Novel Drp1 GTPase Inhibitor, Drpitor1a: Efficacy in Pulmonary Hypertension.

BACKGROUND: Drp1 (dynamin-related protein 1), a large GTPase, mediates the increased mitochondrial fission, which contributes to hyperproliferation of pulmonary artery smooth muscle cells in pulmonary arterial hypertension (PAH). We developed a potent Drp1 GTPase inhibitor, Drpitor1a, but its specificity, pharmacokinetics, and efficacy in PAH are unknown. METHODS: Drpitor1a's ability to inhibit recombinant and endogenous Drp1 GTPase was assessed. Drpitor1a's effects on fission were studied in control and PAH human pulmonary artery smooth muscle cells (hPASMC) and blood outgrowth endothelial cells (BOEC). Cell proliferation and apoptosis were studied in hPASMC. Pharmacokinetics and tissue concentrations were measured following intravenous and oral drug administration. Drpitor1a's efficacy in regressing monocrotaline-PAH was assessed in rats. In a pilot study, Drpitor1a reduced PA remodeling only in females. Subsequently, we compared Drpitor1a to vehicles in control and monocrotaline-PAH females. RESULTS: Drp1 GTPase activity was increased in PAH hPASMC. Drpitor1a inhibited the GTPase activity of recombinant and endogenous Drp1 and reversed the increased fission, seen in PAH hPASMC and PAH BOEC. Drpitor1a inhibited proliferation and induced apoptosis in PAH hPASMC without affecting electron transport chain activity, respiration, fission/fusion mediator expression, or mitochondrial Drp1 translocation. Drpitor1a did not inhibit proliferation or alter mitochondrial dynamics in normal hPASMC. Drpitor1a regressed monocrotaline-PAH without systemic vascular effects or toxicity. CONCLUSIONS: Drpitor1a is a specific Drp1 GTPase inhibitor that reduces mitochondrial fission in PAH hPASMC and PAH BOEC. Drpitor1a reduces proliferation and induces apoptosis in PAH hPASMC and regresses monocrotaline-PAH. Drp1 is a therapeutic target in PAH, and Drpitor1a is a potential therapy with an interesting therapeutic sexual dimorphism.

You are not lab rats at teaching hospitals: A systematic review of resident and fellow participation leads to improved colonoscopy.

BACKGROUND: Participation in colonoscopies is an essential aspect of endoscopic training. The purpose of this study was to explore the impact of fellow/trainee participation on colonoscopy outcomes. METHODS: This meta-analysis was registered on the International Prospective Register of Systematic Reviews (PROSPERO). From database inception to July 2022, studies investigating fellow involvement and colonoscopy outcomes were searched across Cochrane library, PubMed, and other databases. The random-effects model was applied to generate more conservative estimates. Sensitive analysis was conducted to explore whether the result would depend on a particular study. Egger's test and Begg's test were used to estimate the potential for publication bias. RESULTS: Seventeen studies including 30,062 participants were included. We found that fellow/trainee involvement enhanced the overall rates of adenoma detection and polyp detection (OR = 1.26, 95% CI = 1.14-1.40, p < 0.001; OR = 1.29, 95% CI = 1.02-1.63, p = 0.020, respectively). The mean number of adenoma/polyps per colonoscopy was also higher with fellow/trainee participation (MD = 0.12, 95% CI = 0.08-0.17, p < 0.001; MD = 0.15, 95% CI = 0.02-0.28, p = 0.020, respectively). CONCLUSION: In addition to its educational purpose, fellow or trainee involvement is associated with beneficial effects on colonoscopy outcomes.

Association of sugar-sweetened beverages with the risk of colorectal cancer: a systematic review and meta-analysis.

