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Nonalcoholic fatty liver disease (NAFLD) emerges as the most predominant cause of liver disease, tightly linked to metabolic dysfunction. Bile acids (BAs), initially synthesized from cholesterol in the liver, undergo further metabolism by gut bacteria. Increasingly acknowledged as critical modulators of metabolic processes, BAs have been implicated as important signaling molecules. In this review, we will focus on the mechanism of BAs signaling involved in glucose homeostasis, lipid metabolism, energy expenditure, and immune regulation and summarize their roles in the pathogenesis of NAFLD. Furthermore, gut microbiota dysbiosis plays a key role in the development of NAFLD, and the interactions between BAs and intestinal microbiota is elucidated. In addition, we also discuss potential therapeutic strategies for NAFLD, including drugs targeting BA receptors, modulation of intestinal microbiota, and metabolic surgery.

Mammalian target of rapamycin (mTOR) signaling pathway is a major regulator of cell proliferation and metabolism, playing significant roles in proliferation, apoptosis, inflammation, and illness. More and more evidences showed that the mTOR signaling pathway affects hair follicle circulation and maintains the stability of hair follicle stem cells. mTOR signaling may be a critical cog in Vitamin D receptor (VDR) deficiency-mediated hair follicle damage and degeneration and related alopecia disorders. This review examines the function of mTOR signaling in hair follicles and hair diseases, and talks about the underlying molecular mechanisms that mTOR signaling regulates.

Hemophagocytic lymphohistiocytosis (HLH) is a severe and life-threatening hyperinflammatory condition characterized by excessive activation of macrophages and T cells and resulted in multi-organ dysfunction. HLH can be a primary disease or secondary to infections, malignancy, and some autoimmune diseases, including adult-onset Still’s disease (AOSD) and systemic lupus erythematosus (SLE). However, it is rare for HLH to occur as a secondary condition to drug-induced lupus erythematosus (DILE). In this report, we present a case of HLH as an unusual complication during SLE treatment in a 31-year-old male patient. The patient initially suffered from active chronic hepatitis B (CHB) and was treated with pegylated INFα-2b (Peg-INFα-2b), tenofovir disoproxil and lamivudine. After 19 months, CHB obtained biochemical and virological response with HBsAg positive to HBsAb. The patient developed fever, headache, and cytopenia after Peg-INFα-2b treatment for 33 months, and laboratory studies revealed that ANA and anti dsDNA were positive. He displayed 5 features meeting the HLH-2004 criteria for diagnosis including fever, pancytopenia, hyperferritinemia, high levels of soluble CD25, and hemophagocytosis on bone marrow biopsy. The patient was initiated with a combination treatment of intravenous methylprednisolone pulse therapy, oral cyclosporine, and etoposide (VP-16), which was followed by a course of oral prednisolone, intravenous cyclophosphamide pulse therapy, and entecavir with complete response. To our knowledge, this is the first report of IFN-α induced SLE complicating with HLH. Physicians should consider the potential autoimmune side effects of IFN-α therapy and be alert to insidious HLH in patients diagnosed with SLE.

Hepatocytes, the major parenchymal cells in the liver, are responsible for a variety of cellular functions including carbohydrate, lipid and protein metabolism, detoxification and immune cell activation to maintain liver homeotasis. Recent studies show hepatocytes play a pivotal role in liver inflammation. After receiving liver insults and inflammatory signals, hepatocytes may undergo organelle damage, and further respond by releasing mediators and expressing molecules that can act in the microenvironment as well as initiate a robust inflammatory response. In this review, we summarize how the hepatic organelle damage link to liver inflammation and introduce numerous hepatocyte-derived pro-inflammatory factors in response to chronic liver injury.

Emotional labor claims its significance as the key indicator both of the psychological health of contemporary employees, and the productivity of service-based businesses depending upon genuine emotional input of employees. By far, research on emotional labor of employees in an organizational context is still lacking. This study aims to explore the relationships among emotional labor, organizational support, career competences and career commitment to investigate how emotional labor interacts with the organizational context and affects the career management of the employee. Data were collected from a sample of 387 frontline employees working at two luxury hotel brands in China. Structural equation modeling (SEM) was utilized to estimate the relationships among the constructs. It is demonstrated by the findings that organizational support mediates positively on emotional labor, which exerts positive influences on career competences and career commitment. Sound handling of emotional labor, boosted by a supportive organizational environment, has been ascertained to positively predict long-term career paths of the employees at the company. This study provides insights into how the tourism and hospitality industry can optimize the functions of emotional labor for in enhancing service quality and customer satisfaction, as well as promoting the psychological well-being of the employees.

BackgroundMetal components of environmental PM2.5 are associated with the exacerbation of allergic diseases like asthma. In our recent hospital-based population study, exposure to vanadium is shown to pose a significant risk for current asthma, but the causal relationship and its underlying molecular mechanisms remain unclear.ObjectiveWe sought to determine whether vanadium co-exposure can aggravate house dust mite (HDM)-induced allergic airway inflammation and remodeling, as well as investigate its related mechanisms.MethodsAsthma mouse model was generated by using either vanadium pentoxide (V2O5) or HDM alone or in combination, in which the airway inflammation and remodeling was investigated. The effect of V2O5 co-exposure on HDM-induced epithelial-derived cytokine release and oxidative stress (ROS) generation was also examined by in vitro analyses. The role of ROS in V2O5 co-exposure-induced cytokine release and airway inflammation and remodeling was examined by using inhibitors or antioxidant.ResultsCompared to HDM alone, V2O5 co-exposure exacerbated HDM-induced airway inflammation with increased infiltration of inflammatory cells and elevated levels of Th1/Th2/Th17 and epithelial-derived (IL-25, TSLP) cytokines in the bronchoalveolar lavage fluids (BALFs). Intriguingly, V2O5 co-exposure also potentiated HDM-induced airway remodeling. Increased cytokine release was further supported by in vitro analysis in human bronchial epithelial cells (HBECs). Mechanistically, ROS, particularly mitochondrial-derived ROS, was significantly enhanced in HBECs after V2O5 co-exposure as compared to HDM challenge alone. Inhibition of ROS with its inhibitor N-acetyl-L-cysteine (NAC) and mitochondrial-targeted antioxidant MitoTEMPO blocked the increased epithelial release caused by V2O5 co-exposure. Furthermore, vitamin D3 as an antioxidant was found to inhibit V2O5 co-exposure-induced increased airway epithelial cytokine release and airway remodeling.ConclusionsOur findings suggest that vanadium co-exposure exacerbates epithelial ROS generation that contribute to increased allergic airway inflammation and remodeling.

The cardiac function reserve is crucial for the successful weaning of V-A ECMO. During the V-A ECMO weaning phase, the gradual reduction in pump flow converts the blood flow originally driven by the pump to native cardiac output and also transforms afterload (caused by retrograde flow) into ventricular preload, thus introducing a “flow challenge” to the native heart. In this perspective, we propose to use this flow challenge as a test to simulate the preload-to-afterload conversion to assess cardiac functional reserve quantitatively. With this short article we offer the hemodynamic and clinical aspects regarding the flow challenge test.

