Miracle-dz/UniFAR-FTUs huggingface dataset:
Direct Observation of Protein Folding, Aggregation, and a Prion-like Conformational Conversion*

Protein conformational transition from α-helices to β-sheets precedes aggregation of proteins implicated in many diseases, including Alzheimer and prion diseases. Direct characterization of such transitions is often hindered by the complicated nature of the interaction network among amino acids. A recently engineered small protein-like peptide with a simple amino acid composition features a temperature-driven α-helix to β-sheet conformational change. Here we studied the conformational transition of this peptide by molecular dynamics simulations. We observed a critical temperature, below which the peptide folds into an α-helical coiled-coil state and above which the peptide misfolds into β-rich structures with a high propensity to aggregate. The structures adopted by this peptide during low temperature simulations have a backbone root mean square deviation less than 2 Å from the crystal structure. At high temperatures, this peptide adopts an amyloid-like structure, which is mainly composed of coiled anti-parallel β-sheets with the cross-β-signature of amyloid fibrils. Most strikingly, we observed conformational conversions in which an α-helix is converted into a β-strand by proximate stable β-sheets with exposed hydrophobic surfaces and unsaturated hydrogen bonds. Our study suggested a possible generic molecular mechanism of the template-mediated aggregation process, originally proposed by Prusiner (Prusiner, S. B. (1998) Proc. Natl. Acad. Sci. U. S. A. 95, 13363-13383) to account for prion infectivity.
Efficient estimation of transition rates between credit ratings from observations at discrete time points

The paper demonstrates how discrete time credit rating data (e.g. annual observations) can be analysed by means of a continuous-time Markov model. Two methods for estimating the transition intensities are given: the EM algorithm and an MCMC approach. The estimated transition intensities can be used to estimate the matrix of probabilities of transitions between all credit ratings, including default probabilities, over any time horizon. Thus the advantages of a continuous-time model can be obtained without continuous-time data. Estimates of the variance of estimators as well as confidence and credibility intervals are presented, and a test for equality of two intensity matrices is proposed. The methods are demonstrated by analysis of a large data set drawn from Moody's Corporate Bond Default Database, where reasonable estimates are obtained from annual observations.
Counterfactual and prefactual conditionals.

We consider reasoning about prefactual possibilities in the future, for example, "if I were to win the lottery next year I would buy a yacht" and counterfactual possibilities, for example, "if I had won the lottery last year, I would have bought a yacht. " People may reason about indicative conditionals, for example, "if I won the lottery I bought a yacht" by keeping in mind a few true possibilities, for example, "I won the lottery and I bought a yacht. " They understand counterfactuals by keeping in mind two possibilities, the conjecture, "I won the lottery and I bought a yacht" and the presupposed facts, "I did not win the lottery and I did not buy a yacht. " We report the results of three experiments on prefactuals that examine what people judge them to imply, the possibilities they judge to be consistent with them, and the inferences they judge to follow from them. The results show that reasoners keep a single possibility in mind to understand a prefactual.
PRIVACY BY REDESIGN: ALLEVIATING PRIVACY CONCERNS FOR THIRD-PARTY APPLICATIONS Research-in-Progress

In online social networks, the aggressive way of data access and transmission by thirdparty applications (apps) has made privacy concerns particularly salient. Users’ private information can be easily revealed by their and even their friends’ use of apps. A heightened need for empowering user control for third-party apps arises due to the inability to monitor the data use by app providers within and outside of the social networking platform and the inherent uncertainty about their privacy practices. Drawing on the theoretical framework developed by Malhotra et al. (2004), we propose two improved designs of privacy authorization dialogues to encompass control and awareness as the essential factors to address users’ privacy concerns toward thirdparty apps on Facebook. The approach of Privacy by ReDesign is employed to investigate whether users can more adequately represent their preferences for sharing and releasing personal information with these two improved designs.
Cost-based optimization for magic: algebra and implementation

