Miracle-dz/UniFAR-FTUs huggingface dataset:
A View of Pre-mRNA Splicing from RNase R Resistant RNAs

During pre-mRNA splicing, exons in the primary transcript are precisely connected to generate an mRNA. Intron lariat RNAs are formed as by-products of this process. In addition, some exonic circular RNAs (circRNAs) may also result from exon skipping as by-products. Lariat RNAs and circRNAs are both RNase R resistant RNAs. RNase R is a strong 3' to 5' exoribonuclease, which efficiently degrades linear RNAs, such as mRNAs and rRNAs; therefore, the circular parts of lariat RNAs and the circRNAs can be segregated from eukaryotic total RNAs by their RNase R resistance. Thus, RNase R resistant RNAs could provide unexplored splicing information not available from mRNAs. Analyses of these RNAs identified repeating splicing phenomena, such as re-splicing of mature mRNAs and nested splicing. Moreover, circRNA might function as microRNA sponges. There is an enormous variety of endogenous circRNAs, which are generally synthesized in cells and tissues.
Spatial-Temporal Evolution of the Distribution Pattern of Neolithic Sites in Han River Basin, China

ABSTRACT This study analyzed the spatial and temporal distributions of 644 Neolithic sites in the Han River basin, China. The results showed that 31.06% of the Neolithic sites were distributed on low-altitude plains with an average altitude of 144.78 m; 22.98% were located on low platforms with an average altitude of 137.92 m, and 12.73% were distributed on low-altitude hills with an average altitude of 240.77 m. The aggregation fractal dimension (A), the proportion of pottery with carbon (PPMC) and the proportion of polished stone (PPST) were introduced to reveal the social development level. Meanwhile, the temperature anomalies (AT), total organic carbon content (TOC), total nitrogen content (TN), and carbon isotopic ratios (δ13C) were used to reveal the environmental context. Then, the correlation coefficients (hereafter, R) between different indicators were calculated. The result showed that a stable and suitable natural environment was a prerequisite for social development in the Neolithic Age. The persistent improvement in the ability of human beings to identify, manipulate and utilise nature was observed in the Neolithic Age in Han River basin, which marked the transformation of human society from hunting to farming and the start of human interactions with the natural world over time.
Molecular Mechanisms of Calmodulin Action on TRPV5 and Modulation by Parathyroid Hormone

ABSTRACT The epithelial Ca2+ channel transient receptor potential vanilloid 5 (TRPV5) constitutes the apical entry gate for active Ca2+ reabsorption in the kidney. Ca2+ influx through TRPV5 induces rapid channel inactivation, preventing excessive Ca2+ influx. This inactivation is mediated by the last ∼30 residues of the carboxy (C) terminus of the channel. Since the Ca2+-sensing protein calmodulin has been implicated in Ca2+-dependent regulation of several TRP channels, the potential role of calmodulin in TRPV5 function was investigated. High-resolution nuclear magnetic resonance (NMR) spectroscopy revealed a Ca2+-dependent interaction between calmodulin and a C-terminal fragment of TRPV5 (residues 696 to 729) in which one calmodulin binds two TRPV5 C termini. The TRPV5 residues involved in calmodulin binding were mutated to study the functional consequence of releasing calmodulin from the C terminus. The point mutants TRPV5-W702A and TRPV5-R706E, lacking calmodulin binding, displayed a strongly diminished Ca2+-dependent inactivation compared to wild-type TRPV5, as demonstrated by patch clamp analysis. Finally, parathyroid hormone (PTH) induced protein kinase A (PKA)-dependent phosphorylation of residue T709, which diminished calmodulin binding to TRPV5 and thereby enhanced channel open probability. The TRPV5-W702A mutant exhibited a significantly increased channel open probability and was not further stimulated by PTH. Thus, calmodulin negatively modulates TRPV5 activity, which is reversed by PTH-mediated channel phosphorylation.
de Travail du Centre d ’ Economie de la Sorbonne Political Ideology and Economic Growth in a Democracy : The French Experience , 1871-2009

