Miracle-dz/UniFAR-FTUs huggingface dataset:
Liver Cells

We have explored the mechanism(s) related to FIAU-induced liver toxicity, particularly focusing on its effect on mitochondrial function in a human hepatoma cell lineHepG2. The potential role of FMAU and FAU, metabolites detected in FIAU-treated patients were also ascertained. FIAU and FMAU inhibited cell growth and were effectively phosphorylated. A substantial increase in lactic acid production in medium of cells incubated with 1-10 ,uM FIAU or FMAU was consistent with mitochondrial dysfunction. Slot blot analysis demonstrated that a two week exposure to 10 ,uM FIAU or FMAU was not associated with a decrease in total mitochondrial (mt) DNA content. However, FIAU and FMAU were incorporated into nuclear and mtDNA and relative values suggest that both compounds incorporate at a much higher rate into mtDNA. Electron micrographs of cells incubated with 10 ,IM FIAU or FMAU revealed the presence of enlarged mitochondria with higher cristae density and lipid vesicles. In conclusion, these data suggest that despite the lack of inhibition of mtDNA content, incorporation of FIAU and FMAU into mtDNA of HepG2 cells leads to marked mitochondrial dysfunction as evidenced by disturbance in cellular energy metabolism and detection of Address correspondence to Dr. Jean-Pierre Sommadossi, University of Alabama at Birmingham, University Station, Box 600, 1670 University Blvd., VH 113, Birmingham, AL 35294-0019. Phone: 205-934-8226; FAX: 205-975-4871. Receivedfor publication 25 May 1994 and in revisedform 18 August 1994. 1. Abbreviations used in this paper: 3TC, (-)-2'-3'-dideoxy-3'-thiacytidine; AZT, 3 '-azido-3 '-deoxythymidine; ddC,2 ',3 '-dideoxycytidine; ddl,2',3'-dideoxyinosine; dThd, thymidine; FAU, 1-(2-deoxy-2-fluoro1-/3-D-arabinofuranosyl)-uracil; FHMAU, 1-(2-deoxy-2-fluoro-1-f3-Darabinofuranosyl)-5-hydroxythymine; FIAC, 1-(2-deoxy-2-fluoro-1-/3D-arabinofuranosyl)-5-iodocytosine; FIAU, 1-(2-deoxy-2-fluoro-1-f3D-arabinofuranosyl)-5-iodouracil; FIAU-MP, FIAU-5 '-monophosphate; FIAU-DP, FIAU-5 '-diphosphate; FIAU-TP, FIAU-5 '-triphosphate; FMAU, 1-(2-deoxy-2-fluoro-1-/3-D-arabinofuranosyl)-5-thymine; FMAUDP, FMAU-5 '-diphosphate; FMAU-MP, FMAU-5 '-monophosphate; FMAU-TP, FMAU-5'-triphosphate; HBV, hepatitis B virus; LC/MS/ MS, liquid chromatography/mass spectrometry/mass spectrometry; mtDNA, mitochondrial DNA; TMP, thymidine-5 '-monophosphate; TTP, thymidine-5 '-triphosphate. microand macrovesicular steatosis. (J. Clin. Invest. 1995. 95:555-563.)
2GPI) Monoclonal Antibodies with Lupus Anticoagulant-like Activity Enhance the b 2GPI Binding to Phospholipids

