bluuebunny/crossref_metadata_2025_split huggingface dataset:
Minor deviations from randomness have huge repercussions on the functional structuring of sequence space
Authors: Weidmann Laura , Dijkstra Tjeerd , Kohlbacher Oliver , Lupas Andrei N. 
Published: July 2019

Approaches based on molecular evolution have organized natural proteins into a hierarchy of families, superfamilies, and folds, which are often pictured as islands in a great sea of unrealized and generally non-functional polypeptides. In contrast, approaches based on information theory have substantiated a mostly random scatter of natural proteins in global sequence space. We evaluate these opposing views by analyzing fragments of a given length derived from either a natural dataset or different random models. For this, we compile distances in sequence space between fragments within each dataset and compare the resulting distance distributions between sets. Even for 100-mers, more than 95% of distances can be accounted for by a random sequence model that incorporates the natural amino acid frequency of proteins. When further accounting for the specific residue composition of the respective fragments, which would include biophysical constraints of protein folding, more than 99% of all distances can be modeled. Thus, while the local space surrounding a protein is almost entirely shaped by common descent, the global distribution of proteins in sequence space is close to random, only constrained by divergent evolution through the requirement that all intermediates connecting two forms in evolution must be functional.Significance StatementWhen generating new proteins by evolution or design, can the entire sequence space be used, or do viable sequences mainly occur only in some areas of this space? As a result of divergent evolution, natural proteins mostly form families that occupy local areas of sequence space, suggesting the latter. Theoretical work however indicates that these local areas are highly diffuse and do not dramatically affect the statistics of sequence distribution, such that natural proteins can be considered to effectively cover global space randomly, though extremely sparsely. By comparing the distance distribution of natural sequences to that of various random models, we find that they are indeed distributed largely randomly, provided that the amino acid composition of natural proteins is respected.
Live cell kinetic analysis of the LMO2/LDB1 leukemogenic protein complex reveals a hierarchy of turnover with implications for complex assembly
Authors: Layer Justin H. , Christy Michael , Placek Lindsay , Unutmaz Derya , Guo Yan , Davé Utpal P. 
Published: July 2019

SummaryMultisubunit protein complexes operate in many cellular functions. The LDB1/LMO2 macromolecular complex has been posited to be critical in hematopoietic stem and progenitor cell specification and in the development of acute leukemia. This complex is comprised of core subunits of LMO2 and LDB1 as well as bHLH and GATA transcription factors. We analyzed the steady state abundance and kinetic stability of LMO2 and its partners via HALO protein tagging in conjunction with variant proteins deficient in binding their respective direct protein partners. We discovered a hierarchy of protein stability, with half lives in descending order: LDB1>SSBP>LMO2>TAL1. Importantly, LDB1 conferred enhanced stability upon each and every subunit component and nucleated the formation of the multisubunit protein complex. Our studies provide significant insights into LDB1/LMO2 macromolecular protein complex assembly and stability, which has implications for understanding its role in blood cell formation and for therapeutically targeting this complex in human leukemias.
Why we publish where we do: Faculty publishing values and their relationship to review, promotion and tenure expectations
Authors: Niles Meredith T. , Schimanski Lesley A. , McKiernan Erin C. , Alperin Juan P. 
Published: July 2019

AbstractUsing an online survey of academics at 55 randomly selected institutions across the US and Canada, we explore priorities for publishing decisions and their perceived importance within review, promotion, and tenure (RPT). We find that respondents most value journal readership, while they believe their peers most value prestige and related metrics such as impact factor when submitting their work for publication. Respondents indicated that total number of publications, number of publications per year, and journal name recognition were the most valued factors in RPT. Older and tenured respondents (most likely to serve on RPT committees) were less likely to value journal prestige and metrics for publishing, while untenured respondents were more likely to value these factors. These results suggest disconnects between what academics value versus what they think their peers value, and between the importance of journal prestige and metrics for tenured versus untenured faculty in publishing and RPT perceptions.
Transposable elements have contributed human regulatory regions that are activated upon bacterial infection
Authors: Bogdan Lucia , Barreiro Luis , Bourque Guillaume 
Published: July 2019

