection. These analyses reveal that inequality trumps wealth: living in a region with greater inequality in wealth was significantly associated with increased individual risk of HIV infection, net of absolute wealth. The findings also reveal a paradox that supports a dynamic interpretation of epidemic trends: in wealthier regions/countries, individuals with less wealth were more likely to be infected with HIV, whereas in poorer regions/countries, individuals with more wealth were more likely to be infected with HIV. These findings add additional nuance to existing literature on the relationship between HIV and socioeconomic status. © 2012 Cambridge University Press. Source


Duman R.S.,Yale University
Dialogues in Clinical Neuroscience | Year: 2014

Despite the complexity and heterogeneity of mood disorders, basic and clinical research studies have begun to elucidate the pathophysiology of depression and to identify rapid, efficacious antidepressant agents. Stress and depression are associated with neuronal atrophy, characterized by loss of synaptic connections in key cortical and limbic brain regions implicated in depression. This is thought to occur in part via decreased expression and function of growth factors, such as brain-derived neurotrophic factor (BDNF), in the prefrontal cortex (PFC) and hippocampus. These structural alterations are difficult to reverse with typical antidepressants. However, recent studies demonstrate that ketamine, an N-methyl-Daspartate (NMDA) receptor antagonist that produces rapid antidepressant actions in treatment-resistant depressed patients, rapidly increases spine synapses in the PFC and reverses the deficits caused by chronic stress. This is thought to occur by disinhibition of glutamate transmission, resulting in a rapid but transient burst of glutamate, followed by an increase in BDNF release and activation of downstream signaling pathways that stimulate synapse formation. Recent work demonstrates that the rapid-acting antidepressant effects of scopolamine, a muscarinic receptor antagonist, are also associated with increased glutamate transmission and synapse formation. These findings have resulted in testing and identification of additional targets and agents that influence glutamate transmission and have rapid antidepressant actions in rodent models and in clinical trials. Together these studies have created tremendous excitement and hope for a new generation of rapid, efficacious antidepressants. © 2014, AICH - Servier Research Group. Source


Kubes P.,University of Calgary | Mehal W.Z.,Yale University
Gastroenterology | Year: 2012

Inflammation In the absence of pathogens occurs in all tissues in response to a wide range of stimuli that cause tissue stress and injury. Such sterile inflammation (SI) is a key process in drug-induced liver injury, nonalcoholic steatohepatitis, and alcoholic steatohepatitis and is a major determinant of fibrosis and carcinogenesis. In SI, endogenous damage-associated molecular patterns (DAMPS), which are usually hidden from the extracellular environment, are released on tissue injury and activate receptors on immune cells. More than 20 such DAMPS have been identified and activate cellular pattern recognition receptors, which were originally identified as sensors of pathogen-associated molecular patterns. Activation of pattern recognition receptors by DAMPS results in a wide range of immune responses, including production of proinflammatory cytokines and localization of immune cells to the site of injury. DAMPS result in the assembly of a cytosolic protein complex termed the inflammasome, which activates the serine protease caspase-1, resulting in activation and secretion of interleukin-1β and other cytokines. SI-driven liver diseases are responsible for the majority of liver pathology in industrially developed countries and lack specific therapy. Identification of DAMPS, their receptors, signaling pathways, and cytokines now provides a wide range of therapeutic targets for which many antagonists are already available. © 2012 AGA Institute. Source


Schwab M.E.,University of Zurich | Strittmatter S.M.,Yale University
Current Opinion in Neurobiology | Year: 2014

The expression of Nogo-A and the receptor NgR1 limits the recovery of adult mammals from central nervous system injury. Multiple studies have demonstrated efficacy from targeting this pathway for functional recovery and neural repair after spinal cord trauma, ischemic stroke, optic nerve injury and models of multiple sclerosis. Recent molecular studies have added S1PR2 as a receptor for the amino terminal domain of Nogo-A, and have demonstrated shared components for Nogo-A and CSPG signaling as well as novel Nogo antagonists. It has been recognized that neural repair involves plasticity, sprouting and regeneration. A physiologic role for Nogo-A and NgR1 has been documented in the restriction of experience-dependent plasticity with maturity, and the stability of synaptic, dendritic and axonal anatomy. © 2014 Elsevier Ltd. Source


