Miracle-dz/UniFAR-FTUs huggingface dataset:
Functional defect of variants in the adenosine triphosphate–binding sites of ABCB4 and their rescue by the cystic fibrosis transmembrane conductance regulator potentiator, ivacaftor (VX‐770)

ABCB4 (MDR3) is an adenosine triphosphate (ATP)‐binding cassette (ABC) transporter expressed at the canalicular membrane of hepatocytes, where it mediates phosphatidylcholine (PC) secretion. Variations in the ABCB4 gene are responsible for several biliary diseases, including progressive familial intrahepatic cholestasis type 3 (PFIC3), a rare disease that can be lethal in the absence of liver transplantation. In this study, we investigated the effect and potential rescue of ABCB4 missense variations that reside in the highly conserved motifs of ABC transporters, involved in ATP binding. Five disease‐causing variations in these motifs have been identified in ABCB4 (G535D, G536R, S1076C, S1176L, and G1178S), three of which are homologous to the gating mutations of cystic fibrosis transmembrane conductance regulator (CFTR or ABCC7; i.e., G551D, S1251N, and G1349D), that were previously shown to be function defective and corrected by ivacaftor (VX‐770; Kalydeco), a clinically approved CFTR potentiator. Three‐dimensional structural modeling predicted that all five ABCB4 variants would disrupt critical interactions in the binding of ATP and thereby impair ATP‐induced nucleotide‐binding domain dimerization and ABCB4 function. This prediction was confirmed by expression in cell models, which showed that the ABCB4 mutants were normally processed and targeted to the plasma membrane, whereas their PC secretion activity was dramatically decreased. As also hypothesized on the basis of molecular modeling, PC secretion activity of the mutants was rescued by the CFTR potentiator, ivacaftor (VX‐770). Conclusion: Disease‐causing variations in the ATP‐binding sites of ABCB4 cause defects in PC secretion, which can be rescued by ivacaftor. These results provide the first experimental evidence that ivacaftor is a potential therapy for selected patients who harbor mutations in the ATP‐binding sites of ABCB4. (Hepatology 2017;65:560‐570)
Epigenetic landscape of amphetamine and methamphetamine addiction in rodents

Amphetamine and methamphetamine addiction is described by specific behavioral alterations, suggesting long-lasting changes in gene and protein expression within specific brain subregions involved in the reward circuitry. Given the persistence of the addiction phenotype at both behavioral and transcriptional levels, several studies have been conducted to elucidate the epigenetic landscape associated with persistent effects of drug use on the mammalian brain. This review discusses recent advances in our comprehension of epigenetic mechanisms underlying amphetamine- or methamphetamine-induced behavioral, transcriptional, and synaptic plasticity. Accumulating evidence demonstrated that drug exposure induces major epigenetic modifications—histone acetylation and methylation, DNA methylation—in a very complex manner. In rare instances, however, the regulation of a specific target gene can be correlated to both epigenetic alterations and behavioral abnormalities. Work is now needed to clarify and validate an epigenetic model of addiction to amphetamines. Investigations that include genome-wide approaches will accelerate the speed of discovery in the field of addiction.
Exploring the associations between microRNA expression profiles and environmental pollutants in human placenta from the National Children's Study (NCS)

The placenta is the principal regulator of the in utero environment, and disruptions to this environment can result in adverse offspring health outcomes. To better characterize the impact of in utero perturbations, we assessed the influence of known environmental pollutants on the expression of microRNA (miRNA) in placental samples collected from the National Children's Study (NCS) Vanguard birth cohort. This study analyzed the expression of 654 miRNAs in 110 term placentas. Environmental pollutants measured in these placentas included dichlorodiphenyldichloroethylene (DDE), bisphenol A (BPA), polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCBs), arsenic (As), mercury (Hg), lead (Pb), and cadmium (Cd). A moderated t-test was used to identify a panel of differentially expressed miRNAs, which were further analyzed using generalized linear models. We observed 112 miRNAs consistently expressed in >70% of the samples. Consistent with the literature, miRNAs located within the imprinted placenta-specific C19MC cluster, specifically mir-517a, mir-517c, mir-522, and mir-23a, are among the top expressed miRNA in our study. We observed a positive association between PBDE 209 and miR-188–5p and an inverse association between PBDE 99 and let-7c. Both PCBs and Cd were positively associated with miR-1537 expression level. In addition, multiple let-7 family members were downregulated with increasing levels of Hg and Pb. We did not observe DDE or BPA levels to be associated with placental miRNA expression. This is the first birth cohort study linking environmental pollutants and placental expression of miRNAs. Our results suggest that placental miRNA profiles may signal in utero exposures to environmental chemicals.
Prevention of hepatic fibrosis with liver microsomal triglyceride transfer protein deletion in liver fatty acid binding protein null mice

