Hydrogen-bond-regulated mechanochemical synthesis of covalent organic frameworks: cocrystal precursor strategy for confined assembly.

Two-dimensional imine covalent organic frameworks (2D imine-COFs) are crystalline porous materials with broad application prospects. Despite the efforts into their design and synthesis, the mechanisms of their formation are still not fully understood. Herein, a one-pot two-step mechanochemical cocrystal precursor synthetic strategy is developed for efficient construction of 2D imine-COFs. The mechanistic investigation demonstrated that the cocrystal precursors of 4,4',4''-(1,3,5-triazine-2,4,6-triyl)trianiline (TAPT) and p-toluenesulphonic acid (PTSA) sufficiently regulate the crystalline structure of COF. Evidenced by characterizations and theoretical studies, a helical hydrogen-bond network was constructed by the N-H···O supramolecular synthons between amine and sulfate in TAPT-PTSA, demonstrating the role of cocrystals in promoting the organized stacking of interlayer π-π interactions, layer arrangement, and interlayer spacing, thus facilitating the orderly assembly of COFs. Moreover, the protonation degree of TAPT amines, which tuned nucleophilic directionality, enabled the sequential progression of intra- and interlayer imine condensation reactions, inhibiting the formation of amorphous polymers. The transformation from cocrystal precursors to COFs was achieved through comprehensive control of hydrogen bond and covalent bond sites. This work significantly advances the concept of hydrogen-bond-regulated COF assembly and its mechanochemical method in the design and synthesis of 2D imine-COFs, further elucidating the mechanistic aspects of their mechanochemical synthesis.

Activation of the LKB1/AMPK/HIF-1α Pathway by Metformin to Promote Neovascularisation in Cerebral Ischaemia.

As a difficult-to-treat neurological condition, cerebral ischemia is currently limited to treatments such as intravenous recombinant tissue plasminogen activator thrombolysis and thrombectomy. Metformin, a potent antidiabetic drug, has been reported to have an independent function in enhancing the prognosis of stroke patients, in addition to its glucose-lowering effects. However, the mechanism of action of metformin in this context remains unclear. In vivo, a rat model of permanent middle cerebral artery occlusion was established, and after administration of a low dose of 10.5 mg/mL metformin, infarct area was measured by TTC staining, and cortical blood flow was determined by laser Doppler imaging. In vitro, the study established human umbilical vein endothelial cells treated with cobalt chloride. Immunofluorescence, immunohistochemistry, and Western blot experiments were performed to observe the expression of angiogenic factors, tight junction proteins, and apoptotic factors. A TUNEL assay was utilized to appraise cell death by apoptosis. A tube formation assay and scratch assay were conducted to determine the endothelial neovascularization status. Animal experiments have revealed that the administration of the AMPK activator metformin significantly reduced the infarct area, promoted the expression of angiogenic factors, and maintained the stability of tight junction proteins in endothelial cells. Moreover, metformin reduces nerve cells apoptosis by affecting the expression of the apoptotic protein cleaved-caspase3 via the HIF-1α pathway. In vitro, the LKB1/AMPK signaling pathway is activated after hypoxic stimulation, attaining its peak within the early stages of hypoxia (1-12 h) and gradually weakening thereafter. The administration of AMPK pharmacological agonists (between 36 and 48 h) can enhance AMPK activity, which can lead to the expression of angiogenic factors, maintain the stability of tight-junction proteins in endothelial cells, and facilitate endothelial cell migration and vascular structure formation. Conversely, the AMPK inhibitors exert the opposite effects. The activation of the LKB1/AMPK/HIF-1α signaling pathway by metformin in cerebral ischemia contributes to angiogenesis, promotes tissue repair in the injured area, and enhances neurologically functional symptoms.

Fluspirilene exerts an anti-glioblastoma effect through suppression of the FOXM1-KIF20A axis.

