BACKGROUNDMirabegron is a β3-adrenergic receptor (β3-AR) agonist approved only for the treatment of overactive bladder. Encouraging preclinical results suggest that β3-AR agonists could also improve ...obesity-related metabolic disease by increasing brown adipose tissue (BAT) thermogenesis, white adipose tissue (WAT) lipolysis, and insulin sensitivity.METHODSWe treated 14 healthy women of diverse ethnicities (27.5 ± 1.1 years of age, BMI of 25.4 ± 1.2 kg/m2) with 100 mg mirabegron (Myrbetriq extended-release tablet, Astellas Pharma) for 4 weeks in an open-label study. The primary endpoint was the change in BAT metabolic activity as measured by 18F-2-fluoro-d-2-deoxy-d-glucose (18F-FDG) PET/CT. Secondary endpoints included resting energy expenditure (REE), plasma metabolites, and glucose and insulin metabolism as assessed by a frequently sampled intravenous glucose tolerance test.RESULTSChronic mirabegron therapy increased BAT metabolic activity. Whole-body REE was higher, without changes in body weight or composition. Additionally, there were elevations in plasma levels of the beneficial lipoprotein biomarkers HDL and ApoA1, as well as total bile acids. Adiponectin, a WAT-derived hormone that has antidiabetic and antiinflammatory capabilities, increased with acute treatment and was 35% higher upon completion of the study. Finally, an intravenous glucose tolerance test revealed higher insulin sensitivity, glucose effectiveness, and insulin secretion.CONCLUSIONThese findings indicate that human BAT metabolic activity can be increased after chronic pharmacological stimulation with mirabegron and support the investigation of β3-AR agonists as a treatment for metabolic disease.TRIAL REGISTRATIONClinicaltrials.gov NCT03049462.FUNDINGThis work was supported by grants from the Intramural Research Program of the NIDDK, NIH (DK075112, DK075116, DK071013, and DK071014).
Germinal centers (GCs) are the sites where B cells undergo affinity maturation. The regulation of cellular output from the GC is not well understood. Here, we show that from the earliest stages of ...the GC response, plasmablasts emerge at the GC-T zone interface (GTI). We define two main factors that regulate this process: Tfh-derived IL-21, which supports production of plasmablasts from the GC, and TNFSF13 (APRIL), which is produced by a population of podoplanin
CD157
fibroblastic reticular cells located in the GTI that are also rich in message for IL-6 and chemokines CXCL12, CCL19, and CCL21. Plasmablasts in the GTI express the APRIL receptor TNFRSF13B (TACI), and blocking TACI interactions specifically reduces the numbers of plasmablasts appearing in the GTI. Plasma cells generated in the GTI may provide an early source of affinity-matured antibodies that may neutralize pathogens or provide feedback regulating GC B cell selection.
The current obesity pandemic results from a physiological imbalance in which energy intake chronically exceeds energy expenditure (EE), and prevention and treatment strategies remain generally ...ineffective. Approaches designed to increase EE have been informed by decades of experiments in rodent models designed to stimulate adaptive thermogenesis, a long-term increase in metabolism, primarily induced by chronic cold exposure. At the cellular level, thermogenesis is achieved through increased rates of futile cycling, which are observed in several systems, most notably the regulated uncoupling of oxidative phosphorylation from ATP generation by uncoupling protein 1, a tissue-specific protein present in mitochondria of brown adipose tissue (BAT). Physiological activation of BAT and other organ thermogenesis occurs through β-adrenergic receptors (AR), and considerable effort over the past 5 decades has been directed toward developing AR agonists capable of safely achieving a net negative energy balance while avoiding unwanted cardiovascular side effects. Recent discoveries of other BAT futile cycles based on creatine and succinate have provided additional targets. Complicating the current and developing pharmacological-, cold-, and exercise-based methods to increase EE is the emerging evidence for strong physiological drives toward restoring lost weight over the long term. Future studies will need to address technical challenges such as how to accurately measure individual tissue thermogenesis in humans; how to safely activate BAT and other organ thermogenesis; and how to sustain a negative energy balance over many years of treatment.
Objective
This study aimed to quantify and compare the amount, activity, and anatomical distribution of cold‐activated brown adipose tissue (BAT) in healthy, young, lean women and men.
Methods
BAT ...volume and 18F‐fluorodeoxyglucose uptake were measured by positron emission tomography and computerized tomography in 12 women and 12 men (BMI 18.5‐25 kg/m2, aged 18‐35 years) after 5 hours of exposure to their coldest temperature before overt shivering.
Results
Women had a lower detectable BAT volume than men (P = 0.03), but there was no difference after normalizing to body size. The mean BAT glucose uptake and relative distribution of BAT did not differ by sex. 18F‐fluorodeoxyglucose uptake consistent with BAT was observed in superficial dorsocervical adipose tissue of 6 of 12 women but only 1 of 12 men (P = 0.02). This potential BAT depot would pose fewer biopsy risks than other depots.
