bluuebunny/crossref_metadata_2025_split huggingface dataset:
Measurement of organ-specific and acute-phase blood protein levels in early Lyme disease
Authors: Zhou Yong , Qin Shizhen , Sun Mingjuan , Tang Li , Yan Xiaowei , Kim Taek-Kyun , Caballero Juan , Glusman Gustavo , Brunkow Mary E. , Soloski Mark J. , Rebman Alison W. , Scavarda Carol , Cooper Denise , Omenn Gilbert S. , Moritz Robert L. , Wormser Gary P. , Price Nathan D. , Aucott John N. , Hood Leroy 
Published: October 2019

ABSTRACTLyme disease results from infection of humans with the spirocheteBorrelia burgdorferi. The first and most common clinical manifestation is the circular, inflamed skin lesion referred to as erythema migrans; later manifestations result from infections of other body sites. Laboratory diagnosis of Lyme disease can be challenging in patients with erythema migrans because of the time delay in the development of specific diagnostic antibodies against Borrelia. Reliable blood biomarkers for the early diagnosis of Lyme disease in patients with erythema migrans are needed. Here, we performed selected reaction monitoring, a targeted mass spectrometry-based approach, to measure selected proteins that 1) are known to be predominantly expressed in one organ (i.e., organ-specific blood proteins) and whose blood concentrations may change as a result of Lyme disease, or 2) are involved in acute immune responses. In a longitudinal cohort of 40 Lyme disease patients and 20 healthy controls, we identified 10 proteins with significantly altered serum levels in patients at the time of diagnosis, and we also developed a 10-protein panel identified through multivariate analysis. In an independent cohort of patients with erythema migrans, six of these proteins, APOA4, C9, CRP, CST6, PGLYRP2 and S100A9, were confirmed to show significantly altered serum levels in patients at time of presentation. Nine of the 10 proteins from the multivariate panel were also verified in the second cohort. These proteins, primarily innate immune response proteins or proteins specific to liver, skin or white blood cells, may serve as candidate blood biomarkers requiring further validation to aid in the laboratory diagnosis of early Lyme disease.
Evolutionary analyses guide selection of model systems to investigate proto-oncogene function in ALK and LTK
Authors: Wang Zheng , Dornburg Alex , Wang Junrui , Mo Elizabeth S. , Lopez-Giraldez Francesc , Townsend Jeffrey P. 
Published: October 2019

AbstractModel systems to investigate oncogene-driven cancer have played an essential role in the development of therapies for cancer. However, not all systems are appropriate for all therapeutic targets. Knowing where and when proto-oncogenes and their interactors originated in evolutionary history is key to understanding which organisms can serve as models. Here we investigate two tyrosine kinase receptors that underlie tumorigenesis in cancer: anaplastic lymphoma kinase (ALK) and leukocyte tyrosine kinase (LTK). InDrosophila melanogaster, Caenorhabitis elegans, andHomo sapiens, the discovery of putative ligands Jeb, Hen-1, and AUG has the potential to accelerate the development of novel therapeutics. However, homology of these ligands and receptors is unclear. We performed an exhaustive search for their homologs spanning the metazoan tree of life. Jeb and Hen-1 were restricted to species that diverged prior to the origin of all vertebrates. No non-vertebrate species had ligands orthologous to AUG. Instead, an ancestral receptor tyrosine kinase and AUG gene were present in early vertebrates and are still solitary in lamprey; we demonstrate that the early embryonic expression of AUG in lamprey parallels its expression in model mammal systems. The presence of ALK and LTK in jawed vertebrates is an evolutionary innovation, as is a previously unrecognized functional convergence within ALK and LTK occurring between actinopterygians and sarcopterygians. Our results provide the phylogenetic context necessary for the selection of model organisms that will provide informative investigations of the biology of these critically important tyrosine kinase receptors, enabling successful therapeutic development.SignificanceThe anaplastic lymphoma kinase ALK can be oncogenically altered to become a driver of several malignancies, including non-small-cell lung cancer and anaplastic large-cell lymphomas. The development of therapeutics targeting this gene depend on the discovery of its interacting partner ligands in relevant model organisms. ALK is found across most major animal groups including mammals, fishes, and invertebrates. Correspondly, several candidate ligands for ALK and its duplicate LTK have been advanced by research in model species. However their homology to the human ligands and therefore their potential to guide therapeutic development is unknown. Our comparative evolutionary analysis revealed which model organisms had functional receptor-ligand pairings that are informative regarding the role of these genes in human tumorigenesis.
Fluctuating light experiments and semi-automated plant phenotyping enabled by self-built growth racks and simple upgrades to the IMAGING-PAM
Authors: Schneider Dominik , Lopez Laura S. , Li Meng , Crawford Joseph D. , Kirchhoff Helmut , Kunz Hans-Henning 
Published: October 2019

