julilili42/papers huggingface dataset:
Novel Hinge‐Binding Motifs for Janus Kinase 3 Inhibitors: A Comprehensive Structure–Activity Relationship Study on Tofacitinib Bioisosteres
2014-08-19

Abstract The Janus kinases (JAKs) are a family of cytosolic tyrosine kinases crucially involved in cytokine signaling. JAKs have been demonstrated to be valid targets in the treatment of inflammatory and myeloproliferative disorders, and two inhibitors, tofacitinib and ruxolitinib, recently received their marketing authorization. Despite this success, selectivity within the JAK family remains a major issue. Both approved compounds share a common 7 H‐ pyrrolo[2,3‐ d ]pyrimidine hinge binding motif, and little is known about modifications tolerated at this heterocyclic core. In the current study, a library of tofacitinib bioisosteres was prepared and tested against JAK3. The compounds possessed the tofacitinib piperidinyl side chain, whereas the hinge binding motif was replaced by a variety of heterocycles mimicking its pharmacophore. In view of the promising expectations obtained from molecular modeling, most of the compounds proved to be poorly active. However, strategies for restoring activity within this series of novel chemotypes were discovered and crucial structure–activity relationships were deduced. The compounds presented may serve as starting point for developing novel JAK inhibitors and as a valuable training set for in silico models.
Blocked Inverted Indices for Exact Clustering of Large Chemical Spaces
2014-08-19

The calculation of pairwise compound similarities based on fingerprints is one of the fundamental tasks in chemoinformatics. Methods for efficient calculation of compound similarities are of the utmost importance for various applications like similarity searching or library clustering. With the increasing size of public compound databases, exact clustering of these databases is desirable, but often computationally prohibitively expensive. We present an optimized inverted index algorithm for the calculation of all pairwise similarities on 2D fingerprints of a given data set. In contrast to other algorithms, it neither requires GPU computing nor yields a stochastic approximation of the clustering. The algorithm has been designed to work well with multicore architectures and shows excellent parallel speedup. As an application example of this algorithm, we implemented a deterministic clustering application, which has been designed to decompose virtual libraries comprising tens of millions of compounds in a short time on current hardware. Our results show that our implementation achieves more than 400 million Tanimoto similarity calculations per second on a common desktop CPU. Deterministic clustering of the available chemical space thus can be done on modern multicore machines within a few days.
How much bilingual experience is needed to affect executive control?
2014-08-19

A wealth of research on experience-related plasticity has shown that specific experiences, such as musical training (Herholz &amp; Zatorre, 2012) or juggling (Draganski et al., 2004), can modify brain function and structure and induce long-term changes in cognitive behavior throughout the life span. In their comprehensive Keynote Article, Baum and Titone focus on the neural and cognitive implications of lifelong experience with multiple languages. They discuss empirical studies on bilingualism, executive control, and aging to enhance our understanding of the frequently observed executive control advantages in bilinguals and how lifelong bilingualism may contribute to the development of cognitive reserve and buffer age-related declines in executive control functions. In reframing these issues in terms of neuroplasticity, Baum and Titone propose to “embrace the inherent individual variability among bilinguals in all its glory” and identify key issues related to individual variability to pave the way to new avenues of research. We fully concur with Baum and Titone's general recommendation to embrace variability among bilinguals to advance our understanding of bilingualism, aging, and neuroplasticity, but we would like to particularly highlight the importance of the earlier stages of second language (L2) learning and the emergence of executive control advantages, a topic we believe has been understudied in this domain. How much bilingual experience is needed to affect executive control?
The chemokine CCL18 characterisesPseudomonasinfections in cystic fibrosis lung disease
2014-08-19