Kupfer G.M.,Yale University
Yale Journal of Biology and Medicine | Year: 2013

Fanconi anemia (FA) is a fascinating, rare genetic disorder marked by congenital defects, bone marrow failure, and cancer susceptibility. Research in recent years has led to the elucidation of FA as a DNA repair disorder and involved multiple pathways as well as having wide applicability to common cancers, including breast, ovarian, and head and neck. This review will describe the clinical aspects of FA as well as the current state of its molecular pathophysiology. In particular, work from the Kupfer laboratory will be described that demonstrates how the FA pathway interacts with multiple DNA repair pathways, including the mismatch repair system and signal transduction pathway of the DNA damage response. © 2013, Yale Journal of Biology and Medicine. Source


Manuelidis L.,Yale University
Virulence | Year: 2013

Transmissible encephalopathies (TSEs) are believed by many to arise by spontaneous conversion of host prion protein (PrP) into an infectious amyloid (PrP-res, PrPSc) without nucleic acid. Many TSE agents reside in the environment, with infection controlled by public health measures. These include the disappearance of kuru with the cessation of ritual cannibalism, the dramatic reduction of epidemic bovine encephalopathy (BSE) by removal of contaminated feed, and the lack of endemic scrapie in geographically isolated Australian sheep with susceptible PrP genotypes. While prion protein modeling has engendered an intense focus on common types of protein misfolding and amyloid formation in diverse organisms and diseases, the biological characteristics of infectious TSE agents, and their recognition by the host as foreign entities, raises several fundamental new directions for fruitful investigation such as: (1) unrecognized microbial agents in the environmental metagenome that may cause latent neurodegenerative disease, (2) the evolutionary social and protective functions of different amyloid proteins in diverse organisms from bacteria to mammals, and (3) amyloid formation as a beneficial innate immune response to stress (infectious and non-infectious). This innate process however, once initiated, can become unstoppable in accelerated neuronal aging. © 2013 Landes Bioscience. Source


Rizzolo L.J.,Yale University
Experimental Eye Research | Year: 2014

The principal function of an epithelium is to form a dynamic barrier that regulates movement between body compartments. Each epithelium is specialized with barrier functions that are specific for the tissues it serves. The apical surface commonly faces a lumen, but the retinal pigment epithelium (RPE) appears to be unique by a facing solid tissue, the sensory retina. Nonetheless, there exists a thin (subretinal) space that can become fluid filled during pathology. RPE separates the subretinal space from the blood supply of the outer retina, thereby forming the outer blood-retinal barrier. The intricate interaction between the RPE and sensory retina presents challenges for learning how accurately culture models reflect native behavior. The challenge is heightened by findings that detail the variation of RPE barrier proteins both among species and at different stages of the life cycle. Among the striking differences is the expression of claudin family members. Claudins are the tight junction proteins that regulate ion diffusion across the spaces that lie between the cells of a monolayer. Claudin expression by RPE varies with species and life-stage, which implies functional differences among commonly used animal models. Investigators have turned to transcriptomics to supplement functional studies when comparing native and cultured tissue. The most detailed studies of the outer blood-retinal barrier have focused on human RPE with transcriptome and functional studies reported for human fetal, adult, and stem-cell derived RPE. © 2014 Elsevier Ltd. Source


Selemon L.D.,Yale University
Translational psychiatry | Year: 2013

Adolescent brain maturation is characterized by the emergence of executive function mediated by the prefrontal cortex, e.g., goal planning, inhibition of impulsive behavior and set shifting. Synaptic pruning of excitatory contacts is the signature morphologic event of late brain maturation during adolescence. Mounting evidence suggests that glutamate receptor-mediated synaptic plasticity, in particular long-term depression (LTD), is important for elimination of synaptic contacts in brain development. This review examines the possibility (1) that LTD mechanisms are enhanced in the prefrontal cortex during adolescence due to ongoing synaptic pruning in this late developing cortex and (2) that enhanced synaptic plasticity in the prefrontal cortex represents a key molecular substrate underlying the critical period for maturation of executive function. Molecular sites of interaction between environmental factors, such as alcohol and stress, and glutamate receptor mediated plasticity are considered. The accentuated negative impact of these factors during adolescence may be due in part to interference with LTD mechanisms that refine prefrontal cortical circuitry and when disrupted derail normal maturation of executive function. Diminished prefrontal cortical control over risk-taking behavior could further exacerbate negative outcomes associated with these behaviors, as for example addiction and depression. Greater insight into the neurobiology of the adolescent brain is needed to fully understand the molecular basis for heightened vulnerability during adolescence to the injurious effects of substance abuse and stress. Source


