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Recent documents in eScholarship@UMMS
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Mindfulness and Cardiovascular Disease Risk: State of the Evidence, Plausible Mechanisms, and Theoretical Framework

Fri, 01/22/2016 - 10:03am

The purpose of this review is to provide (1) a synopsis on relations of mindfulness with cardiovascular disease (CVD) and major CVD risk factors, and (2) an initial consensus-based overview of mechanisms and theoretical framework by which mindfulness might influence CVD. Initial evidence, often of limited methodological quality, suggests possible impacts of mindfulness on CVD risk factors including physical activity, smoking, diet, obesity, blood pressure, and diabetes regulation. Plausible mechanisms include (1) improved attention control (e.g., ability to hold attention on experiences related to CVD risk, such as smoking, diet, physical activity, and medication adherence), (2) emotion regulation (e.g., improved stress response, self-efficacy, and skills to manage craving for cigarettes, palatable foods, and sedentary activities), and (3) self-awareness (e.g., self-referential processing and awareness of physical sensations due to CVD risk factors). Understanding mechanisms and theoretical framework should improve etiologic knowledge, providing customized mindfulness intervention targets that could enable greater mindfulness intervention efficacy.

Addition of B-Type Natriuretic Peptide to Existing Clinical Risk Scores Enhances Identification of Patients at Risk for Atrial Fibrillation Recurrence After Pulmonary Vein Isolation

Fri, 01/22/2016 - 10:03am

INTRODUCTION: Predicting which patients will be free from atrial fibrillation (AF) after pulmonary vein isolation (PVI) remains challenging. Clinical risk prediction scores show modest ability to identify patients at risk for AF recurrence after PVI. B-type natriuretic peptide (BNP) is associated with risk for incident and recurrent AF but is not currently included in existing AF risk scores. We sought to evaluate the incremental benefit of adding preoperative BNP to existing risk scores for predicting AF recurrence during the 6 months after PVI.

METHODS: One hundred sixty-one patients with paroxysmal or persistent AF underwent an index PVI procedure between 2010 and 2013; 77 patients (48%) had late AF recurrence after PVI ( > 3 months post-PVI) over the 6-month follow-up period.

RESULTS: A BNP greater than or equal to 100 pg/dL (P = 0.01) and AF recurrence within 3 months after PVI (P < 0.001) were associated with late AF recurrence in multivariate analyses. Addition of BNP to existing clinical risk scores significantly improved the areas under the curve for each score, with an integrated discrimination improvement of 0.08 (P = 0.001) and a net reclassification improvement of 60% (P = 0.001) for all risk scores.

CONCLUSIONS: Circulating BNP levels are independently associated with late AF recurrence after PVI. Inclusion of BNP significantly improves the discriminative ability of CHADS2, CHA2DS2-VASc, R2CHADS2, and the HATCH score in predicting clinically significant, late AF recurrence after PVI and should be incorporated in decision-making algorithms for management of AF. B-R2CHADS2 is the best score model for prediction of late AF recurrence.

Promotion of Inflammatory Arthritis by Interferon Regulatory Factor 5 in a Mouse Model

Fri, 01/22/2016 - 10:03am

OBJECTIVE: Polymorphisms in the transcription factor interferon regulatory factor 5 (IRF5) are associated with an increased risk of developing rheumatoid arthritis (RA). This study was undertaken to determine the role of IRF5 in a mouse model of arthritis development.

METHODS: K/BxN serum-transfer arthritis was induced in mice deficient in IRF5, or lacking IRF5 only in myeloid cells, and arthritis severity was evaluated. K/BxN arthritis was also induced in mice deficient in TRIF, Toll-like receptor 2 (TLR2), TLR3, TLR4, and TLR7 to determine the pathways through which IRF5 might promote arthritis. In vitro studies were performed to determine the role of IRF5 in interleukin-1 (IL-1) receptor and TLR signaling.

