Search

Abstract Skin wounds are characterized by injury to the skin due to trauma, tearing, cuts, or contusions. As such injuries are common to all human groups, they may at times represent a serious socioeconomic burden. Currently, increasing numbers of studies have focused on the role of mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) in skin wound repair. As a cell-free therapy, MSC-derived EVs have shown significant application potential in the field of wound repair as a more stable and safer option than conventional cell therapy. Treatment based on MSC-derived EVs can significantly promote the repair of damaged substructures, including the regeneration of vessels, nerves, and hair follicles. In addition, MSC-derived EVs can inhibit scar formation by affecting angiogenesis-related and antifibrotic pathways in promoting macrophage polarization, wound angiogenesis, cell proliferation, and cell migration, and by inhibiting excessive extracellular matrix production. Additionally, these structures can serve as a scaffold for components used in wound repair, and they can be developed into bioengineered EVs to support trauma repair. Through the formulation of standardized culture, isolation, purification, and drug delivery strategies, exploration of the detailed mechanism of EVs will allow them to be used as clinical treatments for wound repair. In conclusion, MSC-derived EVs-based therapies have important application prospects in wound repair. Here we provide a comprehensive overview of their current status, application potential, and associated drawbacks.

Abstract Scar formation is a common physiological process that occurs after injury, but in some cases, pathological scars can develop, leading to serious physiological and psychological effects. Unfortunately, there are currently no effective means to intervene in scar formation, and the structural features of scars and their unclear mechanisms make prevention and treatment even more challenging. However, the emergence of nanotechnology in drug delivery systems offers a promising avenue for the prevention and treatment of scars. Nanomaterials possess unique properties that make them well suited for addressing issues related to transdermal drug delivery, drug solubility, and controlled release. Herein, we summarize the recent progress made in the use of nanotechnology for the prevention and treatment of scars. We examine the mechanisms involved and the advantages offered by various types of nanomaterials. We also highlight the outstanding challenges and questions that need to be addressed to maximize the potential of nanotechnology in scar intervention. Overall, with further development, nanotechnology could significantly improve the prevention and treatment of pathological scars, providing a brighter outlook for those affected by this condition.

AbstractObjectives Data on angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril-valsartan (SV) in patients undergoing maintenance dialysis is scarce. Our study aimed to investigate the effect of SV on patients undergoing dialysis.Methods We retrospectively reviewed the data of end-stage kidney disease (ESRD) patients undergoing either peritoneal dialysis (PD) or hemodialysis (HD) in our center. A total of 51 patients receiving SV treatment were enrolled in the SV group. Another 51 age and sex-matched patients on dialysis without SV treatment were selected as the control group. All the patients were regularly followed up in the dialysis clinic. Their clinical, biochemical, and echocardiographic parameters were all recorded at baseline and during follow-up. The effect and safety of SV were further analyzed.Results A total of 102 ESRD patients on dialysis (51 patients in the SV group and 51 patients in the control group) were finally enrolled. The median follow-up time was 349 days (interquartile range [IQR]: 217–535 days). The level of B-type natriuretic peptide (BNP) (median [IQR] before and after SV treatment: 596.35 pg/ml [190.6–1714.85] vs. 188.7 pg/ml [83.34–600.35], p

Abstract Objective Recent studies indicated that transmembrane protein 40 (TMEM40) is associated with several types of cancers but is not clear in cervical cancer (CC). The study aimed to examine the role of TMEM40 in CC and related mechanisms. Methods The expression of TMEM40 in CC tissues and cell lines was studied with western blot and real-time quantitative RT-PCR. The effect of TMEM40 on proliferation was evaluated by CCK-8, EdU and colony formation assay. The migration, invasion, cell cycle and apoptosis of CC cells were studied with wound healing, transwell assays and flow cytometry. Tumor growth was evaluated in vivo using a xenogenous subcutaneously implant model. Results The results revealed that the TMEM40 elevation in CC tissues and cell lines was closely correlated with tumor size and lymph node metastasis in clinical patients. Upregulation of TMEM40 with OE-TMEM40 vector promoted the invasion, migration and proliferation, inhibited the apoptosis and led to distinct S cell cycle arrest in CC cell lines. Silencing TMEM40 with shRNA inhibited the invasion, migration and proliferation, promoted apoptosis and led to a G0/G1 cell cycle arrest in CC cell lines. Silence of TMEM40 downregulated the expression of c-MYC, Cyclin D1, matrix metalloproteinase-1 (MMP-1) and matrix metalloproteinase-9 (MMP-9), but in contrast, activated p53 and several apoptosis related proteins such as p53, Caspase-3, Caspase-9 and PARP1. In addition, TMEM40 silencing dramatically decreased tumor growth in mice models. Conclusion The present study demonstrates that TMEM40 upregulation can be a potential prognostic biomarker and contribute to CC development.

Abstract Pulmonary arterial hypertension (PAH) is a progressive disease. Although great progress has been made in its diagnosis and treatment in recent years, its mortality rate is still very significant. The pathophysiology and pathogenesis of PAH are complex and involve endothelial dysfunction, chronic inflammation, smooth muscle cell proliferation, pulmonary arteriole occlusion, antiapoptosis and pulmonary vascular remodeling. These factors will accelerate the progression of the disease, leading to poor prognosis. Therefore, accurate etiological diagnosis, treatment and prognosis judgment are particularly important. Here, we systematically review the pathophysiology, diagnosis, genetics, prognosis and treatment of PAH.

The medial septum (MS) contributes in pain processing and regulation, especially concerning persistent nociception. However, the role of MS glutamatergic neurons in pain and the underlying neural circuit mechanisms in pain remain poorly understood. In this study, chronic constrictive injury of the sciatic nerve (CCI) surgery was performed to induce thermal and mechanical hyperalgesia in mice. The chemogenetic activation of MS glutamatergic neurons decreased pain thresholds in naïve mice. In contrast, inhibition or ablation of these neurons has improved nociception thresholds in naïve mice and relieved thermal and mechanical hyperalgesia in CCI mice. Anterograde viral tracing revealed that MS glutamatergic neurons had projections to the lateral hypothalamus (LH) and supramammillary nucleus (SuM). We further demonstrated that MS glutamatergic neurons regulate pain thresholds by projecting to LH but not SuM, because the inhibition of MS-LH glutamatergic projections suppressed pain thresholds in CCI and naïve mice, yet, optogenetic activation or inhibition of MS-SuM glutamatergic projections had no effect on pain thresholds in naïve mice. In conclusion, our results reveal that MS glutamatergic neurons play a significant role in regulating pain perception and decipher that MS glutamatergic neurons modulate nociception via projections to LH.

