The Single-Cell Landscape of Peripheral and Tumor-infiltrating Immune Cells in HPV- HNSCC.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. HPV-negative HNSCC, which arises in the upper airway mucosa, is particularly aggressive, with nearly half of patients succumbing to the disease within five years and limited response to immune checkpoint inhibitors compared to other cancers. There is a need to further explore the complex immune landscape in HPV-negative HNSCC to identify potential therapeutic targets.

Substrate recognition by the 4-hydroxytryptamine kinase PsiK in psilocybin biosynthesis.

Psilocybin, the natural hallucinogen from Psilocybe (magic) mushrooms, is a highly promising drug candidate for the treatment of depression and several other mental health conditions. Biosynthesis of psilocybin from the amino acid l-tryptophan involves four strictly sequential modifications. The third of these, ATP-dependent phosphorylation of the intermediate 4-hydroxytryptamine, is catalysed by PsiK.

The Second Methylation in Psilocybin Biosynthesis Is Enabled by a Hydrogen Bonding Network Extending into the Secondary Sphere Surrounding the Methyltransferase Active Site.

The Psilocybe cubensis SAM-dependent methyltransferase, PsiM, catalyzes the last step in the biosynthesis of psilocybin. Likely evolved from monomethylating RNA methyltransferases, PsiM acquired a key amino acid exchange in the secondary sphere of the active site, M247 N, which is responsible for its capacity to dimethylate. Two variants, PsiM and PsiM, were generated to further examine the role of Asn247 for mono- and dimethylation in PsiM.

CellMag-CARWash: A High Throughput Droplet Microfluidic Device for Live Cell Isolation and Single Cell Applications.

The recent push toward understanding an individual cell's behavior and identifying cellular heterogeneity has created an unmet need for technologies that can probe live cells at the single-cell level. Cells within a population are known to exhibit heterogeneous responses to environmental cues. These differences can lead to varied cellular states, behavior, and responses to therapeutics.

Methyl transfer in psilocybin biosynthesis.

Psilocybin, the natural hallucinogen produced by Psilocybe ("magic") mushrooms, holds great promise for the treatment of depression and several other mental health conditions. The final step in the psilocybin biosynthetic pathway, dimethylation of the tryptophan-derived intermediate norbaeocystin, is catalysed by PsiM. Here we present atomic resolution (0.

Toll-Like Receptor 3 Mediates Aortic Stenosis Through a Conserved Mechanism of Calcification.

Background: Calcific aortic valve disease (CAVD) is characterized by a phenotypic switch of valvular interstitial cells to bone-forming cells. Toll-like receptors (TLRs) are evolutionarily conserved pattern recognition receptors at the interface between innate immunity and tissue repair. Type I interferons (IFNs) are not only crucial for an adequate antiviral response but also implicated in bone formation.

SARS-CoV-2 3CL mutations selected in a VSV-based system confer resistance to nirmatrelvir, ensitrelvir, and GC376.

Protease inhibitors are among the most powerful antiviral drugs. Nirmatrelvir is the first protease inhibitor specifically developed against the SARS-CoV-2 protease 3CL that has been licensed for clinical use. To identify mutations that confer resistance to this protease inhibitor, we engineered a chimeric vesicular stomatitis virus (VSV) that expressed a polyprotein composed of the VSV glycoprotein (G), the SARS-CoV-2 3CL, and the VSV polymerase (L).

Integrated Workflow for the Label-Free Isolation and Genomic Analysis of Single Circulating Tumor Cells in Pancreatic Cancer.

As pancreatic cancer is the third deadliest cancer in the U.S., the ability to study genetic alterations is necessary to provide further insight into potentially targetable regions for cancer treatment.

Employment as HIV Prevention: An Employment Support Intervention for Adolescent Men Who Have Sex With Men and Adolescent Transgender Women of Color.

Background: The purpose of this study was to adapt and pilot-test an employment support, primary HIV intervention tailored to the needs of adolescent men who have sex with men and adolescent transgender women of color.

Setting: The intervention was implemented in 2 settings: controlled environment (Phase 1) and real-world community-based (Phase 2) setting in Chicago, IL.

Methods: Eighty-seven adolescent men who have sex with men and adolescent transgender women of color ages 16-24 participated in Work2Prevent , a 4-session employment and HIV prevention intervention, designed to increase job-readiness and reduce HIV risk.

A VSV-based assay quantifies coronavirus Mpro/3CLpro/Nsp5 main protease activity and chemical inhibition.

Protease inhibitors are among the most powerful antiviral drugs. However, for SARS-CoV-2 only a small number of protease inhibitors have been identified thus far and there is still a great need for assays that efficiently report protease activity and inhibition in living cells. Here, we engineer a safe VSV-based system to report both gain- and loss-of-function of coronavirus main protease (M/3CLpro/Nsp5) activity in living cells.

