bluuebunny/crossref_metadata_2025_split huggingface dataset:
BlackSheep: A Bioconductor and Bioconda package for differential extreme value analysis
Authors: Blumenberg Lili , Kawaler Emily , Cornwell MacIntosh , Smith Shaleigh , Ruggles Kelly , Fenyö David 
Published: October 2019

AbstractUnbiased assays such as shotgun proteomics and RNA-seq provide high-resolution molecular characterization of tumors. These assays measure molecules with highly varied distributions, making interpretation and hypothesis testing challenging. Samples with the most extreme measurements for a molecule can reveal the most interesting biological insights, yet are often excluded from analysis. Furthermore, rare disease subtypes are, by definition, underrepresented in cancer cohorts. To provide a strategy for identifying molecules aberrantly enriched in small sample cohorts, we present BlackSheep--a package for non-parametric description and differential analysis of genome-wide data, available at https://github.com/ruggleslab/blackSheep. BlackSheep is a complementary tool to other differential expression analysis methods that may be underpowered when analyzing small subgroups in a larger cohort.
Mitochondrial ascorbate synthesis acts as a pro-oxidant pathway and down-regulate energy supply in plants
Authors: Morales Luis Miguel Mazorra , Silva Gláucia Michelle Cosme , Santana Diederson Bortolini , Pireda Saulo F. , Cogo Antonio Jesus Dorighetto , Heringer Angelo Schuabb , de Oliveira Tadeu dos Reis , Reis Ricardo S. , dos Santos Prado Luís Alfredo , de Oliveira André Vicente , Silveira Vanildo , Cunha Maura Da , Barros Claudia F. , Facanha Arnoldo R. , Baldet Pierre , Bartoli Carlos , da Silva Marcelo Gomes , de Oliveira Jurandi Gonçalves 
Published: October 2019

ABSTRACTAttempts to improve the ascorbate (AsA) content of plants are still dealing with the limited understanding of why exists a wide variability of this powerful anti-oxidant molecule in different plant sources, species and environmental situations. In plant mitochondria, the last step of AsA synthesis is catalyzed by the enzyme L-galactone-1,4-lactone dehydrogenase (L-GalLDH). By using GalLDH-RNAi silencing plant lines, biochemical and proteomic approaches, we here discovered that, in addition to accumulate this antioxidant, mitochondria synthesize AsA to down-regulate the respiratory activity and the cellular energy provision. The work reveals that the AsA synthesis pathway within mitochondria is a branched electron transfer process that channels electrons towards the alternative oxidase, interfering with conventional electron transport. It was unexpectedly found that significant hydrogen peroxide is generated during AsA synthesis, which affects the AsA level. The induced AsA synthesis shows proteomic alterations of mitochondrial and extra-mitochondrial proteins related to oxidative and energetic metabolism. The most identified proteins were known components of plant responses to high light acclimation, programmed cell death, oxidative stress, senescence, cell expansion, iron and phosphorus starvation, different abiotic stress/pathogen attack responses and others. We propose that changing the electron flux associated with AsA synthesis might be part of a new mechanism by which the L-GalLDH enzyme would adapt plant mitochondria to fluctuating energy demands and redox status occurring under different physiological contexts.
Identification of distinct pathological signatures induced by patient-derived α-synuclein structures in non-human primates
Authors: Bourdenx M. , Nioche A. , Dovero S. , Arotcarena M.-L. , Camus S. , Porras G. , Thiolat M.-L. , Rougier N. P. , Prigent A. , Aubert P. , Bohic S. , Sandt C. , Laferrière F. , Doudnikoff E. , Kruse N. , Mollenhauer B. , Novello S. , Morari M. , Leste-Lasserre T. , Trigo Damas I. , Goillandeau M. , Perier C. , Estrada C. , Garcia-Carrillo N. , Recasens A. , Vaikath N. N. , El-Agnaf O. M. A. , Herrero M. Trinidad , Derkinderen P. , Vila M. , Obeso J. A. , Dehay B. , Bezard E. 
Published: October 2019

