Exploring Integrin α5β1 as a Potential Therapeutic Target for Pulmonary Arterial Hypertension: Insights From Comprehensive Multicenter Preclinical Studies.

Background: Pulmonary arterial hypertension (PAH) is characterized by obliterative vascular remodeling of the small pulmonary arteries (PAs) and progressive increase in pulmonary vascular resistance leading to right ventricular failure. Although several drugs are approved for the treatment of PAH, mortality rates remain high. Accumulating evidence supports a pathological function of integrins in vessel remodeling, which are gaining renewed interest as drug targets.

Implementation of a clinical research "One Signature Initiative" at a large academic medical center.

A clinical research team's goal is to support the implementation, conduct, and monitoring of research studies and corresponding protocols. There is a need to ensure that study teams have adequate resources and regulatory support to successfully adhere to regulations and good clinical research practices. Our team, the UC Davis Division of Infectious Diseases Research Unit (IDRU), sought to establish a One Signature Initiative program for all studies and protocols supported by the IDRU.

The Discovery of MORF-627, a Highly Selective Conformationally-Biased Zwitterionic Integrin αvβ6 Inhibitor for Fibrosis.

Inhibition of integrin αvβ6 is a promising approach to the treatment of fibrotic disease such as idiopathic pulmonary fibrosis. Screening a small library combining head groups that stabilize the bent-closed conformation of integrin αIIbβ3 with αv integrin binding motifs resulted in the identification of hit compounds that bind the bent-closed conformation of αvβ6. Crystal structures of these compounds bound to αvβ6 and related integrins revealed opportunities to increase potency and selectivity, and these efforts were accelerated using accurate free energy perturbation (FEP+) calculations.

Exploring Integrin α5β1 as a Potential Therapeutic Target for Pulmonary Arterial Hypertension: Insights from Comprehensive Multicenter Preclinical Studies.

Unlabelled: Pulmonary arterial hypertension (PAH) is characterized by obliterative vascular remodeling of the small pulmonary arteries (PA) and progressive increase in pulmonary vascular resistance (PVR) leading to right ventricular (RV) failure. Although several drugs are approved for the treatment of PAH, mortality remains high. Accumulating evidence supports a pathological function of integrins in vessel remodeling, which are gaining renewed interest as drug targets.

A recombinant technique for mapping functional sites of heterotrimeric collagen helices: Collagen IV CB3 fragment as a prototype for integrin binding.

Collagen superfamily of proteins is a major component of the extracellular matrix. Defects in collagens underlie the cause of nearly 40 human genetic diseases in millions of people worldwide. Pathogenesis typically involves genetic alterations of the triple helix, a hallmark structural feature that bestows exceptional mechanical resistance to tensile forces and a capacity to bind a plethora of macromolecules.

Transcriptome-wide subtyping of pediatric and adult T cell acute lymphoblastic leukemia in an international study of 707 cases.

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy of T cell progenitors, known to be a heterogeneous disease in pediatric and adult patients. Here we attempted to better understand the disease at the molecular level based on the transcriptomic landscape of 707 T-ALL patients (510 pediatric, 190 adult patients, and 7 with unknown age; 599 from published cohorts and 108 newly investigated). Leveraging the information of gene expression enabled us to identify 10 subtypes (G1–G10), including the previously undescribed one characterized by GATA3 mutations, with GATA3R276Q capable of affecting lymphocyte development in zebrafish.

The Portrait of a Dying Child.

The portrait of a dying child is an homage to a child's journey from initial diagnosis to the terminal stages of illness in metastatic neuroblastoma, raising the critical question of the importance of defining a beautiful death - a concept I first came across as a literature student in Henrik Ibsen's renowned tragedy . In this article, we discuss a case study of a child named Peter (real names have been changed to maintain the confidentiality of the patient) and his family, whom I met during my oncology rotation as a junior pediatric resident, and various aspects of care - ranging from symptom management, pain control, the family as an emotional and spiritual unit and complications of metastatic disease. Interlaced amidst references of current practices related to pain control and palliation of symptoms are quotes from Dr Myra BluebondLangner's books and a personal encounter with the child to construct the child as a child and not another dying patient.

Impact of Self-Preference Community Fitness Interventions in High-Risk African Americans.

