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Find video protocols related to scientific articles indexed in Pubmed.
Patients with nodding syndrome in Uganda improve with symptomatic treatment: a cross-sectional study.
BMJ Open
PUBLISHED: 11-16-2014
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Nodding syndrome (NS) is a poorly understood neurological disorder affecting thousands of children in Africa. In March 2012, we introduced a treatment intervention that aimed to provide symptomatic relief. This intervention included sodium valproate for seizures, management of behaviour and emotional difficulties, nutritional therapy and physical rehabilitation. We assessed the clinical and functional outcomes of this intervention after 12?months of implementation.
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Phenomapping for Novel Classification of Heart Failure with Preserved Ejection Fraction.
Circulation
PUBLISHED: 11-16-2014
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-Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous clinical syndrome in need of improved phenotypic classification. We sought to evaluate whether unbiased clustering analysis using dense phenotypic data ("phenomapping") could identify phenotypically distinct HFpEF categories.
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Cocaine-induced psychotic disorders: presentation, mechanism, and management.
J Dual Diagn
PUBLISHED: 11-14-2014
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Cocaine, the third mostly commonly used illicit drug in the United States, has a wide range of neuropsychiatric effects, including transient psychotic symptoms. When psychotic symptoms occur within a month of cocaine intoxication or withdrawal, the diagnosis is cocaine-induced psychotic disorder (CIPD). Current evidence suggests those with CIPD are likely to be male, have longer severity and duration of cocaine use, use intravenous cocaine, and have a lower body mass index. Differentiating CIPD from a primary psychotic disorder requires a detailed history of psychotic symptoms in relation to substance use and often a longitudinal assessment. Treatment includes providing a safe environment, managing agitation and psychosis, and addressing the underlying substance use disorder. This review begins with a clinical case and summarizes the literature on CIPD, including clinical presentation, differential diagnosis, mechanism and predictors of illness, and treatment.
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Catalytic Z-Selective Cross-Metathesis in Complex Molecule Synthesis: A Convergent Stereoselective Route to Disorazole C1.
J. Am. Chem. Soc.
PUBLISHED: 11-08-2014
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A convergent diastereo- and enantioselective total synthesis of anticancer and antifungal macrocyclic natural product disorazole C1 is reported. The central feature of the successful route is the application of catalytic Z-selective cross-metathesis (CM). Specifically, we illustrate that catalyst-controlled stereoselective CM can be performed to afford structurally complex Z-alkenyl-B(pin) as well as Z-alkenyl iodide compounds reliably, efficiently, and with high selectivity (pin = pinacolato). The resulting intermediates are then joined in a single-step operation through catalytic inter- and intramolecular cross-coupling to furnish the desired 30-membered ring macrocycle containing the critical (Z,Z,E)-triene moieties.
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Systematic mutational analysis of the LytTR DNA binding domain of Staphylococcus aureus virulence gene transcription factor AgrA.
Nucleic Acids Res.
PUBLISHED: 10-28-2014
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Most DNA-binding bacterial transcription factors contact DNA through a recognition ?-helix in their DNA-binding domains. An emerging class of DNA-binding transcription factors, predominantly found in pathogenic bacteria interact with the DNA via a relatively novel type of DNA-binding domain, called the LytTR domain, which mainly comprises ? strands. Even though the crystal structure of the LytTR domain of the virulence gene transcription factor AgrA from Staphylococcus aureus bound to its cognate DNA sequence is available, the contribution of specific amino acid residues in the LytTR domain of AgrA to transcription activation remains elusive. Here, for the first time, we have systematically investigated the role of amino acid residues in transcription activation in a LytTR domain-containing transcription factor. Our analysis, which involves in vivo and in vitro analyses and molecular dynamics simulations of S. aureus AgrA identifies a highly conserved tyrosine residue, Y229, as a major amino acid determinant for maximal activation of transcription by AgrA and provides novel insights into structure-function relationships in S. aureus AgrA.
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Vascular and neural stem cells in the gut: do they need each other?
Histochem. Cell Biol.
PUBLISHED: 10-14-2014
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Enteric neurons and blood vessels form intricate networks throughout the gastrointestinal tract. To support the hypothesis of a possible interaction of both networks, we investigated whether primary mesenteric vascular cells (MVCs) and enteric nervous system (ENS)-derived cells (ENSc) depend on each other using two- and three-dimensional in vitro assays. In a confrontation assay, both cell types migrated in a target-oriented manner towards each other. The migration of MVCs was significantly increased when cultured in ENSc-conditioned medium. Co-cultures of ENSc with MVCs resulted in an improved ENSc proliferation and differentiation. Moreover, we analysed the formation of the vascular and nervous system in developing mice guts. It was found that the patterning of newly formed microvessels and neural stem cells, as confirmed by nestin and SOX2 stainings, is highly correlated in all parts of the developing gut. In particular in the distal colon, nestin/SOX2-positive cells were found in the tissues adjacent to the capillaries and in the capillaries themselves. Finally, in order to provide evidences for a mutual interaction between endothelial and neural cells, the vascular patterns of a RET((-/-)) knockout mouse model as well as human Hirschsprung's cases were analysed. In the distal colon of postnatal RET((-/-)) knockout mice, the vascular and neural networks were similarly disrupted. In aganglionic zones of Hirschsprung's patients, the microvascular density was significantly increased compared with the ganglionic zone within the submucosa. Taken together, these findings indicate a strong interaction between the enteric nervous and vascular system.
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High Plasma Erythropoietin Levels are Associated With Prolonged Coma Duration and Increased Mortality in Children With Cerebral Malaria.
Clin. Infect. Dis.
PUBLISHED: 09-16-2014
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?Elevated endogenous plasma erythropoietin (EPO) levels have been associated with protection from acute neurologic deficits in Kenyan children with cerebral malaria (CM). Based on these findings and animal studies, clinical trials of recombinant human EPO (rHuEPO) have been started in children with CM. Recent clinical trials in adults with acute ischemic stroke have demonstrated increased mortality with rHuEPO treatment. We conducted a study in children with CM to assess the relationship of endogenous plasma and cerebrospinal fluid (CSF) EPO levels with mortality and acute and long-term neurologic outcomes.
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High throughput secondary electron imaging of organic residues on a graphene surface.
Sci Rep
PUBLISHED: 09-10-2014
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Surface organic residues inhibit the extraordinary electronic properties of graphene, hindering the development of graphene electronics. However, fundamental understanding of the residue morphology is still absent due to a lack of high-throughput and high-resolution surface characterization methods. Here, we demonstrate that secondary electron (SE) imaging in the scanning electron microscope (SEM) and helium ion microscope (HIM) can provide sub-nanometer information of a graphene surface and reveal the morphology of surface contaminants. Nanoscale polymethyl methacrylate (PMMA) residues are visible in the SE imaging, but their contrast, i.e. the apparent lateral dimension, varies with the imaging conditions. We have demonstrated a quantitative approach to readily obtain the physical size of the surface features regardless of the contrast variation. The fidelity of SE imaging is ultimately determined by the probe size of the primary beam. HIM is thus evaluated to be a superior SE imaging technique in terms of surface sensitivity and image fidelity. A highly efficient method to reveal the residues on a graphene surface has therefore been established.
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The HIV-1 gp120 V1V2 loop: structure, function and importance for vaccine development.
Expert Rev Vaccines
PUBLISHED: 08-28-2014
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Although the second variable loop (V2) of the HIV-1 gp120 envelope glycoprotein shows substantial sequence diversity between strains, its functional importance imposes critical conservation of structure, and within particular microdomains, of sequence. V2 influences HIV-1 viral entry by contributing to trimer stabilization and co-receptor binding. It is one of 4 key domains targeted by the broadly neutralizing antibodies that arise during HIV-1 infection. HIV-1 uses V1V2 sequence variation and glycosylation to escape neutralizing antibody. In the Thai Phase III HIV-1 vaccine trial, RV144, vaccine-induced IgG against V1V2 inversely correlated with the risk of HIV-1 acquisition, and HIV-1 strains infecting RV144 vaccine recipients differed from those infecting placebo recipients in the V2 domain. Similarly, non-human primate challenge studies demonstrated an inverse correlation between vaccine-induced anti-V2 responses and simian immunodeficiency virus acquisition. We hypothesize that increased magnitude, frequency and duration of vaccine-induced anti-V2 antibody responses should improve efficacy afforded by pox-protein prime-boost HIV vaccine strategies.
