Long Term Ex-Situ Normothermic Machine Perfusion Allows Regeneration of Human Livers with Severe Bile Duct Injury.

Bile duct regeneration is hypothesised to prevent biliary strictures, a leading cause of morbidity after liver transplantation. Assessing the capacity for biliary regeneration may identify grafts as suitable for transplantation that are currently declined, but has been unfeasible until now. This study used Long-Term Ex-Situ Normothermic Machine Perfusion (LT-NMP) to assess biliary regeneration. Human livers that were declined for transplantation were perfused at 36°C for up to 13.5 days. Bile duct biopsies, bile and perfusate were collected throughout perfusion, which were examined for features of injury and regeneration. Biliary regeneration was defined as new Ki-67 positive biliary epithelium following severe injury. Ten livers were perfused for a median duration of 7.5 days. Severe bile duct injury occurred in all grafts, and biliary regeneration occurred in 70% of grafts. Traditional biomarkers of biliary viability such as bile glucose improved during perfusion but this was not associated with biliary regeneration (p>0.05). In contrast, the maintenance of IL-6 and VEGF-A levels in bile were associated with biliary regeneration (p=0.017 for both cytokines). This is the first study to demonstrate biliary regeneration during LT-NMP and identify a cytokine signature in bile as a novel biomarker for biliary regeneration during LT-NMP.

Targeting the SphK1/S1P/PFKFB3 axis suppresses hepatocellular carcinoma progression by disrupting glycolytic energy supply that drives tumor angiogenesis.

BACKGROUND: Hepatocellular carcinoma (HCC) remains a leading life-threatening health challenge worldwide, with pressing needs for novel therapeutic strategies. Sphingosine kinase 1 (SphK1), a well-established pro-cancer enzyme, is aberrantly overexpressed in a multitude of malignancies, including HCC. Our previous research has shown that genetic ablation of Sphk1 mitigates HCC progression in mice. Therefore, the development of PF-543, a highly selective SphK1 inhibitor, opens a new avenue for HCC treatment. However, the anti-cancer efficacy of PF-543 has not yet been investigated in primary cancer models in vivo, thereby limiting its further translation. METHODS: Building upon the identification of the active form of SphK1 as a viable therapeutic target in human HCC specimens, we assessed the capacity of PF-543 in suppressing tumor progression using a diethylnitrosamine-induced mouse model of primary HCC. We further delineated its underlying mechanisms in both HCC and endothelial cells. Key findings were validated in Sphk1 knockout mice and lentiviral-mediated SphK1 knockdown cells. RESULTS: SphK1 activity was found to be elevated in human HCC tissues. Administration of PF-543 effectively abrogated hepatic SphK1 activity and significantly suppressed HCC progression in diethylnitrosamine-treated mice. The primary mechanism of action was through the inhibition of tumor neovascularization, as PF-543 disrupted endothelial cell angiogenesis even in a pro-angiogenic milieu. Mechanistically, PF-543 induced proteasomal degradation of the critical glycolytic enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3, thus restricting the energy supply essential for tumor angiogenesis. These effects of PF-543 could be reversed upon S1P supplementation in an S1P receptor-dependent manner. CONCLUSIONS: This study provides the first in vivo evidence supporting the potential of PF-543 as an effective anti-HCC agent. It also uncovers previously undescribed links between the pro-cancer, pro-angiogenic and pro-glycolytic roles of the SphK1/S1P/S1P receptor axis. Importantly, unlike conventional anti-HCC drugs that target individual pro-angiogenic drivers, PF-543 impairs the PFKFB3-dictated glycolytic energy engine that fuels tumor angiogenesis, representing a novel and potentially safer therapeutic strategy for HCC.

Comprehensive molecular analyses of a 7-m6A-related lncRNAs signature for prognosis, tumor immunity and therapeutic effect in patients with hepatocellular carcinoma.

