The primary mechanism for highly potent inhibition of HIV-1 maturation by lenacapavir.

Unlabelled: Lenacapavir (LEN) is a highly potent, long-acting antiretroviral medication for treating people infected with muti-drug-resistant HIV-1 phenotypes. The inhibitor targets multifaceted functions of the viral capsid protein (CA) during HIV-1 replication. Previous studies have mainly focused on elucidating LEN's mode of action during viral ingress.

Structural and Mechanistic Bases for Resistance of the M66I Capsid Variant to Lenacapavir.

Unlabelled: Lenacapavir (LEN) is the first in class viral capsid protein (CA) targeting antiretroviral for treating multi-drug-resistant HIV-1 infection. Clinical trials and cell culture experiments have identified resistance associated mutations (RAMs) in the vicinity of the hydrophobic CA pocket targeted by LEN. The M66I substitution conferred by far the highest level of resistance to the inhibitor compared to other RAMs.

β-Carboline-3-carboxamide Antimalarials: Structure-Activity Relationship, ADME-Tox Studies, and Resistance Profiling.

The development of parasite resistance to both artemisinin derivatives and their partner drugs jeopardizes the effectiveness of the artemisinin combination therapy. Thus, the discovery of new antimalarial drugs, with new mechanisms of action, is urgently needed. We recently disclosed that β-carboline was orally efficacious in -infected mice and that it showed low cross-resistance between susceptible and four different drug-resistant strains.

The structural and mechanistic bases for the viral resistance to allosteric HIV-1 integrase inhibitor pirmitegravir.

Allosteric HIV-1 integrase (IN) inhibitors (ALLINIs) are investigational antiretroviral agents that potently impair virion maturation by inducing hyper-multimerization of IN and inhibiting its interaction with viral genomic RNA. The pyrrolopyridine-based ALLINI pirmitegravir (PIR) has recently advanced into phase 2a clinical trials. Previous cell culture-based viral breakthrough assays identified the HIV-1 variant that confers substantial resistance to this inhibitor.

Quinolinonyl Derivatives as Dual Inhibitors of the HIV-1 Integrase Catalytic Site and Integrase-RNA interactions.

The HIV-1 integrase (IN) plays a critical role in the viral lifecycle by integrating the viral DNA into the host chromosome. The catalytic function of IN has been exploited as a target, with five drugs acting as active site binders (IN strand transfer inhibitors, INSTIs). However, IN mutations conferring low-level resistance to INSTIs have been reported.

Insight into the adaptive role of arachnid genome-wide duplication through chromosome-level genome assembly of the Western black widow spider.

Although spiders are one of the most diverse groups of arthropods, the genetic architecture of their evolutionary adaptations is largely unknown. Specifically, ancient genome-wide duplication occurring during arachnid evolution ~450 mya resulted in a vast assembly of gene families, yet the extent to which selection has shaped this variation is understudied. To aid in comparative genome sequence analyses, we provide a chromosome-level genome of the Western black widow spider (Latrodectus hesperus)-a focus due to its silk properties, venom applications, and as a model for urban adaptation.

Differential Gene Expression following / Knockout Is Associated with G-Quadruplex Content and Cancer.

G-quadruplexes (G4s) are secondary DNA and RNA structures stabilized by positive cations in a central channel formed by stacked tetrads of Hoogsteen base-paired guanines. G4s form from G-rich sequences across the genome, whose biased distribution in regulatory regions points towards a gene-regulatory role. G4s can themselves be regulated by helicases, such as DHX36 (aliases: G4R1 and RHAU), which possess the necessary activity to resolve these stable structures.

The structural and mechanistic bases for the viral resistance to allosteric HIV-1 integrase inhibitor pirmitegravir.