RESULTS: Arthritis severity was reduced in IRF5-deficient, TRIF-deficient, TLR3-deficient, and TLR7-deficient mice. The expression of multiple genes regulating neutrophil recruitment or function and bioactive IL-1beta formation was reduced in the joints during active arthritis in IRF5-deficient mice. In vitro studies showed that TLR7 and the TRIF-dependent TLR3 pathway induce proinflammatory cytokine production in disease-relevant cell types in an IRF5-dependent manner.

CONCLUSION: Our findings indicate that IRF5 contributes to disease pathogenesis in inflammatory arthritis. This is likely due at least in part to the role of IRF5 in mediating proinflammatory cytokine production downstream of TLR7 and TLR3. Since TLR7 and TLR3 are both RNA-sensing TLRs, this suggests that endogenous RNA ligands present in the inflamed joint promote arthritis development. These findings may be relevant to human RA, since RNA capable of activating TLR7 and TLR3 is present in synovial fluid and TLR7 and TLR3 are up-regulated in the joints of RA patients.

Measuring Diversity and Inclusion in Academic Medicine: The Diversity Engagement Survey

Fri, 01/22/2016 - 10:03am

PURPOSE: To produce a physician and scientific workforce that advances high-quality research and culturally competent care, academic medical centers (AMCs) must assess their capacity for diversity and inclusion and leverage opportunities for improvement. The Diversity Engagement Survey (DES) is presented as a diagnostic and benchmarking tool.

METHOD: The 22-item DES consists of eight factors that connect engagement theory to inclusion and diversity constructs. It was piloted at 1 AMC and then administered at 13 additional U.S. AMCs in 2011-2012. Face and content validity were assessed through a review panel. Cronbach alpha was used to assess internal consistency. Confirmatory factor analysis (CFA) was used to establish construct validity. Cluster analysis was conducted to establish ability of the DES to distinguish between institutions' degrees of engagement and inclusion. Criterion validity was established using observed differences in scores for demographic groups as suggested by the literature.

RESULTS: The sample included 13,694 respondents across 14 AMCs. Cronbach alphas for the engagement and inclusion factors (range: 0.68-0.85), CFA fit indices, and item correlations with latent constructs indicated an acceptable model fit and that items measured the intended concepts. Cluster analysis of DES scores distinguished institutions with higher, middle, and lower degrees of engagement and inclusion by their respondents. Consistent with the literature, black, Hispanic/Latino, female, and LGBTQ (lesbian, gay, bisexual, transgender, queer) respondents reported lower degrees of engagement than their counterparts.

CONCLUSIONS: The DES is a reliable and valid instrument for assessment, evaluation, and external benchmarking of institutional engagement and inclusion.

Integrating Neuroscience Knowledge and Neuropsychiatric Skills Into Psychiatry: The Way Forward

Fri, 01/22/2016 - 10:03am

Increasing the integration of neuroscience knowledge and neuropsychiatric skills into general psychiatric practice would facilitate expanded approaches to diagnosis, formulation, and treatment while positioning practitioners to utilize findings from emerging brain research. There is growing consensus that the field of psychiatry would benefit from more familiarity with neuroscience and neuropsychiatry. Yet there remain numerous factors impeding the integration of these domains of knowledge into general psychiatry.The authors make recommendations to move the field forward, focusing on the need for advocacy by psychiatry and medical organizations and changes in psychiatry education at all levels. For individual psychiatrists, the recommendations target obstacles to attaining expanded neuroscience and neuropsychiatry education and barriers stemming from widely held, often unspoken beliefs. For the system of psychiatric care, recommendations address the conceptual and physical separation of psychiatry from medicine, overemphasis on the Diagnostic and Statistical Manual of Mental Disorders and on psychopharmacology, and different systems in medicine and psychiatry for handling reimbursement and patient records. For psychiatry residency training, recommendations focus on expanding neuroscience/neuropsychiatry faculty and integrating neuroscience education throughout the curriculum.Psychiatry traditionally concerns itself with helping individuals construct meaningful life narratives. Brain function is one of the fundamental determinants of individuality. It is now possible for psychiatrists to integrate knowledge of neuroscience into understanding the whole person by asking, What person has this brain? How does this brain make this person unique? How does this brain make this disorder unique? What treatment will help this disorder in this person with this brain?