African Americans have a high prevalence of obesity and physical inactivity, but few interventions have been successful in the long term. We describe a 1-year intervention program to increase physical activity and reduce cardiometabolic risk. Interventions incorporated the premise that self-selection into flexible venues and varying exercise modalities would result in improvement in fitness and risk factors.

Discovery of Pyrazolopyridones as a Novel Class of Gyrase B Inhibitors Using Structure Guided Design.

The ATPase subunit of DNA gyrase B is an attractive antibacterial target due to high conservation across bacteria and the essential role it plays in DNA replication. A novel class of pyrazolopyridone inhibitors was discovered by optimizing a fragment screening hit scaffold using structure guided design. These inhibitors show potent Gram-positive antibacterial activity and low resistance incidence against clinically important pathogens.

Fragment-based discovery of DNA gyrase inhibitors targeting the ATPase subunit of GyrB.

Inhibitors of the ATPase function of bacterial DNA gyrase, located in the GyrB subunit and its related ParE subunit in topoisomerase IV, have demonstrated antibacterial activity. In this study we describe an NMR fragment-based screening effort targeting Staphylococcus aureus GyrB that identified several attractive and novel starting points with good ligand efficiency. Fragment hits were further characterized using NMR binding studies against full-length S.

Discovery of Indazole Derivatives as a Novel Class of Bacterial Gyrase B Inhibitors.

Antibacterials with a novel mechanism of action offer a great opportunity to combat widespread antimicrobial resistance. Bacterial DNA Gyrase is a clinically validated target. Through physiochemical property optimization of a pyrazolopyridone hit, a novel class of GyrB inhibitors were discovered.

Discovery of Azaindole Ureas as a Novel Class of Bacterial Gyrase B Inhibitors.

The emergence and spread of multidrug resistant bacteria are widely believed to endanger human health. New drug targets and lead compounds exempt from cross-resistance with existing drugs are urgently needed. We report on the discovery of azaindole ureas as a novel class of bacterial gyrase B inhibitors and detail the story of their evolution from a de novo design hit based on structure-based drug design.

Targeting Bacterial Cell Wall Peptidoglycan Synthesis by Inhibition of Glycosyltransferase Activity.

Synthesis of bacterial cell wall peptidoglycan requires glycosyltransferase enzymes that transfer the disaccharide-peptide from lipid II onto the growing glycan chain. The polymerization of the glycan chain precedes cross-linking by penicillin-binding proteins and is essential for growth for key bacterial pathogens. As such, bacterial cell wall glycosyltransferases are an attractive target for antibiotic drug discovery.

Lean Mass and Fat Mass as Contributors to Physical Fitness in an Overweight and Obese African American Population.

Objective: To determine the association of lean vs fat mass with fitness in healthy, overweight and obese African Americans from families with early-onset coronary disease.

Design: Cross-sectional study.

Setting: Baltimore, Maryland.

Age differences in periventricular and deep white matter lesions.

Deep white matter hyperintensity (DWMH) and periventricular (PV) white matter lesion volumes are associated with age and subsequent stroke. We studied age differences in these volumes accounting for collinearity and risk factors. Subjects were 563 healthy family members of early-onset coronary artery disease patients.

A Simple Scalable Association Hypothesis Test Combining Gene-wide Evidence From Multiple Polymorphisms.

Aims: In single-nucleotide polymorphism (SNP) scans, SNP-phenotype association hypotheses are tested, however there is biological interpretation only for genes that span multiple SNPs. We demonstrate and validate a method of combining gene-wide evidence using data for high-density lipoprotein cholesterol (HDLC).

Methodology: In a family based study (N=1782 from 482 families), we used 1000 phenotype-permuted datasets to determine the correlation of z-test statistics for 592 SNP-HDLC association tests comprising 14 genes previously reported to be associated with HDLC.

Extreme deep white matter hyperintensity volumes are associated with African American race.

Background: African Americans (AAs) have a higher prevalence of extreme ischemic white matter hyperintensities (WMHs) on magnetic resonance imaging (MRI) than do European Americans (EAs) based on the Cardiovascular Health Study (CHS) score. Ischemic white matter disease, limited to the deep white matter, may be biologically distinct from disease in other regions and may reflect a previously observed trend toward an increased risk of subcortical lacunar infarcts in AAs. We hypothesized that extreme deep WMH volume (DWMV) or periventricular volume (PV) may also have a higher prevalence in AAs.

