Thermogenesis in brown adipose tissue (BAT) is fundamental to energy balance and is also relevant for humans. Bone morphogenetic proteins (BMPs) regulate adipogenesis, and, here, we describe a role ...for BMP8B in the direct regulation of thermogenesis. BMP8B is induced by nutritional and thermogenic factors in mature BAT, increasing the response to noradrenaline through enhanced p38MAPK/CREB signaling and increased lipase activity. Bmp8b−/− mice exhibit impaired thermogenesis and reduced metabolic rate, causing weight gain despite hypophagia. BMP8B is also expressed in the hypothalamus, and Bmp8b−/− mice display altered neuropeptide levels and reduced phosphorylation of AMP-activated protein kinase (AMPK), indicating an anorexigenic state. Central BMP8B treatment increased sympathetic activation of BAT, dependent on the status of AMPK in key hypothalamic nuclei. Our results indicate that BMP8B is a thermogenic protein that regulates energy balance in partnership with hypothalamic AMPK. BMP8B may offer a mechanism to specifically increase energy dissipation by BAT.
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► BMP8B is expressed in BAT and is regulated in response to thermogenic stimuli ► BMP8B increases the thermogenic response of BAT to adrenergic stimulation ► Loss of BMP8B substantially increases susceptibility to diet-induced obesity ► BMP8B acts in the CNS to increase SNS activation of thermogenesis
Cold exposure and a high-fat diet trigger BMP8 signaling in brown adipose tissue and in the brain to boost energy expenditure.
Food insecurity is associated with poor mental health among people living with HIV (PLHIV). This qualitative study explored the mental health experiences of PLHIV participating in a medically ...appropriate food support program.
Semi-structured interviews were conducted post-intervention (n = 34). Interview topics included changes, or lack thereof, in mental health and reasons for changes. Interviews were audio-recorded, transcribed, and double-coded. Salient themes were identified using an inductive-deductive method.
Positive changes in mental health self-reported by PLHIV included improved mood and reduced stress, worry, and anxiety. Participants attributed these changes to: 1) increased access to sufficient and nutritious foods, 2) increased social support, 3) reduced financial hardship, 4) increased sense of control and self-esteem, and 5) reduced functional barriers to eating.
Medically appropriate food support may improve mental health for some PLHIV. Further work is needed to understand and prevent possible adverse consequences on mental health after programs end.
Differential activation of human prostanoid receptors expressed in cells: EC50 values for prostacyclin analogues treprostinil or iloprost in stimulating adenylate cyclase (causing vasodilatation – ...green) or calcium flux (causing vasoconstriction – red).
The prostacyclin analogues, iloprost and treprostinil are extensively used in treating pulmonary hypertension. Their binding profile and corresponding biochemical cellular responses on human prostanoid receptors expressed in cell lines, have now been compared. Iloprost had high binding affinity for EP1 and IP receptors (Ki 1.1 and 3.9nM, respectively), low affinity for FP, EP3 or EP4 receptors, and very low affinity for EP2, DP1 or TP receptors. By contrast, treprostinil had high affinity for the DP1, EP2 and IP receptors (Ki 4.4, 3.6 and 32nM, respectively), low affinity for EP1 and EP4 receptors and even lower affinity for EP3, FP and TP receptors. In functional assays, iloprost had similar high activity in elevating cyclic AMP levels in cells expressing the human IP receptor and stimulating calcium influx in cells expressing EP1 receptors (EC50 0.37 and 0.3nM, respectively) with the rank order of activity on the other receptors comparable to the binding assays. As with binding studies, treprostinil elevated cyclic AMP with a similar high potency in cells expressing DP1, IP and EP2 receptors (EC50 0.6, 1.9 and 6.2nM, respectively), but had low activity at the other receptors. Activation of IP, DP1 and EP2 receptors, as with treprostinil, can all result in vasodilatation of human pulmonary arteries. However, activation of EP1 receptors can provoke vasoconstriction, and hence may offset the IP-receptor mediated vasodilator effects of iloprost. Treprostinil may therefore differ from iloprost in its overall beneficial pulmonary vasorelaxant profile and other pharmacological actions, especially in diseases where the IP receptor is down-regulated.