CD8+ T cells, a cytotoxic T lymphocyte, are a key component of the tumor immune system, but they enter a hyporeactive T cell state in long-term chronic inflammation, and how to rescue this depleted state is a key direction of research. Current studies on CD8+ T cell exhaustion have found that the mechanisms responsible for their heterogeneity and differential kinetics may be closely related to transcription factors and epigenetic regulation, which may serve as biomarkers and potential immunotherapeutic targets to guide treatment. Although the importance of T cell exhaustion in tumor immunotherapy cannot be overstated, studies have pointed out that gastric cancer tissues have a better anti-tumor T cell composition compared to other cancer tissues, which may indicate that gastrointestinal cancers have more promising prospects for the development of precision-targeted immunotherapy. Therefore, the present study will focus on the mechanisms involved in the development of CD8+ T cell exhaustion, and then review the landscapes and mechanisms of T cell exhaustion in gastrointestinal cancer as well as clinical applications, which will provide a clear vision for the development of future immunotherapies.

Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer. High fibrosis, marked by increased collagen fibers, is widespread in TNBC and correlated with tumor progression. However, the molecular features of fibrosis and why it results in a poor prognosis remain poorly understood. Based on multiomics datasets of TNBC, we evaluated the pathological fibrosis grade of 344 samples for further analysis. Genomic, transcriptomic, and immune changes were analyzed among different subgroups of fibrosis. High fibrosis was an independent adverse prognosis predictor and had interactions with low stromal tumor-infiltrating lymphocytes. Genomic analysis identified copy number gains of 6p22.2–6p22.1 (TRIM27) and 20q13.33 (CDH4) as genomic hallmarks of tumors with high fibrosis. Transcriptome analysis revealed the transforming growth factor-beta pathway and hypoxia pathway were key pro-oncogenic pathways in tumors with high fibrosis. Moreover, we systematically evaluate the relationship between fibrosis and different kinds of immune and stromal cells. Tumors with high fibrosis were characterized by an immunosuppressive tumor microenvironment with limited immune cell infiltration and increased fibroblasts. This study proposes new insight into the genomic and transcriptomic alterations potentially driving fibrosis. Moreover, fibrosis is related to an immunosuppressive tumor microenvironment that contributes to the poor prognosis.

The dry scroll vacuum pump is a kind of variable capacity dry vacuum pump that is applied in chemical, pharmaceutical, semiconductor, and scientific instruments. Analyzing the thermodynamic characteristics of the scroll vacuum pump and studying the impact of operating temperature on its consistent performance are necessary for the design and application of the cooling system of the scroll vacuum pump. Based on the dynamics mesh method, the computational fluid dynamics (CFD) simulation model of a multi-stage dry scroll vacuum pump is established in this study. Under the suction pressure of 1000 Pa, the simulation calculation is carried out at different operating temperatures of fixed scrolls (25 °C, 45 °C, and 65 °C). The results show that the pumping speed, the gas compression power, and the energy efficiency ratio are significantly affected by different temperatures. The operating temperature of the pump has been reduced from 65 °C to 25 °C, the pumping speed is increased by approximately 5.97%, the gas compression power is increased by approximately 4.32%, and the energy efficiency ratio is increased by approximately 1.745%. This research provides a transient simulation method using dynamic mesh technology for the study of the dry scroll vacuum pump, and the results can provide a theoretical basis for the design and application of the cooling system of the dry scroll vacuum pump.

Abstract Background This case report presents a patient diagnosed with sick sinus syndrome who was successfully treated with permanent His-bundle pacing (PHBP). Case presentation A 36-year-old man was transferred to our hospital due to recurrent syncope. He was diagnosed with sick sinus syndrome based on the 24-h Holter and a history of syncope. He was admitted to hospital and successfully treated with PHBP. The postoperative examination showed that the pacing rhythm, pacemaker pacing and perception function were normal. He was discharged without any complications after a successful pacemaker implantation. Conclusions We described a case in which PHBP may become an optimal approach to the management of patients with sick sinus syndrome. Right ventricular pacing has been attempted with inconsistent efficacy outcomes. HBP provides a promising alternative pacing option that might provide symptom resolution to patients with sick sinus syndrome.

Abstract Background Travel restrictions amidst the COVID-19 pandemic reshaped interviewing for fellowships into a predominantly virtual process. How this impacts Obstetrics and Gynecology (OB/GYN) resident approaches to fellowship application and Match navigation is largely unknown. Methods We performed a cross-sectional survey study of fourth year OB/GYN residents in the United States who participated in at least one virtual fellowship interview in 2020. We collected information regarding demographics, application strategy, perceived strengths and weaknesses of virtual interviews, and confidence with rank list creation. Descriptive statistics were used for categorical variables and responses pre- and post-Match were compared using Fisher’s exact test. Results Seventy-five out of an estimated 490 applicants (~ 15% response rate) completed the survey. Of the respondents, 65.3% felt they interviewed at more programs virtually than they would anticipate completing in person, but perceived less confidence in having the necessary information (n = 45, 60%) or understanding the culture of programs (n = 59, 78.7%) to create a rank list. Cost savings were the main benefit of virtual interviews (n = 50, 66.7%), and inability to get a true “feel” for a program was the biggest limitation (n = 43, 57.3%). A majority (46.7%) advocate for a future hybrid interview process. Conclusions OB/GYN residents pursuing fellowship reported interviewing at more programs during the virtual season, but had less confidence with rank list creation. Cost savings benefits are weighed against difficulty getting a “feel” for programs virtually. Most would advocate for a future hybrid interview process.

