Miracle-dz/UniFAR-FTUs huggingface dataset:
Accurate computer-based design of a new backbone conformation in the second turn of protein L.

The rational design of loops and turns is a key step towards creating proteins with new functions. We used a computational design procedure to create new backbone conformations in the second turn of protein L. The Protein Data Bank was searched for alternative turn conformations, and sequences optimal for these turns in the context of protein L were identified using a Monte Carlo search procedure and an energy function that favors close packing. Two variants containing 12 and 14 mutations were found to be as stable as wild-type protein L. The crystal structure of one of the variants has been solved at a resolution of 1.9 A, and the backbone conformation in the second turn is remarkably close to that of the in silico model (1.1 A RMSD) while it differs significantly from that of wild-type protein L (the turn residues are displaced by an average of 7.2 A). The folding rates of the redesigned proteins are greater than that of the wild-type protein and in contrast to wild-type protein L the second beta-turn appears to be formed at the rate limiting step in folding.
Variation in Population Synchrony in a Multi-Species Seabird Community: Response to Changes in Predator Abundance

Ecologically similar sympatric species, subject to typical environmental conditions, may be expected to exhibit synchronous temporal fluctuations in demographic parameters, while populations of dissimilar species might be expected to show less synchrony. Previous studies have tested for synchrony in different populations of single species, and those including data from more than one species have compared fluctuations in only one demographic parameter. We tested for synchrony in inter-annual changes in breeding population abundance and productivity among four tern species on Coquet Island, northeast England. We also examined how manipulation of one independent environmental variable (predator abundance) influenced temporal changes in ecologically similar and dissimilar tern species. Changes in breeding abundance and productivity of ecologically similar species (Arctic Sterna paradisaea, Common S. hirundo and Roseate Terns S. dougallii) were synchronous with one another over time, but not with a species with different foraging and breeding behaviour (Sandwich Terns Thalasseus sandvicensis). With respect to changes in predator abundance, there was no clear pattern. Roseate Tern abundance was negatively correlated with that of large gulls breeding on the island from 1975 to 2013, while Common Tern abundance was positively correlated with number of large gulls, and no significant correlations were found between large gull and Arctic and Sandwich Tern populations. Large gull abundance was negatively correlated with productivity of Arctic and Common Terns two years later, possibly due to predation risk after fledging, while no correlation with Roseate Tern productivity was found. The varying effect of predator abundance is most likely due to specific differences in the behaviour and ecology of even these closely-related species. Examining synchrony in multi-species assemblages improves our understanding of how whole communities react to long-term changes in the environment and suggests that changes in predator abundance may differentially affect populations of sympatric seabird species.
Dynamic bookmarks for the WWW

This paper describes a management tool to support revisiting WWW pages, which we call “WWW Dynamic Bookmark (WDB). ” WDB watches and archives a user’s navigation behavior, analyses the archive, and shows analyzed results as clues for revisiting URLs. We have integrated link analysis and user behavior analysis to evaluate WWW page importance. WDB presents a list of sites that a user has visited, in importance order, via a landmark list in each site, and showing relationships among sites. Experimental implementation shows that importance calculation and structure displays help users to pick up useful URLs.
Stochastic Mortality Under Measure Changes

We provide a self-contained analysis of a class of continuous-time stochastic mortality models that have gained popularity in the last few years. We describe some of their advantages and limitations, examining whether their features survive equivalent changes of measures. This is important when using the same model for both market-consistent valuation and risk management of life insurance liabilities. We provide a numerical example based on the calibration to the French annuity market of a risk-neutral version of the model proposed by Lee and Carter (1992).
The modified Cramer-Rao bound and its application to synchronization problems

