Unraveling Mechanism for Microstructure Engineering toward High-capacity Nickel-rich Cathode Materials.

Microstructural engineering on nickel-rich layered oxide (NRLO) cathode materials is considered a promising approach to increase both the capacity and lifespan of lithium-ion batteries by introducing high valence-state elements. However, rational regulation on NRLO microstructures based on a deep understanding of its capacity enhancement mechanism remains challenging. Herein for the first time, we demonstrate that an increase of 14 mAh·g-1 in reversible capacity at the first cycle can be achieved via tailoring the micro and nano structure of NRLO through introducing tungsten. Aberration-corrected scanning transmission electron microscopy characterization reveals that the formation of a modified microstructure featured as coherent spinel twin boundaries. Theoretical modeling and electrochemical investigations further demonstrate that the capacity increase mechanism is related to such coherent spinel twin boundaries, which could lower the Li+ diffusion barrier and thus allow more Li+ to participate in deeper phase transitions. Meanwhile, the surface and grain boundaries of NRLOs are found to be modified by generating a dense and uniform LiWxOy phase, which further extends its cycle life by reducing side reactions with electrolytes. This work enables a comprehensive understanding of the capacity-increased mechanism and endows the remarkable potential of microstructural engineering for capacity- and lifespan-increased NRLOs. This article is protected by copyright. All rights reserved.

Cardiolipin oxidized by ROS from complex II acts as a target of gasdermin D to drive mitochondrial pore and heart dysfunction in endotoxemia.

Cardiac dysfunction, an early complication of endotoxemia, is the major cause of death in intensive care units. No specific therapy is available at present for this cardiac dysfunction. Here, we show that the N-terminal gasdermin D (GSDMD-N) initiates mitochondrial apoptotic pore and cardiac dysfunction by directly interacting with cardiolipin oxidized by complex II-generated reactive oxygen species (ROS) during endotoxemia. Caspase-4/11 initiates GSDMD-N pores that are subsequently amplified by the upregulation and activation of NLRP3 inflammation through further generation of ROS. GSDMD-N pores form prior to BAX and VDAC1 apoptotic pores and further incorporate into BAX and VDAC1 oligomers within mitochondria membranes to exacerbate the apoptotic process. Our findings identify oxidized cardiolipin as the definitive target of GSDMD-N in mitochondria of cardiomyocytes during endotoxin-induced myocardial dysfunction (EIMD), and modulation of cardiolipin oxidation could be a therapeutic target early in the disease process to prevent EIMD.

Impacts of education level on Montreal Cognitive Assessment and saccades in community residents from Western China.

OBJECTIVES: This cross-sectional study sought to evaluate the effectiveness of the Montreal Cognitive Assessment (MoCA) and saccade in discerning the cognitive function levels among community populations characterized by diverse educational backgrounds. METHODS: Data from 665 Western China individuals encompassed MoCA scores and saccade performance. The study examined how education level and age influenced these assessments and highlighted the contrasting abilities of these measures in detecting cognitive abnormalities. RESULTS: The saccade model revealed a consistent cognitive impairment prevalence (15.5%) compared to previous clinical data (9.7% to 23.3%), while MoCA exhibited variable rates (25.1% to 52.8%). Notably, saccades and MoCA significantly diverged in detecting cognitive dysfunction. Additionally, education level had a greater impact on MoCA (effect size: 0.272) compared to saccades (0.024) affecting all MoCA sub-items, with age exerting a smaller influence on MoCA (0.037) compared to saccades (0.056). CONCLUSION: Saccades are less susceptible to the influence of education level when compared to MoCA, making saccade a potentially more suitable cognitive screening tool for rural community populations. SIGNIFICANCE: This study represents a pioneering approach by employing saccade detection within community populations to distinguish cognitive function status.

Kirkendall effect-induced uniform stress distribution stabilizes nickel-rich layered oxide cathodes.

