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Oxidative stress and cardiomyocyte apoptosis play critical roles in doxorubicin (DOX)-induced cardiotoxicity. Previous studies indicated that fibronectin type III domain-containing 5 (FNDC5) and its cleaved form, irisin, could preserve mitochondrial function and attenuate oxidative damage as well as cell apoptosis, however, its role in DOX-induced cardiotoxicity remains unknown. Our present study aimed to investigate the role and underlying mechanism of FNDC5 on oxidative stress and cardiomyocyte apoptosis in DOX-induced cardiotoxicity. Cardiomyocyte-specific FNDC5 overexpression was achieved using an adeno-associated virus system, and then the mice were exposed to a single intraperitoneal injection of DOX (15 mg/kg) to generate DOX-induced cardiotoxicity. Herein, we found that FNDC5 expression was downregulated in DOX-treated murine hearts and cardiomyocytes. Fndc5 deficiency resulted in increased oxidative damage and apoptosis in H9C2 cells under basal conditions, imitating the phenotype of DOX-induced cardiomyopathy in vitro, conversely, FNDC5 overexpression or irisin treatment alleviated DOX-induced oxidative stress and cardiomyocyte apoptosis in vivo and in vitro. Mechanistically, we identified that FNDC5/Irisin activated AKT/mTOR signaling and decreased DOX-induced cardiomyocyte apoptosis, and moreover, we provided direct evidence that the anti-oxidant effect of FNDC5/Irisin was mediated by the AKT/GSK3β/FYN/Nrf2 axis in an mTOR-independent manner. And we also demonstrated that heat shock protein 20 was responsible for the activation of AKT caused by FNDC5/Irisin. In line with the data in acute model, we also found that FNDC5/Irisin exerted beneficial effects in chronic model of DOX-induced cardiotoxicity (5 mg/kg, i.p., once a week for three times, the total cumulative dose is 15 mg/kg) in mice. Based on these findings, we supposed that FNDC5/Irisin was a potential therapeutic agent against DOX-induced cardiotoxicity.

All species have an environmental niche, and despite technological advances, humans are unlikely to be an exception. Here, we demonstrate that for millennia, human populations have resided in the same narrow part of the climatic envelope available on the globe, characterized by a major mode around ∼11 °C to 15 °C mean annual temperature (MAT). Supporting the fundamental nature of this temperature niche, current production of crops and livestock is largely limited to the same conditions, and the same optimum has been found for agricultural and nonagricultural economic output of countries through analyses of year-to-year variation. We show that in a business-as-usual climate change scenario, the geographical position of this temperature niche is projected to shift more over the coming 50 y than it has moved since 6000 BP. Populations will not simply track the shifting climate, as adaptation in situ may address some of the challenges, and many other factors affect decisions to migrate. Nevertheless, in the absence of migration, one third of the global population is projected to experience a MAT >29 °C currently found in only 0.8% of the Earth’s land surface, mostly concentrated in the Sahara. As the potentially most affected regions are among the poorest in the world, where adaptive capacity is low, enhancing human development in those areas should be a priority alongside climate mitigation.

Speech is one of the most sophisticated human motor skills. Speaker identification is the ability of a software component or hardware to acquire a speech signal, recognize the speakers included in the signal, and identify the speaker after the audio signals have been received. This study proposes a fluctuating equation inversion method using feature extraction for broadcast hosting. Feature extraction aims to provide useful signal features from natural audio that can be applied to various downstream processes, including recitation, evaluation, and categorization. Initially, data were collected from the CASIA dataset. This study evaluated the experimental outcomes of the proposed approach using mel-frequency cepstral coefficients, gammatone frequency cepstral coefficients, and linear frequency cepstral coefficients. The proposed technique was tested on a publicly accessible dataset, and the findings showed that it performed better in terms of recognition accuracy (98%), precision (97%), recall (96.05%), sensitivity (92.56%), and F1-score (95.09%) than the conventional feature extraction methods. The proposed approach can be utilized to improve audio signal quality and user experience across broadcast-hosting applications.

Prudent risk management requires consideration of bad-to-worst-case scenarios. Yet, for climate change, such potential futures are poorly understood. Could anthropogenic climate change result in worldwide societal collapse or even eventual human extinction? At present, this is a dangerously underexplored topic. Yet there are ample reasons to suspect that climate change could result in a global catastrophe. Analyzing the mechanisms for these extreme consequences could help galvanize action, improve resilience, and inform policy, including emergency responses. We outline current knowledge about the likelihood of extreme climate change, discuss why understanding bad-to-worst cases is vital, articulate reasons for concern about catastrophic outcomes, define key terms, and put forward a research agenda. The proposed agenda covers four main questions: 1) What is the potential for climate change to drive mass extinction events? 2) What are the mechanisms that could result in human mass mortality and morbidity? 3) What are human societies' vulnerabilities to climate-triggered risk cascades, such as from conflict, political instability, and systemic financial risk? 4) How can these multiple strands of evidence—together with other global dangers—be usefully synthesized into an “integrated catastrophe assessment”? It is time for the scientific community to grapple with the challenge of better understanding catastrophic climate change.

