Miracle-dz/UniFAR-FTUs huggingface dataset:
Cell entry, efficient RNA replication, and production of infectious hepatitis C virus progeny in mouse liver‐derived cells

Only humans and chimpanzees are susceptible to chronic infection by hepatitis C virus (HCV). The restricted species tropism of HCV is determined by distinct host factor requirements at different steps of the viral life cycle. In addition, effective innate immune targeting precludes efficient propagation of HCV in nonhuman cells. Species‐specificity of HCV host factor usage for cell entry and virus release has been explored. However, the reason for inefficient HCV RNA replication efficiency in mouse liver cells remains elusive. To address this, we generated novel mouse liver‐derived cell lines with specific lesions in mitochondrial antiviral signaling protein (MAVS), interferon regulatory factor 3 (IRF3), or Interferon‐α/β receptor (IFNAR) by in vivo immortalization. Blunted innate immune responses in these cells modestly increased HCV RNA replication. However, ectopic expression of liver‐specific human microRNA 122 (miR‐122) further boosted RNA replication in all knockout cell lines. Remarkably, MAVS−/−miR‐122 cells sustained vigorous HCV RNA replication, attaining levels comparable to the highly permissive human hepatoma cell line Huh‐7.5. RNA replication was dependent on mouse cyclophilin and phosphatidylinositol‐4 kinase III alpha (PI4KIIIα) and was also observed after transfection of full‐length viral RNA. Additionally, ectopic expression of either human or mouse apolipoprotein E (ApoE) was sufficient to permit release of infectious particles. Finally, expression of human entry cofactors rendered these cells permissive to HCV infection, thus confirming that all steps of the HCV replication cycle can be reconstituted in mouse liver‐derived cells. Conclusion: Blunted innate immunity, abundant miR‐122, and HCV entry factor expression permits propagation of HCV in mouse liver‐derived cell lines. (Hepatology 2014;58:78–88)
Relaxin modulates human and rat hepatic myofibroblast function and ameliorates portal hypertension in vivo

Active myofibroblast (MF) contraction contributes significantly to the increased intrahepatic vascular resistance that is the primary cause of portal hypertension (PHT) in cirrhosis. We sought proof of concept for direct therapeutic targeting of the dynamic component of PHT and markers of MF activation using short‐term administration of the peptide hormone relaxin (RLN). We defined the portal hypotensive effect in rat models of sinusoidal PHT and the expression, activity, and function of the RLN‐receptor signaling axis in human liver MFs. The effects of RLN were studied after 8 and 16 weeks carbon tetrachloride intoxication, following bile duct ligation, and in tissue culture models. Hemodynamic changes were analyzed by direct cannulation, perivascular flowprobe, indocyanine green imaging, and functional magnetic resonance imaging. Serum and hepatic nitric oxide (NO) levels were determined by immunoassay. Hepatic inflammation was assessed by histology and serum markers and fibrosis by collagen proportionate area. Gene expression was analyzed by quantitative reverse‐transcription polymerase chain reaction (qRT‐PCR) and western blotting and hepatic stellate cell (HSC)‐MF contractility by gel contraction assay. Increased expression of RLN receptor (RXFP1) was shown in HSC‐MFs and fibrotic liver diseases in both rats and humans. RLN induced a selective and significant reduction in portal pressure in pathologically distinct PHT models, through augmentation of intrahepatic NO signaling and a dramatic reduction in contractile filament expression in HSC‐MFs. Critical for translation, RLN did not induce systemic hypotension even in advanced cirrhosis models. Portal blood flow and hepatic oxygenation were increased by RLN in early cirrhosis. Treatment of human HSC‐MFs with RLN inhibited contractility and induced an antifibrogenic phenotype in an RXFP1‐dependent manner. Conclusion: We identified RXFP1 as a potential new therapeutic target for PHT and MF activation status. (Hepatology 2014;59:1492‐1504)
Sublethal heat treatment promotes epithelial‐mesenchymal transition and enhances the malignant potential of hepatocellular carcinoma

