Profiling cell identity and tissue architecture with single-cell and spatial transcriptomics

Nature Reviews Molecular Cell Biology, Год журнала: 2024, Номер 26(1), С. 11 - 31

Опубликована: Авг. 21, 2024

Язык: Английский

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Pharmacology and Mechanism of Action of Suzetrigine, a Potent and Selective NaV1.8 Pain Signal Inhibitor for the Treatment of Moderate to Severe Pain

Pain and Therapy, Год журнала: 2025, Номер unknown

Опубликована: Янв. 8, 2025

There is a high unmet need for safe and effective non-opioid medicines to treat moderate severe pain without risk of addiction. Voltage-gated sodium channel 1.8 (NaV1.8) genetically pharmacologically validated target that selectively expressed in peripheral pain-sensing neurons not the central nervous system (CNS). Suzetrigine (VX-548) potent selective inhibitor NaV1.8, which has demonstrated clinical efficacy safety multiple acute studies. Our study was designed characterize mechanism action suzetrigine assess both nonclinical data test hypothesis NaV1.8 inhibition translates into safety, including lack addictive potential. Preclinical pharmacology studies were performed vitro using electrophysiology radiolabeled binding methods cells recombinantly expressing human NaV channels, proteins, primary dorsal root ganglion (DRG) sensory neurons. Safety potential assessments included secondary studies, repeat-dose toxicity dependence rats and/or monkeys, systematic analysis adverse event generated from 2447 participants phase 3 suzetrigine. against all other subtypes (≥ 31,000-fold) 180 molecular targets. inhibits by protein's second voltage sensing domain (VSD2) stabilize closed state channel. This novel allosteric results tonic reduces signals DRG Nonclinical with demonstrate no CNS, cardiovascular or behavioral effects evidence dependence. The comprehensive assessment presented here indicates represents first new class analgesics are signal inhibitors acting safely

Язык: Английский

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Claudin-2 upregulation enhances intestinal permeability, immune activation, dysbiosis, and mortality in sepsis

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(10)

Опубликована: Фев. 27, 2024

Intestinal epithelial expression of the tight junction protein claudin-2, which forms paracellular cation and water channels, is precisely regulated during development in disease. Here, we show that small intestinal claudin-2 selectively upregulated septic patients. Similar changes occurred mice, where upregulation coincided with increased flux across pore pathway. In order to define significance these changes, sepsis was induced knockout (KO) wild-type (WT) mice. Sepsis-induced increases pathway permeability were prevented by KO. Moreover, deletion reduced interleukin-17 production T cell activation limited damage. These effects associated numbers neutrophils, macrophages, dendritic cells, bacteria within peritoneal fluid KO Most strikingly, dramatically enhanced survival sepsis. Finally, microbial less pathogenic mice as healthy WT injected cecal slurry collected from 24 h after far worse than Claudin-2 are, therefore, key intermediates contribute dysbiosis, damage, inflammation, ineffective pathogen control, mortality The striking impact on progression lethal cascade activated suggests may be an attractive therapeutic target

Язык: Английский

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Open challenges and opportunities in federated foundation models towards biomedical healthcare

BioData Mining, Год журнала: 2025, Номер 18(1)

Опубликована: Янв. 4, 2025

This survey explores the transformative impact of foundation models (FMs) in artificial intelligence, focusing on their integration with federated learning (FL) biomedical research. Foundation such as ChatGPT, LLaMa, and CLIP, which are trained vast datasets through methods including unsupervised pretraining, self-supervised learning, instructed fine-tuning, reinforcement from human feedback, represent significant advancements machine learning. These models, ability to generate coherent text realistic images, crucial for applications that require processing diverse data forms clinical reports, diagnostic multimodal patient interactions. The incorporation FL these sophisticated presents a promising strategy harness analytical power while safeguarding privacy sensitive medical data. approach not only enhances capabilities FMs diagnostics personalized treatment but also addresses critical concerns about security healthcare. reviews current settings, underscores challenges, identifies future research directions scaling FMs, managing diversity, enhancing communication efficiency within frameworks. objective is encourage further into combined potential FL, laying groundwork healthcare innovations.

Язык: Английский

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The human protein atlas—Integrated omics for single cell mapping of the human proteome

Protein Science, Год журнала: 2023, Номер 32(2)

Опубликована: Янв. 6, 2023

Studying the spatial distribution of proteins provides basis for understanding biology, molecular repertoire, and architecture every human cell. The Human Protein Atlas (HPA) has grown into one world's largest biological databases, in most recent version, a major update structure database was performed. data now been organized 10 different comprehensive sections, each summarizing aspects proteome protein-coding genes. In particular, large datasets with information on single cell type level have integrated, refining tissue specificity detailing expression states an increased resolution. multi-modal constitute important resource both basic translational science, hold promise integration novel emerging technologies at protein RNA level.