b 2-Glycoprotein I ( b 2GPI), a plasma glycoprotein with phospholipid-binding property, is known to be the actual target antigen for autoimmune type anticardiolipin antibodies (aCLs). Certain groups of aCLs (antib 2GPI antibodies) exert lupus anticoagulant (LA) activity and perturb the function of vascular endothelial cells. This investigation aimed at highlighting some insights into the molecular basis by which aCLs exert their biological effects by using antib 2GPI mAbs with well-characterized epitopes from mice and from patients with antiphospholipid syndrome. Antib 2GPI mAbs directed against the third domain (Cof-20 and Cof-22) and fourth domain (Cof-21, EY1C8, and EY2C9) of b 2GPI inhibited the thrombin generation induced by Russell’s viper venom in diluted plasma and that induced by the prothrombinase complex reconstituted with purified clotting factors. This anticoagulant activity was abrogated in the presence of an excess amount of phospholipids, thus resembling the LA activity. In stark contrast, antib 2GPI mAbs directed against the fifth domain and the carboxyterminal region of the fourth domain showed no LA-like activity. These findings suggest that the LA activity of antib 2GPI antibodies depends on their epitope specificity. Experiments carried out to clarify the mechanism of the LA activity showed that antib 2GPI mAbs with LA-like activity, but not those without this effect, enhance the b 2GPI binding to phospholipids. In addition, the F(ab 9 ) 2 fragment, but not the Fab 9 fragment, of the antib 2GPI mAbs was found to enhance the LA activity and the b 2GPI binding to phospholipids, suggesting that antib 2GPI antibodies induce formation of multiple complexes of b 2GPI on the surface of phospholipids because of their bivalent property. This clustering of b 2GPI molecules induced by antib 2GPI antibodies, probably because of their multivalent property and epitope specificity, might hinder the lateral mobility and activation of clotting factors on the surface of phospholipids and thus exert LA activity. Clustering of b 2GPI molecules may also explain the molecular mechanism by which antib 2GPI antibodies alter the function of leukocytes and endothelial cells. The well-documented heterogeneous LA activity of aCLs (antib 2GPI antibodies) may also be explained by their epitope specificity. ( J. Clin. Invest. 1997. 99: 2260–2268.)
Serum levels of IL-6, IL-8 and IL-10 and risks of end-stage kidney disease and mortality

Teresa K. Chen, Michelle M. Estrella, Lawrence J. Appel, Josef Coresh, Shengyuan Luo, Wassim Obeid, Chirag R. Parikh and Morgan E. Grams Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA, Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins Medical Institutions, Baltimore, MD, USA, Kidney Health Research Collaborative and Division of Nephrology, Department of Medicine, University of California, San Francisco, and San Francisco VA Health Care System, San Francisco, CA, USA, Division of General Internal Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA, Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA and Department of Medicine, Rush University Medical Center, Chicago, IL, USA
Physical Activity in Early- and Mid-Adulthood Are Independently Associated With Longitudinal Memory Trajectories in Later Life

Background: Physical activity (PA) in later life may reduce dementia risk, but little is known regarding long-term cognitive effects of PA that occurred earlier in adulthood or mechanisms underlying associations. PA patterns at different ages may independently contribute to dementia risk, which would implicate multiple critical periods for intervention. The current study tested whether retrospective reports of PA in early and mid-adulthood were independently associated with later-life longitudinal memory outcomes and whether associations were mediated by late-life cardiometabolic diseases. Method: Participants comprised 5200 Health and Retirement Study Life History Mail Survey respondents. Latent growth curves estimated independent associations between retrospectively reported PA in early adulthood (age 18–29) and mid-adulthood (age 40–49) and 16-year episodic memory trajectories. Indirect pathways involving the maintenance of PA from earlyto mid-adulthood and the influence of PA on later-life cardiometabolic diseases (hypertension, diabetes, and heart disease) were also estimated. Results: PA in earlyand mid-adulthood independently predicted higher initial memory level and slower memory decline in later life, respectively. Early-adulthood PA was indirectly associated with later-life memory level through higher mid-adulthood PA and lower rates of later-life hypertension, as well as with subsequent memory decline through higher mid-adulthood PA. Conclusions: The current findings highlight the importance of PA throughout adulthood, such that initiating and/or maintaining exercise in earlyor mid-adulthood may be protective for later-life cognitive health, and hypertension appears to represent a key mediator of these effects.
FRACTIONATION OF CHOLESTEROL IN BODY FLUIDS BY MEANS OF SOLVENT EXTRACTION1

