Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder primarily caused by pathogenic variants in the TSC1 or TSC2 genes. It is characterized by multisystem hamartomatous lesions and neuropsychiatric manifestations. Here we report a young male patient with TSC involving multiple organs, caused by a heterozygous frameshift mutation in TSC2 (c.2071delC, p.Arg691Alafs^*7). The patient initially presented with classic facial angiofibromas and hypomelanotic macules, and subsequently developed psychiatric and behavioral disturbances with auditory hallucinations. Neuroimaging revealed an intracranial mass lesion, which was confirmed as a subependymal giant cell astrocytoma on postoperative histopathology following surgery performed at an outside institution. After admission, the patient underwent a comprehensive diagnostic workup, and multidisciplinary treatment evaluation revealed extensive multisystem involve-ment, including the nervous system, skin, kidneys, lungs, heart, eyes, pancreas, liver and bones. Combined with relevant literature, this article discusses the molecular mechanisms, clinical phenotypes, and comprehensive management of TSC, in order to provide a reference for the standardized and individualized management of this disease.

Objective To determine the acute effects of blood flow restriction(BFR)running warm-up on Achilles tendon morphology and function in basketball players in order to provide a theoretical basis for optimizing warm-up protocols for military personnel and athletes susceptible to Achilles tendon injuries.Methods Twenty-seven male basketball players were subjected and asked to participate in 3 different running warm-up protocols:low-speed running(LSR),high-speed running(HSR),and BFR combined with LSR(BFR-LSR).The acute changes in Achilles tendon morphology,mechanical properties,and functional performance across the 3 testing sessions were analyzed and compared.Results Immediately after training,both HSR warm-up and BFR-LSR warm-up significantly improved Achilles tendon thickness,blood flow,stiffness,and gastrocnemius maximal voluntary isometric contraction(MVIC)when compared with LSR warm-up(P<0.05).No statistical differences were observed in above indicators between the BFR-LSR and HSR warm-ups(P>0.05).24 hours after training,compared with LSR warm-up,HSR warm-up still significantly improved Achilles tendon thickness,blood flow,stiffness,and gastrocnemius MVIC(P<0.05).Although BFR-LSR warm-up did not show statistically significant differences in these parameters compared to LSR warm-up,it still demonstrated positive trends.Immediately and 24 h after training,no obvious difference were found in jump performance among the 3 warm-up protocols(P>0.05),but,both BFR-LSR and HSR warm-ups exhibited superior performance than LSR warm-up.Conclusion Immediately after training,BFR-LSR warm-up demonstrates comparable effects to the HSR warm-up on improving Achilles tendon morphology and performance,as well as enhancing jump performance.However,its sustained and long-term effects require further investigation.

Photothermal therapy,as a novel anti-tumor treatment strategy,faces many challenges such as insufficient targeting,limited penetration ability,and inability to achieve long-term inhibition when used alone for anti-tumor treatment.Based on this,in this study,macrophage extracellular vesicles(MEVs)were modified onto the surface of a vector carrying CSF1R-siRNA and photothermal agents to form a multifunctional gene delivery vector MEVs@RNPs.It could induce the macrophages to reprogram from M2 type to M1 type,so as to achieve efficient photothermal and immunotherapy for triple negative breast cancer(TNBC).The basic physicochemical properties of each nanocarrier were characterized using nanoparticle size analyzer,UV-vis spectrometer,fluorescence spectrometer,thermal imaging instrument,etc.TNBC cells 4T1,endothelial cells Bend3,and macrophages 264.7 were used as in vitro experimental subjects for measurement of MEVs@RNPs.The ability to target tumor cells,kill tumor cells,and induce macrophage reprogramming in vitro was investigated.With Balb/c mice as the in vivo research object,a subcutaneous transplant tumor model was established in mice,and the changes in tumor volume and body weight of mice in different treatment groups were measured.In addition,further isolation of mouse blood and tumor tissue was performed,and hematoxylin-eosin(HE)staining,terminal deoxynucleotidyl transferase dUTP nick end labeling(TUNEL)method,and enzyme-linked immunosorbent assay(ELISA)method were used to determine the apoptosis and cytokine secretion of tumor cells for comprehensive evaluation of MEVs@RNPs.The results showed that the MEVs@RNPs could preferentially target tumor cells and induce stronger TNBC cell killing effect under photothermal conditions.Meanwhile,the results of flow cytometry and ELISA analysis showed that the MEVs@RNPs could promote the transformation of macrophages from M2 type to anti-tumor M1 type,significantly enhancing the secretion levels of anti-tumor cytokines tumor necrosis factor-α(TNF-α)and interleukin-12(IL-12).The in vivo anti-tumor treatment effect assessment of the MEVs@RNPs showed that under laser processing conditions,the MEVs@RNPs could significantly induce pathological necrosis and apoptosis of tumor cells,promote macrophage reprogramming and infiltration of CD4+/CD8+T cells into the tumor site,and enhance the secretion levels of TNF-α and IL-12,thereby comprehensively improving the therapeutic effect of TNBC.