AbstractBackgroundOver the last years, several plant science labs have started to employ fluctuating growth light conditions to simulate natural light regimes more closely. Many plant mutants reveal quantifiable effects under fluctuating light despite being indistinguishable from wild-type plants under standard constant light. Moreover, many subtle plant phenotypes become intensified and thus can be studied in more detail. This observation has caused a paradigm shift within the photosynthesis research community and an increasing number of scientists are interested in using fluctuating light growth conditions. However, high installation costs for commercial controllable LED setups as well as costly phenotyping equipment can make it hard for small academic groups to compete in this emerging field.ResultsWe show a simple do-it-yourself approach to enable fluctuating light growth experiments. Our results using previously published fluctuating light sensitive mutants, stn7 and pgr5, confirm that our low-cost setup yields similar results as top-prized commercial growth regimes. Moreover, we show how we increased the throughput of our Walz IMAGING-PAM, also found in many other departments around the world. We have designed a Python and R-based open source toolkit that allows for semi-automated sample segmentation and data analysis thereby reducing the processing bottleneck of large experimental datasets. We provide detailed instructions on how to build and functionally test each setup.ConclusionsWith material costs well below USD$1000, it is possible to setup a fluctuating light rack including a constant light control shelf for comparison. This allows more scientists to perform experiments closer to natural light conditions and contribute to an emerging research field. A small addition to the IMAGING-PAM hardware not only increases sample throughput but also enables larger-scale plant phenotyping with automated data analysis.
Brain rhythms shift and deploy attention
Authors: Richter Craig G. , Bosman Conrado A. , Vezoli Julien , Schoffelen Jan-Mathijs , Fries Pascal 
Published: October 2019

AbstractOne of the most central cognitive functions is attention. Its neuronal underpinnings have primarily been studied during conditions of sustained attention. Much less is known about the neuronal dynamics underlying the processes of shifting attention in space, as compared to maintaining it on one stimulus, and of deploying it to a particular stimulus. Here, we use ECoG to investigate four rhythms across large parts of the left hemisphere of two macaque monkeys during a task that allows investigation of deployment and shifting. Shifting involved a strong transient enhancement of power in a 2-7 Hz theta band in frontal, pre-motor and visual areas, and reductions of power in an 11-20 Hz beta band in a fronto-centro-parietal network and in a 29-36 Hz high-beta band in premotor cortex. Deployment of attention to the contralateral hemifield involved an enhancement of beta power in parietal areas, a concomitant reduction of high-beta power in pre-motor areas and an enhancement of power in a 60-76 Hz gamma band in extra-striate cortex. Effects due to shifting occurred earlier than effects due to deployment. These results demonstrate that the four investigated rhythms are involved in attentional allocation, with striking differences between shifting and deployment between different brain areas.SignificanceWe are often confronted by many visual stimuli, and attentional mechanisms select one stimulus for in-depth processing. This involves that attention is shifted between stimuli and deployed to one stimulus at a time. Prior studies have revealed that these processes are subserved by several brain rhythms. Therefore, we recorded brain activity in macaque monkeys with many electrodes distributed over large parts of their left hemisphere, while they performed a task that involved shifting and deploying attention. We found four dominant rhythms: theta (2-7 Hz), beta (11-20 Hz), high-beta (29-36 Hz) and gamma (60-76 Hz). Attentional shifting and deployment involved dynamic modulations in the strength of those rhythms with high specificity in space and time.
The reliability and heritability of cortical folds and their genetic correlations across hemispheres
Authors: Pizzagalli Fabrizio , Auzias Guillaume , Yang Qifan , Mathias Samuel R. , Faskowitz Joshua , Boyd Joshua , Amini Armand , Rivière Denis , McMahon Katie L. , de Zubicaray Greig I. , Martin Nicholas G. , Mangin Jean-François , Glahn David C. , Blangero John , Wright Margaret J. , Thompson Paul M. , Kochunov Peter , Jahanshad Neda 
Published: October 2019