In an earlier study (1) it was found that cholesterol absorbed from the intestinal lumen differed from cholesterol secreted into the plasma by the liver in that the former entered and circulated in plasma (for a time at least) enmeshed in a lipid aggregate (i.e., as chylomicra) but the latter entered and circulated in plasma as one of its solutes. It was observed that not only could these two types of cholesterol be separated by physical methods (e.g., by ultracentrifugation) but also that they were handled differently by the body. Thus cholesterol in chylomicron form was deposited in the hepatic reticuloendothelial cell but no such disposition occurred in the case of endogenously produced plasma-soluble cholesterol (2). Indeed, it has been observed by several investigators (3-5) that treatment of sera with various fat solvents such as an alcohol-ether solution or chloroform leads to an extraction of cholesterol, the degree of which is dependent seemingly upon the increment of cholesterol which remains unbound with protein and apparently is carried in the other lipids of serum. Since a chylomicron consists of various lipids and may contain cholesterol with but little protein, it seems reasonable to believe on a priori grounds, that its cholesterol content might be more easily removed by suitable extracting agents than cholesterol already bound to protein. If such were the case, then analysis of appropriate extracts of a given serum might offer a means of estimating the respective -amounts of cholesterol present in. lipoprotein form and that present unbound to protein and ostensibly carried in a lipid aggregate. In the present report, extraction of the intestinal lymph and of the serum of the rat under various conditions has been done. Studies of the rabbit
The moderating role of cortisol reactivity on the link between maltreatment and BMI trajectory across adolescence

Purpose: Child maltreatment increases risk for obesity yet differential effects of maltreatment type remain unclear. Cortisol reactivity may help clarify these effects given links among cortisol reactivity, maltreatment, and obesity. We examined these associations in boys and girls across adolescence. Methods: We collected data from 454 adolescents (212 girls) across four waves (ages 8–13 at Time 1), including 303 maltreated youth. We modeled BMI percentile trajectories arrayed by age separately for boys and girls, and tested whether cortisol reactivity at Time 1 moderated the association between maltreatment type and BMI growth. Results: In girls, cortisol reactivity moderated the association between maltreatment type and quadratic change in BMI. At low levels of cortisol, sexually abused girls had a steeper quadratic increase in BMI compared to comparison (−.65, 95% CI −1.09 to −.22) and physically abused (−. 76, 95% CI −1.29, −.24) girls. At high levels of cortisol, sexually abused girls did not differ from comparison (.15, 95% CI −.40 to .70) or physically abused (.21, 95% CI −.38 to .80) girls in quadratic change in BMI. In boys, cortisol reactivity did not moderate the association between maltreatment type and BMI growth. Corresponding Author: Melissa K. Peckins, Mailing address: 1004 East Hall, 530 Church Street, Ann Arbor, MI 48109-1043, mpeckins@umich.edu, Fax: 734-764-2580, Phone: 845-558-7198. Implications and Contribution: Stress reactivity may explain inconsistencies in the literature on how childhood maltreatment impacts BMI across adolescence. This study found low cortisol levels may be a risk profile for an elevated BMI across late adolescence in sexually abused girls compared to girls without child welfare-identified maltreatment experiences and physically abused girls. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Conflicts of Interest: The authors have no financial relationships relevant to this article to disclose. HHS Public Access Author manuscript J Adolesc Health. Author manuscript; available in PMC 2020 August 01. Published in final edited form as: J Adolesc Health. 2019 August ; 65(2): 239–247. doi:10.1016/j.jadohealth. 2019.02. 017. A uhor M anscript
Analysis of 13 C α and 13 C β chemical shifts of cysteine and cystine residues in proteins : a quantum chemical approach

