Objective To study the relationship between serum insulin-like growth factor-1 (IGF-1) and resistin levels and osteoporosis in patients with type 2 diabetes mellitus (T2DM). Methods This study was conducted on 306 T2DM patients admitted to Baoding No.2 Central Hospital from January 2018 to January 2022. According to the detection results of bone mineral density, the patients were divided into osteoporosis group (T≤-2.5) and non-osteoporosis group (T>-2.5). The differences in IGF-1, resistin and bone mineral density were compared between the two groups. Pearson correlation analysis was used to analyze the correlation between serum IGF-1 and resistin levels and bone mineral density in patients with osteoporosis. Receiver operating characteristic (ROC) curve was applied to evaluate the application value of IGF-1 and resistin in predicting osteoporosis in patients with T2DM. Patients with T2DM complicated with osteoporosis were followed up for 2 years, and the occurrence of fractures was assessed. After univariate analysis, multivariate logistic regression analysis was applied to screen the risk factors for fractures in T2DM patients with osteoporosis. Results The incidence rate of osteoporosis in patients with T2DM was 53.59% (164/306). The IGF-1 level and bone mineral density level in the osteoporosis group were lower than those in the non-osteoporosis group, while the level of resistin was higher than that in the non-osteoporosis group (P<0.05). Serum IGF-1 in patients with osteoporosis was positively correlated with bone mineral density, and serum resistin was negatively correlated with bone mineral density (P<0.05). The AUC, sensitivity and specificity of combination of IGF-1 and resistin in predicting osteoporosis were 0.888, 82.93% and 62.68% respectively, which were all higher than those of single factor prediction (P<0.05). The 164 T2DM patients with osteoporosis were followed up for two years, and 15 patients developed fragility fractures, with the incidence of fracture of 9.15% (15/164). Multivariate analysis showed that hypoproteinemia, high-intensity exercise, lack of nutritional management, low IGF-1, and high resistin were risk factors for fractures in patients with T2DM complicated with osteoporosis (P<0.05). Conclusion For patients with T2DM, the incidence rates of osteoporosis and fractures are high. The levels of IGF-1 and resistin are closely related to bone mineral density, which can be combined to predict osteoporosis. Hypoproteinemia, high-intensity exercise, lack of nutritional management, low IGF-1 and high resistin are risk factors for fractures in T2DM patients with osteoporosis. It is necessary to carry out targeted preventive measures in clinical practice to reduce the incidence rate of fractures.

Idiopathic pulmonary fibrosis (IPF), a chronic interstitial lung disease, is characterized by aberrant wound healing, excessive scarring and the formation of myofibroblastic foci. Although the role of alternative splicing (AS) in the pathogenesis of organ fibrosis has garnered increasing attention, its specific contribution to pulmonary fibrosis remains incompletely understood. In this study, we identified an up-regulation of serine/arginine-rich splicing factor 7 (SRSF7) in lung fibroblasts derived from IPF patients and a bleomycin (BLM)-induced mouse model, and further characterized its functional role in both human fetal lung fibroblasts and mice. We demonstrated that enhanced expression of Srsf7 in mice spontaneously induced alveolar collagen accumulation. Mechanistically, we investigated alternative splicing events and revealed that SRSF7 modulates the alternative splicing of pyruvate kinase (PKM), leading to metabolic dysregulation and fibroblast activation. In vivo studies showed that fibroblast-specific knockout of Srsf7 in conditional knockout mice conferred resistance to bleomycin-induced pulmonary fibrosis. Importantly, through drug screening, we identified lomitapide as a novel modulator of SRSF7, which effectively mitigated experimental pulmonary fibrosis. Collectively, our findings elucidate a molecular pathway by which SRSF7 drives fibroblast metabolic dysregulation and propose a potential therapeutic strategy for pulmonary fibrosis.

The identification and optimization of mutations in nanobodies are crucial for enhancing their therapeutic potential in disease prevention and control. However, this process is often complex and time-consuming, which limit its widespread application in practice. In this study, we developed a workflow, named Evolutionary-Nanobody (EvoNB), to predict key mutation sites of nanobodies by combining protein language models (PLMs) and molecular dynamic (MD) simulations. By fine-tuning the ESM2 model on a large-scale nanobody dataset, the ability of EvoNB to capture specific sequence features of nanobodies was significantly enhanced. The fine-tuned EvoNB model demonstrated higher predictive accuracy in the conserved framework and highly variable complementarity-determining regions of nanobodies. Additionally, we selected four widely representative nanobody-antigen complexes to verify the predicted effects of mutations. MD simulations analyzed the energy changes caused by these mutations to predict their impact on binding affinity to the targets. The results showed that multiple mutations screened by EvoNB significantly enhanced the binding affinity between nanobody and its target, further validating the potential of this workflow for designing and optimizing nanobody mutations. Additionally, sequence-based predictions are generally less dependent on structural absence, allowing them to be more easily integrated with tools for structural predictions, such as AlphaFold 3. Through mutation prediction and systematic analysis of key sites, we can quickly predict the most promising variants for experimental validation without relying on traditional evolutionary or selection processes. The EvoNB workflow provides an effective tool for the rapid optimization of nanobodies and facilitates the application of PLMs in the biomedical field.