Bus exterior advertising plays a significant role in outdoor advertising, since it provides frequent exposure to a large number of residents. Traditional route selection methods are generally based on a rough estimation, for example, the number of total passengers of a bus route or the geographical features along the bus route. Targeted bus exterior advertising remains a challenge as little is known about the characteristics of the people along the bus route. In this study, we are aiming at determining a set of bus routes for a given ad category to maximize advertising effectiveness, by mining multiple data sources, including mobile phone data, bus GPS data, smart card data (SCD), and land use data. Specifically, we first estimated the distribution of potential target audiences using mobile phone data and land use data. Two optimization models are proposed considering different advertising requirements. For well-established brands that audiences are familiar with, a wide coverage-oriented bus route selection model is proposed to maximize the coverage of potential target audiences. For new brands that require a high level of exposure before they become recognizable, a deep coverage-oriented bus route selection model is proposed to maximize the total exposure times of the ads. Both models were demonstrated with a case study in Shenzhen, China to explicitly present the outcomes of the models and the differences between them. The calculation results show that the wide coverage-oriented model achieves an average of 84.8% improvement compared with baseline 1 which selects the bus routes with the most passengers, while an average of 9.2% improvement compared with baseline 2 which selects the bus route with the maximum coverage of the target area in reaching more potential target audiences. The exposure intensity of the deep coverage-oriented model is almost 3.7 times of the wide coverage-oriented model. The proposed models provide new options for advertisers to select a suitable advertising strategy according to their needs.

RationaleAryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, has been considered as an important regulator for immune diseases. We have previously shown that AhR protects against allergic airway inflammation. The underlying mechanism, however, remains undetermined.ObjectivesWe sought to determine whether AhR specifically in type II alveolar epithelial cells (AT2) modulates allergic airway inflammation and its underlying mechanisms.MethodsThe role of AhR in AT2 cells in airway inflammation was investigated in a mouse model of asthma with AhR conditional knockout mice in AT2 cells (Sftpc-Cre;AhRf/f). The effect of AhR on allergen-induced autophagy was examined by both in vivo and in vitro analyses. The involvement of autophagy in airway inflammation was analyzed by using autophagy inhibitor chloroquine. The AhR-regulated gene profiling in AT2 cells was also investigated by RNA sequencing (RNA-seq) analysis.ResultsSftpc-Cre;AhRf/f mice showed exacerbation of allergen-induced airway hyperresponsiveness and airway inflammation with elevated Th2 cytokines in bronchoalveolar lavage fluid (BALF). Notably, an increased allergen-induced autophagy was observed in the lung tissues of Sftpc-Cre;AhRf/f mice when compared with wild-type mice. Further analyses suggested a functional axis of AhR-TGF-β1 that is critical in driving allergic airway inflammation through regulating allergen-induced cellular autophagy. Furthermore, inhibition of autophagy with autophagy inhibitor chloroquine significantly suppressed cockroach allergen–induced airway inflammation, Th2 cytokines in BALFs, and expression of autophagy-related genes LC3 and Atg5 in the lung tissues. In addition, RNA-seq analysis suggests that autophagy is one of the major pathways and that CALCOCO2/NDP52 and S1009 are major autophagy-associated genes in AT2 cells that may contribute to the AhR-mediated cockroach allergen–induced airway inflammation and, subsequently, allergic asthma.ConclusionThese results suggest that AhR in AT2 cells functions as a protective mechanism against allergic airway inflammation through controlling cell autophagy.

Graph structured data is ubiquitous in daily life and scientific areas and has attracted increasing attention. Graph Neural Networks (GNNs) have been proved to be effective in modeling graph structured data and many variants of GNN architectures have been proposed. However, much human effort is often needed to tune the architecture depending on different datasets. Researchers naturally adopt Automated Machine Learning on Graph Learning, aiming to reduce human effort and achieve generally top-performing GNNs, but their methods focus more on the architecture search. To understand GNN practitioners' automated solutions, we organized AutoGraph Challenge at KDD Cup 2020, emphasizing automated graph neural networks for node classification. We received top solutions, especially from industrial technology companies like Meituan, Alibaba, and Twitter, which are already open sourced on GitHub. After detailed comparisons with solutions from academia, we quantify the gaps between academia and industry on modeling scope, effectiveness, and efficiency, and show that (1) academic AutoML for Graph solutions focus on GNN architecture search while industrial solutions, especially the winning ones in the KDD Cup, tend to obtain an overall solution (2) with only neural architecture search, academic solutions achieve on average 97.3% accuracy of industrial solutions (3) academic solutions are cheap to obtain with several GPU hours while industrial solutions take a few months' labors. Academic solutions also contain much fewer parameters.

BackgroundSeptic myocardial depression has been associated with increased morbidity and mortality. miR-885-5p has been shown to regulate cell growth, senescence, and/or apoptosis. Published studies demonstrated that Homeobox-containing protein 1 (HMBOX1) inhibits inflammatory response, regulates cell autophagy, and apoptosis. However, the role of miR-885-5p/HMBOX1 in sepsis and septic myocardial depression and the underlying mechanism is not fully understood.Materials and MethodsExosomes (exos) derived from sepsis patients (sepsis-exos) were isolated using ultracentrifugation. Rats were subjected to cecal ligation and puncture surgery and treated with sepsis-exos. HMBOX1 was knocked down or overexpressed in AC16 cells using lentiviral plasmids carrying short interfering RNAs targeting human HMBOX1 or carrying HMBOX1 cDNA. Cell pyroptosis was measured by flow cytometry. The secretion of IL-1β and IL-18 was examined by ELISA kits. Quantitative polymerase chain reaction (PCR) or western blot was used for gene expression.ResultsSepsis-exos increased the level of miR-885-5p, decreased HMBOX1, elevated IL-1β and IL-18, and promoted pyroptosis in AC16 cells. Septic rats treated with sepsis-exos increased the serum inflammatory cytokines is associated with increased pyroptosis-related proteins of hearts. MiR-885-5p bound to the three prime untranslated regions of HMBOX1 to negatively regulate its expression. Overexpressing HMBOX1 reversed miR-885-5p-induced elevation of inflammatory cytokines and upregulation of NLRP3, caspase-1, and GSDMD-N in AC16 cells. The mechanistic study indicated that the effect of HMBOX1 was NF-κB dependent.ConclusionSepsis-exos promoted the pyroptosis of AC16 cells through miR-885-5p via HMBOX1. The results show the significance of the miR-885-5p/HMBOX1 axis in myocardial cell pyroptosis and provide new directions for the treatment of septic myocardial depression.

