Forkhead box M1 mediates metabolic reprogramming in human colorectal cancer cells.

Metabolic reprogramming is recognized as a hallmark of cancer, enabling cancer cells to acquire essential biomolecules for cell growth, often characterized by upregulated glycolysis and/or fatty acid synthesis-related genes. The transcription factor forkhead box M1 (FOXM1) has been implicated in various cancers, contributing significantly to their development, including colorectal cancer (CRC), a major global health concern. Despite FOXM1's established role in cancer, its specific involvement in the Warburg effect and fatty acid biosynthesis in CRC remains unclear. We analyzed The Cancer Genome Atlas (TCGA) Colonic Adenocarcinoma and Rectal Adenocarcinoma (COADREAD) datasets to to derive the correlation of the expression levels between FOXM1 and multiple genes and the survival prognosis based on FOXM1 expression. Using two human CRC cell lines, HT29 and HCT116, we conducted RNAi or plasmid transfection procedures, followed by a series of assays, including RNA extraction, quantitative real-time polymerase chain reaction, Western blot analysis, cell metabolic assays, and immunofluorescence analysis. Higher expression levels of FOXM1 correlated with a poorer survival prognosis, and the expression of FOXM1 was positively correlated with glycolysis-related genes SLC2A1 and LDHA, de novo lipogenesis-related genes ACACA and FASN, and MYC. FOXM1 appeared to modulate AKT/mTOR signaling, the expression of c-Myc, proteins related to glycolysis and fatty acid biosynthesis, as well as extracellular acidification rate in HT29 and HCT116 cells. In summary, FOXM1 plays a regulatory role in glycolysis, fatty acid biosynthesis, and cellular energy consumption, thereby influencing CRC cell growth and patient prognosis.

Highly extensile approach for comminuted ulna coronoid process fractures with mini-plate fixation: a case series of 31 patients.

BACKGROUND: For the treatment of coronoid process fractures, medial, lateral, anterior, anteromedial, and posterior approaches have been increasingly reported; however, there is no general consensus on the method of fixation of coronal fractures. Here, we present a highly-extensile minimally invasive approach to treat coronoid process fractures using a mini-plate that can achieve anatomic reduction, stable fixation, and anterior capsular repair. Further, the study aimed to determine the complication rate of the anterior minimally invasive approach and to evaluate functional and clinical patient-reported outcomes during follow-up. METHODS: Thirty-one patients diagnosed with coronoid fractures accompanied with a "terrible triad" or posteromedial rotational instability between April 2012 and October 2018 were included in the analysis. Anatomical reduction and mini-plate fixation of coronoid fractures were performed using an anterior minimally invasive approach. Patient-reported outcomes were evaluated using the Mayo Elbow Performance Index (MEPI) score, range of motion (ROM), and the visual analog score (VAS). The time of fracture healing and complications were recorded. RESULTS: The mean follow-up time was 26.7 months (range, 14-60 months). The average time to radiological union was 3.6 ± 1.3 months. During the follow-up period, the average elbow extension was 6.8 ± 2.9° while the average flexion was 129.6 ± 4.6°. According to Morrey's criteria, 26 (81%) elbows achieved a normal desired ROM. At the last follow-up, the mean MEPI score was 98 ± 3.3 points. There were no instances of elbow instability, elbow joint stiffness, subluxation or dislocation, infection, blood vessel complications, or nerve palsy. Overall, 10 elbows (31%) experienced heterotopic ossification. CONCLUSION: An anterior minimally invasive approach allows satisfactory fixation of coronoid fractures while reducing incision complications due to over-dissection of soft tissue injuries. In addition, this incision does not compromise the soft tissue stability of the elbow joint and allows the patient a more rapid return to rehabilitation exercises.

Self-neglect as a mediator between family functioning and healthy aging in older adults living alone in rural China: A cross-sectional study.

