The PdxR-PdxKU locus involved in vitamin B salvage is important for group A streptococcal resistance to neutrophil killing and survival in human blood.

(Group A , GAS) is a Gram-positive bacterium that inflicts both superficial and life-threatening diseases on its human host. Analysis of fitness using a transposon mutant library revealed that genes predicted to be involved in vitamin B acquisition are associated with fitness in whole human blood. Vitamin B is essential for all life and is important for many cellular functions.

Impact of HIV-1 tat protein on methamphetamine-induced inhibition of vesicular monoamine transporter2-mediated dopamine transport and methamphetamine conditioned place preference in HIV-1 tat transgenic mice.

Perturbation of dopamine transmission has been implicated as a contributing factor in HIV-1 associated neurocognitive disorders with concurrent methamphetamine (METH) abuse. We have demonstrated that the HIV-1 protein, transactivator of transcription (Tat), decreases dopamine transport through inhibition of vesicular monoamine transporter2 (VMAT2). This study determined the effects of Tat protein on METH-inhibited VMAT2 function and METH-conditioned place preference (CPP).

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The disruption of dopamine neurotransmission by the HIV-1 Transactivator of transcription (Tat) during HIV-1 infection has been linked to the development of neurocognitive disorders, even under combined antiretroviral therapy (cART) treatment. We have demonstrated that SRI-32742, a novel allosteric modulator of dopamine (DA) transporter (DAT), attenuates cocaine- and Tat-binding to DAT, alleviates Tat-induced cognitive deficits and potentiation of cocaine reward in inducible Tat transgenic mice. The current study determined the pharmacological profile of SRI-32743 and its optimized second-generation analogs and their effects as allosteric modulators.

The Impact of Neurotransmitters on the Neurobiology of Neurodegenerative Diseases.

Neurodegenerative diseases affect millions of people worldwide. Neurodegenerative diseases result from progressive damage to nerve cells in the brain or peripheral nervous system connections that are essential for cognition, coordination, strength, sensation, and mobility. Dysfunction of these brain and nerve functions is associated with Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, and motor neuron disease.

Novel Allosteric Modulator Southern Research Institute-32743 Reverses HIV-1 Transactivator of Transcription-Induced Increase in Dopamine Release in the Caudate Putamen of Inducible Transactivator of Transcription Transgenic Mice.

Development of neurocognitive disorder in human immunodeficiency virus (HIV)-infected patients has been linked to dysregulation of dopamine by the HIV-1 transactivator of transcription (Tat) protein, a negative allosteric modulator of dopamine transporter (DAT). Using fast scan cyclic voltammetry, the present study determined the effects of in vivo Tat expression on dopamine release in the caudate putamen of inducible Tat transgenic (iTat-tg) mice and the impact of a novel DAT allosteric modulator, Southern Research Institute (SRI)-32743, on the Tat effect. We found that 7- or 14-day doxycycline (Dox)-induced Tat expression in iTat-tg mice resulted in a 2-fold increase in phasic but not tonic stimulated baseline dopamine release relative to saline control mice.

Mutations of tyrosine 467 in the human norepinephrine transporter attenuate HIV-1 Tat-induced inhibition of dopamine transport while retaining physiological function.

Dysregulation of dopaminergic transmission induced by the HIV-1 transactivator of transcription (Tat) has been implicated as a central factor in the development of HIV-1 associated neurocognitive disorders (HAND). We have demonstrated that the tyrosine470 residue of the human dopamine transporter (hDAT) plays a critical role in Tat-hDAT interaction. Based on the computational modeling predictions, the present study sought to examine the mutational effects of the tyrosine467 residue of the human norepinephrine transporter (hNET), a corresponding residue of the hDAT tyrosine470, on Tat-induced inhibition of reuptake of dopamine through the hNET.

Affective domain predictors of PharmD student pursuit of and successful matching for postgraduate pharmacy residency training.

Purpose: A study was conducted to identify significant associations between affective domain (AD) features identified using the Birkman Method assessment and students' likelihood to pursue and to successfully match for postgraduate residency training (PGRT), while controlling for demographic and academic variables known to impact PGRT match rates.

Methods: A retrospective analysis of 3 graduating classes of PharmD students from 2 colleges of pharmacy was performed. Data points such as PGRT match results, PGRT pursuit, student demographics, academic performance information, and AD data from the Birkman assessment were analyzed.

"Now I just need something sweet": Racism, emotional eating, and health among African Americans.

Background: The Environmental Affordances Model theorizes that systemic racism disproportionately exposes African Americans in the United States to chronic everyday stressors (e.g., individual racism) while simultaneously shaping the availability of coping resources (e.