Studying functional brain connectivity plays an important role in understanding how human brain functions and neuropsychological diseases such as autism, attention-deficit hyperactivity disorder, and Alzheimer's disease (AD). Functional magnetic resonance imaging (fMRI) is one of the most popularly used tool to construct functional brain connectivity. However, the presence of noises and outliers in fMRI blood oxygen level dependent (BOLD) signals might lead to unreliable and unstable results in the construction of connectivity matrix. In this paper, we propose a pipeline that enables us to estimate robust and stable connectivity matrix, which increases the detectability of group differences. In particular, a low-rank plus sparse (L + S) matrix decomposition technique is adopted to decompose the original signals, where the low-rank matrix L recovers the essential common features from regions of interest, and the sparse matrix S catches the sparse individual variability and potential outliers. On the basis of decomposed signals, we construct connectivity matrix using the proposed novel concentration inequality-based sparse estimator. In order to facilitate the comparisons, we also consider correlation, partial correlation, and graphical Lasso-based methods. Hypothesis testing is then conducted to detect group differences. The proposed pipeline is applied to rs-fMRI data in Alzheimer's disease neuroimaging initiative to detect AD-related biomarkers, and we show that the proposed pipeline provides accurate yet more stable results than using the original BOLD signals.

Accounting for biotic interactions is important for predicting species and ecosystem variation under changing climate but difficult to achieve in practice. The proportion of geographical overlap between species, called species geographical sensitivity (SGS), could be used to gauge the potential for species interactions. Species with increasingly high SGS could have the potential to experience more interactions with other species and vice versa, which might have important implications in ecological assessment, particularly at a community level, in the face of climate change. We compiled fish occurrences in the North Sea from 1983 to 2020 and calculated annual mean SGS (mSGS) to systematically evaluate their temporal changes and to estimate influences of species traits on the relative temporal changes in mSGS. The results showed that 36.3% of species significantly changed their mSGS over time, with high correlations between changes in species range size and overlap with other species. The species’ averaged mSGS before warming was highly correlated with the relative change in mSGS. Depth range, body length, and age at maturity together explained most variation in mSGS among these species. Contemporary climate change is expected to reorganize species distributions and interactions and substantially alter marine ecosystem functioning. Our assessment opens a new avenue for evaluating climate change impacts on species geographical interactions, and such geographical changes may be contingent on species traits.

Environmental and climatic changes are expected to redistribute species, altering the strengths of species interaction networks; however, long-term and large-scale evaluations remain elusive. One way to infer species interaction networks is by analyzing their geographical overlaps, which provides indices of species interdependence, such as mean spatial robustness (MSR), which represents the geographical impact of a species on other species, and mean spatial sensitivity (MSS), which indicates how a species is influenced by other species. Integrating MSR and MSS further allows us to assess community coexistence stability and structure, with a stronger negative relationship between MSR and MSS (i.e., species are unequally dependent on each other) within a community at a given time suggesting a more stable community. Here, we assessed multidecadal changes in adult marine fish communities using bottom trawl datasets across latitudes from 1982 to 2011 in the Eastern US Continental Shelf, North Sea, and Eastern Bering Sea. Consistent, significant long-term increasing temporal trends of MSR and MSS were found in all three large marine communities. MSR exhibited strong correlations with species’ range sizes, especially in high-latitude communities, while MSS was strongly positively correlated with species’ median proportion of overlap with interacting species. The relationships between MSR and MSS were generally negative, indicating stably coexisting fish communities. However, the negative relationships weakened over time, implying that the coexisting fish communities gradually became unstable. Our findings provide an assessment of changes in spatially geographical aspects of multiple species, for decades and at mid- to high latitudes, to allow the detection of global ecological changes in marine systems by alternative estimation of geographic overlaps of species interaction networks. Such species co-occurrence estimation can help stay vigilant of strategies for accelerating climate change mitigation particularly at coarser spatial scales.

The olive baboon (Papio anubis) is phylogenetically proximal to humans. Investigation into the baboon brain has shed light on the function and organization of the human brain, as well as on the mechanistic insights of neurological disorders such as Alzheimer’s and Parkinson’s. Non-invasive brain imaging, including positron emission tomography (PET) and magnetic resonance imaging (MRI), are the primary outcome measures frequently used in baboon studies. PET functional imaging has long been used to study cerebral metabolic processes, though it lacks clear and reliable anatomical information. In contrast, MRI provides a clear definition of soft tissue with high resolution and contrast to distinguish brain pathology and anatomy, but lacks specific markers of neuroreceptors and/or neurometabolites. There is a need to create a brain atlas that combines the anatomical and functional/neurochemical data independently available from MRI and PET. For this purpose, a three-dimensional atlas of the olive baboon brain was developed to enable multimodal imaging analysis. The atlas was created on a population-representative template encompassing 89 baboon brains. The atlas defines 24 brain regions, including the thalamus, cerebral cortex, putamen, corpus callosum, and insula. The atlas was evaluated with four MRI images and 20 PET images employing the radiotracers for [11C]benzamide, [11C]metergoline, [18F]FAHA, and [11C]rolipram, with and without structural aids like [18F]flurodeoxyglycose images. The atlas-based analysis pipeline includes automated segmentation, registration, quantification of region volume, the volume of distribution, and standardized uptake value. Results showed that, in comparison to PET analysis utilizing the “gold standard” manual quantification by neuroscientists, the performance of the atlas-based analysis was at >80 and >70% agreement for MRI and PET, respectively. The atlas can serve as a foundation for further refinement, and incorporation into a high-throughput workflow of baboon PET and MRI data. The new atlas is freely available on the Figshare online repository (https://doi.org/10.6084/m9.figshare.16663339), and the template images are available from neuroImaging tools & resources collaboratory (NITRC) (https://www.nitrc.org/projects/haiko89/).

Background: Enteral nutrition (EN) is recommended within the first 24–48 h for patients with hemodynamic stability, following admission to an intensive care unit (ICU). However, for patients with approximate stable hemodynamics requiring mechanical circulatory support and vasoactive drugs, the application of early EN remains controversial. We sought to evaluate the tolerance of early EN in patients with cardiogenic shock who required vasoactive drugs and mechanical circulatory support after cardiac surgery.Methods: This single-center, prospective observational study included patients with cardiogenic shock, requiring vasoactive drugs and mechanical circulatory support after cardiac surgery, undergoing EN. The primary endpoint was EN tolerance and secondary endpoints were mortality, length of mechanical ventilation, and length of ICU stay.Results: From February 2019 to December 2020, 59 patients were enrolled, of which 25 (42.37%) developed intolerance within 3 days of starting EN. Patients in the EN intolerant group had a longer median length of mechanical ventilation (380 vs. 128 h, p = 0.006), a longer median ICU stay (20 vs. 11.5 days, p = 0.03), and a higher proportion of bloodstream infections (44 vs. 14.71%, p = 0.018). The median EN calorie levels for all patients in the first 3 days of EN were 4.00, 4.13, and 4.28 kcal/kg/day, respectively. Median protein intake levels of EN in the first 3 days were 0.18, 0.17, and 0.17 g/kg/day, respectively. No significant difference was observed in the median dose of vasoactive drugs between the groups (0.035 vs. 0.05 μg/kg/min, p = 0.306).Conclusions: Patients with cardiogenic shock after cardiac surgery had a high proportion of early EN intolerance, and patients with EN intolerance had a worse prognosis, but no significant correlation was identified between EN tolerance and the dose of vasoactive drugs.

