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The mammalian brain is highly vulnerable to oxygen deprivation, yet the mechanism underlying the brain’s sensitivity to hypoxia is incompletely understood. Hypoxia induces accumulation of hydrogen sulfide, a gas that inhibits mitochondrial respiration. Here, we show that, in mice, rats, and naturally hypoxia-tolerant ground squirrels, the sensitivity of the brain to hypoxia is inversely related to the levels of sulfide:quinone oxidoreductase (SQOR) and the capacity to catabolize sulfide. Silencing SQOR increased the sensitivity of the brain to hypoxia, whereas neuron-specific SQOR expression prevented hypoxia-induced sulfide accumulation, bioenergetic failure, and ischemic brain injury. Excluding SQOR from mitochondria increased sensitivity to hypoxia not only in the brain but also in heart and liver. Pharmacological scavenging of sulfide maintained mitochondrial respiration in hypoxic neurons and made mice resistant to hypoxia. These results illuminate the critical role of sulfide catabolism in energy homeostasis during hypoxia and identify a therapeutic target for ischemic brain injury. The brain is sensitive to oxygen deprivation. Here, the authors show in experimental animals that sensitivity to hypoxia is inversely related to the level of sulfide:quinone oxidoreductast (SQOR) and the capacity to catabolize sulfide in the brain.

A prevailing paradigm suggests that species richness increases with area in a decelerating way. This ubiquitous power law scaling, the species–area relationship, has formed the foundation of many conservation strategies. In spatially complex ecosystems, however, the area may not be the sole dimension to scale biodiversity patterns because the scale-invariant complexity of fractal ecosystem structure may drive ecological dynamics in space. Here, we use theory and analysis of extensive fish community data from two distinct geographic regions to show that riverine biodiversity follows a robust scaling law along the two orthogonal dimensions of ecosystem size and complexity (i.e., the dual scaling law). In river networks, the recurrent merging of various tributaries forms fractal branching systems, where the prevalence of branching (ecosystem complexity) represents a macroscale control of the ecosystem’s habitat heterogeneity. In the meantime, ecosystem size dictates metacommunity size and total habitat diversity, two factors regulating biodiversity in nature. Our theory predicted that, regardless of simulated species’ traits, larger and more branched “complex” networks support greater species richness due to increased space and environmental heterogeneity. The relationships were linear on logarithmic axes, indicating power law scaling by ecosystem size and complexity. In support of this theoretical prediction, the power laws have consistently emerged in riverine fish communities across the study regions (Hokkaido Island in Japan and the midwestern United States) despite hosting different fauna with distinct evolutionary histories. The emergence of dual scaling law may be a pervasive property of branching networks with important implications for biodiversity conservation.

An elevated intracellular NADH:NAD + ratio, or ‘reductive stress’, has been associated with multiple diseases, including disorders of the mitochondrial electron transport chain. As the intracellular NADH:NAD + ratio can be in near equilibrium with the circulating lactate:pyruvate ratio, we hypothesized that reductive stress could be alleviated by oxidizing extracellular lactate to pyruvate. We engineered LOXCAT, a fusion of bacterial lactate oxidase (LOX) and catalase (CAT), which irreversibly converts lactate and oxygen to pyruvate and water. Addition of purified LOXCAT to the medium of cultured human cells with a defective electron transport chain decreased the extracellular lactate:pyruvate ratio, normalized the intracellular NADH:NAD + ratio, upregulated glycolytic ATP production and restored cellular proliferation. In mice, tail-vein-injected LOXCAT lowered the circulating lactate:pyruvate ratio, blunted a metformin-induced rise in blood lactate:pyruvate ratio and improved NADH:NAD + balance in the heart and brain. Our study lays the groundwork for a class of injectable therapeutic enzymes that alleviates intracellular redox imbalances by directly targeting circulating redox-coupled metabolites. Intracellular redox defects are treated with an extracellular chimeric enzyme.