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Three-dimensional haemodynamics in patients with obstructive and non-obstructive hypertrophic cardiomyopathy assessed by cardiac magnetic resonance.
Eur Heart J Cardiovasc Imaging
PUBLISHED: 08-09-2014
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The left ventricular outflow tract (LVOT) peak pressure gradient is an important haemodynamic descriptor in patients with hypertrophic cardiomyopathy (HCM); however, secondary alterations in aortic blood flow have not been well described in these patients. Aortic flow derangement is not easily assessed by traditional imaging methods, but may provide unique characterization of this disease. In this study, we demonstrated how four-dimensional (4D) flow MRI can assess LVOT peak pressure gradients in HCM patients and also evaluated the ascending aorta (AAo) haemodynamic derangement associated with HCM.
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FCGR2C polymorphisms associate with HIV-1 vaccine protection in RV144 trial.
J. Clin. Invest.
PUBLISHED: 08-08-2014
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The phase III RV144 HIV-1 vaccine trial estimated vaccine efficacy (VE) to be 31.2%. This trial demonstrated that the presence of HIV-1-specific IgG-binding Abs to envelope (Env) V1V2 inversely correlated with infection risk, while the presence of Env-specific plasma IgA Abs directly correlated with risk of HIV-1 infection. Moreover, Ab-dependent cellular cytotoxicity responses inversely correlated with risk of infection in vaccine recipients with low IgA; therefore, we hypothesized that vaccine-induced Fc receptor-mediated (FcR-mediated) Ab function is indicative of vaccine protection. We sequenced exons and surrounding areas of FcR-encoding genes and found one FCGR2C tag SNP (rs114945036) that associated with VE against HIV-1 subtype CRF01_AE, with lysine at position 169 (169K) in the V2 loop (CRF01_AE 169K). Individuals carrying CC in this SNP had an estimated VE of 15%, while individuals carrying CT or TT exhibited a VE of 91%. Furthermore, the rs114945036 SNP was highly associated with 3 other FCGR2C SNPs (rs138747765, rs78603008, and rs373013207). Env-specific IgG and IgG3 Abs, IgG avidity, and neutralizing Abs inversely correlated with CRF01_AE 169K HIV-1 infection risk in the CT- or TT-carrying vaccine recipients only. These data suggest a potent role of Fc-? receptors and Fc-mediated Ab function in conferring protection from transmission risk in the RV144 VE trial.
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Myocardial viability and impact of surgical ventricular reconstruction on outcomes of patients with severe left ventricular dysfunction undergoing coronary artery bypass surgery: Results of the Surgical Treatment for Ischemic Heart Failure trial.
J. Thorac. Cardiovasc. Surg.
PUBLISHED: 07-30-2014
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In the Surgical Treatment for Ischemic Heart Failure trial, surgical ventricular reconstruction plus coronary artery bypass surgery was not associated with a reduction in the rate of death or cardiac hospitalization compared with bypass alone. We hypothesized that the absence of viable myocardium identifies patients with coronary artery disease and left ventricular dysfunction who have a greater benefit with coronary artery bypass graft surgery and surgical ventricular reconstruction compared with bypass alone.
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Assessment of altered three-dimensional blood characteristics in aortic disease by velocity distribution analysis.
Magn Reson Med
PUBLISHED: 06-17-2014
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To test the feasibility of velocity distribution analysis for identifying altered three-dimensional (3D) flow characteristics in patients with aortic disease based on 4D flow MRI volumetric analysis.
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Effects of Septal Myectomy on Left Ventricular Diastolic Function and Left Atrial Volume in Patients With Hypertrophic Cardiomyopathy.
Am. J. Cardiol.
PUBLISHED: 06-12-2014
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Ventricular septal myectomy in patients with obstructive hypertrophic cardiomyopathy (HC) has been shown to reduce left ventricular (LV) outflow tract (LVOT) gradient and improve symptoms, although little data exist regarding changes in left atrial (LA) volume and LV diastolic function after myectomy. We investigated changes in LA size and LV diastolic function in patients with HC after septal myectomy from 2004 to 2011. We studied 25 patients (age 49.2 ± 13.1 years, 48% women) followed for a mean of 527 days after surgery who had serial echocardiography at baseline and at most recent follow-up, at least 6 months after myectomy. In addition to myectomy, 3 patients (12%) underwent Maze surgery and 13 (52%) underwent mitral valve surgery, of whom 5 had a mitral valve replacement or mitral annuloplasty. Patients with mitral valve replacement or mitral annuloplasty were excluded from LV diastolic function analysis. LA volume index decreased (from 47.2 ± 17.6 to 35.9 ± 17.0 ml/m(2), p = 0.001) and LV diastolic function improved with an increase in lateral e' velocity (from 7.3 ± 2.9 to 9.8 ± 3.1 cm/sec, p = 0.01) and a decrease in E/e' (from 14.8 ± 6.3 to 11.7 ± 5.5, p = 0.051). Ventricular septal thickness and LVOT gradient decreased, and symptoms of dyspnea and heart failure improved, with reduction in the New York Heart Association functional class III/IV symptoms from 21 (84%) to 1 (4%). In conclusion, relief of LVOT obstruction in HC by septal myectomy results in improved LV diastolic function and reduction in LA volume with improved symptoms.
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Severe malarial anemia is associated with long-term neurocognitive impairment.
Clin. Infect. Dis.
PUBLISHED: 04-24-2014
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Cerebral malaria (CM) is associated with long-term neurocognitive impairment in children ?5 years of age. No prospective studies to date have assessed neurocognitive impairment in children with CM <5 years of age, or in children with severe malarial anemia (SMA), a form of severe malaria estimated to affect as many as 5 million children annually.
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Developing therapies for heart failure with preserved ejection fraction: current state and future directions.
JACC Heart Fail
PUBLISHED: 04-12-2014
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The burden of heart failure with preserved ejection fraction (HFpEF) is considerable and is projected to worsen. To date, there are no approved therapies available for reducing mortality or hospitalizations for these patients. The pathophysiology of HFpEF is complex and includes alterations in cardiac structure and function, systemic and pulmonary vascular abnormalities, end-organ involvement, and comorbidities. There remain major gaps in our understanding of HFpEF pathophysiology. To facilitate a discussion of how to proceed effectively in future with development of therapies for HFpEF, a meeting was facilitated by the Food and Drug Administration and included representatives from academia, industry, and regulatory agencies. This document summarizes the proceedings from this meeting.
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Performance of point-of-care diagnostics for glucose, lactate, and hemoglobin in the management of severe malaria in a resource-constrained hospital in Uganda.
Am. J. Trop. Med. Hyg.
PUBLISHED: 03-03-2014
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Severe malaria is frequently managed without access to laboratory testing. We report on the performance of point-of-care tests used to guide the management of a cohort of 179 children with severe malaria in a resource-limited Ugandan hospital. Correlation coefficients between paired measurements for glucose (i-STAT and One Touch Ultra), lactate (i-STAT and Lactate Scout), and hemoglobin (Hb; laboratory and i-STAT) were 0.86, 0.85, and 0.73, respectively. The OneTouch Ultra glucometer readings deviated systematically from the i-STAT values by +1.7 mmol/L. Lactate Scout values were systematically higher than i-STAT by +0.86 mmol/L. Lactate measurements from either device predicted subsequent mortality. Hb estimation by the i-STAT instrument was unbiased, with upper and lower limits of agreement of -34 and +34 g/L, and it was 91% sensitive and 89% specific for the diagnosis of severe anemia (Hb < 50 g/L). New commercially available bedside diagnostic tools, although imperfect, may expedite clinical decision-making in the management of critically ill children in resource-constrained settings.
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Effect of aortic aneurysm replacement on outcomes after bicuspid aortic valve surgery: Validation of contemporary guidelines.
J. Thorac. Cardiovasc. Surg.
PUBLISHED: 02-27-2014
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Bicuspid aortic valve (BAV) disease is associated with aortic dilatation and aneurysm (AN) formation. The American College of Cardiology/American Heart Association (ACC/AHA) 2006 guidelines recommend replacement of the ascending aorta for an aortic diameter (AD) > 45 mm in patients undergoing aortic valve replacement (AVR). We evaluated the outcomes of AVR and AVR with aortic replacement (AVR/AN).
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Identification of fibrillin 1 gene mutations in patients with bicuspid aortic valve (BAV) without Marfan syndrome.
BMC Med. Genet.
