Similarities and distinctions in the activation of the Pdr1 regulatory pathway by azole and non-azole drugs.

Unlabelled: Incidences of fluconazole (FLC) resistance among clinical isolates are a growing issue in clinics. The pleiotropic drug response network in confers azole resistance and is defined primarily by the ZnCys zinc cluster-containing transcription factor Pdr1 and target genes such as , which encodes an ATP-binding cassette transporter protein thought to act as an FLC efflux pump. Mutations in the gene that render the transcription factor hyperactive are the most common cause of fluconazole resistance among clinical isolates.

Similarities and distinctions in the activation of the Pdr1 regulatory pathway by azole and non-azole drugs.

Incidences of fluconazole (FLC) resistance among clinical isolates is a growing issue in clinics. The pleiotropic drug response (PDR) network in . confers azole resistance and is defined primarily by the ZnCys zinc cluster-containing transcription factor Pdr1 and target genes such as , that encodes an ATP-binding cassette transporter protein thought to act as a FLC efflux pump.

Exploring attitudes to research involving human subjects among Vietnamese university students: establishing a prospective longitudinal mixed-methods student cohort at the University of Medicine and Pharmacy at Ho Chi Minh City.

Research capacity is increasing in low- and middle-income countries (LMICs), with progressive development in the range and complexity of studies being undertaken, often in collaboration with high-income country partners. Although senior local stakeholders are typically involved in ensuring that research is conducted according to accepted standards for ethical and scientific quality, to date there has been little exploration of the views of younger generations around the ethics of research involving human subjects. We present our protocol to establish a longitudinal mixed-methods student cohort at the University of Medicine and Pharmacy at Ho Chi Minh City, Vietnam, that is investigating students' views around the ethics of clinical and public-health oriented research.

Calcineurin is required for Pdr1 transcriptional activation.

Drug-resistant microorganisms are a problem in the treatment of all infectious diseases; this is an especially acute problem with fungi due to the existence of only three major classes of antifungal drugs, including the azole drug fluconazole. In the pathogenic yeast , mutant forms of a transcription factor called Pdr1 are commonly associated with decreased fluconazole susceptibility and poor clinical outcomes. Here, we identify a protein phosphatase called calcineurin that is required for fluconazole-dependent induction of Pdr1 transcriptional activation and associated drug susceptibility.

Rapid, efficient auxin-inducible protein degradation in pathogens.

A variety of inducible protein degradation (IPD) systems have been developed as powerful tools for protein functional characterization. IPD systems provide a convenient mechanism for rapid inactivation of almost any target protein of interest. Auxin-inducible degradation (AID) is one of the most common IPD systems and has been established in diverse eukaryotic research model organisms.

A Case of Severe Metabolic Acidosis in the Setting of a Strict Ketogenic Diet.

Patients with metabolic acidosis often present with obscure, multifactorial etiologies, making efficient diagnosis and treatment key to preventing poor clinical outcomes. This case report describes a patient with severe metabolic acidosis in which the underlying cause was not immediately apparent. After a thorough work-up and history taking, the patient's strict ketogenic diet was identified as the most likely source of his illness.

Rapid, efficient auxin-inducible protein degradation in pathogens.

A variety of inducible protein degradation (IPD) systems have been developed as powerful tools for protein functional characterization. IPD systems provide a convenient mechanism for rapid inactivation of almost any target protein of interest. Auxin-inducible degradation (AID) is one of the most common IPD systems and has been established in diverse eukaryotic research model organisms.

Caring for the whole person: transgender-competent HIV pre-exposure prophylaxis as part of integrated primary healthcare services in Vietnam.

Introduction: Although HIV prevalence among transgender women who have sex with men in Vietnam is high (16-18%), uptake of pre-exposure prophylaxis (PrEP) is low compared to other populations. When PrEP was initiated in 2017, gender-affirming healthcare was largely unavailable. Lack of access to competent, stigma-free healthcare is a well-documented barrier to transgender women's uptake of PrEP and primary healthcare (PHC).

Nonidentical function of Upc2A binding sites in the Candida glabrata CDR1 promoter.

Increased expression of the Candida glabrata CDR1 gene, encoding an ATP-binding cassette membrane transporter, is routinely observed in fluconazole-resistant isolates of this pathogenic yeast. CDR1 transcription has been well-documented to be due to activity of the Zn2Cys6 zinc cluster-containing transcription factor Pdr1. Gain-of-function mutations in the gene encoding this factor are the most commonly observed cause of fluconazole hyper-resistance in clinical isolates.

Azole-Resistant Alleles of in Candida glabrata Trigger Activation of the Pdr1 and Upc2A Transcription Factors.

Azoles, the most commonly used antifungal drugs, specifically inhibit the fungal lanosterol α-14 demethylase enzyme, which is referred to as Erg11. Inhibition of Erg11 ultimately leads to a reduction in ergosterol production, an essential fungal membrane sterol. Many species, such as Candida albicans, develop mutations in this enzyme which reduces the azole binding affinity and results in increased resistance.

Loss-of-Function Mutations Suppress the Fluconazole Susceptibility of Δ Mutation in Candida glabrata, Implicating Additional Positive Regulators of Ergosterol Biosynthesis.

Two of the major classes of antifungal drugs in clinical use target ergosterol biosynthesis. Despite its importance, our understanding of the transcriptional regulation of ergosterol biosynthesis genes in pathogenic fungi is essentially limited to the role of hypoxia and sterol-stress-induced transcription factors such as Upc2 and Upc2A as well as homologs of sterol response element binding (SREB) factors. To identify additional regulators of ergosterol biosynthesis in Candida glabrata, an important human fungal pathogen with reduced susceptibility to ergosterol biosynthesis inhibitors relative to other spp.