BackgroundConsidered a significant risk to health and survival, type 1 diabetes (T1D) is a heterogeneous autoimmune disease characterized by hyperglycemia caused by an absolute deficiency of insulin, which is mainly due to the immune-mediated destruction of pancreatic beta cells.Scope of reviewIn recent years, the role of immune checkpoints in the treatment of cancer has been increasingly recognized, but unfortunately, little attention has been paid to the significant role they play both in the development of secondary diabetes with immune checkpoint inhibitors and the treatment of T1D, such as cytotoxic T-lymphocyte antigen 4(CTLA-4), programmed cell death protein-1(PD-1), lymphocyte activation gene-3(LAG-3), programmed death ligand-1(PD-L1), and T-cell immunoglobulin mucin protein-3(TIM-3). Here, this review summarizes recent research on the role and mechanisms of diverse immune checkpoint molecules in mediating the development of T1D and their potential and theoretical basis for the prevention and treatment of diabetes.Major conclusionsImmune checkpoint inhibitors related diabetes, similar to T1D, are severe endocrine toxicity induced with immune checkpoint inhibitors. Interestingly, numerous treatment measures show excellent efficacy for T1D via regulating diverse immune checkpoint molecules, including co-inhibitory and co-stimulatory molecules. Thus, targeting immune checkpoint molecules may exhibit potential for T1D treatment and improve clinical outcomes.

Abstract Background This study was sought to report the prevalence of malnutrition in elderly patients with cancer. Validate the predictive value of the nutritional assessment tool (Patient-Generated Subjective Global Assessment Short Form, PG-SGA SF) for clinical outcomes and assist the therapeutic decision. Methods This is a secondary analysis of a multicentric, observational cohort study. Elderly patients with cancer older than 65 years were enrolled after the first admission. Nutritional status was identified using the PG-SGA SF. Results Of the 2724 elderly patients included in the analysis, 65.27% of patients were male (n = 1778); the mean age was 71.00 ± 5.36 years. 31.5% of patients were considered malnourished according to PG-SGA SF. In multivariate analysis, malnutrition(PG-SGA SF > 5) was significantly associated with worse OS (HR: 1.47,95%CI:1.29–1.68), affects the quality of life, and was related to more frequent nutrition impact symptoms. During a median follow-up of 4.5 years, 1176 death occurred. The mortality risk was 41.10% for malnutrition during the first 12 months and led to a rate of 323.98 events per-1000-patient-years. All nutritional assessment tools were correlated with each other (PG-SGA SF vs. PG-SGA: r = 0.98; PG-SGA SF vs. GLIM[Global Leadership Initiative on Malnutrition]: r = 0.48, all P

Abstract Background Although systemic inflammation is an important feature of the cancer cachexia, studies on the association between systemic inflammation and prognostic of cancer cachexia are limited. The objective of this study is to evaluate whether the neutrophil‐to‐lymphocyte ratio (NLR) is associated with outcome and quality of life for patients with cancer cachexia and investigated any interaction between NLR and the clinical parameters. Methods This is a multicentre cohort study of 2612 cancer patients suffering from cachexia diagnosed between June 2012 and December 2019. The main parameters measured were overall survival (OS) time and all‐cause mortality. The association between NLR and all‐cause mortality was evaluated using hazard ratios (HRs) and the restricted cubic spline model with a two‐sided P‐value. Optimal stratification was used to solve threshold points. We also evaluated the cross‐classification of NLR for each variable of survival. Results Of the 2612 participants diagnosed with cancer cachexia, 1533 (58.7%) were male, and the mean (SD) age was 58.7 (11.7) years. Over a median follow‐up of 4.5 years, we observed 1189 deaths. The overall mortality rate for patients with cancer cachexia during the first 12 months was 30.2% (95%CI: 28.4%–32.0%), resulting in a rate of 226.07 events per 1000 patient‐years. An increase in NLR had an inverted L‐shaped dose–response association with all‐cause mortality. The optimal cut‐off point for NLR as a predictor of mortality in cancer patients with cachexia was 3.5. An NLR of 3.5 or greater could independently predict OS (HR, 1.51, 95%CI: 1.33–1.71). These associations were consistent across subtypes of cancer. Several potential effect modifiers were identified including gender, BMI, tumour type, KPS score and albumin in content. Increasing NLRs were independently associated with a worsening in the majority of EORTC QLQ‐C30 domains. Elevated baseline NLR was associated with low response and poor survival in patients treated with immunotherapy. Conclusions The baseline NLR status was found to be a significant negative prognostic biomarker for patients with cachexia; this effect was independent of other known prognostic factors.

Objectives: Shigella flexneri (S. flexneri) is prevalent worldwide and the most common Shigella in many countries, causing highly contagious diarrhea, which seriously threatens public health. This study aimed to develop a colorimetric loop-mediated isothermal amplification (LAMP) for the rapid, accurate, and visualization detection of S. flexneri. Methods: According to the screened specific genes of S. flexneri, three groups of LAMP primers were designed and evaluated, and the colorimetric LAMP reaction volume was optimized. The specificity of the colorimetric LAMP was validated by 20 S. flexneri and 96 non-S. flexneri clinical isolates. In addition, the sensitivity of the developed assay was evaluated by the serial 10-fold dilutions of plasmid DNA. Results: A colorimetric LAMP assay was developed based on the specific S. flexneri hypothetical protein gene (Accession: AE014073 Region: 4170556.4171068). The colorimetric LAMP method had good specificity for detecting S. flexneri and enabled detection of S. flexneri within 30 minutes, with a plasmid detection limit of 7*10° copies/μL. The results of amplification could be easily identified by color. Conclusions: This colorimetric LAMP assay could be used for rapid and accurate diagnosis of S. flexneri infection, especially in remote hospitals and laboratories with under-equipped medical facilities, and in situations where an urgent diagnosis is needed.

Arthritis is a group of highly prevalent joint disorders, and osteoarthritis (OA) and rheumatoid arthritis are the two most common types. The high prevalence of arthritis causes severe burdens on individuals, society and the economy. Currently, the primary treatment of arthritis is to relieve symptoms, but the development of arthritis cannot be effectively prevented. Studies have revealed that the disrupted balance of enzymes determines the pathological changes in arthritis. In particular, the increased levels of matrix metalloproteinases and the decreased expression of endogenous antioxidant enzymes promote the progression of arthritis. New therapeutic strategies have been developed based on the expression characteristics of these enzymes. Biomaterials have been designed that are responsive when the destructive enzymes MMPs are increased or have the activities of the antioxidant enzymes that play a protective role in arthritis. Here, we summarize recent studies on biomaterials associated with MMPs and antioxidant enzymes involved in the pathological process of arthritis. These enzyme-related biomaterials have been shown to be beneficial for arthritis treatment, but there are still some problems that need to be solved to improve efficacy, especially penetrating the deeper layer of articular cartilage and targeting osteoclasts in subchondral bone. In conclusion, enzyme-related nano-therapy is challenging and promising for arthritis treatment.