The association between sugar-sweetened beverages intake and colorectal cancer (CRC) remains controversial. A metaanalysis was performed to clarify the correlation between sugar-sweetened beverages and CRC risk/mortality. A systematic literature search was conducted in PubMed, Web of Science, Embase, China National Knowledge Infrastructure (CNKI), Sinomed (CBM), Wanfang Data Knowledge Service Platform, and China Science and Technology Journal VIP database. Articles were restricted to be available in any language until March 31, 2022. The highest exposed categories were used to calculate the pooled relative risks (RR) values. Pooled relative risks (RR) and 95% confidence intervals (CI) were used to estimate the association of sugar-sweetened beverages with CRC risk and mortality. Heterogeneity was assessed with the Cochran Q statistic and quantified with the I2 statistic. A total of 17 studies (6 case-control and 11 cohort) involving 557,391 subjects were included in this meta-analysis. The pooled RRs for CRC incidence and mortality among people taking sugar-sweetened beverages were 1.17 (95% CI: 1.07-1.28) and 1.13 (95% CI: 0.99-1.29), respectively. In subgroup analysis, a correlation was found in the distal colon with a pooled RR of 1.41 (95% CI: 1.10-1.80). There was no correlation in the proximal colon with a pooled RR of 1.58 (95% CI: 0.79-3.17). We found statistically significant associations between CRC incidence and sugar-sweetened beverages intake in North America and Oceania, with pooled RRs of 1.16 (95% CI: 1.00-1.33) and 1.32 (95% CI: 1.13-1.55), respectively. In sensitivity analysis, after excluding each study and calculating heterogeneity and effect sizes, there was still a correlation between sugar-sweetened beverages intake and CRC risk. This meta-analysis suggests that sugar-sweetened beverages intake may increase CRC risk, independent of CRC mortality. Whether CRC risk increases with increased sugar-sweetened beverage intake needs further investigation in the future. This meta-analysis aimed to indicate the relationship between sugar-sweetened beverages intake and the risk and mortality of colorectal cancer. A total of 17 studies involving 557,391 subjects were included. The results showed that sugar-sweetened beverages may increase the risk of colorectal cancer but may not be associated with colorectal cancer mortality.

Clinical Features and Prognosis of Uncommon Metastatic Breast Cancer: A Retrospective Analysis of 82 Cases.

With the improvement of diagnostic techniques, numerous uncommon metastases derived from breast cancer were reported. However, very few studies explored the clinical characteristics and prognostic patterns of these patients. A total of 82 cases of uncommon metastatic breast cancer (MBC) registered at our hospital from January 1, 2010, to July 1, 2022, were selected for this retrospective study. The diagnoses of uncommon metastases were based on pathology, and the potential prognostic indicators (overall survival [OS], uncommon disease-free interval [uDFI], and remaining survival [RS]) were estimated. The uncommon metastases involved distant soft tissue, parotid gland, thyroid, digestive system, urinary system, reproductive system, bone marrow, and pericardium. Stepwise multivariate Cox regression analysis indicates age ≤ 35 is an independent risk factor of poor outcome of OS, uDFI, and RS in uncommon MBC patients. Meanwhile, uncommon metastasis combined with common visceral metastasis is an independent risk factor for poor RS of uncommon MBC patients, with a hazard ratio of 6.625 (95% confidence interval = 1.490-29.455, P = .013). Post hoc pairwise comparisons showed that uncommon MBC patients who developed bone-only metastasis survived longer than those concomitant with common visceral metastasis (P = .029). Although the incidence is low, uncommon MBC may involve multiple metastatic sites. The delayed diagnosis of uncommon metastases could lead to systemic progression of the disease. However, patients who only develop uncommon metastasis have a significantly better prognosis than that of those combined with common visceral metastasis. Even for those complicated by bone-only metastasis, active treatment of bone metastases can still achieve substantially longer survival.

Electron Leak From the Mitochondrial Electron Transport Chain Complex I at Site IQ Is Crucial for Oxygen Sensing in Rabbit and Human Ductus Arteriosus.