This paper examines the influence of political ideology on economic growth in the French democracy since 1871. It does so by addressing three main issues: the property and the reliability of a political ideology index in the long-run, the robustness of the relationship between ideology and growth and the specific channels through which political ideology affects economic performance. The main conclusion is that, compared with right-wing parties in power, left-wing governments have promoted equity at the expense of economic growth. It also appears that the main channel through which political ideology has impacted economic performance all along the French democratic experience is the budgetary tool (i.e. fiscal and redistributive policies) which influenced employment and income inequalities. By contrast, there seems to be less or even no empirical support for explanations based on the monetary policy or regulation, such as trade policies or the labor market regulation.
N400 Amplitude Reduction Correlates with an Increase in Pupil Size

Pupil dilation is classically associated with increase in cognitive load in humans. Here, we studied the potential link between human pupil dilation and meaning integration effort as indexed by event-related brain potentials (ERPs). We recorded pupil size variation and ERPs simultaneously while participants were presented with matching or unrelated picture–word pairs. Whilst relatedness in meaning between spoken words and pictures typically modulated ERPs, pupil size was also affected quickly after picture onset. Moreover, during the time-window associated with meaning integration, greater pupil dilation correlated with less negative N400 amplitudes elicited by unrelated pictures. Since pupil dilation has been linked to activity of the locus coeruleus–norepinephrine (LC–NE) system, these findings may provide new insights into the suggested link between human high-level cognitive function and activity of the LC–NE system.
Monotonic Calibrated Interpolated Look-Up Tables

Real-world machine learning applications may have requirements beyond accuracy, such as fast evaluation times and interpretability. In particular, guaranteed monotonicity of the learned function with respect to some of the inputs can be critical for user confidence. We propose meeting these goals for low-dimensional machine learning problems by learning flexible, monotonic functions using calibrated interpolated look-up tables. We extend the structural risk minimization framework of lattice regression to monotonic functions by adding linear inequality constraints. In addition, we propose jointly learning interpretable calibrations of each feature to normalize continuous features and handle categorical or missing data, at the cost of making the objective non-convex. We address large-scale learning through parallelization, mini-batching, and random sampling of additive regularizer terms. Case studies on real-world problems with up to sixteen features and up to hundreds of millions of training samples demonstrate the proposed monotonic functions can achieve state-of-the-art accuracy in practice while providing greater transparency to users.
Single-locus species delimitation: a test of the mixed Yule–coalescent model, with an empirical application to Philippine round-leaf bats

Prospects for a comprehensive inventory of global biodiversity would be greatly improved by automating methods of species delimitation. The general mixed Yule–coalescent (GMYC) was recently proposed as a potential means of increasing the rate of biodiversity exploration. We tested this method with simulated data and applied it to a group of poorly known bats (Hipposideros) from the Philippines. We then used echolocation call characteristics to evaluate the plausibility of species boundaries suggested by GMYC. In our simulations, GMYC performed relatively well (errors in estimated species diversity less than 25%) when the product of the haploid effective population size (Ne) and speciation rate (SR; per lineage per million years) was less than or equal to 105, while interspecific variation in Ne was twofold or less. However, at higher but also biologically relevant values of Ne × SR and when Ne varied tenfold among species, performance was very poor. GMYC analyses of mitochondrial DNA sequences from Philippine Hipposideros suggest actual diversity may be approximately twice the current estimate, and available echolocation call data are mostly consistent with GMYC delimitations. In conclusion, we consider the GMYC model useful under some conditions, but additional information on Ne, SR and/or corroboration from independent character data are needed to allow meaningful interpretation of results.
Valsartan combination therapy in the management of hypertension – patient perspectives and clinical utility

