Explore the vast range of titles available.

Background The genus Takifugu includes highly valued fish species known for their delicate flavor, making them popular in multiple countries. However, many species from this genus face significant threats. In order to better understand the genetic diversity and evolutionary dynamics of Takifugu , a syntelog-based pan-genome and graph genome were constructed using the data of seven Takifugu species. Results The analysis of 28,085 syntelog groups (SGs) composed of protein-coding genes revealed that only 57.3% of the SGs were shared among all individuals, whereas the remaining genes presented presence-absence variation (PAV) across the seven genomes. Using the graph genome as a reference, a population of 160 Takifugu individuals was analyzed, from which 20,133,471 SNPs, 4,606,141 Indels, and 152,200 SVs were identified. The gene flow analysis revealed directional gene flow from Takifugu bimaculatus and Takifugu flavidus to Takifugu oblongus . Notably, a 51-bp insertion in the ABCB9 gene differed significantly in frequency between the two migratory populations, suggesting the potential role of this gene in the migratory behavior of these species. Additionally, the expression profiles from 13 tissues or organs (brain, gallbladder, gill, gonad, heart, kidney, liver, muscle, pituitary, skin, spleen, stomach, and swim bladder) revealed a unique expression pattern in the liver, with the tissue-specific genes exhibiting evolutionary conservation to varying degrees. The highest proportion of core genes was found in the pituitary, whereas the lowest was found in the spleen. Conclusions This study provides comprehensive genomic resources that enhance the understanding of the genetic diversity and evolutionary dynamics of Takifugu species. The findings offer insights for research on both breeding and conservation of Takifugu .

Bacteria preferentially accumulating in tumor microenvironments can be utilized as natural vehicles for tumor targeting. However, neither current chemical nor genetic approaches alone can fully satisfy the requirements on both stability and high efficiency. Here, we propose a strategy of “charging” bacteria with a nano-photocatalyst to strengthen their metabolic activities. Carbon nitride (C 3 N 4 ) is combined with Escherichia coli ( E. coli ) carrying nitric oxide (NO) generation enzymes for photo-controlled bacterial metabolite therapy (PMT). Under light irradiation, photoelectrons produced by C 3 N 4 can be transferred to E. coli to promote the enzymatic reduction of endogenous NO 3 – to cytotoxic NO with a 37-fold increase. In a mouse model, C 3 N 4 loaded bacteria are perfectly accumulated throughout the tumor and the PMT treatment results in around 80% inhibition of tumor growth. Thus, synthetic materials-remodeled microorganism may be used to regulate focal microenvironments and increase therapeutic efficiency. Targeting tumors with bacteria as vehicles for metabolite therapy suffers from low efficiency and robustness. Here, the authors combine carbon nitride with nitric oxide generation enzyme-positive E. coli for photo-controlled metabolite therapy (PMT) and observe increased effects both in vitro and in tumor-bearing mice.

Autosomal dominant tubulointerstitial kidney disease - UMOD is characterized by progressive renal interstitial inflammation and fibrosis. However, its underlying mechanisms remain unclear. Here, we identify a large ADTKD pedigree harboring a novel UMOD p.H36Y mutation. Using CRISPR/Cas9 technology, we generated a Umod H36Y/+ mouse model that recapitulates the key phenotypes observed in affected individuals, including renal dysfunction, cyst formation, and interstitial inflammation. Multi-omics analyses in kidneys from male Umod H36Y/+ mice revealed marked macrophage pyroptosis. Mechanistically, the Umod p.H36Y variant activated the amyloid precursor protein (App)-Cd74 axis which mediated the crosstalk between renal mutant tubular cells and macrophages. This axis sustains NF-κB pathway activation in macrophages, initiating pyroptosis and pro-inflammatory cytokine release. The same mechanism is recapitulated in the UMOD p.Trp31Cys cell model. Notably, Pharmacologic inhibition using ARN2966, a small-molecule App inhibitor, attenuated renal injury in male Umod H36Y/+ mice. Collectively, these findings uncover a targetable pathway in ADTKD- UMOD . This study shows that the UMOD p.H36Y mutation promotes kidney inflammation by enabling mutant tubular cells to trigger macrophage pyroptosis through the App–Cd74 pathway.

Zoonotic viral diseases have continued to threaten global public health in recent decades, with rodent-borne viruses being significant contributors. Infection by rodent-carried hantaviruses (HV) can result in hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS) in humans, with varying degrees of morbidity and mortality. However, no Food and Drug Administration (FDA) vaccines or therapeutics have been approved for the treatment of these diseases. In an effort to identify antiviral bioactive molecules, we isolated four oligomeric phloroglucinols from Callistemon rigidus leaves, including two new phloroglucinol trimers, callistemontrimer A and B, along with two previously characterized phloroglucinol dimers, rhodomyrtosone B and rhodomyrtone. We evaluated the anti-Hantaan virus (HTNV) activity of these compounds. Notably, callistemontrimer A demonstrated higher anti-HTNV activity compared to ribavirin. Mechanistic studies revealed that callistemontrimer A exerted its antiviral effects by inhibiting viral replication, likely through interaction with RNA-dependent RNA polymerase (RdRp) of HTNV, as supported by molecular docking analysis. These results highlight oligomeric phloroglucinols as promising lead candidates for the development of anti-HV therapeutics.