Given the infiltrative nature of human glioblastoma (GBM), cocktail drug therapy will remain a vital tool for the treatment of the disease. We investigated fluspirilene, perphenazine, and sulpiride, three classic anti-schizophrenic drugs, as possible anti-GBM agents. The CCK-8 assay demonstrated that fluspirilene possesses the most outstanding anti-GBM effect. We performed molecular mechanisms studies in vitro and an orthotopic xenograft model in mice. Fluspirilene inhibited proliferation and migration in vitro in U87MG and U251 GBM cell lines. Flow cytometry demonstrated that treatment increased apoptosis and cells accumulated in the G2/M phase. Our analysis of publicly available expression data for several cell lines treated with the drug led to the identification of several genes, including KIF20A, that are downregulated by fluspirilene and lead to growth inhibition/apoptosis. We also demonstrated that siRNA knockdown of KIF20A, a member of the kinesin family, attenuated cell proliferation in GBM cells and an orthotopic xenograft model in mice. A regulator of KIF20A, the oncogenic transcription factor FOXM1, was identified using the String database, which harbors protein interaction networks. In fluspirilene-treated cells, FOXM1 protein was decreased, indicating that KIF20A was downregulated in the presence of the drug due to decreased FOXM1 protein. These results demonstrate that fluspirilene is an effective anti-GBM agent that works by suppressing the FOXM1-KIF20A oncogenic axis.

Development and evaluation of 3D composite scaffolds with piezoelectricity and biofactor synergy for enhanced articular cartilage regeneration.

The inability of articular cartilage to self-repair following injuries frequently precipitates osteoarthritis, profoundly affecting patients' quality of life. Given the limitations inherent in current clinical interventions, an urgent need exists for more effective cartilage regeneration methodologies. Previous studies have underscored the potential of electrical stimulation in cartilage repair, thus motivating the investigation of innovative strategies. The present study introduces a three-dimensional scaffold fabricated through a composite technique that leverages the synergy between piezoelectricity and biofactors to enhance cartilage repair. This scaffold is composed of polylactic acid (PLLA) and barium titanate (BT) for piezoelectric stimulation and at the bottom with a collagen-coated layer infused with fibroblast growth factor-18 (FGF-18) for biofactor delivery. Designed to emulate the properties of natural cartilage, the scaffold enables controlled generation of piezoelectric charges and the sustained release of biofactors. In vitro tests confirm that the scaffold promotes chondrocyte proliferation, matrix hyperplasia, cellular migration, and the expression of genes associated with cartilage formation. Moreover, in vivo studies on rabbits have illustrated its efficacy in catalyzing the in situ regeneration of articular cartilage defects and remodeling the extracellular matrix. This innovative approach offers significant potential for enhancing cartilage repair and holds profound implications for regenerative medicine.

Impaired facial emotion recognition in individuals with bipolar disorder.

BACKGROUND: Individuals with bipolar disorder (BD) often struggle with emotional regulation and social interactions, partly due to difficulties in accurately recognizing facial emotions. METHODS: From September 2021 to February 2023, 69 BD individuals-comprising 23 with bipolar manic/hypomanic episode (BME), 23 with bipolar depressive episode (BDE), 23 with bipolar euthymic (EUT)-and 23 healthy controls (HCs) were enrolled. Diagnosis adhered to DSM-IV criteria using M.I.N.I 5.0, alongside assessments via Hamilton Depression Scale 17 and Young Manic Rating Scale. Recognition tasks involving 84 facial expression images across six categories. The Wilcoxon rank-sum test compares two groups, while the Kruskal-Wallis test compares multiple groups with subsequent adjusted pairwise comparisons. RESULTS: The overall correct recognition rate of facial expressions in the BD group (79 %) was significantly lower than that of the HC group (83 %) (P=0.004). Primary differences were noted in neutral (93 % vs. 100 %, P=0.012) and fear (79 % vs. 86 %, P=0.023) expressions. Within the BD group, correct recognition rates were 71 % for BME, 80 % for BDE, and 80 % for EUT, all lower than in the HC group. Significant differences in correct recognition rates of neutral, fear, and joy expressions were observed among the four groups (P<0.05), with the BME group exhibiting the lowest rate. Misidentification of facial expressions was more frequent in the BD group compared to the HC group, particularly among negative expressions. CONCLUSION: Patients with BD demonstrate lower correct recognition and higher misidentification rates of facial expressions, with those experiencing manic episodes showing impaired recognition of neutral, joy, and fear expressions.

