Hippocampal excitation-inhibition balance underlies the 5-HT2C receptor in modulating depressive behaviours.

The implication of 5-hydroxytryptamine 2C receptor (5-HT2CR) in depression is a topic of debate, and the underlying mechanisms remain largely unclear. We now elucidate hippocampal excitation-inhibition (E/I) balance underlies the regulatory effects of 5-HT2CR in depression. Molecular biological analyses showed that chronic mild stress (CMS) reduced the expression of 5-HT2CR in hippocampus. We revealed that inhibition of 5-HT2CR induced depressive-like behaviors, reduced GABA release and shifted the E/I balance towards excitation in CA3 pyramidal neurons by using behavioral analyses, microdialysis coupled with mass spectrum, and electrophysiological recording. Moreover, 5-HT2CR modulated neuronal nitric oxide synthase (nNOS)-carboxy-terminal PDZ ligand of nNOS (CAPON) interaction through influencing intracellular Ca2+ release, as determined by fiber photometry and coimmunoprecipitation. Notably, disruption of nNOS-CAPON by specific small molecule compound ZLc-002 or AAV-CMV-CAPON-125C-GFP, abolished 5-HT2CR inhibition-induced depressive-like behaviors, as well as the impairment in soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex assembly-mediated GABA vesicle release and a consequent E/I imbalance. Importantly, optogenetic inhibition of CA3 GABAergic neurons prevented the effects of AAV-CMV-CAPON-125C-GFP on depressive behaviors in the presence of 5-HT2CR antagonist. Conclusively, our findings disclose the regulatory role of 5-HT2CR in depressive-like behaviors and highlight the hippocampal nNOS-CAPON coupling-triggered E/I imbalance as a pivotal cellular event underpinning the behavioral consequences of 5-HT2CR inhibition.

Clinicopathological characteristics and prognosis of Epstein-Barr virus-associated gastric cancer.

OBJECTIVE: Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC) is a distinct molecular subtype of gastric cancer (GC). At present, the clinical characteristics and prognostic implications of EBV infection and the potential clinical benefits of immune checkpoint blockade in GC remain to be clarified. Hence, this study was designed to analyze the clinical and pathological characteristics of GC patients with varying EBV infection states and compare their overall survival (OS). METHODS: A retrospective study was performed on 1031 consecutive GC patients who underwent gastrectomy at the Affiliated Hospital of Xuzhou Medical University from February 2018 to November 2022. EBV-encoded RNA (EBER) in situ hybridization (ISH) was used for EBV assessment, and immunohistochemical staining was used for evaluation of human epidermal growth factor receptor 2 (HER2), programmed death ligand 1 (PD-L1), and Ki67 expression. EBVaGC was defined as tumors with EBV positivity. In addition, EBV-negative GC (EBVnGC) patients were matched with EBVaGC patients based on seven clinicopathological parameters (age, gender, anatomic subsite, tumor size, Lauren classification, degree of differentiation, and tumor-node-metastasis [TNM] stage). The correlations of clinical features with HER2, PD-L1, and Ki67 expression were evaluated statistically. The survival of patients was assessed through medical records, telephone, or WeChat communication, and prognostic analysis was performed using the logrank test as well as univariable and multivariable regression analysis. RESULTS: Out of 1031 GC patients tested, 35 (3.4%) were diagnosed with EBVaGC. Notably, the EBVaGC group exhibited a distinct predominance of males and younger patients, significantly higher Ki67 and PD-L1 expression levels, and a lower prevalence of pericancerous nerve invasion than the EBVnGC group (P < 0.01). In the 35 EBVaGC cases, Ki67 expression was negatively correlated with age (P < 0.05), suggesting that a younger onset age was associated with higher Ki67 expression. In addition, PD-L1 expression was correlated with the degree of differentiation, T-stage, and clinical stage of the patient. Furthermore, PD-L1 expression was elevated in tumors with lower differentiation or at later stages (P < 0.05). Using univariate analysis, Ki67, PD-L1, and clinical stage were identified as significant factors influencing the overall survival (OS) of EBVaGC patients (P < 0.05). Moreover, multivariate survival analysis revealed that clinical stage and Ki67 expression were independent risk factors for the OS of the patients (P < 0.05), and the three-year OS rate of EBVaGC patients was 64.2%. CONCLUSION: EBV-ISH is a practical and valuable method to identify EBVaGC. Owing to its unique etiological, pathological, and clinical characteristics, patients with EBVaGC might benefit from immune checkpoint blockade therapy.

