bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chemical structure informing statistical hypothesis testing in metabolomics
Authors: Zhu Hongjie , Luo Man 
Published: December 2013

AbstractMotivation: Metabolomics has been shown as an effective tool to study various biological and biomedical phenotypes, whereas interrogating the inherently noisy metabolite concentration data with limited sample size remains a major challenge. Accumulating evidence suggests that metabolites’ structures are relevant to their bioactivities.Results: We present a new strategy to boost the statistical power of hypothesis testing in metabolomics by incorporating quantitative molecular descriptors for each metabolite. The strategy selects potentially informative summary molecular descriptors and outputs chemical structure-informed false discovery rates. The effectiveness of the proposed strategy is demonstrated by both simulation studies and a real application. In a metabolomic study on Alzheimer’s disease, the posterior inclusion probability for summary molecular descriptors reaches 0.97. By incorporating the structure data, our approach uniquely identifies multiple Alzheimer’s disease signatures, which are consistent with existing evidence. These results evidently suggest the value of the proposed approach for metabolomic hypothesis-testing problems.Availability and implementation: A code package implementing the strategy is freely available at https://github.com/HongjieZhu/CIMA.git.Contact: hongjie.zhu@sanofi.comSupplementary information: Supplementary data are available at Bioinformatics online.
Combining evolutionary information extracted from frequency profiles with sequence-based kernels for protein remote homology detection
Authors: Liu Bin , Zhang Deyuan , Xu Ruifeng , Xu Jinghao , Wang Xiaolong , Chen Qingcai , Dong Qiwen , Chou Kuo-Chen 
Published: December 2013

Abstract
Motivation: Owing to its importance in both basic research (such as molecular evolution and protein attribute prediction) and practical application (such as timely modeling the 3D structures of proteins targeted for drug development), protein remote homology detection has attracted a great deal of interest. It is intriguing to note that the profile-based approach is promising and holds high potential in this regard. To further improve protein remote homology detection, a key step is how to find an optimal means to extract the evolutionary information into the profiles.
Results: Here, we propose a novel approach, the so-called profile-based protein representation, to extract the evolutionary information via the frequency profiles. The latter can be calculated from the multiple sequence alignments generated by PSI-BLAST. Three top performing sequence-based kernels (SVM-Ngram, SVM-pairwise and SVM-LA) were combined with the profile-based protein representation. Various tests were conducted on a SCOP benchmark dataset that contains 54 families and 23 superfamilies. The results showed that the new approach is promising, and can obviously improve the performance of the three kernels. Furthermore, our approach can also provide useful insights for studying the features of proteins in various families. It has not escaped our notice that the current approach can be easily combined with the existing sequence-based methods so as to improve their performance as well.
Availability and implementation: For users’ convenience, the source code of generating the profile-based proteins and the multiple kernel learning was also provided at
http://bioinformatics.hitsz.edu.cn/main/∼binliu/remote/
Contact: bliu@insun.hit.edu.cn or bliu@gordonlifescience.org
Supplementary information: Supplementary data are available at Bioinformatics online.
Hyperactive mariner transposons are created by mutations that disrupt allosterism and increase the rate of transposon end synapsis
Authors: Liu Danxu , Chalmers Ronald 
Published: December 2013

AbstractNew applications for transposons in vertebrate genetics have spurred efforts to develop hyperactive variants. Typically, a genetic screen is used to identify several hyperactive point mutations, which are then incorporated in a single transposase gene. However, the mechanisms responsible for the increased activity are unknown. Here we show that several point mutations in the mariner transposase increase their activities by disrupting the allostery that normally serves to downregulate transposition by slowing synapsis of the transposon ends. We focused on the conserved WVPHEL amino acid motif, which forms part of the mariner transposase dimer interface. We generated almost all possible single substitutions of the W, V, E and L residues and found that the majority are hyperactive. Biochemical analysis of the mutations revealed that they disrupt signals that pass between opposite sides of the developing transpososome in response to transposon end binding. In addition to their role in allostery, the signals control the initiation of catalysis, thereby preventing non-productive double-strand breaks. Finally, we note that such breaks may explain the puzzling ‘self-inflicted wounds’ at the ends of the Mos1 transposon in Drosophila.
A cypovirus VP5 displays the RNA chaperone-like activity that destabilizes RNA helices and accelerates strand annealing
Authors: Yang Jie , Cheng Zhenyun , Zhang Songliu , Xiong Wei , Xia Hongjie , Qiu Yang , Wang Zhaowei , Wu Feige , Qin Cheng-Feng , Yin Lei , Hu Yuanyang , Zhou Xi 
Published: December 2013

