Miracle-dz/UniFAR-FTUs huggingface dataset:
CXCR6 Inhibits Hepatocarcinogenesis by Promoting Natural Killer T- and CD4+ T-Cell-Dependent Control of Senescence.

BACKGROUND & AIMS Inflammation in the liver provokes fibrosis, but inflammation is also important for tumor surveillance. Inhibitors of chemokine pathways, such as CXCL16 and CXCR6 regulation of lymphocyte trafficking, are being tested as antifibrotic agents, but their effects on the development of hepatocellular carcinoma (HCC) are unclear. We assessed the roles of CXCR6-dependent immune mechanisms in hepatocarcinogenesis. METHODS C57BL/6J wild-type (WT) mice and CXCR6-deficient mice (Cxcr6eGfp/eGfp) were given injections of diethylnitrosamine (DEN) to induce liver cancer and α-galactosylceramide to activate natural killer T (NKT) cells. We also performed studies in mice with conditional, hepatocyte-specific deletion of NEMO, which develop inflammation-associated liver tumors (NemoLPC-KO and NemoLPC-KOCxcr6eGfp/eGfp mice). We collected liver tissues from patients with cirrhosis (n = 43), HCC (n = 35), and neither of these diseases (control individuals, n = 25). Human and mouse liver tissues were analyzed by histology, immunohistochemistry, flow cytometry, RNA expression arrays (from sorted hepatic lymphocytes), and matrix-assisted laser desorption/ionization imaging. Bone marrow was transferred from Cxcr6eGfp/eGfp or WT mice to irradiated C57BL/6J mice, and spleen and liver cells were analyzed by flow cytometry. CD4+ T cells or NKT cells were isolated from the spleen and liver of CD45.1+ WT mice and transferred into CXCR6-deficient mice after DEN injection. RESULTS After DEN injection, CXCR6-deficient mice had a significantly higher tumor burden than WT mice and increased tumor progression, characterized by reduced intrahepatic numbers of invariant NKT and CD4+ T cells that express tumor necrosis factor and interferon gamma. Livers of NemoLPC-KOCxcr6eGfp/eGfp mice had significantly more senescent hepatocytes than livers of NemoLPC-KO mice. In studies of bone-marrow chimeras, adoptive cell transfer experiments, and analyses of NemoLPC-KO mice, we found that NKT and CD4 T cells promote the removal of senescent hepatocytes to prevent hepatocarcinogenesis, and that this process required CXCR6. Injection of WT with α-galactosylceramide increased removal of senescent hepatocytes by NKT cells. We observed peritumoral accumulation of CXCR6-associated lymphocytes in human HCC, which appeared reduced compared with cirrhosis tissues. CONCLUSIONS In studies of mice with liver tumors, we found that CXCR6 mediated NKT-cell and CD4+ T-cell removal of senescent hepatocytes. Antifibrotic strategies to reduce CXCR6 activity in liver, or to reduce inflammation or modulate the immune response, should be tested for their effects on hepatocarcinogenesis.
Associations between pre-sleep arousal and insomnia symptoms in early adulthood: a twin and sibling study.

STUDY OBJECTIVES This study examines the associations between overall pre-sleep arousal, its cognitive and somatic subscales and insomnia symptoms. Furthermore, the relative contribution of genetic and environmental influences on overall pre-sleep arousal, cognitive pre-sleep arousal, somatic pre-sleep arousal, and insomnia symptoms and the association between these variables is estimated. METHODS The cross-sectional data came from G1219 (wave 5), a twin/sibling study which comprised 862 individuals (aged 22-32 years, 34% males). Pre-sleep arousal was measured using the pre-sleep arousal scale and insomnia symptoms using the insomnia symptoms questionnaire. RESULTS Both cognitive and somatic pre-sleep arousal were significant, independent factors associated with insomnia symptoms. Overall and somatic pre-sleep arousal showed a significant, substantial genetic influence (47% and 49% respectively) and non-shared environmental influence. For cognitive pre-sleep arousal and insomnia symptoms, non-shared environment appeared to be most important (74% and 61% respectively), and familiality was indicated. A strong, significant association of the genetic influences on overall pre-sleep arousal and insomnia symptoms was found (genetic correlation = .88). Strong, significant genetic correlations were found between cognitive pre-sleep arousal, somatic pre-sleep arousal and insomnia symptoms (genetic correlations .93 to 1). Non-shared environmental influences between these three variables were moderately, significantly correlated (non-shared environmental correlation .22 to .41). CONCLUSION The large overlap of genetic influences between pre-sleep arousal and insomnia symptoms provides novel insight into the associations between these variables. The results indicate that those with cognitive and/or somatic pre-sleep arousal may also have a genetic vulnerability to insomnia symptoms.
Fruit and vegetable consumption, cigarette smoke, and leukocyte mitochondrial DNA copy number.

