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Showing papers by "University of Kentucky published in 2014"


Journal ArticleDOI
01 Jan 2014-Nature
TL;DR: In this paper, the authors report molecular profiling of 230 resected lung adnocarcinomas using messenger RNA, microRNA and DNA sequencing integrated with copy number, methylation and proteomic analyses.
Abstract: Adenocarcinoma of the lung is the leading cause of cancer death worldwide. Here we report molecular profiling of 230 resected lung adenocarcinomas using messenger RNA, microRNA and DNA sequencing integrated with copy number, methylation and proteomic analyses. High rates of somatic mutation were seen (mean 8.9 mutations per megabase). Eighteen genes were statistically significantly mutated, including RIT1 activating mutations and newly described loss-of-function MGA mutations which are mutually exclusive with focal MYC amplification. EGFR mutations were more frequent in female patients, whereas mutations in RBM10 were more common in males. Aberrations in NF1, MET, ERBB2 and RIT1 occurred in 13% of cases and were enriched in samples otherwise lacking an activated oncogene, suggesting a driver role for these events in certain tumours. DNA and mRNA sequence from the same tumour highlighted splicing alterations driven by somatic genomic changes, including exon 14 skipping in MET mRNA in 4% of cases. MAPK and PI(3)K pathway activity, when measured at the protein level, was explained by known mutations in only a fraction of cases, suggesting additional, unexplained mechanisms of pathway activation. These data establish a foundation for classification and further investigations of lung adenocarcinoma molecular pathogenesis.

4,104 citations


Journal ArticleDOI
TL;DR: It is proposed that downstream topographical biomarkers of the disease, such as volumetric MRI and fluorodeoxyglucose PET, might better serve in the measurement and monitoring of the course of disease.
Abstract: In the past 8 years, both the International Working Group (IWG) and the US National Institute on Aging-Alzheimer's Association have contributed criteria for the diagnosis of Alzheimer's disease (AD) that better define clinical phenotypes and integrate biomarkers into the diagnostic process, covering the full staging of the disease. This Position Paper considers the strengths and limitations of the IWG research diagnostic criteria and proposes advances to improve the diagnostic framework. On the basis of these refinements, the diagnosis of AD can be simplified, requiring the presence of an appropriate clinical AD phenotype (typical or atypical) and a pathophysiological biomarker consistent with the presence of Alzheimer's pathology. We propose that downstream topographical biomarkers of the disease, such as volumetric MRI and fluorodeoxyglucose PET, might better serve in the measurement and monitoring of the course of disease. This paper also elaborates on the specific diagnostic criteria for atypical forms of AD, for mixed AD, and for the preclinical states of AD.

2,581 citations


Journal ArticleDOI
TL;DR: The newly recommended evidence-based new DC/TMD protocol is appropriate for use in both clinical and research settings and includes both a valid screener for detecting any pain-related TMD as well as valid diagnostic criteria for differentiating the most common pain- related TMD.
Abstract: Temporomandibular disorders (TMD) are a significant public health problem affecting approximately 5% to 12% of the population.1 TMD is the second most common musculoskeletal condition (after chronic low back pain) resulting in pain and disability.1 Pain-related TMD can impact the individual's daily activities, psychosocial functioning, and quality of life. Overall, the annual TMD management cost in the USA, not including imaging, has doubled in the last decade to $4 billion.1 Patients often seek consultation with dentists for their TMD, especially for pain-related TMD. Diagnostic criteria for TMD with simple, clear, reliable, and valid operational definitions for the history, examination, and imaging procedures are needed to render physical diagnoses in both clinical and research settings. In addition, biobehavioral assessment of pain-related behavior and psychosocial functioning—an essential part of the diagnostic process—is required and provides the minimal information whereby one can determine whether the patient's pain disorder, especially when chronic, warrants further multidisciplinary assessment. Taken together, a new dual-axis Diagnostic Criteria for TMD (DC/TMD) will provide evidence-based criteria for the clinician to use when assessing patients, and will facilitate communication regarding consultations, referrals, and prognosis.2 The research community benefits from the ability to use well-defined and clinically relevant characteristics associated with the phenotype in order to facilitate more generalizable research. When clinicians and researchers use the same criteria, taxonomy, and nomenclature, then clinical questions and experience can be more easily transferred into relevant research questions, and research findings are more accessible to clinicians to better diagnose and manage their patients. The Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) have been the most widely employed diagnostic protocol for TMD research since its publication in 1992.3 This classification system was based on the biopsychosocial model of pain4 that included an Axis I physical assessment, using reliable and well-operationalized diagnostic criteria, and an Axis II assessment of psychosocial status and pain-related disability. The intent was to simultaneously provide a physical diagnosis and identify other relevant characteristics of the patient that could influence the expression and thus management of their TMD. Indeed, the longer the pain persists, the greater the potential for emergence and amplification of cognitive, psychosocial, and behavioral risk factors, with resultant enhanced pain sensitivity, greater likelihood of additional pain persistence, and reduced probability of success from standard treatments.5 The RDC/TMD (1992) was intended to be only a first step toward improved TMD classification, and the authors stated the need for future investigation of the accuracy of the Axis I diagnostic algorithms in terms of reliability and criterion validity—the latter involving the use of credible reference standard diagnoses. Also recommended was further assessment of the clinical utility of the Axis II instruments. The original RDC/TMD Axis I physical diagnoses have content validity based on the critical review by experts of the published diagnostic approach in use at that time and were tested using population-based epidemiologic data.6 Subsequently, a multicenter study showed that, for the most common TMD, the original RDC/TMD diagnoses exhibited sufficient reliability for clinical use.7 While the validity of the individual RDC/TMD diagnoses has been extensively investigated, assessment of the criterion validity for the complete spectrum of RDC/TMD diagnoses had been absent until recently.8 For the original RDC/TMD Axis II instruments, good evidence for their reliability and validity for measuring psychosocial status and pain-related disability already existed when the classification system was published.9–13 Subsequently, a variety of studies have demonstrated the significance and utility of the original RDC/TMD biobehavioral measures in such areas as predicting outcomes of clinical trials, escalation from acute to chronic pain, and experimental laboratory settings.14–20 Other studies have shown that the original RDC/TMD biobehavioral measures are incomplete in terms of prediction of disease course.21–23 The overall utility of the biobehavioral measures in routine clinical settings has, however, yet to be demonstrated, in part because most studies have to date focused on Axis I diagnoses rather than Axis II biobehavioral factors.24 The aims of this article are to present the evidence-based new Axis I and Axis II DC/TMD to be used in both clinical and research settings, as well as present the processes related to their development.

