The atypical antipsychotic aripiprazole alters the outcome of disseminated infections.

Invasive fungal infections impose an enormous clinical, social, and economic burden on humankind. One of the most common species responsible for invasive fungal infections is . More than 30% of patients with disseminated candidiasis fail therapy with existing antifungal drugs, including the widely used azole class.

Biophysical library screening using a Thermo-FMN assay to identify and characterize Clostridioides difficile FabK inhibitors.

Clostridioides difficile, a gram-positive anaerobic bacterium, is one of the most frequent causes of nosocomial infections. C. difficile infection (CDI) results in almost a half a million infections and approximately 30,000 deaths in the U.

The atypical antipsychotic aripiprazole alters the outcome of disseminated infections.

Invasive fungal infections (IFIs) impose an enormous clinical, social, and economic burden on humankind. For many IFIs, ≥ 30% of patients fail therapy with existing antifungal drugs, including the widely used azole class. We previously identified a collection of 13 approved medications that antagonize azole activity.

Glycogen Metabolism in Candida albicans Impacts Fitness and Virulence during Vulvovaginal and Invasive Candidiasis.

The polymorphic fungus Candida albicans remains a leading cause of both invasive and superficial mycoses, including vulvovaginal candidiasis (VVC). Metabolic plasticity, including carbohydrate catabolism, confers fitness advantages at anatomical site-specific host niches. C.

Identifying Specific Small Molecule-Protein Interactions Using Target Abundance-Based Fitness Screening (TAFiS).

Traditional small molecule antifungal discovery efforts often utilize high-throughput (HTP) biochemical or whole-cell phenotypic screens to identify novel candidates. However, both methods have limitations which hinder the rapid identification of physiologically active compounds that act via a defined mechanism of action. The method described herein is an efficient, sensitive, and HTP compatible approach that utilizes the principles of competitive fitness to rapidly identify small molecules that functionally interact with a specific target protein within whole cells.

Single-item depression screening with the Neurobehavioral Symptom Inventory (NSI): Do scores assist clinicians with predicting need for mental health interventions?

The purpose of this study was to examine the relationship between a single item for depression from the Neurobehavioral Symptom Inventory (NSI) and a common depression screening measure to predict need for further mental health consultation for veterans with traumatic brain injury (TBI). Three hundred eighty veterans referred to a Veterans Affairs Health Care System TBI clinic for evaluation were administered the NSI and a common depression screening measure (Beck Depression Inventory-Second Edition; BDI-II). Receiver Operating Characteristic (ROC) curve analyses were conducted to determine best cutoff scores on the BDI-II corresponding with a single item of the NSI item pertaining to depression (i.

Titration of C-5 Sterol Desaturase Activity Reveals Its Relationship to Candida albicans Virulence and Antifungal Susceptibility Is Dependent upon Host Immune Status.

The azole antifungals inhibit sterol 14α-demethylase (S14DM), which depletes cellular ergosterol and promotes synthesis of the dysfunctional lipid 14α-methylergosta-8,24(28)-dien-3β,6α-diol, ultimately arresting growth. Mutations that inactivate sterol Δ-desaturase (Erg3p), the enzyme that produces the sterol-diol upon S14DM inhibition, enhances Candida albicans growth in the presence of the azoles. However, null mutants are sensitive to some physiological stresses and can be less virulent than the wild type.

Delineation of the Direct Contribution of Candida auris Mutations to Clinical Triazole Resistance.

Resistance to fluconazole is one of clinical characteristics most frequently challenging the treatment of invasive Candida auris infections, and is observed among >90% of all characterized clinical isolates. In this work, the native C. auris allele in a previously characterized fluconazole-susceptible clinical isolate was replaced with the alleles from three highly fluconazole-resistant clinical isolates (MIC ≥256 mg/L), encoding the amino acid substitutions VF125AL, Y132F, and K143R, using Cas9-ribonucleoprotein (RNP) mediated transformation system.

Identification of Inhibitors of Fungal Fatty Acid Biosynthesis.

Fungal fatty acid (FA) synthase and desaturase enzymes are essential for the growth and virulence of human fungal pathogens. These enzymes are structurally distinct from their mammalian counterparts, making them attractive targets for antifungal development. However, there has been little progress in identifying chemotypes that target fungal FA biosynthesis.

A variant ECE1 allele contributes to reduced pathogenicity of Candida albicans during vulvovaginal candidiasis.

Vulvovaginal candidiasis (VVC), caused primarily by the human fungal pathogen Candida albicans, results in significant quality-of-life issues for women worldwide. Candidalysin, a toxin derived from a polypeptide (Ece1p) encoded by the ECE1 gene, plays a crucial role in driving immunopathology at the vaginal mucosa. This study aimed to determine if expression and/or processing of Ece1p differs across C.

Anxiety Screening in Polytrauma Patients by Use of Single-Item Reporting With the Neurobehavioral Symptom Inventory: How Brief Is Too Brief?

Purpose/objective: This study examined the clinical utility of a single item for anxiety from the Neurobehavioral Symptom Inventory (NSI) in determining the need for mental health referral for veterans with traumatic brain injury (TBI).

Research Method/design: Three hundred eighty veterans referred for TBI evaluation were administered the NSI and a common anxiety screening measure (Beck Anxiety Inventory; BAI). Receiver Operating Characteristic (ROC) curve analyses were conducted to determine ideal BAI total cutoff scores for a single item of the NSI pertaining to anxiety (i.

