Abstract
Electron transport chain (ETC) defects occurring from mitochondrial disease mutations compromise ATP synthesis and render cells vulnerable to nutrient and oxidative stress conditions. This ...bioenergetic failure is thought to underlie pathologies associated with mitochondrial diseases. However, the precise metabolic processes resulting from a defective mitochondrial ETC that compromise cell viability under stress conditions are not entirely understood. We design a whole genome gain-of-function CRISPR activation screen using human mitochondrial disease complex I (CI) mutant cells to identify genes whose increased function rescue glucose restriction-induced cell death. The top hit of the screen is the cytosolic Malic Enzyme (ME1), that is sufficient to enable survival and proliferation of CI mutant cells under nutrient stress conditions. Unexpectedly, this metabolic rescue is independent of increased ATP synthesis through glycolysis or oxidative phosphorylation, but dependent on ME1-produced NADPH and glutathione (GSH). Survival upon nutrient stress or pentose phosphate pathway (PPP) inhibition depends on compensatory NADPH production through the mitochondrial one-carbon metabolism that is severely compromised in CI mutant cells. Importantly, this defective CI-dependent decrease in mitochondrial NADPH production pathway or genetic ablation of SHMT2 causes strong increases in inflammatory cytokine signatures associated with redox dependent induction of ASK1 and activation of stress kinases p38 and JNK. These studies find that a major defect of CI deficiencies is decreased mitochondrial one-carbon NADPH production that is associated with increased inflammation and cell death.
MicroRNAs (miRNAs) circulate in the bloodstream in a highly stable, extracellular form and are being developed as blood-based biomarkers for cancer and other diseases. However, the mechanism ...underlying their remarkable stability in the RNase-rich environment of blood is not well understood. The current model in the literature posits that circulating miRNAs are protected by encapsulation in membrane-bound vesicles such as exosomes, but this has not been systematically studied. We used differential centrifugation and size-exclusion chromatography as orthogonal approaches to characterize circulating miRNA complexes in human plasma and serum. We found, surprisingly, that the majority of circulating miRNAs cofractionated with protein complexes rather than with vesicles. miRNAs were also sensitive to protease treatment of plasma, indicating that protein complexes protect circulating miRNAs from plasma RNases. Further characterization revealed that Argonaute2 (Ago2), the key effector protein of miRNA-mediated silencing, was present in human plasma and eluted with plasma miRNAs in size-exclusion chromatography. Furthermore, immunoprecipitation of Ago2 from plasma readily recovered non-vesicle-associated plasma miRNAs. The majority of miRNAs studied copurified with the Ago2 ribonucleoprotein complex, but a minority of specific miRNAs associated predominantly with vesicles. Our results reveal two populations of circulating miRNAs and suggest that circulating Ago2 complexes are a mechanism responsible for the stability of plasma miRNAs. Our study has important implications for the development of biomarker approaches based on capture and analysis of circulating miRNAs. In addition, identification of extracellular Ago2-miRNA complexes in plasma raises the possibility that cells release a functional miRNA-induced silencing complex into the circulation.
Abstract
CMOS-based computing systems that employ the von Neumann architecture are relatively limited when it comes to parallel data storage and processing. In contrast, the human brain is a living ...computational signal processing unit that operates with extreme parallelism and energy efficiency. Although numerous neuromorphic electronic devices have emerged in the last decade, most of them are rigid or contain materials that are toxic to biological systems. In this work, we report on biocompatible bilayer graphene-based artificial synaptic transistors (BLAST) capable of mimicking synaptic behavior. The BLAST devices leverage a dry ion-selective membrane, enabling long-term potentiation, with ~50 aJ/µm
2
switching energy efficiency, at least an order of magnitude lower than previous reports on two-dimensional material-based artificial synapses. The devices show unique metaplasticity, a useful feature for generalizable deep neural networks, and we demonstrate that metaplastic BLASTs outperform ideal linear synapses in classic image classification tasks. With switching energy well below the 1 fJ energy estimated per biological synapse, the proposed devices are powerful candidates for bio-interfaced online learning, bridging the gap between artificial and biological neural networks.