The Candida glabrata Upc2A transcription factor is a global regulator of antifungal drug resistance pathways.

The most commonly used antifungal drugs are the azole compounds, which interfere with biosynthesis of the fungal-specific sterol: ergosterol. The pathogenic yeast Candida glabrata commonly acquires resistance to azole drugs like fluconazole via mutations in a gene encoding a transcription factor called PDR1. These PDR1 mutations lead to overproduction of drug transporter proteins like the ATP-binding cassette transporter Cdr1.

Prepped for PrEP? Acceptability, continuation and adherence among men who have sex with men and transgender women enrolled as part of Vietnam's first pre-exposure prophylaxis program.

Unlabelled: Background HIV prevalence among men who have sex with men (MSM) and transgender women (TGW) in Vietnam is high, whereas coverage of effective HIV prevention services has been inadequate. Studies have measured MSM and TGW demand for pre-exposure prophylaxis (PrEP) services, which led to the design of the first ever PrEP program in Vietnam, Prepped for PrEP (P4P).

Methods: In March 2017, PrEP services were offered in Ho Chi Minh City as part of the P4P demonstration project, enabling same-day enrolment in three key population (KP)-led clinics and four public clinics.

Interaction of carbohydrate binding module 20 with starch substrates.

CBM20s are starch-binding domains found in many amylolytic enzymes, including glucoamylase, alpha-amylase, beta-amylases, and a new family of starch-active polysaccharide monooxygenases (AA13 PMOs). Previous studies of CBM20-substrate interaction only concerned relatively small or soluble amylose molecules, while amylolytic enzymes often work on extended chains of insoluble starch molecules. In this study, we utilized molecular simulation techniques to gain further insights into the interaction of CBM20 with substrates of various sizes its two separate binding sites, termed as BdS1 and BdS2.

Evidence that Ergosterol Biosynthesis Modulates Activity of the Pdr1 Transcription Factor in Candida glabrata.

A crucial limitation in antifungal chemotherapy is the limited number of antifungal drugs currently available. Azole drugs represent the most commonly used chemotherapeutic, and loss of efficacy of these drugs is a major risk factor in successful treatment of a variety of fungal diseases. is a pathogenic yeast that is increasingly found associated with bloodstream infections, a finding likely contributed to by its proclivity to develop azole drug resistance.

Lay provider HIV testing: A promising strategy to reach the undiagnosed key populations in Vietnam.

Background: In Vietnam, reaching the remaining one-third of undiagnosed people living with HIV and facilitating their antiretroviral therapy (ART) enrollment requires breakthrough approaches. We piloted lay provider HIV testing as an innovative approach to reach at-risk populations that never or infrequently HIV test at facility-based services.

Methods: We conducted a cross-sectional survey and analysis of routine program data in two urban provinces (Hanoi and Ho Chi Minh City) and two rural mountainous provinces (Nghe An and Dien Bien) from October 2015 through September 2017.

From conventional to disruptive: upturning the HIV testing status quo among men who have sex with men in Vietnam.

Introduction: HIV prevalence among men who have sex with men (MSM) in Vietnam is increasing, while annual HIV testing uptake has remained consistently low, posing a significant challenge to reaching the 90-90-90 goals. Barriers to MSM seeking HIV testing include concerns regarding confidentiality and lack of convenient testing options. Two new HIV testing strategies-HIV lay provider and HIV self-testing (HIVST)-were piloted alongside intensive social media outreach to increase access to and uptake of HIV testing among MSM not actively engaged in services.

Construction and Use of a Recyclable Marker To Examine the Role of Major Facilitator Superfamily Protein Members in Drug Resistance Phenotypes.

is the second most common species causing candidiasis. C. glabrata can also readily acquire resistance to azole drugs, complicating its treatment.

Phenotypes and Virulence among Staphylococcus aureus USA100, USA200, USA300, USA400, and USA600 Clonal Lineages.

Staphylococcus aureus diseases affect ~500,000 individuals per year in the United States. Worldwide, the USA100, USA200, USA400, and USA600 lineages cause many of the life-threatening S. aureus infections, such as bacteremia, infective endocarditis, pneumonia, toxic shock syndrome, and surgical site infections.

Novel Tissue Level Effects of the Staphylococcus aureus Enterotoxin Gene Cluster Are Essential for Infective Endocarditis.

Background: Superantigens are indispensable virulence factors for Staphylococcus aureus in disease causation. Superantigens stimulate massive immune cell activation, leading to toxic shock syndrome (TSS) and contributing to other illnesses. However, superantigens differ in their capacities to induce body-wide effects.

Staphylococcus aureus β-Toxin Mutants Are Defective in Biofilm Ligase and Sphingomyelinase Activity, and Causation of Infective Endocarditis and Sepsis.

β-Toxin is an important virulence factor of Staphylococcus aureus, contributing to colonization and development of disease [Salgado-Pabon, W., et al. (2014) J.

Determining the Presence of Superantigens in Coagulase Negative Staphylococci from Humans.

Superantigens (SAgs) are important virulence factors in S. aureus. Recent studies identified their presence in animal coagulase-negative staphylococci (CNS).

Chronic superantigen exposure induces systemic inflammation, elevated bloodstream endotoxin, and abnormal glucose tolerance in rabbits: possible role in diabetes.

Unlabelled: Excessive weight and obesity are associated with the development of diabetes mellitus type 2 (DMII) in humans. They also pose high risks of Staphylococcus aureus colonization and overt infections. S.