An Unbiased Drug Screen for Seizure Suppressors in Duplication 15q Syndrome Reveals 5-HT and Dopamine Pathway Activation as Potential Therapies.

Background: Duplication 15q (Dup15q) syndrome is a rare neurogenetic disorder characterized by autism and pharmacoresistant epilepsy. Most individuals with isodicentric duplications have been on multiple medications to control seizures. We recently developed a model of Dup15q in Drosophila by elevating levels of fly Dube3a in glial cells using repo-GAL4, not neurons.

Remasking of Candida albicans β-Glucan in Response to Environmental pH Is Regulated by Quorum Sensing.

is a commensal yeast of the human gut which is tolerated by the immune system but has the potential to become an opportunistic pathogen. One way in which achieves this duality is through concealing or exposing cell wall pathogen-associated molecular patterns (PAMPs) in response to host-derived environment cues (pH, hypoxia, and lactate). This cell wall remodeling allows to evade or hyperactivate the host's innate immune responses, leading to disease.

Differential requirements of protein geranylgeranylation for the virulence of human pathogenic fungi.

Protein prenylation is a crucial post-translational modification largely mediated by two heterodimeric enzyme complexes, farnesyltransferase and geranylgeranyltransferase type-I (GGTase-I), each composed of a shared α-subunit and a unique β-subunit. GGTase-I enzymes are validated drug targets that contribute to virulence in and to the yeast-to-hyphal transition in . Therefore, we sought to investigate the importance of the α-subunit, RamB, and the β-subunit, Cdc43, of the GGTase-I complex to hyphal growth and virulence.

Titrating Gene Function in the Human Fungal Pathogen Candida albicans through Poly-Adenosine Tract Insertion.

A recent study demonstrated that the insertion of poly-adenosine (poly-A) tracts into an open reading frame can suppress expression of the encoded protein in both prokaryotic and eukaryotic species. Furthermore, the degree of suppression is proportional to the length of the poly-A insertion, which can therefore provide a reliable and predictable means to titrate a specific protein's expression. The goal of this study was to determine if this methodology can be applied to modulate the expression of proteins in the prevalent human fungal pathogen, Insertion of increasing numbers of AAA codons encoding lysine at the N terminus of the lanosterol demethylase (Erg11p) progressively diminished expression without significantly reducing the levels of mRNA.

A Systematic Screen Reveals a Diverse Collection of Medications That Induce Antifungal Resistance in Species.

The increasing incidence of and high mortality rates associated with invasive fungal infections (IFIs) impose an enormous clinical, social, and economic burden on humankind. In addition to microbiological resistance to existing antifungal drugs, the large number of unexplained treatment failures is a serious concern. Due to the extremely limited therapeutic options available, it is critical to identify and understand the various causes of treatment failure if patient outcomes are to improve.

A Comparison Between the Involuntary and Voluntary Treatment of Patients With Alcohol Use Disorder in a Residential Rehabilitation Treatment Program.

Objective: The purpose of the study was to determine if there was a significant difference between veterans who received treatment voluntarily versus involuntarily in regard to length of sobriety.

Method: A sample of 120 veterans being treated for alcohol use disorder in a residential rehabilitation treatment program was used for this study. Veterans who were admitted under recommendation by court order (n = 60) were matched with veterans who were admitted without recommendation of court order (n = 60).

Abrogation of Triazole Resistance upon Deletion of in a Clinical Isolate of .

has rapidly emerged as a health care-associated and multidrug-resistant pathogen of global concern. In this work, we examined the relative expression of the four genes with the highest degree of homology to and among three triazole-resistant clinical isolates as compared to the triazole-susceptible genome reference clinical isolate. We subsequently utilized a novel Cas9-mediated system for genetic manipulations to delete and in both a triazole-resistant clinical isolate and a susceptible reference strain and observed that MICs for all clinically available triazoles decreased as much as 128-fold in the deletion strains.

Detection Rate of Colorectal Cancer or Precancer Adenoma by Colonoscopy After 1, 2, or 3 Positive Results via Fecal Immunochemical Testing.

Background: Single-vial fecal immunochemical testing (FIT) is an accepted method of colorectal cancer (CRC) screening. The available 3-vial FIT data set allows for comparison of colonoscopy results using various screening methods.

Objective: To determine the optimal number of vials for a strong FIT-screening program by examining whether using only a single vial impacts the use of colonoscopy for CRC screening.

Use of Chlorhexidine to Prevent Ventilator-Associated Pneumonia in a Long-term Care Setting: A Retrospective Medical Record Review.

Background: The purpose of this study was to explore the use of the oral decontamination solution chlorhexidine (CHX) to reduce ventilator-associated pneumonia (VAP) in a long-term ventilator care setting over time. Most of the research in this area has been conducted in acute and intensive care settings.

Methods: This study was a retrospective medical record review conducted in a long-term care facility with a dedicated ventilator unit.

Loss of C-5 Sterol Desaturase Activity in : Azole Resistance or Merely Trailing Growth?

Increased expression of drug efflux pumps and changes in the target enzyme Erg11p are known to contribute to azole resistance in , one of the most prevalent fungal pathogens. Mutations that inactivate , which encodes sterol Δ-desaturase, also confer azole resistance. However, it is unclear whether the loss of Erg3p activity is sufficient to confer resistance within the mammalian host, and relatively few mutants have been reported among azole-resistant clinical isolates.