63,978 Works

Midlife Alcohol Consumption and the Risk of Stroke in the Atherosclerosis Risk in Communities Study

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Alcohol consumption is common in the US and may confer beneficial cardiovascular effects at light-to-moderate doses. The alcohol-stroke relationship remains debated. We estimated the relationship between mid-life, self-reported alcohol consumption and ischemic stroke (IS) and intracerebral hemorrhage (ICH) in a biracial cohort.

White Matter Lesion Progression: Genome-Wide Search for Genetic Influences

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White matter lesion (WML) progression on magnetic resonance imaging (MRI) is related to cognitive decline and stroke, but its determinants besides baseline WML burden are largely unknown. Here, we estimated heritability of WML progression, and sought common genetic variants associated with WML progression in elderly participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.

Structural and Thermodynamic Basis for Enhanced DNA Binding by a Promiscuous Mutant EcoRI Endonuclease

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Promiscuous mutant EcoRI endonucleases bind to the canonical site GAATTC more tightly than does the wild-type endonuclease, yet cleave variant (EcoRI*) sites more rapidly than does wild-type. The crystal structure of the A138T promiscuous mutant homodimer in complex with a GAATTC site is nearly identical to that of the wild-type complex, except that the Thr138 side chains make novel packing interactions with bases in the 5′-flanking regions outside the recognition hexanucleotide, while excluding two bound...

Computer-Based Redesign of a β Sandwich Protein Suggests that Extensive Negative Design Is Not Required for De Novo β Sheet Design

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The de novo design of globular β-sheet proteins remains largely an unsolved problem. It is unclear if most designs are failing because the designed sequences do not have favorable energies in the target conformations or if more emphasis should be placed on negative design, i.e. explicitly identifying sequences that have poor energies when adopting undesired conformations. We tested if we could redesign the sequence of a naturally occurring β-sheet protein, tenascin, with a design algorithm...

Mg2+-Assisted Catalysis by B. Stearothermophilus TrpRS Is Promoted by Allosteric Effects

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Mn2+-assisted catalysis by B. stearothermophilus TrpRS parallels that in polymerases and reduces specificity in amino acid activation. As predicted by non-equilibrium molecular dynamics simulations, multi-variant thermodynamic cycles with [ATP]-dependent Michaelis-Menten kinetics and Mn2+ for Mg2+ substitution demonstrate energetic coupling of ATP affinities to the metal; to lysines K111 and K192, which interact via the PPi leaving group; and to K195, which couples differently to the metal via the α–phosphate. However, net coupling to the metal...

A Master Switch Couples Mg2+-Assisted Catalysis to Domain Motion in B. Stearothermophilus Tryptophanyl-tRNA Synthetase

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We demonstrate how Tryptophanyl-tRNA synthetase (TrpRS) uses conformation-dependent Mg2+ activation to couple catalysis of tryptophan activation to specific, functional domain movements. Rate acceleration by Mg2+ requires ~ -6.0 kcal/mole in protein•Mg2+ interaction energy, none of which arises from the active site. A highly cooperative interaction between Mg2+ and four residues from a remote, conserved motif that mediates the shear of domain movement: (i) destabilizes the pre-transition state conformation, thereby (ii) inducing the Mg2+ to stabilize...

Treatment Guidelines for Substance Use Disorders and Serious Mental Illnesses: Do They Address Co-Occurring Disorders?

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Practice guidelines are important tools for improving the delivery of evidence-based practices and reducing inappropriate variation in current treatment approaches. This study examined the degree to which guidelines targeted to the treatment of substance use disorders or serious mental illness address treatment of co-occurring disorders. Guidelines archived by the National Guideline Clearinghouse (NGC) were retrieved in December 2007 and content analyzed. Nineteen pertinent guidelines were identified, and 11 included recommendations regarding the assessment and/or treatment...

Correlates of a good death and the impact of hospice involvement: findings from the national survey of households affected by cancer

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Knowing how to improve the dying experience for patients with end-stage cancer is essential for cancer professionals. However, there is little evidence on the relationship between clinically relevant factors and quality of death. Also, while hospice has been linked with improved outcomes, our understanding of factors that contribute to a “good death” when hospice is involved remains limited. This study (1) identified correlates of a good death; and, (2) provided evidence on the impact of...