AbstractDopaminergic neuronal cell death, associated with intracellular α-synuclein (α-syn)-rich protein aggregates (termed ‘Lewy bodies’), is a well-established characteristic of Parkinson’s disease. Much evidence, accumulated from multiple experimental models has suggested that α-syn plays a role in PD pathogenesis, not only as a trigger of pathology but also as a mediator of disease progression through pathological spreading. Here we have used a machine learning-based approach to identify unique signatures of neurodegeneration in monkeys induced by distinct α-syn pathogenic structures derived from PD patients. Unexpectedly, our results show that, in non-human primates, a small amount of singular α-syn aggregates is as toxic as larger amyloid fibrils present in the LBs, thus reinforcing the need for preclinical research in this species. Furthermore, our results provide evidence supporting the true multifactorial nature of PD as multiple causes can induce similar outcome regarding dopaminergic neurodegeneration.
FrogCap: A modular sequence capture probe set for phylogenomics and population genetics for all frogs, assessed across multiple phylogenetic scales
Authors: Hutter Carl R. , Cobb Kerry A. , Portik Daniel M. , Travers Scott L. , Wood Perry L. , Brown Rafe M. 
Published: October 2019

ABSTRACTDespite the increasing use of high-throughput sequencing in phylogenetics, many phylogenetic relationships remain difficult to resolve because of conflict between gene trees and species trees. Selection of different types of markers (i.e. protein-coding exons, non-coding introns, ultra-conserved elements) is becoming important to alleviate these phylogenomic challenges. For evolutionary studies in frogs, we introduce the new publicly available FrogCap suite of genomic resources, which is a large and flexible collection of probes corresponding to ∼15,000 markers that unifies previous frog sequencing work. FrogCap is designed to be modular, such that subsets of markers can be selected based on the phylogenetic scale of the intended study. FrogCap uses a variety of molecular marker types that include newly obtained exons and introns, previously sequenced UCEs, and Sanger-sequencing markers, which span a range of alignment lengths (100–12,000 base pairs). We tested three probe sets from FrogCap using 105 samples across five phylogenetic scales, comparing probes designed using a consensus- or genome-based approach. We also tested the effects of using different bait kit sizes on depth of coverage and missing data. We found that larger bait kits did not result in lowered depth of coverage or increased missing data. We also found that sensitivity, specificity, and missing data are not related to genetic distance in the consensus-based probe design, suggesting that this approach has greater success and overcomes a major hurdle in probe design. We observed sequence capture success (in terms of missing data, quantity of sequence data, recovered marker length, and number of informative sites) and compared them at all phylogenetic scales. The incorporation of different molecular marker types allowed recovery of the variation required for resolving difficult phylogenetic relationships and for performing population genetic studies. Altogether, FrogCap is a valuable and adaptable resource for performing high-throughput sequencing projects across variable timescales.
Phosphorylation of the CAMTA3 transcription factor triggers its destabilization and nuclear export
Authors: Jiang Xiyuan , Hoehenwarter Wolfgang , Scheel Dierk , Lee Justin 
Published: October 2019

AbstractThe calmodulin-binding transcription activator 3 (CAMTA3) is a repressor of immunity-related genes but an activator of cold-induced genes in plants. Post-transcriptional or -translational mechanisms have been proposed to control CAMTA3’s role in the crosstalk between immune and chilling responses. Here, we show that treatment with the bacterial flg22 elicitor, but not cold stress, induces a phospho-mobility shift of CAMTA3 proteins. Correspondingly, CAMTA3 is directly phosphorylated by two flg22-responsive mitogen-activated protein kinases (MAPKs), MPK3 and MPK6, which triggers CAMTA3 nuclear export and destabilization. SR1IP1, a substrate E3 ubiquitin ligase adaptor required for pathogen-induced CAMTA3 degradation, is shown here to be likely plasma-membrane-localized and therefore cannot physically interact with the nuclear CAMTA3. Despite the flg22-inducible re-localization of CAMTA3 to the cytoplasm, we failed to detect CAMTA3-SR1IP1 complexes. Hence, the role of SR1IP1 for CAMTA3 degradation needs to be re-evaluated. Surprisingly, flg22 elicitation can still induce nuclear export and phospho-mobility shift of a phospho-null CAMTA3 that cannot be phosphorylated by MAPKs, suggesting the participation of additional flg22-responsive kinase(s). A constitutively-active calcium-dependent protein kinase, CPK5, can stimulate a phospho-mobility shift in CAMTA3 similar to that induced by flg22. Although CPK5 can interact with CAMTA3, it did not directly phosphorylate CAMTA3, suggesting the requirement of a still unidentified downstream kinase or additional components. Overall, at least two flg22-responsive kinase pathways target CAMTA3 to induce degradation that presumably serves to remove CAMTA3 from target promoters and de-repress expression of defence genes.One sentence summaryTreatment with flg22 activates two independent kinase pathways that effect CAMTA3 phosphorylation and degradation.
Preparation for upcoming attentional states in the hippocampus and medial prefrontal cortex
Authors: Günseli Eren , Aly Mariam 
Published: October 2019