We introduce the modified Cramer-Rao bound (CRB) which, like the true CRB, is a lower bound to the error variance of any parameter estimator. The modified CRB proves useful when, in addition to the parameter to be estimated, the observed data also depend on other unwanted parameters. The relationship between the modified and true CRB is established and applications are discussed regarding the estimation of carrier-frequency offset, carrier phase, and timing epoch in linearly modulated signals. Modified CRBs for phase and timing estimation have been already discussed in previous works where it is shown that several practical carrier-phase and clock recovery circuits do attain such bounds. Frequency discrimination, instead, is not so well-represented in the literature and a significant contribution of this paper is the calculation of the modified CRB for frequency estimation. This bound is compared with the performance of some frequency detectors and it is concluded that further work is needed in search of more efficient frequency discrimination methods. >
Response to 'Survival advantage for etoposide/cisplatin over paclitaxel/carboplatin concurrent chemoradiation in patients with inoperable stage III NSCLC: a subgroup analysis for ECOG 2 patients would be of great interest'.

dium. A notable exception was shown in the plenary session where the authors concluded with data from nearly 13 000 patients and a difference of <1% in 3 year disease-free survival that overall noninferiority was not established [3]—a formally correct interpretation that might be even too strict from a practical point of view. In the article by Kwakman et al. non-inferiority not used explicitly, but the results are discussed this way. Moreover, it is important not to look only at P-values and point estimates but also at confidence intervals. Looking at overall survival the data at hand are concordant with a risk reduction of 18%, but also with an increase of 86% when comparing S-1 with capecitabine! A much larger sample size would be required to support claims of similar efficacy by adequately narrow confidence intervals. To that end the question of efficacy and safety of S-1 and capecitabine has been investigated in gastric cancer by meta-analytic approaches [4, 5]. In conclusion, more than 20 years after the instructive article by Altman and Bland methodological rigor is still required in the interpretation of non-significant differences.
Induction of fibronectin matrix assembly in human fibrosarcoma cells by dexamethasone

Previous studies have suggested that the assembly of fibronectin into the extracellular matrix of cultured fibroblasts is mediated by specific matrix assembly receptors that recognize a binding site in the amino terminus of the fibronectin molecule (McKeown-Longo, P.J., and D.F. Mosher, 1985, J. Cell Biol., 100:364-374). In the presence of dexamethasone, human fibrosarcoma cells (HT-1080) acquired the ability to specifically bind exogenous plasma fibronectin and incorporate it into a detergent-insoluble extracellular matrix. Dexamethasone-induced fibronectin binding to HT-1080 cells was time dependent, dose dependent, and inhibited by cycloheximide. Saturation binding curves indicated that dexamethasone induced the appearance of 7.7 X 10(4) matrix assembly receptors per cell. The induced receptors exhibited a dissociation constant (KD) for soluble fibronectin of 5.0 X 10(-8) M. In parallel experiments, normal fibroblasts exhibited 4.1 X 10(5) receptors (KD = 5.3 X 10(-8) M) per cell. In the presence of cycloheximide, the induced fibronectin-binding activity on HT-1080 cells returned to uninduced levels within 12 h. In contrast, fibronectin-binding activity on normal fibroblasts was stable in the presence of cycloheximide for up to 54 h. The first-order rate constant (Kt = 2.07 X 10(-4) min-1) for the transfer of receptor-bound fibronectin to extracellular matrix was four- to fivefold less than that for normal fibroblasts (Kt = 1.32 X 10(-3) min-1). Lactoperoxidase- catalyzed iodination of HT-1080 monolayers indicated that a 48,000-mol- wt cell surface protein was enhanced with dexamethasone. The results from these experiments suggest that dexamethasone induces functional matrix assembly receptors on the surface of HT-1080 cells; however, the rate of incorporation of fibronectin into the matrix is much slower than that of normal fibroblasts.
Identifying Emotions in Social Media: Comparison of Word-Emotion Lexicons

In recent years, emotions expressed in social media messages have become a vivid research topic due to their influence on the spread of misinformation and online radicalization over online social networks. Thus, it is important to correctly identify emotions in order to make inferences from social media messages. In this paper, we report on the performance of three publicly available word-emotion lexicons (NRC, DepecheMood, EmoSenticNet) over a set of Facebook and Twitter messages. To this end, we designed and implemented an algorithm that applies natural language processing (NLP) techniques along with a number of heuristics that reflect the way humans naturally assess emotions in written texts. In order to evaluate the appropriateness of the obtained emotion scores, we conducted a questionnaire-based survey with human raters. Our results show that there are noticeable differences between the performance of the lexicons as well as with respect to emotion scores the human raters provided in our survey.
Emigration and Wages: The EU Enlargement Experiment

