Miracle-dz/UniFAR-FTUs huggingface dataset:
Activation of autophagy protects against acetaminophen‐induced hepatotoxicity

Autophagy can selectively remove damaged organelles, including mitochondria, and, in turn, protect against mitochondria‐damage–induced cell death. Acetaminophen (APAP) overdose can cause liver injury in animals and humans by inducing mitochondria damage and subsequent necrosis in hepatocytes. Although many detrimental mechanisms have been reported to be responsible for APAP‐induced hepatotoxicity, it is not known whether APAP can modulate autophagy to regulate hepatotoxicity in hepatocytes. To test the hypothesis that autophagy may play a critical protective role against APAP‐induced hepatotoxicity, primary cultured mouse hepatocytes and green fluorescent protein/light chain 3 transgenic mice were treated with APAP. By using a series of morphological and biochemical autophagic flux assays, we found that APAP induced autophagy both in the in vivo mouse liver and in primary cultured hepatocytes. We also found that APAP treatment might suppress mammalian target of rapamycin in hepatocytes and that APAP‐induced autophagy was suppressed by N‐acetylcysteine, suggesting APAP mitochondrial protein binding and the subsequent production of reactive oxygen species may play an important role in APAP‐induced autophagy. Pharmacological inhibition of autophagy by 3‐methyladenine or chloroquine further exacerbated APAP‐induced hepatotoxicity. In contrast, induction of autophagy by rapamycin inhibited APAP‐induced hepatotoxicity. Conclusion: APAP overdose induces autophagy, which attenuates APAP‐induced liver cell death by removing damaged mitochondria. (HEPATOLOGY 2012)
The Outline of Prognosis and New Advances in Diagnosis of Oral Squamous Cell Carcinoma (OSCC): Review of the Literature

Objective. Oral squamous cell carcinoma (OSCC) has a remarkable incidence over the world and a fairly strenuous prognosis, encouraging further research on the prognostic factors and new techniques for diagnosis that might modify disease outcome. Data Sources. A web-based search for all types of articles published was initiated using Medline/Pub Med, with the key words such as oral cancer, prognostic factors of oral cancer, diagnostic method of oral cancer, and imaging techniques for diagnosis of oral cancer. The search was restricted to articles published in English, with no publication date restriction (last update April, 2013). Review Methods. In this paper, I approach the factors of prognosis of OSCC and the new advances in diagnostic technologies as well. I also reviewed available studies of the tissue fluorescence spectroscopy and other noninvasive diagnostic aids for OSCC. Results. The outcome is greatly influenced by the stage of the disease (especially TNM). Prognosis also depends or varies with tumour primary site, nodal involvement, tumour thickness, and the status of the surgical margins. Conclusion. Tumour diameter is not the most accurate when compared to tumour thickness or depth of invasion, which can be related directly to prognosis. There is a wide agreement on using ultrasound guided fine needle aspiration biopsies in the evaluation of lymph node metastasis.
A mouse model of accelerated liver aging caused by a defect in DNA repair

The liver changes with age, leading to an impaired ability to respond to hepatic insults and increased incidence of liver disease in the elderly. Therefore, there is critical need for rapid model systems to study aging‐related liver changes. One potential opportunity is murine models of human progerias or diseases of accelerated aging. Ercc1−/Δ mice model a rare human progeroid syndrome caused by inherited defects in DNA repair. To determine whether hepatic changes that occur with normal aging occur prematurely in Ercc1−/Δ mice, we systematically compared liver from 5‐month‐old progeroid Ercc1−/Δ mice to old (24‐36‐month‐old) wild‐type (WT) mice. Both displayed areas of necrosis, foci of hepatocellular degeneration, and acute inflammation. Loss of hepatic architecture, fibrosis, steatosis, pseudocapillarization, and anisokaryosis were more dramatic in Ercc1−/Δ mice than in old WT mice. Liver enzymes were significantly elevated in serum of Ercc1−/Δ mice and old WT mice, whereas albumin was reduced, demonstrating liver damage and dysfunction. The regenerative capacity of Ercc1−/Δ liver after partial hepatectomy was significantly reduced. There was evidence of increased oxidative damage in Ercc1−/Δ and old WT liver, including lipofuscin, lipid hydroperoxides and acrolein, as well as increased hepatocellular senescence. There was a highly significant correlation in genome‐wide transcriptional changes between old WT and 16‐week‐old, but not 5‐week‐old, Ercc1−/Δ mice, emphasizing that the Ercc1−/Δ mice acquire an aging profile in early adulthood. Conclusion: There are strong functional, regulatory, and histopathological parallels between accelerated aging driven by a DNA repair defect and normal aging. This supports a role for DNA damage in driving aging and validates a murine model for rapidly testing hypotheses about causes and treatment for aging‐related hepatic changes. (HEPATOLOGY 2012)
Condensin recruitment to chromatin is inhibited by Chk2 kinase in response to DNA damage

