Multi-omics integration reveals underlying toxicological mechanisms of triclosan in the freshwater fish model Zacco platypus.

Although the partial mechanisms of triclosan toxicity have been suggested in fish models, integrated omics approaches for understanding its overall effects are still lacking in non-model fish species. In this study, we utilized a multi-omics platform that integrates the transcriptome, proteome, and metabolome to understand the underlying molecular toxicological mechanisms of triclosan (TCS) in the pale chub, Zacco platypus. Z.

Complement Proteins Identify Rapidly Progressive Diabetic Kidney Disease.

Introduction: Mechanisms underlying diabetic kidney disease (DKD) progression remain incompletely understood. This study used untargeted and targeted mass spectrometry-based proteomics in 2 independent cohorts to capture rapidly progressive DKD.

Methods: We conducted untargeted and targeted mass spectrometry on urine samples from Korean patients with type 2 diabetes and biopsy-confirmed diabetic nephropathy (SNUH-DN cohort; = 64) and a DKD subgroup of the Chronic Renal Insufficiency Cohort (CRIC-T2D; = 282), respectively.

Genome-scale knockout simulation and clustering analysis of drug-resistant breast cancer cells reveal drug sensitization targets.

Anticancer chemotherapy is an essential part of cancer treatment, but the emergence of resistance remains a major hurdle. Metabolic reprogramming is a notable phenotype associated with the acquisition of drug resistance. Here, we develop a computational framework that predicts metabolic gene targets capable of reverting the metabolic state of drug-resistant cells to that of drug-sensitive parental cells, thereby sensitizing the resistant cells.

The Fragility of Social Capital: How Lack of Specific Trust Undermines Sustainability in Comprehensive Welfare Centers for the Elderly-A Case Study of Permanent Lease Housing Areas in South Korea.

Social capital is recognized as a key mechanism for alleviating poverty among older adults, yet its long-term sustainability remains underexplored. This study analyzes 62 semi-structured interviews with elderly individuals at a welfare center in Seoul, selecting 15 representative cases for in-depth thematic analysis. While social participation fosters initial trust, exclusion, institutional constraints, and unequal exchanges hinder the transition from generalized trust, weakening the sustainability of social capital.

Tumor-promoting UBR4 coordinates impaired mitophagy-associated senescence and lung adenocarcinoma pathogenesis.

Cellular senescence, an irreversible cell cycle arrest, plays a pivotal role in development, aging, and tumor suppression. However, the fundamental pathway coordinating senescence and neoplastic transformation remains unclear. Here, we describe the tumorigenic involvement of ubiquitin protein ligase E3 component n-recognin 4 (UBR4), an E3 ubiquitin ligase of the N-degron pathway, in lung adenocarcinoma (LUAD).

Comparative Analysis of Primary Sarcopenia and End-Stage Renal Disease-Related Muscle Wasting Using Multi-Omics Approaches.

Background: Age-related primary sarcopenia and end-stage renal disease (ESRD)-related muscle wasting are discrete entities; however, both manifest as a decline in skeletal muscle mass and strength. The etiological pathways differ, with aging factors implicated in sarcopenia and a combination of uremic factors, including haemodialysis, contributing to ESRD-related muscle wasting. Understanding these molecular nuances is imperative for targeted interventions, and the integration of proteomic and metabolomic data elucidate these intricate processes.

Long-term physical exercise facilitates putative glymphatic and meningeal lymphatic vessel flow in humans.

Regular voluntary exercise has been shown to increase waste transport through the glymphatic system in mice. Here, we investigate the impact of physical exercise on both upstream and downstream brain waste clearance in healthy volunteers via noninvasive MR imaging. Putative glymphatic influx, evaluated using intravenous contrast-enhanced dynamic T1 mapping, increases significantly at the putamen after 12 weeks of long-term exercise using a cycle ergometer.

Proteomic Analyses of Clots Identify Stroke Etiologies in Patients Undergoing Endovascular Therapy.

Aims: This study aimed to investigate the correlation between clot composition and stroke mechanisms in patients undergoing endovascular therapy (EVT), using proteomic analysis.

Methods: This study included 35 patients with ischemic stroke (cardioembolism [CE], n = 17; large artery atherosclerosis [LAA], n = 6; cancer-related [CR], n = 4; and undetermined (UD) cause, n = 8) who underwent EVT. Retrieved clots were proteomically analyzed to identify differentially expressed proteins associated with the three stroke mechanisms and to develop the machine learning model.

Multi-omic insights into molecular mechanism and therapeutic targets in spinocerebellar ataxia type 7.

Recent advances in molecular science have significantly enlightened our mechanistic understanding of spinocerebellar ataxia type 7. To further close remaining gaps, we performed a multi-omics analysis using SCA7 mice. Entire brain tissue samples were collected from 12-week-old mice, and RNA sequencing, methylation analysis, and proteomic analysis were performed.

Cd99l2 regulates excitatory synapse development and restrains immediate-early gene activation.

Cd99 molecule-like 2 (Cd99l2) is a type I transmembrane protein that plays a role in the transmigration of leukocytes across vascular endothelial cells. Despite its high expression in the brain, the role of Cd99l2 remains elusive. We find that Cd99l2 is expressed primarily in neurons and positively regulates neurite outgrowth and the development of excitatory synapses.

NS1 binding protein regulates stress granule dynamics and clearance by inhibiting p62 ubiquitination.

