Miracle-dz/UniFAR-FTUs huggingface dataset:
Identification of the Drosophila Ortholog of HSPB8

Protein aggregation is a hallmark of many neuronal disorders, including the polyglutamine disorder spinocerebellar ataxia 3 and peripheral neuropathies associated with the K141E and K141N mutations in the small heat shock protein HSPB8. In cells, HSPB8 cooperates with BAG3 to stimulate autophagy in an eIF2α-dependent manner and facilitates the clearance of aggregate-prone proteins (Carra, S., Seguin, S. J., Lambert, H., and Landry, J. (2008) J. Biol. Chem. 283, 1437–1444; Carra, S. , Brunsting, J. F. , Lambert, H. , Landry, J., and Kampinga, H. H. (2009) J. Biol. Chem. 284, 5523–5532). Here, we first identified Drosophila melanogaster HSP67Bc (Dm-HSP67Bc) as the closest functional ortholog of human HSPB8 and demonstrated that, like human HSPB8, Dm-HSP67Bc induces autophagy via the eIF2α pathway. In vitro, both Dm-HSP67Bc and human HSPB8 protected against mutated ataxin-3-mediated toxicity and decreased the aggregation of a mutated form of HSPB1 (P182L-HSPB1) associated with peripheral neuropathy. Up-regulation of both Dm-HSP67Bc and human HSPB8 protected and down-regulation of endogenous Dm-HSP67Bc significantly worsened SCA3-mediated eye degeneration in flies. The K141E and K141N mutated forms of human HSPB8 that are associated with peripheral neuropathy were significantly less efficient than wild-type HSPB8 in decreasing the aggregation of both mutated ataxin 3 and P182L-HSPB1. Our current data further support the link between the HSPB8-BAG3 complex, autophagy, and folding diseases and demonstrate that impairment or loss of function of HSPB8 might accelerate the progression and/or severity of folding diseases.
Health Behavior Changes After Genetic Risk Assessment for Alzheimer Disease: The REVEAL Study

Risk information for Alzheimer disease (AD) may be communicated through susceptibility gene disclosure, even though this is not currently in clinical use. The REVEAL Study is the first randomized clinical trial of risk assessment for AD with apolipoprotein E (APOE) genotype and numerical risk estimate disclosure. We examined whether APOE genotype and numerical risk disclosure to asymptomatic individuals at high risk for AD alters health behaviors. One hundred sixty-two participants were randomized to either intervention (APOE disclosure) or control (no genotype disclosure) groups. Subjects in both groups received numerical lifetime risk estimates of future AD development based on sex and family history of AD. The intervention group received their APOE genotype. Subjects were informed that no proven preventive measures for AD existed and given an information sheet on preventative therapies under investigation. Participants who learned they were ϵ4 positive were significantly more likely than ϵ4 negative participants to report AD-specific health behavior change 1 year after disclosure (adjusted odds ratio: 2.73; 95% confidence interval: 1.14, 6.54; P=0.02). Post hoc analyses revealed similar significant associations between numerical lifetime risk estimates and self-report of AD-specific health behavior change. Despite lack of preventive measures for AD, knowledge of APOE genotype, numerical lifetime risk, or both, influences health behavior.
Assessment of cell‐signaling pathways in the regulation of mammalian target of rapamycin (mTOR) by amino acids in rat adipocytes

