bluuebunny/crossref_metadata_2025_split huggingface dataset:
Treatment of Myasthenia Gravis With High-Dose Cholinesterase Inhibitors and Calcineurin Inhibitors Caused Spontaneous Muscle Cramps in Patients
Authors: Masuda Masayuki , Utsumi Hiroya , Tanaka Sachiko , Maeno Akemi , Yamamoto Mamiko , Sugiyama Kentaro , Hirano Toshihiko , Aizawa Hitoshi 
Published: August 2018

Objectives
The objective of this study was to investigate the influence of treatment with cholinesterase inhibitors (ChEIs) and calcineurin inhibitors (CNIs) on the occurrence of cramps in myasthenia gravis (MG) patients.

Methods
The frequency and duration of cramp and serum electrolytes were evaluated in 81 patients with MG. The patients were classified using Myasthenia Gravis Foundation of America postintervention status scores based on the treatment and the responsiveness to the treatment. Quantitative MG score, MG activities of daily living score, MG composite score, or MG quality of life 15 score was used to assess the health-related quality of life (QOL).

Results
Muscle cramps developed in 44 (54.3%) of 81 MG patients. The scores of MG activities of daily living, MG composite, or MG-QOL 15-item questionnaire in patients with cramp were significantly higher than those in patients without cramps (P = 0.002, P = 0.01, or P = 0.0022, respectively). The serum magnesium concentrations were lower in patients treated with CNI (n = 16) than in those not treated with CNI (n = 65) (P = 0.002). The probability of cramps was significantly higher in patients treated with ChEIs (≥180 mg/d) in addition to CNI than in patients who were treated with a low dose of ChEIs (≤60 mg/d) without concomitant CNI treatment (P = 0.017).

Conclusions
Our data suggested that treatment with a high dose of ChEI and CNI accelerated the probability of cramps and reduced the QOL in MG patients.
Increased rates of genomic mutation in a biofilm co-culture model of Pseudomonas aeruginosa and Staphylococcus aureus
Authors: Frapwell C.J. , Howlin R.P. , Soren O. , McDonagh B.T. , Duignan C.M. , Allan R.N. , Horswill A.R. , Stoodley P. , Hu Y. , Coates A.R.M. , Webb J. S. 
Published: August 2018

AbstractBiofilms are major contributors to disease chronicity and are typically multi-species in nature. Pseudomonas aeruginosa and Staphylococcus aureus are leading causes of morbidity and mortality in a variety of chronic diseases but current in vitro dual-species biofilms models involving these pathogens are limited by short co-culture times (24 to 48 hours). Here, we describe the establishment of a stable (240 hour) co-culture biofilm model of P. aeruginosa and S. aureus that is reproducible and more representative of chronic disease.The ability of two P. aeruginosa strains, (PAO1 and a cystic fibrosis isolate, PA21), to form co-culture biofilms with S. aureus was investigated. Co-culture was stable for longer periods using P. aeruginosa PA21 and S. aureus viability within the model improved in the presence of exogenous hemin. Biofilm co-culture was associated with increased tolerance of P. aeruginosa to tobramycin and increased susceptibility of S. aureus to tobramycin and a novel antimicrobial, HT61, previously shown to be more effective against non-dividing cultures of Staphylococcal spp. Biofilm growth was also associated with increased short-term mutation rates; 10-fold for P. aeruginosa and 500-fold for S. aureus.By describing a reproducible 240 hour co-culture biofilm model of P. aeruginosa and S. aureus, we have shown that interspecies interactions between these organisms may influence short-term mutation rates and evolution, which could be of importance in understanding the adaptive processes that lead to the development of antimicrobial resistance.
Selecting causal risk factors from high-throughput experiments using multivariable Mendelian randomization
Authors: Zuber Verena , Colijn Johanna Maria , Klaver Caroline , Burgess Stephen 
Published: August 2018

