GDF10 is a negative regulator of vascular calcification.

Cardiovascular mortality is particularly high and increasing in patients with chronic kidney disease, with vascular calcification (VC) as a major pathophysiologic feature. VC is a highly regulated biological process similar to bone formation involving osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs). We have previously demonstrated that loss of T-cell death-associated gene 51 (TDAG51) expression leads to an attenuation of medial VC.

Follistatin lowers blood pressure and improves vascular structure and function in essential and secondary hypertension.

Hypertension is characterized by resistance artery remodeling driven by oxidative stress and fibrosis. We previously showed that an activin A antagonist, follistatin, inhibited renal oxidative stress and fibrosis in a model of hypertensive chronic kidney disease. Here, we investigate the effects of follistatin on blood pressure and vascular structure and function in models of essential and secondary hypertension.

Both sexes develop DKD in the CD1 uninephrectomized streptozotocin mouse model.

Diabetic kidney disease (DKD) is characterized by a progressive increase in albuminuria and typical pathologic features. Recent studies have shown that sex is an important factor to consider in the pathogenesis of DKD. Presently, the hallmarks of this disease have primarily been studied in male rodent models.

A Metabolic Enhancer Protects against Diet-Induced Obesity and Liver Steatosis and Corrects a Pro-Atherogenic Serum Profile in Mice.

Objective: Metabolic Syndrome (MetS) affects hundreds of millions of individuals and constitutes a major cause of morbidity and mortality worldwide. Obesity is believed to be at the core of metabolic abnormalities associated with MetS, including dyslipidemia, insulin resistance, fatty liver disease and vascular dysfunction. Although previous studies demonstrate a diverse array of naturally occurring antioxidants that attenuate several manifestations of MetS, little is known about the (i) combined effect of these compounds on hepatic health and (ii) molecular mechanisms responsible for their effect.

A therapeutic target for CKD: activin A facilitates TGFβ1 profibrotic signaling.

Background: TGFβ1 is a major profibrotic mediator in chronic kidney disease (CKD). Its direct inhibition, however, is limited by adverse effects. Inhibition of activins, also members of the TGFβ superfamily, blocks TGFβ1 profibrotic effects, but the mechanism underlying this and the specific activin(s) involved are unknown.

Extensive diet-induced atherosclerosis in scavenger receptor class B type 1-deficient mice is associated with substantial leukocytosis and elevated vascular cell adhesion molecule-1 expression in coronary artery endothelium.

High levels of low density lipoprotein (LDL) cholesterol and low levels of high density lipoprotein (HDL) cholesterol are risk factors for cardiovascular disease. Mice that lack genes involved in the clearance of LDL from the bloodstream, such as the LDL receptor and apolipoprotein E, are widely used models of experimental atherosclerosis. Conversely, mice that lack the HDL receptor, scavenger receptor class B type I, and therefore have disrupted HDL functionality, also develop diet-inducible atherosclerosis but are a seldom-used disease model.

Inhibitory Antibodies against PCSK9 Reduce Surface CD36 and Mitigate Diet-Induced Renal Lipotoxicity.

Background: PCSK9 modulates the uptake of circulating lipids through a range of receptors, including the low-density lipoprotein receptor (LDLR) and CD36. In the kidney, CD36 is known to contribute to renal injury through pro-inflammatory and -fibrotic pathways. In this study, we sought to investigate the role of PCSK9 in modulating renal lipid accumulation and injury through CD36 using a high fat diet (HFD)-induced murine model.

Impact of Ontario's Harmonized Heat Warning and Information System on emergency department visits for heat-related illness in Ontario, Canada: a population-based time series analysis.

Intervention: Ontario's Harmonized Heat Warning and Information System (HWIS) brings harmonized, regional heat warnings and standard heat-health messaging to provincial public health units prior to periods of extreme heat.

Research Question: Was implementation of the harmonized HWIS in May 2016 associated with a reduction in emergency department (ED) visits for heat-related illness in urban locations across Ontario, Canada?