Nickel-rich layered oxide cathodes promise ultrahigh energy density but is plagued by the mechanical failure of the secondary particle upon (de)lithiation. Existing approaches for alleviating the structural degradation could retard pulverization, yet fail to tune the stress distribution and root out the formation of cracks. Herein, we report a unique strategy to uniformize the stress distribution in secondary particle via Kirkendall effect to stabilize the core region during electrochemical cycling. Exotic metal/metalloid oxides (such as Al2O3 or SiO2) is introduced as the heterogeneous nucleation seeds for the preferential growth of the precursor. The calcination treatment afterwards generates a dopant-rich interior structure with central Kirkendall void, due to the different diffusivity between the exotic element and nickel atom. The resulting cathode material exhibits superior structural and electrochemical reversibility, thus contributing to a high specific energy density (based on cathode) of 660 Wh kg-1 after 500 cycles with a retention rate of 86%. This study suggests that uniformizing stress distribution represents a promising pathway to tackle the structural instability facing nickel-rich layered oxide cathodes.

Atlas of Cell Repertoire Within Neointimal Lesions Is Metabolically Altered in Hypertensive Rats.

BACKGROUND: High blood pressure has been suggested to accelerate vascular injury-induced neointimal formation and progression. However, little is known about the intricate relationships between vascular injury and hypertension in the context of arterial remodeling. METHODS: Single-cell RNA-sequencing analysis was used to depict the cell atlas of carotid arteries of Wistar Kyoto rats and spontaneously hypertensive rats with or without balloon injury. RESULTS: We found that hypertension significantly aggravated balloon injury-induced arterial stenosis. A total of 36 202 cells from carotid arteries with or without balloon injury were included in single-cell RNA-sequencing analysis. Cell composition analysis showed that vascular injury and hypertension independently induced distinct aortic cell phenotypic alterations including immune cells, endothelial cells (ECs), and smooth muscle cells. Specifically, our data showed that injury and hypertension-induced specific EC phenotypic alterations, and revealed a transition from functional ECs to hypermetabolic, and eventually dysfunctional ECs in hypertensive rats upon balloon injury. Importantly, our data also showed that vascular injury and hypertension-induced different smooth muscle cell phenotypic alterations, characterized by deferential expression of synthetic signatures. Interestingly, pathway analysis showed that dysregulated metabolic pathways were a common feature in monocytes/macrophages, ECs, and smooth muscle cells in response to injury and hypertension. Functionally, we demonstrate that inhibition of mitochondrial respiration significantly ameliorated injury-induced neointimal formation in spontaneously hypertensive rats. CONCLUSIONS: This study provides the cell landscape changes of the main aortic cell phenotypic alterations in response to injury and hypertension. Our findings suggest that targeting cellular mitochondrial respiration could be a novel therapeutic for patients with hypertension undergoing vascular angioplasty.

The noncanonical inflammasome-induced pyroptosis and septic shock.

Sepsis remains one of the most common and lethal conditions globally. Currently, no proposed target specific to sepsis improves survival in clinical trials. Thus, an in-depth understanding of the pathogenesis of sepsis is needed to propel the discovery of effective treatment. Recently attention to sepsis has intensified because of a growing recognition of a non-canonical inflammasome-triggered lytic mode of cell death termed pyroptosis upon sensing cytosolic lipopolysaccharide (LPS). Although the consequences of activation of the canonical and non-canonical inflammasome are similar, the non-canonical inflammasome formation requires caspase-4/5/11, which enzymatically cleave the pore-forming protein gasdermin D (GSDMD) and thereby cause pyroptosis. The non-canonical inflammasome assembly triggers such inflammatory cell death by itself; or leverages a secondary activation of the canonical NLRP3 inflammasome pathway. Excessive cell death induced by oligomerization of GSDMD and NINJ1 leads to cytokine release and massive tissue damage, facilitating devastating consequences and death. This review summarized the updated mechanisms that initiate and regulate non-canonical inflammasome activation and pyroptosis and highlighted various endogenous or synthetic molecules as potential therapeutic targets for treating sepsis.

Broad Spectrum Image Deblurring via an Adaptive Super-Network.