Abstract Background Capillary leak syndrome (CLS) is a rare disease characterized by profound vascular leakage and presents as a classic triad of hypotension, hypoalbuminemia and hemoconcentration. Severe CLS is mostly induced by sepsis and generally life-threatening in newborns, especially in premature infants. Continuous renal replacement therapy (CRRT) plays an important role of supportive treatment for severe CLS. Unfortunately, CRRT in preterm infants has rarely been well defined. Case presentation We report the case of a 11-day-old girl with CLS caused by sepsis, who was delivered by spontaneous vaginal delivery (SVD) at gestational age of 25 weeks and 4 days, and a birth weight of 0.89 Kilograms(kg). The infant received powerful management consisting of united antibiotics, mechanical ventilation, intravenous albumin and hydroxyethyl starch infusion, vasoactive agents, small doses of glucocorticoids and other supportive treatments. However, the condition rapidly worsened with systemic edema, hypotension, pulmonary exudation, hypoxemia and anuria in about 40 h. Finally, we made great efforts to perform CRRT for her. Fortunately, the condition improved after 82 h’ CRRT, and the newborn was rescued and gradually recovered. Conclusion CRRT is an effective rescue therapeutic option for severe CLS and can be successfully applied even in extremely-low-birth-weight premature.

Hexavalent chromium Cr(VI) is a well-known environmental toxic metal that causes reprotoxicity in pregnant females. There are currently no appropriate interventions or treatments for Cr(VI) exposure during pregnancy. Herein, the protective effect of melatonin (MLT) against Cr(VI)-induced reprotoxicity is investigated by administrating MLT to pregnant mice exposed to Cr(VI). The results indicate that MLT effectively alleviates Cr(VI)-induced adverse pregnancy outcomes, restoring the decreased fetal weight and increased fetal resorption and malformation caused by Cr(VI) exposure to normal levels. MLT reduces the negative effects of Cr(VI) on follicular atresia and the development of primordial follicle in the maternal ovarian, thereby mitigating the decline in the reserve of primordial follicles. MLT alleviates Cr(VI)-induced oxidative stress, hence reducing the excessive accumulation of malondialdehyde in the maternal ovary. MLT inhibits Cr(VI)-induced apoptosis of ovarian granulosa cells and the expression of cleaved caspase-3 in the ovary. MLT reduces the increase in serum follicle-stimulating hormone caused by Cr(VI) exposure, while elevating anti-Mullerian hormone levels. We demonstrate that MLT reverses Cr(VI)-induced reprotoxicity in pregnant mice, opening up a new avenue for treating reproductive defects caused by environmental stress.

Introduction: Epigenetic-targeted therapy has been increasingly applied in the treatment of cancers. Lysine (K)-specific demethylase 6B (KDM6B) is an epigenetic enzyme involved in the coordinated control between cellular intrinsic regulators and the tissue microenvironment whereas the pan-cancer analysis of KDM6B remains unavailable.Methods: The dual role of KDM6B in 33 cancers was investigated based on the GEO (Gene Expression Omnibus) and TCGA (The Cancer Genome Atlas) databases. TIMER2 and GEPIA2 were applied to investigate the KDM6B levels in different subtypes or stages of tumors. Besides, the Human Protein Atlas database allowed us to conduct a pan-cancer study of the KDM6B protein levels. GEPIA2 and Kaplan–Meier plotter were used for the prognosis analysis in different cancers. Characterization of genetic modifications of the KDM6B gene was analyzed by the cBioPortal. DNA methylation levels of different KDM6B probes in different TCGA tumors were analyzed by MEXPRESS. TIMER2 was applied to determine the association of the KDM6B expression and immune infiltration and DNA methyltransferases. Spearman correlation analysis was used to assess the association of the KDM6B expression with TMB (tumor mutation burden) and MSI (microsatellite instability). The KEGG (Kyoto encyclopedia of genes and genomes) pathway analysis and GO (Gene ontology) enrichment analysis were used to further investigate the potential mechanism of KDM6B in tumor pathophysiology.Results: KDM6B was downregulated in 11 cancer types and upregulated across five types. In KIRC (kidney renal clear cell carcinoma) and OV (ovarian serous cystadenocarcinoma), the KDM6B level was significantly associated with the pathological stage. A high level of KDM6B was related to poor OS (overall survival) outcomes for THCA (thyroid carcinoma), while a low level was correlated with poor OS and DFS (disease-free survival) prognosis of KIRC. The KDM6B expression level was associated with TMB, MSI, and immune cell infiltration, particularly cancer-associated fibroblasts, across various cancer types with different correlations. Furthermore, the enrichment analysis revealed the relationship between H3K4 and H3K27 methylation and KDM6B function.Conclusion: Dysregulation of the DNA methyltransferase activity and methylation levels of H3K4 and H3K27 may involve in the dual role of KDM6B in tumorigenesis and development. Our study offered a relatively comprehensive understanding of KDM6B’s dual role in cancer development and response to immunotherapy.

Abstract Background While the perforation of the atrial wall and aortic sinus after closure of an atrial septal defect (ASD) is rare, it’s life-threatening, with rapid progress and high mortality. To the best of our knowledge, 21 similar cases have been reported since 1976. Case presentation We report a 16-year-old male whose atrial septal defect (ASD) was closed using a 12-mm Amplatzer septal occluder (ASO). Atrial wall and aortic sinus perforation occurred 3 months after transcatheter closure, and the patient was discharged after emergency operation. He was discharged on the 12th postoperative day in good overall condition. Conclusions With this case report, we want to illustrate that although percutaneous closure of ASD is regarded as a routine procedure, we should not forget the potentially lethal complications, especially cardiac erosion. Therefore, we should carefully evaluate the risk of erosion before surgery, and careful lifelong follow-up is needed.