Time patterns in online survey completion and offline psychological symptoms among college students in China.

Background: Online psychological surveys allow for swift data collection among college students, thus providing a foundation for psychological interventions, particularly during emergent public health events. However, the association between online survey completion behaviors and offline psychological symptoms has yet to be explored. Methods: A large-scale web-based survey was conducted from December 31, 2022, to January 7, 2023, involving 22,624 participants. Psychological symptoms were assessed using standardized measures, while the time taken to complete the survey and the time of completion were recorded by the online survey platform. Results: As the time duration increased, the prevalence of anxiety, depression, insomnia, and PTSD also increased significantly (P for trend < 0.001). The highest odds ratios were observed in the longer duration group. Only a longer duration was significantly associated with PTSD. The time period for completing the questionnaire from 7 p.m. to 10 p.m. was found to be significantly linked with anxiety symptoms and depression symptoms. Conversely, completing the questionnaire at other times was specifically associated with anxiety symptoms and insomnia symptoms. The prolonged duration needed to complete the questionnaire was more closely related to the comorbidity of anxiety, depression, and insomnia than to the comorbidity of those symptoms with PTSD. When questionnaires were completed during other times, specifically referring to the late-night and early morning hours, individuals were more likely to exhibit comorbid symptoms of insomnia. Conclusion: The study identified the specific associations between time durations, time points for completing online survey, and psychological symptoms/comorbidity among college students. Further exploration of their causal relationships and the underlying mechanisms is warranted.

Coke oven emissions exacerbate allergic asthma by promoting ferroptosis in airway epithelial cells.

Epidemiological studies have shown that coke oven emissions (COEs) affect the deterioration of asthma, but has not been proven by experimental results. In this study, we found for the first time that COEs exacerbate allergen house dust mite (HDM)-induced allergic asthma in the mouse model. The findings reveal that airway inflammation, airway remodeling and allergic reaction were aggravated in the COE + HDM combined exposure group compared with the individual exposure group. Mechanism studies indicated higher levels of iron and MDA in the COE + HDM combined exposure group, along with increased expression of Ptgs2 and reduced GPX4 expression. Iron chelator deferoxamine (DFO) effectively inhibited ferroptosis induced by COE synergistically with HDM in vitro. Further studies highlighted the role of ferritinophagy in the COE + HDM-induced ferroptosis. 3-methyladenine (3-MA) could inhibit ferroptosis in the COE + HDM exposure group. Interestingly, we injected DFO intraperitoneally into mice in the combined exposure group and found DFO could significantly inhibit the COE-exacerbated ferroptosis and allergic asthma. Our findings link ferroptosis with COE-exacerbated allergic asthma, implying that ferroptosis may have important therapeutic potential for asthma in patients with occupational exposure of COE.

Research progress of brain organoids in the field of diabetes.

Human embryonic stem cells and human induced pluripotent stem cells may be used to create 3D tissues called brain organoids. They duplicate the physiological and pathological characteristics of human brain tissue more faithfully in terms of both structure and function, and they more precisely resemble the morphology and cellular structure of the human embryonic brain. This makes them valuable models for both drug screening and in vitro studies on the development of the human brain and associated disorders. The technical breakthroughs enabled by brain organoids have a significant impact on the research of different brain regions, brain development and sickness, the connections between the brain and other tissues and organs, and brain evolution. This article discusses the development of brain organoids, their use in diabetes research, and their progress.

The associations of socioeconomic status, social activities, and loneliness with depressive symptoms in adults aged 50 years and older across 24 countries: findings from five prospective cohort studies.

