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Background: In recent years, artificial neural network is advocated in modeling complex multivariable relationships due to its ability of fault tolerance; while decision tree of data mining technique was recommended because of its richness of classification arithmetic rules and appeal of visibility. The aim of our research was to compare the performance of ANN and decision tree models in predicting hospital charges on gastric cancer patients.Methods: Data about hospital charges on 1008 gastric cancer patients and related demographic information were collected from the First Affiliated Hospital of Anhui Medical University from 2005 to 2007 and preprocessed firstly to select pertinent input variables. Then artificial neural network (ANN) and decision tree models, using same hospital charge output variable and same input variables, were applied to compare the predictive abilities in terms of mean absolute errors and linear correlation coefficients for the training and test datasets. The transfer function in ANN model was sigmoid with 1 hidden layer and three hidden nodes.Results: After preprocess of the data, 12 variables were selected and used as input variables in two types of models. For both the training dataset and the test dataset, mean absolute errors of ANN model were lower than those of decision tree model (1819.197 vs. 2782.423, 1162.279 vs. 3424.608) and linear correlation coefficients of the former model were higher than those of the latter (0.955 vs. 0.866, 0.987 vs. 0.806). The predictive ability and adaptive capacity of ANN model were better than those of decision tree model.Conclusion: ANN model performed better in predicting hospital charges of gastric cancer patients of China than did decision tree model. [ABSTRACT FROM AUTHOR]

This study aims to explore the regulating effect and mechanism of naringenin (NGN) on the hepatic stellate cells (HSCs) apoptosis and its preventive effects on MASH fibrosis. C57BL/6 mice were subjected to either high-fat diet (HFD) plus carbon tetrachloride (CCl 4 ) injection (HFD + CCl 4 ) for 8 weeks to induce a MASH fibrosis model or bile duct ligation (BDL) to establish a liver fibrosis model, NGN was administered by gavage. LX2 cells were stimulated by oleic acid (OA) and lipopolysaccharide (LPS) (OA + LPS) to study the effects of NGN on activated hepatic stellate cell (HSC). Additionally, LO2 cells stimulated with OA + LPS were used to assess the protective effects of NGN on lipotoxicity of hepatocytes. Our in vivo results showed that NGN administration effectively inhibited mouse liver fibrosis in both of the MASH model and BDL model. The in vitro results indicate that NGN directly inhibited HSCs activation and promoted apoptosis of the activated HSCs, while it suppressed the apoptosis of LO2 cells induced by OA + LPS. The underlying mechanisms were mainly elucidated through the reduction of TAK1 phosphorylation, leading to the downregulation of p-JNK and p-ERK expression. This in turn, inhibited the phosphorylation of FoxO3a and promoted the nuclear localization of FoxO3a. Consequently, this may enhance the transcription of apoptosis-related genes, resulting in the apoptosis of activated HSCs. In conclusion, NGN ameliorates MASH fibrosis by enhancing apoptosis of the activated HSCs. The inhibitory effects of NGN on the TAK1/MAPK/FoxO3a pathway were demonstrated as its preventive mechanisms against MASH fibrosis., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Rong Qi reports was provided by National Natural Science Foundation of China. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The biological function against obesity of heat shock protein Hsp72 in adipose tissue has remained unclear. Our findings demonstrated that the expression levels of Hsp72 increased during the triglyceride (TG) accumulation process both in adipose tissue and 3T3-L1 cells. A significant decrease in adipogenic gene expression and TG levels was observed upon Hsp72 knockdown in 3T3-L1 cells, suggesting that Hsp72 promoted adipogenic differentiation and lipid synthesis processes. Encouraged by these findings, we further confirmed the allosteric Hsp72 inhibitors YK5 and MKT-077 also exhibited inhibition of both these processes. Further evaluation revealed that Hsp72 played a key role in interacting with numerous novel metabolic and cytomorphologic-related client proteins, thereby mediating the adipogenesis and lipogenesis process. Hsp72 inhibitors had the potential to disrupt these interactions, leading to the downregulation of adipogenic and lipogenic gene expression, as well as the suppression of TG accumulation. These findings suggested that inhibiting Hsp72 to disrupt adipogenic differentiation and lipid synthesis in adipocytes may be a promising anti-obesity strategy., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

Knockouts mediated by CRISPR/Cas9 technology are widely used to study insect gene functions, but the efficiency in Hemiptera is low. New strategies are urgently needed to improve gene knockout efficiency. This study initially explored the impact of modifying the fundamental backbone structure of single guide RNA (sgRNA) on knockout efficiency. The results indicated that both in vitro and in vivo transcription of sgRNA structures (Loop 5bp  + M T/C type) increased average knockout efficiency by 0.61-fold compared to the original sgRNA. In addition, the PTG/Cas9 system was observed to induce a 0.64-fold increase in average knockout efficiency using the original sgRNA. Notably, an integrated PTG/Cas9 system (iPTG/Cas9 system), the integration of optimized sgRNA structures (Loop 5bp  + M T/C type) into the conventional PTG/Cas9 system, demonstrated a synergistic effect, resulting in a 1.45-fold increase in average knockout efficiency compared to the original sgRNA structure. The iPTG/Cas9 system was effectively used to simultaneously knockout two different target sites within a single gene and to co-knockout two genes. This study represents the first application of the iPTG/Cas9 system to establish a double knockout system in Hemiptera, offering a promising approach to enhance knockout efficiency in species with low efficiency and improve genetic manipulation tools for pest control., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: WenQing Zhang reports financial support was provided by National Natural Science Foundation of China. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