Objective: Primary graft dysfunction (PGD) is the leading cause of early death after heart transplantation. Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) can provide temporary mechanical circulatory support and time for functional recovery of the transplanted heart. The purpose of this study was to analyze the timing and prognoses of VA-ECMO in patients with severe PGD after heart transplantation.Methods: A total of 130 patients underwent heart transplantation at the Zhongshan Hospital Affiliated with Fudan University between January 2014 and December 2020. All patients received basiliximab immunoinduction and a classic double vena cava anastomosis orthotopic heart transplantation. Among them, 29 patients (22.3%) developed severe PGD in the early postoperative period. VA-ECMO was performed in patients with difficulty weaning from cardiopulmonary bypass (CPB) or postoperative refractory cardiogenic shock. Patients were divided into two groups according to whether or not they were successfully weaned from VA-ECMO (patients who survived for 48 h after weaning and did not need VA-ECMO assistance again). The perioperative clinical data were recorded, and all patients were followed up until discharge. Early outcomes were compared between groups.Results: A total of 29 patients with VA-ECMO support after heart transplantation were included in this study. The proportion of patients receiving VA-ECMO was 22.3% (29/130). Nineteen patients (65.5%) needed VA-ECMO due to difficulty with weaning from CPB, and 10 patients required VA-ECMO for postoperative cardiogenic shock. Nineteen patients (65.5%) were successfully weaned from VA-ECMO. Overall, in-hospital mortality of VA-ECMO support patients was 55.2%. The main causes of death were ventricular fibrillation (four cases), major bleeding (three cases), infection (four cases), and graft failure (five cases).Conclusion: Despite advances in heart transplantation, severe PGD remains a lethal complication after heart transplantation. At present, the treatment for severe PGD after heart transplantation is a challenge. VA-ECMO provides an effective treatment for severe PGD after heart transplantation, which can promote graft function recovery.

BackgroundDespite long-standing recognition in the significance of mucus overproduction in asthma, its etiology remains poorly understood. Muc5ac is a secretory mucin that has been associated with reduced pulmonary function and asthma exacerbations.ObjectivesWe sought to investigate the immunological pathway that controls Muc5ac expression and allergic airway inflammation in asthma.MethodsCockroach allergen-induced Muc5ac expression and aryl hydrocarbon receptor (AhR) signaling activation was examined in the human bronchial epithelial cells (HBECs) and mouse model of asthma. AhR regulation of Muc5ac expression, mitochondrial ROS (Mito-ROS) generation, and NLRP3 inflammasome was determined by AhR knockdown, the antagonist CH223191, and AhR-/- mice. The role of NLRP3 inflammasome in Muc5ac expression and airway inflammation was also investigated.ResultsCockroach allergen induced Muc5ac overexpression in HBECs and airways of asthma mouse model. Increased expression of AhR and its downstream genes CYP1A1 and CYP1B1 was also observed. Mice with AhR deletion showed increased allergic airway inflammation and MUC5AC expression. Moreover, cockroach allergen induced epithelial NLRP3 inflammasome activation (e.g., NLRP3, Caspase-1, and IL-1β), which was enhanced by AhR knockdown or the antagonist CH223191. Furthermore, AhR deletion in HBECs led to enhanced ROS generation, particularly Mito-ROS, and inhibition of ROS or Mito-ROS subsequently suppressed the inflammasome activation. Importantly, inhibition of the inflammasome with MCC950, a NLRP3-specifc inhibitor, attenuated allergic airway inflammation and Muc5ac expression. IL-1β generated by the activated inflammasomes mediated cockroach allergen-induced Muc5ac expression in HBECs.ConclusionsThese results reveal a previously unidentified functional axis of AhR-ROS-NLRP3 inflammasome in regulating Muc5ac expression and airway inflammation.

Background: Cardiopulmonary support, as extracorporeal membrane oxygenation (ECMO) or mechanical ventilation (MV), is crucial for ICU patients. However, some of these patients are difficult to wean. Therefore, we aimed to assess the efficacy and safety of levosimendan in facilitating weaning from cardiorespiratory support in this patient population.Methods: We searched for potentially relevant articles in PubMed, Embase, China National Knowledge Infrastructure, Wanfang, and the Cochrane database from inception up to Feb 30, 2021. Studies focusing on weaning data in MV/ECMO adult patients who received levosimendan compared to controls were included. We used the Cochrane risk of bias tool or the Newcastle-Ottawa Quality Assessment Scale to evaluate the study quality. The primary outcome was the weaning rate from MV/ECMO. Secondary outcomes were mortality, duration of MV, and ICU stay. Subgroup analysis, sensitivity analysis, and publication bias were also conducted.Results: Eighteen studies with 2,274 patients were included. The quality of the included studies was low to moderate. Overall, levosimendan effectively improved weaning rates from MV/ECMO [odds ratio (OR) = 2.32; 95%CI, 1.60–3.36; P < 0.00001, I2 = 68%]. Subgroup analyses confirmed the higher successful weaning rates in ventilated patients with low left ventricular ejection fractions (OR = 4.06; 95%CI, 2.16–7.62), patients with ECMO after cardiac surgery (OR = 2.04; 95%CI, 1.25–3.34), and patients with ECMO and cardiogenic shock (OR = 1.98; 95%CI, 1.34–2.91). However, levosimendan showed no beneficial effect on patients with MV weaning difficulty (OR = 2.28; 95%CI, 0.72–7.25). Additionally, no differences were found concerning the secondary outcomes between the groups.Conclusions: Levosimendan therapy significantly increased successful weaning rates in patients with cardiopulmonary support, especially patients with combined cardiac insufficiency. Large-scale, well-designed RCTs will be needed to define the subgroup of patients most likely to benefit from this strategy.

Acute kidney injury (AKI) is a common and potential life-threatening disease in patients admitted to hospital, affecting 10%–15% of all hospitalizations and around 50% of patients in the intensive care unit. Severe, recurrent, and uncontrolled AKI may progress to chronic kidney disease or end-stage renal disease. AKI thus requires more efficient, specific therapies, rather than just supportive therapy. Mesenchymal stem cells (MSCs) are considered to be promising cells for cellular therapy because of their ease of harvesting, low immunogenicity, and ability to expand in vitro. Recent research indicated that the main therapeutic effects of MSCs were mediated by MSC-derived extracellular vesicles (MSC-EVs). Furthermore, compared with MSCs, MSC-EVs have lower immunogenicity, easier storage, no tumorigenesis, and the potential to be artificially modified. We reviewed the therapeutic mechanism of MSCs and MSC-EVs in AKI, and considered recent research on how to improve the efficacy of MSC-EVs in AKI. We also summarized and analyzed the potential and limitations of EVs for the treatment of AKI to provide ideas for future clinical trials and the clinical application of MSC-EVs in AKI.

