The Min system disassembles FtsZ-rings after septation in Bacillus subtilis and is localized to the nascent division plane and cell poles by the protein MinJ. The N-terminal region of MinJ contains transmembrane segments while the C-terminal region contains a PDZ domain, but its membrane topology and functional domains are poorly understood. Here, we empirically tested competing topology models and found that MinJ is a nine-pass transmembrane protein with an extracellular N terminus and a cytoplasmic C terminal PDZ domain. Deletion of the PDZ domain resembled a MinJ null mutation but retained polar localization and interaction with both MinD and DivIVA. Deletion of transmembrane segments 6 and 7 abolished polar localization and interaction with MinD and DivIVA but conferred a hyper-minicell phenotype that was additive in the absence of MinD. Structural prediction by AlphaFold3 suggests that segments 6 and 7 may constitute an unusual transmembrane β-sheet, making MinJ perhaps the first of its kind to have such a secondary structure in the plasma membrane. Finally, phylogenetic analyses and structural comparison showed that MinJ sequence and structure are highly conserved within the Firmicutes and tightly co-conserved with MinD and DivIVA with which it interacts. Our work clarifies the membrane topology and functional organization of MinJ and supports models in which MinJ contributes to bacterial cell division through mechanisms beyond canonical Min system regulation.

Muscle satellite cells play a major role in skeletal muscle regeneration following skeletal muscle injury. However, our understanding of the molecular mechanisms that coordinate the proliferation and myogenic differentiation of muscle satellite cells remains incomplete. SLIT and NTRK-like family member 1 (SLITRK1) is a transmembrane protein. We previously reported that Slitrk1 is involved in osteoblast differentiation. In contrast, the function of Slitrk1 in muscle, a closely related mesenchymal lineage, remains largely unknown. In this study, we demonstrated that muscle regeneration in Slitrk1-null mice is impaired following injury whereas Slitrk1-null mice exhibit no significant differences compared to wild-type mice in intact muscles. Furthermore, we revealed that deletion of Slitrk1 led to reduced cell proliferation and premature myogenic differentiation of muscle satellite cells ex vivo. Additionally, Slitrk1 deletion resulted in increased expression of RhoA, a small GTPase protein known to inhibit muscle fiber fusion. These findings suggest that Slitrk1 may play an important role in the proliferation and myogenic differentiation of muscle satellite cells.

Tumorigenesis is a multi-step process shaped by the accumulation of somatic driver mutations, but identifying the earliest steps and cell of origin of tumorigenesis remains challenging. Single cell genomics in >1.7 million single cells across donors with the cancer predisposition syndrome neurofibromatosis type 1 (NF-1), shows that somatic 'second-hit' mutations in NF1 are pervasive and show positive clonal selection in oligodendrocytes (OLs) and OL precursor cells (OPCs), but are exceedingly rare in neurons and other lineages. Combined spatial genotyping and transcriptomic analysis enabled dissection of cell autonomous and non-autonomous effects of second-hit mutations including clonal expansion of mutant OPCs with strong bias for cerebral gray matter versus white matter, suggesting that gray matter influences OPC proliferation and differentiation via non-cell autonomous interactions between OPCs and neurons. NF1 -null OL lineage cells upregulate CDKN2A -a tumor suppressor frequently lost in NF1 -mutant tumors- whereas brain cancers from these same individuals show CDKN2A loss across multiple cancer cell states, suggesting CDKN2A loss in OPCs is a critical step in tumor progression. Our findings reveal developmentally early, exquisitely lineage-specific NF1 somatic mutations in premalignant NF-1 brain, suggest cell autonomous and non-autonomous roles in clonal selection in brain, and suggest that clones harboring cancer driver mutations can persist over a lifetime in phenotypically normal tissues.

