bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I assessments of first-in-human administration of a novel malaria anti-sporozoite vaccine candidate, R21 in matrix-M adjuvant, in UK and Burkinabe volunteers
Authors: Venkatraman Navin , Tiono Alfred B. , Bowyer Georgina , Powlson Jonathan , Collins Katharine A. , Coulibaly Sam , Datoo Mehreen , Silman Daniel , Ouedraogo Alphonse , Nébié Issa , Imoukhuede Egeruan , Brod Florian , Folegatti Pedro , Dickinson Emma , Jamieson Sophie , Bougouma Edith C. , Wright Daniel , Bellamy Duncan , Diarra Amidou , Bliss Carly M. , Morter Richard , Glenn Greg , Fries Louis F. , Reimer Jenny , Lovgren-Bengtsson Karin , Baker Megan , Poulton Ian , Moyle Sarah , Berrie Eleanor , Green Nicola , Mukhopadhyay Ekta , Viebig Nicola , Angus Brian , Lawrie Alison , Roberts Rachel , Gilbert Sarah C. , Lewis David J.M. , Sirima Sodiomon B. , Ewer Katie J. , Hill Adrian V. S. 
Published: October 2019

ABSTRACTBackgroundImprovements in malaria control have stalled recently and new tools are needed. The R21 vaccine is comprised of the malaria circumsporozoite protein fused to hepatitis B surface antigen (HBsAg). It forms particles that lack the excess HBsAg in the frequently tested malaria vaccine candidate, RTS,S/AS01B.MethodsWe conducted an open-label, first-in-human, Phase Ia study evaluating safety and immunogenicity of R21 administered alone and with the saponin-based adjuvant, Matrix-M™ (MM). Twenty-eight healthy adults received three doses of R21 given intramuscularly 4 weeks apart. We subsequently conducted a Phase Ib randomised, controlled trial in West African adults.FindingsVaccinations were well tolerated, and the majority of local and systemic adverse events were mild. Reactogenicity was significantly lower in Burkinabe than UK vaccinees (p<0.0001). Antibody responses increased significantly 28 days after the 2nd vaccination in UK volunteers. Antibody responses to R21 in all dose groups (2μg, 10μg and 50μg) were comparable to those of 50μg RTS,S/AS01B in malaria-naïve adults at 28 days after final vaccination. The 10μg dose induced more durable responses, with 2-fold higher NANP-specific IgG titres at 6 months compared with the 2μg and 50μg dose groups. R21 also boosted baseline humoral responses in Burkinabe adults with well-maintained responses suggesting natural boosting.InterpretationR21 adjuvanted with MM is safe and has comparable immunogenicity to RTS,S/AS01B, even when administered at a five-fold lower 10μg dose in UK and African populations. This forms the basis for efficacy testing of this vaccine which could prove to be particularly cost-effective to manufacture and deploy.
Immune response and endocytosis pathways are associated with the resilience against Alzheimer’s Disease
Authors: Tesi Niccolò , van der Lee Sven J. , Hulsman Marc , Jansen Iris E. , Stringa Najada , van Schoor Natasja M. , Scheltens Philip , van der Flier Wiesje M. , Huisman Martijn , Reinders Marcel J. T. , Holstege Henne 
Published: October 2019