Hepatocellular carcinoma is the most common form of liver tumor. m6A modification and noncoding RNA show indispensable roles in HCC. We sought to establish and verify an appropriate m6A-related long noncoding RNA prognostic tool for predicting hepatocellular carcinoma progression. We extracted the RNA expression levels and the clinicopathologic data from GTEx and TCGA databases. Multivariate Cox regression analysis and receiver operating characteristic curves were performed to test the model's predictive ability. We further built a nomogram for overall survival according to the risk score and clinical features. A competing endogenous RNA network and Gene Ontology assessment were implemented to identify related biological mechanisms and processes. By bioinformatics analysis, a risk model comprising GABPB1-AS1, AC025580.1, LINC01358, AC026356.1, AC009005.1, HCG15, and AC026368.1 was built to offer a prognostic prediction for hepatocellular carcinoma independently. The prognostic tool could better prognosticate hepatocellular carcinoma patients' survival than other clinical characteristics. Then, a nomogram with risk score and clinical characteristics was created, which had strong power to calculate the survival probability in hepatocellular carcinoma. The immune-associated processes involving the differentially expressed genes between the two subgroups were displayed. Analyses of prognosis, clinicopathological characteristics, tumor mutation burden, immune checkpoint molecules, and drug response showed significant differences among the two risk subtypes, hinting that the model could appraise the efficacy of immunotherapy and chemotherapy. The tool can independently predict the prognosis in patients with hepatocellular carcinoma, which benefits drug selection in hepatocellular carcinoma patients.

Targeting miR-27a/VE-cadherin interactions rescues cerebral cavernous malformations in mice.

Cerebral cavernous malformations (CCMs) are vascular lesions predominantly developing in the central nervous system (CNS), with no effective treatments other than surgery. Loss-of-function mutation in CCM1/krev interaction trapped 1 (KRIT1), CCM2, or CCM3/programmed cell death 10 (PDCD10) causes lesions that are characterized by abnormal vascular integrity. Vascular endothelial cadherin (VE-cadherin), a major regulator of endothelial cell (EC) junctional integrity is strongly disorganized in ECs lining the CCM lesions. We report here that microRNA-27a (miR-27a), a negative regulator of VE-cadherin, is elevated in ECs isolated from mouse brains developing early CCM lesions and in cultured ECs with CCM1 or CCM2 depletion. Furthermore, we show miR-27a acts downstream of kruppel-like factor (KLF)2 and KLF4, two known key transcription factors involved in CCM lesion development. Using CD5-2 (a target site blocker [TSB]) to prevent the miR-27a/VE-cadherin mRNA interaction, we present a potential therapy to increase VE-cadherin expression and thus rescue the abnormal vascular integrity. In CCM1- or CCM2-depleted ECs, CD5-2 reduces monolayer permeability, and in Ccm1 heterozygous mice, it restores dermal vessel barrier function. In a neonatal mouse model of CCM disease, CD5-2 normalizes vasculature and reduces vascular leakage in the lesions, inhibits the development of large lesions, and significantly reduces the size of established lesions in the hindbrain. Furthermore, CD5-2 limits the accumulation of inflammatory cells in the lesion area. Our work has established that VE-cadherin is a potential therapeutic target for normalization of the vasculature and highlights that targeting miR-27a/VE-cadherin interaction by CD5-2 is a potential novel therapy for the devastating disease, CCM.

Liver-specific deletion of miR-181ab1 reduces liver tumour progression via upregulation of CBX7.

MiR-181 expression levels increased in hepatocellular carcinoma (HCC) compared to non-cancerous tissues. MiR-181 has been widely reported as a possible driver of tumourigenesis but also acts as a tumour suppressor. In addition, the miR-181 family regulates the development and function of immune and vascular cells, which play vital roles in the progression of tumours. More complicatedly, many genes have been identified as miR-181 targets to mediate the effects of miR-181. However, the role of miR-181 in the development of primary tumours remains largely unexplored. We aimed to examine the function of miR-181 and its vital mediators in the progression of diethylnitrosamine-induced primary liver cancers in mice. The size of liver tumours was significantly reduced by 90% in global (GKO) or liver-specific (LKO) 181ab1 knockout mice but not in hematopoietic and endothelial lineage-specific knockout mice, compared to WT mice. In addition, the number of tumours was significantly reduced by 50% in GKO mice. Whole-genome RNA-seq analysis and immunohistochemistry showed that epithelial-mesenchymal transition was partially reversed in GKO tumours compared to WT tumours. The expression of CBX7, a confirmed miR-181 target, was up-regulated in GKO compared to WT tumours. Stable CBX7 expression was achieved with an AAV/Transposase Hybrid-Vector System and up-regulated CBX7 expression inhibited liver tumour progression in WT mice. Hepatic CBX7 deletion restored the progression of LKO liver tumours. MiR-181a expression was the lowest and CBX7 expression the highest in iClust2 and 3 subclasses of human HCC compared to iClust1. Gene expression profiles of GKO tumours overlapped with low-proliferative peri-portal-type HCCs. Liver-specific loss of miR-181ab1 inhibited primary liver tumour progression via up-regulating CBX7 expression, but tumour induction requires both hepatic and non-hepatic miR-181. Also, miR-181ab1-deficient liver tumours may resemble low-proliferative periportal-type human HCC. miR-181 was increased with liver tumour growth. More miR-181, darker colour and higher shape. CBX7 was very low in pericentral hepatocytes, increased in early liver tumours, but reduced in advanced liver tumours. Its levels were maintained in miR-181 KO liver tumours. In tumours (T), brown (darker is more) represents miR-181, the blue circle (thicker is more) represents CBX7.

