63,978 Works

RhoA Regulates Calcium-Independent Periodic Contractions of the Cell Cortex

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When microtubules are depolymerized in spreading cells, they experience morphological oscillations characterized by a period of about a minute, indicating that normal interactions between the microfilament and microtubule systems have been significantly altered. This experimental system provides a test bed for the development of both fine- and coarse-grained models of complex motile processes, but such models need to be adequately informed by experiment. Using criteria based on Fourier transform analysis, we detect spontaneous oscillations in...

Stiffening of Individual Fibrin Fibers Equitably Distributes Strain and Strengthens Networks

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As the structural backbone of blood clots, fibrin networks carry out the mechanical task of stemming blood flow at sites of vascular injury. These networks exhibit a rich set of remarkable mechanical properties, but a detailed picture relating the microscopic mechanics of the individual fibers to the overall network properties has not been fully developed. In particular, how the high strain and failure characteristics of single fibers affect the overall strength of the network is...

SNAP23 Is Selectively Expressed in Airway Secretory Cells and Mediates Baseline and Stimulated Mucin Secretion

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Airway mucin secretion is important pathophysiologically and as a model of polarized epithelial regulated exocytosis. We find the trafficking protein, SNAP23 (23-kDa paralogue of synaptosome-associated protein of 25 kDa), selectively expressed in secretory cells compared with ciliated and basal cells of airway epithelium by immunohistochemistry and FACS, suggesting that SNAP23 functions in regulated but not constitutive epithelial secretion. Heterozygous SNAP23 deletant mutant mice show spontaneous accumulation of intracellular mucin, indicating a defect in baseline secretion....

Fabrication of nitric oxide-releasing polyurethane glucose sensor membranes

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Despite clear evidence that polymeric nitric oxide (NO) release coatings reduce the foreign body response (FBR) and may thus improve the analytical performance of in vivo continuous glucose monitoring devices when used as sensor membranes, the compatibility of the NO release chemistry with that required for enzymatic glucose sensing remains unclear. Herein, we describe the fabrication and characterization of NO-releasing polyurethane sensor membranes using NO donor-modified silica vehicles embedded within the polymer. In addition to...

A general framework for studying genetic effects and gene-environment interactions with missing data

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Missing data arise in genetic association studies when genotypes are unknown or when haplotypes are of direct interest. We provide a general likelihood-based framework for making inference on genetic effects and gene–environment interactions with such missing data. We allow genetic and environmental variables to be correlated while leaving the distribution of environmental variables completely unspecified. We consider 3 major study designs—cross-sectional, case–control, and cohort designs—and construct appropriate likelihood functions for all common phenotypes (e.g. case–control...

Hormonal contraceptive use before and after conception in relation to preterm birth and small for gestational age: an observational cohort study

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To evaluate whether hormonal contraceptives, used before or in early pregnancy, confer increased risk of preterm birth or reduced fetal growth.

Safety and efficacy of factor IX gene transfer to skeletal muscle in murine and canine hemophilia B models by adeno-associated viral vector serotype 1

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Adeno-associated viral (AAV) vectors (serotype 2) efficiently transduce skeletal muscle, and have been used as gene delivery vehicles for hemophilia B and for muscular dystrophies in experimental animals and humans. Recent reports suggest that AAV vectors based on serotypes 1, 5, and 7 transduce murine skeletal muscle much more efficiently than AAV-2, with reported increases in expression ranging from 2-fold to 1000-fold. We sought to determine whether this increased efficacy could be observed in species...

Re-establishment of VWF-dependent Weibel-Palade bodies in VWD endothelial cells

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Type 3 von Willebrand disease (VWD) is a severe hemorrhagic defect in humans. We now identify the homozygous mutation in the Chapel Hill strain of canine type 3 VWD that results in premature termination of von Willebrand factor (VWF) protein synthesis. We cultured endothelium from VWD and normal dogs to study intracellular VWF trafficking and Weibel-Palade body formation. Weibel-Palade bodies could not be identified in the canine VWD aortic endothelial cells (VWD-AECs) by P-selectin, VWFpp,...