Bacterial-dependent up-regulation of intestinal bile acid binding protein and transport is FXR-mediated following ileo-cecal resection

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Bile acid reclamation following ileo-cecal resection (ICR) may prevent colonic mucosa from chronic injury. In this study, we hypothesized that in a murine model of ICR the remnant colon would upregulate the cellular machinery necessary for BA reclamation and would do so in an FXR- and bacteria-dependent manner.

Serum leptin levels are inversely correlated with omental gene expression of adiponectin and markedly decreased after gastric bypass surgery

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Adipose tissue is the most abundant endocrine tissue in the body, producing leptin, a hormone important in regulating hunger, and adiponectin, a hormone involved in insulin sensitivity and inflammation. The aim of this study was to assess the impact of gastric bypass surgery (GBS) on leptin levels and its relation to adipose tissue expression of adiponectin.

Evaluation of a Minimally Invasive Image-Guided Surgery System for Hepatic Ablation Procedures

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The Explorer Minimally Invasive Liver (MIL) system uses imaging to create a 3-dimensional model of the liver. Intraoperatively, the system displays the position of instruments relative to the virtual liver. A prospective clinical study compared it with intraoperative ultrasound (iUS) in laparoscopic liver ablations.

Targeted Therapies in Melanoma

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Advances in understanding the biology of melanoma have provided great insights about the mechanisms of chemoresistance and its genetic heterogeneity in parallel with advances in drug design culminating in recent major treatment breakthroughs using small molecules inhibitors in metastatic melanoma (MM). While clinical benefit of targeted therapies has been unquestionable, future advances can only be possible if we better understand the interplay between genetic aberrations and role of other crucial non-genetic changes yet to be...

Distinct patterns of ΔFosB induction in brain by drugs of abuse

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The transcription factor ΔFosB accumulates and persists in brain in response to chronic stimulation. This accumulation after chronic exposure to drugs of abuse has been demonstrated previously by Western blot most dramatically in striatal regions, including dorsal striatum (caudate/putamen) and nucleus accumbens. In the present study, we used immunohistochemistry to define with greater anatomical precision the induction of ΔFosB throughout the rodent brain after chronic drug treatment. We also extended previous research involving cocaine, morphine,...

A Scalable Protocol for the Regioselective Alkylation of 2-Methylcyclohexane-1,3-dione with Unactivated sp3 Electrophiles

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A method for the C-selective alkylation of 2-methylcyclohexane-1,3-dione with unactivated sp3 electrophiles is accomplished via alkylation and subsequent deprotection of the derived ketodimethyl hydrazones. The present method provides a high-yielding entry to dialkyl cycloalkanones that cannot be accessed via direct alkylation of 2-methylcyclohexane-1,3-dione. The title reaction may be useful in the scalable preparation of terpene and steroidal building blocks in the arena of natural product synthesis.

Genome-Scale Phylogenetics: Inferring the Plant Tree of Life from 18,896 Gene Trees

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Phylogenetic analyses using genome-scale data sets must confront incongruence among gene trees, which in plants is exacerbated by frequent gene duplications and losses. Gene tree parsimony (GTP) is a phylogenetic optimization criterion in which a species tree that minimizes the number of gene duplications induced among a set of gene trees is selected. The run time performance of previous implementations has limited its use on large-scale data sets. We used new software that incorporates recent...

Robust Analysis of High Throughput Screening (HTS) Assay Data

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Quantitative high throughput screening (qHTS) assays use cells or tissues to screen thousands of compounds in a short period of time. Data generated from qHTS assays are then evaluated using nonlinear regression models, such as the Hill model, and decisions regarding toxicity are made using the estimates of the parameters of the model. For any given compound, the variability in the observed response may either be constant across dose groups (homoscedasticity) or vary with dose...

Anti-AIDS agents 83. Efficient microwave-assisted one-pot preparation of angular 2,2-dimethyl-2H-chromone containing compounds

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A novel and efficient microwave-assisted one-pot reaction was developed to synthesize angular 2,2-dimethyl-2H-chromone containing compounds, which is the first and key step in the synthesis of potent DCK and DCP anti-HIV agents. The newly developed microwave synthesis conditions dramatically shortened the reaction time from 2 days to 4 hours with improved yields.

