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Ergosterol, a terpenoid compound produced by fungi, is an economically important metabolite serving as the direct precursor of steroid drugs. Herein, ergsosterol biosynthetic pathway modification combined with storage capacity enhancement was proposed to synergistically improve the production of ergosterol in Saccharomyces cerevisiae . S. cerevisiae strain S1 accumulated the highest amount of ergosterol [7.8 mg/g dry cell weight (DCW)] among the wild-type yeast strains tested and was first selected as the host for subsequent metabolic engineering studies. Then, the push and pull of ergosterol biosynthesis were engineered to increase the metabolic flux, overexpression of the sterol acyltransferase gene ARE2 increased ergosterol content to 10 mg/g DCW and additional overexpression of a global regulatory factor allele ( UPC2-1 ) increased the ergosterol content to 16.7 mg/g DCW. Furthermore, considering the hydrophobicity sterol esters and accumulation in lipid droplets, the fatty acid biosynthetic pathway was enhanced to expand the storage pool for ergosterol. Overexpression of ACC1 coding for the acetyl-CoA carboxylase increased ergosterol content from 16.7 to 20.7 mg/g DCW. To address growth inhibition resulted from premature accumulation of ergosterol, auto-inducible promoters were employed to dynamically control the expression of ARE2 , UPC2-1 , and ACC1 . Consequently, better cell growth led to an increase of ergosterol content to 40.6 mg/g DCW, which is 4.2-fold higher than that of the starting strain. Finally, a two-stage feeding strategy was employed for high-density cell fermentation, with an ergosterol yield of 2986.7 mg/L and content of 29.5 mg/g DCW. This study provided an effective approach for the production of ergosterol and other related terpenoid molecules.

As essential structural molecules of fungal cell membrane, ergosterol is not only an important component of fungal growth and stress-resistance but also a key precursor for manufacturing steroid drugs of pharmaceutical or agricultural significance. So far, ergosterol biosynthesis in yeast has been elucidated elaborately, and efforts have been made to increase ergosterol production through regulation of ergosterol metabolism and storage. Furthermore, the same intermediates shared by yeasts and animals or plants make the construction of heterologous sterol pathways in yeast a promising approach to synthesize valuable steroids, such as phytosteroids and animal steroid hormones. During these challenging processes, several obstacles have arisen and been combated with great endeavors. This paper reviews recent research progress of yeast metabolic engineering for improving the production of ergosterol and heterologous steroids. The remaining tactics are also discussed.

Whole-exome sequencing has been successful in identifying genetic factors contributing to familial or sporadic Parkinson’s disease (PD). However, this approach has not been applied to explore the impact of de novo mutations on PD pathogenesis. Here, we sequenced the exomes of 39 early onset patients, their parents, and 20 unaffected siblings to investigate the effects of de novo mutations on PD. We identified 12 genes with de novo mutations (MAD1L1, NUP98, PPP2CB, PKMYT1, TRIM24, CEP131, CTTNBP2, NUS1, SMPD3, MGRN1, IFI35, and RUSC2), which could be functionally relevant to PD pathogenesis. Further analyses of two independent case-control cohorts (1,852 patients and 1,565 controls in one cohort and 3,237 patients and 2,858 controls in the other) revealed that NUS1 harbors significantly more rare nonsynonymous variants (P = 1.01E-5, odds ratio = 11.3) in PD patients than in controls. Functional studies in Drosophila demonstrated that the loss of NUS1 could reduce the climbing ability, dopamine level, and number of dopaminergic neurons in 30-day-old flies and could induce apoptosis in fly brain. Together, our data suggest that de novo mutations could contribute to early onset PD pathogenesis and identify NUS1 as a candidate gene for PD.

Diabetic kidney disease (DKD), a major microvascular complication of diabetes, affects 30-40% of patients and is the leading cause of end-stage renal disease. The Wnt/β-catenin signaling pathway plays a dual role in DKD pathogenesis: its moderate activation protects against hyperglycemia-induced mesangial apoptosis, while chronic overactivation exacerbates renal fibrosis, podocyte injury, and tubular dysfunction. This review synthesizes current evidence on the pathway's context-dependent mechanisms. Emerging therapeutic strategies-including small-molecule inhibitors (eg, Dickkopf-1), monoclonal antibodies, and natural compounds like curcumin and Salvia miltiorrhiza extracts-show preclinical promise in modulating Wnt/β-catenin activity. However, clinical translation faces challenges such as pathway redundancy, off-target effects, and the need for precise dosing to balance protective and injurious outcomes. Recent advances in biomarker discovery (eg, urinary β-catenin) and ongoing clinical trials highlight the pathway's potential as a therapeutic target. Future research must prioritize patient stratification, combination therapies (eg, Wnt inhibitors + RAAS blockers), and mechanistic studies to address unresolved controversies in Wnt signaling dynamics. This work underscores the therapeutic implications of targeting Wnt/β-catenin in DKD while advocating for a nuanced approach to harness its protective roles.