AbstractGoal-directed attention is usually studied by providing individuals with explicit instructions on what they should attend to. But in daily life, we often use past experiences to guide our attentional states. Given the importance of memory for predicting upcoming events, we hypothesized that memory-guided attention is supported by neural preparation for anticipated attentional states. We examined preparatory coding in the human hippocampus and mPFC, two regions that are important for memory-guided behaviors, in two tasks: one where attention was guided by memory and another in which attention was explicitly instructed. Hippocampus and mPFC exhibited higher activity for memory-guided vs. explicitly instructed attention. Furthermore, representations in both regions contained information about upcoming attentional states. In the hippocampus, this preparation was stronger for memory-guided attention, and occurred alongside stronger coupling with visual cortex during attentional guidance. These results highlight the mechanisms by which memories are used to prepare for upcoming attentional goals.Competing InterestsNone.
Cofilin loss inDrosophilacontributes to myopathy through defective sarcomerogenesis and aggregate formation during muscle growth
Authors: Balakrishnan Mridula , Yu Shannon F. , Chin Samantha M. , Soffar David B. , Windner Stefanie E. , Goode Bruce L. , Baylies Mary K. 
Published: October 2019

SUMMARYSarcomeres, the fundamental contractile units of muscles, are conserved structures composed of actin thin filaments and myosin thick filaments. How sarcomeres are formed and maintained is not well understood. Here, we show that knockdown ofDrosophilaCofilin (DmCFL), an actin depolymerizing factor, leads to the progressive disruption of sarcomere structure and muscle functionin vivo. Loss ofDmCFLalso results in the formation of sarcomeric protein aggregates and impairs sarcomere addition during growth. Strikingly, activation of the proteasome delayed muscle deterioration in our model. Further, we investigate how a point mutation in CFL2 that causes nemaline myopathy (NM) in humans, affects CFL function and leads to the muscle phenotypes observedin vivo. Our data provide significant insights to the role of CFLs during sarcomere formation as well as mechanistic implications for disease progression in NM patients.
ChpC controls twitching motility-mediated expansion ofPseudomonas aeruginosabiofilms in response to serum albumin, mucin and oligopeptides
Authors: Nolan Laura M. , McCaughey Laura C. , Merjane Jessica , Turnbull Lynne , Whitchurch Cynthia B. 
Published: October 2019

AbstractTwitching motility-mediated biofilm expansion occurs via coordinated, multi-cellular collective behaviour to allow bacteria to actively expand across surfaces. Type-IV pili (T4P) are cell-associated virulence factors which mediate this expansion via rounds of extension, surface attachment and retraction. The Chp chemosensory system is thought to respond to environmental signals to regulate the biogenesis, assembly and twitching motility function of T4P. In other well characterised chemosensory systems, methyl-accepting chemotaxis proteins (MCPs) feed environmental signals through a CheW adapter protein to the histidine kinase CheA to modulate motility. ThePseudomonas aeruginosaChp system has two CheW adapter proteins, PilI and ChpC, and an MCP PilJ that likely interacts via PilI with the histidine kinase ChpA. It is thought that ChpC associates with other MCPs to feed environmental signals into the system, however no such signals have been identified. In the current study we show that ChpC is involved in the response to host-derived signals serum albumin, mucin and oligopeptides. We demonstrate that these signals stimulate an increase in twitching motility, as well as in levels of 3’-5’-cyclic adenosine monophosphate (cAMP) and surface-assembled T4P. Interestingly, our data shows that changes in cAMP and surface piliation levels are independent of ChpC but that the twitching motility response to these environmental signals requires ChpC. Based upon our data we propose a model whereby ChpC associates with an MCP other than PilJ to feed these environmental signals through the Chp system to control twitching motility. The MCP PilJ and the CheW adapter PilI then modulate T4P surface levels to allow the cell to continue to undergo twitching motility. Our study is the first to link environmental signals to the Chp chemosensory system and refines our understanding of how this system controls twitching motility-mediated biofilm expansion inP. aeruginosa.
Biases in arginine codon usage correlate with genetic disease risk
Authors: Schulze Katharina V. , Hanchard Neil A. , Wangler Michael F. 
Published: October 2019

