Application of Organoids in Regenerative Medicine.

Regenerative medicine mainly relies on heterologous transplantation, often hindered by sample availability and ethical issues. Furthermore, patients are required to take immunosuppressive medications to prevent adverse side effects. Stem cell-derived 3D-organoid culture has provided new alternatives for transplantation and regenerative medicine. Scholars have combined organoids with tissue engineering technology to improve reproducibility, the accuracy of constitution and throughput, and genetic correction to achieve a more personalized therapy. Here, we review the available applications of organoids in regenerative medicine and the current challenges concerning this field.

Association among abnormal glycolipids, reproductive hormones, and cognitive dysfunction in female patients with bipolar disorder.

BACKGROUND: Patients with bipolar disorder (BD) show abnormalities in glucolipid metabolism and reproductive hormone levels, which are of concern in women with BD. This study was dedicated to investigating the glucolipid and reproductive hormone levels of female patients, and to preliminarily investigating their relationships with cognition. METHODS: A total of 58 unmedicated female BD patients, 61 stable-medicated female BD patients, and 63 healthy controls (HC) were recruited in this study. Serum glycolipid indexes and reproductive hormones were measured. Cognitive function was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the Stroop Color-Word Test (Stroop test). RESULTS: Patients with BD showed significant cognitive impairment (p < 0.05), which was not affected by medication. Triglycerides (TG), luteinizing hormone (LH), and high-density lipoprotein cholesterol (HDL-c) were altered in stable-medicated BD patients. In addition, regression analysis showed that progesterone (PRGE) and prolactin (PRL) were negatively associated with cognitive performance in stable-medicated BD patients. CONCLUSIONS: Female BD patients may have cognitive deficits and abnormal levels of glycolipids and reproductive hormones. And abnormal levels of glycolipids and reproductive hormones may be associated with cognitive dysfunction in female BD patients.

Association of metabolically healthy obesity in young adulthood with myocardial structure and function.

BACKGROUND: Obesity is major cause of cardiovascular diseases. Metabolically healthy obesity (MHO) may increase heart failure risk early in life, and may be reflected in impaired cardiac structure and function. Therefore, we aimed to examine the relationship between MHO in young adulthood and cardiac structure and function. METHODS: A total of 3066 participants from the Coronary Artery Risk Development in Young Adults (CARDIA) study were included, who completed echocardiography in young adulthood and middle age. The participants were grouped by obesity status (body mass index ≥30 kg/m2) and poor metabolic health (≥2 criteria for metabolic syndrome) into four metabolic phenotypes as follows: metabolically healthy non-obesity (MHN), MHO, metabolically unhealthy non-obesity (MUN), metabolically unhealthy obesity (MUO). The associations of the metabolic phenotypes (MHN serving as the reference) with left ventricular (LV) structure and function were evaluated using multiple linear regression models. RESULTS: At baseline, mean age was 25 years, 56.4% were women, and 44.7% were black. After a follow-up 25 years, MUN in young adulthood was associated with worse LV diastolic function (E/é ratio, ß [95% CI], 0.73 [0.18, 1.28]), worse systolic function (global longitudinal strain [GLS], 0.60 [0.08, 1.12]) in comparison with MHN. MHO and MUO were associated with LV hypertrophy (LV mass index, 7.49 g/m2 [4.63, 10.35]; 18.23 g/m2 [12.47, 23.99], respectively), worse diastolic function (E/é ratio, 0.67 [0.31, 1.02]; 1.47 [0.79, 2.14], respectively), and worse systolic function (GLS, 0.72 [0.38, 1.06]; 1.35 [0.64, 2.05], respectively) in comparison with MHN. These results were consistent in several sensitivity analyses. CONCLUSIONS: In this community-based cohort using data from the CARDIA study, obesity in young adulthood was significantly associated with LV hypertrophy, worse systolic and diastolic function regardless of metabolic status. Relationship of Baseline Metabolic Phenotypes with Young Adulthood and Midlife Cardiac Structure and Function. Adjusted for year 0 covariates: age, sex, race, educational level, smoking status, drinking status, and physical activity; metabolically healthy non-obesity was used as a reference category for comparison. † Criteria for metabolic syndrome are listed in Supplementary Table S6. MUN metabolically unhealthy non-obesity, MHO metabolically healthy obesity, LVMi left ventricular mass index, LVEF left ventricular ejection fraction, E/A early to late peak diastolic mitral flow velocity ratio, E/é mitral inflow velocity to early diastolic mitral annular velocity, CI confidence interval.