Acute or chronic kidney disease can cause micronutrient deficiency. Patients with end-stage renal disease, kidney transplantation or on dialysis have reduced circulating levels of folate, an essential B vitamin. However, the molecular mechanism is not well understood. Reabsorption of folate in renal proximal tubules through folate transporters is an important process to prevent urinary loss of folate. The present study investigated the impact of acute kidney injury (AKI) on folate transporter expression and the underlying mechanism. AKI was induced in Sprague-Dawley rats that were subjected to kidney ischemia (45 min)-reperfusion (24 h). Both male and female rats displayed kidney injury and low plasma folate levels compared with sham-operated rats. The plasma folate levels were inversely correlated to plasma creatinine levels. There was a significant increase in neutrophil gelatinase-associated lipocalin (NGAL) and IL-6 mRNA expression in the kidneys of rats with ischemia-reperfusion, indicating kidney injury and increased inflammatory cytokine expression. Ischemia-reperfusion decreased mRNA and protein expression of folate transporters including folate receptor 1 (FOLR1) and reduced folate carrier (RFC); and inhibited transcription factor Sp1/DNA binding activity in the kidneys. Simulated ischemia-reperfusion through hypoxia-reoxygenation or Sp1 siRNA transfection in human proximal tubular cells inhibited folate transporter expression and reduced intracellular folate levels. These results suggest that ischemia-reperfusion injury downregulates renal folate transporter expression and decreases folate uptake by tubular cells, which may contribute to low folate status in AKI. In conclusion, ischemia-reperfusion injury can downregulate Sp1 mediated-folate transporter expression in tubular cells, which may reduce folate reabsorption and lead to low folate status.

Objectives: Acute type A aortic dissection (aTAAD) is usually lethal without emergency surgery. Although veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is widely used in patients with cardiogenic shock following cardiac surgery, VA-ECMO support following aTAAD surgery has not been well-described. Based on our 6-year experience, we aimed to retrospectively analyze risk factors, application and timing of VA-ECMO, and outcomes in aTAAD patients.Methods: In this retrospective, single-center study, we enrolled adult patients who underwent aTAAD surgery from January 2014 to December 2019 and were supported with VA-ECMO. Patients were divided into two groups according to whether or not they were successfully weaned from VA-ECMO. Preoperative, intraoperative and postoperative variables were assessed and analyzed. Outcomes of the patients were followed up until discharge.Results: Twenty-seven patients who received aTAAD surgery with VA-ECMO support were included in the study. Nine patients (33.3%) were successfully weaned from VA-ECMO. The median VA-ECMO support time and length of hospital stay in the successfully weaned group were significantly longer than in the group could not be successfully weaned (192 [111–327] vs. 55 [23–95] h, p < 0.01; 29 [18–40] vs. 4 [3–8] days, p < 0.01). Overall in-hospital mortality was 81.5%. The main causes of death were bleeding (37%), neurological complications (15%), and multiple organ dysfunction syndrome (15%). Preoperative levels of creatine kinase-MB (CK-MB) were lower in patients who were successfully weaned from VA-ECMO than in the failed group (14 [6–30] vs. 55 [28–138] U/L, p < 0.01). Postoperative peak levels of CK-MB, cardiac troponin T, lactate dehydrogenase, and lactate were significantly lower in the successful group than in the failed group.Conclusion: Postoperative VA-ECMO support was rarely used in aTAAD patients. Our study showed that VA-ECMO can be considered as a salvage treatment in aTAAD patients, despite the high rate of complications and mortality.

Background: Extubation failure (EF) can lead to an increased chance of ventilator-associated pneumonia, longer hospital stays, and a higher mortality rate. This study aimed to develop and validate an accurate machine-learning model to predict EF in intensive care units (ICUs).Methods: Patients who underwent extubation in the Medical Information Mart for Intensive Care (MIMIC)-IV database were included. EF was defined as the need for ventilatory support (non-invasive ventilation or reintubation) or death within 48 h following extubation. A machine-learning model called Categorical Boosting (CatBoost) was developed based on 89 clinical and laboratory variables. SHapley Additive exPlanations (SHAP) values were calculated to evaluate feature importance and the recursive feature elimination (RFE) algorithm was used to select key features. Hyperparameter optimization was conducted using an automated machine-learning toolkit (Neural Network Intelligence). The final model was trained based on key features and compared with 10 other models. The model was then prospectively validated in patients enrolled in the Cardiac Surgical ICU of Zhongshan Hospital, Fudan University. In addition, a web-based tool was developed to help clinicians use our model.Results: Of 16,189 patients included in the MIMIC-IV cohort, 2,756 (17.0%) had EF. Nineteen key features were selected using the RFE algorithm, including age, body mass index, stroke, heart rate, respiratory rate, mean arterial pressure, peripheral oxygen saturation, temperature, pH, central venous pressure, tidal volume, positive end-expiratory pressure, mean airway pressure, pressure support ventilation (PSV) level, mechanical ventilation (MV) durations, spontaneous breathing trial success times, urine output, crystalloid amount, and antibiotic types. After hyperparameter optimization, our model had the greatest area under the receiver operating characteristic (AUROC: 0.835) in internal validation. Significant differences in mortality, reintubation rates, and NIV rates were shown between patients with a high predicted risk and those with a low predicted risk. In the prospective validation, the superiority of our model was also observed (AUROC: 0.803). According to the SHAP values, MV duration and PSV level were the most important features for prediction.Conclusions: In conclusion, this study developed and prospectively validated a CatBoost model, which better predicted EF in ICUs than other models.

We have previously demonstrated that benzo(a)pyrene (BaP) co-exposure with dermatophagoides group 1 allergen (Der f 1) can potentiate Der f 1-induced airway inflammation. The underlying mechanism, however, remains undetermined. Here we investigated the molecular mechanisms underlying the potentiation of BaP exposure on Der f 1-induced airway inflammation in asthma. We found that BaP co-exposure potentiated Der f 1-induced TGFβ1 secretion and signaling activation in human bronchial epithelial cells (HBECs) and the airways of asthma mouse model. Moreover, BaP exposure alone or co-exposure with Der f 1-induced aryl hydrocarbon receptor (AhR) activity was determined by using an AhR-dioxin-responsive element reporter plasmid. The BaP and Der f 1 co-exposure-induced TGFβ1 expression and signaling activation were attenuated by either AhR antagonist CH223191 or AhR knockdown in HBECs. Furthermore, AhR knockdown led to the reduction of BaP and Der f 1 co-exposure-induced active RhoA. Inhibition of RhoA signaling with fasudil, a RhoA/ROCK inhibitor, suppressed BaP and Der f 1 co-exposure-induced TGFβ1 expression and signaling activation. This was further confirmed in HBECs expressing constitutively active RhoA (RhoA-L63) or dominant-negative RhoA (RhoA-N19). Luciferase reporter assays showed prominently increased promoter activities for the AhR binding sites in the promoter region of RhoA. Inhibition of RhoA suppressed BaP and Der f 1 co-exposure-induced airway hyper-responsiveness, Th2-associated airway inflammation, and TGFβ1 signaling activation in asthma. Our studies reveal a previously unidentified functional axis of AhR–RhoA in regulating TGFβ1 expression and signaling activation, representing a potential therapeutic target for allergic asthma.