PUBLISHED: 02-14-2014
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Bicuspid aortic valve (BAV) is the most frequent congenital heart disease with frequent involvement in thoracic aortic dilatation, aneurysm and dissection. Although BAV and Marfan syndrome (MFS) share some clinical features, and some MFS patients with BAV display mutations in FBN1, the gene encoding fibrillin-1, the genetic background of isolated BAV is poorly defined.
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An approach to the rational use of revascularization in heart failure patients.
Can J Cardiol
PUBLISHED: 02-04-2014
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The most common cause of heart failure with reduced ejection fraction (HFrEF) is coronary artery disease. A multitude of factors come into play when deciding whether a patient with HFrEF and coronary artery disease should have coronary artery bypass graft (CABG) surgery, percutaneous coronary intervention, or medical therapy alone. For candidates for percutaneous coronary intervention and CABG, evidence from large registries would suggest that patients with 2-vessel coronary artery diseases and proximal left anterior descending disease and all patients with 3-vessel coronary artery disease do better with CABG. For patients that are candidates for medical therapy with or without CABG, the results of the Surgical Treatment for Ischemic Heart Failure (STICH) trial indicate that with CABG, the reduction of mortality is not statistically significant (hazard ratio [HR], 0.86; P = 0.12). However, CABG is superior in reducing cardiovascular deaths (HR, 0.81; P = 0.05), and the combination of cardiovascular deaths and cardiovascular hospitalizations (HR, 0.74; P < 0.001). Patients undergoing CABG have an upfront risk that is eliminated by 2 years and thereafter do better. The assessment of cardiac viability or reversible ischemia does not appear to be helpful in determining which individuals will improve more with CABG. Patients with severe mitral regurgitation who undergo CABG appear to benefit from simultaneous valve repair but not from the addition of surgical ventricular reconstruction of the left ventricle, although in specific patients this might be considered. The totality of evidence would thus suggest that patients with HFrEF should be evaluated for the possibility of coronary revascularization if they are candidates for CABG.
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Use of a three-band HRP2/pLDH combination rapid diagnostic test increases diagnostic specificity for falciparum malaria in Ugandan children.
Malar. J.
PUBLISHED: 01-27-2014
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Rapid diagnostic tests (RDTs) for malaria provide a practical alternative to light microscopy for malaria diagnosis in resource-limited settings. Three-band RDTs incorporating two parasite antigens may have enhanced diagnostic specificity, relative to two-band RDTs with a single parasite antigen (typically histidine-rich protein 2 [HRP2]).
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Therapeutic targets in heart failure: refocusing on the myocardial interstitium.
J. Am. Coll. Cardiol.
PUBLISHED: 01-14-2014
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New therapeutic targets, agents, and strategies are needed to prevent and treat heart failure (HF) after a decade of failed research efforts to improve long-term patient outcomes, especially in patients after hospitalization for HF. Conceptually, an accurate assessment of left ventricular structure is an essential step in the development of novel therapies because heterogeneous pathophysiologies underlie chronic HF and hospitalization for HF. Improved left ventricular characterization permits the identification and targeting of the intrinsic fundamental disease-modifying pathways that culminate in HF. Interstitial heart disease is one such pathway, characterized by extracellular matrix (ECM) expansion that is associated with mechanical, electrical, and vasomotor dysfunction and adverse outcomes. Previous landmark trials that appear to treat interstitial heart disease were effective in improving outcomes. Advances in cardiovascular magnetic resonance now enable clinicians and researchers to assess the interstitium and quantify ECM expansion using extracellular volume fraction measures and other derangements in cardiovascular structure. These capabilities may provide a mechanistic platform to advance understanding of the role of the ECM, foster the development of novel therapeutics, and target specific disease-modifying pathways intrinsic to the ventricle. Refocusing on the interstitium may potentially improve care through the identification and targeted treatment of key patient subgroups.
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CD8 and CD4 Epitope Predictions in RV144: No Strong Evidence of a T-Cell Driven Sieve Effect in HIV-1 Breakthrough Sequences from Trial Participants.
PLoS ONE
PUBLISHED: 01-01-2014
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The modest protection afforded by the RV144 vaccine offers an opportunity to evaluate its mechanisms of protection. Differences between HIV-1 breakthrough viruses from vaccine and placebo recipients can be attributed to the RV144 vaccine as this was a randomized and double-blinded trial. CD8 and CD4 T cell epitope repertoires were predicted in HIV-1 proteomes from 110 RV144 participants. Predicted Gag epitope repertoires were smaller in vaccine than in placebo recipients (p?=?0.019). After comparing participant-derived epitopes to corresponding epitopes in the RV144 vaccine, the proportion of epitopes that could be matched differed depending on the protein conservation (only 36% of epitopes in Env vs 84-91% in Gag/Pol/Nef for CD8 predicted epitopes) or on vaccine insert subtype (55% against CRF01_AE vs 7% against subtype B). To compare predicted epitopes to the vaccine, we analyzed predicted binding affinity and evolutionary distance measurements. Comparisons between the vaccine and placebo arm did not reveal robust evidence for a T cell driven sieve effect, although some differences were noted in Env-V2 (0.022?p-value?0.231). The paucity of CD8 T cell responses identified following RV144 vaccination, with no evidence for V2 specificity, considered together both with the association of decreased infection risk in RV 144 participants with V-specific antibody responses and a V2 sieve effect, lead us to hypothesize that this sieve effect was not T cell specific. Overall, our results did not reveal a strong differential impact of vaccine-induced T cell responses among breakthrough infections in RV144 participants.
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In vitro reconstitution and analysis of the 6-deoxyerythronolide B synthase.
J. Am. Chem. Soc.
PUBLISHED: 11-01-2013
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Notwithstanding an extensive literature on assembly line polyketide synthases such as the 6-deoxyerythronolide B synthase (DEBS), a complete naturally occurring synthase has never been reconstituted in vitro from purified protein components. Here, we describe the fully reconstituted DEBS and quantitatively characterize some of the properties of the assembled system that have never been explored previously. The maximum turnover rate of the complete hexamodular system is 1.1 min(-1), comparable to the turnover rate of a truncated trimodular derivative (2.5 min(-1)) but slower than that of a bimodular derivative (21 min(-1)). In the presence of similar concentrations of methylmalonyl- and ethylmalonyl-CoA substrates, DEBS synthesizes multiple regiospecifically modified analogues, one of which we have analyzed in detail. Our studies lay the foundation for biochemically interrogating and rationally engineering polyketide assembly lines in an unprecedented manner.
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Transcatheter aortic valve replacement: current status and future directions.
Semin. Thorac. Cardiovasc. Surg.
PUBLISHED: 09-16-2013
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Transcatheter aortic valve replacement (TAVR) is a revolutionary therapy for patients with aortic stenosis. Large registries and randomized controlled trials have demonstrated that TAVR is safe and effective in patients considered inoperable because of severe comorbidities and those who are high-risk surgical candidates. As TAVR evolves for lower-risk patients, attention will need to focus on reducing the rates of vascular injury, stroke, and paravalvular regurgitation. In this review, we discuss the status of TAVR in clinical practice, including patient selection, preoperative evaluation, techniques, and complications.
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Computational identification and analysis of orphan assembly-line polyketide synthases.
J. Antibiot.
PUBLISHED: 08-29-2013
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The increasing availability of DNA sequence data offers an opportunity for identifying new assembly-line polyketide synthases (PKSs) that produce biologically active natural products. We developed an automated method to extract and consolidate all multimodular PKS sequences (including hybrid PKS/non-ribosomal peptide synthetases) in the National Center for Biotechnology Information (NCBI) database, generating a non-redundant catalog of 885 distinct assembly-line PKSs, the majority of which were orphans associated with no known polyketide product. Two in silico experiments highlight the value of this search method and resulting catalog. First, we identified an orphan that could be engineered to produce an analog of albocycline, an interesting antibiotic whose gene cluster has not yet been sequenced. Second, we identified and analyzed a hitherto overlooked family of metazoan multimodular PKSs, including one from Caenorhabditis elegans. We also developed a comparative analysis method that identified sequence relationships among known and orphan PKSs. As expected, PKS sequences clustered according to structural similarities between their polyketide products. The utility of this method was illustrated by highlighting an interesting orphan from the genus Burkholderia that has no close relatives. Our search method and catalog provide a community resource for the discovery of new families of assembly-line PKSs and their antibiotic products.The Journal of Antibiotics advance online publication, 4 December 2013; doi:10.1038/ja.2013.125.
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Retinoblastoma protein prevents enteric nervous system defects and intestinal pseudo-obstruction.