This study delves into the pivotal role of the gut microbiota and the brain-gut axis in Parkinson’s Disease (PD), a neurodegenerative disorder with significant motor and non-motor implications. It posits that disruptions in gut microbiota—dysbiosis—and alterations in the brain-gut axis contribute to PD’s pathogenesis. Our findings highlight the potential of the gastrointestinal system’s early involvement in PD, suggested by the precedence of gastrointestinal symptoms before motor symptoms emerge. This observation implies a possible gut-originated disease pathway. The analysis demonstrates that dysbiosis in PD patients leads to increased intestinal permeability and systemic inflammation, which in turn exacerbates neuroinflammation and neurodegeneration. Such insights into the interaction between gut microbiota and the brain-gut axis not only elucidate PD’s underlying mechanisms but also pave the way for novel therapeutic interventions. We propose targeted treatment strategies, including dietary modifications and fecal microbiota transplantation, aimed at modulating the gut microbiota. These approaches hold promise for augmenting current PD treatment modalities by alleviating both motor and non-motor symptoms, thereby potentially improving patient quality of life. This research underscores the significance of the gut microbiota in the progression and treatment of PD, advocating for an integrated, multidisciplinary approach to develop personalized, efficacious management strategies for PD patients, combining insights from neurology, microbiology, and nutritional science. [ABSTRACT FROM AUTHOR]

Background: While cerebral infarction in children is rare, its prognosis is poor, and this condition can seriously burden society and families. A correlation between patent foramen ovale (PFO) and ischemic stroke has not been found in pediatric patients. Case presentation: We report a 7-year-old boy who suffered from multiple cerebral infarctions. Subsequently, the patient was diagnosed with an abnormal shunt of PFO. He underwent PFO closure and was followed up for 1 year. The patient did not experience any further cerebral infarction. Conclusions: With this case report, we want to illustrate that although the incidence rate of ischemic cerebral infarction in adolescents is very low, we should not neglect the role of PFO. Therefore, after exclusion other causes of cerebral infarction, PFO should be considered in adolescent and adult stroke patients with adult closure criteria in the same way. [ABSTRACT FROM AUTHOR]

Abstract. Background:. Liver fibrosis (LF) continues to develop and eventually progresses to cirrhosis. However, LF and early-stage cirrhosis (ESC) can be reversed in some cases, while advanced cirrhosis is almost impossible to cure. Advances in quantitative imaging techniques have made it possible to replace the gold standard biopsy method with non-invasive imaging, such as radiomics. Therefore, the purpose of this study is to develop a radiomics model to identify LF and ESC. Methods:. Patients with LF (n = 108) and ESC (n = 116) were enrolled in this study. As a control, patients with healthy livers were involved in the study (n = 145). Diffusion-weighted imaging (DWI) data sets with three b-values (0, 400, and 800 s/mm2) of enrolled cases were collected in this study. Then, radiomics features were extracted from manually delineated volumes of interest. Two modeling strategies were performed after univariate analysis and feature selection. Finally, an optimal model was determined by the receiver operating characteristic area under the curve (AUC). Results:. The optimal models were built in plan 1. For model 1 in plan 1, the AUCs of the training and validation cohorts were 0.973 (95% confidence interval [CI] 0.946–1.000) and 0.948 (95% CI 0.903–0.993), respectively. For model 2 in plan 1, the AUCs of the training and validation cohorts were 0.944, 95% CI 0.905 to 0.983, and 0.968, 95% CI 0.940 to 0.996, respectively. Conclusions:. Radiomics analysis of DWI images allows for accurate identification of LF and ESC, and the non-invasive biomarkers extracted from the functional DWI images can serve as a better alternative to biopsy.

Shigella flexneri is a serious threat to global public health, and a rapid detection method is urgently needed. The CRISPR/Cas (clustered regularly interspaced short palindromic repeats/CRISPR-associated) system is widely used in gene editing, gene therapy, and in vitro diagnosis. Here, we combined loop-mediated isothermal amplification (LAMP) and CRISPR/Cas12a to develop a novel diagnostic test (CRISPR/Cas12a-E-LAMP) for the diagnosis of S. flexneri. The CRISPR/Cas12a-E-LAMP protocol conducts LAMP reaction for S. flexneri templates followed by CRISPR/Cas12a detection of predefined target sequences. LAMP primers and sgRNAs were designed to the highly conserved gene hypothetical protein (accession: AE014073, region: 4170556–4171,068) of S. flexneri. After the LAMP reaction at 60°C for 20 min, the pre-loaded CRISPR/Cas12a regents were mixed with the LAMP products in one tube at 37°C for 20 min, and the final results can be viewed by naked eyes with a total time of 40 min. The sensitivity of CRISPR/Cas12a-E-LAMP to detect S. flexneri was 4 × 100 copies/μl plasmids and without cross-reaction with other six closely related non-S. flexneri. Therefore, the CRISPR/Cas12a-E-LAMP assay is a useful method for the reliable and quick diagnosis of S. flexneri and may be applied in other pathogen infection detection.

Abstract Brucellosis is a neglected zoonosis. It causes acute febrile illness and a potentially debilitating chronic infection in humans, and livestock infection has substantial socioeconomic impact. Over the past two decades, improvements have been made to better understand the various aspects of human and animal brucellosis. Meanwhile, especially in the developing world, immense challenges that remain in controlling and eradicating brucellosis are novel diagnostics tools and efficacious vaccines. Here, we will focus on the remarkable issues on epidemiological survey, as well as the priority and challenge of brucellosis in China. Brucellosis will be controlled with meaningful collaboration between local and public partnerships effectively applying a One Health framework.