Allosteric HIV-1 integrase (IN) inhibitors (ALLINIs) are investigational antiretroviral agents which potently impair virion maturation by inducing hyper-multimerization of IN and inhibiting its interaction with viral genomic RNA. The pyrrolopyridine-based ALLINI pirmitegravir (PIR) has recently advanced into Phase 2a clinical trials. Previous cell culture based viral breakthrough assays identified the HIV-1 variant that confers substantial resistance to this inhibitor.

Cephalotane-type C diterpenoids from var. .

Seventeen new cephalotane-type diterpenoids, fortalides A-Q (1-17), along with five known analogues, were isolated from the seeds of var. . Their structures were determined by extensive spectroscopic methods, as well as electronic circular dichroism (ECD) and X-ray crystallographic data analyses.

Structural and Mechanistic Bases of Viral Resistance to HIV-1 Capsid Inhibitor Lenacapavir.

Lenacapavir (LEN) is a long-acting, highly potent HIV-1 capsid (CA) inhibitor. The evolution of viral variants under the genetic pressure of LEN identified Q67H, N74D, and Q67H/N74D CA substitutions as the main resistance associated mutations (RAMs). Here, we determined high-resolution structures of CA hexamers containing these RAMs in the absence and presence of LEN.

Manipulation of pantothenate kinase in Anopheles stephensi suppresses pantothenate levels with minimal impacts on mosquito fitness.

Pantothenate (Pan) is an essential nutrient required by both the mosquito vector and malaria parasite. We previously demonstrated that increasing pantothenate kinase (PanK) activity and co-enzyme A (CoA) biosynthesis led to significantly decreased parasite infection prevalence and intensity in the malaria mosquito Anopheles stephensi. In this study, we demonstrate that Pan stores in A.

Malaria Box-Inspired Discovery of -Aminoalkyl-β-carboline-3-carboxamides, a Novel Orally Active Class of Antimalarials.

Virtual ligand screening of a publicly available database of antimalarial hits using a pharmacophore derived from antimalarial MMV008138 identified TCMDC-140230, a tetrahydro-β-carboline amide, as worthy of exploration. All four stereoisomers of this structure were synthesized, but none potently inhibited growth of the malaria parasite . Interestingly, , a minor byproduct of these syntheses, proved to be potent against and was orally efficacious (40 mg/kg) in an mouse model of malaria.

Cropping management in a livestock-pasture-crop integration modifies microbial communities, activity, and soil health score.

Understanding indicators of soil health is crucial for developing agricultural systems that are sustainable and climate resilient. Labile soil carbon (C), microbial properties, and nutrient status are all incorporated into the Haney Soil Health Tool with the goal of summarizing several indicators into one index. Monthly soil samples from an integrated crop-livestock system in Central Texas were collected from 2017 to 2019.

Correlation between protein secondary structure and mechanical performance for the ultra-tough dragline silk of Darwin's bark spider.

The spider major ampullate (MA) silk exhibits high tensile strength and extensibility and is typically a blend of MaSp1 and MaSp2 proteins with the latter comprising glycine-proline-glycine-glycine-X repeating motifs that promote extensibility and supercontraction. The MA silk from Darwin's bark spider () is estimated to be two to three times tougher than the MA silk from other spider species. Previous research suggests that a unique MaSp4 protein incorporates proline into a novel glycine-proline-glycine-proline motif and may explain MA silk's extraordinary toughness.

Longitudinal accuracy analysis of ultrasound performed during a four-year emergency medicine residency.

Background: The objective of this study was to analyze patterns of point-of-care ultrasound (POCUS) performance over 4 years of emergency medicine (EM) residency. Specifically, we aimed to study how accuracy and adherence to standards of scanning changed by postgraduate year (PGY).

Methods: This was a retrospective observational study of resident-performed POCUS at an academic emergency department over 6 years.

Regulatory involvement of the PerR and SloR metalloregulators in the oxidative stress response.

is a commensal of the human oral microbiome that can promote dental caries under conditions of dysbiosis. This study investigates metalloregulators and their involvement in the oxidative stress response. Oxidative stress in the human mouth can derive from temporal increases in reactive oxygen species (ROS) after meal consumption and from endogenous bacterial ROS-producers that colonize the dentition.

