Mammalian motile cilia: Structure, formation, organization, and function.

Cilia are membrane-covered hair-like organelles built on specialized centrioles and conserved throughout eukaryotic evolution. They are either motile or immotile, serving respectively as versatile signaling antennae or elegant beating nanomachines. Accordingly, their dysfunctions cause a wide variety of developmental and degenerative disorders, which in human are syndromes termed ciliopathies.

Coalescing single-cell genomes and transcriptomes to decode breast cancer progression.

Understanding epithelial lineages of breast cancer and genotype-phenotype relationships requires direct measurements of the genome and transcriptome of the same single cells at scale. To achieve this, we developed wellDR-seq, a high-genomic-resolution, high-throughput method to simultaneously profile the genome and transcriptome of thousands of single cells. We profiled 33,646 single cells from 12 estrogen-receptor-positive breast cancers and identified ancestral subclones in multiple patients that showed a luminal hormone-responsive lineage, indicating a potential cell of origin.

Sympathetic Activation Promotes Kidney Fibrosis in Mice via Macrophage-Derived N2ICD-Enriched Extracellular Vesicles.

Persistent overactivation of the renal sympathetic nervous system drives kidney inflammation and fibrosis. Macrophages contribute to fibrogenesis by secreting various pro-fibrogenic mediators. However, whether the sympathetic nervous system regulates renal fibrosis by modulating macrophage-fibroblast interaction remains unclear.

Autonomously self-healing and elastic hydrogel sensor with long-chain colloidal scaffold.

Physical hydrogels, hydrophilic polymer networks with reversible crosslinks, have drawn attention in cutting-edge applications due to high tunability and biocompatibility. The self-healing capability and elasticity are crucial to ensure the robustness and lifespan of the hydrogel, but achieving these exclusive properties remains challenging. Herein, fully self-healable and elastic hydrogel is achieved through long-chain polyacrylic acid (PAA) scaffold and follow-up polymerization of polyacrylamide (PAM).

Connexin hemichannel blockade by abEC1.1 disrupts glioblastoma progression, suppresses invasiveness, and reduces hyperexcitability in preclinical models.

Background: Connexin (Cx) hemichannels (HCs) contribute to glioblastoma (GBM) progression by facilitating intercellular communication and releasing pro-tumorigenic molecules, including ATP and glutamate.

Methods: The efficacy of abEC1.1, a monoclonal antibody that inhibits Cx26, Cx30, and Cx32 HCs, was assessed in vitro by measuring invasion capability, dye and Ca uptake, glutamate and ATP release in patient-derived GBM cultures or organoids.

circARHGAP10 as a candidate biomarker and therapeutic target in myotonic dystrophy type 1.

Myotonic dystrophy type 1 (DM1) is a multisystemic disorder caused by expanded CTG repeats in the 3'-UTR of the gene that lead to nuclear foci accumulation and splicing defects. Circular RNAs (circRNAs) are emerging regulators of muscular disorders, but their role in DM1 remains largely unknown. By analyzing available RNA-sequencing datasets from DM1 patients, followed by validation in patients and matching control muscle biopsies, we identified seven circRNAs that were significantly increased in DM1 muscles and displayed high circular-to-linear isoform ratios.

Broad-spectrum antitumor analysis of the telomerase activity inhibitor TPCH derived from the human constitutively expressed protein LPTS/PinX1.

Background: The human liver-related putative tumor suppressor LPTS/PinX1 is a gene encoding a telomerase inhibitory protein. Overexpression of LPTS/PinX1 protein can inhibit the growth of multiple telomerase-positive cancer cell lines. LPTS/PinX1 has therapeutic potential for cancer.

Homocysitaconate controls inflammation through reshaping methionine metabolism and N-homocysteinylation.

Inflammation and its metabolic-network interactions generate novel regulatory molecules with translational implications. Here, we identify the immunometabolic crosstalk that generates homocysitaconate, a metabolite formed by homocysteine and itaconate adduction catalyzed by S-adenosyl-L-homocysteine hydrolase (AHCY). Homocysitaconate increases 152-fold during inflammation and exhibits anti-inflammatory effects.

Toward the DNA methylation haplotype map of 11 common solid cancers.

In heterogeneous tumors, adjacent CpG sites form methylation haplotype blocks (MHBs), genomic regions where methylation status reflects local epigenetic concordance. While MHBs have been implicated in gene dysregulation, their pan-cancer dynamics and clinical relevance remain unclear. We profiled 110 primary tumors across 11 common solid cancer types, identifying 81,567 MHBs.

α-Ketoglutarate dictates AMPK protein synthesis for energy sensing in human cancers.

The energy sensor AMP-activated protein kinase (AMPK) promotes tumor cell survival under stress but how to prevent AMPK activation to blunt tumor progression remains unclear. Here we show that the metabolite α-ketoglutarate (α-KG) dictates AMPK translation through a TET-YBX1 axis, which can be exploited to sensitize human cancer cells to energy stress. α-KG-deficient cells fail to activate AMPK under glucose starvation, which elicits cytosolic NADPH depletion and disulfidptosis.

Astrocyte Secretome Profiling via Biorthogonal Labeling Unveils Novel Factors Relevant to Neurodegenerative Diseases.

Secreted proteins are key mediators of intercellular communication in multicellular organisms. However, progress in secretomics has been hindered by the lack of effective methods for capturing secreted proteins. Here, we present a two-step secretome enrichment method (tsSEM) that integrates unnatural amino acid labeling with click chemistry-based biorthogonal reaction, enabling robust in vitro secretome profiling in the presence of serum.

Spatio-Temporal Proliferative Heterogeneity of Intra-Organ Endothelial Cells.