Development and validation of the patient-reported outcome for older people living with HIV/AIDS in China (PROHIV-OLD).

BACKGROUND: The involvement of quality of life as the UNAIDS fourth 90 target to monitor the global HIV response highlighted the development of patient-reported outcome (PRO) measures to help address the holistic needs of people living with HIV/AIDS (PLWHA) beyond viral suppression. This study developed and tested preliminary measurement properties of a new patient-reported outcome (PROHIV-OLD) measure designed specifically to capture influences of HIV on patients aged 50 and older in China. METHODS: Ninety-three older people living with HIV/AIDS (PLWHA) were interviewed to solicit items and two rounds of patient cognitive interviews were conducted to modify the content and wording of the initial items. A validation study was then conducted to refine the initial instrument and evaluate measurement properties. Patients were recruited between February 2021 and November 2021, and followed six months later after the first investigation. Classical test theory (CTT) and item response theory (IRT) were used to select items using the baseline data. The follow-up data were used to evaluate the measurement properties of the final instrument. RESULTS: A total of 600 patients were recruited at the baseline. Of the 485 patients who completed the follow-up investigation, 483 were included in the validation sample. The final scale of PROHIV-OLD contained 25 items describing five dimensions (physical symptoms, mental status, illness perception, family relationship, and treatment). All the PROHIV-OLD dimensions had satisfactory reliability with Cronbach's alpha coefficient, McDonald's ω, and composite reliability of each dimension being all higher than 0.85. Most dimensions met the test-retest reliability standard except for the physical symptoms dimension (ICC = 0.64). Confirmatory factor analysis supported the structural validity of the final scale, and the model fit index satisfied the criterion. The correlations between dimensions of PROHIV-OLD and MOS-HIV met hypotheses in general. Significant differences on scores of the PROHIV-OLD were found between demographic and clinical subgroups, supporting known-groups validity. CONCLUSIONS: The PROHIV-OLD was found to have good feasibility, reliability and validity for evaluating health outcome of Chinese older PLWHA. Other measurement properties such as responsiveness and interpretability will be further examined.

Clinicopathological features, psychological status, and prognosis of 33 patients with occult breast cancer.

BACKGROUND: Occult breast cancer (OBC) has traditionally been considered to be a carcinoma of unknown primary origin with a favorable prognosis and can be treated as stage II-III breast cancer. Due to the small number of cases and limited clinical ex-perience, treatments vary greatly around the world and no standardized treat-ment has yet been established. AIM: To investigate the clinicopathological features, psychological status and prog-nostic features of patients with OBC. METHODS: The clinicopathological data of 33 OBC patients diagnosed and treated in the Affiliated Hospital of Xuzhou Medical University and Xuzhou Central Hospital from November 2015 to November 2022 were retrospectively analyzed. The psychological status of OBC patients was evaluated by the Self-rating Anxiety Scale and Self-rating Depression Scale. Patients' emotions, stress perception and psychological resilience were evaluated by the Positive and Negative Affect Schedule, the Chinese Perceived Stress Scale, and the Connor-Davidson Resilience Scale (CD-RISC), respectively. Patient survival was calculated using the Kaplan-Meier method, and survival curves were plotted for analysis with the log-rank test. Univariate and multivariate survival analyses were performed using the Cox regression model. RESULTS: The 33 OBC patients included 32 females and 1 male. Of the 33 patients, 30 (91%) had axillary tumors, 3 (9%) had a neck mass as the primary symptom; 18 (54.5%) had estrogen receptor-positive tumors, 17 (51.5%) had progesterone receptor-positive tumors, and 18 (54.5%) had Her-2-positive tumors; 24 (72.7%) received surgical treatment, including 18 patients who underwent modified radical mastectomy, 1 patient who underwent breast-conserving surgery plus axillary lymph node dissection (ALND), and 5 patients who underwent ALND alone; 12 patients received preoperative neoadjuvant therapy. All 30 patients developed anxiety and depression, with low positive affect scores and high negative affect scores, accompanied by a high stress level and poor psychological resilience. There were no differences in the psychological status of patients according to age, body mass index, or menopausal status. The overall survival and disease-free survival (DFS) of all the patients were 83.3% and 55.7%, respectively. Univariate analysis demonstrated that the initial tumor site (P = 0.021) and node stage (P = 0.020) were factors that may affect patient prognosis. The 5-year DFS rate of OBC patients who received radiotherapy was greater (P < 0.001), while the use of different surgical methods (P = 0.687) had no statistically significant effect on patient outcomes. Multivariate analysis revealed that radiotherapy (P = 0.031) was an independent prognostic factor. Receiving radiotherapy had a significant effect on the CD-RISC score (P = 0.02). CONCLUSION: OBC is a rare breast disease whose diagnosis and treatment are currently controversial. There was no significant difference in the efficacy of other less invasive surgical procedures compared to those of modified radical mastectomy. In addition, radiotherapy can significantly improve patient outcomes. We should pay attention to the psychological state of patients while they receive antitumor therapy.