Background Mitochondrial dysfunction is an important component of the aging process and has been implicated in the development of many human diseases. Mitochondrial DNA copy number (mtDNAcn), an indirect biomarker of mitochondrial function, is sensitive to oxidative damage. Few population-based studies have investigated the impact of fruit and vegetable consumption and cigarette smoke (2 major sources of exogenous antioxidants and oxidants) on leukocyte mtDNAcn. Objectives We investigated the association between fruit and vegetable consumption, cigarette smoke, and leukocyte mtDNAcn based on data from the Nurses' Health Study (NHS). Methods Data from 2769 disease-free women in the NHS were used to examine the cross-sectional associations between dietary sources of antioxidants, cigarette smoke, and leukocyte mtDNAcn. In vitro cell-based experiments were conducted to support the findings from the population-based study. Results In the multivariable-adjusted model, both whole-fruit consumption and intake of flavanones (a group of antioxidants abundant in fruit) were positively associated with leukocyte mtDNAcn (P-trend = 0.005 and 0.02, respectively), whereas pack-years of smoking and smoking duration were inversely associated with leukocyte mtDNAcn (P-trend = 0.01 and 0.007, respectively). These findings are supported by in vitro cell-based experiments showing that the administration of naringin, a major flavanone in fruit, led to a substantial increase in mtDNAcn in human leukocytes, whereas exposure to nicotine-derived nitrosamine ketone, a key carcinogenic ingredient of cigarette smoke, resulted in a significant decrease in mtDNAcn of cells (all P < 0.05). Further in vitro studies showed that alterations in leukocyte mtDNAcn were functionally linked to the modulation of mitochondrial biogenesis and function. Conclusions Fruit consumption and intake of dietary flavanones were associated with increased leukocyte mtDNAcn, whereas cigarette smoking was associated with decreased leukocyte mtDNAcn, which is a promising biomarker for oxidative stress-related health outcomes.
Successes, failures, and future prospects of prodrugs and their clinical impact

ABSTRACT Introduction: Ample efforts have been carried out to improve the efficacy of a variety of drugs. The prodrugs approach was found to be a safe haven for providing medications with improved pharmacokinetic and pharmacodynamic properties. Areas covered: Herein, several selected successful prodrugs are reported and categorized. These include prodrugs for the treatment of the cardiovascular system, the central nervous system, the gastrointestinal tract, ophthalmology, the immune system, and oncology. In addition, some successful antiviral, antibacterial, antifungal, antiprotozoal, and several other miscellaneous prodrugs are documented. Further, a number of failed prodrugs are reported followed by those potentially promising prodrugs of the future. Expert opinion: The molecular revolution and accumulation of knowledge on the chemistry of enzymes and transporters has opened the door widely to novel successful prodrugs. For example, newer platelet aggregation inhibitors could signal the end of the warfarin era with their demanding treatment follow-up. The discovery of prodrugs can significantly improve the quality of patient care. Future attention should be focused towards directed enzyme prodrug therapy (DEPT). This strategy employs the design of artificial enzymes to activate prodrugs at specific sites. Agents designed for use in DEPT medicine can be directed at antibodies, genes, viruses, and clostridia.
Are Subchondral Intraosseous Injections Effective and Safe for the Treatment of Knee Osteoarthritis? A Systematic Review

