Gastric Mammalian Target of Rapamycin Signaling Contributes to Inhibition of Ghrelin Expression Induced by Roux-En-Y Gastric Bypass

Background/Aims: Roux-en-Y Gastric Bypass, RYGB, is the most effective strategy to control body weight in morbid obesity. RYGB leads to rapid improvement of glycemic status and weight loss, which are largely attributed to the alteration of gastrointestinal hormones including ghrelin. The current study examined potential mechanisms of altered ghrelin synthesis after RYGB. Methods: Gastric mammalian target of rapamycin (mTOR) signaling, ghrelin synthesis and secretion were determined in lean or obese male mice with or without RYGB operation, as well as in obese patients pre- and post-RYGB surgery. Ghrelin expression and mTOR signaling were investigated by western blotting and immunohistochemistry. Ghrelin mRNA levels were detected by real-time PCR. Plasma ghrelin was measured by enzyme immunoassay. Results: mTOR activity in the gastric fundus was significantly lower than in the forestomachs. Both of them were decreased after 24h fasting. A significant negative correlation was found between gastric levels of phospho-S6 (phospho-S6 ribosomal protein) and proghrelin during changes of energy status. mTOR activity was activated, whereas ghrelin expression was inhibited by Roux-en-Y Gastric Bypass in both rodents and human beings. Increment of ghrelin synthesis and decline of mTOR signaling induced by rapamycin were significantly reversed by RYGB in both lean and obese mice. Administration of Ad-S6K1 (adenovirus-mediated p70 ribosomal protein subunit 6 kinase 1) from tail vein suppressed the expression of ghrelin in RYGB-operated mice relative to control animals. Conclusion: mTOR is therefore a gastric fuel sensor whose activity is linked to the regulation of ghrelin after Roux-en-Y Gastric Bypass

Cell metabolism-based optimization strategy of CAR-T cell function in cancer therapy

Adoptive cell therapy (ACT) using chimeric antigen receptor (CAR)-modified T cells has revolutionized the field of immune-oncology, showing remarkable efficacy against hematological malignancies. However, its success in solid tumors is limited by factors such as easy recurrence and poor efficacy. The effector function and persistence of CAR-T cells are critical to the success of therapy and are modulated by metabolic and nutrient-sensing mechanisms. Moreover, the immunosuppressive tumor microenvironment (TME), characterized by acidity, hypoxia, nutrient depletion, and metabolite accumulation caused by the high metabolic demands of tumor cells, can lead to T cell “exhaustion” and compromise the efficacy of CAR-T cells. In this review, we outline the metabolic characteristics of T cells at different stages of differentiation and summarize how these metabolic programs may be disrupted in the TME. We also discuss potential metabolic approaches to improve the efficacy and persistence of CAR-T cells, providing a new strategy for the clinical application of CAR-T cell therapy

Cell transcriptomic atlas of the non-human primate Macaca fascicularis.

Studying tissue composition and function in non-human primates (NHPs) is crucial to understand the nature of our own species. Here we present a large-scale cell transcriptomic atlas that encompasses over 1 million cells from 45 tissues of the adult NHP Macaca fascicularis. This dataset provides a vast annotated resource to study a species phylogenetically close to humans. To demonstrate the utility of the atlas, we have reconstructed the cell-cell interaction networks that drive Wnt signalling across the body, mapped the distribution of receptors and co-receptors for viruses causing human infectious diseases, and intersected our data with human genetic disease orthologues to establish potential clinical associations. Our M. fascicularis cell atlas constitutes an essential reference for future studies in humans and NHPs.We thank W. Liu and L. Xu from the Huazhen Laboratory Animal Breeding Centre for helping in the collection of monkey tissues, D. Zhu and H. Li from the Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory) for technical help, G. Guo and H. Sun from Zhejiang University for providing HCL and MCA gene expression data matrices, G. Dong and C. Liu from BGI Research, and X. Zhang, P. Li and C. Qi from the Guangzhou Institutes of Biomedicine and Health for experimental advice or providing reagents. This work was supported by the Shenzhen Basic Research Project for Excellent Young Scholars (RCYX20200714114644191), Shenzhen Key Laboratory of Single-Cell Omics (ZDSYS20190902093613831), Shenzhen Bay Laboratory (SZBL2019062801012) and Guangdong Provincial Key Laboratory of Genome Read and Write (2017B030301011). In addition, L.L. was supported by the National Natural Science Foundation of China (31900466), Y. Hou was supported by the Natural Science Foundation of Guangdong Province (2018A030313379) and M.A.E. was supported by a Changbai Mountain Scholar award (419020201252), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA16030502), a Chinese Academy of Sciences–Japan Society for the Promotion of Science joint research project (GJHZ2093), the National Natural Science Foundation of China (92068106, U20A2015) and the Guangdong Basic and Applied Basic Research Foundation (2021B1515120075). M.L. was supported by the National Key Research and Development Program of China (2021YFC2600200).S

