bluuebunny/crossref_metadata_2025_split huggingface dataset:
A multi-tissue transcriptome analysis of human metabolites guides the interpretability of associations based on multi-SNP models for gene expression
Authors: Ndungu Anne , Payne Anthony , Torres Jason , van de Bunt Martijn , McCarthy Mark I. 
Published: September 2019

AbstractThere is particular interest in transcriptome-wide association studies (TWAS) - gene-level tests based on multi-SNP predictive models of gene expression - for identifying causal genes at loci associated with complex traits. However, interpretation of TWAS associations may be complicated by divergent effects of model SNPs on trait phenotype and gene expression. We developed an iterative modelling scheme for obtaining multi-SNP models of gene expression and applied this framework to generate expression models for 43 human tissues from the Genotype-Tissues Expression (GTEx) Project. We characterized the performance of single- and multi-SNP TWAS models for identifying causal genes in GWAS data for 46 circulating metabolites. We show that: (a) multi-SNP models captured more variation in expression than the topcis-eQTL (median 2 fold improvement); (b) predicted expression based on multi-SNP models was associated (FDR<0.01) with metabolite levels for 826 unique gene-metabolite pairs, but, after step-wise conditional analyses, 90% were dominated by a single eQTL SNP; (c) amongst the 35% of associations where a SNP in the expression model was a significantcis-eQTL and metabolomic-QTL (met-QTL), 92% demonstrated colocalization between these signals, but interpretation was often complicated by incomplete overlap of QTLs in multi-SNP models; (d) using a “truth” set of causal genes at 61 met-QTLs, the sensitivity was high (67%), but the positive predictive value was low, as only 8% of TWAS associations at met-QTLs involved true causal genes. These results guide the interpretation of TWAS and highlight the need for corroborative data to provide confident assignment of causality.
Dysregulation of external globus pallidus-subthalamic nucleus network dynamics in Parkinsonian mice
Authors: Kovaleski Ryan F. , Callahan Joshua W. , Chazalon Marine , Baufreton Jérôme , Bevan Mark D. 
Published: September 2019

AbstractReciprocally connected GABAergic external globus pallidus (GPe) and glutamatergic subthalamic nucleus (STN) neurons form a key, centrally-positioned network within the basal ganglia, a group of subcortical brain nuclei critical for voluntary movement. In Parkinson’s disease (PD) and its models, abnormal rates and patterns of GPe-STN network activity are linked to motor dysfunction. Using cell class-specific optogenetic identification and inhibition approaches during cortical slow-wave activity and activation, we report that in dopamine-depleted mice 1) D2 dopamine receptor expressing striatal projection neurons (D2-SPNs) are hyperactive 2) prototypic parvalbumin (PV)-expressing GPe neurons are excessively patterned by D2-SPNs 3) despite being disinhibited, STN neurons are not hyperactive 4) the STN opposes rather than facilitates abnormal striatopallidal patterning. Together with recent studies, these data argue that in Parkinsonian mice abnormal, temporally offset PV GPe neuron and STN activity results from increased striatopallidal transmission and that compensatory plasticity within the STN prevents its hyperactivity.
Genetic changes of P. vivax tempers host tissue-specific responses in Anopheles stephensi
Authors: Tevatiya Sanjay , Kumari Seena , Chauhan Charu , Singla Deepak , De Tanwee Das , Sharma Punita , Thomas Tina , Rani Jyoti , Pandey Kailash C , Pande Veena , Dixit Rajnikant 
Published: September 2019