AbstractDeveloping Alzheimer’s disease (AD) is influenced by multiple genetic variants that are involved in five major AD-pathways. Per individual, these pathways may differentially contribute to the modification of the AD-risk. The pathways involved in the resilience against AD have thus far been poorly addressed. Here, we investigated to what extent each molecular mechanism associates with (i) the increased risk of AD and (ii) the resilience against AD until extreme old age, by comparing pathway-specific polygenic risk scores (pathway-PRS). We used 29 genetic variants associated with AD to develop pathway-PRS for five major pathways involved in AD. We developed an integrative framework that allows multiple genes to associate with a variant, and multiple pathways to associate with a gene. We studied pathway-PRS in the Amsterdam Dementia Cohort of well-phenotyped AD patients (N=1,895), Dutch population controls from the Longitudinal Aging Study Amsterdam (N=1,654) and our unique 100-plus Study cohort of cognitively healthy centenarians who avoided AD (N=293). Last, we estimated the contribution of each pathway to the genetic risk of AD in the general population. All pathway-PRS significantly associated with increased AD-risk and (in the opposite direction) with resilience against AD (except for angiogenesis, p<0.05). The pathway that contributed most to the overall modulation of AD-risk was β-amyloid metabolism (29.6%), which was driven mainly by APOE-variants. After excluding APOE variants, all pathway-PRS associated with increased AD-risk (except for angiogenesis, p<0.05), while specifically immune response (p=0.003) and endocytosis (p=0.0003) associated with resilience against AD. Indeed, the variants in these latter two pathways became the main contributors to the overall modulation of genetic risk of AD (45.5% and 19.2%, respectively). The genetic variants associated with the resilience against AD indicate which pathways are involved with maintained cognitive functioning until extreme ages. Our work suggests that a favorable immune response and a maintained endocytosis pathway might be involved in general neuro-protection, which highlight the need to investigate these pathways, next to β-amyloid metabolism.
Matching the forecast horizon with the relevant spatial and temporal processes and data sources
Authors: Adler Peter B. , White Ethan P. , Cortez Michael H. 
Published: October 2019

AbstractMost phenomenological, statistical models used to generate ecological forecasts take either a time-series approach, based on long-term data from one location, or a space-for-time approach, based on data describing spatial patterns across environmental gradients. Here we consider how the forecast horizon determines whether more accurate predictions come from the time-series approach, the space-for-time approach, or a combination of the two. We use two simulated case studies to show that forecasts for short and long forecast horizons need to focus on different ecological processes, which are reflected in different kinds of data. In the short-term, dynamics reflect initial conditions and fast processes such as birth and death, and the time-series approach makes the best predictions. In the long-term, dynamics reflect the additional influence of slower processes such as evolutionary and ecological selection, colonization and extinction, which the space-for-time approach can effectively capture. At intermediate time-scales, a weighted average of the two approaches shows promise. However, making this weighted model operational will require new research to predict the rate at which slow processes begin to influence dynamics.
Systematic Identification of Novel Cancer Genes through Analysis of Deep shRNA Perturbation Screens
Authors: Montazeri Hesam , Coto-Llerena Mairene , Bianco Gaia , Zangene Ehsan , Taha-Mehlitz Stephanie , Paradiso Viola , Srivatsa Sumana , de Weck Antoine , Roma Guglielmo , Lanzafame Manuela , Bolli Martin , Beerenwinkel Niko , von Flüe Markus , Terracciano Luigi M. , Piscuoglio Salvatore , Ng Charlotte K. Y. 
Published: October 2019

AbstractBackgroundSystematic perturbation screens provide comprehensive resources for the elucidation of cancer driver genes, including rarely mutated genes that are missed by approaches focused on frequently mutated genes and driver genes for which the basis for oncogenicity is non-genetic. The perturbation of many genes in relatively few cell lines in such functional screens necessitates the development of specialized computational tools with sufficient statistical power.ResultsHere we developed APSiC (Analysis ofPerturbationScreens foridentifying novelCancer genes) that can identify genetic and non-genetic drivers even with a limited number of samples. Applying APSiC to the large-scale deep shRNA screen Project DRIVE, APSiC identified well-known, pan-cancer genetic drivers, novel putative genetic drivers known to be dysregulated in specific cancer types and the context dependency of mRNA-splicing between cancer types. Additionally, APSiC discovered a median of 28 and 35 putative non-genetic oncogenes and tumor suppressor genes, respectively, for individual cancer types, including genes involved in genome stability maintenance and cell cycle. We functionally demonstrated thatLRRC4B, a putative non-genetic tumor suppressor gene that has not previously been associated with carcinogenesis, suppresses proliferation by delaying cell cycle and modulates apoptosis in breast cancer.ConclusionWe demonstrate APSiC is a robust statistical framework for discovery of novel cancer genes through analysis of large-scale perturbation screens. The analysis of DRIVE using APSiC is provided as a web portal and represents a valuable resource for the discovery of novel cancer genes.
Multi-taxon inventory reveals highly consistent biodiversity responses to ecospace variation
Authors: Brunbjerg Ane Kirstine , Bruun Hans Henrik , Dalby Lars , Classen Aimée T. , Fløjgaard Camilla , Frøslev Tobias G. , Hansen Oskar Liset Pryds , Høye Toke Thomas , Moeslund Jesper Erenskjold , Svenning Jens-Christian , Ejrnæs Rasmus 
Published: October 2019