This study examines effects of mixing municipal solid waste incineration bottom ash (MSWI-BA) with reddish laterite clay (RLC), evaluating factors such as vertical stress, mixing ratio, curing period, and the addition of lime. A total of 153 direct shear tests were conducted to thoroughly assess the mixture's strength characteristics. Vertical stress levels of 85.5 kPa, 172.4 kPa, and 259.3 kPa were used to simulate varying stress conditions, while mixing ratios of 40 %, 80 %, 100 %, and 120 % were applied to explore potential applications of recycled MSWI-BA with clayey soils. A fast-curing approach was employed, with curing periods of 24, 48, and 72 h, to investigate the time-dependent strength development under controlled conditions. A three-way ANOVA analysis confirmed that mixing ratio, curing period, and vertical stress significantly impacted both peak and residual shear strength. The 100 % MSWI-BA mixture, with or without 1 % lime, exhibited optimal performance, providing the pronounced shear strengths and dilative behavior. The study found that MSWI-BA significantly improved shear strength ratios compared to the RLC, with improvement ratios ranging from 1.439 to 2.460 across stress levels. Additionally, upper and lower bound equations for peak and residual strength ratios were developed, providing predictive tools for mixture design. Cohesion values in the range of 8.3-128.9 kPa and friction angles from 40.6° to 44.1° were achieved, surpassing or matching those reported in similar research. The study employed Bolton's (1986) dilatancy model, finding α values between 0.61 and 0.71, comparable to those in studies of granular materials. These results highlight the effectiveness of adding MSWI-BA and lime in enhancing reddish laterite soil stabilization through both chemical and mechanical means, making it a sustainable and cost-effective approach for civil engineering projects by improving material strength, reusing local soils, recycling waste, and reducing carbon footprints., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Background: This study aimed to identify the roles of L-tryptophan (Trp) and its rate-limiting enzymes on the receptivity of bovine endometrial epithelial cells. Real-time PCR was conducted to analyze the differential expression of genes between different groups of bovine endometrial epithelial cells. Western blot was performed to detect Cyclooxygenase-2 (COX2) expression after treatment with Trp or kynurenine (the main metabolites of Trp). The kynurenine assay was used to examine if Trp or prostaglandin E2 (PGE2) can increase the production of kynurenine in the bovine endometrial epithelial cells., Results: Trp significantly stimulates insulin growth factor binding protein 1 (IGFBP1) expression, a common endometrial marker of conceptus elongation and uterus receptivity for ruminants. When bovine endometrial epithelial cells are treated with Trp, tryptophan hydroxylase-1 remains unchanged, but tryptophan 2,3-dioxygenase 2 (TDO2) is significantly increased, suggesting tryptophan is mainly metabolized through the kynurenine pathway. Kynurenine significantly stimulates IGFBP1 expression. Furthermore, Trp and kynurenine significantly increase the expression of aryl hydrocarbon receptor (AHR). CH223191, an AHR inhibitor, abrogates the induction of Trp and kynurenine on IGFBP1. PGE2 significantly induces the expression of TDO2, AHR, and IGFBP1., Conclusions: The regulation between Trp / kynurenine and PGE2 may be crucial for the receptivity of the bovine uterus., (© 2024. The Author(s).)

The glomus tumor is a rare neoplasm that is typically found subungually in the extremities and functions as a specialized neurovascular organ. An extremely rare site for glomus tumors is the breast, with only a few reported cases. Breast glomus tumors present with three typical clinical signs: dull pain, focal tenderness, and cold sensitivity. Less than 10% of all glomus tumors are malignant. We herein present a case of a malignant glomus tumor originating in the breast. Distant metastasis was ruled out, and the tumor was completely resected. However, the patient unexpectedly developed rapid systemic metastasis, detected 5 weeks after tumor removal. Despite the administration of analgesics and targeted therapy, the patient died 1 month later. When treating patients with undiagnosed breast tumors, clinicians should pay attention to unexplained and repeatedly reported symptoms and consider the possibility of a rare disease. Our literature search revealed no cases of malignant glomus tumors originating in the breast, making this case the first of its kind., Competing Interests: Declaration of conflicting interestsThe authors declare that they have no competing interests.

Background: Sanqi, the root of Panax notoginseng, has long been recognized for its therapeutic effects on cardiovascular diseases. Saponins, including ginsenosides and notoginsenosides, are the main bioactive components of P. notoginseng. The biosynthesis of saponins is closely related to the defense responses orchestrated by endogenous hormones., Results: To provide new insights into the underlying role of phytohormone jasmonic acid (JA) in the synthesis and regulation of saponins, we performed an ultra-performance liquid chromatography analysis of different tissues of P. notoginseng aged 2-4 years. Moreover, by combined evaluation of saponin content and transcriptome profiling of each tissue, the spatial and temporal distribution of saponins was analyzed. N notoginsenoside R1, ginsenoside Rb1 and ginsenoside Rd accumulated in the underground tissues, including the root, tuqi, fibril and rhizome. In agreement with this data, the corresponding genes of the endogenous hormone JAs, especially coronatine insensitive 1 (COI1) and myelocytomatosis proteins 2 (MYC2), were predominantly expressed in the underground tissues. The tissue- and age-specific distribution of saponins was consistent with the expression of genes involved in JA biosynthetic, metabolic and signaling pathways., Conclusion: The present study has revealed the temporal and spatial effects of endogenous phtohormones in the synthesis and regulation of notoginsenosides, which will provide a significant impact on improving the ecological planting technology, cultivating new high-quality varieties and protecting the rare resources of medicinal P. notoginseng. © 2024 Society of Chemical Industry., (© 2024 Society of Chemical Industry.)

Due to the emerging global epidemic of obesity, developing safe and effective agents for anti-obesity is urgently needed. Our previous study found that 2-pyrimidinylindole derivative Wd3d exhibited potential anti-obesity activity. Herein, to further optimize the potential moiety, structural modifications were proceeded for two rounds in this study. Firstly, we designed, synthesized, and evaluated 36 new derivatives of 2-pyrimidinylindole scaffold with different substituents on the indole ring and pyrimidine ring to investigate their structure-activity relationship (SAR). Then, analogs with potent activity had the aldehyde group replaced with the acylhydrazone group to reduce cytotoxicity and improve metabolic stability. Detailed SAR studies and animal evaluation experiments led to the discovery of the compound 9ga, which significantly reduced TG accumulation with an EC 50 value of 0.07 μM and showed relatively low cytotoxicity with an IC 50 value of around 24 μM. Oral administration of 9ga effectively prevented the excessive growth of body weight and lessened fat mass as well as liver mass, decreased lipid accumulation in the liver and blood, and improved the heart injury parameter in the diet-induced obesity mouse model significantly better than Wd3d. A mechanism study showed that 9ga regulated the lipid metabolism during early adipogenesis by inhibiting PPARγ pathway. In conclusion, our study further highlights the anti-obesity potential of 2-pyrimidinylindole derivatives in diet-induced obesity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

The discovery of effective and safe antiobesity agents remains a challenging yet promising field. Our previous studies identified Bouchardatine derivatives as potential antiobesity agents. However, the 8a-aldehyde moiety rendered them unsuitable for drug development. In this study, we designed two series of novel derivatives to modify this structural feature. Through a structure-activity relationship study, we elucidated the role of the 8a-aldehyde group in toxicity induction. We identified compound 14d , featuring an 8a- N -acylhydrazone moiety, which exhibited significant lipid-lowering activity and reduced toxicity. Compound 14d shares a similar lipid-lowering mechanism with our lead compound 3 , but demonstrates improved pharmacokinetic properties and safety profile. Both oral and injectable administration of 14d significantly reduced body weight gain and ameliorated metabolic syndrome in diet-induced obese mice. Our findings identify 14d as a promising antiobesity agent and highlight the potential of substituting the aldehyde group with an N -acylhydrazone to enhance drug-like properties.