2,283 citations


Journal ArticleDOI
01 Dec 2014-Thyroid
TL;DR: It is concluded that levothyroxine should remain the standard of care for treating hypothyroidism and no consistently strong evidence for the superiority of alternative preparations is found.
Abstract: Background: A number of recent advances in our understanding of thyroid physiology may shed light on why some patients feel unwell while taking levothyroxine monotherapy. The purpose of this task force was to review the goals of levothyroxine therapy, the optimal prescription of conventional levothyroxine therapy, the sources of dissatisfaction with levothyroxine therapy, the evidence on treatment alternatives, and the relevant knowledge gaps. We wished to determine whether there are sufficient new data generated by well-designed studies to provide reason to pursue such therapies and change the current standard of care. This document is intended to inform clinical decision-making on thyroid hormone replacement therapy; it is not a replacement for individualized clinical judgment. Methods: Task force members identified 24 questions relevant to the treatment of hypothyroidism. The clinical literature relating to each question was then reviewed. Clinical reviews were supplemented, when relevant, with related...

1,128 citations


Journal ArticleDOI
TL;DR: MaNGA (Mapping Nearby Galaxies at Apache Point Observatory) as mentioned in this paper employs dithered observations with 17 fiber-bundle integral field units that vary in diameter from 12'' (19 fibers) to 32'' (127 fibers).
Abstract: We present an overview of a new integral field spectroscopic survey called MaNGA (Mapping Nearby Galaxies at Apache Point Observatory), one of three core programs in the fourth-generation Sloan Digital Sky Survey (SDSS-IV) that began on 2014 July 1. MaNGA will investigate the internal kinematic structure and composition of gas and stars in an unprecedented sample of 10,000 nearby galaxies. We summarize essential characteristics of the instrument and survey design in the context of MaNGA's key science goals and present prototype observations to demonstrate MaNGA's scientific potential. MaNGA employs dithered observations with 17 fiber-bundle integral field units that vary in diameter from 12'' (19 fibers) to 32'' (127 fibers). Two dual-channel spectrographs provide simultaneous wavelength coverage over 3600-10300 A at R ~ 2000. With a typical integration time of 3 hr, MaNGA reaches a target r-band signal-to-noise ratio of 4-8 (A–1 per 2'' fiber) at 23 AB mag arcsec–2, which is typical for the outskirts of MaNGA galaxies. Targets are selected with M * 109 M ☉ using SDSS-I redshifts and i-band luminosity to achieve uniform radial coverage in terms of the effective radius, an approximately flat distribution in stellar mass, and a sample spanning a wide range of environments. Analysis of our prototype observations demonstrates MaNGA's ability to probe gas ionization, shed light on recent star formation and quenching, enable dynamical modeling, decompose constituent components, and map the composition of stellar populations. MaNGA's spatially resolved spectra will enable an unprecedented study of the astrophysics of nearby galaxies in the coming 6 yr.