Anti-AIDS agents 88. Anti-HIV conjugates of betulin and betulinic acid with AZT prepared via click chemistry

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In the present study, a new strategy to link AZT with betulin/betulinic acid (BA) by click chemistry was designed and achieved. This conjugation via a triazole linkage offers a new direction for modification of anti-HIV triterpenes. Click chemistry provides an easy and productive way for linking two molecules, even when one of them is a large natural product. Among the newly synthesized conjugates, compounds 15 and 16 showed potent anti-HIV activity with EC50 values of...

Biventricular Assist Device Terminates Polymorphic Ventricular Tachycardia in Giant Cell Myocarditis

We present the case of a 55-year-old woman with giant cell myocarditis who experienced a rapid deterioration in her condition. As her heart failure progressed, she developed more ventricular ectopic beats, which culminated in a polymorphic ventricular tachycardia that did not improve despite immunosuppressive and antiarrhythmic therapy. Emergent biventricular assist device placement, however, did eliminate her arrhythmia.

Pulmonary Immunization of Guinea Pigs with Diphtheria CRM-197 Antigen as Nanoparticle Aggregate Dry Powders Enhance Local and Systemic Immune Responses

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This study establishes the immune response elicited in guinea pigs after pulmonary and parenteral immunizations with diphtheria CRM-197 antigen (CrmAg). Several spray-dried powders of formalin-treated/untreated CrmAg nanoaggregates with L-leucine were delivered to the lungs of guinea pigs. A control group consisting of alum with adsorbed CrmAg in saline was administered by intramuscular injection. Animals received three doses of powder vaccines containing 20 or 40 μg of CrmAg. The serum IgG titers were measured for 16...

Radionuclide Decorporation: Matching the Biokinetics of Actinides by Transdermal Delivery of Pro-chelators

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The threat of nuclear terrorism by the deliberate detonation of a nuclear weapon or radiological dispersion device ("dirty bomb") has made emergency response planning a priority. The only FDA-approved treatments for contamination with isotopes of the transuranic elements Am, Pu, and Cm are the Ca and Zn salts of diethylenetriaminepentaacetic acid (DTPA). These injectable products are not well suited for use in a mass contamination scenario as they require skilled professionals for their administration and...

Looking for Trouble: Preventive Genomic Sequencing in the General Population and the Role of Patient Choice

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Advances in genomics have led to calls for developing population-based preventive genomic sequencing (PGS) programs with the goal of identifying genetic health risks in adults without known risk factors. One critical issue for minimizing the harms and maximizing the benefits of PGS is determining the kind and degree of control individuals should have over the generation, use, and handling of their genomic information. In this article we examine whether PGS programs should offer individuals the...

A Clinical Risk Score for Atrial Fibrillation in a Biracial Prospective Cohort (from the Atherosclerosis Risk In Communities [ARIC] Study)

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A risk score for AF has been developed by the Framingham Heart Study; however the applicability of this risk score, derived from whites, to predict new-onset AF in non-whites is uncertain. Therefore, we developed a 10-year risk score for new-onset AF using risk factors commonly measured in clinical practice using 14,546 individuals from the Atherosclerosis Risk in Communities study, a prospective community-based cohort of blacks and whites in the United States. During 10 years of...

Association of Serum Uric Acid With Incident Atrial Fibrillation (from the Atherosclerosis Risk in Communities [ARIC] Study)

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Atrial fibrillation (AF) is one of the most common arrhythmias seen in clinical practice. Current evidence suggests that serum uric acid (SUA) could be a marker of oxidative damage a factor reported as part of the mechanisms of AF. The purpose of this study was to evaluate if SUA predicted AF in the Atherosclerosis Risk in Communities study (ARIC). This analysis included 15,382 AF-free black and white men and women, aged 45-64, from the ARIC...

Relation Between Digital Peripheral Arterial Tonometry and Brachial Artery Ultrasound Measures of Vascular Function in Patients With Coronary Artery Disease and in Healthy Volunteers

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Digital peripheral arterial tonometry (PAT) is an emerging, non-invasive method to assess vascular function. The physiology underlying this phenotype, however, remains unclear. Therefore, we evaluated the relationship between digital PAT and established brachial artery ultrasound measures of vascular function under basal conditions and following reactive hyperemia. Using a cross-sectional study design, digital PAT and brachial artery ultrasound with pulsed wave Doppler were simultaneously completed at baseline and following reactive hyperemia in both individuals with established...

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