Context Nephrolithiasis is a major public health problem worldwide and Fu-Fang-Jin-Qian-Cao granules (FFJQC) is a traditional Chinese herbal formula that is used to treat nephrolithiasis. The main component of nephrolithiasis is calcium oxalate (CaOx) and the epithelial-mesenchymal transition (EMT) shown to play a crucial role in CaOx-induced kidney injury. However, the mechanism underlying the therapeutic effect of FFJQC on the CaOx-induced renal EMT is unknown. Objective This study explores the therapeutic benefits and mechanism of FFJQC in oxalate-induced kidney injury. Materials and methods 60 male C57BL/6 mice were used in this experiment and divided into 6 groups. A mouse kidney stone model was created by intraperitoneal injection of glyoxylate at a dose of 100 mg/kg for 6 days. The standardized FFJQC was used to treat mouse crystal kidney injury by gavage at 1.35 and 2.7 g/kg, respectively. Western blotting and immunostaining for E-cadherin, cytokeratin 18 (CK18), vimentin, smooth muscle α-actin (α-SMA) and transforming growth factor β (TGF-β)/Smad pathway were conducted on renal tissues. Results Following CaOx-induced kidney injury, the levels of E-cadherin and CK18 in kidney decreased, while vimentin and α-SMA levels increased. The FFJQC treatment increased the levels of E-cadherin and CK18 and decreased vimentin and α-SMA levels in varying degrees. What’s more, the FFJQC reduced the expression of CaOx-induced fibrosis marker collagen II. Conclusion FFJQC alleviated the CaOx-induced renal EMT and fibrosis by regulating TGF-β/smad pathway. Therefore, the FFJQC is an important traditional Chinese medicine for the treatment of CaOx-induced renal injury and fibrosis.

Abstract Background Mesenchymal stem cell (MSC)-derived exosomes have been recognized as new candidate agents for treating critical-sized bone defects; they promote angiogenesis and may be an alternative to cell therapy. In this study, we evaluated whether exosomes derived from bone marrow-derived MSCs (BMSCs) preconditioned with a low dose of dimethyloxaloylglycine (DMOG), DMOG-MSC-Exos, exert superior proangiogenic activity in bone regeneration and the underlying mechanisms involved. Methods To investigate the effects of these exosomes, scratch wound healing, cell proliferation, and tube formation assays were performed in human umbilical vein endothelial cells (HUVECs). To test the effects in vivo, a critical-sized calvarial defect rat model was established. Eight weeks after the procedure, histological/histomorphometrical analysis was performed to measure bone regeneration, and micro-computerized tomography was used to measure bone regeneration and neovascularization. Results DMOG-MSC-Exos activated the AKT/mTOR pathway to stimulate angiogenesis in HUVECs. This contributed to bone regeneration and angiogenesis in the critical-sized calvarial defect rat model in vivo. Conclusions Low doses of DMOG trigger exosomes to exert enhanced proangiogenic activity in cell-free therapeutic applications.

Summary: CCR4-NOT deadenylase is a major regulator of mRNA turnover. It contains two heterogeneous catalytic subunits CNOT7/8 and CNOT6/6L in vertebrates. The physiological function of each catalytic subunit is unclear due to the gene redundancy. In this study, Cnot6/6l double knockout mice are generated. Cnot6l−/− female mice are infertile, with poor ovarian responses to gonadotropins. Follicle-stimulating hormone (FSH) stimulates the transcription and translation of Cnot6 and Cnot6l in ovarian granulosa cells. CNOT6/6L function as key effectors of FSH in granulosa cells and trigger the clearance of specific transcripts in granulosa cells during preantral to antral follicle transition. These results demonstrate that FSH modulates granulosa cell function by stimulating selective translational activation and degradation of existing mRNAs, in addition to inducing de novo gene transcription. Meanwhile, this study provides in vivo evidence that CNOT6/6L-mediated mRNA deadenylation is dispensable in most somatic cell types, but is essential for female reproductive endocrine regulation.

Background: Colorectal cancers (CRCs) continue to be the leading cause of cancer-related deaths worldwide. The exact landscape of the molecular features of TGF-β pathway-inducing CRCs remains uncharacterized. Methods: Unsupervised hierarchical clustering was performed to stratify samples into two clusters based on the differences in TGF-β pathways. Weighted gene co-expression network analysis was applied to identify the key gene modules mediating the different characteristics between two subtypes. An algorithm integrating the least absolute shrinkage and selection operator (LASSO), XGBoost, and random forest regression was performed to narrow down the candidate genes. Further bioinformatic analyses were performed focusing on COMP-related immune infiltration and functions. Results: The integrated machine learning algorithm identified COMP as the hub gene, which exhibited a significant predictive value for two subtypes with an area under the curve (AUC) value equaling 0.91. Further bioinformatic analysis revealed that COMP was significantly upregulated in various cancers, especially in advanced CRCs, and regulated the immune infiltration, especially M2 macrophages and cancer-associated fibroblasts in CRCs. Conclusions: Comprehensive immune analysis and experimental validation demonstrate that COMP is a reliable signature for subtype prediction. Our results could provide a new point for TGFβ-targeted anticancer drugs and contribute to guiding clinical decision making for CRC patients.

Background: Malnutrition is common in patients with cancer and is associated with adverse outcomes, but few data exist in elderly patients. The aim of this study was to report the prevalence of malnutrition using three different scoring systems and to examine the possible clinical relationship and prognostic consequence of malnutrition in elderly patients with cancer.Methods: Nutritional status was assessed by using controlling nutritional status (CONUT), the prognostic nutritional index (PNI), and the nutritional risk index (NRI). Quality-of-life (Qol) was assessed during admission by using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C-30. Performance status (PS) was assessed by using the Eastern Cooperative Oncology Group (ECOG) classification. The relationship between nutritional status and overall survival and Qol were examined.Results: Data were available for 1,494 elderly patients with cancer (63.65% male), the mean age was 70.76 years. According to the CONUT, NRI, and PNI, 55.02, 58.70, and 11.65% patients were diagnosed with malnutrition, respectively. Worse nutritional status was related to older, lower BMI, lower hand grip strength, and more advanced tumor stage. All malnutrition indexes were correlated with each other (CONUT vs. PNI, r = −0.657; CONUT vs. NRI scores, r = −0.672; PNI vs. NRI scores, r = 0.716, all P < 0.001). During a median follow-up of 43.1 months, 692 (46.32%) patients died. For patients malnourished, the incidence rate (events-per-1,000person-years) was as follows: CONUT (254.18), PNI (429.91), and NRI (261.87). Malnutrition was associated with increased risk for all-cause mortality (adjust HR [95%CI] for CONUT: 1.09 [1.05–1.13], P < 0.001; PNI: 0.98[0.97–0.99], P < 0.001; NRI: 0.98 [0.98–0.99], P < 0.001). All malnutrition indexes improved the predictive ability of the TNM classification system for all-cause mortality. Deterioration of nutritional status was associated with deterioration in Qol parameters and immunotherapeutic response (P < 0.001).Conclusions: Malnutrition was prevalent in elderly patients with cancer, regardless of the assessment tools used, and associated with lower Qol and the immunotherapy response.