Magic sets rewriting is a well-known optimization heuristic for complex decision-support queries. There can be many variants of this rewriting even for a single query, which differ greatly in execution performance. We propose cost-based techniques for selecting an efficient variant from the many choices.Our first contribution is a practical scheme that models magic sets rewriting as a special join method that can be added to any cost-based query optimizer. We derive cost formulas that allow an optimizer to choose the best variant of the rewriting and to decide whether it is beneficial. The order of complexity of the optimization process is preserved by limiting the search space in a reasonable manner. We have implemented this technique in IBM's DB2 C/S V2 database system. Our performance measurements demonstrate that the cost-based magic optimization technique performs well, and that without it, several poor decisions could be made.Our second contribution is a formal algebraic model of magic sets rewriting, based on an extension of the multiset relational algebra, which cleanly defines the search space and can be used in a rule-based optimizer. We introduce the multiset &theta;-semijoin operator, and derive equivalence rules involving this operator. We demonstrate that magic sets rewriting for non-recursive SQL queries can be modeled as a sequential composition of these equivalence rules.
The Choice of Titling System in Land

This paper analyzes the choice of the socially optimal titling system assuming rational individual choices about recording, assurance and registration decisions. It focuses on the enforcement of property rights on land under private titling and the two existing public titling systems, recording and registration. When the reduction in the expected costs of eviction compensates the higher cost of initial registration, it is more efficient to introduce a registration system rather than a recording system. The development of private "title assurance" improves the standing of recording as compared to registration. This improvement depends, however, on the efficiency of the assurance technology and, also, on corrective taxation that is needed to align individual optimization, which disregards the transfer element in eviction, with social objectives.
Keratin 8/18 Regulation of Cell Stiffness-Extracellular Matrix Interplay through Modulation of Rho-Mediated Actin Cytoskeleton Dynamics

Cell mechanical activity generated from the interplay between the extracellular matrix (ECM) and the actin cytoskeleton is essential for the regulation of cell adhesion, spreading and migration during normal and cancer development. Keratins are the intermediate filament (IF) proteins of epithelial cells, expressed as pairs in a lineage/differentiation manner. Hepatic epithelial cell IFs are made solely of keratins 8/18 (K8/K18), hallmarks of all simple epithelia. Notably, our recent work on these epithelial cells has revealed a key regulatory function for K8/K18 IFs in adhesion/migration, through modulation of integrin interactions with ECM, actin adaptors and signaling molecules at focal adhesions. Here, using K8-knockdown rat H4 hepatoma cells and their K8/K18-containing counterparts seeded on fibronectin-coated substrata of different rigidities, we show that the K8/K18 IF-lacking cells lose their ability to spread and exhibit an altered actin fiber organization, upon seeding on a low-rigidity substratum. We also demonstrate a concomitant reduction in local cell stiffness at focal adhesions generated by fibronectin-coated microbeads attached to the dorsal cell surface. In addition, we find that this K8/K18 IF modulation of cell stiffness and actin fiber organization occurs through RhoA-ROCK signaling. Together, the results uncover a K8/K18 IF contribution to the cell stiffness-ECM rigidity interplay through a modulation of Rho-dependent actin organization and dynamics in simple epithelial cells.
Asymmetric isolating barriers between different microclimatic environments caused by low immigrant survival

Spatially variable selection has the potential to result in local adaptation unless counteracted by gene flow. Therefore, barriers to gene flow will help facilitate divergence between populations that differ in local selection pressures. We performed spatially and temporally replicated reciprocal field transplant experiments between inland and coastal habitats using males of the common blue damselfly (Enallagma cyathigerum) as our study organism. Males from coastal populations had lower local survival rates than resident males at inland sites, whereas we detected no differences between immigrant and resident males at coastal sites, suggesting asymmetric local adaptation in a source–sink system. There were no intrinsic differences in longevity between males from the different environments suggesting that the observed differences in male survival are environment-dependent and probably caused by local adaptation. Furthermore, the coastal environment was found to be warmer and drier than the inland environment, further suggesting local adaptation to microclimatic factors has lead to differential survival of resident and immigrant males. Our results suggest that low survival of immigrant males mediates isolation between closely located populations inhabiting different microclimatic environments.
Korean version of Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised: A Pilot Study on the Reliability and Validity