Deconstructing the Dimensions of Mycobiome Fingerprints in Luohandu Cave, Guilin, Southern China.

Subterranean karst caves are windows into the terrestrial subsurface to deconstruct the dimensions of mycobiome fingerprints. However, impeded by the constraints of remote locations, the inaccessibility of specimens and technical limitations, the mycobiome of subterranean karst caves has remained largely unknown. Weathered rock and sediment samples were collected from Luohandu cave (Guilin, Southern China) and subjected to Illumina Hiseq sequencing of ITS1 genes. A total of 267 known genera and 90 known orders in 15 phyla were revealed in the mycobiomes. Ascomycota dominated all samples, followed by Basidiomycota and Mortierellomycota. The sediments possessed the relatively highest alpha diversity and were significantly different from weathered rocks according to the diversity indices and richness metrics. Fifteen families and eight genera with significant differences were detected in the sediment samples. The Ca/Mg ratio appeared to significantly affect the structure of the mycobiome communities. Ascomycota appeared to exert a controlling influence on the mycobiome co-occurrence network of the sediments, while Ascomycota and Basidiomycota were found to be the main phyla in the mycobiome co-occurrence network of weathered rocks. Our results provide a more comprehensive dimension to the mycobiome fingerprints of Luohandu cave and a new window into the mycobiome communities and the ecology of subterranean karst cave ecosystems.

Individualized Use of 6-Mercaptopurine in Chinese Children with ALL: A Multicenter Randomized Controlled Trial.

Continuous 6-mercaptopurine (6-MP) dose titration is necessary because of its narrow therapeutic index and frequently encountered dose-limiting hematopoietic toxicity. However, evidence-based guidelines for gene-based 6-MP dosing have not been established for Chinese children with acute lymphoblastic leukemia (ALL). This multicenter, randomized, open-label, active-controlled clinical trial randomly assigned Chinese children with low- or intermediate-risk ALL in a 1:1 ratio to receive TPMT-NUDT15 gene-based dosing of 6-MP (N = 44, 10 to 50 mg/m2 /day) or standard dosing (N = 44, 50 mg/m2 /day) during maintenance therapy. The primary end point was the incidence of 6-MP myelosuppression in both groups. Secondary end points included frequencies of 6-MP hepatotoxicity, duration of myelosuppression and leukopenia, event-free survival, and steady-state concentrations of active metabolites (6-thioguaninenucleotides and 6-methylmercaptopurine nucleotides) in erythrocytes. A 2.2-fold decrease in myelosuppression, the primary end point, was observed in the gene-based-dose group using ~ 50% of the standard initial 6-MP dose (odds ratio, 0.26, 95% confidence interval, 0.11 to 0.64, P = 0.003). Patients in the gene-based-dose group had a significantly lower risk of developing thiopurine-induced myelosuppression and leukopenia (P = 0.015 and P = 0.022, respectively). No significant differences were observed in the secondary end points of the incidence of hepatotoxicity and steady-state concentrations of active metabolites in erythrocytes between the two groups. TPMT- and NUDT15-based dosing of 6-MP will significantly contribute toward further reducing the incidence of leukopenia in Chinese children with ALL. This trial is registered at www.clinicaltrial.gov as #NCT04228393.