AbstractModern high-throughput experiments provide a rich resource to investigate causal determinants of disease risk. Mendelian randomization (MR) is the use of genetic variants as instrumental variables to infer the causal effect of a specific risk factor on an outcome. Multivariable MR is an extension of the standard MR framework to consider multiple potential risk factors in a single model. However, current implementations of multivariable MR use standard linear regression and hence perform poorly with many risk factors.Here, we propose a novel approach to two-sample multivariable MR based on Bayesian model averaging (MR-BMA) that scales to high-throughput experiments. In a realistic simulation study, we show that MR-BMA can detect true causal risk factors even when the candidate risk factors are highly correlated. We illustrate MR-BMA by analysing publicly-available summarized data on metabolites to prioritise likely causal biomarkers for age-related macular degeneration.
Circadian control of lung inflammation in influenza infection
Authors: Sengupta Shaon , Tang Soon Yew , Devine Jill , Nayak Soumyashant , Zhang Shirley , Valenzuela Alex , Lopez Carolina B. , Grant Gregory , FitzGerald Garret A. 
Published: August 2018

AbstractInfluenza is a leading cause of respiratory mortality and morbidity. While inflammation is necessary for fighting infection, a fine balance of anti-viral defense and host tolerance is necessary for recovery. Circadian rhythms have been known to modulate inflammation. However, the importance of diurnal variability in the timing of influenza infection is not well understood. Here we demonstrate that endogenous rhythms influence the cellular response to infection in bronchoalveolar lavage (BAL), the pulmonary transcriptomic profile and lesional histology. This time dependent variability does not reflect alterations in viral replication. Rather, we found that better time-dependent outcomes were associated with a preponderance of NK and NKT cells and lower proportion of monocytes in the lung. Thus, host tolerance, rather than viral burden underlies the diurnal gating of influenza induced lung injury.Significance statementOur work demonstrates the importance of circadian rhythms in influenza infection --a condition with significant public health implications. Our findings, which establish the role of the circadian rhythms in maintaining the balance between host tolerance pathways and anti-viral responses confers a new framework for evaluating the relevance of circadian influences on immunity.
Streptomycesvolatile compounds influence exploration and microbial community dynamics by altering iron availability
Authors: Jones Stephanie E. , Pham Christine A. , McKillip Joseph , Zambri Matthew , Carlson Erin E. , Elliot Marie A. 
Published: August 2018

ABSTRACTBacteria and fungi produce a wide array of volatile organic compounds (VOCs), and these can act as infochemicals or as competitive tools. Recent work has shown that the VOC trimethylamine (TMA) can promote a new form ofStreptomycesgrowth, termed ‘exploration’. Here, we report that TMA also serves to alter nutrient availability in the area surrounding exploring cultures: TMA dramatically increases the environmental pH, and in doing so, reduces iron availability. This, in turn, compromised the growth of other soil bacteria and fungi. In contrast,Streptomycesthrives in these iron-depleted niches by secreting a suite of differentially modified siderophores, and by upregulating genes associated with siderophore uptake. Further reducing iron levels by siderophore piracy, limiting siderophore uptake, or growing cultures in the presence of iron chelators, unexpectedly enhanced exploration. Our work reveals a new role for VOCs in modulating iron levels in the environment, and implies a critical role for VOCs in modulating the behaviour of microbes and the makeup of their communities.
Zebrafish Otolith Biomineralization Requires Polyketide Synthase
Authors: Thiessen Kevin D. , Grzegorski Steven J. , Higuchi Lisa , Shavit Jordan A. , Kramer Kenneth L. 
Published: August 2018