Exosomal Mir-3613-3p derived from oxygen-glucose deprivation-treated brain microvascular endothelial cell promotes microglial M1 polarization.

BACKGROUND: Brain microvascular endothelial cell (BMEC) injury can affect neuronal survival by modulating immune responses through the microenvironment. Exosomes are important vehicles of transport between cells. However, the regulation of the subtypes of microglia by BMECs through the exosome transport of microRNAs (miRNAs) has not been established. METHODS: In this study, exosomes from normal and oxygen-glucose deprivation (OGD)-cultured BMECs were collected, and differentially expressed miRNAs were analyzed. BMEC proliferation, migration, and tube formation were analyzed using MTS, transwell, and tube formation assays. M1 and M2 microglia and apoptosis were analyzed using flow cytometry. miRNA expression was analyzed using real-time polymerase chain reaction (RT-qPCR), and IL-1ß, iNOS, IL-6, IL-10, and RC3H1 protein concentrations were analyzed using western blotting. RESULTS: We found that miR-3613-3p was enriched in BMEC exosome by miRNA GeneChip assay and RT-qPCR analysis. miR-3613-3p knockdown enhanced cell survival, migration, and angiogenesis in the OGD-treated BMECs. In addition, BMECs secrete miR-3613-3p to transfer into microglia via exosomes, and miR-3613-3p binds to the RC3H1 3' untranslated region (UTR) to reduce RC3H1 protein levels in microglia. Exosomal miR-3613-3p promotes microglial M1 polarization by inhibiting RC3H1 protein levels. BMEC exosomal miR-3613-3p reduces neuronal survival by regulating microglial M1 polarization. CONCLUSIONS: miR-3613-3p knockdown enhances BMEC functions under OGD conditions. Interfering with miR-3613-3p expression in BMSCs reduced the enrichment of miR-3613-3p in exosomes and enhanced M2 polarization of microglia, which contributed to reduced neuronal apoptosis.

Role of exosomes in the pathogenesis, diagnosis, and treatment of central nervous system diseases.

Central nervous system (CNS) diseases, such as multiple sclerosis, Alzheimer's disease (AD), and Parkinson's disease (PD), affect millions of people around the world. Great efforts were put in disease related research, but few breakthroughs have been made in the diagnostic and therapeutic approaches. Exosomes are cell-derived extracellular vesicles containing diverse biologically active molecules secreted by their cell of origin. These contents, including nucleic acids, proteins, lipids, amino acids, and metabolites, can be transferred between different cells, tissues, or organs, regulating various intercellular cross-organ communications and normal and pathogenic processes. Considering that cellular environment and cell state strongly impact the content and uptake efficiency of exosomes, their detection in biological fluids and content composition analysis potentially offer a multicomponent diagnostic readout of several human diseases. Recently, studies have found that aberrant secretion and content of exosomes are closely related to the pathogenesis of CNS diseases. Besides, loading natural cargoes, exosomes can deliver drugs cross the blood brain barrier, making them emerging candidates of biomarkers and therapeutics for CNS diseases. In this review, we summarize and discuss the advanced research progress of exosomes in the pathological processes of several CNS diseases in regarding with neuroinflammation, CNS repair, and pathological protein aggregation. Moreover, we propose the therapeutic strategies of applying exosomes to the diagnosis, early detection, and treatment of CNS diseases.

X-box binding protein 1 as a key modulator in "healing endothelial cells", a novel EC phenotype promoting angiogenesis after MCAO.