Purpose: The aim of this work was to determine whether locally advanced rectal cancer (LARC) with negative mesorectal fascia (MRF) predicted by magnetic resonance imaging (MRI) can be excluded from preoperative radiation therapy treatment., Methods and Materials: This multicenter, open-label, non-inferiority, randomized clinical trial enrolled patients with LARC within 6 to 12 cm from the anal verge and with negative MRI-predicted MRF. Participants were randomized to the intervention group (primary surgery, in which the patients with positive pathologic [CRM] circumferential margins were subjected to chemoradiotherapy [CRT] and those with negative CRM underwent adjuvant chemotherapy according to pathologic staging) or the control group (preoperative CRT, in which all patients underwent subsequent surgery and adjuvant chemotherapy). The primary endpoint was 3-year disease-free survival (DFS)., Results: A total of 275 patients were randomly assigned to the intervention (n = 140) and control (n = 135) groups, in which 33.57% and 28.15% patients were at clinical T4 stage and 85.92% and 80.45% patients were at "bad" or "ugly" risk in the intervention and control groups, respectively. There were 2 patients (1.52%) and 1 patient (0.77%) with positive CRM in the intervention and control groups, respectively (P > .05). The non-adherence rates for the intervention and control groups were 3.6% and 23.7%, respectively. After a median follow-up of 34.6 months (IQR, 18.2-45.7), 43 patients had positive events (28 patients and 15 patients in the intervention and control groups, respectively). There were 6 patients (4.4%) with local recurrence in the intervention group and none in the control group, which led to the termination of the trial. The 3-year DFS rate was 81.82% in the intervention group (95% CI, 78.18%-85.46%) and 85.37% in the control group (95% CI, 81.75%-88.99%), with a difference of -3.55% (95% CI, -3.71% to -3.39%; hazard ratio, 1.76; 95% CI, 0.94-3.30). In the per-protocol data set, the difference between 3-year DFS rates was -5.44% (95% CI, -5.63% to -5.25%; hazard ratio, 2.02; 95% CI, 1.01-4.06)., Conclusions: Based on the outcomes of this trial, in patients with LARC and MRI-negative MRF, primary surgery could negatively influence their DFS rates. Therefore, primary surgery was an inferior strategy compared with preoperative CRT followed by surgery and cannot be recommended for patients with LARC., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: X-linked agammaglobulinemia (XLA) is an inborn error of immunity that renders boys susceptible to life-threatening infections due to loss of mature B cells and circulating immunoglobulins. It is caused by defects in the gene encoding the Bruton tyrosine kinase (BTK) that mediates the maturation of B cells in the bone marrow and their activation in the periphery. This paper reports on a gene editing protocol to achieve "knock-in" of a therapeutic BTK cassette in hematopoietic stem and progenitor cells (HSPCs) as a treatment for XLA., Methods: To rescue BTK expression, this study employed a clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 system that creates a DNA double-strand break in an early exon of the BTK locus and an adeno-associated virus 6 virus that carries the donor template for homology-directed repair. The investigators evaluated the efficacy of the gene editing approach in HSPCs from patients with XLA that were cultured in vitro under B-cell differentiation conditions or that were transplanted in immunodeficient mice to study B-cell output in vivo., Results: A (feeder-free) B-cell differentiation protocol was successfully applied to blood-mobilized HSPCs to reproduce in vitro the defects in B-cell maturation observed in patients with XLA. Using this system, the investigators could show the rescue of B-cell maturation by gene editing. Transplantation of edited XLA HSPCs into immunodeficient mice led to restoration of the human B-cell lineage compartment in the bone marrow and immunoglobulin production in the periphery., Conclusions: Gene editing efficiencies above 30% could be consistently achieved in human HSPCs. Given the potential selective advantage of corrected cells, as suggested by skewed X-linked inactivation in carrier females and by competitive repopulating experiments in mouse models, this work demonstrates the potential of this strategy as a future definitive therapy for XLA., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Thymic egress is a crucial process for thymocyte maturation, strictly regulated by sphingosine-1-phosphate lyase (S1PL). Recently, cystathionine γ-lyase (CSE), one of the enzymes producing hydrogen sulfide (H 2 S), has emerged as a vital immune process regulator. However, the molecular connection between CSE, H 2 S and thymic egress remains largely unexplored. In this study, we investigated the regulatory function of CSE in the thymic egress of immune cells. We showed that genetic knockout of CSE or pharmacological inhibition by CSE enzyme inhibitor NSC4056 or D,L-propargylglycine (PAG) significantly enhanced the migration of mature lymphocytes and monocytes from the thymus to the peripheral blood, and this redistribution effect could be reversed by treatment with NaHS, an exogenous donor of H 2 S. In addition, the CSE-generated H 2 S significantly increased the levels of S1P in the peripheral blood, thymus and spleen of mice, suppressed the production of proinflammatory cytokines and rescued pathogen-induced sepsis in cells and in vivo. Notably, H 2 S or polysulfide inhibited S1PL activity in cells and an in vitro purified enzyme assay. We found that this inhibition relied on a newly identified C 203 XC 205 redox motif adjacent to the enzyme's active site, shedding light on the biochemical mechanism of S1PL regulation. In conclusion, this study uncovers a new function and mechanism for CSE-derived H 2 S in thymic egress and provides a potential drug target for treating S1P-related immune diseases., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Spatial variability of throughfall ( i.e. the non-uniform characteristics of throughfall at different canopy positions) and its temporal persistence ( i.e. time stability) are related to the quantity and efficiency of soil moisture replenishment, and affect plant competition and community succession dynamics by affecting resource availability. We carried out a meta-analysis with 554 papers (from 2000 to 2022) retrieved from Web of Science and China National Knowledge Infrastructure (CNKI) based on keyword search, quantified and compared the amount, spatial heterogeneity, and temporal stability characteristics of penetrating rain in different climate zones and plant functional types. Our results that throughfall proportion was lower in arid regions (72.0%±13.6%) than humid (75.1%±9.3%) and semi-humid areas (79.9%±10.4%). Cold climates had lower values (74.1%±14.6%) than temperate (74.2%±7.5%) and tropical climates (80.9%±14.6%). Shrubs (68.9%±14.9%) generally had lower throughfall proportion than trees (76.7%±9.1%). Broad-leaved trees (75.2%±11.1%) and conifers (75.1%±9.9%) showed similar throughfall proportions, as did evergreen (76.7%±10.0%) and deciduous species (74.7%±11.9%). Additionally, spatial variability (coefficient of variation) did not significantly differ across rainfall zones, temperature zones, or vegetation types. The spatial distribution of throughfall was relatively stable. Canopy structure was the dominant factor affecting temporal stability of throughfall. However, there was a lack of comparison between typical geographic units ( i.e. spatial units with basically consistent geographical environmental conditions) at various temporal scales. Future research should expand upwards to the summary of global spatial scale rules and downwards to the analysis of process based temporal scale mechanisms, to depict the dynamic distribution of penetrating rain and unify observation standards to enhance comparability of different studies, in order to efficiently promote research on canopy penetrating rain and provide ecological and hydrological basis for protecting nature, managing artificial activities, and restoring degraded ecosystems.

