A single-cell hematopoietic microenvironmental atlas reveals progressive maturation of bone marrow vascular niche.

Fruit quality traits such as fruit weight, firmness, total soluble solids content, and color strongly influence consumer acceptance, market value, postharvest shelf life, and processing efficiency in tomato. Therefore, these traits are central to breeding programs but remain challenging to dissect due to their polygenic and pleiotropic nature. We evaluated 167 accessions from the Varitome collection, encompassing Solanum pimpinellifolium, Solanum lycopersicum var. cerasiforme, and Solanum lycopersicum var. lycopersicum. The Varitome collection represents a rich source of genetic and phenotypic diversity, making it a powerful resource for mapping complex traits. Genome-wide association studies (GWAS) were conducted using the FarmCPU and Blink models, utilizing a dataset of 3,879,252 SNPs, 831,152 INDELs, and 11,447 structural variants (SVs). Six fruit-quality traits were phenotyped: fruit weight, firmness, total soluble solids, lightness (L*), chroma (C*), and hue (h°). Our multi-variant GWAS uncovered both known and novel determinants of fruit quality. Known loci such as PSY1 and fw11.3/CSR were validated, while robust new signals were detected on chromosomes 1, 4, 6, 8, and 12 for °Brix and on chromosome 7 for fruit weight. Several pleiotropic hotspots were identified, particularly on chromosomes 1, 5, 6, and 8 for fruit color, supported by convergent SNP, INDEL, and SV associations. Candidate genes included biosynthetic enzymes (PSY homologs, LIN5), sugar transporters (SWEETs, SUTs, and sugar facilitator proteins), transcriptional regulators (MADS-box, bHLH, TCP, NAC, and MYB families), and genes linked to plastid remodeling, light signaling, and oxidative turnover. Integration of INDELs and SVs across models improved mapping resolution and robustness, enabling the detection of loci that would remain hidden in SNP-only scans. This study demonstrates the multilayered genetic networks governing tomato fruit quality and expands the catalog of loci contributing to polygenic traits. By using SNPs, INDELs, and SVs with FarmCPU and Blink models, we provide validated and novel targets for marker-assisted breeding, genomic selection, and functional validation. These findings establish a framework for accelerating the development of tomato cultivars with enhanced fruit weight, sweetness, firmness, and color, thereby supporting both market competitiveness and nutritional quality.

Genomic variants of uncertain significance (VUS) impede clinical decision-making. In this study, we employ a knock-in strategy in zebrafish to evaluate the COL1A2 c.2123G>A VUS, identified in a 78-year-old female with atypical femoral fractures. Using prime editing, we generated different col1a2 zebrafish lines respectively harboring the VUS, a known pathogenic variant, and a known benign variant. Comprehensive skeletal phenotyping revealed no significant abnormalities in zebrafish harboring the VUS. In contrast, zebrafish with the pathogenic variant showed an increased eye diameter, scoliosis, vertebral fusions, vertebral compressions, fractures, and increased mineralization of the notochord and intervertebral ligament compared to wild type controls. Our findings represent the first demonstration that COL1A2 variant modeling via prime editing in zebrafish not only aids in functional validation, but also holds promise for uncovering the underlying pathogenic mechanisms. This approach can be applied to investigate VUS in other genes as well.