AbstractIn our preceding study (Sharma et al., 2019; BioRxiv) we showed that in the gut lumen Plasmodium vivax follows a unique strategy of immuno-suppression by disabling gut flora proliferation. Here, we further demonstrate that post gut invasion, a shrewd molecular relationship with individual tissues such as midgut, hemocyte, salivary glands, and strategic changes in the genetic makeup of P. vivax favors its survival in the mosquito host. A transient suppression of ‘metabolic machinery by early oocysts, and increased immunity’ against late oocysts suggested a unique mechanism of gut homeostasis restoration and Plasmodium population regulation. Though a hyper immune response of hemocyte was a key to remove free circulating sporozoites, but a strong suppression of salivary metabolic activities, may favor successful survival of invaded sporozoites. Finally, genetic alteration of P. vivax ensures evasion of mosquito responses. Conclusively, our system-wide RNAseq analysis provides first genetic evidences of direct mosquito-Plasmodium interaction and establishes a functional correlation.Author SummaryMalaria transmission dynamics is heavily influenced by mosquito –parasite interaction. When passing through tissue specific barriers, Plasmodium have to compromise by losing its own population, but genetic relation is unknown. To win the developmental race Plasmodium need to overcome two important immuno-physiological barriers. First one accounts an indirect 24-30hr long pre-invasive gut-microbe-parasite interaction in the gut lumen. And second one follows a direct post gut invasive 14-18 days interaction with midgut, hemocyte and salivary glands. During pre-invasive phase of interaction, we showed Plasmodium vivax follows immuno-suppression strategy by restricting microbial growth in the gut lumen. Here, we demonstrate that switch of parasite from one stage to another stage within mosquito vector is accompanied by genetic changes of parasite. Our data suggests genetic makeup change enables the parasite to manipulate the metabolism of mosquito tissues. This strategy not only clear off multifaceted mosquito’s tissue specific immune responses, but also favors Plasmodium own survival and transmission. Comprehending this tissue specific interaction between host and parasite at molecular level could provide new tool to intervene the plasmodium life cycle within vector.
The trajectory of gait development in mice
Authors: Akula Shyam , McCullough Katherine B. , Weichselbaum Claire , Dougherty Joseph D. , Maloney Susan E. 
Published: September 2019

AbstractGait irregularities are prevalent in neurodevelopmental diseases and disorders (NDDs). However, there is a paucity of information on gait phenotypes in the NDD experimental models. This is in part due to the lack of understanding of the normal developmental trajectory of gait maturation in the mouse. Using the DigiGait system, we have developed a quantitative, standardized, and reproducible assay of developmental gait metrics in commonly used mouse strains that can be added to the battery of mouse model phenotyping. With this assay, we characterized the trajectory of gait in the developing C57BL/6J and FVB/AntJ mouse lines. In both lines, maturation of mouse gait between P21 and P30 was best reflected by aspects of the stance phase of the stride. Additionally, in C57BL/6J mice, gait maturation was observed through how the paw is loaded and unloaded during the stance phase of a stride. In FVB/AntJ mice, gait maturity during this developmental window was best observed through the decreased variability in paw area on the belt during stance. Our results also underscore the importance of considering body length when interpreting gait metrics. Further, our results show that background strain needs to be considered when comparing gait across models. Overall, our results show that aspects of mouse gait development parallel a timeline of normal human gait development, such as the percent of stride that is stance phase and swing phase. This study may be used as a standard reference for developmental gait phenotyping of a variety of murine models, such as models of neurodevelopmental disease.
The power of mixed survey methodologies for detecting decline of the Bornean orangutan
Authors: Santika Truly , Wilson Kerrie A. , Meijaard Erik , Ancrenaz Marc 
Published: September 2019

ABSTRACTFor many threatened species, it is difficult to assess precisely for large areas the change in their abundances over time and the relative impacts of climate and anthropogenic land use. This is because surveys of such species are typically restricted to small geographic areas, are conducted during short time periods, and use different survey protocols. We assessed the change in the abundance of Bornean orangutanPongo pygmaeus morioin Sabah, Malaysia, and to identify environmental drivers affecting the change by integrating different types of survey data. We used nest count data obtained from aerial and ground transect surveys and occurrence data obtained from reconnaissance walks and interview survey over the past decade. We built a spatially-explicit dynamic population model within the Bayesian framework allowing these varying survey data to be analyzed jointly by explicitly accounting for each survey’s sampling rate. We found that sampling rates vary across survey types, reflecting each survey’s associated effort. Orangutan survival rates were strongly determined by natural forest extent and moderately by temperature. Orangutan migration rates across more than 1 km distance between forest patches were low, which underlines the importance of maintaining ecological connectivity. The paucity of species abundance data collected in a consistent manner over many years across broad extents often hinders the assessment of species population trend and their persistence across regional scales. We demonstrate that this can be addressed by integrating multiple survey data across different localities, provided that sampling rate inherent to each survey is accounted for.
Multiple testing correction over contrasts for brain imaging
Authors: Alberton Bianca A. V. , Nichols Thomas E. , Gamba Humberto R. , Winkler Anderson M. 
Published: September 2019

