eIF3a is a N ⁶-methyladenosine (m⁶A) reader that regulates mRNA translation by recognizing m⁶A modifications of these mRNAs. It has been suggested that eIF3a may play an important role in regulating translation initiation via m⁶A during infection when canonical cap-dependent initiation is inhibited. However, the death of animal model studies impedes our understanding of the functional significance of eIF3a in immunity and regulation in vivo. In this study, we investigated the in vivo function of eIF3a using eIF3a knockout and knockdown mouse models and found that eIF3a deficiency resulted in splenic tissue structural disruption and multi-organ damage, which contributed to severe sepsis induced by Lipopolysaccharide (LPS). Ectopic eIF3a overexpression in the eIF3a knockdown mice rescued mice from LPS-induced severe sepsis. We further showed that eIF3a maintains a functional and healthy immune system by regulating B cell function and quantity through m⁶A modification of mRNAs. These findings unveil a novel mechanism underlying sepsis, implicating the pivotal role of B cells in this complex disease process regulated by eIF3a. Furthermore, eIF3a may be used to develop a potential strategy for treating sepsis.

Background::The goal of the assisted reproductive treatment is to transfer one euploid blastocyst and to help infertile women giving birth one healthy neonate. Some algorithms have been used to assess the ploidy status of embryos derived from couples with normal chromosome, who subjected to preimplantation genetic testing for aneuploidy (PGT-A) treatment. However, it is currently unknown whether artificial intelligence model can be used to assess the euploidy status of blastocyst derived from populations with chromosomal rearrangement.Methods::From February 2020 to May 2021, we collected the whole raw time-lapse videos at multiple focal planes from in vitro cultured embryos, the clinical information of couples, and the comprehensive chromosome screening results of those blastocysts that had received PGT treatment. Initially, we developed a novel deep learning model called the Attentive Multi-Focus Selection Network (AMSNet) to analyze time-lapse videos in real time and predict blastocyst formation. Building upon AMSNet, we integrated additional clinically predictive variables and created a second deep learning model, the Attentive Multi-Focus Video and Clinical Information Fusion Network (AMCFNet), to assess the euploidy status of embryos. The efficacy of the AMCFNet was further tested in embryos with parental chromosomal rearrangements. The receiver operating characteristic curve (ROC) was used to evaluate the superiority of the model. Results::A total of 4112 embryos with complete time-lapse videos were enrolled for the blastocyst formation prediction task, and 1422 qualified blastocysts received PGT-A ( n = 589) or PGT for chromosomal structural rearrangement (PGT-SR, n = 833) were enrolled for the euploidy assessment task in this study. The AMSNet model using seven focal raw time-lapse videos has the best real-time accuracy. The real-time accuracy for AMSNet to predict blastocyst formation reached above 70% on the day 2 of embryo culture, and then increased to 80% on the day 4 of embryo culture. Combing with 4 clinical features of couples, the AUC of AMCFNet with 7 focal points increased to 0.729 in blastocysts derived from couples with chromosomal rearrangement. Conclusion::Integrating seven focal raw time-lapse images of embryos and parental clinical information, AMCFNet model have the capability of assessing euploidy status in blastocysts derived from couples with chromosomal rearrangement.

