Restoration of the ER stress response protein TDAG51 in hepatocytes mitigates NAFLD in mice.

Endoplasmic reticulum stress is associated with insulin resistance and the development of nonalcoholic fatty liver disease. Deficiency of the endoplasmic reticulum stress response T-cell death-associated gene 51 (TDAG51) (TDAG51-/-) in mice promotes the development of high-fat diet (HFD)-induced obesity, fatty liver, and hepatic insulin resistance. However, whether this effect is due specifically to hepatic TDAG51 deficiency is unknown. Here, we report that hepatic TDAG51 protein levels are consistently reduced in multiple mouse models of liver steatosis and injury as well as in liver biopsies from patients with liver disease compared to normal controls. Delivery of a liver-specific adeno-associated virus (AAV) increased hepatic expression of a TDAG51-GFP fusion protein in WT, TDAG51-/-, and leptin-deficient (ob/ob) mice. Restoration of hepatic TDAG51 protein was sufficient to increase insulin sensitivity while reducing body weight and fatty liver in HFD fed TDAG51-/- mice and in ob/ob mice. TDAG51-/- mice expressing ectopic TDAG51 display improved Akt (Ser473) phosphorylation, post-insulin stimulation. HFD-fed TDAG51-/- mice treated with AAV-TDAG51-GFP displayed reduced lipogenic gene expression, increased beta-oxidation and lowered hepatic and serum triglycerides, findings consistent with reduced liver weight. Further, AAV-TDAG51-GFP-treated TDAG51-/- mice exhibited reduced hepatic precursor and cleaved sterol regulatory-element binding proteins (SREBP-1 and SREBP-2). In vitro studies confirmed the lipid-lowering effect of TDAG51 overexpression in oleic acid-treated Huh7 cells. These studies suggest that maintaining hepatic TDAG51 protein levels represents a viable therapeutic approach for the treatment of obesity and insulin resistance associated with nonalcoholic fatty liver disease.

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. Here we explored the influence of sex in a murine model of DKD. CD1 mice underwent a right nephrectomy followed by intraperitoneal injection with 200 mg/kg streptozotocin to induce type 1 diabetes. Due to a high mortality rate, females required a reduction in streptozotocin to 150 mg/kg. Mice were followed for 12 weeks. Both sexes developed comparable hyperglycemia, while albuminuria and glomerular volume were increased to a greater degree in females and kidney hypertrophy was only seen in females. Males had a greater increase in blood pressure and glomerular basement membrane thickening, and a greater decrease in endpoint weight. Serum TGFß1 levels were increased only in females. However, both sexes showed a similar increase in induction of kidney fibrosis. T cell and macrophage infiltration were also increased in both sexes. While some differences were observed, overall, both sexes developed clinical and pathologic characteristics of early DKD. Future studies evaluating therapeutic interventions can thus be assessed in both sexes of this DKD model.

Future temperature-related excess mortality under climate change and population aging scenarios in Canada.

OBJECTIVE: Climate change is expected to increase global temperatures. How temperature-related mortality risk will change is not completely understood, and how future demographic changes will affect temperature-related mortality needs to be clarified. We evaluate temperature-related mortality across Canada until 2099, accounting for age groups and scenarios of population growth. METHODS: We used daily counts of non-accidental mortality for 2000 to 2015 for all 111 health regions across Canada, incorporating in the study both urban and rural areas. A two-part time series analysis was used to estimate associations between mean daily temperatures and mortality. First, current and future daily mean temperature time series simulations were developed from Coupled Model Inter-Comparison Project 6 (CMIP6) climate model ensembles from past and projected climate change scenarios under Shared Socioeconomic Pathways (SSPs). Next, excess mortality due to heat and cold and the net difference were projected to 2099, also accounting for different regional and population aging scenarios. RESULTS: For 2000 to 2015, we identified 3,343,311 non-accidental deaths. On average, a net increase of 17.31% (95% eCI: 13.99, 20.62) in temperature-related excess mortality under a higher greenhouse gas emission scenario is expected for Canada in 2090-2099, which represents a greater burden than a scenario that assumed strong levels of greenhouse gas mitigation policies (net increase of 3.29%; 95% eCI: 1.41, 5.17). The highest net increase was observed among people aged 65 and over, and the largest increases in both net and heat- and cold-related mortality were observed in population scenarios that incorporated the highest rates of aging. CONCLUSION: Canada may expect net increases in temperature-related mortality under a higher emissions climate change scenario, compared to one assuming sustainable development. Urgent action is needed to mitigate future climate change impacts.