This study established a rat model of obesity by using a high-fat diet(HFD) to explore the effect of polymethoxylated flavonoids on glucose and lipid metabolism in the model rats and decipher the role and mechanism of polymethoxylated flavonoids in mitigating obesity. Thirty normal SD rats were selected and randomized into normal, model, ezetimibe(0.1 mg·kg~(-1)), and polymethoxylated flavonoids(62.5 mg·kg~(-1) and 125 mg·kg~(-1)) groups based on the body weight. Except the normal group receiving a conventional diet, the other groups received a HFD. Rats were administrated with corresponding doses of drugs by gavage. During the administration period, the body weight of each group of rats was regularly weighed, and the serum lipid and glucose levels were measured by a fully automated biochemical analyzer. Islet homeostasis and serum levels of obesity factors were measured by ELISA. The 16S rRNA high-throughput sequencing was employed to study the gut microbiota. Hematoxylin-eosin staining was employed to observe the histomorphology of white fat, brown fat, and pancreas. After the wet weights of white fat and brown fat were measured, the organ index was calculated. Immunohistochemistry and Western blot were employed to determine the protein levels. The results showed that polymethoxylated flavonoids reduced the body weight and Lee's index and improved blood lipid levels of the model rats. Polymethoxylated flavonoids reduced blood glucose and insulin secretion, increased insulin responsiveness, and alleviated insulin resistance. In addition, polymethoxylated flavonoids regulated the serum levels of obesity factors and reduced the weights and indexes of white fat and brown fat, the diameter of white adipocytes, and the number of fat vacuoles in brown fat and pancreatic islet cells. The intervention with polymethoxylated flavonoids increased the diversity of gut microbiota in the model rats, increasing the beneficial bacteria associated with glucose and lipid metabolism and reduced the harmful bacteria at the genus level. In addition, polymethoxylated flavonoids up-regulated the protein levels of glucose transporter 4(GLUT4), phosphorylated AMP-activated protein kinase(p-AMPK), peroxisome proliferator-activated receptor gamma coactivator-1α(PGC-1α), and uncoupling protein 1(UCP1). In summary, polymethoxylated flavonoids may increase the body utilization of glucose and lipids by regulating the homeostasis of insulin, the serum levels of obesity factors, the diversity of gut microbiota, and the expression of mitochondrial metabolism-related proteins in brown adipocytes, thereby mitigating obesity in rats.

The incidence and mortality rates of early-onset colorectal cancer (EOCRC) among people under 50 years old are showing an upward trend. Although traditional epidemiological studies have conducted relatively deep research and screened out environmental factors related to EOCRC, our understanding of the causes, mechanisms, and treatment of this disease is still far from sufficient. In this review, we clarify the current progress of EOCRC, with a particular focus on epidemiology, screening status, clinical symptoms, and prognosis. This provides new evidence for secondary prevention, including precision screening, and offers new ideas for improving the diagnosis and treatment of EOCRC.

Competing Interests: The authors have no conflicts of interest relevant to this article.

Interleukin 7 Receptor alpha Severe Combined Immunodeficiency (IL7R-SCID) is a life-threatening disorder caused by homozygous mutations in the IL7RA gene. Defective IL7R expression in humans hampers T cell precursors' proliferation and differentiation during lymphopoiesis resulting in the absence of T cells in newborns, who succumb to severe infections and death early after birth. Previous attempts to tackle IL7R-SCID by viral gene therapy have shown that unregulated IL7R expression predisposes to leukemia, suggesting the application of targeted gene editing to insert a correct copy of the IL7RA gene in its genomic locus and mediate its physiological expression as a more feasible therapeutic approach. To this aim, we have first developed a CRISPR/Cas9-based IL7R-SCID disease modeling system that recapitulates the disease phenotype in primary human T cells and hematopoietic stem and progenitor cells (HSPCs). Then, we have designed a knockin strategy that targets IL7RA exon 1 and introduces through homology-directed repair a corrective, promoterless IL7RA cDNA followed by a reporter cassette through AAV6 transduction. Targeted integration of the corrective cassette in primary T cells restored IL7R expression and rescued functional downstream IL7R signaling. When applied to HSPCs further induced to differentiate into T cells in an Artificial Thymic Organoid system, our gene editing strategy overcame the T cell developmental block observed in IL7R-SCID patients, while promoting full maturation of T cells with physiological and developmentally regulated IL7R expression. Finally, genotoxicity assessment of the CRISPR/Cas9 platform in HSPCs using biased and unbiased technologies confirmed the safety of the strategy, paving the way for a new, efficient, and safe therapeutic option for IL7R-SCID patients.

Alzheimer's disease (AD) is more prevalent in women than men, supposing due to the decline of estrogens in menopause, accompanied by increased gonadotropins such as luteinizing hormone (LH). We and others found that the transcription factor early growth response-1 (EGR1) regulates cholinergic function including the expression of acetylcholinesterase (AChE) and plays a significant role in cognitive decline of AD. Here we investigated in APP/PS1 mice by ovariectomy (OVX) and estradiol (E2) supplementation or inhibition of LH the effect on hippocampus-related cognition and related molecular changes. We found that OVX-associated cognitive impairment was accompanied by increased dorsal hippocampal EGR1 expression, which was rescued by downregulating peripheral LH rather than by supplementing E2. We also found in postmortem AD brains a higher expression of pituitary LH-mRNA and higher EGR1 expression in the posterior hippocampus. Both, in human and mice, there was a significant positive correlation between respectively posterior/dorsal hippocampal EGR1 and peripheral LH expression. We conclude that peripheral increased LH and increased posterior hippocampal EGR1 plays a significant role in AD pathology., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Numerous investigations have underscored the causal effect between chronic pain (CP) and gut microbiota, jointly contributing to the onset and development of widespread CP. Nonetheless, there was still uncertainty about the causal effect between gut microbiota and chronic regional pain (CRP)., Methods: Genome-wide association study (GWAS) summary data of gut microbial taxa (MiBioGen Consortium: 211 microbiotas and the Dutch Microbiome Project: 207 microbiotas) and eight types of CRP were used to reveal the causal effect between persistent pain in a specific region of the body and gut microbiota. A two-sample bidirectional Mendelian randomization (MR) design was used. In order to ensure the accuracy of the results, multiple sensitivity analyses were employed., Results: This study uncovered significant causal associations between six gut microbial taxa and three types of CRP (forward: Genus Parabacteroides for general pain; Class Bacteroidia , Order Bacteroidales, and Phylum Bacteroidetes for back pain. Reverse: knee pain for Genus Howardella and Order Coriobacteriales ) by forward and reverse MR analysis. These findings had been verified by a rigorous Bonferroni correction. Furthermore, this research identified 19 microbial taxa that exhibited potential correlations with four types of CRP. There are no significant or potential gut microbiotas that were associated with other types of CRP, including fascial pain, stomach or abdominal pain, and hip pain., Conclusion: This two-sample bidirectional MR analysis unveiled the causality between gut microbial taxa and eight CRP conditions. The findings reveal the interplay between CRP and 6 gut microbiotas while also delineating 19 potential specific microbial taxa corresponding to diverse locations of persistent pain., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Xiao, Qin, Yu, Hu, Ai, Wang, Xia and Zhang.)

Current studies on the immune microenvironment of colorectal cancer (CRC) were mostly limited to the tissue level, lacking relevant studies in the peripheral blood, and failed to describe its alterations in the whole process of adenocarcinoma formation, especially of adenoma carcinogenesis. Here, we constructed a large-scale population cohort and used the CyTOF to explore the changes of various immune cell subsets in peripheral blood of CRC. We found monocytes and basophils cells were significantly higher in adenocarcinoma patients. Compared with early-stage CRC, effector CD4 + T cells and naive B cells were higher in patients with lymph node metastasis, whereas the basophils were lower. We also performed random forest algorithm and found monocytes play the key role in carcinogenesis. Our study draws a peripheral blood immune cell landscape of the occurrence and development of CRC at the single-cell level and provides a reference for other researchers., Competing Interests: The authors declare no competing interests., (© 2024 The Authors.)