The six known specimens of
and casts made from their negative impressions were examined to reassess the osteological evidence that has been used to interpret
s locomotion and phylogenetic ...relationships. It was found that the trunk was dorsoventrally compressed. The upper temporal fenestra was on the lateral surface of skull and two-thirds the size of the lower, the jaw joint posteriorly placed with short retroarticular process, and teeth short and subconical, but no evidence of external nares or antorbital fossae was found. The posterior trunk was covered with ~20 rows of closely spaced transversely elongate dorsal osteoderms. The coracoid was robust and elongate. The acetabulum was imperforate and the femoral head hemispherical and only weakly inturned such that the hip joint was unsuited to swinging in a parasagittal plane. The presence of four distal tarsals is confirmed. The marked disparity of tibial and fibular shaft diameters and of proximal tarsal dimensions indicates that the larger proximal tarsal is the astragalus and the significantly smaller tarsal is the calcaneum. The astragalus and calcaneum bear little resemblance to those of
, and the prominent calcaneal tuber confirms that the ankle was crurotarsal. There is no evidence that preserved body and limb postures are unnatural, and most specimens are preserved in what is interpreted as a typical sprawling resting pose. A principal component analysis of skeletal measurements of
and other vertebrates of known locomotor type found
to plot with frogs, and that finding combined with skeletal morphology suggests
was a sprawling quadrupedal hopper. Phylogenetic analyses found that
was not an ornithodiran, but was either within the Doswelliidae or outside the clade consisting of the most recent common ancestor of the Erythrosuchidae and Archosauria and all its descendants.
We describe the current US emergency physician workforce.
We analyzed the 2020 American Medical Association Physician Masterfile data set. All physicians who designated emergency medicine as their ...primary or secondary specialty were included; nonactive physicians, residents, primarily research or teaching faculty, or those primarily involved in administration or nonclinical work were excluded. We calculated emergency physician population density, using 2018 Census Bureau estimates of the US population; urban-rural assignments were based on Urban Influence Codes. We compared 2020 results with our previous analysis of the 2008 emergency physician workforce. Again, we were unable to account for American Osteopathic Board of Emergency Medicine certification.
There were 48,835 clinically active emergency physicians in 2020. The median age was 50 years (interquartile range IQR 41 to 62 years) and 28% were women. Overall density of emergency physicians per 100,000 population was 14.9. Most emergency physicians were in urban areas (92%), whereas 2,730 (6%) were in large rural areas and 1,197 (2%) in small rural areas. Urban emergency physicians were younger (median age 50 years; IQR 41 to 61 years) than those in large rural areas (median age 58 years; IQR 47 to 67 years) or small rural areas (median age 62 years; IQR 51 to 68 years), and more likely to be women (29%, 20%, and 19%, respectively). Most emergency physicians in small rural areas (71%) completed their medical training more than 20 years ago. Compared with 2008, the total number of clinically active emergency physicians has increased by 9,774, but, per 100,000 US population in 2020, emergency physician density decreased in both large rural (–0.4) and small rural (–3.7) areas.
Urban emergency physicians in 2020 remain substantially younger than rural emergency physicians, with many rural ones near the US retirement age. We did not observe a continued increase in the percentage of female physicians among emergency physicians. Given the ongoing demand for physicians in all US emergency departments, this analysis provides essential information for understanding the current emergency physician workforce and the challenges ahead.
This study examines differences in proportions of US medical school faculty who self-identified as Black or African American between 1990 and 2020 based on data from the Association of American ...Medical Colleges Faculty Roster.