Exosomes are membranous structures secreted by nearly all cell types. As critical messengers for intercellular communication, exosomes deliver bioactive cargoes to recipient cells and are involved in multiple physiopathological processes, including immunoregulation. Our pioneering study revealed that cancer cells release programmed death-ligand 1-positive exosomes into the circulation to counter antitumor immunity systemically via T cells. Tumor cell-derived exosomes (TDEs) also play an immunosuppressive role in other immunocytes, including dendritic cells (DCs), macrophages, natural killer (NK) cells, and myeloid-derived suppressor cells (MDSCs). Moreover, exosomes secreted by nontumor cells in the tumor microenvironments (TMEs) also exert immunosuppressive effects. This review systematically provides a summary of the immunosuppression induced by exosomes in tumor microenvironments, which modulates tumor growth, invasion, metastasis, and immunotherapeutic resistance. Additionally, therapeutic strategies targeting the molecular mechanism of exosome-mediated tumor development, which may help overcome several obstacles, such as immune tolerance in oncotherapy, are also discussed. Detailed knowledge of the specific functions of exosomes in antitumor immunity may contribute to the development of innovative treatments.

In patients with chronic kidney disease, the abnormal activation of inflammatory pathways is usually an important factor leading to renal fibrosis and further deterioration of renal function. Finding effective intervention targets of the inflammatory signaling pathway is an important way to treat chronic kidney disease. As a newly discovered lysosomal membrane protein, the correlation between SID1 transmembrane family member 2 (Sidt2) and the inflammatory signaling pathway has not been reported. The aim of this study was to investigate the effect of Sidt2 on inflammation by inhibiting the expression of the Sidt2 gene in a mouse mesangial cell line mediated by a lentiviral CRISPR/Cas9 vector. Hematoxylin and eosin staining and microscopy found that the mesangial cells lost their normal morphology after inhibiting the expression of Sidt2, showing that the cell body became smaller, the edge between the cells was unclear, and part of the nucleus was pyknotic and fragmented, appearing blue-black. The expressions of IKK β, p-IKK α/β, NF-κB p65, p-NF-κB p65, p-IκBα, IκBα, and TNF-α in the NF-κB pathway of the Sidt2-/- group were higher than those of the Sidt2+/+ group. p-Jak2 and IL6 increased in the Jak/Stat pathway, and p-ERK and p-P38 increased in the MAPK pathway. The expressions of IKK β, p-IKK α/β, NF-κB p65, p-NF-κB p65, p-IκBα, IκBα, and TNF-α in the NF-κB pathway of the Sidt2+/++LPS group were significantly higher than those in the Sidt2+/+ group. The expressions of IKK β, p-IKK α/β, NF-κB p65, p-NF-κB p65, p-IκBα, IκBα, and TNF-α in the Sidt2-/-+LPS group were higher than those in the Sidt2-/- group. The expressions of p-IKK α/β, NF-κB p65, p-NF-κB p65, p-IκBα, IκBα, and TNF-α in the Sidt2-/-+LPS group were higher than those in the Sidt2+/++LPS group. In the Jak/Stat pathway, the protein expressions of p-Jak2 and IL6 in the Sidt2+/++LPS group were higher than those in the Sidt2+/+ group. The expressions of p-Jak2 and IL6 in the Sidt2-/-+LPS group were higher than those in the Sidt2-/- group. The expressions of p-Jak2 and IL6 in the Sidt2-/-+LPS group were higher than those in the Sidt2+/++LPS group. The expressions of p-JNK, p-ERK, p-P38, and ERK in the MAPK pathway in the Sidt2+/++LPS group were higher than those in the Sidt2+/+ group. The expressions of p-JNK, p-ERK, p-P38, and ERK in the Sidt2-/-+LPS group were higher than those in the Sidt2-/- group. The expressions of p-JNK, p-ERK, p-P38, and ERK in the Sidt2-/-+LPS group were higher than those in the Sidt2+/++LPS group. These data suggested that deletion of the Sidt2 gene changed the three inflammatory signal pathways, eventually leading to the damage of glomerular mesangial cells in mice.

Background/Aims: Micro RNAs (miRNAs) play a very important role in myocardial ischemia/ reperfusion injury (MIRI), including in inflammation, apoptosis, and angiogenesis. Previous studies have demonstrated up-regulation of miR-327 in renal ischemia/reperfusion injury and MIRI. Via TargetScan, we found RP105 is a possible target gene of miR-327; our previous studies have also confirmed that RP105 acted as a cardioprotective protein in MIRI by reducing inflammation. However, the regulatory effect of miR-327 on RP105 has not previously been proposed. In our study, we aimed to identify the regulatory effect of miR-327 on RP105 protein in MIRI rats. Methods: Sixty male Sprague–Dawley rats were randomly divided into five groups, which were pre-treated with saline (sham and ischemia/reperfusion group), adenovirus-expressing miR-327-RNAi (Ad-miR-327-i group), control (Ad-NC group), or pri-miR-327 (Ad-miR-327 group) treatments. Three days later, the rat MIRI model was established by ischemia for 30 min, followed by reperfusion for 3 h. Myocardium and plasma were harvested and assessed. Results: miR-327 was increased by nearly 3-fold both in myocardium and plasma, which down-regulated RP105 in a 3′-untranslated region-dependent manner, and down-regulation of miR-327 via adenovirus transfection indirectly suppressed the TLR4/ TLR2-MyD88-NF-κB signaling axis activation via up-regulation of RP105, which subsequently resulted in reduced myocardial infarct size, attenuated cardiomyocyte destruction, and alleviated inflammation. In contrast, up-regulation of miR-327 induced the opposite effect. Conclusion: Down-regulation of miR-327 exerts a cardioprotective effect against MIRI by reducing inflammation, which may constitute a promising molecular therapeutic target for treating MIRI.