ABSTRACTTransposable elements (TEs) are increasingly recognized as important contributors to mammalian regulatory systems. For instance, they have been shown to play a role in the human interferon response. However, their involvement in other mechanisms of immune cell activation remains poorly understood. We investigated the profile of accessible chromatin enhanced in stimulated human macrophages using ATAC-Seq to assess the role of different TE subfamilies in regulating the immune response. We found that both previously identified and new repeats belonging to the MER44, THE1, Tigger3 and MLT1 families provide 14 subfamilies that are enriched in differentially accessible chromatin and found near differentially expressed genes. These TEs also harbour binding motifs for several candidate transcription factors, including important immune regulators AP-1 and NF-kB, present in 96% of accessible MER44B and 83% of THE1C instances, respectively. To more directly assess their regulatory potential, we evaluated their presence in regions putatively affecting gene expression, as defined by quantitative trait locus (QTL) analysis, and find that repeats are also contributing to accessible elements near QTLs. Together, these results suggest that a number of TE families have contributed to the regulation of the immunogenomic response to infection in humans.
Vascular Expression of Hemoglobin Alpha in Antarctic Icefish Supports Iron Limitation as Novel Evolutionary Driver
Authors: Corliss Bruce A. , Delalio Leon J. , Keller T.C. Stevenson , Keller Alexander S. , Keller Douglas A. , Corliss Bruce H. , Bjork Adam C , Beers Jody M. , Peirce Shayn M. , Isakson Brant E. 
Published: July 2019

AbstractFrigid temperatures of the Southern Ocean are known to be an evolutionary driver in Antarctic fish. For example, many fish have reduced red blood cell (RBC) concentration to minimize vascular resistance. Via the oxygen-carrying protein hemoglobin, RBCs contain the vast majority of the body’s iron, which is known to be a limiting nutrient in marine ecosystems. Since lower RBC levels also lead to reduced iron requirements, we hypothesized that low iron availability was an additional evolutionary driver of Antarctic fish speciation. Antarctic Icefish of the familyChannichthyidaeare known to have extreme alteration of iron metabolism due to loss of two iron-binding proteins, hemoglobin and myoglobin, and no RBCs. Loss of hemoglobin is considered a maladaptive trait allowed by relaxation of predator selection, since extreme adaptations are required to compensate for the loss of oxygen-carrying capacity. However, iron dependency minimization may have driven hemoglobin loss instead of a random evolutionary event. Given the variety of functions that hemoglobin serves in the endothelium, we suspected the protein corresponding to the 3’ truncated Hbα fragment (Hbα-3’f) that was not genetically excluded by icefish, may still be expressed as a protein. Using whole mount confocal microscopy, we show that Hbα-3’f is expressed in the vascular endothelium of icefish retina, suggesting this Hbα fragment may still serve an important role in the endothelium. These observations support a novel hypothesis that iron minimization could have influenced icefish speciation with the loss of the iron-binding portion of Hbα in Hbα-3’f, as well as hemoglobin β and myoglobin.
Apple ripening is controlled by a NAC transcription factor
Authors: Migicovsky Zoë , Yeats Trevor H. , Watts Sophie , Song Jun , Forney Charles F. , Burgher-MacLellan Karen , Somers Daryl J. , Gong Yihi , Zhang Zhaoqi , Vrebalov Julia , Giovannoni James G. , Rose Jocelyn K. C. , Myles Sean 
Published: July 2019