AbstractDeflecting biomineralized crystals attached to vestibular hair cells are necessary for maintaining balance. Zebrafish (Danio rerio) are useful organisms to study these biomineralized crystals called otoliths, as many required genes are homologous to human otoconial development. We sought to identify and characterize the causative gene in a trio of mutants,no content (nco)andcorkscrew (csr), andvanished (vns), which fail to develop otoliths during early ear development. We show thatnco, csr, andvnshave potentially deleterious mutations in polyketide synthase (pks1), a multi-modular protein that has been previously implicated in biomineralization events in chordates and echinoderms. We found that Otoconin-90 (Oc90) expression within the otocyst is normal inncoandcsr; therefore, it is not sufficient for otolith biomineralization in zebrafish. Similarly, normal localization of Otogelin, a protein required for otolith tethering in the otolithic membrane, is not sufficient for Oc90 attachment. Furthermore, eNOS signaling and Endothelin-1 signaling were the most up- and down-regulated pathways during otolith agenesis innco, respectively. Our results demonstrate distinct processes for otolith nucleation and biomineralization in vertebrates and will be a starting point for models that are independent of Oc90-mediated seeding. This study will serve as a basis for investigating the role of eNOS signaling and Endothelin-1 signaling during otolith formation.
Divine: Prioritizing Genes for Rare Mendelian Disease in Whole Exome Sequencing Data
Authors: Hong Changjin , Clemenceau Jean R. , Yeu Yunku , Hwang TaeHyun 
Published: August 2018

AbstractMotivationRecent studies showed that a phenotype-driven analysis of whole exome sequencing (WES) could provide more accurate and clinically relevant genetic variants.ResultsWe develop a computational tool called Divine that integrates patients’ phenotype(s) and WES data with 30 prior biological knowledge (e.g., human phenotype ontology, gene ontology, pathway database, protein-protein interaction networks, pathogenicity by the amino acid change due to polymorphism, and hot-spot protein domains) to prioritize potential disease-causing genes. In a retrospective study with 22 real and four simulated data set, Divine ranks the same pathogenic genes confirmed by the original studies 5th on average out of a thousand of mutated genes and outperforms existing state-of-the-art methods.Availabilityhttps://github.com/hwanglab/divineContacthwangt@ccf.orgSupplementary informationSupplementary Document is attached at the end of the page.
Altered dendritic spine function and integration in a mouse model of Fragile X Syndrome
Authors: Booker Sam A. , Domanski Aleksander P.F. , Dando Owen R. , Jackson Adam D. , Isaac John T.R. , Hardingham Giles E. , Wyllie David J.A. , Kind Peter C. 
Published: August 2018

AbstractCellular and circuit hyperexcitability are core features of Fragile X Syndrome and related autism spectrum disorder models. However, a synaptic basis for this hyperexcitability has proved elusive. We show in a mouse model of Fragile X Syndrome, glutamate uncaging onto individual dendritic spines yields stronger single-spine excitation than wild-type, with more silent spines. Furthermore, near-simultaneous uncaging at multiple spines revealed fewer spines are required to trigger an action potential. This arose, in part, from increased dendritic gain due to increased intrinsic excitability, resulting from reduced hyperpolarization-activated currents. Super-resolution microscopy revealed no change in dendritic spine morphology, pointing to an absence of a structure-function relationship. However, ultrastructural analysis revealed a 3-fold increase in multiply-innervated spines, accounting for the increased single-spine excitatory currents following glutamate uncaging. Thus, loss of FMRP causes abnormal synaptogenesis, leading to large numbers of poly-synaptic spines despite normal spine morphology, thus explaining the synaptic perturbations underlying circuit hyperexcitability.
A neuromechanistic model for rhythmic beat generation
Authors: Bose Amitabha , Byrne Áine , Rinzel John 
Published: August 2018