Yoshida et al. reported that they exposed three human HCC cell lines (HEPG2, HuH7, and HEP3B) to 45 C-55 C for 10 minutes, simulating the marginal zone of radiofrequency ablation (RFA) treatment. They demonstrated that sublethal heat treatment skews hepatocellular carcinoma (HCC) cells towards epithelialmesenchymal transition (EMT) and transforms them to a progenitor-like, highly proliferative cellular phenotype in vitro and in vivo. Of note, the expression of two central EMT markers (Snail and procollagen-a1(I)) and EMT-related transcript levels increased at day 5 after heat exposure, which returned to baseline at day 12. However, this study raises several confusing questions. First, the experimental protocol used to simulate the marginal zone of RFA treatment was notably different from the conditions in the clinical setting to some extent. For example, a single ablation takes from 8 to 25 minutes, but the durations of heat treatments are always less or more than 10 minutes in the clinical setting. What’s more, the temperatures in the remainder of the ablation zone cannot maintain a constant temperature for 10 minutes. Because water vaporization and char act as electrical insulators, the increase in impedance with tissue boiling and charring can significantly reduce the thermal conductivity. Second, Yoshida et al. reported that the Shc expression dramatically increased in HCC tissue, but was absent in healthy liver. However, the HCC specimens studied may not equal that which patients with recurrence of HCC after RFA treatment have. Therefore, it cannot reflect the true expression level of Shc in HCC tissue after RFA treatment. Third, this study indicated that HEPG2 cells pretreated at 48 C and 50 C were subcutaneously implanted on day 3 after heating and displayed faster HCC growth compared to tumors arising from untreated cells. Moreover, early proliferation and EMT-like changes were observed in hepatoma cells at day 3 after heat treatment. Since all these changes clearly found in heatexposed HCC cells at day 5 returned to baseline at day 12, we wonder whether the transplant heat-pretreated HCC cells at day 5 into nude mice with HCC cells exposed to 48 C and 50 C display faster growth compared to tumors arising from untreated cells or HCC cells at day 3 after heat treatment. Furthermore, to transplant heat-pretreated HCC cells at day 12 into nude mice, we wonder whether the HCC growth will slow down or even stop compared to heat-pretreated HCC cells at day 3 and 5 in nude mice. We believe the answers to the above questions will help clarify the underlying mechanism of the rapid growth of residual HCC after sublethal heat treatment.
Análise da atenção pré-hospitalar ao acidente vascular cerebral e ao infarto agudo do miocárdio na população idosa de minas gerais

OBJETIVO: Analisar a associacao entre os componentes pre-hospitalares da Politica Nacional de Atencao as Urgencias (PNAU), a Estrategia de Saude da Familia (ESF) e o Servico de Atendimento Movel de Urgencia (SAMU) e indicadores de morbimortalidade por acidente vascular cerebral (AVC) e infarto agudo do miorcardio (IAM) na populacao idosa de municipios selecionados do Estado de Minas Gerais. METODOS: Foi realizado um estudo ecologico, com delineamento longitudinal. A analise dos dados foi realizada por um conjunto de modelos de regressao multinivel. Os indicadores de saude foram analisados para os anos de 2001 a 2007. RESULTADOS: Encontrou-se associacao estatisticamente significativa entre os indicadores da cobertura da ESF e a presenca do SAMU com os indicadores de mortalidade por AVC e IAM, para ambos os sexos, com excecao do IAM masculino. Em relacao as taxas de internacao, os efeitos mais consistentes foram identificados para o IAM feminino. CONCLUSAO: A heterogeneidade dos resultados aponta para uma fase incipiente da PNAU, que ainda nao permite a observacao de efeitos evidentes, o que tambem pode sugerir que esta politica nao tem sido ainda capaz de atingir suas metas em relacao aos idosos. A continuidade dos processos de avaliacao da PNAU e essencial para o estabelecimento de estrategias que aprimorem sua efetividade.
Prevalence and proposed mechanisms of chronic low back pain in baseball: part i

ABSTRACT The prevalence of low back pain (LBP) among active baseball players ranges between 3 and 15%. The execution of baseball-specific manoeuvres, such as pitching or batting, may be related to the onset of LBP. These baseball motions are complex and require appropriate activation of the core musculature to produce a well-timed motion with forces minimized at the extremities. The spine, core and back musculature are involved with acceleration and deceleration of rotational motions. This narrative review synopsizes the available evidence of the prevalence of and mechanical factors underlying LBP in the baseball population. Possible mechanical mechanisms linking baseball play to LBP include aberrant motion, improper timing, high lumbar stress due to mechanical loading and lumbopelvic strength deficits. Potential clinical implications relating to these possible mechanical mechanisms will also be highlighted. The state of the evidence suggests that there are deficits in understanding the role of baseball motion and playing history in the development of spine conditions.
Hepatic oxidative stress activates the Gadd45b gene by way of degradation of the transcriptional repressor STAT3