AbstractThe multiple testing problem arises not only when there are many voxels or vertices in an image representation of the brain, but also when multiple contrasts of parameter estimates (that is, hypotheses) are tested in the same general linear model. Here we argue that a correction for this multiplicity must be performed to avoid excess of false positives. Various methods have been proposed in the literature, but few have been applied to brain imaging. Here we discuss and compare different methods to make such correction in different scenarios, showing that one classical and well known method is invalid, and argue that permutation is the best option to perform such correction due to its exactness and flexibility to handle a variety of common imaging situations.
Middle-down proteomics reveals dense sites of methylation and phosphorylation in arginine-rich RNA-binding proteins
Authors: Kundinger Sean R. , Bishof Isaac , Dammer Eric B. , Duong Duc M. , Seyfried Nicholas T. 
Published: September 2019

AbstractArginine (Arg)-rich RNA-binding proteins play an integral role in RNA metabolism. Post-translational modifications (PTMs) within Arg-rich domains, such as phosphorylation and methylation, regulate multiple steps in RNA metabolism. However, the identification of PTMs within Arg-rich domains with complete trypsin digestion is extremely challenging due to the high density of Arg residues within these proteins. Here, we report a middle-down proteomic approach coupled with electron transfer dissociation (ETD) mass spectrometry to map previously unknown sites of phosphorylation and methylation within the Arg-rich domains of U1-70K and structurally similar RNA-binding proteins from nuclear extracts of HEK293 cells. Remarkably, the Arg-rich domains in RNA-binding proteins are densely modified by methylation and phosphorylation compared with the remainder of the proteome, with di-methylation and phosphorylation favoring RSRS motifs. Although they favor a common motif, analysis of combinatorial PTMs within RSRS motifs indicate that phosphorylation and methylation do not often co-occur, suggesting they may functionally oppose one another. Collectively, these findings suggest that the level of PTMs within Arg-rich domains may be among the highest in the proteome, and a possible unexplored regulator of RNA metabolism. These data also serve as a resource to facilitate future mechanistic studies of the role of PTMs in RNA-binding protein structure and function.BriefsMiddle-down proteomics reveals arginine-rich RNA-binding proteins contain many sites of methylation and phosphorylation.
Draft genome of a porcupinefish, Diodon Holocanthus
Authors: Xu Mengyang , Su Xiaoshan , Zhang Mengqi , Li Ming , Huang Xiaoyun , Fan Guangyi , Liu Xin , Zhang He 
Published: September 2019

AbstractThe long-spine porcupinefish, Diodon holocanthus (Diodontidae, Tetraodontiformes, Actinopterygii), also known as the freckled porcupinefish, attracts great interest of ecology and economy. Its distinct characteristics including inflation reaction, spiny skin and tetradotoxin, however, have not been fully studied without a complete genome assembly.In this study, the whole genome of a single individual was sequenced using single tube-Long Fragment Read co-barcode reads, generating 154.3 Gb of paired-end data (219.8× depth). The gap was further filled using small amount of Oxford Nanopore MinION long read dataset (11.4Gb, 15.9× depth). Taking full use of long, medium, short-range of genome assembly information, the final assembled sequences with a total length of 650.02 Mb obtained contig and scaffold N50 sizes of 2.15 Mb and 8.13 Mb, respectively, despite of high repetitive content. Benchmarking Universal Single-Copy Orthologs captured 95.7% (2,474) of core genes to assess the completeness. In addition, 206.5 Mb (32.10%) of repetitive sequences were identified, and 20,840 protein-coding genes were annotated, among which 18,281 (87.72%) proteins were assigned with possible functions.This is the first demonstration of de novo genome of the porcupinefish, which will benefit downstream analysis of ontogeny, phylogeny, and evolution, and improve the exploration of its unique defensive mechanism.
Distinctive tasks of different cyanobacteria and associated bacteria in carbon as well as nitrogen fixation and cycling in a late stage Baltic Sea bloom
Authors: Eigemann Falk , Vogts Angela , Voss Maren , Zoccarato Luca , Schulz-Vogt Heide 
Published: September 2019

