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Background Jaundice is a common symptom of inherited or acquired liver diseases or a manifestation of diseases involving red blood cell metabolism. Recent progress has elucidated the molecular mechanisms of bile metabolism, hepatocellular transport, bile ductular development, intestinal bile salt reabsorption, and the regulation of bile acids homeostasis. Main body The major genetic diseases causing jaundice involve disturbances of bile flow. The insufficiency of bile salts in the intestines leads to fat malabsorption and fat-soluble vitamin deficiencies. Accumulation of excessive bile acids and aberrant metabolites results in hepatocellular injury and biliary cirrhosis. Progressive familial intrahepatic cholestasis (PFIC) is the prototype of genetic liver diseases manifesting jaundice in early childhood, progressive liver fibrosis/cirrhosis, and failure to thrive. The first three types of PFICs identified (PFIC1, PFIC2, and PFIC3) represent defects in FIC1 ( ATP8B1 ), BSEP ( ABCB11 ), or MDR3 ( ABCB4 ). In the last 5 years, new genetic disorders, such as TJP2, FXR, and MYO5B defects, have been demonstrated to cause a similar PFIC phenotype. Inborn errors of bile acid metabolism also cause progressive cholestatic liver injuries. Prompt differential diagnosis is important because oral primary bile acid replacement may effectively reverse liver failure and restore liver functions. DCDC2 is a newly identified genetic disorder causing neonatal sclerosing cholangitis. Other cholestatic genetic disorders may have extra-hepatic manifestations, such as developmental disorders causing ductal plate malformation (Alagille syndrome, polycystic liver/kidney diseases), mitochondrial hepatopathy, and endocrine or chromosomal disorders. The diagnosis of genetic liver diseases has evolved from direct sequencing of a single gene to panel-based next generation sequencing. Whole exome sequencing and whole genome sequencing have been actively investigated in research and clinical studies. Current treatment modalities include medical treatment (ursodeoxycholic acid, cholic acid or chenodeoxycholic acid), surgery (partial biliary diversion and liver transplantation), symptomatic treatment for pruritus, and nutritional therapy. New drug development based on gene-specific treatments, such as apical sodium-dependent bile acid transporter (ASBT) inhibitor, for BSEP defects are underway. Short conclusion Understanding the complex pathways of jaundice and cholestasis not only enhance insights into liver pathophysiology but also elucidate many causes of genetic liver diseases and promote the development of novel treatments.

This work aims to provide a reliable and intelligent prediction model for future trends in sharing economy. Moreover, it presents valuable insights for decision-making and policy development by relevant governmental bodies. Furthermore, the study introduces a predictive system that incorporates an enhanced Harris Hawk Optimization (HHO) algorithm and a K-Nearest Neighbor (KNN) forecasting framework. The method utilizes an improved simulated annealing mechanism and a Gaussian bare bone structure to improve the original HHO, termed SGHHO. To achieve optimal prediction performance and identify essential features, a refined simulated annealing mechanism is employed to mitigate the susceptibility of the original HHO algorithm to local optima. The algorithm employs a mechanism that boosts its global search ability by generating fresh solution sets at a specific likelihood. This mechanism dynamically adjusts the equilibrium between the exploration and exploitation phases, incorporating the Gaussian bare bone strategy. The best classification model (SGHHO-KNN) is developed to mine the key features with the improvement of both strategies. To assess the exceptional efficacy of the SGHHO algorithm, this investigation conducted a series of comparative trials employing the function set of IEEE CEC 2014. The outcomes of these experiments unequivocally demonstrate that the SGHHO algorithm outperforms the original HHO algorithm on 96.7% of the functions, substantiating its remarkable superiority. The algorithm can achieve the optimal value of the function on 67% of the tested functions and significantly outperforms other competing algorithms. In addition, the key features selected by the SGHHO-KNN model in the prediction experiment, including \" Form of sharing economy in your region \" and \" Attitudes to the sharing economy \", are important for predicting the future trends of the sharing economy in this study. The results of the prediction demonstrate that the proposed model achieves an accuracy rate of 99.70% and a specificity rate of 99.38%. Consequently, the SGHHO-KNN model holds great potential as a reliable tool for forecasting the forthcoming trajectory of the sharing economy.