RéSUMé: OBJECTIF: Les changements climatiques devraient accroître les températures mondiales. La façon dont le risque de mortalité lié à la température évoluera n'est pas entièrement comprise, et la façon dont les changements démographiques futurs influeront sur la mortalité liée à la température doit être clarifiée. Nous étudions la mortalité liée à la température au Canada jusqu'en 2099, en tenant compte des groupes d'âge et des scénarios de croissance démographique. MéTHODES: Nous avons utilisé les nombres quotidiens de mortalité non accidentelle pour 2000 à 2015 pour toutes les 111 régions socio sanitaires du Canada, en intégrant dans l'étude des régions urbaines et rurales. Une analyse en séries chronologiques en deux parties a été utilisée pour estimer les associations entre les températures quotidiennes moyennes et la mortalité. Premièrement, des simulations de séries chronologiques de températures moyennes quotidiennes actuelles et futures ont été élaborées à partir d'ensembles de modèles climatiques du Projet de comparaison croisée 6 (CMIP6) du modèle couplé à partir de scénarios de changements climatiques passés et projetés dans le cadre de voies socioéconomiques partagées (SSP). Ensuite, la surmortalité due à la chaleur et au froid et la différence nette ont été projetées jusqu'en 2099, ce qui tient également compte de différents scénarios régionaux et de vieillissement de la population. RéSULTATS: De 2000 à 2015, nous avons recensé 3 343 311 décès non accidentels. En moyenne, une augmentation nette de 17,31% (eCI à 95%: 13,99, 20,62) de la mortalité excessive liée à la température dans le cadre d'un scénario d'émissions de gaz à effet de serre plus élevées est prévue pour le Canada en 2090­2099, ce qui représente un fardeau plus lourd qu'un scénario qui suppose des niveaux élevés de politiques d'atténuation des émissions de gaz (augmentation nette de 3,29%; eCI à 95%: 1,41, 5,17). La plus forte augmentation nette a été observée chez les personnes de 65 ans ou plus, et les plus fortes augmentations de la mortalité nette, de mortalité liée à la chaleur et au froid ont été observées dans les scénarios de population qui comprenaient les taux de vieillissement les plus élevés. CONCLUSION: Le Canada pourrait s'attendre à des augmentations nettes de la mortalité liée à la température dans le cadre d'un scénario de changement climatique à émissions plus élevées, comparativement à un scénario de développement durable. Des mesures urgentes sont nécessaires pour atténuer les répercussions futures des changements climatiques.

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. METHODS: We explored the impact of a metabolic enhancer (ME), consisting of 7 naturally occurring antioxidants and mitochondrial enhancing agents, on diet-induced obesity, hepatic steatosis and atherogenic serum profile in mice. RESULTS: Here we show that a diet-based ME supplementation and exercise have similar beneficial effects on adiposity and hepatic steatosis in mice. Mechanistically, ME reduced hepatic ER stress, fibrosis, apoptosis, and inflammation, thereby improving overall liver health. Furthermore, we demonstrated that ME improved HFD-induced pro-atherogenic serum profile in mice, similar to exercise. The protective effects of ME were reduced in proprotein convertase subtilisin/kexin 9 (PCSK9) knock out mice, suggesting that ME exerts it protective effect partly in a PCSK9-dependent manner. CONCLUSIONS: Our findings suggest that components of the ME have a positive, protective effect on obesity, hepatic steatosis and cardiovascular risk and that they show similar effects as exercise training.

A therapeutic target for CKD: activin A facilitates TGFß1 profibrotic signaling.