Diffusion Model of Cement Slurry in Porous Media Considering Porosity Variation and Percolation Effect

The porosity of porous media is a key factor affecting cement slurry diffusion. In this paper, a theoretical model of cement slurry diffusion in porous media considering the variation of porosity is proposed. The model is validated through comparison with the experimental results in the literature. The influence of injection parameters (i.e., the water–cement ratio and the pore fractal dimension) on the porosity and strength of porous media is analyzed. The results indicate that: under the same pore fractal dimension, the porosity of the specimen increases gradually with the increase in diffusion distance, and the rate increases rapidly in the later stage. However, when the fractal dimension of porosity increases to 2.1, the porosity of the consolidated body after grouting does not change with the diffusion distance. The water–cement ratio also affects the porosity of the sample. At a distance below 1.0 m, the sample porosity is larger at a larger water–cement ratio of 1.5. When the distance is more than 1.0 m, the smaller the porosity decreases with increasing water–cement ratios. With the increase in distance, the compressive strength of the specimen first decreases slowly, and then rapidly from 90 kPa to 0 kPa. This is further verified by the pore variation law obtained by SEM. The model is applied to selecting grouting parameter design in road maintenance. The pavement deflection after grouting is effectively reduced, verifying the theoretical model’s applicability

Diffusion Model of Cement Slurry in Porous Media Considering Porosity Variation and Percolation Effect

The porosity of porous media is a key factor affecting cement slurry diffusion. In this paper, a theoretical model of cement slurry diffusion in porous media considering the variation of porosity is proposed. The model is validated through comparison with the experimental results in the literature. The influence of injection parameters (i.e., the water–cement ratio and the pore fractal dimension) on the porosity and strength of porous media is analyzed. The results indicate that: under the same pore fractal dimension, the porosity of the specimen increases gradually with the increase in diffusion distance, and the rate increases rapidly in the later stage. However, when the fractal dimension of porosity increases to 2.1, the porosity of the consolidated body after grouting does not change with the diffusion distance. The water–cement ratio also affects the porosity of the sample. At a distance below 1.0 m, the sample porosity is larger at a larger water–cement ratio of 1.5. When the distance is more than 1.0 m, the smaller the porosity decreases with increasing water–cement ratios. With the increase in distance, the compressive strength of the specimen first decreases slowly, and then rapidly from 90 kPa to 0 kPa. This is further verified by the pore variation law obtained by SEM. The model is applied to selecting grouting parameter design in road maintenance. The pavement deflection after grouting is effectively reduced, verifying the theoretical model’s applicability

Development and validation of the Convalescence Symptom Assessment Scale for EsophageCtomy patients