Abstract Knee osteoarthritis (OA) is a highly prevalent disease and treatment options for early stages of OA are needed. Intraosseous injections of bone substitute and biologic materials have been proposed to expand the therapeutic arsenal by potentially halting OA progression and delaying the need for knee arthroplasty in patients with early/moderate-stage disease. Therefore, the goal of this study was assessed the efficacy and safety of subchondral intraosseous injection for the treatment of knee OA. A systematic review was performed on PubMed-Medline, and the Cochrane Database of systematic reviews. English and Spanish retrospective and prospective studies assessing the results of subchondral intraosseous injection of bone substitute materials and/or biologicals in human patients with knee OA, with a minimum of 6 months of follow-up were collected. A total of 1,081 potential articles were identified through our search. Six studies were included with a total of 163 patients. The mean follow-up was 18 months (range: 6–24 months). Patient reported outcomes measures (PROMs), complications, and conversion to total knee arthroplasty (TKA) were collected. All six studies showed PROMs improvement relative to baseline. Overall, the five studies reporting visual-analog scale (VAS) pain outcomes improved from a baseline mean score of 6.68 to 2.74. Also, knee injury and osteoarthritis score (KOOS), Tegner-Lysholm, and/or international knee documentation committee (IKDC) scores rose compared with baseline scores in all studies. Overall, 2.5% (4/163) of patients had a complication attributed to study-related treatment. Most patients (81%, 86/106) remained TKA-free at a 1-year follow-up. Subchondral intraosseous injections of bone substitute materials and platelet-rich plasma (PRP) suggest (1) improved PROMs of pain and functional status, (2) low complication rate, and (3) relatively low rates of conversion to TKA. However, the current studies investigating these treatments exhibited high degree of heterogeneity in both measurement of outcomes and delivery of treatment, with a high risk of bias. This procedure should not be utilized in advanced knee OA. In light of the limitations of the current literature, advising in favor or against this therapy for early to moderate knee OA is challenging.
Temporal Change of Extracellular Matrix during Vein Arterialization Remodeling in Rats

The global expression profile of the arterialized rat jugular vein was established to identify candidate genes and cellular pathways underlying the remodeling process. The arterialized jugular vein was analyzed on days 3 and 28 post-surgery and compared with the normal jugular vein and carotid artery. A gene array platform detected 9846 genes in all samples. A heatmap analysis uncovered patterns of gene expression showing that the arterialized vein underwent a partial transition from vein to artery from day 3 to 28 post-surgery. The same pattern was verified for 1845 key differentially expressed genes by performing a pairwise comparison of the jugular vein with the other groups. Interestingly, hierarchical clustering of 60 genes with altered expression on day 3 and day 28 displayed an expression pattern similar to that of the carotid artery. Enrichment analysis results and the network relationship among genes modulated during vein arterialization showed that collagen might play a role in the early remodeling process. Indeed, the total collagen content was increased, with the augmented expression of collagen I, collagen IV, and collagen V in arterialized veins. Additionally, there was an increase in the expression of versican and Thy-1 and a decrease in the expression of biglycan and β1-integrin. Overall, we provide evidence that vein arterialization remodeling is accompanied by consistent patterns of gene expression and that collagen may be an essential element underlying extracellular matrix changes that support the increased vascular wall stress of the new hemodynamic environment.
Transplantation of Human Fetal-Derived Neural Stem Cells Improves Cognitive Function following Cranial Irradiation