Individualized Implementation of Youth Quality of Life Instrument-Research Version (YQOL-R) Among Chinese Adolescents with Different Weight Status.

Purpose: This study implemented the individualized Youth Quality of Life Instrument-Research Version (YQOL-R) to estimate the quality of life (QoL) among Chinese adolescents with three different Body Mass Index (BMI) levels. The study aims to explore and provide a reference for developing individualized QoL (IQoL) measurements in China. Methods: The sample consisted of 822 aged 11-18 from nine schools. The data collection included all participants' primary characters (age, sex, annual household income, parental education, and recruitment community) and their self-report QoL. Precisely, based on the generic measurement of YQOL-R, we developed IQoL measurements by asking adolescents' perceived five most important things to them (IQOLimportance) and the aspects they most want to change (IQOLchange) from 19 facets, respectively. The one-way analysis of variance (ANOVA) was applied to compare total and subscale scores of IQOLimportance, IQOLchange, and YQOL-R among adolescents with three different weight status. Also, the data analysis used multivariable linear regression modeling to test the effects on scores of IQOLimportance and IQOLchange. Results: Overall, the obese adolescents identified "Having good physical health" as the most important (54.03%) and most like-to-change (42.65%); in contrast, the normal-weight group ranked "Being myself" as the top facet of IQOLimportance (52.42%) and "Having good friends" as the top facet of IQOLchange (43.12%). The obese adolescents' reported IQOLimportance scores are significantly lower than those of the normal-weight group (P=0.039). However, there is no significant difference in IQOLchange score among the three weight-status groups. The multivariable linear regression models indicated that adolescents who are girls (P=0.035), have higher educated fathers (P=0.049), and are overweight/obese (P=0.041) self-reported worse IQOLimportance score; yet, the girls (P=0.023) and older adolescents (P=0.004) answered lower IQOLchange scores. In addition, adolescents who had higher educated mothers (P=0.047; 0.023) and responded with higher total YQOL-R scores (P<0.001; <0.001) reported higher IQOLimportance and IQOLchange scores. Conclusion: In the current study, although the self-reported YQOL-R scores from different weight status did not present a significant difference, the obese group reported a statistical trend towards lower IQOLimportance scores than the normal-weight and overweight adolescents. These findings emphasize that IQOLimportance and IQOLchange could capture adolescents' perspectives with different weight statuses about their lives, which are unique as complementary health outcomes accompanying YQOL-R in health surveys and interventions among Chinese adolescents.

Seasonal dynamics of soil nitrogen mineralization and their influencing factors during shrub anthropogenic introduction in desert steppe.

We selected enclosed grassland, grazed grassland and shrublands with different planting years (3, 12, 22 years)/densities (intervals of 2, 6, 40 m) to investigate soil N mineralization dynamics in the growing season (April-October) and its influencing factors during the process of desert steppe-degradation-shrub introduction. The results showed that soil moisture at 0-200 cm layer was decreased with increases of shrub age and density, and that the variations of soil moisture at 0-10 cm layer coincided with seasonal change. Compared with grazed grassland and enclosed grassland, the positive effect of shrubs on soil carbon, nitrogen and phosphorus contents first increased and then decreased with the increases of age and density. Moreover, soil N mineralization significantly varied across months and sites. Soil NO3- content and microbial biomass carbon and nitrogen were significantly higher from June to August. The proportion of NO3- to inorganic nitrogen significantly increased from 30.5% in enclosed grassland to 69.5% in shrublands. NH4+ content was mainly affected by months compared with sites. In the process of steppe-degradation-shrub introduction, the increases of shrub age and density significantly enhanced seasonal differences of soil nitrification and ammonification, but not on the seasonal mineralization of microbial biomass carbon and nitrogen. Soil NH4+ and NO3- contents were significantly and positively correlated with total nitrogen, organic carbon and N/P. Soil stoichiometric ratios (C/N and N/P) directly regulated N mineralization process.

