Skeletogenesis depends on the activity of bone-forming cells derived from mesenchymal cells. The pathways that control mesenchymal cell differentiation are not well understood. We propose that Foxo1 is an early molecular regulator during mesenchymal cell differentiation into osteoblasts. In mouse embryos, Foxo1 expression is higher in skeletal tissues, while Foxo1 silencing has a drastic impact on skeletogenesis and craniofacial development, specially affecting pre-maxilla, nasal bone, mandible, tibia, and clavicle. Similarly, Foxo1 activity and expression increase in mouse mesenchymal cells under the influence of osteogenic stimulants. In addition, silencing Foxo1 blocks the expression of osteogenic markers such as Runx2, alkaline phosphatase, and osteocalcin and results in decreased culture calcification even in the presence of strong osteogenic stimulants. Conversely, the expression of these markers increases significantly in response to Foxo1 overexpression. One mechanism through which Foxo1 affects mesenchymal cell differentiation into osteoblasts is through regulation of a key osteogenic transcription factor, Runx2. Indeed, our results show that Foxo1 directly interacts with the promoter of Runx2 and regulates its expression. Using a tibia organ culture model, we confirmed that silencing Foxo1 decreases the expression of Runx2 and impairs bone formation. Furthermore, our data reveals that Runx2 and Foxo1 interact with each other and cooperate in the transcriptional regulation of osteoblast markers. In conclusion, our in vitro, ex vivo, and in vivo results strongly support the notion that Foxo1 is an early molecular regulator in the differentiation of mesenchymal cells into osteoblast.Undifferentiated mesenchymal cells can differentiate into osteoblasts (bone-forming cells), adipocytes (fat cells), chondrocytes (cartilage cells), and myocytes (muscle cells) under the influence of various hormones and growth factors (1). Commitment and differentiation of mesenchymal cells into osteoblasts is crucial during skeletal development and bone growth.Whether mesenchymal cells differentiate along the osteogenic or other pathway depends on the activation of specific transcription factors. The importance of transcription factors in controlling skeletal development can be appreciated in the human skeletal disorder cleidocranial dysplasia. In this condition, deregulation of an important osteogenic transcription factor, Runx2, produces a striking phenotype with anterior fontanelle, hypoplasia or aplasia of the clavicle, wide pubic symphysis, and short stature (2).Although some of the transcription factors that control osteoblast differentiation are well characterized, the role of others remains unclear. One such factor is Foxo1 (forkhead box class O). Foxo1 belongs to the winged helix/forkhead family of transcription factors that is characterized by a 100-amino acid monomeric DNA-binding domain called the FOX domain. Other portions of the forkhead proteins, such as the DNA transactivation or DNA transrepression domains, a...

Oxidative stress in SHR was associated with a lack of coordinate upregulation of the antioxidant enzymes and discordance between their protein abundance and enzymatic activity. These findings suggest an impaired antioxidant defense system and the presence of functionally abnormal enzymes in the SHR kidney. Lifelong antioxidant therapy improved expression, activity and activity-to-mass relationship of the measured enzymes. The latter suggests oxidative and nitrosative modification of these molecules in the SHR kidney.

