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Diabetes mellitus is prevalent among women of reproductive age, and many women are left undiagnosed or untreated 1 . Gestational diabetes has profound and enduring effects on the long-term health of the offspring 2 , 3 . However, the link between pregestational diabetes and disease risk into adulthood in the next generation has not been sufficiently investigated. Here we show that pregestational hyperglycaemia renders the offspring more vulnerable to glucose intolerance. The expression of TET3 dioxygenase, responsible for 5-methylcytosine oxidation and DNA demethylation in the zygote 4 , is reduced in oocytes from a mouse model of hyperglycaemia (HG mice) and humans with diabetes. Insufficient demethylation by oocyte TET3 contributes to hypermethylation at the paternal alleles of several insulin secretion genes, including the glucokinase gene ( Gck ), that persists from zygote to adult, promoting impaired glucose homeostasis largely owing to the defect in glucose-stimulated insulin secretion. Consistent with these findings, mouse progenies derived from the oocytes of maternal heterozygous and homozygous Tet3 deletion display glucose intolerance and epigenetic abnormalities similar to those from the oocytes of HG mice. Moreover, the expression of exogenous Tet3 mRNA in oocytes from HG mice ameliorates the maternal effect in offspring. Thus, our observations suggest an environment-sensitive window in oocyte development that confers predisposition to glucose intolerance in the next generation through TET3 insufficiency rather than through a direct perturbation of the oocyte epigenome. This finding suggests a potential benefit of pre-conception interventions in mothers to protect the health of offspring. Pregestational hyperglycaemia in mothers increases the probability of glucose intolerance in the offspring, an effect controlled by TET3-dependent DNA demethylation of genes involved in insulin secretion.

The comorbidity of autism spectrum disorder and anxiety is common, but the underlying circuitry is poorly understood. Here, Tmem74 -/- mice showed autism- and anxiety-like behaviors along with increased excitability of pyramidal neurons (PNs) in the prelimbic cortex (PL), which were reversed by Tmem74 re-expression and chemogenetic inhibition in PNs of the PL. To determine the underlying circuitry, we performed conditional deletion of Tmem74 in the PNs of PL of mice, and we found that alterations in the PL projections to fast-spiking interneurons (FSIs) in the dorsal striatum (dSTR) (PL PNs –dSTR FSIs ) mediated the hyperexcitability of FSIs and autism-like behaviors and that alterations in the PL projections to the PNs of the basolateral amygdaloid nucleus (BLA) (PL PNs –BLA PNs ) mediated the hyperexcitability of PNs and anxiety-like behaviors. However, the two populations of PNs in the PL had different spatial locations, optogenetic manipulations revealed that alterations in the activity in the PL–dSTR or PL–BLA circuits led to autism- or anxiety-like behaviors, respectively. Collectively, these findings highlight that the hyperactivity of the two populations of PNs in the PL mediates autism and anxiety comorbidity through the PL–dSTR and PL–BLA circuits, which may lead to the development of new therapeutics for the autism and anxiety comorbidity.

Many marine microorganisms synthesize exopolysaccharides (EPSs), and some of these EPSs have been reported to have potential in different fields. However, the pharmaceutical potentials of marine EPSs are rarely reported. The EPS secreted by the Artic marine bacterium Polaribacter sp. SM1127 has good antioxidant activity, outstanding moisture-retention ability, and considerable protective property on human dermal fibroblasts (HDFs) at low temperature. Here, the effects of SM1127 EPS on skin wound healing and frostbite injury prevention were studied. Scratch wound assay showed that SM1127 EPS could stimulate the migration of HDFs. In the full-thickness cutaneous wound experiment of Sprague–Dawley (SD) rats, SM1127 EPS increased the wound healing rate and stimulated tissue repair detected by macroscopic observation and histologic examination, showing the ability of SM1127 EPS to promote skin wound healing. In the skin frostbite experiment of SD rats, pretreatment of rat skin with SM1127 EPS increased the rate of frostbite wound healing and promoted the repair of the injured skin significantly, indicating the good effect of SM1127 EPS on frostbite injury prevention. These results suggest the promising potential of SM1127 EPS in the pharmaceutical area to promote skin wound healing and prevent frostbite injury.

