Humanized Candida and NanoBiT Assays Expedite Discovery of Bdf1 Bromodomain Inhibitors With Antifungal Potential.

The fungal Bromodomain and Extra-Terminal (BET) protein Bdf1 is a potential antifungal target against invasive fungal infections. However, the need to selectively inhibit both Bdf1 bromodomains (BDs) over human orthologs and the lack of molecular tools to assess on-target antifungal efficacy hamper efforts to develop Bdf1 BD inhibitors as antifungal therapeutics. This study reports a phenyltriazine compound that inhibits both Bdf1 BDs from the human fungal pathogen Candida glabrata with selectivity over the orthologous BDs from the human BET protein Brd4.

Population pharmacokinetics and exposure-response analysis of durvalumab in combination with gemcitabine and cisplatin in patients with advanced biliary tract cancer.

Purpose: Durvalumab in combination with gemcitabine/cisplatin has shown a favorable benefit-risk profile in the TOPAZ-1 study for advanced biliary tract cancers (BTC). This analysis evaluated the population pharmacokinetics (PopPK) of durvalumab, and exposure-response for efficacy and safety (ERES) of TOPAZ-1.

Methods: The PopPK model for durvalumab was updated using data from 5 previously analysed studies and TOPAZ-1.

Emotion regulation strategy and its relationship with emotional dysregulation in children with attention-deficit/hyperactivity disorder: behavioral and brain findings.

Important associations between emotional dysregulation (ED) and ADHD have been identified in adults, with a key manifestation of this being differential use of emotion regulation strategies: reduced use of cognitive reappraisal (CR), but elevated expressive suppression (ES). These associations have been observed at both behavioral and neuroimaging levels. The present study aims to explore the use of CR and ES in children with ADHD, and their relationship to ED.

Non-Stoichiometric Amorphous Calcium Carbonate Forms in Macromolecular Condensates via Interphase Diffusion.

Transient amorphous phases are known as functional precursors in the formation of crystalline materials, both in vivo and in vitro. A common route to regulate amorphous calcium carbonate (ACC) crystallization is via direct interactions with negatively charged macromolecules. However, a less explored phenomenon that can influence such systems is the electrostatically driven formation of Ca-macromolecule dense phases.

Characterisation of intestinal amino acid and oleic acid absorption and their interaction in the Pacific spiny dogfish (Squalus suckleyi).

Elasmobranchs are commonly carnivores and are important in energy transfer across marine ecosystems. Despite this, relatively few studies have examined the physiological underpinnings of nutrient acquisition in these animals. Here, we investigated the mechanisms of uptake at the spiral valve intestine for two representative amino acids (-alanine, -leucine) and one representative fatty acid (oleic acid), each common to the diet of a carnivore, the Pacific spiny dogfish (Squalus suckleyi).

Engineered Age-Mimetic Breast Cancer Models Reveal Differential Drug Responses in Young and Aged Microenvironments.

Aging is one of the most significant risk factors for breast cancer. With the growing interest in the alterations of the aging breast tissue microenvironment, it is identified that aging is related to tumorigenesis, invasion, and drug resistance. However, current pre-clinical disease models often neglect the impact of aging and sometimes result in worse clinical outcomes.

Impact of Lookback Duration on the Performance of a Claims-Based Frailty Proxy in Women With Stage I-III Breast Cancer.

Background: Frailty is an important prognostic indicator in older women with breast cancer. The Faurot frailty index, a validated claims-based frailty proxy measure, uses healthcare billing codes during a user-specified ascertainment window to predict frailty. We assessed how the duration of frailty ascertainment affected the ability of the Faurot frailty index to predict one-year mortality in women with stage I-II breast cancer.

Association of Alzheimer's Disease Polygenic Risk Score with Concussion Severity and Recovery Metrics.

Background: Identification of genetic alleles associated with both Alzheimer's disease (AD) and concussion severity/recovery could help explain the association between concussion and elevated dementia risk. However, there has been little investigation into whether AD risk genes associate with concussion severity/recovery, and the limited findings are mixed.

Objective: We used AD polygenic risk scores (PRS) and APOE genotypes to investigate any such associations in the NCAA-DoD Grand Alliance CARE Consortium (CARE) dataset.

Psychosocial Support Needs and Preferences Among Family Caregivers of ICU Patients with Severe Acute Brain Injury: A Qualitative Thematic Analysis.