The morbidity and mortality benefits of lowering blood pressure (BP) in hypertensive patients are well established, with most individuals requiring multiple agents to achieve BP control. Considering the important role of the renin-angiotensin-aldosterone system (RAAS) in the pathophysiology of hypertension, a key component of combination therapy should include a RAAS inhibitor. Angiotensin receptor blockers (ARBs) lower BP, reduce cardiovascular risk, provide organ protection, and are among the best tolerated class of antihypertensive therapy. In this article, we discuss two ARB combinations (valsartan/hydrochlorothiazide [HCTZ] and amlodipine/valsartan), both of which are indicated for the treatment of hypertension in patients not adequately controlled on monotherapy and as initial therapy in patients likely to need multiple drugs to achieve BP goals. Randomized, double-blind studies that have assessed the antihypertensive efficacy and safety of these combinations in the first-line treatment of hypertensive patients are reviewed. Both valsartan/HCTZ and amlodipine/valsartan effectively lower BP and are well tolerated in a broad range of patients with hypertension, including difficult-to-treat populations such as those with severe BP elevations, prediabetes and diabetes, patients with the cardiometabolic syndrome, and individuals who are obese, elderly, or black. Also discussed herein are patient-focused perspectives related to the use of valsartan/HCTZ and amlodipine/valsartan, and the rationale for use of single-pill combinations as one approach to enhance patient compliance with antihypertensive therapy.
Scaling up to food webs: Effects of temperature on structure and function along a latitudinal gradient

ix List of Abbreviations Used . x Acknowledgments . xi CHAPTER 1 Introduction . 1 1.1 General Introduction . 1 1.2 Climate Change . 1 1.2.1 Direct Effects . 1 1.2.2 Effects on Biota . 2 1.2.3 Changes in Species Interactions . 3 1.3 Scaling up to Food Webs . 3 1.4 Rock Pools as Model Systems . 5 1.5 Thesis Outline . 6 CHAPTER 2 Robustness of Ecological Communities to Environmental Warming along a Latitudinal Gradient . 8 2.1 Abstract . 8 2.2 Introduction . 8 2.3 Methods. 9 2.3. 1 Sample Collection . 9 2.3. 2 Experimental Design . 10 2.3. 3 Data Analysis . 11 2.4 Results . 12
Predicting Relapsing-Remitting Dynamics in Multiple Sclerosis Using Discrete Distribution Models: A Population Approach

Background Relapsing-remitting dynamics are a hallmark of autoimmune diseases such as Multiple Sclerosis (MS). A clinical relapse in MS reflects an acute focal inflammatory event in the central nervous system that affects signal conduction by damaging myelinated axons. Those events are evident in T1-weighted post-contrast magnetic resonance imaging (MRI) as contrast enhancing lesions (CEL). CEL dynamics are considered unpredictable and are characterized by high intra- and inter-patient variability. Here, a population approach (nonlinear mixed-effects models) was applied to analyse of CEL progression, aiming to propose a model that adequately captures CEL dynamics. Methods and Findings We explored several discrete distribution models to CEL counts observed in nine MS patients undergoing a monthly MRI for 48 months. All patients were enrolled in the study free of immunosuppressive drugs, except for intravenous methylprednisolone or oral prednisone taper for a clinical relapse. Analyses were performed with the nonlinear mixed-effect modelling software NONMEM 7.2. Although several models were able to adequately characterize the observed CEL dynamics, the negative binomial distribution model had the best predictive ability. Significant improvements in fitting were observed when the CEL counts from previous months were incorporated to predict the current month’s CEL count. The predictive capacity of the model was validated using a second cohort of fourteen patients who underwent monthly MRIs during 6-months. This analysis also identified and quantified the effect of steroids for the relapse treatment. Conclusions The model was able to characterize the observed relapsing-remitting CEL dynamic and to quantify the inter-patient variability. Moreover, the nature of the effect of steroid treatment suggested that this therapy helps resolve older CELs yet does not affect newly appearing active lesions in that month. This model could be used for design of future longitudinal studies and clinical trials, as well as for the evaluation of new therapies.
Longitudinally extensive transverse myelitis with and without aquaporin 4 antibodies.