ABSTRACT The DNA damage checkpoint, when activated in response to genotoxic damage during S phase, arrests cells in G2 phase of the cell cycle. ATM, ATR, Chk1 and Chk2 kinases are the main effectors of this checkpoint pathway. The checkpoint kinases prevent the onset of mitosis by eliciting well characterized inhibitory phosphorylation of Cdk1. Since Cdk1 is required for the recruitment of condensin, it is thought that upon DNA damage the checkpoint also indirectly blocks chromosome condensation via Cdk1 inhibition. Here we report that the G2 damage checkpoint prevents stable recruitment of the chromosome-packaging-machinery components condensin complex I and II onto the chromatin even in the presence of an active Cdk1. DNA damage-induced inhibition of condensin subunit recruitment is mediated specifically by the Chk2 kinase, implying that the condensin complexes are targeted by the checkpoint in response to DNA damage, independently of Cdk1 inactivation. Thus, the G2 checkpoint directly prevents stable recruitment of condensin complexes to actively prevent chromosome compaction during G2 arrest, presumably to ensure efficient repair of the genomic damage.
Physical Health Correlates of Pathological and Healthy Dependency in Urban Women

This study assessed the relationship between dependency and indicators of health/illness, healthcare costs, and utilization. Dependency ratings were obtained using the Relationship Profile Test (Bornstein and Languirand, 2003), a questionnaire that assesses healthy and pathological dependency: destructive overdependence (DO), dysfunctional detachment (DD), and healthy dependency (HD). The sample consisted of primarily low-income, African-American, and female primary care patients (N = 110). DO and DD were significantly associated with indices of increased illness, with DO evidencing slightly larger effect sizes than DD. HD was significantly (negatively) associated with 1 health/illness variable. DD and DO were associated with higher total outpatient costs with DD also being associated with average costs per visit. DO and HD were associated with utilization (increased hospital days and fewer emergency room visits, respectively). Further research is recommended to inform researchers and clinicians about the dependency-illness relationship and to develop interventions that maximize HD and minimize pathological dependency.
Association of coffee and caffeine consumption with fatty liver disease, nonalcoholic steatohepatitis, and degree of hepatic fibrosis

Coffee caffeine consumption (CC) is associated with reduced hepatic fibrosis in patients with chronic liver diseases, such as hepatitis C. The association of CC with nonalcoholic fatty liver disease (NAFLD) has not been established. The aim of this study was to correlate CC with the prevalence and severity of NAFLD. Patients involved in a previously published NAFLD prevalence study, as well as additional NASH patients identified in the Brooke Army Medical Center Hepatology clinic, were queried about their caffeine intake. A validated questionnaire for CC was utilized to assess for a relationship between caffeine and four groups: ultrasound negative (controls), bland steatosis/not‐NASH, NASH stage 0‐1, and NASH stage 2‐4. A total of 306 patients responded to the CC questionnaire. Average milligrams of total caffeine/coffee CC per day in controls, bland steatosis/not‐NASH, NASH stage 0‐1, and NASH stage 2‐4 were 307/228, 229/160, 351/255, and 252/152, respectively. When comparing patients with bland steatosis/not‐NASH to those with NASH stage 0‐1, there was a significant difference in CC between the two groups (P = 0.005). Additionally, when comparing patients with NASH stage 0‐1 to those with NASH stage 2‐4, there was a significant difference in coffee CC (P = 0.016). Spearman's rank correlation analysis further supported a negative relationship between coffee CC and hepatic fibrosis (r = −0.215; P = 0.035). Conclusion: Coffee CC is associated with a significant reduction in risk of fibrosis among NASH patients. (Hepatology 2012)
The Sequence of Recovery in Long-Term Dynamic Psychotherapy