1,104 citations


Journal ArticleDOI
TL;DR: In this article, a Bayesian framework was developed for model comparison and parameter estimation of X-ray spectra of active galactic nuclei (AGN) in the 4 Ms Chandra Deep Field South.
Abstract: Context. Aims. Active galactic nuclei are known to have complex X-ray spectra that depend on both the properties of the accreting super-massive black hole (e.g. mass, accretion rate) and the distribution of obscuring material in its vicinity (i.e. the “torus”). Often however, simple and even unphysical models are adopted to represent the X-ray spectra of AGN, which do not capture the complexity and diversity of the observations. In the case of blank field surveys in particular, this should have an impact on e.g. the determination of the AGN luminosity function, the inferred accretion history of the Universe and also on our understanding of the relation between AGN and their host galaxies. Methods. We develop a Bayesian framework for model comparison and parameter estimation of X-ray spectra. We take into account uncertainties associated with both the Poisson nature of X-ray data and the determination of source redshift using photometric methods. We also demonstrate how Bayesian model comparison can be used to select among ten different physically motivated X-ray spectral models the one that provides a better representation of the observations. This methodology is applied to X-ray AGN in the 4 Ms Chandra Deep Field South.Results. For the ~350 AGN in that field, our analysis identifies four components needed to represent the diversity of the observed X-ray spectra: (1) an intrinsic power law; (2) a cold obscurer which reprocesses the radiation due to photo-electric absorption, Compton scattering and Fe-K fluorescence; (3) an unabsorbed power law associated with Thomson scattering off ionised clouds; and (4) Compton reflection, most noticeable from a stronger-than-expected Fe-K line. Simpler models, such as a photo-electrically absorbed power law with a Thomson scattering component, are ruled out with decisive evidence (B > 100). We also find that ignoring the Thomson scattering component results in underestimation of the inferred column density, N H , of the obscurer. Regarding the geometry of the obscurer, there is strong evidence against both a completely closed (e.g. sphere), or entirely open (e.g. blob of material along the line of sight), toroidal geometry in favour of an intermediate case. Conclusions. Despite the use of low-count spectra, our methodology is able to draw strong inferences on the geometry of the torus. Simpler models are ruled out in favour of a geometrically extended structure with significant Compton scattering. We confirm the presence of a soft component, possibly associated with Thomson scattering off ionised clouds in the opening angle of the torus. The additional Compton reflection required by data over that predicted by toroidal geometry models, may be a sign of a density gradient in the torus or reflection off the accretion disk. Finally, we release a catalogue of AGN in the CDFS with estimated parameters such as the accretion luminosity in the 2−10 keV band and the column density, N H , of the obscurer.

1,072 citations


Journal ArticleDOI
TL;DR: A new term is recommended, “primary age-related tauopathy” (PART), to describe a pathology that is commonly observed in the brains of aged individuals, yet this pathological process cannot be specifically identified pre-mortem at the present time.
Abstract: We recommend a new term, "primary age-related tauopathy" (PART), to describe a pathology that is commonly observed in the brains of aged individuals. Many autopsy studies have reported brains with neurofibrillary tangles (NFTs) that are indistinguishable from those of Alzheimer's disease (AD), in the absence of amyloid (Aβ) plaques. For these "NFT+/Aβ-" brains, for which formal criteria for AD neuropathologic changes are not met, the NFTs are mostly restricted to structures in the medial temporal lobe, basal forebrain, brainstem, and olfactory areas (bulb and cortex). Symptoms in persons with PART usually range from normal to amnestic cognitive changes, with only a minority exhibiting profound impairment. Because cognitive impairment is often mild, existing clinicopathologic designations, such as "tangle-only dementia" and "tangle-predominant senile dementia", are imprecise and not appropriate for most subjects. PART is almost universally detectable at autopsy among elderly individuals, yet this pathological process cannot be specifically identified pre-mortem at the present time. Improved biomarkers and tau imaging may enable diagnosis of PART in clinical settings in the future. Indeed, recent studies have identified a common biomarker profile consisting of temporal lobe atrophy and tauopathy without evidence of Aβ accumulation. For both researchers and clinicians, a revised nomenclature will raise awareness of this extremely common pathologic change while providing a conceptual foundation for future studies. Prior reports that have elucidated features of the pathologic entity we refer to as PART are discussed, and working neuropathological diagnostic criteria are proposed.

1,016 citations


Journal ArticleDOI
TL;DR: In this paper, the galaxy size-mass distribution over the redshift range 0 3 × 10{sup 9} M {sub ☉}, and steep, R{sub eff}∝M{sub ∗}{sup 0.75}, for early-type galaxies with stellar mass > 2 × 10,sup 10} M{sub ǫ, and the intrinsic scattermore is ≲0.2 dex for all galaxy types and redshifts.
Abstract: Spectroscopic+photometric redshifts, stellar mass estimates, and rest-frame colors from the 3D-HST survey are combined with structural parameter measurements from CANDELS imaging to determine the galaxy size-mass distribution over the redshift range 0 3 × 10{sup 9} M {sub ☉}, and steep, R{sub eff}∝M{sub ∗}{sup 0.75}, for early-type galaxies with stellar mass >2 × 10{sup 10} M {sub ☉}. The intrinsic scattermore » is ≲0.2 dex for all galaxy types and redshifts. For late-type galaxies, the logarithmic size distribution is not symmetric but is skewed toward small sizes: at all redshifts and masses, a tail of small late-type galaxies exists that overlaps in size with the early-type galaxy population. The number density of massive (∼10{sup 11} M {sub ☉}), compact (R {sub eff} < 2 kpc) early-type galaxies increases from z = 3 to z = 1.5-2 and then strongly decreases at later cosmic times.« less

1,004 citations


Journal ArticleDOI
TL;DR: The current epidemiology of GBM is reported with new data from the Central Brain Tumor Registry of the United States 2006 to 2010 as well as demonstrate and discuss trends in incidence and survival.
Abstract: Glioblastoma multiforme (GBM) is the most common and aggressive primary central nervous system malignancy with a median survival of 15 months. The average incidence rate of GBM is 3.19/100,000 population, and the median age of diagnosis is 64 years. Incidence is higher in men and individuals of white race and non-Hispanic ethnicity. Many genetic and environmental factors have been studied in GBM, but the majority are sporadic, and no risk factor accounting for a large proportion of GBMs has been identified. However, several favorable clinical prognostic factors are identified, including younger age at diagnosis, cerebellar location, high performance status, and maximal tumor resection. GBMs comprise of primary and secondary subtypes, which evolve through different genetic pathways, affect patients at different ages, and have differences in outcomes. We report the current epidemiology of GBM with new data from the Central Brain Tumor Registry of the United States 2006 to 2010 as well as demonstrate and discuss trends in incidence and survival. We also provide a concise review on molecular markers in GBM that have helped distinguish biologically similar subtypes of GBM and have prognostic and predictive value.