IMPORTANCE Aquaporin 4 antibody (AQP4-Ab)-negative patients with longitudinally extensive transverse myelitis (LETM) behave differently from those with AQP4-Ab. Aquaporin 4 antibody-negative neuromyelitis optica (NMO) is rare when good assays are used. OBJECTIVE To assess if AQP4-Ab-negative patients with LETM share similar disease characteristics with AQP4-Ab-positive patients or whether they have distinct features and alternative diagnoses. DESIGN We collated clinical and paraclinical data on patients with LETM identified through the Oxford NMO clinical database. Aquaporin 4 antibodies were tested using 2 sensitive assays. We describe the features of patients with LETM, compare findings between patients with and without AQP4-Ab, and describe alternative diagnoses in AQP4-Ab-negative patients. SETTING Single specialist UK center for NMO. PARTICIPANTS Seventy-six adult patients with LETM. MAIN OUTCOMES AND MEASURES Comparison of clinical and paraclinical data. RESULTS Fifty-eight percent of patients were AQP4-Ab positive. Alternative diagnoses could usually be identified in AQP4-Ab-negative patients, including those fulfilling NMO diagnostic criteria. Only 6.5% of patients had "true" seronegative NMO and 6.5% had idiopathic LETM. There were some important differences between AQP4-Ab-positive and -negative cases, including older onset age, higher proportion of females, lower incidence of simultaneous optic neuritis, lower frequency of conus involvement, and higher prevalence of coexisting autoimmune disorders in AQP4-Ab-positive cases. Attack severity and degree of recovery were similar in the 2 groups. CONCLUSIONS AND RELEVANCE Patients with LETM without AQP4-Ab include a number of different diagnostic categories and it is not surprising therefore that they show important differences compared with AQP4-Ab-positive patients, even when considering only those fulfilling current NMO diagnostic criteria. Thus, we suggest that diagnoses such as myelin-oligodendrocyte glycoprotein antibody disease, multiple sclerosis, acute disseminated encephalomyelitis, and postinfectious disorders should be exclusions in the NMO diagnostic criteria and AQP4-Ab-positive and antibody-negative NMO/NMO spectrum disorder cohorts should be analyzed separately.
An Empirical Study of the Impacts of Clones in Software Maintenance

The impacts of clones on software maintenance is a long-lived debate on whether clones are beneficial or not. Some researchers argue that clones lead to additional changes during the maintenance phase and thus increase the overall maintenance effort. Moreover, they note that inconsistent changes to clones may introduce faults during evolution. On the other hand, other researchers argue that cloned code exhibits more stability than non-cloned code. Studies resulting in such contradictory outcomes may be a consequence of using different methodologies, using different clone detection tools, defining different impact assessment metrics, and evaluating different subject systems. In order to understand the conflicting results from the studies, we plan to conduct a comprehensive empirical study using a common framework incorporating nine existing methods that yielded mostly contradictory findings. Our research strategy involves implementing each of these methods using four clone detection tools and evaluating the methods on more than fifteen subject systems of different languages and of a diverse nature. We believe that our study will help eliminate tool and study biases to resolve conflicts regarding the impacts of clones on software maintenance.
Making the Right Decision for My Child With Cancer: The Parental Imperative

Background: Making major treatment decisions with life-altering consequences is a significant challenge faced by parents of children with cancer. The unique experience of parents is not well represented in the growing literature on cancer treatment decision making (TDM). Objective: The objective of this study was to describe the process of parents making major treatment decisions for their children with cancer. Methods: Using grounded theory methods, we interviewed 15 parents of 13 children with cancer facing major treatment decisions. Results: Parents’ determination to make the right decision was both a demanding responsibility and a natural extension of the parental role. Everything parents encountered and undertook during the TDM process was in the service of making the right decision for their child. All parents expressed conviction that they had made the right decision, but conviction was tempered by doubts triggered by the pervasive uncertainty of the childhood cancer experience. Parents described limited TDM participation by extended family members and the affected children themselves, asserting their primary responsibility to act as their child’s surrogate in partnership with the child’s medical team. Conclusions: Making the right decision for one’s child under challenging conditions is an extension of the parental obligation to act in the child’s best interest and a responsibility that parents claim as their own. Implications for Practice: The findings from this study can serve as the foundation for future studies to refine the conceptualization of TDM in childhood cancer, which will in turn ground the development and evaluation of interventions to support parents in their critical TDM role.
Hydrophobic ligand binding properties of the human lipocalin apolipoprotein M Published, JLR Papers in Press, May 24, 2007.