Objective: To characterize the clinical and genetic features of 2 patients with interleukin-1 receptor associated kinase (IRAK) 4 deficiency and to assess the pathogenicity of their genetic variants. Methods: This case series included two patients diagnosed with IRAK4 gene deficiency at Shenzhen Children's Hospital and The University of Hong Kong-Shenzhen Hospital between 2019 and 2024. Six healthy children without recent infections or immunodeficiency served as controls. Peripheral blood mononuclear cells were stimulated in vitro with Toll-like receptor 4 (TLR4) agonists, and cytokine levels were quantified using a protein chip assay. Results: The 2 patients, a 5-year-old boy and a 10-year-old girl, presented with recurrent invasive or non-invasive bacterial infections and impaired acute-phase inflammatory responses. Genetic testing identified a homozygous frameshift variant (c.540delT, p.F180Lfs*26) in Patient 1 and compound heterozygous frameshift variants (c.166delT, c.629delG and p.F56fs, p.R210fs) in Patient 2, all predicted to result in truncated IRAK4 proteins. Both patients received regular infection prophylaxis with favorable clinical outcomes. Controls consists of 3 males and 3 females, aged 5-17 years. Following TLR4 stimulation, cytokine levels in Patient 1, Patient 2, and controls (tumor necrosis factor-α 68.6, 103.0, 618.7 (392.7, 824.1); interleukin (IL) 1β 39.8, 10.8, 1 975.5 (1 556.0, 2 096.5); interferon γ 8.6, 6.2, 13.5 (12.7, 14.9); granulocyte colony-stimulating factor 17.6, 15.9, 2 890.0 (1 622.0, 4 692.8); IL-6 140.1, 352.7, 7 222.5 (5 768.5, 8 043.5); and IL-17 47.5, 44.5, 59.7 (43.4, 69.5), respectively. Conclusion: IRAK4 deficiency should be suspected in patients with early-onset recurrent bacterial infections and attenuated inflammatory response. Homozygous and compound heterozygous frameshift variants in IRAK4 gene lead to truncated IRAK4 proteins and impared innate immune signaling.

Both metabolic dysregulation and the immunosuppressive tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC) contribute to the recalcitrance of this lethal disease to treatment. Accordingly, we aimed to identify and characterize a target that elicits an anti-cancer response through both disrupting cancer cell redox homeostasis and increasing the immunogenicity of PDAC. First, mitochondrial metabolic dependencies in PDAC were identified by using a CRISPR-Cas9 screening system with a custom sgRNA library. Functional validation analyses revealed GFER, a mitochondrial FAD-dependent sulfhydryl oxidase, as an essential regulator of tumor growth. In vitro and in vivo methodologies demonstrated that GFER depletion perturbed redox homeostasis and stimulated tumor immunogenicity, including sensitization to immune checkpoint blockade. In patient-derived xenograft models of PDAC, the growth-inhibitory response induced by GFER depletion was mediated by an altered oxidative balance that released damaged mitochondrial DNA into the cytoplasm of tumor cells, leading to the activation of the cGAS-STING pathway and expression of type I interferons. This effect was recapitulated in a mouse immunocompetent syngeneic PDAC model, where GFER depletion suppressed tumor growth and promoted T cell infiltration to enhance tumor-killing effects. Consequently, GFER depletion significantly increased the anti-tumor efficacy of immune checkpoint blockade. Overall, these findings identify GFER as a critical node for both mitochondrial redox homeostasis and immunomodulation in PDAC and reveal a therapeutic opportunity for sensitizing PDAC to immune checkpoint blockade.

SGIV and RGNNV regulate fish innate immune responses by mediating ubiquitinated modifications of proteasome and ribosomal proteins.

SKAP2 as a novel prognostic biomarker in HNSCC: Genetic and functional validation

Genome-wide analysis of C2H2 transcription factors reveals that PbeCH1 and PbeCH4 are associated with Valsa canker resistance in Pyrus betulifolia.

Analysis of the mechanosensitive channel of small conductance-like (MSL) gene family in cotton and the role of GhMSL2-3 in response to salt tolerance in upland cotton.

Identification of MFS gene family in tomato and functional characterization of SlZIF1/SlMFS4 under salt stress.