Targeted cancer therapies, although often effective, have limited utility owing to preexisting primary or acquired secondary resistance. Consequently, agents are sometimes used in combination to simultaneously affect multiple targets. MicroRNA mimics are excellent therapeutic candidates because of their ability to repress multiple oncogenic pathways at once. Here we treated the aggressive Kras;p53 non-small cell lung cancer mouse model and demonstrated efficacy with a combination of two tumor-suppressive microRNAs (miRNAs). Systemic nanodelivery of miR-34 and let-7 suppressed tumor growth leading to survival advantage. This combinatorial miRNA therapeutic approach engages numerous components of tumor cell-addictive pathways and highlights the ability to deliver multiple miRNAs in a safe and effective manner to target lung tissue.Oncogene advance online publication, 1 September 2014; doi:10.1038/onc.2014.282. Source


Butcher S.E.,University of Wisconsin - Madison | Pyle A.M.,Yale University | Pyle A.M.,Howard Hughes Medical Institute
Accounts of Chemical Research | Year: 2011

RNA molecules adopt specific three-dimensional structures critical to their function. Many essential metabolic processes, including protein synthesis and RNA splicing, are carried out by RNA molecules with elaborate tertiary structures (e.g. 3QIQ, right). Indeed, the ribosome and self-splicing introns are complex RNA machines. But even the coding regions in messenger RNAs and viral RNAs are flanked by highly structured untranslated regions, which provide regulatory information necessary for gene expression.RNA tertiary structure is defined as the three-dimensional arrangement of RNA building blocks, which include helical duplexes, triple-stranded structures, and other components that are held together through connections collectively termed RNA tertiary interactions. The structural diversity of these interactions is now a subject of intense investigation, involving the techniques of NMR, X-ray crystallography, chemical genetics, and phylogenetic analysis. At the same time, many investigators are using biophysical techniques to elucidate the driving forces for tertiary structure formation and the mechanisms for its stabilization. RNA tertiary folding is promoted by maximization of base stacking, much like the hydrophobic effect that drives protein folding. RNA folding also requires electrostatic stabilization, both through charge screening and site binding of metals, and it is enhanced by desolvation of the phosphate backbone. In this Account, we provide an overview of the features that specify and stabilize RNA tertiary structure.A major determinant for overall tertiary RNA architecture is local conformation in secondary-structure junctions, which are regions from which two or more duplexes project. At junctions and other structures, such as pseudoknots and kissing loops, adjacent helices stack on one another, and these coaxial stacks play a major role in dictating the overall architectural form of an RNA molecule. In addition to RNA junction topology, a second determinant for RNA tertiary structure is the formation of sequence-specific interactions. Networks of triple helices, tetraloop-receptor interactions, and other sequence-specific contacts establish the framework for the overall tertiary fold. The third determinant of tertiary structure is the formation of stabilizing stacking and backbone interactions, and many are not sequence specific. For example, ribose zippers allow 2'-hydroxyl groups on different RNA strands to form networks of interdigitated hydrogen bonds, serving to seal strands together and thereby stabilize adjacent substructures. These motifs often require monovalent and divalent cations, which can interact diffusely or through chelation to specific RNA functional groups.As we learn more about the components of RNA tertiary structure, we will be able to predict the structures of RNA molecules from their sequences, thereby obtaining key information about biological function. Understanding and predicting RNA structure is particularly important given the recent discovery that although most of our genome is transcribed into RNA molecules, few of them have a known function. The prevalence of RNA viruses and pathogens with RNA genomes makes RNA drug discovery an active area of research. Finally, knowledge of RNA structure will facilitate the engineering of supramolecular RNA structures, which can be used as nanomechanical components for new materials. But all of this promise depends on a better understanding of the RNA parts list, and how the pieces fit together. © 2011 American Chemical Society. Source


Schmitz O.J.,Yale University
Annals of the New York Academy of Sciences | Year: 2013