Cysteines possess a unique property among the 20 naturally occurring amino acids: it can be present in proteins in either the reduced or oxidized form, and can regulate the activity of some proteins. Consequently, to augment our previous treatment of the other types of residues, the 13Cα and 13Cβ chemical shifts of 837 cysteines in disulfide-bonded cystine from a set of seven non-redundant proteins, determined by X-ray crystallography and NMR spectroscopy, were computed at the DFT level of theory. Our results indicate that the errors between observed and computed 13Cα chemical shifts of such oxidized cysteines can be attributed to several effects such as: (a) the quality of the NMR-determined models, as evaluated by the conformational-average (ca) rmsd value; (b) the existence of high B-factor or crystal-packing effects for the X-ray-determined structures; (c) the dynamics of the disulfide bonds in solution; and (d) the differences in the experimental conditions under which the observed 13Cα chemical shifts and the protein models were determined by either Xray crystallography or NMR-spectroscopy. These quantum-chemical-based calculations indicate the existence of two, almost non-overlapped, basins for the oxidized and reduced –SH 13Cβ, but not for the 13Cα, chemical shifts, in good agreement with the observation of 375 13Cα and 337 13Cβ resonances from 132 proteins by Sharma and Rajarathnam (2000). Overall, our results indicate that explicit consideration of the disulfide bonds is a necessary condition for an accurate prediction of 13Cα and 13Cβ chemical shifts of cysteines in cystines. © Springer Science+Business Media B.V. 2010 Correspondence to: Harold A. Scheraga, has5@cornell.edu. Electronic supplementary material The online version of this article (doi:10.1007/s10858-010-9396-x) contains supplementary material, which is available to authorized users. NIH Public Access Author Manuscript J Biomol NMR. Author manuscript; available in PMC 2011 March 1. Published in final edited form as: J Biomol NMR. 2010 March ; 46(3): 217–225. doi:10.1007/s10858-010-9396-x. N IH PA Athor M anscript N IH PA Athor M anscript N IH PA Athor M anscript
Psychological impact of family history risk assessment in primary care: a mixed methods study

Background. Routine family history risk assessment for chronic diseases could enable primary care practitioners to efficiently identify at-risk patients and promote preventive management strategies. Objectives. To investigate patients’ understanding and responses to family history risk assessment in primary care. Method. A mixed methods study set in 10 Eastern England general practices. Participants in a family history questionnaire validation study were triaged into population or increased risk for four chronic diseases (type 2 diabetes, cardiovascular disease, breast cancer, colorectal cancer). Questionnaires completed immediately prior to the family history consultation (baseline) and 4 weeks later (follow-up) assessed the psychological impact, including State-Trait Anxiety Inventory scores. Semi-structured interviews explored the meaning participants gave to their personal familial disease risk. Results. Four hundred and fifty-three participants completed both baseline and follow-up questionnaires and 30 were interviewed. At follow-up, there was no increase in anxiety among either group, or differences between the groups [difference in mean change 0.02, 95% confidence interval −2.04, 2.08, P = 0.98]. There were no significant changes over time in self-rated health in either group. At follow-up, participants at increased risk (n = 153) were more likely to have recent changes to behaviour and they had stronger intentions to make changes to diet (P = 0.001), physical activity (P = 0.006) and to seek further information in the future than those at population risk (n = 300; P < 0.001). Using qualitative analysis, five themes were developed representing ways in which participants gave meaning to familial disease risk (‘Being reassured’, ‘Controlling risk’, ‘Dealing with it later’, ‘Beyond my control’, ‘Disbelieving the risk’). The meanings they attributed to increased risk appeared to shape their intention to undertake behaviour change. Conclusion. Routine assessment for familial risk of chronic diseases may be undertaken in primary care without causing anxiety or reducing self-rated health. Patient responses to family history risk assessment may inform promotion of preventive management strategies.
Retinal microvascular and neurodegenerative changes in Alzheimer’s disease and mild cognitive impairment compared to controls