Mitochondria are central to immune regulation, inflammation, and cellular metabolism. Growing evidence suggests that mitochondrial dysfunction contributes to autoimmune disease (AD) pathogenesis by modulating inflammatory pathways and immune cell function. However, the causal relationships between mitochondria-related proteins and ADs remain unclear. We conducted a bidirectional two-sample Mendelian randomization (MR) analysis to examine causal associations between 67 mitochondria-related proteins and 10 ADs, using GWAS data from the IEU OpenGWAS and FinnGen databases. Colocalization analysis assessed whether genetic signals for mitochondrial proteins and ADs overlapped. Protein-protein interaction (PPI) networks and functional enrichment analyses were used to explore biological functions. Sensitivity analyses evaluated pleiotropy and heterogeneity to ensure robustness. MR analysis revealed significant causal associations, including SLC9B2 with rheumatoid arthritis (RA), MRM3 with ulcerative colitis (UC) and inflammatory bowel disease (IBD), and PDK1 with UC and IBD. Reverse MR indicated bidirectional effects, with UC influencing SLC9B2 and C1QBP expression. Colocalization analysis confirmed shared genetic variants, linking mitochondrial proteins to inflammatory regulation. This study provides genetic evidence for the causal role of mitochondrial proteins in autoimmune inflammation, identifying potential biomarkers and therapeutic targets. Future research integrating multi-omic and functional validation is needed to advance mitochondria-targeted therapies for ADs. The online version contains supplementary material available at 10.1007/s13755-025-00358-2.

Pathogen-bound C-type lectin and ficolin enhance toll receptor signaling is activated through Spätzle1 cleavage in response to White Spot Syndrome Virus (WSSV) in Penaeusmonodon.

PoSCPL61 as a negative regulator of seed size in tree peony of Paeonia ostii revealing by genome-wide identification of SCPL genes and functional validation

High levels of HBV DNA and HBsAg titres increase the risk of mother-to-child transmission. Development of adaptive immunity post HBV vaccination in neonates born to HBsAg-positive mothers may be determined by maternal HBsAg titres. We analysed pre- and post-HBV vaccination immune status in neonates. PBMCs were collected before and after vaccination for single cell multi-omics sequencing for infants born to mothers with low (Gr.1, sAgLo 1.65 × 102 IU/mL) and high (Gr.2, sAgHi 1.4 × 104IU/mL) HBsAg titres. Integrative analysis of whole transcriptome and surface marker expression was done using the Seurat R package. Functional validation of single-cell data was performed through immunophenotyping in both groups. scRNAseq revealed that, at pre-HBV vaccine, CD8+T cells of neonates born to mothers with HBsAgHi levels showed increased expression (p < 0.05) of TOX, CTLA4, PD1, LAG3, CD38 and CREM exhaustion markers and decreased expression of ATP1B3, MREG and TGFβ1 compared to sAgLo. Monocytes and NK cells had elevated CXCR3, TNFSF9, HIVEP3, WDPCP, ATP6V1G2, IL-6, GMCSF and GCSF (p < 0.0001) driving the inflammation and mitochondrial biogenesis through MAP/ERK kinase in sAgHi compared to sAgLo. Post-vaccination, despite anti-HBs titre ≥ 10 IU/mL, sAgHi, neonates showed persistently high TOX, CTLA4, PD1 and CREM in CD8+T cells (p < 0.0001). Functional validations by immune phenotyping also showed higher expression of LAG3, PD1, TIGIT and BTLA (p < 0.05) on CD8+T cells pre- and post-vaccination in sAgHi compared to sAgLo. HBV exposure compromises adaptive immunity at birth; despite post-vaccination anti-HBs titres generation, there was a sustained pro-inflammatory state by the innate immune activation via metabolic alterations that persisted in neonates born to sAgHi mothers.

CYP71P2 regulated by MYB44 modulates oxygenated sesquiterpenoids biosynthesis in Atractylodes lancea.

Synaptotagmin-1 regulates egg production by con trolling luteinizing hormone secretion in chickens.

The influence of genetic variation on late effects in childhood cancer survivors: An updated systematic review.

A novel visual-magnetic relaxation switch sensor based on an organic framework nanozyme for ultrasensitive norovirus detection.

Genome editing of detoxification gene repertoires in insects using clustered regularly interspaced short palindromic repeats (CRISPR): A systematic review and meta-analysis.

Comparative transcriptome profiling reveals key lncRNAs and regulatory mechanisms for salt tolerance in hulless barley.