BACKGROUND: Depression is the leading cause of mortality among mental health disorders. Evidence about the associations of socioeconomic status, social activities, and loneliness with depression is scarce. We aimed to identify whether social activities and loneliness mediate the association between socioeconomic status and depression, and the extent of interactive or joint relationships between social activities, loneliness, and socioeconomic status on depression. METHODS: In this population-based, cross-national cohort study we used data from five nationally representative surveys across 24 countries between Feb 15, 2008, and Feb 27, 2019: the Health and Retirement Study (HRS); the English Longitudinal Study of Ageing (ELSA); the Survey of Health, Ageing and Retirement in Europe (SHARE); the China Health and Retirement Longitudinal Study (CHARLS); and the Mexican Health and Ageing Study (MHAS). We included participants who were aged 50 years and older with reported information on socioeconomic status, social activities, and loneliness at baseline, and who had been assessed at least twice. We excluded participants with depressive symptoms at baseline; those with missing data on depressive symptoms and covariates; and those lost to follow-up. We defined socioeconomic status as high and low using latent class analysis based on family income, education, and employment status. Depression was assessed using the Center for Epidemiological Studies Depression Scale (CES-D) or EURO-D. We applied Cox proportional hazard models to estimate the association of socioeconomic status with depression. We used random-effects models to obtain pooled results. Joint and interactive effects of socioeconomic status, social activities, and loneliness on depression were explored, and the mediating roles of social activities and loneliness in the association between socioeconomic status and depression were explored using causal mediation analysis. FINDINGS: A total of 69 160 participants were included in our study and, during a median follow-up of 5 years, a total of 20 237 participants developed depression with a pooled incidence of 7·2 (95% CI 4·4-10·0) per 100 person-years. Compared with participants with high socioeconomic status, those with low socioeconomic status had a higher risk of depression (pooled hazard ratio [HR] 1·34; 95% CI 1·23-1·44). The proportion of the associations between socioeconomic status and depression mediated by social activities and loneliness were 6·12% (1·14-28·45) and 5·54% (0·71-27·62), respectively. We only observed a significant multiplicative interaction of socioeconomic status and loneliness with depression (pooled HR 0·84; 0·79-0·90). Compared with participants with high socioeconomic status and who were socially active and not lonely, those with low socioeconomic status and who were socially inactive and lonely had a higher risk of depression (pooled HR 2·45; 2·08-2·82). INTERPRETATION: Social inactivity and loneliness positively mediated a small proportion of the association between socioeconomic status and depression, indicating that other approaches in addition to interventions targeting social isolation and loneliness are required to mitigate the risk of depression in older adults. Additionally, the joint effects of socioeconomic status, social activities, and loneliness highlight the benefits of simultaneous and integrated interventions to reduce the global burden of depression. FUNDING: National Natural Science Foundation of China.

Young TSPC-Derived Exosomal circPVT1 Ameliorates Aging-Impaired Cell Function via SIRT1/NF-κB.

Tendon stem/progenitor cell (TSPC) senescence is often associated with age-dependent tendon diseases and greatly reduces the capacities for tendon repair and replacement. Exosomes contain bioactive molecules and have been increasingly used in regenerative medicine. In the present study, we demonstrated the antiaging effects of young exosomes from circPVT1-overexpressing TSPCs at early passages (circPVT1-exo). These exosomes attenuated the phenotypes of aged TSPCs at late passages (L-TSPCs) by enhancing self-renewal and proliferation abilities, suppressing cell senescence, maintaining their tenogenic capacity, and weakening their osteogenic differentiation. Mechanistically, circPVT1-exo inhibited the NF-κB pathway and increased SIRT1 expression in L-TSPCs. Knockdown of SIRT1 reversed these effects as evidenced by increased senescence, decreased proliferation, and tenogenic differentiation. These results suggest that circPVT1-exo may ameliorate aging-impaired TSPC function by modulating the SIRT1/NF-κB pathway, suggesting that circPVT1-exo has therapeutic potential for age-related diseases.