In blurry images, the degree of image blurs may vary drastically due to different factors, such as varying speeds of shaking cameras and moving objects, as well as defects of the camera lens. However, current end-to-end models failed to explicitly take into account such diversity of blurs. This unawareness compromises the specialization at each blur level, yielding sub-optimal deblurred images as well as redundant post-processing. Therefore, how to specialize one model simultaneously at different blur levels, while still ensuring coverage and generalization, becomes an emerging challenge. In this work, we propose Ada-Deblur, a super-network that can be applied to a "broad spectrum" of blur levels with no re-training on novel blurs. To balance between individual blur level specialization and wide-range blur levels coverage, the key idea is to dynamically adapt the network architectures from a single well-trained super-network structure, targeting flexible image processing with different deblurring capacities at test time. Extensive experiments demonstrate that our work outperforms strong baselines by demonstrating better reconstruction accuracy while incurring minimal computational overhead. Besides, we show that our method is effective for both synthetic and realistic blurs compared to these baselines. The performance gap between our model and the state-of-the-art becomes more prominent when testing with unseen and strong blur levels. Specifically, our model demonstrates surprising deblurring performance on these images with PSNR improvements of around 1 dB. Our code is publicly available at https://github.com/wuqiuche/Ada-Deblur.

Meta-Analysis of Single-Cell RNA-Seq Data Reveals the Mechanism of Formation and Heterogeneity of Tertiary Lymphoid Organ in Vascular Disease.

BACKGROUND: Tertiary lymphoid organs (TLOs) are ectopic lymphoid organs developed in nonlymphoid tissues with chronic inflammation, but little is known about their existence in different types of vascular diseases and the mechanism that mediated their development. METHODS: To take advantage of single-cell RNA sequencing techniques, we integrated 28 single-cell RNA sequencing data sets containing 5 vascular disease models (atherosclerosis, abdominal aortic aneurysm, intimal hyperplasia, isograft, and allograft) to explore TLOs existence and environment supporting its growth systematically. We also searched Medline, Embase, PubMed, and Web of Science from inception to January 2022 for published histological images of vascular remodeling for histological evidence to support TLO genesis. RESULTS: Accumulation and infiltration of innate and adaptive immune cells have been observed in various remodeling vessels. Interestingly, the proportion of such immune cells incrementally increases from atherosclerosis to intimal hyperplasia, abdominal aortic aneurysm, isograft, and allograft. Importantly, we uncovered that TLO structure cells, such as follicular helper T cells and germinal center B cells, present in all remodeled vessels. Among myeloid cells and lymphocytes, inflammatory macrophages, and T helper 17 cells are the major lymphoid tissue inducer cells which were found to be positively associated with the numbers of TLO structural cells in remodeled vessels. Vascular stromal cells also actively participate in vascular TLO genesis by communicating with myeloid cells and lymphocytes via CCLs (C-C motif chemokine ligands), CXCL (C-X-C motif ligand), lymphotoxin, BMP (bone morphogenetic protein) chemotactic, FGF-2 (fibroblast growth factor-2), and IGF (insulin growth factor) proliferation mechanisms, particularly for lymphoid tissue inducer cell aggregation. Additionally, the interaction between stromal cells and immune cells modulates extracellular matrix remodeling. Among TLO structure cells, follicular helper T, and germinal center B cells have strong interactions via TCR (T-cell receptor), CD40 (cluster of differentiation 40), and CXCL signaling, to promote the development and maturation of the germinal center in TLO. Consistently, by reviewing the histological images from the literature, TLO genesis was found in those vascular remodeling models. CONCLUSIONS: Our analysis showed the existence of TLOs across 5 models of vascular diseases. The mechanisms that support TLOs formation in different models are heterogeneous. This study could be a valuable resource for understanding and discovering new therapeutic targets for various forms of vascular disease.

Unique Tridentate Coordination Tailored Solvation Sheath Toward Highly Stable Lithium Metal Batteries.

Electrolyte optimization by solvent molecule design is recognized as an effective approach for stabilizing lithium (Li) metal batteries. However, the coordination pattern of Li ions (Li+ ) with solvent molecules is sparsely considered. Here, an electrolyte design strategy is reported based on bi/tridentate chelation of Li+ and solvent to tune the solvation structure. As a proof of concept, a novel solvent with multi-oxygen coordination sites is demonstrated to facilitate the formation of an anion-aggregated solvation shell, enhancing the interfacial stability and de-solvation kinetics. As a result, the as-developed electrolyte exhibits ultra-stable cycling over 1400 h in symmetric cells with 50 µm-thin Li foils. When paired with high-loading LiFePO4 , full cells maintain 92% capacity over 500 cycles and deliver improved electrochemical performances over a wide temperature range from -10 to 60 °C. Furthermore, the concept is validated in a pouch cell (570 mAh), achieving a capacity retention of 99.5% after 100 cycles. This brand-new insight on electrolyte engineering provides guidelines for practical high-performance Li metal batteries.