OBJECTIVE: To compare the efficacy and safety of intravenous colistin sulfate combined with nebulized inhalation versus intravenous monotherapy for pulmonary infections caused by carbapenem-resistant organism (CRO). METHODS: A multicenter retrospective cohort study was conducted. Clinical data were collected from patients admitted to the intensive care unit (ICU) of 10 tertiary class-A hospitals in Henan Province between July 2021 and May 2023, who received colistin sulfate for CRO pulmonary infections. Data included baseline characteristics, inflammatory markers [white blood cell count (WBC), neutrophil count (NEU), procalcitonin (PCT), C-reactive protein (CRP)], renal function indicators [serum creatinine (SCr), blood urea nitrogen (BUN)], life support measures, anti-infection regimens, clinical efficacy, microbiological clearance rate, and prognostic outcomes. Patients were divided into two groups: intravenous group (colistin sulfate monotherapy via intravenous infusion) and combination group ((intravenous infusion combined with nebulized inhalation of colistin sulfate). Changes in parameters before and after treatment were analyzed. RESULTS: A total of 137 patients with CRO pulmonary infections were enrolled, including 89 in the intravenous group and 48 in the combination group. Baseline characteristics, life support measures, daily colistin dose, and combination regimens (most commonly colistin sulfate plus carbapenems in both groups) showed no significant differences between two groups. The combination group exhibited higher clinical efficacy [77.1% (37/48) vs. 59.6% (52/89)] and microbiological clearance rate [60.4% (29/48) vs. 39.3% (35/89)], both P < 0.05. Pre-treatment inflammatory and renal parameters showed no significant differences between two groups. Post-treatment, the combination group showed significantly lower WBC and CRP [WBC (×10⁹/L): 8.2±0.5 vs. 10.9±0.6, CRP (mg/L): 14.0 (5.7, 26.6) vs. 52.1 (24.4, 109.6), both P < 0.05], whereas NEU, PCT, SCr, and BUN levels showed no significant between two groups. ICU length of stay was shorter in the combination group [days: 16 (10, 25) vs. 21 (14, 29), P < 0.05], although mechanical ventilation duration and total hospitalization showed no significant differences between two groups. CONCLUSIONS Intravenous colistin sulfate combined with nebulized inhalation improved clinical efficacy and microbiological clearance in CRO pulmonary infections with an acceptable safety profile.
Humans ; Colistin/therapeutic use* ; Retrospective Studies ; Administration, Inhalation ; Anti-Bacterial Agents/therapeutic use* ; Carbapenems/pharmacology* ; Male ; Female ; Middle Aged ; Gram-Negative Bacteria/drug effects* ; Aged ; Treatment Outcome ; Respiratory Tract Infections/drug therapy*

OBJECTIVE: This study aimed to explore the association between body mass index (BMI) and mortality based on the 10-year population-based multicenter prospective study. METHODS: A general population-based multicenter prospective study was conducted at four sites in rural China between 2013 and 2023. Multivariate Cox proportional hazards models and restricted cubic spline analyses were used to assess the association between BMI and mortality. Stratified analyses were performed based on the individual characteristics of the participants. RESULTS: Overall, 19,107 participants with a sum of 163,095 person-years were included and 1,910 participants died. The underweight (< 18.5 kg/m ²) presented an increase in all-cause mortality (adjusted hazards ratio [ aHR] = 2.00, 95% confidence interval [ CI]: 1.66-2.41), while overweight (≥ 24.0 to < 28.0 kg/m ²) and obesity (≥ 28.0 kg/m ²) presented a decrease with an aHR of 0.61 (95% CI: 0.52-0.73) and 0.51 (95% CI: 0.37-0.70), respectively. Overweight ( aHR = 0.76, 95% CI: 0.67-0.86) and mild obesity ( aHR = 0.72, 95% CI: 0.59-0.87) had a positive impact on mortality in people older than 60 years. All-cause mortality decreased rapidly until reaching a BMI of 25.7 kg/m ² ( aHR = 0.95, 95% CI: 0.92-0.98) and increased slightly above that value, indicating a U-shaped association. The beneficial impact of being overweight on mortality was robust in most subgroups and sensitivity analyses. CONCLUSION This study provides additional evidence that overweight and mild obesity may be inversely related to the risk of death in individuals older than 60 years. Therefore, it is essential to consider age differences when formulating health and weight management strategies.
Humans ; Body Mass Index ; China/epidemiology* ; Male ; Female ; Middle Aged ; Prospective Studies ; Rural Population/statistics & numerical data* ; Aged ; Follow-Up Studies ; Adult ; Mortality ; Cause of Death ; Obesity/mortality* ; Overweight/mortality*