Enhanced phosphorylation of the ribosomal protein s6 kinase, p70s6k, and the translational repressor, 4E‐BP1, are associated with either insulin‐induced or amino acid‐induced protein synthesis. Hyperphosphorylation of p70s6k and 4E‐BP1 in response to insulin or amino acids is mediated through the mammalian target of rapamycin (mTOR). In several cell lines, mTOR or its downstream targets can be regulated by phosphatidylinositol (PI) 3‐kinase; protein kinases A, B, and C; heterotrimeric G‐proteins; a PD98059‐sensitive kinase or calcium; as well as by amino acids. Regulation by amino acids appears to involve detection of levels of charged t‐RNA or t‐RNA synthetase activity and is sensitive to inhibition by amino acid alcohols. In the present article, however, we show that the rapamycin‐sensitive regulation of 4E‐BP1 and p70s6k in freshly isolated rat adipocytes is not inhibited by either L‐leucinol or L‐histidinol. This finding is in agreement with other recent studies from our laboratory suggesting that the mechanism by which amino acids regulate mTOR in freshly isolated adipocytes may be different than the mechanism found in a number of cell lines. Therefore we investigated the possible role of growth factor‐regulated and G‐protein–regulated signaling pathways in the rapamycin‐sensitive, amino acid alcohol‐insensitive actions of amino acids on 4E‐BP1 phosphorylation. We found, in contrast to previously published results using 3T3‐L1 adipocytes or other cell lines, that the increase in 4E‐BP1 phosphorylation promoted by amino acids was insensitive to agents that regulate protein kinase A, mobilize calcium, or inhibit protein kinase C. Furthermore, amino acid‐induced 4E‐BP1 phosphorylation was not blocked by pertussis toxin nor was it mimicked by the G‐protein agonists fluoroaluminate or MAS‐7. However, amino acids failed to activate either PI 3‐kinase, protein kinase B, or mitogen‐activated protein kinase and failed to promote tyrosine phosphorylation of cellular proteins, similar to observations made using cell lines. In summary, amino acids appear to use an amino acid alcohol‐insensitive mechanism to regulate mTOR in freshly isolated adipocytes. This mechanism is independent of cell‐signaling pathways implicated in the regulation of mTOR or its downstream targets in other cells. Overall, our study emphasizes the need for caution when extending results obtained using established cell lines to the differentiated nondividing cells found in most tissues. J. Cell. Biochem. 79:427–441, 2000. © 2000 Wiley‐Liss, Inc.
The impact of scandal on sport consumption: do different scandal types have different levels of influence on different consumer segments?

ABSTRACT Research question: How, and to what extent, do different scandal types influence sport consumption behaviors – measured as intended media viewership – across different consumer profiles? Research methods: A Best–Worst Scaling choice experiment is run on data gathered from consumers who are fans of the Australian Football League and latent class modelling is used to identify consumer profiles. Results and findings: The findings suggest that different scandal types lead to different viewing intention effects on consumers, sexual assault, illicit substance use, doping and organized match fixing are likely to produce the most negative outcomes of the 13 scandal types examined. Five distinct consumer profiles emerge from the results in terms of their relative reactions to a scandal. Implications: Conceptually, the study indicates that consumers respond to different types of scandals and the responses vary by consumer profile. The findings demonstrate that sports managers need to consider a contingency-based approach when managing scandal based on the heterogeneity this study observed across both scandal types and consumer profiles.
Liver Ischemia Contributes to Early Islet Failure Following Intraportal Transplantation: Benefits of Liver Ischemic‐Preconditioning

Early graft failure following intraportal islet transplantation (IPIT) represents a major obstacle for successful islet transplantation. Here, we examined the role of islet emboli in the induction of early graft failure and utilized a strategy of ischemic‐preconditioning (IP) to prevent early islet destruction in a model of syngeneic IPIT in STZ‐induced diabetic mice. Numerous focal areas of liver necrosis associated with the islet emboli were observed within 24 h post‐IPIT. Pro‐inflammatory cytokines, IL‐1β and IL‐6, were significantly increased 3 h after IPIT, while TNF‐α was elevated for up to 5 days post‐IPIT. Caspase‐3 and terminal deoxynucleotidyl transferase‐mediated dUTP nick‐end labeling positive cells were observed in the transplanted islets trapped in areas of necrotic liver at 3 h and 1 day post‐IPIT. Hyperglycemia was corrected immediately following IPIT of 200 islets, but recurrence of hyperglycemia was observed within 14 days associated with a poor response to glucose challenge. IP, a procedure of pre‐exposure of the liver to transient ischemia and reperfusion, protected the liver from embolism‐induced ischemic injury and prevented early islet graft failure. These data suggest that islet embolism in the portal vein is a major cause of functional loss following IPIT that can be prevented by liver IP.
Corneal Sensitivity and Tear Function in Neurodegenerative Diseases