Effect and safety of probiotics for treating urticaria: A systematic review and meta-analysis.

BACKGROUND: To assess the effect and safety of probiotics for treating urticaria. METHODS: Randomized controlled trial (RCT) papers on the probiotics treatment published before May 2019 were retrieved from various databases like PubMed, EMbase, MEDLINE (Ovid), SCI-Hub, Springer, ClinicalKey, VIP, and CNKI. The treatment plan that we include are oral administration of single probiotic, multiple probiotics, and the combination of probiotics and antihistamines. Meta-analysis of the data was performed by RevMan 5.3 software. RESULTS: A total of nine RCT papers were included: four papers for oral administration of single probiotic, three papers for oral administration of multiple probiotics, and two papers for oral administration of a probiotic combined with antihistamines. The results of meta-analysis showed that the therapeutic effect of the probiotic group was significantly higher than the control group (placebo or antihistamines) (RR = 1.09, 95% CI: 1.03-1.16, p = 0.006). And compared with the placebo group, the therapeutic effect of single probiotic group was significantly improved (RR = 1.11, 95% CI: 1.01-1.21, p = 0.03). Regarding therapeutic effect, there was no statistically significant difference between the multiple probiotics group and placebo group (RR = 1.00, 95% CI: 0.94 ~ 1.07, p = 0.91); the therapeutic effect of single probiotic combined antihistamine group was significantly higher than the antihistamine group (RR = 1.13, 95% CI: 1.07-1.19, p < 0.0001). Regarding the incidence of adverse reactions, there was no significant difference between the probiotic group and the control group (p = 0.46). CONCLUSION: The treatment plan of oral administration of probiotics has significant therapeutic effects on urticaria, but the therapeutic effects of the administration of multiple probiotics and the safety of probiotic therapy are still not yet obvious. Some large-scale, multi-centered RCT studies are needed in the future for clarification.

ROS-responsive modified chitosan oligosaccharide nanocapsules for improving pesticide efficiency and intelligent release.

BACKGROUND: Some traditional pesticide formulations are inefficient, leading to excessive use and abuse of pesticides, which in turn effects environment. Intelligent release pesticide formulations are ideal for improving pesticide utilization and persistence while reducing environmental pollution. RESULTS: We designed a benzil-modified chitosan oligosaccharide (CO-BZ) to encapsulate avermectin (Ave). Ave@CO-BZ nanocapsules are prepared based on a simple interfacial method via cross-linking of CO-BZ with diphenylmethane diisocyanate (MDI). The Ave@CO-BZ nanocapsules have an average particle size of 100 nm and exhibited a responsive release performance for ROS. The cumulative release rate of nanocapsules at 24 h with ROS increased by about 11.4% compared to that without ROS. The Ave@CO-BZ nanocapsules displayed good photostability. Ave@CO-BZ nanocapsules can penetrate root-knot nematodes more easily and exhibited better nematicidal activity against root-knot nematodes. The pot experiment showed that the control effect of Ave CS at low concentration was 53.31% at the initial stage of application (15 d), while Ave@CO-BZ nanocapsules was 63.54%. Under the same conditions, the control effect of Ave@CO-BZ nanocapsules on root-knot nematodes was 60.00% after 45 days of application, while Ave EC was only 13.33%. The acute toxicity experiments of earthworms showed that the toxicity of nanocapsules was significantly lower than that of EC. CONCLUSION: The ROS-responsive nanocapsules can improve the utilization of pesticides and non-target biosafety. This modified chitosan oligosaccharide has great potential as a bio stimuli-responsive material, and this simple and convenient method for preparing Ave@CO-BZ nanocapsules provides a direction for the effective utilization of pesticides. © 2023 Society of Chemical Industry.

[Emission Inventory of Building Material Industry in Henan Province Based on Multi-source Data Integration].