Cystic fibrosis (CF) lung disease is characterised by chronic Pseudomonas aeruginosa infection and leukocyte infiltration. Chemokines recruit leukocytes to sites of infection. Gene expression analysis identified the chemokine CCL18 as upregulated in CF leukocytes. We hypothesised that CCL18 characterises infection and inflammation in patients with CF lung disease. Therefore, we quantified CCL18 protein levels in the serum and airway fluids of CF patients and healthy controls, and studied CCL18 protein production by airway cells ex vivo . These studies demonstrated that CCL18 levels were increased in the serum and airway fluids from CF patients compared with healthy controls. Within CF patients, CCL18 levels were increased in P. aeruginosa -infected CF patients. CCL18 levels in the airways, but not in serum, correlated with severity of pulmonary obstruction in CF. Airway cells isolated from P. aeruginosa -infected CF patients produced significantly higher amounts of CCL18 protein compared with airway cells from CF patients without P. aeruginosa infection or healthy controls. Collectively, these studies show that CCL18 levels characterise chronic P. aeruginosa infection and pulmonary obstruction in patients with CF. CCL18 may, thus, serve as a potential biomarker and therapeutic target in CF lung disease.
OptiType: precision HLA typing from next-generation sequencing data
2014-08-20

Abstract Motivation: The human leukocyte antigen (HLA) gene cluster plays a crucial role in adaptive immunity and is thus relevant in many biomedical applications. While next-generation sequencing data are often available for a patient, deducing the HLA genotype is difficult because of substantial sequence similarity within the cluster and exceptionally high variability of the loci. Established approaches, therefore, rely on specific HLA enrichment and sequencing techniques, coming at an additional cost and extra turnaround time. Result: We present OptiType, a novel HLA genotyping algorithm based on integer linear programming, capable of producing accurate predictions from NGS data not specifically enriched for the HLA cluster. We also present a comprehensive benchmark dataset consisting of RNA, exome and whole-genome sequencing data. OptiType significantly outperformed previously published in silico approaches with an overall accuracy of 97% enabling its use in a broad range of applications. Contact: szolek@informatik.uni-tuebingen.de Supplementary information: Supplementary data are available at Bioinformatics online.
Production of an Attenuated Phenol-Soluble Modulin Variant Unique to the MRSA Clonal Complex 30 Increases Severity of Bloodstream Infection
2014-08-21

Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of morbidity and death. Phenol-soluble modulins (PSMs) are recently-discovered toxins with a key impact on the development of Staphylococcus aureus infections. Allelic variants of PSMs and their potential impact on pathogen success during infection have not yet been described. Here we show that the clonal complex (CC) 30 lineage, a major cause of hospital-associated sepsis and hematogenous complications, expresses an allelic variant of the PSMα3 peptide. We found that this variant, PSMα3N22Y, is characteristic of CC30 strains and has significantly reduced cytolytic and pro-inflammatory potential. Notably, CC30 strains showed reduced cytolytic and chemotactic potential toward human neutrophils, and increased hematogenous seeding in a bacteremia model, compared to strains in which the genome was altered to express non-CC30 PSMα3. Our findings describe a molecular mechanism contributing to attenuated pro-inflammatory potential in a main MRSA lineage. They suggest that reduced pathogen recognition via PSMs allows the bacteria to evade elimination by innate host defenses during bloodstream infections. Furthermore, they underscore the role of point mutations in key S. aureus toxin genes in that adaptation and the pivotal importance PSMs have in defining key S. aureus immune evasion and virulence mechanisms.
‘Behr syndrome’ with OPA1 compound heterozygote mutations
2014-08-21