Environmental warming due to global climate change is an important stressor that stands to alter organismal physiology and, ultimately, carbon cycling in ecosystems. Yet the theoretical framework for predicting warming effects on whole-ecosystem carbon balance by way of changes in organismal physiology remains rudimentary. This is because ecosystem science has yet to embrace principles of evolutionary ecology that offer the means to explain how environmental stress on organisms mediates ecosystem carbon dynamics. Here, using selected case studies and a theoretical model, I sketch out one framework that shows how increases in animal metabolic rates in response to thermal stress lead to phenotypically plastic shifts in animal elemental demand, from nitrogen-rich proteins that support production to carbon-rich soluble carbohydrates that support elevated energy demands. I further show how such a switch in resource selection alters the fate of carbon between atmospheric versus animal, plant, and soil pools. The framework shows that animals, despite having relatively low biomass representation in ecosystems, can nonetheless have disproportionately larger effects on carbon cycling in ecosystems whose effects are exacerbated by environmental stressors like climate warming. © 2013 New York Academy of Sciences. Source


Lockwood C.J.,Yale University
Menopause | Year: 2011

Expression of tissue factor (TF), the primary initiator of coagulation, is enhanced in decidualized human endometrial stromal cells (HESCs) during the progesterone-dominated luteal phase. Progesterone also augments a second HESC hemostatic factor, plasminogen activator inhibitor 1 (PAI-1). In contrast, progestins inhibit HESC matrix metalloproteinase (MMP) 1, 3, and 9 expression to stabilize endometrial stromal and vascular extracellular matrix. Through these mechanisms, decidualized endometrium is rendered both hemostatic and resistant to excess trophoblast invasion in the midluteal phase and throughout gestation to prevent hemorrhage and accreta. In nonfertile cycles, progesterone withdrawal results in decreased HESC TF and PAI-1 expression and increased MMP activity and inflammatory cytokine production promoting the controlled hemorrhage of menstruation and related tissue sloughing. In contrast to these well-ordered biochemical processes, unpredictable endometrial bleeding associated with anovulation reflects the absence of progestational effects on TF, PAI-1, and MMP activities as well as unrestrained angiogenesis rendering the endometrium nonhemostatic, proteolytic, and highly vascular. Abnormal bleeding associated with long-term progestin-only contraceptives results not from impaired hemostasis but from unrestrained angiogenesis leading to large, fragile endometrial vessels. This abnormal angiogenesis reflects the progestational inhibition of endometrial blood flow promoting local hypoxia and the generation of reactive oxygen species that increase the production of angiogenic factors such as vascular endothelial growth factor in HESCs and angiopoietin 2 in endometrial endothelial cells while decreasing HESC expression of angiostatic, angiopoietin 1. The resulting vessel fragility promotes bleeding. Aberrant angiogenesis also underlies abnormal bleeding associated with myomas and endometrial polyps; however, there are gaps in our understanding of this pathology. © 2011 by The North American Menopause Society. Source


Boyer J.L.,Yale University
Comprehensive Physiology | Year: 2013

Bile is a unique and vital aqueous secretion of the liver that is formed by the hepatocyte and modified down stream by absorptive and secretory properties of the bile duct epithelium. Approximately 5% of bile consists of organic and inorganic solutes of considerable complexity. The bile-secretory unit consists of a canalicular network which is formed by the apical membrane of adjacent hepatocytes and sealed by tight junctions. The bile canaliculi (̃1 μm in diameter) conduct the flow of bile countercurrent to the direction of portal blood flow and connect with the canal of Hering and bile ducts which progressively increase in diameter and complexity prior to the entry of bile into the gallbladder, common bile duct, and intestine. Canalicular bile secretion is determined by both bile salt-dependent and independent transport systems which are localized at the apical membrane of the hepatocyte and largely consist of a series of adenosine triphosphate-binding cassette transport proteins that function as export pumps for bile salts and other organic solutes. These transporters create osmotic gradients within the bile canalicular lumen that provide the driving force for movement of fluid into the lumen via aquaporins. Species vary with respect to the relative amounts of bile salt-dependent and independent canalicular flow and cholangiocyte secretion which is highly regulated by hormones, second messengers, and signal transduction pathways. Most determinants of bile secretion are now characterized at the molecular level in animal models and in man. Genetic mutations serve to illuminate many of their functions. © 2013 American Physiological Society. Source