Squeeze-and-excitation-attention-based mobile vision transformer for grading recognition of bladder prolapse in pelvic MRI images.

BACKGROUND: Bladder prolapse is a common clinical disorder of pelvic floor dysfunction in women, and early diagnosis and treatment can help them recover. Pelvic magnetic resonance imaging (MRI) is one of the most important methods used by physicians to diagnose bladder prolapse; however, it is highly subjective and largely dependent on the clinical experience of physicians. The application of computer-aided diagnostic techniques to achieve a graded diagnosis of bladder prolapse can help improve its accuracy and shorten the learning curve. PURPOSE: The purpose of this study is to combine convolutional neural network (CNN) and vision transformer (ViT) for grading bladder prolapse in place of traditional neural networks, and to incorporate attention mechanisms into mobile vision transformer (MobileViT) for assisting in the grading of bladder prolapse. METHODS: This study focuses on the grading of bladder prolapse in pelvic organs using a combination of a CNN and a ViT. First, this study used MobileNetV2 to extract the local features of the images. Next, a ViT was used to extract the global features by modeling the non-local dependencies at a distance. Finally, a channel attention module (i.e., squeeze-and-excitation network) was used to improve the feature extraction network and enhance its feature representation capability. The final grading of the degree of bladder prolapse was thus achieved. RESULTS: Using pelvic MRI images provided by a Huzhou Maternal and Child Health Care Hospital, this study used the proposed method to grade patients with bladder prolapse. The accuracy, Kappa value, sensitivity, specificity, precision, and area under the curve of our method were 86.34%, 78.27%, 83.75%, 95.43%, 85.70%, and 95.05%, respectively. In comparison with other CNN models, the proposed method performed better. CONCLUSIONS: Thus, the model based on attention mechanisms exhibits better classification performance than existing methods for grading bladder prolapse in pelvic organs, and it can effectively assist physicians in achieving a more accurate bladder prolapse diagnosis.

Prevalence and correlates of mental health problems among different occupations of medical workers during COVID-19 outbreak in China.

Background: Health workers involved in the fight to prevent the COVID-19 outbreak were exposed to hazards. Detailed information on mental health problems in different medical occupations is crucial. To examined the prevalence of mental health issues in three medical occupations as well as the relationships between mental health problems and correlates in each occupation. Methods: This study utilizing the Questionnaire Star program was conducted among medical workers working at medical institutions in China from February 17 to 24, 2020. The Self-Reporting Questionnaire (SRQ-20), the Zung Self-rating Anxiety Scale (SAS), and the Zung Self-rating Depression Scale (SDS) were used to assess mental health problems. Results: The prevalence of any mental health problems in the three occupations was 43.6, 34.6, and 32.9% for nurses, paramedical workers (PMWs), and doctors, respectively. Three occupations shared some correlates, such as being overworked, not having enough time to rest, support from colleagues, and previous mental health status. There were specific factors for each occupation. For doctors, age, educational level, living status, support from family, and previous physical status were related factors in mental health problems. Working in a designated hospital for treating COVID-19, having COVID-19 event exposures, and receiving support from family were associated with the mental health problems of the nurses. PMWs' mental health problems was linked to educational level and care from supervisors or heads of department. Conclusion: Different medical occupations have distinct impacts on mental health issues. Policy makers and mental health professionals working to prepare for potential disease outbreaks should be aware of multiple factors in different occupations.

miR-145a-5p/SIK1/cAMP-dependent alteration of synaptic structural plasticity drives cognitive impairment induced by coke oven emissions.