Sir, We have been following with great interest the developments in the field of phenotypic diversity associated with mutations in the OPA1 gene, having contributed to describe the DOA ‘ plus ’ phenotype in a joint effort with other groups (Amati-Bonneau et al. , 2008; Hudson et al. , 2008; Yu-Wai-Mann et al. , 2010). A developing story concerns the increasingly recognized cases associated with OPA1 mutations presenting with a childhood onset syndrome combining optic atrophy with spastic paraplegia, cerebellar ataxia and possibly other neurological features (Yu-Wai-Mann et al. , 2010; Marelli et al. , 2011; Pretegiani et al. , 2011; Schaaf et al. , 2011). This phenotype fits the description of Behr in 1909, who presented a series of cases of ‘complicated familial optic atrophy with childhood onset’ including pyramidal signs, ataxia, posterior column sensory loss and mental retardation (Behr, 1909). While most of these cases apparently harboured heterozygous OPA1 mutations (Yu-Wai-Mann et al. , 2010; Marelli et al. , 2011; Pretegiani et al. , 2011), the case presented by Schaaf et al. (2011) had the peculiar occurrence of compound heterozygosity for two different OPA1 mutations, the p.V903GfsX3 frameshift deletion and the p.I382M missense mutation, respectively, which suggested that bi-allelic OPA1 mutations may lead to a complicated form of optic atrophy, i.e. Behr syndrome. Most recently, Bonifert et al. (2014) further confirmed the occurrence of DOA ‘ plus ’ cases with bi-allelic OPA1 mutations, one of the alleles carrying the same p.I382M missense mutation. We here add our observation of a similar bi-allelic OPA1 case with Behr syndrome. This proband is a 20-year-old Italian boy, born from unrelated parents (Fig. 1A, IV-4 in the pedigree), who presented a congenital nystagmus at birth and bilateral optic atrophy was recognized in the first ...
Functional Specialization Among Members Of Knickkopf Family Of Proteins In Insect Cuticle Organization
2014-08-21

Our recent study on the functional analysis of the Knickkopf protein from T. castaneum (TcKnk), indicated a novel role for this protein in protection of chitin from degradation by chitinases. Knk is also required for the laminar organization of chitin in the procuticle. During a bioinformatics search using this protein sequence as the query, we discovered the existence of a small family of three Knk-like genes (including the prototypical TcKnk) in the T. castaneum genome as well as in all insects with completed genome assemblies. The two additional Knk-like genes have been named TcKnk2 and TcKnk3. Further complexity arises as a result of alternative splicing and alternative polyadenylation of transcripts of TcKnk3, leading to the production of three transcripts (and by inference, three proteins) from this gene. These transcripts are named TcKnk3-Full Length (TcKnk3-FL), TcKnk3-5' and TcKnk3-3'. All three Knk-family genes appear to have essential and non-redundant functions. RNAi for TcKnk led to developmental arrest at every molt, while down-regulation of either TcKnk2 or one of the three TcKnk3 transcripts (TcKnk3-3') resulted in specific molting arrest only at the pharate adult stage. All three Knk genes appear to influence the total chitin content at the pharate adult stage, but to variable extents. While TcKnk contributes mostly to the stability and laminar organization of chitin in the elytral and body wall procuticles, proteins encoded by TcKnk2 and TcKnk3-3' transcripts appear to be required for the integrity of the body wall denticles and tracheal taenidia, but not the elytral and body wall procuticles. Thus, the three members of the Knk-family of proteins perform different essential functions in cuticle formation at different developmental stages and in different parts of the insect anatomy.
Development of a Microsimulation of Melanoma Mortality for Evaluating the Effectiveness of Population-Based Skin Cancer Screening
2014-08-21

Background. A nationwide skin cancer screening (SCS) was implemented in Germany in 2008. It aims at improving early detection of melanoma in order to reduce melanoma mortality. While the idea of early detection is compelling, demonstrating the effectiveness of melanoma screening is crucial. Since it is not feasible to conduct epidemiological studies to investigate the impact of factors such as screening interval or targeted age groups, we developed a microsimulation model that is able to predict melanoma mortality in Germany under several SCS conditions. Methods. Using German cancer registry data, population data, and other published data on melanoma progression and screening participation, we developed a stochastic microsimulation model. With this model, 10,000 populations of 100,000 persons and their melanoma-related life histories were simulated separately for women and for men and calibrated to observed melanoma incidence. In a second step, life histories of melanoma were changed by an SCS. Results. Compared with a nonscreening scenario (age-standardized mortality rate: 1.6 and 2.9 per 100,000 for women and men), a biennial SCS of the 35- to 85-year-old population with a participation probability of 20% for each screening-eligible individual and a test sensitivity of 80% reduced mortality by up to 0.7 and 1.4 deaths per 100,000 person-years for women and men, respectively, corresponding to a relative reduction of melanoma mortality by 45% in women and men. Conclusions. We developed a microsimulation model of melanoma mortality that can be used to evaluate the effectiveness of population-based skin cancer screening. The simulation provided plausible melanoma mortality predictions and is a tool for comparing different SCS scenarios. However, it does not provide estimates on total costs of SCS.
Treatment and Outcomes of Urethral Recurrence of Urinary Bladder Cancer in Women after Radical Cystectomy and Orthotopic Neobladder: A Series of 12 Cases
2014-08-21