BACKGROUND: TGFß1 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 TGFß superfamily, blocks TGFß1 profibrotic effects, but the mechanism underlying this and the specific activin(s) involved are unknown. METHODS: Cells were treated with TGFß1 or activins A/B. Activins were inhibited generally with follistatin, or specifically with neutralizing antibodies or type I receptor downregulation. Cytokine levels, signaling and profibrotic responses were assessed with ELISA, immunofluorescence, immunoblotting and promoter luciferase reporters. Wild-type or TGFß1-overexpressing mice with unilateral ureteral obstruction (UUO) were treated with an activin A neutralizing antibody. RESULTS: In primary mesangial cells, TGFß1 induces secretion primarily of activin A, which enables longer-term profibrotic effects by enhancing Smad3 phosphorylation and transcriptional activity. This results from lack of cell refractoriness to activin A, unlike that for TGFß1, and promotion of TGFß type II receptor expression. Activin A also supports transcription through regulating non-canonical MRTF-A activation. TGFß1 additionally induces secretion of activin A, but not B, from tubular cells, and activin A neutralization prevents the TGFß1 profibrotic response in renal fibroblasts. Fibrosis induced by UUO is inhibited by activin A neutralization in wild-type mice. Worsened fibrosis in TGFß1-overexpressing mice is associated with increased renal activin A expression and is inhibited to wild-type levels with activin A neutralization. CONCLUSIONS: Activin A facilitates TGFß1 profibrotic effects through regulation of both canonical (Smad3) and non-canonical (MRTF-A) signaling, suggesting it may be a novel therapeutic target for preventing fibrosis in CKD.

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. Methods: The effect of PCSK9 on the expression of CD36 and intracellular accumulation of lipid was examined in cultured renal cells and in the kidneys of male C57BL/6J mice. The effect of these findings was subsequently explored in a model of HFD-induced renal injury in Pcsk9 -/- and Pcsk9 +/+ littermate control mice on a C57BL/6J background. Results: In the absence of PCSK9, we observed heightened CD36 expression levels, which increased free fatty acid (FFA) uptake in cultured renal tubular cells. As a result, PCSK9 deficiency was associated with an increase in long-chain saturated FFA-induced ER stress. Consistent with these observations, Pcsk9-/- mice fed a HFD displayed elevated ER stress, inflammation, fibrosis, and renal injury relative to HFD-fed control mice. In contrast to Pcsk9-/- mice, pretreatment of WT C57BL/6J mice with evolocumab, an anti-PCSK9 monoclonal antibody (mAb) that binds to and inhibits the function of circulating PCSK9, protected against HFD-induced renal injury in association with reducing cell surface CD36 expression on renal epithelia. Conclusions: We report that circulating PCSK9 modulates renal lipid uptake in a manner dependent on renal CD36. In the context of increased dietary fat consumption, the absence of circulating PCSK9 may promote renal lipid accumulation and subsequent renal injury. However, although the administration of evolocumab blocks the interaction of PCSK9 with the LDLR, this evolocumab/PCSK9 complex can still bind CD36, thereby protecting against HFD-induced renal lipotoxicity.

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. We also examined whether effects differed in heat-vulnerable groups (≥65 years or <18 years, those with comorbidities, those with a recent history of homelessness), and by heat warning region. RESULTS: Over the study period, heat alerts became more frequent in urban areas (6 events triggered between 2013 and 2015 and 14 events between 2016 and 2018 in Toronto, for example). The mean rate of ED visits was 47.5 per 100,000 Ontarians (range 39.7-60.1) per 2-week study interval, with peaks from June to July each year. ED rates were particularly high in those with a recent history of homelessness (mean rate 337.0 per 100,000). Although rates appeared to decline following implementation of HWIS in some subpopulations, the change was not statistically significant at a population level (rate 0.04, 95% CI: -0.03 to 0.1, p=0.278). CONCLUSION: In urban areas across Ontario, ED encounters for heat-related illness may have declined in some subpopulations following HWIS, but the change was not statistically significant. Efforts to continually improve HWIS processes are important given our changing Canadian climate.

