Microexon in action: How tiny fragments in a protein tune function, drive disease.

Intrinsically disordered regions (IDRs) of proteins can regulate function through phase separation. In a recent article in Nature, Garcia-Cabau et al. reveal that including or excluding a microexon within the IDR of CPEB4 alters its condensation properties, suggesting a potential mechanism underlying autism spectrum disorder.

Uncovering the Role of in Prostate Cancer: Insights from Genetic and Expression Analyses.

Biochemical recurrence (BCR) is a critical concern in prostate cancer management; however, its underlying genetic determinants remain poorly understood. The () gene family is involved in cellular detoxification and biosynthetic processes and has been implicated in various cancers. This study investigated the association between the family members and prostate cancer recurrence.

Transcriptomic predictors of rapid progression from mild cognitive impairment to Alzheimer's disease.

Background: Effective treatment for Alzheimer's disease (AD) remains an unmet need. Thus, identifying patients with mild cognitive impairment (MCI) who are at high-risk of progressing to AD is crucial for early intervention.

Methods: Blood-based transcriptomics analyses were performed using a longitudinal study cohort to compare progressive MCI (P-MCI, n = 28), stable MCI (S-MCI, n = 39), and AD patients (n = 49).

Protogenin facilitates trunk-to-tail HOX code transition via modulating GDF11/SMAD2 signaling in mammalian embryos.

During embryogenesis, vertebral axial patterning is intricately regulated by multiple signaling networks. This study elucidates the role of protogenin (Prtg), an immunoglobulin superfamily member, in vertebral patterning control. Prtg knockout (Prtg) mice manifest anterior homeotic transformations in their vertebral columns and significant alterations in homeobox (Hox) gene expression.

A dominant negative Kcnd3 F227del mutation in mice causes spinocerebellar ataxia type 22 (SCA22) by impairing ER and Golgi functioning.

Spinocerebellar ataxia type 22 (SCA22) caused by KCND3 mutations is an autosomal dominant disorder. We established a mouse model carrying the Kcnd3 F227del mutation to study the molecular pathogenesis. Four findings were pinpointed.

Proteo-metabolomic insights for early dual physical and cognitive impairments: A search for biomarkers of healthy aging based on muscle-brain crosstalk.

We employed an untargeted proteo-metabolomic approach to profile circulating biomarkers in plasma samples from the I-Lan Longitudinal Aging Study, aiming to identify biomarkers and pathways associated with physio-cognitive decline syndrome (PCDS). In 115 propensity score-matched PCDS case-control pairs, pathway analyses implicated dysregulation of fatty acid metabolism and inflammation in PCDS pathogenesis. Sex-specific associations were observed, with disruptions in central carbon metabolism (elevated PKM, MDH1, and GAPDH; decreased MINPP1) and tyrosine metabolism (decreased MIF, DBH; increased thyroxine) characterizing in men.

T cell death-associated gene 8-mediated distinct signaling pathways modulate the early and late phases of neuropathic pain.

Peripheral nerve injury alters the transduction of nociceptive signaling. The coordination of neurons, glia, and immune cells results in persistent pain and inflammation. T cell death-associated gene 8 (TDAG8), located at nociceptors and immune cells, is involved in inflammatory pain and arthritis-induced pain.

Next-Generation Integrated Sequencing Identifies Poor Prognostic Factors in Patients with MYD88-Mutated Chronic Lymphocytic Leukemia in Taiwan.

Introduction: Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in the Western countries and is very rare in Asia.

Methods: Peripheral blood or bone marrow mononuclear cells obtained at initial diagnosis from 215 patients with CLL were analyzed by using next-generation sequencing to investigate the ethnic differences in genetic abnormalities.

Results: Whole-genome sequencing and whole-exome sequencing analyses on 30 cases showed that 9 genes, including IGLL5, MYD88, TCHH, DSCAM, AXDND1, BICRA, KMT2D, MYT1L, and RBM43, were more frequently mutated in our Taiwanese cohort compared with those of the Western cohorts.

A Few Charged Residues in Galectin-3's Folded and Disordered Regions Regulate Phase Separation.

Proteins with intrinsically disordered regions (IDRs) often undergo phase separation to control their functions spatiotemporally. Changing the pH alters the protonation levels of charged sidechains, which in turn affects the attractive or repulsive force for phase separation. In a cell, the rupture of membrane-bound compartments, such as lysosomes, creates an abrupt change in pH.

The SAR analysis of dietary polyphenols and their antagonistic effects on bortezomib at physiological concentrations.

Bortezomib (BTZ), a primary treatment for MM, but its effectiveness can be reduced by interactions with vicinal diol moieties (VDMs) in polyphenols. Despite this, it's debated whether BTZ therapy necessitates avoiding polyphenol-rich products, given the low bioavailability of polyphenols. Additionally, it remains unclear whether the structure of polyphenols contributes to their BTZ antagonism.

Structural and Mutational Analyses of Trehalose Synthase from Reveal the Interconversion of Maltose-Trehalose Mechanism.