Abstract Aim A specific, valid and reliable measure is much needed to dynamically assess the recovery of symptoms in oesophagectomy patients. This study describes developing and validating the Convalescent Symptom Assessment Scale for oesophagectomy patients (CSAS_EC). Design An instrument development and cross‐sectional validation study was conducted. Methods This study consists of two components: instrument development and psychometric tests. In instrument development, the literature review, qualitative interviews, Delphi method expert consultation and face validation were used to develop and refine scale content. In psychometric tests, the clinical test version scale was used to conduct a cross‐sectional in the thoracic surgery department from 17 June to 20 November 2022. The Classical Test Theory and Multidimensional Item Response Theory (MIRT) analyses examined psychometric properties. Results In instrument development, literature review (n = 20), qualitative interviews (n = 21), expert consultation (n = 12) and pre‐survey (n = 15) led to the development of the clinical test version scale. In psychometric tests, a total of 331 participants were enrolled. Confirmatory factor analysis and MIRT analysis verified that a model with 28 items in four dimensions was good. The four dimensions were early recovery symptoms, late recovery symptoms, persistent present symptoms and psychosocial symptoms. The Cronbach's α is 0.827. The validity and reliability were demonstrated to be acceptable. Conclusions The CSAS_EC scale can be used as a tool to evaluate the recovery status of oesophagectomy patients

Spatio-temporal patterns of ovarian development and VgR gene silencing reduced fecundity in parthenogenetic Artemia

The halophilic zooplankton brine shrimp Artemia has been used as an experimental animal in multidisciplinary studies. However, the reproductive patterns and its regulatory mechanisms in Artemia remain unclear. In this study, the ovarian development process of parthenogenetic Artemia (A. parthenogenetica) was divided into five stages, and oogenesis or egg formation was identified in six phases. The oogenesis mode was assumed to be polytrophic. We also traced the dynamic translocation of candidate germline stem cells (cGSCs) using EdU labelling and elucidated several key cytological events in oogenesis through haematoxylin and eosin staining and fluorescence imaging. Distinguished from the ovary structure of insects and crustaceans, Artemia germarium originated from ovariole buds and are located at the base of the ovarioles. RNA-seq based on five stages of ovarian development identified 2657 upregulated genes related to reproduction by pair-to-pair comparison. Gbb, Dpp, piwi, vasa, nanos, VgA and VgR genes associated with cGSCs recognition and reproductive development were screened and verified using qPCR. Silencing of the VgR gene in A. parthenogenetica (Ap-VgR) at ovarian development Stage II led to a low level of gene expression (less than 10%) within 5 days, which resulted in variations in oogenesis-related gene expression and significantly inhibited vitellogenesis, impeded oocyte maturation, and eventually decreased the number of offspring. In conclusion, we have illustrated the patterns of ovarian development, outlined the key spatio-temporal features of oogenesis and identified the negative impacts of VgR gene knockdown on oogenesis using A. parthenogenetica as an experimental animal. The findings of this study also lay a foundation for the further study of reproductive biology of invertebrates

FengLiao affects gut microbiota and the expression levels of Na+/H+ exchangers, aquaporins and acute phase proteins in mice with castor oil-induced diarrhea.

The severe side effects of chemosynthetic anti-diarrhea drugs have created an interest in low-toxic alternative plant-derived compounds. FengLiao consists of Polygonum hydropiper Linn. and Daphniphyllum calycinum Bench., and is widely used in China to treat diarrhea due to low levels of toxicity. In this study, the effects of FengLiao were analyzed in a castor oil-induced diarrhea model, using the anti-diarrhea drug, loperamide, as the positive control. The effects were evaluated using stool characteristics and the expression levels of various diarrhea-related factors in the jejunum and liver, as well as changes in the microbiota of the jejunum. The symptoms of diarrhea and stool consistency were improved through FengLiao and loperamide treatment. Furthermore, FengLiao down-regulated alpha 1-acid glycoprotein (AGP) and C-reactive protein (CRP) levels, and up-regulated transferrin (TRF) mRNA levels in the liver, and down-regulated Aquaporin 3 (AQP3) and Na+/H+ exchanger isoform 8 (NHE8) expression in the epithelial cells of the jejunum. It also increased the relative abundance of Bifidobacterium, Aerococcus, Corynebacterium_1 and Pseudomonas, and lowered the Firmicutes/Bacteroidetes (F/B) ratio, which maintained the balance between immunity and intestinal health. Taken together, FengLiao alleviated castor oil-induced diarrhea by altering gut microbiota, and levels of jejunum epithelial transport proteins and acute phase proteins