This study explored the potential therapeutic targets and mechanisms of Danggui Shaoyao San(DSS) in the prevention and treatment of Alzheimer's disease(AD) through transcriptomics and metabolomics, combined with animal experiments. Fifty male C57BL/6J mice, aged seven weeks, were randomly divided into the following five groups: control, model, positive drug, low-dose DSS, and high-dose DSS groups. After the intervention, the Morris water maze was used to assess learning and memory abilities of mice, and Nissl staining and hematoxylin-eosin(HE) staining were performed to observe pathological changes in the hippocampal tissue. Transcriptomics and metabolomics were employed to sequence brain tissue and identify differential metabolites, analyzing key genes and metabolites related to disease progression. Reverse transcription-quantitative polymerase chain reaction(RT-qPCR) was employed to validate the expression of key genes. The Morris water maze results indicated that DSS significantly improved learning and cognitive function in scopolamine(SCOP)-induced model mice, with the high-dose DSS group showing the best results. Pathological staining showed that DSS effectively reduced hippocampal neuronal damage, increased Nissl body numbers, and reduced nuclear pyknosis and neuronal loss. Transcriptomics identified seven key genes, including neurexin 1(Nrxn1) and sodium voltage-gated channel α subunit 1(Scn1a), and metabolomics revealed 113 differential metabolites, all of which were closely associated with synaptic function, oxidative stress, and metabolic regulation. RT-qPCR experiments confirmed that the expression of these seven key genes was consistent with the transcriptomics results. This study suggests that DSS significantly improves learning and memory in SCOP model mice and alleviates hippocampal neuronal pathological damage. The mechanisms likely involve the modulation of synaptic function, reduction of oxidative stress, and metabolic balance, with these seven key genes serving as important targets for DSS in the treatment of AD.
Animals ; Alzheimer Disease/genetics* ; Male ; Drugs, Chinese Herbal/administration & dosage* ; Mice ; Mice, Inbred C57BL ; Metabolomics ; Transcriptome/drug effects* ; Maze Learning/drug effects* ; Hippocampus/metabolism* ; Humans ; Disease Models, Animal ; Memory/drug effects*

This study established the HPLC fingerprints, characteristic chromatograms, and a multi-component content determination method for Bidens bipinnata and B. biternata. The chemical pattern recognition analysis was then employed to clarify the characteristic indexes of quality differences between the two original plants of Bidentis Herba, providing a reference for establishing the quality standards of Bidentis Herba. HPLC was launched on an Agilent Poroshell 120 EC-C_(18) chromatographic column(4.6 mm×250 mm, 4 μm) by gradient elution with a mobile phase of 0.1% aqueous phosphoric acid-acetonitrile at a flow rate of 0.7 mL·min~(-1), detection wavelength of 270 nm, column temperature of 25 ℃, and an injection volume of 5 μL. The similarity between the fingerprints of 18 batches of Bidentis Herba samples and the common pattern(R) ranged from 0.572 to 0.933. A total of 23 chromatographic peaks were calibrated. Through comparison with the reference substances, six components(neochlorogenic acid, chlorogenic acid, isochlorogenic acid A, isochlorogenic acid B, rutin, and hyperoside) were identified and subjected to quantitative analysis. The characteristic fingerprints of B. bipinnata and B. biternata were calibrated with 20 and 17 characteristic peaks, respectively. Among them, peaks 8, 9, 22, and 23 were the characteristic peaks of B. bipinnata, and peak 7 was the characteristic peak of B. biternata, which can be used to distinguish the two original plants of Bidentis Herba. The relative standard deviation of the content of the above-mentioned six components ranged from 36% to 123%. The cluster analysis, principal component analysis, and orthogonal partial least squares-discriminant analysis(OPLS-DA) classified the 18 batches of Bidentis Herba samples into two categories. Additionally, through the analysis of variable importance in projection(VIP) under OPLS-DA, three characteristic indexes, rutin, isochlorogenic acid A, and isochlorogenic acid B, were identified. The analytical method established in this study can comprehensively evaluate the consistency of Bidentis Herba samples derived from different original plants, specifically identify the differential components between them, and effectively distinguish the two original plants of Bidentis Herba, providing a basis for the differentiation between different original plants and the quality control of Bidentis Herba.
Chromatography, High Pressure Liquid/methods* ; Drugs, Chinese Herbal/chemistry* ; Quality Control ; Bidens/chemistry*