Язык: Английский

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Identification of novel biomarkers based on lipid metabolism-related molecular subtypes for moderately severe and severe acute pancreatitis

Lipids in Health and Disease, Год журнала: 2024, Номер 23(1)

Опубликована: Янв. 2, 2024

Abstract Background Acute pancreatitis (AP) is an unpredictable and potentially fatal disorder. A derailed or unbalanced immune response may be the root of disease’s severe course. Disorders lipid metabolism are highly correlated with occurrence severity AP. We aimed to characterize contribution immunological characteristics metabolism-related genes (LMRGs) in non-mild acute (NMAP) identify a robust subtype biomarker for NMAP. Methods The expression mode LMRGs NMAP were examined. Then LMRG-derived subtypes identified using consensus clustering. weighted gene co-expression network analysis (WGCNA) was utilized determine hub perform functional enrichment analyses. Multiple machine learning methods used build diagnostic model patients. To validate predictive effectiveness, nomograms, receiver operating characteristic (ROC), calibration, decision curve (DCA) used. Using set variation (GSVA) single-cell study biological roles genes. Results Dysregulated responses between normal individuals. individuals divided into two LMRG-related significant differences function. cluster-specific primarily engaged regulation defense response, T cell activation, positive cytokine production. Moreover, we constructed two-gene prediction good performance. CARD16 MSGT1 significantly increased samples positively neutrophil mast infiltration. GSVA results showed that they mainly upregulated receptor complex, immunoglobulin complex circulating, some immune-related routes. Single-cell indicated distributed mixed cells macrophages, MGST1 exocrine glandular cells. Conclusions This presents novel approach categorizing different clusters based on developing reliable

Язык: Английский

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In Vitro Functional Validation of an Anti-FREM2 Nanobody for Glioblastoma Cell Targeting

Antibodies, Год журнала: 2025, Номер 14(1), С. 8 - 8

Опубликована: Янв. 24, 2025

Background/Objectives: Glioblastomas are the most common brain malignancies. Despite implementation of multimodal therapy, patient life expectancy after diagnosis is barely 12 to 18 months. highly heterogeneous at genetic and epigenetic level comprise multiple different cell subpopulations. Therefore, small molecules such as nanobodies, able target membrane proteins specific glioblastoma cells or types within tumor being investigated novel tools treat glioblastomas. Methods: Here, we describe identification a nanobody its in silico vitro validation. NB3F18, named it, directed against membrane-associated protein FREM2, overexpressed stem cells. Results: Three dimensional modeling indicated that NB3F18 FREM2 form stable complex. Surface plasmon resonance confirmed their interaction with moderate affinity. As demonstrated by flow cytometry, binds greater extent than differentiated astrocytes. Immunocytochemistry revealed surface localization on cells, whereas cytoplasmic was observed other lines. detected transmission electron microscopy plasma various compartments endocytic pathway, from vesicles multivesicular bodies (endosomes) lysosomes. Interestingly, cytotoxic Conclusions: Collectively, has been qualified an interesting tool potential vehicle deliver biological pharmaceutical agents these

Язык: Английский

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TNIP1 Impacts Prognosis by Modulating the Immune Microenvironment in BRCA

Biochemical Genetics, Год журнала: 2025, Номер unknown

Опубликована: Янв. 27, 2025

Язык: Английский

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The Human Protein Atlas: A Molecular Journey Inside Our Bodies to Understand Health and Disease

Frontiers for Young Minds, Год журнала: 2025, Номер 13

Опубликована: Янв. 30, 2025

In this article, we will talk about a way to explore the intricate universe of human body—an online resource called Human Protein Atlas. Using Atlas as kind “map” body, scientists can play role modern-day explorers, equipped with advanced tools and techniques. The helps researchers study biological questions involving various organs, tissues, cells body. “maps” were created using techniques that enable visualize locations specific proteins choice within organs tissues. Information contained in help reveal mechanisms health disease, here provide couple important examples problems investigate these “maps”, namely function fallopian tubes mysteries ovarian cancer.

Язык: Английский

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Mendelian randomization identifies proteins involved in neurodegenerative diseases

Brain, Год журнала: 2025, Номер unknown

Опубликована: Март 3, 2025

Proteins are involved in multiple biological functions. High-throughput technologies have allowed the measurement of thousands proteins population biobanks. In this study, we aimed to identify related Alzheimer's disease, Parkinson's sclerosis and amyotrophic lateral by leveraging large-scale genetic proteomic data. We performed a two-sample cis Mendelian randomization study selecting instrumental variables for abundance >2700 measured either Olink or SomaScan platforms plasma from UK Biobank deCODE Health Study. also used latest publicly available genome-wide association studies neurodegenerative diseases interest. The potentially causal effect on was estimated based Wald ratio. tested 13 377 protein-disease associations, identifying 169 associations that were statistically significant (5% false discovery rate). Evidence co-localization between protein disease risk (posterior probability > 0.80) identified 61 pairs, leading 50 unique associations. Notably, 23 corresponded loci not previously reported studies. analysis showed APOE associated with three subcortical volumes (hippocampus, amygdala nucleus accumbens) white matter hyper-intensities, whereas PILRA PILRB caudate volume. Our provided comprehensive assessment human proteome is currently measurable through two different diseases. newly indicated involvement complement (C1S C1R), microglia (SIRPA, SIGLEC9 PRSS8) lysosomes (CLN5) disease; interleukin-6 pathway (CTF1) (TPP1), blood-brain barrier integrity (MFAP2) astrocytes (TNFSF13) sclerosis; (VEGFB), oligodendrocytes (PARP1), node Ranvier dorsal root ganglion (NCS1, FLRT3 CDH15) innate immune system (CR1, AHSG WARS) sclerosis. demonstrates how harnessing genomic data can yield new insights into role pathogenesis

Язык: Английский

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