Aquatic Exposure to Abscisic Acid Transstadially Enhances Resistance to Malaria Parasite Infection.

The ancient stress signaling molecule abscisic acid (ABA) is ubiquitous in animals and plants but is perhaps most well-known from its early discovery as a plant hormone. ABA can be released into water by plants and is found in nectar, but is also present in mammalian blood, three key contexts for mosquito biology. We previously established that addition of ABA to larval rearing water altered immature development and life history traits of females derived from treated larvae, while addition of ABA to an infected bloodmeal increased resistance of adult female to human malaria parasite infection.

G-Quadruplex Helicase DHX36/G4R1 Engages Nuclear Lamina Proteins in Quiescent Breast Cancer Cells.

G-quadruplexes (G4s) are nucleic acid structures found enriched within gene regulatory sequences. G4s control fundamental cellular processes, including replication, transcription, and translation. Proto-oncogenes are enriched with G4 sequences, while tumor-suppressor genes are depleted, suggesting roles for G4s in cell survival and proliferation.

Description of Pharmacogenomic Testing Among Patients Admitted to the Intensive Care Unit After Cardiovascular Surgery.

Background: Pharmacogenomic (PGx) testing has the potential to provide information on specific drug-metabolizing enzymes that may lead to an absence, reduction, or increase in medication effect in patients. There is a paucity of prospective studies examining PGx testing in the intensive care unit (ICU) setting.

Research Aims: To (1) obtain a PGx panel in a sample of cardiovascular (CV) surgical patients with a planned ICU stay and identify phenotypes, and (2) identify PGx variants that may inform treatment regimens and may warrant prescribing adjustments.

Clinical Integration of Point-of-care Ultrasound by Emergency Medicine Residents: A Single-center Mixed-methods Study.

Background: Point-of-care ultrasound (POCUS) competence consists of image acquisition, image interpretation, and clinical integration. Limited data exist on POCUS usage patterns and clinical integration by emergency medicine (EM) residents. We sought to determine actual POCUS usage and clinical integration patterns by EM residents and to explore residents' perspectives on POCUS clinical integration.

Interdisciplinary approach to enhance trauma residents education of Extended-Focused Assessment for Sonography in Trauma in the emergency department.

Background: Despite the utilization of point-of-care ultrasound (POCUS) by trauma surgeons, formal POCUS requirements do not exist for general surgery residents. We sought to evaluate surgery resident comfort with performing and interpreting of Extended-Focused Assessment for Sonography in Trauma (E-FAST) scans after a brief educational session.

Methods: A pre-survey, sent to PGY-2 and -3 surgical residents before their trauma rotation, evaluated comfort with eight components of the E-FAST.

Comprehensive and Durable Modulation of Growth, Development, Lifespan and Fecundity in Following Larval Treatment With the Stress Signaling Molecule and Novel Antimalarial Abscisic Acid.

The larval environment of holometabolous insects determines many adult life history traits including, but not limited to, rate and success of development and adult lifespan and fecundity. The ancient stress signaling hormone abscisic acid (ABA), released by plants inundated with water and by leaf and root fragments in water, is likely ubiquitous in the mosquito larval environment and is well known for its wide ranging effects on invertebrate biology. Accordingly, ABA is a relevant stimulus and signal for mosquito development.

Ovarian Transcriptomic Analyses in the Urban Human Health Pest, the Western Black Widow Spider.

Due to their abundance and ability to invade diverse environments, many arthropods have become pests of economic and health concern, especially in urban areas. Transcriptomic analyses of arthropod ovaries have provided insight into life history variation and fecundity, yet there are few studies in spiders despite their diversity within arthropods. Here, we generated a ovarian transcriptome from 10 individuals of the western black widow spider (), a human health pest of high abundance in urban areas, to conduct comparative ovarian transcriptomic analyses.