The regulatory role of metabolic organ-secreted factors in the nonalcoholic fatty liver disease and cardiovascular disease.

Nonalcoholic fatty liver disease (NAFLD) is a chronic metabolic disease characterized by an excessive accumulation of fat in the liver, which is becoming a major global health problem, affecting about a quarter of the population. In the past decade, mounting studies have found that 25%-40% of NAFLD patients have cardiovascular disease (CVD), and CVD is one of the leading causes of death in these subjects. However, it has not attracted enough awareness and emphasis from clinicians, and the underlying mechanisms of CVD in NAFLD patients remain unclear. Available research reveals that inflammation, insulin resistance, oxidative stress, and glucose and lipid metabolism disorders play indispensable roles in the pathogenesis of CVD in NAFLD. Notably, emerging evidence indicates that metabolic organ-secreted factors, including hepatokines, adipokines, cytokines, extracellular vesicles, and gut-derived factors, are also involved in the occurrence and development of metabolic disease and CVD. Nevertheless, few studies have focused on the role of metabolic organ-secreted factors in NAFLD and CVD. Therefore, in this review, we summarize the relationship between metabolic organ-secreted factors and NAFLD as well as CVD, which is beneficial for clinicians to comprehensive and detailed understanding of the association between both diseases and strengthen management to improve adverse cardiovascular prognosis and survival.

Serine/threonine kinase TBK1 promotes cholangiocarcinoma progression via direct regulation of ß-catenin.

Cholangiocarcinoma (CCA) is a highly heterogeneous and metastatic malignancy with a poor prognosis even after curative hepatectomy. Studies exploring its pathogenesis and identifying effective therapeutic targets are urgently needed. In this study, we found that TANK-binding kinase 1 (TBK1), a serine/threonine-protein kinase, showed a dynamic increase during the different stages of murine spontaneous CCA carcinogenesis (hyperplasia, dysplasia, and CCA). TBK1 was upregulated in human tissues, including intrahepatic (n = 182) and extrahepatic (n = 40) CCA tissues, compared with nontumor tissues, and the elevated expression of TBK1 was positively correlated with larger tumour diameter, lymph node metastasis, and advanced TNM stage. Functional studies indicated that TBK1 promoted CCA growth and metastasis both in vitro and in vivo. TBK1 directly interacts with ß-catenin, promoting its phosphorylation at the S552 site and its nuclear translocation, which further activates EMT-related transcriptional reprogramming. GSK-8612, a TBK1 inhibitor or a kinase-inactivating mutation, effectively suppresses the above processes. In addition, we found that low-density lipoprotein receptor (LDLR), which mediates the endocytosis of cholesterol, was upregulated in CCA. Therefore, we designed a cholesterol-conjugated DNA/RNA heteroduplex oligonucleotide targeting TBK1 (Cho-TBK1-HDO), which could accumulate in CCA cells via LDLR, reduce the TBK1 mRNA level and inhibit intrahepatic metastasis of CCA. Besides, in the experimental group of 182 ICC patients, high TBK1 expression combined with high nuclear ß-catenin expression predicted a worse prognosis. In summary, TBK1 might serve as a potential prognostic biomarker and therapeutic target for patients with CCA.

Clinical characteristics and prognosis differences between isolated right and left ventricular myocardial infarction in the Chinese population: a retrospective study.