Aberrant and persistent production of interferon-α (IFN-α) by plasmacytoid dendritic cells (pDCs) is known to play a key role in the pathogenesis of systemic lupus erythematosus (SLE). To assess the precise function of pDCs in SLE patients, we investigated the differential regulation of Toll-like receptor 7 (TLR7) and TLR9 responses during IFN-α production by pDCs. Peripheral blood mononuclear cells (PBMCs) in SLE patients without hydroxychloroquine treatment, rheumatoid arthritis patients and heathy controls were stimulated with TLR7 and TLR9 agonists. To investigate the priming effect by cytokines, PBMCs from healthy controls were pre-treated with various cytokines and stimulated with TLR7 and TLR9 agonists. The IFN-α production in pDCs was detected by flow cytometry. TLR7-mediated IFN-α production was up-regulated and correlated positively with disease activity in SLE. Conversely, TLR9-mediated IFN-α production was down-regulated. Differential regulation of TLR7/9 response in SLE was independent of TLR7 and TLR9 expression levels. Furthermore, experiments indicated that TLR7-mediated IFN-α production was up-regulated by pre-treatment with type I IFN, whereas TLR9-mediated IFN-α production was down-regulated by pre-treatment with type II IFN. Our study indicates the association between up-regulation of TLR7- mediated IFN-α production by pDCs and disease activity and that TLR7 and TLR9 responses were reversely regulated on pDCs in SLE patients. Thus, type I IFN and TLR7-mediated IFN-α production were involved in a vicious cycle, causing hyper production of IFN-α by pDCs during the pathogenic processes of SLE.

Long-distance dispersal of freshwater mussels (order Unionoida) has been assumed to occur mainly during a parasitic larval stage (glochidia) via movements of host fishes, but its empirical evidence is largely lacking. Here, we applied a “parasite-tag” approach to the riverine mussel Margaritifera laevis and its obligate host fish Oncorhynchus masou masou. This method examines the relationship between the prevalence of glochidia and distance from the nearest mussel population (i.e., the putative source of glochidia), a proxy that should quantify distance moved by host fish. We hypothesized that infected fish would be found in wider habitats at the end of the parasitic period (August) than at the beginning (July) if they were functioning as effective dispersal agents. In July, the prevalence of glochidia was highest in the vicinity of mussel beds but decreased rapidly with distance from the nearest mussel bed. In August, however, infected fish were distributed diffusively across the riverine network and dispersed over 4.8 km, demonstrating substantial dispersal of glochidia by the host fish. The results of our study build upon current knowledge of mussel’s dispersal ecology by providing highly needed evidence: host fish can be effective in mediating long-distance dispersal of a riverine mussel species.

The increasing geriatric population across the world has necessitated the early detection of frailty through the analysis of daily-life behavioral patterns. This paper presents a system for ambient, automatic, and the continuous measurement and analysis of ascent and descent motions and long-term handrail-use behaviors of participants in their homes using an RGB-D camera. The system automatically stores information regarding the environment and three-dimensional skeletal coordinates of the participant only when they appear within the camera’s angle of view. Daily stair ascent and descent motions were measured in two houses: one house with two participants in their 20s and two in their 50s, and another with two participants in their 70s. The recorded behaviors were analyzed in terms of the stair ascent/descent speed, handrail grasping points, and frequency determined using the decision tree algorithm. The participants in their 70s exhibited a decreased stair ascent/descent speed compared to other participants; those in their 50s and 70s exhibited increased handrail usage area and frequency. The outcomes of the study indicate the system’s ability to accurately detect a decline in physical function through the continuous measurement of daily stair ascent and descent motions.

Large biodiversity datasets are currently being collected not only by experts and amateur researchers, but also by the general public. In this study, records of non-native and Japanese Red List fishes observed by citizens were extracted from all 85,453 posts on the bulletin board system of WEB sakana-zukan, a web-based encyclopedia of Japanese fishes that went online in 2002. We found 681 (0.8%) and 549 (0.6%) posts containing attached images of non-native and Red Data Book fishes, resulting in 418 and 362 Japanese distributional records respectively. The number of posts and the composition of non-native species reflected the Japanese inland fisheries policy to increase target species. These data included records of exotic species (eleven taxa) whose introduction to Japan had been unknown previously, as well as records of nine exotic/domestic species whose introductions into specific Japanese regions had been unknown. Additionally, we identified the range extension of one Red Data Book species. These photographs were stored in a public museum’s photographic collection for ongoing scientific use. Three heavy users of the website combined contributed 26.7% of the new distribution records (8/30 lots), while 15 light users contributed 50.0% (15/30 lots), suggesting that overall there is a greater contribution by light users. This indicates that a web community with abundant users can accumulate new biodiversity observations better than one with fewer users but many posts per user. Our results show that this web-community was able to contribute to monitoring non-native and Red List fishes in conjunction with expert participation, and therefore that web-communities targeting living organisms can contribute to biodiversity conservation.