AbstractSoftening is a hallmark of ripening in fleshy fruits, and has both desirable and undesirable implications for texture and postharvest stability. Accordingly, the timing and extent of ripening and associated textural changes are key targets for improving fruit quality through breeding. Previously, we identified a large effect locus associated with harvest date and firmness in apple (Malus domestica) using genome-wide association studies (GWAS). Here, we present additional evidence that polymorphisms in or around a transcription factor gene,NAC18.1, may cause variation in these traits. First, we confirmed our previous findings with new phenotype and genotype data from ∼800 apple accessions. In this population, we compared a genetic marker withinNAC18.1to markers targeting three other firmness-related genes currently used by breeders (ACS1,ACO1, andPG1), and found that theNAC18.1marker was the strongest predictor of both firmness at harvest and firmness after three months of cold storage. By sequencingNAC18.1across 18 accessions, we revealed two predominant haplotypes containing the single nucleotide polymorphism (SNP) previously identified using GWAS, as well as dozens of additional SNPs and indels in both the coding and promoter sequences.NAC18.1encodes a protein with high similarity to the NON-RIPENING (NOR) transcription factor, a regulator of ripening in tomato (Solanum lycopersicum). To test whether these genes are functionally orthologous, we introduced bothNAC18.1transgene haplotypes into the tomatonormutant and showed that both haplotypes complement thenorripening deficiency. Taken together, these results indicate that polymorphisms inNAC18.1may underlie substantial variation in apple firmness through modulation of a conserved ripening program.
Laboratory culture of the California Sea Firefly Vargula tsujii (Ostracoda: Cypridinidae): Developing a model system for the evolution of marine bioluminescence
Authors: Goodheart Jessica A. , Minsky Geetanjali , Brynjegard-Bialik Mira N. , Drummond Michael S. , Munoz J. David , Fallon Timothy R. , Schultz Darrin T. , Weng Jing-Ke , Torres Elizabeth , Oakley Todd H. 
Published: July 2019

AbstractBioluminescence, or the production of light by living organisms via chemical reaction, is widespread across Metazoa. Culture of bioluminescent organisms from diverse taxonomic groups is important for determining the biosynthetic pathways of bioluminescent substrates, which may lead to new tools for biotechnology and biomedicine. Some bioluminescent groups may be cultured, including some cnidarians, ctenophores, and brittle stars, but those use luminescent substrates (luciferins) obtained from their diets, and therefore are not informative for determination of the biosynthethic pathways of the luciferins. Other groups, including terrestrial fireflies, do synthesize their own luciferin, but culturing them is difficult, and the biosynthetic pathway for firefly luciferin remains unclear. An additional independent origin of endogenous bioluminescence is found within ostracods from the family Cypridinidae, which use their luminescence for defense and, in Caribbean species, for courtship displays. Here, we report the first complete life cycle of a luminous ostracod (Vargula tsujii Kornicker & Baker, 1977, the California Sea Firefly) in the laboratory. We also describe the late-stage embryogenesis of Vargula tsujii and discuss the size classes of instar development. We find embryogenesis in V. tsujii ranges from 25-38 days, and this species appears to have five instar stages, consistent with ontogeny in other cypridinid lineages. We estimate a complete life cycle at 3-4 months. We also present the first complete mitochondrial genome for Vargula tsujii. Bringing a luminous ostracod into laboratory culture sets the stage for many potential avenues of study, including learning the biosynthetic pathway of cypridinid luciferin and genomic manipulation of an autogenic bioluminescent system.
Describing the fecal metabolome in cryogenically collected samples from healthy participants
Authors: Trošt Kajetan , Ahonen Linda , Suvitaival Tommi , Christiansen Nina , Nielsen Trine , Thiele Maja , Jacobsen Suganya , Krag Aleksander , Rossing Peter , Hansen Torben , Dragsted Lars Ove , Legido-Quigley Cristina 
Published: July 2019

AbstractIntroductionThe chemical composition of feces plays an important role in human metabolism. Metabolomics and lipidomics are valuable tools for screening the metabolite composition in feces. Here we set out to describe fecal metabolite composition in healthy participants in frozen stools.MethodsFrozen stool samples were collected from 10 healthy volunteers and cryogenically drilled in four areas along the specimen. Polar metabolites were analyzed using derivatization followed by two-dimensional gas chromatography and time of flight mass spectrometry. Lipids were detected using ultra high-performance liquid chromatography coupled with quadruple time-of-flight mass spectrometry. The technical variation threshold was set to 30% in pooled quality control samples and metabolite variation was then assessed in four areas per specimen. A data-generated network using metabolites found in all areas was computed for healthy participants.Results2326 metabolic features were detected. Out of a total of 298 metabolites that were annotated we report here 185 that showed a technical variation of x< 30%. These metabolites included amino acids, fatty acid derivatives, carboxylic acids and phenolic compounds. Lipids predominantly belonged to the groups of diacylglycerols, triacylglycerols and ceramides. Metabolites varied between sampling areas (14%-80%). A network using metabolites present in all areas showed two main clusters, DAG lipids and phenyllactic acid.ConclusionsIn feces from healthy participants, the main groups detected were phenolic compounds, ceramides, diacylglycerols and triacylglycerols. Metabolite levels differed considerably depending on the sampling area.
Graphing and reporting heterogeneous treatment effects through reference classes
Authors: Watson James A. , Holmes Chris C. 
Published: July 2019