Cardiac aging is evident by a reduction in function which subsequently contributes to heart failure. The metabolic microenvironment has been identified as a hallmark of malignancy, but recent studies have shed light on its role in cardiovascular diseases (CVDs). Various metabolic pathways in cardiomyocytes and noncardiomyocytes determine cellular senescence in the aging heart. Metabolic alteration is a common process throughout cardiac degeneration. Importantly, the involvement of cellular senescence in cardiac injuries, including heart failure and myocardial ischemia and infarction, has been reported. However, metabolic complexity among human aging hearts hinders the development of strategies that targets metabolic susceptibility. Advances over the past decade have linked cellular senescence and function with their metabolic reprogramming pathway in cardiac aging, including autophagy, oxidative stress, epigenetic modifications, chronic inflammation, and myocyte systolic phenotype regulation. In addition, metabolic status is involved in crucial aspects of myocardial biology, from fibrosis to hypertrophy and chronic inflammation. However, further elucidation of the metabolism involvement in cardiac degeneration is still needed. Thus, deciphering the mechanisms underlying how metabolic reprogramming impacts cardiac aging is thought to contribute to the novel interventions to protect or even restore cardiac function in aging hearts. Here, we summarize emerging concepts about metabolic landscapes of cardiac aging, with specific focuses on why metabolic profile alters during cardiac degeneration and how we could utilize the current knowledge to improve the management of cardiac aging.

Aging is an important risk factor for cardiovascular diseases, and aging‐related cardiac dysfunction serves as a major determinant of morbidity and mortality in elderly populations. Our previous study has identified fibronectin type III domain‐containing 5 (FNDC5) and its cleaved form, irisin, as the cardioprotectant against doxorubicin‐induced cardiomyopathy. Herein, aging or matched young mice were overexpressed with FNDC5 by adeno‐associated virus serotype 9 (AAV9) vectors, or subcutaneously infused with irisin to uncover the role of FNDC5 in aging‐related cardiac dysfunction. To verify the involvement of nucleotide‐binding oligomerization domain‐like receptor with a pyrin domain 3 (NLRP3) and AMP‐activated protein kinase α (AMPKα), Nlrp3 or Ampkα2 global knockout mice were used. Besides, young mice were injected with AAV9‐FNDC5 and maintained for 12 months to determine the preventive effect of FNDC5. Moreover, neonatal rat cardiomyocytes were stimulated with tumor necrosis factor‐α (TNF‐α) to examine the role of FNDC5 in vitro. We found that FNDC5 was downregulated in aging hearts. Cardiac‐specific overexpression of FNDC5 or irisin infusion significantly suppressed NLRP3 inflammasome and cardiac inflammation, thereby attenuating aging‐related cardiac remodeling and dysfunction. In addition, irisin treatment also inhibited cellular senescence in TNF‐α‐stimulated cardiomyocytes in vitro. Mechanistically, FNDC5 activated AMPKα through blocking the lysosomal degradation of glucagon‐like peptide‐1 receptor. More importantly, FNDC5 gene transfer in early life could delay the onset of cardiac dysfunction during aging process. We prove that FNDC5 improves aging‐related cardiac dysfunction by activating AMPKα, and it might be a promising therapeutic target to support cardiovascular health in elderly populations. FNDC5 is downregulated in aging hearts, and cardiac‐specific overexpression of FNDC5 or irisin infusion attenuates aging‐related inflammation, cardiac remodeling, and dysfunction. Mechanistically, FNDC5 activates AMPKα through blocking the lysosomal degradation of GLP‐1R.

