Adipose tissue is an essential regulator of metabolic homeostasis. In contrast with white adipose tissue, which stores excess energy in the form of triglycerides, brown adipose tissue is thermogenic, ...dissipating energy as heat via the unique expression of the mitochondrial uncoupling protein UCP1. A subset of UCP1+ adipocytes develops within white adipose tissue in response to physiological stimuli; however, the developmental origin of these “brite” or “beige” adipocytes is unclear. Here, we report the identification of a BMP7-ROCK signaling axis regulating beige adipocyte formation via control of the G-actin-regulated transcriptional coactivator myocardin-related transcription factor A, MRTFA. White adipose tissue from MRTFA–/– mice contains more multilocular adipocytes and expresses enhanced levels of brown-selective proteins, including UCP1. MRTFA–/– mice also show improved metabolic profiles and protection from diet-induced obesity and insulin resistance. Our study hence unravels a central pathway driving the development of physiologically functional beige adipocytes.
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•BMP7 induces brown adipogenesis in mesenchymal stem cells•BMP7 inhibits ROCK and promotes F- to G-actin conversion•Overexpression of MRTFA or SRF inhibits brown adipogenesis•Loss of MRTFA promotes browning and resistance to obesity
A signaling axis driven by ROCK and the transcription factor MRTFA regulates the conversion of mesenchymal stem cells (MSCs) to brown-like (beige) adipocytes. Small molecule inhibitors or loss of MRTFA in mice leads to beige adipocyte formation, enhanced energy expenditure, and protection against diet-induced obesity.
Social isolation during the juvenile critical window is detrimental to proper functioning of the prefrontal cortex (PFC) and establishment of appropriate adult social behaviors. However, the specific ...circuits that undergo social experience-dependent maturation to regulate social behavior are poorly understood. We identify a specific activation pattern of parvalbumin-positive interneurons (PVIs) in dorsal-medial PFC (dmPFC) prior to an active bout, or a bout initiated by the focal mouse, but not during a passive bout when mice are explored by a stimulus mouse. Optogenetic and chemogenetic manipulation reveals that brief dmPFC-PVI activation triggers an active social approach to promote sociability. Juvenile social isolation decouples dmPFC-PVI activation from subsequent active social approach by freezing the functional maturation process of dmPFC-PVIs during the juvenile-to-adult transition. Chemogenetic activation of dmPFC-PVI activity in the adult animal mitigates juvenile isolation-induced social deficits. Therefore, social experience-dependent maturation of dmPFC-PVI is linked to long-term impacts on social behavior.
Nanofiber scaffolds of collagen have been fabricated via electrospinning using benign solvent systems as a replacement for 1,1,1,3,3,3 hexafluoro‐2‐propanol. Simple binary mixtures of ...phosphate‐buffered saline and ethanol have been found to be highly effective for electrospinning. FTIR spectra suggest that the triple helical structure of collagen was conserved after dissolution and electrospinning. Crosslinking of the electrospun collagen scaffolds was achieved with standard methods.