Background and aims: Acute myocardial infarction (AMI) is divided into left ventricular myocardial infarction (LVMI) and right ventricular myocardial infarction (RVMI) according to the regions of myocardial ischemic necrosis. Clinical characteristics, treatment strategies, and prognosis differences between isolated RVMI and LVMI have not been well characterized. This study aimed to explore this difference of patients with isolated RVMI and LVMI. Methods: This retrospective cohort study included 3,506 patients hospitalized with coronary angiography diagnosed type 1 myocardial infarction (MI). Characteristics of admission and treatment strategies were compared in patients with isolated RVMI and LVMI. COX proportional hazards models with and without inverse probability of treatment weighting (IPTW) adjustment were performed to estimate the difference in all-cause and cardiovascular mortality between the two groups. Results: In this retrospective study, we found the frequency of isolated RVMI was significantly lower in the population than that of isolated LVMI (406 (11.6%) vs 3,100 (88.4%)). Patients with isolated RVMI have similar age, sex, and comorbidities to the patients with isolated LVMI. However, patients with isolated RVMI have lower heart rate and blood pressure, but higher rates of cardiogenic shock and atrioventricular block. It is noteworthy that patients with isolated RVMI are more likely to be complicated with the multivessel lesion. Patients with isolated RVMI have lower risk of all-cause mortality (HR 0.36; 95% CI [0.24-0.54], p < 0.001) and cardiovascular mortality (HR 0.37; 95% CI [0.22-0.62], p < 0.001) than patients with isolated LVMI. Conclusions: This study showed that patients with isolated RVMI and LVMI have similar baseline characteristics. However, the clinical manifestations were different in the isolated RVMI and LVMI patients. This study revealed a better prognosis of isolated RVMI patients compared to isolated LVMI, which indicates the ischemic region could be considered in AMI risk stratification models for better assessment of risk for adverse clinical events.

High-dimensional proteomics identifies organ injury patterns associated with outcomes in human trauma.

INTRODUCTION: Severe traumatic injury with shock can lead to direct and indirect organ injury; however, tissue-specific biomarkers are limited in clinical panels. We used proteomic and metabolomic databases to identify organ injury patterns after severe injury in humans. METHODS: Plasma samples (times 0, 24, and 72 hours after arrival to trauma center) from injured patients enrolled in two randomized prehospital trials were subjected to multiplexed proteomics (SomaLogic Inc., Boulder, CO). Patients were categorized by outcome: nonresolvers (died >72 hours or required ≥7 days of critical care), resolvers (survived to 30 days and required <7 days of critical care), and low Injury Severity Score (ISS) controls. Established tissue-specific biomarkers were identified through a literature review and cross-referenced with tissue specificity from the Human Protein Atlas. Untargeted plasma metabolomics (Metabolon Inc., Durham, NC), inflammatory mediators, and endothelial damage markers were correlated with injury biomarkers. Kruskal-Wallis/Mann-Whitney U tests with false discovery rate correction assessed differences in biomarker expression across outcome groups (significance; p < 0.1). RESULTS: Of 142 patients, 78 were nonresolvers (median ISS, 30), 34 were resolvers (median ISS, 22), and 30 were low ISS controls (median ISS, 1). A broad release of tissue-specific damage markers was observed at admission; this was greater in nonresolvers. By 72 hours, nine cardiac, three liver, eight neurologic, and three pulmonary proteins remained significantly elevated in nonresolvers compared with resolvers. Cardiac damage biomarkers showed the greatest elevations at 72 hours in nonresolvers and had significant positive correlations with proinflammatory mediators and endothelial damage markers. Nonresolvers had lower concentrations of fatty acid metabolites compared with resolvers, particularly acyl carnitines and cholines. CONCLUSION: We identified an immediate release of tissue-specific biomarkers with sustained elevation in the liver, pulmonary, neurologic, and especially cardiac injury biomarkers in patients with complex clinical courses after severe injury. The persistent myocardial injury in nonresolvers may be due to a combination of factors including metabolic stress, inflammation, and endotheliopathy.

Inner Lithium Fluoride (LiF)-Rich Solid Electrolyte Interphase Enabled by a Smaller Solvation Sheath for Fast-Charging Lithium Batteries.