Background Cell wall integrity (CWI) is crucial for fungal growth, pathogenesis, and adaptation to extracellular environments. Calcofluor white (CFW) is a cell wall perturbant that inhibits fungal growth, yet little is known about how phytopathogenic fungi respond to the CFW-induced stress. Results In this study, we unveiled a significant discovery that CFW triggered the translocation of the transcription factor CgCrzA from the cytoplasm to the nucleus in Colletotrichum gloeosporioides . This translocation was regulated by an interacting protein, CgMkk1, a mitogen-activated protein kinase involved in the CWI pathway. Further analysis revealed that CgMkk1 facilitated nuclear translocation by phosphorylating CgCrzA at the Ser280 residue. Using chromatin immunoprecipitation sequencing, we identified two downstream targets of CgCrzA, namely CgCHS5 and CgCHS6 , which are critical for growth, cell wall integrity, and pathogenicity as chitin synthase genes. Conclusions These findings provide a novel insight into the regulatory mechanism of CgMkk1-CgCrzA-CgChs5/6, which enables response of the cell wall inhibitor CFW and facilitates infectious growth for C. gloeosporioides .

Alginate is abundant in the cell walls of brown algae. Alginate lyases can degrade alginate, and thus play an important role in the marine carbon cycle and industrial production. Currently, most reported alginate lyases contain only one functional alginate lyase domain. AlyC8 is a putative alginate lyase with two alginate lyase domains (CD1 and CD2) from the marine alginate-degrading strain Vibrio sp. C42. To characterize AlyC8 and its two catalytic domains, AlyC8 and its two catalytic domain-deleted mutants, AlyC8-CD1 and AlyC8-CD2, were expressed in Escherichia coli. All three proteins have noticeable activity toward sodium alginate and exhibit optimal activities at pH 8.0–9.0 and at 30–40 °C, demonstrating that both CD1 and CD2 are functional. However, CD1 and CD2 showed opposite substrate specificity. The differences in substrate specificity and degradation products of alginate between the mutants and AlyC8 demonstrate that CD1 and CD2 can act synergistically to enable AlyC8 to degrade various alginate substrates into smaller oligomeric products. Moreover, kinetic analysis indicated that AlyC8-CD1 plays a major role in the degradation of alginate by AlyC8. These results demonstrate that AlyC8 is a novel alginate lyase with two functional catalytic domains that are synergistic in alginate degradation, which is helpful for a better understanding of alginate lyases and alginate degradation.

Background Alginate oligosaccharides (AOs) are the degradation products of alginate, a natural polysaccharide abundant in brown algae. AOs generated by enzymatic hydrolysis have diverse bioactivities and show broad application potentials. AOs production via enzymolysis is now generally with sodium alginate as the raw material, which is chemically extracted from brown algae. In contrast, AOs production by direct degradation of brown algae is more advantageous on account of its cost reduction and is more eco-friendly. However, there have been only a few attempts reported in AOs production from direct degradation of brown algae. Results In this study, an efficient Laminaria japonica -decomposing strain Pseudoalteromonas agarivorans A3 was screened. Based on the secretome and mass spectrum analyses, strain A3 showed the potential as a cell factory for AOs production by secreting alginate lyases to directly degrade L. japonica . By using the L. japonica roots, which are normally discarded in the food industry, as the raw material for both fermentation and enzymatic hydrolysis, AOs were produced by the fermentation broth supernatant of strain A3 after optimization of the alginate lyase production and hydrolysis parameters. The generated AOs mainly ranged from dimers to tetramers, among which trimers and tetramers were predominant. The degradation efficiency of the roots reached 54.58%, the AOs production was 33.11%, and the AOs purity was 85.03%. Conclusion An efficient, cost-effective and green process for AOs production directly from the underutilized L. japonica roots by using strain A3 was set up, which differed from the reported processes in terms of the substrate and strain used for fermentation and the AOs composition. This study provides a promising platform for scalable production of AOs, which may have application potentials in industry and agriculture.