Blocking hepatic very low‐density lipoprotein secretion through genetic or pharmacologic inhibition of microsomal triglyceride transfer protein (Mttp) causes hepatic steatosis, yet the risks for developing hepatic fibrosis are poorly understood. We report that liver‐specific Mttp knockout mice (Mttp‐LKO) exhibit both steatosis and fibrosis, which is exacerbated by a high‐transfat/fructose diet. When crossed into germline liver fatty acid (FA) binding protein null mice (Mttp‐LKO, i.e., double knockout mice) hepatic steatosis was greatly diminished and fibrosis prevented, on both low‐fat and high‐fat diets. The mechanisms underlying protection include reduced long chain FA uptake, shifts in FA distribution (lipidomic profiling), and metabolic turnover, specifically decreased hepatic 18:2 FA and triglyceride species and a shift in 18:2 FA use for oxidation versus incorporation into newly synthesized triglyceride. Double knockout mice were protected against fasting‐induced hepatic steatosis (a model of enhanced exogenous FA delivery) yet developed steatosis upon induction of hepatic de novo lipogenesis with fructose feeding. Mttp‐LKO mice, on either the liver FA binding protein null or Apobec‐1 null background (i.e., apolipoprotein B100 only) exhibited only subtle increases in endoplasmic reticulum stress, suggesting that an altered unfolded protein response is unlikely to account for the attenuated phenotype in double knockout mice. Acute, antisense‐mediated liver FA binding protein knockdown in Mttp‐LKO mice also reduced FA uptake, increased oxidation versus incorporation of 18:2 species with complete reversal of hepatic steatosis, increased hepatic injury, and worsened fibrosis. Conclusion: Perturbing exogenous hepatic FA use modulates both hepatic steatosis and fibrosis in the setting of hepatic Mttp deletion, adding new insight into the pathophysiological mechanisms and consequences of defective very low‐density lipoprotein secretion. (Hepatology 2017;65:836‐852).
Effect of high fat diet on paternal sperm histone distribution and male offspring liver gene expression

Several studies have described phenotypic changes in the offspring of mice exposed to a variety of environmental factors, including diet, toxins, and stress; however, the molecular pathways involved in these changes remain unclear. Using a high fat diet (HFD)-induced obesity mouse model, we examined liver gene expression in male offspring and analyzed chromatin of paternal spermatozoa. We found that the hepatic mRNA level of 7 genes (out of 20 evaluated) was significantly altered in HFD male offspring compared to control mice, suggesting that phenotypic changes in the offspring depend on parental diet. We examined 7 imprinted loci in spermatozoa DNA from HFD-treated and control fathers by bisulfite sequencing, but did not detect changes in DNA methylation associated with HFD. Using chromatin immunoprecipitation followed by high-throughput sequencing, we found differential histone H3-occupancy at genes involved in the regulation of embryogenesis and differential H3K4me1-enrichment at transcription regulatory genes in HFD fathers vs. control mice. These results suggest that dietary exposure can modulate histone composition at regulatory genes implicated in developmental processes.
A new class of hepatitis B and D virus entry inhibitors, proanthocyanidin and its analogs, that directly act on the viral large surface proteins