With the widespread application of colorectal cancer screening, the surveillance and management of the increasing number of screened population has become a pivotal aspect in preventing and controlling colorectal cancer. In recent years, researches have been conducted on the risk of colorectal cancer incidence and mortality in the population after screening. At the same time, various organizations in Europe and the United States have continuously updated colonoscopy surveillance after screening and polypectomy based on the latest research evidence. In this review, we summarized the current progress of studies on colorectal cancer risk in post-screening colorectal cancer populations and the key points of relevant guideline updates, in order to provide a reference for conducting relevant studies and formulating surveillance guidelines or consensus in China.

Background: In the majority of clinical environments, the treponema pallidum particle agglutination (TPPA) test is known for its higher specificity compared to the rapid plasma reagin (RPR) test and is commonly employed for the diagnosis of syphilis, but their use for serological monitoring after syphilis therapy is controversial., Objectives: We aim to evaluate whether the TPPA titers is suitable for monitoring syphilis treatment efficacy., Methods: At first, 232 patients with primary syphilis were recruited. Serological testing was performed at baseline (initial visit) and at 6 months (±1 month) after benzathine penicillin G (BPG) treatment. Second, New Zealand white male rabbits were infected with Treponema pallidum (T. pallidum) to evaluate the changes in TPPA titers after BPG therapy. Finally, we compared the TPPA titers in the culture supernatant of rabbit splenocytes stimulated with T. pallidum with or without BPG., Results: After 6 months of treatment, 150 (64.7%) of 232 primary syphilis patients achieved serological cure, and 82 (35.3%) had adverse outcomes. Among 110 patients with TPPA titers decreased by more than fourfold, 109 of them were serological cure patients (≥4-fold decrease in RPR titers) (P ＜ 0.0001). In the rabbit model of syphilis, the TPPA titers was significantly decreased in the treatment subgroup (P = 0.016) and remained constant (±2-fold) or increased (≥4-fold) in the nontreatment subgroup. In addition, T. pallidum resulted in a positive TPPA titers in the culture supernatant of splenocytes (median titers was 1: 80), while BPG could directly reduce the TPPA titers in the culture supernatant (median titers was 1: 40) (P = 0.032)., Conclusions: A 4-fold or greater decrease in TPPA titers may indicate effective treatment in primary syphilis. Combining TPPA titers with RPR titers results may potentially aid in the early diagnosis of syphilis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Repetitive transcranial magnetic stimulation (rTMS) at left dorsolateral prefrontal cortex (lDLPFC) is commonly used in major depressive disorder (MDD), even though its therapeutic efficacy is limited. Given that many MDD patients show psychomotor retardation, we aim to examine whether the left motor cortex (lMC) as a novel rTMS target would provide effective and well-tolerated treatment as being comparable to lDLPFC-rTMS., Methods: In this prospective double-blind randomized single-center study, 131 MDD patients were randomly assigned to the lDLPFC or lMC group and were treated with 10 Hz rTMS (90 % motor threshold) applied twice daily for 4000 pulses continuously over five days. The primary endpoint was the Hamilton Depression Scale (HAMD) total score change after treatment., Results: After the five-day rTMS treatment, there was no significant difference in both HAMD reduction rate (lDLPFC 59.3 % ± 20.4 %, lMC 51.3 % ± 26.3 %, P = 0.10) and adverse effects (P = 0.79) between 48 (73.8 %) lMC subjects and 51 (77.3 %) lDLPFC subjects. Furthermore, the lMC study group showed stable HAMD scores at follow-up compared to their endpoint scores (P = 0.08)., Limitations: Sham-control group was not included and the sample size was small. Therefore, our results should be seen as exploratory and preliminary., Conclusions: The preliminary good therapeutic response, comparability, and tolerability of lMC-rTMS suggest lMC a potential and more easily accessible rTMS target. Together, our findings raise the possibility of symptom-specific rTMS in motor cortex (psychomotor retardation) or lDLPFC (cognitive deficits). This warrants larger clinical trials of rTMS in MDD with symptom-specific stimulation targets., Competing Interests: Declaration of competing interest All authors declared no competing interests for this study. There are no other disclosures., (Copyright © 2023. Published by Elsevier B.V.)

Porous cryptomelane-type Mn oxide (OMS-2) has an outstanding redox property, making it a highly desirable substitute for noble metal catalysts for CO oxidation, but its catalytic activity still needs to be improved, especially in the presence of water. Given the strong structure-performance correlation of OMS-2 for oxidation reactions, herein, OMS-2 is synthesized by solid state (OMS-2 S ), reflux (OMS-2 R ), and hydrothermal (OMS-2 H ) methods, aiming to improve its CO oxidation performance through manipulating synthesis parameters to tailor its particle size, morphology, and crystallinity. Characterization shows that OMS-2 S has the highest CO oxidation activity in the absence of water due to its low crystallinity, high specific surface area, large oxygen vacancy content, and good redox property, but the presence of water can greatly reduce its CO oxidation activity. Doping Cu into an OMS-2 can not only improve its CO oxidation activity but also greatly improve its water tolerance. The Cu-doped OMS-2 S catalyst with ∼4 wt % Cu can achieve a T 90 of 49 °C (1% CO/10% O 2 /N 2 and WHSV = 60,000 mL·g -1 ·h -1 ), ranking among the lowest reported T 90 values for Mn oxide-based CO oxidation catalysts, and it can maintain nearly 100% CO conversion in the presence of 5 vol % water for over 50 h. In situ DRIFTs characterization indicates that the good water resistance of Cu-doped OMS-2 S can be attributed to the significantly suppressed surface hydroxyl group generation because of Cu doping. This work demonstrates the importance of the synthesis method and Cu doping in determining the CO oxidation activity and water resistance of OMS-2 and will provide guidance for synthesizing highly active and water-resistant CO oxidation catalysts.

Amino acids along the conformational motion pathway of the enzyme molecule correlated to its flexibility and rigidity. To enhance the enzyme activity and thermal stability, the motion pathway of Geobacillus stearothermophilus α-amylase has been identified and molecularly modified by using the neural relational inference model and deep learning tool. The significant differences in substrate specificity, enzymatic kinetics, optimal temperature, and thermal stability were observed among the mutants with modified amino acids along the pathway. Mutants especially the P44E demonstrated enhanced hydrolytic activity and catalytic efficiency (k cat /K M ) than the wild-type enzyme to 95.0% and 93.8% respectively, with the optimum temperature increased to 90°C. This mutation from proline to glutamic acid has increased the number and the radius of the bottleneck of the channels, which might facilitate transporting large starch substrates into the enzyme. The mutation could also optimize the hydrogen bonding network of the catalytic center, and diminish the spatial hindering to the substrate entry and exit from the catalytic center., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Hu, Hong, Li, Yang, Shen, Wang and Liu.)