Regulation of hepatic insulin signaling and glucose homeostasis by sphingosine kinase 2.

Sphingolipid dysregulation is often associated with insulin resistance, while the enzymes controlling sphingolipid metabolism are emerging as therapeutic targets for improving insulin sensitivity. We report herein that sphingosine kinase 2 (SphK2), a key enzyme in sphingolipid catabolism, plays a critical role in the regulation of hepatic insulin signaling and glucose homeostasis both in vitro and in vivo. Hepatocyte-specific Sphk2 knockout mice exhibit pronounced insulin resistance and glucose intolerance. Likewise, SphK2-deficient hepatocytes are resistant to insulin-induced activation of the phosphoinositide 3-kinase (PI3K)-Akt-FoxO1 pathway and elevated hepatic glucose production. Mechanistically, SphK2 deficiency leads to the accumulation of sphingosine that, in turn, suppresses hepatic insulin signaling by inhibiting PI3K activation in hepatocytes. Either reexpressing functional SphK2 or pharmacologically inhibiting sphingosine production restores insulin sensitivity in SphK2-deficient hepatocytes. In conclusion, the current study provides both experimental findings and mechanistic data showing that SphK2 and sphingosine in the liver are critical regulators of insulin sensitivity and glucose homeostasis.

Natural gas spot price prediction research under the background of Russia-Ukraine conflict - based on FS-GA-SVR hybrid model.

The ongoing Russia-Ukraine conflict has led to significant upheaval in the worldwide natural gas sector. Accurate natural gas price forecasting, as an essential tool for mitigating market uncertainty, plays a crucial role in commodity trading and regulatory decision-making. This study aims to develop a hybrid forecasting model, the FS-GA-SVR model, which integrates feature selection (FS), genetic algorithm (GA), and support vector regression (SVR) to investigate Henry Hub natural gas price prediction amidst the Russia-Ukraine conflict. The results show that: (1) The feature selection automates model input variable selection, decreasing the time required while improving the model's accuracy. (2) The use of genetic algorithm for selecting support vector regression hyperparameters significantly improves the accuracy of natural gas price predictions. The algorithm leads to a decrease of approximately 70% in measurement indicators. (3) During the Russia-Ukraine conflict, the FS-GA-SVR hybrid model demonstrates more consistent and accurate predictions for natural gas spot prices than the base SVR model. This study serves as a valuable theoretical reference for energy policymakers and natural gas market investors worldwide, supporting their ability to anticipate fluctuations in natural gas prices.

Catalytic Chemistry Derived Artificial Solid Electrolyte Interphase for Stable Lithium Metal Anodes Working at 20†mA cm-2 and 20†mAh cm-2.