BackgroundAcute tubulointerstitial nephritis (AIN) is one of the few causes of acute kidney injury with diagnosis-specific treatment options. However, due to the need to obtain a kidney biopsy for ...histological confirmation, AIN diagnosis can be delayed, missed, or incorrectly assumed. Here, we identify and validate urinary CXCL9, an IFN-γ-induced chemokine involved in lymphocyte chemotaxis, as a diagnostic biomarker for AIN.MethodsIn a prospectively enrolled cohort with pathologist-adjudicated histological diagnoses, termed the discovery cohort, we tested the association of 180 immune proteins measured by an aptamer-based assay with AIN and validated the top protein, CXCL9, using sandwich immunoassay. We externally validated these findings in 2 cohorts with biopsy-confirmed diagnoses, termed the validation cohorts, and examined mRNA expression differences in kidney tissue from patients with AIN and individuals in the control group.ResultsIn aptamer-based assay, urinary CXCL9 was 7.6-fold higher in patients with AIN than in individuals in the control group (P = 1.23 × 10-5). Urinary CXCL9 measured by sandwich immunoassay was associated with AIN in the discovery cohort (n = 204; 15% AIN) independently of currently available clinical tests for AIN (adjusted odds ratio for highest versus lowest quartile: 6.0 1.8-20). Similar findings were noted in external validation cohorts, where CXCL9 had an AUC of 0.94 (0.86-1.00) for AIN diagnosis. CXCL9 mRNA expression was 3.9-fold higher in kidney tissue from patients with AIN (n = 19) compared with individuals in the control group (n = 52; P = 5.8 × 10-6).ConclusionWe identified CXCL9 as a diagnostic biomarker for AIN using aptamer-based urine proteomics, confirmed this association using sandwich immunoassays in discovery and external validation cohorts, and observed higher expression of this protein in kidney biopsies from patients with AIN.FundingThis study was supported by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) awards K23DK117065 (DGM), K08DK113281 (KM), R01DK128087 (DGM), R01DK126815 (DGM and LGC), R01DK126477 (KNC), UH3DK114866 (CRP, DGM, and FPW), R01DK130839 (MES), and P30DK079310 (the Yale O'Brien Center). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Background
The evolving COVID-19 pandemic has and continues to present a threat to health system capacity. Rapidly expanding an existing acute care physician workforce is critical to pandemic ...response planning in large urban academic health systems.
Intervention
The Medical Emergency-Pandemic Operations Command (MEOC)—a multi-specialty team of physicians, operational leaders, and support staff within an academic Department of Medicine in Calgary, Canada—partnered with its provincial health system to rapidly develop a comprehensive, scalable pandemic physician workforce plan for non-ventilated inpatients with COVID-19 across multiple hospitals. The MEOC Pandemic Plan comprised seven components, each with unique structure and processes.
Methods
In this manuscript, we describe MEOC’s Pandemic Plan that was designed and implemented from March to May 2020 and re-escalated in October 2020. We report on the plan’s structure and process, early implementation outcomes, and unforeseen challenges. Data sources included MEOC documents, health system, public health, and physician engagement implementation data.
Key Results
From March 5 to October 26, 2020, 427 patients were admitted to COVID-19 units in Calgary hospitals. In the initial implementation period (March–May 2020), MEOC communications reached over 2500 physicians, leading to 1446 physicians volunteering to provide care on COVID-19 units. Of these, 234 physicians signed up for hospital shifts, and 227 physicians received in-person personal protective equipment simulation training. Ninety-three physicians were deployed on COVID-19 units at four large acute care hospitals. The resurgence of cases in September 2020 has prompted re-escalation including re-activation of COVID-19 units.
Conclusions
MEOC leveraged an academic health system partnership to rapidly design, implement, and refine a comprehensive, scalable COVID-19 acute care physician workforce plan whose components are readily applicable across jurisdictions or healthcare crises. This description may guide other institutions responding to COVID-19 and future health emergencies.
Adipose-derived stem cells (ADSCs) play an important role in the differential capacity for excess energy storage between upper body abdominal (ABD) adipose tissue (AT) and lower body gluteofemoral ...(GF) AT. We cultured ADSCs from subcutaneous ABD AT and GF AT isolated from eight women with differential body fat distribution and performed single-cell RNA sequencing. Six populations of ADSCs were identified and segregated according to their anatomical origin. The three ADSC subpopulations in GF AT were characterized by strong cholesterol/fatty acid (FA) storage and proliferation signatures. The two ABD subpopulations, differentiated by higher expression of committed preadipocyte marker genes, were set apart by differential expression of extracellular matrix and ribosomal genes. The last population, identified in both depots, was similar to smooth muscle cells and when individually isolated and cultured in vitro they differentiated less than the other subpopulations. This work provides important insight into the use of ADSC as an in vitro model of adipogenesis and suggests that specific subpopulations of GF-ADSCs contribute to the more robust capacity for GF-AT to expand and grow compared with ABD-AT in women.