An Analysis of 24-Hour Ambulatory Blood Pressure Monitoring Data using Orthonormal Polynomials in the Linear Mixed Model

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The use of 24-hour ambulatory blood pressure monitoring (ABPM) in clinical practice and observational epidemiological studies has grown considerably in the past 25 years. ABPM is a very effective technique for assessing biological, environmental, and drug effects on blood pressure.

Development and Initial Validation of Quality-of-Life Questionnaires for Intermittent Exotropia

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We report the development and initial validation of patient–derived, health related quality of life (HRQOL) questionnaires for intermittent exotropia (IXT).

Antenatal corticosteroids for management of preterm birth: a multi-country analysis of health system bottlenecks and potential solutions

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BackgroundPreterm birth complications are the leading cause of deaths for children under five years. Antenatal corticosteroids (ACS) are effective at reducing mortality and serious morbidity amongst infants born at <34 weeks gestation. WHO guidelines strongly recommend use of ACS for women at risk of imminent preterm birth where gestational age, imminent preterm birth, and risk of maternal infection can be assessed, and appropriate maternal/newborn care provided. However, coverage remains low in high-burden countries for reasons...

Trust in Community-Engaged Research Partnerships: A Methodological Overview of Designing a Multisite Clinical and Translational Science Awards (CTSA) Initiative

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Community-engaged research (CEnR) builds on the strengths of the Clinical and Translational Science Awards (CTSA) framework to address health in underserved and minority communities. There is a paucity of studies that identify the process from which trust develops in CEnR partnerships. This study responds to the need for empirical investigation of building and maintaining trust from a multistakeholder perspective. We conducted a multi-institutional pilot study using concept mapping with to better understand how trust, a...

Predictors of Caregiver Communication About Reproductive and Sexual Health and Sensitive Sex Topics

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Numerous studies examining parent–teen communication about sex (PTCS) have focused on reproductive and sexual health information (i.e., pregnancy, physical development, contraception), with significantly fewer addressing communication about sensitive sex topics (i.e., sexual pleasure, masturbation). This study compares predictors of communication about reproductive and sexual health to those of sensitive sex topics with early adolescents. Participants were 465 rural caregivers and their African American youth. Positive attitudes and self-efficacy for PTCS, open communication style, and older...

Conceptualizing trust in community-academic research partnerships using concept mapping approach: A multi-CTSA study

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Objectives Collaborations between communities, healthcare practices and academic institutions are a strategy to address health disparities. Trust is critical in the development and maintaining of effective collaborations. The aim of this pilot study was to engage stakeholders in defining determinants of trust in community academic research partnerships and to develop a framework for measuring trust. Methods The study was conducted by five collaborating National Institute of Health’ Clinical and Translational Sciences Awardees. We used concept...

State of the evidence

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This review focuses on recent studies of osteoarthritis epidemiology, including research on prevalence, incidence, and a broad array of potential risk factors at the person level and joint level.

Advances in RNA Secondary and Tertiary Structure Analysis by Chemical Probing

RNA is arguably the most versatile biological macromolecule due to its ability both to encode and to manipulate genetic information. The diverse roles of RNA depend on its ability to fold back on itself to form biologically functional structures that bind small molecules and large protein ligands, to change conformation, and to affect the cellular regulatory state. These features of RNA biology can be structurally interrogated using chemical mapping experiments. The usefulness and applications of...

How do persistent infections with hepatitis C virus cause liver cancer?

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Persistent infection with hepatitis C virus (HCV) is associated with an increased risk of hepatocellular carcinoma (HCC). Cancer typically develops in a setting of chronic hepatic inflammation and advanced fibrosis or cirrhosis, and such tissue represents a pre-neoplastic “cancer field”. However, not all persistent infections progress to HCC and a combination of viral and host immune factors likely to contribute to carcinogenesis. HCV may disrupt cellular pathways involved in detecting and responding to DNA damage,...