OBJECTIVE: This study aims to investigate the mediating role of self-neglect among older adults in the relationship between family functioning and healthy aging. METHODS: A questionnaire survey was conducted between June and September 2023, involving 255 older adults living alone in rural China. The healthy ageing, self-neglect, and family functioning was assessed using the Healthy Aging Instrument;the Elderly Self-neglect Assessment (Rural);and Family Adaptation, Partnership, Growth, Affection, and Resolve (APGAR) scale. RESULTS: Positive correlations were found between family functioning and healthy aging (r = 0.363, p < 0.05). Moreover, self-neglect was identified as a significant mediator, explaining 40.84 % of the total effect. CONCLUSION: Among older adults living alone in rural China, family functioning is significantly associated with healthy aging, with self-neglect mediating this relationship. These findings suggest that community-based interventions aimed at improving family functioning and addressing self-neglect behaviors might be beneficial for promoting healthy aging in this population.

A novel NIR-II albumin-escaping probe for cerebral arteries and perfusion imaging in stroke mice model.

In order to guide the formulation of post-stroke treatment strategy in time, it is necessary to have real-time feedback on collateral circulation and revascularization. Currently used near-infrared II (NIR-II) probes have inherent binding with endogenous albumin, resulting in significant background signals and uncontrollable pharmacokinetics. Therefore, the albumin-escaping properties of the new probe, IR-808AC, was designed, which achieved timely excretion and low background signal, enabling the short-term repeatable injection for visualization of cerebral vessels and perfusion. We further achieved continuous observation of changes in collateral vessels and perfusion during the 7-d period in middle cerebral artery occlusion mice using IR-808AC in vivo. Furthermore, using IR-808AC, we confirmed that remote ischemic conditioning could promote collateral vessels and perfusion. Finally, we evaluated the revascularization after thrombolysis on time in embolic stroke mice using IR-808AC. Overall, our study introduces a novel methodology for safe, non-invasive, and repeatable assessment of collateral circulation and revascularization in real-time that is crucial for the optimization of treatment strategies.

Graphene Oxide-Enhanced and Dynamically Crosslinked Bio-Elastomer for Poly(lactic acid) Modification.

Being a bio-sourced and biodegradable polymer, polylactic acid (PLA) has been considered as one of the most promising substitutes for petroleum-based plastics. However, its wide application is greatly limited by its very poor ductility, which has driven PLA-toughening modifications to be a topic of increasing research interest in the past decade. Toughening enhancement is achieved often at the cost of a large sacrifice in strength, with the toughness-strength trade-off having remained as one of the main bottlenecks of PLA modification. In the present study, a bio-elastomeric material of epoxidized soybean oil (ESO) crosslinked with sebacic acid (SA) and enhanced by graphene oxide (GO) nanoparticles (NPs) was employed to toughen PLA with the purpose of simultaneously preserving strength and achieving additional functions. The even dispersion of GO NPs in ESO was aided by ultrasonication and guaranteed during the following ESO-SA crosslinking with GO participating in the carboxyl-epoxy reaction with both ESO and SA, resulting in a nanoparticle-enhanced and dynamically crosslinked elastomer (GESO) via a ß-hydroxy ester. GESO was then melt-blended with PLA, with the interfacial reaction between ESO and PLA offering good compatibility. The blend morphology, and thermal and mechanical properties, etc., were evaluated and GESO was found to significantly toughen PLA while preserving its strength, with the GO loading optimized at ~0.67 wt%, which gave an elongation at break of ~274.5% and impact strength of ~10.2 kJ/m2, being 31 times and 2.5 times higher than pure PLA, respectively. Moreover, thanks to the presence of dynamic crosslinks and GO NPs, the PLA-GESO blends exhibited excellent shape memory effect and antistatic properties.

Comparison of Short Curved Stems and Standard-length Single Wedged Stems for Cementless Total Hip Arthroplasty.

Purpose: The purpose of this study was to compare the clinical and radiographic outcomes with use of short-curved stems versus standard-length single wedged stems over a minimum follow-up period of five years. Materials and Methods: A retrospective study of primary total hip arthroplasties performed using the Fitmore® stem (127 hips, 122 patients) and the M/L taper® stem (195 hips, 187 patients) between October 2012 and June 2014 was conducted. The clinical and radiographic outcomes were obtained for evaluation over a minimum follow-up period of five years. Results: In both the Fitmore® and M/L taper® groups, the mean Harris hip score improved from 52.4 and 48.9 preoperatively to 93.3 and 94.5 at the final follow-up, respectively (P=0.980). The mean Western Ontario and McMaster Universities Osteoarthritis Index scores also improved from 73.3 and 76.8 preoperatively to 22.9 and 25.6 at the final follow-up, respectively (P=0.465). Fifteen hips (Fitmore®: 14 hips; M/L taper®: one hip, P<0.001) developed intraoperative cracks and were treated simultaneously with cerclage wiring. Radiography showed a radiolucent line in 24 hips in the Fitmore® group and 12 hips in the M/L taper® group (P=0.125). Cortical hypertrophy was detected in 29 hips (Fitmore® group: 28 hips; M/L taper® group: one hip, P<0.001). Conclusion: Similarly favorable clinical and radiographic outcomes were achieved with use of both short-curved stems and standard-length single wedged stems. However, higher cortical hypertrophy and a higher rate of femoral crack were observed with use of Fitmore® stems.