J. Clin. Invest.
PUBLISHED: 08-15-2013
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The retinoblastoma 1 (RB1) tumor suppressor is a critical regulator of cell cycle progression and development. To investigate the role of RB1 in neural crest-derived melanocytes, we bred mice with a floxed Rb1 allele with mice expressing Cre from the tyrosinase (Tyr) promoter. TyrCre+;Rb1fl/fl mice exhibited no melanocyte defects but died unexpectedly early with intestinal obstruction, striking defects in the enteric nervous system (ENS), and abnormal intestinal motility. Cre-induced DNA recombination occurred in all enteric glia and most small bowel myenteric neurons, yet phenotypic effects of Rb1 loss were cell-type specific. Enteric glia were twice as abundant in mutant mice compared with those in control animals, while myenteric neuron number was normal. Most myenteric neurons also appeared normal in size, but NO-producing myenteric neurons developed very large nuclei as a result of DNA replication without cell division (i.e., endoreplication). Parallel studies in vitro found that exogenous NO and Rb1 shRNA increased ENS precursor DNA replication and nuclear size. The large, irregularly shaped nuclei in NO-producing neurons were remarkably similar to those in progeria, an early-onset aging disorder that has been linked to RB1 dysfunction. These findings reveal a role for RB1 in the ENS.
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Prosthesis-patient mismatch in bovine pericardial aortic valves: evaluation using 3 different modalities and associated medium-term outcomes.
Circ Cardiovasc Imaging
PUBLISHED: 08-07-2013
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The prevalence of prosthesis-patient mismatch (PPM) and its impact on survival after aortic valve replacement have not been clearly defined. Historically, the presence of PPM was identified from postoperative echocardiograms or preoperative manufacturer-provided charts, resulting in wide discrepancies. The 2009 American Society of Echocardiography (ASE) guidelines proposed an algorithmic approach to calculate PPM. This study compared PPM prevalence and its impact on survival using 3 modalities: (1) the ASE guidelines-suggested algorithm (ASE PPM); (2) the manufacturer-provided charts (M PPM); and (3) the echocardiographically measured, body surface area-indexed, effective orifice area (EOAi PPM) measurement.
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Current management of calcific aortic stenosis.
Circ. Res.
PUBLISHED: 07-09-2013
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Calcific aortic stenosis is a progressive disease with no effective medical therapy that ultimately requires aortic valve replacement (AVR) for severe valve obstruction. Echocardiography is the primary diagnostic approach to define valve anatomy, measure aortic stenosis severity, and evaluate the left ventricular response to chronic pressure overload. In asymptomatic patients, markers of disease progression include the degree of leaflet calcification, hemodynamic severity of stenosis, adverse left ventricular remodeling, reduced left ventricular longitudinal strain, myocardial fibrosis, and pulmonary hypertension. The onset of symptoms portends a predictably high mortality rate unless AVR is performed. In symptomatic patients, AVR improves symptoms, improves survival, and, in patients with left ventricular dysfunction, improves systolic function. Poor outcomes after AVR are associated with low-flow low-gradient aortic stenosis, severe ventricular fibrosis, oxygen-dependent lung disease, frailty, advanced renal dysfunction, and a high comorbidity score. However, in most patients with severe symptoms, AVR is lifesaving. Bioprosthetic valves are recommended for patients aged >65 years. Transcatheter AVR is now available for patients with severe comorbidities, is recommended in patients who are deemed inoperable, and is a reasonable alternative to surgical AVR in high-risk patients.
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Recognizing hospitalized heart failure as an entity and developing new therapies to improve outcomes: academics, clinicians, industrys, regulators, and payers perspectives.
Heart Fail Clin
PUBLISHED: 07-02-2013
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Hospitalized heart failure (HHF) is associated with unacceptably high postdischarge mortality and rehospitalization rates. This heterogeneous group of patients, however, is still treated with standard, homogenous therapies that are not preventing their rapid deterioration. The costs associated with HHF have added demands from society, government, and payers to improve outcomes. With coordinated and committed efforts in the development of new therapies, improvements may be seen in outcomes for patients with HHF. This article summarizes concepts in developing therapies for HHF discussed during a multidisciplinary panel at the Heart Failure Society of Americas Annual Scientific Meeting, September 2012.
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Viscous energy loss in the presence of abnormal aortic flow.
Magn Reson Med
PUBLISHED: 06-07-2013
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To present a theoretical basis for noninvasively characterizing in vivo fluid-mechanical energy losses and to apply it in a pilot study of patients known to express abnormal aortic flow patterns.
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Nonproteinogenic amino acid building blocks for nonribosomal peptide and hybrid polyketide scaffolds.
Angew. Chem. Int. Ed. Engl.
PUBLISHED: 05-31-2013
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Freestanding nonproteinogenic amino acids have long been recognized for their antimetabolite properties and tendency to be uncovered to reactive functionalities by the catalytic action of target enzymes. By installing them regiospecifically into biogenic peptides and proteins, it may be possible to usher a new era at the interface between small molecule and large molecule medicinal chemistry. Site-selective protein functionalization offers uniquely attractive strategies for posttranslational modification of proteins. Last, but not least, many of the amino acids not selected by nature for protein incorporation offer rich architectural possibilities in the context of ribosomally derived polypeptides. This Review summarizes the biosynthetic routes to and metabolic logic for the major classes of the noncanonical amino acid building blocks that end up in both nonribosomal peptide frameworks and in hybrid nonribosomal peptide-polyketide scaffolds.
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HIV Vaccine Efficacy and Immune Correlates of Risk.
Curr. HIV Res.
PUBLISHED: 05-23-2013
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Although immune correlates of protection for HIV vaccines have remained an intractable question, RV144 provided the first evidence that an HIV vaccine could provide protective efficacy against HIV acquisition. The study of correlates of risk has opened large and unforeseen avenues of exploration and hope for the most exciting time of HIV vaccine development. Several elements in the RV144 post-hoc analysis and recent macaque challenge studies suggest that antibodies directed against the V2 loop of gp120 are functional and may have played a protective role against virus acquisition. Several protective mechanisms against sexual transmission of HIV are evoked including blocking the gp120-?4 ?7 interaction and ADCC although possibly mitigated by high levels of Env-specific IgA, both mechanisms contributing at least partially to the protective effect. Several questions remain unanswered that will deserve intensive assessments, in particular, IgG and IgA Env antibodies in mucosal secretions, Env-specific IgG subclasses, cross-reaction of V2 antibodies, role of T-follicular helper cells, and B-cell memory. Whether the RV144 correlates of risk are universal and apply at least partially to other populations at higher risk for HIV acquisition and other modes of transmission (rectal, injecting drug users) is unknown and remains to be explored. Future efficacy trials using the same vaccine concept tested in high-risk heterosexual populations and in men having sex with men may answer this question. In addition, the determination of early events in the pathogenesis among HIV-infected vaccine recipients based on current correlates knowledge would offer unprecedented information about correlates biomarkers in the peripheral blood and gut mucosa during early acute HIV infection.
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Retinaldehyde dehydrogenase enzymes regulate colon enteric nervous system structure and function.
Dev. Biol.
PUBLISHED: 05-08-2013
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The enteric nervous system (ENS) forms from the neural crest-derived precursors that colonize the bowel before differentiating into a network of neurons and glia that control intestinal function. Retinoids are essential for normal ENS development, but the role of retinoic acid (RA) metabolism in development remains incompletely understood. Because RA is produced locally in the tissues where it acts by stimulating RAR and RXR receptors, RA signaling during development is absolutely dependent on the rate of RA synthesis and degradation. RA is produced by three different enzymes called retinaldehyde dehydrogenases (RALDH1, RALDH2 and RALDH3) that are all expressed in the developing bowel. To determine the relative importance of these enzymes for ENS development, we analyzed whole mount preparations of adult (8-12-week old) myenteric and submucosal plexus stained with NADPH diaphorase (neurons and neurites), anti-TuJ1 (neurons and neurites), anti-HuC/HuD (neurons), and anti-S100? (glia) in an allelic series of mice with mutations in Raldh1, Raldh2, and Raldh3. We found that Raldh1-/-, Raldh2+/-, Raldh3+/- (R1(KO)R2(Het)R3(Het)) mutant mice had a reduced colon myenteric neuron density, reduced colon myenteric neuron to glia ratio, reduced colon submucosal neuron density, and increased colon myenteric fibers per neuron when compared to the wild type (WT; Raldh1WT, Raldh2WT, Raldh3WT) mice. These defects are unlikely to be due to defective ENS precursor migration since R1(KO)R2(Het)R3(KO) mice had increased enteric neuron progenitor migration into the distal colon compared to WT during development. RALDH mutant mice also have reduced contractility in the colon compared to WT mice. These data suggest that RALDH1, RALDH2 and RALDH3 each contribute to ENS development and function.