The NS1 binding protein, known for interacting with the influenza A virus protein, is involved in RNA processing, cancer, and nerve cell growth regulation. However, its role in stress response independent of viral infections remains unclear. This study investigates NS1 binding protein's function in regulating stress granules during oxidative stress through interactions with GABARAP subfamily proteins.

The N-degron pathway mediates the autophagic degradation of cytosolic mitochondrial DNA during sterile innate immune responses.

The human body reacts to tissue damage by generating damage-associated molecular patterns (DAMPs) that activate sterile immune responses. To date, little is known about how DAMPs are removed to avoid excessive immune responses. Here, we show that proteasomal dysfunction induces the release of mitochondrial DNA (mtDNA) as a DAMP that activates the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon gene (STING) pathway and is subsequently degraded through the N-degron pathway.

In-Depth Proteome Profiling of the Hippocampus of LDLR Knockout Mice Reveals Alternation in Synaptic Signaling Pathway.

The low-density lipoprotein receptor (LDLR) is a major apolipoprotein receptor that regulates cholesterol homeostasis. LDLR deficiency is associated with cognitive impairment by the induction of synaptopathy in the hippocampus. Despite the close relationship between LDLR and neurodegenerative disorders, proteomics research for protein profiling in the LDLR knockout (KO) model remains insufficient.

Identifying clinical and proteomic markers for early diagnosis and prognosis prediction of major psychiatric disorders.

Background: To clarify if blood proteins can predict disease progression among individuals at clinical high-risk of severe mental illness (CHR-SMI), we developed a statistical model incorporating clinical and blood protein markers to distinguish the transition group (who developed severe mental illness) (CHR-SMI-T) and from non-transition group (CHR-SMI-NT) at baseline.

Methods: Ninety individuals (74 at CHR-SMI: 16 patients) were monitored for ≤4 years and were the focus of predictive models. Three predictive models (1 [100 clinical variables], 2 [158 peptides], and 3 [100 clinical variables +158 peptides]) were evaluated using area under the receiver operating characteristic (AUROC) values.

Proteomic profiling of cerebrospinal fluid reveals TKT as a potential biomarker for medulloblastoma.

Cerebrospinal fluid (CSF) plays an important role in brain tumors, including medulloblastoma (MBL). Recent advancements in mass spectrometry systems and 'Omics' data analysis methods enable unbiased, high proteome depth research. We conducted proteomic profiling of the total CSF in MBL patients with the purpose of finding a potential diagnostic biomarker for MBL.

Prognosis prediction and immunotherapy optimisation for cryptogenic new-onset refractory status epilepticus.

Background: Cryptogenic new-onset refractory status epilepticus (cNORSE) currently lacks comprehensive knowledge regarding its clinical dynamics, prognostic factors and treatment guidance. Here we present the longitudinal clinical profiles, predictive factors for outcomes and the optimal duration of immunotherapy in patients with cNORSE.

Methods: This retrospective secondary endpoint analysis investigated patients with cNORSE identified from a prospective autoimmune encephalitis cohort at a national referral centre in Korea.

Quantitative proteomics and immunohistochemistry uncover NT5DC2 as a diagnostic biomarker for papillary urothelial carcinoma.

The accurate diagnosis of papillary urothelial carcinoma (PUC) is frequently challenging due to benign mimickers. Other than morphology-based diagnostic criteria, reliable biomarkers for differentiating benign and malignant papillary urothelial neoplasms remain elusive, so we sought to discover new markers to address this challenge. We first performed tandem mass spectrometry-based quantitative proteomics using diverse papillary urothelial lesions, including PUC, urothelial papilloma (UP), inverted urothelial papilloma, and cystitis cystica.

Comprehensive immune cell spectral library for large-scale human primary T, B, and NK cell proteomics.

Although proteomics is extensively used in immune research, there is currently no publicly accessible spectral assay library for the comprehensive proteome of immune cells. This study generated spectral assay libraries for five human immune cell lines and four primary immune cells: CD4 T, CD8 T, natural killer (NK) cells, and B cells. This was achieved by utilizing data-dependent acquisition (DDA) and employing fractionated samples from over 100 µg of proteins, which was applied to acquire the highest-quality MS/MS spectral data.

Genome-wide CRISPR screening identifies tyrosylprotein sulfotransferase-2 as a target for augmenting anti-PD1 efficacy.

Background: Immune checkpoint therapy (ICT) provides durable responses in select cancer patients, yet resistance remains a significant challenge, prompting the exploration of underlying molecular mechanisms. Tyrosylprotein sulfotransferase-2 (TPST2), known for its role in protein tyrosine O-sulfation, has been suggested to modulate the extracellular protein-protein interactions, but its specific role in cancer immunity remains largely unexplored.

Methods: To explore tumor cell-intrinsic factors influencing anti-PD1 responsiveness, we conducted a pooled loss-of-function genetic screen in humanized mice engrafted with human immune cells.

De novo missense variants in HDAC3 leading to epigenetic machinery dysfunction are associated with a variable neurodevelopmental disorder.

Histone deacetylase 3 (HDAC3) is a crucial epigenetic modulator essential for various developmental and physiological functions. Although its dysfunction is increasingly recognized in abnormal phenotypes, to our knowledge, there have been no established reports of human diseases directly linked to HDAC3 dysfunction. Using trio exome sequencing and extensive phenotypic analysis, we correlated heterozygous de novo variants in HDAC3 with a neurodevelopmental disorder having variable clinical presentations, frequently associated with intellectual disability, developmental delay, epilepsy, and musculoskeletal abnormalities.