BACKGROUND: Endothelial cells (ECs) play an important role in angiogenesis and vascular reconstruction in the pathophysiology of ischemic stroke. Previous investigations have provided a profound cerebral vascular atlas under physiological conditions, but have failed to identify new disease-related cell subtypes. We aimed to identify new EC subtypes and determine the key modulator genes. METHODS: Two datasets GSE174574 and GSE137482 were included in the study. Seurat was utilized as the standard quality-control pipeline. UCell was used to calculate single-cell scores to validate cellular identity. Monocle3 and CytoTRACE were utilized in aid of pseudo-time differentiation analysis. CellChat was utilized to infer the intercellular communication pathways. The angiogenesis ability of ECs was validated by MTS, Transwell, tube formation, flow cytometry, and immunofluorescence assays in vitro and in vivo. A synchrotron radiation-based propagation contrast imaging was introduced to comprehensively portray cerebral vasculature. RESULTS: We successfully identified a novel subtype of EC named "healing EC" that highly expressed pan-EC marker and pro-angiogenic genes but lowly expressed all the arteriovenous markers identified in the vascular single-cell atlas. Further analyses showed its high stemness to differentiate into other EC subtypes and potential to modulate inflammation and angiogenesis via excretion of signal molecules. We therefore identified X-box binding protein 1 (Xbp1) as a key modulator in the healing EC phenotype. In vitro and in vivo experiments confirmed its pro-angiogenic roles under both physiological and pathological conditions. Synchrotron radiation-based propagation contrast imaging further proved that Xbp1 could promote angiogenesis and recover normal vasculature conformation, especially in the corpus striatum and prefrontal cortex under middle cerebral artery occlusion (MCAO) condition. CONCLUSIONS: Our study identified a novel disease-related EC subtype that showed high stemness to differentiate into other EC subtypes. The predicted molecule Xbp1 was thus confirmed as a key modulator that can promote angiogenesis and recover normal vasculature conformation.

Lynch syndrome-associated repeated stroke with MLH1 frame-shift mutation.

Lynch syndrome (LS) is an autosomal dominant inherited disease caused by germline mutations in DNA mismatch repair (MMR) genes, including MLH1, MSH2, MSH6, and PMS2, which predisposes patients to various malignant neoplasms. Previous studies showed that MLH1, MSH2, MSH6, and PMS2 mutation in LS were associated with an elevated risk of colorectal, gastric, endometria, ovarian, and other cancers among family members. Patients of these kinds of cancers had high incidence of synchronous and metasynchronus. We describe the case of a 34-year-old female patient with 50 days of sudden dizziness and left limb weakness, whose head CT scan showed large infarction in the right frontal temporal parietal lobe and basal ganglia area. Imaging examinations and pathological biopsy indicated high-grade serous carcinoma (HGSC) IIIA1 of the right ovary. In addition, a novel frame-shift mutation in the MLH1 gene (c.1621dupG, p.A541Gfs*16) was found in the genetic panel sequence. It may render declining of MLH1 protein and also associate with the patient's progressive clinical manifestations of multiple systems. Therefore, the timely use of prenatal diagnosis to prevent unnecessary new cases of this severe genetic disease is available.

Knowledge, attitudes and anxiety toward COVID-19 among domestic and overseas Chinese college students.

BACKGROUND: To investigate the knowledge, attitudes and anxiety toward COVID-19 among Chinese college students studying in China and abroad. METHOD: A structured questionnaire, comprised of demographic characteristics, knowledge and attitudes toward COVID-19 and the State-Trait Anxiety Inventory (STAI), was used to collect data for 566 domestic students and 126 students studying abroad. RESULTS: Domestic students were better than students abroad in knowledge of epidemiology and manifestations. Domestic students showed a significant higher enthusiasm for voluntary services than students abroad, including medical science popularization, community services, traffic dispersion, logistics transportation and being volunteers for vaccine trials. The scores (Mean ± SD) of S-AI and T-AI among students abroad were 59.48 ± 8.63 and 54.10 ± 7.20, respectively, which were significantly higher than those of domestic students (39.46 ± 8.16 and 39.25 ± 7.72). CONCLUSIONS: Our study showed a better understanding of knowledge, more positive attitudes and less anxiety toward COVID-19 among domestic students, compared with students studying abroad. In light of this information, more attention and appropriate psychological and social intervention should be paid to college students with anxiety, especially those studying abroad.

3D digital anatomic angioarchitecture of the mouse brain using synchrotron-radiation-based propagation phase-contrast imaging.

