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.

Age-Associated Contraction of Tumor-Specific T Cells Impairs Antitumor Immunity.

Progressive decline of the adaptive immune system with increasing age coincides with a sharp increase in cancer incidence. In this study, we set out to understand whether deficits in antitumor immunity with advanced age promote tumor progression and/or drive resistance to immunotherapy. We found that multiple syngeneic cancers grew more rapidly in aged versus young adult mice, driven by dysfunctional CD8+ T-cell responses.

Overlapping coactivator function is required for transcriptional activation by the Candida glabrata Pdr1 transcription factor.

Azole resistance in the pathogenic yeast Candida glabrata is a serious clinical complication and increasing in frequency. The majority of resistant organisms have been found to contain a substitution mutation in the Zn2Cys6 zinc cluster-containing transcription factor Pdr1. These mutations typically lead to this factor driving high, constitutive expression of target genes like the ATP-binding cassette transporter-encoding gene CDR1.

Overlapping coactivator function is required for transcriptional activation by the Pdr1 transcription factor.

Azole resistance in the pathogenic yeast is a serious clinical complication and increasing in frequency. The majority of resistant organisms have been found to contain a substitution mutation in the Zn2Cys6 zinc cluster-containing transcription factor Pdr1. These mutations typically lead to this factor driving high, constitutive expression of target genes like the ATP-binding cassette transporter-encoding gene .

A Mechanically Resilient Soft Hydrogel Improves Drug Delivery for Treating Post-Traumatic Osteoarthritis in Physically Active Joints.

Intra-articular delivery of disease-modifying osteoarthritis drugs (DMOADs) is likely to be most effective in early post-traumatic osteoarthritis (PTOA) when symptoms are minimal and patients are physically active. DMOAD delivery systems therefore must withstand repeated mechanical loading without affecting the drug release kinetics. Although soft materials are preferred for DMOAD delivery, mechanical loading can compromise their structural integrity and disrupt drug release.

The overlap between randomised evaluations of recruitment and retention interventions: An updated review of recruitment (Online Resource for Recruitment in Clinical triAls) and retention (Online Resource for Retention in Clinical triAls) literature.

Background: The Online Resource for Recruitment in Clinical triAls (ORRCA) and the Online Resource for Retention in Clinical triAls (ORRCA2) were established to organise and map the literature addressing participant recruitment and retention within clinical research. The two databases are updated on an ongoing basis using separate but parallel systematic reviews. However, recruitment and retention of research participants is widely acknowledged to be interconnected.

CWHM-974 is a fluphenazine derivative with improved antifungal activity against due to reduced susceptibility to multidrug transporter-mediated resistance mechanisms.

Multidrug resistance (MDR) transporters such as ATP-Binding Cassette (ABC) and Major Facilitator Superfamily proteins are important mediators of antifungal drug resistance, particularly with respect to azole class drugs. Consequently, identifying molecules that are not susceptible to this mechanism of resistance is an important goal for new antifungal drug discovery. As part of a project to optimize the antifungal activity of clinically used phenothiazines, we synthesized a fluphenazine derivative (CWHM-974) with 8-fold higher activity against spp.

CWHM-974 is a fluphenazine derivative with improved antifungal activity against due to reduced susceptibility to multidrug transporter-mediated resistance mechanisms.

Multidrug resistance (MDR) transporters such as ATP Binding Cassette (ABC) and Major Facilitator Superfamily (MFS) proteins are important mediators of antifungal drug resistance, particularly with respect to azole class drugs. Consequently, identifying molecules that are not susceptible to this mechanism of resistance is an important goal for new antifungal drug discovery. As part of a project to optimize the antifungal activity of clinically used phenothiazines, we synthesized a fluphenazine derivative (CWHM-974) with 8-fold higher activity against spp.

Conditional Protein Depletion in the Analysis of Antifungal Drug Resistance in Candida glabrata.

This chapter illustrates a method to generate Candida glabrata conditional depletion mutants for SNF2, an ATPase subunit of the SWI/SNF chromatin remodeling complex with potential roles in the response to azole drugs. The strategy employed utilizes a plant-specific proteolysis pathway which allows for the rapid degradation of a target protein in the presence of the phytohormone, auxin. The steps taken to generate strains expressing the auxin-inducible plant F-box protein, Tir1, and in which the auxin-binding target, IAA17, is C-terminally fused to Snf2 are described.

Pediatric electrolyte emergencies: recognition and management in the emergency department.

Early recognition and treatment of electrolyte abnormalities protect the patient from derangements in the renal, myocardiac, and central nervous systems. Correction of electrolyte derangements decreases both morbidity and mortality. This issue reviews sodium, potassium, calcium, magnesium, and phosphorus abnormalities and provides a systematic approach to the evaluation and management of the ill child with an electrolyte emergency.

Findings from precision oncology in the clinic: rare, novel variants are a significant contributor to scaling molecular diagnostics.