DNA double-strand breaks （DSBs） are highly cytotoxic lesions and pose a major threat to genome stability if not properly repaired. We and others have previously shown that a class of DSB-induced small RNAs （diRNAs） is produced from sequences around DSB sites. DiRNAs are associated with Argonaute （Ago） proteins and play an im- portant role in DSB repair, though the mechanism through which they act remains unclear. Here, we report that the role of diRNAs in DSB repair is restricted to repair by homologous recombination （HR） and that it specifically relies on the effector protein Ago2 in mammalian cells. Interestingly, we show that Ago2 forms a complex with RadS1 and that the interaction is enhanced in cells treated with ionizing radiation. We demonstrate that RadS1 accumulation at DSB sites and HR repair depend on catalytic activity and small RNA-binding capability of Ago2. In contrast, DSB resection as well as RPA and Mrell loading is unaffected by Ago2 or Dicer depletion, suggesting that Ago2 very likely functions directly in mediating RadS1 accumulation at DSBs. Taken together, our findings suggest that guided by diRNAs, Ago2 can promote RadS1 recruitment and/or retention at DSBs to facilitate repair by HR.

Background Auxin transcription factor (ARF) is an important transcription factor that transmits auxin signals and is involved in plant growth and development as well as stress response. However, genome-wide identification and responses to abiotic and pathogen stresses of the ARF gene family in Cucurbita pepo L, especially pathogen stresses, have not been reported. Results Finally, 33 ARF genes ( CpARF01 to CpARF33 ) were identified in C.pepo from the Cucurbitaceae genome database using bioinformatics methods. The putative protein contains 438 to 1071 amino acids, the isoelectric point is 4.99 to 8.54, and the molecular weight is 47759.36 to 117813.27 Da, the instability index ranged from 40.74 to 68.94, and the liposoluble index ranged from 62.56 to 76.18. The 33 genes were mainly localized in the nucleus and cytoplasm, and distributed on 16 chromosomes unevenly. Phylogenetic analysis showed that 33 CpARF proteins were divided into 6 groups. According to the amino acid sequence of CpARF proteins, 10 motifs were identified, and 1,3,6,8,10 motifs were highly conserved in most of the CpARF proteins. At the same time, it was found that genes in the same subfamily have similar gene structures. Cis-elements and protein interaction networks predicted that CpARF may be involved in abiotic factors related to the stress response. QRT-PCR analysis showed that most of the CpARF genes were upregulated under NaCl, PEG, and pathogen treatment compared to the control. Subcellular localization showed that CpARF22 was localized in the nucleus. The transgenic Arabidopsis thaliana lines with the CpARF22 gene enhanced their tolerance to salt and drought stress. Conclusion In this study, we systematically analyzed the CpARF gene family and its expression patterns under drought, salt, and pathogen stress, which improved our understanding of the ARF protein of zucchini, and laid a solid foundation for functional analysis of the CpARF gene.

Background Low muscle mass (LMM) and mild anemia (MA) are prevalent yet often overlooked conditions in middle-aged and older adults, each independently associated with adverse health outcomes. However, evidence regarding their combined effect on mortality remains limited. This study aimed to investigate the joint association of LMM and MA with all-cause, cardiovascular, and cancer mortality in a national sample of U.S. adults. Methods We analyzed data from 10,313 participants aged 45 years and older from the National Health and Nutrition Examination Survey (NHANES) 1999–2006 and 2011–2018, with mortality follow-up through December 2019. LMM was defined using appendicular skeletal muscle mass index (ASM/BMI), and MA was classified based on hemoglobin levels according to WHO criteria. Multivariable Cox proportional hazards models were used to assess individual and joint associations, adjusting for sociodemographic, lifestyle, and clinical factors. Results Over a median follow-up of 15.3 years, individuals with both LMM and MA had significantly elevated risks of all-cause (HR = 2.43; 95% CI: 1.82–3.26), cardiovascular (HR = 3.57; 95% CI: 2.31–5.52), and cancer mortality (HR = 3.86; 95% CI: 2.22–6.71) compared to those with neither condition. Significant additive and multiplicative interactions were observed between LMM and MA. Subgroup analyses revealed that the combined effect on cancer mortality was particularly pronounced in males and adults aged 65 years or older. Conclusions The co-occurrence of LMM and MA is strongly associated with increased risks of all-cause, cardiovascular, and cancer mortality among middle-aged and older adults. These findings highlight the importance of integrated screening and management of both conditions to mitigate mortality risks.

