MaveDB 2024: a curated community database with over seven million variant effects from multiplexed functional assays.

Multiplexed assays of variant effect (MAVEs) are a critical tool for researchers and clinicians to understand genetic variants. Here we describe the 2024 update to MaveDB ( https://www.mavedb.

Early assessment of IL8 and PD1+ Treg predicts response and guides treatment monitoring in cemiplimab-treated cutaneous squamous cell carcinoma.

Purpose: Anti-programmed cell death 1 (PD1) is the first-choice treatment in patients with advanced cutaneous squamous cell carcinoma (cSCC), when curative options are unavailable. However, reliable biomarkers for patient selection are still lacking.

Experimental Design: In this translational study, clinical annotations, tissue and liquid biopsies were acquired to investigate the association between sustained objective responses and transcriptional profiles, immune cell dynamics in tumor tissue and peripheral blood samples, as well as circulating cytokine levels.

A High-Throughput Screening Pipeline to Identify Methyltransferase and Exonuclease Inhibitors of SARS-CoV-2 NSP14.

SARS-CoV-2 infections led to a worldwide pandemic in 2020. As of 2024, therapeutics against SARS-CoV-2 have continued to be desirable. NSP14 is a dual-function methyltransferase (MTase) and exonuclease (ExoN) with key roles in SARS-CoV-2 genome propagation and host immune system evasion.

Structural insights into isoform-specific RAS-PI3Kα interactions and the role of RAS in PI3Kα activation.

Mutations in RAS and PI3Kα are major drivers of human cancer. Their interaction plays a crucial role in activating PI3Kα and amplifying the PI3K-AKT-mTOR pathway. Disrupting RAS-PI3Kα interaction enhances survival in lung and skin cancer models and reduces tumor growth and angiogenesis, although the structural details of this interaction remain unclear.

Evaluating the Effectiveness of mRNA-1273.815 Against COVID-19 Hospitalization Among Adults Aged ≥ 18 Years in the United States.

Introduction: In September 2023 the Food and Drug Administration (FDA) approved an updated mRNA COVID-19 vaccine targeting the XBB.1.5 sublineage.

The differential interactomes of the KRAS splice variants identify BIRC6 as a ubiquitin ligase for KRAS4A.

Transcripts of the KRAS locus are alternatively spliced to generate two proteins, KRAS4A and KRAS4B, which differ in their membrane-targeting sequences. These splice variants have been conserved for more than 450 million years, suggesting non-overlapping functions driven by differential membrane association. Here, we use proximity labeling to map the differential interactomes of the KRAS splice variants.

Improvements in large-scale production of tobacco etch virus protease.

Tobacco-etch-virus (TEV) protease is the workhorse of many laboratories in which protein expression is the linchpin of downstream experiments. TEV protease is remarkable in its sequence specificity as the cleavage sequence rarely appears in higher organisms and its ability to cleave fusion tag proteins from proteins of interest. Herein we report work done on large-scale production of TEV protease using different promotors, media, fusion tags, and expression platforms.

The Neisseria meningitidis urethritis clade (NmUC) acts as a "chimeric pathogen" during infection of primary, human male, urethral epithelial cells.

Background: Clusters of male urethritis cases, caused by a novel clade of non-groupable Neisseria meningitidis (NmUC, "the clade"), have been reported globally. Genetic features unique to NmUC isolates include: the acquisition of the gonococcal denitrification loci, norB-aniA; a unique factor H binding protein (fHbp) variant; and loss of group C capsule and intrinsic lipooligosaccharide sialylation. We hypothesized that these characteristics might confer a colonization and survival advantage to NmUC during male urethral infection relative to non-clade group C Neisseria meningitidis.

Toward Spatial Control of Reaction Selectivity on Photocatalysts Using Area-Selective Atomic Layer Deposition on the Model Dual Site Electrocatalyst Platform.