Background: Next generation sequencing for oncology patient management is now routine in clinical pathology laboratories. Although wet lab, sequencing and pipeline tasks are largely automated, the analysis of variants for clinical reporting remains largely a manual task. The increasing volume of sequencing data and the limited availability of genetic experts to analyse and report on variants in the data is a key scalability limit for molecular diagnostics.

Developing an online, searchable database to systematically map and organise current literature on retention research (ORRCA2).

Background: Addressing recruitment and retention challenges in trials is a key priority for methods research, but navigating the literature is difficult and time-consuming. In 2016, ORRCA (www.orrca.

Role of the Promoter of Candida albicans in Opaque Commitment.

During induced differentiation, the process often involves a commitment event, after which induced cells, when returned to noninducing conditions, continue to differentiate. The commitment event is rarely identified. Candida albicans differentiates from the white to opaque phenotype, a prerequisite for mating and a process accompanying colonization of the lower gastrointestinal tract and skin.

The Use of High-Flow Nasal Cannula and the Timing of Safe Feeding in Children with Bronchiolitis.

Objective The use of high-flow nasal cannula (HFNC) as non-invasive respiratory support in children with bronchiolitis has increased over the last several years. Several studies have investigated enteral feeding safety while on HFNC. This study compares the safety of oral feeding prior to and following implementation of an HFNC feeding guideline.

Battling the COVID-19 infodemic in an Irish context: the role of iHealthFacts.

On the 11 of March 2020, the World Health Organisation (WHO) declared a global pandemic due to the SARS-CoV-2 virus, which causes coronavirus disease 2019 (COVID-19). This was one month after Dr. Tedros Adhanom Ghebreyesus, Director-General of the WHO declared that we are also fighting an 'infodemic'.

Strategies to improve retention in randomised trials.

Background: Poor retention of participants in randomised trials can lead to missing outcome data which can introduce bias and reduce study power, affecting the generalisability, validity and reliability of results. Many strategies are used to improve retention but few have been formally evaluated.

Objectives: To quantify the effect of strategies to improve retention of participants in randomised trials and to investigate if the effect varied by trial setting.

Multiple BCL2 mutations cooccurring with Gly101Val emerge in chronic lymphocytic leukemia progression on venetoclax.

There is a Commentary on this article in this issue.

Reciprocal signaling and direct physical interactions between fibroblasts and breast cancer cells in a 3D environment.

Tumorigenic cells undergo cell aggregation and aggregate coalescence in a 3D Matrigel environment. Here, we expanded this 3D platform to assess the interactions of normal human dermal fibroblasts (NHDFs) and human primary mammary fibroblasts (HPMFs) with breast cancer-derived, tumorigenic cells (MDA-MB-231). Medium conditioned by MDA-MB-231 cells activates both types of fibroblasts, imbuing them with the capacity to accelerate the rate of aggregation and coalescence of MDA-MB-231 cells more than four fold.

Roles of the Transcription Factors Sfl2 and Efg1 in White-Opaque Switching in a/α Strains of Candida albicans.

remains the most pervasive fungal pathogen colonizing humans. The majority of isolates from hosts are heterozygous at the mating type locus (/α), and a third of these have recently been shown to be capable of switching to the opaque phenotype. Here we have investigated the roles of two transcription factors (TFs) Sfl2 and Efg1, in repressing switching in /α strains.

Generating a Battery of Monoclonal Antibodies Against Firefly Luciferase for Dot Blot Analysis, Western Blot Analysis, and Immunostaining of Cells in Culture and Paraffin Sections.

Firefly luciferase (FLuc) is commonly used as a reporter gene PpyLuc1 in bioanalytical assays. We have produced five mouse-derived monoclonal antibodies (mAbs) that recognize FLuc. The mAbs, DSHB-LUC-2, DSHB-LUC-3, DSHB-LUC-9, DSHB-LUC-16, and DSHB-LUC-24, were generated by immunizing mice with purified 6xHIS-tagged FLuc (6xHis-FLuc) in suspension with an adjuvant.

PathOS: a decision support system for reporting high throughput sequencing of cancers in clinical diagnostic laboratories.

Background: The increasing affordability of DNA sequencing has allowed it to be widely deployed in pathology laboratories. However, this has exposed many issues with the analysis and reporting of variants for clinical diagnostic use. Implementing a high-throughput sequencing (NGS) clinical reporting system requires a diverse combination of capabilities, statistical methods to identify variants, global variant databases, a validated bioinformatics pipeline, an auditable laboratory workflow, reproducible clinical assays and quality control monitoring throughout.

An Objective Measure of Noseband Tightness and Its Measurement Using a Novel Digital Tightness Gauge.

Noseband tightness is difficult to assess in horses participating in equestrian sports such as dressage, show jumping and three-day-eventing. There is growing concern that nosebands are commonly tightened to such an extent as to restrict normal equine behaviour and possibly cause injury. In the absence of a clear agreed definition of noseband tightness, a simple model of the equine nose-noseband interface environment was developed in order to guide further studies in this area.