Abstract
For double-stranded RNA (dsRNA) viruses in the family Reoviridae, their inner capsids function as the machinery for viral RNA (vRNA) replication. Unlike other multishelled reoviruses, cypovirus has a single-layered capsid, thereby representing a simplified model for studying vRNA replication of reoviruses. VP5 is one of the three major cypovirus capsid proteins and functions as a clamp protein to stabilize cypovirus capsid. Here, we expressed VP5 from type 5 Helicoverpa armigera cypovirus (HaCPV-5) in a eukaryotic system and determined that this VP5 possesses RNA chaperone-like activity, which destabilizes RNA helices and accelerates strand annealing independent of ATP. Our further characterization of VP5 revealed that its helix-destabilizing activity is RNA specific, lacks directionality and could be inhibited by divalent ions, such as Mg2+, Mn2+, Ca2+ or Zn2+, to varying degrees. Furthermore, we found that HaCPV-5 VP5 facilitates the replication initiation of an alternative polymerase (i.e. reverse transcriptase) through a panhandle-structured RNA template, which mimics the 5′-3′ cyclization of cypoviral positive-stranded RNA. Given that the replication of negative-stranded vRNA on the positive-stranded vRNA template necessitates the dissociation of the 5′-3′ panhandle, the RNA chaperone activity of VP5 may play a direct role in the initiation of reoviral dsRNA synthesis.
Expanding the catalog of cas genes with metagenomes
Authors: Zhang Quan , Doak Thomas G. , Ye Yuzhen 
Published: December 2013

Abstract
The CRISPR (clusters of regularly interspaced short palindromic repeats)–Cas adaptive immune system is an important defense system in bacteria, providing targeted defense against invasions of foreign nucleic acids. CRISPR–Cas systems consist of CRISPR loci and cas (CRISPR-associated) genes: sequence segments of invaders are incorporated into host genomes at CRISPR loci to generate specificity, while adjacent cas genes encode proteins that mediate the defense process. We pursued an integrated approach to identifying putative cas genes from genomes and metagenomes, combining similarity searches with genomic neighborhood analysis. Application of our approach to bacterial genomes and human microbiome datasets allowed us to significantly expand the collection of cas genes: the sequence space of the Cas9 family, the key player in the recently engineered RNA-guided platforms for genome editing in eukaryotes, is expanded by at least two-fold with metagenomic datasets. We found genes in cas loci encoding other functions, for example, toxins and antitoxins, confirming the recently discovered potential of coupling between adaptive immunity and the dormancy/suicide systems. We further identified 24 novel Cas families; one novel family contains 20 proteins, all identified from the human microbiome datasets, illustrating the importance of metagenomics projects in expanding the diversity of cas genes.
Human RECQ5 helicase promotes repair of DNA double-strand breaks by synthesis-dependent strand annealing
Authors: Paliwal Shreya , Kanagaraj Radhakrishnan , Sturzenegger Andreas , Burdova Kamila , Janscak Pavel 
Published: December 2013

AbstractMost mitotic homologous recombination (HR) events proceed via a synthesis-dependent strand annealing mechanism to avoid crossing over, which may give rise to chromosomal rearrangements and loss of heterozygosity. The molecular mechanisms controlling HR sub-pathway choice are poorly understood. Here, we show that human RECQ5, a DNA helicase that can disrupt RAD51 nucleoprotein filaments, promotes formation of non-crossover products during DNA double-strand break-induced HR and counteracts the inhibitory effect of RAD51 on RAD52-mediated DNA annealing in vitro and in vivo. Moreover, we demonstrate that RECQ5 deficiency is associated with an increased occupancy of RAD51 at a double-strand break site, and it also causes an elevation of sister chromatid exchanges on inactivation of the Holliday junction dissolution pathway or on induction of a high load of DNA damage in the cell. Collectively, our findings suggest that RECQ5 acts during the post-synaptic phase of synthesis-dependent strand annealing to prevent formation of aberrant RAD51 filaments on the extended invading strand, thus limiting its channeling into potentially hazardous crossover pathway of HR.
Greater trochanteric pain syndrome: Does imaging‐identified pathology influence the outcome of interventions?
Authors: Wilson Shayne A. , Shanahan Ernst M. , Smith Malcolm D. 
Published: December 2013