Exposure to fine particulate matter (PM) is associated with the neurodegenerative diseases. Coke oven emissions (COEs) in occupational environment are important sources of PM. However, its neurotoxicity is still unclear. Therefore, evaluating the toxicological effects of COE on the nervous system is necessary. In the present study, we constructed mouse models of COE exposure by tracheal instillation. Mice exposed to COE showed signs of cognitive impairment. This was accompanied by a decrease in miR-145a-5p and an increase in SIK1 expression in the hippocampus, along with synaptic structural damage. Our results demonstrated that COE-induced miR-145a-5p downregulation could increase the expression of SIK1 and phosphorylated SIK1, inhibiting the cAMP/PKA/CREB pathway by activating PDE4D, which was associated with reduced synaptic structural plasticity. Furthermore, restoring of miR-145a-5p expression based on COE exposure in HT22 cells could partially reversed the negative effects of COE exposure through the SIK1/PDE4D/cAMP axis. Collectively, our findings link epigenetic regulation with COE-induced neurotoxicity and imply that miR-145a-5p could be an early diagnostic marker for neurological diseases in patients with COE occupational exposure.

755-nm picosecond laser plus topical 20% azelaic acid compared to topical 20% azelaic acid alone for the treatment of melasma: a randomized, split-face and controlled trial.

PURPOSE: Melasma remains a refractory skin condition that needs to be actively explored. Azelaic acid has been used for decades as a topical agent to improve melasma through multiple mechanisms, however, there is a lack of research on its combination with laser therapy. This study evaluated the effectiveness of isolated treatment with topical 20% azelaic acid and its combination with 755-nm picosecond laser in facial melasma patients. METHODS: A randomized, evaluator-blinded, controlled study was conducted on 30 subjects with facial melasma in a single center from October 2021 to April 2022. All subjects received topical 20% azelaic acid cream (AA) for 24 weeks, and after 4 weeks, a hemiface was randomly assigned to receive 755-nm picosecond (PS) laser therapy once every 4 weeks for 3 treatments. Treatment efficacy was determined by mMASI score evaluations, dermoscopic assessment, reflectance confocal microscopy (RCM) assessments and patient's satisfaction assessments (PSA). RESULTS: Treatment with 20% azelaic acid, with or without picosecond laser therapy, significantly reduced the hemi-mMASI score (P < 0.0001) and resulted in higher patient satisfaction. Improvements in dermoscopic and RCM assessments were observed in both sides of the face over time, with no difference between the two sides. RCM exhibited better dentritic cell improvement in the combined treatment side. No patients had serious adverse effects at the end of treatment or during the follow-up period. CONCLUSION: The additional use of picosecond laser therapy showed no clinical difference except for subtle differences detected by RCM assessments.The study was registered in the Chinese Clinical Trial Registry (ChiCTR2100051294; 18 September 2021).

Study on the interaction protein of transcription factor Smad3 based on TurboID proximity labeling technology.

TurboID is a highly efficient biotin-labelling enzyme, which can be used to explore a number of new intercalating proteins due to the very transient binding and catalytic functions of many proteins. TGF-ß/Smad3 signaling pathway is involved in many diseases, especially in diabetic nephropathy and inflammation. In this paper, a stably cell line transfected with Smad3 were constructed by using lentiviral infection. To further investigate the function of TGF-ß/Smad3, the protein labeling experiment was conducted to find the interacting protein with Smad3 gene. Label-free mass spectrometry analysis was performed to obtain 491 interacting proteins, and the interacting protein hnRNPM was selected for IP and immunofluorescence verification, and it was verified that the Smad3 gene had a certain promoting effect on the expression of hnRNPM gene, and then had an inhibitory effect on IL-6. It lays a foundation for further study of the function of Smad3 gene and its involved regulatory network.

Observation of the Effects of Different Enzyme Digestion Time and Enzyme Digestion Methods on the Extraction of Primary Renal Tubular Epithelial Cells from Sprague-Dawley Suckling Mice.