The Pediatric Imaging, Neurocognition, and Genetics (PING) Data Repository

Fri, 01/22/2016 - 10:03am

The main objective of the multi-site Pediatric Imaging, Neurocognition, and Genetics (PING) study was to create a large repository of standardized measurements of behavioral and imaging phenotypes accompanied by whole genome genotyping acquired from typically-developing children varying widely in age (3 to 20 years). This cross-sectional study produced sharable data from 1493 children, and these data have been described in several publications focusing on brain and cognitive development. Researchers may gain access to these data by applying for an account on the PING portal and filing a data use agreement. Here we describe the recruiting and screening of the children and give a brief overview of the assessments performed, the imaging methods applied, the genetic data produced, and the numbers of cases for whom different data types are available. We also cite sources of more detailed information about the methods and data. Finally we describe the procedures for accessing the data and for using the PING data exploration portal.

Design of shRNA and miRNA for Delivery to the CNS

Fri, 01/22/2016 - 10:03am

Neurologic diseases tend to target various areas of the central nervous system (CNS) and can therefore result in paralysis, dementia, and death. Neurodegenerative diseases distinguish themselves from other diseases by affecting nerve cells, which unlike many other cells in our body cannot regenerate when severely injured. The discovery of RNA interference (RNAi) has enabled scientist to design new therapeutic approaches based on specific gene silencing rather than the canonical gene therapy through gene augmentation. Two types of molecules can be used for viral vector-mediated gene silencing: short hairpin RNAs (shRNAs) and artificial microRNAs (miRNAs) that have the ability to enter the RNAi pathway. Although both shRNAs and miRNAs can be used to silence genes, they enter the RNAi pathway at different points. Unlike shRNAs, miRNAs require an additional cleavage step inside the nucleus before being exported to the cytoplasm. These molecules can then be incorporated into the RNA-induced silencing complex (RISC) which utilizes sequence complementarity to recognize target mRNAs and activate either translational repression, in the case of partial complementarity, or induce mRNA cleavage in the case of complete complementarity. Elevated amounts of shRNAs, which are commonly driven by strong polymerase III promoters, can cause saturation of the endogenous RNAi machinery due to competition between endogenous and artificial molecules. Switching to a DNA polymerase II promoter is an alternative to reduce shRNA production, thereby reducing toxicity. Even though the molecules are designed to target specific mRNAs there may be off-target effects due to nonspecific binding that must be accounted for during the design process. In this chapter we discuss the design and in vitro screening of shRNAs and artificial miRNAs.

Clinical epidemiology of heart failure with preserved ejection fraction (HFpEF) in comparatively young hospitalized patients

Fri, 01/22/2016 - 10:03am

BACKGROUND: While heart failure with preserved ejection fraction (HFpEF) is primarily a disease of old age, risk factors that contribute to HFpEF are not limited to older patients. The objectives of this population-based observational study were to describe the clinical epidemiology of HFpEF in younger ( < 65years) as compared with older ( > /=65years) patients hospitalized with acute decompensated heart failure.

METHODS AND RESULTS: We reviewed the medical records of residents of central Massachusetts hospitalized with HFpEF at all 11 greater Worcester (MA) medical centers during the 5 study years of 1995, 2000, 2002, 2004, and 2006. Among the 2398 patients hospitalized with confirmed HFpEF, 357 (14.9%) were < 65years old. Younger patients were more likely to be male, non-Caucasian, obese, and to have a history of diabetes and chronic kidney disease than older patients with HFpEF. Younger patients hospitalized with HFpEF were less likely to have received commonly prescribed cardiac medications, had a longer hospital stay, and experienced significantly lower post-discharge death rates than older hospitalized patients.

CONCLUSION: While HFpEF is predominantly a disease of old age, data from longitudinal studies remain needed to identify risk factors in younger individuals that may predispose them to the development of HFpEF.