Mitochondrial dysfunction is increasingly appreciated as a central contributor to human disease. Oxidative metabolism at the mitochondrial respiratory chain produces ATP and is intricately tied to ...redox homeostasis and biosynthetic pathways. Metabolic stress arising from genetic mutations in mitochondrial genes and environmental factors such as malnutrition or overnutrition is perceived by the cell and leads to adaptive and maladaptive responses that can underlie pathology. Here, we will outline cellular sensors that react to alterations in energy production, organellar redox, and metabolites stemming from mitochondrial disease (MD) mutations. MD is a heterogeneous group of disorders primarily defined by defects in mitochondrial oxidative phosphorylation from nuclear or mitochondrial‐encoded gene mutations. Preclinical therapies that improve fitness of MD mouse models have been recently identified. Targeting metabolic/energetic deficiencies, maladaptive signaling processes, and hyper‐oxygenation of tissues are all strategies aside from direct genetic approaches that hold therapeutic promise. A further mechanistic understanding of these curative processes as well as the identification of novel targets will significantly impact mitochondrial biology and disease research.
Mutations in mitochondrial genes, from either mitochondrial or nuclear genomes, result in aberrant mitochondrial function. As the hub of metabolism and bioenergetics, dysfunctional mitochondria result in perturbed cellular homeostasis. Molecular sensors of mitochondrial bioenergetics regulate cell survival, proliferation, and death processes that modulate tissue pathology. Hence, understanding the adaptive cellular responses to mitochondrial defects provides therapeutic opportunities for these rare but detrimental mitochondrial diseases.
The mitochondrial unfolded protein response is a conserved pathway that allows mitochondrial chaperones and other factors to be induced in response to mitochondrial dysfunction. Activation of this ...pathway has been proposed to underlie lifespan extension from knockdown or mutation of several nuclear encoded mitochondrial genes in Caenorhabditis elegans. In some cases, however, induction of the mitochondrial unfolded protein response is associated with a reduction of lifespan in both yeast and C. elegans. It also has yet to be demonstrated that induction of the mitochondrial unfolded protein response is sufficient to increase lifespan in the absence of overt mitochondrial dysfunction. In this perspective, we briefly review the evidence for and against a direct pro-longevity role of the mitochondrial unfolded protein response and suggest important areas of investigation for experimentally addressing this question.
•The UPRmt is a conserved response to mitochondrial stress.•Several perturbations that induce the UPRmt extend lifespan in C. elegans.•In some cases, the UPRmt is associated with shortened or normal lifespan.•The UPRmt is proposed to promote longevity in C. elegans.•Key experimental support of the UPRmt longevity model is lacking.
The mechanisms underlying biological aging have been extensively studied in the past 20 years with the avail of mainly four model organisms: the budding yeast Saccharomyces cerevisiae, the nematode ...Caenorhabditis elegans, the fruitfly Drosophila melanogaster, and the domestic mouse Mus musculus. Extensive research in these four model organisms has identified a few conserved genetic pathways that affect longevity as well as metabolism and development. Here, we review how the mechanistic target of rapamycin (mTOR), sirtuins, adenosine monophosphate-activated protein kinase (AMPK), growth hormone/insulin-like growth factor 1 (IGF-1), and mitochondrial stress-signaling pathways influence aging and life span in the aforementioned models and their possible implications for delaying aging in humans. We also draw some connections between these biochemical pathways and comment on what new developments aging research will likely bring in the near future.
Spintronic devices based on domain wall (DW) motion through ferromagnetic nanowire tracks have received great interest as components of neuromorphic information processing systems. Previous proposals ...for spintronic artificial neurons required external stimuli to perform the leaking functionality, one of the three fundamental functions of a leaky integrate-and-fire (LIF) neuron. The use of this external magnetic field or electrical current stimulus results in either a decrease in energy efficiency or an increase in fabrication complexity. In this article, we modify the shape of previously demonstrated three-terminal magnetic tunnel junction neurons to perform the leaking operation without any external stimuli. The trapezoidal structure causes a shape-based DW drift, thus intrinsically providing the leaking functionality with no hardware cost. This LIF neuron, therefore, promises to advance the development of spintronic neural network crossbar arrays.
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