ABSTRACTPurposeThe persistence of hypermutable ‘CGN’ (CGG, CGA, CGC, CGU) arginine codons at high frequency suggests the possibility of negative selective pressure at these sites and that arginine codon usage could be a predictive indicator of human disease genes.MethodsWe analyzed arginine codons (CGN, AGG, AGA) from all ‘canonical’ Ensembl protein coding gene transcripts before comparing the frequency of CGN codons between genes with and without human disease associations and with gnomAD constraint metrics.ResultsThe frequency of CGN codons among a gene’s total arginine codon count was higher in genes linked to syndromic autism spectrum disorder (ASD) compared to genes not associated with ASD. A comparison of genes annotated as dominant or recessive with control genes not matching either classification revealed a progressive increase in CGN codon frequency. Moreover, CGN frequency was positively correlated with a gene’s probability of loss-of-function intolerance (pLI) score and negatively correlated with ‘observed-over-expected’ ratios for both loss of function and missense mutations.ConclusionOur findings indicate that genes utilizing CGN arginine codons rather than AGG or AGA are more likely to underlie single gene disorders, particularly for dominant phenotypes, and thus constitute candidate genes for the study of human genetic disease.
CloneSig can jointly infer intra-tumor heterogeneity and mutational signature activity in bulk tumor sequencing data
Authors: Abécassis Judith , Reyal Fabien , Vert Jean-Philippe 
Published: October 2019

AbstractSystematic DNA sequencing of cancer samples has highlighted the importance of two aspects of cancer genomics: intra-tumor heterogeneity (ITH) and mutational processes. These two aspects may not always be independent, as different mutational processes could be involved in different stages or regions of the tumor, but existing computational approaches to study them largely ignore this potential dependency. Here, we present CloneSig, a computational method to jointly infer ITH and mutational processes in a tumor from bulk-sequencing data. Extensive simulations show that CloneSig outperforms current methods for ITH inference and detection of mutational processes when the distribution of mutational signatures changes between clones. Applied to a large cohort of 8,951 tumors with whole-exome sequencing data from The Cancer Genome Atlas, and on a pan-cancer dataset of 2,632 whole-genome sequencing tumor samples from the Pan-Cancer Analysis of Whole Genomes initiative, CloneSig obtains results overall coherent with previous studies.
Identification of conserved proteomic networks in neurodegenerative dementia
Authors: Swarup Vivek , Chang Timothy S. , Duong Duc M. , Dammer Eric B. , Lah James J. , Johnson Erik E.C.B. , Seyfried Nicholas T. , Levey Allan I. , Geschwind Daniel H. 
Published: October 2019

