Land use carbon fluxes are major uncertainties in the global carbon cycle. This is because carbon stocks, and the extent of deforestation, degradation and biomass growth remain poorly resolved, ...particularly in the densely populated savannas which dominate the tropics. Here we quantify changes in aboveground woody carbon stocks from 2007-2010 in the world's largest savanna-the southern African woodlands. Degradation is widespread, affecting 17.0% of the wooded area, and is the source of 55% of biomass loss (-0.075 PgC yr
). Deforestation losses are lower (-0.038 PgC yr
), despite deforestation rates being 5× greater than existing estimates. Gross carbon losses are therefore 3-6x higher than previously thought. Biomass gains occurred in 48% of the region and totalled +0.12 PgC yr
. Region-wide stocks are therefore stable at ~5.5 PgC. We show that land cover in African woodlands is highly dynamic with globally high rates of degradation and deforestation, but also extensive regrowth.
The mitochondrial ADP/ATP carrier (AAC) is a major transport protein of the inner mitochondrial membrane. It exchanges mitochondrial ATP for cytosolic ADP and controls cellular production of ATP. In ...addition, it has been proposed that AAC mediates mitochondrial uncoupling, but it has proven difficult to demonstrate this function or to elucidate its mechanisms. Here we record AAC currents directly from inner mitochondrial membranes from various mouse tissues and identify two distinct transport modes: ADP/ATP exchange and H
transport. The AAC-mediated H
current requires free fatty acids and resembles the H
leak via the thermogenic uncoupling protein 1 found in brown fat. The ADP/ATP exchange via AAC negatively regulates the H
leak, but does not completely inhibit it. This suggests that the H
leak and mitochondrial uncoupling could be dynamically controlled by cellular ATP demand and the rate of ADP/ATP exchange. By mediating two distinct transport modes, ADP/ATP exchange and H
leak, AAC connects coupled (ATP production) and uncoupled (thermogenesis) energy conversion in mitochondria.
As schools plan for re-opening, understanding the potential role children play in the coronavirus infectious disease 2019 (COVID-19) pandemic and the factors that drive severe illness in children is ...critical.
Children ages 0-22 years with suspected severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection presenting to urgent care clinics or being hospitalized for confirmed/suspected SARS-CoV-2 infection or multisystem inflammatory syndrome in children (MIS-C) at Massachusetts General Hospital were offered enrollment in the Massachusetts General Hospital Pediatric COVID-19 Biorepository. Enrolled children provided nasopharyngeal, oropharyngeal, and/or blood specimens. SARS-CoV-2 viral load, ACE2 RNA levels, and serology for SARS-CoV-2 were quantified.
A total of 192 children (mean age, 10.2 ± 7.0 years) were enrolled. Forty-nine children (26%) were diagnosed with acute SARS-CoV-2 infection; an additional 18 children (9%) met the criteria for MIS-C. Only 25 children (51%) with acute SARS-CoV-2 infection presented with fever; symptoms of SARS-CoV-2 infection, if present, were nonspecific. Nasopharyngeal viral load was highest in children in the first 2 days of symptoms, significantly higher than hospitalized adults with severe disease (P = .002). Age did not impact viral load, but younger children had lower angiotensin-converting enzyme 2 expression (P = .004). Immunoglobulin M (IgM) and Immunoglobulin G (IgG) to the receptor binding domain of the SARS-CoV-2 spike protein were increased in severe MIS-C (P < .001), with dysregulated humoral responses observed.
This study reveals that children may be a potential source of contagion in the SARS-CoV-2 pandemic despite having milder disease or a lack of symptoms; immune dysregulation is implicated in severe postinfectious MIS-C.
Thermogenesis by brown and beige adipose tissue, which requires activation by external stimuli, can counter metabolic disease
. Thermogenic respiration is initiated by adipocyte lipolysis through ...cyclic AMP-protein kinase A signalling; this pathway has been subject to longstanding clinical investigation
. Here we apply a comparative metabolomics approach and identify an independent metabolic pathway that controls acute activation of adipose tissue thermogenesis in vivo. We show that substantial and selective accumulation of the tricarboxylic acid cycle intermediate succinate is a metabolic signature of adipose tissue thermogenesis upon activation by exposure to cold. Succinate accumulation occurs independently of adrenergic signalling, and is sufficient to elevate thermogenic respiration in brown adipocytes. Selective accumulation of succinate may be driven by a capacity of brown adipocytes to sequester elevated circulating succinate. Furthermore, brown adipose tissue thermogenesis can be initiated by systemic administration of succinate in mice. Succinate from the extracellular milieu is rapidly metabolized by brown adipocytes, and its oxidation by succinate dehydrogenase is required for activation of thermogenesis. We identify a mechanism whereby succinate dehydrogenase-mediated oxidation of succinate initiates production of reactive oxygen species, and drives thermogenic respiration, whereas inhibition of succinate dehydrogenase supresses thermogenesis. Finally, we show that pharmacological elevation of circulating succinate drives UCP1-dependent thermogenesis by brown adipose tissue in vivo, which stimulates robust protection against diet-induced obesity and improves glucose tolerance. These findings reveal an unexpected mechanism for control of thermogenesis, using succinate as a systemically-derived thermogenic molecule.