Introduction of direct‐acting antivirals against hepatitis C virus (HCV) has provided a revolutionary improvement in the treatment outcome. In contrast to HCV, however, the strategy for developing new antiviral agents against hepatitis B virus (HBV), especially viral‐targeting compounds, is limited because HBV requires only four viral genes for its efficient replication/infection. Here, we identify an oligomeric flavonoid, proanthocyanidin (PAC) and its analogs, which inhibit HBV entry into host cells by targeting the HBV large surface protein (LHBs). Through cell‐based chemical screening, PAC was identified to inhibit HBV infection with little cytotoxic effect. PAC prevented the attachment of the preS1 region in the LHBs to its cellular receptor, sodium taurocholate cotransporting polypeptide (NTCP). PAC was shown to target HBV particles and impair their infectivity, whereas it did not affect the NTCP‐mediated bile acid transport activity. Chemical biological techniques demonstrated that PAC directly interacted with the region essential for receptor binding in the preS1 region in the LHBs protein. Importantly, PAC had a pan‐genotypic anti‐HBV activity and was also effective against a clinically relevant nucleoside analog‐resistant HBV isolate. We further showed that PAC augmented the ability of a nucleoside analog, tenofovir, to interrupt HBV spread over time in primary human hepatocytes by cotreatment. Moreover, derivative analysis could identify small molecules that demonstrated more‐potent anti‐HBV activity over PAC. Conclusion: PAC and its analogs represent a new class of anti‐HBV agents that directly target the preS1 region of the HBV large surface protein. These agents could contribute to the development of a potent, well‐tolerated, and broadly active inhibitor of HBV infection. (Hepatology 2017;65:1104‐1116).
Hepatocyte autotaxin expression promotes liver fibrosis and cancer

Autotaxin (ATX) is a secreted lysophospholipase D that catalyzes the production of lysophosphatidic acid (LPA), a pleiotropic growth‐factor–like lysophospholipid. Increased ATX expression has been detected in various chronic inflammatory disorders and different types of cancer; however, little is known about its role and mode of action in liver fibrosis and cancer. Here, increased ATX expression was detected in chronic liver disease (CLD) patients of different etiologies, associated with shorter overall survival. In mice, different hepatotoxic stimuli linked with the development of different forms of CLDs were shown to stimulate hepatocyte ATX expression, leading to increased LPA levels, activation of hepatic stellate cells (HSCs), and amplification of profibrotic signals. Hepatocyte‐specific, conditional genetic deletion and/or transgenic overexpression of ATX established a liver profibrotic role for ATX/LPA, whereas pharmacological ATX inhibition studies suggested ATX as a possible therapeutic target in CLDs. In addition, hepatocyte ATX ablation and the consequent deregulation of lipid homeostasis was also shown to attenuate hepatocellular carcinoma (HCC) development, thus implicating ATX/LPA in the causative link of cirrhosis and HCC. Conclusion: ATX is a novel player in the pathogenesis of liver fibrosis and cancer and a promising therapeutic target. (Hepatology 2017;65:1369‐1383).
Metabolic and histological implications of intrahepatic triglyceride content in nonalcoholic fatty liver disease

The cut‐off point of intrahepatic triglyceride (IHTG) content to define nonalcoholic fatty liver disease (NAFLD) by proton magnetic resonance spectroscopy (1H‐MRS) was established based on the 95th percentile in a group of healthy individuals (i.e., ≥5.56%). Whether this threshold correlates with metabolic and histological changes and whether a further accumulation of IHTG is associated with worsening of these parameters has not been properly assessed in a large cohort of patients. In this cross‐sectional study, 352 subjects were carefully characterized with the following studies: liver 1H‐MRS; euglycemic insulin clamp with measurement of glucose turnover; oral glucose tolerance test; and a liver biopsy. Hepatic insulin sensitivity (suppression of endogenous glucose production by insulin) was affected early on after IHTG content was ∼1.5% and remained uniformly impaired (∼40%‐45%), regardless of further IHTG accumulation. Skeletal muscle insulin sensitivity showed a gradual impairment at low degrees of IHTG accumulation, but remained unchanged after IHTG content reached the ∼6 ± 2% threshold. A similar pattern was observed for metabolic changes typically associated with NAFLD, such as hypertriglyceridemia and low high‐density lipoprotein cholesterol (HDL‐C). In contrast, adipose tissue insulin sensitivity (suppression of free fatty acids by insulin) showed a continuous worsening across the spectrum of IHTG accumulation in NAFLD (r = –0.38; P < 0.001). Histological severity of liver disease (inflammation, ballooning, and fibrosis) was not associated with the amount of IHTG content. Conclusion: IHTG accumulation is strongly associated with adipose tissue insulin resistance (IR), supporting the current theory of lipotoxicity as a driver of IHTG accumulation. Once IHTG accumulation reaches ∼6 ± 2%, skeletal muscle IR, hypertriglyceridemia, and low HDL‐C become fully established. Histological activity appears to have an early threshold and is not significantly influenced by increasing amounts of IHTG accumulation. (Hepatology 2017;65:1132‐1144).
Prevalence of Chlamydia trachomatis and Neisseria gonorrhoeae and Repeat Infection Among Pregnant Urban Adolescents