Background: Family caregivers of patients with severe acute brain injury (SABI) are at risk for clinically significant chronic emotional distress, including depression, anxiety, and posttraumatic stress. Existing psychosocial interventions for caregivers of intensive care unit (ICU) patients are not tailored to the unique needs of caregivers of patients with SABI, do not demonstrate long-term efficacy, and may increase caregiver burden. In this study, we explored the needs and preferences for psychosocial services among SABI caregivers to inform the development and adaptation of interventions to reduce their emotional distress during and after their relative's ICU admission.

Ultrasmall α-MnO with Low Aspect Ratio: Applications to Electrochemical Multivalent-Ion Intercalation Hosts and Aerobic Oxidation Catalysts.

Hollandite-type α-MnO exhibits exceptional promise in current industrial applications and in advancing next-generation green energy technologies, such as multivalent (Mg, Ca, and Zn) ion battery cathodes and aerobic oxidation catalysts. Considering the slow diffusion of multivalent cations within α-MnO tunnels and the catalytic activity at edge surfaces, ultrasmall α-MnO particles with a lower aspect ratio are expected to unlock the full potential. In this study, ultrasmall α-MnO (<10 nm) with a low aspect ratio (c/a ≈ 2) is synthesized using a newly developed alcohol solution process.

Rethinking speech sound disorder (SSD) in non-syndromic cleft lip and palate: The importance of recognizing phonological and language difficulties.

Background: Children born with cleft palate ± lip (CP ± L) are at risk of speech sound disorder (SSD). Up to 40% continue to have SSD at age 5-6 years. These difficulties are typically described as articulatory in nature and often include cleft speech characteristics (CSC) hypothesized to result from structural differences.

Self-reported experiences and perspectives on using psychedelics to manage opioid use among participants of two Reddit communities.

Background And Aims: The opioid crisis continues to exert a tremendous toll in North America, with existing interventions often falling short of addressing ongoing needs. Psychedelics are emerging as a possible alternative therapy for mental health and substance use disorders. This study aimed to gather insights on how people use or are considering using psychedelics to manage opioid use disorder (OUD), how these experiences are perceived to impact opioid use and what these lessons imply for future research and practice.

Associations of KRAS Point Mutations with Survival of Patients Who Underwent Curative-Intent Resection of Colorectal Liver Metastases.

Background: The oncologic significance of specific KRAS point mutations for patients with colorectal liver metastases (CLM) is uncertain. This study aimed to assess the prognostic impact of KRAS point mutations on patients who underwent surgery for CLM.

Methods: Patients who underwent curative-intent surgery for CLM from 2001 to 2020 were selected for the study.

TRPM4 contributes to cell death in prostate cancer tumor spheroids, and to extravasation and metastasis in a zebrafish xenograft model system.

Transient receptor potential melastatin-4 (TRPM4) ion channel expression is upregulated in prostate cancer (PCa), contributing to increased cell proliferation, migration, adhesion, epithelial-to-mesenchymal transition, cell cycle shift, and alterations of intracellular Ca signaling. GEO2R platform analysis of messenger RNA (mRNA) expression of ~ 6350 genes in normal and malignant prostate tissue samples from 15 PCa patients demonstrates that TRPM4 expression is upregulated sixfold and is among the most significantly upregulated genes in PCa. We find that absence of TRPM4 reduced PCa tumor spheroid size and decreased PCa tumor spheroid outgrowth.

Unmasking Long QT Syndrome in a Serviceman: Effects of Hypoglycemia and a Flight Duty Medical Examination.

We report the case of a 29-year-old male soldier with a time in service above 10 years, found to have asymptomatic long QT syndrome (LQTS), a condition associated with increased risk of potentially fatal ventricular arrhythmias, during a flight physical. A review of his past medical history revealed a transient QT prolongation during an episode of hypoglycemia due to endogenous hyperinsulinism caused by an insulinoma, as an infantryman 7 years earlier; the resolution of the QT prolongation was spontaneous. He was evaluated and considered fit for duty by cardiology.

Impacts of seasonality on mercury concentrations, polyunsaturated fatty acids, and stable isotopes: implications for the use of tetragnathid spiders as sentinels.

