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It is widely recognized that inflammation plays a critical role in cardiac hypertrophy and heart failure. However, clinical trials targeting cytokines have shown equivocal effects, indicating the need for a deeper understanding of the precise role of inflammation and inflammatory cells in heart failure. Leukocytes from human subjects and a rodent model of heart failure were characterized by a marked reduction in expression of Klf2 mRNA. Using a mouse model of angiotensin II-induced nonischemic cardiac dysfunction, we showed that neutrophils played an essential role in the pathogenesis and progression of heart failure. Mechanistically, chronic angiotensin II infusion activated a neutrophil KLF2/NETosis pathway that triggered sporadic thrombosis in small myocardial vessels, leading to myocardial hypoxia, cell death, and hypertrophy. Conversely, targeting neutrophils, neutrophil extracellular traps (NETs), or thrombosis ameliorated these pathological changes and preserved cardiac dysfunction. KLF2 regulated neutrophil activation in response to angiotensin II at the molecular level, partly through crosstalk with HIF1 signaling. Taken together, our data implicate neutrophil-mediated immunothrombotic dysregulation as a critical pathogenic mechanism leading to cardiac hypertrophy and heart failure. This neutrophil KLF2-NETosis-thrombosis mechanism underlying chronic heart failure can be exploited for therapeutic gain by therapies targeting neutrophils, NETosis, or thrombosis.

Chronic neurodegeneration in survivors of traumatic brain injury (TBI) is a major cause of morbidity, with no effective therapies to mitigate this progressive and debilitating form of nerve cell death. Here, we report that pharmacologic restoration of the blood–brain barrier (BBB), 12 mo after murine TBI, is associated with arrested axonal neurodegeneration and cognitive recovery, benefits that persisted for months after treatment cessation. Recovery was achieved by 30 d of once-daily administration of P7C3-A20, a compound that stabilizes cellular energy levels. Four months after P7C3-A20, electron microscopy revealed full repair of TBI-induced breaks in cortical and hippocampal BBB endothelium. Immunohistochemical staining identified additional benefits of P7C3-A20, including restoration of normal BBB endothelium length, increased brain capillary pericyte density, increased expression of BBB tight junction proteins, reduced brain infiltration of immunoglobulin, and attenuated neuroinflammation. These changes were accompanied by cessation of TBI-induced chronic axonal degeneration. Specificity for P7C3-A20 action on the endothelium was confirmed by protection of cultured human brain microvascular endothelial cells from hydrogen peroxide-induced cell death, as well as preservation of BBB integrity in mice after exposure to toxic levels of lipopolysaccharide. P7C3-A20 also protected mice from BBB degradation after acute TBI. Collectively, our results provide insights into the pathophysiologic mechanisms behind chronic neurodegeneration after TBI, along with a putative treatment strategy. Because TBI increases the risks of other forms of neurodegeneration involving BBB deterioration (e.g., Alzheimer’s disease, Parkinson’s disease, vascular dementia, chronic traumatic encephalopathy), P7C3-A20 may have widespread clinical utility in the setting of neurodegenerative conditions.