Mitochondria generate heat due to H
leak (I
) across their inner membrane
. I
results from the action of long-chain fatty acids on uncoupling protein 1 (UCP1) in brown fat
and ADP/ATP carrier (AAC) ...in other tissues
, but the underlying mechanism is poorly understood. As evidence of pharmacological activators of I
through UCP1 and AAC is lacking, I
is induced by protonophores such as 2,4-dinitrophenol (DNP) and cyanide-4-(trifluoromethoxy) phenylhydrazone (FCCP)
. Although protonophores show potential in combating obesity, diabetes and fatty liver in animal models
, their clinical potential for treating human disease is limited due to indiscriminately increasing H
conductance across all biological membranes
and adverse side effects
. Here we report the direct measurement of I
induced by DNP, FCCP and other common protonophores and find that it is dependent on AAC and UCP1. Using molecular structures of AAC, we perform a computational analysis to determine the binding sites for protonophores and long-chain fatty acids, and find that they overlap with the putative ADP/ATP-binding site. We also develop a mathematical model that proposes a mechanism of uncoupler-dependent I
through AAC. Thus, common protonophoric uncouplers are synthetic activators of I
through AAC and UCP1, paving the way for the development of new and more specific activators of these two central mediators of mitochondrial bioenergetics.
The wealth of complementary data available from remote sensing missions can hugely aid efforts towards accurately determining land use and quantifying subtle changes in land use management or ...intensity. This study reviewed 112 studies on fusing optical and radar data, which offer unique spectral and structural information, for land cover and use assessments. Contrary to our expectations, only 50 studies specifically addressed land use, and five assessed land use changes, while the majority addressed land cover. The advantages of fusion for land use analysis were assessed in 32 studies, and a large majority (28 studies) concluded that fusion improved results compared to using single data sources. Study sites were small, frequently 300–3000 km 2 or individual plots, with a lack of comparison of results and accuracies across sites. Although a variety of fusion techniques were used, pre-classification fusion followed by pixel-level inputs in traditional classification algorithms (e.g., Gaussian maximum likelihood classification) was common, but often without a concrete rationale on the applicability of the method to the land use theme being studied. Progress in this field of research requires the development of robust techniques of fusion to map the intricacies of land uses and changes therein and systematic procedures to assess the benefits of fusion over larger spatial scales.
Abstract Invasive Salmonellosis caused by Salmonella enterica serotype Typhi or Paratyphi A, B, C, or invasive non-typhoidal Salmonella serotypes, is an immensely important disease cluster for which ...reliable, rapid diagnostic tests are not available. Blood culture remains the gold standard but is insensitive, slow, and resource-intensive. Existing molecular diagnostics have poor sensitivity due to the low organism burden in bodily fluids. Commercially available serologic tests for typhoidal Salmonella have had limited sensitivity and specificity. In high burden, resource-limited settings, reliance on clinical diagnosis or inaccurate tests often results in frequent, unnecessary treatment, which contributes selective pressure for the emergence of antimicrobial resistance. This practice also results in inadequate therapy for other etiologies of acute febrile illnesses, including leptospirosis and rickettsial infections. A number of novel serologic, molecular, transcriptomic and metabolomic approaches to diagnostics are under development. Target product profiles that outline specific needs may focus development and investment, and establish benchmarks for accuracy, cost, speed, and portability of new diagnostics. Of note, a critical barrier to diagnostic assay rollout will be the low cost and low perceived harm of empiric therapy on behalf of providers and patients, which leaves few perceived incentives to utilize diagnostics. Approaches that align incentives with societal goals of limiting inappropriate antimicrobial use, such as subsidizing diagnostics, may be essential for stimulating development and uptake of such assays in resource-limited settings. New diagnostics for invasive Salmonellosis should be developed and deployed alongside diagnostics for alternative etiologies of acute febrile illnesses to improve targeted use of antibiotics.