876 citations


Journal ArticleDOI
TL;DR: Several key differences between traditional offline social networks and online social media networks are outlined by juxtaposing an established typology of social network research with a well-regarded definition of social media platforms that articulates four key features.
Abstract: In recent years, we have witnessed the rapid proliferation and widespread adoption of a new class of information technologies, commonly known as social media. Researchers often rely on social network analysis (SNA) when attempting to understand these technologies, often without considering how the novel capabilities of social media platforms might affect the underlying theories of SNA, which were developed primarily through studies of offline social networks. This article outlines several key differences between traditional offline social networks and online social media networks by juxtaposing an established typology of social network research with a well-regarded definition of social media platforms that articulates four key features. The results show that at four major points of intersection, social media has considerable theoretical implications for SNA. In exploring these points of intersection, this study outlines a series of theoretically distinct research questions for SNA in social media contexts. These points of intersection offer considerable opportunities for researchers to investigate the theoretical implications introduced by social media and lay the groundwork for a robust social media agenda potentially spanning multiple disciplines.

787 citations


Journal ArticleDOI
TL;DR: The addition of trastuzumab to paclitaxel after doxorubicin and cyclophosphamide in early-stage HER2-positive breast cancer results in a substantial and durable improvement in survival as a result of a sustained marked reduction in cancer recurrence.
Abstract: Purpose Positive interim analysis findings from four large adjuvant trials evaluating trastuzumab in patients with early-stage human epidermal growth factor receptor 2 (HER2) –positive breast cancer were first reported in 2005. One of these reports, the joint analysis of North Central Cancer Treatment Group NCCTG N9831 (Combination Chemotherapy With or Without Trastuzumab in Treating Women With HER2-Overexpressing Breast Cancer) and the National Surgical Adjuvant Breast and Bowel Project NSABP B-31 (Doxorubicin and Cyclophosphamide Plus Paclitaxel With or Without Trastuzumab in Treating Women With Node-Positive Breast Cancer That Overexpresses HER2), was updated in 2011. We now report the planned definitive overall survival (OS) results from this joint analysis along with updates on the disease-free survival (DFS) end point. Methods In all, 4,046 patients with HER2-positive operable breast cancer were enrolled to receive doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab i...

Journal ArticleDOI
Gaofeng Xiong1, Lei Deng1, Jieqing Zhu1, Piotr G. Rychahou1, Ren Xu1 
TL;DR: It is shown that P4HA2 was associated with expression of Col1A1, Col3A2, and Col4A1 during breast cancer development and progression and identified P4 HA2 as a potential therapeutic target and biomarker for breast cancer progression.
Abstract: Background Increased collagen deposition provides physical and biochemical signals to support tumor growth and invasion during breast cancer development. Therefore, inhibition of collagen synthesis and deposition has been considered a strategy to suppress breast cancer progression. Collagen prolyl-4-hydroxylase α subunit 2 (P4HA2), an enzyme hydroxylating proline residues in -X-Pro-Gly- sequences, is a potential therapeutic target for the disorders associated with increased collagen deposition. However, expression and function of P4HA2 in breast cancer progression are not well investigated.