Psychotherapy has generally been found both efficacious and effective in producing improvement, but the sequence of recovery across different measures is less studied. A total of 53 patients with mood, anxiety, and/or personality disorders were enrolled in an effectiveness study of long-term dynamic psychotherapy of whom 49 gave some follow-up data. Follow-up interviews over a median of 5 years systematically rated 16 measures of Axis I disorders, symptoms, and functioning. Linear models estimated the rate and amount of improvement and time to recovery for each subject initially not well on each measure. The proportion recovering on each measure varied from 0% to 66.7% with self-destructive symptoms and working half-time leading, followed by self-reported measures of distress and defensive functioning, working full-time and satisfaction, then by observer-rated depression and anxiety, attaining a global assessment of functioning of 61, Axis I disorders, and social role functioning. Participants recovering on satisfaction had higher net proportions of other measures attaining recovery (46.9% versus 2.5%, p < 0.0001) compared with those not satisfied. Sustained recovery unfolds sequentially across a variety of symptoms and functioning measures and is associated with patient satisfaction.
Antagonism of peripheral hepatic cannabinoid receptor‐1 improves liver lipid metabolism in mice: Evidence from cultured explants

It is well established that inactivation of the central endocannabinoid system (ECS) through antagonism of cannabinoid receptor 1 (CB1R) reduces food intake and improves several pathological features associated with obesity, such as dyslipidemia and liver steatosis. Nevertheless, recent data indicate that inactivation of peripheral CB1R could also be directly involved in the control of lipid metabolism independently of central CB1R. To further investigate this notion, we tested the direct effect of the specific CB1R antagonist, SR141716, on hepatic carbohydrate and lipid metabolism using cultured liver slices. CB1R messenger RNA expression was strongly decreased by SR141716, whereas it was increased by the CB1R agonist, arachidonic acid N‐hydroxyethylamide (AEA), indicating the effectiveness of treatments in modulating ECS activity in liver explants both from lean or ob/ob mice. The measurement of O2 consumption revealed that SR141716 increased carbohydrate or fatty acid utilization, according to the cellular hormonal environment. In line with this, SR141716 stimulated ß‐oxidation activity, and the role of CB1R in regulating this pathway was particularly emphasized when ECS was hyperactivated by AEA and in ob/ob tissue. SR141716 also improved carbohydrate and lipid metabolism, blunting the AEA‐induced increase in gene expression of proteins related to lipogenesis. In addition, we showed that SR141716 induced cholesterol de novo synthesis and high‐density lipoprotein uptake, revealing a relationship between CB1R and cholesterol metabolism. Conclusion: These data suggest that blocking hepatic CB1R improves both carbohydrate and lipid metabolism and confirm that peripheral CB1R should be considered as a promising target to reduce cardiometabolic risk in obesity. (HEPATOLOGY 2011)
Mucin‐type O‐glycosylation – putting the pieces together

The O‐glycosylation of Ser and Thr by N‐acetylgalactosamine‐linked (mucin‐type) oligosaccharides is often overlooked in protein analysis. Three characteristics make O‐linked glycosylation more difficult to analyse than N‐linked glycosylation, namely: (a) no amino acid consensus sequence is known; (b) there is no universal enzyme for the release of O‐glycans from the protein backbone; and (c) the density and number of occupied sites may be very high. For significant biological conclusions to be drawn, the complete picture of O‐linked glycosylation on a protein needs to be determined. This review specifically addresses the analytical approaches that have been used, and the challenges remaining, in the characterization of both the composition and structure of mucin‐type O‐glycans, and the determination of the occupancy and heterogeneity at each amino acid attachment site.
Proteolytic activation and function of the cytokine Spätzle in the innate immune response of a lepidopteran insect, Manduca sexta