Treatment of central nervous system (CNS) malignancies typically involves radiotherapy to forestall tumor growth and recurrence following surgical resection. Despite the many benefits of cranial radiotherapy, survivors often suffer from a wide range of debilitating and progressive cognitive deficits. Thus, while patients afflicted with primary and secondary malignancies of the CNS now experience longer local regional control and progression-free survival, there remains no clinical recourse for the unintended neurocognitive sequelae associated with their cancer treatments. Multiple mechanisms contribute to disrupted cognition following irradiation, including the depletion of radiosensitive populations of stem and progenitor cells in the hippocampus. We have explored the potential of using intrahippocampal transplantation of human stem cells to ameliorate radiation-induced cognitive dysfunction. Past studies demonstrated the capability of cranially transplanted human embryonic (hESCs) and neural (hNSCs) stem cells to functionally restore cognition in rats 1 and 4 months after cranial irradiation. The present study employed an FDA-approved fetal-derived hNSC line capable of large scale-up under good manufacturing practice (GMP). Animals receiving cranial transplantation of these cells 1 month following irradiation showed improved hippocampal spatial memory and contextual fear conditioning performance compared to irradiated, sham surgery controls. Significant newly born (doublecortin positive) neurons and a smaller fraction of glial subtypes were observed within and nearby the transplantation core. Engrafted cells migrated and differentiated into neuronal and glial subtypes throughout the CA1 and CA3 subfields of the host hippocampus. These studies expand our prior findings to demonstrate that transplantation of fetal-derived hNSCs improves cognitive deficits in irradiated animals, as assessed by two separate cognitive tasks.
Epidemiology of chikungunya based on laboratory surveillance data—India, 2016–2018

BACKGROUND We analysed the laboratory surveillance data generated by the network of virology laboratories from January 2016 to July 2018 to describe the epidemiology of chikungunya in India. METHODS Suspected patients reporting to virology laboratories are investigated for the presence of immunoglobulin M (IgM) antibodies against chikungunya virus (CHIKV) as evidence of recent infection. We analysed the data to describe the distribution of seropositive individuals by time, place and demographic characteristics. RESULTS Of the 49 380 sera tested from suspected patients, 20.5% were seropositive. CHIKV IgM positivity was seen throughout the year, with a peak between September and December. The laboratories diagnosed 28 outbreaks of chikungunya during the study period. CONCLUSIONS Laboratory surveillance data indicate continued transmission of CHIKV in many regions of India.
Immunoglobulin M Is Required for Protection Against Atherosclerosis in Low-Density Lipoprotein Receptor–Deficient Mice

Background— Immunoglobulin M (IgM) natural antibodies bind oxidatively-modified low-density lipoprotein (LDL) and apoptotic cells and have been implicated as being important for protection against atherosclerosis. We have directly investigated the requirement for IgM by studying the effects of IgM deficiency in LDL receptor–deficient (Ldlr−/−) mice. Methods and Results— Mice deficient in serum IgM (sIgM) or complement C1q were crossed with Ldlr−/− mice and studied on both low-fat and high-fat semisynthetic diets. On both diets, en face and aortic root atherosclerotic lesions in sIgM.Ldlr−/− mice were substantially larger and more complex, with accelerated cholesterol crystal formation and increased smooth muscle cell content in aortic root lesions. Combined C1q and IgM deficiency had the same effect as IgM deficiency alone. Increased apoptosis was observed in aortic root lesions of both sIgM.Ldlr−/− and C1qa.Ldlr−/− mice. Because lesions were significantly larger in IgM-deficient mice than in the absence of C1q, IgM protective mechanisms appear to be partially independent of classical pathway activation and apoptotic cell clearance. Levels of IgG antibodies against copper-oxidized LDL were lower in sIgM.Ldlr−/− mice fed a high-fat diet, suggesting compensatory consumption of IgG in the absence of IgM. Conclusions— This study provides direct evidence that IgM antibodies play a central role in protection against atherosclerosis. The mechanism appears to be at least partly independent of classical pathway complement activation by C1q.
Nutrition-Related Practices of Family Child Care Providers and Differences by Ethnicity.