Thorough investigation of the three-dimensional (3D) configuration of the vasculature of mouse brain remains technologically difficult because of its complex anatomical structure. In this study, a systematic analysis is developed to visualize the 3D angioarchitecture of mouse brain at ultrahigh resolution using synchrotron-radiation-based propagation phase-contrast imaging. This method provides detailed restoration of the intricate brain microvascular network in a precise 3D manner. In addition to depicting the delicate 3D arrangements of the vascular network, 3D virtual micro-endoscopy is also innovatively performed to visualize randomly a selected vessel within the brain for both external 3D micro-imaging and endoscopic visualization of any targeted microvessels, which improves the understanding of the intrinsic properties of the mouse brain angioarchitecture. Based on these data, hierarchical visualization has been established and a systematic assessment on the 3D configuration of the mouse brain microvascular network has been achieved at high resolution which will aid in advancing the understanding of the role of vasculature in the perspective of structure and function in depth. This holds great promise for wider application in various models of neurovascular diseases.

Synchrotron radiation micro-tomography for high-resolution neurovascular network morphology investigation.

There has been increasing interest in using high-resolution micro-tomography to investigate the morphology of neurovascular networks in the central nervous system, which remain difficult to characterize due to their microscopic size as well as their delicate and complex 3D structure. Synchrotron radiation X-ray imaging, which has emerged as a cutting-edge imaging technology with a high spatial resolution, provides a novel platform for the non-destructive imaging of microvasculature networks at a sub-micrometre scale. When coupled with computed tomography, this technique allows the characterization of the 3D morphology of vasculature. The current review focuses on recent progress in developing synchrotron radiation methodology and its application in probing neurovascular networks, especially the pathological changes associated with vascular abnormalities in various model systems. Furthermore, this tool represents a powerful imaging modality that improves our understanding of the complex biological interactions between vascular function and neuronal activity in both physiological and pathological states.

Modifiable lifestyle factors influencing psychiatric disorders mediated by plasma proteins: A systemic Mendelian randomization study.

BACKGROUND: Psychiatric disorders are emerging as a serious public health hazard, influencing an increasing number of individuals worldwide. However, the effect of modifiable lifestyle factors on psychiatric disorders remains unclear. METHODS: Genome-wide association studies (GWAS) summary statistics were obtained mainly from Psychiatric Genomics Consortium and UK Biobank, with sample sizes varying between 10,000 and 1,200,000. The two-sample Mendelian randomization (MR) method was applied to investigate the causal associations between 45 lifestyle factors and 13 psychiatric disorders, and screen potential mediator proteins from 2992 candidate plasma proteins. We implemented a four-step framework with step-by-step screening incorporating two-step, univariable, and multivariable MR. RESULTS: We found causal effects of strenuous sports or other exercise on Tourette's syndrome (OR [95%CI]: 0.0047 [5.24E-04-0.042]); lifelong smoking index on attention-deficit hyperactivity disorder (10.53 [6.96-15.93]), anxiety disorders (3.44 [1.95-6.05]), bipolar disorder (BD) (2.25 [1.64-3.09]), BD II (2.89 [1.81-4.62]), and major depressive disorder (MDD) (2.47 [1.90-3.20]); and educational years on anorexia nervosa (AN) (1.47 [1.22-1.76]), and MDD (0.74 [0.66-0.83]). Five proteins were found to have causal associations with psychiatric disorders, namely ADH1B, GHDC, STOM, CD226, and TP63. STOM, a membrane protein deficient in the erythrocytes of hereditary stomatocytosis patients, may mediate the effect of educational attainment on AN. LIMITATIONS: The mechanisms underlying the effects of lifestyle factors on psychiatric disorders require further investigation. CONCLUSIONS: These findings could help assess the risk of psychiatric disorders based on lifestyle factors and also support lifestyle interventions as a prevention strategy for mental illness.

Effect of Intensive Lifestyle Intervention on Cardiovascular Risk Factors: Analysis From the Perspective of Long-Term Variability.