Obesity, a global pandemic posing a growing threat to human health, necessitates the development of effective and safe anti-obesity agents. Our previous studies highlighted the lipid-lowering effects of indolylquinazoline Bouchardatine and its derivatives. In this study, we employed scaffold hopping and simplification strategies to design and synthesize two new series derivatives by modifying the D ring. Extensive discussions have been conducted regarding the structure-activity relationship between lipid-lowering activity and the new compounds. These discussions have resulted in the discovery of 2-pyrimidinylindole derivatives as a promising scaffold for anti-obesity treatment. The new 2-pyrimidinylindole derivatives exhibited comparable lipid-lowering activity to the previously reported indolylquinazoline derivatives, including SYSU-3d and R17, with reduced toxicity. The most potent compound, 5a, demonstrated a larger therapeutic index, improved aqueous solubility and oral bioavailability compared to the previous lead compounds. In vivo evaluation indicated that 5a effectively reduced lipid accumulation in adipose tissue, improved glucose tolerance, and mitigated insulin resistance and liver function damage caused by a high-fat and high-cholesterol diet. Mechanism studies indicated that 5a may regulate lipid metabolism through the modulation of the PPARγ signaling pathway. Overall, our study has identified a highly active compound 5a, and provided the basis for further development of 2-pyrimidinylindole as a promising scaffold for obesity treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Background and Aim: Previous studies have reported an association between gut microbiota and cirrhosis. However, the causality between intestinal flora and liver cirrhosis still remains unclear. In this study, bi-directional Mendelian randomization (MR) analysis was used to ascertain the potential causal effect between gut microbes and cirrhosis., Methods: Large-scale Genome Wide Association Study (GWAS) data of cirrhosis and gut microbes were obtained from FinnGen, Mibiogen consortium, and a GWAS meta-analysis of Alcoholic cirrhosis (ALC). Two-sample MR was performed to determine the causal relationship between gut microbiota and cirrhosis. Furthermore, a bi-directional MR analysis was employed to examine the direction of the causal relations., Result: In MR analysis, we found that 21 gut microbiotas were potentially associated with cirrhosis. In reverse MR analysis, 11 gut microbiotas displayed potentially associations between genetic liability in the gut microbiome and cirrhosis. We found that the family Lachnospiraceae (OR: 1.59, 95% CI:1.10-2.29) might be harmful in cirrhotic conditions (ICD-10: K74). Furthermore, the genus Erysipelatoclostridium might be a protective factor for cirrhosis (OR:0.55, 95% CI:0.34-0.88) and PBC (OR:0.68, 95% CI:0.52-0.89). Combining the results from the MR analysis and reverse MR analysis, we firstly identified the Genus Butyricicoccus had a bi-directional causal effect on PBC (Forward: OR: 0.37, 95% CI:0.15-0.93; Reverse: OR: 1.03, 95% CI:1.00-1.05)., Conclusion: We found a new potential causal effect between cirrhosis and intestinal flora and provided new insights into the role of gut microbiota in the pathological progression of liver cirrhosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Xiao, Yang, Chen, Xie, Li, Fu, Han, Qin, Tian, Zhao, Cai, Hu, Ai, Li, Chen, Wang, Tan, Xia and Zhang.)

IgA nephropathy (IgAN), the most common form of primary glomerulonephritis, is mainly observed in young adults and children. Clinical and basic studies indicate the role of immunity in IgAN pathogenesis; however, corticosteroid therapy has been controversial in past decades. The TESTING study, initiated in 2012, is an international, multicenter, double-blinded, randomized, placebo-controlled trial that aimed to evaluate oral methylprednisolone's safety and long-term efficacy under conditions of optimized supportive treatment in patients with IgAN whose risk of progression is high. After a decade of effort, the successful completion of the TESTING study showed that a 6- to 9-month course of oral methylprednisolone is an effective regimen to protect kidney function in high-risk patients with IgAN, but also demonstrated safety concerns. Compared with the full-dose regimen, the reduced-dose regimen was reported to be beneficial, with successfully increased safety. Overall, the TESTING trial provided more data regarding the treatment dosage and safety of corticosteroids, a cost-effective therapy, in IgAN, which have important implications for pediatric patients with IgAN. With a deeper understanding of the disease pathogenesis of IgAN, ongoing studies of novel therapeutic regimens would help further optimize the benefit-risk ratio., (© 2023. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Introduction: Women are more vulnerable to Alzheimer's disease (AD) than men. The entorhinal cortex (EC) is one of the earliest structures affected in AD. We identified in cognitively intact elderly different molecular changes in the EC in relation to age., Methods: Changes in 12 characteristic molecules in relation to age were determined by quantitative immunohistochemistry or in situ hybridization in the EC. They were arbitrarily grouped into sex steroid-related molecules, markers of neuronal activity, neurotransmitter-related molecules, and cholinergic activity-related molecules., Results: The changes in molecules indicated increasing local estrogenic and neuronal activity accompanied by a higher and faster hyperphosphorylated tau accumulation in women's EC in relation to age, versus a mainly stable local estrogenic/androgenic and neuronal activity in men's EC., Discussion: EC employs a different neurobiological strategy in women and men to maintain cognitive function, which seems to be accompanied by an earlier start of AD in women., Highlights: Local estrogen system is activated with age only in women's entorhinal cortex (EC). EC neuronal activity increased with age only in elderly women with intact cognition. Men and women have different molecular strategies to retain cognition with aging. P-tau accumulation in the EC was higher and faster in cognitively intact elderly women., (© 2023 the Alzheimer's Association.)