AbstractCyanobacteria and associated heterotrophic bacteria hold key roles in carbon as well as nitrogen fixation and cycling in the Baltic Sea due to massive cyanobacterial blooms each summer. The species specific activities of different cyanobacterial species as well as the N- and C-exchange of associated heterotrophic bacteria in these processes, however, are widely unknown. Within one time series experiment we tested the cycling in a natural, late stage cyanobacterial bloom by adding13C bi-carbonate and15N2, and performed sampling after 10 min, 30 min, 1 h, 6 h and 24 h in order to determine the fixing species as well as the fate of the fixed carbon and nitrogen in the associations. Uptake of15N and13C isotopes by the most abundant cyanobacterial species as well as the most abundant associated heterotrophic bacterial groups was then analysed with a NanoSIMS. Overall, the filamentous, heterocystous speciesDolichospermumsp.,Nodulariasp., andAphanizomenonsp. revealed no or erratic uptake of carbon and nitrogen, indicating mostly inactive cells. In contrary, non-heterocystousPseudanabaenasp. dominated the nitrogen and carbon fixation, with uptake rates up to 1.49 ± 0.47 nmol N h-1l-1and 2.55 ± 0.91 nmol C h-1l-1. Associated heterotrophic bacteria dominated the subsequent nitrogen cycling with uptake rates up to 1.2 ± 1.93 fmol N h-1cell-1, but were also indicative for fixation of di-nitrogen.
Blood pressure variability from intra-arterial recordings in humans
Authors: Mukadam Farhan Adam , Gangadharan Naveen , Baskaran Bowya , Baskaran S , Subramani Kandasamy , Wankhar Syrpailyne , Devasahayam Suresh , Subramani Sathya 
Published: September 2019

AbstractSystolic and diastolic blood pressures are reported as single point values by the non-invasive techniques used in clinical practice, while, in fact, they are highly varying signals. The objective of this study was to document the magnitude of variation of systolic and diastolic pressures over a few minutes by analysing intra-arterial pressure recordings made in 51 haemodynamically stable patients in an intensive care unit. Intra-arterial pressure data were acquired by a validated data acquisition system. Fast-Flush test was performed and the dynamic characteristics of the catheter transducer system namely natural frequency and damping co-efficient were calculated. Only those recordings with acceptable dynamic characteristics were included in the analysis. Power spectral calculation using the Discrete Fourier transform (DFT) of the pressure recording revealed two frequency peaks below the peak at heart rate. The lower and higher frequency peaks below the heart rate peak are referred to as Mayer and Traube waves in this study. Mayer wave peaks were observed in DFT spectra of 49 out of 51 patients. The Mayer wave frequency peaks ranged between 0.045 Hz to 0.065 Hz in 41 out of 51 patients. The frequency of Traube waves or the respiratory variations was more than 0.14 Hz. Three categories of systolic and diastolic pressure variabilities namely beat-to-beat variability, Respiratory variability (Traube wave amplitude) and Total magnitude of variation are reported for all 51 patients. The mean systolic and diastolic pressure variations (in a period of about 10 minutes) in the study sample were 21 ± 9 mm Hg and 14 ± 5 mm Hg respectively. Given the magnitude of systolic and diastolic pressure variations over a few minutes, the validity of reporting single point values for these pressures and using single point cut-offs for diagnosis and treatment of hypertension must be re-evaluated.
Coiled-coil registry shifts in the F684I mutant of Bicaudal result in cargo-independent activation of dynein motility
Authors: Cui Heying , Trybus Kathleen M. , Yusuf Ali M. , Goyal Puja , Zhang Kaiqi , Loh Jia Ying , Solmaz Sozanne R. 
Published: September 2019