AbstractBackgroundExploration and modelling of individual treatment effects and treatment heterogeneity is an important aspect of precision medicine in randomized controlled trials (RCTs). The usual approach is to develop a predictive model for individual outcomes and then look for an interaction effect between treatment allocation and important patient covariates. However, such models are prone to overfitting and multiple testing, and typically demand a transformation of the outcome measurement, for example, from the absolute risk in the original RCT to log-odds of risk in the predictive model.MethodsWe show how reference classes derived from background information can be used to alleviate this problem through a two-stage approach where we first estimate a key aspect of heterogeneity in the trial population and then explore for an interaction with the treatment effect along this axis of variation. This bypasses the search for interactions, protecting against multiple testing, and allows for exploration of heterogeneous treatment effects on the original outcome scale of the RCT. This would typically be applied to multivariate models of baseline risk to assess the stability of average treatment effects with respect to the distribution of risk in the population studied. We show how ‘local’ and ‘tilting’ schemes based on ranking patients by baseline risk can be used as a general approach for exploring heterogeneity of treatment effect.ResultsWe illustrate this approach using the single largest randomised treatment trial in severe falciparum malaria and show how the estimated treatment effect in terms of absolute mortality risk reduction increases considerably for higher risk strata.
Biases in GWAS – the dog that did not bark
Authors: Schooling C M 
Published: July 2019

AbstractBackgroundGenome wide association studies (GWAS) of specific diseases are central to scientific discovery. Bias from inevitably recruiting only survivors of genetic make-up and disease specific competing risk has not been comprehensively considered.MethodsWe identified sources of bias using directed acyclic graphs, and tested for them in the UK Biobank GWAS by making comparisons across the survival distribution, proxied by age at recruitment.ResultsAssociations of genetic variants with some diseases depended on their effect on survival. Variants associated with common harmful diseases had weaker or reversed associations with subsequent diseases that shared causes.ConclusionGenetic studies of diseases that involve surviving other common diseases are open to selection bias that can generate systematic type 2 error. GWAS ignoring such selection bias are most suitable for monogenetic diseases. Genetic effects on age at recruitment may indicate potential bias in disease-specific GWAS and relevance to population health.
PEMA: from the raw .fastq files of 16S rRNA and COI marker genes to the (M)OTU-table, a thorough metabarcoding analysis
Authors: Zafeiropoulos Haris , Viet Ha Quoc , Vasileiadou Katerina , Potirakis Antonis , Arvanitidis Christos , Topalis Pantelis , Pavloudi Christina , Pafilis Evangelos 
Published: July 2019

AbstractBackgroundEnvironmental DNA (eDNA) and metabarcoding, allow the identification of a mixture of individuals and launch a new era in bio- and eco-assessment. A number of steps are required to obtain taxonomically assigned (Molecular) Operational Taxonomic Unit ((M)OTU) tables from raw data. For most of these, a plethora of tools is available; each tool’s execution parameters need to be tailored to reflect each experiment’s idiosyncrasy. Adding to this complexity, for such analyses, the computation capacity of High Performance Computing (HPC) systems is frequently required.Software containerization technologies ease the sharing and running of software packages across operating systems; thus, they strongly facilitate pipeline development and usage. Likewise are programming languages specialized for big data pipelines, incorporating features like roll-back checkpoints and on-demand partial pipeline execution.FindingsPEMA is a containerized assembly of key metabarcoding analysis tools with a low effort in setting up, running and customizing to researchers’ needs. Based on third party tools, PEMA performs reads’ pre-processing, clustering to (M)OTUs and taxonomy assignment for 16S rRNA and COI marker gene data. Due to its simplified parameterisation and checkpoint support, PEMA allows users to explore alternative algorithms for specific steps of the pipeline without the need of a complete re-execution. PEMA was evaluated against previously published datasets and achieved comparable quality results.ConclusionsGiven its time-efficient performance and its quality results, it is suggested that PEMA can be used for accurate eDNA metabarcoding analysis, thus enhancing the applicability of next-generation biodiversity assessment studies.
Adaptations of energy metabolism in cetaceans have consequences for their response to foraging disruption
Authors: Derous Davina , Sahu Jagajjit , Douglas Alex , Lusseau David , Wenzel Marius 
Published: July 2019