Background As partial pressure of oxygen (pO2) rises with the first breath, the ductus arteriosus (DA) constricts, diverting blood flow to the pulmonary circulation. The DA's O2 sensor resides within smooth muscle cells. The DA smooth muscle cells' mitochondrial electron transport chain (ETC) produces reactive oxygen species (ROS) in proportion to oxygen tension, causing vasoconstriction by regulating redox-sensitive ion channels and enzymes. To identify which ETC complex contributes most to DA O2 sensing and determine whether ROS mediate O2 sensing independent of metabolism, we used electron leak suppressors, S1QEL (suppressor of site IQ electron leak) and S3QEL (suppressor of site IIIQo electron leak), which decrease ROS production by inhibiting electron leak from quinone sites IQ and IIIQo, respectively. Methods and Results The effects of S1QEL, S3QEL, and ETC inhibitors (rotenone and antimycin A) on DA tone, mitochondrial metabolism, O2-induced changes in intracellular calcium, and ROS were studied in rabbit DA rings, and human and rabbit DA smooth muscle cells. S1QEL's effects on DA patency were assessed in rabbit kits, using micro computed tomography. In DA rings, S1QEL, but not S3QEL, reversed O2-induced constriction (P=0.0034) without reducing phenylephrine-induced constriction. S1QEL did not inhibit mitochondrial metabolism or ETC-I activity. In human DA smooth muscle cells, S1QEL and rotenone inhibited O2-induced increases in intracellular calcium (P=0.02 and 0.001, respectively), a surrogate for DA constriction. S1QEL inhibited O2-induced ROS generation (P=0.02). In vivo, S1QEL prevented O2-induced DA closure (P<0.0001). Conclusions S1QEL, but not S3QEL, inhibited O2-induced rises in ROS and DA constriction ex vivo and in vivo. DA O2 sensing relies on pO2-dependent changes in electron leak at site IQ in ETC-I, independent of metabolism. S1QEL offers a therapeutic means to maintain DA patency.

Using omics to breathe new life into our understanding of the ductus arteriosus oxygen response.

The ductus arteriosus (DA) connects the aorta to the pulmonary artery (PA), directing placentally oxygenated blood away from the developing lungs. High pulmonary vascular resistance and low systemic vascular resistance facilitate shunting of blood in utero from the pulmonary to the systemic circulation through the widely patent DA, thereby optimizing fetal oxygen (O2) delivery. With the transition from fetal (hypoxia) to neonatal (normoxia) oxygen conditions, the DA constricts while the PA dilates. This process often fails in prematurity, promoting congenital heart disease. Impaired O2-responsivness in the DA promotes persistent ductus arteriosus (PDA), the most common form of congenital heart disease. Knowledge of DA oxygen sensing has greatly advanced in the past few decades, however we still lack a complete understanding of the sensing mechanism. The genomic revolution of the past two decades has facilitated unprecedented discovery in every biological system. This review will demonstrate how multiomic integration of data generated from the DA can breathe new life into our understanding of the DA's oxygen response.

Comparison of short-term efficacy and safety between total robotic and total 3D laparoscopic distal radical gastrectomy for gastric cancer in Enhanced Recovery After Surgery (ERAS) protocol: a propensity score matching study.

BACKGROUND: The application of Enhanced Recovery After Surgery (ERAS) protocol in gastrointestinal surgery has been widely accepted. The aim of this study was to compare the effect of ERAS in total robotic distal gastrectomy (TRDG) versus 3D total laparoscopic distal gastrectomy (3D-TLDG) for gastric cancer. METHODS: We retrospectively evaluated 73 patients underwent TRDG and 163 patients who received 3D-TLDG. The propensity score was used for matching analysis according to a 1:1 ratio, so that there was no significant difference in the baseline data between the two groups. The short-term effect and safety of the two groups were compared. RESULTS: The TRDG group had a less intraoperative bleeding (30.21 ± 13.78 vs. 41.44 ± 17.41 ml, P < 0.001), longer intraoperative preparation time (31.05 ± 4.93 vs. 15.48 ± 2.43 min, P < 0.001), shorter digestive tract reconstruction time (32.67 ± 4.41 vs. 39.78 ± 4.95 min, P < 0.001), shorter postoperative ambulation time (14.07 ± 8.97 vs. 17.49 ± 5.98 h, P = 0.007), shorter postoperative anal exhaust time (1.78 ± 0.79 vs. 2.18 ± 0.79 days, P = 0.003), shorter postoperative hospital stay (7.74 ± 3.15 vs. 9.97 ± 3.23 days, P < 0.001), lower postoperative pain score (P = 0.006) and higher hospitalization cost (89,907.15 ± 17,147.19 vs. 125,615.82 ± 11,900.80 RMB, P < 0.001) than the 3D-TLDG group. CONCLUSION: TRDG and 3D-TLDG under ERAS protocol are safe and feasible. Compared with 3D-TLDG, the TRDG has better intraoperative bleeding control effect and greater advantages in digestive tract reconstruction. After the combination of ERAS protocol, TRDG also has certain advantages in the recovery process of patients after surgery.

