bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hidden heterogeneity and its influence on dengue vaccination impact
Authors: Walters Magdalene K. , Perkins T. Alex 
Published: September 2019

ABSTRACTThe CYD-TDV vaccine was recently developed to combat dengue, a mosquito-borne viral disease that afflicts millions of people each year throughout the tropical and subtropical world. Its rollout has been complicated by recent findings that vaccinees with no prior exposure to dengue virus (DENV) experience an elevated risk of severe disease in response to their first DENV infection subsequent to vaccination. As a result of these findings, guidelines for use of CYD-TDV now require serological screening prior to vaccination to establish that an individual does not fall into this high-risk category. These complications mean that the public health impact of CYD-TDV vaccination is expected to be higher in areas with higher transmission. One important practical difficulty with tailoring vaccination policy to local transmission contexts is that DENV transmission is spatially heterogeneous, even at the scale of neighborhoods or blocks within a city. This raises the question of whether models based on data that average over spatial heterogeneity in transmission could fail to capture important aspects of CYD-TDV impact in spatially heterogeneous populations. We explored this question with a deterministic model of DENV transmission and CYD-TDV vaccination in a population comprised of two communities with differing transmission intensities. Compared to the full model, a version of the model based on the average of the two communities failed to capture benefits of targeting the intervention to the high-transmission community, which resulted in greater impact in both communities than we observed under even coverage. In addition, the model based on the average of the two communities substantially overestimated impact among vaccinated individuals in the low-transmission community. In the event that the specificity of serological screening is not high, this result suggests that models that ignore spatial heterogeneity could overlook the potential for harm to this segment of the population.
Low-intensity environmental education can enhance perceptions of culturally taboo wildlife
Authors: Williams Samual T. , Williams Kathryn S. , Constant Natasha , Swanepoel Lourens H. , Taylor Peter J. , Belmain Steven R. , Evans Steven W. 
Published: September 2019

1.AbstractTraditional cultural beliefs influence perceptions of animals, and in some cases can result in persecution of wildlife. Stigmas against species associated with witchcraft, for example, can act as a barrier to the uptake of more cost effective, sustainable, and environmentally sound practices such as reducing crop damage by controlling rodent agricultural pests by relying on indigenous predators rather than pesticides. One way of enhancing perceptions of wildlife to increase participation in such ecologically-based rodent management (EBRM) schemes, is the development of environmental education initiatives. Low intensity programmes are cost-effective and can produce positive attitudinal shifts, but their impact has not been assessed for species strongly associated with witchcraft. We set out to test whether a single presentation on the natural history of owls (order Strigiformes) could improve perceptions of these species, and increase willingness to participate in an EBRM scheme that involved the installation of owl boxes to increase owl populations and reduce rodent populations and crop damage in agricultural fields. We used a questionnaire survey to assess perceptions of owls at four schools in two villages in South Africa. Our initial survey sampled perceptions of respondents before listening to the presentation. A follow-up survey conducted three months later sampled the perceptions of respondents that had listened to the presentation as well as perceptions of a control group that did not listen to the presentation. We found that associations between owls and witchcraft was a common theme driving negative perceptions of owls. Respondents that watched the presentation had more positive perceptions of owls than respondents that had not watched the presentation, and they were more likely to be willing to put up owl boxes near their home. Despite this shift, negative perceptions of owls still dominated responses due to cultural associations with the occult. These findings indicate that even low-intensity programmes can be effective at enhancing perceptions of wildlife associated with witchcraft. We suggest that environmental education programmes featuring culturally taboo species should adopt a culturally sensitive and locally tailored approach, focus on the benefits these species provide, and may be more effective when delivered with greater intensity.
Non-Coding and Loss-of-Function Coding Variants in TET2 are Associated with Multiple Neurodegenerative Diseases
Authors: Cochran J. Nicholas , Geier Ethan G. , Bonham Luke W. , Scott Newberry J. , Amaral Michelle D. , Thompson Michelle L. , Lasseigne Brittany N. , Karydas Anna M. , Roberson Erik D. , Cooper Gregory M. , Rabinovici Gil D. , Miller Bruce L. , Myers Richard M. , Yokoyama Jennifer S. 
Published: September 2019

