Alzheimer's disease (AD) remains a formidable challenge in modern healthcare, necessitating innovative approaches for its early detection and intervention. This study aimed to enhance the identification of individuals with mild cognitive impairment (MCI) at risk of developing AD. Leveraging advances in computational power and the extensive availability of healthcare data, we explored the potential of deep learning models for early prediction using medical claims data. We employed a bidirectional gated recurrent unit (BiGRU) deep learning model for predictive modeling of MCI progression across various prediction intervals, extending up to five years post-initial MCI diagnosis. The performance of the BiGRU model was rigorously compared with several machine-learning model baselines to evaluate its efficacy. Using a robust cross-validation methodology, the BiGRU emerged as the top-performing model, achieving an Area Under the Receiver Operating Characteristic Curve (AUC-ROC) of 0.833 (95% CI: 0.822, 0.843), an Area Under the Precision-Recall Curve (AUC-PR) of 0.856 (95% CI: 0.845, 0.867), and an F1-Score of 0.71 (95% CI: 0.694, 0.724) for a five-year prediction interval. The results indicate that BiGRU, utilizing longitudinal claims data, reliably predicts MCI-to-AD progression over a lengthy interval following the initial MCI diagnosis, offering clinicians a valuable tool for targeted risk identification and stratification.

Periodontal bone defects, primarily caused by periodontitis, are highly prevalent in clinical settings and manifest as bone fenestration, dehiscence, or attachment loss, presenting a significant challenge to oral health. In regenerative medicine, harnessing developmental principles for tissue repair offers promising therapeutic potential. Of particular interest is the condensation of progenitor cells, an essential event in organogenesis that has inspired clinically effective cell aggregation approaches in dental regeneration. However, the precise cellular coordination mechanisms during condensation and regeneration remain elusive. Here, taking the tooth as a model organ, we employed single-cell RNA sequencing to dissect the cellular composition and heterogeneity of human dental follicle and dental papilla, revealing a distinct Platelet-derived growth factor receptor alpha (PDGFRA) mesenchymal stem/stromal cell (MSC) population with remarkable odontogenic potential. Interestingly, a reciprocal paracrine interaction between PDGFRA⁺ dental follicle stem cells (DFSCs) and CD31⁺ Endomucin⁺ endothelial cells (ECs) was mediated by Vascular endothelial growth factor A (VEGFA) and Platelet-derived growth factor subunit BB (PDGFBB). This crosstalk not only maintains the functionality of PDGFRA⁺ DFSCs but also drives specialized angiogenesis. In vivo periodontal bone regeneration experiments further reveal that communication between PDGFRA⁺ DFSC aggregates and recipient ECs is essential for effective angiogenic-osteogenic coupling and rapid tissue repair. Collectively, our results unravel the importance of MSC-EC crosstalk mediated by the VEGFA and PDGFBB-PDGFRA reciprocal signaling in orchestrating angiogenesis and osteogenesis. These findings not only establish a framework for deciphering and promoting periodontal bone regeneration in potential clinical applications but also offer insights for future therapeutic strategies in dental or broader regenerative medicine.
Receptor, Platelet-Derived Growth Factor alpha/metabolism* ; Humans ; Neovascularization, Physiologic/physiology* ; Dental Sac/cytology* ; Single-Cell Analysis ; Transcriptome ; Mesenchymal Stem Cells/metabolism* ; Bone Regeneration ; Animals ; Dental Papilla/cytology* ; Periodontium/physiology* ; Stem Cells/metabolism* ; Regeneration ; Angiogenesis

Patients with chronic obstructive pulmonary disease have the disease phenomenon of fear of exercise because of dyspnea, which can accelerate the body degradation rate, weaken muscle strength, reverse increase dyspnea, and delay the recovery of the disease. As a result, this article examines the theoretical underpinnings and specific measures of dyspnea belief intervention programs for chronic obstructive pulmonary disease patients at home and abroad, summarizes the limitations of previous studies, and makes pertinent recommendations in an effort to serve as a guide for early patient prevention and the development of scientific and feasible intervention programs.