Tricellulin, a key tricellular tight junction (TJ) protein, is essential for maintaining the barrier integrity of acinar epithelia against macromolecular passage in salivary glands. This study aims to explore the role and regulatory mechanism of tricellulin in the development of salivary gland hypofunction in Sjögren's syndrome (SS). Employing a multifaceted approach involving patient biopsies, non-obese diabetic (NOD) mice as a SS model, salivary gland acinar cell-specific tricellulin conditional knockout (Tric^CKO) mice, and IFN-γ-stimulated salivary gland epithelial cells, we investigated the role of tricellulin in SS-related hyposalivation. Our data revealed diminished levels of tricellulin in salivary glands of SS patients. Similarly, NOD mice displayed a reduction in tricellulin expression from the onset of the disease, concomitant with hyposecretion and an increase in salivary albumin content. Consistent with these findings, Tric^CKO mice exhibited both hyposecretion and leakage of macromolecular tracers when compared to control animals. Mechanistically, the JAK/STAT1/miR-145 axis was identified as mediating the IFN-γ-induced downregulation of tricellulin. Treatment with AT1001, a TJ sealer, ameliorated epithelial barrier dysfunction, restored tricellulin expression, and consequently alleviated hyposalivation in NOD mice. Importantly, treatment with miR-145 antagomir to specifically recover the expression of tricellulin in NOD mice significantly alleviated hyposalivation and macromolecular leakage. Collectively, we identified that tricellulin deficiency in salivary glands contributed to hyposalivation in SS. Our findings highlight tricellulin as a potential therapeutic target for hyposecretion, particularly in the context of reinforcing epithelial barrier function through preventing leakage of macromolecules in salivary glands.
Sjogren's Syndrome/complications* ; Animals ; Xerostomia/etiology* ; Mice ; Mice, Inbred NOD ; MARVEL Domain Containing 2 Protein/metabolism* ; Humans ; Mice, Knockout ; Disease Models, Animal ; Interferon-gamma ; Salivary Glands/metabolism* ; Tight Junctions/metabolism* ; MicroRNAs/metabolism* ; Female

Glutamine provides carbon and nitrogen to support the proliferation of cancer cells. However, the precise reason why cancer cells are particularly dependent on glutamine remains unclear. In this study, we report that glutamine modulates the tumor suppressor F-box and WD repeat domain-containing 7 (FBW7) to promote cancer cell proliferation and survival. Specifically, lysine 604 (K604) in the sixth of the 7 substrate-recruiting WD repeats of FBW7 undergoes glutaminylation (Gln-K604) by glutaminyl tRNA synthetase. Gln-K604 inhibits SCFFBW7-mediated degradation of c-Myc and Mcl-1, enhances glutamine utilization, and stimulates nucleotide and DNA biosynthesis through the activation of c-Myc. Additionally, Gln-K604 promotes resistance to apoptosis by activating Mcl-1. In contrast, SIRT1 deglutaminylates Gln-K604, thereby reversing its effects. Cancer cells lacking Gln-K604 exhibit overexpression of c-Myc and Mcl-1 and display resistance to chemotherapy-induced apoptosis. Silencing both c-MYC and MCL-1 in these cells sensitizes them to chemotherapy. These findings indicate that the glutamine-mediated signal via Gln-K604 is a key driver of cancer progression and suggest potential strategies for targeted cancer therapies based on varying Gln-K604 status.
Glutamine/metabolism* ; Myeloid Cell Leukemia Sequence 1 Protein/genetics* ; Humans ; Proto-Oncogene Proteins c-myc/genetics* ; Cell Proliferation ; Signal Transduction ; Neoplasms/pathology* ; F-Box-WD Repeat-Containing Protein 7/genetics* ; Cell Survival ; Cell Line, Tumor ; Apoptosis