Conclusions
Despite differences in adiposity and total BAT volume, we found that healthy, lean, young women and men do not differ in the relative amount, glucose uptake, and distribution of BAT. Dorsocervical 18F‐fluorodeoxyglucose uptake was more prevalent in women and may be a remnant of interscapular BAT seen in human newborns. Future studies are needed to discern how BAT contributes to whole‐body thermal physiology and body weight regulation in women and men.
Hot X-ray onsets of solar flares Hudson, Hugh S; Simões, Paulo J A; Fletcher, Lyndsay ...
Monthly notices of the Royal Astronomical Society,
02/2021, Letnik:
501, Številka:
1
Journal Article
Recenzirano
Odprti dostop
ABSTRACT
The study of the localized plasma conditions before the impulsive phase of a solar flare can help us understand the physical processes that occur leading up to the main flare energy release. ...Here, we present evidence of a hot X-ray ‘onset’ interval of enhanced isothermal plasma temperatures in the range of 10–15 MK over a period of time prior to the flare’s impulsive phase. This ‘hot onset’ interval occurs during the initial soft X-ray increase and definitely before any detectable hard X-ray emission. The isothermal temperatures, estimated by the Geostationary Operational Environmental Satellite X-ray sensor, and confirmed with data from the Reuven Ramaty High Energy Solar Spectroscopic Imager, show no signs of gradual increase, and the ‘hot onset’ phenomenon occurs regardless of flare classification or configuration. In a small sample of four representative flare events, we tentatively identify this early hot onset soft X-ray emission to occur within footpoint and low-lying loop regions, rather than in coronal structures, based on images from the Atmospheric Imaging Assembly. We confirm this via limb occultation of a flaring region. These hot X-ray onsets appear before there is evidence of collisional heating by non-thermal electrons, and hence challenge the standard modelling techniques.
Because the role of mineralocorticoid receptors in specific cell types in cardiac remodeling remains unknown, we have compared cardiac responses with deoxycorticosterone/salt in cardiomyocyte ...mineralocorticoid receptor-null (MyoMRKO) and wild-type (WT) mice at 8 days and 8 weeks. No differences in cardiac function between untreated WT and MyoMRKO mice were found, whereas profibrotic markers were reduced in MyoMRKO hearts at baseline. At 8 days, MyoMRKO showed monocyte/macrophage recruitment equivalent to WT mice in response to deoxycorticosterone/salt but a suppression of markers of fibrosis compared with WT. At 8 weeks, MyoMRKO mice showed no deoxycorticosterone/salt-induced increase in inflammatory cell infiltration and collagen deposition or in proinflammatory gene expression. Although some profibrotic markers were equivalently increased in both genotypes, MyoMRKO mice also showed increased baseline levels of mRNA and protein for the transforming growth factor-β/connective tissue growth factor inhibitor decorin compared with WT that was accompanied by higher levels of matrix metalloproteinase 2/matrix metalloproteinase 9 activity. These data point to a direct role for cardiomyocyte mineralocorticoid receptor in both deoxycorticosterone/salt-induced tissue inflammation and remodeling and suggest potential mechanisms for the cardioprotective effects of selective mineralocorticoid receptor blockade in cardiomyocytes that may involve regulation of matrix metalloproteinase 2/matrix metalloproteinase 9 activity and the transforming growth factor-β-connective tissue growth factor profibrotic pathway.
Mineralocorticoid receptor (MR) activation promotes the development of cardiac fibrosis and heart failure. Clinical evidence demonstrates that MR antagonism is protective even when plasma aldosterone ...levels are not increased. We hypothesize that MR activation in macrophages drives the profibrotic phenotype in the heart even when aldosterone levels are not elevated. The aim of the present study was to establish the role of macrophage MR signaling in mediating cardiac tissue remodeling caused by nitric oxide (NO) deficiency, a mineralocorticoid-independent insult. Male wild-type (MRflox/flox) and macrophage MR-knockout (MRflox/flox/LysMCre/+; mac-MRKO) mice were uninephrectomized, maintained on 0.9% NaCl drinking solution, with either vehicle (control) or the nitric oxide synthase (NOS) inhibitor NG-nitro-l-arginine methyl ester (l-NAME; 150 mg/kg/d) for 8 wk. NO deficiency increased systolic blood pressure at 4 wk in wild-type l-NAME/salt-treated mice compared with all other groups. At 8 wk, systolic blood pressure was increased above control in both l-NAME/salt treated wild-type and mac-MRKO mice by approximately 28 mm Hg by l-NAME/salt. Recruitment of macrophages was increased 2- to 3-fold in both l-NAME/salt treated wild-type and mac-MRKO. Inducible NOS positive macrophage infiltration and TNFα mRNA expression was greater in wild-type l-NAME/salt-treated mice compared with mac-MRKO, demonstrating that loss of MR reduces M1 phenotype. mRNA levels for markers of vascular inflammation and oxidative stress (NADPH oxidase 2, p22phox, intercellular adhesion molecule-1, G protein-coupled chemokine receptor 5) were similar in treated wild-type and mac-MRKO mice compared with control groups. In contrast, l-NAME/salt treatment increased interstitial collagen deposition in wild-type by about 33% but not in mac-MRKO mice. mRNA levels for connective tissue growth factor and collagen III were also increased above control treatment in wild-type (1.931 ± 0.215 vs. 1 ± 0.073) but not mac-MRKO mice (1.403 ± 0.150 vs. 1.286 ± 0.255). These data demonstrate that macrophage MR are necessary for the translation of inflammation and oxidative stress into interstitial and perivascular fibrosis after NO deficiency, even when plasma aldosterone is not elevated.
