The translation of genetic findings from genome-wide association studies into actionable therapeutics persists as a critical challenge in Alzheimer's disease (AD) research. Here, we present PI4AD, a computational medicine framework that integrates multi-omics data, systems biology, and artificial neural networks for therapeutic discovery. This framework leverages multi-omic and network evidence to deliver three core functionalities: clinical target prioritisation; self-organising prioritisation map construction, distinguishing AD-specific targets from those linked to neuropsychiatric disorders; and pathway crosstalk-informed therapeutic discovery. PI4AD successfully recovers clinically validated targets like APP and ESR1, confirming its prioritisation efficacy. Its artificial neural network component identifies disease-specific molecular signatures, while pathway crosstalk analysis reveals critical nodal genes (e.g., HRAS and MAPK1), drug repurposing candidates, and clinically relevant network modules. By validating targets, elucidating disease-specific therapeutic potentials, and exploring crosstalk mechanisms, PI4AD bridges genetic insights with pathway-level biology, establishing a systems genetics foundation for rational therapeutic development. Importantly, its emphasis on Ras-centred pathways-implicated in synaptic dysfunction and neuroinflammation-provides a strategy to disrupt AD progression, complementing conventional amyloid/tau-focused paradigms, with the future potential to redefine treatment strategies in conjunction with mRNA therapeutics and thereby advance translational medicine in neurodegeneration.

Objective:To summarize the clinicopathological features, evolving trends in treatment and surgical approaches, and survival outcomes of patients who underwent D2 radical gastrectomy for gastric cancer in Shanxi Provincial Cancer Hospital over the past 11 years with the goal of providing a reference for the clinical practice of gastric cancer in this region.Methods:A retrospective observational study was conducted to analyze the clinicopathological data of patients who underwent D2 radical gastrectomy for pathologically confirmed gastric malignancy at the Department of Gastrointestinal Surgery, Shanxi Provincial Cancer Hospital from January, 2013 to December, 2023. Exclusion criteria consisted of: (1) residual gastric cancer or recurrent gastric cancer after surgery; (2) emergency gastric cancer resection due to bleeding, perforation, obstruction, or other causes; (3) comorbidity with other primary malignant tumors; (4) severe preoperative cardiopulmonary insufficiency or hepatic and renal insufficiency who cannot tolerate radical surgery; and (5) inconsistent main diagnosis information across the medical record system, pathological system, and gastric cancer-specific database. Patients were divided into three groups based on treatment methods: the surgery-only group, the perioperative chemotherapy group, and the adjuvant chemotherapy group. Endpoints included: (1) baseline patient characteristics; (2) trends in tumor location and pathological features; (3) evolution of treatment modalities; and (4) survival outcomes.Results:A total of 15,644 patients were included in the analysis, with 12,591 males and 3,053 females, the male-to-female gender ration was approximately 4∶1; the mean age was (61.2±9.5) years. The tumor sites were mainly concentrated in the esophagogastric junction (EGJ) (57.4%), followed by the antrum (25.9%). The incidence of EGJ cancer initially rose and then declined. However, gastric antrum tumors remained stable, and gastric body tumors showed a slow upward trend after 2020, accounting for 16.7%. In terms of pathological types, poorly differentiated carcinoma was the most prevalent, accounting for 55.9%, followed by moderately differentiated carcinoma (24.2%), mucinous adenocarcinoma (or signet ring cell carcinoma,14.1%), neuroendocrine carcinoma (4.8%), and well-differentiated carcinoma (0.9%). The proportion of poorly differentiated adenocarcinoma showed a significant upward trend overall as well, peaking at 65.6% in 2022 and decreasing to 57.5% in 2023. Mucinous adenocarcinoma (or signet ring cell carcinoma) exhibited fluctuations with a first increase followed by a decrease: it peaked at 17.3% in 2018, dropped sharply to 8.4% in 2022, and rose back to 13.8% in 2023. The proportions of well-differentiated adenocarcinoma, moderately differentiated adenocarcinoma, and neuroendocrine tumors remained stable year by year. In terms of pathological staging, the overall proportions of gastric cancer at Stage 0, Stage I, Stage II, Stage III, and Stage IVa were 0.5%, 17.3%, 25.1%, 54.9%, and 2.3%, respectively. For Stage III, its proportion was 74.6% in 2013, which decreased to 46.4% by 2023. Stages I and II gastric cancer showed an upward trend, with their proportions rising from 10.2% and 12.1% in 2013 to nearly 21.0% and 29.6% in 2023, respectively. Between 2013 and 2023, the proportion of patients who received surgery alone continued to decrease, with this proportion dropping to 34.7% in 2023. In contrast, the number of patients who received adjuvant chemotherapy increased year by year, reaching 54.2% in 2023. Since 2017, the application of perioperative chemotherapy has gradually increased, rising to 11.1% in 2023. Immunotherapy showed an almost synchronous growth trend with perioperative chemotherapy. However, targeted therapy exhibited a downward trend after a period of growth. There were 10,704 cases of open surgery (68.4%), 4,744 cases of laparoscopic surgery (30.3%), and 193 cases of transthoracic surgery (1.2%). Pathological margin positivity was observed in 443 cases (2.8%), and the volume of gastric cancer surgeries gradually increased, peaked in 2021 before subsequently decreasing gradually. However, the volume of laparoscopic surgeries did not decrease; instead, it showed an upward trend. The main resection method for EGJ tumors was total gastrectomy, accounting for 78.5% of the total, followed by proximal gastrectomy, which accounted for 21.5%. After total gastrectomy, esophagojejunal Roux-en-Y anastomosis was the primary anastomotic method, and for proximal gastrectomy, the main anastomotic method was esophagogastric anastomosis, which accounted for 68.0% of the total. For distal gastrectomy, Billroth II anastomosis was the most common anastomotic technique, accounting for 92.7% of these procedures. The overall incidence of postoperative complications was 14.5% (2,264/15,644), among which the incidence of severe complications (grades III-IV) was 4.5% (706/15,644). The entire cohort was followed up with for (47.1±36.8) months, and the 1-year, 3-year, and 5-year overall survival rates were 86.4%, 65.9%, and 58.1%, respectively. For patients with stage 0, I, II, III, and IV gastric adenocarcinoma, the 1-year overall survival rates were 95.7%, 98.0%, 89.4%, 81.0%, and 49.1%, respectively; the 3-year overall survival rates were 92.1%, 94.6%, 81.9%, 51.4%, and 14.7%, respectively; and the 5-year overall survival rates were 89.4%, 91.7%, 75.1%, 41.5%, and 10.0%, respectively. For patients with stage I, II, III, and IV gastric neuroendocrine carcinoma, the 1-year overall survival rates were 96.7%, 91.1%, 73.8%, and 52.6%, respectively; the 3-year overall survival rates were 87.2%, 69.6%, 46.1%, and 32.1%, respectively; and the 5-year overall survival rates were 87.2%, 62.2%, 36.7%, and 32.1%, respectively.Conclusions:Gastric cancer in Shanxi Province is characterized by a male predominance, a high prevalence of tumors at the esophagogastric junction, a large proportion of poorly differentiated adenocarcinoma, and presentation at advanced stages (predominantly Stage III). The detection rate of early gastric cancer has been increasing year by year, the volume of laparoscopic surgeries has been on the rise annually, and the treatment model has shifted from single surgery to comprehensive treatment.