AbstractAmidst the global biodiversity crisis, identifying drivers of biodiversity variation remains a key challenge. Scientific consensus is limited to a few macroecological rules, such as species richness increasing with area, which provide limited guidance for conservation. In fact, few agreed ecological principles apply at the scale of sites or reserve management, partly because most community-level studies are restricted to single habitat types and species groups. We used the recently proposedecospaceframework and a comprehensive data set for aggregating environmental variation to predict multi-taxon diversity. We studied richness of plants, fungi, and arthropods in 130 sites representing the major terrestrial habitat types in Denmark. We found the abiotic environment (ecospace position) to be pivotal for the richness of primary producers (vascular plants, mosses, and lichens) and, more surprisingly, little support for ecospace continuity as a driver. A peak in richness at intermediate productivity adds new empirical evidence to a long-standing debate over biodiversity responses to productivity. Finally, we discovered a dominant and positive response of fungi and insect richness to organic matter accumulation and diversification (ecospace expansion). Two simple models of producer and consumer richness accounted for 77 % of the variation in multi-taxon species richness suggesting a significant potential for generalization beyond individual species responses. Our study widens the traditional conservation focus on vegetation and vertebrate populations unravelling the importance of diversification of carbon resources for diverse heterotrophs, such as fungi and insects.
manta- a clustering algorithm for weighted ecological networks
Authors: Röttjers Lisa , Faust Karoline 
Published: October 2019

AbstractMicrobial network inference and analysis has become a successful approach to generate biological hypotheses from microbial sequencing data. Network clustering is a crucial step in this analysis. Here, we present a novel heuristic flow-based network clustering algorithm, which equals or outperforms existing algorithms on noise-free synthetic data.mantacomes with unique strengths such as the ability to identify nodes that represent an intermediate between clusters, to exploit negative edges and to assess the robustness of cluster membership.mantadoes not require parameter tuning, is straightforward to install and run, and can easily be combined with existing microbial network inference tools.
Mitochondrial-Y chromosome epistasis inDrosophila melanogaster
Authors: Ågren J. Arvid , Munasinghe Manisha , Clark Andrew G. 
Published: October 2019

AbstractThe coordination between mitochondrial and nuclear genes is crucial to eukaryotic organisms. Predicting the nature of these epistatic interactions can be difficult because of the transmission asymmetry of the genes involved. While autosomes and X-linked genes are transmitted through both sexes, genes on the Y chromosome and in the mitochondrial genome are uniparentally transmitted through males and females respectively. Here, we generate 36 otherwise isogenicDrosophila melanogasterstrains differing only in the geographical origin of their mitochondrial genome and Y chromosome to experimentally examine the effects of the uniparentally inherited parts of the genome, as well as their interaction, in males. We assay longevity and gene expression through RNA-sequencing. We detect an important role for both mitochondrial and Y-linked genes, as well as extensive mitochondrial-Y chromosome epistasis, in both traits. In particular, genes involved in male reproduction appear to be especially sensitive. Despite these interactions, we find no evidence that the mitochondrial genome and Y chromosome are co-adapted within a geographic region. Overall, our study demonstrates a key role for the uniparentally inherited parts of the genome for male biology, but also that mito-nuclear interactions are complex and not easily predicted from simple transmission asymmetries.
Reliability of single-subject neural activation patterns in speech production tasks
Authors: Frankford Saul A. , Nieto-Castañón Alfonso , Tourville Jason A. , Guenther Frank H. 
Published: October 2019

