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Epilepsy, a common neurological disorder, is featured with recurrent seizures. Its underlying pathological mechanisms remain elusive. Here, we provide evidence for loss of neogenin (NEO1), a coreceptor for multiple ligands, including netrins and bone morphological proteins, in the development of epilepsy. NEO1 is reduced in hippocampi from patients with epilepsy based on transcriptome and proteomic analyses. Neo1 knocking out (KO) in mouse brains displays elevated epileptiform spikes and seizure susceptibility. These phenotypes were undetectable in mice, with selectively depleted NEO1 in excitatory (NeuroD6-Cre⁺) or inhibitory (parvalbumin⁺) neurons, but present in mice with specific hippocampal astrocytic Neo1 KO. Additionally, neurons in hippocampal dentate gyrus, a vulnerable region in epilepsy, in mice with astrocyte-specific Neo1 KO show reductions in inhibitory synaptic vesicles and the frequency of miniature inhibitory postsynaptic current(mIPSC), but increase of the duration of miniature excitatory postsynaptic current and tonic NMDA receptor currents, suggesting impairments in both GABAergic transmission and extracellular glutamate clearance. Further proteomic and cell biological analyses of cell-surface proteins identified GLAST, a glutamate–aspartate transporter that is marked reduced in Neo1 KO astrocytes and the hippocampus. NEO1 interacts with GLAST and promotes GLAST surface distribution in astrocytes. Expressing NEO1 or GLAST in Neo1 KO astrocytes in the hippocampus abolishes the epileptic phenotype. Taken together, these results uncover an unrecognized pathway of NEO1-GLAST in hippocampal GFAP⁺ astrocytes, which is critical for GLAST surface distribution and function, and GABAergic transmission, unveiling NEO1 as a valuable therapeutic target to protect the brain from epilepsy.

Background Stress tolerance is one of the important desired microbial traits for industrial bioprocesses, and global regulatory protein engineering is an efficient approach to improve strain tolerance. In our study, IrrE, a global regulatory protein from the prokaryotic organism Deinococcus radiodurans, was engineered to confer yeast improved tolerance to the inhibitors in lignocellulose hydrolysates or high temperatures. Results Three IrrE mutations were developed through directed evolution, and the expression of these mutants could improve the yeast fermentation rate by threefold or more in the presence of multiple inhibitors. Subsequently, the tolerance to multiple inhibitors of single-site mutants based on the mutations from the variants were then evaluated, and 11 mutants, including L65P, I103T, E119V, L160F, P162S, M169V, V204A, R244G, Base 824 Deletion, V299A, and A300V were identified to be critical for the improved representative inhibitors, i.e., furfural, acetic acid and phenol (FAP) tolerance. Further studies indicated that IrrE caused genome-wide transcriptional perturbation in yeast, and the mutant I24 led to the rapid growth of Saccharomyces cerevisiae by primarily regulating the transcription level of transcription activators/factors, protecting the intracellular environment and enhancing the antioxidant capacity under inhibitor environments, which reflected IrrE plasticity. Meanwhile, we observed that the expression of the wild-type or mutant IrrE could also protect Saccharomyces cerevisiae from the damage caused by thermal stress. The recombinant yeast strains were able to grow with glucose at 42 ℃. Conclusions IrrE from Deinococcus radiodurans can be engineered as a tolerance-enhancer for Saccharomyces cerevisiae. Systematic research on the regulatory model and mechanism of a prokaryotic global regulatory factor IrrE to increase yeast tolerance provided valuable insights for the improvements in microbial tolerance to complex industrial stress conditions.

Eukaryotic DNA replication begins with multiple origins of replication (ORIs) and thus exploring and identifying ORIs is essential for further understanding of the DNA replication process. In budding yeast, certain autonomously replicating sequences (ARSs) initiate the replication as ORIs, maintaining the stability of chromosomes and plasmids during genome replication. Currently, ARS identification was further facilitated by the DNA microarray technology and bioinformatics, which is based on the previous experimental methods. The structural and functional properties of ARSs on yeast chromosomes are gradually explored in this field. In addition to the function of initiating replication, there is a growing interest for researchers in the effects of ARSs on gene silencing and expression of genes, particularly the relationship between ARSs and chromosome structure. In this review, we summarized the identification methods of ARSs, especially for the bioinformatics prediction methods over the past few years. The functions of ARSs are discussed in this research, moreover, ARS modification that combined with the high‐throughput sequencing was elaborated as well, shedding further light on the understanding of the roles of ARSs, and providing deep insights towards the optimization of ARSs.