Objective:To summarize the clinicopathological features, evolving trends in treatment and surgical approaches, and survival outcomes of patients who underwent D2 radical gastrectomy for gastric cancer in Shanxi Provincial Cancer Hospital over the past 11 years with the goal of providing a reference for the clinical practice of gastric cancer in this region.Methods:A retrospective observational study was conducted to analyze the clinicopathological data of patients who underwent D2 radical gastrectomy for pathologically confirmed gastric malignancy at the Department of Gastrointestinal Surgery, Shanxi Provincial Cancer Hospital from January, 2013 to December, 2023. Exclusion criteria consisted of: (1) residual gastric cancer or recurrent gastric cancer after surgery; (2) emergency gastric cancer resection due to bleeding, perforation, obstruction, or other causes; (3) comorbidity with other primary malignant tumors; (4) severe preoperative cardiopulmonary insufficiency or hepatic and renal insufficiency who cannot tolerate radical surgery; and (5) inconsistent main diagnosis information across the medical record system, pathological system, and gastric cancer-specific database. Patients were divided into three groups based on treatment methods: the surgery-only group, the perioperative chemotherapy group, and the adjuvant chemotherapy group. Endpoints included: (1) baseline patient characteristics; (2) trends in tumor location and pathological features; (3) evolution of treatment modalities; and (4) survival outcomes.Results:A total of 15,644 patients were included in the analysis, with 12,591 males and 3,053 females, the male-to-female gender ration was approximately 4∶1; the mean age was (61.2±9.5) years. The tumor sites were mainly concentrated in the esophagogastric junction (EGJ) (57.4%), followed by the antrum (25.9%). The incidence of EGJ cancer initially rose and then declined. However, gastric antrum tumors remained stable, and gastric body tumors showed a slow upward trend after 2020, accounting for 16.7%. In terms of pathological types, poorly differentiated carcinoma was the most prevalent, accounting for 55.9%, followed by moderately differentiated carcinoma (24.2%), mucinous adenocarcinoma (or signet ring cell carcinoma,14.1%), neuroendocrine carcinoma (4.8%), and well-differentiated carcinoma (0.9%). The proportion of poorly differentiated adenocarcinoma showed a significant upward trend overall as well, peaking at 65.6% in 2022 and decreasing to 57.5% in 2023. Mucinous adenocarcinoma (or signet ring cell carcinoma) exhibited fluctuations with a first increase followed by a decrease: it peaked at 17.3% in 2018, dropped sharply to 8.4% in 2022, and rose back to 13.8% in 2023. The proportions of well-differentiated adenocarcinoma, moderately differentiated adenocarcinoma, and neuroendocrine tumors remained stable year by year. In terms of pathological staging, the overall proportions of gastric cancer at Stage 0, Stage I, Stage II, Stage III, and Stage IVa were 0.5%, 17.3%, 25.1%, 54.9%, and 2.3%, respectively. For Stage III, its proportion was 74.6% in 2013, which decreased to 46.4% by 2023. Stages I and II gastric cancer showed an upward trend, with their proportions rising from 10.2% and 12.1% in 2013 to nearly 21.0% and 29.6% in 2023, respectively. Between 2013 and 2023, the proportion of patients who received surgery alone continued to decrease, with this proportion dropping to 34.7% in 2023. In contrast, the number of patients who received adjuvant chemotherapy increased year by year, reaching 54.2% in 2023. Since 2017, the application of perioperative chemotherapy has gradually increased, rising to 11.1% in 2023. Immunotherapy showed an almost synchronous growth trend with perioperative chemotherapy. However, targeted therapy exhibited a downward trend after a period of growth. There were 10,704 cases of open surgery (68.4%), 4,744 cases of laparoscopic surgery (30.3%), and 193 cases of transthoracic surgery (1.2%). Pathological margin positivity was observed in 443 cases (2.8%), and the volume of gastric cancer surgeries gradually increased, peaked in 2021 before subsequently decreasing gradually. However, the volume of laparoscopic surgeries did not decrease; instead, it showed an upward trend. The main resection method for EGJ tumors was total gastrectomy, accounting for 78.5% of the total, followed by proximal gastrectomy, which accounted for 21.5%. After total gastrectomy, esophagojejunal Roux-en-Y anastomosis was the primary anastomotic method, and for proximal gastrectomy, the main anastomotic method was esophagogastric anastomosis, which accounted for 68.0% of the total. For distal gastrectomy, Billroth II anastomosis was the most common anastomotic technique, accounting for 92.7% of these procedures. The overall incidence of postoperative complications was 14.5% (2,264/15,644), among which the incidence of severe complications (grades III-IV) was 4.5% (706/15,644). The entire cohort was followed up with for (47.1±36.8) months, and the 1-year, 3-year, and 