Noncalcified coronary plaque volumes in healthy people with a family history of early onset coronary artery disease.

Background: Although age and sex distributions of calcified coronary plaque have been well described in the general population, noncalcified plaque (NCP) distributions remain unknown. This is important because NCP is a putative precursor for clinical coronary artery disease and could serve as a sentinel for aggressive primary prevention, especially in high-risk populations. We examined the distributions of NCP and calcified coronary plaque in healthy 30- to 74-year-old individuals from families with early onset coronary artery disease.

The association of brachial artery diameter with noncalcified coronary plaque burden in apparently healthy individuals.

Objective: Coronary atherosclerosis has been associated with systemic arterial remodeling even in nonatherosclerotic vessels. However, it is not known whether systemic remodeling is differentially associated with the cumulative atherosclerotic process, reflected by putatively quiescent calcified plaque (CP), or with active atherosclerosis, consisting of noncalcified plaque (NCP). We thus examined the association of brachial artery diameter (BAD), an artery that does not suffer clinical atherosclerosis, with the presence and the extent of coronary CP and NCP.

Effect of positive well-being on incidence of symptomatic coronary artery disease.

Although negative emotions and psychiatric morbidity have often been found to increase incident coronary artery disease (CAD) risk, fewer studies have shown positive emotions to be protective against CAD; none have been performed in high-risk healthy populations, taking risk factors into account. Thus, we examined the effect of positive well-being on incident CAD in both a high-risk initially healthy population and a national probability sample. We screened healthy siblings of probands with documented early-onset CAD from 1985 to 2007 in the GeneSTAR (Genetic Study of Atherosclerosis Risk) population and examined sociodemographic data, risk factors, and positive well-being using the General Well-Being Schedule.

Ethnic-specific determinants of exercise capacity in a healthy high-risk population.

Purpose: African Americans (AA) have been shown to have lower exercise capacities and a higher prevalence of related risk for cardiovascular disease (CVD) compared to European Americans (EA). Broad biopsychosocial models that may inform the design of ethnic-specific exercise programs have not been well examined. We thus examined exercise capacity and its biopsychosocial correlates in a healthy population of AA and EA at increased risk of CVD.

Evaluating the activity of the RNA polymerase inhibitor myxopyronin B against Staphylococcus aureus.

Myxopyronin B (MyxB) binds to the switch region of RNA polymerase (RNAP) and inhibits transcriptional initiation. To evaluate the potential development of MyxB as a novel class of antibiotic, we characterized the antimicrobial activity of MyxB against Staphylococcus aureus. Spontaneous MyxB resistance in S.

Method development and application to determine potential plant uptake of antibiotics and other drugs in irrigated crop production systems.

Studies have shown the detection of emerging contaminants (ECs), of which pharmaceuticals are a subset, in surface waters across the United States. The objective of this study was to develop methods, and apply them, to evaluate the potential for food chain transfer when EC-containing waters are used for crop irrigation. Greenhouse experiments were performed in which select food crops were irrigated with water spiked with three antibiotics.

A common variant in the Von Willebrand factor gene is associated with multiple functional consequences.

Von Willebrand Factor (vWF) is a plasma protein involved in thrombosis and hemostasis [1]. We examined whether common single nucleotide polymorphisms (SNPs) in the vWF gene were associated with vWF levels and platelet aggregation-related functional consequences in1230 Whites and 837 African Americans in a cross-sectional family based genetic study of platelet function. From a high-density scan, 28 SNPs with a minor allele frequency > 5% in both races were tested for association using age and sex adjusted variance components analysis in MERLIN.

Berberine-INF55 (5-nitro-2-phenylindole) hybrid antimicrobials: effects of varying the relative orientation of the berberine and INF55 components.

Hybrid antimicrobials containing an antibacterial linked to a multidrug resistance (MDR) pump inhibitor make up a promising new class of agents for countering efflux-mediated bacterial drug resistance. This study explores the effects of varying the relative orientation of the antibacterial and efflux pump inhibitor components in three isomeric hybrids (SS14, SS14-M, and SS14-P) which link the antibacterial alkaloid and known substrate for the NorA MDR pump berberine to different positions on INF55 (5-nitro-2-phenylindole), an inhibitor of NorA. The MICs for all three hybrids against wild-type, NorA-knockout, and NorA-overexpressing Staphylococcus aureus cells were found to be similar (9.