Background: Negative maternal and fetal consequences associated with Chlamydia trachomatis and Neisseria gonorrhoeae during pregnancy make diagnosis essential. The Centers for Disease Control and Prevention recommend routine screening for sexually transmitted infections at the first prenatal visit, and third trimester repeat screening, specifically for C. trachomatis, is recommended for women under age 25 or at increased infection risk. The effect of repeat screening on diagnosis during pregnancy is not well documented among adolescents. Methods: A prospective cohort of 125 pregnant adolescents with at least one prenatal screening for C. trachomatis and N. gonorrhoeae was analyzed. All participants received prenatal care and delivered at one urban teaching hospital in Washington, DC. Screening results were documented for both sexually transmitted infections. Descriptive and univariate analyses were performed to describe disease prevalence. Results: Of pregnant adolescents, 31% were diagnosed with either C. trachomatis or N. gonorrhoeae infection during pregnancy. Of the 75% (95/125) of patients who had more than one screening test, 11% (10/95) had a reinfection, and 7% (7/95) had a new infection on repeat testing. Nine percent (9/95) had recurrent C. trachomatis, whereas 4% (4/95) had a new diagnosis. Three percent (3/95) had recurrent N. gonorrhoeae, whereas 4% (4/95) had a new diagnosis. Some experienced coinfection at either initial or repeat testing. Conclusions: Screening for C. trachomatis and N. gonorrhoeae is recommended during pregnancy. In this sample of pregnant adolescents, the overall high incidence and recurrence of C. trachomatis and N. gonorrhoeae support Centers for Disease Control and Prevention screening and rescreening recommendations, regardless of initial test results.
Fecal microbiota transplantation induces hepatitis B virus e‐antigen (HBeAg) clearance in patients with positive HBeAg after long‐term antiviral therapy

For hepatitis B virus (HBV) e-antigen (HBeAg)-positive chronic hepatitis B (CHB) patients, HBeAg seroconversion is a prerequisite for a definite course of antiviral treatment. Unfortunately, for both entecavir (ETV) and tenofovir disoproxil fumarate (TDF), HBeAg clearance or seroconversion only occurs in a minority of patients even after multiple years of antiviral therapy. The gut microbiota appears to play a critical role in age-related immune clearance of HBV. Several studies have indicated that CHB patients with liver cirrhosis have different microbiota compared to healthy people. The “leakage hypothesis” has linked gut microbiota to the onset and progression of liver diseases. Thus, we reported on a case-controlled, open-label pilot trial of fecal microbiota transplantation (FMT) for CHB patients. Methods and Results
Motivations and future aspirations of dental interns: A cross-sectional study

Background: Career choice is one of the most important and critical decisions in a student's life. Educators and admission committees are also interested in researching the factors that affect a student's decision to opt for dentistry. Objectives: To identify dental interns' motivation for studying dentistry and to study their future aspirations after graduation. Materials and Methods: This was a cross-sectional, descriptive survey. A detailed, anonymous, structured questionnaire to assess motivating factors for joining dentistry as a profession was administered to the study group of 78 dental undergraduate students undergoing internship (interns). The questionnaire consisted of sections on demographic details, motivational factors, and career choice items. Data was analyzed using counts and percentages and ranking of motivating factors was based on calculation of mean and standard deviation. Results: The response rate was 94%. Majority of the respondents were females (80%). The most popular reasons for choosing dentistry as a career were family advice, prestige and social status, interest in medical sciences and altruistic motives. The majority of the students planned to do postgraduation (35.1%) or practice dentistry (18.9%) after graduation. The dental students had a positive attitude towards the dental profession. Conclusion: The motives for joining dentistry were primarily related to personal factors. The students took responsibility for their career choice and parents' approval played a major role. Majority of the students planned to pursue a postgraduation degree after completing graduation and few were inclined to be employed in public or private sector.
TET1 deficiency attenuates the DNA damage response and promotes resistance to DNA damaging agents