Working Experiences of Care Aides in Long-Term Care Institutions Following the Relaxation of COVID-19 Regulations in Taiwan: A Qualitative Study.

Care aides in long-term care (LTC) institutions care for older disabled residents at high risk for COVID-19. However, they experienced many stressors during the COVID-19 pandemic. This study aims to explore the working experiences of care aides in LTC institutions following the relaxation of COVID-19 regulations in Taiwan. This qualitative descriptive study included 20 care aides who had cared for residents with COVID-19. Data were obtained via semi-structured interviews. Caring for residents with COVID-19 and the difficulties, resources and teamwork, and impact of care aides' work on their lives were discussed. Consequently, four themes were identified. First, difficulties in care, which included physical limitations by protection, workload, and impact of work schedule on the lives of the care aides. Second, psychological impact, such as worry, social isolation, and burnout. Third, interpersonal relationships with supervisors, colleagues, residents, and their families. Fourth, infection control policy from the institution and government. When infection control policies were relaxed, care aides had difficulties in caring for residents; furthermore, their family and social lives were also affected. They were required to learn knowledge of and skills for COVID-19 management. Institutions were required to provide support in materials, care processes, environment, and management.

The trajectory of smoking cessation after treatment and its related factors in Taiwan.

Smoking has multiple negative effects on health; therefore, the Taiwanese government provides smoking cessation clinics to smokers. This study aimed to explore the trajectory of smoking cessation after smokers received treatment and the variables related to different trajectories. A retrospective longitudinal study was conducted, in which 735 adult smokers who received smoking cessation medications were recruited. The participants' demographic characteristics, chronic diseases, smoking characteristics, and cigarette dependence were collected from chart review. The amount of smoking was collected at baseline, and at 1 week, 1 month, 3 months, and 6 months after treatment. The Proc Traj procedure for group-based modeling and multinomial logistic regression were used for statistical analysis. Three trajectories were identified: early quitters (28.03%), late quitters (11.43%) and reducers (60.54%). Compared with early quitters, reducers were younger and had a higher probability of severe cigarette dependence. Compared with early quitters, late quitters had a higher number of taking smoking cessation medications. The findings revealed that approximately 60% of participants who received smoking cessation treatment could not completely quit smoking, and that age, number of medications taken, and cigarette dependence were significant predictors of different trajectories.

MicroRNAs in Umbilical Cord Blood and Development in Full-Term Newborns: A Prospective Study.

Background: Exploring the epigenetic regulations, such as microRNA, in newborns holds significant promise for enhancing our ability to address and potentially prevent early-life developmental delays. Objectives: Hence, this research seeks to investigate if the expression of miRNA in the umbilical cord blood of infants can forecast their developmental outcomes as they grow older. Design and method: We enrolled 143 full-term newborns, delivered either via cesarean section (CS) or through natural spontaneous delivery (NSD). We then analyzed the profiles of specific miRNAs (miR-486-5p, miR-126-5p, miR-140-3p, miR-151a-3p, miR-142-5p, and miR-30e-5p) in the umbilical cord blood of these infants. Subsequently, we performed follow-up assessments using Bayley-III scores when the cohort reached 1 year of age. Furthermore, we conducted pathway-enrichment analyses on the target genes associated with these examined miRNAs. Results: When comparing newborns delivered via cesarean section (CS) to those born via natural spontaneous delivery (NSD), we observed notable differences. Specifically, newborns through NSD displayed significantly higher ΔCt values for miR-486-5p, alongside lower ΔCt values for miR-126-5p and miR-151a-3p in their cord blood. At 1 year of age, cognitive development was significantly linked to the ΔCt values of miR-140-3p and miR-142-5p, while language development showed a significant association with the ΔCt values of miR-140-3p. Moreover, our pathway enrichment analyses revealed that the target genes of these miRNAs were consistently involved in the pathways related to neurons, such as axon guidance and the neurotrophin signaling pathway. Conclusion: In summary, this study represents a pioneering effort in elucidating the potential connections between miRNA levels in cord blood and the health indicators and neurodevelopment of newborns at 1 year of age. Our findings underscore the significance of miRNA levels at birth in influencing mechanisms related to neurodevelopment.