AbstractWhen listening to music, humans can easily identify and move to the beat. Numerous experimental studies have identified brain regions that may be involved with beat perception and representation. Several theoretical and algorithmic approaches have been proposed to account for this ability. Related to, but different from the issue of how we perceive a beat, is the question of how we learn to generate and hold a beat. In this paper, we introduce a neuronal framework for a beat generator that is capable of learning isochronous rhythms over a range of frequencies that are relevant to music and speech. Our approach combines ideas from error-correction and entrainment models to investigate the dynamics of how a biophysically-based neuronal network model synchronizes its period and phase to match that of an external stimulus. The model makes novel use of on-going faster gamma rhythms to form a set of discrete clocks that provide estimates, but not exact information, of how well the beat generator spike times match those of a stimulus sequence. The beat generator is endowed with plasticity allowing it to quickly learn and thereby adjust its spike times to achieve synchronization. Our model makes generalizable predictions about the existence of asymmetries in the synchronization process, as well as specific predictions about resynchronization times after changes in stimulus tempo or phase. Analysis of the model demonstrates that accurate rhythmic time keeping can be achieved over a range of frequencies relevant to music, in a manner that is robust to changes in parameters and to the presence of noise.Author summaryMusic is integral to human experience and is appreciated across a wide range of cultures. Although many features distinguish different musical traditions, rhythm is central to nearly all. Most humans can detect and move along to the beat through finger or foot tapping, hand clapping or other bodily movements. But many people have a hard time “keeping a beat”, or say they have “no sense of rhythm”. There appears to be a disconnect between our ability to perceive a beat versus our ability to produce a beat, as a drummer would do as part of a musical group. Producing a beat requires beat generation, the process by which we learn how to keep track of the specific time intervals between beats, as well as executing the motor movement needed to produce the sound associated with a beat. In this paper, we begin to explore neural mechanisms that may be responsible for our ability to generate and keep a beat. We develop a computational model that includes different neurons and shows how they cooperate to learn a beat and keep it, even after the stimulus is removed, across a range of frequencies relevant to music. Our dynamical systems model leads to predictions for how the brain may react when learning a beat. Our findings and techniques should be widely applicable to those interested in understanding how the brain processes time, particularly in the context of music.
Long fragments achieve lower base quality in Illumina paired-end sequencing
Authors: Tan Ge , Opitz Lennart , Schlapbach Ralph , Rehrauer Hubert 
Published: August 2018

AbstractIllumina’s technology provides high quality reads of DNA fragments with error rates below 1/1000 per base. Runs typically generate a millions of reads where the vast majority of the reads has also an average error rate below 1/1000. However, some paired-end sequencing data show the presence of a subpopulation of reads where the second read has lower average qualities. We show that the fragment length is a major driver of increased error rates in the R2 reads. Fragments above 500 nt tend to yield lower base qualities and higher error rates than shorter fragments. We demonstrate the fragment length dependency of the R2 read qualities using publicly available Illumina data generated by various library protocols, in different labs and using different sequencer models. Our finding extends the understanding of the Illumina read quality and has implications on error models for Illumina reads. It also sheds a light on the importance of the fragmentation during library preparation and the resulting fragment length distribution.
A spike-timing-dependent plasticity rule for single, clustered and distributed dendritic spines
Authors: Tazerart Sabrina , Mitchell Diana E. , Miranda-Rottmann Soledad , Araya Roberto 
Published: August 2018

SUMMARYSpike-timing-dependent plasticity (STDP) has been extensively studied in cortical pyramidal neurons, however, the precise structural organization of excitatory inputs that supports STDP, as well as the structural, molecular and functional properties of dendritic spines during STDP remain unknown. Here we performed a spine STDP protocol using two-photon glutamate uncaging to mimic presynaptic glutamate release (pre) paired with somatically generated postsynaptic spikes (post). We found that the induction of STDP in single spines follows a classical Hebbian STDP rule, where pre-post pairings at timings that trigger LTP (t-LTP) produce shrinkage of the activated spine neck and a concomitant increase in its synaptic strength; and post-pre pairings that trigger LTD (t-LTD) decrease synaptic strength without affecting the activated spine shape. Furthermore, we tested whether the single spine-Hebbian STDP rule could be affected by the activation of neighboring (clustered) or distant (distributed) spines. Our results show that the induction of t-LTP in two clustered spines (<5 μm apart) enhances LTP through a mechanism dependent on local spine calcium accumulation and actin polymerization-dependent neck shrinkage, whereas t-LTD was disrupted by the activation of two clustered spines but recovered when spines were separated by >40 μm. These results indicate that synaptic cooperativity, induced by the co-activation of only two clustered spines, provides local dendritic depolarization and local calcium signals sufficient to disrupt t-LTD and extend the temporal window for the induction of t-LTP, leading to STDP only encompassing LTP.
A Tumor Suppressor-Regulated Cell Cycle Derived Gene Signature is Prognostic of Recurrence Risk in Prostate Cancer
Authors: Georgescu Constantin , Corbin Joshua M. , Thibivilliers Sandra , Webb Zachary D. , Zhao Yan D. , Koster Jan , Fung Kar-Ming , Asch Adam S. , Wren Jonathan D. , Ruiz-Echevarría Maria J. 
Published: August 2018