Trehalose synthase (TreS) catalyzes the reversible interconversion of maltose to trehalose, playing a vital role in trehalose production. Understanding the catalytic mechanism of TreS is crucial for optimizing the enzyme activity and enhancing its suitability for industrial applications. Here, we report the crystal structures of both the wild type and the E324D mutant of trehalose synthase in complex with the trehalose analogue, validoxylamine A.

Andrographolide suppresses the malignancy of pancreatic cancer via alleviating DNMT3B-dependent repression of tumor suppressor gene ZNF382.

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer type that urgently requires effective therapeutic strategies. Andrographolide, a labdane diterpenoid compound abundant in Andrographis paniculata, has anticancer effects against various cancer types, but its anticancer activity and mechanism against PDAC remain largely uncharacterized.

Purpose: This study explores novel drug target(s) and underlying molecular mechanism of andrographolide against PDAC.

A distinct dimer configuration of a diatom Get3 forming a tetrameric complex with its tail-anchored membrane cargo.

Background: Most tail-anchored (TA) membrane proteins are delivered to the endoplasmic reticulum through a conserved posttranslational pathway. Although core mechanisms underlying the targeting and insertion of TA proteins are well established in eukaryotes, their role in mediating TA protein biogenesis in plants remains unclear. We reported the crystal structures of algal arsenite transporter 1 (ArsA1), which possesses an approximately 80-kDa monomeric architecture and carries chloroplast-localized TA proteins.

The role of Atg5 gene in tumorigenesis under autophagy deficiency conditions.

Autophagy is a self-recycling machinery to maintain cellular homeostasis by degrading harmful materials in the cell. Autophagy-related gene 5 (Atg5) is required for autophagosome maturation. However, the role of Atg5 in tumorigenesis under autophagy deficient conditions remains unclear.

Revealing potential Rab proteins participate in regulation of secretory autophagy machinery.

Autophagy can be classified as degradative and secretory based on distinct functions. The small GTPase proteins Rab8a and Rab37 are responsible for secretory autophagy-mediated exocytosis of IL-1β, insulin, and TIMP1 (tissue inhibitor of 54 metalloproteinase 1). Other Rab family members participating in secretory autophagy are poorly understood.

Shp2 contributes to the regulation of nuclear shape and cellular viscoelasticity in response to substrate spatial cues.

Cell polarization can be guided by substrate topology through space constraints and adhesion induction, which are part of cellular mechanosensing pathways. Here, we demonstrated that protein tyrosine phosphatase Shp2 plays a crucial role in mediating the response of cells to substrate spatial cues. When compared to cells spreading on surfaces coated uniformly with fibronectin (FN), cells attached to 10 μm-width FN-strip micropattern (MP), which provides spatial cues for uniaxial spreading, exhibited elongated focal adhesions (FAs) and aligned stress fibers in the direction of the MP.

Protein degradation of Lsd1 is mediated by Bre1 yet opposed by during fly follicle development.

Tissue development, homeostasis, and repair all require efficient progenitor expansion. Lysine-specific demethylase 1 (Lsd1) maintains plastic epigenetic states to promote progenitor proliferation while overexpressed Lsd1 protein causes oncogenic gene expression in cancer cells. However, the precise regulation of Lsd1 protein expression at the molecular level to drive progenitor differentiation remains unclear.

Exome sequencing and genome-wide association analyses unveils the genetic predisposition in hydroxychloroquine retinopathy.

Objectives: To unveil the candidate susceptibility genes in chloroquine/hydroxychloroquine (CQ/HCQ) retinopathy using whole exome sequencing (WES) and genome-wide association study (GWAS).

Methods: Patients with a diagnosis of CQ/HCQ retinopathy based on the comprehensive demographic and ocular examination were included. The peripheral blood was extracted for WES and GWAS analyses.

HBV DNA Integration into Telomerase or MLL4 Genes and TERT Promoter Point Mutation as Three Independent Signatures in Subgrouping HBV-Related HCC with Distinct Features.

Introduction: A set of genetic mutations to classify hepatocellular carcinoma (HCC) useful to clinical studies is an unmet need. Hepatitis B virus-related HCC (HBV-HCC) harbors a unique genetic mutation, namely, the HBV integration, among other somatic endogenous gene mutations. We explored a combination of HBV DNA integrations and common somatic mutations to classify HBV-HCC by using a capture-sequencing platform.

Degradative autophagy regulates the homeostasis of miRnas to control cancer development.

Macroautophagy/autophagy acts as an anti-tumor mechanism in early cancer stages but promotes growth in established tumors. Similarly, miRNAs function as tumor suppressors or oncogenes, depending on their target genes. This reciprocal relationship between autophagy and miRNAs is a well-studied area, primarily focused on how miRNAs regulate autophagy-related genes.

Hesperetin activates CISD2 to attenuate senescence in human keratinocytes from an older person and rejuvenates naturally aged skin in mice.

Background: CDGSH iron-sulfur domain-containing protein 2 (CISD2), a pro-longevity gene, mediates healthspan in mammals. CISD2 is down-regulated during aging. Furthermore, a persistently high level of CISD2 promotes longevity and ameliorates an age-related skin phenotype in transgenic mice.