AbstractSpeech neuroimaging research targeting individual speakers could help elucidate differences that may be crucial to understanding speech disorders. However, this research necessitates reliable brain activation across multiple speech production sessions. In the present study, we evaluated the reliability of speech-related brain activity measured by functional magnetic resonance imaging data from twenty neuro-typical subjects who participated in two experiments involving reading aloud simple speech stimuli. Using traditional methods like the Dice and intraclass correlation coefficients, we found that most individuals displayed moderate to high reliability. We also found that a novel machine-learning subject classifier could identify these individuals by their speech activation patterns with 97% accuracy from among a dataset of seventy-five subjects. These results suggest that single-subject speech research would yield valid results and that investigations into the reliability of speech activation in people with speech disorders are warranted.
Topography, Spectral Characteristics, and Extra-to-Intracranial Propagation Pathways of EMG
Authors: Lahr J. , Fiederer L.D.J. , Glanz O. , Schulze-Bonhage A. , Ball T. 
Published: October 2019

AbstractObjectiveIntracranial EEG (iEEG) plays an increasingly important role in neuroscientific research and can provide informative control signal for brain-machine interfaces (BMI). While it is clear that electromyographic (EMG) activity of extracranial origin reaches intracranial recordings, the topographic and spectral characteristics of intracranial EMG have been scarcely investigated. It is currently unclear how these characteristics compare to those of physiological brain activity. Little is also known about the exact pathways of extra- to intracranial volume conduction, including the role of craniotomy defects.MethodsIn 5 epilepsy patients under invasive pre-neurosurgical EEG monitoring, we examined chewing-related effects (ChREs) as a source of intracranial EMG activity and compared those effects with physiological brain activity of 9 patients during several behavioural tasks. These included speech production, finger movements, and music perception. Further, we analyzed the association of craniotomy defects (burr-holes and saw-lines) and the intracranial EMG-effects based on the individual post-operative images.ResultsChRE presented with a spatially smooth distribution across almost all intracranial electrodes with the maximum below the temporal muscle. In contrast, the responses of neural origin were spatially more focalized. ChREs were broad-banded and had a higher spectral power and affected higher frequencies than event-related neural activity. ChRE were largely independent of the individual configuration of craniotomy defects. However, we found indications that the silicone sheet, in which electrocorticography (ECoG) electrodes are embedded, attenuates EMG influences, when sufficiently large.ConclusionThe present work is the first comprehensive evaluation of topographic and spectral characteristics of EMG effects in iEEG based on a large sample of subjects. It shows that chewing-related EMG can affect iEEG recordings with higher power than typical physiological brain activity, especially in higher spectral frequencies. As the topographic pattern of ChRE is largely independent of the individual position of craniotomy defects, a direct pathway of volume conduction through the intact skull plays an important role for extra- to-intracranial signal propagation. Intracranial EMG activity related to natural behavior should be accounted for in neuroscientific and BMI applications, especially when based on high-frequency iEEG components. A detailed knowledge of EMG properties may help to design both EMG-reducing algorithms and ECoG grids with a high shielding factor.HighlightsFirst comprehensive description of chewing-related EMG artifacts in iEEG recordingsEMG artifacts and brain activity have distinct topographic and spectral iEEG characteristicsChewing EMG reaches the brain with higher spectral power than task-related brain activityChewing-related EMG artifacts are largely independent of the the position of craniotomy defects
Transcriptional Profiling of Primate Central Nucleus of the Amygdala Neurons to Understand the Molecular Underpinnings of Early Life Anxious Temperament
Authors: Kovner Rothem , Souaiaia Tade , Fox Andrew S. , French Delores A. , Goss Cooper. E. , Roseboom Patrick H. , Oler Jonathan A. , Riedel Marissa K. , Fekete Eva M. , Fudge Julie L. , Knowles James A. , Kalin Ned H. 
Published: October 2019