ObjectiveTo investigate the impact of yang deficiency syndrome on the progression to end-point events of diabetic kidney disease （DKD）. MethodsA retrospective study among patients with stage Ⅳ DKD admitted to Dongzhimen Hospital of Beijing University of Chinese Medicine from September 1st， 2016 to September 30th， 2021 was conducted. Data on the patients' general information， clinical indicators including duration of diabetes， duration of proteinuria， history of smoking and drinking， hemoglobin （HGB）， fasting blood glucose （FBG）， albumin （ALB）， serum creatinine （Scr）， urea nitrogen （BUN）， uric acid （UA）， cholesterol （TC） ， triglycerides （TG）， low-density lipoprotein （LDL）， 24-hour urine protein quantification （24h-UTP） and estimated glomerular filtration rate （eGFR）， and TCM syndromes including symptoms， tongue and pulse， and syndrome scores were collected. The patients were divided into exposure group （yang-deficiency group） and non-exposure group （non-yang-deficiency group）. The general information， clinical indicators and incidence rates of end-point events were compared， and the impact of yang deficiency syndrome on the end-point events of stage Ⅳ DKD was analyzed. Survival analysis was performed using Kaplan-Meier method， and multivariate Cox proportional risk models were used to identify independent predictors of end-point events. ResultsA total of 160 patients with stage Ⅳ DKD were included in the study， including 43 cases of yang deficiency syndrome and 117 cases of non-yang deficiency syndrome. Compared to those in the non-yang deficiency group， the waist circumference， BUN and the incidence of end-point events in the yang deficiency group were significantly higher （P＜0.05 or P＜0.01）. Spearman correlation analysis showed that yang deficiency syndrome was positively correlated with incidence of end-point events of stage Ⅳ DKD （r = 0.167， P = 0.035）. Furthermore， 24h-UTP and BUN levels were also positively correlated with end-point events in stage Ⅳ DKD patients （P＜0.01）， while ALB and HGB levels were negatively correlated （P＜0.01）. Kaplan-Meier survival curves showed that yang deficiency syndrome was associated with an increased risk of end-point events （Log Rank P = 0.011）. Moreover， 24h-UTP levels ≥3500 mg， BUN level ≥8 mmol/L， ALB level ＜30 g and HGB level ＜11 g were all associated with the increase of the risk of end-point events （P＜0.05 or P＜0.01）. Multivariate Cox regression analysis showed that yang deficiency syndrome was an independent risk factor for patients with stage Ⅳ DKD to progress into end-point events （HR = 2.36， 1.32 to 4.21； P = 0.004）， as well as 24h-UTP ≥ 3500 mg， BUN ≥ 8 mmol/L， HGB＜11 g and ALB＜30 g （P＜0.05 or P＜0.01）. ConclusionsFor stage Ⅳ DKD， patients with yang deficiency syndrome are more likely to have end-point events， which is an independent risk factor for the progression into end-point events.

Objective: To investigate cardiovascular disease (CVD) prevention status among residents with intra-urban migration in Central China, so as to provide insights into targeted prevention and control of CVD. Methods: Basic data of residents aged 35 to 75 years who participated in Early Screening and Comprehensive Intervention Project for CVD high-risk populations in Central China from September 2015 to August 2020 were collected. According to birth place, type of registered residence and current residence, residents were divided into four groups: local residents in old urban area, local residents in new urban area, other urban migrants and other rural migrants. The status of CVD primary and secondary prevention, were analysed by using a robust Poisson regression model. Results: A total of 76 513 residents were recruited, including 29 420 males (38.45%) and 47 093 females (61.55%), and had a mean age of (56.36±9.84) years. There were 45 087 (58.93%) local residents in old urban area, 23 868 (31.19%) local residents in new urban area, 5 668 (7.41%) other urban migrants and 1 890 (2.47%) other rural migrants. After adjusting for variables such as age, gender and educational level, the results of robust Poisson regression analysis showed that compared with local residents in old urban area, local residents in new urban area had lower compliance rates of non- or moderate-drinking (RR=0.987, 95%CI: 0.975-1.000) and healthy diet (RR=0.535, 95%CI: 0.365-0.782), lower proportion of using aspirin as primary prevention in CVD high-risk population (RR=0.616, 95%CI: 0.511-0.741), lower awareness (RR=0.873, 95%CI: 0.782-0.974) and control rates (RR=0.730, 95%CI: 0.627-0.849) of hypertension; other urban migrants had higher compliance rate of non-smoking (RR=1.045, 95%CI: 1.017-1.075); other rural migrants had lower proportion of using aspirin as primary prevention in CVD high-risk population (RR=0.826, 95%CI: 0.707-0.966). Conclusion The CVD primaryprevention among local residents in new urban area is relatively poor among four groups of residents in Central China, and key interventions are needed.