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Enteric nervous system development: migration, differentiation, and disease.
Am. J. Physiol. Gastrointest. Liver Physiol.
PUBLISHED: 05-02-2013
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The enteric nervous system (ENS) provides the intrinsic innervation of the bowel and is the most neurochemically diverse branch of the peripheral nervous system, consisting of two layers of ganglia and fibers encircling the gastrointestinal tract. The ENS is vital for life and is capable of autonomous regulation of motility and secretion. Developmental studies in model organisms and genetic studies of the most common congenital disease of the ENS, Hirschsprung disease, have provided a detailed understanding of ENS development. The ENS originates in the neural crest, mostly from the vagal levels of the neuraxis, which invades, proliferates, and migrates within the intestinal wall until the entire bowel is colonized with enteric neural crest-derived cells (ENCDCs). After initial migration, the ENS develops further by responding to guidance factors and morphogens that pattern the bowel concentrically, differentiating into glia and neuronal subtypes and wiring together to form a functional nervous system. Molecules controlling this process, including glial cell line-derived neurotrophic factor and its receptor RET, endothelin (ET)-3 and its receptor endothelin receptor type B, and transcription factors such as SOX10 and PHOX2B, are required for ENS development in humans. Important areas of active investigation include mechanisms that guide ENCDC migration, the role and signals downstream of endothelin receptor type B, and control of differentiation, neurochemical coding, and axonal targeting. Recent work also focuses on disease treatment by exploring the natural role of ENS stem cells and investigating potential therapeutic uses. Disease prevention may also be possible by modifying the fetal microenvironment to reduce the penetrance of Hirschsprung disease-causing mutations.
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Intracoronary cardiosphere-derived cells after myocardial infarction: evidence for therapeutic regeneration in the final 1-year results of the CADUCEUS trial.
J. Am. Coll. Cardiol.
PUBLISHED: 05-01-2013
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To report full 1-year results, detailed magnetic resonance imaging (MRI) analysis, and determinants of efficacy in the prospective randomized controlled CADUCEUS trial.
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Composite risk factors predict survival after transplantation for congenital heart disease.
J. Thorac. Cardiovasc. Surg.
PUBLISHED: 04-26-2013
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Previous studies have shown that individual risk factors are poor predictors of mortality after heart transplantation in patients with congenital heart disease. We developed composite risk factor groups to better predict mortality after cardiac transplantation.
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An aromatic residue switch in enhancer-dependent bacterial RNA polymerase controls transcription intermediate complex activity.
Nucleic Acids Res.
PUBLISHED: 04-22-2013
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The formation of the open promoter complex (RPo) in which the melted DNA containing the transcription start site is located at the RNA polymerase (RNAP) catalytic centre is an obligatory step in the transcription of DNA into RNA catalyzed by RNAP. In the RPo, an extensive network of interactions is established between DNA, RNAP and the ?-factor and the formation of functional RPo occurs via a series of transcriptional intermediates (collectively RPi). A single tryptophan is ideally positioned to directly engage with the flipped out base of the non-template strand at the +1 site. Evidence suggests that this tryptophan (i) is involved in either forward translocation or DNA scrunching and (ii) in ?(54)-regulated promoters limits the transcription activity of at least one intermediate complex (RPi) before the formation of a fully functional RPo. Limiting RPi activity may be important in preventing the premature synthesis of abortive transcripts, suggesting its involvement in a general mechanism driving the RPi to RPo transition for transcription initiation.
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Synthesis of Z-(pinacolato)allylboron and Z-(pinacolato)alkenylboron compounds through stereoselective catalytic cross-metathesis.
J. Am. Chem. Soc.
PUBLISHED: 04-15-2013
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The first examples of catalytic cross-metathesis (CM) reactions that furnish Z-(pinacolato)allylboron and Z-(pinacolato)alkenylboron compounds are disclosed. Products are generated with high Z selectivity by the use of a W-based monoaryloxide pyrrolide (MAP) complex (up to 91% yield and >98:2 Z:E). The more sterically demanding Z-alkenylboron species are obtained in the presence of Mo-based MAP complexes in up to 93% yield and 97% Z selectivity. Z-selective CM with 1,3-dienes and aryl olefins are reported for the first time. The utility of the approach, in combination with catalytic cross coupling, is demonstrated by a concise and stereoselective synthesis of anticancer agent combretastatin A-4.
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A year-long caregiver training program to improve neurocognition in preschool Ugandan HIV-exposed children.
J Dev Behav Pediatr
PUBLISHED: 03-29-2013
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Mediational intervention for sensitizing caregivers (MISC) is a structured program enabling caregivers to enhance their childs cognitive and emotional development through daily interactions. The principal aim was to evaluate if a year-long MISC caregiver training program produced greater improvement in child cognitive and emotional development compared with a control program.
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Exploring mechanisms of excess mortality with early fluid resuscitation: insights from the FEAST trial.
BMC Med
PUBLISHED: 03-14-2013
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Early rapid fluid resuscitation (boluses) in African children with severe febrile illnesses increases the 48-hour mortality by 3.3% compared with controls (no bolus). We explored the effect of boluses on 48-hour all-cause mortality by clinical presentation at enrolment, hemodynamic changes over the first hour, and on different modes of death, according to terminal clinical events. We hypothesize that boluses may cause excess deaths from neurological or respiratory events relating to fluid overload.
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Hirschsprung-like disease is exacerbated by reduced de novo GMP synthesis.
J. Clin. Invest.
PUBLISHED: 03-08-2013
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Hirschsprung disease (HSCR) is a partially penetrant oligogenic birth defect that occurs when enteric nervous system (ENS) precursors fail to colonize the distal bowel during early pregnancy. Genetic defects underlie HSCR, but much of the variability in the occurrence and severity of the birth defect remain unexplained. We hypothesized that nongenetic factors might contribute to disease development. Here we found that mycophenolate, an inhibitor of de novo guanine nucleotide biosynthesis, and 8 other drugs identified in a zebrafish screen impaired ENS development. In mice, mycophenolate treatment selectively impaired ENS precursor proliferation, delayed precursor migration, and induced bowel aganglionosis. In 2 different mouse models of HSCR, addition of mycophenolate increased the penetrance and severity of Hirschsprung-like pathology. Mycophenolate treatment also reduced ENS precursor migration as well as lamellipodia formation, proliferation, and survival in cultured enteric neural crest-derived cells. Using X-inactivation mosaicism for the purine salvage gene Hprt, we found that reduced ENS precursor proliferation most likely causes mycophenolate-induced migration defects and aganglionosis. To the best of our knowledge, mycophenolate is the first medicine identified that causes major ENS malformations and Hirschsprung-like pathology in a mammalian model. These studies demonstrate a critical role for de novo guanine nucleotide biosynthesis in ENS development and suggest that some cases of HSCR may be preventable.
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Prevalence of regional myocardial thinning and relationship with myocardial scarring in patients with coronary artery disease.
JAMA
PUBLISHED: 03-07-2013
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Regional left ventricular (LV) wall thinning is believed to represent chronic transmural myocardial infarction and scar tissue. However, recent case reports using delayed-enhancement cardiovascular magnetic resonance (CMR) imaging raise the possibility that thinning may occur with little or no scarring.
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Promoter independent abortive transcription assays unravel functional interactions between TFIIB and RNA polymerase.
Methods Mol. Biol.
PUBLISHED: 02-26-2013
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TFIIB-like general transcription factors are required for transcription initiation by all eukaryotic and archaeal RNA polymerases (RNAPs). TFIIB facilitates both recruitment and post-recruitment steps of initiation; in particular, TFIIB stimulates abortive initiation. X-ray crystallography of TFIIB-RNAP II complexes shows that the TFIIB linker region penetrates the RNAP active center, yet the impact of this arrangement on RNAP activity and underlying mechanisms remains elusive. Promoter-independent abortive initiation assays exploit the intrinsic ability of RNAP enzymes to initiate transcription from nicked DNA templates and record the formation of the first phosphodiester bonds. These assays can be used to measure the effect of transcription factors such as TFIIB and RNAP mutations on abortive transcription.