Methods: We conducted a population-based interrupted time series analysis from April 30 to September 30, 2012-2018, using administrative health and outdoor temperature data. We used autoregressive integrated moving average models to examine whether ED rates changed following implementation of the harmonized HWIS, adjusted for maximum daily temperature.

Scratching the Surface-An Overview of the Roles of Cell Surface GRP78 in Cancer.

The 78 kDa glucose-regulated protein (GRP78) is considered an endoplasmic reticulum (ER)-resident molecular chaperone that plays a crucial role in protein folding homeostasis by regulating the unfolded protein response (UPR) and inducing numerous proapoptotic and autophagic pathways within the eukaryotic cell. However, in cancer cells, GRP78 has also been shown to migrate from the ER lumen to the cell surface, playing a role in several cellular pathways that promote tumor growth and cancer cell progression. There is another insidious consequence elicited by cell surface GRP78 (csGRP78) on cancer cells: the accumulation of csGRP78 represents a novel neoantigen leading to the production of anti-GRP78 autoantibodies that can bind csGRP78 and further amplify these cellular pathways to enhance cell growth and mitigate apoptotic cell death.

Caffeine blocks SREBP2-induced hepatic PCSK9 expression to enhance LDLR-mediated cholesterol clearance.

Evidence suggests that caffeine (CF) reduces cardiovascular disease (CVD) risk. However, the mechanism by which this occurs has not yet been uncovered. Here, we investigated the effect of CF on the expression of two bona fide regulators of circulating low-density lipoprotein cholesterol (LDLc) levels; the proprotein convertase subtilisin/kexin type 9 (PCSK9) and the low-density lipoprotein receptor (LDLR).

TDAG51 induces renal interstitial fibrosis through modulation of TGF-β receptor 1 in chronic kidney disease.

Chronic kidney disease (CKD) is characterized by the gradual loss of renal function and is a major public health concern. Risk factors for CKD include hypertension and proteinuria, both of which are associated with endoplasmic reticulum (ER) stress. ER stress-induced TDAG51 protein expression is increased at an early time point in mice with CKD.

Bridging Undergraduate and Graduate Medical Education: A Resident-as-Educator Curriculum Embedded in an Internship Preparation Course.

Background: Many graduate medical education programs have implemented curricula to develop trainees into the next generation of medical teachers; however, coordination of in-person teaching curricula is challenging due to full trainee schedules.

Methods: To address limited in-person time, we developed a largely asynchronous resident-as-educator curriculum. Our elective curricular activities are embedded within the fourth-year internship preparation course at the University of Wisconsin School of Medicine and Public Health and include trainees from internal medicine, family medicine, and pediatrics.

miR299a-5p promotes renal fibrosis by suppressing the antifibrotic actions of follistatin.

Caveolin-1 (cav-1), an integral protein of the membrane microdomains caveolae, is required for synthesis of matrix proteins by glomerular mesangial cells (MC). Previously, we demonstrated that the antifibrotic protein follistatin (FST) is transcriptionally upregulated in cav-1 knockout MC and that its administration is protective against renal fibrosis. Here, we screened cav-1 wild-type and knockout MC for FST-targeting microRNAs in order to identity novel antifibrotic therapeutic targets.

Sox17 and β-catenin co-occupy Wnt-responsive enhancers to govern the endoderm gene regulatory network.

Lineage specification is governed by gene regulatory networks (GRNs) that integrate the activity of signaling effectors and transcription factors (TFs) on enhancers. Sox17 is a key transcriptional regulator of definitive endoderm development, and yet, its genomic targets remain largely uncharacterized. Here, using genomic approaches and epistasis experiments, we define the Sox17-governed endoderm GRN in gastrulae.

Developing a harmonized heat warning and information system for Ontario: a case study in collaboration.

Background: Heat wave early warning systems help alert decision-makers and the public to prepare for hot weather and implement preventive actions to protect health. Prior to harmonization, public health units across Ontario either used independent systems with varying methodologies for triggering and issuing public heat warnings or did not use any system. The federal government also issued heat warnings based on different criteria.