Abstract Purpose: To measure corneal sensitivity and tear function in neurodegenerative diseases (NDs) and to compare them with age and sex-matched controls. Methods: Twenty patients with Alzheimer's disease (AD), 20 patients with multiple sclerosis (MS), 30 patients with Parkinson's disease (PD), 10 patients with Friedreich's ataxia (FA) and 21 patients with epilepsy (EP) who were recruited from the Kırıkkale University Neurology Department during 2012 were included in this prospective study. Five groups of age and sex-matched subjects were selected as controls. Corneal sensitivity was measured using a Cochet–Bonnet esthesiometer. Tear function tests included tear break-up time (TBUT) and Schirmer's 1 tests. Results: Compared to their controls, mean corneal sensitivity was significantly reduced in AD, MS, PD and EP patients (all p < 0.05), mean TBUT level was significantly shorter in patients with AD and MS (all p < 0.05) and mean Schirmer's 1 test score was significantly lower in EP patients (p < 0.05). When all groups were compared with each other, reduction of mean corneal sensitivity in AD and PD groups were significantly more than in FA and MS groups (overall p = 0.034). Mean TBUT levels in AD, MS and PD groups were significantly shorter than in FA and EP groups (overall p = 0.001). Mean Schirmer's 1 test scores in AD and PD groups were significantly lower than in MS, FA and EP groups (overall p = 0.040). Conclusions: Neurodegenerative diseases may be associated with reduced corneal sensitivity and abnormal tear function.
Work–Life Program Participation and Employee Work Attitudes: A Quasi-Experimental Analysis Using Matching Methods

Work–life programs (WLPs) have been widely adopted and implemented by public organizations as a means of providing employees with greater choices and flexibility in coordinating their work and personal lives. Although previous research has shown that these programs are positively related to various employee attitudes and behaviors, empirical evidence about whether and how such relationships vary by type of WLP is relatively scant. In this study, we categorize WLPs into two different types—work-oriented and life-oriented programs—and explore whether and how participating in distinct types of WLPs has varying impacts on employee work attitudes. A series of Mahalanobis distance matching is conducted using data from the 2011 Federal Employee Viewpoint Survey. The results indicate that the use of life-oriented programs has a positive and substantive impact on employee satisfaction and commitment, while the effect of participating in work-oriented programs is not statistically significant.
AGRICULTURAL MODELS IN EU FADN REGIONS AND CHANGES IN FARM PRODUCTIVITY AND INCOMES

The purpose of this paper is to present and comparethe level of and changes in (total and partial) productivityand basic income categories in FADN regions. The regionswere grouped into 4 clusters where relatively similar types ofagriculture predominate. Changes in total factor productivity(TFP) were evaluated using the Malmquist index and Tokarski’smethod. The research showed that regions with extremelyintensive agriculture achieved a high level of productivityand income. However, while there is little potential for productivitygrowth (especially through improved technical efficiency)in these areas, local farms implement technologicalprogress. Regions with ‘industrial’ agriculture generally demonstratelow levels of TFP, which is however accompanied bygrowth due to advances in both efficiency and technology. Inregions where less developed or more traditional agriculturepredominates, low to medium levels of incomes and of partialand total productivity were observed whereas the growth ratesfor labor and land productivity were relatively high. Also, thekey economic category for the farming sector, i.e. incomefrom labor inputs, was observed to grow at a relatively highpace. Note that an analysis of productivity and profitability inagricultural holdings based on only one measure or researchmethod can lead to hasty conclusions.
Risk Preferences and Climate Smart Technology Adoption: A Duration Model Approach for India

This paper examines the role of individual risk preferences in the decision of a climate smart technology in two northern states of India. We conducted a household survey and a field experiment using real cash with Indian farmers to elicit their risk preferences, and used them to explain their adoption of laser land leveler. The analysis extended the measurement of risk preferences beyond the expected utility theory to incorporate prospect theory. We use duration analysis approach to model the time to adoption and find that risk averse farmers and farmers who overvalue smaller probabilities adopt his technology sooner than others. Acknowledgement : We are really thankful to strengthening Impact Assessment in the CGIAR and Michigan State University's Asian Study Center for thier generous funding for this study.
Analysis of Antibiotic Resistance Genes and its Associated SCCmec Types among Nasal Carriage of Methicillin Resistant Coagulase Negative Staphylococci from Community Settings, Chennai, Southern India.