BACKGROUND Child care settings play an important role in shaping children's eating behaviors; yet few studies have included family child care homes (FCCHs). We examined provider-reported nutrition-related practices in FCCHs and observed adherence to nutrition guidelines from the Nutrition and Physical Activity Self-Assessment for Child Care (NAP SACC), exploring differences by provider ethnicity. METHODS We assessed baseline data from a cluster-randomized trial, including surveys with FCCH providers and observational data collected at the FCCH. We examined provider-reported nutrition-related practices and if providers met NAP SACC guidelines using observational data. Differences by ethnicity were assessed using chi-square and multivariate log-linear analysis adjusting for education. RESULTS Providers completed a telephone survey (n = 166, 100% female and 72% Hispanic) and participated in 2 full-day observations (n = 119). Many providers reported engaging in positive nutrition-related practices. Significant differences by ethnicity included the following: Hispanic providers less likely to report feeding practices that were responsive to children's self-regulation, but also less likely to report eating and drinking unhealthy foods/beverages in front of children and having screens on during meals and more likely to report seeking nutrition trainings. Using observational data, only 10 of 26 NAP SACC practices were met by >60% of providers. Few ethnic differences in meeting guidelines were found (7 of 26 practices). CONCLUSIONS While providers engage in some positive nutrition practices, improvement is needed to ensure that all providers actually meet evidence-based guidelines. Ethnic differences in certain practices underscore the need for culturally relevant trainings. TRIAL REGISTRATION NUMBER NCT02452645.
Previous diet affects the amount but not the type of bait consumed by an invasive ant.

BACKGROUND Recent research on multiple invasive ant species has revealed the importance of carbohydrates for achieving high activity levels and outcompeting native ants. However, comparatively little is known about the role of diet and macronutrient preferences for uptake of insecticidal baits used to control invasive ants. We tested whether diet affected yellow crazy ant (Anoplolepis gracilipes Fr Smith) survival and behavior, and whether bait preference would be complementary to past diet. RESULTS We found that colonies fed only crickets for 28 days had fewer live workers and queens, and less brood per live queen than colonies fed crickets + honeydew but did not differ significantly from colonies fed only honeydew. Colonies that had been fed only crickets were more active (as assessed by interaction with a novel object), retrieved 16-17 times more bait per worker overall, and consumed more of the six bait types than cricket + honeydew and honeydew-only fed colonies. However, prior diet did not affect bait choice. The two highest sugar bait formulations combined accounted for most of the bait consumed across all treatments (cricket-only 74.8% ± 28.1; cricket + honeydew 69.2% ± 12.4; honeydew-only 62.5% ± 30.4). CONCLUSION Yellow crazy ant colonies fare better without protein than without carbohydrates. Yellow crazy ants ate the most bait when fed only crickets but did not choose baits complementary to their previous diet. Baits in a sugar-rich carrier may be most effective for the control of yellow crazy ants, regardless of the relative availability of macronutrients. © 2019 Society of Chemical Industry.
A Vitellogenin Antibody in Honey Bees (Apis mellifera): Characterization and Application as Potential Biomarker for Insecticide Exposure

The insect yolk precursor vitellogenin is a lipoglycoprotein synthesized and stored in the fat body and secreted into the hemolymph. In honey bees, vitellogenin displays crucial functions in hormone signaling, behavioral transition of nurse bees to foragers, stress resistance, and longevity in workers. Plant protection products such as neonicotinoids, pyrethroids, and organophosphates alter the transcriptional expression of vitellogenin. To assess plant protection product‐induced alterations on the protein level, we developed a rabbit polyclonal vitellogenin antibody. After characterization, we assessed its specificity and vitellogenin levels in different tissues of worker bees. The vitellogenin antibody recognized full‐length 180‐kDa vitellogenin and the lighter fragment of 150 kDa in fat body, hemolymph, and brain. In hemolymph, a band of approximately 75 kDa was detected. Subsequent mass spectrometric analysis (liquid chromatography–mass spectrometry) confirmed the 180‐ and 150‐kDa bands as vitellogenin. Subsequently, we evaluated vitellogenin expression in brain, fat body, and hemolymph on 24‐h exposure of bees to 3 ng/bee to the neonicotinoid clothianidin. Full‐length vitellogenin was upregulated 3‐fold in the fat body, and the 150‐kDa fragment was upregulated in the brain of exposed honey bees, whereas no alteration occurred in the hemolymph. Upregulation of the vitellogenin protein by the neonicotinoid clothianidin is in line with the previously shown induction of its transcript. We conclude that vitellogenin might serve as a potential biomarker for neonicotinoid and other pesticide exposure in bees. Environ Toxicol Chem 2019;00:1–10. © 2019 SETAC