<b><i>Introduction:</i></b> Cardiovascular comorbidities may predispose to adverse outcomes in hospitalized patients with coronavirus disease 2019 (COVID-19). However, across the USA, the burden of cardiovascular comorbidities varies significantly. Whether clinical outcomes of hospitalized patients with COVID-19 differ between regions has not yet been studied systematically. Here, we report differences in underlying cardiovascular comorbidities and clinical outcomes of patients hospitalized with COVID-19 in Texas and in New York state. <b><i>Methods:</i></b> We established a multicenter retrospective registry including patients hospitalized with COVID-19 between March 15 and July 12, 2020. Demographic and clinical data were manually retrieved from electronic medical records. We focused on the following outcomes: mortality, need for pharmacologic circulatory support, need for mechanical ventilation, and need for hemodialysis. Univariate and multivariate logistic regression analyses were performed. <b><i>Results:</i></b> Patients in the Texas cohort (<i>n</i> = 296) were younger (57 vs. 63 years, <i>p</i> value &#x3c;0.001), they had a higher BMI (30.3 kg/m² vs. 28.5 kg/m², <i>p</i> = 0.015), and they had higher rates of diabetes mellitus (41 vs. 30%; <i>p</i> = 0.014). In contrast, patients in the New York state cohort (<i>n</i> = 218) had higher rates of coronary artery disease (19 vs. 10%, <i>p</i> = 0.005) and atrial fibrillation (11 vs. 5%, <i>p</i> = 0.012). Pharmacologic circulatory support, mechanical ventilation, and hemodialysis were more frequent in the Texas cohort (21 vs. 13%, <i>p</i> = 0.020; 30 vs. 12%, <i>p</i> &#x3c; 0.001; and 11 vs. 5%, <i>p</i> = 0.009, respectively). In-hospital mortality was similar between the 2 cohorts (16 vs. 18%, <i>p</i> = 0.469). After adjusting for differences in underlying comorbidities, only the use of mechanical ventilation remained significantly higher in the participating Texas hospitals (odds ratios [95% CI]: 3.88 [1.23, 12.24]). Median time to pharmacologic circulatory support was 8 days (interquartile range: 2, 13.8) in the Texas cohort compared to 1 day (0, 3) in the New York state cohort, while median time to in-hospital mortality was 16 days (10, 25.5) and 7 days (4, 14), respectively (both <i>p</i> &#x3c; 0.001). In-hospital mortality was higher in the late versus the early study phase in the New York state cohort (24 vs. 14%, <i>p</i> = 0.050), while it was similar between the 2 phases in the Texas cohort (16 vs. 15%, <i>p</i> = 0.741). <b><i>Conclusions:</i></b> Geographical differences, including practice pattern variations and the impact of disease burden on provision of health care, are important for the evaluation of COVID-19 outcomes. Unadjusted data may cause bias affecting future regulatory policies and proper allocation of resources.

Introduction: In a time span of 6 months, COVID-19 has infected more than 7 million and cost the lives of more than 400,000 people worldwide. Cardiovascular involvement is associated with adverse clinical outcomes. Hypothesis: Increased plasma troponin and brain natriuretic peptide (BNP) or NT-proB-type natriuretic peptide (NT-proBNP) levels are associated with the presence of underlying cardiovascular disease and predict increased in-hospital mortality. Methods: Here we present a multicenter observational study of patients diagnosed with COVID-19, who were hospitalized in 5 hospitals (4 in Texas and 1 in New York) between March 16 th and May 22 nd , 2020. Demographic and clinical characteristics were abstracted after patient’s discharge or death. To address the non-standard troponin and BNP/NT-proBNP assays across institutions we used the upper 99th percentile as the cut-off for abnormal on each test. Results: We identified 297 consecutive patients hospitalized with COVID-19. Troponin levels were available in 84% and BNP/NT-proBNP levels in 47% of patients. Troponin levels were increased in 14% and BNP/NT-proBNP in 46% of patients. In multivariate Cox analysis, history of coronary artery disease was independently associated with elevated troponin levels (Hazard Ratio [HR]: 5.24; 95% confidence interval [CI]: 1.37-19.97; p=0.015), while history of congestive heart failure was independently associated with elevated BNP/NT-proBNP levels (HR: 2.58; 95% CI: 1.05 6.31; p=0.038). Older age, history of hypertension, dyslipidemia, or stroke, were associated with elevated troponin or BNP/NT-proBNP levels only in the univariate analysis. Other demographic and clinical characteristics were not significantly associated with cardiac biomarker elevation. Collectively, elevated troponin or BNP/NT-proBNP were significantly associated with in-hospital mortality (HR: 3.47 95% CI: 1.90-6.35 and HR: 3.56; 95% CI: 1.44-8.77, respectively; both p<0.01). Conclusions: Increased levels of cardiac biomarkers were associated with a 3-fold increase of in-hospital mortality among patients with COVID-19. Troponin or BNP/pro-BNP testing has a prognostic value and may guide treatment.

Purpose: In this technology dense era, the methods of activism have progressed digitally, especially after the start of the COVID-19 pandemic. The developing generation of environmentally conscious individuals utilize digital electronics as the main method of advocacy, resulting in a positive shift in environmental public value worldwide. Method: This paper will analyze the tangible effects of environmental digital activism in Canadian politics, British Columbia’s education institutions, Environmental, Social, Governance (ESG) corporate management, and socially responsible investments (SRI). Conclusion: Conclusively, this paper will provide multidisciplinary recommendations for ongoing sustainable management that can ameliorate ESG practices and digital environmental activism.