The enlargement of the European Union provides a unique opportunity to study the impact of the lifting of migration restrictions on the migrant sending countries. With EU enlargement in 2004, 1.2 million workers from Eastern Europe emigrated to the UK and Ireland. I use this emigration wave to show that emigration significantly changed the wage distribution in the sending country, in particular between young and old workers. Using a novel dataset from Lithuania, the UK and Ireland for the calibration of a structural model of labor demand, I find that over the period of five years emigration increased the wages of young workers by 6%, while it had no effect on the wages of old workers. Contrary to the immigration literature, there is no significant effect of emigration on the wage distribution between high-skilled and low-skilled workers.
A Cell Line for Detection of Botulinum Neurotoxin Type B

Botulinum neurotoxins (BoNTs) type A and type B are commonly used as biopharmaceutics for neurological diseases, uniquely allowing months-long paralysis of target muscles. Their exquisite neuronal specificity is conferred by a multistep process of binding, internalization, cytosolic escape and cleavage of the neuron-specific proteins, SNAP-25 and vesicle-associated membrane proteins (VAMPs), ultimately to inhibit secretion of neurotransmitters. Currently the mouse lethality bioassay is the only available method for quality control testing of VAMP-cleaving botulinum products. Refined assays for botulinum product testing are urgently needed. Specifically, in vitro replacement assays which can account for all steps of BoNT intoxication are in high demand. Here, we describe a novel SiMa cell-based approach where re-engineering of the VAMP molecule allows detection of all BoNT/B intoxication steps using a luminescent enzymatic reaction with sensitivity comparable to mouse LD50 bioassay. The presented one-step enzyme-linked immunosorbent assay meets 3Rs (replacement, reduction, and refinement of the use of animals) objectives, is user-friendly and will accelerate development of new botulinum drugs. The sensitive enzymatic reporter cell line could also be adapted for the detection of toxin activity during the manufacture of botulinum and tetanus vaccines.
Characterization of a Novel Potassium-Competitive Acid Blocker of the Gastric H,K-ATPase, 1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine Monofumarate (TAK-438)

Inhibition of the gastric H,K-ATPase by the potassium-competitive acid blocker (P-CAB) 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine (TAK-438), is strictly K+-competitive with a Ki of 10 nM at pH 7. In contrast to previous P-CABs, this structure has a point positive charge (pKa 9.06) allowing for greater accumulation in parietal cells compared with previous P-CABs [e.g., (8-benzyloxy-2-methyl-imidazo(1,2-a)pyridin-3-yl)acetonitrile (SCH28080), pKa 5.6]. The dissociation rate of the compound from the isolated ATPase is slower than other P-CABs, with the t1/2 being 7.5 h in 20 mM KCl at pH 7. The stoichiometry of binding of TAK-438 to the H,K-ATPase is 2.2 nmol/mg in the presence of Mg-ATP, vanadate, or MgPi. However, TAK-438 also binds enzyme at 1.3 nmol/mg in the absence of Mg2+. Modeling of the H,K-ATPase to the homologous Na,K-ATPase predicts a close approach and hydrogen bonding between the positively charged N-methylamino group and the negatively charged Glu795 in the K+-binding site in contrast to the planar diffuse positive charge of previous P-CABs. This probably accounts for the slow dissociation and high affinity. The model also predicts hydrogen bonding between the hydroxyl of Tyr799 and the oxygens of the sulfonyl group of TAK-438. A Tyr799Phe mutation resulted in a 3-fold increase of the dissociation rate, showing that this hydrogen bonding also contributes to the slow dissociation rate. Hence, this K+-competitive inhibitor of the gastric H,K-ATPase should provide longer-lasting inhibition of gastric acid secretion compared with previous drugs of this class.
StoryGraphs: Visualizing Character Interactions as a Timeline