SummaryData-driven analyses of human brain across neurodegenerative diseases possess the potential for identifying disease-specific and shared biological processes. We integrated functional genomics data from postmortem brain, including label-free quantitative proteomics and RNA-seq based transcriptomics in an unprecedented dataset of over 1000 individuals across 5 cohorts representing Alzheimer’s disease (AD), asymptomatic AD, Progressive Supranuclear Palsy (PSP), and control patients, as a core analysis of the Accelerating Medicines Project – Alzheimer’s Disease (AMP-AD) consortium. We identified conserved, high confidence proteomic changes during the progression of dementias that were absent in other neurodegenerative disorders. We defined early changes in asymptomatic AD cases that included microglial, astrocyte, and immune response modules and later changes related to synaptic processes and mitochondria, many, but not all of which were conserved at the transcriptomic level. This included a novel module C3, which is enriched in MAPK signaling, and only identified in proteomic networks. To understand the relationship of core molecular processes with causal genetic drivers, we identified glial, immune, and cell-cell interaction processes in modules C8 and C10, which were robustly preserved in multiple independent data sets, up-regulated early in the disease course, and enriched in AD common genetic risk. In contrast to AD, PSP genetic risk was enriched in module C1, which represented synaptic processes, clearly demonstrating that despite shared pathology such as synaptic loss and glial inflammatory changes, AD and PSP have distinct causal drivers. These conserved, high confidence proteomic changes enriched in genetic risk represent new targets for drug discovery.HighlightsWe distinguish robust early and late proteomic changes in AD in multiple cohorts.We identify changes in dementias that are not preserved in other neurodegenerative diseases.AD genetic risk is enriched in early up-regulated glial-immune modules and PSP in synaptic modules.Almost half of the variance in protein expression reflects gene expression, but an equal fraction is post-transcriptional or -translational.
Bidirectional modulation of human emotional conflict resolution using intracranial stimulation
Authors: Paulk Angelique C. , Yousefi Ali , Ellard Kristen K. , Farnes Kara , Peled Noam , Crocker Britni , Zelmann Rina , Vallejo-Lopez Deborah , Belok Gavin , Zorowitz Sam , Basu Ishita , Afzal Afsana , Gilmour Anna , Weisholtz Daniel S. , Cosgrove G. Reese , Chang Bernard S. , Arle Jeffrey E. , Williams Ziv M. , Eden Uri T. , Deckersbach Thilo , Dougherty Darin D. , Eskandar Emad N. , Widge Alik S. , Cash Sydney S. 
Published: October 2019

AbstractThe ability to regulate emotions in the service of meeting ongoing goals and task demands is a key aspect of adaptive human behavior in our volatile social world. Consequently, difficulties in processing and responding to emotional stimuli underlie many psychiatric diseases ranging from depression to anxiety, the common thread being effects on behavior. Behavior, which is made up of shifting, difficult to measure hidden states such as attention and emotion reactivity, is a product of integrating external input and latent mental processes. Directly measuring, and differentiating, separable hidden cognitive, emotional, and attentional states contributing to emotion conflict resolution, however, is challenging, particularly when only using task-relevant behavioral measures such as reaction time. State-space representations are a powerful method for investigating hidden states underlying complex systems. Using state-space modeling of behavior, we identified relevant hidden cognitive states and predicted behavior in a standardized emotion regulation task. After identifying and validating models which best fit the behavior and narrowing our focus to one model, we used targeted intracranial stimulation of the emotion regulation-relevant neurocircuitry, including prefrontal structures and the amygdala, to causally modulate separable states. Finally, we focused on this one validated state-space model to perform real-time, bidirectional closed-loop adaptive stimulation in a subset of participants. These approaches enable an improved understanding of how to sample and understand emotional processing in a way which could be leveraged in neuromodulatory therapy for disorders of emotional regulation.
A performant bridge between fixed-size and variable-size seeding
Authors: Kutzner Arne , Kim Pok-Son , Schmidt Markus 
Published: October 2019

AbstractBackgroundSeeding is usually the initial step of high-throughput sequence aligners. Two popular seeding strategies are fixed-size seeding (k-mers, minimizers) and variable-size seeding (MEMs, SMEMs, maximal spanning seeds). The former strategy supports fast seed computation, while the latter one benefits from a high seed entropy. Algorithmic bridges between instances of both seeding strategies are of interest for combining their respective advantages.ResultsWe introduce an efficient strategy for computing MEMs out of fixed-size seeds (k-mers or minimizers). In contrast to previously proposed extend-purge strategies, our merge-extend strategy prevents the creation and filtering of duplicate MEMs. Further, we describe techniques for extracting SMEMs or maximal spanning seeds out of MEMs. A comprehensive benchmarking shows the applicability, strengths, shortcomings and computational requirements of all discussed seeding techniques. Additionally, we report the effects of seed occurrence filters in the context of these techniques.Aside from our novel algorithmic approaches, we analyze hierarchies within fixed-size and variable-size seeding along with a mapping between instances of both seeding strategies.ConclusionBenchmarking shows that our proposed merge-extend strategy for MEM computation outperforms previous extend-purge strategies in the context of PacBio reads. The observed superiority grows with increasing read size and read quality. Further, the presented filters for extracting SMEMs or maximal spanning seeds out of MEMs outperform FMD-index based extension techniques. All code used for benchmarking is available via GitHub at https://github.com/ITBE-Lab/seed-evaluation.