Binding Mode of Human Norepinephrine Transporter Interacting with HIV-1 Tat.

The increase of HIV infection in macrophages results in HIV proteins being released, like HIV Tat which impairs the function of monoamine transporters. HIV-infected patients have displayed increased synaptic levels of dopamine (DA) due to reduced binding and function of monoamine transporters such as the norepinephrine transporter (NET) and the dopamine transporter (DAT). Development of a three-dimensional model of the HIV-1 Tat-human NET (hNET) binding complex would help reveal how HIV-1 Tat causes toxicity in the neuron by affecting DA uptake.

Rat prostaglandin EP3 receptor is highly promiscuous and is the sole prostanoid receptor family member that regulates INS-1 (832/3) cell glucose-stimulated insulin secretion.

Chronic elevations in fatty acid metabolites termed prostaglandins can be found in circulation and in pancreatic islets from mice or humans with diabetes and have been suggested as contributing to the β-cell dysfunction of the disease. Two-series prostaglandins bind to a family of G-protein-coupled receptors, each with different biochemical and pharmacological properties. Prostaglandin E receptor (EP) subfamily agonists and antagonists have been shown to influence β-cell insulin secretion, replication, and/or survival.

Phosphotransferase System Uptake and Metabolism of the β-Glucoside Salicin Impact Group A Streptococcal Bloodstream Survival and Soft Tissue Infection.

(group A [GAS]), a major human-specific pathogen, relies on efficient nutrient acquisition for successful infection within its host. The phosphotransferase system (PTS) couples the import of carbohydrates with their phosphorylation prior to metabolism and has been linked to GAS pathogenesis. In a screen of an insertional mutant library of all 14 annotated PTS permease (EIIC) genes in MGAS5005, the annotated β-glucoside PTS transporter () was found to be crucial for GAS growth and survival in human blood and was validated in another M1T1 GAS strain, 5448.

Enhancement of fast scan cyclic voltammetry detection of dopamine with tryptophan-modified electrodes.

Fast scan cyclic voltammetry (FSCV) allows for real -time analysis of phasic neurotransmitter levels. Tryptophan (TRP) is an aromatic amino acid responsible for facilitating electron transfer kinetics in oxidoreductase enzymes. Previous work with TRP-modified electrodes showed increased sensitivity for cyclic voltammetry detection of dopamine (DA) when used with slower scan rates (0.

Weekly Osteopathic Manipulative Treatment to Improve Measures of Sympathetic Tone in Women With Polycystic Ovary Syndrome: A Randomized, Controlled Pilot Study.

Background: Polycystic ovary syndrome (PCOS), a common hormone disorder affecting reproductive and metabolic health of reproductive-age women, was shown in a previous study from these authors to be associated with increased sympathetic tone. Increased sympathetic tone contributes to long-term health risks for cardiovascular disease and promotes PCOS pathogenesis.

Objective: To determine whether weekly osteopathic manipulative treatment (OMT) improves physiologic measures of sympathetic tone in women with PCOS.

The effect of the EP3 antagonist DG-041 on male mice with diet-induced obesity.

Background/aims: The prostaglandin E (PGE) EP3 receptor has a multifaceted role in metabolism. Drugs targeting EP3 have been proposed as therapeutics for diabetes; however, studies utilizing global EP3 knockout mice suggest that EP3 blockade increases obesity and insulin resistance. The present studies attempt to determine the effect of acute EP3 antagonist treatment on the diabetic phenotype.

Exposure of Candida albicans β (1,3)-glucan is promoted by activation of the Cek1 pathway.

Candida albicans is among the most common causes of human fungal infections and is an important source of mortality. C. albicans is able to diminish its detection by innate immune cells through masking of β (1,3)-glucan in the inner cell wall with an outer layer of heavily glycosylated mannoproteins (mannan).

Correlation Between Physiologic and Osteopathic Measures of Sympathetic Activity in Women With Polycystic Ovary Syndrome.

Background: Polycystic ovary syndrome (PCOS) is a common hormone disorder that affects the reproductive, metabolic, and psychological health of reproductive-aged females, with a number of long-term health risks, including type 2 diabetes mellitus and cardiovascular sequelae. Sympathetic hyperactivity in affected persons may be involved in the pathogenesis of the disorder.

Objective: To determine whether physiologic and osteopathic measures of increased sympathetic tone correlate in a population of women with PCOS.

Transcriptional Profiling of Patient Isolates Identifies a Novel TOR/Starvation Regulatory Pathway in Cryptococcal Virulence.