Treponema pallidum (Tp) has a well-known ability to evade the immune system and can cause neurosyphilis by invading the central nervous system (CNS). Microglia are resident macrophages of the CNS that are essential for host defense against pathogens, this study aims to investigate the interaction between Tp and microglia and the potential mechanism. Here, we found that Tp can exert significant toxic effects on microglia in vivo in Tg (mpeg1: EGFP) transgenic zebrafish embryos. Single-cell RNA sequencing results showed that Tp downregulated autophagy-related genes in human HMC3 microglial cells, which is negatively associated with apoptotic gene expression. Biochemical and cell biology assays further established that Tp inhibits microglial autophagy by interfering with the autophagosome-lysosome fusion process. Transcription factor EB (TFEB) is a master regulator of lysosome biogenesis, Tp activates the mechanistic target of rapamycin complex 1 (mTORC1) signaling to inhibit the nuclear translocation of TFEB, leading to decreased lysosomal biogenesis and accumulated autophagosome. Importantly, the inhibition of autophagosome formation reversed Tp-induced apoptosis and promoted microglial clearance of Tp. Taken together, these findings show that Tp blocks autophagic flux by inhibiting TFEB-mediated lysosomal biosynthesis in human microglia. Autophagosome accumulation was demonstrated to be a key mechanism underlying the effects of Tp in promoting apoptosis and preventing itself from clearing by human microglia. This study offers novel perspectives on the potential mechanism of immune evasion employed by Tp within CNS. The results not only establish the pivotal role of autophagy dysregulation in the detrimental effects of Tp on microglial cells but also bear considerable implications for the development of therapeutic strategies against Tp, specifically involving mTORC1 inhibitors and autophagosome formation inhibitors, in the context of neurosyphilis patients., Competing Interests: The authors have declared that no conflict of interest exists., (Copyright: © 2023 Hu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Colorectal cancer (CRC) is a major malignancy threatening the health of people in China and screening could be effective for preventing the occurrence and reducing the mortality of CRC. We conducted a multicenter, prospective clinical study which recruited 4,245 high-risk CRC individuals defined as having positive risk-adapted scores or fecal immunochemical test (FIT) results, to evaluate the clinical performance of the multitarget fecal immunochemical and stool DNA (FIT-sDNA) test for CRC screening. Each participant was asked to provide a stool sample prior to bowel preparation, and FIT-sDNA test and FIT were performed independently of colonoscopy. We found that 186 (4.4%) were confirmed to have CRC, and 375 (8.8%) had advanced precancerous neoplasia among the high CRC risk individuals. The sensitivity of detecting CRC for FIT-sDNA test was 91.9% (95% CI, 86.8-95.3), compared with 62.4% (95% CI, 54.9-69.3) for FIT ( P  < 0.001). The sensitivity for detecting advanced precancerous neoplasia was 63.5% (95% CI, 58.3-68.3) for FIT-sDNA test, compared with 30.9% (95% CI, 26.3-35.6) for FIT ( P  < 0.001). Multitarget FIT-sDNA test detected more colorectal advanced neoplasia than FIT. Overall, these findings indicated that in areas with limited colonoscopy resources, FIT-sDNA test could be a promising further risk triaging modality to select patients for colonoscopy in CRC screening., Competing Interests: Xiao‐Tian Yu is the Medical Director, Ning Lv is the Chief Technology Officer, and Yi‐You Chen is the Chief Scientist at Hangzhou New Horizon Health Technology Company. The other authors declare no conflicts of interest., (© 2023 The Authors. MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.)

Changes in nitrogen (N) deposition and litter mixtures have been shown to influence ecosystem processes such as litter decomposition. However, the interactive effects of litter mixing and N-deposition on decomposition process in desert regions remain poorly identified. We assessed the simultaneous effects of both N addition and litter mixture on mass loss in a litterbag decomposition experiment using six native plants in single-species samples with diverse quality and 14-species combinations in the Gurbantunggut Desert under two N addition treatments (control and N addition). The N addition had no significant effect on decomposition rate of single-species litter (expect Haloxylon ammodendron ), whereas litter mass loss and decomposition rate differed significantly among species, with variations positively correlated with initial phosphorus concentration and negatively correlated with initial lignin concentration. After 18 months, the average mass loss across litter mixtures did not overall differ from those predicted from single species either in control or N addition treatments, that is, mixing of different species had no non-additive effects on decomposition. The N addition, however, did modify the direction of mixture effects and interacted with incubation time. Added N transformed synergistic effects of litter mixtures to antagonistic effects on mass loss after 1 month of decomposition, while transforming neutral effects of litter mixture to synergistic effects after 6 months of decomposition. Our results demonstrated that initial chemical properties played an important role in litter decomposition, while no effects of litter mixture on decomposition process in this desert region. The N addition altered the litter mixture effects on mass loss with incubation time, implying that increased N deposition in the future may have profound effects on carbon turnover to a greater extent than previously thought in desert ecosystems., Competing Interests: The authors have no conflict of interest., (© 2023 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

Generation and acceleration of energetic positrons based on laser plasma have attracted intense attention due to their potential applications in medical physics, high energy physics, astrophysics and nuclear physics. However, such compact positron sources face a series of challenges including the beam dispersion, dephasing and unstability. Here, we propose a scheme that couples the all-optical generation of electron-positron pairs and rapid acceleration of copious positrons in the terahertz (THz) field. In the scheme, nanocoulomb-scale electrons are first captured in the wakefield and accelerated to 2.5 GeV. Then these energetic electrons emit strong THz radiation when they go through an aluminum foil. Subsequently, abundant γ photons and positrons are generated during the collision of GeV electron beam and the scattering laser. Due to the strong longitudinal acceleration field and the transvers confining field of the emitted THz wave, the positrons can be efficiently accelerated to 800 MeV, with the peak beam brilliance of 2.26 × 10 12 s -1 mm -2 mrad -2 eV -1 . This can arouse potential research interests from PW-class laser facilities together with a GeV electron beamline.

A ruthenium complex [Ru(phen) 2 (phen-5-amine)-C14] (Ru-C14) with broad-spectrum antibacterial activity was designed and synthesized; positively charged Ru-C14 could target bacteria via electrostatic interactions and showed high binding effectiveness to cell membranes. In addition, Ru-C14 could act as a photosensitizer. Under 465 nm light irradiation, Ru-C14 could generate 1 O 2 , thus disrupting the bacterial intracellular redox balance and leading to bacterial death. Ru-C14 also exhibited minimum inhibitory concentration values of 6.25 μM against Escherichia coli and 3.125 μM against Staphylococcus aureus ; these values are lower than those of streptomycin and methicillin. This work combined the merits of cell membrane targeting and photodynamic therapy for antibacterial activity. The findings might open up a new avenue for effective anti-infection treatment and other medical applications.

Metabolic reprogramming is a crucial hallmark of tumorigenesis. Modulating the reprogrammed energy metabolism is an attractive anticancer therapeutic strategy. We previously found a natural product, bouchardatine , modulated aerobic metabolism and inhibited proliferation in the colorectal cancer cell (CRC). Herein, we designed and synthesized a new series of bouchardatine derivatives to discover more potential modulators. We applied the dual-parametric high-content screening (HCS) to evaluate their AMP-activated protein kinase (AMPK) modulation and CRC proliferation inhibition effect simultaneously. And we found their antiproliferation activities were highly correlated to AMPK activation. Among them, 18a was identified with nanomole-level antiproliferation activities against several CRCs. Interestingly, the evaluation found that 18a selectively upregulated oxidative phosphorylation (OXPHOS) and inhibited proliferation by modulating energy metabolism. Additionally, this compound effectively inhibited the RKO xenograft growth along with AMPK activation. In conclusion, our study identified 18a as a promising candidate for CRC treatment and suggested a novel anti-CRC strategy by AMPK activating and OXPHOS upregulating.