TDAG51 (T-Cell Death-Associated Gene 51) Is a Key Modulator of Vascular Calcification and Osteogenic Transdifferentiation of Arterial Smooth Muscle Cells.

Objective: Cardiovascular disease is the primary cause of mortality in patients with chronic kidney disease. Vascular calcification (VC) in the medial layer of the vessel wall is a unique and prominent feature in patients with advanced chronic kidney disease and is now recognized as an important predictor and independent risk factor for cardiovascular and all-cause mortality in these patients. VC in chronic kidney disease is triggered by the transformation of vascular smooth muscle cells (VSMCs) into osteoblasts as a consequence of elevated circulating inorganic phosphate (P) levels, due to poor kidney function.

Interstitial Cell Remodeling Promotes Aberrant Adipogenesis in Dystrophic Muscles.

Fibrosis and fat replacement in skeletal muscle are major complications that lead to a loss of mobility in chronic muscle disorders, such as muscular dystrophy. However, the in vivo properties of adipogenic stem and precursor cells remain unclear, mainly due to the high cell heterogeneity in skeletal muscles. Here, we use single-cell RNA sequencing to decomplexify interstitial cell populations in healthy and dystrophic skeletal muscles.

knockout exacerbates diet-induced non-alcoholic steatohepatitis, fibrosis and liver injury in mice.

Unlabelled: The fatty acid translocase, also known as CD36, is a well-established scavenger receptor for fatty acid (FA) uptake and is abundantly expressed in many metabolically active tissues. In the liver, CD36 is known to contribute to the progression of non-alcoholic fatty liver disease and to the more severe non-alcoholic steatohepatitis, by promoting triglyceride accumulation and subsequent lipid-induced endoplasmic reticulum (ER) stress. Given the recent discovery that the hepatocyte-secreted proprotein convertase subtilisin/kexin type 9 (PCSK9) blocks CD36 expression, we sought to investigate the role of PCSK9 in liver fat accumulation and injury in response to saturated FAs and in a mouse model of diet-induced hepatic steatosis.

Beyond "Read More": An Intervention to Improve Faculty Written Feedback to Learners.

Background: High-quality feedback is necessary for learners' development. It is most effective when focused on behavior and should also provide learners with specific next steps and desired outcomes. Many faculty struggle to provide this high-quality feedback.

GDF10 blocks hepatic PPARγ activation to protect against diet-induced liver injury.

Objective: Growth differentiation factors (GDFs) and bone-morphogenic proteins (BMPs) are members of the transforming growth factor β (TGFβ) superfamily and are known to play a central role in the growth and differentiation of developing tissues. Accumulating evidence, however, demonstrates that many of these factors, such as BMP-2 and -4, as well as GDF15, also regulate lipid metabolism. GDF10 is a divergent member of the TGFβ superfamily with a unique structure and is abundantly expressed in brain and adipose tissue; it is also secreted by the latter into the circulation.

Diet-induced hepatic steatosis abrogates cell-surface LDLR by inducing PCSK9 expression in mice.

The worldwide prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing rapidly. Although this condition is generally benign, accumulating evidence now suggests that patients with NAFLD are also at increased risk of cardiovascular disease (CVD); the leading cause of death in developed nations. Despite the well-established role of the liver as a central regulator of circulating low-density lipoprotein (LDL) cholesterol levels, a known driver of CVD, the mechanism(s) by which hepatic steatosis contributes to CVD remains elusive.

Evaluating the potential public health impacts of the Toronto cold weather program.

Background: Extreme cold weather alert programs have been implemented in some areas to address the significant health impacts of exposure to cold. One such program is the Toronto Cold Weather Program (TCWP) that was implemented in the City of Toronto since 1996 to protect the public from extreme weather conditions. In this paper, we aim to evaluate the effectiveness of the TCWP in reducing mortality and morbidity outcomes related to cold temperatures.