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Inducible myocardial ischemia and outcomes in patients with coronary artery disease and left ventricular dysfunction.
J. Am. Coll. Cardiol.
PUBLISHED: 01-30-2013
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The study objectives were to test the hypotheses that ischemia during stress testing has prognostic value and identifies those patients with coronary artery disease (CAD) with left ventricular (LV) dysfunction who derive the greatest benefit from coronary artery bypass grafting (CABG) compared with medical therapy.
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A year-long caregiver training program improves cognition in preschool Ugandan children with human immunodeficiency virus.
J. Pediatr.
PUBLISHED: 01-28-2013
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To evaluate mediational intervention for sensitizing caregivers (MISC). MISC biweekly caregiver training significantly enhanced child development compared with biweekly training on health and nutrition (active control) and to evaluate whether MISC training improved the emotional well-being of the caregivers compared with controls.
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Aortic valve and ascending aorta guidelines for management and quality measures: executive summary.
Ann. Thorac. Surg.
PUBLISHED: 01-02-2013
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The Society of Thoracic Surgeons Clinical Practice Guidelines are intended to assist physicians and other health care providers in clinical decision making by describing a range of generally acceptable approaches for the diagnosis, management, or prevention of specific diseases or conditions. These guidelines should not be considered inclusive of all proper methods of care or exclusive of other methods of care reasonably directed at obtaining the same results. Moreover, these guidelines are subject to change over time, without notice. The ultimate judgment regarding the care of a particular patient must be made by the physician in light of the individual circumstances presented by the patient.
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Impact of HIV-1 Backbone on Neutralization Sensitivity: Neutralization Profiles of Heterologous Envelope Glycoproteins Expressed in Native Subtype C and CRF01_AE Backbone.
PLoS ONE
PUBLISHED: 01-01-2013
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Standardized assays to assess vaccine and antiviral drug efficacy are critical for the development of protective HIV-1 vaccines and drugs. These immune assays will be advanced by the development of standardized viral stocks, such as HIV-1 infectious molecular clones (IMC), that i) express a reporter gene, ii) are representative of globally diverse subtypes and iii) are engineered to easily exchange envelope (env) genes for expression of sequences of interest. Thus far, a subtype B IMC backbone expressing Renilla luciferase (LucR), and into which the ectodomain of heterologous env coding sequences can be expressed has been successfully developed but as execution of HIV-1 vaccine efficacy trials shifts increasingly to non-subtype B epidemics (Southern African and Southeast Asia), non-subtype B HIV-1 reagents are needed to support vaccine development. Here we describe two IMCs derived from subtypes C and CRF01_AE HIV-1 primary isolates expressing LucR (IMC.LucR) that were engineered to express heterologous gp160 Envs. 18 constructs expressing various subtypes C and CRF01_AE Envs, mostly acute, in subtype-matched and -unmatched HIV backbones were tested for functionality and neutralization sensitivity. Our results suggest a possible effect of non-env HIV-1 genes on the interaction of Env and neutralizing antibodies and highlight the need to generate a library of IMCs representative of the HIV-1 subtype spectrum to be used as standardized neutralization assay reagents for assessing HIV-1 vaccine efficacy.
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Is hospital admission for heart failure really necessary?: the role of the emergency department and observation unit in preventing hospitalization and rehospitalization.
J. Am. Coll. Cardiol.
PUBLISHED: 01-01-2013
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Approximately 800,000 times a year, an emergency physician admits a patient with symptomatic heart failure (HF). Yet only a minority of emergency department patients with HF are severely ill as a result of pulmonary edema, myocardial ischemia, or cardiogenic shock. The majority of patients are not in need of an acute intervention beyond decongestion, and few patients during hospitalization undergo invasive diagnostic testing or therapeutic procedures that require intense monitoring. Although hospitalization is clearly an inflection point, marking a threshold that independently predicts a worse outcome, the exact impact of hospitalization on post-discharge events has not been well elucidated. Thus, large subsets of patients with HF are hospitalized without a clear need for time-sensitive therapies or procedures. The authors estimate that up to 50% of emergency department patients with HF could be safely discharged after a brief period of observation, thus avoiding unnecessary admissions and minimizing readmissions. Observation unit management may be beneficial for low-risk and intermediate-risk patients with HF as continued treatment, and more precise risk stratification may ensue, avoiding inpatient admission. Whether observation unit management is comparable with or superior to the current approach must be determined in a randomized clinical trial. Critical end points include time to symptom resolution and discharge, post-discharge event rates, and a cost-effective analysis of each management strategy. It is the authors strong assertion that now is the time for such a trial and that the results will be critically important if we are to effectively influence hospitalizations for HF in the near future.
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Effects of peripherally restricted ? opioid receptor agonists on pain-related stimulation and depression of behavior in rats.
J. Pharmacol. Exp. Ther.
PUBLISHED: 11-29-2011
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? opioid receptor agonists that do not readily cross the blood-brain barrier are peripherally restricted and distribute poorly to the central nervous system after systemic administration. Peripherally restricted ? agonists have promise as candidate analgesics, because they may produce antinociception mediated by peripheral ? receptors more potently than they produce undesirable sedative and psychotomimetic effects mediated by central ? receptors. The present study used assays of pain-related stimulation and depression of behavior in rats to compare effects of 1) two peripherally restricted ? agonists [the tetrapeptide D-Phe-D-Phe-D-Ile-D-Arg-NH(2) (ffir) and the nonpeptidic compound ((R,S)-N-[2-(N-methyl-3,4-dichlorophenylacetamido)-2-(3-carboxyphenyl)-ethyl]pyrrolidine hydrochloride (ICI204448)], 2) a centrally penetrating ? agonist (salvinorin A), and 3) several reference drugs, including a nonsteroidal anti-inflammatory drug (NSAID; ketoprofen). Intraperitoneal injection of dilute lactic acid served as a noxious stimulus to stimulate a stretching response and depress intracranial self-stimulation (ICSS) maintained by the delivery of electrical brain stimulation to the medial forebrain bundle. Acid-stimulated stretching was blocked by ketoprofen, the peripherally restricted ? agonists, and salvinorin A. However, acid-induced depression of ICSS was blocked only by ketoprofen. The peripherally restricted ? agonists had little effect, and salvinorin A exacerbated acid-induced depression of ICSS. These results suggest that peripherally restricted ? agonists may be safer than centrally penetrating ? agonists but less efficacious than NSAIDS or ? opioid receptor agonists to block pain-related depression of behavior; however, the peripheral selectivity of ffir and ICI204448 is limited, and future studies with ? agonists capable of greater peripheral selectivity are warranted.
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Revealing the functions of TFIIB.
Transcription
PUBLISHED: 11-01-2011
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The TFIIB linker domain stimulates the catalytic activity of archaeal RNAP. By characterising a range of super-stimulating mutants we identified a novel rate-limiting step in transcription initiation. Our results help to interpret structural findings and pave the way towards higher-resolution structures of the RNAP-TFIIB linker interface.
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Beta adrenergic receptor blockade causing severe left ventricular systolic dysfunction during dobutamine stress echocardiography in a patient with no structural heart disease.
Echocardiography
PUBLISHED: 10-12-2011
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A 41-year-old woman with a history of neurocardiogenic syncope treated with beta-blockers was admitted with chest pain. Dobutamine echocardiogram images demonstrated decreased global LV systolic wall motion and thickening. Coronary angiograms were normal. Beta-blockers were stopped and dobutamine stress echocardiogram (DSE) was repeated. Dobutamine images demonstrated increased global LV systolic wall motion and thickening. Beta-blockers were restarted and again dobutamine produced global LV dysfunction. This case suggests that DSE wall motion response may be falsely abnormal in a patient on beta-blockers. Physicians should be aware of this possibility when interpreting dobutamine echocardiography in patients taking beta-blockers.
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Differential regional and subtype-specific vulnerability of enteric neurons to mitochondrial dysfunction.