OBJECTIVE The study was designed to find the distribution of SCCmec types and the various antibiotic resistance genes amongst MR-CoNS isolates from asymptomatic individuals. MATERIALS AND METHODS A total of 145 nasal swabs were collected from asymptomatic healthy individuals from community settings. Identification and speciation of CoNS were done by standard biochemical methods. Screening of methicillin resistance (mecA gene) and detection of various antibiotic resistant genes were done using multiplex PCR method. SCCmec types (I - V) were determined using multiplex PCR. RESULTS 50 (44.6%) isolates were found to be methicillin resistant both by cefoxitin method and multiplex PCR. S. epidermidis (40%) was the predominant species followed by S. haemolyticus (28%), S. hominis (20%) and S. warneri (12%). Highest resistance was shown for cotrimoxazole (26%), followed by ciprofloxacin (24%), tetracycline (20%), erythromycin (18%), fusidic acid (10%) and mupirocin (6%). Among SCCmec types, 44 isolates showed single type, including type I (30%), type IV (24%), type II (18%), type V (14%) and type III (2%). 6 isolates showed two types, III+IV (n= 2), II+V (n=2), IV+V (n=1) and type I+V (n=1). CONCLUSION In conclusion, to the best of our knowledge, this is the first study in India to study the distribution of antibiotic resistant genes and SCCmec types among MR-CoNS from community settings. This study highlights high prevalence of MR-CoNS in community and its role in harbouring genetically diverse SCCmec elements as antibiotic resistance determinant.
Selective activation of nociceptors by P2X receptor agonists in normal and inflamed rat skin

1 ATP can elicit pain in humans and, together with other P2X channel agonists, can produce nocifensive responses in rodents. We used the rat in vitro skin‐nerve preparation to quantify primary afferent responses to ATP and its stable analogue α,β‐methylene ATP in normal and carrageenan‐inflamed skin. 2 Both ATP and α,β‐methylene ATP were found to specifically activate the peripheral terminals of Aδ and C‐fibre nociceptors in the skin. Thirty‐nine per cent of the nociceptors tested responded to the maximal dose of α,β‐methylene ATP (5 mm). In contrast, non‐nociceptive, low‐threshold mechano‐sensitive fibres were never activated by the same agonist concentrations. 3 Amongst the nociceptor population, C‐mechanoheat fibres (C‐MH or polymodal nociceptors) were markedly more responsive to P2X agonists than mechanonociceptors (C‐M nociceptors) with Aδ‐ or C‐fibre axons. Both C‐mechanoheat and C‐mechanonociceptors were activated by α,β‐methylene ATP doses as low as 50 μm. 4 In skin inflamed with carrageenan 3‐4 h before recording both the number of responsive C‐fibre nociceptors and their response magnitude increased. The increased neural response under inflammatory conditions was largely observed in C‐mechanoheat or polymodal nociceptors. After low doses of P2X agonists C‐MH fibres but not C‐M fibres developed elevated ongoing activity and this effect was only seen after carrageenan inflammation. The time course of α,β‐methylene ATP‐evoked discharges in nociceptors was found to correlate well with the time course of behavioural nocifensive responses in rats to the same agonist described in a previous study ( Hamilton et al. 1999 ). 5 We conclude that the rapid increase in the number of α,β‐methylene ATP responsive nociceptors and the increased magnitude of the neural response following carrageenan inflammation explains why very low concentrations of such agonists can cause pain in inflammatory states.
Feasibility of MRI-based reference images for image-guided radiotherapy of the pelvis with either cone-beam computed tomography or planar localization images

Abstract Purpose. This study introduces methods to conduct image-guided radiotherapy (IGRT) of the pelvis with either cone-beam computed tomography (CBCT) or planar localization images by relying solely on magnetic resonance imaging (MRI)-based reference images. Material and methods. Feasibility of MRI-based reference images for IGRT was evaluated against kV CBCT (50 scans, 5 prostate cancer patients) and kV & MV planar (5 & 5 image pairs and patients) localization images by comparing the achieved patient position corrections to those obtained by standard CT-based reference images. T1/T2*-weighted in-phase MRI, Hounsfield unit conversion-based heterogeneous pseudo-CT, and bulk pseudo-CT images were applied for reference against localization CBCTs, and patient position corrections were obtained by automatic image registration. IGRT with planar localization images was performed manually by 10 observers using reference digitally reconstructed radiographs (DRRs) reconstructed from the pseudo-CTs and standard CTs. Quality of pseudo-DRRs against CT-DRRs was evaluated with image similarity metrics. Results. The SDs of differences between CBCT-to-MRI and CBCT-to-CT automatic gray-value registrations were ≤ 1.0 mm & ≤ 0.8° and ≤ 2.5 mm & ≤ 3.6° with 10 cm diameter cubic VOI and prostate-shaped VOI, respectively. The corresponding values for reference heterogeneous pseudo-CT were ≤ 1.0 mm & ≤ 0.7° and ≤ 2.2 mm & ≤ 3.3°, respectively. Heterogeneous pseudo-CT was the only type of MRI-based reference image working reliably with automatic bone registration (SDs were ≤ 0.9 mm & ≤ 0.7°). The differences include possible residual errors from planning CT to MRI registration. The image similarity metrics were significantly (p ≤ 0.01) better in agreement between heterogeneous pseudo-DRRs and CT-DRRs than between bulk pseudo-DRRs and CT-DRRs. The SDs of differences in manual registrations (3D) with planar kV and MV localization images were ≤ 1.0 mm and ≤ 1.7 mm, respectively, between heterogeneous pseudo-DRRs and CT-DRRs, and ≤ 1.4 mm and ≤ 2.1 mm between bulk pseudo-DRRs and CT-DRRs. Conclusion. This study demonstrated that it is feasible to conduct IGRT of the pelvis with MRI-based reference images.
Clearance Prediction Methodology Needs Fundamental Improvement: Trends Common to Rat and Human Hepatocytes/Microsomes and Implications for Experimental Methodology