Leigh syndrome is the most common inherited mitochondrial disease in children and is often fatal within the first few years of life. In 2020, mutations in the gene encoding sulfide:quinone oxidoreductase (SQOR), a mitochondrial protein, were identified as a cause of Leigh syndrome. Here, we report that mice with a mutation in the gene encoding SQOR (Sqor ΔN/ΔN mice), which prevented SQOR from entering mitochondria, had clinical and pathological manifestations of Leigh syndrome. Sqor ΔN/ΔN mice had increased blood lactate levels that were associated with markedly decreased complex IV activity and increased hydrogen sulfide (H 2 S) levels. Because H 2 S is produced by both gut microbiota and host tissue, we tested whether metronidazole (a broad-spectrum antibiotic) or a sulfur-restricted diet rescues Sqor ΔN/ΔN mice from developing Leigh syndrome. Daily treatment with metronidazole alleviated increased H 2 S levels, normalized complex IV activity and blood lactate levels, and prolonged the survival of Sqor ΔN/ΔN mice. Similarly, a sulfur-restricted diet normalized blood lactate levels and inhibited the development of Leigh syndrome. Taken together, these observations suggest that mitochondrial SQOR is essential to prevent systemic accumulation of H 2 S. Metronidazole administration and a sulfur-restricted diet may be therapeutic approaches to treatment of patients with Leigh syndrome caused by mutations in SQOR .

Early diagnosis of colorectal cancer is needed to reduce the mortal consequence by cancer. Lipid mediators play critical role in progression of colitis and colitis-associated colon cancer (CAC) and some of their metabolites are excreted in urine. Here, we attempted to find novel biomarkers in urinary lipid metabolite of a murine model of CAC. Mice were received single administration of azoxymethane (AOM) and repeated administration of dextran sulfate sodium (DSS). Lipid metabolites in their urine was measured by liquid chromatography mass spectrometry and their colon was collected to perform morphological study. AOM and DSS caused inflammation and tumor formation in mouse colon. Liquid chromatography mass spectrometry-based comprehensive analysis of lipid metabolites showed that cyclooxygenase-mediated arachidonic acid (AA) metabolites, prostaglandins, and reactive oxygen species (ROS)-mediated AA metabolites, isoprostanes, were predominantly increased in the urine of tumor-bearing mice. Among that, urinary prostaglandin (PG)E 2 metabolite tetranor-PGEM and PGD 2 metabolite tetranor-PGDM were significantly increased in both of urine collected at the acute phase of colitis and the carcinogenesis phase. On the other hand, two F 2 isoprostanes (F 2 -IsoPs), 8-iso PGF 2α and 2,3-dinor-8-iso PGF 2α , were significantly increased only in the carcinogenesis phase. Morphological study showed that infiltrated monocytes into tumor mass strongly expressed ROS generator NADPH (p22 phox ). These observations suggest that urinary 8-iso PGF 2α and 2,3-dinor-8-iso PGF 2α can be indexes of CAC.

ObjectiveExtracting immunological and clinical heterogeneity across autoimmune rheumatic diseases (AIRDs) is essential towards personalised medicine.MethodsWe conducted large-scale and cohort-wide immunophenotyping of 46 peripheral immune cells using Human Immunology Protocol of comprehensive 8-colour flow cytometric analysis. Dataset consisted of >1000 Japanese patients of 11 AIRDs with deep clinical information registered at the FLOW study, including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). In-depth clinical and immunological characterisation was conducted for the identified RA patient clusters, including associations of inborn human genetics represented by Polygenic Risk Score (PRS).ResultsMultimodal clustering of immunophenotypes deciphered underlying disease-cell type network in immune cell, disease and patient cluster resolutions. This provided immune cell type specificity shared or distinct across AIRDs, such as close immunological network between mixed connective tissue disease and SLE. Individual patient-level clustering dissected patients with AIRD into several clusters with different immunological features. Of these, RA-like or SLE-like clusters were exclusively dominant, showing immunological differentiation between RA and SLE across AIRDs. In-depth clinical analysis of RA revealed that such patient clusters differentially defined clinical heterogeneity in disease activity and treatment responses, such as treatment resistance in patients with RA with SLE-like immunophenotypes. PRS based on RA case–control and within-case stratified genome-wide association studies were associated with clinical and immunological characteristics. This pointed immune cell type implicated in disease biology such as dendritic cells for RA-interstitial lung disease.ConclusionCohort-wide and cross-disease immunophenotyping elucidate clinically heterogeneous patient subtypes existing within single disease in immune cell type-specific manner.