Abscisic acid induces PpeKIL1 to terminate fruit growth and promote fruit abortion in peach (Prunus persica).

Abnormal pollination from chance events or hybridization between species leads to unusual embryo development, resulting in fruit abortion. To elucidate the mechanism underlying fruit abortion, we conducted a comprehensive analysis of the transcriptome and hormone profiles in aborting fruits (AF) derived from an interspecific cross between the peach cultivar 'Huangjinmi 3' and the Prunus mume cultivar 'Jiangmei', as well as in normal-seeded fruits (NF) resulting from an intraspecific cross of 'Huangjinmi 3' with the 'Manyuanhong' peach cultivars. Growth of AF was inhibited during the exponential growth phase, with up-regulation of oxidative stress related genes and down-regulation of DNA replication and cell cycle genes. Accumulation of the tissue growth-related hormones auxin and cytokinin was reduced in AF, while levels of the growth inhibiting hormone abscisic acid (ABA) were higher compared to NF. The increased ABA concentration aligned with down-regulation of the ABA catabolism gene CYP707A2, which encodes abscisic acid 8'-hydroxylase. Correlation analysis showed ABA could explain the maximum proportion of differently expressed genes between NF and AF. We also showed that expression of KIRA1-LIKE1 (PpeKIL1), a peach ortholog of the Arabidopsis KIRA1 gene, was up-regulated in AF. PpeKIL1 promotes senescence or delays normal growth in tobacco and Arabidopsis, and its promoter activity increases with exogenous ABA treatment. Our study demonstrates a candidate mechanism where ABA induces expression of PpeKIL1, which further blocks normal fruit growth and triggers fruit abscission.

Mapping Hydrogen Positions along the Proton Transfer Pathway in an Organic Crystal by Computational X-ray Spectra.

Understanding proton transfer (PT) dynamics in condensed phases is crucial in chemistry. We computed a 2D map of N 1s X-ray photoelectron/absorption spectroscopy (XPS/XAS) for an organic donor-acceptor salt crystal against two varying N-H distances to track proton motions. Our results provide a continuous spectroscopic mapping of O-H···N↔O-··· H+-N processes via hydrogen bonds at both nitrogens, demonstrating the sensitivity of N 1s transient XPS/XAS to hydrogen positions and PT. By reducing the O-H length at N1 by only 0.2 Å, we achieved excellent theory-experiment agreement in both XPS and XAS. Our study highlights the challenge in refining proton positions in experimental crystal structures by periodic geometry optimizations and proposes an alternative scaled snapshot protocol as a more effective approach. This work provides valuable insights into X-ray spectra for correlated PT dynamics in complex crystals, benefiting future experimental studies.

Prevalence and plasma exosome-derive microRNA diagnostic biomarker screening of adolescent idiopathic scoliosis in Yunnan Province, China.