BACKGROUND: An association between variability of cardiovascular risk factors and cardiovascular events has been reported. We examined whether intensive lifestyle intervention (ILI) for weight loss decreased variability of cardiovascular risk factors with a view to additional cardiometabolic benefits. METHODS AND RESULTS: This study was a post hoc secondary analysis of the Look AHEAD (Action for Health in Diabetes) study. Cardiovascular risk factors were measured at 1-year intervals for 4 years in 4249 adults with overweight or obesity and type 2 diabetes who were randomly assigned to ILI or diabetes support and education. Long-term variability was defined as the SD of cardiovascular risk factors during 4-year follow-up. At multiple linear regression analysis, compared with the diabetes support and education group, the ILI group was associated with reduced variability of fasting blood glucose (ß=-1.49 [95% CI, -2.39 to -0.59]), total cholesterol (ß=-1.12 [95% CI, -1.75 to -0.48]), and low-density lipoprotein cholesterol (ß=-1.04 [95% CI, -1.59 to -0.49]), as well as increased variability of systolic blood pressure (ß=0.27 [95% CI, 0.00-0.54]). No significant effect of ILI was found on the variability of diastolic blood pressure (ß=-0.08 [95% CI, -0.22 to 0.05]). CONCLUSIONS: Among adults with overweight or obesity and type 2 diabetes, ILI may reduce long-term variability of fasting blood glucose, total cholesterol, and low-density lipoprotein cholesterol. Our results support that ILI should be recommended to individuals with diabetes as part of management of long-term glycemic and blood lipid control.

Serum Klotho Modifies the Associations of 25-Hydroxy Vitamin D With All-Cause and Cardiovascular Mortality.

BACKGROUND: The association between 25-hydroxyvitamin D and mortality remains controversial. Klotho, a biomarker of vitamin D activation and metabolism, may play a key role in this association. However, it is unclear whether the association between vitamin D deficiency and mortality risk is modified by klotho levels. Therefore, this study investigated the joint association of serum 25-hydroxyvitamin D [25(OH)D] and klotho with mortality risk in American community-dwelling adults. METHODS: A total of 9870 adults from the National Health and Nutrition Examination Survey (2007-2016) were included in our study. Mortality data were ascertained by linking participants to National Death Index records. Cox proportional hazards models were used to assess the association among serum 25(OH)D, serum klotho, and all-cause and cardiovascular disease (CVD) mortality. RESULTS: We found a significant interaction between klotho and serum 25(OH)D in all-cause mortality (P = .028). With klotho > 848.4 pg/mL (risk threshold on mortality), no significant all-cause and CVD mortality risk was observed at any level of serum 25(OH)D. However, with klotho < 848.4 pg/mL, a significant all-cause and CVD mortality risk was observed with serum 25(OH)D < 50 nmol/L [hazards ratio (HR), 1.36; 95% confidence interval (CI), 1.10-1.69; HR, 1.78; 95% CI, 1.16-3.45) and serum 25(OH)D of continuous variable (HR, 0.98; 95% CI, .97-.99; HR, 0.98; 95% CI, .98-.99). In addition, vitamin D metabolism disruption accessed by the combination of decreasing serum 25(OH)D (<50 nmol/L) and klotho (<848.4 pg/mL) was associated with significant all-cause mortality (HR, 1.48; 95% CI, 1.11-1.96) and CVD mortality (HR, 2.36; 95% CI, 1.48-3.75). CONCLUSIONS: Vitamin D-associated mortality risk is observed only with concurrently decreasing klotho, indicating that vitamin D metabolism dysfunction increases the risk of mortality. Klotho levels could help predict long-term mortality outcomes and thus may be useful concurrently for guiding vitamin D supplementation therapy decision-making in populations with vitamin D deficiency.

Cardiovascular effects of weight loss in old adults with overweight/obesity according to change in skeletal muscle mass.