Fast-charging lithium-ion batteries (LIBs) have been severely hampered by the slow development of their electrolytes. Herein, we demonstrate that the size effect of solvent sheath would pose a great effect on the fast-charging performance of LIBs. Three similar ethers, including diethyl ether (DEE), dipropyl ether (DPE), and dibutyl ether (DBE), were mixed with 1,1,2,2-tetrafluoroethyl-2,2,3,3-tetrafluoropropyl ether (TTE) and lithium bis(fluorosulfonyl)imide (1 M) to form an electrolyte for fast-charging LIBs, respectively. The results showed that it is more difficult to form ternary graphite intercalation compounds (GICs) in the electrolyte with a larger solvation sheath. The DEE electrolyte can form stable GICs and generate an inner LiF-rich solid electrolyte interphase (SEI), lowering the diffusion barrier of Li+. Therefore, the graphite anode powered by the DEE electrolyte can maintain a capacity of 190 mAh g-1 at 4 C after 500 cycles. This kind of size effect of solvation sheath is also applicable to lithium metal batteries.

The Performance of Saccade Tasks Correlates with Cognitive Test Scores in Elderly Population: Evidence for the Usefulness of Oculomotor Tests in Cognitive Assessment.

BACKGROUND: Among the elderly, dementia is a common and disabling disorder with primary manifestations of cognitive impairments. Diagnosis and intervention in its early stages is the key to effective treatment. Nowadays, the test of cognitive function relies mainly on neuropsychological tests, such as the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). However, they have noticeable shortcomings, e.g., the biases of subjective judgments from physicians and the cost of the labor of these well-trained physicians. Thus, advanced and objective methods are urgently needed to evaluate cognitive functions. METHODS: We developed a cognitive assessment system through measuring the saccadic eye movements in three tasks. The cognitive functions were evaluated by both our system and the neuropsychological tests in 310 subjects, and the evaluating results were directly compared. RESULTS: In general, most saccadic parameters correlate well with the MMSE and MoCA scores. Moreover, some subjects with high MMSE and MoCA scores have high error rates in performing these three saccadic tasks due to various errors. The primary error types vary among tasks, indicating that different tasks assess certain specific brain functions preferentially. Thus, to improve the accuracy of evaluation through saccadic tasks, we built a weighted model to combine the saccadic parameters of the three saccadic tasks, and our model showed a good diagnosis performance in detecting patients with cognitive impairment. CONCLUSION: The comprehensive analysis of saccadic parameters in multiple tasks could be a reliable, objective, and sensitive method to evaluate cognitive function and thus to help diagnose cognitive impairments.

Plasma proteomics reveals early, broad release of chemokine, cytokine, TNF, and interferon mediators following trauma with delayed increases in a subset of chemokines and cytokines in patients that remain critically ill.

Severe injury is known to cause a systemic cytokine storm that is associated with adverse outcomes. However, a comprehensive assessment of the time-dependent changes in circulating levels of a broad spectrum of protein immune mediators and soluble immune mediator receptors in severely injured trauma patients remains uncharacterized. To address this knowledge gap, we defined the temporal and outcome-based patterns of 184 known immune mediators and soluble cytokine receptors in the circulation of severely injured patients. Proteomics (aptamer-based assay, SomaLogic, Inc) was performed on plasma samples drawn at 0, 24, and 72 hours (h) from time of admission from 150 trauma patients, a representative subset from the Prehospital Plasma during Air Medical Transport in Trauma Patients at Risk for Hemorrhagic Shock (PAMPer) trial. Patients were categorized into outcome groups including Early Non-Survivors (died within 72 h; ENS; n=38), Non-Resolvers (died after 72 h or required ≥7 days of intensive care; NR; n=78), and Resolvers (survivors that required < 7 days of intensive care; R; n=34), with low Injury Severity Score (ISS) patients from the Tranexamic Acid During Prehospital Transport in Patients at Risk for Hemorrhage After Injury (STAAMP) trial as controls. The major findings include an extensive release of immune mediators and cytokine receptors at time 0h that is more pronounced in ENS and NR patients. There was a selective subset of mediators elevated at 24 and 72 h to a greater degree in NR patients, including multiple cytokines and chemokines not previously described in trauma patients. These findings were validated in a quantitative fashion using mesoscale discovery immunoassays (MSD) from an external validation cohort (VC) of samples from 58 trauma patients matched for R and NR status. This comprehensive longitudinal description of immune mediator patterns associated with trauma outcomes provides a new level of characterization of the immune response that follows severe injury.