Background As the second most abundant polysaccharide in nature, hemicellulose can be degraded to xylose as the feedstock for bioconversion to fuels and chemicals. To enhance xylose conversion, the engineered Saccharomyces cerevisiae with xylose metabolic pathway is usually adapted with xylose as the carbon source in the laboratory. However, the mechanism under the adaptation phenomena of the engineered strain is still unclear. Results In this study, xylose-utilizing S. cerevisiae was constructed and used for the adaptation study. It was found that xylose consumption rate increased 1.24-fold in the second incubation of the yYST12 strain in synthetic complete-xylose medium compared with the first incubation. The study figured out that it was observed at the single-cell level that the stagnation time for xylose utilization was reduced after adaptation with xylose medium in the microfluidic device. Such transient memory of xylose metabolism after adaptation with xylose medium, named “xylose consumption memory”, was observed in the strains with both xylose isomerase pathway and xylose reductase and xylitol dehydrogenase pathways. In further, the proteomic acetylation of the strains before and after adaptation was investigated, and it was revealed that H4K5 was one of the most differential acetylation sites related to xylose consumption memory of engineered S. cerevisiae. We tested 8 genes encoding acetylase or deacetylase, and it was found that the knockout of the GCN5 and HPA2 encoding acetylases enhanced the xylose consumption memory. Conclusions The behavior of xylose consumption memory in engineered S. cerevisiae can be successfully induced with xylose in the adaptation. H4K5Ac and two genes of GCN5 and HPA2 are related to xylose consumption memory of engineered S. cerevisiae during adaptation. This study provides valuable insights into the xylose adaptation of engineered S. cerevisiae.

Rigorous compliance with food hygienic rules is essential to guarantee food safety and prevent foodborne diseases. This study was aimed to evaluate of food safety knowledge, attitudes and practices among handlers employed in college canteen in Northwestern China. A cross-sectional study based on cultural structured self-report questionnaire and convenient sampling was conducted in 12 cities or districts from May 1, 2024, to June 30, 2024. Chi-square test, T-test, Linear regression analysis and Logistic regression were conducted. Realization of data analysis was based on IBM SPSS Statistics 25. 479 valid questionnaires were collected. The majority of food handlers were female (70.56%), under 50 years old (91.65%), and with health card (95.82%). The mean score of knowledge, attitude and practice among all surveyed individuals were 10.05 ± 2.182 (full grade = 15), 45.23 ± 5.133 (full grade = 50) and 48.18 ± 3.612 (full grade = 50) respectively. There was a positive correlation among knowledge, attitude and practice. Multivariable logistic regression analysis revealed that female (OR = 2.586, 95%CI: 1.598-4.189), low knowledge score (OR = 0.509, 95%CI: 0.314-0.825) and low attitude score (OR = 0.225, 95%CI: 0.143-0.354) was significantly related to higher practice score. All surveyed individuals had an inclination to study food safety knowledge, with professional training being the most favored approach, followed by lectures, new media platforms, on-site supervision and peer instruction. The surveyed Food handlers demonstrated sufficient knowledge, but inferior when compared to attitudes and practices related to food safety. Food safety health education focusing on regulations and operational details should be implemented base on multiple approaches to deepen employe's awareness and prevent foodborne diseases.

Background Stress tolerance is one of the important desired microbial traits for industrial bioprocesses, and global regulatory protein engineering is an efficient approach to improve strain tolerance. In our study, IrrE, a global regulatory protein from the prokaryotic organism Deinococcus radiodurans, was engineered to confer yeast the improved tolerances to the inhibitors in lignocellulose hydrolysates or high temperatures. Results Three IrrE mutations were developed through directed evolution, and the expression of these mutants could improve the yeast fermentation rate by 3-fold or more in the presence of multiple inhibitors. Subsequently, the tolerance to multiple inhibitors of single-site mutants based on the mutations from the variants were then evaluated, and eleven mutants, including L65P, I103T, E119V, L160F, P162S, M169V, V204A, R244G, Base 824 Deletion, V299A, and A300V were identified to be critical for the improved representative inhibitors, i.e., furfural, acetic acid and phenol (FAP) tolerance. Further studies indicated that IrrE caused genome-wide transcriptional perturbation in yeast, and the mutant I24 led to the rapid growth of Saccharomyces cerevisiae by primarily regulating the transcription level of transcription activators/factors, protecting the intracellular environment and enhancing the antioxidant capacity under inhibitor environments, which reflected IrrE plasticity. Meanwhile, we observed that the expression of the wild-type or mutant IrrE could also protect Saccharomyces cerevisiae from the damage caused by thermal stress. The recombinant yeast strains were able to grow with glucose at 42 ºC. Conclusions IrrE from Deinococcus radiodurans can be engineered as a tolerance-enhancer for Saccharomyces cerevisiae. Systematic research on the regulatory model and mechanism of a prokaryotic global regulatory factor IrrE to increase yeast tolerance provided valuable insights for the improvements in microbial tolerance to complex industrial stress conditions.