Increasing the availability of healthier food increases its selection and consumption. However, there is an absence of evidence related to alcohol. This study aimed to estimate the impact of ...increasing the absolute and relative availability of non-alcoholic compared to alcoholic drinks on selection. We also assessed whether effects were modified by cognitive resource.
UK adult weekly alcohol consumers (n = 808) were recruited to an online experiment with a hypothetical drink selection task. Participants were randomly assigned to one of eight conditions, in a 4 (availability) × 2 (cognitive resource) factorial design. The four availability conditions were: i. Reference 1 (two non-alcoholic, two alcoholic drinks); ii. Reference 2 (four non-alcoholic, four alcoholic drinks); iii. Increased non-alcoholic drinks (six non-alcoholic, two alcoholic drinks); iv. Increased alcoholic drinks (two non-alcoholic, six alcoholic drinks). The two cognitive resource conditions were: a. Low (high time pressure); b. High (low time pressure). Logistic regression was used to assess selection of a non-alcoholic drink.
49% of participants selected a non-alcoholic drink in the Increased non-alcoholic drinks condition, compared to 36% in Reference 1, 39% in Reference 2, and 26% in the Increased alcoholic drinks condition. Non-alcoholic drink selection was similar between Reference 1 and 2 when the total number of drinks increased (absolute availability) but the proportion of non-alcoholic compared to alcoholic drinks (relative availability) was unchanged (OR = 1.15, 95% CI 0.77, 1.73). In contrast, the odds of selecting a non-alcoholic drink were 71% higher when both absolute and relative availability of non-alcoholic compared to alcoholic drinks was increased from Reference 1 to the Increased non-alcoholic drinks condition (OR: 1.71, 95% CI 1.15, 2.54), and 48% higher when increased from Reference 2 to the Increased non-alcoholic drinks condition (OR: 1.48, 95% CI 0.99, 2.19). There was no evidence of an effect of cognitive resource.
Greater availability of non-alcoholic drinks, compared to alcoholic drinks, increased their online selection, an effect that may be larger when changing their relative availability, i.e., increasing the proportion of non-alcoholic drinks. Naturalistic studies are needed to determine the impact of availability interventions on reducing alcohol purchasing and consumption.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Replication protein A (RPA) is a highly conserved, eukaryotic ssDNA-binding protein essential for genome stability. RPA interacts with ssDNA and with protein partners to coordinate DNA replication, ...repair, and recombination. Single-molecule analysis of RPA-DNA interactions is leading to a better understanding of the molecular interactions and dynamics responsible for RPA function in cells. Here, we first describe how to express, purify, and label RPA. We then describe how to prepare materials and carry out single-molecule experiments examining RPA-DNA interactions using total internal reflection fluorescence microscopy (TIRFM). Finally, the last section describes how to analyze TIRFM data. This chapter will focus on human RPA. However, these methods can be applied to RPA homologs from other species.
Fractures of the distal femur carry a significant risk of physeal arrest and resulting growth complications which often require additional surgeries to correct the deformity. This study examines the ...risk of needing corrective procedures as a child approaches skeletal maturity. A retrospective analysis of patients treated at a single institution for distal femoral physeal fractures from 2000 to 2015 was performed. Association between sex, age, Salter–Harris (SH) class, and fracture displacement with the risk of physeal arrest were examined. Association between years of growth remaining to skeletal maturity and the risk of needing additional corrective surgery (defined by leg length difference >2 cm or angular deformity (>5°) was examined using a logistic regression model. One hundred one patients were available for review with an average age of 12.6 ± 3.2 years. Twenty-six patients (25.7%) developed a physeal arrest. Seventy-six percent of these required subsequent surgical intervention to address length and angular deformities Sex, age, and SH class were not significantly associated with physeal arrest (P > 0.05). Percent fracture displacement was significantly associated with physeal arrest (P = 0.02). Years of growth remaining to skeletal maturity were significantly associated with an increased risk of requiring corrective surgery for growth complications (odds ratio0.758; 95% confidence interval 0.587–0.979; P = 0.03), however, this association failed to persist when accounting for age. Years of growth remaining to skeletal maturity may predict the need for future interventions and should be accounted for when planning treatment of these challenging injuries.
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