BackgroundPostoperative cerebral edema is common in patients with meningioma. It is of great clinical significance to predict the postoperative cerebral edema exacerbation (CEE) for the development of individual treatment programs in patients with meningioma.ObjectiveTo evaluate the value of three-dimensional radiomics Features from Multi-Parameter MRI in predicting the postoperative CEE in patients with meningioma.MethodsA total of 136 meningioma patients with complete clinical and radiological data were collected for this retrospective study, and they were randomly divided into primary and validation cohorts. Three-dimensional radiomics features were extracted from multisequence MR images, and then screened through Wilcoxon rank sum test, elastic net and recursive feature elimination algorithms. A radiomics signature was established based support vector machine method. By combining clinical with the radiomics signature, a clin-radiomics combined model was constructed for individual CEE prediction.ResultsThree significance radiomics features were selected to construct a radiomics signature, with areas under the curves (AUCs) of 0.86 and 0.800 in the primary and validation cohorts, respectively. Two clinical characteristics (peritumoral edema and tumor size) and radiomics signature were determined to establish the clin-radiomics combined model, with an AUC of 0.91 in the primary cohort and 0.83 in the validation cohort. The clin-radiomics combined model showed good discrimination, calibration, and clinically useful for postoperative CEE prediction.ConclusionsBy integrating clinical characteristics with radiomics signature, the clin-radiomics combined model could assist in postoperative CEE prediction before surgery, and provide a basis for surgical treatment decisions in patients with meningioma.

Background: Early Warning Scores (EWS), including the National Early Warning Score 2 (NEWS2) and Modified NEWS (NEWS-C), have been recommended for triage decision in patients with COVID-19. However, the effectiveness of these EWS in COVID-19 has not been fully validated. The study aimed to investigate the predictive value of EWS to detect clinical deterioration in patients with COVID-19.Methods: Between February 7, 2020 and February 17, 2020, patients confirmed with COVID-19 were screened for this study. The outcomes were early deterioration of respiratory function (EDRF) and need for intensive respiratory support (IRS) during the treatment process. The EDRF was defined as changes in the respiratory component of the sequential organ failure assessment (SOFA) score at day 3 (ΔSOFAresp = SOFA resp at day 3–SOFAresp on admission), in which the positive value reflects clinical deterioration. The IRS was defined as the use of high flow nasal cannula oxygen therapy, noninvasive or invasive mechanical ventilation. The performances of EWS including NEWS, NEWS 2, NEWS-C, Modified Early Warning Scores (MEWS), Hamilton Early Warning Scores (HEWS), and quick sepsis-related organ failure assessment (qSOFA) for predicting EDRF and IRS were compared using the area under the receiver operating characteristic curve (AUROC).Results: A total of 116 patients were included in this study. Of them, 27 patients (23.3%) developed EDRF and 24 patients (20.7%) required IRS. Among these EWS, NEWS-C was the most accurate scoring system for predicting EDRF [AUROC 0.79 (95% CI, 0.69–0.89)] and IRS [AUROC 0.89 (95% CI, 0.82–0.96)], while NEWS 2 had the lowest accuracy in predicting EDRF [AUROC 0.59 (95% CI, 0.46–0.720)] and IRS [AUROC 0.69 (95% CI, 0.57–0.81)]. A NEWS-C ≥ 9 had a sensitivity of 59.3% and a specificity of 85.4% for predicting EDRF. For predicting IRS, a NEWS-C ≥ 9 had a sensitivity of 75% and a specificity of 88%.Conclusions: The NEWS-C was the most accurate scoring system among common EWS to identify patients with COVID-19 at risk for EDRF and need for IRS. The NEWS-C could be recommended as an early triage tool for patients with COVID-19.

In response to a variety of stresses, mammalian cells activate the inflammasome for targeted caspase-dependent pyroptosis. The research community has recently begun to deduce that the activation of inflammasome is instigated by several known oncogenic stresses and metabolic perturbations; nevertheless, the role of inflammasomes in the context of cancer biology is less understood. In manipulating the expression of inflammasome, researchers have found that NLRP3 serves as a deterministic player in conducting tumor fate decisions. Understanding the mechanistic underpinning of pro-tumorigenic and anti-tumorigenic pathways might elucidate novel therapeutic onco-targets, thereby providing new opportunities to manipulate inflammasome in augmenting the anti-tumorigenic activity to prevent tumor expansion and achieve metastatic control. Accordingly, this review aims to decode the complexity of NLRP3, whereby summarizing and clustering findings into cancer hallmarks and tissue contexts may expedite consensus and underscore the potential of the inflammasome in drug translation.

PurposeTo analyze the outcomes and toxicities of induction chemotherapy (ICT) followed by concurrent chemoradiotherapy (CCRT) plus adjuvant chemotherapy (ACT) in patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC).MethodsRetrospective analysis of 163 patients with LA-NPC referred from August 2015 to December 2018 was carried out. All patients underwent platinum-based ICT followed by CCRT plus ACT.ResultsThe median follow-up time was 40 months, ranging from 5 to 69 months. The 3-year disease-free survival (DFS), overall survival (OS), locoregional recurrence-free survival (LRRFS), and distant metastasis-free survival (DMFS) rates were 80.8, 90.0, 91.6, and 87.4%, respectively. The most frequent acute grade 3/4 adverse events were leukopenia (66.8%), neutropenia (55.8%), mucositis (41.1%), thrombocytopenia (27.0%), and anemia (14.7%).ConclusionICT followed by CCRT plus ACT did not seemingly enhance DFS and OS in LA-NPC patients compared to the addition of ICT to CCRT (historical controls). In contrast, ICT followed by CCRT plus ACT had more acute adverse events than ICT followed by CCRT. Longer-term clinical studies are required to examine the treatment outcomes and late toxicities.

BackgroundRadioresistance-induced local failure, which can result in residual or recurrent tumors, remains one of the major causes of treatment failure in nasopharyngeal carcinoma (NPC). Lipocalin 2 (LCN2) is known to play important roles in cancer initiation, progression, and treatment responses. However, its role in the radioresistance of NPC remains unclear.MethodsMicroarray data from the Gene Expression Omnibus (GEO) was screened for candidate biomarkers relating to the radioresistance of NPC. The expression of LCN2 in NPC cell lines was verified by quantitative real-time PCR (RT-qPCR) and western blotting. The effects of knockdown or overexpression of LCN2 on NPC radiosensitivity were examined using a soft agar colony formation assay and a γH2AX assay. LCN2 expression in NPC specimens was evaluated by immunohistochemistry. Survival outcomes were analyzed. A possible correlation between LCN2 and hypoxia-inducible factor 1-alpha (HIF-1A) was examined by western blotting and a tissue microarray.ResultsLCN2 was highly expressed in the radioresistant NPC cell line CNE2R. Knocking down LCN2 enhanced the radiosensitivity of NPC cells by impairing their ability to repair DNA damage or proliferate, while ectopic expression of LCN2 conferred additional radioresistance to NPC cells. Immunohistochemical analysis of 100 NPC specimens revealed that LCN2 expression was significantly upregulated in radioresistant NPC tissues and was associated with NPC recurrence. Furthermore, a significant correlation between the expression of LCN2 and HIF-1A was detected.ConclusionLCN2 is associated with radioresistance and recurrence in NPC and may facilitate the development of a radioresistant phenotype through interacting with HIF-1A. Our data indicate that LCN2 is a promising target for predicting and overcoming radioresistance in NPC.