Journal ArticleDOI
TL;DR: The SORs and three very different types of SOD enzymes are redox-active metalloenzymes that have evolved entirely independently from one another for the purpose of lowering superoxide concentrations, suggesting that, from the start of the rise of O2 on Earth, the chemistry of superoxide has been an important factor during evolution.
Abstract: Superoxide, O2•–, is formed in all living organisms that come in contact with air, and, depending upon its biological context, it may act as a signaling agent, a toxic species, or a harmless intermediate that decomposes spontaneously Its levels are limited in vivo by two different types of enzymes, superoxide reductase (SOR) and superoxide dismutase (SOD) Although superoxide has long been an important factor in evolution, it was not so when life first emerged on Earth at least 35 billion years ago At that time, the early biosphere was highly reducing and lacking in any significant concentrations of dioxygen (O2), very different from what it is today Consequently, there was little or no O2•– and therefore no reason for SOR or SOD enzymes to evolve Instead, the history of biological O2•– probably commences somewhere around 24 billion years ago, when the biosphere started to experience what has been termed the “Great Oxidation Event”, a transformation driven by the increase in O2 levels, formed by cyanobacteria as a product of oxygenic photosynthesis1 The rise of O2 on Earth caused a reshaping of existing metabolic pathways, and it triggered the development of new ones2 Its appearance led to the formation of the so-called “reactive oxygen species” (ROS), for example, superoxide, hydrogen peroxide, and hydroxyl radical, and to a need for antioxidant enzymes and other antioxidant systems to protect against the growing levels of oxidative damage to living systems Dioxygen is a powerful four-electron oxidizing agent, and the product of this reduction is water 1 When O2 is reduced in four sequential one-electron steps, the intermediates formed are the three major ROS, that is, O2•–, H2O2, and HO• 2 3 4 5 Each of these intermediates is a potent oxidizing agent The consequences of their presence to early life must have been an enormous evolutionary challenge In the case of superoxide, we find the SOD and SOR enzymes to be widely distributed throughout current living organisms, both aerobic and anaerobic, suggesting that, from the start of the rise of O2 on Earth, the chemistry of superoxide has been an important factor during evolution The SORs and three very different types of SOD enzymes are redox-active metalloenzymes that have evolved entirely independently from one another for the purpose of lowering superoxide concentrations SORs catalyze the one-electron reduction of O2•– to give H2O2, a reaction requiring two protons per superoxide reacted as well as an external reductant to provide the electron (eq 6) SODs catalyze the disproportionation of superoxide to give O2 and H2O2, a reaction requiring one proton per superoxide reacted, but no external reductant (eq 7) 6 7 All of the SOR enzymes contain only iron, while the three types of SODs are the nickel-containing SODs (NiSOD), the iron- or manganese-containing SODs (FeSOD and MnSOD), and the copper- and zinc-containing SODs (CuZnSOD) Although the structures and other properties of these four types of metalloenzymes are quite different, they all share several characteristics, including the ability to react rapidly and selectively with the small anionic substrate O2•– Consequently, there are some striking similarities between these otherwise dissimilar enzymes, many of which can be explained by considering the nature of the chemical reactivity of O2•– (see below) Numerous valuable reviews describing the SOD and SOR enzymes have appeared over the years, but few have covered and compared all four classes of these enzymes, as we attempt to do here Thus, the purpose of this Review is to describe, compare, and contrast the properties of the SOR and the four SOD enzymes; to summarize what is known about their evolutionary pathways; and to analyze the properties of these enzymes in light of what is known of the inherent chemical reactivity of superoxide

Journal ArticleDOI
24 Apr 2014-Nature
TL;DR: Testing the hypothesis that herbaceous plant species losses caused by eutrophication may be offset by increased light availability due to herbivory demonstrates that nutrients and herbivores can serve as counteracting forces to control local plant diversity through light limitation, independent of site productivity, soil nitrogen, herbivore type and climate.
Abstract: Human alterations to nutrient cycles and herbivore communities are affecting global biodiversity dramatically. Ecological theory predicts these changes should be strongly counteractive: nutrient addition drives plant species loss through intensified competition for light, whereas herbivores prevent competitive exclusion by increasing ground-level light, particularly in productive systems. Here we use experimental data spanning a globally relevant range of conditions to test the hypothesis that herbaceous plant species losses caused by eutrophication may be offset by increased light availability due to herbivory. This experiment, replicated in 40 grasslands on 6 continents, demonstrates that nutrients and herbivores can serve as counteracting forces to control local plant diversity through light limitation, independent of site productivity, soil nitrogen, herbivore type and climate. Nutrient addition consistently reduced local diversity through light limitation, and herbivory rescued diversity at sites where it alleviated light limitation. Thus, species loss from anthropogenic eutrophication can be ameliorated in grasslands where herbivory increases ground-level light.

Journal ArticleDOI
TL;DR: This review discusses how behavioral tests in mice relate to the pathological and neuropsychological features seen in human Alzheimer's disease, and presents a comprehensive analysis of the temporal progression of behavioral impairments in commonly used AD mouse models that contain mutations in amyloid precursor protein (APP).
Abstract: The goal of this review is to discuss how behavioral tests in mice relate to the pathological and neuropsychological features seen in human Alzheimer’s disease (AD), and present a comprehensive analysis of the temporal progression of behavioral impairments in commonly used AD mouse models that contain mutations in amyloid precursor protein. We provide a brief overview of neuropathological changes seen in AD brain, and some of the clinical neuropsychological assessments used to measure cognitive deficits. This is followed by a critical assessment of behavioral tasks that are used in AD mice to model the cognitive changes seen in humans. Behavioral tests discussed include spatial memory tests (Morris water maze, radial arm water maze, Barnes maze), associative learning tasks (passive avoidance, fear conditioning), alternation tasks (Y-Maze/T-Maze), recognition memory tasks (Novel Object Recognition), attentional tasks (3 & 5 choice serial reaction time), set-shifting tasks, and reversal learning tasks. We discuss the strengths and weaknesses of each of these tests, and how they may correlate with clinical assessments in humans. Finally, the temporal progression of both cognitive and non-cognitive deficits in ten AD mouse models (PDAPP, TG2576, APP23, TgCRND8, J20, APP/PS1, TG2576 + PS1(M146L), APP/PS1 KI, 5xFAD and 3xTg-AD) are discussed. Mouse models of AD and the behavioral tasks used in conjunction with those models are immensely important in contributing to our knowledge of disease progression, and are useful tools to study AD pathophysiology and the resulting cognitive deficits. However, investigators need to be aware of the potential weaknesses of the available preclinical models in terms of their ability to model cognitive changes observed in human AD. It is our hope that this review will assist investigators in selecting an appropriate mouse model, and accompanying behavioral paradigms to investigate different aspects of AD pathology and disease progression.