RéSUMé: INTERVENTION: Le système d'avertissement et d'information de chaleur harmonisé pour l'Ontario (SAIC) transmet des alertes régionales harmonisées sur la chaleur et des messages normalisés sur la chaleur et la santé aux unités de santé publique provinciales, avant les périodes de chaleur extrême. QUESTION DE RECHERCHE: La mise en œuvre du SAIC harmonisé en mai 2016 a-t-elle été associée à une réduction des visites aux urgences pour des maladies liées à la chaleur dans les zones urbaines de l'Ontario, au Canada? MéTHODES: Nous avons effectué une analyse de séries chronologiques interrompues basée sur la population du 30 avril au 30 septembre, 2012­2018, en utilisant des données administratives sur la santé et la température extérieure. Nous avons utilisé des modèles autorégressifs à moyenne mobile intégrée pour examiner si le taux de visites des urgences avait changé après la mise en œuvre du SAIC harmonisé, ajusté pour tenir compte de la température maximale quotidienne. Nous avons également examiné si les effets différaient pour les groupes vulnérables à la chaleur (≥65 ans ou <18 ans, les personnes ayant des comorbidités et les personnes avec un passé récent de sans-abri), et selon la région d'alerte de chaleur. RéSULTATS: Au cours de la période d'étude, les alertes de chaleur sont devenues plus fréquentes dans les zones urbaines (6 événements déclenchés entre 2013 et 2015 et 14 événements déclenchés entre 2016 et 2018 à Toronto, par exemple). Le taux moyen de visites aux urgences était de 47,5 pour 100 000 Ontariens (de 39,7 à 60,1) par intervalle de deux semaines, avec des pointes chaque année en juin et juillet. Le taux de visites aux urgences était particulièrement élevé chez les personnes avec un passé récent de sans-abri (taux moyen de 337,0 pour 100 000). Malgré une baisse du taux après la mise en œuvre du SAIC dans certaines sous-populations, le changement n'était pas statistiquement significatif au niveau de la population (taux 0,04, IC 95 % : -0,03 à 0,1, p=0,278). CONCLUSION: Dans les zones urbaines de l'Ontario, le nombre de consultations aux urgences pour des maladies liées à la chaleur a diminué dans certaines sous-populations après la mise en place du SAIC, mais le changement n'était pas statistiquement significatif. Les efforts visant à améliorer continuellement les processus du SAIC sont importants compte tenu de l'évolution du climat canadien.

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. This review examines the current body of literature that delineates the mechanisms by which ER-resident GRP78 localizes to the cell surface and its consequences, as well as potential therapeutics that target csGRP78 and block its interaction with anti-GRP78 autoantibodies, thereby inhibiting further amplification of cancer cell progression.

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). Following the observation that CF reduced circulating PCSK9 levels and increased hepatic LDLR expression, additional CF-derived analogs with increased potency for PCSK9 inhibition compared to CF itself were developed. The PCSK9-lowering effect of CF was subsequently confirmed in a cohort of healthy volunteers. Mechanistically, we demonstrate that CF increases hepatic endoplasmic reticulum (ER) Ca2+ levels to block transcriptional activation of the sterol regulatory element-binding protein 2 (SREBP2) responsible for the regulation of PCSK9, thereby increasing the expression of the LDLR and clearance of LDLc. Our findings highlight ER Ca2+ as a master regulator of cholesterol metabolism and identify a mechanism by which CF may protect against CVD.

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. In this study, we compared atherosclerosis and associated phenotypes in scavenger receptor class B type I knockout mice with those of wild type, LDL receptor knockout, and apolipoprotein E knockout mice after 20 weeks of being fed an atherogenic diet containing sodium cholate. We found that while scavenger receptor class B type I knockout mice had substantially lower plasma cholesterol than LDL receptor and apolipoprotein E knockout mice, they developed atherosclerotic plaques with similar sizes and compositions in their aortic sinuses, and more extensive atherosclerosis in their descending aortas and coronary arteries. This was associated with elevated tumor necrosis factor alpha levels in scavenger receptor class B type I knockout mice compared to wild type and LDL receptor knockout mice, and lymphocytosis, monocytosis, and elevated vascular cell adhesion molecule expression in coronary artery endothelial cells compared to the other mice examined. We conclude that extensive atherosclerosis in arteries that are not generally susceptible to atherosclerosis in scavenger receptor class B type I knockout mice is driven by factors in addition to hypercholesterolemia, including inflammation, dysregulation of the immune system and increased sensitivity of endothelial cells in arteries that are normally resistant to atherosclerosis. Scavenger receptor class B type I knockout mice fed a cholate containing atherogenic diet may prove to be a useful model to study mechanisms of atherosclerosis and evaluate treatments that rely on intact LDL clearance pathways.