OBJECTIVE: To develop a digital intelligent multimodal shift handover system for the intensive care unit (ICU) and evaluate its application effect in ICU shift handovers. METHODS: A research and development team was established, consisting of 1 department director, 1 head nurse, 3 information technology engineers, 3 nurses, and 2 doctors. Team members were assigned responsibilities including overall coordination and planning, platform design and maintenance, pre-application training, collection and organization of clinical feedback, and research investigation respectively. A digital intelligent multimodal shift handover system was developed for ICU based on the Shannon-Weaver linear transmission model. This innovative system integrated automated data collection, intelligent dynamic monitoring, multidimensional condition analysis and visual reporting functions. A cloud platform was used to gather data from multi-parameter vital signs monitors, infusion pumps, ventilators and other devices. Artificial intelligence algorithms were employed to standardize and analyze the data, providing personalized recommendations for healthcare professionals. A self-controlled before-after method was adopted. Before the application of the ICU digital intelligent multimodal shift handover system (from December 2023 to March 2024), the traditional verbal bedside handover was used; from June 2024 to March 2025, the ICU digital intelligent multimodal shift handover system was applied for shift handovers. Questionnaires before the application of the shift handover system were collected in April 2024, and those after the application were collected in April 2025. The shift handover time, handover quality (scored by the nursing handover evaluation scale), satisfaction with doctor-nurse communication (scored by the ICU doctor-nurse scale) before and after the application of the handover system were compared, and nurses' satisfaction with the shift handover system (scored by the clinical nursing information system effectiveness evaluation scale) was investigated. RESULTS: After the application of the ICU digital intelligent multimodal shift handover system, the shift handover time was significantly shorter than that before the application [minutes: 20 (15, 25) vs. 30 (22, 40)], the handover quality was significantly higher than that before the application [score: 84.0 (78.0, 88.5) vs. 71.0 (55.0, 79.0)], and the satisfaction with doctor-nurse communication was also significantly higher than that before the application (score: 84.58±6.79 vs. 74.50±11.30). All differences were statistically significant (all P < 0.05). In addition, the nurses' system effectiveness evaluation scale score was 102.30±10.56, which indicated that nurses had a very high level of satisfaction with the ICU digital intelligent multimodal shift handover system. CONCLUSIONS The application of the ICU digital intelligent multimodal shift handover system can shorten the shift handover time, improve the handover quality, and enhance the satisfaction with doctor-nurse communication. Nurses have a high level of satisfaction with this system.
Intensive Care Units ; Humans ; Patient Handoff ; Artificial Intelligence ; Algorithms

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*

OBJECTIVE: To investigate the whole-genome differential methylation profile of patients with high-altitude polycythemia (HAPC). METHODS: In this study, a total of 20 adult male patients with HAPC were included, including 10 Tibetan and 10 Han patients. The control group consisted of 20 healthy adult males, including 10 Tibetan and 10 Han patients. Peripheral blood was collected from each group for DNA extraction and quality inspection, and DNA libraries were constructed. The differential methylation regions (DMRs) between groups were detected using reduced representation bisulfite sequencing, with enriched regions compared to those of the control group. The differential enrichment regions were selected, and the intersection of the enriched regions was associated with genes. The methylation enrichment regions that differed significantly between groups were filtered based on the number of enriched samples in the enriched regions between the groups. GO, KEGG functional, and pathway analysis were performed on the differentially associated gene sets to reveal significant differences between the patients and control groups at the functional and pathway levels. RESULTS: In comparison with the control group, 17 152 sites with more than 25% difference and 15 558 sites with less than -25% difference were identified in Tibetan patients. The top 5 genes with the largest methylation differences between the two groups were MCCC2, RP3-399L15.3, ZNF621, RP11-394A14.2 and SLC39A10. The top significantly different pathways annotated in the differentially expressed genes pathway was serotonergic synapse. In comparison with the control group, 2 687 CpG sites with a greater than 25% difference and 2 602 CpG sites with a less than -25% difference were identified in Han patients. The top 5 genes with the largest methylation differences between the two groups were NAA25, CORO2B, PDC, ZNF853, and MLLT10. The top significantly different pathways annotated in the differentially expressed genes pathway were glutamatergic synapse, retrograde endocannabinoid signaling, Rap1 signaling pathway and cholinergic synapse. In comparison with the control group, 3 895 CpG sites with a greater than 25% difference and 3 969 CpG sites with a less than -25% difference were identified in HAPC patients. The maximum methylation difference between the two groups could reach 78.1%, while the minimum was -42.6%. The top 5 genes with the largest methylation differences between the two groups were MCCC2, ARSJ, CTNNA3, SLC39A10, and SWAP70. The top significantly different pathways annotated in the differentially expressed genes pathway was signaling pathways regulating pluripotency of stem cells. CONCLUSION The occurrence of HAPC may be related to abnormal changes in DNA methylation, and methylation sites may be helpful for the early diagnosis of HAPC.
Humans ; DNA Methylation ; Altitude ; Polycythemia/genetics* ; Male ; Adult ; CpG Islands