Photocatalytic water splitting is a promising route to low-cost, green H. However, this approach is currently limited in its solar-to-hydrogen conversion efficiency. One major source of efficiency loss is attributed to the high rates of undesired side and back reactions, which are exacerbated by the proximity of neighboring oxidation and reduction sites.

Discovery of BBO-8520, a first-in-class direct and covalent dual inhibitor of GTP-bound (ON) and GDP-bound (OFF) KRASG12C.

Approved inhibitors of KRASG12C prevent oncogenic activation by sequestering the inactive, GDP-bound (OFF) form rather than directly binding and inhibiting the active, GTP-bound (ON) form. This approach provides no direct target coverage of the active protein. Expectedly, adaptive resistance to KRASG12C (OFF)-only inhibitors is observed in association with increased expression and activity of KRASG12C(ON).

Happy new ears: Rapid adaptation to novel spectral cues in vertical sound localization.

Humans can adapt to changes in the acoustic properties of the head and exploit the resulting novel spectral cues for sound source localization. However, the adaptation rate varies across studies and is not associated with the aftereffects commonly found after adaptation in other sensory domains. To investigate the adaptation' rate and measure potential aftereffects, our participants wore new-ears to alter the spectral cues for sound localization and underwent sensorimotor training to induce rapid adaptation.

Comprehensive structure-function analysis reveals gain- and loss-of-function mechanisms impacting oncogenic KRAS activity.

To dissect variant-function relationships in the KRAS oncoprotein, we performed deep mutational scanning (DMS) screens for both wild-type and KRAS mutant alleles. We defined the spectrum of oncogenic potential for nearly all possible variants, identifying several novel transforming alleles and elucidating a model to describe the frequency of mutations in human cancer as a function of transforming potential, mutational probability, and tissue-specific mutational signatures. Biochemical and structural analyses of variants identified in a KRAS second-site suppressor DMS screen revealed that attenuation of oncogenic KRAS can be mediated by protein instability and conformational rigidity, resulting in reduced binding affinity to effector proteins, such as RAF and PI3-kinases, or reduced SOS-mediated nucleotide exchange activity.

Multisensory temporal processing in schizophrenia and bipolar disorder: implications for psychosis.

Structuring sensory events in time is essential for interacting with the environment and producing adaptive behaviors. Over the past years, the microstructure of temporality received increasing attention, recognized as a fundamental factor influencing cognitive, affective, and social abilities, whose alteration can underlie the etiopathogeneses of some clinical symptoms in psychiatric disorders. The present research investigated multisensory temporal processing in individuals with schizophrenia (N = 21), bipolar disorder (N = 20) and healthy controls (N = 21) in order to explore a plausible link between multisensory alterations in the temporal order of events and the psychopathological dimensions underlying psychosis.

Humoral Immunity Profiling to Pandemic and Bat-Derived Coronavirus Variants: A Geographical Comparison.

Dynamic pathogen exposure may impact the immunological response to SARS-CoV-2 (SCV2). One potential explanation for the lack of severe SCV2-related morbidity and mortality in Southeast Asia is prior exposure to related betacoronaviruses. Recent discoveries of SCV2-related betacoronaviruses from horseshoe bats (Rhinolophus sinicus) in Thailand, Laos, and Cambodia suggest the potential for bat-to-human spillover exposures in the region.

Exploring the binding mode of phenyl and vinyl boronic acids to human carbonic anhydrases.

Boronic acids are an interesting but still poorly studied class of carbonic anhydrase inhibitors. Previous investigations proved that derivatives incorporating aromatic, arylalkyl, and arylalkenyl moieties are low micromolar to millimolar inhibitors for several α- and β-CAs involved in pathologic states. Here we report a high-resolution X-ray study on two classes of boronic acids (phenyl and vinyl) in complex with hCA II.

Scrolling through adolescence: a systematic review of the impact of TikTok on adolescent mental health.