AbstractAimTo assess the outcomes for patients seen in a rheumatology service presenting with features of the greater trochanteric pain syndrome (GTPS) and the impact of imaging results on the outcomes of treatment.MethodsRetrospective audit, using a phone interview was performed to establish links between results of imaging undertaken in the diagnostic work‐up of patients with lateral hip pain and clinical outcomes for these patients. Patient perceptions of the effectiveness of interventions were also assessed.ResultsForty‐five patients were included (82% female, mean age 69.6 years). Sixty‐nine percent underwent radiological work‐up, including plain X‐rays (55%), computed tomography scans (64%), magnetic resonance imaging (48%) and ultrasound (90%). Coexistent trochanteric bursitis (TB) and gluteal tendinopathy were the most commonly elucidated pathologies accounting for the symptomatic presentation of 40% of patients. Forty‐one patients underwent some form of intervention, most commonly injection of local anesthetic and corticosteroid (LACS) into the region of the TB (87%), two‐thirds of which were undertaken under radiological guidance. Pain reduction was maximal following the third injection, with a significantly better response to unguided interventions and levels of symptomatic relief following the first injection being a good indicator of the probability of complete remission. Radiological demonstration of isolated TB correlated with a greater reduction in lateral hip symptoms following LACS TB injections both in the immediate post‐injection phase and in the long‐term.ConclusionThe results of this audit suggest that the management of GTPS has reasonable patient outcomes; however, a prospective study with greater patient numbers is needed to confirm these results.
Phenotype and Functionality of CD4+ and CD8+ T Cells in the Upper Reproductive Tract of Healthy Premenopausal Women
Authors: Shanmugasundaram Uma , Critchfield J. William , Pannell Jane , Perry Jean , Giudice Linda C. , Smith‐McCune Karen , Greenblatt Ruth M. , Shacklett Barbara L. 
Published: December 2013

ProblemThe goal of this study was to investigate the phenotype and functional responsiveness of CD4+ and CD8+ T‐cells in the upper reproductive tract of healthy premenopausal women. The lower reproductive tract is frequently studied as a site of sexually transmitted infections; however, the upper reproductive tract may also be a portal of entry and dissemination for pathogens, including HIV‐1.Method of StudyEndometrial biopsy, endocervical curettage, cytobrush, and blood were collected during mid‐luteal phase from 23 healthy women. T‐cells were isolated and analyzed by flow cytometry.ResultsAs compared with their counterparts in blood, endometrial and endocervical T‐cells had enhanced CCR5 expression, and were enriched for activated, effector memory cells. Endometrial T‐cells were more responsive to polyclonal stimuli, producing a broad range of cytokines and chemokines.ConclusionThese findings underscore the responsiveness of endometrial T‐cells to stimulation, and reveal their activated phenotype. These findings also suggest susceptibility of the upper reproductive tract to HIV‐1 infection.
Addiction‐Related Effects of DOV 216,303 and Cocaine: A Comparative Study in the Mouse
Authors: Sørensen Gunnar , Husum Henriette , Brennum Lise T. , Bundgaard Christoffer , Montezinho Liliana C. P. , Mørk Arne , Wörtwein Gitta , Woldbye David P. D. 
Published: December 2013