The building materials industry is a typical resource and energy-consuming industry, as well as one of the major sources of air pollution. As the world's largest producer and consumer of building material products, China thus far has insufficient research on the emissions of the building materials industry, and the data sources are short of multiplicity. In this study, the building materials industry in Henan Province was chosen,and the control measures inventory for pollution emergency response (CMIPER) was applied to the development of the emission inventory for the first time. Through the integration of multi-source data such as CMIPER, a pollution discharge permit, and environmental statistics, the activity data of the building materials industry was refined, and a more accurate emission inventory of the building materials industry in Henan Province was established. The results showed that the SO2, NOx, primary PM2.5, and PM10 emissions of the building materials industry in Henan Province in 2020 were 21788, 51427, 10107, and 14471 t, respectively. Cement and bricks and tiles were the two categories with the highest contribution of emissions from the building materials industry in Henan Province, accounting for more than 50% in total. TheNOx emission of the cement industry was a key issue, and the overall emission control level of the brick and tile industry was relatively unadvanced. The central and northern parts of Henan Province contributed the most emissions in the building materials industry, accounting for more than 60%. It is recommended to further implement ultra-low emission retrofit in the cement industry, and for other industries such as the bricks and tiles, the improvement of local emission standards is encouraged to persistently promote the emission control of the building materials industry.

miR-181b promotes angiogenesis and neurological function recovery after ischemic stroke.

Promotion of new blood vessel formation is a new strategy for treating ischemic stroke. Non-coding miRNAs have been recently considered potential therapeutic targets for ischemic stroke. miR-181b has been shown to promote angiogenesis in hypoxia and traumatic brain injury model, while its effect on ischemic stroke remains elusive. In this study, we found that overexpression of miR-181b in brain microvascular endothelial cells subjected to oxygen-glucose deprivation in vitro restored cell proliferation and enhanced angiogenesis. In rat models of focal cerebral ischemia, overexpression of miR-181b reduced infarction volume, promoted angiogenesis in ischemic penumbra, and improved neurological function. We further investigated the molecular mechanism by which miR-181b participates in angiogenesis after ischemic stroke and found that miR-181b directly bound to the 3'-UTR of phosphatase and tensin homolog (PTEN) mRNA to induce PTEN downregulation, leading to activation of the protein kinase B (Akt) pathway, upregulated expression of vascular endothelial growth factors, down-regulated expression of endostatin, and promoted angiogenesis. Taken together, these results indicate that exogenous miR-181b exhibits neuroprotective effects on ischemic stroke through activating the PTEN/Akt signal pathway and promoting angiogenesis.

Bone marrow-derived mesenchymal stem cell-conditioned medium ameliorates diabetic foot ulcers in rats.

OBJECTIVES: This study aimed to explore the effects of bone marrow-derived Mesenchymal Stem Cell-Conditioned Medium (MSC-CM) treating diabetic foot ulcers in rats. METHODS: Models of T2DM rats were induced by a high-fat diet and intraperitoneal injection of STZ in SD rats. Models of Diabetic Foot Ulcers (DFUs) were made by operation on hind limbs in diabetic rats. Rats were divided into four groups (n = 6 for each group), i.e., Normal Control group (NC), Diabetes Control group (DM-C), MSC-CM group and Mesenchymal Stem Cells group (MSCs). MSC-CM group was treated with an injection of conditioned medium derived from preconditioned rats' bone marrow MSCs around ulcers. MSCs group were treated with an injection of rats' bone marrow MSCs. The other two groups were treated with an injection of PBS. After the treatment, wound closure, re-epithelialization (thickness of the stratum granulosums of the skin, by H&E staining), cell proliferation (Ki67, by IHC), angiogenesis (CD31, by IFC), autophagy (LC3B, by IFC and WB; autolysosome, by EM) and pyroptosis (IL-1ß, NLRP3, Caspase-1, GSDMD and GSDMD-N, by WB) in ulcers were evaluated. RESULTS: After the treatment wound area rate, IL-1ß by ELISA, and IL-1ß, Caspase-1, GSDMD and GSDMD-N by WB of MSC-CM group were less than those of DM group. The thickness of the stratum granulosums of the skin, proliferation index of Ki67, mean optic density of CD31 and LC3B by IFC, and LC3B by WB of MSC-CM group were more than those of DM group. The present analysis demonstrated that the injection of MSC-CM into rats with DFUs enhanced the wound-healing process by accelerating wound closure, promoting cell proliferation and angiogenesis, enhancing cell autophagy, and reducing cell pyroptosis in ulcers. CONCLUSIONS: Studies conducted indicate that MSC-CM administration could be a novel cell-free therapeutic approach to treat DFUs accelerating the wound healing process and avoiding the risk of living cells therapy.