The Fly Neuromuscular Junction: Structure and Function

Thu, 01/21/2016 - 2:37pm

The Drosophila larval neuromuscular junction (NMJ) has become one of the most powerful model systems to ask key neurobiological questions. This synapse is unparalleled by its accessibility, its simplicity, and the ability to manipulate genes important for synapse development and function. Its synapses have properties shared by many organisms including humans. The vast majority of genes that when mutated cause congenital disorders of the nervous system in humans, are present in the fruit fly genome, and fly models of human disorders are available. Thus, this preparation is a powerful tool to understand the normal function of these genes. This book reviews outstanding work by recognized leaders in the fields of Drosophila cellular neurogenetics including developmental neurobiology, mechanisms of synaptic function, and experience dependent changes at synapses. The book also includes step-by-step protocols to study the cellular biology of the NMJ, making it a vital resource for researchers beginning their investigations with this system, for those who are training students and postdoctoral fellows in this area, or simply as a general reference material for neuroscientists and neuroscience professors in general.

Wnts and TGF beta in synaptogenesis: old friends signalling at new places

Thu, 01/21/2016 - 2:37pm

The formation of mature synaptic connections involves the targeted transport and aggregation of synaptic vesicles, the gathering of presynaptic release sites and the clustering of postsynaptic neurotransmitter receptors and ion channels. Positional cues are required to orient the cytoskeleton in the direction of neuronal outgrowth, and also to direct the juxtaposition of synaptic protein complexes at the pre- and postsynaptic membranes. Both anterograde and retrograde factors are thought to contribute positional information during synaptic differentiation, and recent studies in vertebrates and invertebrates have begun to uncover a new role in this process for proteins that are essential for pattern formation in the early embryo.

Exosomes go with the Wnt

Thu, 01/21/2016 - 2:37pm

Exosomes, small secreted microvesicles, are implicated in intercellular communication in diverse cell types, transporting protein, lipid and nucleic acid cargo that impact the physiology of recipient cells. Besides the signaling function of exosomes they also serve as a mechanism to dispose obsolete cellular material. Particularly exciting is the involvement of exosomal communication in the nervous system, as this has important implications for brain development and function. The properties of exosomes are also beginning to entice the biomedical community since they represent potentially novel avenues for the targeted delivery of customized exosome cargo, such as miRNAs, during disease. Our findings implicating exosomes in trans-synaptic communication emerged from the serendipitous observation that at the Drosophila larval neuromuscular junction (NMJ) the release of a signaling molecule, Wnt1/Wingless (Wg) and its binding partner Evenness Interrupted (Evi)/Wntless (Wls)/Sprint (Srt), were released by motorneurons in association with vesicles, which we postulated to be exosomes. In our most recent paper using in vivo analysis at the Drosophila NMJ as well as in cultured insect cells we formally demonstrate that Evi rides in exosomes that are released to the extracellular space and identify some of the players involved in their release. In addition, a proteomic analysis of exosomes highlights novel potential function of exosomes.

Nucleus to Synapse Nesprin1 Railroad Tracks Direct Synapse Maturation through RNA Localization

Thu, 01/21/2016 - 2:37pm

An important mechanism underlying synapse development and plasticity is the localization of mRNAs that travel from the nucleus to synaptic sites. Here we demonstrate that the giant nuclear-associated Nesprin1 (dNesp1) forms striated F-actin-based filaments, which we dubbed "railroad tracks," that span from muscle nuclei to postsynaptic sites at the neuromuscular junction in Drosophila. These railroad tracks specifically wrap around immature boutons formed during development and in response to electrical activity. In the absence of dNesp1, mRNAs normally localized at postsynaptic sites are lacking and synaptic maturation is inhibited. This dNesp1 function does not depend on direct association of dNesp1 isoforms with the nuclear envelope. We also show that dNesp1 functions with an unconventional myosin, Myo1D, and that both dNesp1 and Myo1D are mutually required for their localization to immature boutons. These studies unravel a novel pathway directing the transport of mRNAs from the nucleus to postsynaptic sites during synaptic maturation.

Implementing Standardized Patients to Teach Cultural Competency to Graduate Nursing Students

Fri, 01/15/2016 - 4:07pm

Background: Although many programs emphasize knowledge enhancement on caring for patients from diverse cultural backgrounds, few integrate cultural assessments, skills, and encounters with these patients. To fill this gap, an objective structured clinical examination (OSCE) with culturally diverse standardized patients was introduced to 29 first-year graduate nursing students.