Growth arrest and DNA damage‐inducible beta (GADD45b) plays an important role in many intracellular events, such as cell cycle arrest, DNA repair, cell survival, apoptosis, and senescence. However, its mechanism of transcriptional regulation remains unclear. In this study the mechanism of peroxisome proliferator‐activated receptor α (PPARα) ligand induction of the Gadd45b gene in mouse liver was investigated. Gadd45b messenger RNA (mRNA) was markedly induced by the PPARα agonist Wy‐14,643 in wild‐type mice but not in Ppara‐null mice. Signal transducer and activator of transcription 3 (STAT3) was found to be a repressor of the Gadd45b gene through binding to upstream regulatory elements. The role of STAT3 in control of Gadd45b was confirmed using liver‐specific Stat3‐null mice. Wy‐14,643 treatment stimulated STAT3 ubiquitination leading to activation of the Gadd45b gene as a result of loss of Gadd45b repression by STAT3. STAT3 degradation was induced by forced overexpression of the PPARα target gene‐encoded enzyme ACOX1, which produces increased H2O2 as a byproduct of fatty acid β‐oxidation. H2O2 also stimulated expression of Gadd45b in cultured cells. Conclusion: PPARα indirectly induces the Gadd45b gene in liver through promoting degradation of the repressor STAT3 as a result of elevated oxidative stress. (Hepatology 2014;59:695–704)
Transforming growth factor beta signaling in hepatocytes participates in steatohepatitis through regulation of cell death and lipid metabolism in mice

Transforming growth factor beta (TGF‐β) signaling activates Smad‐ and TGF‐β‐activated kinase 1 (TAK1)‐dependent signaling to regulate cell survival, proliferation, fibrosis, and tumorigenesis. The effects of TGF‐β signaling on metabolic syndrome, including nonalcoholic fatty liver disease, remain elusive. Wild‐type (WT) and hepatocyte‐specific TGF‐β receptor type II‐deficient (Tgfbr2ΔHEP) mice were fed a choline‐deficient amino acid (CDAA)‐defined diet for 22 weeks to induce NASH. WT mice fed a CDAA diet displayed increased activation of Smad2/3 and had marked lipid accumulation, inflammatory cell infiltration, hepatocyte death, and fibrosis; in comparison, Tgfbr2ΔHEP mice fed a CDAA diet had suppressed liver steatosis, inflammation, and fibrosis. Both palmitate‐induced steatotic hepatocytes and hepatocytes isolated from WT mice fed a CDAA diet had increased susceptibility to TGF‐β‐mediated death. TGF‐β‐mediated death in steatotic hepatocytes was inhibited by silencing Smad2 or blocking reactive oxygen species (ROS) production and was enhanced by inhibiting TAK1 or nuclear factor kappa B. Increased hepatic steatosis in WT mice fed a CDAA diet was associated with the increased expression of lipogenesis genes (Dgat1 and Srebp1c), whereas the decreased steatosis in Tgfbr2ΔHEP mice was accompanied by the increased expression of genes involved in β‐oxidation (Cpt1 and Acox1). In combination with palmitate treatment, TGF‐β signaling promoted lipid accumulation with induction of lipogenesis‐related genes and suppression of β‐oxidation‐related genes in hepatocytes. Silencing Smad2 decreased TGF‐β‐mediated lipid accumulation and corrected altered gene expression related to lipid metabolism in hepatocytes. Finally, we confirmed that livers from patients with nonalcoholic steatohepatitis (NASH) displayed phosphorylation and nuclear translocation of Smad2/3. Conclusions: TGF‐β signaling in hepatocytes contributes to hepatocyte death and lipid accumulation through Smad signaling and ROS production that promote the development of NASH. (Hepatology 2014;59:483–495)
Indocyanine green retention test as a noninvasive marker of portal hypertension and esophageal varices in compensated liver cirrhosis

