bluuebunny/crossref_metadata_2025_split huggingface dataset:
HIV-2 Primary Infection in a French 69-Year-Old Bisexual Man
Authors: Cazals Nicolas , Le Hingrat Quentin , Abraham Bruno , Da Silva Patricia , Guindre Laure , Goffart Sylvie , Damond Florence , Visseaux Benoît , Charpentier Charlotte , Ranger-Rogez Sylvie , Descamps Diane 
Published: September 2018

Abstract
More than 1 million individuals, mainly in West Africa, are thought to be infected with HIV-2. Acute HIV-2 infection is rarely observed, only 2 primary infections have been described to date. We report a detailed case of HIV-2 primary infection in a 69-year-old French bisexual Caucasian man, thereby providing valuable insights into HIV-2 early infection.
The Canadian Reference Power: Delegation to the Courts and the Navigation of Federalism
Authors: Puddister Kate 
Published: September 2018

AbstractThe Canadian reference power allows governments to ask appellate courts for an advisory opinion without a live dispute. Reference cases have been an important element of Canadian federalism since their creation in 1875 but have not been subject to a comprehensive analysis. Shifting the focus to understanding government decisions to rely on the courts to navigate federalism, this article has two objectives. First, through analysis of an original dataset of Canadian appellate reference cases from 1875 to 2017, the article provides an examination of how references have been used by governments, with particular attention to issues related to federalism. Second, the article considers how the reference power can be employed as a political strategy by governments. The reference power demonstrates clear support for the blame avoidance and credit-claiming thesis and provides compelling evidence on how the dynamics of intergovernmental relations can shape a government’s decision to delegate decision-making to the courts.
Treatment of Ciprofloxacin-resistant Ear Infections
Authors: Noonan Kathryn Y. , Kim Soo Yeon , Wong Lye Yeng , Martin Isabella W. , Schwartzman Joseph D. , Saunders James E. 
Published: September 2018

Objective:
Ciprofloxacin resistance has been reported in 4.5% of patients with otorrhea and is increasing in prevalence. Due to ototoxicity, only fluoroquinolones are Food and Drug Administration approved for topical therapy in the middle ear. Furthermore, there is an assumption that antibiotic resistance is less relevant to topical therapy due to in vivo concentrations much higher than the minimum inhibitory concentration used to determine resistance. This study investigates ciprofloxacin-resistant infections and seeks to develop a better understanding of treatment options and outcomes.

Study Design:
Retrospective review of 141 ciprofloxacin-resistant otologic infections.

Setting:
Tertiary-care hospital.

Patients:
Patients with culture-proven ciprofloxacin-resistant infections from 2008 to 2017.

Intervention(s):
Antibiotic treatment with ciprofloxacin topical drops, ciprofloxacin plus oral antibiotics, and nonciprofloxacin therapy.

Main Outcome Measure(s):
Bacteriology for ciprofloxacin-resistant infections and treatment effectiveness of various therapies.

Results:
Methicillin-resistant Staphylococcus aureus (33%), Corynebacterium striatum (19%), and non-Methicillin-resistant Staphylococcus aureus (11%) are the most frequent causes of ciprofloxacin-resistant infections. Topical ciprofloxacin monotherapy was successful in 2.7% of infections compared with a 64.7% success rate with the addition of an oral antibiotic (p < 0.001). Nonciprofloxacin drops are more effective with a 70% cure rate compared with the 2.7% of the ciprofloxacin drops p < 0.001. There was no difference in treatment efficacy when comparing nonciprofloxacin topical therapy (70% cure) to nonciprofloxacin topical therapy plus oral antibiotic (83% cure, p = 0.17).

Conclusions:
Using ciprofloxacin drops to treat ciprofloxacin-resistant bacteria is ineffective and patients do significantly better with alternative therapy. This finding supports the conclusion that high concentrations achieved in topical applications are not sufficient to overcome antibiotic resistance.
Phase resetting in human auditory cortex to visual speech
Authors: Mégevand Pierre , Mercier Manuel R. , Groppe David M. , Golumbic Elana Zion , Mesgarani Nima , Beauchamp Michael S. , Schroeder Charles E. , Mehta Ashesh D. 
Published: September 2018