Total synthesis of bi-magnolignan.

Bi-magnolignan, isolated from the leaves of Magnolia officinalis, has shown excellent physiological activity against tumor cells. An efficient strategy for the first total synthesis of bi-magnolignan is reported. The bi-dibenzofuran skeleton was constructed via functional group interconversions of commercially available materials 1,2,4-trimethoxybenzene and 4-allylanisole. Then, the dibenzofuran skeleton was afforded by subsequent Suzuki coupling and intramolecular dehydration. The total synthesis of natural product was accomplished through FeCl3 catalyzed oxidative coupling.

Bacteria and filamentous fungi running a relay race in Daqu fermentation enable macromolecular degradation and flavor substance formation.

As the saccharifying and fermentative agent, medium-temperature Daqu (MT-Daqu) plays an irreplaceable role in the production of strong-flavor Baijiu. Numerous studies have focused on the microbial community structure and potential functional microorganisms, however, little is known about the succession of active microbial community and the formation mechanism of community function during MT-Daqu fermentation. In this study, we presented an integrated analysis of metagenomics, metatranscriptomics, and metabonomics covering the whole fermentation process of MT-Daqu to reveal the active microorganisms and their participations in metabolic networks. The results showed that dynamic of metabolites were time-specific, and the metabolites and co-expressed active unigenes were further classified into four clusters according to their accumulation patterns, with members within each cluster displaying a uniform and clear pattern of abundance across fermentation. Based on KEGG enrichment analysis in co-expression clusters and succession of active microbial community, we revealed that Limosilactobacillus, Staphylococcus, Pichia, Rhizopus, and Lichtheimia were metabolically active members at the early stage, and their metabolic activities were conducive to releasing abundant energy to drive multiple basal metabolisms such as carbohydrates and amino acids. Thereafter, during the high temperature period and at the end of fermentation, multiple heat-resistant filamentous fungi were transcriptionally active populations, and they acted as both the saccharifying agents and flavor compound producers, especially aromatic compounds, suggesting their crucial contribution to enzymatic activity and aroma of mature MT-Daqu. Our findings revealed the succession and metabolic functions of the active microbial community, providing a deeper understanding of their contribution to MT-Daqu ecosystem.

Integration of metabolomics and transcriptomics analyses reveals sphingosine-1-phosphate-mediated S1PR2/PI3K/Akt pathway involved in Talaromyces marneffei infection of macrophages.

Talaromycosis is a fatal mycosis caused by the thermally dimorphic fungus Talaromyces marneffei (T. marneffei). The pathogenic mechanisms of talaromycosis are still poorly understood. This work combined metabolomics, transcriptomics, and verification experiments in vivo and in vitro to detect metabolic profiles and differentially expressed genes (DEGs) in T. marneffei infected and uninfected macrophages to explore possible pathogenesis and underlying mechanisms. A total of 256 differential metabolites (117 up-regulated and 148 down-regulated) and 1320 DEGs (1286 up-regulated and 34 down-regulated) were identified between the two groups. Integrative metabolomics and transcriptomics analysis showed sphingolipid signaling pathway is the most influential. Verification experiments showed that compared with the control group, the production of sphingosine-1-phosphate (S1P) and the expression of the S1PR1, S1PR2, phosphor-PI3K, and phosphor-Akt genes involved in the sphingolipid signaling pathway have significantly increased in the T. marneffei infection group (p < 0.05). T. marneffei activates the S1PR2/PI3K/Akt pathways in J774A.1 macrophage, regulation of the S1P singling might serve as a promising therapeutic strategy for talaromycosis.