We present a novel way to automatically summarize and represent the storyline of a TV episode by visualizing character interactions as a chart. We also propose a scene detection method that lends itself well to generate over-segmented scenes which is used to partition the video. The positioning of character lines in the chart is formulated as an optimization problem which trades between the aesthetics and functionality of the chart. Using automatic person identification, we present StoryGraphs for 3 diverse TV series encompassing a total of 22 episodes. We define quantitative criteria to evaluate StoryGraphs and also compare them against episode summaries to evaluate their ability to provide an overview of the episode.
Oral Health Literacy And Its Impact On Oral Health Status Among Institutionalised Elderly Population

OBJECTIVES: To determine oral health literacy among institutionalized elderly south Indian population and correlate the effect of oral health literacy on their oral health status. METHODS: A cross-sectional descriptive epidemiological study was conducted on a sample of 450 institutionalized elderly subjects who were randomly selected from 10 institutions from two capital cities of two states selected by multistage sampling. Oral health literacy was assessed by making the subjects pronounce a list of 30 words from REALD-30. Oral health status was assessed using modified WHO (1997) proforma. Pearson’s correlation was done to correlate oral health status with oral health literacy. Multiple linear regression analysis was done to assess the impact of various independent variables on oral health literacy. RESULTS: The mean age of participants was 77.45±9.04 years and the majority of them were from lower middle class (35.8%). Overall the mean oral health literacy rate of participants was 21.64±4.16. High oral health literacy (OHL≥26) was reported in just 19.3% of elderly subjects. Correlation of oral health literacy scores with oral health status revealed a negative correlation with oral hygiene status (-0.23) and dental caries prevalence (-0.420). When the impact of various independent variables on oral health literacy was assessed with multiple linear regression analysis sex, socioeconomic status, education, frequency of brushing, periodontal status and DMFT showed a significant association. CONCLUSION: Institutionalized elderly subjects showed an overall low oral health literacy rate and subjects with poor oral health literacy had poor oral health status.
Crosstalk between the urokinase-type plasminogen activator receptor and EGF receptor variant III supports survival and growth of glioblastoma cells

A truncated and constitutively active form of the EGF receptor, variant III (EGFRvIII), is a major determinant of tumor growth and progression in glioblastoma multiforme (GBM). Extensive bidirectional crosstalk occurs in the cell-signaling pathways downstream of the EGFR and the urokinase-type plasminogen activator receptor (uPAR); however, crosstalk between EGFRvIII and uPAR has not been examined. Here, we show that uPAR does not regulate ERK activation in EGFRvIII-expressing GBM cells; however, in GBM cells isolated from four separate xenografts in which EGFRvIII expression was down-regulated in vivo, uPAR assumed a major role in sustaining ERK activation. Phosphorylation of Tyr-845 in the EGFR, which is mediated by Src family kinases, depended on uPAR in EGFRvIII-expressing GBM cells. Activation of the mitogenic and prosurvival transcription factor, STAT5b, downstream of EGFRvIII, also required uPAR. The EGFR-selective tyrosine kinase inhibitors, erlotinib and gefitinib, blocked not only EGFRvIII signaling to ERK but also uPAR-dependent STAT5b activation. uPAR gene silencing in EGFRvIII-expressing GBM cells and in cells from tumors that escaped dependency on EGFRvIII decreased cell survival and proliferation. Xenografts of EGFRvIII-expressing cancer cell lines and a human GBM, which was propagated as a xenograft, were robustly immunopositive for uPAR and phospho–Tyr-845 by immunohistochemistry. A human GBM in which the EGFR gene was amplified without truncation was immunonegative for both uPAR and phospho–Tyr-845. These studies identify distinct cell-signaling activities for uPAR in GBM cells that express EGFRvIII and in cells released from dormancy when EGFRvIII is neutralized. uPAR and its crosstalk pathways with EGFRvIII emerge as logical targets for therapeutics development in GBM.
Nigrostriatal collaterals to thalamus degenerate in parkinsonian animal models