Objective:To discuss the effect of Wnt/β-catenin signaling pathway inhibitor methyl 3-｛[(4-methyl-phenyl)sulfonyl]amino ｝ benzoate(MS AB)on the fibrogenic response of the human endometrial stromal cells(HESCs),and to provide the foundation for the application of MSAB in the target therapy of intrauteriue adhesion(JUA).Methods:The normal HESCs were cultured in vitro and divided into two groups:control group and transforming growth factor β1(TGF-β1)group;the HESCs from the adhesion part of the IUA patients were cultured in vitro,regarded as IUA group.Western blotting method was used to detect the expression levels of fibrotic marker protein type Ⅰ collagen α1(COL1A1)in the cells in various groups at different time points(0,12,24,48,and 60 h)after treated with TGF-β1.MTT assay was used to detect the proliferation activities of the cells in various groups.Western blotting method was used to detect the expression levels of the fibrotic marker protein COL1A1,stromal marker proteins such as N-cadherin and α-smooth muscle actin(α-SMA),and Wnt/β-catenin signaling pathway-related protein β-catenin in the cells in control and IUA groups.Based on the MSAB concentrations,the normal HESCs were divided into 0(control),0.25,0.50,0.75,and 1.00 μmol·L-1 MSAB groups,and MTT assay was used to detect the survival rates of the cells in various groups.After treated with MSAB,the normal HESCs were divided into control group(normal HESCs),TGF-β1 group(10 μg·L-1 TGF-β1 induced normal HESCs for 24 h then the drug was withdrawn,replaced with complete culture medium,and the cells continued to be cultured for 24 h),and MSAB group(10 μg·L-1 TGF-β1 induced normal HESCs for 24 h then the drug was withdrawn,replaced with a complete medium containing 0.75 μmol·L-1 MSAB and the cells continued to be cultured for 24 h).Real-time fluorescence quantitative PCR(RT-qPCR)method was used to detect the expression levels of epithelial-mesenchymal transition(EMT)-related transcription factors Snail,Slug,Smuc,ZEB1,and ZEB2,and COL1A1 mRNA in the cells in various groups.Western blotting method was used to detect the expression levels of COL1A1,N-cadherin,α-SMA,β-catenin,and c-myc proteins in the cells in various groups.Results:Compared with control group(after treated with TGF-β1 for 0 h),the expression levels of COL1A1 proteins in the HESCs after treated with TGF-β1 for 12,24,48,and 60 h in TGF-β1 group were increased(P＜0.05 or P＜0.01).Compared with control group,there was no significant difference in the proliferation activity of the HESCs in IUA and TGF-β1 groups(P＞0.05).Compared with control group,the expression levels of COL1A1,β-catenin,N-cadherin,and α-SMA proteins in the cells in IUA group were increased(P＜0.05 or P＜0.01).Compared with control group,the survival rates of the cells in 0.75 and 1.00 μmol·L-1 MSAB groups were decreased(P＜0.05 or P＜0.01).Compared with control group,the expression levels of Snail,Slug,and COL1A1 mRNA in the cells in TGF-β1 group were increased(P＜0.05 or P＜0.01);compared with TGF-β1 group,the expression levels of Snail,Slug,and COL1A1 mRNA in the cells in MSAB group were decreased(P＜0.05 or P＜0.01).Compared with control group,after treated with TGF-β1 for 24 h,the expression levels of COL1A1,N-cadherin,α-SMA,β-catenin,and c-myc proteins in the cells in TGF-β1 group were increased(P＜0.01);compared with TGF-β1 group,the expression levels of COL1A1,N-cadherin,α-SMA,β-catenin,and c-myc proteins in the cells in MSAB group were decreased(P＜0.05 or P＜0.01).Conclusion:MSAB can inhibit the fibrogenic responses of the HESCs in vitro,and the results provide the theoretical basis for the application of MSAB in the target therapy of IUA.

Objective To observe the effect on clinical efficacy and renal microcirculation(RMC)of Shenshuai Ⅱ Prescription Granules in the treatment of patients with stage 3-4 chronic kidney disease(CKD)caused by primary glomerulonephritis(PGN)with deficiency of spleen and kidney qi syndrome.Methods Using a randomized,double-blind clinical trial design,70 patients with CKD stage 3-4 were divided into the treatment group and the control group,with 35 cases in each group.The control group was given CKD integrated treatment combined with placebo granules,and the treatment group was given CKD integrated treatment combined with Shenshuai Ⅱ Prescription Granules.The clinical efficacy of both groups was observed.TCM symptom scores,renal function indexes and RMC indexes before and after treatment of the two groups were compared.Safety indexes of both groups were monitored.Results The total effective rate was 82.86％(29/35)in the treatment group and 54.29％(19/35)in the control group,with statistical significance(P<0.05).Compared with before treatment,all the TCM symptom scores of the 2 groups were reduced after treatment(P<0.05,P<0.01);after treatment,the 5 spleen and kidney qi deficiency symptom scores and the total score of the treatment group were lower than those of the control group(P<0.05).The mean values of renal cortical and medullary blood flow were elevated in the treatment group after treatment compared with the pre-treatment period in this group(P<0.05,P<0.01);the mean values of renal cortical and medullary blood flow were elevated in the treatment group compared with the control group in the post-treatment period(P<0.05,P<0.01).Compared with before treatment,the serum content of NO increased(P<0.01),ET-1 and VEGF decreased(P<0.01);after treatment,the serum content of NO in the treatment group was higher than that in the control group(P<0.05),and ET-1 and VEGF in the treatment group were lower than those in the control group(P<0.01).Compared with before treatment,SCr,BUN,24 hUP decreased and eGFR increased in the treatment group(P<0.05,P<0.01);after treatment,SCr,BUN,and 24 hUP in the treatment group were lower than those in the control group,and eGFR in the treatment group was higher than that in the control group(P<0.01).Compared with this group before treatment and between groups after treatment,the difference in Uric acid between the 2 groups was not statistically significant(P>0.05).There was no abnormal change in safety indexes before and after treatment in both groups(P>0.05).Conclusion Shenshuai Ⅱ Prescription Granules combined with CKD integrated treatment can effectively improve clinical symptoms and renal function related indexes of CKD stage 3-4 patients with spleen and kidney qi deficiency syndrome,increase renal blood flow,improve RMC disorder,and improve clinical efficacy.