The urgent need for an effective SARS-CoV-2 vaccine has forced development to progress in the absence of well-defined correlates of immunity. While neutralization has been linked to protection ...against other pathogens, whether neutralization alone will be sufficient to drive protection against SARS-CoV-2 in the broader population remains unclear. Therefore, to fully define protective humoral immunity, we dissected the early evolution of the humoral response in 193 hospitalized individuals ranging from moderate to severe. Although robust IgM and IgA responses evolved in both survivors and non-survivors with severe disease, non-survivors showed attenuated IgG responses, accompanied by compromised Fcɣ receptor binding and Fc effector activity, pointing to deficient humoral development rather than disease-enhancing humoral immunity. In contrast, individuals with moderate disease exhibited delayed responses that ultimately matured. These data highlight distinct humoral trajectories associated with resolution of SARS-CoV-2 infection and the need for early functional humoral immunity.
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•IgA and IgM evolve rapidly across all levels of disease severity•Rapid and potent IgG class switching is linked to survival•Moderate disease is associated with a delay but ultimate convergence of IgG•Early S2-cross-reactivity is linked to survival after severe disease
Analyses of the functional humoral trajectories associated with the resolution of SARS-CoV-2 infection find that despite equivalent IgM and IgA immunity to the virus across all levels of disease severity, survival and recovery are linked to early class switching to IgG and the ability to leverage Fcγ receptors targeting the spike protein.
As SARS-CoV-2 infections and death counts continue to rise, it remains unclear why some individuals recover from infection, whereas others rapidly progress and die. Although the immunological ...mechanisms that underlie different clinical trajectories remain poorly defined, pathogen-specific antibodies often point to immunological mechanisms of protection. Here, we profiled SARS-CoV-2-specific humoral responses in a cohort of 22 hospitalized individuals. Despite inter-individual heterogeneity, distinct antibody signatures resolved individuals with different outcomes. Although no differences in SARS-CoV-2-specific IgG levels were observed, spike-specific humoral responses were enriched among convalescent individuals, whereas functional antibody responses to the nucleocapsid were elevated in deceased individuals. Furthermore, this enriched immunodominant spike-specific antibody profile in convalescents was confirmed in a larger validation cohort. These results demonstrate that early antigen-specific and qualitative features of SARS-CoV-2-specific antibodies point to differences in disease trajectory, highlighting the potential importance of functional antigen-specific humoral immunity to guide patient care and vaccine development.
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•Limited early differences were observed in titers and neutralization across groups•Five antibody features could collectively differentiate convalescents and deceased•A shift in the balance of spike versus nucleocapsid immunity separated the groups•Spike-specific phagocytic and complement fixing activity was enriched in convalescents
Although most SARS-CoV-2-infected individuals experience mild disease, a significant fraction of individuals become severely infected. Early biomarkers that predict outcome are urgently needed. Atyeo et al. demonstrate that distinct acute SARS-CoV-2 humoral immune responses exist across severely ill individuals who ultimately convalesce or pass away.
In response to skeletal muscle contraction during exercise, paracrine factors coordinate tissue remodeling, which underlies this healthy adaptation. Here we describe a pH-sensing metabolite signal ...that initiates muscle remodeling upon exercise. In mice and humans, exercising skeletal muscle releases the mitochondrial metabolite succinate into the local interstitium and circulation. Selective secretion of succinate is facilitated by its transient protonation, which occurs upon muscle cell acidification. In the protonated monocarboxylic form, succinate is rendered a transport substrate for monocarboxylate transporter 1, which facilitates pH-gated release. Upon secretion, succinate signals via its cognate receptor SUCNR1 in non-myofibrillar cells in muscle tissue to control muscle-remodeling transcriptional programs. This succinate-SUCNR1 signaling is required for paracrine regulation of muscle innervation, muscle matrix remodeling, and muscle strength in response to exercise training. In sum, we define a bioenergetic sensor in muscle that utilizes intracellular pH and succinate to coordinate tissue adaptation to exercise.
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•Mouse and human muscle selectively release succinate during exercise•Muscle cells release succinate by pH-gated secretion via MCT1•Extracellular succinate regulates paracrine responses to exercise through SUCNR1•SUCNR1 signaling mediates muscle remodeling responses to exercise training
Reddy et al. identify a bioenergetic sensor that uses pH and succinate to regulate muscle tissue adaptation to exercise.
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