Psychosocial interprofessional perinatal education: Design and evaluation of an interprofessional learning experience to improve students' collaboration skills in perinatal mental health.

BACKGROUND: Perinatal mental health disorders are one of the leading causes of maternal illness and suffering and care and services need to be well coordinated by an interprofessional team who are skilled in working collaboratively. AIM: The aim of this paper is to describe the design and evaluation of an innovative interprofessional education initiative to increase midwives and other health professional students' knowledge and skills in caring collaboratively for women with psychosocial issues in the perinatal period, including women experiencing domestic and family violence. METHODS: The Psychosocial Interprofessional Perinatal Education workshop was designed for midwifery, psychology, social work and medical students. It provided a simulated learning experience with case studies based on real life situations. Students undertook pre and post surveys to measure changes in students' perceptions of interprofessional collaboration and their experiences of participating in the interprofessional simulation-based learning activity. Quantitative survey data were analysed using paired t-tests and a qualitative content analysis was undertaken on the open-ended questions in the survey. FINDINGS: Comparison of pre and post surveys found students from all disciplines reported feeling more confident working interprofessionally following the workshop. The following categories were generated from analysis of the open ended survey data: Greater understanding of each others' roles; Recognising benefits of interprofessional collaboration; Building on sense of professional identity; Respecting each other and creating a level playing field; and Filling a pedagogical gap. CONCLUSION: Through this innovative, simulated interprofessional education workshop students developed skills essential for future collaborative practice to support women and families experiencing psychosocial distress.

Association between household air pollution and all-cause and cause-specific mortality: a systematic review and meta-analysis.

Recently, a growing number of epidemiological studies have examined the relationship between household air pollution (HAP) and all-cause and cause-specific mortality. While the results were not entirely consistent, the current study followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) protocol to conduct a comprehensive review and meta-analysis. Data sources were PubMed, Web of Science, Embase, and Cochrane Library for studies published up to 12 May 2022. The pooled relative risks (RRs) with 95% confidence intervals (CI) were used to estimate the effect of household air pollution on all-cause and cause-special mortality. Then I square value (I2) was used to assess heterogeneity, and random-effects model was used as the pooling method. Seventeen studies were included in the quantitative analysis. Our results showed a significant association between household air pollution and increased risks of all-cause mortality (RR = 1.12, 95% CI = 1.06-1.19) and cardiovascular disease mortality (RR = 1.13, 95% CI = 1.04-1.24). Similarly, the associations between household air pollution and mortality from other specific causes (respiratory, ischemic heart disease, stroke, and total cancer) were positive, although they were not statistically significant. The study suggests that exposure to household air pollution increases the risk of all-cause mortality and cardiovascular disease mortality. In addition, our results found a trend of increased mortality from the respiratory system, ischemic heart disease, stroke, and total cancer, with household air pollution.

Combined exposure to multiple dioxins and dioxin-like polychlorinated biphenyls on hypertension among US adults in NHANES: a cross-sectional study under three statistical models.

Dioxins and dioxin-like polychlorinated biphenyls (DL-PCBs) are mainly released as by-products of human activities, often in the form of mixtures, and the potential harm on human health deserves attention. Therefore, our study aimed to analyze the combined effect of dioxins and DL-PCB exposures on hypertension (HTN) among US adults. Data of eligible participants were acquired from the National Health and Nutrition Examination Survey (NHANES). Multiple logistic regression models with adjustment for covariates were applied to explore the associations between 13 persistent organic pollutants (POPs) and HTN. Stratified analyses and interaction analyses were then conducted by age and gender. Finally, the combined effects of dioxins and DL-PCBs on HTN were assessed by the weighted quantile sum (WQS) model and the Bayesian kernel machine regression (BKMR) model. A total of 976 adults were included in our study, of whom 397 had HTN. Spearman correlations indicated positive correlations among 13 POPs. And most of them (except PCB28, PCB66, and 1,2,3,4,7,8,9-hpcdf) had significant effects on HTN. The result of WQS revealed that mixed exposure to dioxins and DL-PCBs was significantly associated with increased risk of HTN (OR: 2.205; 95% CIs: 1.555, 3.127). The BKMR model also presented a positive trend of HTN risk with exposure to multiple dioxins and DL-PCBs. And 1,2,3,4,6,7,8,9-ocdd may be the main factor for this positive association. Considering the limitations of our cross-sectional study with the small sample, further prospective studies are necessary to validate our findings.

