Objective To investigate the differences of type 2 innate lymphocytes (ILC2) and interlukin 9 (IL-9) between chronic lymphocytic leukemia (CLL) patients and healthy controls, and to understand the effects of ILC2 on the function of regulatory T cells (Tregs), CD8⁺ T cells and CLL cells through IL-9. Methods Flow cytometry was used to detect the levels of ILC2 and Tregs in the peripheral blood of 45 newly diagnosed CLL patients and 24 healthy controls, and the expressions of granzyme B and perforin in CD8⁺ T cells in the peripheral blood of 28 patients and 15 healthy controls; ELISA was used to detect the level of IL-9 in the serum. ILC2 of patients and healthy controls was sorted by immunomagnetic beads and cultured separately, and the level of IL-9 in the culture supernatant was measured by ELISA. ILC2 sorted from CLL patients and healthy control-derived peripheral blood mononuclear cells(PBMCs) were co-cultured with the B cell leukemia MEC-1 cells, one group was supplemented with IL-9 antibody and the other group was not. After 72 hours of culture, the ratio of Tregs, programmed death 1 (PD-1), T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT), cytotoxic T lymphocyte antigen 4 (CTLA-4) on Tregs, granzyme B and perforin in CD8⁺ T cells were measured by flow cytometry, IL-9 level of the culture supernatant was measured by ELISA, the apoptosis of MEC-1 cells was measured by Annexin V-PI. Results Compared with the healthy control group, the levels of ILC2, Tregs and IL-9 in the CLL group increased significantly. The levels of granzyme B and perforin in CD8⁺ T cells were positively correlated in the peripheral blood of CLL patients. Compared with the healthy control group, IL-9 levels in the supernatant of sorted ILC2 from CLL patients increased. In the anti-IL9 antibody group, the level of PD-1 and TIGIT on Tregs decreased, and the level of granzyme B in CD8⁺ T cells increased significantly. The level of IL-9 in the anti-IL9 antibody group decreased statistically. And MEC-1 cells showed increased early apoptotic rate in the anti-IL9 antibody group statistically. Conclusion In CLL, ILC2 affects CD8⁺ T cells and Tregs through IL-9, which weakens the anti-tumor effect of CD8⁺ T cells, enhances the immunosuppressive effect of Tregs, and plays a role in the occurrence and development of CLL disease.
Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/immunology* ; CD8-Positive T-Lymphocytes/immunology* ; T-Lymphocytes, Regulatory/immunology* ; Middle Aged ; Male ; Female ; Interleukin-9/blood* ; Aged ; Granzymes/metabolism* ; Perforin/metabolism* ; Immunity, Innate ; Adult ; Lymphocytes/immunology*

Delirium is a common cause and complication of hospitalization in the elderly and is associated with higher risk of future dementia and progression of existing dementia, of which 70% is Alzheimer's disease (AD). AD and delirium, which are known to be aggravated by one another, represent significant societal challenges, especially in light of the absence of effective treatments. The intricate biological mechanisms have led to numerous clinical trial setbacks and likely contribute to the limited efficacy of existing therapeutics. Artificial intelligence (AI) presents a promising avenue for overcoming these hurdles by deploying algorithms to uncover hidden patterns across diverse data types. This review explores the pivotal role of AI in revolutionizing drug discovery for AD and delirium from target identification to the development of small molecule and protein-based therapies. Recent advances in deep learning, particularly in accurate protein structure prediction, are facilitating novel approaches to drug design and expediting the discovery pipeline for biological and small molecule therapeutics. This review concludes with an appraisal of current achievements and limitations, and touches on prospects for the use of AI in advancing drug discovery in AD and delirium, emphasizing its transformative potential in addressing these two and possibly other neurodegenerative conditions.