OBJECTIVE To compare the anti-thymic atrophy effects of petroleum ether(PEE), ethyl acetate(EAE), n-butanol(BE) and water extract(WE) fractions from root tubers of Tetrastigma hemsleyanum Diels et. Gilg based on mice thymic atrophy model established by intraperitoneal injection of PolyI:C to preliminarily investigate the mechanisms of its effects. METHODS One hunderd ICR mice were randomly divided into 10 groups: control group, model group, low- and high-dose groups of the four extract fractions, with 10 mice in each group. The control group and model group were given equal volume of purified water and gavaged for 10 d. Starting on the 9th day, PolyI:C solution of 16 mg·kg−1 was injected intraperitoneally for 2 consecutive days, except for the control group, which was injected intraperitoneally with physiological saline. Samples of thymics were weighed and and visceral index was calculated, blood samples were taken for analysis of IL-2, TNF-α and WBC, thymic histopathology was analyzed using hematoxylin-eosin staining, Western blotting was performed to detect the expression of TNF-α, p-NF-κB and NF-κB. RESULTS Compared with the model group, all groups of extracts could enhance the thymus weight and thymus index, as well as the cortex and medulla area ratio and the number of thymic corpuscles in 1 mm2 of medulla to different degrees, and at the same time, significantly reduce the level of TNF-α in plasma, evidently inhibited the phosphorylation of NF-κB, and reduced the protein expression of TNF-α, and each of them having distinct advantages and disadvantages. Peripheral blood white blood cell, lymphocyte absolute count and lymphocyte percentage were elevated in the low-dose WE group, low-dose EAE group and high dose PEE group, IL-2 levels were significantly elevated in the low-dose WE group and high dose BE group, and these effects were particularly well demonstrated. CONCLUSION Four extracts from root tubers of Tetrastigma Hemsleyanum Diels et. Gilg can improve morphological changes and atrophy of the thymus tissue in different degrees, regulate of peripheral blood leukocyte imbalance in post-modeling mice, it may be related to the inhibition of PolyI:C-induced phosphorylation of the NF-κB and reduction of protein expression of pro-inflammatory factors.

Background and objective Neoantigen reactive T cell(NRT)has the ability to inhibit the growth of tumors expressing specific neoantigens.However,due to the difficult immune infiltration and the inhibition of tumor micro en-vironment,the therapeutic effect of NRT in solid tumors is limited.In this study,we designed NRT cells(7×19 NRT)that can express both interleukin-7(IL-7)and chemokine C-C motif ligand 19(CCL19)in mouse lung cancer cells,and evaluated the difference in anti-tumor effect between 7×19 NRT cells and conventional NRT cells.Methods We performed next-generation sequencing and neoantigen prediction for mouse Lewis lung carcinoma(LLC),prepared RNA vaccine,cultured NRT cells,constructed retroviral vectors encoding IL-7 and CCL19,transduced NRT cells and IL-7 and CCL19 were successfully ex-pressed,and 7×19 NRT was successfully obtained.The anti-tumor effect was evaluated in vivo and in vitro in mice.Results The 7×19 NRT cells significantly enhanced the proliferation and invasion ability of T cells by secreting IL-7 and CCL19,achieved significant tumor inhibition in the mouse lung cancer and extended the survival period of mice.The T cell infiltration into tumor tissue and the necrosis of tumor tissue increased significantly after 7×19 NRT treatment.In addition,both 7×19 NRT treatment and conventional NRT treatment were safe.Conclusion The anti-solid tumor ability of NRT cells is significantly enhanced by the arming of IL-7 and CCL19,which is a safe and effective genetic modification of NRT.