Purpose: To evaluate and compare the retinal microvasculature in the superficial capillary plexus (SCP) in persons with Alzheimer’s disease (AD), mild cognitive impairment (MCI), and cognitively intact controls using optical coherence tomography angiography (OCTA). Various OCT parameters were also compared. Design: Cross-sectional study. Participants: 70 eyes from 39 AD subjects, 72 eyes from 37 MCI subjects, and 254 eyes from 133 control subjects were enrolled. Methods: Subjects were imaged using the Zeiss Cirrus HD-5000 with AngioPlex. All subjects underwent cognitive evaluation with Mini Mental State Examination (MMSE). Main Outcome Measures: The vessel density (VD) and perfusion density (PD) in the SCP within the Early Treatment Diabetic Retinopathy Study (ETDRS) 6mm circle, 3mm circle, and 3mm ring were compared between groups. The foveal avascular zone (FAZ) area, central subfield thickness (CST), macular ganglion cell-inner plexiform layer (GC-IPL) thickness, and peripapillary retinal nerve fiber layer (RNFL) thickness were also compared. Results: AD subjects had a significantly decreased SCP VD and PD in the 3mm ring (p=0.001 and 0.002 respectively) and 3mm circle (p=0.003 and 0.004 respectively) as well as VD in the 6mm circle (p=0.047) when compared to MCI and a significantly decreased SCP VD and PD in Corresponding Author: Sharon Fekrat, MD, Box 3802, Duke University Medical Center, Durham, NC 27710-3802, sharon.fekrat@duke.edu, Tel: 919 684 4524. aS.P.Y. and D.S. G. contributed equally to this work. Conflict of Interest: No conflicting relationship exists for any author. Meeting Presentation: Association for Research in Vision and Ophthalmology, April 29-May 2, 2018, Honolulu, Hawaii; Duke Residents’ and Fellows’ Day, June 13–15, 2018, Durham, NC; American Academy of Ophthalmology, October 27–30, 2018, Chicago, Illinois Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. HHS Public Access Author manuscript Ophthalmol Retina. Author manuscript; available in PMC 2020 June 01. Published in final edited form as: Ophthalmol Retina. 2019 June ; 3(6): 489–499. doi:10.1016/j.oret. 2019.02. 002. A uhor M anscript
Adolescent Mental Health in the Digital Age: Facts, Fears and Future Directions

Adolescents are spending an increasing amount of their time online and connected to each other via digital technologies. Mobile device ownership and social media usage have reached unprecedented levels, and concerns have been raised that this constant connectivity is harming adolescents’ mental health. This review synthesized data from three sources: (a) narrative reviews and meta-analyses conducted between 2014 and 2019, (b) large-scale preregistered cohort studies and (c) intensive longitudinal and ecological momentary assessment studies, to summarize what is known about linkages between digital technology usage and adolescent mental health, with a specific focus on depression and anxiety. The review highlights that most research to date has been correlational, focused on adults versus adolescents, and has generated a mix of often conflicting small positive, negative and null associations. The most recent and rigorous large-scale preregistered studies report small associations between the amount of daily digital technology usage and adolescents’ well-being that do not offer a way of distinguishing cause from effect and, as estimated, are unlikely to be of clinical or practical significance. Implications for improving future research and for supporting adolescents’ mental health in the digital age are discussed.
Stimulation of Monovalent Cation Active Transport

trations >10 nM. Preincubation with the f-adrenergic antagonist propranolol (1 ,uM) completely blocked stimulation of active transport of Rb+ by 3 nM ouabain. Norepinephrine, 10 nM, increased Rb+ active transport 29±10% (P < 0.02) above control values. The /8adrenergic agonist 1-isoproterenol, 10 nM, increased active transport of Rb+ by 33±10% (P < 0.01) above control levels. This stimulatory effect was abolished if tissues were first exposed to propranolol. Tyramine (0.1 ,uM), a stimulator of endogenous catecholamine release, increased active transport of Rb+ 26±12% (P < 0.05) above control values. Rb+ active transport was not significantly changed when left atrial tissues were incubated with a-adrenergic agonists or antagonists. Ouabain stimulation of Rb+ active transport was prevented by in vivo depletion of myocardial endogenous catecholamines by either reserpine or 6-hydroxydopamine. These findings indicated that in myocardial tissue, Na-K pump stimulation by low concentrations of ouabain is mediated at least in part through j8-adrenergic effects of endogenous catecholamines.