Diabetic kidney disease (DKD), a major microvascular complication of diabetes, affects 30-40% of patients and is the leading cause of end-stage renal disease. The Wnt/[beta]-catenin signaling pathway plays a dual role in DKD pathogenesis: its moderate activation protects against hyperglycemia-induced mesangial apoptosis, while chronic overactivation exacerbates renal fibrosis, podocyte injury, and tubular dysfunction. This review synthesizes current evidence on the pathway's context-dependent mechanisms. Emerging therapeutic strategies--including small-molecule inhibitors (eg, Dickkopf-1), monoclonal antibodies, and natural compounds like curcumin and Salvia miltiorrhiza extracts--show preclinical promise in modulating Wnt/[beta]-catenin activity. However, clinical translation faces challenges such as pathway redundancy, off-target effects, and the need for precise dosing to balance protective and injurious outcomes. Recent advances in biomarker discovery (eg, urinary [beta]-catenin) and ongoing clinical trials highlight the pathway's potential as a therapeutic target. Future research must prioritize patient stratification, combination therapies (eg, Wnt inhibitors + RAAS blockers), and mechanistic studies to address unresolved controversies in Wnt signaling dynamics. This work underscores the therapeutic implications of targeting Wnt/[beta]-catenin in DKD while advocating for a nuanced approach to harness its protective roles. Keywords: Wnt/[beta]-catenin pathway, diabetic kidney disease, therapy

Limited by the tiny structure of axons,the effects of these axonal hyperpolarizing inputs on neuronal activity have not been directly elucidated.Here,we imitated these processes by simultaneously recording the activities of the somas and proximal axons of cortical pyramidal neurons.We found that spikes and subthreshold potentials propagate between somas and axons with high fidelity.Furthermore,inhibitory inputs on axons have opposite effects on neuronal activity according to their temporal integration with upstream signals.Concurrent with somatic depolarization,inhibitory inputs on axons decrease neuronal excitability and impede spike generation.In addition,following action potentials,inhibitory inputs on an axon increase neuronal spike capacity and improve spike precision.These results indicate that inhibitory inputs on proximal axons have dual regulatory functions in neuronal activity（suppression or facilitation）according to neuronal network patterns.

Based on social capital theory,related factors of three dimensions( structure dimension,cognition dimension and relation dimension) of farmer social capital are taken as independent variables,and famer’s willingness to cooperatively supply agricultural disaster reduction public goods is taken as dependent variable. Taking 515 farmers in 27 villages of Hubei Province as investigation objects,the influence of farmer social capital on cooperative supply willingness of agricultural disaster reduction public goods is explored by Logistic regression model. Research results show that social solidarity,common value concept,social trust and reciprocal content have positive impact on farmer’s willingness of cooperative supply,while annual household income,number of agricultural disaster reduction public goods and social network have negative impact on farmer’s willingness of cooperative supply.

Objective Helicobacter pylori infection is mostly a family-based infectious disease. To facilitate its prevention and management, a national consensus meeting was held to review current evidence and propose strategies for population-wide and family-based H. pylori infection control and management to reduce the related disease burden.MethodsFifty-seven experts from 41 major universities and institutions in 20 provinces/regions of mainland China were invited to review evidence and modify statements using Delphi process and grading of recommendations assessment, development and evaluation system. The consensus level was defined as ≥80% for agreement on the proposed statements.ResultsExperts discussed and modified the original 23 statements on family-based H. pylori infection transmission, control and management, and reached consensus on 16 statements. The final report consists of three parts: (1) H. pylori infection and transmission among family members, (2) prevention and management of H. pylori infection in children and elderly people within households, and (3) strategies for prevention and management of H. pylori infection for family members. In addition to the ‘test-and-treat’ and ‘screen-and-treat’ strategies, this consensus also introduced a novel third ‘family-based H. pylori infection control and management’ strategy to prevent its intrafamilial transmission and development of related diseases.Conclusion H. pylori is transmissible from person to person, and among family members. A family-based H. pylori prevention and eradication strategy would be a suitable approach to prevent its intra-familial transmission and related diseases. The notion and practice would be beneficial not only for Chinese residents but also valuable as a reference for other highly infected areas.