Background: Idiopathic scoliosis significantly affects the physical and mental health of children and adolescents, with varying prevalence rates in different regions. The occurrence of idiopathic scoliosis is associated with genetic regulation and biochemical factors, but the changes in exosome-derived miRNA profiles among idiopathic scoliosis patients remain unclear. This study aimed to determine the prevalence of idiopathic scoliosis in Yunnan Province, China, and identify key exosome-derived miRNAs in idiopathic scoliosis through a cohort study. Methods: From January 2018 to December 2020, a cross-sectional study on idiopathic scoliosis in children and adolescents was conducted in Yunnan Province. A total of 84,460 students from 13 cities and counties in Yunnan Province participated in a scoliosis screening program, with ages ranging from 7 to 19 years. After confirmation through screening and imaging results, patients with severe idiopathic scoliosis and normal control individuals were selected using propensity matching. Subsequently, plasma exosome-derived miRNA sequencing and RT-qPCR validation were performed separately. Based on the validation results, diagnostic performance analysis and target gene prediction were conducted for differential plasma exosome-derived miRNAs. Results: The overall prevalence of idiopathic scoliosis in children and adolescents in Yunnan Province was 1.10%, with a prevalence of 0.87% in males and 1.32% in females. The peak prevalence was observed at age 13. Among patients diagnosed with idiopathic scoliosis, approximately 12.8% had severe cases, and there were more cases of double curvature than of single curvature, with thoracolumbar curvature being the most common in the single-curvature group. Sequencing of plasma exosome-derived miRNAs associated with idiopathic scoliosis revealed 56 upregulated and 153 downregulated miRNAs. Further validation analysis confirmed that hsa-miR-27a-5p, hsa-miR-539-5p, and hsa-miR-1246 have potential diagnostic value. Conclusions: We gained insights into the epidemiological characteristics of idiopathic scoliosis in Yunnan Province and conducted further analysis of plasma exosome-derived miRNA changes in patients with severe idiopathic scoliosis. This study has provided new insights for the prevention and diagnosis of idiopathic scoliosis, paving the way for exploring clinical biomarkers and molecular regulatory mechanisms. However, further validation and elucidation of the detailed biological mechanisms underlying these findings will be required in the future.

Clinical manifestations, diagnosis and long-term prognosis of adult autoimmune enteropathy: Experience from Peking Union Medical College Hospital.

BACKGROUND: Autoimmune enteropathy (AIE) is a rare disease whose diagnosis and long-term prognosis remain challenging, especially for adult AIE patients. AIM: To improve overall understanding of this disease's diagnosis and prognosis. METHODS: We retrospectively analyzed the clinical, endoscopic and histopathological characteristics and prognoses of 16 adult AIE patients in our tertiary medical center between 2011 and 2023, whose diagnosis was based on the 2007 diagnostic criteria. RESULTS: Diarrhea in AIE patients was characterized by secretory diarrhea. The common endoscopic manifestations were edema, villous blunting and mucosal hyperemia in the duodenum and ileum. Villous blunting (100%), deep crypt lymphocytic infiltration (67%), apoptotic bodies (50%), and mild intraepithelial lymphocytosis (69%) were observed in the duodenal biopsies. Moreover, there were other remarkable abnormalities, including reduced or absent goblet cells (duodenum 94%, ileum 62%), reduced or absent Paneth cells (duodenum 94%, ileum 69%) and neutrophil infiltration (duodenum 100%, ileum 69%). Our patients also fulfilled the 2018 diagnostic criteria but did not match the 2022 diagnostic criteria due to undetectable anti-enterocyte antibodies. All patients received glucocorticoid therapy as the initial medication, of which 14/16 patients achieved a clinical response in 5 (IQR: 3-20) days. Immunosuppressants were administered to 9 patients with indications of steroid dependence (6/9), steroid refractory status (2/9), or intensified maintenance medication (1/9). During the median of 20.5 months of follow-up, 2 patients died from multiple organ failure, and 1 was diagnosed with non-Hodgkin's lymphoma. The cumulative relapse-free survival rates were 62.5%, 55.6% and 37.0% at 6 months, 12 months and 48 months, respectively. CONCLUSION: Certain histopathological findings, including a decrease or disappearance of goblet and Paneth cells in intestinal biopsies, might be potential diagnostic criteria for adult AIE. The long-term prognosis is still unsatisfactory despite corticosteroid and immunosuppressant medications, which highlights the need for early diagnosis and novel medications.

Effect of Zinc and Severe Plastic Deformation on Mechanical Properties of AZ61 Magnesium Alloy.