Journal ArticleDOI
TL;DR: It is suggested that increases in absolute brain size provided the biological foundation for evolutionary increases in self-control, and implicate species differences in feeding ecology as a potential selective pressure favoring these skills.
Abstract: Cognition presents evolutionary research with one of its greatest challenges. Cognitive evolution has been explained at the proximate level by shifts in absolute and relative brain volume and at the ultimate level by differences in social and dietary complexity. However, no study has integrated the experimental and phylogenetic approach at the scale required to rigorously test these explanations. Instead, previous research has largely relied on various measures of brain size as proxies for cognitive abilities. We experimentally evaluated these major evolutionary explanations by quantitatively comparing the cognitive performance of 567 individuals representing 36 species on two problem-solving tasks measuring self-control. Phylogenetic analysis revealed that absolute brain volume best predicted performance across species and accounted for considerably more variance than brain volume controlling for body mass. This result corroborates recent advances in evolutionary neurobiology and illustrates the cognitive consequences of cortical reorganization through increases in brain volume. Within primates, dietary breadth but not social group size was a strong predictor of species differences in self-control. Our results implicate robust evolutionary relationships between dietary breadth, absolute brain volume, and self-control. These findings provide a significant first step toward quantifying the primate cognitive phenome and explaining the process of cognitive evolution.

Journal ArticleDOI
TL;DR: In this paper, the use of modern 3D photo-based surface reconstruction techniques for high fidelity surveys of trenches, rock exposures and hand specimens is discussed, highlighting their potential for paleoseismology and structural geology.

Journal ArticleDOI
TL;DR: Data indicate that recency of tweets impacts source credibility; however, this relationship is mediated by cognitive elaboration, which suggests many implications for theory and application, both in computer-mediated communication and crisis communication.
Abstract: Social media are increasingly being used as an information source, including information related to risks and crises. The current study examines how pieces of information available in social media impact perceptions of source credibility. Specifically, participants in the study were asked to view 1 of 3 mockTwitter.compages that varied the recency with which tweets were posted and then to report on their perceived source credibility of the page owner. Data indicate that recency of tweets impacts source credibility; however, this relationship is mediated by cognitive elaboration. These data suggest many implications for theory and application, both in computer-mediated communication and crisis communication. These implications are discussed, along with limitations of the current study and directions for future research.

Journal ArticleDOI
TL;DR: This paper developed hypotheses regarding the influence of four factors: (1) greater opioid prescription in rural areas, creating availability from which illegal markets can arise; (2) an out-migration of young adults; (3) greater rural social and kinship network connections, which may facilitate drug diversion and distribution; and (4) economic stressors that may create vulnerability to drug use more generally.
Abstract: Nonmedical prescription opioid misuse remains a growing public problem in need of action and is concentrated in areas of US states with large rural populations such as Kentucky, West Virginia, Alaska, and Oklahoma. We developed hypotheses regarding the influence of 4 factors: (1) greater opioid prescription in rural areas, creating availability from which illegal markets can arise; (2) an out-migration of young adults; (3) greater rural social and kinship network connections, which may facilitate drug diversion and distribution; and (4) economic stressors that may create vulnerability to drug use more generally. A systematic consideration of the contexts that create differences in availability, access, and preferences is critical to understanding how drug use context varies across geography.

Journal ArticleDOI
TL;DR: Copper homeostasis is tightly regulated through a complex system of Cu transporters and chaperone proteins, and altered cellular events, including lipid metabolism, gene expression, alpha-synuclein aggregation, and temporal and spatial distribution of Cu in hepatocytes, have been suggested to play a role in Cu toxicity.
Abstract: Copper (Cu) is a vital mineral essential for many biological processes. The vast majority of all Cu in healthy humans is associated with enzyme prosthetic groups or bound to proteins. Cu homeostasis is tightly regulated through a complex system of Cu transporters and chaperone proteins. Excess or toxicity of Cu, which is associated with the pathogenesis of hepatic disorder, neurodegenerative changes and other disease conditions, can occur when Cu homeostasis is disrupted. The capacity to initiate oxidative damage is most commonly attributed to Cu-induced cellular toxicity. Recently, altered cellular events, including lipid metabolism, gene expression, alpha-synuclein aggregation, activation of acidic sphingomyelinase and release of ceramide, and temporal and spatial distribution of Cu in hepatocytes, as well as Cu-protein interaction in the nerve system, have been suggested to play a role in Cu toxicity. However, whether these changes are independent of, or secondary to, an altered cellular redox state of Cu remain to be elucidated.