ABSTRACTBackgroundThe clinical behavior of prostate cancer (PCa) is variable, and while the majority of cases remain indolent, 10% of patients progress to deadly forms of the disease. Current clinical predictors used at the time of diagnosis have limitations to accurately establish progression risk. Here we describe the development of a tumor suppressor regulated, cell-cycle gene expression based prognostic signature for PCa, and validate its independent contribution to risk stratification in several radical prostatectomy (RP) patient cohorts.MethodsWe used RNA interference experiments in PCa cell lines to identify a gene expression based gene signature associated withTmeff2,an androgen regulated, tumor suppressor gene whose expression shows remarkable heterogeneity in PCa. Gene expression was confirmed by qRT-PCR. Correlation of the signature with disease outcome (time to recurrence) was retrospectively evaluated in four geographically different cohorts of patients that underwent RP (834 samples), using multivariate logistical regression analysis. Multivariate analysis were adjusted for standard clinicopathological variables. Performance of the signature was compared to previously described gene expression based signatures using the SIgCheck software.ResultsLow levels of Tmeff2 mRNA significantly (p<0.0001) correlated with reduced disease-free survival (DFS) in patients from the Memorial Sloan Kettering Cancer Center (MSKCC) dataset. We identified a panel of 11 TMEFF2 regulated cell cycle related genes (TMCC11), with strong prognostic value. TMCC11 expression was significantly associated with time to recurrence after prostatectomy in four geographically different patient cohorts (2.9≤HR≥4.1; p≤0.002), served as an independent indicator of poor prognosis in the four RP cohorts (1.96≤HR≥4.28; p≤0.032) and improved the prognostic value of standard clinicopathological markers. The prognostic ability of TMCC11 panel exceeded previously published oncogenic gene signatures (p=0.00017).ConclusionsThis study provides evidence that the TMCC11 gene signature is a robust independent prognostic marker for PCa, reveals the value of using highly heterogeneously expressed genes, likeTmeff2, as guides to discover prognostic indicators, and suggests the possibility that lowTmeff2expression marks a distinct subclass of PCa.
Hiring decisions on certified manpower
Authors: Pao Huei-Wen , Lee Cheng-Yu , Chung Pi-Hui , Wu Hsueh-Liang 
Published: August 2018

PurposeThe industry-wide adoption of a novel practice is often considered to be an institutional change. Although research on institutionalization has been accumulating, how and why embedded actors in the field become motivated to embrace change that remains sidelined. Viewing the introduction of a new human resource management practice, the recruitment of non-compulsory certified manpower, which is still in its infancy in the service sector of Taiwan, as a new institution, the purpose of this paper is to identify the distinct motives behind firms’ hiring decisions, and examine the extent to which such hiring decisions are contingent on institutional conditions and firm attributes.Design/methodology/approachThe data used to test the hypotheses were drawn from a survey on service firms in Taiwan in the second half of 2011. Hypotheses were examined through moderated hierarchical regression analyses in a sample of 254 Taiwanese service firms across major sectors.FindingsIntegrating the resource dependency and social contagion views, the study contends that resource scarcity drives, or legitimacy enables, service firms to deviate from traditional hiring patterns and instead adopt new preferences toward certified manpower. The study not only shows that social factors should be incorporated into the diffusion of a new HR recruitment practice in the service sector, which is traditionally based upon economic considerations, but also sheds light on the context-dependent nature of the process of institutional innovation.Originality/valueThis study is an attempt not only to test a dual-theoretical model on the extent to which a service firm’s new hiring pattern is influenced by two distinct types of motivation, but also to evidence how an institutional innovation, in terms of the regime of service manpower certification, takes root and spreads in the field. The managerially discretional account of the resource dependence theory needs to be reconciled with social contagion theory, which highlights the influence of collective actions and so provides a better understanding of the diffusion of new HR recruitment practices in the service industry.