5-year overall survival rates were 86.4%, 65.9%, and 58.1%, respectively. For patients with stage 0, I, II, III, and IV gastric adenocarcinoma, the 1-year overall survival rates were 95.7%, 98.0%, 89.4%, 81.0%, and 49.1%, respectively; the 3-year overall survival rates were 92.1%, 94.6%, 81.9%, 51.4%, and 14.7%, respectively; and the 5-year overall survival rates were 89.4%, 91.7%, 75.1%, 41.5%, and 10.0%, respectively. For patients with stage I, II, III, and IV gastric neuroendocrine carcinoma, the 1-year overall survival rates were 96.7%, 91.1%, 73.8%, and 52.6%, respectively; the 3-year overall survival rates were 87.2%, 69.6%, 46.1%, and 32.1%, respectively; and the 5-year overall survival rates were 87.2%, 62.2%, 36.7%, and 32.1%, respectively.Conclusions:Gastric cancer in Shanxi Province is characterized by a male predominance, a high prevalence of tumors at the esophagogastric junction, a large proportion of poorly differentiated adenocarcinoma, and presentation at advanced stages (predominantly Stage III). The detection rate of early gastric cancer has been increasing year by year, the volume of laparoscopic surgeries has been on the rise annually, and the treatment model has shifted from single surgery to comprehensive treatment.

Objective:To explore the mechanism of Kechuan'an Oral Liquid in treating asthma based on network pharmacology; To carry out experimental verification.Methods:The effective components and targets of Kechuan'an Oral Liquid were obtained through TCMSP and literature search. The related targets of asthma were screened by GEO database, and the intersection targets of drug and disease were selected. The PPI network was constructed by STRING database, and the GO function and KEGG pathway were enriched and analyzed for key targets by DAVID database. The rats were divided into blank control group, model group and Kechuan'an Oral Liquid group according to the method of random number table. Kechuan'an Oral Liquid group received Kechuan'an Oral Liquid 12.34 ml/kg for gavage, and blank control group and model group were perfused with distilled water of the same volume for gavage, once a day for 3 days. The asthma model of rats was prepared by atomizing the mixture of acetylcholine chloride and histamine phosphate, and HE staining was used to observe the pathological changes of lung tissue; Western blot was used to detect the protein expressions of IL-6, TLR4, MyD88 and TAK1, and the network pharmacological prediction results were verified.Results:A total of 153 active components, 1 896 targets and 2 982 differentially expressed genes of Kechuan'an Oral Liquid were screened out, and 25 intersection targets of drugs and diseases were obtained. The enrichment results showed that toll-like receptor signaling pathway, TNF signaling pathway and Nod-like receptor signaling pathway were the main mechanisms of immune inflammation. Compared with the control group, the lung tissue of rats in the model group showed morphological changes such as thickening of air duct wall and infiltration of inflammatory cells, which were significantly improved in the Kechuan'an Oral Liquid group. Compared with the control group, the expressions of IL-6, TLR4, MyD88 and TAK1 in the model group significantly increased ( P<0.01), and compared with model group, the expressions of IL-6, TLR4, MyD88 and TAK1 in Kechuan'an Oral Liquid group significantly decreased ( P<0.05 or P<0.01). Conclusion:Kechuan'an Oral Liquid can inhibit toll-like receptor signaling pathway and mediate anti-inflammatory effect to treat asthma.

Objective:To summarize the genetic etiology, clinical characteristics and outcomes of neonatal hypotonia in the early stage of NICU, to provide basis for clinicians to early identify diseases and choose reasonable treatments.Methods:The clinical data of neonates with hypotonia admitted to the Department of Neonatology of Children′s Hospital of Xinjiang Uygur Autonomous Region and People′s Hospital of Xinjiang Uygur Autonomous Region from July 2017 to July 2020 were analyzed.Results:A total of 49 children were enrolled in the study, all clinically manifested as unexplained hypotonia, accompanied by special appearance 29 cases(59.18%), metabolic abnormality 18 cases(36.73%), and cranial imagin abnormality 23 cases(46.93%). After gene sequencing a, total of 22(44.89%)patients were confirmed.Thirteen (26.53%) of them were copy number variation, and gene mutation in nine cases(18.36%). The oldest age of these patients was 3 years and 2 months now, while the youngest was 4 months.A total of 16 patients were dead(32.65%). Four (8.16%) patients were lost to follow-up.At present, eighteen (62.07%) patients had mental retardation, and eleven (37.93%) of whom still existed severe physical retardation.Conclusion:We could conduct genetic testing in NICU to improve the diagnosis rate of neonates with unexplained hypotonia, which have high rate of adverse events.Neonates with a clear diagnosis should be treated promptly and give the genetic counseling to reduce the risk for the next children.