This study aimed to investigate the effects of different light treatments on the growth, antioxidant activity, and metabolite profiles of . Mycelial biomass, bioactive components, antioxidant capacity, and metabolomic profiles were analyzed under dark, continuous light, and 12 h light/12 h dark cycle conditions. The results showed that the 12 h light/dark cycle significantly reduced dry mycelial weight compared to the dark and continuous light groups ( < 0.001), while no significant difference in biomass was observed between the latter two. Polysaccharide (Pol) content did not differ significantly among the three groups. In terms of antioxidant activity, the continuous light group exhibited the highest protein (Prot) content, total phenolic (TP) content, DPPH radical scavenging activity, and ferric reducing antioxidant power (FRAP) as well as the lowest superoxide anion (·O ) content. The dark group showed the highest activities of superoxide dismutase (SOD) and catalase (CAT). Correlation analysis revealed that total phenolic (TP) content was significantly positively correlated with 2,2-Diphenyl-1-picrylhydrazy (DPPH) and FRAP ( < 0.01), and significantly negatively correlated with superoxide anion content ( < 0.05). Non-targeted metabolomics identified 3643 metabolites, primarily amino acids and derivatives, organic acids, and glycerophospholipids. KEGG enrichment analysis indicated significant accumulation of differential metabolites such as linoleic acid, tyrosine, and phosphatidylcholine across comparison groups. These findings provide insights into the regulatory role of light exposure on the antioxidant capacity of and support its further development in fermented mycelial products.

The ATP6V0A4 gene encodes the a4 subunit of vacuolar H + -ATPase (V-ATPase), which mediates hydrogen ion transport across the membrane. Previous studies have suggested that mutations in ATP6V0A4 consistently result in a loss of function, impairing the hydrogen ion transport efficacy of V-ATPase and leading to distal renal tubular acidosis and sensorineural hearing loss. Here, we identified a 32-year-old male patient and his father, both of whom harbored a heterozygous ATP6V0A4 p.V512L mutation and exhibited hypochloremic metabolic alkalosis, acidic urine, and hypokalemia. Through a series of protein structural analyses and functional experiments, the V512L mutation was confirmed as a gain-of-function mutation in the ATP6V0A4 gene. V512-a4 increased a4 subunit expression abundance by enhancing V512L-a4 stability and reducing its degradation, which in turn potentiated the capacity of V-ATPase to acidify the tubular lumen, leading to acidic urine and metabolic alkalosis. Through mutant V512L-a4 subunit structure-based virtual and experimental screening, we identified F351 (C 25 H 26 FN 3 O 2 S), a small-molecule inhibitor specifically targeting the V512L-a4 mutant. In conclusion, we identified a gain-of-function mutation in the ATP6V0A4 gene, broadening its phenotypic and mutational spectrum, and we provide valuable insights into potential therapeutic approaches for diseases associated with ATP6V0A4 mutations.

In clinical practice, surgical removal of tumors often leaves behind small tumors and circulating tumor cells, increasing the risk of metastasis and recurrence, which seriously affects treatment outcomes. Immunotherapy activates the immune system to monitor and inhibit tumor metastasis and recurrence long‐term. However, inflammatory microenvironments at surgical sites lead to immunosuppressive tumor‐associated macrophages (TAMs), causing immune evasion. Additionally, tumor cells overexpress the immune checkpoint CD47, further weakening the phagocytic and cytotoxic functions of macrophages. Here, the bacterial outer membrane vesicles (OMV) hitchhiking on neutrophils are utilized to precisely deliver immune checkpoint blockade antibodies to the tumor resection site. Escherichia coli is reprogrammed to express CD47 antibody and used to extract CD47 antibody‐containing OMV, followed by insertion of Ce6 photosensitizer into the membrane (OC47‐Ce6). Purified autologous neutrophils phagocytose and carry OC47‐Ce6 for precise targeting to the postoperative tumor resection site, mediating tumor cell killing, aCD47 release, and tumor‐associated antigen presentation by light. In vitro and in vivo experiments demonstrate that OC47‐Ce6 enhances TAM phagocytic function through TAM polarization and CD47 blockade. This approach effectively activates T‐cell anti‐tumor immune responses and significantly reduces the risk of postoperative tumor recurrence and metastasis. This study employs neutrophils for the precise delivery of anti‐CD47 antibodies, combined with bacterial outer membrane vesicles, to enhance macrophage phagocytic function in the tumor microenvironment. This approach effectively activates T‐cell anti‐tumor immune responses and significantly reduces the risk of postoperative tumor recurrence and metastasis, providing an effective strategy for tumor immunotherapy.