A multiplex method for rapidly identifying viral protease inhibitors.

With current treatments addressing only a fraction of pathogens and new viral threats constantly evolving, there is a critical need to expand our existing therapeutic arsenal. To speed the rate of discovery and better prepare against future threats, we establish a high-throughput platform capable of screening compounds against 40 diverse viral proteases simultaneously. This multiplex approach is enabled by using cellular biosensors of viral protease activity combined with DNA-barcoding technology, as well as several design innovations that increase assay sensitivity and correct for plate-to-plate variation.

New Hydrogenated Phenanthrene Glycosides from the Edible Vegetable W.T.Wang with DPP-IV Inhibitory and Hepatoprotective Activity.

Based on molecular networking-guided isolation, 15 previously undescribed hydrogenated phenanthrene glycosides, including eight hexahydro-phenanthrenone glycosides, four tetrahydro-phenanthrenone glycosides, one dihydro-phenanthrenol glycoside, two dimers, and two known dihydrophenanthrene glycosides, were isolated from W.T.Wang, a popular regional edible vegetable at the northwest region of Vietnam.

Brief Report: Precision Language and Deletion of the "S" Word.

Introduction: In 2021, the International Association for the Study of Lung Cancer (IASLC) published the IASLC Language Guide as guidance on preferred language and phrasing in oral and written communications, including presentations at conferences. This study analyzed presentations from the 2022 IASLC World Conference on Lung Cancer (WCLC) one year after implementation of the Language Guide to identify adoption rates of non-stigmatizing language and to determine correlations with presenter characteristics.

Methods: We downloaded 522 slide presentations from the IASLC WCLC 2022 conference attendee portal.

Suppression of thrombospondin-1-mediated inflammaging prolongs hematopoietic health span.

Chronic low-grade inflammation observed in older adults, termed inflammaging, is a common feature underlying a multitude of aging-associated maladies including a decline in hematopoietic activity. However, whether suppression of inflammaging can preserve hematopoietic health span remains unclear, in part because of a lack of tools to measure inflammaging within hematopoietic stem cells (HSCs). Here, we identify thrombospondin-1 (Thbs1) as an essential regulator of inflammaging within HSCs.

From motion to emotion: exploring challenging behaviors in autism spectrum disorder through analysis of wearable physiology and movement.

Objective: This study aims to evaluate the efficacy of wearable physiology and movement sensors in identifying a spectrum of challenging behaviors, including self-injurious behavior (SIB), in children and teenagers with autism spectrum disorder (ASD) in real-world settings.

Approach: We utilized a long-short-term memory (LSTM) network with features derived using the wavelet scatter transform to analyze physiological biosignals, including electrodermal activity and skin temperature, alongside three-dimensional movement data captured via accelerometers. The study was conducted in naturalistic environments, focusing on participants' daily activities.

Drug resistant Mycobacterium tuberculosis strains have altered cell envelope hydrophobicity that influences infection outcomes in human macrophages.

In recent decades, drug resistant (DR) strains of Mycobacterium tuberculosis (M.tb), the cause of tuberculosis (TB), have emerged that threaten public health. Although M.

Understanding the development of tuberculous granulomas: insights into host protection and pathogenesis, a review in humans and animals.

Granulomas, organized aggregates of immune cells which form in response to (), are characteristic but not exclusive of tuberculosis (TB). Despite existing investigations on TB granulomas, the determinants that differentiate host-protective granulomas from granulomas that contribute to TB pathogenesis are often disputed. Thus, the goal of this narrative review is to help clarify the existing literature on such determinants.

Identification of an antibiotic from an HTS targeting EF-Tu:tRNA interaction: a prospective topical treatment for MRSA skin infections.

Because of the urgent need for new antibiotics to treat drug-resistant bacterial pathogens, we employed an assay that rapidly screens large quantities of compounds for their ability to interfere with bacterial protein synthesis, in particular, the delivery of amino acids to the ribosome via tRNA and elongation factor Tu (EF-Tu). We have identified a drug lead, named MGC-10, which kills Gram-positive bacteria, including methicillin-resistant (MRSA), with a MIC of 6 µM, while being harmless to mammalian cells in that concentration range. The antibacterial activity of MGC-10 was broad against over 50 strains of antibiotic-resistant samples obtained from hospital infections, where MGC-10 inhibited all tested strains of MRSA.

Durlobactam in combination with β-lactams to combat .

() presents significant clinical challenges. This study evaluated the synergistic effects of a β-lactam and β-lactamase inhibitor combination against and explored the underlying mechanisms. Synergy was assessed through MIC tests and time-kill studies, and binding affinities of nine β-lactams and BLIs to eight target receptors (L,D-transpeptidases [LDT] 1-5, D,D-carboxypeptidase, penicillin-binding protein [PBP] B, and PBP-lipo) were assessed using mass spectrometry and kinetic studies.

Virus replication is not required for oncolytic bovine herpesvirus-1 immunotherapy.

Oncolytic viruses are a promising approach for cancer treatment where viruses selectively target and kill cancer cells while also stimulating an immune response. Among viruses with this ability, bovine herpesvirus-1 (BoHV-1) has several advantages, including observations suggesting it may not require viral replication for its anti-cancer effects. We previously demonstrated that binding and penetration of enveloped virus particles are sufficient to trigger intrinsic and innate immune signaling in normal cells, while other groups have published the efficacy of non-replicating viruses as viable immunotherapies in different cancer models.

Biased Language in Simulated Handoffs and Clinician Recall and Attitudes.

Importance: Poor-quality handoffs can lead to medical errors when transitioning patient care. Biased language within handoffs may contribute to errors and lead to disparities in health care delivery.

Objective: To compare clinical information recall accuracy and attitudes toward patients among trainees in paired cases of biased vs neutral language in simulated handoffs.