ABSTRACTNatural conversation is multisensory: when we can see the speaker’s face, visual speech cues influence our perception of what is being said. The neuronal basis of this phenomenon remains unclear, though there is indication that phase modulation of neuronal oscillations—ongoing excitability fluctuations of neuronal populations in the brain—provides a mechanistic contribution. Investigating this question using naturalistic audiovisual speech with intracranial recordings in humans, we show that neuronal populations in auditory cortex track the temporal dynamics of unisensory visual speech using the phase of their slow oscillations and phase-related modulations in high-frequency activity. Auditory cortex thus builds a representation of the speech stream’s envelope based on visual speech alone, at least in part by resetting the phase of its ongoing oscillations. Phase reset could amplify the representation of the speech stream and organize the information contained in neuronal activity patterns.SIGNIFICANCE STATEMENTWatching the speaker can facilitate our understanding of what is being said. The mechanisms responsible for this influence of visual cues on the processing of speech remain incompletely understood. We studied those mechanisms by recording the human brain’s electrical activity through electrodes implanted surgically inside the skull. We found that some regions of cerebral cortex that process auditory speech also respond to visual speech even when it is shown as a silent movie without a soundtrack. This response can occur through a reset of the phase of ongoing oscillations, which helps augment the response of auditory cortex to audiovisual speech. Our results contribute to discover the mechanisms by which the brain merges auditory and visual speech into a unitary perception.
Classification and monomer-by-monomer annotation of suprachromosomal family 1 alpha satellite higher-order repeats in hg38 human genome assembly
Authors: Uralsky L. , Shepelev V.A. , Alexandrov A.A. , Yurov Y.B. , Rogaev E.I. , Alexandrov I.A. 
Published: September 2018

AbstractIn the latest hg38 human genome assembly, centromeric gaps has been filled in by alpha satellite (AS) reference models (RMs) which are statistical representations of homogeneous higher-order repeat (HOR) arrays that make up the bulk of the centromeric regions. We studied these models to compose an atlas of human HORs where each monomer of a HOR could be characterized and represented by a number of its polymorphic sequence variants. We further used these data and HMMER sequence analysis platform to annotate AS HORs in the assembly. This led to discovery and annotation of a new type of low copy number highly divergent HORs which were not represented by RMs. The annotation can be viewed as UCSC Genome Browser custom track (the HOR-track) and used together with our previous annotation of AS SFs in the same assembly where each AS monomer can be viewed in its genomic context together with its classification into one of the 5 major SFs (the SF-track). To catalog the diversity of AS HORs in the human genome we introduced a new naming system. Each HOR received a name which showed its SF, chromosomal location and index number. Here we present the first installment of the HOR-track covering only the 17 HORs that belong to SF1 which forms live functional centromeres in chromosomes 1, 3, 5, 6, 7, 10, 12, 16 and 19 and also a large number of minor dead HOR domains, both homogeneous (pseudo) and divergent (relic). The 4 newly discovered divergent SF1 HORs have provided the missing links in SF1 early evolution and substantiated its partition into 2 generations, archaic and modern, which we reported earlier. Additionally, we demonstrated that monomer-by-monomer HOR annotation was useful for mapping and quantification of various structural variants of AS HORs which would be important for studies of inter-individual polymorphism of AS including centromeric functional epialleles.
Integrative analysis of rare variants and pathway information shows convergent results between immune pathways, drug targets and epilepsy genes
Authors: Nguyen Hoang T. , Dobbyn Amanda , Charney Alexander W. , Bryois Julien , Kim April , Mcfadden Whitney , Skene Nathan G. , Huckins Laura M. , Wang Weiqing , Ruderfer Douglas M , Xu Xinyi , Fromer Menachem , Purcell Shaun M , Lage Kasper , Verhage Matthijs , Smit August B. , Hjerling-Leffler Jens , Buxbaum Joseph D. , Pinto Dalila , He Xin , Sullivan Patrick F , Stahl Eli A. 
Published: September 2018