Acute-on-chronic liver failure (ACLF) is a group of clinical syndromes related to severe acute liver function impairment and multiple-organ failure caused by various acute triggering factors on the basis of chronic liver disease. Due to its severe condition, rapid progression, and high mortality, it has received increasing attention. Recent studies have shown that the pathogenesis of ACLF mainly includes direct injury and immune injury. In immune injury, cytotoxic T lymphocytes (CTLs), dendritic cells (DCs), and CD4 + T cells accumulate in the liver tissue, secrete a variety of proinflammatory cytokines and chemokines, and recruit more immune cells to the liver, resulting in immune damage to the liver tissue, massive hepatocyte necrosis, and liver failure, but the key molecules and signaling pathways remain unclear. The “danger hypothesis” holds that in addition to the need for antigens, damage-associated molecular patterns (DAMPs) also play a very important role in the occurrence of the immune response, and this hypothesis is related to the pathogenesis of ACLF. Here, the research status and development trend of ACLF, as well as the mechanism of action and research progress on various DAMPs in ACLF, are summarized to identify biomarkers that can predict the occurrence and development of diseases or the prognosis of patients at an early stage.

Hydrogen is well known to embrittle high-strength steels and impair their corrosion resistance. One of the most attractive methods to mitigate hydrogen embrittlement employs nanoprecipitates, which are widely used for strengthening, to trap and diffuse hydrogen from enriching at vulnerable locations within the materials. However, the atomic origin of hydrogen-trapping remains elusive, especially in incoherent nanoprecipitates. Here, by combining in-situ scanning Kelvin probe force microscopy and aberration-corrected transmission electron microscopy, we unveil distinct scenarios of hydrogen-precipitate interaction in a high-strength low-alloyed martensitic steel. It is found that not all incoherent interfaces are trapping hydrogen; some may even exclude hydrogen. Atomic-scale structural and chemical features of the very interfaces suggest that carbon/sulfur vacancies on the precipitate surface and tensile strain fields in the nearby matrix likely determine the hydrogen-trapping characteristics of the interface. These findings provide fundamental insights that may lead to a better coupling of precipitation-strengthening strategy with hydrogen-insensitive designs. By trapping hydrogen, nanoprecipitates can mitigate the hydrogen embrittlement of high strength steels. Here, the authors report direct evidences on the structural and chemical features underlying distinct hydrogen-trapping behaviors at the incoherent interfaces of precipitates and steel matrix.

Aims/hypothesis Oxidative stress, inflammation and cell death are closely involved in the development of diabetic cardiomyopathy (DCM). C1q/tumour necrosis factor-related protein-3 (CTRP3) has anti-inflammatory properties but its role in DCM remains largely unknown. The aims of this study were to determine whether CTRP3 could attenuate DCM and to clarify the underlying mechanisms. Methods Streptozotocin (STZ) was injected intraperitoneally to induce diabetes in Sprague–Dawley rats. Cardiomyocyte-specific CTRP3 overexpression was achieved using an adeno-associated virus system 12 weeks after STZ injection. Results CTRP3 expression was significantly decreased in diabetic rat hearts. Knockdown of CTRP3 in cardiomyocytes at baseline resulted in increased oxidative injury, inflammation and apoptosis in vitro. Cardiomyocyte-specific overexpression of CTRP3 decreased oxidative stress and inflammation, attenuated myocyte death and improved cardiac function in rats treated with STZ. CTRP3 significantly activated AMP­activated protein kinase α (AMPKα) and Akt (protein kinase B) in H9c2 cells. CTRP3 protected against high-glucose-induced oxidative stress, inflammation and apoptosis in vitro. AMPKα deficiency abolished the protective effects of CTRP3 in vitro and in vivo. Furthermore, we found that CTRP3 activated AMPKα via the cAMP–exchange protein directly activated by cAMP (EPAC)–mitogen-activated protein kinase kinase (MEK) pathway. Conclusions/interpretation CTRP3 protected against DCM via activation of the AMPKα pathway. CTRP3 has therapeutic potential for the treatment of DCM.

Climate warming disproportionately impacts countries in the Global South by increasing extreme heat exposure. However, geographic disparities in adaptation capacity are unclear. Here, we assess global inequality in green spaces, which urban residents critically rely on to mitigate outdoor heat stress. We use remote sensing data to quantify daytime cooling by urban greenery in the warm seasons across the ~500 largest cities globally. We show a striking contrast, with Global South cities having ~70% of the cooling capacity of cities in the Global North (2.5 ± 1.0 °C vs. 3.6 ± 1.7 °C). A similar gap occurs for the cooling adaptation benefits received by an average resident in these cities (2.2 ± 0.9 °C vs. 3.4 ± 1.7 °C). This cooling adaptation inequality is due to discrepancies in green space quantity and quality between cities in the Global North and South, shaped by socioeconomic and natural factors. Our analyses further suggest a vast potential for enhancing cooling adaptation while reducing global inequality. A 1.5-fold gap exists in green space cooling adaptation between cities in the Global South and North. Enhancing urban green space quality and quantity offers vast potential for improving outdoor cooling adaptation and reducing its global inequality.