Movement, cognition, emotion, and positive reinforcement are influenced by mesostriatal, mesocortical, and mesolimbic dopamine systems. Here, we describe a fourth major pathway originating from mesencephalic dopamine neurons: a mesothalamic system. The dopamine transporter, specific to dopamine containing axons, was histochemically visualized in thalamic motor and limbic‐related nuclei and regions that modulate behavioral state as opposed to sensory nuclei in rats, nonhuman primates, and humans. Anatomical tracing established this innervation's origin via axon collaterals from the mesostriatal pathway. These findings implicate the thalamus as a novel site for disease specific alterations in dopamine neurotransmission, such as exist with nigral degeneration attending Parkinson's disease. This was confirmed in hemiparkinsonian animals where reduction of thalamic dopamine innervation occurred coincident with signs of active axonal degeneration. Individual mesencephalic dopamine neurons therefore have the potential to modulate normal and pathologic behavior not only through traditional nigrostriatal pathways but also by way of axon collaterals that innervate the thalamus.
Time-Frequency Analysis of Classical Trajectories of polyatomic molecules

We present a new method of frequency analysis for Hamiltonian Systems of 3 degrees of freedom and more. The method is based on the concept of instantaneous frequency extracted numerically from the continuous wavelet transform of the trajectories. Knowing the time-evolution of the frequencies of a given trajectory, we can define a frequency map, resonances, and diffusion in frequency space as an indication of chaos. The time-frequency analysis method is applied to the Baggott Hamiltonian to characterize the global dynamics and the structure of the phase space in terms of resonance channels. This 3-degree-of-freedom system results from the classical version of the quantum Hamiltonian for the water molecule given by Baggott [1988]. Since another first integral of the motion exists, the so-called Polyad number, the system can be reduced to 2 degrees of freedom. The dynamics is therefore simplified and we give a complete characterization of the phase space, and at the same time we could validate the results of the time-frequency analysis.
Integrated analysis of microRNA and mRNA expression: adding biological significance to microRNA target predictions

Current microRNA target predictions are based on sequence information and empirically derived rules but do not make use of the expression of microRNAs and their targets. This study aimed to improve microRNA target predictions in a given biological context, using in silico predictions, microRNA and mRNA expression. We used target prediction tools to produce lists of predicted targets and used a gene set test designed to detect consistent effects of microRNAs on the joint expression of multiple targets. In a single test, association between microRNA expression and target gene set expression as well as the contribution of the individual target genes on the association are determined. The strongest negatively associated mRNAs as measured by the test were prioritized. We applied our integration method to a well-defined muscle differentiation model. Validation of our predictions in C2C12 cells confirmed predicted targets of known as well as novel muscle-related microRNAs. We further studied associations between microRNA–mRNA pairs in human prostate cancer, finding some pairs that have been recently experimentally validated by others. Using the same study, we showed the advantages of the global test over Pearson correlation and lasso. We conclude that our integrated approach successfully identifies regulated microRNAs and their targets.
Functional magnetic resonance imaging of reward prediction

Purpose of reviewTechnical and conceptual advances in functional magnetic resonance imaging now allow visualization of real-time changes in oxygenation of deep subcortical regions, leading to rapid advances in scientific characterization of the neural substrates that underlie reward prediction in humans. Recent findingsNeuroimaging research over the past year has focused on determining the necessary neural substrates for reward prediction. SummaryWhile the orbitofrontal cortex has long been implicated in modality-specific reward representation, the ventral striatum (particularly the nucleus accumbens) may play a role in modality-independent representations of predicted reward. On the other hand, the mesial prefrontal cortex appears to play a role in representing reward prediction error and the dorsal caudate in linking reward to behavior. Theoretically, future studies will need to establish the specificity of these responses to reward versus punishment and anticipation versus outcome. Clinically, current findings suggest that patients can predict reward without a prefrontal cortex, but should experience difficulty correcting their behavior when reward predictions are violated.