BackgroundUnder hyperglycemic conditions, impaired intestinal barrier integrity leads to heightened level of inflammation, playing important roles in driving diabetic complications. Emerging evidence supports the implications of neutrophil extracellular traps (NETs) in the pathogenesis of diabetes. However, whether NETs contribute to hyperglycemia-linked intestinal barrier impairment remains to be investigated. Moreover, baicalin, the major chemical component of Scutellaria baicalensis Georgi, is equipped with twofold intestinal protective and neutrophil suppressive activities. Yet, it is unclear if baicalin is effective at mitigating hyperglycemia-linked NETs-mediated intestinal barrier impairment.MethodsTo directly address the mechanistic implications of NETs in hyperglycemia-linked intestinal epithelial barrier impairment, the impact of DNase I treatment or Padi4 gene deficiency on intestinal epithelial integrity was first examined in the streptozotocin (STZ)-induced hyperglycemic mice in vivo . Next, the pharmacological impact of baicalin on NETs formation and intestinal epithelial barrier impairment was investigated in high glucose- and/or lipopolysaccharides (LPS)-stimulated neutrophils in vitro and in STZ-induced hyperglycemic mice in vivo , respectively.ResultsThe in vitro experiments confirmed that high glucose and/or LPS induced NETs formation. NETs directly impaired the viability and tight junction of the intestinal epithelial cells. The histological and immunohistochemical examinations unveiled that along with impaired intestinal epithelial morphology, citrullinated histone H3 (H3Cit), a marker of NETs, and neutrophil specific Ly6G were readily detected in the intestinal epithelium in the hyperglycemic mice. Without affecting the presence of neutrophils, DNase I treatment or Padi4 gene deficiency markedly mitigated intestinal NETs formation and improved the intestinal morphology in the hyperglycemic mice. Notably, baicalin suppressed NETs formation and inhibited histone H3 citrullination stimulated by high glucose, LPS or both in vitro . Furthermore, baicalin blunted NETs formation and partially preserved the integrity of the intestinal epithelium in the hyperglycemic mice in vivo .ConclusionsThe current study sheds new light on the pathophysiological implications of NETs in intestinal epithelial barrier impairment under hyperglycemic conditions. Most importantly, the findings here demonstrate for the first time that baicalin directly inhibits NETs formation stimulated by high glucose and/or LPS, which may in part account for its pharmacological effects at protecting against hyperglycemia-linked intestinal epithelial barrier impairment.

Takotsubo syndrome (TTS) is an acute, stress-induced cardiomyopathy that occurs predominantly in women after extreme physical and/or emotional stress. To date, our understanding of the molecular basis for TTS remains unknown and, consequently, specific therapies are lacking. Myocardial infiltration of monocytes and macrophages in TTS has been documented in clinical studies. However, the functional importance of these findings remains poorly understood. Here, we show that a single high dose of isoproterenol (ISO) in mice induced a TTS-like cardiomyopathy phenotype characterized by female predominance, severe cardiac dysfunction, and robust myocardial infiltration of macrophages. Single-cell RNA-Seq studies of myocardial immune cells revealed that TTS-like cardiomyopathy is associated with complex activation of innate and adaptive immune cells in the heart, and macrophages were identified as the dominant immune cells. Global macrophage depletion (via clodronate liposome administration) or blockade of macrophage infiltration (via a CCR2 antagonist or in CCR2-KO mice) resulted in recovery of cardiac dysfunction in ISO-challenged mice. In addition, damping myeloid cell activation by HIF1α deficiency or exposure to the immunomodulatory agent bortezomib ameliorated ISO-induced cardiac dysfunction. Collectively, our findings identify macrophages as a critical regulator of TTS pathogenesis that can be targeted for therapeutic gain.

It is widely recognized that inflammation plays a critical role in cardiac hypertrophy and heart failure. However, clinical trials targeting cytokines have shown equivocal effects, indicating the need for a deeper understanding of the precise role of inflammation and inflammatory cells in heart failure. Leukocytes from human subjects and a rodent model of heart failure were characterized by a marked reduction in expression of Klf2 mRNA. Using a mouse model of angiotensin II-induced nonischemic cardiac dysfunction, we showed that neutrophils played an essential role in the pathogenesis and progression of heart failure. Mechanistically, chronic angiotensin II infusion activated a neutrophil KLF2/NETosis pathway that triggered sporadic thrombosis in small myocardial vessels, leading to myocardial hypoxia, cell death, and hypertrophy. Conversely, targeting neutrophils, neutrophil extracellular traps (NETs), or thrombosis ameliorated these pathological changes and preserved cardiac dysfunction. KLF2 regulated neutrophil activation in response to angiotensin II at the molecular level, partly through crosstalk with HIF1 signaling. Taken together, our data implicate neutrophil-mediated immunothrombotic dysregulation as a critical pathogenic mechanism leading to cardiac hypertrophy and heart failure. This neutrophil KLF2NETosis-thrombosis mechanism underlying chronic heart failure can be exploited for therapeutic gain by therapies targeting neutrophils, NETosis, or thrombosis.