ABSTRACTWe conducted genome sequencing to search for rare variation contributing to early onset Alzheimer’s disease (EOAD) and frontotemporal dementia (FTD). Discovery analysis was conducted on 493 cases and 671 controls of European ancestry. Burden testing for rare variation associated with disease was conducted using filters based on variant rarity (less than 1 in 10,000 or private), computational prediction of deleteriousness (CADD 10 or 15 thresholds), and molecular function (protein loss-of-function only, coding alteration only, or coding plus non-coding variants in experimentally predicted regulatory regions).Replication analysis was conducted on 16,871 independent cases and 15,941 independent controls. Rare variants in TET2 were enriched in the discovery combined EOAD and FTD cohort (p=6.5×10−8, genome-wide corrected p=0.0037). Most of these variants were canonical loss-of-function or non-coding in predicted regulatory regions. This enrichment replicated across several cohorts of AD and FTD (replication only p=0.0071). The combined analysis odds ratio was 2.2 (95% CI 1.5–3.2) for AD and FTD. The odds ratio for qualifying non-coding variants considered independently from coding variants was 2.1 (95% CI 1.2–3.9). For loss-of-function variants, the combined odds ratio (for AD, FTD, and amyotrophic lateral sclerosis, which shares clinicopathological overlap with FTD) was 3.2 (95% CI 2.0–5.3). TET2 catalyzes DNA demethylation. Given well-defined changes in DNA methylation that occur during aging, rare variation in TET2 may confer risk for neurodegeneration by altering the homeostasis of key aging-related processes. Additionally, our study emphasizes the relevance of non-coding variation in genetic studies of complex disease.
Changes in barnacle recruitment and recruit body size with intertidal elevation on wave-exposed rocky shores in Nova Scotia
Authors: Scrosati Ricardo A. 
Published: September 2019

AbstractBarnacle recruitment is often studied in rocky intertidal habitats due to the relevant role that barnacles can play in intertidal communities. In 2014, barnacle (Semibalanus balanoides) recruitment was measured at high elevations in wave-exposed intertidal habitats on the NW Atlantic coast in Nova Scotia, Canada. Values were considerably lower than previously reported for middle elevations in wave-exposed intertidal habitats on the NE Atlantic and NE Pacific coasts. To determine if such differences in recruitment may have resulted from elevation influences, I did a field experiment in 2019 in wave-exposed intertidal habitats in Nova Scotia to test the hypothesis that recruitment is higher at middle than at high elevations, based on known environmental differences between both elevation zones. Based on data from three locations spanning 158 km of the Nova Scotia coast, barnacle recruitment was, on average, nearly 200 % higher (and recruits were larger) at middle than at high elevations. However, even with this increase, barnacle recruitment on this NW Atlantic coast is still lower than for comparable habitats on the NE Atlantic and NE Pacific coasts, and also lower than previously reported for wave-exposed locations farther south on the NW Atlantic coast, in Maine, USA. Therefore, barnacle recruitment in wave-exposed intertidal environments in Nova Scotia appears to be only moderate relative to other shores. This difference in the supply of barnacle recruits might influence the intensity of interspecific interactions involving barnacles.
Enhancement of endothelialization by topographical features is mediated by PTP1B-dependent endothelial adherens junctions remodeling
Authors: Gorji Azita , Toh Pearlyn Jia Ying , Toh Yi-Chin , Toyama Yusuke , Kanchanawong Pakorn 
Published: September 2019