Anti-PD-1-based immunotherapy has emerged as a promising therapy for several cancers. However, it only benefits a small subset of colorectal cancer (CRC) patients. Mounting data supports the pivotal role of gut microbiota in shaping immune system. Pectin, a widely consumed soluble fiber, has been reported to ameliorate the imbalance of gut microbiota. Therefore, we aimed to explore the effect and the underlying mechanisms of pectin in improving anti-PD-1 mAb efficacy. The C57BL/6 mice were treated with a broad-spectrum antibiotic (ATB) cocktail to depleted endogenous gut microbiota and subsequently humanized with feces from healthy controls or newly diagnosed CRC patients. The antitumor efficacies of anti-PD-1 mAb combined with or without pectin were assessed using these mice. Flow cytometry and immunohistochemistry (IHC) were conducted to investigate the tumor immune microenvironment after treatment. The gut microbiota profiles and short-chain fatty acids (SCFAs) levels were determined by 16S ribosomal RNA (16S rRNA) gene sequencing and gas chromatography-mass spectrometry (GC-MS), respectively. The effect of gut microbiota on anti-PD-1 mAb efficacy after pectin supplement was further tested by fecal microbiota transplantation (FMT). The anti-PD-1 mAb efficacy was largely impaired in the mice humanized with feces from newly diagnosed CRC patients compared to those from healthy controls. However, pectin significantly enhanced the anti-PD-1 mAb efficacy in the tumor-bearing mice humanized with CRC patient gut microbiota. Flow cytometry and IHC analysis revealed increased T cell infiltration and activation in the tumor microenvironment of mice treated with anti-PD-1 mAb plus pectin. In vivo depletion of CD8 T cells diminished the anti-tumor effect of anti-PD-1 mAb combined with pectin. 16S rRNA gene sequencing showed that pectin significantly increased gut microbial diversity and beneficially regulated microbial composition. In addition, we identified unique bacterial modules that were significantly enriched in the anti-PD-1 mAb + pectin group, which composed of butyrate-producing bacteria indicative of good response to immunotherapy. Meanwhile, GC-MS showed that pectin altered the level of SCFA butyrate. Furthermore, butyrate, a main product of dietary fiber in gut microbial fermentation, was found to be sufficient to promote T cells infiltration and thus enhance the efficacy of anti-PD-1 mAb. In addition, FMT demonstrated the effects of pectin were dependent on gut microbiota. Importantly, the beneficial effects of pectin were confirmed in the mice humanized with gut microbiota from patient with resistance to anti-PD-1 mAb. Pectin facilitated the anti-PD-1 mAb efficacy in CRC via regulating the T cell infiltration in the tumor microenvironment, which was potentially mediated by the metabolite butyrate.

Smoking tobacco is the major risk factor for developing lung cancer. However, most Han Chinese women with lung cancer are nonsmokers. Chinese cooking methods usually generate various carcinogens in fumes that may inevitably be inhaled by those who cook the food, most of whom are female. We investigated the associations of cooking habits and exposure to cooking fumes with lung cancer among non-smoking Han Chinese women. This study was conducted on 1,302 lung cancer cases and 1,302 matched healthy controls in Taiwan during 2002–2010. Two indices, “cooking time-years” and “fume extractor use ratio,” were developed. The former was used to explore the relationship between cumulative exposure to cooking oil fumes and lung cancer; the latter was used to assess the impact of fume extractor use for different ratio-of-use groups. Using logistic models, we found a dose–response association between cooking fume exposure and lung cancer (odds ratios of 1, 1.63, 1.67, 2.14, and 3.17 across increasing levels of cooking time-years). However, long-term use of a fume extractor in cooking can reduce the risk of lung cancer by about 50%. Furthermore, we provide evidence that cooking habits, involving cooking methods and oil use, are associated with risk of lung cancer.