AbstractTrio family and case-control studies of next-generation sequencing data have proven integral to understanding the contribution of rare inherited andde novosingle-nucleotide variants to the genetic architecture of complex disease. Ideally, such studies should identify individual risk genes of moderate to large effect size to generate novel treatment hypotheses for further follow-up. However, due to insufficient power, gene set enrichment analyses have come to be relied upon for detecting differences between cases and controls, implicating sets of hundreds of genes rather than specific targets for further investigation. Here, we present a Bayesian statistical framework, termed gTADA, that integrates gene-set membership information with gene-levelde novoand rare inherited case-control counts, to prioritize risk genes with excess rare variant burden within enriched gene sets. Applying gTADA to available whole-exome sequencing datasets for several neuropsychiatric conditions, we replicated previously reported gene set enrichments and identified novel risk genes. For epilepsy, gTADA prioritized 40 risk genes (posterior probabilities > 0.95), 6 of which replicate in an independent whole-genome sequencing study. In addition, 30/40 genes are novel genes. We found that epilepsy genes had high protein-protein interaction (PPI) network connectivity, and show specific expression during human brain development. Some of the top prioritized EPI genes were connected to a PPI subnetwork of immune genes and show specific expression in prenatal microglia. We also identified multiple enriched drug-target gene sets for EPI which included immunostimulants as well as known antiepileptics. Immune biology was supported specifically by case-control variants from familial epilepsies rather than do novo mutations in generalized encephalitic epilepsy.
New genetic variants associated with major adverse cardiovascular events in patients with acute coronary syndromes and treated with clopidogrel and aspirin
Authors: Liu Xiaomin , Xu Hanshi , Xu Huaiqian , Geng Qingshan , Mak Wai-Ho , Ling Fei , Su Zheng , Yang Fang , Zhang Tao , Chen Jiyan , Yang Huanming , Wang Jian , Zhang Xiuqing , Xu Xun , Jia Huijue , Zhang Zhiwei , Liu Xiao , Zhong Shilong 
Published: September 2018

AbstractImportanceAlthough a few studies have reported the effects of several polymorphisms on major adverse cardiovascular events (MACE) in patients with acute coronary syndromes (ACS) and those undergoing percutaneous coronary intervention (PCI), these genotypes account for only a small fraction of the variation and evidence is insufficient. This study aims to identify new genetic variants associated with MACE by large-scale sequencing data.ObjectiveTo identify the genetic variants that caused MACE.DesignAll patients in this study were allocated to dual antiplatelet therapy for up to 12 months and have the follow-up duration of 18 months.SettingA two-stage association study was performed.ParticipantsWe evaluated the associations of genetic variants and MACE in 1961 patients with ACS undergoing PCI (2009-2012), including high-depth whole exome sequencing of 168 patients in the discovery cohort and high-depth targeted sequencing of 1793 patients in the replication cohort.Main Outcomes and MeasureThe primary clinical efficacy endpoint was the major adverse cardiovascular events (MACE) composite endpoint, including cardiovascular death, myocardial infarction (MI), stroke (CT or MR scan confirmed) and repeated revascularization (RR).ResultsWe discovered and confirmed six new genotypes associated with MACE in patients with ACS. Of which, rs17064642 at MYOM2 increased the risk of MACE (hazard ratio [HR] 2.76; P = 2.95 × 10-9) and reached genome-wide significance. The other five suggestive variants were KRTAP10-4 (rs201441480), WDR24 (rs11640115), ECHS1 (rs140410716), AGAP3 (rs75750968) and NECAB1 (rs74569896). Notably, the expressions of MYOM2 and ECHS1 are down-regulated in both animal models and patients with phenotypes related to MACE. Importantly, we developed the first superior classifier for predicting MACE and achieved high predictive accuracy (0.809).Conclusions and RelevanceWe identified six new genotypes associated with MACE and developed a superior classifier for predicting MACE. Our findings shed light on the pathogenesis of cardiovascular outcomes and may help clinician to make decision on the therapeutic intervention for ACS patients.Trial RegistrationThis study has been registered in the Chinese Clinical Trial Registry (http://www.chictr.org.cn, Registration number: ChiCTR-OCH-11001198).
Learning Gene Networks Underlying Clinical Phenotypes Using SNP Perturbations
Authors: McCarter Calvin , Howrylak Judie , Kim Seyoung 
Published: September 2018