Natural lignocellulosic materials contain cellulose, hemicellulose, and lignin. Cellulose hydrolysis to glucose requires a series of lignocellulases. Recently, the research on the synergistic effect of lignocellulases has become a new research focus. Here, four lignocellulase genes encoding β-glucosidase, endo-1,4-β-glucanase, xylanase and laccase from termite and their endosymbionts were cloned into pETDuet-1 and pRSFDuet-1 and expressed in Escherichia coli. After SDS-PAGE analysis, the corresponding protein bands consistent with the theoretical values were observed and all the proteins showed enzyme activities. We used phosphoric acid swollen cellulose (PASC) as substrate to measure the synergistic effect of crude extracts of co-expressing enzymes and the mixture of single enzyme. The co-expressed enzymes increased the degradation efficiency of PASC by 44% compared with the single enzyme mixture; while the degradation rate increased by 34% and 20%, respectively when using filter paper and corn cob pretreated with phosphoric acid as substrates. The degradation efficiency of the co-expressed enzymes was higher than the total efficiency of the single enzyme mixture.
Animals ; Cellulase ; Cellulose ; Hydrolysis ; Isoptera ; Lignin ; Symbiosis ; beta-Glucosidase

Objective To evaluate the changes in the expression of c-fos protein in the spinal cord in a rat model of oxycodone dependence or withdrawal response.Methods Thirty SPF adult male Sprague-Dawley rats,aged 6-8 weeks,weighing 180-220 g,were divided into 3 groups (n=10 each) using a random number table method:normal saline group (group NS),oxycodone dependence group (group OD),and oxycodone withdrawal group (group OW).In OD and OW groups,oxycodone was injected subcutaneously in back,5 days in total,with the dose of 2,3,4,5 and 6 mg/kg in turn,3 times a day (8:00/15:00/22:00).The equal volume of normal saline was given instead in group NS.The mechanical paw withdrawal threshold was measured at 3 days before administration and 30 min after the last administration every day.The oxycodone withdrawal was induced by intraperitoneal injection of naloxone 4 mg/kg at 8 h after the last administration of oxycodone on 5th day in group OW.The withdrawal response scores and range of weight changes were recorded within 15 min after giving naloxone or normal saline in NS and OW groups.Spinal cord tissues were collected at 1 h after the last administration on 5th day in group OD and at 1 h after giving normal saline or naloxone on 5th day in NS and OW groups for determination of the expression of c-fos protein by Western blot.Results Compared with group NS,the mechanical paw withdrawal threshold was significantly increased on 1 and 2 days after administration,and the expression of c-fos protein in the spinal cord was up-regulated in OD and OW groups,and withdrawal response scores were significantly increased,and the range of weight change was increased in group OW (P＜0.05).The expression of c-fos protein was significantly down-regulated in group OW as compared with group OD (P＜0.05).Conclusion Oxycodone dependence or withdrawal response may be related to the expression of c-fos protein in the spinal cord of rats,and the expression is up-regulated during oxycodone dependence,while down-regulated during oxycodone withdrawal.