Human infection with causes up to a quarter of a million AIDS-related deaths annually and is the most common cause of nonviral meningitis in the United States. As an opportunistic fungal pathogen, is distinguished by its ability to adapt to diverse host environments, including plants, amoebae, and mammals. In the present study, comparative transcriptomics of the fungus within human cerebrospinal fluid identified expression profiles representative of low-nutrient adaptive responses.

Candida albicans Cannot Acquire Sufficient Ethanolamine from the Host To Support Virulence in the Absence of Phosphatidylethanolamine Synthesis.

mutants for phosphatidylserine (PS) synthase (ΔΔ) and PS decarboxylase (ΔΔ ΔΔ) are compromised for virulence in mouse models of systemic infection and oropharyngeal candidiasis (OPC). Both of these enzymes are necessary to synthesize phosphatidylethanolamine (PE) by the pathway, but these mutants are still capable of growth in culture media, as they can import ethanolamine from media to synthesize PE through the Kennedy pathway. Given that the host has ethanolamine in its serum, the exact mechanism by which virulence is lost in these mutants is not clear.

Integrated Community Strategies for Linking Youth to Adolescent Reproductive Health Services: A Case Study.

Purpose: This article describes the development and promotion of a full-service adolescent health center at a local health department intended to increase teen access to contraceptive and reproductive health care. This work was conducted as part of a multicomponent, community-based teen pregnancy prevention initiative in Gaston County, North Carolina.

Methods: To increase access to adolescent reproductive health services, we implemented multiple integrated strategies: (1) building community support for adolescent reproductive health services; (2) providing technical assistance to the health department in opening the Teen Wellness Center (TWC), a teen-centered, full-service clinic; (3) strengthening referral partnerships between community organizations and clinical services; and (4) educating teens on how to access reproductive health services.

Adaptive Randomization of Veliparib-Carboplatin Treatment in Breast Cancer.

Background: The genetic and clinical heterogeneity of breast cancer makes the identification of effective therapies challenging. We designed I-SPY 2, a phase 2, multicenter, adaptively randomized trial to screen multiple experimental regimens in combination with standard neoadjuvant chemotherapy for breast cancer. The goal is to match experimental regimens with responding cancer subtypes.

Adaptive Randomization of Neratinib in Early Breast Cancer.

Background: The heterogeneity of breast cancer makes identifying effective therapies challenging. The I-SPY 2 trial, a multicenter, adaptive phase 2 trial of neoadjuvant therapy for high-risk clinical stage II or III breast cancer, evaluated multiple new agents added to standard chemotherapy to assess the effects on rates of pathological complete response (i.e.

INTERSESSION RELIABILITY OF UPPER EXTREMITY ISOKINETIC PUSH-PULL TESTING.

Background: Based on the frequency pushing and pulling patterns are used in functional activities, there is a need to establish an objective method of quantifying the muscle performance characteristics associated with these motions, particularly during the later stages of rehabilitation as criteria for discharge. While isokinetic assessment offers an approach to quantifying muscle performance, little is known about closed kinetic chain (CKC) isokinetic testing of the upper extremity (UE).

Purpose: To determine the intersession reliability of isokinetic upper extremity measurement of pushing and pulling peak force and average power at slow (0.

Serial expression analysis of breast tumors during neoadjuvant chemotherapy reveals changes in cell cycle and immune pathways associated with recurrence and response.

Introduction: The molecular biology involving neoadjuvant chemotherapy (NAC) response is poorly understood. To elucidate the impact of NAC on the breast cancer transcriptome and its association with clinical outcome, we analyzed gene expression data derived from serial tumor samples of patients with breast cancer who received NAC in the I-SPY 1 TRIAL.

Methods: Expression data were collected before treatment (T1), 24-96 hours after initiation of chemotherapy (T2) and at surgery (TS).

Masking of β(1-3)-glucan in the cell wall of Candida albicans from detection by innate immune cells depends on phosphatidylserine.

The virulence of Candida albicans in a mouse model of invasive candidiasis is dependent on the phospholipids phosphatidylserine (PS) and phosphatidylethanolamine (PE). Disruption of the PS synthase gene CHO1 (i.e.

The Wsc1p cell wall signaling protein controls biofilm (Mat) formation independently of Flo11p in Saccharomyces cerevisiae.

Saccharomyces cerevisiae strains of the ∑1278b background generate biofilms, referred to as mats, on low-density agar (0.3%) plates made with rich media (YPD). Mat formation involves adhesion of yeast cells to the surface of the agar substrate and each other as the biofilm matures, resulting in elaborate water channels that create filigreed patterns of cells.