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.

Carbapenem-resistant Enterobacterales in solid organ transplant recipients.

Carbapenem-resistant Enterobacterales (CRE) are an important threat to the health of solid organ transplant recipients (SOTr); data comparing outcomes of SOTr with CRE to non-SOTr with CRE are lacking. A matched cohort study was performed within 2 prospective, multicenter, cohort studies (Consortium on Resistance Against Carbapenems in Klebsiella and other Enterobacterales and Consortium on Resistance Against Carbapenems in Klebsiella and other Enterobacterales 2). The epidemiology, desirability of outcome rankings outcomes, and mortality of SOTr and non-SOTr hospitalized in the United States (December 2011-August 2017) with clinical isolates with Centers for Disease Control and Prevention-defined CRE were compared.

Growth differentiation factor 15 (GDF15) predicts relapse free and overall survival in unresected locally advanced non-small cell lung cancer treated with chemoradiotherapy.

Introduction: Growth differentiation factor 15 (GDF15) is a cytokine of the TGFβ family. Here, we analyzed GDF15 levels in patients with locally advanced non-small cell lung cancer (LA-NSCLC) who participated in OCOG-ALMERA (NCT02115464), a phase II randomized clinical trial, that investigated metformin in combination with standard of care concurrent chemoradiotherapy (cCRT). OCOG-ALMERA was not able to demonstrate benefit in the metformin arm.

Cancer survivor preferences on the timing and content of interventions to mitigate financial toxicity associated with cancer treatment.

Purpose: Despite growing research on financial toxicity among cancer survivors, large gaps remain in understanding how to intervene to minimize financial toxicity. Uptake and efficacy of interventions mitigating cancer financial toxicity, though promising, remain limited and inconsistent. To date, survivor preferences for financial toxicity interventions are underexplored.

A study protocol for a mixed-method environmental scan of contextual factors that influence lung cancer screening adherence.

Background: The efficacy of lung cancer screening (LCS) to reduce lung cancer specific mortality is heavily dependent on adherence to recommended screening guidelines, with real-world adherence rates reported to be drastically lower than rates described in clinical trials. There is a dearth in the literature on reminder processes and clinical workflows used to address adherence and robust data is needed to fully understand which clinical set-ups, processes, and context enhance and increase continued LCS participation. This paper describes a protocol for an environmental scan of adherence and reminder processes that are currently used in LCS programs across the United States.

Distinct RORγt-dependent Th17 immune responses are required for autoimmune pathogenesis and protection against bacterial infection.

T helper (Th)17 cells mediate both protective anti-bacterial immune responses and autoimmune pathogenesis, but the distinct pathways regulating these Th17 responses remain unclear. Retinoid-related orphan receptor γ t (RORγt) is a master transcription factor that governs Th17 cell generation and effector functions. We found that a K256R mutation in RORγt impairs Th17-mediated experimental autoimmune encephalomyelitis (EAE) without affecting the clearance of Citrobacter rodentium.

A mutant BCL11B-N440K protein interferes with BCL11A function during T lymphocyte and neuronal development.

Genetic studies in mice have shown that the zinc finger transcription factor BCL11B has an essential role in regulating early T cell development and neurogenesis. A de novo heterozygous missense BCL11B variant, BCL11B, was isolated from a patient with T cell deficiency and neurological disorders. Here, we show that mice harboring the corresponding Bcl11b mutation show the emergence of natural killer (NK)/group 1 innate lymphoid cell (ILC1)-like NKp46 cells in the thymus and reduction in TBR1 neurons in the neocortex, which are observed with loss of Bcl11a but not Bcl11b.

Synthesis and Biological Evaluation of New Chalcogen Semicarbazone (, ) and Their Azole Derivatives against Chagas Disease.

Chagas disease is caused by the eukaryote parasite . Current treatment exhibits limited efficacy and selenium-based compounds emerged as promising candidates for new therapies which is surpassing its bioisoster, sulfur. We designed new thiosemicarbazones, thiazoles, selenosemicarbazones and selenazoles, using isosteric substitution.

Neonatal Morbidities, Neurodevelopmental Impairments, and Positive Health among Children Surviving Birth before 32 Weeks of Gestation.

Objectives: To evaluate positive health outcomes among children born at < 32 weeks of gestation and to determine whether children with three common neonatal morbidities and 2 neurodevelopmental impairments would have similar positive health outcomes to children and adolescents without these exposures and impairments.

Study Design: In this secondary analysis of prospectively acquired data derived from 3 multicenter cohorts of children born very preterm (the Extremely Low Gestational Age Newborn cohort [birth years 2001 to 2004], the Neurobehavior And Outcomes in Very Preterm Infants cohort [birth years 2014 to 2016], and the Developmental Impact of Neurobehavior And Outcomes in Very Preterm Infants Exposures cohort [birth years 2010 to 2020]), we examined associations between the 3 common neonatal morbidities (bronchopulmonary dysplasia, necrotizing enterocolitis, and intraventricular hemorrhage, diagnosed before hospital discharge), 2 neurodevelopmental impairments (developmental delays and cerebral palsy, diagnosed at preschool age follow-up), and perceptions of physical, mental, and social well-being (in either early childhood or adolescence), using the Patient-Reported Outcomes Measurement Information System scales for positive health.

Results: After adjusting for confounders, bronchopulmonary dysplasia, intraventricular hemorrhage, and cerebral palsy were associated with lower positive health scores, reported by parent-proxy during early childhood.

Multidrug tolerance conferred by loss-of-function mutations in anti-sigma factor RshA of .

Low-level drug resistance in noncanonical pathways can constitute steppingstones toward acquisition of high-level on-target resistance mutations in the clinic. To capture these intermediate steps in (Mab), we performed classic mutant selection experiments with moxifloxacin at twofold its minimum inhibitory concentration (MIC) on solid medium. We found that low-level resistance emerged reproducibly as loss-of-function mutations in RshA (MAB_3542c), an anti-sigma factor that negatively regulates activity of SigH, which orchestrates a response to oxidative stress in mycobacteria.

Computational Workflow to Design Novel Vaccine Candidates and Small-Molecule Therapeutics for Schistosomiasis.

Human schistosomiasis, caused by the trematode, is a neglected parasitic disease affecting over 250 million people worldwide. There is no vaccine, and the single available drug is threatened by drug resistance. This study presents a computational approach to designing multiepitope vaccines (MEVs) targeting the cercarial (CMEV) and schistosomular (SMEV) stages of schistosomes, and identifies potential schistosomicidal compounds from the Medicine for Malaria Ventures (MMV) and SuperNatural Database (SND) libraries.

Azole Combinations and Multi-Targeting Drugs That Synergistically Inhibit .

Limited antifungal treatment options and drug resistance require innovative approaches to effectively combat fungal infections. Combination therapy is a promising strategy that addresses these pressing issues by concurrently targeting multiple cellular sites. The drug targets usually selected for combination therapy are from different cellular pathways with the goals of increasing treatment options and reducing development of resistance.

The proteasome as a drug target for treatment of parasitic diseases.

The proteasome is a proteolytically active molecular machine comprising many different protein subunits. It is essential for growth and survival in eukaryotic cells and has long been considered a drug target. Here, we summarize the biology of the proteasome, the early research relating to the development of specific proteasome inhibitors (PIs) for treatment of various cancers, and their translation and eventual evolution as exciting therapies for parasitic diseases.