AbstractRecent technologies are generating an abundance of genome sequence data and molecular and clinical phenotype data, providing an opportunity to understand the genetic architecture and molecular mechanisms underlying diseases. Previous approaches have largely focused on the co-localization of single-nucleotide polymorphisms (SNPs) associated with clinical and expression traits, each identified from genome-wide association studies and expression quantitative trait locus (eQTL) mapping, and thus have provided only limited capabilities for uncovering the molecular mechanisms behind the SNPs influencing clinical phenotypes. Here we aim to extract rich information on the functional role of trait-perturbing SNPs that goes far beyond this simple co-localization. We introduce a computational framework called Perturb-Net for learning the gene network that modulates the influence of SNPs on phenotypes, using SNPs as naturally occurring perturbation of a biological system. Perturb-Net uses a probabilistic graphical model to directly model both the cascade of perturbation from SNPs to the gene network to the phenotype network and the network at each layer of molecular and clinical phenotypes. Perturb-Net learns the entire model by solving a single optimization problem with an extremely fast algorithm that can analyze human genome-wide data within a few hours. In our analysis of asthma data, for a locus that was previously implicated in asthma susceptibility but for which little is known about the molecular mechanism underlying the association, Perturb-Net revealed the gene network modules that mediate the influence of the SNP on asthma phenotypes. Many genes in this network module were well supported in the literature as asthma-related.
Transmission mode is associated with environment type and taxa across bacteria-eukaryote symbioses
Authors: Russell Shelbi L 
Published: September 2018

AbstractSymbiotic associations between bacteria and eukaryotes exhibit a range of transmission strategies. Anecdotal observations suggest that symbionts of terrestrial hosts tend to be strictly vertically inherited through host tissues, whereas symbionts of marine hosts tend towards horizontal transmission. Aside from a few cursory investigations, the rates and distributions of transmission modes have not been investigated in depth across associations, despite the consequences for symbiont and host evolution. To address this empirically and estimate the rate of each mode, I compiled data from the literature and for associations between transmission mode and the environment, transmission route, symbiont function, and taxa involved in the symbiosis. Of the 441 analyzed symbioses, 50.1% were strictly vertically transmitted, 34.0% exhibited some form of mixed mode transmission, and 15.9% were strictly horizontally transmitted. Binning symbioses by their environment revealed a significant skew towards vertical transmission on land and horizontal transmission in aquatic environments, with mixed modes abundant in both. However, host and symbiont taxa were not randomly distributed, which prevented the full separation of these variables. Overall, the data suggest that many symbiotic taxa are capable of horizontal transmission and barriers exist that reduce the rate of these events. Thus, both the environment type and host/symbiont taxa combined influence symbiont transmission mode evolution.One sentence summaryThrough an intensive analysis of the literature on symbiosis transmission modes, estimated rates for each transmission mode were calculated, revealing bias for horizontal transmission in the ocean and vertical transmission on land.
Treatment-Specific Composition of Gut Microbiota Is Associated with Disease Remission in a Pediatric Crohn’s Disease Cohort
Authors: Sprockett Daniel , Fischer Natalie , Boneh Rotem Sigall , Turner Dan , Kierkus Jarek , Sladek Malgorzata , Escher Johanna C. , Wine Eytan , Yerushalmi Baruch , Dias Jorge Amil , Shaoul Ron , Kori Michal , Snapper Scott B. , Holmes Susan , Bousvaros Athos , Levine Arie , Relman David A. 
Published: September 2018

AbstractBackgroundThe beneficial effects of antibiotics in Crohn’s disease (CD) depend in part on the gut microbiota but are inadequately understood. We investigated the impact of metronidazole (MET) and metronidazole plus azithromycin (MET+AZ) on the microbiota in pediatric CD, and the use of microbiota features as classifiers or predictors of disease remission.Methods16S rRNA-based microbiota profiling was performed on stool samples from 67 patients in a multinational, randomized, controlled, longitudinal, 12-week trial of MET vs. MET+AZ in children with mild to moderate CD. Profiles were analyzed together with disease activity, and then used to construct Random Forest models to classify remission or predict treatment response.ResultsBoth MET and MET+AZ significantly decreased diversity of the microbiota and caused large treatment-specific shifts in microbiota structure at week 4. Disease remission was associated with a treatment-specific microbiota configuration. Random Forest models constructed from microbiota profiles pre- and during antibiotic treatment with metronidazole accurately classified disease remission in this treatment group (AUC of 0.879, 95% CI 0.683, 0.9877; sensitivity 0.7778; specificity 1.000, P < 0.001). A Random Forest model trained on preantibiotic microbiota profiles predicted disease remission at week 4 with modest accuracy (AUC of 0.8, P = 0.24).ConclusionsMET and MET+AZ antibiotic regimens in pediatric CD lead to distinct gut microbiota structures at remission. It may be possible to classify and predict remission based in part on microbiota profiles, but larger cohorts will be needed to realize this goal.SummaryWe investigated the impact of metronidazole and metronidazole plus azithromycin on the gut microbiota in pediatric Crohn’s disease. Disease remission was associated with a treatment-specific microbiota configuration, and could be predicted based on pre-antibiotic microbiota profiles.
Maternal inflammation has a profound effect on cortical interneuron development in a stage and subtype-specific manner
Authors: Vasistha Navneet A. , Pardo-Navarro Maria , Gasthaus Janina , Weijers Dilys , Müller Michaela K. , García-González Diego , Malwade Susmita , Korshunova Irina , Pfisterer Ulrich , von Engelhardt Jakob , Hougaard Karin S. , Khodosevich Konstantin 
Published: September 2018