The innate immune response of insects includes induced expression of genes encoding a variety of antimicrobial peptides. The signaling pathways that stimulate this gene expression have been well characterized by genetic analysis in Drosophila melanogaster, but are not well understood in most other insect species. One such pathway involves proteolytic activation of a cytokine called Spätzle, which functions in dorsal–ventral patterning in early embryonic development and in the antimicrobial immune response in larvae and adults. We have investigated the function of Spätzle in a lepidopteran insect, Manduca sexta, in which hemolymph proteinases activated during immune responses have been characterized biochemically. Two cDNA isoforms for M. sexta Spätzle‐1 differ because of alternative splicing, resulting in a 10 amino acid residue insertion in the pro‐region of proSpätzle‐1B that is not present in proSpätzle‐1A. The proSpätzle‐1A cDNA encodes a 32.7 kDa polypeptide that is 23% and 44% identical to D. melanogaster and Bombyx mori Spätzle‐1, respectively. Recombinant proSpätzle‐1A was a disulfide‐linked homodimer. M. sexta hemolymph proteinase 8 cleaved proSpätzle‐1A to release Spätzle‐C108, a dimer of the C‐terminal 108 residue cystine‐knot domain. Injection of Spätzle‐C108, but not proSpätzle‐1A, into larvae stimulated expression of several antimicrobial peptides and proteins, including attacin‐1, cecropin‐6, moricin, lysozyme, and the immunoglobulin domain protein hemolin, but did not significantly affect the expression of two bacteria‐inducible pattern recognition proteins, immulectin‐2 and β‐1,3‐glucan recognition protein‐2. The results of this and other recent studies support a model for a pathway in which the clip‐domain proteinase pro‐hemolymph proteinase 6 becomes activated in plasma upon exposure to Gram‐negative or Gram‐positive bacteria or to β‐1,3‐glucan. Hemolymph proteinase 6 then activates pro‐hemolymph proteinase 8, which in turn activates Spätzle‐1. The resulting Spätzle‐C108 dimer is likely to function as a ligand to activate a Toll pathway in M. sexta as a response to a wide variety of microbial challenges, stimulating a broad response to infection.
The starch‐binding capacity of the noncatalytic SBD2 region and the interaction between the N‐ and C‐terminal domains are involved in the modulation of the activity of starch synthase III from Arabidopsis thaliana

Starch synthase III from Arabidopsis thaliana contains an N‐terminal region, including three in‐tandem starch‐binding domains, followed by a C‐terminal catalytic domain. We have reported previously that starch‐binding domains may be involved in the regulation of starch synthase III function. In this work, we analyzed the existence of protein interactions between both domains using pull‐down assays, far western blotting and co‐expression of the full and truncated starch‐binding domains with the catalytic domain. Pull‐down assays and co‐purification analysis showed that the D(316–344) and D(495–535) regions in the D2 and D3 domains, respectively, but not the individual starch‐binding domains, are involved in the interaction with the catalytic domain. We also determined that the residues W366 and Y394 in the D2 domain are important in starch binding. Moreover, the co‐purified catalytic domain plus site‐directed mutants of the D123 protein lacking these aromatic residues showed that W366 was key to the apparent affinity for the polysaccharide substrate of starch synthase III, whereas either of these amino acid residues altered ADP‐glucose kinetics. In addition, the analysis of full‐length and truncated proteins showed an almost complete restoration of the apparent affinity for the substrates and Vmax of starch synthase III. The results presented here suggest that the interaction of the N‐terminal starch‐binding domains, particularly the D(316–344) and D(495–535) regions, with the catalytic domains, as well as the full integrity of the starch‐binding capacity of the D2 domain, are involved in the modulation of starch synthase III activity.
Hepatitis C viral kinetics with the nucleoside polymerase inhibitor mericitabine (RG7128)