To better investigate the behavior of titanium (Ti) isotopes during magmatic processes, we report high-precision Ti isotope compositions for 60 terrestrial igneous rocks from different geological settings worldwide. Based on their major element compositions and petrographic descriptions, these samples can be subdivided into two groups: Fe-Ti oxide unsaturated and Fe-Ti oxide saturated. The Fe-Ti oxide unsaturated group samples show a narrow δ49/47Ti (δ49/47Ti = [(49Ti/47Ti)sample/(49Ti/47Ti)OL-Ti] × 1000) range (− 0.036 ± 0.043‰ to 0.082 ± 0.021 ‰), and no correlation between δ49/47Ti and the degree of differentiation is observed. By contrast, Fe-Ti oxide saturated group samples show a remarkable δ49/47Ti variation, ranging from 0.005 ± 0.018‰ to 1.914 ± 0.006 ‰, which are positively correlated with SiO2 contents, and negatively correlated with MgO contents. In particular, multiple SiO2 vs. δ49/47Ti trends are observed in Fe-Ti oxide saturated group, which are controlled by crystal fractionation degrees, magma SiO2 compositions, and Fe-Ti oxide compositions during magma differentiation.

In recent years, the application of deep learning models for underwater target recognition has become a popular trend. Most of these are pure 1D models used for processing time-domain signals or pure 2D models used for processing time-frequency spectra. In this paper, a recent temporal 2D modeling method is introduced into the construction of ship radiation noise classification models, combining 1D and 2D. This method is based on the periodic characteristics of time-domain signals, shaping them into 2D signals and discovering long-term correlations between sampling points through 2D convolution to compensate for the limitations of 1D convolution. Integrating this method with the current state-of-the-art model structure and using samples from the Deepship database for network training and testing, it was found that this method could further improve the accuracy (0.9%) and reduce the parameter count (30%), providing a new option for model construction and optimization. Meanwhile, the effectiveness of training models using time-domain signals or time-frequency representations has been compared, finding that the model based on time-domain signals is more sensitive and has a smaller storage footprint (reduced to 30%), whereas the model based on time-frequency representation can achieve higher accuracy (1–2%).

The Middle‒Late Mesozoic massive volcanism formed a considerable thickness of volcanic‐sedimentary strata in western Liaoning, northern China. Concomitantly, it elevated phosphorus (P) availability for the rapid bloom of the terrestrial Yanliao and Jehol biotas, which developed highly abundant biodiversity and biomass. Hence, systematic tectonic and geochemical analyses of these volcanic‐sedimentary sequences with a significant P fluctuation would advance our understanding of the coevolutionary relationship between terrestrial biotas and regional tectonics. Here, we show that the secular variation of P availability in the Mesozoic volcanic rocks were the immediate results of the changes in volcanic intensity and lithospheric thickness controlled by the geological background of the cratonic destruction resulting from the paleo‐Pacific plate subduction. This study reveals the constraint effect of regional tectonics on the evolution of terrestrial ecosystems through the volcanism and P cycle. Plain Language Summary The phosphorus (P) is necessary for biotas and mainly comes from volcanics in areas dominated by volcanism closely related to deep‐Earth processes. Thus, the origin of P changes in volcanics can provide key evidence for the intrinsic relations between deep processes and biota evolution. Here, we present tectonic and geochemical analyses for the Mesozoic fossil‐bearing volcanic‐sedimentary strata in northern China. The westward subduction of the paleo‐Pacific plate triggered the crustal thickening and subsequent lithospheric thinning of the East Asia continent. These dynamic processes controlled the volcanic intensity and P variation, resulting in remarkable changes in P availability that led to the rise and fall of terrestrial biotas. Hence, P variations in volcanic sequences reveal the linkage between regional tectonics and biota evolution. This study represents an effort to explore how tectonic processes constrained terrestrial biotas involving multidisciplinary methods. Key Points The paleo‐Pacific subduction triggered the cratonic destruction and thus controlled the intensity of volcanism in the Middle‒Late Mesozoic The change of lithospheric thickness triggered by the paleo‐Pacific subduction caused the variation of P content in the volcanics Regional tectonics could impact the evolution of terrestrial ecosystems through the volcanism and nutrient P cycle