Highlights 1. Recent literature suggests that LODDS and LNR have superior predictive values, while the values of LODDS and LNR in GSRC based remain poorly understood. 2. Our study indicated that LODDS and LNR enhance the precision of survival risk prognosis in patients with gastric signet ring cell carcinoma, as compared to the N-category. 3. LODDS and LNR could be regarded as viable alternatives to the N-category in predicting the prognosis of GSRC patients. Background Accurate staging is essential in cancer care. The American Joint Committee on Cancer (AJCC) TNM staging system is commonly used but is subject to the risk of stage migration. Recent literature suggests that the log odds of positive lymph nodes (LODDS) and positive lymph node ratio (LNR) may have superior predictive values and are considered alternatives to the N-category. However, their predictive performance in gastric signet ring cell carcinoma (GSRC) remains vague. This study aims to explore the association between three lymph node (LN) staging systems (AJCC N-category, LODDS, and LNR) and outcomes in GSRC, and assess the predictive power. Methods Eligible patients with GSRC from 2004 to 2015 were collected from the Surveillance, Epidemiology, and End Results database. The time-dependent receiver-operating characteristic (ROC) analysis, area under the curve (AUC), and integrated discrimination improvement (IDI) were used to assess the predictive performance of the three LN stages (AJCC N-category, LODDS, and LNR). Results In the multivariate analysis of all GSRC patients and the subgroup of patients with ≤ 15 LNs examined, both the LODDS and LNR were significant survival prognostic factors. The time-dependent ROC curves of the LODDS and LNR exhibited higher sensitivity and specificity when compared to the N-category curve. The AUCs at 1, 3, and 5 years demonstrated that the predictive performance of LODDS and LNR was significantly better than the N-category (all P  < 0.05). IDI of LODDS and LNR also showed sufficient fit and attractive net benefit in prediction and clinical application. Conclusions LODDS and LNR were remarkable prognosticators for survival in GSRC patients. Their predictive performance was better than that of the N-category, indicating that LODDS and LNR could ameliorate the predictive precision of survival risk and could replace the N-category in predicting the outcomes of GSRC patients.

This study provides crucial insights into phosphate acquisition in SAR11 bacteria, a key group of oligotrophic microorganisms that thrive in nutrient-limited marine ecosystems. By characterizing the unique structural features of Cp PstS, including its distinct hydrogen-bonding network and expanded substrate-binding cavity, this research sheds light on how SAR11 bacteria adapt to limited phosphorus availability. The discovery that Cp PstS may also accommodate organic phosphorus compounds broadens our understanding of microbial nutrient acquisition. These findings have significant implications for marine biogeochemical cycles and offer new perspectives on the evolution of nutrient transport mechanisms in marine microorganisms.

The volatile trimethylamine (TMA) plays an important role in promoting cardiovascular diseases and depolarizing olfactory sensory neurons in humans and serves as a key nutrient source for a variety of ubiquitous marine microbes. While the TMA transporter TmaT has been identified from a marine bacterium, the structure of TmaT and the molecular mechanism involved in TMA transport remain unclear. In this study, we elucidated the high-resolution cryo-EM structures of TmaT and TmaT-TMA complexes and revealed the TMA binding and transport mechanisms by structural and biochemical analyses. The results advance our understanding of the TMA transport processes across biological membranes.

Purpose To investigate the role of lymph node ratio (LNR) in young patients with gastric cancer (GC) and develop nomograms to predict the survival of young GC patients. Methods This retrospective study enrolled stage I-III GC patients before the age of 40 between 2010 and 2016 from the Surveillance, Epidemiology, and End Results (SEER) database. Cox proportional hazards models were used to determine the prognosticators and create the nomograms incorporating LNR to predict overall survival (OS) and cancer-specific survival (CSS). The discriminating superiority of the nomograms was examined using calibration curves, C-index, receiver operating characteristic (ROC) curves, decision curve analysis (DCA), and integrated discrimination improvement (IDI) by comparing with the TNM staging. The performance of the nomograms for risk stratification was analyzed by the Kaplan–Meier method. Results Based on the significant prognosticators identified in multivariate survival analysis, the nomograms were established and showed LNR as the third strongest predictor. The C-index of the nomograms for OS and CSS were higher than those of the TNM staging (OS: 0.773 vs 0.665; CSS: 0.769 vs 0.666). The ROC curves for the nomograms to predict survival exhibited superior sensitivity and specificity when compared with the TNM staging. The calibration plots, DCA curves, and IDI values of the nomograms also demonstrated adequate fit and ideal net benefit in prediction and clinical utility. The Kaplan–Meier analysis observed remarkable differences in patients divided into different risk subgroups (P < .001). Conclusions These results found the clinical outperformance of the LNR-based nomograms for predicting survival in young stage I-III GC patients. Our nomograms may improve accuracy of survival risk prediction and facilitate individualized care of young stage I-III GC patients.