A stable solid electrolyte interphase (SEI) layer is crucial for lithium metal anode (LMA) to survive in long-term cycling. However, chaotic structures and chemical inhomogeneity of natural SEI make LMA suffering from exasperating dendrite growth and severe electrode pulverization, which hinder the practical application of LMAs. Here, we design a catalyst-derived artificial SEI layer with an ordered polyamide-lithium hydroxide (PA-LiOH) bi-phase structure to modulate ion transport and enable dendrite-free Li deposition. The PA-LiOH layer can substantially suppress the volume changes of LMA during Li plating/stripping cycles, as well as alleviate the parasitic reactions between LMA and electrolyte. The optimized LMAs demonstrate excellent stability in Li plating/stripping cycles for over 1000 hours at an ultra-high current density of 20 mA cm-2 in Li||Li symmetric cells. A high coulombic efficiency up to 99.2 % in Li half cells in additive-free electrolytes is achieved even after 500 cycles at a current density of 1 mA cm-2 with a capacity of 1 mAh cm-2 .

Distortion spot correction and center location base on deep neural network and MBAS in measuring large curvature aspheric optical element.

Large curvature aspheric optical elements are widely used in visual system. But its morphological detection is very difficult because its accuracy requirement is very high. When we use the self-developed multi-beam angle sensor (MBAS) to detect large curvature aspheric optical elements, the accuracy will be reduced due to spot distortion. Therefore, we propose a scheme combining distorted spot correction neural network (DSCNet) and gaussian fitting method to improve the detection accuracy of distorted spot center. We develop a spot discrimination method to determine spot region in multi-spot images. The spot discrimination threshold is obtained by the quantitative distribution of pixels in the connected domain. We design a DSCNet, which corrects the distorted spot to Gaussian spot, to extract the central information of distorted spot images by multiple pooling. The experimental results demonstrate that the DSCNet can effectively correct the distorted spot, and the spot center can be extracted to sub-pixel level, which improves the measurement accuracy of the MBAS. The standard deviations of plano-convex lenses with curvature radii of 500 mm, 700 mm and 1000 mm measured with the proposed method are respectively 0.0112 um, 0.0086 um and 0.0074 um.

High levels of platelet-to-lymphocyte ratio may predict reduced risk of end stage of renal disease in Chinese patients with MPO-ANCA associated vasculitis. / 血小板/淋巴细胞比率比值升高可能预示中国MPO-ANCAç›¸å ³æ€§è¡€ç®¡ç‚Žæ‚£è€ è¿›å±•è‡³ç»ˆæœ«æœŸè‚¾ç— çš„é£Žé™©è¾ƒä½Ž.

OBJECTIVES: Platelet-to-lymphocyte ratio (PLR) has recently been investigated as a new inflammatory marker in many inflammatory diseases, including systemic lupus erythematosus and immunoglobulin A vasculitis. However, there were very few reports regarding the clinical role of PLR in patients with anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis. This study was thus undertaken to investigate the relationship between inflammatory response and disease activity in Chinese patients with myeloperoxidase-anti-neutrophil cytoplasmic antibody (MPO-ANCA) associated vasculitis. Furthermore, we evaluated whether PLR predicts the progression of end stage of renal disease (ESRD) and all-cause mortality. METHODS: The clinical, laboratory and pathological data, and the outcomes of MPO-ANCA associated vasculitis patients were collected. The Spearman correlation coefficient was computed to examine the association between 2 continuous variables. Cox regression analysis was used to estimate the association between PLR and ESRD or all-cause mortality. RESULTS: A total of 190 consecutive patients with MPO-ANCA associated vasculitis were included in this study. Baseline PLR was positively correlated with CRP (r=0.333, P<0.001) and ESR (r=0.218, P=0.003). PLR had no obvious correlation with Birmingham Vasculitis Activity Score (BVAS). Patients having PLR≥330 exhibited better cumulative renal survival rates than those having PLR<330 (P=0.017). However, there was no significant difference in the cumulative patient survival rates between patients with PLR≥330 and those with PLR<330 at diagnosis (P>0.05). In multivariate analysis, PLR is associated with the decreased risk of ESRD (P=0.038, HR=0.518, 95% CI 0.278 to 0.963). We did not find an association between PLR with all-cause mortality using multivariate analysis (HR=1.081, 95% CI 0.591 to 1.976, P=0.801). CONCLUSIONS: PLR is positively correlated with CRP and ESR. Furthermore, PLR may independently predict the risk of ESRD.

Platelet activating factor receptor acts to limit colitis-induced liver inflammation.