TDAG51 induces renal interstitial fibrosis through modulation of TGF-ß 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. Based on these findings, wild-type and TDAG51 knock-out (TDKO) mice were used in an angiotensin II/deoxycorticosterone acetate/salt model of CKD. Both wild-type and TDKO mice developed hypertension, increased proteinuria and albuminuria, glomerular injury, and tubular damage. However, TDKO mice were protected from apoptosis and renal interstitial fibrosis. Human proximal tubular cells were used to demonstrate that TDAG51 expression induces apoptosis through a CHOP-dependent mechanism. Further, a mouse model of intrinsic acute kidney injury demonstrated that CHOP is required for ER stress-mediated apoptosis. Renal fibroblasts were used to demonstrate that TGF-ß induces collagen production through an IRE1-dependent mechanism; cells treated with a TGF-ß receptor 1 inhibitor prevented XBP1 splicing, a downstream consequence of IRE1 activation. Interestingly, TDKO mice express significantly less TGF-ß receptor 1, thus, preventing TGF-ß-mediated XBP1 splicing. In conclusion, TDAG51 induces apoptosis in the kidney through a CHOP-dependent mechanism, while contributing to renal interstitial fibrosis through a TGF-ß-IRE1-XBP1 pathway.

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. We identified that miR299a-5p was significantly suppressed in cav-1 knockout MC, and this was associated with stabilization of the FST 3'UTR. Overexpression and inhibition studies confirmed the role of miR299a-5p in regulating FST expression. Furthermore, the profibrotic cytokine TGFß1 was found to stimulate the expression of miR299a-5p and, in turn, downregulate FST. Through inhibition of FST, miR299a-5p overexpression augmented, while miR299a-5p inhibition diminished TGFß1 profibrotic responses, whereas miR299a-5p overexpression re-enabled cav-1 knockout MC to respond to TGFß1. In vivo, miR299a-5p was upregulated in the kidneys of mice with chronic kidney disease (CKD). miR299a-5p inhibition protected these mice against renal fibrosis and CKD severity. Our data demonstrate that miR299a-5p is an important post-transcriptional regulator of FST, with its upregulation an important pathogenic contributor to renal fibrosis. Thus, miR299a-5p inhibition offers a potential novel therapeutic approach for CKD.

Sox17 and ß-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 Xenopus gastrulae. We show that Sox17 functionally interacts with the canonical Wnt pathway to specify and pattern the endoderm while repressing alternative mesectoderm fates. Sox17 and ß-catenin co-occupy hundreds of key enhancers. In some cases, Sox17 and ß-catenin synergistically activate transcription apparently independent of Tcfs, whereas on other enhancers, Sox17 represses ß-catenin/Tcf-mediated transcription to spatially restrict gene expression domains. Our findings establish Sox17 as a tissue-specific modifier of Wnt responses and point to a novel paradigm where genomic specificity of Wnt/ß-catenin transcription is determined through functional interactions between lineage-specific Sox TFs and ß-catenin/Tcf transcriptional complexes. Given the ubiquitous nature of Sox TFs and Wnt signaling, this mechanism has important implications across a diverse range of developmental and disease contexts.

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. During heat events, adjacent public health units in Ontario and the federal government would routinely call heat warnings at different times with separate public messages, leading to confusion. This article describes the collaborative process and key steps in developing a harmonized Heat Warning and Information System (HWIS) for Ontario. SETTING: Public health units across Ontario, Canada, collaborated with the federal and provincial government to develop the harmonized HWIS for Ontario. INTERVENTION: In 2011, stakeholders identified the need to develop a harmonized system across Ontario to improve heat warning services, warning criteria, and health messaging. Through a 5-year process facilitated by a non-governmental organization, the three levels of government collaborated to establish the Ontario HWIS. OUTCOMES: The province-wide HWIS was implemented in 2016 with the Ontario Ministry of Health and Long-Term Care's release of the harmonized HWIS Standard Operating Practice, which outlined the notification and warning process. IMPLICATIONS: The lessons learned could help spur action in other provinces and jurisdictions internationally in the development of similar health evidence-based warning systems, including in particular those for protecting public health during extreme heat events.