Background: Blood vessels play a crucial role in supplying tissues with oxygen and nutrients. The maintenance of normal blood vessel number and integrity requires a continuous supply of new endothelial cells (ECs) through self-replication. While it is established that ECs across different tissues exhibit heterogeneity in molecular signatures and regenerative capacities, the extent of proliferation heterogeneity among ECs within the same organ or tissue remains largely unexplored.

A pancreatic cancer organoid biobank links multi-omics signatures to therapeutic response and clinical evaluation of statin combination therapy.

Chemotherapy remains the primary treatment for pancreatic ductal adenocarcinoma (PDAC), but most patients ultimately develop resistance. Here, we established 260 pancreatic cancer organoid lines, followed by extensive multi-omics profiling and therapeutic sensitivity assessments. Integrated analyses uncovered 6 novel coding and 35 noncoding driver candidates.

SIRT6 Lysine-Demyristoylates ATF2 to Ameliorate Vascular Injury via PRKCD/VE-Cadherin Pathway Regulating Vascular Endothelial Barrier.

Cardiovascular diseases (CVDs) progression is significantly modulated by epigenetic mechanisms, particularly through Sirtuin 6 (SIRT6), a key NAD⁺-dependent deacetylase in the sirtuin family. Though essential for cardiovascular homeostasis, the effects of SIRT6-mediated lysine myristoylation on CVDs progression remain largely unexplored due to detection limitations. This study developes an innovative lysine-myristoylated peptide enrichment technique, identifying mutant SIRT6 (H133Y) with high myristoyl affinity but deficient demyristoylase activity.

Glial Cells and Aging: From the CNS to the Cerebellum.

Among brain regions, the cerebellum (CBL) has traditionally been associated with motor control. However, increasing evidence from connectomics and functional imaging has expanded this view, revealing its involvement in a wide range of cognitive and integrative processes. Despite this emerging relevance, the CBL has received comparatively less attention in aging research, which has focused mainly on other central nervous system (CNS) regions such as the neocortex and hippocampus.

Establishment of chromatin architecture interplays with embryo hypertranscription.

After fertilization, early embryos undergo dissolution of conventional chromatin organization, including topologically associating domains (TADs). Zygotic genome activation then commences amid unusually slow de novo establishment of three-dimensional chromatin architecture. How chromatin organization is established and how it interplays with transcription in early mammalian embryos remain elusive.

A common structural mechanism for RNA recognition by the SF3B complex in mRNA splicing and export.

The SF3B complex plays a critical role in branch point adenosine recognition during pre-mRNA splicing. Its largest subunit SF3B1 is frequently mutated in cancers, leading to aberrant alternative splicing. Besides its function in pre-mRNA splicing, the SF3B complex also binds mature or intronless mRNAs to facilitate their nuclear export.

YY1 regulates vascular resistance and blood pressure dynamics through epigenetic control of m6A RNA modifications in VSMCs.

Aims: Recent GWAS analysis has identified YY1 as a novel locus associated with blood pressure traits; however, whether YY1 directly controls vasoreactivity remains unknown. The principal function of vascular smooth muscle cells (VSMCs) is to contract, which is essential for regulating vascular tone, blood flow, and blood pressure. We hypothesized that YY1, a transcription factor, facilitates vascular function by epigenetically regulating gene expression in VSMCs.

PEELing: an integrated and user-centric platform for spatially resolved proteomics data analysis.

Summary: Molecular compartmentalization is vital for cellular physiology. Spatially resolved proteomics allows biologists to survey protein composition and dynamics with subcellular resolution. Here, we present PEELing, an integrated package and user-friendly web service for analyzing spatially resolved proteomics data.

A pancreas-hippocampus feedback mechanism regulates circadian changes in depression-related behaviors.

Individuals with neuropsychiatric disorders often show metabolic symptoms. However, the mechanisms underlying this co-occurrence remain unclear. Here we show that induced pluripotent stem cell-derived pancreatic islets from individuals with bipolar disorder have insulin secretion deficits caused by increased expression of RORβ, a susceptibility gene for bipolar disorder.

Identification of RAPGEF3 as the therapeutic vulnerability of basal-subtype lung squamous cell carcinoma.

Lung squamous cell carcinoma (LUSC), particularly the basal-subtype, remains a leading cause of cancer-related mortality, with limited therapeutic options and poor survival rates. In this study, we identify RAPGEF3 as a critical driver of malignant progression in basal-subtype LUSC. Our findings show that RAPGEF3 is significantly upregulated in basal-subtype LUSC and plays a pivotal role in tumor progression by activating the RAP1A-AKT signaling axis, essential for cell proliferation and survival.

Bioactive LDH nanoplatforms for cancer therapy: Advances in modulating programmed cell death.

In recent years, the rapid advancement of nanotechnology and tumor biology has significantly expanded the application of nanomaterials in cancer therapy, particularly through the induction of programmed cell death (PCD) in cancer cells. Layered double hydroxides (LDH), a class of two-dimensional inorganic nanomaterials, have attracted considerable attention due to its tunable structures, excellent biocompatibility, and superior drug delivery capabilities. Emerging research has highlighted the great potential of LDH in modulating various forms of PCD.

Effects of chromosome number reduction on mitotic and meiotic stability in fission yeast.

Background: Genetic information is stored on multiple chromosomes in eukaryotic organisms and is passed on to offspring through cell division. How chromosome number influences cell division and chromosome segregation is not yet understood.

Results: In this study, we use artificial chromosome-fusion fission yeast cells, which contain one or two chromosomes, as models to investigate the effects of a reduced chromosome number on mitosis and meiosis.