Background: Sepsis-induced coagulopathy (SIC) denotes an increased mortality rate and poorer prognosis in septic patients.Objectives: Our study aimed to develop and validate machine-learning models to dynamically predict the risk of SIC in critically ill patients with sepsis.Methods: Machine-learning models were developed and validated based on two public databases named Medical Information Mart for Intensive Care (MIMIC)-IV and the eICU Collaborative Research Database (eICU-CRD). Dynamic prediction of SIC involved an evaluation of the risk of SIC each day after the diagnosis of sepsis using 15 predictive models. The best model was selected based on its accuracy and area under the receiver operating characteristic curve (AUC), followed by fine-grained hyperparameter adjustment using the Bayesian Optimization Algorithm. A compact model was developed, based on 15 features selected according to their importance and clinical availability. These two models were compared with Logistic Regression and SIC scores in terms of SIC prediction.Results: Of 11,362 patients in MIMIC-IV included in the final cohort, a total of 6,744 (59%) patients developed SIC during sepsis. The model named Categorical Boosting (CatBoost) had the greatest AUC in our study (0.869; 95% CI: 0.850–0.886). Coagulation profile and renal function indicators were the most important features for predicting SIC. A compact model was developed with an AUC of 0.854 (95% CI: 0.832–0.872), while the AUCs of Logistic Regression and SIC scores were 0.746 (95% CI: 0.735–0.755) and 0.709 (95% CI: 0.687–0.733), respectively. A cohort of 35,252 septic patients in eICU-CRD was analyzed. The AUCs of the full and the compact models in the external validation were 0.842 (95% CI: 0.837–0.846) and 0.803 (95% CI: 0.798–0.809), respectively, which were still larger than those of Logistic Regression (0.660; 95% CI: 0.653–0.667) and SIC scores (0.752; 95% CI: 0.747–0.757). Prediction results were illustrated by SHapley Additive exPlanations (SHAP) values, which made our models clinically interpretable.Conclusions: We developed two models which were able to dynamically predict the risk of SIC in septic patients better than conventional Logistic Regression and SIC scores.

The accumulation of lipid droplets in the cytoplasm of hepatocytes, known as hepatic steatosis, is a hallmark of non-alcoholic fatty liver disease (NAFLD). Inhibiting hepatic steatosis is suggested to be a therapeutic strategy for NAFLD. The present study investigated the actions of Neurotropin (NTP), a drug used for chronic pain in Japan and China, on lipid accumulation in hepatocytes as a possible treatment for NAFLD. NTP inhibited lipid accumulation induced by palmitate and linoleate, the two major hepatotoxic free fatty acids found in NAFLD livers. An RNA sequencing analysis revealed that NTP altered the expression of mitochondrial genes. NTP ameliorated palmitate-and linoleate-induced mitochondrial dysfunction by reversing mitochondrial membrane potential, respiration, and β-oxidation, suppressing mitochondrial oxidative stress, and enhancing mitochondrial turnover. Moreover, NTP increased the phosphorylation of AMPK, a critical factor in the regulation of mitochondrial function, and induced PGC-1β expression. Inhibition of AMPK activity and PGC-1β expression diminished the anti-steatotic effect of NTP in hepatocytes. JNK inhibition could also be associated with NTP-mediated inhibition of lipid accumulation, but we did not find the association between AMPK and JNK. These results suggest that NTP inhibits lipid accumulation by maintaining mitochondrial function in hepatocytes via AMPK activation, or by inhibiting JNK.

Blood-brain barrier opening (BBBO) with pulsed Focused Ultrasound (pFUS) and microbubbles (MB) has received increasing interest as a method for neurotherapeutics of the central nervous system. In general, conventional MRI [i.e., T2w, T2∗w, gadolinium (Gd) enhanced T1w] is used to monitor the effects of pFUS+MB on BBBO and/or assess whether sonication results in parenchymal damage. This study employed multimodal MRI techniques and 18F-Fludeoxyglucose (FDG) PET to evaluate the effects of single and multiple weekly pFUS+MB sessions on morphology and glucose utilization levels in the rat cortex and hippocampus. pFUS was performed with 0.548 MHz transducer with a slow infusion over 1 min of OptisonTM (5–8 × 107 MB) in nine focal points in cortex and four in hippocampus. During pFUS+MB treatment, Gd-T1w was performed at 3 T to confirm BBBO, along with subsequent T2w, T2∗w, DTI and glucose CEST (glucoCEST)-weighted imaging by high field 9.4 T and compared with FDG-PET and immunohistochemistry. Animals receiving a single pFUS+MB exhibited minimal hypointense voxels on T2∗w. Brains receiving multiple pFUS+MB treatments demonstrated persistent T2w and T2∗ abnormalities associated with changes in DTI and glucoCEST when compared to contralateral parenchyma. Decreased glucoCEST contrast was substantiated by FDG-PET in cortex following multiple sonications. Immunohistochemistry showed significantly dilated vessels and decreased neuronal glucose transporter (GLUT3) expression in sonicated cortex and hippocampus without changes in neuronal counts. These results suggest the importance to standardize MRI protocols in concert with advanced imaging techniques when evaluating long term effects of pFUS+MB BBBO in clinical trials for neurological diseases.

Background: N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a useful cardiac biomarker that is associated with acute kidney injury (AKI) and mortality after cardiac surgery. However, its prognostic value in cardiac surgical patients receiving renal replacement therapy (RRT) remains unclear.Objectives: Our study aimed to assess the prognostic value of NT-proBNP in patients with established AKI receiving RRT after cardiac surgery.Methods: A total of 163 cardiac surgical patients with AKI requiring RRT were enrolled in this study. Baseline characteristics, hemodynamic variables at RRT initiation, and NT-proBNP level before surgery, at RRT initiation, and on the first day after RRT were collected. The primary outcome was 28-day mortality after RRT initiation.Results: Serum NT-proBNP levels in non-survivors was markedly higher than survivors before surgery (median: 4,096 [IQR, 962.0–9583.8] vs. 1,339 [IQR, 446–5,173] pg/mL; P < 0.01), at RRT initiation (median: 10,366 [IQR, 5,668–20,646] vs. 3,779 [IQR, 1,799–11,256] pg/mL; P < 0.001), and on the first day after RRT (median: 9,055.0 [IQR, 4,392–24,348] vs. 5,255 [IQR, 2,134–9,175] pg/mL; P < 0.001). The area under the receiver operating characteristic curve of NT-proBNP before surgery, at RRT initiation, and on the first day after RRT for predicting 28-day mortality was 0.64 (95% CI, 0.55–0.73), 0.71 (95% CI, 0.63–0.79), and 0.68 (95% CI, 0.60–0.76), respectively. Consistently, Cox regression revealed that NT-proBNP levels before surgery (HR: 1.27, 95% CI, 1.06–1.52), at RRT initiation (HR: 1.11, 95% CI, 1.06–1.17), and on the first day after RRT (HR: 1.17, 95% CI, 1.11–1.23) were independently associated with 28-day mortality.Conclusions: Serum NT-proBNP was an independent predictor of 28-day mortality in cardiac surgical patients with AKI requiring RRT. The prognostic role of NT-proBNP needs to be confirmed in the future.