The identification and optimization of mutations in nanobodies are crucial for enhancing their thera-peutic potential in disease prevention and control.However,this process is often complex and time-consuming,which limit its widespread application in practice.In this study,we developed a work-flow,named Evolutionary-Nanobody(EvoNB),to predict key mutation sites of nanobodies by combining protein language models(PLMs)and molecular dynamic(MD)simulations.By fine-tuning the ESM2 model on a large-scale nanobody dataset,the ability of EvoNB to capture specific sequence features of nanobodies was significantly enhanced.The fine-tuned EvoNB model demonstrated higher predictive accuracy in the conserved framework and highly variable complementarity-determining regions of nanobodies.Additionally,we selected four widely representative nanobody-antigen complexes to verify the predicted effects of mutations.MD simulations analyzed the energy changes caused by these mu-tations to predict their impact on binding affinity to the targets.The results showed that multiple mu-tations screened by EvoNB significantly enhanced the binding affinity between nanobody and its target,further validating the potential of this workflow for designing and optimizing nanobody mutations.Additionally,sequence-based predictions are generally less dependent on structural absence,allowing them to be more easily integrated with tools for structural predictions,such as AlphaFold 3.Through mutation prediction and systematic analysis of key sites,we can quickly predict the most promising variants for experimental validation without relying on traditional evolutionary or selection processes.The EvoNB workflow provides an effective tool for the rapid optimization of nanobodies and facilitates the application of PLMs in the biomedical field.

Objective To evaluate the quality and authenticity of Ophiopogon japonicus in Shengmaiyin,establish ultra performance liquid chromatography tandem mass spectrometry(UPLC-MS/MS)for the determination of three characteristic components(methylophiopogonanone A,liriopeside B and liriope muscari baily saponin C),and provide technical support for drug supervision.Methods Samples were analyzed on a Phenomenex Kinetex F5 C18 column(100 mm×3.0 mm,2.6 μm)in a gradient elution mode with 0.1％formic acid water and-0.1％formic acid acetonitrile as the mobile phase at a flow rate of 0.4 mL/min,the column temperature was 30 ℃,and the injection volume was 1 μL.Mass spectrometer detector,electro spray ion source of positive and negative ions,and multi-reaction monitoring mode were used.Results The linear ranges of methylophiopogonanone A,liriopeside B and liriope muscari baily saponin C were 0.016 7-1.666 0,0.039 7-15.872 0 and 0.022 5～8.988 0 ng(r＞0.999 9),respectively.The average recovery rates of these three components were 85.16％,86.95％and 95.07％,respectively,with RSSDs of 2.65％,1.45％and 1.14％(n=6).The content of methylophiopogonanone A in thirty-eight batches was quite different.Seven batches of liriopeside B or liriope muscari baily saponin C were detected.Conclusion The method is simple and sensitive,and suitable for determining of three characteristic components in Shengmaiyin,which provides references for the quality control of Ophiopogon japonicus in Shengmaiyin.

Objective To investigate the levels of soluble tyrosine kinase-1(sFlt-1)and chemokine C-C ligand 3(CCL3)in serum of patients with coronary heart disease(CHD)and their correlation with the severity of the disease.Methods A total of 230 elderly CHD patients admitted to the De-partment of Cardiovascular Medicine of Xinxiang Central Hospital from November 2020 to No-vember 2022 were collected as the study subjects(CHD group),and according to their Gensini score,they were divided into mild(n=89),moderate(n=95),and severe(n=46)CHD sub-groups.Another 230 healthy individuals who taking physical examination during the same period served as the control group.ELISA was applied to measure serum levels of sFlt-1 and CCL3.ROC curve was plotted to analyze the diagnostic values of serum sFlt-1 and CCL3 levels for CHD.Pear-son correlation analysis was employed to analyze the relationship between serum sFlt-1 and CCL3 levels and the CHD severity.Results The serum levels of sFlt-1 and CCL3 were obviously higher in the CHD group than the control group(121.71±29.80 ng/L vs 98.70±17.57 ng/L,18.22± 5.41 ng/L vs 13.68±3.89 ng/L,P＜0.01).ROC curve analysis showed that the AUC value of the two indicators combined together was significantly greater than that of them alone in diagnosis of CHD(0.886 vs 0.791,0.775,P＜0.01).The serum levels of sFlt-1 and CCL3 were increased along with the severity of the disease and Gensini score when the levels and the score were compared among the mild,moderate and severe subgroups(P＜0.05).Pearson correlation analysis indicated that the serum levels of sFlt-1 and CCL3 were positively correlated with the Gensini score(r=0.420,r=0.479,P＜0.01).Conclusion The levels of serum sFlt-1 and CCL3 are obviously ele-vated in CHD patients,and closely associated with the severity of coronary lesions.