Liver inflammation is a common extraintestinal manifestation in inflammatory bowel disease (IBD), yet, the mechanisms driving gut-liver axis inflammation remain poorly understood. IBD leads to a breakdown in the integrity of the intestinal barrier causing an increase in portal and systemic gut-derived antigens, which challenge the liver. Here, we examined the role of platelet activating factor receptor (PAFR) in colitis-associated liver damage using dextran sulfate sodium (DSS) and anti-CD40-induced colitis models. Both DSS and anti-CD40 models exhibited liver inflammation associated with colitis. Colitis reduced global PAFR protein expression in mouse livers causing an exclusive re-localization of PAFR to the portal triad. The global decrease in liver PAFR was associated with increased sirtuin 1 while relocalized PAFR expression was limited to Kupffer cells (KCs) and co-localized with toll-like receptor 4. DSS activated the NLRP3-inflammasome and increased interleukin (IL)-1ß in the liver. Antagonism of PAFR amplified the inflammasome response by increasing NLRP3, caspase-1, and IL-1ß protein levels in the liver. LPS also increased NLRP3 response in human hepatocytes, however, overexpression of PAFR restored the levels of NLPR3 and caspase-1 proteins. Interestingly, KCs depletion also increased IL-1ß protein in mouse liver after DSS challenge. These data suggest a protective role for PAFR-expressing KCs during colitis and that regulation of PAFR is important for gut-liver axis homeostasis.

Knowledge-aware multi-center clinical dataset adaptation: Problem, method, and application.

Adaptable utilization of clinical data collected from multiple centers, prompted by the need to overcome the shifts between the dataset distributions, and exploit these different datasets for potential clinical applications, has received significant attention in recent years. In this study, we propose a novel approach to this task by infusing an external knowledge graph (KG) into multi-center clinical data mining. Specifically, we propose an adversarial learning model to capture shared patient feature representations from multi-center heterogeneous clinical datasets, and employ an external KG to enrich the semantics of the patient sample by providing both clinical center-specific and center-general knowledge features, which are trained with a graph convolutional autoencoder. We evaluate the proposed model on a real clinical dataset extracted from the general cardiology wards of a Chinese hospital and a well-known public clinical dataset (MIMIC III, pertaining to ICU clinical settings) for the task of predicting acute kidney injury in patients with heart failure. The achieved experimental results demonstrate the efficacy of our proposed model.

Clinical characteristics and prognosis in 269 patients with antineutrophil cytoplasimc antibody associated vasculitis. / 269ä¾‹æŠ—ä¸­æ€§ç²’ç»†èƒžèƒžæµ†æŠ—ä½“ç›¸å ³æ€§è¡€ç®¡ç‚Žæ‚£è€ çš„ä¸´åºŠç— ç†ç‰¹å¾åŠé¢„åŽ.

OBJECTIVES: To investigate the clinic-pathological characteristics, prognosis and its risk factors for antineutrophil cytoplasimc antibody (ANCA)-associated vasculitis (AAV). METHODS: The basic information and clinic-pathological characteristics of AAV patients, who was diagnosed from January 2010 to January 2018 in Xiangya Hospital, Central South University, were retrospectively collected. The renal survival and patient survival were regular followed up, and their clinical pathological, prognosis data and risk factors for renal were analyzed. RESULTS: Among 269 AAV patients, 225 patients (83.64%) were microscopic polyangiitis (MPA), 33 patients (12.27%) were granulomatosis with polyangiitis (GPA), and 11 patients (4.09%) were eosinophilic granulomatosis with polyangiitis (EGPA). Male-to-female ratio was almost 1∶1 for MPA (147/122), but GPA and EGPA was more frequent among man. The medium time from disease onset to diagnosis was 64.0 (32.5, 148.5) days, 65 patients (24.16%) were diagnosed within 30 days. A total of 94.67% patients had kidney involvement in MPA patients, which was significantly higher than that in patients with GPA (63.63%), but ear, nose, and throat manifestations were more frequent in GPA patients. The 1-year kidney survival rates of GPA and MPA patients in this study were 75% and 59.3%, respectively. The 1-year death rates were 16.7% and 16.9%, respectively. The multivariable logistic regression analysis revealed that the low platelet level, low globulin level, low immunoglobin G, and high serum creatinine level were independent risk factors for the 1-year renal survival rate in AAV patients. Multiple factor logistic regression analysis showed that the serum creatinine level was an independent risk factor for all-cause mortality. CONCLUSIONS: MPA is the priority in the AAV patients. The proportion of patients with advanced end-stage renal disease and mortality is still high, and the early diagnosis and treatment in time is crucial for the improvement of prognosis for AAV.