Journal ArticleDOI
TL;DR: This guideline provides clinicians with a logical framework to improve patient care and mitigate the personal and social effects of persistent, bothersome tinnitus.
Abstract: Objective. Tinnitus is the perception of sound without an external source. More than 50 million people in the United States have reported experiencing tinnitus, resulting in an estimated prevalence of 10% to 15% in adults. Despite the high prevalence of tinnitus and its potential significant effect on quality of life, there are no evidence-based, multidisciplinary clinical practice guidelines to assist clinicians with management. The focus of this guideline is on tinnitus that is both bothersome and persistent (lasting 6 months or longer), which often negatively affects the patient’s quality of life. The target audience for the guideline is any clinician, including nonphysicians, involved in managing patients with tinnitus. The target patient population is limited to adults (18 years and older) with primary tinnitus that is persistent and bothersome. Purpose. The purpose of this guideline is to provide evidence-based recommendations for clinicians managing patients with tinnitus. This guideline provides clinicians with a logical framework to improve patient care and mitigate the personal and social effects of persistent, bothersome tinnitus. It will discuss the evaluation of patients with tinnitus, including selection and timing of diagnostic testing and specialty referral to identify potential underlying treatable pathology. It will then focus on the evaluation and treatment of patients with persistent primary tinnitus, with recommendations to guide the evaluation and measurement of the effect of tinnitus and to determine the most appropriate interventions to improve symptoms and quality of life for tinnitus sufferers. Action Statements. The development group made a strong recommendation that clinicians distinguish patients with bothersome tinnitus from patients with nonbothersome tinnitus. The development group made a strong recommendation against obtaining imaging studies of the head and neck in patients with tinnitus, specifically to evaluate tinnitus that does not localize to 1 ear, is nonpulsatile, and is not associated with focal neurologic abnormalities or an asymmetric hearing loss. The panel made the following recommendations: Clinicians should (a) perform a targeted history and physical examination at the initial evaluation of a patient with presumed primary tinnitus to identify conditions that if promptly identified and managed may relieve tinnitus; (b) obtain a prompt, comprehensive audiologic examination in patients with tinnitus that is unilateral, persistent (≥ 6 months), or associated with hearing difficulties; (c) distinguish patients with bothersome tinnitus of recent onset from those with persistent symptoms (≥ 6 months) to prioritize intervention and facilitate discussions about natural history and follow-up care; (d) educate patients with persistent, bothersome tinnitus about management strategies; (e) recommend a hearing aid evaluation for patients who have persistent, bothersome tinnitus associated with documented hearing loss; and (f) recommend cognitive behavioral therapy to patients with persistent, bothersome tinnitus. The panel recommended against (a) antidepressants, anticonvulsants, anxiolytics, or intratympanic medications for the routine treatment of patients with persistent, bothersome tinnitus; (b) Ginkgo biloba, melatonin, zinc, or other dietary supplements for treating patients with persistent, bothersome tinnitus; and (c) transcranial magnetic stimulation for the routine treatment of patients with persistent, bothersome tinnitus. The development group provided the following options: Clinicians may (a) obtain an initial comprehensive audiologic examination in patients who present with tinnitus (regardless of laterality, duration, or perceived hearing status); 545325

Journal ArticleDOI
TL;DR: A review of neurotoxic lead exposure's pathophysiology, etiology, and epidemiology is presented in this article, where commonly associated neuropsychological difficulties in intelligence, memory, executive functioning, attention, processing speed, language, visuospatial skills, motor skills, and affect/mood are explored.
Abstract: Neurotoxicity is a term used to describe neurophysiological changes caused by exposure to toxic agents. Such exposure can result in neurocognitive symptoms and/or psychiatric disturbances. Common toxic agents include heavy metals, drugs, organophosphates, bacterial, and animal neurotoxins. Among heavy metal exposures, lead exposure is one of the most common exposures that can lead to significant neuropsychological and functional decline in humans. In this review, neurotoxic lead exposure's pathophysiology, etiology, and epidemiology are explored. In addition, commonly associated neuropsychological difficulties in intelligence, memory, executive functioning, attention, processing speed, language, visuospatial skills, motor skills, and affect/mood are explored.

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TL;DR: In this paper, the progress, current status, and open challenges of QCD-driven physics, in theory and in experiment, are highlighted, highlighting how the strong interaction is intimately connected to a broad sweep of physical problems, in settings ranging from astrophysics and cosmology to strongly coupled, complex systems in particle and condensed-matter physics, as well as searches for physics beyond the Standard Model.
Abstract: We highlight the progress, current status, and open challenges of QCD-driven physics, in theory and in experiment. We discuss how the strong interaction is intimately connected to a broad sweep of physical problems, in settings ranging from astrophysics and cosmology to strongly coupled, complex systems in particle and condensed-matter physics, as well as to searches for physics beyond the Standard Model. We also discuss how success in describing the strong interaction impacts other fields, and, in turn, how such subjects can impact studies of the strong interaction. In the course of the work we offer a perspective on the many research streams which flow into and out of QCD, as well as a vision for future developments.

Journal ArticleDOI
L. Adamczyk1, J. K. Adkins2, G. Agakishiev3, Madan M. Aggarwal4  +352 moreInstitutions (54)
23 Jan 2014
TL;DR: The beam energy and collision centrality dependence of the mean, standard deviation, skewness, and kurtosis of the net-proton multiplicity distributions in Au+Au collisions and the products of moments are found to be significantly below the Skellam expectation and close to expectations based on independent proton and antiproton production.
Abstract: We report the beam energy (root S-NN = 7.7-200 GeV) and collision centrality dependence of the mean (M), standard deviation (sigma), skewness (S), and kurtosis (kappa) of the net-proton multiplicity distributions in Au + Au collisions. The measurements are carried out by the STAR experiment at midrapidity (vertical bar y vertical bar < 0.5) and within the transverse momentum range 0.4 < p(T) < 0.8 GeV/c in the first phase of the Beam Energy Scan program at the Relativistic Heavy Ion Collider. These measurements are important for understanding the quantum chromodynamic phase diagram. The products of the moments, S sigma and K sigma(2), are sensitive to the correlation length of the hot and dense medium created in the collisions and are related to the ratios of baryon number susceptibilities of corresponding orders. The products of moments are found to have values significantly below the Skellam expectation and close to expectations based on independent proton and antiproton production. The measurements are compared to a transport model calculation to understand the effect of acceptance and baryon number conservation and also to a hadron resonance gas model.