BACKGROUND: Patients with overweight/obesity and type 2 diabetes are encouraged to lose weight, but not all losing weight gain better cardiovascular health, especially old adults. The change in skeletal muscle mass (SMM) could be the key that explains the heterogenous cardiovascular effects of weight loss. This study aims to assess whether the cardiovascular effects of weight loss vary for those gaining skeletal muscle along with weight loss. METHODS: The old adults with overweight/obesity and type 2 diabetes in the Look AHEAD study having muscle measurement from dual-energy X-ray absorptiometry were included. Based on the weight change (WC) and SMM change (SMMC) between baseline and the 4-year follow-up, participants were allocated into three groups-weight gain (WG) group, weight loss with muscle loss (WL-ML) group and weight loss with muscle gain (WL-MG) group. Cox proportional hazards regression was performed to evaluate the cardiovascular risk of those gaining or losing SMM with weight loss compared with those gaining weight. Among the participants with weight loss, the ratio of SMMC/WC was calculated, and the association of SMMC/WC with primary cardiovascular outcome was assessed. RESULTS: A total of 491 participants were included in the study with an average age of 64.56 ± 3.81 years old. A total of 47.0% were male and 49.9% were from the intensive lifestyle intervention arm. Based on their WC and SMMC, 43 were assigned to the WG group, 373 to the WL-ML group and 75 to the WL-MG group. Over a follow-up of almost 10 years, 97 participants encountered the primary endpoint. The WG group had the highest incidence of 25.59%, the WL-MG group had the lowest incidence of 9.33% and the WL-ML group had 21.18% (P = 0.040). In the fourth adjusted Cox model, the WL-MG group achieved significantly decreased odds of the primary endpoint compared with the WG group (hazard ratio [HR] 0.33, 95% confidence interval [CI] [0.12, 0.87], P = 0.026), whilst the WL-ML group did not (HR 0.91, 95% CI [0.47, 1.78], P = 0.670). Among the participants with weight loss, when SMMC/WC reached around 50%, this HR soared to approximately two-fold. CONCLUSIONS: The participants gaining SMM along with weight loss achieved the lowest odds of adverse cardiovascular events, whilst those who lost SMM along with weight loss had comparable cardiovascular risk with those gaining weight. The more muscle lost during weight loss, the greater the harm. The cardiovascular effects of weight loss were modulated by whether the participants gained SMM meanwhile losing weight.

Interplay of heart rate variability and resting heart rate on mortality in type 2 diabetes.

AIMS: Heart rate variability (HRV) and resting heart rate (RHR) are usually analyzed and interpreted separately. We aimed to assess the interplay of HRV and RHR on mortality in type 2 diabetes. METHODS: The study included 7,529 participants from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. HRV metrics included standard deviation of all normal-to-normal intervals (SDNN) and root mean square of successive differences between normal-to-normal intervals (rMSSD). Abnormal values were defined based on <25th percentile for HRV and >75th percentile for RHR. Interactions of HRV status and RHR status were tested on multiplicative and additive scales. Results were validated in a subset of patients with type 2 diabetes (n = 745) from the Multi-Ethnic Study of Atherosclerosis. RESULTS: Low SDNN was associated with increased all-cause mortality in the high RHR group (HR 1.60; 95% CI 1.29-1.97), but not in the normal RHR group. Compared with those who had neither low SDNN nor high RHR, the presence of either low SDNN or high RHR was not significantly associated with an increased risk of all-cause mortality. In contrast, the combination of low SDNN and high RHR was associated with a significantly increased risk of all-cause mortality (HR 1.68; 95% CI 1.43-1.97). Significant multiplicative and additive interactions were found between HRV status and RHR status on risk of all-cause mortality (all Pinteraction < 0.05). Similar findings were observed for cardiovascular mortality, in analyses using rMSSD, and in the Multi-Ethnic Study of Atherosclerosis. CONCLUSIONS: The association between HRV and mortality risk is modified by RHR levels. Furthermore, low HRV and high RHR have interdependent and synergistic associations with mortality risk.

Comprehensive analyses indicated the association between m6A related long non-coding RNAs and various pathways in glioma.