A Systematic Review and Meta-analysis of the Association Between SARS-CoV-2 Vaccination and Myocarditis or Pericarditis.

INTRODUCTION: There have been reports of potential negative cardiovascular effects from the COVID-19 vaccine, such as myocarditis or pericarditis. This study sought to ascertain the risk of myocarditis/pericarditis after COVID-19 vaccination by conducting an extensive meta-analysis of published cases. METHODS: A systematic literature search was conducted in 7 online databases by March 31, 2022. Heterogeneity was tested by I2 index. RR and 95% CI were pooled through either random-effect or fixed-effect models. Sensitivity analysis and publication bias were also conducted. RESULTS: A total of 11 studies with 58,620,611 subjects were included. COVID-19 vaccination correlated with an increased risk of myocarditis or pericarditis (RR=2.04; 95% CI=1.33, 3.14). In addition, an increased risk of myocarditis or pericarditis in people who received the second dose of COVID-19 vaccine compared with that in those who received only the first dose of COVID-19 vaccine was also found (RR=4.06; 95% CI=2.08, 7.92). An increased incidence of pericarditis or myocarditis was noted predominantly in those who received BNT162b2 and mRNA-1273 vaccines (RR=2.19; 95% CI=1.46, 3.29 and RR=4.15; 95% CI=1.87, 9.22, respectively). DISCUSSION: Study results indicate that a higher incidence of myocarditis or pericarditis was found after COVID-19 vaccination. In addition, the risk of developing myocarditis or pericarditis was greater after the second dose than after the first dose. Nevertheless, the risks of myocarditis and pericarditis in COVID-19 vaccine recipients are still significantly lower than the health risks observed in patients with COVID-19. Therefore, the benefits and harms must be carefully assessed to determine the best management option for patients who are in the high-risk group of myocarditis or pericarditis.

Does aspirin reduce the incidence, recurrence, and mortality of hepatocellular carcinoma? A GRADE-assessed systematic review and dose-response meta-analysis.

PURPOSE: Aspirin has been suggested to reduce the risk of cancer. However, previous studies have been inconsistent regarding the relationship between aspirin use and the risk of occurrence of hepatocellular carcinoma (HCC). The purpose of this study was to assess the effect of aspirin on clinical outcomes in patients with HCC in a meta-analysis and to explore the possible dose-response relationship. METHODS: A systematic literature search was conducted in 10 electronic databases and 4 registries. The combined hazard ratios (HRs) were calculated using a random-effects model with 95% confidence interval (CIs) to assess the effect of aspirin on the risk of HCC. Relevant subgroup analyses and sensitivity analyses were performed. RESULTS: The results show that aspirin use correlated with lower incidence of HCC (HR: 0.75, 95% CI: 0.71-0.80), decreased risk of HCC recurrence (HR: 0.79, 95% CI: 0.65-0.96), and reduced mortality (HR: 0.72, 95% CI: 0.60-0.87). The results of the subgroup analysis showed that aspirin use was consistently associated with reduced incidence of HCC across different regions, study designs, and populations. A linear relationship was found for both dosage and duration of aspirin use. An increased of bleeding with aspirin use among patients was also observed (HR 1.10, 95% CI: 1.02-1.20). CONCLUSIONS: This meta-analysis found that aspirin use was independently associated with a reduced risk of HCC incidence, recurrence, and death. Furthermore, aspirin use influenced HCC occurrence in a dose-dependent and duration-dependent manner. However, an increased risk of bleeding with aspirin use was noted.

Exploratory analysis of the association between organophosphate ester mixtures with high blood pressure of children and adolescents aged 8-17 years: cross-sectional findings from the National Health and Nutrition Examination Survey.