Renal tubular epithelial cells are one of the essential functional cells in the kidney. Optimizing the isolation and culture method of primary renal tubular epithelial cells from SD mammary rats provides better experimental materials for renal tubule-related studies, which is essential for studying the pathogenesis of renal diseases, especially diabetic nephropathy and drug screening. SD rat renal tubular epithelial cells were isolated and purified by 2.5-mg/ml collagenase II or 2 mg/ml trypsin + 2.5 mg/ml collagenase II enzymatic digestion. The isolation and purification were observed at different time points (15 min, 30 min, 45 min, and 60 min) to determine the optimal extraction time for the enzymatic digestion method. After comparing the two enzymatic methods, it was determined that the trypsin + collagenase II enzymatic method was more effective. The primary renal tubular epithelial cells extracted by the trypsin + collagenase II digestion method were identified by the marker Cytokeratin 18 of renal tubular epithelial cells at 45 min of digestion with high purity. We established a simple, efficient, and reproducible method for isolation and culture of renal tubular epithelial cells in SD mammary gland rats.

Associations of demographics, aggravating factors, comorbidities, and treatments with atopic dermatitis severity in China: A national cross-sectional study.

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disorder impacting populations worldwide, although its clinical characteristics and patient demographics remain uncharacterized in China. The aim of this study was to investigate the demographics, comorbidities, aggravating factors, and treatments in AD patients across different age groups in China. METHODS: This cross-sectional study included Chinese AD patients from 205 hospitals spanning 30 provinces. Patients completed dermatologist-led surveys of general medical history, comorbidities, AD-related aggravating factors, and medications. Two-level mixed-ordered logistic regression was used to evaluate aggravating factors. RESULTS: Overall, 16,838 respondents were included in the final analysis (age 30.9 ± 24.1 years). The proportion of severe AD was the highest in patients with AD onset at ≥60 years (26.73%). Allergic rhinitis and hypertension were the most common atopic and metabolism-related non-atopic comorbidities, respectively. AD severity was significantly associated with chronic urticaria, food allergies, and diabetes. Aggravating factors including foods, seasonal changes, and psychological factors were also linked to AD severity. The cross-sectional survey implied that severe AD may be related to the undertreatment of effective systemic or topical interventions. CONCLUSION: To enhance the management of AD, it is crucial to consider both aggravating factors and the increased utilization of systemic immunotherapy. REGISTRATION: ClinicalTrials.gov Identifier: NCT05316805, CORNERSTONE.

Dynamic Changes and Effects of H2S, IGF-1, and GH in the Traumatic Brain Injury.

The aim of this study was to examine the expression changes of H2S, IGF-1, and GH in traumatic brain injury (TBI) patients and to detect their neuroprotective functions after TBI. In this study, we first collected cerebrospinal fluid (CSF) and plasma from TBI patients at different times after injury and evaluated the concentrations of H2S, IGF-1, and GH. In vitro studies were using the scratch-induced injury model and cell-cell interaction model (HT22 hippocampal neurons co-cultured with LPS-induced BV2 microglia cells). In vivo studies were using the controlled cortical impact (CCI) model in mice. Cell viability was assessed by CCK-8 assay. Pro-inflammatory cytokines expression was determined by qRT-PCR, ELISA, and nitric oxide production. Western blot was performed to assess the expression of CBS, CSE, IGF-1, and GHRH. Moreover, the recovery of TBI mice was evaluated for behavioral function by applying the modified Neurological Severity Score (mNSS), the Rotarod test, and the Morris water maze. We discovered that serum H2S, CSF H2S, and serum IGF-1 concentrations were all adversely associated with the severity of the TBI, while the concentrations of IGF-1 and GH in CSF and GH in the serum were all positively related to TBI severity. Experiments in vitro and in vivo indicated that treatment with NaHS (H2S donor), IGF-1, and MR-409 (GHRH agonist) showed protective effects after TBI. This study gives novel information on the functions of H2S, IGF-1, and GH in TBI.

Association of perceived discrimination with the risk of depression among US older adults: A prospective population-based cohort study.