This study investigates the effects of zinc (4 wt.%) and severe plastic deformation on the mechanical properties of AZ61 magnesium alloy through the stir-casting process. Severe plastic deformation (Equal Channel Angular Pressing (ECAP)) has been performed followed by T4 heat treatment. The microstructural examinations revealed that the addition of 4 wt.% Zn enhances the uniform distribution of ß-phase, contributing to a more uniformly corroded surface in corrosive environments. Additionally, dynamic recrystallization (DRX) significantly reduces the grain size of as-cast alloys after undergoing ECAP. The attained mechanical properties demonstrate that after a single ECAP pass, AZ61 + 4 wt.% Zn alloy exhibits the highest yield strength (YS), ultimate compression strength (UCS), and hardness. This research highlights the promising potential of AZ61 + 4 wt.% Zn alloy for enhanced mechanical and corrosion-resistant properties, offering valuable insights for applications in diverse engineering fields.

Specific long-term changes in anti-SARS-CoV-2 IgG modifications and antibody functions in mRNA, adenovector, and protein subunit vaccines.

Various vaccine platforms were developed and deployed against the COVID-19 disease. The Fc-mediated functions of IgG antibodies are essential in the adaptive immune response elicited by vaccines. However, the long-term changes of protein subunit vaccines and their combinations with mRNA vaccines are unknown. A total of 272 serum and plasma samples were collected from individuals who received first to third doses of the protein subunit Medigen, the mRNA (BNT), or the adenovector AstraZeneca vaccines. The IgG subclass level was measured using enzyme-linked immunosorbent assay, and Fc-N glycosylation was measured using LC-MS/MS. Antibody-dependent phagocytosis (ADCP) and complement deposition (ADCD) of anti-spike (S) IgG antibodies were measured. IgG1 and 3 reached the highest anti-S IgG subclass level. IgG1, 2, and 4 subclass levels significantly increased in mRNA- and Medigen-vaccinated individuals. Fc-glycosylation was stable, except in female BNT vaccinees, who showed increased bisection and decreased galactosylation. Female BNT vaccinees had a higher anti-S IgG titer than that of males. ADCP declined in all groups. ADCD increased in Medigen-vaccinated individuals after the third dose. Each vaccine produced specific long-term changes in Fc structure and function. This finding is critical when selecting a vaccine platform or combination to achieve the desired immune response.

Environmentally relevant concentrations of benzophenones exposure disrupt intestinal homeostasis, impair the intestinal barrier, and induce inflammation in mice.

The aim of this study is to investigate the adverse effects of benzophenones (BPs) on the intestinal tract of mice and the potential mechanism. F1-generation ICR mice were exposed to BPs (benzophenone-1, benzophenone-2, and benzophenone-3) by breastfeeding from birth until weaning, and by drinking water after weaning until maturity. The offspring mice were executed on postnatal day 56, then their distal colons were sampled. AB-PAS staining, HE staining, immunofluorescence, Transmission Electron Microscope, immunohistochemistry, Western Blot and RT-qPCR were used to study the effects of BPs exposure on the colonic tissues of offspring mice. The results showed that colonic microvilli appeared significantly deficient in the high-dose group, and the expression of tight junction markers Zo-1 and Occludin was significantly down-regulated and the number of goblet cells and secretions were reduced in all dose groups, and the expression of secretory cell markers MUC2 and KI67 were decreased, as well as the expression of intestinal stem cell markers Lgr5 and Bmi1, suggesting that BPs exposure caused disruption of intestinal barrier and imbalance in the composition of the intestinal stem cell pool. Besides, the expression of cellular inflammatory factors such as macrophage marker F4/80 and tumor necrosis factor TNF-α was elevated in the colonic tissues of all dose groups, and the inflammatory infiltration was observed, which means the exposure of BPs caused inflammatory effects in the intestinal tract of F1-generation mice. In addition, the contents of Notch/Wnt signaling pathway-related genes, such as Dll-4, Notch1, Hes1, Ctnnb1and Sfrp2 were significantly decreased in each high-dose group (P < 0.05), suggesting that BPs may inhibit the regulation of Notch/Wnt signaling pathway. In conclusion, exposure to BPs was able to imbalance colonic homeostasis, disrupt the intestinal barrier, and trigger inflammation in the offspring mice, which might be realized through interfering with the Notch/Wnt signaling pathway.