Bone marrow-derived mesenchymal stem cell-conditioned medium ameliorates diabetic foot ulcers in rats

Abstract Objectives: This study aimed to explore the effects of bone marrow-derived Mesenchymal Stem Cell-Conditioned Medium (MSC-CM) treating diabetic foot ulcers in rats. Methods: Models of T2DM rats were induced by a high-fat diet and intraperitoneal injection of STZ in SD rats. Models of Diabetic Foot Ulcers (DFUs) were made by operation on hind limbs in diabetic rats. Rats were divided into four groups (n = 6 for each group), i.e., Normal Control group (NC), Diabetes Control group (DM-C), MSC-CM group and Mesenchymal Stem Cells group (MSCs). MSC-CM group was treated with an injection of conditioned medium derived from preconditioned rats' bone marrow MSCs around ulcers. MSCs group were treated with an injection of rats' bone marrow MSCs. The other two groups were treated with an injection of PBS. After the treatment, wound closure, re-epithelialization (thickness of the stratum granulosums of the skin, by H&E staining), cell proliferation (Ki67, by IHC), angiogenesis (CD31, by IFC), autophagy (LC3B, by IFC and WB; autoly-sosome, by EM) and pyroptosis (IL-1β, NLRP3, Caspase-1, GSDMD and GSDMD-N, by WB) in ulcers were evaluated. Results: After the treatment wound area rate, IL-1β by ELISA, and IL-1β, Caspase-1, GSDMD and GSDMD-N by WB of MSC-CM group were less than those of DM group. The thickness of the stratum granulosums of the skin, proliferation index of Ki67, mean optic density of CD31 and LC3B by IFC, and LC3B by WB of MSC-CM group were more than those of DM group. The present analysis demonstrated that the injection of MSC-CM into rats with DFUs enhanced the wound-healing process by accelerating wound closure, promoting cell proliferation and angiogenesis, enhancing cell autophagy, and reducing cell pyroptosis in ulcers. Conclusions: Studies conducted indicate that MSC-CM administration could be a novel cell-free therapeutic approach to treat DFUs accelerating the wound healing process and avoiding the risk of living cells therapy.

Corrigendum: IL36G is associated with cutaneous antiviral competence in psoriasis.

[This corrects the article DOI: 10.3389/fimmu.2022.971071.].

Influence of age as a continuous variable on the prognosis of patients with pT1-2N1 breast cancer.

PURPOSE: To assess the influence of age as a continuous variable on the prognosis of pT1-2N1 breast cancer and examine its decision-making value for postmastectomy radiotherapy (PMRT). METHODS: We retrospectively evaluated 5438 patients with pT1-2N1 breast cancer after mastectomy in 11 hospitals. A multivariable Cox proportional hazards regression model with penalized splines was used to examine the relationship between age and oncologic outcomes. RESULTS: The median follow-up was 67.0 months. After adjustments for confounding characteristics, nonsignificant downward trend in locoregional recurrence (LRR) risk was observed with increasing age (P-non-linear association = 0.640; P-linear association = 0.078). A significant non-linear association was found between age and disease-free survival (DFS) and overall survival (OS) (P-non-linear association <0.05; P-linear association >0.05, respectively). The DFS and OS exhibited U-shaped relationships, with the hazard ratios (HRs), reaching a nadir at 50 years old. A decreased risk of LRR with PMRT vs. no PMRT (HR = 0.304, 95% CI: 0.204-0.454) was maintained in all ages. The HR of PMRT vs. no PMRT for DFS and OS gradually increased with age. In patients ≤50 years old, PMRT was independently associated with favorable LRR, DFS, and OS, all P < 0.05). In patients >50 years old, PMRT was independently associated with reduced LRR (P = 0.004), but had no effect on DFS or OS. CONCLUSIONS: Age was an independent prognostic factor for pT1-2N1 breast cancer; PMRT provided survival benefits for patients ≤50 years old, but not for patients >50 years old.