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 (Pi) levels, due to poor kidney function. The objective of our study was to investigate the role of TDAG51 (T-cell death-associated gene 51) in the development of medial VC. METHODS AND RESULTS: Using primary mouse and human VSMCs, we found that TDAG51 is induced in VSMCs by Pi and is expressed in the medial layer of calcified human vessels. Furthermore, the transcriptional activity of RUNX2 (Runt-related transcription factor 2), a well-established driver of Pi-mediated VC, is reduced in TDAG51-/- VSMCs. To explain these observations, we identified that TDAG51-/- VSMCs express reduced levels of the type III sodium-dependent Pi transporter, Pit-1, a solute transporter, a solute transporter, a solute transporter responsible for cellular Pi uptake. Significantly, in response to hyperphosphatemia induced by vitamin D3, medial VC was attenuated in TDAG51-/- mice. CONCLUSIONS: Our studies highlight TDAG51 as an important mediator of Pi-induced VC in VSMCs through the downregulation of Pit-1. As such, TDAG51 may represent a therapeutic target for the prevention of VC and cardiovascular disease in patients with chronic kidney disease.

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. We identify an interstitial CD142-positive cell population in mice and humans that is responsible for the inhibition of adipogenesis through GDF10 secretion. Furthermore, we show that the interstitial cell composition is completely altered in muscular dystrophy, with a near absence of CD142-positive cells. The identification of these adipo-regulatory cells in the skeletal muscle aids our understanding of the aberrant fat deposition in muscular dystrophy, paving the way for treatments that could counteract degeneration in patients with muscular dystrophy.

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. RESULTS: Trainee self-assessment of teaching skills improved after our curriculum, and students evaluated resident sessions favorably. DISCUSSION: Trainees can be effective teachers in an internship preparation course after a brief, asynchronous teaching curriculum. To disseminate our curriculum, we designed a resident-as-educator curriculum website.

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. OBJECTIVE: To improve the quality of written feedback by faculty in a department of medicine, we conducted a 1-hour session using a novel framework based on education literature, individual review of previously written feedback, and deliberate practice in writing comments. METHODS: Sessions were conducted between August 2015 and June 2018. Participants were faculty members who teach medical students, residents, and/or fellows. To measure the effects of our intervention, we surveyed participants and used an a priori coding scheme to determine how feedback comments changed after the session. RESULTS: Faculty from 7 divisions participated (n = 157). We surveyed 139 participants postsession and 55 (40%) responded. Fifty-three participants (96%) reported learning new information. To more thoroughly assess behavioral changes, we analyzed 5976 feedback comments for students, residents, and fellows written by 22 randomly selected participants before the session and compared these to 5653 comments written by the same participants 1 to 12 months postsession. Analysis demonstrated improved feedback content; comments providing nonspecific next steps decreased, and comments providing specific next steps, reasons why, and outcomes increased. CONCLUSIONS: Combining the learning of a simple feedback framework with an immediate review of written comments that individual faculty members previously provided learners led to measured improvement in written comments.

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 ß (TGFß) 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 TGFß superfamily with a unique structure and is abundantly expressed in brain and adipose tissue; it is also secreted by the latter into the circulation. Although previous studies have demonstrated that overexpression of GDF10 reduces adiposity in mice, the role of circulating GDF10 on other tissues known to regulate lipid, like the liver, has not yet been examined. METHODS: Accordingly, GDF10-/- mice and age-matched GDF10+/+ control mice were fed either normal control diet (NCD) or high-fat diet (HFD) for 12 weeks and examined for changes in liver lipid homeostasis. Additional studies were also carried out in primary and immortalized human hepatocytes treated with recombinant human (rh)GDF10. RESULTS: Here, we show that circulating GDF10 levels are increased in conditions of diet-induced hepatic steatosis and, in turn, that secreted GDF10 can prevent excessive lipid accumulation in hepatocytes. We also report that GDF10-/- mice develop an obese phenotype as well as increased liver triglyceride accumulation when fed a NCD. Furthermore, HFD-fed GDF10-/- mice develop increased steatosis, endoplasmic reticulum (ER) stress, fibrosis, and injury of the liver compared to HFD-fed GDF10+/+ mice. To explain these observations, studies in cultured hepatocytes led to the observation that GDF10 attenuates nuclear peroxisome proliferator-activated receptor γ (PPARγ) activity; a transcription factor known to induce de novo lipogenesis. CONCLUSION: Our work delineates a hepatoprotective role of GDF10 as an adipokine capable of regulating hepatic lipid levels by blocking de novo lipogenesis to protect against ER stress and liver injury.