Reactive astrocytes, which exhibit a correlation with the degeneration of dopaminergic neurons, are present in a considerable number during the progression of Parkinson's disease (PD). However, the underlying factors shaping astrocyte reactivity and neuroinflammation in PD remain inadequately elucidated. Here, we demonstrate that fibroblast growth factor 7 (FGF7)/FGF receptor 2 (FGFR2) autocrine signaling intensifies astrocyte reactivity and inflammation. Genetic deletion of Arrb2, β-Arrestin2 encoding gene, led to escalated astrocyte reactivity in MPTP-treated mice, which was further substantiated in astrocyte-specific Arrb2 knockdown mice. RNA sequencing profiling of Arrb2 knockout astrocytes identified Fgf7 as a critical effector of astrocyte reactivity. Subsequently, conditional knockdown of Fgf7 and its receptor Fgfr2 in astrocytes elicited advantageous effects for MPTP-treated mice by restraining the inflammatory phenotypic transition of reactive astrocytes. Furthermore, deletion of astrocytic Fgf7 mitigated MPTP-induced pathology in Arrb2 knockout mice. Mechanistically, STAT1 was distinguished as the transcription factor suppressing Fgf7 expression, while β-Arrestin2 counteracted the proteasomal degradation of STAT1 by binding to RNF220, an E3 ubiquitin ligase for STAT1. More importantly, selectively engaging dopamine D2 receptor (Drd2)/β-Arrestin2-biased signaling using the agonist UNC9995 exhibited therapeutic potential in MPTP-treated mice via moderation of astrocytic FGF7 production, thereby restoring balance in astrocyte reactivity. Collectively, our study bridges a crucial knowledge gap by elucidating the novel functions of FGF family members within the central nervous system, particularly within the context of PD. The autocrine signaling of FGF7/FGFR2 represents a novel mechanism and a potential druggable target for modulating astrocyte-derived inflammation.

Objective:The purpose of this study is to explore the clinical characteristics of Coronavirus Disease 2019 (COVID-19) in patients with type 2 diabetes mellitus (T2DM), and analyze the risk factors for adverse outcomes.Methods:2 052 patients diagnosed with COVID-19 who were hospitalized in Shanxi Bethune Hospital between December 1, 2022 and March 20, 2023 were included. They were divided into diabetes group ( n=70) and non-diabetes group ( n=1 982) according to the presence or absence of comorbid T2DM. The two groups were matched at 1:1 via propensity score matching. Clinical characteristics and laboratory examination results of the two groups were compared. According to the outcomes during hospitalization, the two groups were further divided into two subgroups respectively. Univariate analysis and subsequent binary Logistic regression was used to analyze the risk factors of adverse outcomes in patients with COVID-19 and type 2 diabetes. Results:After the propensity score matching, the most common comorbid condition in diabetes group and non-diabetes group was hypertension. The proportion of patients with severe or critical disease in diabetes group was higher compared with non-diabetes group. The levels of hemoglobin A1c (HbA1c), fasting blood glucose (FBG), blood urea, IL-4, IL-6, IL-10, IFN-γ and TNF-α were significantly higher in the diabetes group ( P<0.05). Logistic regression analysis within the diabetes group showed that hypertension ( OR=3.640, 95% CI: 3.156 to 4.290), FBG>11 mmol/L ( OR=3.283, 95% CI: 1.416 to 7.611), HbA1c>10% ( OR=2.718, 95% CI: 1.024 to 7.213) were independent risk factors for adverse outcomes in patients with COVID-19 and type 2 diabetes(all P<0.05). Conclusions:Compared with the non-diabetes group, patients with COVID-19 and T2DM have worse inflammatory response and higher levels of inflammatory cytokines. The elevated levels of FBG and HbA1c are related to the adverse outcome in patients with COVID-19 and T2DM.

Objective:To evaluate the clinical relevant effect of hospital-wide blood glucose management in perioperative cholelithiasis patients with type 2 diabetes.Methods:The subjects of the study were patients with type 2 diabetes mellitus complicated with cholelithiasis who were treated at the Baiqiu'en Hospital in Shanxi from September 2022 to October 2023. The patients were divided into hospital-wide blood sugar management group and conventional treatment group, according to different blood glucose management they received. The differences in preoperative blood glucose control, length of stay, postoperative complications, and hospitalization expenses between the two groups were compared.Results:Compare based on the median (quartiles) of the observed indicators, patients with cholelithiasis who underwent hospital-wide blood glucose management based on insulin pumps had a higher proportion of time in range [72.00(70.21, 82.90)% vs. 64.80 (61.55,70.50)%, P<0.001)], lower average blood glucose level [9.00 (8.55, 10.44) mmol/L vs. 11.50 (10.50, 12.50) mmol/L, P<0.001], and shorter hospital stay [8.00 (7.00,13.00) days vs. 10.00 (8.00, 12.00) ) days, P<0.05]. Moreover, the incidence of postoperative complications was lower [5(11.11)% vs. 15(33.33)%, P<0.05], and hospitalization expenses were lower [16 535.34 (14 271.44, 29 569.23) yuan vs. 18 633.85 (17 482.66) yuan , 22 855.02) yuan, P<0.05] in patients who received hospital-wide blood glucose management. Conclusion:Hospital-wide blood glucose management based on insulin pumps showed favorable effects in the perioperative clinical application in cholelithiasis patients with type 2 diabetes, and could contribute to shortening the average length of stay, reducing hospitalization costs, and reducing postoperative complications.