a , Korea Background: The Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) is a quantitative measure of ALS-related physical deficit with established reliability and validity in prospective clinical research. This study aimed to test the reliability and validity of the Korean version of ALSFRS-R (K-ALSFRS-R). Methods: The subjects of the study were 51 patients with ALS diagnosed on the basis of El Escorial criteria. The patients were evaluated by one rater using K-ALSFRS-R, Norris scale, and Appel ALS rating scale on the same day. Subsequently, K-ALSFRS-R was measured by two other raters using a videotape design. Test-retest data were obtained within the time interval of 7 days. Results: Internal consistency and test-retest reliability were high. Inter-rater comparisons showed significant reliability with Kappa or Kendall's tau-b value. Moreover, K-ALSFRS-R scores correlated significantly with clinical status as measured by Norris and Appel ALS rating scale. Conclusions: Our results showed that K-ALSFRS-R would be a reliable and use ful instrument for the evaluation of functional status in patients with ALS. J Korean Neurol Assoc 25(2):149-154, 2007
Subclinical toxicity of calcineurin inhibitors in repeated protocol biopsies: an independent risk factor for chronic kidney allograft damage

The purpose of the prospective study was to determine the prevalence of subclinical toxicity of calcineurin inhibitors (CI) in repeated protocol renal allograft biopsies and to assess its impact on the development of chronic graft changes. A total of 424 biopsies were conducted in a cohort of 158 patients; of these biopsies, 158 were in the third week, 142 were in the third month and 124 were in the first year after transplantation. Histological signs of toxicity occurred in the third week in 33 (20.1%) patients, with persistence after CI dose reduction in the third month in 27 (19.0%) and in the first year in 23 (18.5%) patients. Of the toxic changes, 52% were clinically silent. At the end of the one‐year follow‐up, both subclinical and clinically manifest toxicity resulted in a similar progression of chronic changes quantified by Banff chronicity score and they significantly differed from the control group (P < 0.05). Subclinical toxicity affects a significant percentage of grafts; it occurs independently of dosage, blood level and type of applied CI. It is associated with the progression of chronic changes as early as in the first year after transplantation and represents an independent risk factor for chronic allograft damage. We report here our clinical approach to toxicity.
An Lnc RNA (GAS5)/SnoRNA-derived piRNA induces activation of TRAIL gene by site-specifically recruiting MLL/COMPASS-like complexes

PIWI-interacting RNA (piRNA) silences the transposons in germlines or induces epigenetic modifications in the invertebrates. However, its function in the mammalian somatic cells remains unknown. Here we demonstrate that a piRNA derived from Growth Arrest Specific 5, a tumor-suppressive long non-coding RNA, potently upregulates the transcription of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a proapoptotic protein, by inducing H3K4 methylation/H3K27 demethylation. Interestingly, the PIWIL1/4 proteins, which bind with this piRNA, directly interact with WDR5, resulting in a site-specific recruitment of the hCOMPASS-like complexes containing at least MLL3 and UTX (KDM6A). We have indicated a novel pathway for piRNAs to specially activate gene expression. Given that MLL3 or UTX are frequently mutated in various tumors, the piRNA/MLL3/UTX complex mediates the induction of TRAIL, and consequently leads to the inhibition of tumor growth.
Conservation/Mutation in the Splice Sites of Cytokine Receptor Genes of Mouse and Human

Conservation/mutation in the intronic initial and terminal hexanucleotides was studied in 26 orthologous cytokine receptor genes of Mouse and Human. Introns began and ended with the canonical dinucleotides GT and AG, respectively. Identical configurations were found in 57% of the 5′ hexanucleotides and 28% of the 3′ hexanucleotides. The actual conservation percentages of the individual variable nucleotides at each position in the hexanucleotides were determined, and the theoretical rates of conservation of groups of three nucleotides were calculated under the hypothesis of a mutual evolutionary independence of the neighboring nucleotides (random association). Analysis of the actual conservation of groups of variable nucleotides showed that, at 5′, GTGAGx was significantly more expressed and GTAAGx was significantly less expressed, as compared to the random association. At 3′, TTTxAG and xTGCAG were overexpressed as compared to a random association. Study of Mouse and Human transcript variants involving the splice sites showed that most variants were not inherited from the common ancestor but emerged during the process of speciation. In some variants the silencing of a terminal hexanucleotide determined skipping of the downstream exon; in other variants the constitutive splicing hexanucleotide was replaced by another potential, in-frame, splicing hexanucleotide, leading to alterations of exon lengths.
Risk Factors for Cerebrovascular Disease Mortality among the Elderly in Beijing: A Competing Risk Analysis