Deletion of sphingosine kinase 1 ameliorates hepatic steatosis in diet-induced obese mice: Role of PPARγ.

Sphingolipid metabolites have emerged playing important roles in the pathogenesis of nonalcoholic fatty liver disease, whereas the underlying mechanism remains largely unknown. In the present study, we provide both in vitro and in vivo evidence showing a pathogenic role of sphingosine kinase 1 (SphK1) in hepatocellular steatosis. We found that levels of SphK1 expression were significantly increased in steatotic hepatocytes. Enforced overexpression of SphK1 or treatment with sphingosine 1-phosphate (S1P) markedly enhanced hepatic lipid accumulation. In contrast, the siRNA-mediated knockdown of SphK1 or S1P receptors, S1P2 and S1P3, profoundly inhibited lipid accumulation in hepatocytes. Moreover, Sphk1(-/-) mice exhibited a significant amelioration of hepatosteatosis under diet-induced obese (DIO) conditions, compared to wild-type littermates. In addition, DIO-induced up-regulation of PPARγ and its target genes were significantly reduced by SphK1 deficiency. Furthermore, treatment of hepatocytes with S1P induces a dose-dependent increase in PPARγ expression at the transcriptional level. Blockage of S1P receptors and the Akt-mTOR signaling profoundly inhibited S1P-induced PPARγ expression. Notably, down-regulation of PPARγ by using its siRNA significantly diminished the pro-steatotic effect of SphK1/S1P. Thus, the study demonstrates a new pathway connecting SphK1 and PPARγ involved in the pathogenesis of hepatocellular steatosis.

Sphingosine Kinase 1 Protects Hepatocytes from Lipotoxicity via Down-regulation of IRE1α Protein Expression.

Aberrant deposition of fat including free fatty acids in the liver often causes damage to hepatocytes, namely lipotoxicity, which is a key pathogenic event in the development and progression of fatty liver diseases. This study demonstrates a pivotal role of sphingosine kinase 1 (SphK1) in protecting hepatocytes from lipotoxicity. Exposure of primary murine hepatocytes to palmitate resulted in dose-dependent cell death, which was enhanced significantly in Sphk1-deficient cells. In keeping with this, expression of dominant-negative mutant SphK1 also markedly promoted palmitate-induced cell death. In contrast, overexpression of wild-type SphK1 profoundly protected hepatocytes from lipotoxicity. Mechanistically, the protective effect of SphK1 is attributable to suppression of ER stress-mediated pro-apoptotic pathways, as reflected in the inhibition of IRE1α activation, XBP1 splicing, JNK phosphorylation, and CHOP induction. Of note, SphK1 inhibited the IRE1α pathway by reducing IRE1α expression at the transcriptional level. Moreover, S1P mimicked the effect of SphK1, suppressing IRE1α expression in a receptor-dependent manner. Furthermore, enforced overexpression of IRE1α significantly blocked the protective effect of SphK1 against lipotoxicity. Therefore, this study provides new insights into the role of SphK1 in hepatocyte survival and uncovers a novel mechanism for protection against ER stress-mediated cell death.

Semilocal convergence theorem for the inverse-free Jarratt method under new Hölder conditions.

Under the new Hölder conditions, we consider the convergence analysis of the inverse-free Jarratt method in Banach space which is used to solve the nonlinear operator equation. We establish a new semilocal convergence theorem for the inverse-free Jarratt method and present an error estimate. Finally, three examples are provided to show the application of the theorem.

[Disease spectrum and causes of death in hospitalized children in an upper first-class hospital in Hunan Province, China, from 2010 to 2014].