Despite decades of research,cancer continues to be a major global health concern.The human mouth appears to be a multiplicity of local environments communicating with other organs and causing diseases via microbes.Nowadays,the role of oral microbes in the development and progression of cancer has received increasing scrutiny.At the same time,bioengineering technology and nanotechnology is growing rapidly,in which the physiological activities of natural bacteria are modified to improve the therapeutic efficiency of cancers.These engineered bacteria were transformed to achieve directed genetic reprogramming,selective functional reorganization and precise control.In contrast to endotoxins produced by typical genetically modified bacteria,oral flora exhibits favorable biosafety characteristics.To outline the current cognitions upon oral microbes,engineered microbes and human cancers,related literatures were searched and reviewed based on the PubMed database.We focused on a number of oral microbes and related mechanisms associated with the tumor microenvironment,which involve in cancer occurrence and development.Whether engineering oral bacteria can be a possible application of cancer therapy is worth consideration.A deeper understanding of the relationship between engineered oral bacteria and cancer therapy may enhance our knowledge of tumor pathogenesis thus providing new insights and strategies for cancer prevention and treatment.

Objective:To explore the structural characteristics of intestinal microflora in children with non-alcoholic fatty liver disease（NAFLD）and the relationship between intestinal microflora and the occurrence as well as development of NAFLD in children.Methods:Fifteen children with NAFLD diagnosed at the First People's Hospital of Yunnan Province from January 2022 to December 2022 were selected as subjects，and 15 healthy children who received routine physical examinations at the outpatient clinic during the same period were randomly selected as healthy control group.The height，weight，waist circumference，blood pressure，blood biochemistry of all children were collected.At the same time，the fresh fecal samples of all children were collected，and the biological information of intestinal flora was analyzed by 16S rRNA sequencing.Results:In the NAFLD group，there were eight males and seven females，with an average age of（11.13±1.77）years.In healthy control group，there were seven males and eight females，with an average age of（9.73±2.25）years.There were no significant differences in sex，age，blood pressure between two groups.Compared with the healthy control group，the levels of body mass index，waist circumference，waist-to-height ratio，alanine aminotransferase，aspartate transaminase，gamma-glutamyl transpeptidase，total bilirubin，direct bilirubin，unconjugated bilirubin，low density lipoprotein cholesterol，uric acid and serum insulin significantly increased and high density lipoprotein cholesterol significantly decreased in NAFLD group（ P<0.05）.The results of species diversity analysis showed that chaol index and observed-species index in NAFLD group were significantly higher than those in healthy control group（ P<0.05）.Species diversity analysis showed that the species with increased abundance in NAFLD group included：Proteobacteria，Gammaproteobacteria，Enterobacteriaceae，Klebsiella，Escherichia-Shigella，Escherichia-Shigella-unclassified.Differential species with increased abundance in the healthy control group included：Bifidobacterium species，Bifidobacterium，Bifidobacteriaceae，Bifidobacteriales，Actinobacteria，Actinobacteriota，Bacteroidia，Bacteroidales，Streptococcus-thermophilus. Conclusion:There are metabolic abnormalities and obvious changes in the structure of intestinal flora in children with NAFLD.Exogenous supplementation of Bifidobacterium，Streptococcus thermophilus and Bacteroides may prevent the occurrence of NAFLD，delay the progression of disease and improve fat deposition in the liver.