Noninvasive markers would be useful for the assessment of portal hypertension (PH) and esophageal varices (EV) in patients with cirrhosis. The aim of our study was to evaluate the performance of the indocyanine green (ICG) retention test as a noninvasive marker of PH and EV, measured against the gold standards (hepatic venous pressure gradient [HVPG] measurement and upper endoscopy). We prospectively enrolled patients with compensated cirrhosis referral to our unit. All patients underwent laboratory tests, abdominal ultrasound, upper gastrointestinal endoscopy, HVPG measurement, and the ICG 15‐minute retention (ICG‐r15) test. We evaluated the sensitivity and specificity of the ICG retention test and other noninvasive tools for the diagnosis of PH and EV. Ninety‐six consecutive Child‐Pugh A patients (67 male and 29 female; 60.3 ± 11.8 years of age) were enrolled. Seventy‐four patients had clinically significant portal hypertension (CSPH), of whom 59 had severe portal hypertension (SPH). ICG‐r15 and Lok index were independently related to the presence of both CSPH and SPH, whereas ICG‐r15 and INR were related to EV. ICG‐r15 values (<6.7% and <6.9%, respectively) were able to rule out the presence of CSPH and SPH (LR− 0.15 and 0.14); ICG‐r15 <10% provided a 97.8% sensitivity (LR− 0.042) for the exclusion of EV and a 100% sensitivity (LR− 0.0) for large EV. Conclusion: The ICG‐r15 test is an effective tool for assessment of PH in patients with compensated cirrhosis. Although this would not replace endoscopy, the ICG‐r15 appears able to identify patients with advanced liver disease in which endoscopy is mandatory as well as rule out the presence of EV in patients with compensated cirrhosis. (Hepatology 2014;59:643–650)
Influence of Feeding Type on Gut Microbiome Development in Hospitalized Preterm Infants

Background Premature infants have a high risk for dysbiosis of the gut microbiome. Mother’s own milk (MOM) has been found to favorably alter gut microbiome composition in infants born at term. Evidence about the influence of feeding type on gut microbial colonization of preterm infants is limited. Objective The purpose of this study was to explore the effect of feeding types on gut microbial colonization of preterm infants in the neonatal intensive care unit. Methods Thirty-three stable preterm infants were recruited at birth and followed up for the first 30 days of life. Daily feeding information was used to classify infants into six groups (MOM, human donor milk [HDM], Formula, MOM + HDM, MOM + Formula, and HDM + Formula) during postnatal days 0–10, 11–20, and 21–30. Stool samples were collected daily. DNA extracted from stool was used to sequence the 16S rRNA gene. Exploratory data analysis was conducted with a focus on temporal changes of microbial patterns and diversities among infants from different feeding cohorts. Prediction of gut microbial diversity from feeding type was estimated using linear mixed models. Results Preterm infants fed MOM (at least 70% of the total diet) had highest abundance of Clostridiales, Lactobacillales, and Bacillales compared to infants in other feeding groups, whereas infants fed primarily HDM or formula had a high abundance of Enterobacteriales compared to infants fed MOM. After controlling for gender, postnatal age, weight, and birth gestational age, the diversity of gut microbiome increased over time and was constantly higher in infants fed MOM relative to infants with other feeding types (p < .01). Discussion MOM benefits gut microbiome development of preterm infants, including balanced microbial community pattern and increased microbial diversity in early life.
Gankyrin promotes tumor growth and metastasis through activation of IL‐6/STAT3 signaling in human cholangiocarcinoma