Objective To examine the associations of combined lifestyle factors and physical conditions with cerebrovascular diseases (CBVD) mortality, after accounting for competing risk events, including death from cardiovascular diseases, cancers and other diseases. Methods Data on 2010 subjects aged over 55 years were finally analyzed using competing risk models. All the subjects were interviewed by the Beijing Longitudinal Study of Aging (BLSA), in China, between 1 January 1992 and 30 August 2009. Results Elderly females were at a lower risk of death from CBVD than elderly males (HR = 0.639, 95% CI = 0.457–0.895). Increasing age (HR = 1.543, 95% CI = 1.013–2.349), poor self-rated health (HR = 1.652, 95% CI = 1.198–2.277), hypertension (HR = 2.201, 95% CI = 1.524–3.178) and overweight (HR = 1.473, 95% CI = 1.013–2.142) or obesity (HR = 1.711, 95% CI = 1.1754–2.490) was associated with higher CBVD mortality risk. Normal cognition function (HR = 0.650, 95% CI = 0.434–0.973) and living in urban (HR = 0.456, 95% CI = 0.286–0.727) was associated with lower CBVD mortality risk. Gray’s test also confirmed the cumulative incidence (CIF) of CBVD was lower in the ‘married’ group than those without spouse, and the mortality was lowest in the ‘nutrition sufficient’ group among the ‘frequent consumption of meat group’ and the ‘medial type group’ (P value<0.001). Conclusions CBVD mortality was associated with gender, age, blood pressure, residence, BMI, cognitive function, nutrition and the result of self-rated health assessment in the elderly in Beijing, China.
Vascular Endothelial Growth Factor Induces Shc Association With Vascular Endothelial Cadherin: A Potential Feedback Mechanism to Control Vascular Endothelial Growth Factor Receptor-2 Signaling

Vascular endothelial (VE)-cadherin is endothelium specific, mediates homophilic adhesion, and is clustered at intercellular junctions. VE-cadherin is required for normal development of the vasculature in the embryo and for angiogenesis in the adult. Here, we report that VE-cadherin is associated with VE growth factor (VEGF) receptor-2 (VEGFR-2) on the exposure of endothelial cells to VEGF. The binding parallels receptor phosphorylation on tyrosine residues, which is maximal at 5 minutes and then declines within 30 minutes. Tyrosine phosphorylation of VE-cadherin was maximal at 30 minutes after the addition of the growth factor. At this time point, the protein could be coimmunoprecipitated with the adaptor protein Shc. Pull-down experiments with different Shc domains and mutants of the VE-cadherin cytoplasmic tail have shown that Shc binds to the carboxy-terminal domain of the VE-cadherin tail through its Src homology 2 domain (SH2). We found that Shc phosphorylation lasts longer in endothelial cells carrying a targeted null mutation in the VE-cadherin gene than in VE-cadherin–positive cells. These data suggest that VE-cadherin expression exerts a negative effect on Shc phosphorylation by VEGFR-2. We speculate that VE-cadherin binding to Shc promotes its dephosphorylation through associated phosphatases.
Association of extinction risk of saproxylic beetles with ecological degradation of forests in Europe