AbstractDOV 216,303, an inhibitor of serotonin, noradrenaline and dopamine reuptake, belongs to a new line of drugs called ‘triple reuptake inhibitors’ that have been proposed for treatment of depression. The addictive drug cocaine has similar mechanism of action and exerts rewarding effects by blocking reuptake of dopamine, leading to increased extracellular concentrations of dopamine in the nucleus accumbens. Thus, DOV 216,303 and other triple reuptake inhibitors might be speculated to exhibit abuse potential, limiting their future therapeutic use. To further elucidate potential addictive properties of DOV 216,303, we conducted a comparative study of addiction‐related effects of DOV 216,303 and cocaine in mice using acute self‐administration, conditioned place preference (CPP) and drug‐induced hyperlocomotion. Effects on accumbal extracellular dopamine levels were determined using microdialysis, and we measured monoamine receptor occupancy as well as brain and plasma exposure. DOV 216,303 was self‐administered acutely in the same dose range as cocaine. However, in the CPP model, DOV 216,303 did not induce place preference at doses where cocaine caused place preference. Higher doses of DOV 216,303 than cocaine were needed to induce hyperlocomotion and increase extracellular accumbal dopamine with effective doses being higher than effective doses used in depression models. Moreover, DOV 216,303 displayed a pharmacokinetic profile with lower potential for addiction than cocaine. Thus, high levels of DAT occupancy were reached slower and decayed more slowly after DOV 216,303 than cocaine administration. The present study shows that acute administration of DOV 216,303 displays some addictive‐like properties in mice, but these were less pronounced than cocaine, most likely due to different pharmacokinetic profiles.
IMAGe syndrome: clinical and genetic implications based on investigations in three Japanese patients
Authors: Kato Fumiko , Hamajima Takashi , Hasegawa Tomonobu , Amano Naoko , Horikawa Reiko , Nishimura Gen , Nakashima Shinichi , Fuke Tomoko , Sano Shinichirou , Fukami Maki , Ogata Tsutomu 
Published: December 2013

SummaryObjectiveArboleda et al. have recently shown that IMAGe (intra‐uterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita and genital abnormalities) syndrome is caused by gain‐of‐function mutations of maternally expressed gene CDKN1C on chromosome 11p15.5. However, there is no other report describing clinical findings in patients with molecularly studied IMAGe syndrome. Here, we report clinical and molecular findings in Japanese patients.PatientsWe studied a 46,XX patient aged 8·5 years (case 1) and two 46,XY patients aged 16·5 and 15·0 years (cases 2 and 3).ResultsClinical studies revealed not only IMAGe syndrome‐compatible phenotypes in cases 1–3, but also hitherto undescribed findings including relative macrocephaly and apparently normal pituitary‐gonadal endocrine function in cases 1–3, familial glucocorticoid deficiency (FGD)‐like adrenal phenotype and the history of oligohydramnios in case 2, and arachnodactyly in case 3. Sequence analysis of CDKN1C, pyrosequencing‐based methylation analysis of KvDMR1 and high‐density oligonucleotide array comparative genome hybridization analysis for chromosome 11p15.5 were performed, showing an identical de novo and maternally inherited CDKN1C gain‐of‐function mutation (p.Asp274Asn) in cases 1 and 2, respectively, and no demonstrable abnormality in case 3.ConclusionsThe results of cases 1 and 2 with CDKN1C mutation would argue the following: [1] relative macrocephaly is consistent with maternal expression of CDKN1C in most tissues and biparental expression of CDKN1C in the foetal brain; [2] FGD‐like phenotype can result from CDKN1C mutation; and [3] genital abnormalities may primarily be ascribed to placental dysfunction. Furthermore, lack of CDKN1C mutation in case 3 implies genetic heterogeneity in IMAGe syndrome.
Conservative management, surgery and radiosurgery for treatment of vestibular schwannomas: a model‐based approach to cost‐effectiveness
Authors: Gait C. , Frew E.J. , Martin T.P.C. , Jowett S. , Irving R. 
Published: December 2013