PLoS ONE
PUBLISHED: 09-17-2011
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Mitochondrial dysfunction is a central mediator of disease progression in diverse neurodegenerative diseases that often present with prominent gastrointestinal abnormalities. Gastrointestinal dysfunction in these disorders is related, at least in part, to defects in the enteric nervous system (ENS). The role of mitochondrial deficits in ENS neurodegeneration and their relative contribution to gastrointestinal dysfunction, however, are unclear. To better understand how mitochondrial abnormalities in the ENS influence enteric neurodegeneration and affect intestinal function, we generated mice (Tfam-ENSKOs) with impaired mitochondrial metabolism in enteric neurons and glia through the targeted deletion of the mitochondrial transcription factor A gene (Tfam). Tfam-ENSKO mice were initially viable but, at an early age, they developed severe gastrointestinal motility problems characterized by intestinal pseudo-obstruction resulting in premature death. This gastrointestinal dysfunction was caused by extensive, progressive neurodegeneration of the ENS involving both neurons and glia. Interestingly, mitochondrial defects differentially affected specific subpopulations of enteric neurons and regions of the gastrointestinal tract. Mitochondrial deficiency-related neuronal and glial loss was most prominent in the proximal small intestine, but the first affected neurons, nitrergic inhibitory neurons, had the greatest losses in the distal small intestine. This regional and subtype-specific variability in susceptibility to mitochondrial defects resulted in an imbalance of inhibitory and excitatory neurons that likely accounts for the observed phenotype in Tfam-ENSKO mice. Mitochondrial dysfunction, therefore, is likely to be an important driving force of neurodegeneration in the ENS and contribute to gastrointestinal symptoms in people with neurodegenerative disorders.
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The Bridge Helix of RNA polymerase acts as a central nanomechanical switchboard for coordinating catalysis and substrate movement.
Archaea
PUBLISHED: 09-01-2011
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The availability of in vitro assembly systems to produce recombinant archaeal RNA polymerases (RNAPs) offers one of the most powerful experimental tools for investigating the still relatively poorly understood molecular mechanisms underlying RNAP function. Over the last few years, we pioneered new robot-based high-throughput mutagenesis approaches to study structure/function relationships within various domains surrounding the catalytic center. The Bridge Helix domain, which appears in numerous X-ray structures as a 35-amino-acid-long alpha helix, coordinates the concerted movement of several other domains during catalysis through kinking of two discrete molecular hinges. Mutations affecting these kinking mechanisms have a direct effect on the specific catalytic activity of RNAP and can in some instances more than double it. Molecular dynamics simulations have established themselves as exceptionally useful for providing additional insights and detailed models to explain the underlying structural motions.
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ACCF/AHA methodology for the development of quality measures for cardiovascular technology: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Performance Measures.
J. Am. Coll. Cardiol.
PUBLISHED: 08-29-2011
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Consistent with the growing national focus on healthcare quality, the American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) have taken a leadership role over the past decade in developing measures of the quality of cardiovascular care by convening a joint ACCF/AHA Task Force on Performance Measures. The Task Force is charged with identifying the clinical topics appropriate for the development of performance measures and with assembling writing committees composed of clinical and methodological experts in collaboration with appropriate subspecialty societies. The Task Force has also created methodology documents that offer guidance in the development of process, outcome, composite, and efficiency measures. Cardiovascular performance measures using existing ACCF/AHA methodology are based on Class I or Class III guidelines recommendations, usually with Level A evidence. These performance measures, based on evidence-based ACCF/AHA guidelines, remain the most rigorous quality measures for both internal quality improvement and public reporting. However, many of the tools for diagnosis and treatment of cardiovascular disease involve advanced technologies, such as cardiac imaging, for which there are often no underlying guideline documents. Because these technologies affect the quality of cardiovascular care and also have the potential to contribute to cardiovascular health expenditures, there is a need for more critical assessment of the use of technology, including the development of quality and performance measures in areas in which guideline recommendations are absent. The evaluation of quality in the use of cardiovascular technologies requires consideration of multiple parameters that differ from other healthcare processes. The present document describes methodology for development of 2 new classes of quality measures in these situations, appropriate use measures and structure/safety measures. Appropriate use measures are based on specific indications, processes, or parameters of care for which high level of evidence data and Class I or Class III guideline recommendations may be lacking but are addressed in ACCF appropriate use criteria documents. Structure/safety measures represent measures developed to address structural aspects of the use of healthcare technology (e.g., laboratory accreditation, personnel training, and credentialing) or quality issues related to patient safety when there are neither guidelines recommendations nor appropriate use criteria. Although the strength of evidence for appropriate use measures and structure/safety measures may not be as strong as that for formal performance measures, they are quality measures that are otherwise rigorously developed, reviewed, tested, and approved in the same manner as ACCF/AHA performance measures. The ultimate goal of the present document is to provide direction in defining and measuring the appropriate use-avoiding not only underuse but also overuse and misuse-and proper application of cardiovascular technology and to describe how such appropriate use measures and structure/safety measures might be developed for the purposes of quality improvement and public reporting. It is anticipated that this effort will help focus the national dialogue on the use of cardiovascular technology and away from the current concerns about volume and cost alone to a more holistic emphasis on value.
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ACCF/AHA methodology for the development of quality measures for cardiovascular technology: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Performance Measures.
Circulation
PUBLISHED: 08-29-2011
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Consistent with the growing national focus on healthcare quality, the American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) have taken a leadership role over the past decade in developing measures of the quality of cardiovascular care by convening a joint ACCF/AHA Task Force on Performance Measures. The Task Force is charged with identifying the clinical topics appropriate for the development of performance measures and with assembling writing committees composed of clinical and methodological experts in collaboration with appropriate subspecialty societies. The Task Force has also created methodology documents that offer guidance in the development of process, outcome, composite, and efficiency measures. Cardiovascular performance measures using existing ACCF/AHA methodology are based on Class I or Class III guidelines recommendations, usually with Level A evidence. These performance measures, based on evidence-based ACCF/AHA guidelines, remain the most rigorous quality measures for both internal quality improvement and public reporting. However, many of the tools for diagnosis and treatment of cardiovascular disease involve advanced technologies, such as cardiac imaging, for which there are often no underlying guideline documents. Because these technologies affect the quality of cardiovascular care and also have the potential to contribute to cardiovascular health expenditures, there is a need for more critical assessment of the use of technology, including the development of quality and performance measures in areas in which guideline recommendations are absent. The evaluation of quality in the use of cardiovascular technologies requires consideration of multiple parameters that differ from other healthcare processes. The present document describes methodology for development of 2 new classes of quality measures in these situations, appropriate use measures and structure/safety measures. Appropriate use measures are based on specific indications, processes, or parameters of care for which high level of evidence data and Class I or Class III guideline recommendations may be lacking but are addressed in ACCF appropriate use criteria documents. Structure/safety measures represent measures developed to address structural aspects of the use of healthcare technology (e.g., laboratory accreditation, personnel training, and credentialing) or quality issues related to patient safety when there are neither guidelines recommendations nor appropriate use criteria. Although the strength of evidence for appropriate use measures and structure/safety measures may not be as strong as that for formal performance measures, they are quality measures that are otherwise rigorously developed, reviewed, tested, and approved in the same manner as ACCF/AHA performance measures. The ultimate goal of the present document is to provide direction in defining and measuring the appropriate use-avoiding not only underuse but also overuse and misuse-and proper application of cardiovascular technology and to describe how such appropriate use measures and structure/safety measures might be developed for the purposes of quality improvement and public reporting. It is anticipated that this effort will help focus the national dialogue on the use of cardiovascular technology and away from the current concerns about volume and cost alone to a more holistic emphasis on value.
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Quality of care and outcomes in women hospitalized for heart failure.
Circ Heart Fail
PUBLISHED: 08-23-2011
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Although women account for a significant proportion of heart failure (HF) hospitalizations, data on the quality of care and in-hospital outcomes in women are limited.
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Hemodynamic progression and outcome of asymptomatic aortic stenosis in primary care.
Am. J. Cardiol.
PUBLISHED: 08-03-2011
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The prognostic relevance of a rapid rate of hemodynamic progression of aortic stenosis (AS) has been predominantly investigated in tertiary centers. We reviewed the clinical and echocardiographic data from 153 asymptomatic patients with AS (age 77 ± 9 years; 65% men), with normal left ventricular function and paired echocardiograms ?4 months apart (mean 2.9 ± 2.1 years), evaluated in a nonreferral echocardiographic laboratory. The severity of AS was graded by the peak aortic velocity (Vmax) and progression was classified as slow or fast according to a cutoff value of 0.3 m/s increase annually. The end points were all-cause mortality and a composite of all-cause mortality and aortic valve replacement (AVR). At baseline, 135 patients (88%) had mild-to-moderate and 18 (12%) severe AS. Of the 153 patients, 49 (32%) showed fast progression (0.61 ± 0.32 m/s/yr) and 104 (68%) had slow progression (0.10 ± 0.16 m/s/yr). Among the 144 patients (94%) with clinical follow-up data, 40 died and 48 underwent AVR. The mortality rate was greater than that of the general population (p <0.001). On multivariate analysis, the independent predictors of mortality were the yearly change in Vmax (hazard ratio [HR] 13.352 per m/s increase, 95% confidence interval [CI] 5.136 to 34.713, p <0.001) and age (HR 1.122 per year, 95% CI 1.0728 to 1.735, p <0.001). The predictors of the composite end point of death and AVR were the yearly change in Vmax (HR 12.307, 95% CI 6.024 to 25.140, p <0.001) and Vmax on the initial echocardiogram (HR 2.684, 95% CI 1.921 to 3.750, p <0.001). In conclusion, primary care patients with asymptomatic AS are usually elderly and frequently develop rapid hemodynamic progression, which independently predicts, not only AVR, but also overall mortality.