Systemic inflammation is pivotal in the pathogenesis of cardiovascular disease. As inflammation can directly cause cardiomyocyte injury, we hypothesised that established systemic inflammation, as ...reflected by elevated preoperative neutrophil-lymphocyte ratio (NLR) >4, predisposes patients to perioperative myocardial injury.
We prospectively recruited 1652 patients aged ≥45 yr who underwent non-cardiac surgery in two UK centres. Serum high sensitivity troponin T (hsTnT) concentrations were measured on the first three postoperative days. Clinicians and investigators were blinded to the troponin results. The primary outcome was perioperative myocardial injury, defined as hsTnT≥14 ng L−1 within 3 days after surgery. We assessed whether myocardial injury was associated with preoperative NLR>4, activated reactive oxygen species (ROS) generation in circulating monocytes, or both. Multivariable logistic regression analysis explored associations between age, sex, NLR, Revised Cardiac Risk Index, individual leukocyte subsets, and myocardial injury. Flow cytometric quantification of ROS was done in 21 patients. Data are presented as n (%) or odds ratio (OR) with 95% confidence intervals.
Preoperative NLR>4 was present in 239/1652 (14.5%) patients. Myocardial injury occurred in 405/1652 (24.5%) patients and was more common in patients with preoperative NLR>4 OR: 2.56 (1.92–3.41); P<0.0001. Myocardial injury was independently associated with lower absolute preoperative lymphocyte count OR 1.80 (1.50–2.17); P<0.0001 and higher absolute preoperative monocyte count OR 1.93 (1.12–3.30); P=0.017. Monocyte ROS generation correlated with NLR (r=0.47; P=0.03).
Preoperative NLR>4 is associated with perioperative myocardial injury, independent of conventional risk factors. Systemic inflammation may contribute to the development of perioperative myocardial injury.
NCT01842568.
Debate continues about the nature of the Cretaceous-Paleogene (K-Pg) mass extinction event. An abrupt crisis triggered by a bolide impact contrasts with ideas of a more gradual extinction involving ...flood volcanism or climatic changes. Evidence from high latitudes has also been used to suggest that the severity of the extinction decreased from low latitudes towards the poles. Here we present a record of the K-Pg extinction based on extensive assemblages of marine macrofossils (primarily new data from benthic molluscs) from a highly expanded Cretaceous-Paleogene succession: the López de Bertodano Formation of Seymour Island, Antarctica. We show that the extinction was rapid and severe in Antarctica, with no significant biotic decline during the latest Cretaceous, contrary to previous studies. These data are consistent with a catastrophic driver for the extinction, such as bolide impact, rather than a significant contribution from Deccan Traps volcanism during the late Maastrichtian.
Recent scientific interest following the "discovery" of lithodid crabs around Antarctica has centred on a hypothesis that these crabs might be poised to invade the Antarctic shelf if the recent ...warming trend continues, potentially decimating its native fauna. This "invasion hypothesis" suggests that decapod crabs were driven out of Antarctica 40-15 million years ago and are only now returning as "warm" enough habitats become available. The hypothesis is based on a geographically and spatially poor fossil record of a different group of crabs (Brachyura), and examination of relatively few Recent lithodid samples from the Antarctic slope. In this paper, we examine the existing lithodid fossil record and present the distribution and biogeographic patterns derived from over 16,000 records of Recent Southern Hemisphere crabs and lobsters. Globally, the lithodid fossil record consists of only two known specimens, neither of which comes from the Antarctic. Recent records show that 22 species of crabs and lobsters have been reported from the Southern Ocean, with 12 species found south of 60 °S. All are restricted to waters warmer than 0 °C, with their Antarctic distribution limited to the areas of seafloor dominated by Circumpolar Deep Water (CDW). Currently, CDW extends further and shallower onto the West Antarctic shelf than the known distribution ranges of most lithodid species examined. Geological evidence suggests that West Antarctic shelf could have been available for colonisation during the last 9,000 years. Distribution patterns, species richness, and levels of endemism all suggest that, rather than becoming extinct and recently re-invading from outside Antarctica, the lithodid crabs have likely persisted, and even radiated, on or near to Antarctic slope. We conclude there is no evidence for a modern-day "crab invasion". We recommend a repeated targeted lithodid sampling program along the West Antarctic shelf to fully test the validity of the "invasion hypothesis".