Method: The learning experience was implemented in three phases: (a) Pretest, (b) didactic introduction to culturally sensitive issues, and (c) video-recorded OSCE with two ethnically diverse, standardized patients. A posttest and final evaluation concluded the experience.

Results/Conclusions: The objective scoring of student competency from the SPs was positive, especially their assessment of patient use of alternative therapies. The students perceived that their critical thinking skills were enhanced.

A Novel Initialization Method for Particle Swarm Optimization-based FCM in Big Biomedical Data

Fri, 01/15/2016 - 9:53am

Based on empirical studies, the feature of random initialization in Particle Swarm Optimization (PSO) based Fuzzy c-means (FCM) methods affects the computational performance especially in big data. As the data points in high-density areas are more likely near the cluster centroids, we design a new algorithm to guide the initialization according to the data density patterns. Our algorithm is initialized by fusing the data characteristics near the cluster centers. Our evaluation results from real data show that our approach can significantly improve the computational performance of PSO-based Fuzzy clustering methods, while preserving comparable clustering performance.

Using Probabilistic Approach to Joint Clustering and Statistical Inference: Analytics for Big Investment Data

Fri, 01/15/2016 - 9:53am

This paper proposes a Contrarian Probabilistic Model (CPM) to evaluate the effectiveness of contrarians' investment in preferred stocks using big data from Tradeline. CPM accommodates the unique features of investment data which are often correlated, nested, heterogeneous, non-normal with missing values. The clustering and statistical inference are integrated in CPM, which enables joint investment behavior trajectory pattern recognition and risk analyses based on the entire variance-covariance structure between and within clusters. The empirical study using CPM provides a finer and comprehensive evaluation of contrarian investment in preferred stocks. Two distinctive investment behavior trajectory clusters were identified, showing a few high-risk-seeking contrarians achieved high returns over five year long-term investment, while the majority of contrarians did not outperform glamour stockholders in preferred stock investment. Although CPM was developed using historical data, it could be developed into an analytical tool for online near real time big investment data analyses.

Tachykinin acts upstream of autocrine Hedgehog signaling during nociceptive sensitization in Drosophila

Thu, 01/14/2016 - 4:31pm

Pain signaling in vertebrates is modulated by neuropeptides like Substance P (SP). To determine whether such modulation is conserved and potentially uncover novel interactions between nociceptive signaling pathways we examined SP/Tachykinin signaling in a Drosophila model of tissue damage-induced nociceptive hypersensitivity. Tissue-specific knockdowns and genetic mutant analyses revealed that both Tachykinin and Tachykinin-like receptor (DTKR99D) are required for damage-induced thermal nociceptive sensitization. Electrophysiological recording showed that DTKR99D is required in nociceptive sensory neurons for temperature-dependent increases in firing frequency upon tissue damage. DTKR overexpression caused both behavioral and electrophysiological thermal nociceptive hypersensitivity. Hedgehog, another key regulator of nociceptive sensitization, was produced by nociceptive sensory neurons following tissue damage. Surprisingly, genetic epistasis analysis revealed that DTKR function was upstream of Hedgehog-dependent sensitization in nociceptive sensory neurons. Our results highlight a conserved role for Tachykinin signaling in regulating nociception and the power of Drosophila for genetic dissection of nociception.

Cross-talk between PRMT1-mediated methylation and ubiquitylation on RBM15 controls RNA splicing

Thu, 01/14/2016 - 4:31pm

RBM15, an RNA binding protein, determines cell-fate specification of many tissues including blood. We demonstrate that RBM15 is methylated by protein arginine methyltransferase 1 (PRMT1) at residue R578 leading to its degradation via ubiquitylation by an E3 ligase (CNOT4). Overexpression of PRMT1 in acute megakaryocytic leukemia cell lines blocks megakaryocyte terminal differentiation by downregulation of RBM15 protein level. Restoring RBM15 protein level rescues megakaryocyte terminal differentiation blocked by PRMT1 overexpression. At the molecular level, RBM15 binds to pre-mRNA intronic regions of genes important for megakaryopoiesis such as GATA1, RUNX1, TAL1 and c-MPL. Furthermore, preferential binding of RBM15 to specific intronic regions recruits the splicing factor SF3B1 to the same sites for alternative splicing. Therefore, PRMT1 regulates alternative RNA splicing via reducing RBM15 protein concentration. Targeting PRMT1 may be a curative therapy to restore megakaryocyte differentiation for acute megakaryocytic leukemia.