SummaryChildren exhibiting extreme anxious temperament (AT) are at an increased risk to develop anxiety and depression. Work in young rhesus monkeys mechanistically links the central nucleus of the amygdala (Ce) to AT. Here, we used laser capture microscopy and RNA sequencing in 47 young rhesus monkeys to investigate AT‘s molecular underpinnings by focusing on lateral Ce (CeL) neurons. We found 528 AT-related transcripts, including protein kinase C type-delta (PKCδ), a CeL microcircuit cell marker implicated in rodent threat processing. We characterized PKCδ neurons in the rhesus CeL, compared their distribution to the mouse, and demonstrated that a subset of these neurons project to the laterodorsal bed nucleus of the stria terminalis (BSTLd). These findings present evidence in the primate of a CeL to BSTLd circuit that maybe relevant to understanding human anxiety and points to specific molecules within this circuit that could serve as potential treatment targets for anxiety disorders.
Phenotypic and Genotypic Antiviral Resistance Testing of HSV-1 Causing Recurrent Cutaneous Lesions in a Patient with DOCK8 Deficiency
Authors: Casto Amanda M. , Stout Sean C. , Selvarangan Rangaraj , Freeman Alexandra F. , Newell Brandon D. , Stahl Erin D. , Greninger Alexander L. , Yin Dwight E. 
Published: October 2019

AbstractAntiviral resistance frequently complicates treatment of herpes simplex virus (HSV) infections in immunocompromised patients. Here we review the case of an adolescent boy with dedicator of cytokinesis 8 (DOCK8) deficiency, who experienced recurrent infections with resistant HSV-1. We used both phenotypic and genotypic methodologies to characterize the resistance profile of HSV-1 in the patient and conclude that genotypic testing outperformed phenotypic testing. We also present the first analysis of intrahost HSV-1 evolution in an immunocompromised patient. While HSV-1 can remain static in an immunocompetent individual for decades, the virus from this patient rapidly acquired genetic changes throughout its genome.
Dissecting the Roles of Mitochondrial Complex I Intermediate Assembly (MCIA) Complex Factors in the Biogenesis of Complex I
Authors: Formosa Luke E. , Muellner-Wong Linden , Reljic Boris , Sharpe Alice J. , Beilharz Traude H. , Lazarou Michael , Stroud David A. , Ryan Michael T. 
Published: October 2019

ABSTRACTMitochondrial Complex I harbors 7 mitochondrial and 38 nuclear-encoded subunits. Its biogenesis requires the assembly and integration of distinct intermediate modules, mediated by numerous assembly factors. The Mitochondrial Complex I Intermediate Assembly (MCIA) complex, containing assembly factors NDUFAF1, ECSIT, ACAD9, and TMEM126B, is required for building the intermediate ND2-module. The role of the MCIA complex and the involvement of other proteins in the biogenesis of this module is unclear. Cell knockout studies reveal that while each MCIA component is critical for complex I assembly, a hierarchy of stability exists centred on ACAD9. We also identify TMEM186 and COA1 asbona fidecomponents of the MCIA complex with loss of either resulting in in MCIA complex defects and reduced complex I assembly. TMEM186 enriches with newly translated ND3, while COA1 enriches with ND2. Our findings provide new functional insights into the essential nature of the MCIA complex in complex I assembly.
A toolbox of Stable Integration Vectors (SIV) in the fission yeastSchizosaccharomyces pombe
Authors: Vještica Aleksandar , Marek Magdalena , N’kosi Pedro , Merlini Laura , Liu Gaowen , Bérard Melvin , Billault-Chaumartin Ingrid , Martin Sophie G 
Published: October 2019

AbstractSchizosaccharomyces pombeis a widely used model organism that resembles higher eukaryotes in many aspects of cell physiology. Its popularity as an experimental system partially stems from the ease of genetic manipulations, where the innate homology-targeted repair is exploited to precisely edit the genome. While vectors to incorporate exogenous sequences into the chromosomes are available, most are poorly characterized. Here we show that commonly used fission yeast vectors, which upon integration produce repetitive genomic regions, yield unstable genomic loci. We overcome this problem by designing a new series of Stable Integration Vectors (SIV) that target four different prototrophy genes. SIV produce non-repetitive, stable genomic loci and integrate predominantly as single copy. Additionally, we develop a set of complementary auxotrophic alleles that preclude false-positive integration events. We expand the vector series to include antibiotic resistance markers, promoters, fluorescent tags and terminators, and build a highly modular toolbox to introduce heterologous sequences. Finally, as proof of concept, we generate a large set of ready-to-use, fluorescent probes to mark organelles and cellular processes with a wide range of applications in fission yeast research.