While the frequency of constipation increases sharply with age, the genetic links between constipation and aging-related phenotypes remain largely unexplored. So far, research has typically focused only on individual characteristics while neglecting broader genetic connections. In this study, we evaluated the shared genetic architecture of constipation and aging-related phenotypes in order to better understand the causes of aging-related intestinal dysfunction. Using publicly available genome-wide association study summary statistics, we developed a multi-stage analysis pipeline to identify common signals at the variation and genetic levels. We studied 4 aging-related phenotypes: frailty index (FI), telomere length, facial aging and GrimAge acceleration. Our approach combines linkage disequilibrium score regression and high-definition likelihood with Pleiotropy Analysis under Composite Null Hypothesis, functional mapping and annotation and Bayesian colocalization to identify pleiotropic loci, followed by tissue-specific mapping via Multi-marker Analysis of GenoMic Annotation and stratified linkage disequilibrium score regression. Constipation showed a moderate positive genetic correlation with FI in both linkage disequilibrium score regression and high-definition likelihood. The inverse correlation with TL was weak and method-dependent. No significant genome-wide genetic correlation was detected with facial aging or GrimAge acceleration. Multi-layer locus mapping and gene-based analyses prioritized several candidate genes, including MSL2, STAG1, and SRSF9, through different combinations of association-based evidence. However, no gene showed multiple-testing-corrected summary-data-based Mendelian randomization evidence shared between constipation and any of the 4 aging-related phenotypes. Multi-marker Analysis of GenoMic Annotation suggested cerebellar enrichment for genes associated with the constipation-FI pair, whereas stratified linkage disequilibrium score regression identified broader central nervous system enrichment for FI but no significant cell-type enrichment for constipation. These findings support a shared genetic component between constipation and selected aging-related phenotypes and provide candidate loci, genes and tissues for further functional investigation.

Oral squamous cell carcinoma (OSCC) and oral potentially malignant disorders (OPMDs) affect many individuals, where exposure to xenobiotics such as tobacco, alcohol, and betel quid is highly prevalent. Inter-individual variability plays a key role regarding genetic polymorphisms in xenobiotic‑metabolizing enzymes. In this study, we searched PubMed, Scopus and Web of Science (up to April 2026) for observational studies and meta‑analyses evaluating CYP1A1, CYP1B1, CYP2E1, GSTM1, GSTT1, GSTP1 and GSTM3 polymorphisms in OSCC and OPMDs. Twenty-one studies met the inclusion criteria. Data on exposures, genotypes and risk estimates were extracted and synthesized qualitatively. Most studies showed that GSTM1 and/or GSTT1 null genotypes are associated with increased risk of OSCC, particularly in Asian cohorts with heavy tobacco and/or betel quid exposure. CYP1A1 and CYP2E1 variants exhibited more heterogeneous results, but several studies indicated elevated risk in smokers, drinkers and betel quid users. Stronger effects consistently appeared in gene-environment interaction models. Polymorphisms in Phase I and Phase II metabolizing enzymes, especially GSTM1/GSTT1 null and selected CYP1A1/CYP2E1 variants, modulate susceptibility to OSCC in exposed individuals, supporting their potential use in risk stratification and targeted prevention strategies.

In ruminants, embryonic interferon tau (IFNT) is widely considered the indispensable signal for maternal recognition of pregnancy, driving endometrial gene expression to prevent luteolysis. However, this canonical paradigm has never been directly tested using genomic loss-of-function models. Here we show that IFNT is completely dispensable for pregnancy recognition, luteal maintenance, and full-term gestation in cattle. Using CRISPR-Cas9, we generate bovine fibroblasts lacking all functional copies of the multigene IFNT locus for somatic cell nuclear transfer. IFNT-null embryos develop into blastocysts in vitro at normal rates and exhibit typical elongation at day 18 post-transfer without inducing endometrial interferon-stimulated genes. Crucially, these IFNT-null conceptuses successfully prevent luteal regression, establish normal placentation, and progress through full-term gestations, culminating in the birth of healthy female calves. These findings provide the first direct genetic evidence that embryonic IFNT is dispensable for pregnancy recognition and establishment in cattle, fundamentally revising the long-standing model of ruminant reproduction and uncovering alternative embryo-maternal signaling mechanisms.