Background/Aims: Extensive osteoclast formation plays a critical role in bone diseases, including rheumatoid arthritis, periodontitis and the aseptic loosening of orthopedic implants. Thus, identification of agents that can suppress osteoclast formation and bone resorption is important for the treatment of these diseases. Monocrotaline (Mon), the major bioactive component of crotalaria sessiliflora has been investigated for its anti-cancer activities. However, the effect of Mon on osteoclast formation and osteolysis is not known. Methods: The bone marrow macrophages (BMMs) were cultured with M-CSF and RANKL followed by Mon treatment. Then the effects of Mon on osteoclast differentiation were evaluated by counting TRAP (+) multinucleated cells. Moreover, effects of Mon on hydroxyapatite resorption activity of mature osteoclast were studied through resorption areas measurement. The involved potential signaling pathways were analyzed by performed Western blotting and quantitative real-time PCR examination. Further, we established a mouse calvarial osteolysis model to measure the osteolysis suppressing effect of Mon in vivo. Results: In this study, we show that Mon can inhibit RANKL-induced osteoclast formation and function in a dose-dependent manner. Mon inhibits the expression of osteoclast marker genes such as tartrate-resistant acid phosphatase (TRAP) and cathepsin K. Furthermore, Mon inhibits RANKL-induced the activation of p38 and JNK. Consistent with in vitro results, Mon exhibits protective effects in an in vivo mouse model of LPS-induced calvarial osteolysis. Conclusion: Taken together our data demonstrate that Mon may be a potential prophylactic anti-osteoclastic agent for the treatment of osteolytic diseases caused by excessive osteoclast formation and function.

Objective: To investigate FAM20A gene variants and histological features of amelogenesis imperfecta and to further explore the functional impact of these variants. Methods: Whole-exome sequencing (WES) and Sanger sequencing were used to identify pathogenic gene variants in three Chinese families with amelogenesis imperfecta. Bioinformatics analysis, in vitro histological examinations and experiments were conducted to study the functional impact of gene variants, and the histological features of enamel, keratinised oral mucosa and dental follicle. Results: The authors identified two nonsense variants c. 406C > T (p.Arg136*) and c.826C > T (p.Arg176*) in a compound heterozygous state in family 1, two novel frameshift variants c.936dupC (p.Val313Argfs*67) and c.1483dupC (p.Leu495Profs*44) in a compound heterozygous state in family 2, and a novel homozygous frameshift variant c.530_531insGGTC (p.Ser178Valfs*21) in family 3. The enamel structure was abnormal, and psammomatoid calcifications were identified in both the gingival mucosa and dental follicle. The bioinformatics and subcellular localisation analyses indicated these variants to be pathogenic. The secondary and tertiary structure analysis speculated that these five variants would cause structural damage to FAM20A protein. Conclusion: The present results broaden the variant spectrum and clinical and histological findings of diseases associated with FAM20A, and provide useful information for future genetic counselling and functional investigation. [ABSTRACT FROM AUTHOR]

Background/Aims: Oxidative stress is strongly implicated in the pathogenesis of myocardial damage caused by ischemia reperfusion (I/R). Previous studies have confirmed that cardiac CD47 drives left ventricular heart failure. However, the role for CD47 in myocardial I/R injury (MIRI) has not previously been proposed. This study was designed to investigate whether down-regulation of CD47 using RNA interference (RNAi) technology can relieve inhibition of nitric oxide signaling and attenuate myocardial damage in a rat model of I/R. Methods: Male Sprague-Dawley rats (n = 40) were randomly allocated to four groups and pre-treated either with saline (Sham and I/R groups), or adenovirus expressing either control (Ad-EGFP-N) or CD47-targeting (Ad-EGFP-CD47) RNAi. After four days, the rat MIRI model was established by occluding the left anterior descending coronary artery for 30 min, followed by reperfusion for 3 h. Heart tissue was harvested and assessed by immunohistochemistry, western blot, and quantitative RT-PCR. Outcome measures included infarct size, myocardial enzyme (creatine kinase, creatine kinase-MB, and lactate dehydrogenase) levels in serum, markers of oxidative stress, and morphological changes to the myocardium. Results: Delivery of Ad-EGFP-CD47 RNAi into the myocardium remarkably decreased CD47 expression levels. Down-regulation of CD47 was significantly associated with reduced infarct size and serum levels of myocardial enzymes, increased activity of endothelial nitric oxide synthase, increased levels of nitric oxide, and decreased levels of oxidative stress. Conclusion: These data indicate that down-regulation of CD47 exerts a protective effect against MIRI, which may be attributable to attenuation of oxidative stress via activation of the eNOS/NO signaling pathway.

The gut microbiota of amphibians is affected by exogenous and endogenous factors. We performed a comprehensive analysis using high-throughput sequencing technology and functional predictions and observed general changes in the gut microbiota of frogs in different growth stages, seasons, and growth environments. There were no significant differences in microbial richness and diversity between juvenile and adult wild frogs, between the summer and autumn groups of captive frogs, or between wild and captive frogs. There were significant differences in the gut microbiota community structure of Rana dybowskii between the summer and autumn groups of captive frogs and between wild and captive R. dybowskii, whereas the differences between juvenile and adult wild frogs were not significant. The dominant gut bacterial phyla in frogs from both captive and wild environments included Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria. Linear discriminant effect size (LEfSe) analysis showed that Bacteroidetes and Firmicutes were significantly enriched in captive and wild R. dybowskii, respectively linear discriminant analysis (LDA > 4). The core operational taxonomical units (OTUs) that were found in >90% of all frogs tested encompassed 15 core OTUs. The captive frogs exhibited 15 core OTUs in addition to the above overall core microbiota, whereas the wild frogs exhibited 19 core OTUs in addition to the above overall core microbiota. Predictions made using Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) suggested that eleven KEGG pathways, such as infectious diseases, immune system diseases, metabolism, metabolism of other amino acids, metabolism of cofactors and vitamins, metabolism of terpenoids and polyketides, neurodegenerative diseases, and transport and catabolism, were enriched in captive frogs. The relative abundance of several red-leg-syndrome-related pathogens increased significantly in captive frogs compared with that in wild frogs. To our knowledge, this is the first study on the effects of individual seasons and captivity on the gut microbiota of frogs.