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Safety and reactogenicity of canarypox ALVAC-HIV (vCP1521) and HIV-1 gp120 AIDSVAX B/E vaccination in an efficacy trial in Thailand.
PLoS ONE
PUBLISHED: 06-22-2011
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A prime-boost vaccination regimen with ALVAC-HIV (vCP1521) administered intramuscularly at 0, 4, 12, and 24 weeks and gp120 AIDSVAX B/E at 12 and 24 weeks demonstrated modest efficacy of 31.2% for prevention of HIV acquisition in HIV-uninfected adults participating in a community-based efficacy trial in Thailand.
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Mortality after fluid bolus in African children with severe infection.
N. Engl. J. Med.
PUBLISHED: 05-26-2011
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The role of fluid resuscitation in the treatment of children with shock and life-threatening infections who live in resource-limited settings is not established.
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Myocardial viability and survival in ischemic left ventricular dysfunction.
N. Engl. J. Med.
PUBLISHED: 04-04-2011
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The assessment of myocardial viability has been used to identify patients with coronary artery disease and left ventricular dysfunction in whom coronary-artery bypass grafting (CABG) will provide a survival benefit. However, the efficacy of this approach is uncertain.
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Detecting Fleeting MRI Signals with Frequency-Modulated Pulses.
AIP Conf Proc
PUBLISHED: 03-29-2011
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We describe a fundamentally different approach to MRI referred to as SWIFT (sweep imaging with Fourier transformation). SWIFT exploits time-shared RF excitation and signal acquisition, allowing capture of signal from spins with extremely short transverse relaxation time, T(2)*. The MR signal is acquired in gaps inserted into a broadband frequency-swept excitation pulse, which results in acquisition delays of only 1 - 2 microseconds. In SWIFT, 3D k-space is sampled in a radial manner, whereby one projection of the object is acquired in the gaps of each frequency-swept pulse, allowing a repetition time (TR) on the order of the pulse length (typically 1 - 3 milliseconds). Since the orientation of consecutive projections varies in a smooth manner (i.e., only small increments in the values of the x, y, z gradients occur from view to view), SWIFT scanning is close to inaudible and is insensitive to gradient timing errors and eddy currents. SWIFT images can be acquired in scan times similar to and sometimes faster than conventional 3D gradient echo techniques. With its ability to capture signals from ultrashort T(2)* spins, SWIFT promises to expand the role of MRI in areas of research where MRI previously played no or negligible role. In this article, we show wood and tooth images obtained with SWIFT as examples of materials with ultrashort T(2)*. Early experience suggests SWIFT can play a role in materials science and porous media research.
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Activity map of the Escherichia coli RNA polymerase bridge helix.
J. Biol. Chem.
PUBLISHED: 02-25-2011
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Transcription, the synthesis of RNA from a DNA template, is performed by multisubunit RNA polymerases (RNAPs) in all cellular organisms. The bridge helix (BH) is a distinct feature of all multisubunit RNAPs and makes direct interactions with several active site-associated mobile features implicated in the nucleotide addition cycle and RNA and DNA binding. Because the BH has been captured in both kinked and straight conformations in different crystals structures of RNAP, recently supported by molecular dynamics studies, it has been proposed that cycling between these conformations is an integral part of the nucleotide addition cycle. To further evaluate the role of the BH, we conducted systematic alanine scanning mutagenesis of the Escherichia coli RNAP BH to determine its contributions to activities required for transcription. Combining our data with an atomic model of E. coli RNAP, we suggest that alterations in the interactions between the BH and (i) the trigger loop, (ii) fork loop 2, and (iii) switch 2 can help explain the observed changes in RNAP functionality associated with some of the BH variants. Additionally, we show that extensive defects in E. coli RNAP functionality depend upon a single previously not studied lysine residue (Lys-781) that is strictly conserved in all bacteria. It appears that direct interactions made by the BH with other conserved features of RNAP are lost in some of the E. coli alanine substitution variants, which we infer results in conformational changes in RNAP that modify RNAP functionality.
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Cation-? interactions induce kinking of a molecular hinge in the RNA polymerase bridge-helix domain.
Biochem. Soc. Trans.
PUBLISHED: 01-27-2011
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RNAPs (RNA polymerases) are complex molecular machines that contain a highly conserved catalytic site surrounded by conformationally flexible domains. High-throughput mutagenesis in the archaeal model system Methanocaldococcus jannaschii has demonstrated that the nanomechanical properties of one of these domains, the bridge-helix, exert a key regulatory role on the rate of the NAC (nucleotide-addition cycle). Mutations that increase the probability and/or half-life of kink formation in the BH-HC (bridge-helix C-terminal hinge) cause a substantial increase in specific activity (superactivity). Fully atomistic molecular dynamics simulations show that kinking of the BH-HC appears to be driven by cation-? interactions and involve amino acid side chains that are exceptionally highly conserved in all prokaryotic and eukaryotic species.
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Catalytic Z-selective olefin cross-metathesis for natural product synthesis.
Nature
PUBLISHED: 01-25-2011
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Alkenes are found in many biologically active molecules, and there are a large number of chemical transformations in which alkenes act as the reactants or products (or both) of the reaction. Many alkenes exist as either the E or the higher-energy Z stereoisomer. Catalytic procedures for the stereoselective formation of alkenes are valuable, yet methods enabling the synthesis of 1,2-disubstituted Z alkenes are scarce. Here we report catalytic Z-selective cross-metathesis reactions of terminal enol ethers, which have not been reported previously, and of allylic amides, used until now only in E-selective processes. The corresponding disubstituted alkenes are formed in up to >98% Z selectivity and 97% yield. These transformations, promoted by catalysts that contain the highly abundant and inexpensive metal molybdenum, are amenable to gram-scale operations. Use of reduced pressure is introduced as a simple and effective strategy for achieving high stereoselectivity. The utility of this method is demonstrated by its use in syntheses of an anti-oxidant plasmalogen phospholipid, found in electrically active tissues and implicated in Alzheimers disease, and the potent immunostimulant KRN7000.
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Inhaled nitric oxide for the adjunctive therapy of severe malaria: protocol for a randomized controlled trial.
Trials
PUBLISHED: 01-24-2011
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Severe malaria remains a major cause of global morbidity and mortality. Despite the use of potent anti-parasitic agents, the mortality rate in severe malaria remains high. Adjunctive therapies that target the underlying pathophysiology of severe malaria may further reduce morbidity and mortality. Endothelial activation plays a central role in the pathogenesis of severe malaria, of which angiopoietin-2 (Ang-2) has recently been shown to function as a key regulator. Nitric oxide (NO) is a major inhibitor of Ang-2 release from endothelium and has been shown to decrease endothelial inflammation and reduce the adhesion of parasitized erythrocytes. Low-flow inhaled nitric oxide (iNO) gas is a US FDA-approved treatment for hypoxic respiratory failure in neonates.
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Surgery for asymptomatic degenerative aortic and mitral valve disease.
Nat Rev Cardiol
PUBLISHED: 01-18-2011
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Degenerative valvular heart disease, the most common form of valve disease in the Western world, can lead to aortic stenosis (AS) or mitral regurgitation (MR). In current guidelines for the management of patients with degenerative valvular disease, surgical intervention is recommended at the onset of symptoms or in the presence of left ventricular systolic impairment. Whether surgery is appropriate for asymptomatic patients remains a controversial issue. We argue the case for early pre-emptive intervention in selected, asymptomatic individuals with AS or MR, drawing on contemporary perioperative data, predictors of disease progression, and studies of the natural history of degenerative valvular heart disease.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

How does it work?

We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.