Objective: To study the expression and significance of Notch1-Jagged1 in nasal mucosa of allergic rhinitis (AR) mouse model in various stages and in the serum of AR patients. Methods: Thirty-six mice were divided into 3 groups: control group, basal sensitization group (OVA) and OVA/AR group, with 12 mice in each group. Allergic symptom in each group were scored after AR model establishment. HE staining method was used to observe the nasal mucosa eosinophils infiltration. ELISA was used to detect the serum level of total IgE. Flow cytometry was used to detect the change of Treg cells in each group. Western blot was used to detect the expression of Notch1 and Jagged1 in nasal mucosa. Flow cytometric bead array (CBA) was used to detect the level of Th1/Th2/Th17 cytokines in splenic lymphocytes. The serum was obtained from 50 patients with AR and 30 control volunteers in Department of Otorhinolaryngology Head and Neck Surgery, Renmin Hospital of Wuhan University from June to October 2017. ELISA was used to detect the expression of Notch1 and Jagged1. Results: Compared with the control group, the allergy symptom, the number of nasal mucosal eosinophils and the level of total IgE were not significantly different in basal sensitization group, but increased significantly in OVA/AR group (6.11±0.78 vs 0.67±0.50, 77.67±5.61 vs 10.33±0.82, (106.80±11.91) pg/ml vs (82.45±19.80) pg/ml, t value was 19.471, 34.848, 2.542, respectively, all P<0.05). Compared with the control group, the ratio of Treg cell increased in basal sensitization group but decreased in OVA/AR group ((10.29±0.47)% vs (9.28±0.16)%, (8.49±0.15)% vs (9.28±0.16)%, t value was 5.838, 4.540, respectively, all P<0.01). Compared with control group, the expression of Notch1 increased significantly both in basal sensitization group and OVA/AR group (1.04±0.05 vs 0.71±0.05, 1.83±0.10 vs 0.71±0.05, t value was 9.293, 31.363, respectively, all P<0.01); and the expression of Jagged1 only increased significantly in OVA/AR group (0.41±0.04 vs 0.21±0.01, t=13.472, P<0.01). It was found that Notch1 was positively correlated with the level of IL-6, IL-10 by Pearson test (r value was 0.98, 0.87, respectively, all P<0.01). Compared with control volunteers, the expression of Notch1 and Jagged1 increased significantly in AR group patients ((1 135.0±254.9) pg/ml vs (436.0±139.3) pg/ml, (1 200.2±401.0) pg/ml vs (559.9±124.2) pg/ml, t value was 13.99, 11.94, respectively, all P<0.01). Conclusions The expression of Notch1 receptor and ligand increased significantly in the pathogenesis of AR. Notch1-Jagged1 may promote the occurrence and development of AR by up-regulating the expression of IL-6 and IL-10.

Pulmonary drug delivery has become a research focus in recent years, while the action between particles and pulmonary macrophages after particles transportation to lung tissue was paid little attention. Therapeutic efficacy can be enhanced by regulating the particles uptake action of pulmonary macrophages according to different diseases. Referring to a lot of articles, the relationship between common diseases and macrophages was reviewed and the influencing factors in the particles uptake of alveolar macrophages were sum-marized. The review laid foundation for the development of preparations and clinical application of pulmonary drug delivery systems.

Objective To evaluate the clinical significance of prenatal ultrasonography in diagnosis of retroaortic left innominate vein ( LINV ) . Methods Thirty fetus with retroaortic LINV were involved , including 17 cases of isolated retroaortic LINV and 13 cases of complicated retroaortic LINV . Three-vessel and trachea ( 3VT ) view was focused in the routine second trimester ultrasound screening to observe whether LINV existing or not . And then the transducer was rotated to the fetal sagittal view to assess the relationship between LINV and aortic arch and the convergence of left subclavian vein and left internal jugular vein into the LINV . Results The characteristic feature of retroaortic LINV was the LINV converge into right superior vena cava ( SVC) under the aortic arch ,not above the aortic arch . The most important plane to detect the retroaortic LINV was the 3VT view ,which revealed the abnormal vein lying to the left of pulmonary artery . The abnormal vein then could be traced and revealed its connection with the right SVC beneath the aortic arch on the transverse plane inferior to the 3VT view and on the fetal sagittal plane . Conclusions The whole course of retroaortic LINV can be revealed by ultrasound prenatally ,which can not only account for the abnormal vein to the left of pulmonary artery on 3VT view ,but also play an important role in surgery decision and future cardiac intervention treatment .