Riparian spiders are used in ecotoxicology as sentinels of bioavailable contaminants that are transferred from aquatic to terrestrial habitats via emergent aquatic insects. Spiders in the family Tetragnathidae are particularly of interest because a high proportion of their diet consists of emergent aquatic insects and their contaminant loads reflect the amount transferred through the food web to riparian predators. The transfer of contaminants can be determined through food web tracers such as stable isotopes and polyunsaturated fatty acids; however, it is unclear how contaminants and tracers vary over the course of a year.

Manuscript publication of abstracts presented at gynecologic surgery societies' annual meetings.

Purpose: To study characteristics and identify factors associated with full manuscript publication of oral abstracts presented at gynecologic surgery societies' annual meetings.

Study Design: We reviewed all oral abstracts presented at four major gynecologic surgery meetings in 2018. Oral abstracts subsequently published as peer-reviewed manuscripts were compared to those that were not published.

Identification and quantitative trait locus mapping of Tartary buckwheat pre-harvest sprouting.

Background: Tartary buckwheat (Fagopyrum tartaricum) is particularly vulnerable to pre-harvest sprouting (PHS) due to its extended flowering and fruiting cycle, especially during periods of prolonged rainfall. This susceptibility has significant adverse effects on yield, quality and post-harvest processing. In this study, a recombinant inbred lines (RILs) population (XJ-RILs) was developed from a cross between the PHS-susceptible Tartary buckwheat variety 'Xiaomiqiao' (female parent) and the highly PHS-resistant variety 'Jinqiaomai 2' (male parent).

A phase I study of MLN4924 and belinostat in relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome.

Purpose: Relapsed and/or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome continue to have a poor prognosis with limited treatment options despite advancements in rational combination and targeted therapies. Belinostat (an HDAC inhibitor) and Pevonedistat (a NEDD8 inhibitor) have each been independently studied in hematologic malignancies and have tolerable safety profiles with limited single-agent activity. Preclinical studies in AML cell lines and primary AML cells show the combination to be highly synergistic, particularly in high-risk phenotypes such as p53 mutant and FLT-3-ITD positive cells.

Protective role of triiodothyronine in sepsis‑induced cardiomyopathy through phospholamban downregulation.

Sepsis is often a cause of mortality in patients admitted to the intensive care unit. Notably, the heart is the organ most susceptible to the impact of sepsis and this condition is referred to as sepsis‑induced cardiomyopathy (SIC). Low triiodothyronine (T3) syndrome frequently occurs in patients with sepsis, and the heart is one of the most important target organs for the action of T3.

Atrial Fibrillation Recurrence Risk After Catheter Ablation in Patients With Rheumatoid Arthritis: A Systematic Review and Meta-Analysis.

Background: The association between rheumatoid arthritis (RA) and the risk of developing atrial fibrillation (AF) is well-established. However, data on the impact of RA on AF recurrence postcatheter ablation (CA) remain unclear. This current study aimed to assess the impact of RA on AF recurrence after catheter-based pulmonary vein isolation.

Synchrotron X-ray Fluorescence Microscopy Reveals Trace Elemental Indicators of Life History in Marsupial Teeth.

As teeth develop, their mineralised composition is a bio-recorder of diet, environment, and growth. High-resolution elemental mapping provides a tool to reveal records of life history within teeth. The relative concentrations of a range of trace elements change between in utero development, birth, and weaning in eutherian mammals.

The thyroid hormone activating enzyme, DIO2, is a potential pan-cancer biomarker and immunotherapy target.

Purpose: Type 2 deiodinase (D2), encoded by DIO2 gene, catalyzes the activation of the prohormone thyroxine (T4) into the bioactive hormone triiodothyronine (T3) in peripheral tissues, thereby regulating the intracellular Thyroid Hormone (TH) availability. Recently, several studies have demonstrated that a drastic increase in the peripheral activation of TH, via D2, fosters tumor progression, metastasis, and immunity.

Methods: To further prove the clinical relevance of D2 in human cancer, based on public Database of The Cancer Genome Atlas (TCGA), we conducted a pan-cancer analysis of DIO2 expression in various cancer types and investigated the association of DIO2 expression with the tumor microenvironment (TME) components and immune cell infiltration, along with the DIO2 genetic alteration types.

Brain-wide neuronal circuit connectome of human glioblastoma.

Glioblastoma (GBM) infiltrates the brain and can be synaptically innervated by neurons, which drives tumor progression. Synaptic inputs onto GBM cells identified so far are largely short-range and glutamatergic. The extent of GBM integration into the brain-wide neuronal circuitry remains unclear.