Abundance- and Activity-Based Proteomics in Platelet Biology

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Human platelets are thought to express approximately 2000–3000 proteins, but post-translational modifications, alternatively spliced variants and a rich diversity of vertebrate domain architectures likely make this a conservative estimate. Even though rapidly advancing proteomic techniques have facilitated the identification of roughly one third of the platelet proteome, a combination of abundance-based and activity-based proteomics methodologies is needed for elucidation of platelet functional characteristics including the definition of a “core proteome” and recognition of diverse enzyme...

Choice of atypical antipsychotic therapy for patients with schizophrenia: An analysis of a medicaid population

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In patients treated at Veterans Affairs facilities, demographicand clinical characteristics have been found to influence the choice of atypical antipsychotic drugs. However, little is known about the influences on the choice between olanzapine and risperidone in patients with schizophrenia enrolled in Medicaid.

Tuning hERG Out: Antitarget QSAR Models for Drug Development

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Several non-cardiovascular drugs have been withdrawn from the market due to their inhibition of hERG K+ channels that can potentially lead to severe heart arrhythmia and death. As hERG safety testing is a mandatory FDA-required procedure, there is a considerable interest for developing predictive computational tools to identify and filter out potential hERG blockers early in the drug discovery process. In this study, we aimed to generate predictive and well-characterized quantitative structure–activity relationship (QSAR) models...

Applying whole-genome studies of epigenetic regulation to study human disease

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Epigenetics may be broadly defined as the study of processes that produce a heritable phenotype that is not strictly dependent on DNA sequence. The definition has traditionally been restricted to processes that occur in the cell’s nucleus, with the term ‘heritable’ having a loose meaning that can be applied to either the entire organism or single cells. For example, a process that produces a phenotype only in a specific cell type (for instance, chromatin-mediated maintenance...

Biochemical and bioinformatic analysis of the MYO19 motor domain

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Mitochondrial dynamics are dependent on both the microtubule and actin cytoskeletal systems. Evidence for the involvement of myosin motors has been described in many systems, and until recently a candidate mitochondrial transport motor had not been described in vertebrates. Myosin-XIX (MYO19) was predicted to represent a novel class of myosin and had previously been shown to bind to mitochondria and increase mitochondrial network dynamics when ectopically expressed. Our analyses comparing ∼40 MYO19 orthologs to ∼2000...

Spatiotemporal relationships between the cell shape and the actomyosin cortex of periodically protruding cells

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We investigate the dynamics of cell shape and analyze the actin and myosin distributions of cells exhibiting cortical density traveling waves. These waves propagate by repeated cycles of cortical compression (folding) and dilation (unfolding) that lead to periodic protrusions (oscillations) of the cell boundary. The focus of our detailed analysis is the remarkable periodicity of this phenotype, in which both the overall shape transformation and distribution of actomyosin density are repeated from cycle to cycle...

Characterization of microfluidic human epidermal keratinocyte culture

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Human epidermal keratinocytes (HEK) are skin cells of primary importance in maintaining the body’s defensive barrier and are used in vitro to assess the irritation potential and toxicity of chemical compounds. Microfluidic systems hold promise for high throughput irritant and toxicity assays, but HEK growth kinetics have yet to be characterized within microscale culture chambers. This research demonstrates HEK patterning on microscale patches of Type I collagen within microfluidic channels and maintenance of these cells...

Symbiotic Bacterial Metabolites Regulate Gastrointestinal Barrier Function via the Xenobiotic Sensor PXR and Toll-like Receptor 4

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Intestinal microbial metabolites are conjectured to affect mucosal integrity through an incompletely characterized mechanism. Here we showed microbial-specific indoles regulated intestinal barrier function through the xenobiotic sensor, pregnane X receptor (PXR). Indole 3-propionic acid (IPA), in the context of indole, is as a ligand for PXR in vivo, and IPA down-regulated enterocyte TNF–α while up-regulated junctional protein-coding mRNAs. PXR-deficient (Nr1i2−/−) mice showed a distinctly “leaky” gut physiology coupled with up-regulation of the Toll-like receptor (TLR)...

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