Apolipoprotein M (apoM) is a plasma protein associated mainly with HDL. ApoM is suggested to be important for the formation of preβ-HDL, but its mechanism of action is unknown. Homology modeling has suggested apoM to be a lipocalin. Lipocalins share a structurally conserved β-barrel, which in many lipocalins bind hydrophobic ligands. The aim of this study was to test the ability of apoM to bind different hydrophobic substances. ApoM was produced both in Escherichia coli and in HEK 293 cells. Characterization of both variants with electrophoretic and immunological methods suggested apoM from E. coli to be correctly folded. Intrinsic tryptophan fluorescence of both apoM variants revealed that retinol, all-trans-retinoic acid, and 9-cis-retinoic acid bound (dissociation constant = 2–3 μM), whereas other tested substances (e.g., cholesterol, vitamin K, and arachidonic acid) did not. The intrinsic fluorescence of two apoM mutants carrying single tryptophans was quenched by retinol and retinoic acid to the same extent as wild-type apoM, indicating that the environment of both tryptophans was affected by the binding. In conclusion, the binding of retinol and retinoic acid supports the hypothesis that apoM is a lipocalin. The physiological relevance of this binding has yet to be elucidated.
Competitive binding-based optical DNA mapping for fast identification of bacteria - multi-ligand transfer matrix theory and experimental applications on Escherichia coli

We demonstrate a single DNA molecule optical mapping assay able to resolve a specific Escherichia coli strain from other strains. The assay is based on competitive binding of the fluorescent dye YOYO-1 and the AT-specific antibiotic netropsin. The optical map is visualized by stretching the DNA molecules in nanofluidic channels. We optimize the experimental conditions to obtain reproducible barcodes containing as much information as possible. We implement a multi-ligand transfer matrix method for calculating theoretical barcodes from known DNA sequences. Our method extends previous theoretical approaches for competitive binding of two types of ligands to many types of ligands and introduces a recursive approach that allows long barcodes to be calculated with standard computer floating point formats. The identification of a specific E. coli strain (CCUG 10979) is based on mapping of 50–160 kilobasepair experimental DNA fragments onto the theoretical genome using the developed theory. Our identification protocol introduces two theoretical constructs: a P-value for a best experiment-theory match and an information score threshold. The developed methods provide a novel optical mapping toolbox for identification of bacterial species and strains. The protocol does not require cultivation of bacteria or DNA amplification, which allows for ultra-fast identification of bacterial pathogens.
CLIMATE AND HABITAT INFLUENCE PREVALENCE OF MENINGEAL WORM INFECTION IN NORTH DAKOTA, USA

Abstract The meningeal worm (Parelaphostrongylus tenuis) is a parasite of white-tailed deer (Odocoileus virginianus) and is also a significant pathogen of moose (Alces alces) and other ungulates. Changes in climate or habitat may facilitate range expansion or increase the prevalence of meningeal worm infection in white-tailed deer, resulting in increased exposure to susceptible ungulates. We examined 3,730 white-tailed deer during 2002–05 to determine the prevalence and range of meningeal worm infection in North Dakota, US, and investigated whether these had changed since earlier surveys. We used multiple logistic regression to model potential effects of habitat and climate on prevalence in white-tailed deer. We also examined how habitat influences intermediate hosts by comparing gastropod abundance and microclimate among habitat types. Prevalence in deer was 14% statewide, and prevalence and geographic range had increased since the early 1990s. Natural woodlands provided the best habitat for intermediate hosts, and increases in prevalence of infection in deer may be due to recent patterns in growing-season precipitation. This study has redefined the geographic distribution of meningeal worm infection and increased understanding of how climate and habitat influence the prevalence and distribution of this parasite.