Background Macrophages engulf oxidized-LDL (oxLDL) leading to accumulation of cellular cholesterol and formation of foam cells, which is a hallmark of atherosclerosis. Moreover, recent studies showed that accumulation of free cholesterol in macrophages leading to activation of NLRP3 inflammasome and production of interleukin-1β (IL-1β) has been linked to atherosclerosis-associated inflammation. However, it is not clear if cholesterol accumulation is associated with hepatic inflammation and fibrosis in the liver. In this study, we investigated the association of free cholesterol and oxLDL accumulation in portal vein with the inflammation, atherosclerosis, and fibrosis in human nonalcoholic fatty liver disease (NAFLD). Methods Serial sections derived from surgical specimens of NAFLD were stained with filipin and antibodies against IL-1β, CD68, α-smooth muscle actin (α-SMA), oxLDL and lectin-like oxLDL receptor-1 (LOX-1). Results We show that free cholesterol was colocalized with oxLDL in the wall of portal vein, and which was associated with lumen narrowing, plaque formation, endothelium deformation, and portal venous inflammation. The inflammation was evidenced by the colocalization of Kupffer cells and IL-1β and the expression of LOX-1. Notably, ruptured plaque was closely associated with portal venous inflammation. Moreover, free cholesterol and oxLDL accumulation in periportal and sinusoidal fibrosis, which was associated with regional stellate cell activation and chicken-wire fibrosis. Conclusion These findings reveal a direct association between cholesterol accumulation, portal venous inflammation and fibrosis in NAFLD.

Zika virus is a Flavivirus, transmitted via Aedes mosquitos, that causes a range of symptoms including Zika congenital syndrome. Zika has posed a challenging situation for health, public and economic sectors of affected countries. To quantitate Zika virus neutralizing antibody titers in serum samples, we developed a high throughput plate based Zika virus reporter virus particle (RVP) assay that uses an infective, non-replicating particle encoding Zika virus surface proteins and capsid (CprME) and a reporter gene ( Renilla luciferase). This is the first characterization of a Zika virus RVP assay in 384-well format using a Dengue replicon Renilla reporter construct. Serially diluted test sera were incubated with RVPs, followed by incubation with Vero cells. RVPs that have not been neutralized by antibodies in the test sera entered the cells and expressed Renilla luciferase. Quantitative measurements of neutralizing activity were determined using a plate-based assay and commercially available substrate. The principle of limiting the infection to a single round increases the precision of the assay measurements. RVP log 10 EC 50 titers correlated closely with titers determined using a plaque reduction neutralization test (PRNT) (R 2 >95%). The plate-based Zika virus RVP assay also demonstrated high levels of precision, reproducibility and throughput. The assay employs identical reagents for human, rhesus macaque and mouse serum matrices. Spiking studies indicated that the assay performs equally well in different species, producing comparable titers irrespective of the serum species. The assay is conducted in 384-well plates and can be automated to simultaneously achieve high throughput and high reproducibility.

Population aging is creating critical issues in Taiwan, and adults are being forced to maintain productivity at work; in other words, they need to work longer. Therefore, their fitness and health warrant immediate attention. Although the association between health and anthropometric characteristics has been reported, few profiles on Taiwanese adults can be found. The purpose of this study was to provide a suitable reference on the anthropometric data of Taiwanese adults. We recruited 60,056 anthropometric measurements from a representative database. Significant differences were found in every measurement for each gender and age group. Statistically, our results indicated anthropometric differences in different ages. However, CVs showed that the dispersions are minor. This study presents a sufficient profile on Taiwanese adults from a representative database to practitioners and other potential users.