Enhanced Expression of ARK5 in Hepatic Stellate Cell and Hepatocyte Synergistically Promote Liver Fibrosis.

AMPK-related protein kinase 5 (ARK5) is involved in a broad spectrum of physiological and cell events, and aberrant expression of ARK5 has been observed in a wide variety of solid tumors, including liver cancer. However, the role of ARK5 in liver fibrosis remains largely unexplored. We found that ARK5 expression was elevated in mouse fibrotic livers, and showed a positive correlation with the progression of liver fibrosis. ARK5 was highly expressed not only in activated hepatic stellate cells (HSCs), but also in hepatocytes. In HSCs, ARK5 prevents the degradation of transforming growth factor ß type I receptor (TßRI) and mothers against decapentaplegic homolog 4 (Smad4) proteins by inhibiting the expression of Smad ubiquitin regulatory factor 2 (Smurf2), thus maintaining the continuous transduction of the transforming growth factor ß (TGF-ß) signaling pathway, which is essential for cell activation, proliferation and survival. In hepatocytes, ARK5 induces the occurrence of epithelial-mesenchymal transition (EMT), and also promotes the secretion of inflammatory factors. Inflammatory factors, in turn, further enhance the activation of HSCs and deepen the degree of liver fibrosis. Notably, we demonstrated in a mouse model that targeting ARK5 with the selective inhibitor HTH-01-015 attenuates CCl4-induced liver fibrosis in mice. Taken together, the results indicate that ARK5 is a critical driver of liver fibrosis, and promotes liver fibrosis by synergy between HSCs and hepatocytes.

Lipidomic signatures align with inflammatory patterns and outcomes in critical illness.

Alterations in lipid metabolism have the potential to be markers as well as drivers of pathobiology of acute critical illness. Here, we took advantage of the temporal precision offered by trauma as a common cause of critical illness to identify the dynamic patterns in the circulating lipidome in critically ill humans. The major findings include an early loss of all classes of circulating lipids followed by a delayed and selective lipogenesis in patients destined to remain critically ill. The previously reported survival benefit of early thawed plasma administration was associated with preserved lipid levels that related to favorable changes in coagulation and inflammation biomarkers in causal modelling. Phosphatidylethanolamines (PE) were elevated in patients with persistent critical illness and PE levels were prognostic for worse outcomes not only in trauma but also severe COVID-19 patients. Here we show selective rise in systemic PE as a common prognostic feature of critical illness.

Periplaneta americana extract alleviates steatohepatitis in a mouse model by modulating HMGB1-mediated inflammatory response.

Alcoholic abuse and obesity are the most common lifestyle implications of chronic liver injury, and always act synergistically to increase the risk of mortality. Periplaneta americana has a long history of being applied in medicine, including wound healing, antitumor, antibacterial, antiviral, antifibrotic, and cardiomyocyte-protecting. Ganlong capsule (GLC), a natural prescription drug extracted from Periplaneta americana, has been widely used in HBV-related symptoms. However, the anti-steatohepatitis efficacy and mechanisms of GLC have not yet been characterized. Here, we found the protective effect of GLC on the development of hepatic steatosis, oxidative stress, and inflammation in vivo under alcohol exposure combined with a high-fat and high-cholesterol diet (HFHC). Consistently, GLC exhibited a hepatoprotective property by preventing hepatocytes from oxidative stress injury and lipid accumulation in vitro. In addition, it exerted an anti-inflammation characteristic by reducing macrophage recruitment and decreasing the expression of pro-inflammatory genes in vivo and in vitro. Mechanically, GLC serum, isolated from GLC-treated mice, reduced extracellular high-mobility group box 1 (HMGB1) of dying hepatocytes; and suppressed subsequent M1 polarization of macrophages in the co-culture system. Furthermore, GLC serum inhibited inflammatory response via suppressing the HMGB1 release and blocking the downstream TLR4/NF-kB pathway. Collectively, GLC alleviates steatohepatitis induced by alcohol consumption and obesity through inhibition of the HMGB1-mediated inflammatory cascade. GLC might be a therapeutic candidate for the treatment of steatohepatitis developed by alcohol abuse and metabolic disorders.