Objective·To investigate the effects of the cancer-testis antigen 14(CT14)on embryonic and larval development in nematodes by using the model organism Caenorhabditis elegans(C.elegans),aiming to uncover its potential functions and mechanisms during development.Methods·Transgenic C.elegans strains were constructed by using microinjection for the inducible expression of human CT14(HsCT14),a truncated mutant of CT14(HsCT14?CIR)lacking CT14-specific intermediate region(CIR),and a green fluorescent protein(GFP)control.The impacts of full-length and truncated mutant CT14 on nematode embryonic and larval development were analyzed and compared.Additionally,transgenic C.elegans strains with inducible expression of CT14 from various primates,including the crab-eating macaque(Macaca fascicularis)and mouse lemur(Microcebus murinus),were also constructed to assess the effects on egg hatching and larval-to-adult transformation rates.The differential gene expression in nematode embryos induced by CT14 was analyzed by Smart-seq transcriptome sequencing,with further insights gained through KEGG(Kyoto Encyclopedia of Genes and Genomes)and GSEA(Gene Set Enrichment Analysis),to explore the involved biological processes and pathways.Results·The induced expression of HsCT14 and its truncated mutant HsCT14?CIR significantly reduced the hatching rate of nematode eggs,with a more pronounced effect observed in HsCT14-expressing strains.Differential interference contrast(DIC)microscopy imaging revealed significant morphological abnormalities in embryos expressing HsCT14 during the comma stage.Nematodes expressing HsCT14 or HsCT14?CIR exhibited developmental arrest in larvae and substantially lower larval-to-adult transformation rates compared to the GFP control.The impact was more pronounced in nematodes expressing HsCT14 than those with HsCT14?CIR.The expression of Macaca fascicularis CT14(MfCT14)exhibited significant effects on the hatching rate and adult transformation rate,similar to that of HsCT14,while the expression of Microcebus murinus CT14(MmCT14)displayed significantly reduced impact compared to HsCT14 and MfCT14.Smart-seq results indicated that CT14 expression affected various biological processes in nematode embryos,related to ATP-dependent chromatin remodeling and DNA replication.Conclusion·Ectopic expression of the cancer-testis antigen CT14 significantly disrupts both embryonic and larval developments in C.elegans,with the CIR sequence substantially enhancing this effect.It suggests that CT14 may play an important regulatory role in biological development by affecting gene expression in multiple pathways,including chromatin remodeling.

Objective:It explores critical issues of discounting in health technology assessment to provide a reference for improving discount rates in China.Methods:Based on literature review and empirical cases,it compares and analyzes the practical experience of the UK and Canada and the basis for discount rate setting in pharmacoeconomic evaluation and guidelines of various countries.Results:It is found that the social time preference and social opportunity cost approach provide research perspectives for discount rate calculation.How-ever,there are differences in the choice of discounting in international guidelines and pharmacoeconomic evaluation practices,which may reflect differences among countries regarding economic environment,healthcare systems,and values.Conclusion:It calls for more basic research on discounting and suggests the formulation of discount rates that align with our China's economic environment to provide deci-sion-makers with a reliable information foundation.

Objective:It explores critical issues of discounting in health technology assessment to provide a reference for improving discount rates in China.Methods:Based on literature review and empirical cases,it compares and analyzes the practical experience of the UK and Canada and the basis for discount rate setting in pharmacoeconomic evaluation and guidelines of various countries.Results:It is found that the social time preference and social opportunity cost approach provide research perspectives for discount rate calculation.How-ever,there are differences in the choice of discounting in international guidelines and pharmacoeconomic evaluation practices,which may reflect differences among countries regarding economic environment,healthcare systems,and values.Conclusion:It calls for more basic research on discounting and suggests the formulation of discount rates that align with our China's economic environment to provide deci-sion-makers with a reliable information foundation.

Objective:It explores critical issues of discounting in health technology assessment to provide a reference for improving discount rates in China.Methods:Based on literature review and empirical cases,it compares and analyzes the practical experience of the UK and Canada and the basis for discount rate setting in pharmacoeconomic evaluation and guidelines of various countries.Results:It is found that the social time preference and social opportunity cost approach provide research perspectives for discount rate calculation.How-ever,there are differences in the choice of discounting in international guidelines and pharmacoeconomic evaluation practices,which may reflect differences among countries regarding economic environment,healthcare systems,and values.Conclusion:It calls for more basic research on discounting and suggests the formulation of discount rates that align with our China's economic environment to provide deci-sion-makers with a reliable information foundation.