Aims: Association between perceived discrimination and depression has been demonstrated in some sources of discrimination, such as age, sex, and race. However, the effects of perceived discrimination both in any domain and each domain on development of depression are still unclear. We aimed to estimate the association of any and each domain of perceived discrimination with the risk of depression among US older adults. Methods: We did a population-based cohort study using eight waves (from 2006 to 2020) of data from the Health and Retirement Study (HRS), a nationally representative study of US older adults aged 51 years and above. Perceived discrimination was measured by the shortened 5-item version of Williams' discrimination scale, including five domains (less courtesy, service setting, not smart, threatened or harassed, and medical setting). Depressive symptoms were assessed with shortened 8-item version of the Center for Epidemiological Depression scale (8-item CES-D). Cox proportional hazards models were used to estimate the crude and adjusted hazards ratio (HRs) and their 95 % confidence intervals (CIs) between perceived discrimination and risk of depression, after controlling for potential confounders. Results: A total of 18502 participants were included in our final analyses. 42.8 % of them had any perceived discrimination at baseline, and the most prevalent perceived discrimination was feeling less courtesy, which was observed in 5893 people (31.6 %). During a median of 9.8 years follow-up, 44.7 % of participants developed depression. The risk of depression was 46 % (adjusted HR: 1.46, 95 % CI: 1.39-1.52) higher among people with perceived discrimination than those without. The associations between perceived discrimination in each domain and risk of depression were all prominent. Conclusions: Both any and each domain of perceived discrimination were associated with an increased risk of depression. Considering the high prevalence of perceived discrimination and the following poor health outcomes, our findings suggested the integrated measures of providing public education and diversified communication to reduce discrimination, as well as accessible emotional supports to prevent depression are urgently needed.

HPF1 regulates tendon stem/progenitor cell senescence and tendon repair via PARP1-mediated poly-ADP ribosylation of HuR.

BACKGROUND: Tendon stem/progenitor cells (TSPCs) play a vital role in tendon repair, regeneration and homeostasis. However, the specific mechanism of TSPCs aging is still unclear. OBJECTIVE: This study aims to explore the role and molecular mechanism of HPF1 in the aging of TSPCs. METHODS: Young and aged TSPCs (Y-TSPCs and A-TSPCs) were acquired from 3 to 4 and 24-26-month-old Sprague-Dawley male rats, TSPCs (Y-TSPCs and A-TSPCs) were subjected to senescence-associated ß-galactosidase (SA-ß-Gal))staining and telomerase activity detection, p16, p21, Scx, Tnmd, Col1, Col3HPF1 and PAPR1 expression levels were detected by Western blot or Reverse Transcription-quantitative Polymerase Chain Reaction (RT-qPCR), Reciprocal co-immunoprecipitation (co-IP) was used to explore the interaction between HPF1 and PARP1. Ribonucleoprotein immunoprecipitation (RNP-IP) was used to analyze the binding of HuR to the senescence marker gene mRNAs, IP was used to perform HPF1 to the PARylation of HuR, and the half-life of p16 and p21 were detected. Finally, we established an in vivo model, and the tendon tissue was used to perform hematoxylin and eosin (HE) and masson's trichrome staining, as well as the immunohistochemical analysis of Col I and TNMD. RESULTS: Compared with Y-TSPCs, A-TSPCs had significantly enhanced cell senescence and significantly reduced tendon differentiation ability, and significantly increased the expression of HPF1 and PARP1. In addition, HPF1 and PARP1 interacted and coordinated the senescence and differentiation of TSPCs, HPF1 could also regulate the expression of p21 and p21, the interaction of p16 or p21 with HuR, and the poly-ADP ribosylation of PARP1 to HuR. HPF1 overexpression and siHuR co-transfection significantly reduced the half-life of p16 and p21, and HPF1 and PARP1 regulated the mRNA levels of p16 and p21 through HuR. Finally, in vivo experiments have shown that HPF1 or PARP1 overexpression could both inhibit the ability of tendon differentiation and promote cell senescence. CONCLUSIONS: HPF1 promoted the senescence of TSPCs and inhibits the tendon differentiation of TSPCs through PARP1-mediated poly-ADP ribosylation of HuR.