RationaleFailure of small synthetic vascular grafts is largely due to late endothelialization and has been an ongoing challenge in the treatment of cardiovascular diseases.ObjectivePrevious strategies developed to promote graft endothelialization include surface topographical modulation and biochemical modifications. However, these have been met with limited success. Importantly, although the integrity of Endothelial Cell (EC) monolayer is crucial for endothelialization, the crosstalk between surface topography and cell-cell connectivity is still not well understood. Here we explored a combined strategy that utilizes both topographical features and pharmacological perturbations.Methods and resultWe characterized EC behaviors in response to micron-scale grating topography in conjunction with pharmacological perturbations of endothelial adherens junctions (EAJ) regulators. We studied the EA.hy 926 cell-cell junctions and monolayer integrity using the junctional markers upon the inhibitory effect of EAJ regulator on both planar and grating topographies substrates.We identified a protein tyrosine phosphatase, PTP1B, as a potent regulator of EAJ stability. Next, we studied the physiologically relevant behaviors of EC using primary human coronary arterial endothelial cells (HCAEC). Our results showed that PTP1B inhibition synergized with grating topographies to modulate EAJ rearrangement, thereby controlling global EC monolayer sheet orientation, connectivity and collective cell migration to promote endothelialization.Our results showed that PTP1B inhibition synergized with grating topographies to modulate EAJ rearrangement, thereby controlling global EC monolayer sheet orientation, connectivity and collective cell migration and proliferation.ConclusionThe synergistic effect of PTP1B inhibition and grating topographies could be useful for the promotion of endothelialization by enhancing EC migration and proliferation.
Slowly-conducting pyramidal tract neurons in macaque and rat
Authors: Kraskov A , Soteropoulos D , Glover I , Lemon RN , Baker SN 
Published: September 2019

SummaryAnatomical studies report a large proportion of fine myelinated fibres in the primate pyramidal tract (PT), while very few pyramidal tract neurons (PTNs) with slow conduction velocities (CV) (< ∼10 m/s) are reported electrophysiologically. This discrepancy might reflect recording bias towards fast PTNs or prevention of antidromic invasion by recurrent inhibition of slow PTNs from faster axons. We investigated these factors in recordings made with a polyprobe (32 closely-spaced contacts) from motor cortex of anaesthetised rats (n=2) and macaques (n=3), concentrating our search on PTNs with long antidromic latencies. We identified 21 rat PTNs with antidromic latencies > 2.6 ms and estimated CV 3-8 m/s, and 67 macaque PTNs (> 3.9ms, CV 6-12 m/s). Spikes of most slow PTNs were small and present on only some recording contacts, while spikes from simultaneously recorded fast-conducting PTNs were large and appeared on all contacts. Antidromic thresholds were similar for fast and slow PTNS, while spike duration was considerably longer in slow PTNs. Most slow PTNs showed no signs of failure to respond antidromically. A number of tests, including intracortical microinjection of bicuculline (GABAA antagonist), failed to provide any evidence that recurrent inhibition prevented antidromic invasion of slow PTNs. Our results suggest that recording bias is the main reason why previous studies were dominated by fast PTNs.
Low spontaneous mutation rate and Pleistocene radiation of pea aphids
Authors: Fazalova Varvara , Nevado Bruno 
Published: September 2019

AbstractAccurate estimates of divergence times are essential to understand the evolutionary history of species. It allows linking evolutionary histories of the diverging lineages with past geological, climatic and other changes in environment and shed light on the processes involved in speciation. The pea aphid radiation includes multiple host races adapted to different legume host plants. It is thought that diversification in this system occurred very recently, over the past 8,000 to 16,000 years. This young age estimate was used to link diversification in pea aphids to the onset of human agriculture, and lead to the establishment of the pea aphid radiation as a model system in the study of speciation with gene flow. Here, we re-examine the age of the pea aphid radiation, by combining a mutation accumulation experiment with a genome-wide estimate of divergence between distantly related pea aphid host races. We estimate the spontaneous mutation rate for pea aphids as 2.27 × 10−10 per haploid genome per parthenogenic generation. Using this estimate of mutation rate and the genome-wide genetic differentiation observed between pea aphid host races, we show that the pea aphid radiation is much more ancient than assumed previously, predating Neolithic agriculture by several hundreds of thousands of years. Our results rule out human agriculture as the driver of diversification of the pea aphid radiation, and call for re-assessment of the role of allopatric isolation during Pleistocene climatic oscillations in divergence of the pea aphid complex.
Yap1-driven intestinal repair is controlled by group 3 innate lymphoid cells
Authors: Romera-Hernández Mónica , Aparicio-Domingo Patricia , Papazian Natalie , Karrich Julien J. , Cornelissen Ferry , Hoogenboezem Remco M. , Samsom Janneke N. , Cupedo Tom 
Published: September 2019