&lt;b&gt;&lt;i&gt;Introduction:&lt;/i&gt;&lt;/b&gt; The incidence, treatment, and outcome of urethral recurrence (UR) after radical cystectomy (RC) for muscle-invasive bladder cancer with orthotopic neobladder in women have rarely been addressed in the literature. &lt;b&gt;&lt;i&gt;Patients and Methods:&lt;/i&gt;&lt;/b&gt; A total of 12 patients (median age at recurrence: 60 years) who experienced UR after RC with an orthotopic neobladder were selected for this study from a cohort of 456 women from participating institutions. The primary clinical and pathological characteristics at RC, including the manifestation of the UR and its treatment and outcome, were reviewed. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; The primary bladder tumors in the 12 patients were urothelial carcinoma in 8 patients, squamous cell carcinoma and adenocarcinoma in 1 patient each, and mixed histology in 2 patients. Three patients (25%) had lymph node-positive disease at RC. The median time from RC to the detection of UR was 8 months (range 4-55). Eight recurrences manifested with clinical symptoms and 4 were detected during follow-up or during a diagnostic work-up for clinical symptoms caused by distant metastases. Treatment modalities were surgery, chemotherapy, radiotherapy, and bacillus Calmette-Guérin urethral instillations. Nine patients died of cancer. The median survival after the diagnosis of UR was 6 months. &lt;b&gt;&lt;i&gt;Conclusions:&lt;/i&gt;&lt;/b&gt; UR after RC with an orthotopic neobladder in females is rare. Solitary, noninvasive recurrences have a favorable prognosis when detected early. Invasive recurrences are often associated with local and distant metastases and have a poor prognosis.
Neurophysiological correlates of various mental perspectives
2014-08-21

A common view of consciousness is that our mind presents emotions, experiences, and images in an internal mental (re-)presentation space which in a state of wakefulness is triggered by the world outside. Consciousness can be defined as the observation of this inner mental space. We propose a new model, in which the state of the conscious observer is defined by the observer's mental position and focus of attention. The mental position of the observer can either be within the mental self (intrapersonal space), in the mental outer world (extrapersonal space) or in an empathic connection, i.e., within the intrapersonal space of another person (perspective taking). The focus of attention can be directed toward the self or toward the outside world. This mental space model can help us to understand the patterns of relationships and interactions with other persons as they occur in social life. To investigate the neurophysiological correlates and discriminability of the different mental states, we conducted an EEG experiment measuring the brain activity of 16 subjects via 64 electrodes while they engaged in different mental positions (intrapersonal, extrapersonal, perspective taking) with different attentional foci (self, object). Compared to external mental locations, internal ones showed significantly increased alpha2 power, especially when the observer was focusing on an object. Alpha2 and beta2 were increased in the empathic condition compared to the extrapersonal perspective. Delta power was significantly higher when the attentional focus was directed toward an object in comparison to the participant's own self. This exploratory study demonstrates highly significant differences between various mental locations and foci, suggesting that the proposed categories of mental location and intra- and interpersonal attentional foci are not only helpful theoretical concepts but are also physiologically relevant and therefore may relate to basic brain processing mechanisms.
Reduced Motivation in the BACHD Rat Model of Huntington Disease Is Dependent on the Choice of Food Deprivation Strategy
2014-08-21