To reduce future loss of biodiversity and to allocate conservation funds effectively, the major drivers behind large‐scale extinction processes must be identified. A promising approach is to link the red‐list status of species and specific traits that connect species of functionally important taxa or guilds to resources they rely on. Such traits can be used to detect the influence of anthropogenic ecosystem changes and conservation efforts on species, which allows for practical recommendations for conservation. We modeled the German Red List categories as an ordinal index of extinction risk of 1025 saproxylic beetles with a proportional‐odds linear mixed‐effects model for ordered categorical responses. In this model, we estimated fixed effects for intrinsic traits characterizing species biology, required resources, and distribution with phylogenetically correlated random intercepts. The model also allowed predictions of extinction risk for species with no red‐list category. Our model revealed a higher extinction risk for lowland and large species as well as for species that rely on wood of large diameter, broad‐leaved trees, or open canopy. These results mirror well the ecological degradation of European forests over the last centuries caused by modern forestry, that is the conversion of natural broad‐leaved forests to dense conifer‐dominated forests and the loss of old growth and dead wood. Therefore, conservation activities aimed at saproxylic beetles in all types of forests in Central and Western Europe should focus on lowlands, and habitat management of forest stands should aim at increasing the amount of dead wood of large diameter, dead wood of broad‐leaved trees, and dead wood in sunny areas.
A Multicentre, Double-Blind, Randomised, Parallel-Group, Placebo-Controlled Study of Effect of Long-Term Sativex Treatment on Cognition and Mood of Patients with Spasticity Due to Multiple Sclerosis

Objective: When Sativex i THC:CBD cannabinoid-based oromucosal spray was first approved as a prescription medicine for multiple sclerosis (MS) spasticity, there was some concern about its possible long-term impact on cognition and mood. The objective of this study was therefore to assess the long-term impact of Sativex on cognitive function and mood in MS patients with spasticity. Methods: 121 patients were randomly assigned Sativex or placebo in a double-blind manner. Patients selfadministered treatment daily for 48 weeks while maintaining anti-spasticity therapy. The primary endpoint was the difference between treatments in Paced Auditory Serial Addition Test (PASAT) score from baseline to end of treatment. Secondary measures included Beck Depression Inventory-II (BDI-II), Subject-, Physician- and Caregiver Global Impression of Change, and Columbia-Suicide Severity Rating Scale. Results: 62 patients were randomised to Sativex and 59 to placebo. There was no difference in the effect of Sativex on PASAT and BDI-II scores compared with placebo. Subject-, Physician- and Caregiver-rated improvements in spasticity with Sativex were all statistically significant. The mean daily dose of Sativex declined gradually to 6.4 sprays per day. Conclusion: Long-term treatment with Sativex was not associated with cognitive decline or significant changes in mood in this prone population sample. Sativex was efficacious and well tolerated across the study period and no new safety concerns were identified.
Metabolomics Tools for Describing Complex Pesticide Exposure in Pregnant Women in Brittany (France)

Background The use of pesticides and the related environmental contaminations can lead to human exposure to various molecules. In early-life, such exposures could be responsible for adverse developmental effects. However, human health risks associated with exposure to complex mixtures are currently under-explored. Objective This project aims at answering the following questions: What is the influence of exposures to multiple pesticides on the metabolome? What mechanistic pathways could be involved in the metabolic changes observed? Methods Based on the PELAGIE cohort (Brittany, France), 83 pregnant women who provided a urine sample in early pregnancy, were classified in 3 groups according to the surface of land dedicated to agricultural cereal activities in their town of residence. Nuclear magnetic resonance-based metabolomics analyses were performed on urine samples. Partial Least Squares Regression-Discriminant Analysis (PLS-DA) and polytomous regressions were used to separate the urinary metabolic profiles from the 3 exposure groups after adjusting for potential confounders. Results The 3 groups of exposure were correctly separated with a PLS-DA model after implementing an orthogonal signal correction with pareto standardizations (R2 = 90.7% and Q2 = 0.53). After adjusting for maternal age, parity, body mass index and smoking habits, the most statistically significant changes were observed for glycine, threonine, lactate and glycerophosphocholine (upward trend), and for citrate (downward trend). Conclusion This work suggests that an exposure to complex pesticide mixtures induces modifications of metabolic fingerprints. It can be hypothesized from identified discriminating metabolites that the pesticide mixtures could increase oxidative stress and disturb energy metabolism.