Although bone marrow mesenchymal stem cells (BMSCs) might have therapeutic potency in ischemic stroke, the benefits are limited. The current study investigated the effects of BMSCs engineered to overexpress vascular endothelial growth factor (VEGF) on behavioral defects in a rat model of transient cerebral ischemia, which was induced by middle cerebral artery occlusion. VEGF-BMSCs or control grafts were injected into the left striatum of the infarcted hemisphere 24 hours after stroke. We found that compared with the stroke-only group and the vehicle- and BMSCs-control groups, the VEGF-BMSCs treated animals displayed the largest benefits, as evidenced by attenuated behavioral defects and smaller infarct volume 7 days after stroke. Additionally, VEGF-BMSCs greatly inhibited destruction of the blood-brain barrier, increased the regeneration of blood vessels in the region of ischemic penumbra, and reducedneuronal degeneration surrounding the infarct core. Further mechanistic studies showed that among all transplant groups, VEGF-BMSCs transplantation induced the highest level of brain-derived neurotrophic factor. These results suggest that BMSCs transplantation with vascular endothelial growth factor has the potential to treat ischemic stroke with better results than are currently available., Competing Interests: None

Objectives: Hepatectomy is the best treatment for patients with intrahepatic cholangiocarcinoma (ICC) at present, but there has been controversy about the width of surgical margins. In this study, we systematically investigated the effects of different surgical margin widths on the prognosis of patients with ICC undergoing hepatectomy., Design: Systematic review and meta-analysis., Data Sources: PubMed, Embase and Web of Science databases were systematically searched from inception to June 2022., Eligibility Criteria: Cohort studies reported in English with patients who underwent negative marginal (R0) resection were included. The effects of surgical margin width on overall survival (OS), disease-free survival (DFS) and recurrence-free survival (RFS) in patients with ICC were assessed., Data Extraction and Synthesis: Two investigators independently conducted literature screening and data extraction. Risk of bias was assessed using funnel plots and quality was assessed by the Newcastle-Ottawa Scale. Forest plots of HRs and their 95% CIs for outcome indicators were plotted. Heterogeneity was assessed and determined quantitatively using I 2 , and the stability of the study results was evaluated using sensitivity analysis. Analyses were performed using Stata software., Results: Nine studies were included. With the wide margin group (≥10 mm) as the control, pooled HR of OS in the narrow margin group (<10 mm) was 1.54 (95% CI 1.34 to 1.77). HRs of OS in three subgroups where the margin was less than 5 mm ranged from 5 mm to 9 mm, or was less than 10 mm in length were 1.88 (1.45 to 2.42), 1.33 (1.03 to 1.72) and 1.49 (1.20 to 1.84), respectively. Pooled HR of DFS in the narrow margin group (<10 mm) was 1.51 (1.14 to 2.00). Pooled HR of RFS in the narrow margin group (<10 mm) was 1.35 (1.19 to 1.54). HRs of RFS in three subgroups where the margin was less than 5 mm ranged from 5 mm to 9 mm, or was less than 10 mm in length were 1.38 (1.07 to 1.78), 1.39 (1.11 to 1.74) and 1.30 (1.06 to 1.60), respectively. Neither lymph node lesions (HR 1.44, 95% CI 1.22 to 1.70) nor lymph node invasion (2.14, 1.39 to 3.28) was favourable for postoperative OS in patients with ICC. Lymph node metastasis (1.31, 1.09 to 1.57) was unfavourable for RFS in patients with ICC., Conclusion: Patients with ICC who underwent curative hepatectomy with a negative margin ≥10 mm may have a long-term survival advantage, but lymph node dissection also needs to be considered. In addition, tumour-related pathological features need to be explored to see if they affect the surgical outcome of R0 margins., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

In the period of the Republic of China, the maternal and infant mortality rates were high, most of which were caused by puerperal fever and neonatal tetanus. In this sense, Chinese traditional midwives were often regarded as "dirty". After western obstetrics was introduced into China in the late Qing Dynasty and the early period of the Republic of China,the occurrence of postpartum infection was effectively reduced with childbirth disinfection. To improve the health status of women and infants, the government of the Republic of China put in place measures to develop midwifery. The training of the traditional midwives was included in midwifery education. The delivery basket was used to help promote the new method of delivery and popularise the concept of sterilization of delivery. Thus, midwifery was remodeled and the remodeled midwives played an important role in family midwifery education.

Bone marrow-derived mesenchymal stem cells (BMSCs) can differentiate into hepatocyte-like cells (HLCs) to alleviate acute liver injury (ALI). Herpetfluorenone (HPF), as an active ingredient in the dried, mature seeds Herpetospermum caudigerum Wall, used in Tibetan medicine, has been proven to effectively alleviate ALI. Therefore, the purpose of this study was to determine whether HPF can promote the differentiation of BMSCs into HLCs and promote ALI recovery. Mouse BMSCs were isolated, and the BMSCs' differentiation into HLCs was induced by HPF and hepatocyte growth factor (HGF). Under the induction of HPF and HGF, the expression of hepatocellular specific markers and the accumulation of glycogen and lipids in the BMSCs increased, indicating that BMSCs successfully differentiated into HLCs. Then, the ALI mouse model was established, using carbon tetrachloride, followed by an intravenous injection of BMSCs. Then, only HPF was injected intraperitoneally, in order to verify the effect of HPF in vivo. In vivo imaging was used to detect the homing ability of HPF-BMSCs, and it was detected that HPF-BMSCs significantly increased the levels of serum AST, ALT and ALP in the liver of ALI mice, and alleviated liver cell necrosis, oxidative stress and liver pathology. In conclusion, HPF can promote the differentiation of BMSCs into HLCs and promote the recovery of ALI in mice.

Background: F-box and leucine-rich repeat 6 (FBXL6) have reportedly been associated with several cancer types. However, the role and mechanisms of FBXL6 in gastric cancer (GC) require further elucidation., Aim: To investigate the effect of FBXL6 in GC tissues and cells and the underlying mechanisms., Methods: TCGA and GEO database analysis was performed to evaluate the expression of FBXL6 in GC tissues and adjacent normal tissues. Reverse transcription-quantitative polymerase chain reaction, immunofluorescence, and western blotting were used to detect the expression of FBXL6 in GC tissue and cell lines. Cell clone formation, 5-ethynyl-2'-deoxyuridine (EdU) assays, CCK-8, transwell migration assay, and wound healing assays were performed to evaluate the malignant biological behavior in GC cell lines after transfection with FBXL6-shRNA and the overexpression of FBXL6 plasmids. Furthermore, in vivo tumor assays were performed to prove whether FBXL6 promoted cell proliferation in vivo ., Results: FBXL6 expression was upregulated more in tumor tissues than in adjacent normal tissues and positively associated with clinicopathological characteristics. The outcomes of CCK-8, clone formation, and Edu assays demonstrated that FBXL6 knockdown inhibited cell proliferation, whereas upregulation of FBXL6 promoted proliferation in GC cells. Additionally, the transwell migration assay revealed that FBXL6 knockdown suppressed migration and invasion, whereas the overexpression of FBXL6 showed the opposite results. Through the subcutaneous tumor implantation assay, it was evident that the knockdown of FBXL6 inhibited GC graft tumor growth in vivo . Western blotting showed that the effects of FBXL6 on the expression of the proteins associated with the epithelial-mesenchymal transition-associated proteins in GC cells., Conclusion: Silencing of FBXL6 inactivated the EMT pathway to suppress GC malignancy in vitro . FBXL6 can potentially be used for the diagnosis and targeted therapy of patients with GC., Competing Interests: Conflict-of-interest statement: There is no conflict of interest in this study., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)