OBJECTIVE: To study the disease spectrum and causes of death in hospitalized children in an upper first-class hospital in Hunan Province, China. METHODS: The medical records of hospitalized children between 2010 and 2014 in this hospital were collected and analyzed retrospectively. RESULTS: From 2010 to 2014, the number of hospitalized children increased from 7 303 in 2010 to 10 902 in 2014, and the case fatality rate declined from 0.33% to 0.20% (P<0.05). The case fatality rate was highest (0.41%) in infants and lowest (0.11%) in newborns. As for the disease spectrum for these hospitalized children, in 2010, the top three diseases were leukemia, congenital heart disease, and pneumonia; in 2011, the top three diseases were tumor chemotherapy, congenital heart disease, and pneumonia; since 2012, tumor chemotherapy, epilepsy, and pneumonia had remained the top three diseases. The top three causes of death in hospitalized children were congenital malformation (39%, 39/99), tumor (13%, 13/99), and infectious diseases/parasitic diseases (8%, 8/99). CONCLUSIONS: The number of hospitalized children is increasing, while the case fatality rate tends to decrease in this hospital. Tumor, epilepsy, pneumonia, and congenital heart disease are major diseases in hospitalized children, and congenital malformation is the primary cause of death.

Loss of sphingosine kinase 1 predisposes to the onset of diabetes via promoting pancreatic ß-cell death in diet-induced obese mice.

Lipotoxic stress-induced ß-cell death (lipotoxicity) is recognized as a key contributor to the development of type 2 diabetes mellitus (T2DM). The current study reports a critical role of sphingosine kinase 1 (SphK1) in ß-cell survival under lipotoxic conditions. In an attempt to investigate the role of SphK1 in lipotoxicity in vivo, we fed Sphk1(-/-) and wild-type (WT) mice with a high-fat diet (HFD) or normal chow diet. Remarkably, while HFD-fed WT mice developed glucose intolerance and compensatory hyperinsulinemia, all HFD-fed Sphk1(-/-) mice manifested evident diabetes, accompanied by a nearly 3-fold reduction in insulin levels compared with the WT mice. Pancreatic ß-cell mass was increased by 140% in HFD-fed WT mice but decreased to 50% in HFD-fed Sphk1(-/-) mice, in comparison with the chow diet control groups, respectively. Accordingly, by blocking the enzyme activity, expression of a dominant negative form of SphK1 markedly promoted palmitate-induced cell death in MIN6 and INS-1 ß-cell lines. Moreover, primary islets isolated from Sphk1(-/-) mice exhibited higher susceptibility to lipotoxicity than WT controls. Of note, sphingosine 1-phosphate (S1P) profoundly abrogated lipotoxicity in ß cells or the cells lacking SphK1 activity and Sphk1(-/-) islets, highlighting a pivotal role of S1P in ß-cell survival under lipotoxic conditions. These findings could suggest a new therapeutic strategy for preventing ß-cell death and thus the onset of T2DM.

Solid Electrolyte Interphase on Lithium Metal Anodes.

Lithium metal batteries (LMBs) represent the most promising next-generation high-energy density batteries. The solid electrolyte interphase (SEI) film on the lithium metal anode plays a crucial role in regulating lithium deposition and improving the cycling performance of LMBs. In this review, we comprehensively present the formation process of the SEI film, while elucidating the key properties such as electronic conductivity, ionic conductivity, and mechanical performance. Furthermore, various approaches for constructing the SEI film are discussed from both electrolyte regulation and artificial coating design perspectives. Lastly, future research directions along with development recommendations are also provided. This review aims to provide possible strategies for the further improvement of SEI film in LMBs and highlight their inspiration for future research directions.

The Role of the MiR-181 Family in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the fourth-leading cause of cancer-related death worldwide. Due to the high mortality rate in HCC patients, discovering and developing novel systemic treatment options for HCC is a vital unmet medical need. Among the numerous molecular alterations in HCCs, microRNAs (miRNAs) have been increasingly recognised to play critical roles in hepatocarcinogenesis. We and others have recently revealed that members of the microRNA-181 (miR-181) family were up-regulated in some, though not all, human cirrhotic and HCC tissues-this up-regulation induced epithelial-mesenchymal transition (EMT) in hepatocytes and tumour cells, promoting HCC progression. MiR-181s play crucial roles in governing the fate and function of various cells, such as endothelial cells, immune cells, and tumour cells. Previous reviews have extensively covered these aspects in detail. This review aims to give some insights into miR-181s, their targets and roles in modulating signal transduction pathways, factors regulating miR-181 expression and function, and their roles in HCC.