Objective:To investigate damaging effects of clomifene citrate(CC)on endometrial stromal cells(hEndoSCs),and to study effects of spermidine on autophagy and inflammatory cytokine expression in damaged endometrial stromal cells.Methods:Groups were firstly divided into control group,spermidine group,clomiphene group(CC group),CC+Spermidine group.MTT assay was used to detect cell survival rate of hEndoSCs after co-incubation with different concentrations of CC or Spermidine for 24 h.Con-tent of intracellular reactive oxygen species(ROS)and level of apoptosis in cells of the 4 groups were detected by flow cytometry tech-nique.Western blot was used to detect expressions of autophagy pathway-related proteins ULK1,p-ULK1,LC-3Ⅱ,and apoptosis-re-lated proteins Bax,Bcl-2,Cleaved-caspase 3.RT-qPCR was used to detect mRNA expressions of IL-6,IL-1β and TNF-α.Results:Compared with control group,CC group showed decreased cell survival,increased apoptosis rate,ROS content,Bax,Cleaved-cas-pase 3 expressions,decreased Bcl-2 expression,decreased levels of autophagy-related proteins p-ULK1 and LC-3Ⅱ/Ⅰ,and elevated expressions of inflammatory factors IL-6,IL-1β and TNF-α mRNA(P<0.01).There was no significant changes viability of cells in spermidine group compared with control group(P>0.05).Compared with CC group,cell survival rate in CC+spermidine group was sig-nificantly increased,apoptosis rate,ROS content,Bax and Cleaved-caspase 3 expressions were decreased,Bcl-2 expression was in-creased,expressions of autophagy-related proteins p-ULK1 and LC-3Ⅱ/Ⅰ were elevated,while expressions of inflammatory factors IL-6,IL-1β and TNF-α mRNA were decreased(P<0.01).Conclusion:CC can inhibit endometrial stromal cell proliferation,promote apoptosis,and increase the transcript levels of inflammatory factors IL-6,IL-1β and TNF-α.Spermidine can reduce intracellular ROS in clomiphene-injured endometrial stromal cells by activating cellular autophagy,increase cell survival,and inhibit the expressions of inflammatory factors IL-6,IL-1β and TNF-α.