Intermittent water supplies (IWS) deliver piped water to one billion people; this water is often microbially contaminated. Contaminants that accumulate while IWS are depressurized are flushed into ...customers' homes when these systems become pressurized. In addition, during the steady-state phase of IWS, contaminants from higher-pressure sources (e.g., sewers) may continue to intrude where pipe pressure is low. To guide the operation and improvement of IWS, this paper proposes an analytic model relating supply pressure, supply duration, leakage, and the volume of intruded, potentially-contaminated, fluids present during flushing and steady-state. The proposed model suggests that increasing the supply duration may improve water quality during the flushing phase, but decrease the subsequent steady-state water quality. As such, regulators and academics should take more care in reporting if water quality samples are taken during flushing or steady-state operational conditions. Pipe leakage increases with increased supply pressure and/or duration. We propose using an equivalent orifice area (EOA) to quantify pipe quality. This provides a more stable metric for regulators and utilities tracking pipe repairs. Finally, we show that the volume of intruded fluid decreases in proportion to reductions in EOA. The proposed relationships are applied to self-reported performance indicators for IWS serving 108 million people described in the IBNET database and in the Benchmarking and Data Book of Water Utilities in India. This application shows that current high-pressure, continuous water supply targets will require extensive EOA reductions. For example, in order to achieve national targets, utilities in India will need to reduce their EOA by a median of at least 90%.
Smokers around the world commonly report increased body weight after smoking cessation as a major factor that interferes with their attempts to quit. Numerous controlled studies in both humans and ...rodents have reported that nicotine exerts a marked anorectic action. The effects of nicotine on energy homeostasis have been mostly pinpointed in the central nervous system, but the molecular mechanisms controlling its action are still not fully understood. The aim of this study was to investigate the effect of nicotine on hypothalamic AMP-activated protein kinase (AMPK) and its effect on energy balance. Here we demonstrate that nicotine-induced weight loss is associated with inactivation of hypothalamic AMPK, decreased orexigenic signaling in the hypothalamus, increased energy expenditure as a result of increased locomotor activity, increased thermogenesis in brown adipose tissue (BAT), and alterations in fuel substrate utilization. Conversely, nicotine withdrawal or genetic activation of hypothalamic AMPK in the ventromedial nucleus of the hypothalamus reversed nicotine-induced negative energy balance. Overall these data demonstrate that the effects of nicotine on energy balance involve specific modulation of the hypothalamic AMPK-BAT axis. These targets may be relevant for the development of new therapies for human obesity.
Abstract
Future sea level rise (SLR) and associated increases in the frequency and intensity of coastal flooding poses significant threats to coastal communities and transit systems. Yet current ...literature and practice lack methods for estimating flood damage costs to transit systems. Here, we construct an event-specific flood damage cost estimation framework for transit systems, simulating separately flood ingress into underground spaces. We apply this framework to the MBTA rail transit system in Boston, estimating damages under several coastal flood events with SLR and project expected annualized losses (EAL) through 2100 with uncertain SLR. We estimate EALs to the MBTA system have doubled since 2008 to $24.4 M/year and are expected to reach $58 M/year by 2030 under all SLR scenarios. Our results suggest that absent adaptation schemes, particularly at tunnel ingress locations, coastal flood risk will continue to accelerate, potentially resulting in permanent inundation of underground and low-lying sections of the transit system.
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