ObjectiveTo undertake a cost‐effectiveness analysis comparing conservative management, surgery and radiosurgery for treating small‐to‐medium (1–20 mm)‐sized vestibular schwannomas.DesignModel‐based economic evaluation using individual‐level data from a Birmingham‐based longitudinal patient database and from published sources. Both a decision tree and state‐transition (Markov) model were developed, from an National Health Service (NHS) perspective. Sensitivity analyses were also carried out.SettingSecondary care treatment for patients with small‐to‐medium‐sized vestibular schwannomas.ParticipantsThree hypothetical cohorts of adult patients receiving conservative management, radiosurgery or surgery treatment, aged 58 years as starting age within model.Main outcome measuresCost‐effectiveness based on cost per quality‐adjusted life year (QALY).ResultsConservative management is the preferred strategy for the treatment of small‐to‐medium‐sized vestibular schwannomas. Conservative management is both cheaper (−£722 and −£2764) and more effective (0.136 and 0.554 quality‐adjusted life years) than both radiosurgery and surgery, respectively. A conservative strategy can therefore be considered as highly cost‐effective. This result is sensitive to the assumed quality‐of‐life parameters in the model. Sensitivity analysis suggests that the probability of a conservative strategy being the most cost‐effective approach compared with surgery and radiosurgery at a willingness to pay of £20 000/quality‐adjusted life year gained is 80% and 55%, respectively.ConclusionsA conservative approach is the preferred strategy for treatment of small‐to‐medium vestibular schwannomas. This result is sensitive to quality‐of‐life values used in the analysis. More research is required to assess the impact of treatment upon patients’ health‐related quality of life over time.
Crawling and walking infants elicit different verbal responses from mothers
Authors: Karasik Lana B. , Tamis‐LeMonda Catherine S. , Adolph Karen E. 
Published: December 2013

AbstractWe examined mothers' verbal responses to their crawling or walking infants' object sharing (i.e. bids). Fifty mothers and their 13‐month‐olds were observed for 1 hour at home. Infants bid from a stationary position or they bid after carrying the object to their mothers. Mothers responded with affirmations (e.g. ‘thank you’), descriptions (‘red box’), or action directives (‘open it’). Infants' locomotor status and the form of their bids predicted how mothers responded. Mothers of walkers responded with action directives more often than mothers of crawlers. Notably, differences in the responses of mothers of walkers versus those of crawlers were explained by differences in bid form between the two groups of infants. Walkers were more likely to engage in moving bids than crawlers, who typically shared objects from stationary positions. When crawlers displayed moving bids, their mothers offered action directives just as often as did mothers of walkers. Findings illustrate developmental cascades, wherein Infants' locomotor status affects how infants share objects with mothers, which in turn shapes mothers' verbal responses.
Pancreas transplantation: a treatment option for people with diabetes
Authors: Mittal S. , Gough S. C. L. 
Published: December 2013

AbstractSince the first pancreas transplants in the early 1960s, whole‐organ pancreas transplantation, either alone or combined with kidney transplantation, has become commonplace in many countries around the world. Whole‐organ pancreas transplantation is available in the UK, with ~200 transplants currently carried out per year. Patient survival and pancreas graft outcome rates are now similar to other solid organ transplant programmes, with high rates of long‐term insulin independence. In the present review, we will discuss whole‐pancreas transplantation as a treatment for diabetes, focusing on indications for transplantation, the nature of the procedure performed, graft survival rates and the consequences of pancreas transplantation on metabolic variables and the progression of diabetes‐related complications.
Using an audience response system to improve learning success in practical skills training courses in dental studies – a randomised, controlled cross‐over study
Authors: Wenz H.‐J. , Zupanic M. , Klosa K. , Schneider B. , Karsten G. 
Published: December 2013

AbstractIntroductionThe aim of this study was to examine whether the use of an audience response system (ARS) in a high‐quality study design, in a course in pre‐clinical dentistry leads to an improvement in cognitive and psycho‐motor performance.Materials and MethodsAs part of the Phantom Course I, a randomised, controlled study in cross‐over design with 63 students was conducted over 4 weeks. The intervention was carried out by means of an ARS (TurningPoint®), while a verbal question‐and‐answer session was conducted within the control group. Differences in learning success were determined via a formative multiple‐choice (MC) test (cognitive) and a summative practical test (psycho‐motor).ResultsBoth groups achieved significantly better results in the MC tests with the use of the intervention, when compared with the control group (group A 11.6 vs. 9.5 and group B 13.7 vs. 12.1, maximum 16 points). A further analysis of the results showed that the overall effect was induced primarily by a marked improvement in below‐average students. The practical tests showed no clear effect. Despite the careful selection and set‐up of the conditions for the study in the regular course of the semester, a cohort effect emerged. This was due to varying degrees of performance between the two groups, because no adequate performance parameters were available, which could have been taken into account for the stratified randomisation.ConclusionsThe results indicate that the use of the ARS leads to better results in cognitive performance, especially where independent learning is required and should be encouraged. Weaker students in particular seem to benefit.