Amidst rising concerns about mental health in adolescents, the role of social media (SM), particularly highly visual platforms such as TikTok, has become a growing focus of investigation. In the extant literature, conclusive evidence is limited by the aggregate analysis of very heterogeneous SM platforms. This systematic scoping review examines the relationship between TikTok and mental health in adolescents.

Clinical Efficacy of Isatuximab Plus Carfilzomib and Dexamethasone in Relapsed/Refractory Multiple Myeloma Patients.

Isatuximab, a novel anti-CD38 monoclonal antibody, is approved in combination with carfilzomib and dexamethasone (Isa-Kd) in relapsed/refractory multiple myeloma (RRMM) patients. Because of its recent introduction, real-world efficacy and safety are poorly reported. In this Italian multicenter real-life observational retrospective study, efficacy and safety of the Isa-Kd regimen were evaluated in a cohort of 103 RRMM patients.

Free-Cell Area Impact on Stroke Prevention in Asymptomatic Patients Undergoing Carotid Artery Stenting: The "Carotid Artery sTenting And CeLl-area Impact on Stroke and Major Adverse events" (CATACLISMA) Multicenter Registry.

Purpose: The study investigated the association between cell-stent area and cerebrovascular events incidence in asymptomatic patients undergoing carotid artery stenting (CAS).

Materials And Methods: This is an observational, retrospective, multicenter, cohort study. Between 2012 and 2022, all patients undergoing primary CAS for severe asymptomatic carotid artery stenosis were evaluated.

Systemic inflammatory markers and volume of enhancing tissue on post-contrast T1w MRI images in differentiating true tumor progression from pseudoprogression in high-grade glioma.

Background: High-grade glioma (HGG) patients post-radiotherapy often face challenges distinguishing true tumor progression (TTP) from pseudoprogression (PsP). This study evaluates the effectiveness of systemic inflammatory markers and volume of enhancing tissue on post-contrast T1 weighted (T1WCE) MRI images for this differentiation within the first six months after treatment.

Material And Methods: We conducted a retrospective analysis on a cohort of HGG patients from 2015 to 2021, categorized per WHO 2016 and 2021 criteria.

Bacterial α-CAs: a biochemical and structural overview.

Carbonic anhydrases belonging to the α-class are widely distributed in bacterial species. These enzymes have been isolated from bacteria with completely different characteristics including both Gram-negative and Gram-positive strains. α-CAs show a considerable similarity when comparing the biochemical, kinetic and structural features, with only small differences which reflect the diverse role these enzymes play in Nature.

Overexpression of CCL-20 and CXCL-8 genes enhances tumor escape and resistance to cemiplimab, a programmed cell death protein-1 (PD-1) inhibitor, in patients with locally advanced and metastatic cutaneous squamous cell carcinoma.

Cemiplimab has demonstrated relevant clinical activity in cutaneous squamous cell carcinoma (cSCC) but mechanisms of primary and acquired resistance to immunotherapy are still unknown. We collected clinical data from locally advanced and/or metastatic cSSC patients treated with cemiplimab in two Italian University centers. In addition, gene expression analysis by using Nanostring Technologies platform to evaluate 770 cancer- and immune-related genes on 20 tumor tissue samples (9 responders and 11 non-responders to cemiplimab) was performed.

The Impact of Growing Area on the Expression of Fruit Traits Related to Sensory Perception in Two Tomato Cultivars.

Environmental conditions greatly influence the quality of tomato fruit by affecting the expression of genes, the abundance of metabolites, and the perception of sensorial attributes. In this study, a fruit transcriptome investigation, a sensory test, and a metabolomic analysis were performed to evaluate the impact of the environment on two popular tomato cultivars grown in two Italian regions. The transcriptional profile of each cultivar, cultivated in two different areas, highlighted differential expression in genes involved in pathways related to cell wall components such as pectin, lignin, and hemicellulose and sugars as well as in amino acids, phenylpropanoids, and pigment synthesis.