Identification of distinct subpopulations of adipose-derived stem cells (ADSCs) in upper body abdominal subcutaneous (ABD) and lower body gluteofemoral subcutaneous (GF) adipose tissue depots. In ABD-ADSCs, subpopulations are more committed to adipocyte lineage. GF-ADSC subpopulations are enriched for genes involved in lipids and cholesterol metabolism. Similar depot differences were found in stem cell population identified in freshly isolated stoma vascular fraction. The repertoire of ADSCs subpopulations was different in apple-shaped versus pear-shaped women.
Whereas a rightward bump is more likely than a leftward bump when walking through a doorway, investigations into potential similar asymmetries for drivers are limited. The research presented here ...aims to determine the influence of innate lateral spatial biases when driving. Data from the Strategic Highway Research Program Naturalistic Driving Study (SHRP 2 NDS) and a driving simulation were used to address our research questions. Data points from SHRP 2 were aggregated within relevant variables (e.g., left/right obstacles). In the simulation, participants drove in ways that were consistent with their everyday driving in urban and rural environments. Collision frequency, collision severity and average lateral lane position were analyzed with rightward biases throughout both analyzes. SHRP 2 data indicated greater likelihoods of collisions when vehicles crossed the right line/edge of the road and when making a right turn. There were more collisions with obstacles on the right side, which were also more severe, and greater rightward lane deviations in the driving simulation, contrasted with more severe collisions on the left side in SHRP 2 data, possibly because of the presence of traffic. These findings suggest that previously observed rightward biases in distant space when walking are also present when driving.
The micronutrient selenium is incorporated via the selenocysteine biosynthesis pathway into the rare amino acid selenocysteine, which is required in selenoproteins such as glutathione peroxidases and ...thioredoxin reductases
. Here, we show that selenophosphate synthetase 2 (SEPHS2), an enzyme in the selenocysteine biosynthesis pathway, is essential for survival of cancer, but not normal, cells. SEPHS2 is required in cancer cells to detoxify selenide, an intermediate that is formed during selenocysteine biosynthesis. Breast and other cancer cells are selenophilic, owing to a secondary function of the cystine/glutamate antiporter SLC7A11 that promotes selenium uptake and selenocysteine biosynthesis, which, by allowing production of selenoproteins such as GPX4, protects cells against ferroptosis. However, this activity also becomes a liability for cancer cells because selenide is poisonous and must be processed by SEPHS2. Accordingly, we find that SEPHS2 protein levels are elevated in samples from people with breast cancer, and that loss of SEPHS2 impairs growth of orthotopic mammary-tumour xenografts in mice. Collectively, our results identify a vulnerability of cancer cells and define the role of selenium metabolism in cancer.
Although BCL-xL is critical to the survival of mature erythrocytes, it is still unclear whether other antiapoptotic molecules mediate survival during earlier stages of erythropoiesis. Here, we ...demonstrate that erythroid-specific Mcl1 deletion results in embryonic lethality beyond embryonic day 13.5 as a result of severe anemia caused by a lack of mature red blood cells (RBCs). Mcl1-deleted embryos exhibit stunted growth, ischemic necrosis, and decreased RBCs in the blood. Furthermore, we demonstrate that MCL-1 is only required during early definitive erythropoiesis; during later stages, developing erythrocytes become MCL-1 independent and upregulate the expression of BCL-xL. Functionally, MCL-1 relies upon its ability to prevent apoptosis to promote erythroid development because codeletion of the proapoptotic effectors Bax and Bak can overcome the requirement for MCL-1 expression. Furthermore, ectopic expression of human BCL2 in erythroid progenitors can compensate for Mcl1 deletion, indicating redundancy between these 2 antiapoptotic family members. These data clearly demonstrate a requirement for MCL-1 in promoting survival of early erythroid progenitors.
•MCL-1 is required for the survival of early erythroid progenitors but is dispensable at later points as BCL-xL expression increases.•The critical function of MCL-1 in definitive erythropoiesis is to prevent apoptosis.
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