The Jehol and Yanliao biotas of northern China, two world‐class Lagerstätten with abundant biomass and biodiversity, provide critical clues to Mesozoic terrestrial ecosystems. Their evolution is a response to the destruction of the North China craton. However, the impetus for the rapid bloom of the biotas remains a mystery. Mesozoic large‐scale volcanic‐sedimentary strata in northern China are rich in terrestrial organisms. Statistical analyses show that volcanic nutrient element delivery, biomass, and biodiversity in these stratigraphic sequences increase synchronously, while harmful elements have the opposite change with them. These observations reveal the coevolutionary relationship between volcanism and terrestrial biotas. The increased nutrient element supply and inhibited harmful element delivery to terrestrial ecosystems from the voluminous volcanic products, produced under the geodynamic regime of paleo‐Pacific subduction and cratonic destruction, could create a conducive environment for the biodiversity and high prosperity of Mesozoic terrestrial biotas. Plain Language Summary The weathering of volcanic products can quickly provide material supply for ecosystems, including nutrient and harmful elements. The availability of these elements in volcanic‐sedimentary sequences can provide key evidence for the intrinsic relations between volcanism and terrestrial biological evolution. Through statistically‐based big data analyses, we determine the changes in nutrient/harmful element delivery, biomass, and vertebrate and entomic diversity of the Mesozoic fossil‐bearing volcanic‐sedimentary strata in northern China. Excluding the interference of pyroclastic flows on the fossil records, the results reveal the significant contributions of elevated volcanic nutrient supply to the flourishing of the Jehol and Yanliao biotas. Meanwhile, the inhibited release of harmful elements has limited impacts on the biotas. This study opens a new path for multidisciplinary investigations to explore the feedback relationship among regional tectonics, volcanism, and terrestrial biotas. Key Points Mesozoic terrestrial biotas in northern China coevolved with volcanism during the paleo‐Pacific subduction and cratonic destruction The increasing supply of volcanic nutrients promoted the flourishing of the Jehol and Yanliao biotas Inhibited volcanic toxic delivery facilitated the rapid bloom of the terrestrial biotas

Lactylation was initially discovered on human histones. Given its nascence, its occurrence on nonhistone proteins and downstream functional consequences remain elusive. Here we report a cyclic immonium ion of lactyllysine formed during tandem mass spectrometry that enables confident protein lactylation assignment. We validated the sensitivity and specificity of this ion for lactylation through affinity-enriched lactylproteome analysis and large-scale informatic assessment of nonlactylated spectral libraries. With this diagnostic ion-based strategy, we confidently determined new lactylation, unveiling a wide landscape beyond histones from not only the enriched lactylproteome but also existing unenriched human proteome resources. Specifically, by mining the public human Meltome Atlas, we found that lactylation is common on glycolytic enzymes and conserved on ALDOA. We also discovered prevalent lactylation on DHRS7 in the draft of the human tissue proteome. We partially demonstrated the functional importance of lactylation: site-specific engineering of lactylation into ALDOA caused enzyme inhibition, suggesting a lactylation-dependent feedback loop in glycolysis. This article reports the cyclic immonium ion as a diagnostic fragment ion for lysine lactylation. The approach was used for identifying lactylation in various enriched and unenriched proteome databases, demonstrating prevalence of lactylation beyond histones.