Tanshinone IIA improves Alzheimer's disease via RNA nuclear-enriched abundant transcript 1/microRNA-291a-3p/member RAS oncogene family Rab22a axis.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative condition characterized by oxidative stress and neuroinflammation. Tanshinone IIA (Tan-IIA), a bioactive compound isolated from Salvia miltiorrhiza plants, has shown potential neuroprotective effects; however, the mechanisms underlying such a function remain unclear. AIM: To investigate potential Tan-IIA neuroprotective effects in AD and to elucidate their underlying mechanisms. METHODS: Hematoxylin and eosin staining was utilized to analyze structural brain tissue morphology. To assess changes in oxidative stress and neuroinflammation, we performed enzyme-linked immunosorbent assay and western blotting. Additionally, the effect of Tan-IIA on AD cell models was evaluated in vitro using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Genetic changes related to the long non-coding RNA (lncRNA) nuclear-enriched abundant transcript 1 (NEAT1)/microRNA (miRNA, miR)-291a-3p/member RAS oncogene family Rab22a axis were assessed through reverse transcription quantitative polymerase chain reaction. RESULTS: In vivo, Tan-IIA treatment improved neuronal morphology and attenuated oxidative stress and neuroinflammation in the brain tissue of AD mice. In vitro experiments showed that Tan-IIA dose-dependently ameliorated the amyloid-beta 1-42-induced reduction of neural stem cell viability, apoptosis, oxidative stress, and neuroinflammation. In this process, the lncRNA NEAT1 - a potential therapeutic target - is highly expressed in AD mice and downregulated via Tan-IIA treatment. Mechanistically, NEAT1 promotes the transcription and translation of Rab22a via miR-291a-3p, which activates nuclear factor kappa-B (NF-κB) signaling, leading to activation of the pro-apoptotic B-cell lymphoma 2-associated X protein and inhibition of the anti-apoptotic B-cell lymphoma 2 protein, which exacerbates AD. Tan-IIA intervention effectively blocked this process by inhibiting the NEAT1/miR-291a-3p/Rab22a axis and NF-κB signaling. CONCLUSION: This study demonstrates that Tan-IIA exerts neuroprotective effects in AD by modulating the NEAT1/miR-291a-3p/Rab22a/NF-κB signaling pathway, serving as a foundation for the development of innovative approaches for AD therapy.

[ADAMTS13-Mediated Proteolytic Cleavage of Unusually Large von Willebrand Factor Polymers on Endothelial Cells in the Absence of Fluid Shear Stress].

OBJECTIVE: To investigate the molecular mechanism of proteolytic cleavage of unusually large von Willebrand Factor(ULVWF) on endothelial cells by ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats-13) in the absence of fluid shear stress, so as to provide a theoretical basis for the pathogenesis of thrombotic thrombocytopenic purpura (TTP) and other thrombotic disorders. METHODS: The ADAMTS13-mediated proteolysis of ULVWF on the surface of endothelial cells in the absence of fluid shear stress was observed through immunofluorescence microscopy. The variation in VWF antigen levels in the conditioned media were determined by ELISA assay. The levels of VWF and the proteolytic fragments released into the conditioned media were determined by ELISA assay and Western blot in the absence and presence of fluid shear stress or FVIII. The effect of ADAMTS13-mediated ULVWF cleavage on the normal distribution of plasma VWF multimers was evaluated by multimer analysis. Histamine stimulated human umbilical vein endothelial cells (HUVECs) were incubated with ADAMTS13 and various N- and C-terminally truncated mutants. Then the ULVWF that maintained binding to the cells were observed through immunofluorescence microscopy and the soluble ULVWF released from endothelial cells was determined by ELISA, so as to demonstrate the domains of ADAMTS13 required for proteolysis of ULVWF on endothelial cells. RESULTS: The ULVWF strings on the endothelial cell surface were rapidly proteolyzed by recombinant and plasma ADAMTS13 in the absence of fluid shear stress. This proteolytic processing of ULVWF depended on incubation time and ADAMTS13 concentration, but not shear stress and FVIII. The distribution of VWF releaseded by ADAMTS13-mediated proteolysis was quite similar to that secreted by endothelial cells under histamine stimulation, suggesting the ULVWF cleavage occured at the cell surface. The proteolysis of the ULVWF on endothelial cells required the Cys-rich(CysR) and spacer domains, but not the TSP1 2-8 and CUB domains of ADAMTS13. CONCLUSION: The ULVWF polymers on endothelial cells are sensitive to ADAMTS13-mediated cleavage even in the absence of fluid shear stress. The findings provide novel insight into the molecular mechanism of ADAMTS13-mediated ULVWF cleavage at the cellular level and may contribute to understanding of the pathogenesis of TTP and other thrombotic disorders.