AbstractSevere infections during pregnancy are one of the major risk factors for cognitive brain impairment in offspring. It has been suggested that maternal inflammation leads to dysfunction of cortical GABAergic interneurons that in turn underlies cognitive impairment of the affected offspring. However, the evidence comes largely from studies of adult or mature brain and how impairment of inhibitory circuits arises upon maternal inflammation is unknown. Here we show that maternal inflammation affects multiple steps of cortical GABAergic interneuron development, i.e. proliferation of precursor cells, migration and positioning of neuroblasts as well as neuronal maturation. Importantly, the development of distinct subtypes of cortical GABAergic interneurons was discretely impaired as a result of maternal inflammation. This translated into a reduction in cell numbers, redistribution across cortical regions and layers, changes in morphology and cellular properties. Furthermore, selective vulnerability of GABAergic interneuron subtypes was associated with the stage of brain development. Thus, we propose that maternally-derived insults have developmental stage-dependent effects which contribute to the complex etiology of cognitive impairment in the affected offspring.
Inter-individual differences in human brain structure and morphometry link to population variation in demographics and behavior
Authors: Llera A. , Wolfers T. , Mulders P. , Beckmann C. F. 
Published: September 2018

AbstractWe perform a comprehensive integrative analysis of multiple structural MR-based brain features and find strong evidence relating inter-individual structural variations to demographic and behavioral variates across a large cohort of healthy human volunteers. In particular, our findings shed some light on functional & structural integration, as we find a mode of structural variation that relates to and extends the ‘positive-negative’ behavioral spectrum which was recently reported as being associated with variations in functional connectivity.Significance statementThis work provides for the first-time strong evidence relating human brain structure variations to a wide range of demographic and behavioral measures. We show that several measures previously associated to variation in functional MRI connectivity are in fact already associated at the structural level, pointing towards structure-function integration.
Checkpoint kinase 1 is essential for establishing fetal haematopoiesis and hematopoietic stem and progenitor cell survival
Authors: Schuler Fabian , Afreen Sehar , Manzl Claudia , Häcker Georg , Erlacher Miriam , Villunger Andreas 
Published: September 2018

ABSTRACTCheckpoint kinase 1 is critical for S-phase fidelity and preventing premature mitotic entry in the presence of DNA damage. Tumour cells have developed a strong dependence on CHK1 for survival and hence this kinase has developed into a popular drug-target.Chk1-deficiency in mice results in blastocyst death due to G2/M checkpoint-failure showing that it is an essential gene and may be difficult to target therapeutically without side-effects. Here, we show that chemical inhibition of CHK1 kills murine hematopoietic stem and progenitor cells (HSPCs) as well as human CD34+HSPCs by the induction of BCL2-regulated but p53-independent apoptosis. Moreover,Chk1is essential for stem cell survival and definite hematopoiesis in the mouse embryo. Remarkably though, cell death inhibition in hematopoietic stem cells (HSC) cannot restore blood cell formationin uteroasChk1loss causes severe DNA damage that ultimately prevents HSC expansion. Our findings establish a previously unrecognized role for CHK1 in establishing hematopoiesis; they also suggest adverse effects of therapeutic CHK1-inhibtion, particularly under conditions forcing stem cells out of dormancy, such as chemotherapy-induced myelosuppression.