Although gankyrin is involved in the tumorigenicity and metastasis of some malignancies, the role of gankyrin in cholangiocarcinoma (CCA) is unclear. In this study we investigated the expression of gankyrin in human CCA tissues and cell lines. The effects of gankyrin on CCA tumor growth and metastasis were determined both in vivo and in vitro. The results showed that gankyrin was overexpressed in CCA tissues and cell lines. Gankyrin expression was associated with CCA histological differentiation, TNM stage, and metastasis. The multivariate Cox analysis revealed that gankyrin was an independent prognostic indicator for overall survival. Gankyrin overexpression promoted CCA cell proliferation, migration, and invasion, while gankyrin knockdown inhibited CCA tumor growth, metastasis, and induced Rb‐dependent senescence and G1 phase cell cycle arrest. Gankyrin increased the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and promoted the nuclear translocation of p‐STAT3. Suppression of STAT3 signaling by small interfering RNA (siRNA) or STAT3 inhibitor interfered with gankyrin‐mediated carcinogenesis and metastasis, while interleukin (IL)‐6, a known upstream activator of STAT3, could restore the proliferation and migration of gankyrin‐silenced CCA cells. The IL‐6 level was decreased by gankyrin knockdown, while increased by gankyrin overexpression. Gankyrin regulated IL‐6 expression by way of facilitating the phosphorylation of Rb; meanwhile, rIL‐6 treatment increased the expression of gankyrin, suggesting that IL‐6 was regulated by a positive feedback loop involving gankyrin in CCA. In the xenograft experiments, gankyrin overexpression accelerated tumor formation and increased tumor weight, whereas gankyrin knockdown showed the opposite effects. The in vivo spontaneous metastasis assay revealed that gankyrin promoted CCA metastasis through IL‐6/STAT3 signaling pathway. Conclusion: Gankyrin is crucial for CCA carcinogenesis and metastasis by activating IL‐6/STAT3 signaling pathway through down‐regulating Rb protein. (Hepatology 2014;59:935–946)
Differentiating Non-Asbestiform Amphibole and Amphibole Asbestos by Size Characteristics

Mining or processing asbestos minerals can liberate isolated fibers or fiber bundles regulated as airborne asbestos fibers. Coarsely crystalline amphibole minerals are more common than asbestos in many geologic environments, and disturbance can result in the release of prismatic or acicular single crystals or cleavage fragments resembling asbestos fibers or fiber bundles but that are not currently regulated as asbestos. Bulk samples of six coarsely crystalline amphiboles and their five asbestos analogs were processed to maximize the number of particles meeting the criterion for counting under the current U.S. National Institute for Occupational Safety and Health Method 7400 “A” counting rules (> 5 μm long with an aspect ratio ≥ 3:1) and also within the respirable width range, i.e. < 3 μm width. The length distributions of the particles produced showed substantial overlap between cleavage fragments and asbestos fibers. Available data sets generally confirmed the relevance of the size distributions of particles generated from reference materials to airborne particles. The length criterion in the current ASTM International standard D7200-06 causes a large proportion (e.g., 40% grunerite and 39% tremolite) of the non-asbestiform particles to be considered potential asbestos. An alternative procedure may be to use a distinction based on width alone as some, but not the majority of, cleavage fragments were thinner than 1 μm (e.g., 9% of actinolite and 20% of grunerite particles), and not many amphibole asbestos particles were wider (e.g., 5% of crocidolite and 18% of amosite particles). This proposal would need further testing. This research should not be considered as addressing any controversy with regard to the toxicity of non-asbestiform amphibole particles of similar dimensions to asbestos particles.
Toxic effects of Francoeuria crispa in rats

The toxicity to rats of Saudi Francoeuria crispa used in traditional medicine for the treatment of various disorders was investigated. Francoeuria crispa leaves were fed to rats at 2% and 10% of the diet for 8 weeks. In rats on the 10% F. crispa diet, there was a decrease in average body weight gain and feed efficiency, soft faeces and enterohepatonephrotoxicity. These changes were accompanied by raised serum AST and GGT activities and urea and cholesterol concentrations, decreased total protein and albumin levels, leucopenia and normocytic normochromic anaemia. Growth of rats on the 2% F. crispa diet was promoted compared with rats on a control diet. Copyright © 1998 John Wiley & Sons, Ltd.
Correlates of substance use disorder in bipolar disorder: a systematic review and meta-analysis

Substance use disorders (SUDs) are common in those with bipolar disorder (BD) and are linked to a number of negative outcomes. The aim of the present study was to systematically review and perform a meta-analysis on correlates of SUDs in those with BD. A systematic review was performed on the online database PsychINFO, with specific keywords and inclusion criteria employed. A total of 1794 papers were produced and 49 were accepted. A meta-analysis was performed on all available data. Correlates of SUD reported by individual studies included various socio-demographic, clinical history, developmental, personality and family history variables. A series of meta-analyses found that lower current age and lower age ofsymptom onset, male gender, being unmarried, having BD type I, having a co-morbid anxiety disorder and a history of suicide attempts all predicted co-morbid SUD. Variables such as years spent in education, number of lifetime psychiatric hospitalisations and ethnic minority status did not reach signi.