Epidemiological studies on the effect of organophosphate esters (OPEs) on high blood pressure (BP) among children and adolescents are scant. Therefore, the main objective of the present study was to explore the effect of exposure to OPEs on high BP among children and adolescents. A total of 1340 participants were included in the current analyses. Multivariable logistic regression models were implemented to calculate odds ratios (ORs) and corresponding 95% confidence intervals (CIs) to examine the association between OPE metabolites and high BP. We also assessed the modified effect of sex, age, and overweight/obesity on this association. Furthermore, quantile g-computation (Qgcomp) and Bayesian kernel machine regression (BKMR) were exhibited to analyze the association between multiple OPE metabolite mixtures and high BP. After adjusting for covariates, the highest (vs. lowest) tertiles of bis (1-choloro-2-propyl) phosphate (BCPP), bis-2-chloroethyl phosphate (BCEP), and di-n-butyl phosphate (DBUP) were associated with 1.23 (95% CI: 0.83, 1.83), 1.27 (95% CI: 0.85, 1.92), and 1.01 (95% CI: 0.67, 1.53) odds ratios for high BP, respectively. In the Qgcomp, a quartile increase in OPE metabolite mixtures was weakly associated with an elevated risk of high BP (adjusted OR: 1.06, 95CI%: 0.81, 1.37). The results from BKMR showed a positive trend of association between OPE metabolite mixture on the risk of high BP. In conclusion, our study demonstrated that higher levels of BCPP, BCEP, and DBUP were weakly associated with high BP among US children and adolescents. Moderate evidence suggested OPE metabolite mixtures had positive joint effects on high BP. Consequently, longitudinal studies with repeated measurements are warranted to examine the relationships between multiple OPE metabolites and high blood pressure among children and adolescents.

A deep belief network-based clinical decision system for patients with osteosarcoma.

Osteosarcoma was the most frequent type of malignant primary bone tumor with a poor survival rate mainly occurring in children and adolescents. For precision treatment, an accurate individualized prognosis for Osteosarcoma patients is highly desired. In recent years, many machine learning-based approaches have been used to predict distant metastasis and overall survival based on available individual information. In this study, we compared the performance of the deep belief networks (DBN) algorithm with six other machine learning algorithms, including Random Forest, XGBoost, Decision Tree, Gradient Boosting Machine, Logistic Regression, and Naive Bayes Classifier, to predict lung metastasis for Osteosarcoma patients. Therefore the DBN-based lung metastasis prediction model was integrated as a parameter into the Cox proportional hazards model to predict the overall survival of Osteosarcoma patients. The accuracy, precision, recall, and F1 score of the DBN algorithm were 0.917/0.888, 0.896/0.643, 0.956/0.900, and 0.925/0.750 in the training/validation sets, respectively, which were better than the other six machine-learning algorithms. For the performance of the DBN survival Cox model, the areas under the curve (AUCs) for the 1-, 3- and 5-year survival in the training set were 0.851, 0.806 and 0.793, respectively, indicating good discrimination, and the calibration curves showed good agreement between the prediction and actual observations. The DBN survival Cox model also demonstrated promising performance in the validation set. In addition, a nomogram integrating the DBN output was designed as a tool to aid clinical decision-making.

SARS-CoV-2 mitochondriopathy in COVID-19 pneumonia exacerbates hypoxemia.