ABSTRACTThe dynein adaptorDrosophilaBicaudal D (BicD) is auto-inhibited and activates dynein motility only after cargo is bound, but the underlying mechanism is elusive. In contrast, we show that the full-length BicD/F684I mutant activates dynein processivity even in the absence of cargo. Our X-ray structure of the C-terminal domain of the BicD/F684I mutant reveals a coiled-coil registry shift; in the N-terminal region, the two helices of the homodimer are aligned, whereas they are vertically shifted in the wild-type. One chain is partially disordered and this structural flexibility is confirmed by computations, which reveal that the mutant transitions back and forth between the two registries. We propose that a coiled-coil registry shift upon cargo binding activates BicD for dynein recruitment. Moreover, the human homolog BicD2/F743I exhibits diminished binding of cargo adaptor Nup358, implying that a coiled-coil registry shift may be a mechanism to modulate cargo selection for BicD2–dependent transport pathways.
Fabrication of sharp silicon arrays to wound Caenorhabditis elegans
Authors: Belougne Jérôme , Ozerov Igor , Caillard Céline , Bedu Frédéric , Ewbank Jonathan J. 
Published: September 2019

ABSTRACTUnderstanding how animals respond to injury and how wounds heal remains a challenge. These questions can be addressed using genetically tractable animals, including the nematode Caenorhabditis elegans. Given its small size, the current methods for inflicting wounds in a controlled manner are demanding. To facilitate and accelerate the procedure, we fabricated regular arrays of pyramidal features (“pins”) sharp enough to pierce the tough nematode cuticle. The pyramids were made from monocrystalline silicon wafers that were micro-structured using optical lithography and alkaline wet etching. The fabrication protocol and the geometry of the pins, determined by electron microscopy, are described in detail. Upon wounding, C. elegans expresses genes encoding antimicrobial peptides. A comparison of the induction of antimicrobial peptide gene expression using traditional needles and the pin arrays demonstrates the utility of this new method.
The Evolution of Social Organization: Climate Influences Variation in Drosophilid Social Networks
Authors: Jezovit Jacob A. , Rooke Rebecca , Schneider Jonathan , Levine Joel D. 
Published: September 2019

SummaryCultural norms, collective decisions, reproductive behaviour, and pathogen transmission all emerge from interaction patterns within animal social groups. These patterns of interaction support group-level phenomena that can influence an individual’s fitness. The aim of this study is to understand the evolution of social organization in Drosophila. Using a comparative ecological, phylogenetic and behavioural approach, we studied the different properties of social interaction networks (SINs) formed by 20 drosophilids and the different ways these species interact. We investigate whether animal network structures arise from common ancestry, a response to the species’ past ecological environment, other social behaviours, or a combination of these factors. We demonstrate that differences in past climate predicted the species’ current SIN properties. The drosophilid phylogeny offered no value to predicting species’ differences in SINs through phylogenetic signal tests. This suggests group-level social behaviours in drosophilid species are shaped by divergent climates. However, we find that the distance at which flies interact correlated with the drosophilid phylogeny, indicating that behavioural elements that comprise SINs have remained largely unchanged in their recent evolutionary history. We find a significant correlation of leg length to social distance, outlining the interdependence of anatomy and complex social structures. Although SINs display a complex evolutionary relationship across drosophilids, this study provides evidence of selective pressures acting on social behaviour in Drosophila. We speculate that conserved molecular mechanisms may be shared across drosophilids deep in their evolutionary history, similar to other pervasive mechanisms, like biological clocks.