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TL;DR: This review highlights the in vivo effects of resveratrol treatment on breast, colorectal, liver, pancreatic, and prostate cancers and suggests that many factors need to be considered before resver atrol can be used for human cancer prevention or therapy.
Abstract: Resveratrol is a naturally occurring polyphenol that provides a number of anti-aging health benefits including improved metabolism, cardioprotection, and cancer prevention. Much of the work on resveratrol and cancer comes from in vitro studies looking at resveratrol actions on cancer cells and pathways. There are, however, comparatively fewer studies that have investigated resveratrol treatment and cancer outcomes in vivo, perhaps limited by its poor bioavailability when taken orally. Although research in cell culture has shown promising and positive effects of resveratrol, evidence from rodents and humans is inconsistent. This review highlights the in vivo effects of resveratrol treatment on breast, colorectal, liver, pancreatic, and prostate cancers. Resveratrol supplementation in animal models of cancer has shown positive, neutral as well as negative outcomes depending on resveratrol route of administration, dose, tumor model, species, and other factors. Within a specific cancer type, there is variability between studies with respect to strain, age, and sex of animal used, timing and method of resveratrol supplementation, and dose of resveratrol used to study cancer endpoints. Together, the data suggest that many factors need to be considered before resveratrol can be used for human cancer prevention or therapy.

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TL;DR: In this article, the role of continuous warfarin therapy in preventing periprocedural thromboembolic and hemorrhagic events after radiofrequency catheter ablation was investigated.
Abstract: Background—Periprocedural thromboembolic and hemorrhagic events are worrisome complications of catheter ablation for atrial fibrillation (AF). The periprocedural anticoagulation management could play a role in the incidence of these complications. Although ablation procedures performed without warfarin discontinuation seem to be associated with lower thromboembolic risk, no randomized study exists. Methods and Results—This was a prospective, open-label, randomized, parallel-group, multicenter study assessing the role of continuous warfarin therapy in preventing periprocedural thromboembolic and hemorrhagic events after radiofrequency catheter ablation. Patients with CHADS2 score ≥1 were included. Patients were randomly assigned in a 1:1 ratio to the off-warfarin or on-warfarin arm. The incidence of thromboembolic events in the 48 hours after ablation was the primary end point of the study. The study enrolled 1584 patients: 790 assigned to discontinue warfarin (group 1) and 794 assigned to continuous warfa...

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TL;DR: The study indicates that the interaction with BRD4 is critical for the oncogenic function of Twist in BLBC, and Pharmacologic inhibition of the Twist-BRD4 association reduced WNT5A expression and suppressed invasion, cancer stem cell (CSC)-like properties, and tumorigenicity of BLBC cells.


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TL;DR: Findings identify alterations in SMARCA4 as the major cause of SCCOHT, which could lead to improvements in genetic counseling and new treatment approaches, and at least one germline or somatic deleterious SMarCA4 mutation in 30 of 32 cases.
Abstract: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is the most common undifferentiated ovarian malignancy in women under 40 years of age. We sequenced the exomes of six individuals from three families with SCCOHT. After discovering segregating deleterious germline mutations in SMARCA4 in all three families, we tested DNA from a fourth affected family, which also carried a segregating SMARCA4 germline mutation. All the familial tumors sequenced harbored either a somatic mutation or loss of the wild-type allele. Immunohistochemical analysis of these cases and additional familial and non-familial cases showed loss of SMARCA4 (BRG1) protein in 38 of 40 tumors overall. Sequencing of cases with available DNA identified at least one germline or somatic deleterious SMARCA4 mutation in 30 of 32 cases. Additionally, the SCCOHT cell line BIN-67 had biallelic deleterious mutations in SMARCA4. Our findings identify alterations in SMARCA4 as the major cause of SCCOHT, which could lead to improvements in genetic counseling and new treatment approaches.

Journal ArticleDOI
24 Apr 2014-Nature
TL;DR: This paper analyzed diversity-stability relationships from 41 grasslands on five continents and examined how these relationships are affected by chronic fertilization, one of the strongest drivers of species loss globally.
Abstract: Studies of experimental grassland communities have demonstrated that plant diversity can stabilize productivity through species asynchrony, in which decreases in the biomass of some species are compensated for by increases in others. However, it remains unknown whether these findings are relevant to natural ecosystems, especially those for which species diversity is threatened by anthropogenic global change. Here we analyse diversity-stability relationships from 41 grasslands on five continents and examine how these relationships are affected by chronic fertilization, one of the strongest drivers of species loss globally. Unmanipulated communities with more species had greater species asynchrony, resulting in more stable biomass production, generalizing a result from biodiversity experiments to real-world grasslands. However, fertilization weakened the positive effect of diversity on stability. Contrary to expectations, this was not due to species loss after eutrophication but rather to an increase in the temporal variation of productivity in combination with a decrease in species asynchrony in diverse communities. Our results demonstrate separate and synergistic effects of diversity and eutrophication on stability, emphasizing the need to understand how drivers of global change interactively affect the reliable provisioning of ecosystem services in real-world systems.