Objective To investigate the predictive value of preoperative blood inflammatory markers for the recurrence risk in patients with basal cell carcinoma(BCC).Methods A total of 225 patients with BCC were divided into the high-risk recurrence group(155 cases)and the low-risk recurrence group(70 cases).General information and preoperative hematological indicators were collected in the two groups of patients.The neutrophil-to-lymphocyte ratio(NLR),lymphocyte-to-monocyte ratio(LMR),systemic inflammation marker(SIM)and platelet-to-lymphocyte ratio(PLR)were calculated.Receiver operating characteristic(ROC)curves were used to determine the predictive value of hematological markers with statistically significant differences between the two groups for BCC recurrence and to establish optimal cutoff values.Univariate and multivariate Logistic regression analyses were conducted to identify factors influencing BCC recurrence.A multivariate Logistic regression model was established to predict the recurrence risk of BCC.Area under the curve(AUC)and the Hosmer-Lemeshow test were used to evaluate the prediction efficiency and goodness-of-fit of the model.Results ROC analysis identified that optimal cutoff values for LMR and SIM were 5.12 and 0.86,respectively.Univariate Logistic regression analysis showed that LMR,SIM,ulceration at the primary tumor site,UV exposure and tumor maximum diameter were factors influencing BCC recurrence.Multivariate Logistic regression revealed that SIM≥0.86,tumor maximum diameter≥2.0 cm and UV exposure were risk factors for BCC recurrence,while LMR≥5.12 had a protective effect.The Logistic prediction model for BCC recurrence risk was Logit(P)=-1.598-1.517×LMR+1.323×SIM+2.406×UV exposure+3.465×tumor maximum diameter,with good model fit(P=0.725)and an AUC of 0.869(95%CI:0.822-0.917)for predicting BCC recurrence risk.Conclusion Monitoring preoperative LMR and SIM levels can assist in assessing the risk of recurrence in BCC patients and provide important guidance for clinical decision-making.

Objective:To analyze and compare the effects of conventional treatment and the dynamic 3C therapy, continuous glucose monitoring system, and on outcomes, length of hospital stay and medical costs in patients with type 2 diabetes mellitus.Methods:A total of 122 type 2 diabetes mellitus patients who visited the Department of Endocrinology of Shanxi Baiqiu'en Hospital between June 2022 and December 2022 were selected and randomized at 1:1 into the control group and the experimental group using the randomized numerical table method. The t-test and non-parametric test were used as appropriate to compare the glycemic control, length of hospital stay and medical costs of the two groups.Results:Before treatment, there was no significant difference in the indicators for blood glucose levels and fluctuations between the two groups ( P>0.05). After treatment, the glycosylated hemoglobin, fasting plasma glucose, and 2-hour postprandial blood glucose decreased in both groups. Moreover, the glycosylated hemoglobin, fasting plasma glucose, and 2-hour postprandial blood glucose showed more significant decreases in the experimental group compared with the control group after treatment. The glycemic variability indicators, including the time out of range, standard deviation of blood glucose, and the largest amplitude of glycemic excursion, decreased after treatment in both groups. The time in range increased after treatment. After treatment, the standard deviation of blood glucose and the largest amplitude of glycemic excursion in the experimental group were lower than those in the control group, and the length of hospital stay in the experimental group was shortened (all P<0.05). Conclusion:3C therapy contributes to better glycemic control and shorter hospital stay in patients with type 2 diabetes mellitus.

Purpose To investigate the difference of resting-state functional connectivity density(FCD)between chronic primary insomnia patients and healthy controls via resting state functional magnetic resonance imaging(rs-fMRI).Materials and Methods All rs-fMRI data of 35 patients with chronic primary insomnia from Xidian Group Hospital and Xi'an Encephalopathy Hospital of Traditional Chinese Medicine,and 35 healthy controls were prospectively collected from August 2020 to December 2021.The voxel-wise FCD approach was applied to explore the differences of whole-brain functional networks between chronic primary insomnia patients and healthy controls.The relationships between FCD value and Pittsburgh sleep quality index,self-rating scale of sleep,insomnia severity index,self-rating anxiety scale and self-rating depression scale in primary insomnia patients were investigated,respectively.Results Compared with healthy controls,the decreased FCD values were showed in the right insula,bilateral anterior cingulate gyrus,left orbitofrontal middle gyrus,left dorsolateral superior frontal gyrus,right medial superior frontal gyrus and bilateral thalamus(t<-5.271,Padjust<0.05),while the increased FCD values showed in the right superior temporal gyrus,bilateral middle temporal gyrus,bilateral precuneus and left posterior cingulate gyrus(t>4.379,Padjust<0.05)in the chronic primary insomnia patients group.The FCD values of bilateral thalamus(r=-0.620,P<0.001;r=-0.562,P<0.005)and right insula(r=-0.651,P<0.001)were negatively correlated with insomnia severity index in the chronic primary insomnia patients group,respectively.Conclusion The extensive functional connectivity abnormalities are observed in primary insomnia patients via FCD analysis.These findings explain the neural mechanisms of underlying emotional regulation and cognitive impairment in chronic insomnia from the perspective of functional integration and functional separation.