RATIONALE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19 pneumonia. We hypothesize that SARS-CoV-2 causes alveolar injury and hypoxemia by damaging mitochondria in airway epithelial cells (AEC) and pulmonary artery smooth muscle cells (PASMC), triggering apoptosis and bioenergetic impairment, and impairing hypoxic pulmonary vasoconstriction (HPV), respectively. OBJECTIVES: We examined the effects of: A) human betacoronaviruses, SARS-CoV-2 and HCoV-OC43, and individual SARS-CoV-2 proteins on apoptosis, mitochondrial fission, and bioenergetics in AEC; and B) SARS-CoV-2 proteins and mouse hepatitis virus (MHV-1) infection on HPV. METHODS: We used transcriptomic data to identify temporal changes in mitochondrial-relevant gene ontology (GO) pathways post-SARS-CoV-2 infection. We also transduced AECs with SARS-CoV-2 proteins (M, Nsp7 or Nsp9) and determined effects on mitochondrial permeability transition pore (mPTP) activity, relative membrane potential, apoptosis, mitochondrial fission, and oxygen consumption rates (OCR). In human PASMC, we assessed the effects of SARS-CoV-2 proteins on hypoxic increases in cytosolic calcium, an HPV proxy. In MHV-1 pneumonia, we assessed HPV via cardiac catheterization and apoptosis using the TUNEL assay. RESULTS: SARS-CoV-2 regulated mitochondrial apoptosis, mitochondrial membrane permeabilization and electron transport chain (ETC) GO pathways within 2 hours of infection. SARS-CoV-2 downregulated ETC Complex I and ATP synthase genes, and upregulated apoptosis-inducing genes. SARS-CoV-2 and HCoV-OC43 upregulated and activated dynamin-related protein 1 (Drp1) and increased mitochondrial fission. SARS-CoV-2 and transduced SARS-CoV-2 proteins increased apoptosis inducing factor (AIF) expression and activated caspase 7, resulting in apoptosis. Coronaviruses also reduced OCR, decreased ETC Complex I activity and lowered ATP levels in AEC. M protein transduction also increased mPTP opening. In human PASMC, M and Nsp9 proteins inhibited HPV. In MHV-1 pneumonia, infected AEC displayed apoptosis and HPV was suppressed. BAY K8644, a calcium channel agonist, increased HPV and improved SpO2. CONCLUSIONS: Coronaviruses, including SARS-CoV-2, cause AEC apoptosis, mitochondrial fission, and bioenergetic impairment. SARS-CoV-2 also suppresses HPV by targeting mitochondria. This mitochondriopathy is replicated by transduction with SARS-CoV-2 proteins, indicating a mechanistic role for viral-host mitochondrial protein interactions. Mitochondriopathy is a conserved feature of coronaviral pneumonia that may exacerbate hypoxemia and constitutes a therapeutic target.

An integrated proteomic and transcriptomic signature of the failing right ventricle in monocrotaline induced pulmonary arterial hypertension in male rats.

Aim: Pulmonary arterial hypertension (PAH) is an obstructive pulmonary vasculopathy that results in death from right ventricular failure (RVF). There is limited understanding of the molecular mechanisms of RVF in PAH. Methods: In a PAH-RVF model induced by injection of adult male rats with monocrotaline (MCT; 60 mg/kg), we performed mass spectrometry to identify proteins that change in the RV as a consequence of PAH induced RVF. Bioinformatic analysis was used to integrate our previously published RNA sequencing data from an independent cohort of PAH rats. Results: We identified 1,277 differentially regulated proteins in the RV of MCT rats compared to controls. Integration of MCT RV transcriptome and proteome data sets identified 410 targets that are concordantly regulated at the mRNA and protein levels. Functional analysis of these data revealed enriched functions, including mitochondrial metabolism, cellular respiration, and purine metabolism. We also prioritized 15 highly enriched protein:transcript pairs and confirmed their biological plausibility as contributors to RVF. We demonstrated an overlap of these differentially expressed pairs with data published by independent investigators using multiple PAH models, including the male SU5416-hypoxia model and several male rat strains. Conclusion: Multiomic integration provides a novel view of the molecular phenotype of RVF in PAH which includes dysregulation of pathways involving purine metabolism, mitochondrial function, inflammation, and fibrosis.

Association between solid fuel combustion and diabetes mellitus: a systematic review and meta-analysis.

In recent years, many epidemiological studies have investigated the relationship between solid fuel combustion and diabetes mellitus (DM). This meta-analysis was performed to explore the potential association between solid fuel combustion and DM. A comprehensive literature search was conducted to identify all relevant studies published prior to January 14, 2022. The pooled odds ratios (OR) with 95% confidence intervals (CI) were used to estimate the effect of solid fuel combustion on DM. The I square value (I2) was used to assess heterogeneity. Due to the heterogeneity of the studies (I2 = 66.70%), a random-effect model was used as the pooling method. A total of 9 articles (10 available datasets) were used for this systematic review and meta-analysis, involving 45,620 study subjects. The results of the meta-analysis showed a statistically positive relationship between household solid fuel combustion and the risk of DM (OR = 1.46, 95% CI = 1.09-1.97). Subgroup analysis based on fuel type revealed a statistically significant association in the mixed solid fuel group (OR = 2.03, 95% CI = 1.59-2.59), but not in the single biomass group (OR = 1.04, 95% CI = 0.73-1.49). This meta-analysis suggests that solid fuel combustion may be associated with an increased risk of DM.