Exercise training (ExT) is beneficial for cardiovascular health, yet the central mechanism by which aerobic ExT attenuates the hypertensive responses remains unclear. Activation of pro-inflammatory cytokines (PICs) in the hypothalamic paraventricular nucleus (PVN) is important for the sympathoexcitation and hypertensive response. We thus hypothesized that aerobic ExT can decrease the blood pressure of hypertensive rats by reducing the levels of PICs through TLR4/MyD88/NF-κB signaling within the PVN. To examine this hypothesis, two-kidney-one-clip (2K1C) renovascular hypertensive rats were assigned to two groups: sedentary or exercise training and examined for 8 weeks. At the same time, bilateral PVN infusion of vehicle or TAK242, a TLR4 inhibitor, was performed on both groups. As a result, the systolic blood pressure (SBP), renal sympathetic nerve activity (RSNA) and plasma levels of norepinephrine (NE), epinephrine (EPI) were found significantly increased in 2K1C hypertensive rats. These rats also had higher levels of Fra-like activity, NF-κB p65 activity, TLR4, MyD88, IL-1β and TNF-α in the PVN than SHAM rats. Eight weeks of ExT attenuated the RSNA and SBP, repressed the NF-κB p65 activity, and reduced the increase of plasma levels of NE, EPI, and the expression of Fra-like, TLR4, MyD88, IL-1β and TNF-α in the PVN of 2K1C rats. These findings are highly similar to the results in 2K1C rats with bilateral PVN infusions of TLR4 inhibitor (TAK242). This suggests that 8 weeks of aerobic ExT may decrease blood pressure in hypertensive rats by reducing the PICs activation through TLR4/MyD88/NF-κB signaling within the PVN, and thus delays the progression of 2K1C renovascular hypertension.

BackgroundProximal symphalangism (SYM1) is a rare genetic bone disorder characterized by the fusion of proximal interphalangeal joints in the hands and feet. Genetic studies have identified two genes underlying SYM1 as the noggin (NOG) and the growth differentiation factor 5 (GDF5).Case ReportIn the present report, a 43-year-old gravida at 11 weeks of gestation was referred for evaluation of abnormal fusions of the joints. In the initial diagnosis, physical examination was undertaken. However, traditional radiological examination was not applied due to the need to protect the fetus, making diagnosis results inefficient to determine the exact disease affecting the proband. To acquire alternative clinical evidences, we conducted radiological examinations on two other affected family members. The radiological examination revealed that they carried the symphalangism accompanied with tarsal coalition, a very rare manifestation of SYM1. A combination of whole exome sequencing (WES) and Sanger sequencing revealed a novel heterozygous missense mutation (c.163G > T; p.Asp55Tyr) in the NOG gene, which could be associated with the observed pathogenic SYM1 in the studied family. The p.Asp55Tyr mutation co-segregated with SYM1 through the affected and unaffected family members. In silico structural modeling of the p.Asp55Tyr mutation showed that it abolishes the interaction with the Arg167 residue and causes a change in the electrostatic potential profile of the type II binding site of the noggin protein.ConclusionOur findings indicate that the genetic test based on WES can be useful in diagnosing SYM1 patients, with particular advantages in preventing the fetus from contacting harmful X-ray through the traditional radiography. The novel pathogenic mutation identified would further expand our understanding of the mutation spectrum of NOG in association with SYM1 disease and provide a guidance on how to determine whether the fetus is affected by SYM1 through the prenatal diagnosis.

Cold-induced sweetening (CIS) caused by reducing sugar (RS) accumulation during storage in low temperature in potato tubers is a critical factor influencing the quality of fried potato products. The reconditioning (REC) by arising storage temperature is a common measure to lower down RS. However, both CIS and REC are genotype-dependent and the genetic basis remains uncertain. In the present study, with a diploid potato population with broad genetic background, four reproducible QTL of CIS and two of REC were resolved on chromosomes 5, 6, and 7 of the CIS-sensitive parent and chromosomes 5 and 11 of the CIS-resistant parent, respectively, implying that these two traits may be genetically independent. This hypothesis was also supported by the colocalization of two functional genes, a starch synthesis gene AGPS2 mapped in QTL CIS_E_07-1 and a starch hydrolysis gene GWD colocated with QTL REC_B_05-1. The cumulative effects of identified QTL were proved to contribute largely and stably to CIS and REC and confirmed with a natural population composed of a range of cultivars and breeding lines. The present research identified reproducible QTL for CIS and REC of potato in diverse conditions and elucidated for the first time their cumulative genetic effects, which provides theoretical bases and applicable means for tuber quality improvement.

Hemophagocytic lymphohistiocytosis (HLH) is a severe and life-threatening hyperinflammatory condition characterized by excessive activation of macrophages and T cells and resulted in multi-organ dysfunction. HLH can be a primary disease or secondary to infections, malignancy, and some autoimmune diseases, including adult-onset Still’s disease (AOSD) and systemic lupus erythematosus (SLE). However, it is rare for HLH to occur as a secondary condition to drug-induced lupus erythematosus (DILE). In this report, we present a case of HLH as an unusual complication during SLE treatment in a 31-year-old male patient. The patient initially suffered from active chronic hepatitis B (CHB) and was treated with pegylated INFα-2b (Peg-INFα-2b), tenofovir disoproxil and lamivudine. After 19 months, CHB obtained biochemical and virological response with HBsAg positive to HBsAb. The patient developed fever, headache, and cytopenia after Peg-INFα-2b treatment for 33 months, and laboratory studies revealed that ANA and anti dsDNA were positive. He displayed 5 features meeting the HLH-2004 criteria for diagnosis including fever, pancytopenia, hyperferritinemia, high levels of soluble CD25, and hemophagocytosis on bone marrow biopsy. The patient was initiated with a combination treatment of intravenous methylprednisolone pulse therapy, oral cyclosporine, and etoposide (VP-16), which was followed by a course of oral prednisolone, intravenous cyclophosphamide pulse therapy, and entecavir with complete response. To our knowledge, this is the first report of IFN-α induced SLE complicating with HLH. Physicians should consider the potential autoimmune side effects of IFN-α therapy and be alert to insidious HLH in patients diagnosed with SLE. [ABSTRACT FROM AUTHOR]