Molecular epidemiology and clinical characterization of carbapenemase-producing Enterobacter spp. from an international cohort.

Background: Despite the global public health threat posed by carbapenem-resistant Enterobacter spp., clinical and molecular epidemiological studies on international isolates remain scarce. Historically, the taxonomy of Enterobacter has been challenging, limiting our understanding of the clinical characteristics and outcomes of carbapenemase-producing Enterobacter spp.

Small-molecule inhibition of SARS-CoV-2 NSP14 RNA cap methyltransferase.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The rapid development of highly effective vaccines against SARS-CoV-2 has altered the trajectory of the pandemic, and antiviral therapeutics have further reduced the number of COVID-19 hospitalizations and deaths. Coronaviruses are enveloped, positive-sense, single-stranded RNA viruses that encode various structural and non-structural proteins, including those critical for viral RNA replication and evasion from innate immunity.

Nanomolar activity of coumarin-3-thiosemicarbazones targeting Trypanosoma cruzi cruzain and the T. brucei cathepsin L-like protease.

Trypanosoma cruzi (T. cruzi) and Trypanosoma brucei (T. brucei) urgently demand innovative drug development due to their impact on public health worldwide.

Deconstructing the self and reshaping perceptions: An intensive whole-brain 7T MRI case study of the stages of insight during advanced investigative insight meditation.

The stages of insight (SoI) are a series of psychological realizations experienced through advanced investigative insight meditation (AIIM). SoI provide a powerful structured framework of AIIM for understanding and evaluating insight-based meditative development through changes in perception, experiences of self, cognition, and emotional processing. Yet, the neurophenomenology of SoI remains unstudied due to methodological difficulties, rarity of suitable advanced meditation practitioners, and dominant research emphasis on attention-based meditative practices.

Phenotypic and genotypic correlates of the sodium bicarbonate-responsive phenotype among methicillin-resistant Staphylococcus aureus isolates from skin and soft-tissue infections.

Objectives: The objective of this study is to assess the frequency of the novel sodium bicarbonate (NaHCO)-responsive phenotype, wherein clinical methicillin-resistant Staphylococcus aureus (MRSA) isolates are rendered susceptible to standard-of-care β-lactams in the presence of NaHCO, in a collection of 103 clinical U.S. MRSA skin and soft-tissue infection (SSTI) isolates and 22 clinical European SSTI isolates.

Evolution of Rapid Clonal Dynamics and Non-Cross-Resistance in Response to Alternating Targeted Therapy and Chemotherapy in BRAF-V600E-Mutant Colon Cancer.

Purpose: Combined BRAF, MEK, and EGFR inhibition can induce clinical responses in BRAF-V600E-mutant colon cancer, but rapid resistance often occurs.

Methods: We use serial monitoring of circulating tumor DNA cell-free plasma DNA (cfDNA) in a patient case study in addition to organoids derived from mouse models of BRAF-V600E-mutant intestinal cancer, which emulated the patient's mutational profile to assess drug treatment efficacy.

Results: We demonstrate dynamic evolution of resistance to combined EGFR/BRAF/MEK inhibition in a pediatric patient with metastatic BRAF-V600E-mutant, mismatch repair-stable colon cancer.

Use of epigenetically modified bacteriophage and dual beta-lactams to treat a Mycobacterium abscessus sternal wound infection.

Nontuberculous mycobacterium (NTM) infections are challenging to manage and are frequently non-responsive to aggressive but poorly-tolerated antibiotic therapies. Immunosuppressed lung transplant patients are susceptible to NTM infections and poor patient outcomes are common. Bacteriophages present an alternative treatment option and are associated with favorable clinical outcomes.

Carmaphycin B-Based Proteasome Inhibitors to Treat Human African Trypanosomiasis: Structure-Activity Relationship and Efficacy.

The proteasome is essential for eukaryotic cell proteostasis, and inhibitors of the 20S proteasome are progressing preclinically and clinically as antiparasitics. We screened, the causative agent of human and animal African trypanosomiasis, with a set of 27 carmaphycin B analogs, irreversible epoxyketone inhibitors that were originally developed to inhibit the20S (Pf20S). The structure-activity relationship was distinct from that of the human c20S antitarget by the acceptance of d-amino acids at the P3 position of the peptidyl backbone to yield compounds with greatly decreased toxicity to human cells.

Durlobactam to boost the clinical utility of standard of care β-lactams against lung disease.

β-Lactams present several desirable pharmacodynamic features leading to the rapid eradication of many bacterial pathogens. Imipenem (IPM) and cefoxitin (FOX) are injectable β-lactams recommended during the intensive treatment phase of pulmonary infections caused by (Mab). However, their potency against Mab is many-fold lower than against Gram-positive and Gram-negative pathogens for which they were optimized, putting into question their clinical utility.

Structure elucidation, biosynthetic gene cluster distribution, and biological activities of ketomemicin analogs in .

We report three new ketomemicin pseudopeptides (-) from extracts of the marine actinomycete strain CNY-498. Their constitution and relative configuration were elucidated using NMR, mass spectrometry, and quantum chemical calculations. Using GNPS molecular networking and publicly available LCMS datasets, five additional ketomemicin analogs (-) were identified with ketomemicin production detected broadly across species.

A multidimensional assessment of in-host fitness costs of drug resistance in the opportunistic fungal pathogen Candida glabrata.

Drug-resistant microbes typically carry mutations in genes involved in critical cellular functions and may therefore be less fit under drug-free conditions than susceptible strains. Candida glabrata is a prevalent opportunistic yeast pathogen with a high rate of fluconazole resistance (FLZR), echinocandin resistance (ECR), and multidrug resistance (MDR) relative to other Candida. However, the fitness of C.