SUMMARYTissue repair requires temporal control of progenitor cell proliferation and differentiation to replenish damaged cells. In response to acute insult, group 3 innate lymphoid cells (ILC3) regulate intestinal stem cell maintenance and subsequent tissue repair. ILC3-derived IL-22 is important for stem cell protection, but the mechanisms of ILC3-driven tissue regeneration remain incompletely defined. Here we report that group 3 innate lymphoid cell (ILC3)-driven epithelial proliferation and tissue regeneration are independent of IL-22. In contrast, ILC3 amplify the magnitude of Hippo-Yap1 signaling in intestinal crypt cells, ensuring adequate initiation of tissue repair and preventing excessive pathology. Mechanistically, ILC3-driven tissue repair is Stat3-independent, but involves activation of Src family kinases. Our findings reveal that ILC3-driven intestinal repair entails distinct transcriptional networks to control stem cell maintenance and epithelial regeneration which implies that tissue repair and crypt proliferation can be influenced by targeting innate immune cells independent of the well-established effects of IL-22.
Weak-Instrument Robust Tests in Two-Sample Summary-Data Mendelian Randomization
Authors: Wang Sheng , Kang Hyunseung 
Published: September 2019

AbstractMendelian randomization (MR) is a popular method in genetic epidemiology to estimate the effect of an exposure on an outcome using genetic variants as instrumental variables (IV), with two-sample summary-data MR being the most popular due to privacy. Unfortunately, many MR methods for two-sample summary data are not robust to weak instruments, a common phenomena with genetic instruments; many of these methods are biased and no existing MR method has Type I error control under weak instruments. In this work, we propose test statistics that are robust to weak instruments by extending Anderson-Rubin, Kleibergen, and conditional likelihood ratio tests in econometrics to the two-sample summary data setting. We conclude with a simulation and an empirical study and show that the proposed tests control size and have better power than current methods.
COMET: A toolkit for composing customizable genetic programs in mammalian cells
Authors: Donahue Patrick S. , Draut Joseph W. , Muldoon Joseph J. , Edelstein Hailey I. , Bagheri Neda , Leonard Joshua N. 
Published: September 2019

ABSTRACTEngineering mammalian cells to carry out sophisticated and customizable genetic programs requires a toolkit of multiple orthogonal and well-characterized transcription factors (TFs). To address this need, we developed the COmposable Mammalian Elements of Transcription (COMET)—an ensemble of TFs and promoters that enable the design and tuning of gene expression to an extent not previously possible. COMET currently comprises 44 activating and 12 inhibitory zinc-finger TFs and 83 cognate promoters, combined in a framework that readily accommodates new parts. This system can tune gene expression over three orders of magnitude, provides chemically inducible control of TF activity, and enables single-layer Boolean logic. We also develop a mathematical model that provides mechanistic insights into COMET performance characteristics. Altogether, COMET enables the design and construction of customizable genetic programs in mammalian cells.
CytoMAP: a spatial analysis toolbox reveals features of myeloid cell organization in lymphoid tissues
Authors: Stoltzfus Caleb R , Filipek Jakub , Gern Benjamin H , Olin Brandy E , Leal Joseph M , Lyons-Cohen Miranda R , Huang Jessica , Paz-Stoltzfus Clarissa L , Plumlee Courtney R , Pöschinger Thomas , Urdahl Kevin B , Perro Mario , Gerner Michael Y 
Published: September 2019

ABSTRACTRecently developed approaches for highly-multiplexed 2-dimensional (2D) and 3D imaging have revealed complex patterns of cellular positioning and cell-cell interactions with important roles in both cellular and tissue level physiology. However, robust and accessible tools to quantitatively study cellular patterning and tissue architecture are currently lacking. Here, we developed a spatial analysis toolbox, Histo-Cytometric Multidimensional Analysis Pipeline (CytoMAP), which incorporates neural network based data clustering, positional correlation, dimensionality reduction, and 2D/3D region reconstruction to identify localized cellular networks and reveal fundamental features of tissue organization. We apply CytoMAP to study the microanatomy of innate immune subsets in murine lymph nodes (LNs) and reveal mutually exclusive segregation of migratory dendritic cells (DCs), regionalized compartmentalization of SIRPa− dermal DCs, as well as preferential association of resident DCs with select LN vasculature. These studies provide new insights into the organization of myeloid cells in LNs, and demonstrate that CytoMAP is a comprehensive analytics toolbox for revealing fundamental features of tissue organization in quantitative imaging datasets.
Rapid dissemination and monopolization of viral populations in mice revealed using a panel of barcoded viruses
Authors: McCune Broc T. , Lanahan Matthew R. , tenOever Benjamin R. , Pfeiffer Julie K. 
Published: September 2019