Objective:To develop and validate a predictive model of 28-day mortality in sepsis based on lactate dehydrogenase-to-albumin ratio (LAR).Methods:Sepsis patients diagnosed in the department of intensive care medicine of the First Affiliated Hospital of Soochow University from August 1, 2017 to September 1, 2022 were retrospective selected. Clinical data, laboratory indicators, disease severity scores [acute physiology and chronic health evaluation Ⅱ(APACHEⅡ), sequential organ failure assessment (SOFA)] were collected. Patients were divided into death group and survival group according to whether they died at 28 days, and the difference between the two groups was compared. The dataset was randomly divided into training set and validation set according to 7∶3. Lasso regression method was used to screen the risk factors affecting the 28-day death of sepsis patients, and incorporating multivariate Logistic regression analysis (stepwise regression) were included, a prediction model was constructed based on the independent risk factors obtained, and a nomogram was drawn. The nomogram prediction model was established. Receiver operator characteristic curve (ROC curve) was drawn to analyze and evaluate the predictive efficacy of the model. Hosmer-Lemeshow test, calibration curve and decision curve analysis (DCA) were used to evaluate the accuracy and clinical practicability of the model, respectively.Results:A total of 394 patients with sepsis were included, with 248 survivors and 146 non-survivors at 28 days. Compared with the survival group, the age, proportion of chronic obstructive pneumonia, respiratory rate, lactic acid, red blood cell distribution width, prothrombin time, activated partial thromboplastin time, alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, creatinine, blood potassium, blood phosphorus, LAR, SOFA score, and APACHEⅡ score in the death group were significantly increased, while oxygenation index, monocyte count, platelet count, fibrinogen, total cholesterol, triglycerides, high-density lipoprotein, low-density lipoprotein, and blood calcium were significantly reduced. In the training set, LAR, age, oxygenation index, blood urea nitrogen, lactic acid, total cholesterol, fibrinogen, blood potassium and blood phosphorus were screened by Lasso regression. Multivariate Logistic regression analysis finally included LAR [odds ratio ( OR) = 1.029, 95% confidence interval (95% CI) was 1.014-1.047, P < 0.001], age ( OR = 1.023, 95% CI was 1.005-1.043, P = 0.012), lactic acid ( OR = 1.089, 95% CI was 1.003-1.186, P = 0.043), oxygenation index ( OR = 0.996, 95% CI was 0.993-0.998, P = 0.002), total cholesterol ( OR = 0.662, 95% CI was 0.496-0.865, P = 0.003) and blood potassium ( OR = 1.852, 95% CI was 1.169-2.996, P = 0.010). A total of 6 predictor variables were used to establish a prediction model. ROC curve showed that the area under the curve (AUC) of the model in the training set and validation set were 0.773 (95% CI was 0.715-0.831) and 0.793 (95% CI was 0.703-0.884), which was better than APACHEⅡ score (AUC were 0.699 and 0.745) and SOFA score (AUC were 0.644 and 0.650), and the cut-off values were 0.421 and 0.309, the sensitivity were 62.4% and 82.2%, and the specificity were 82.2% and 68.9%, respectively. The results of Hosmer-Lemeshow test and calibration curve showed that the predicted results of the model were in good agreement with the actual clinical observation results, and the DCA showed that the model had good clinical application value. Conclusion:The prediction model based on LAR has a good predictive value for 28-day mortality in patients with sepsis and can guide clinical decision-making.

Acute leukemias caused by mixed lineage leukemia(MLL)gene rearrangements(MLL-r)are characterized by high invasiveness and a poor prognosis,with few specific treatment options available.MLL protein is essential in embryonic development and hematopoiesis.It exhibits histone methyltransferase activity and can interact with various proteins through its functional domains,thus regulating downstream target gene expression through epigenetic modifications.MLL-r leads to the formation of MLL fusion proteins(MLL-FPs),in which the C-terminal is replaced by fusion partner proteins;over 100 such partner proteins have been identified to date.In numerous studies of the molecular mechanism,Menin serves as an important cofacter in the leukemogenesis of MLL-FPs and participates in forming the key complex when interacting with the N terminal of MLL protein,resulting in the disregulation of certain targeted genes,which makes the development of Menin-MLL inhibitors theoretically possible.To date,several small molecules have been identified that inhibit Menin-MLL interaction,including thienopyrimidine derivatives,piperidine derivatives,pyrimidine derivatives,and macrocyclic mimic peptides.Based on these prototypes,at least seven drugs are currently undergoing clinical evaluation,with some promising preliminary data regarding safety,tolerability,and efficacy.This review summarizes the structure and function of MLL,the mechanism of the occurrence of MLL-r leukemia,and current Menin-MLL inhibitors tested in MLL-r leukemia.

The changes in intestinal flora are usually associated with different gastrointestinal diseases, and intestinal flora homeostasis can enhance immune tolerance and regulate intestinal immune balance.Previous studies have found that the increase of the relative abundance of Bacteroides fragilis (B.fragilis) in Bacteroides intestinalis can significantly enhance the expression of intestinal regulatory T cells (Treg) and anti-inflammatory cytokines, thus alleviating intestinal inflammation.However, the mechanism of B.fragilis regulating intestinal immunity is still unclear.In this study, an acute colitis model was constructed by giving 3% DSS in drinking water solution to SPF-grade C57BL/6 mice for 7 days, and exogenous supplementation B.fragilis was given to mice by gastric gavage to study its regulatory effect on intestinal immunity and its mechanism of action.The results showed that B.fragilis could improve the intestinal flora disorder in mice with colitis and increase the content of short-chain fatty acids (SCFAs), the main metabolite of the intestinal flora.By extracting mouse tissue lymphocytes, naive CD4+ T cells, and liposome-modified siRNA knockdown mouse Smad3, it was further discovered by flow cytometry that B.fragilis induced the expression of intestinal Treg cells and related cytokines through the TGF-β/Smad3 signaling pathway, which enhanced intestinal regulatory immunity and alleviated colitis.It was also found that B.fragilis activated TGF-β by increasing the expression of reactive oxygen species (ROS), thus inducing Treg cell differentiation and playing an immunomodulatory role.