Social network and related factors in older people with sensory impairment in the community: Using principal component analysis.

AIM: Older people with sensory impairment are more likely to have smaller and weaker social network due to their reduced ability, which lowers their quality of life. However, there is little research on the social network in older people with sensory impairment, especially the related factors. The aim of the study was to explore the related factors of social network and to provide evidence for the improvement of social network to promote successful aging in older people with sensory impairment. METHODS: A cross-sectional study was conducted among 374 participants for hearing and vision assessment and questionnaire survey in a community, Beijing. Data were collected and analyzed by principal component analysis (PCA) and multiple logistic regression using IBM SPSS 25.0 software. RESULTS: PCA showed that there were six risk factors whose eigenvalues >1 were extracted, with a total variance of 56.555%. Multiple logistic regression analysis of principal component indicated that five factors including physical health factor, social interaction factor, psychological status factor, lifestyle factor, and family condition factor, were statistically significant (p < 0.05). CONCLUSIONS: The social network of older people with sensory impairment is relatively poor. Physical health factor, social interaction factor, psychological status factor, lifestyle factor, and family condition factor may be related factors. Medical staff should pay attention to physical, psychological and social characteristics of older people, especially with sensory impairment, to carry out necessary measures to improve social network and avoid social isolation.

Construction and validation of m6A-related diagnostic model for psoriasis.

Background: Psoriasis is a chronic immune-mediated inflammatory disease. N6-methyladenosine (m6A) is involved in numerous biological processes in both normal and diseased states. Herein, we aimed to explore the potential role of m6A regulators in the diagnosis of psoriasis and predict molecular mechanisms by which m6A regulators impact psoriasis. Methods: GSE30999 (170 human skin tissue samples) and GSE13355 (180 human skin tissue samples) were downloaded as the training analysis dataset and validation dataset respectively. M6A-related genes were obtained from the literature and their expression levels in GSE30999 samples were measured to identify M6A-related DEGs between psoriasis lesions (LS) and non-lesional lesions (NL). We identified m6A-related DEGs using differential expression analysis and assessed their interactions through correlation analysis and network construction. A logistic regression analysis followed by LASSO optimization was employed to select m6A-related DEGs for the construction of a diagnostic model. The performance of the model was validated using support vector machine (SVM) methodology with sigmoid kernel function and extensive cross-validation. Additionally, the correlation between m6A-related DEGs and immune cell infiltration was analyzed, as well as the association of these DEGs with psoriasis subtypes. Functional analysis of the m6A-related DEGs included the construction of regulatory networks involving miRNAs, transcription factors (TFs), and small-molecule drugs. The m6A modification patterns were also explored by examining the gene expression differences between psoriasis subtypes and their enriched biological pathways. Finally, the expression of significant m6A regulators involved in the diagnostic model was examined by RT-qPCR. Results: In this study, ten optimal m6A-related DEGs were identified, including FTO, IGF2BP2, METTL3, YTHDC1, ZC3H13, HNRNPC, IGF2BP3, LRPPRC, YTHDC2, and HNRNPA2B1. A diagnostic model based on these m6A-related DEGs was constructed, demonstrating high diagnostic accuracy with an area under the curve (AUC) in GSE30999 and GSE13355 of 0.974 and 0.730, respectively. Meanwhile, the expression level of m6A regulators verified by RT-qPCR was consistent with the results in GSE30999. The infiltration of activated mast cells and NK cells was significantly associated with all ten m6A-related DEGs in psoriasis. Among them, YTHDC1, HNRNPC, and FTO were targeted by most miRNAs and were regulated by nine related TFs. Therefore, patients may benefit from dorsomorphin and cyclosporine therapy. Between the two subgroups, 1,592 DEGs were identified, including LRPPRC and METTL3. These DEGs were predicted to be involved in neutrophil activation, cytokine-cytokine receptor interactions, and chemokine signaling pathways. Conclusions: A diagnostic model based on ten m6A-related DEGs in patients with psoriasis was constructed, which may provide early diagnostic biomarkers and therapeutic targets for psoriasis.