AbstractThe gastrointestinal tract presents a formidable barrier for pathogens to initiate infection. Despite this barrier, enteroviruses, including coxsackievirus B3 (CVB3), successfully penetrate the intestine to initiate infection and spread systemically prior to shedding in stool. However, the effect of the gastrointestinal barrier on CVB3 population dynamics is relatively unexplored, nor are the selective pressures acting on CVB3 in the intestine well-characterized. To examine viral population dynamics in orally infected mice, we produced over one hundred CVB3 viruses harboring unique nine nucleotide “barcodes.” Using this collection of barcoded viruses, we found diverse viral populations throughout each mouse within the first day post-infection, but by 48 hours the viral populations were dominated by less than three barcoded viruses in intestinal and extra-intestinal tissues. Using light-sensitive viruses to track replication status, we found diverse viruses had replicated prior to loss of diversity. Sequencing whole viral genomes from samples later in infection did not reveal detectable viral adaptations. Surprisingly, orally inoculated CVB3 was detectable in pancreas and liver as soon as 20 minutes post inoculation, indicating rapid systemic dissemination. These results suggest rapid dissemination of diverse viral populations, followed by a major restriction in population diversity and monopolization in all examined tissues. These results underscore a complex dynamic between dissemination and clearance for an enteric virus.ImportanceEnteric viruses initiate infection in the gastrointestinal tract but can disseminate to systemic sites. However, the dynamics of viral dissemination are unclear. In this study, we created a library of 135 barcoded coxsackieviruses to examine viral population diversity across time and space following oral inoculation of mice. Overall, we found that the broad population of viruses disseminates early, followed by monopolization of mouse tissues with three or fewer pool members at later time points. Interestingly, we detected virus in systemic tissues such as pancreas and liver just 20 minutes post-oral inoculation. These results suggest rapid dissemination of diverse viral populations, followed by a major restriction in population diversity and monopolization in all examined tissues.
MreC and MreD balance the interaction between the elongasome proteins PBP2 and RodA
Authors: Liu Xiaolong , Biboy Jacob , Vollmer Waldemar , den Blaauwen Tanneke 
Published: September 2019

AbstractRod-shape of most bacteria is maintained by the elongasome, which mediates the synthesis and insertion of peptidoglycan into the cylindrical part of the cell wall. The elongasome contains several essential proteins, such as RodA, PBP2, and the MreBCD proteins, but how its activities are regulated remains poorly understood. UsingE. colias a model system, we investigated the interactions between core elongasome proteinsin vivo. Our results show that PBP2 and RodA form a complex mediated by their transmembrane and periplasmic parts and independent of their catalytic activity. MreC and MreD also interact directly with PBP2. MreC elicits a chance in the interaction between PBP2 and RodA, which is suppressed by MreD. The cytoplasmic domain of PBP2 is required for this suppression. We hypothesize that thein vivomeasured PBP2-RodA interaction change induced by MreC corresponds to the conformational change in PBP2 as observed in the MreC-PBP2 crystal structure, which was suggested to be the “on state” of PBP2. Our results indicate that the balance between MreC and MreD determines the activity of PBP2, which could open new strategies for antibiotic drug development.ImportanceThe cell envelope ofEscherichia colibears the protective and shape-determining peptidoglycan layer sandwiched between the outer and inner membranes. Length growth in bacteria is accomplished by a protein complex termed elongasome. We used Förster Resonance Energy Transfer (FRET) that reports not only on whether proteins interact with each other but also on conformational changes during interactions, to investigate how the elongasome might be activated. RodA and PBP2 provide the peptidoglycan glycosyltransferase and transpeptidase activities needed to synthesize new peptidolgycan during length growth, respectively, and PBP2 activates RodA. We show that the interactions between MreC and MreD with PBP2-RodA alter the nature of the interaction between PBP2 and RodA and hypothesis that the corresponding conformational change in the PBP2-RodA complex allows switching between the ‘on’ and ‘off’ states of the elongasome.