Circulating tumor cells in precision medicine: challenges and opportunities.

The mutational and phenotypic landscape of tumors is dynamic, requiring constant monitoring of cancer patients to provide the most up-to-date and effective care. Circulating tumor cells (CTCs) obtained via liquid biopsy can provide tumor DNA, RNA, and protein information that can aid in the diagnosis, prognosis, and treatment of patients. There have been many recent studies and advances in using CTC enumeration, characterization, and expansion to provide personalized cancer treatment, validating the benefit of using CTCs as a biomarker in standard of care procedures.

Daily Predictors of ART Adherence Among Young Men Living with HIV Who Have Sex with Men: A Longitudinal Daily Diary Study.

Improving adherence to antiretroviral therapy (ART) is essential for limiting HIV disease progression among young sexual minority men living with HIV. Daily diaries allow for a detailed examination of how fluctuations in psychosocial factors are associated with adherence over time. Across three cities in the United States, this study collected 60 days of quantitative data from 44 young men (between 16 and 24 years of age) living with HIV who have sex with men.

The structure of neurofibromin isoform 2 reveals different functional states.

The autosomal dominant monogenetic disease neurofibromatosis type 1 (NF1) affects approximately one in 3,000 individuals and is caused by mutations in the NF1 tumour suppressor gene, leading to dysfunction in the protein neurofibromin (Nf1). As a GTPase-activating protein, a key function of Nf1 is repression of the Ras oncogene signalling cascade. We determined the human Nf1 dimer structure at an overall resolution of 3.

Correlates of High HIV Viral Load and Antiretroviral Therapy Adherence Among Viremic Youth in the United States Enrolled in an Adherence Improvement Intervention.

A sizable portion of youth (ages 13-24) living with HIV in the United States have unsuppressed viral load. The AIDS Interventions (ATN) 152 study [evaluating the Triggered Escalating Real-Time Adherence (TERA) intervention] baseline data were examined to identify correlates of high viremia (>5000 copies/mL) and self-reported adherence, which can help in planning of differentiated services for viremic youth. Depression, HIV-stigma, and cannabis use were common in this sample of 87 youth.

Rapid response to emerging biomedical challenges and threats.

As part of the global mobilization to combat the present pandemic, almost 100 000 COVID-19-related papers have been published and nearly a thousand models of macromolecules encoded by SARS-CoV-2 have been deposited in the Protein Data Bank within less than a year. The avalanche of new structural data has given rise to multiple resources dedicated to assessing the correctness and quality of structural data and models. Here, an approach to evaluate the massive amounts of such data using the resource https://covid19.

Correcting cis-trans-transgressions in macromolecular structure models.

Many macromolecular X-ray and cryo-EM structure models deposited in the PDB contain biologically relevant small molecule ligands with unsaturated fatty acid acyl chains, whose cis-trans stereochemistry is incorrect. The molecules are either not properly defined in their stereochemical restraint files, or the proper stereochemistry is neglected during model building. Often, the same molecules appear in deposited models in both isomeric configurations, one of which is almost always incorrect, and the use of the same moiety (HET) identifier and restraint files in model refinement is wrong.

Crystallographic models of SARS-CoV-2 3CL: in-depth assessment of structure quality and validation.

The appearance at the end of 2019 of the new SARS-CoV-2 coronavirus led to an unprecedented response by the structural biology community, resulting in the rapid determination of many hundreds of structures of proteins encoded by the virus. As part of an effort to analyze and, if necessary, remediate these structures as deposited in the Protein Data Bank (PDB), this work presents a detailed analysis of 81 crystal structures of the main protease 3CL, an important target for the design of drugs against COVID-19. The structures of the unliganded enzyme and its complexes with a number of inhibitors were determined by multiple research groups using different experimental approaches and conditions; the resulting structures span 13 different polymorphs representing seven space groups.

Strategy for Deployment of Integrated Healthy Aging Regions Based Upon an Evidence-Based Regional Ecosystem-The Styria Model.

In 2013, the European Commission founded the platform European Innovation Partnership on Active and Healthy Aging as a communication and innovation network in this domain. The goal of the current study was the development of an integrated regional ecosystem for active and healthy aging for the region of Styria via a step-by-step co-creation process. A mixed model approach was used to establish an ecosystem for active and healthy aging, which includes macro-, meso- and micro-level stakeholders in the province of Styria, Austria.

Covid-19.bioreproducibility.org: A web resource for SARS-CoV-2-related structural models.

The COVID-19 pandemic has triggered numerous scientific activities aimed at understanding the SARS-CoV-2 virus and ultimately developing treatments. Structural biologists have already determined hundreds of experimental X-ray, cryo-EM, and NMR structures of proteins and nucleic acids related to this coronavirus, and this number is still growing. To help biomedical researchers, who may not necessarily be experts in structural biology, navigate through the flood of structural models, we have created an online resource, covid19.