Aim： To determine the efficacy and toxicities of sorafenib in the treatment of patients with multiple recurrences of hepatocellular carcinoma （HCC） after liver transplantation in a Chinese population. Methods： Twenty patients with multiple recurrences of HCC after liver transplantation were retrospectively studied. They received either transarterial chemoembolization （TACE） or TACE combined with sorafenib. Results： The median survival times （MST） after multiple recurrences was 14 months （TACE＋sorafenib group） and 6 months （TACE only group）. The difference was significant in MST between the two groups （P=0.005）. The TACE ＋ sorafenib group had more stable disease （SD） patients than the TACE group. The most frequent adverse events of sorafenib were hand-foot skin reaction and diarrhea. In the univariate analysis, preoperative bilirubin and CHILD grade are found to be significantly associated with tumor-free survival time, the survival time after multiple recurrences and overall survival time. TACE＋sorafenib group showed a better outcome than single TACE treatment group. In the multivariate COX regression modeling, the preoperative high CHILD grade was found to be a risk factor of tumor-free survival time. In addition, the preoperative high bilirubin grade was also found to be a risk factor of survival time after recurrence and overall survival time. Furthermore, survival time after recurrence and overall survival time were also associated with therapeutic schedule, which was indicated by the GROUP. Conclusion： Treatment with TACE and sorafenib is worthy of further study and may have more extensive application prospects.

OBJECTIVE To investigate the expressions of cyclooxygenase 2 (COX-2) and human epidermal growth factor receptor-2 (HER-2) in non-small cell lung cancer (NSCLC) and their clinical significance in identifying the progression and prognosis of the NSCLC patients. METHODS Immunohistochemical indirect method was used to detect the expressions of the COX-2 and HER-2 protein in 54 NSCLC specimens, 16 paraneoplastic specimens, and 10 normal tissue specimens.RESULTS The positive rates of COX-2 and HER-2 protein expressions were respectively 75.9% and 40.7% in the NSCLC specimens, 25% and 12.5% in the paraneoplastic specimens, and 0 in the normal tissue. The COX-2 protein expression in lung cancer (LC) was not only related to the smoking habit of the patients and histological grades of LC, but also to the TNM stages, and lymphatic metastasis (P < 0.05). HER-2 protein expression closely correlated to the pathologic types, histological grades, TNM stages, and lymphatic metastasis (P < 0.05). The result of univariate analysis showed that all the histological grades, TNM stages, lymphatic metastasis, and expressions of COX-2/HER-2 correlated to the prognosis of NSCLC patients (mean of P value < 0.01). The multivariate survival analysis indicated that there were significant differences in comparison of the survival time between the COX-2 (++/+++) /HER-2 (++/+++) and the COX-2 (-+)/HER-2 (-/+) groups (P< 0.001), suggesting the COX-2/HER-2 was a negative prognostic factor. CONCLUSION COX-2 and HER-2 are valuable in identifying the progression of NSCLC and predicting the prognosis of NSCLC patients. COX-2 and HER-2 are useful for judging the NSCLC patient’s condition, and are of great value to the decision of NSCLC prognosis.

Aim： To design and synthesize a novel class of protein tyrosine kinase inhibitors, featuring the N-（2-oxo-1,2-dihydroquinolin-3-yl-methyl）-thiourea framework. Methods： First, compounds 1 and 2 were identified using the virtual screening approach in conjunction with binding assay based on surface plasmon resonance. Subsequently, 3 regions of compounds 1 and 2 were selected for chemical modification. All compounds were characterized potent inhibitory activities toward the human lung adenocarcinoma cell line SPAC 1. Results： Forty new compounds （1- 2, 3a-g, 4a-w, and 5a-1） were designed, synthesized and bioassayed. Six compounds （1, 3e, 41, 4w, 5a, and 5b） were found to show promising inhibitory activity against the SPAC1 tumor cell line. The inhibitory activity of compound 5a increases approximately 10 times more than that of the original compound 1. Conclusion： This study provides a promising new template with potential antitumor activity.