Although prediction of clearance using hepatocytes and liver microsomes has long played a decisive role in drug discovery, it is widely acknowledged that reliably accurate prediction is not yet achievable despite the predominance of hepatically cleared drugs. Physiologically mechanistic methodology tends to underpredict clearance by several fold, and empirical correction of this bias is confounded by imprecision across drugs. Understanding the causes of prediction uncertainty has been slow, possibly reflecting poor resolution of variables associated with donor source and experimental methods, particularly for the human situation. It has been reported that among published human hepatocyte predictions there was a tendency for underprediction to increase with increasing in vivo intrinsic clearance, suggesting an inherent limitation using this particular system. This implied an artifactual rate limitation in vitro, although preparative effects on cell stability and performance were not yet resolved from assay design limitations. Here, to resolve these issues further, we present an up-to-date and comprehensive examination of predictions from published rat as well as human studies (where n = 128 and 101 hepatocytes and n = 71 and 83 microsomes, respectively) to assess system performance more independently. We report a clear trend of increasing underprediction with increasing in vivo intrinsic clearance, which is similar both between species and between in vitro systems. Hence, prior concerns arising specifically from human in vitro systems may be unfounded and the focus of investigation in the future should be to minimize the potential in vitro assay limitations common to whole cells and subcellular fractions.
Significance of neutrophil‐to‐lymphocyte ratio, platelet‐to‐lymphocyte ratio and prognostic nutrition index as preoperative predictors of early mortality after liver resection for huge (≥10 cm) hepatocellular carcinoma

This study aimed to determine preoperative predictors of early (<1 year) mortality from disease recurrence after liver resection (LR) for huge (≥10 cm) HCC, with special emphasis on the importance of neutrophil‐to‐lymphocyte ratio (NLR), platelet‐to‐lymphocyte ratio (PLR), and prognostic nutrition index (PNI).
Depressive symptoms as risk factor of cardiovascular mortality in older European men: the Finland, Italy and Netherlands Elderly (FINE) study

Background Depressive symptoms have been suggested to increase the risk of cardiovascular diseases, but this may reflect reversed causality. We investigated to what extent depressive symptoms are a true risk factor for cardiovascular mortality in elderly men. Design The Finland, Italy and Netherlands Elderly (FINE) study is a prospective cohort study conducted in Finland, Italy and The Netherlands. Methods Depressive symptoms were measured with the Zung self-rating Depression Scale in 799 elderly men, aged 70–90 years, free from cardiovascular diseases. Using Cox models, hazard ratios (HRs) were calculated for specific cardiovascular mortality endpoints. The analyses were adjusted for potential confounders, stratified on country and repeated after exclusion of men who died from cardiovascular diseases up to 5 years after baseline. Results During 10-years of follow-up 224 (28%) men died from cardiovascular diseases. The adjusted hazard for a five-point increase in depressive symptoms was 1.15 [95% confidence interval (CI) 1.08–1.23] for cardiovascular mortality. This risk was stronger for mortality from stroke (HR 1.35; 95% CI 1.19–1.53) and heart failure (HR 1.16; 95% CI 1.00–1.35) in comparison with mortality from coronary heart disease (HR 1.08; 95% CI 0.97–1.20) and other degenerative heart diseases (HR 1.06; 95% CI 0.91–1.23). Exclusion of men who died from cardiovascular diseases within 5 years after baseline did not change the strength of the associations. There were no significant differences in HRs between northern and southern Europe. Conclusions This study provides further and more convincing prospective evidence for depressive symptoms as a risk factor for cardiovascular mortality in elderly men.