AbstractCetaceans have varied their anatomical structure, physiology and metabolism to adapt to the challenges of aquatic life. Key to this change is the deposition of blubber. This adipose tissue plays a significant regulatory and signaling role in mammalian metabolism. As foraging disruption by human activities is emerging as a key conservation threat for cetaceans, we need to understand how selection for aquatic life might have altered key nutrient sensing pathways associated with adipose signaling. We compared selection pressure on those energy metabolism biological pathways by contrasting the rate of substitution observed in genes associated with them in cetacean and artiodactyl genomes. We then estimated the likely consequence of these selection pressures for pathway functions. Here we show that genes involved in the insulin, mTOR, SIRT and NF-κB pathways were under significant positive selection in cetaceans compared to their terrestrial sister taxon. Our results suggest these genes may have been positively selected to adapt to a glucose-poor diet and it is unlikely that fat depots signaling function in the same manner as in terrestrial mammals. Secondary adaptation to life in water significantly affected functions in nutrient sensing pathways in cetaceans. Insulin is not likely to play the same role in energy balance as it does in terrestrial mammals and adiposity is not likely to have the deleterious health consequences it has in terrestrial mammals. The physiological ecology of cetacean fat deposition, and therefore its value as a condition index, needs to be interpreted in this evolutionary context.
Intranasal inoculation ofCryptococcus neoformansin mice produces nasal infection with rapid brain dissemination
Authors: Coelho Carolina , Camacho Emma , Salas Antonio , Alanio Alexandre , Casadevall Arturo 
Published: July 2019

AbstractCryptococcus neoformansis an important fungal pathogen, causing life-threatening pneumonia and meningoencephalitis. Brain dissemination ofC. neoformansis thought to be a consequence of an active infection in the lung which then extravasates to other sites. Brain invasion results from dissemination via the bloodstream, either by free yeast cells in bloodstream or Trojan horse transport within mononuclear phagocytes. We assessed brain dissemination in three mouse models of infection: intravenous, intratracheal, and intranasal. All three modes of infection resulted in dissemination ofC. neoformansto the brain in under 3 hours. Further,C. neoformanswas detected in the entirety of the upper respiratory tract and the ear canals of mice. In recent years, intranasal infection has become a popular mechanism to induce pulmonary infection because it avoids surgery but our findings show that instillation ofC. neoformansproduces cryptococcal nasal infection. These findings imply that immunological studies using intranasal infection should assume the initial sites of infection of infection are brain, lung and upper respiratory tract, including the nasal airways.ImportanceCryptococcus neoformanscauses an estimated 181, 000 deaths each year, mostly associated with untreated HIV/AIDS.C. neoformanshas a ubiquitous worldwide distribution. Humans become infected from exposure to environmental sources and the fungus lays dormant within the human body. Upon immunosuppression, such as AIDS or therapy-induced as required by organ transplant recipients or autoimmune disease patients, cryptococcal disease reactivates and causes life-threatening meningitis and pneumonia. This study has detected that upon contact with the host,C. neoformanscan quickly (a few hours) reach the host brain and will also colonize the nose of infected animals. Therefore, this work paves the way to better knowledge of howC. neoformanstravels through the host body. Understanding howC. neoformansinfects, disseminates and survives within the host is critically required so that we can prevent infections and the disease caused by this deadly fungus.