Mericitabine (RG7128) is a nucleoside polymerase inhibitor (NPI), which requires intracellular uptake and phosphorylation to two active triphosphates. Mathematical modeling has provided important insights for characterizing hepatitis C virus (HCV) RNA decline and estimating in vivo effectiveness of antiviral agents; however, it has not been used to characterize viral kinetics with NPIs. HCV RNA was frequently measured in 32 treatment‐experienced patients infected with HCV genotype 1 during and after mericitabine monotherapy for 14 days with 750 mg or 1500 mg administered once (qd) or twice daily (bid). The initial decline of HCV RNA was typically slower than with interferon‐α or protease inhibitors, and 12 patients presented a novel pattern of HCV RNA kinetics characterized by a monophasic viral decline. Viral kinetics could be well fitted by assuming that the effectiveness in blocking viral production gradually increased over time to reach its final value, ε2, consistent with previous accumulation time estimates of intracellular triphosphates. ε2 was high with bid dosing (mean 750 mg and 1500 mg: 98.0% and 99.8%, respectively; P = 0.018) and significantly higher than in patients treated qd (mean qd versus bid: 90% versus 99%, P < 10−7). Virus rebounded rapidly upon drug discontinuation, which was attributed to the elimination of active drug and the subsequent decline of drug effectiveness, with mean t1/2 = 13.9 hours in the bid regimens. Conclusion: The observed slower initial decline likely represents the time needed to accumulate intracellular triphosphates and is consistent with in vitro data. When administered bid, mericitabine reached a high, dose‐dependent, final effectiveness in blocking viral production that rapidly dropped upon treatment cessation. Understanding HCV RNA kinetics with mericitabine could provide valuable insights for combining it with other direct‐acting antiviral agents. (HEPATOLOGY 2012)
Is a History of School Bullying Victimization Associated With Adult Suicidal Ideation?: A South Australian Population-Based Observational Study

The objective of this research was to determine whether a history of school bullying victimization is associated with suicidal ideation in adult life. A random and representative sample of 2907 South Australian adults was surveyed in Autumn, 2008. Respondents were asked “When you were at school, did you experience traumatic bullying by peers that was particularly severe, for example, being frequently targeted or routinely harassed in any way by ‘bullies’? ” Depression was determined by the mood module of the PRIME-MD which includes a suicidal ideation question; “In the last 2 weeks, have you had thoughts that you would be better off dead or hurting yourself in some way? ” The overall prevalence of suicidal ideation in postschool age respondents was 3.4% (95% confidence interval: 2.8%–4.2%) in 2008. Bullying by peers was recalled by 18.7% (17.2%–20.3%). Respondents with a history of being bullied were approximately 3 times (odds ratio: 3.2) more likely to report suicidal ideation compared with those who did not. The association between being bullied and suicidal ideation remained after controlling for both depression and sociodemographic variables (odds ratio: 2.1). The results from the present research suggest that there is a strong association between a history of childhood bullying victimization and current suicidal ideation that persists across all ages. Bullying prevention programs in schools could hold the potential for longer lasting benefits in this important area of public health.
Childhood Adversity, Mental Disorder Comorbidity, and Suicidal Behavior in Schizotypal Personality Disorder

Schizotypal personality disorder (SPD) is a serious and relatively common psychiatric disorder, yet remains understudied among the personality disorders. The current study examines the psychiatric correlates of SPD in a representative epidemiologic sample, utilizing data from the National Epidemiological Survey on Alcohol and Related Conditions (N = 34,653). Multiple logistic regression compared people with SPD to the general population across a broad range of childhood adversities, comorbid psychiatric disorders, and suicidal behavior. SPD was strongly associated with many adverse childhood experiences. After adjusting for confounding factors, SPD was independently associated with major depression and several anxiety disorders, including post-traumatic stress disorder. Interestingly, SPD was more strongly associated with borderline and narcissistic personality disorders than cluster A personality disorders. Individuals with SPD were also more likely to attempt suicide. As a whole, these results suggest that individuals with SPD experience significant morbidity and may be at increased risk of mortality.
Self-Harm Behaviors in Borderline Personality: An Analysis by Gender

A number of authors have examined gender differences in patients with borderline personality disorder. Current data suggest that for some clinical features, there appear to be genuine gender differences, whereas for other clinical features, there are not apparent differences. In this study, we examined by gender 22 self-harm behaviors in 61 internal medicine outpatients with borderline personality symptomatology. We found that only 2 self-harm behaviors were statistically significantly more common in one of the sexes—head-banging and losing a job on purpose, with both being more common in men. These findings appear to mirror the existing literature—i.e., that there may be some genuine gender differences with regard to specific self-harm behaviors, but the majority of self-harm behaviors overlap between the sexes.