Huntington disease (HD) is an inherited neurodegenerative disease characterized by motor, cognitive, psychiatric and metabolic symptoms. Animal models of HD show phenotypes that can be divided into similar categories, with the metabolic phenotype of certain models being characterized by obesity. Although interesting in terms of modeling metabolic symptoms of HD, the obesity phenotype can be problematic as it might confound the results of certain behavioral tests. This concerns the assessment of cognitive function in particular, as tests for such phenotypes are often based on food depriving the animals and having them perform tasks for food rewards. The BACHD rat is a recently established animal model of HD, and in order to ensure that behavioral characterization of these rats is done in a reliable way, a basic understanding of their physiology is needed. Here, we show that BACHD rats are obese and suffer from discrete developmental deficits. When assessing the motivation to lever push for a food reward, BACHD rats were found to be less motivated than wild type rats, although this phenotype was dependent on the food deprivation strategy. Specifically, the phenotype was present when rats of both genotypes were deprived to 85% of their respective free-feeding body weight, but not when deprivation levels were adjusted in order to match the rats' apparent hunger levels. The study emphasizes the importance of considering metabolic abnormalities as a confounding factor when performing behavioral characterization of HD animal models.
Selective regression testing for web applications created with google web toolkit
2014-08-21

Today's web applications are highly dynamic and powerful software components that may change often. Mostly, they are based on JavaScript or AJAX. A common way to ensure correct behaviour is to use selective regression tests. Nevertheless, especially on the client side, testing is hard. One way to ease the development and the testing process of dynamic web applications is to use the Google Web Toolkit (GWT). This framework enables the development in Java and transfers the code via a compiler into JavaScript. However, it does not support regression testing with test selection. As far as we know, this paper presents the first selective regression testing technique for GWT-based web applications. In order to determine test cases that have to be rerun, it compares the Java code of two versions of the application, localizes and classifies changes in the code, and traces the mapping of Java source code to JavaScript code. We have implemented our technique as a prototype Eclipse plug-in and have conducted an evaluation of the tool.
Ribosylhopane, a Novel Bacterial Hopanoid, as Precursor of C35 Bacteriohopanepolyols in Streptomyces coelicolor A3(2)
2014-08-22

Abstract Wild‐type Streptomyces coelicolor A3(2) produces aminobacteriohopanetriol as the only elongated C 35 hopanoid. The hopanoid phenotype of two mutants bearing a deletion of genes from a previously identified hopanoid biosynthesis gene cluster provides clues to the formation of C 35 bacteriohopanepolyols. orf14 encodes a putative nucleosidase; its deletion induces the accumulation of adenosylhopane as it cannot be converted into ribosylhopane. orf18 encodes a putative transaminase; its deletion results in the accumulation of adenosylhopane, ribosylhopane, and bacteriohopanetetrol. Ribosylhopane was postulated twenty years ago as a precursor for bacterial hopanoids but was never identified in a bacterium. Absence of the transaminase encoded by orf18 prevents the reductive amination of ribosylhopane into aminobacteriohopanetriol and induces its accumulation. Its reduction by an aldose‐reductase‐like enzyme produces bacteriohopanetetrol, which is normally not present in S . coelicolor .
Expected number of supergiant fast X-ray transients in the Milky Way
2014-08-22

\\n In the past fifteen years a new generation of X-ray satellites led to the discovery of a subclass of high-mass X-ray binaries (HMXBs) with supergiant companions and a peculiar transient behaviour: supergiant fast X-ray transients (SFXTs). We calculate the expected number of Galactic SFXTs for the first time, using two different statistical approaches and two sets of data based on Swift and INTEGRAL surveys, with the aim to determine how common the SFXT phenomenon really is. We find that the expected number of SFXTs in the Galaxy is 37+53-22, which shows that SFXTs constitute a large portion of X-ray binaries with supergiant companions in the Galaxy. We compare our estimate with the expected number of Galactic HMXBs predicted from observations and evolutionary models and discuss the implications for the nature of SFXTs.\\n