A core network in the SARS-CoV-2 nucleocapsid NTD mediates structural integrity and selective RNA-binding.

The SARS-CoV-2 nucleocapsid protein is indispensable for viral RNA genome processing. Although the N-terminal domain (NTD) is suggested to mediate specific RNA-interactions, high-resolution structures with viral RNA are still lacking. Available hybrid structures of the NTD with ssRNA and dsRNA provide valuable insights; however, the precise mechanism of complex formation remains elusive.

A framework for neural organoids, assembloids and transplantation studies.

As the field of neural organoids and assembloids rapidly expands, there is an emergent need for guidance and advice on designing, conducting and reporting experiments to increase the reproducibility and utility of these models. Here, our consortium- representing specialized laboratories from around the world- presents a framework for the experimental process that ranges from ensuring the quality and integrity of human pluripotent stem cells to characterizing and manipulating neural cells in vitro, and from transplantation techniques to considerations for modeling human development, evolution, and disease. As with all scientific endeavors, we advocate for rigorous experimental designs tailored to explicit scientific questions, and transparent methodologies and data sharing, to provide useful knowledge for both current research practices and for developing regulatory standards.

Ustilago maydis Trf2 ensures genome stability by antagonizing Blm-mediated telomere recombination: Fine-tuning DNA repair factor activity at telomeres through opposing regulations.

TRF2 is an essential and conserved double-strand telomere binding protein that stabilizes chromosome ends by suppressing DNA damage response and aberrant DNA repair. Herein we investigated the mechanisms and functions of the Trf2 ortholog in the basidiomycete fungus Ustilago maydis, which manifests strong resemblances to metazoans with regards to the telomere and DNA repair machinery. We showed that UmTrf2 binds to Blm in vitro and inhibits Blm-mediated unwinding of telomeric DNA substrates.

Androgen receptor inhibition increases MHC Class I expression and improves immune response in prostate cancer.

Tumors escape immune detection and elimination through a variety of mechanisms. Here, we used prostate cancer as a model to examine how androgen-dependent tumors undergo immune evasion through downregulation of the major histocompatibility complex class I (MHCI). We report that response to immunotherapy in late-stage prostate cancer is associated with elevated MHC expression.

Respiratory Syncytial Virus Disease Burden and Nirsevimab Effectiveness in Young Children From 2023-2024.

Importance: During the 2023-2024 respiratory syncytial virus (RSV) season in the United States, 2 new RSV prevention products were recommended to protect infants in their first RSV season: nirsevimab and Pfizer's maternal RSV vaccine. Postlicensure studies are needed to assess prevention product impact and effectiveness.

Objective: To compare the epidemiology and disease burden of medically attended RSV-associated acute respiratory illness (ARI) among children younger than 5 years during the 2023-2024 RSV season with 3 prepandemic RSV seasons (2017-2020), estimate nirsevimab effectiveness against medically attended RSV-associated ARI, and compare nirsevimab binding site mutations among circulating RSV in infants with and without nirsevimab receipt.

Isolation and Molecular Profiling of Nuclei of Specific Neuronal Types from Human Cerebral Cortex and Striatum.

Most pathological conditions of the central nervous system do not affect all cell types to the same extent. Delineation of molecular events underlying disease symptoms, including genetic, epigenetic, and transcriptional changes, thus relies on the ability to characterize a specific cell type separately from others. We have developed a methodology for the collection of nuclear RNA and genomic DNA of specific cell types from frozen post-mortem striatum and cerebral cortex.

Blinatumomab in Standard-Risk B-Cell Acute Lymphoblastic Leukemia in Children.

Background: B-cell acute lymphoblastic leukemia (B-cell ALL) is the most common childhood cancer. Despite a high overall cure rate, relapsed B-cell ALL remains a leading cause of cancer-related death among children. The addition of the bispecific T-cell engager molecule blinatumomab (an anti-CD19 and anti-CD3 single-chain molecule) to therapy for newly diagnosed standard-risk (as defined by the National Cancer Institute) B-cell ALL in children may improve outcomes.

Deciphering genomic codes using advanced NLP techniques: a scoping review.

Objectives: The vast and complex nature of human genomic sequencing data presents challenges for effective analysis. This review aims to investigate the application of Natural Language Processing (NLP) techniques, particularly Large Language Models (LLMs) and transformer architectures, in deciphering genomic codes, focusing on tokenization, transformer models, and regulatory annotation prediction. This review aims to assess data and model accessibility in the most recent literature, gaining a better understanding of the existing capabilities and constraints of these tools in processing genomic sequencing data.

Convergent molecular signatures across eating disorders and obsessive-compulsive disorder in the human brain.

Eating disorders (ED) and obsessive-compulsive disorder (OCD) exhibit significant clinical and genetic overlap, yet their shared molecular mechanisms remain unclear. We conducted a transcriptomic investigation of the dorsolateral prefrontal cortex (DLPFC) and caudate from 86 controls, 57 ED, and 27 OCD cases. ED was associated with robust differentially expressed genes (DEGs): 102 DEGs the DLPFC and 222 in the caudate (FDR < 1%) and replicated in an independent cohort.

Single-cell transcriptomic and neuropathologic analysis reveals dysregulation of the integrated stress response in progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) is a sporadic neurodegenerative tauopathy variably affecting brainstem and cortical structures, and characterized by tau inclusions in neurons and glia. The precise mechanism whereby these protein aggregates lead to cell death remains unclear. To investigate the contribution of these different cellular abnormalities to PSP pathogenesis, we performed single-nucleus RNA sequencing (snRNA-seq) and analyzed 50,708 high quality nuclei targeting the diencephalon, including the subthalamic nucleus and adjacent structures, from human post-mortem PSP brains with varying degrees of pathology compared to controls.