Membrane-bound and soluble Fas ligands have opposite functions in photoreceptor cell death following separation from the retinal pigment epithelium

Thu, 01/14/2016 - 4:31pm

Fas ligand (FasL) triggers apoptosis of Fas-positive cells, and previous reports described FasL-induced cell death of Fas-positive photoreceptors following a retinal detachment. However, as FasL exists in membrane-bound (mFasL) and soluble (sFasL) forms, and is expressed on resident microglia and infiltrating monocyte/macrophages, the current study examined the relative contribution of mFasL and sFasL to photoreceptor cell death after induction of experimental retinal detachment in wild-type, knockout (FasL-/-), and mFasL-only knock-in (DeltaCS) mice. Retinal detachment in FasL-/- mice resulted in a significant reduction of photoreceptor cell death. In contrast, DeltaCS mice displayed significantly more apoptotic photoreceptor cell death. Photoreceptor loss in DeltaCS mice was inhibited by a subretinal injection of recombinant sFasL. Thus, Fas/FasL-triggered cell death accounts for a significant amount of photoreceptor cell loss following the retinal detachment. The function of FasL was dependent upon the form of FasL expressed: mFasL triggered photoreceptor cell death, whereas sFasL protected the retina, indicating that enzyme-mediated cleavage of FasL determines, in part, the extent of vision loss following the retinal detachment. Moreover, it also indicates that treatment with sFasL could significantly reduce photoreceptor cell loss in patients with retinal detachment.

Chromatin Dynamics and the RNA Exosome Function in Concert to Regulate Transcriptional Homeostasis

Thu, 01/14/2016 - 4:31pm

The histone variant H2A.Z is a hallmark of nucleosomes flanking promoters of protein-coding genes and is often found in nucleosomes that carry lysine 56-acetylated histone H3 (H3-K56Ac), a mark that promotes replication-independent nucleosome turnover. Here, we find that H3-K56Ac promotes RNA polymerase II occupancy at many protein-coding and noncoding loci, yet neither H3-K56Ac nor H2A.Z has a significant impact on steady-state mRNA levels in yeast. Instead, broad effects of H3-K56Ac or H2A.Z on RNA levels are revealed only in the absence of the nuclear RNA exosome. H2A.Z is also necessary for the expression of divergent, promoter-proximal noncoding RNAs (ncRNAs) in mouse embryonic stem cells. Finally, we show that H2A.Z functions with H3-K56Ac to facilitate formation of chromosome interaction domains (CIDs). Our study suggests that H2A.Z and H3-K56Ac work in concert with the RNA exosome to control mRNA and ncRNA expression, perhaps in part by regulating higher-order chromatin structures.

The PsychENCODE project

Thu, 01/14/2016 - 4:31pm

Recent research on disparate psychiatric disorders has implicated rare variants in genes involved in global gene regulation and chromatin modification, as well as many common variants located primarily in regulatory regions of the genome. Understanding precisely how these variants contribute to disease will require a deeper appreciation for the mechanisms of gene regulation in the developing and adult human brain. The PsychENCODE project aims to produce a public resource of multidimensional genomic data using tissue- and cell type–specific samples from approximately 1,000 phenotypically well-characterized, high-quality healthy and disease-affected human post-mortem brains, as well as functionally characterize disease-associated regulatory elements and variants in model systems. We are beginning with a focus on autism spectrum disorder, bipolar disorder and schizophrenia, and expect that this knowledge will apply to a wide variety of psychiatric disorders. This paper outlines the motivation and design of PsychENCODE.