The cGMP-gated channel β-subunit is required for phototransduction, disc morphogenesis, and structural integrity of rod cells. Its structural role may be mediated by its GARP2 (glutamic acid rich protein) domain. To assess domain functions, we generated transgenic mice expressing a truncated protein lacking the N-terminal region on a Cngb1 null background. In these mice, light microscopy showed normal disk morphology up to 6 months, and cryo-electron tomography revealed disc-to-plasma membrane connections similar to WT. However, the truncated protein was insufficient to prevent progressive degeneration leading to photoreceptor loss by 12-14 months. Truncated protein expression levels resembled WT β-subunit levels. The truncated protein localized both to the outer segment, like WT, but also elsewhere in rods. Electroretinography showed CNG channel function was comparable to WT at 1-month and remained so up to 7.5 months postnatal when marked declines appeared. Thus, the N-terminal extension of the β-subunit is required for long-term maintenance and survival of rod photoreceptors, whereas the major structural defects observed at early ages in the knockouts cannot be attributed to loss of the CNGB1a GARP2 domain or the GARP1 and GARP2 soluble proteins.

Bi-allelic variants in IDUA classically cause mucopolysaccharidosis type I (MPS I), a multisystem lysosomal storage disorder. This study describes 14 individuals from 12 families presenting with retinitis pigmentosa, later attributed to bi-allelic IDUA genotypes. Notably, seven individuals, despite comprehensive systemic assessments, showed no features consistent with MPS I at last assessment (aged 46-73 years). Leukocyte α-L-iduronidase activity was reduced but not abolished across all individuals assessed (n = 9), supporting a shared mechanistic basis for the mild, retina-predominant, or exclusively retinal phenotype. No individual carried bi-allelic null genotypes; most had a loss-of-function allele paired with a missense variant, consistent with an overall hypomorphic genotype. Variant-level functional assays, using a cell-based expression platform assessing enzyme activity and protein abundance to derive relative specific activity (RSA), showed that several missense alleles confer very low residual activity and/or impaired abundance/processing, with RSA typically in the ∼0.5%-1.5% range. The recurrent missense c.298A>G (p.Arg100Gly) variant showed no protein or catalytic effect; targeted long-read transcript analysis instead demonstrated predominant loss-of-function mis-splicing with a small fraction of correctly spliced transcript (∼1%-2%), explaining residual activity in vivo. Together, these data expand the phenotypic spectrum of IDUA-associated disease to include late-onset retinal-predominant or apparently isolated retinitis pigmentosa and indicate that residual enzyme activity likely contributes to systemic sparing, highlighting the value of integrated genomic, biochemical, and functional analyses to advance understanding in attenuated metabolic disease.

Immune-active hepatocellular carcinoma (HCC) is commonly treated as a single inflamed phenotype, although its internal immune heterogeneity remains incompletely defined. We integrated public bulk transcriptomic, single-cell, spatial transcriptomic, proteomic, phosphoproteomic, and treatment-cohort data to test whether this heterogeneity is better represented by discrete states or a continuous immune axis. In 112 checkpoint-high TCGA-LIHC tumors, an inflamed-minus-myeloid axis showed structured heterogeneity but no robust empirical bimodality: the observed kernel-density curve had one prominent mode and none of 1,000 bootstrap resamples contained two or more prominent modes. IFNγ-responsive-associated and myeloid-suppressive-associated labels were therefore retained only as operational summaries of opposing axis tendencies, and the biological polarity persisted across alternative definitions of immune-active entry. A fixed 10-gene within-sample rank template-contrast score transferred the axis to independent HCC cohorts. Transcriptomic analyses based on gene sets non-overlapping with the compact panel and original state-defining genes supported the IFNγ-oriented end, whereas spatial analyses showed local cross-end coexistence with reduced immediate-neighbor mixing relative to a count-preserving random-label null, and paired proteomic/phosphoproteomic analyses showed concordant myeloid-oriented associations involving macrophage, fibroblast/extracellular-matrix, hypoxia, SPP1-integrin-FAK, and myeloid-receptor programs. Direct application of the frozen transfer score to four public HCC immunotherapy cohorts yielded heterogeneous, imprecise response associations (pooled Hedges' g = 0.10, 95% CI -0.42 to 0.61) and did not establish clinical response prediction. These results support a structured IFNγ-responsive-to-myeloid-suppressive continuum within immune-active HCC. The framework is transferable across public datasets but requires prospective HCC-specific clinical validation, while functional perturbation studies are needed before causal or therapeutic claims.