Treatment sequence with tebentafusp and immune checkpoint inhibitors in patients with metastatic uveal melanoma and metastatic GNA11/GNAQ mutant melanocytic tumors.

Background: Metastatic uveal melanoma (mUM) is rare. Immune checkpoint inhibitors (ICIs) have shown modest efficacy in mUM. Tebentafusp prolonged overall survival (OS) in a phase 3 study.

Association between genomic instability score and progression-free/overall survival in patients with newly diagnosed non-BRCA1/2 ovarian cancer.

Objective: We sought to describe the association between genomic instability score (GIS) and progression-free survival (PFS) and overall survival (OS) in patients with newly diagnosed, non-BRCA1/2 ovarian cancer.

Methods: Homologous recombinant deficiency (HRD) status was based on a cutoff of ≥42 GIS; patients <42 were categorized with homologous recombination proficiency (HRP). We collected type and duration of maintenance therapy, among other variables, and built a multivariate model with landmark analysis at 6 months from baseline and applied it for time-dependent variables.

High precision newborn screening for mucopolysaccharidosis type I by enzymatic activity followed by endogenous, non-reducing end glycosaminoglycan analysis.

Measurement of enzymatic activity in newborn dried blood spots (DBS) is the preferred first-tier method in newborn screening (NBS) for mucopolysaccharidosis (MPS) disorders. However, false positives are observed due mainly to the presence of pseudodeficiencies. Our previous publications on glycosaminoglycan (GAG) biomarker levels in dried blood spots (DBS) for mucopolysaccharidoses demonstrated that second-tier GAG biomarker analysis can dramatically reduce the false positive rate in NBS.

Through thick and thin: confronting the aggressive cutaneous T-cell lymphomas.

The cutaneous T-cell lymphomas (CTCLs) comprise a diverse set of diseases with equally diverse presentations ranging from asymptomatic solitary lesions to highly aggressive diseases with propensity for visceral spread. The more aggressive CTCLs, which herein we consider as certain cases of advanced-stage mycosis fungoides/Sézary syndrome (MF/SS), primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma (PCAETCL), and primary cutaneous gamma delta T-cell lymphoma (PCGDTCL), require systemic therapy. Over the last 5 years, treatment options for MF/SS have expanded with biological insights leading to new therapeutic options and increasingly unique management strategies.

Mapping the microRNA landscape in the older adult brain and its genetic contribution to neuropsychiatric conditions.

MicroRNAs (miRNAs) play a crucial role in regulating gene expression and influence many biological processes. Despite their importance, understanding of how genetic variation affects miRNA expression in the brain and how this relates to brain disorders remains limited. Here we investigated these questions by identifying microRNA expression quantitative trait loci (miR-QTLs), or genetic variants associated with brain miRNA levels, using genome-wide small RNA sequencing profiles from dorsolateral prefrontal cortex samples of 604 older adult donors of European ancestry.

Remote monitoring of social attention in neurogenetic syndromes and idiopathic neurodevelopmental disability.

Social attention is a key aspect of neurodevelopment and is significantly altered in neurodevelopmental genetic syndromes and many individuals with idiopathic autism spectrum disorder (ASD). The primary aim of the present study was to examine the psychometric properties of webcam-collected social attention measurements, including four new specific aspects of social attention, in three genetic syndromes (PTEN Hamartoma Tumor Syndrome-PHTS; Malan Syndrome-NFIX; and SYNGAP1-related disorder-SYNGAP1), a mixed group of other neurodevelopmental genetic syndromes (Other NDGS), and individuals with a range of idiopathic neurodevelopmental disorder (NDD). The secondary aim was to evaluate the construct validity of these social attention measurements, including evaluating known-groups validity across study groups and concurrent validity for separating ASD and non-ASD cases.

Inhibitors of malaria parasite cyclic nucleotide phosphodiesterases block asexual blood-stage development and mosquito transmission.

Cyclic nucleotide-dependent phosphodiesterases (PDEs) play essential roles in regulating the malaria parasite life cycle, suggesting that they may be promising antimalarial drug targets. PDE inhibitors are used safely to treat a range of noninfectious human disorders. Here, we report three subseries of fast-acting and potent PDEβ inhibitors that block asexual blood-stage parasite development and that are also active against human clinical isolates.

Amyotrophic lateral sclerosis diagnosis using machine learning and multi-omic data integration.

Amyotrophic Lateral Sclerosis (ALS) is a complex and rare neurodegenerative disorder characterized by significant genetic, molecular, and clinical heterogeneity. Despite numerous endeavors to discover the genetic factors underlying ALS, a significant number of these factors remain unknown. This knowledge gap highlights the necessity for personalized medicine approaches that can provide more comprehensive information for the purposes of diagnosis, prognosis, and treatment of ALS.

The role of the tricellular junction protein ILDR2 in glomerulopathies: Expression patterns and functional insights.

The tricellular tight junctions are crucial for the regulation of paracellular flux at tricellular junctions, where tricellulin (MARVELD2) and angulins (ILDR1, ILDR2, or LSR) are localized. The role of ILDR2 in podocytes, specialized epithelial cells in the kidney, is still unknown. We investigated the role of ILDR2 in glomeruli and its influence on blood filtration.