ABSTRACT Recent studies have shown that loss of TET1 may play a significant role in the formation of tumors. Because genomic instability is a hallmark of cancer, we examined the potential involvement of 10-11 translocation 1 (TET1) in the DNA damage response (DDR). Here we demonstrate that, in response to clinically relevant doses of ionizing radiation (IR), human glial cells made TET1-deficient with lentiviral vectors displayed greater numbers of colony forming units and lower levels of apoptotic markers compared with glial cells transduced with control vectors; yet, they harbored greater DNA strand breaks. The G2/M check point and expression of cyclin B1 were greatly diminished in TET1-deficient cells, and TET1-deficient cells displayed lower levels of γH2A. x following exposure to IR. Levels of DNA-PKcs, which are DNA-PK complex members, were lower in TET1-deficient cells compared with control cell lines. However, levels of ATM were similar in both cell lines. Cyclin B1, DNA-PKcs, and γH2A. x levels were each rescued by reintroduction of the TET1 catalytic domain. Finally, cytosine methylation within intron 1 of PRKDC, the gene encoding DNA-PKcs, was significantly higher upon depletion of TET1. Taken together, this study illustrates the involvement of TET1 in the different arms of the DDR and suggests its loss results in the continued survival of cells with genomic instability.
Dynamic epimarks in sex-related genes predict gonad phenotype in the European sea bass, a fish with mixed genetic and environmental sex determination

ABSTRACT The integration of genomic and environmental influences into methylation patterns to bring about a phenotype is of central interest in developmental epigenetics, but many details are still unclear. The sex ratios of the species used here, the European sea bass, are determined by genetic and temperature influences. We created four families from parents known to produce offspring with different sex ratios, exposed larvae to masculinizing temperatures and examined, in juvenile gonads, the DNA methylation of seven genes related to sexual development by a targeted sequencing approach. The genes most affected by both genetics and environment were cyp19a1a and dmrt1, with contrasting sex-specific methylation and temperature responses. The relationship between cyp19a1a methylation and expression is relevant to the epigenetic regulation of vertebrate sex, and we report the evidence of such relationship only below a methylation threshold, ~ 80%, and that it was sex-specific: negatively correlated in females but positively correlated in males. From parents to offspring, the methylation in gonads was midway between oocytes and sperm, with bias towards oocytes for amh-r2, er-β2, fsh-r and cyp19a1a. In contrast, dmrt1 levels resembled those of sperm. The methylation of individual CpGs from foxl2, er-β2 and nr3c1 were conserved from parents to offspring, whereas those of cyp19a1a, dmrt1 and amh-r2 were affected by temperature. Utilizing a machine-learning procedure based on the methylation levels of a selected set of CpGs, we present the first, to our knowledge, system based on epigenetic marks capable of predicting sex in an animal with ~ 90% accuracy and discuss possible applications.
Augmenter of liver regeneration: A fundamental life protein

Augmenter of liver regeneration (ALR, essential for respiration and vegetative growth-1 [Erv1], growth factor Erv1-like, hepatopoietin) was first recognized in regenerating rat livers, thereby destining the protein for inclusion in an everexpanding constellation of hepatic growth factors. However, the later identification of ALR as a protein with significant homology to yeast Erv1 hinted at a more elemental function. Subsequent studies revealed short (15 kDa) and long (22 kDa) forms of this ancient protein, with profound effects on fundamental processes such as energy transduction, cell survival and regeneration, metabolic homeostasis, iron metabolism, and stem cell maintenance.