BACKGROUND: Glioma is one of the most malignant brain tumors and diseases. N6-methyladenosine modification (m6A) is the most abundant and prevalent internal chemical modification of mRNA and long non-coding RNAs (lncRNAs) in eukaryotes. Nevertheless, the correlated pathways and clinical utilization of m6A-related lncRNAs have not been fully evaluated in glioma. METHODS: Public RNA-sequencing and clinical annotation data were retrieved from TCGA, CGGA and GEO database. Differential expression analysis and univariate Cox regression analysis were performed to identify the m6A-related and differentially expressed lncRNAs with prognostic function (m6A-DELPF). The consensus clustering was performed to identify the expression pattern of m6A-DELPF. LASSO Cox regression analysis was performed to construct the lncRNA-based signature. The CIBERSORT and ESTIMATE algorithms were performed to analyze immune infiltration and tumor microenvironment, respectively. Immunotherapy sensitivity analysis was performed using data from TCIA. The small molecule drugs prediction analysis was performed using The Connectivity Map (CMap) database and STITCH database. A competing endogenous RNAs (ceRNA) network was constructed based on miRcode, miRDB, miRTarBase, TargetScan database. RESULTS: Two clusters (cluster1 and cluster2) were identified after unsupervised cluster analysis based on m6A-DELPF. Additionally, a 15-gene prognostic signature namely m6A-DELPFS was constructed. Analyses of epithelial-mesenchymal-transition score, tumor microenvironment, immune infiltration, clinical characterization analysis, and putative drug prediction were performed to confirm the clinical utility and efficacy of m6A-DELPFS. The potential mechanisms including tumor immune microenvironment of m6A-DELPF influence the initiation and progression of glioma. A clinically accessible nomogram was also constructed based on the m6A-DELPF and other survival-relevant clinical parameters. Two miRNAs and 114 mRNAs were identified as the downstream of seven m6A-related lncRNAs in a ceRNA network. CONCLUSION: Our present research confirmed the clinical value of m6A related lncRNAs and their high correlation with tumor immunity, tumor microenvironment, tumor mutation burden and drug sensitivity in glioma.

m6A methylation: Critical roles in aging and neurological diseases.

N6-methyladenosine (m6A) is the most abundant internal RNA modification in eukaryotic cells, which participates in the functional regulation of various biological processes. It regulates the expression of targeted genes by affecting RNA translocation, alternative splicing, maturation, stability, and degradation. As recent evidence shows, of all organs, brain has the highest abundance of m6A methylation of RNAs, which indicates its regulating role in central nervous system (CNS) development and the remodeling of the cerebrovascular system. Recent studies have shown that altered m6A levels are crucial in the aging process and the onset and progression of age-related diseases. Considering that the incidence of cerebrovascular and degenerative neurologic diseases increase with aging, the importance of m6A in neurological manifestations cannot be ignored. In this manuscript, we focus on the role of m6A methylation in aging and neurological manifestations, hoping to provide a new direction for the molecular mechanism and novel therapeutic targets.

Strategies for the Emergency Treatment of Pregnant Women with Neurological Symptoms during the COVID-19 Pandemic.

Coronavirus disease-19 (COVID-19) has been spreading all over the world for more than two years. Though several kinds of vaccines are currently available, emergence of new variants, spike mutations and immune escape have raised new challenges. Pregnant women are vulnerable to respiratory infections due to their altered immune defence and surveillance functions. Besides, whether pregnant persons should receive a COVID-19 vaccine is still under debate because limited data are available on the efficacy and safety of receiving a vaccine during pregnancy. Physiological features and lack of effective protection making pregnant women at high risk of getting infected. Another concern is that pregnancy may trigger the onset of underlying existing neurological disease, which is highly similar to those neurological symptoms of pregnant women caused by COVID-19. These similarities interfere with diagnosis and delay timely and effective management. Therefore, providing efficient emergency support for pregnant women suffering from neurological symptoms caused by COVID-19 remains a challenge among neurologists and obstetricians. To improve the diagnosis and treatment efficiency of pregnant women with neurological symptoms, we propose an emergency management framework based on the clinicians' experience and available resources. This emergency care system aimed at addressing the conundrums faced by the emergency guarantee system under COVID-19 pandemic and could serve as a potential multisystem project for clinical practice and medical education.

Arterial Calcification and Its Association With Stroke: Implication of Risk, Prognosis, Treatment Response, and Prevention.

Stroke is a leading cause of death worldwide. Vascular calcification (VC), defined as deposition of calcium-phosphate complexes in the vessels, is considered as the characteristic of vascular aging. Calcifications at different vessel layers have different implications. Intimal calcification is closely related to atherosclerosis and affects plaque stability, while medial calcification can cause arterial stiffening and reduce compliance. Accumulating evidence suggested that arterial calcifications, including calcifications in the intracranial artery, coronary artery, and carotid artery, are associated with the risk, prognosis, and treatment response of stroke. VC can not only serve as a marker of atherosclerosis, but cause cerebral hemodynamic impairment. In addition, calcifications in large arteries are associated with cerebral small vessel disease. In this review, we summarize the findings of recently published studies focusing on the relationship between large artery calcification and the risk, prognosis, treatment response, and prevention of stroke and also discuss possible mechanisms behind those associations.