In this paper, a novel recognition algorithm based on discriminant tensor subspace analysis (DTSA) and extreme learning machine (ELM) is introduced. DTSA treats a gray facial image as a second order tensor and adopts two-sided transformations to reduce dimensionality. One of the many advantages of DTSA is its ability to preserve the spatial structure information of the images. In order to deal with micro-expression video clips, we extend DTSA to a high-order tensor. Discriminative features are generated using DTSA to further enhance the classification performance of ELM classifier. Another notable contribution of the proposed method includes significant improvements in face and micro-expression recognition accuracy. The experimental results on the ORL, Yale, YaleB facial databases and CASME micro-expression database show the effectiveness of the proposed method.

Background The bile salt export pump (BSEP) is a pivotal apical/canalicular bile salt transporter in hepatocytes that drives the bile flow. Defects in BSEP function and canalicular expression could lead to a spectrum of cholestatic liver diseases. One prominent manifestation of BSEP-associated cholestasis is the defective canalicular localization and cytoplasmic retention of BSEP. However, the etiology of impaired BSEP targeting to the canalicular membrane is not fully understood. Our goal was to discover what molecule could interact with BSEP and affect its post-Golgi sorting. Methods The human BSEP amino acids (a.a.) 491-630 was used as bait to screen a human fetal liver cDNA library through yeast two-hybrid system. We identified a BSEP-interacting candidate and showed the interaction and colocalization in the co-immunoprecipitation in hepatoma cell lines and histological staining in human liver samples. Temperature shift assays were used to study the post-Golgi trafficking of BSEP. We further determine the functional impacts of the BSEP-interacting candidate on BSEP in vitro. A hydrodynamically injected mouse model was established for in vivo characterizing the long-term impacts on BSEP. Results We identified that charged multivesicular body protein 5 (CHMP5), a molecule of the endosomal protein complex required for transport subcomplex-III (ESCRT-III), interacted and co-localized with BSEP in the subapical compartments (SACs) in developing human livers. Cholestatic BSEP mutations in the CHMP5-interaction region have defects in canalicular targeting and aberrant retention at the SACs. Post-Golgi delivery of BSEP and bile acid secretion were impaired in ESCRT-III perturbation or CHMP5-knockdown hepatic cellular and mouse models. This ESCRT-III-mediated BSEP sorting preceded Rab11A-regulated apical cycling of BSEP. Conclusions Our results showed the first example that ESCRT-III is essential for canalicular trafficking of apical membrane proteins, and provide new targets for therapeutic approaches in BSEP associated cholestasis.

Background Hypoxia‐inducible factors (HIFs) are thought to play important roles in the carcinogenesis and progression of VHL‐deficient clear cell renal cell carcinoma (ccRCC). Methods The roles of HIF‐1/2α in VHL‐deficient clear cell renal cell carcinoma were evaluated by bioinformatics analysis, immunohistochemistry staining and Kaplan‐Meier survival analysis. The downstream genes that counteract the cancer‐promoting effect of HIF were analysed by unbiased proteomics and verified by in vitro and in vivo assays. Results There was no correlation between the high protein level of HIF‐1/2α and the poor prognosis of ccRCC patients in our large set of clinical data. Furthermore, NDRG1 was found to be up‐regulated by both HIF‐1α and −2α at the cellular level and in ccRCC tissues. Intriguingly, the high NDRG1 expression was correlated with lower Furman grade, TNM stage and longer survival for ccRCC patients compared with the low NDRG1 expression. In addition, NDRG1 suppressed the expression of series oncogenes as well as the proliferation, metastasis and invasion of VHL‐deficient ccRCC cells in vitro and vivo. Conclusions Our study demonstrated that HIF downstream gene of NDRG1 may counteract the cancer‐promoting effect of HIF. These results provided evidence that NDRG1 may be a potential prognostic biomarker as well as a therapeutic target in ccRCC.