AbstractThe structure of the brain’s cortical folds varies considerably in human populations. Specific patterns of cortical variation arise with development and aging, and cortical traits are partially influenced by genetic factors. The degree to which genetic factors affect cortical folding patterning remains unknown, yet may be estimated with large-scale in-vivo brain MRI. Using multiple MRI datasets from around the world, we estimated the reliability and heritability of sulcal morphometric characteristics including length, depth, width, and surface area, for 61 sulci per hemisphere of the human brain. Reliability was assessed across four distinct test-retest datasets. We meta-analyzed the heritability across three independent family-based cohorts (N > 3,000), and one cohort of largely unrelated individuals (N~9,000) to examine the robustness of our findings. Reliability was high (interquartile range for ICC: 0.65−0.85) for sulcal metrics. Most sulcal measures were moderately to highly heritable (heritability estimates = 0.3−0.7). These genetic influences vary regionally, with the earlier forming sulci having higher heritability estimates. The central sulcus, the subcallosal and the collateral fissure were the most highly heritable regions. For some frontal and temporal sulci, left and right genetic influences did not completely overlap, suggesting some lateralization of genetic effects on the cortex.
Parallel and Population-specific Gene Regulatory Evolution in Cold-Adapted Fly Populations
Authors: Huang Yuheng , Lack Justin B. , Hoppel Grant T. , Pool John E. 
Published: October 2019

AbstractChanges in gene regulation at multiple levels may comprise an important share of the molecular changes underlying adaptive evolution in nature. However, few studies have assayed within- and between-population variation in gene regulatory traits at a transcriptomic scale, and therefore inferences about the characteristics of adaptive regulatory changes have been elusive. Here, we assess quantitative trait differentiation in gene expression levels and alternative splicing (intron usage) between three closely-related pairs of natural populations ofDrosophila melanogasterfrom contrasting thermal environments that reflect three separate instances of cold tolerance evolution. The cold-adapted populations were known to show population genetic evidence for parallel evolution at the SNP level, and here we find evidence for parallel expression evolution between them, with stronger parallelism at larval and adult stages than for pupae. We also implement a flexible method to estimatecis- versustrans-encoded contributions to expression or splicing differences at the adult stage. The apparent contributions ofcis-versustrans-regulation to adaptive evolution vary substantially among population pairs. While two of three population pairs show a greater enrichment ofcis-regulatory differences among adaptation candidates,trans-regulatory differences are more likely to be implicated in parallel expression changes between population pairs. Genes with significantcis-effects are enriched for signals of elevated genetic differentiation between cold- and warm-adapted populations, suggesting that they are potential targets of local adaptation. These findings expand our knowledge of adaptive gene regulatory evolution and our ability to make inferences about this important and widespread process.
Upstream translation initiation expands the coding capacity of segmented negative-strand RNA viruses
Authors: Sloan Elizabeth , Alenquer Marta , Chung Liliane , Clohisey Sara , Dinan Adam M. , Gifford Robert , Gu Quan , Irigoyen Nerea , Jones Joshua D. , van Knippenberg Ingeborg , Rezelj Veronica , Wang Bo , Wise Helen M. , Amorim Maria Joao , Baillie J Kenneth , Brierley Ian , Digard Paul , Firth Andrew E. , MacLeod Megan K. , Hutchinson Edward 
Published: October 2019

AbstractSegmented negative-strand RNA viruses (sNSVs) include the influenza viruses, the bunyaviruses, and other major pathogens of humans, other animals and plants. The genomes of these viruses are extremely short. In response to this severe genetic constraint, sNSVs use a variety of strategies to maximise their coding potential. Because the eukaryotic hosts parasitized by sNSVs can regulate gene expression through low levels of translation initiation upstream of their canonical open reading frames (ORFs), we asked whether sNSVs could use upstream translation initiation to expand their own genetic repertoires. Consistent with this hypothesis, we showed that influenza A viruses (IAVs) and bunyaviruses were capable of upstream translation initiation. Using a combination of reporter assays and viral infections, we found that upstream translation in IAVs can initiate in two unusual ways: through non-AUG initiation in virally encoded ‘untranslated’ regions, and through the appropriation of an AUG-containing leader sequence from host mRNAs through viral cap-snatching, a process we termed ‘start-snatching.’ Finally, while upstream translation of cellular genes is mainly regulatory, for sNSVs it also has the potential to create novel viral gene products. If in frame with a viral ORF, this creates N-extensions of canonical viral proteins. If not, it allows the expression of cryptic overlapping ORFs, which we found were highly conserved in IAV and widely distributed in peribunyaviruses. Thus, by exploiting their host’s capacity for upstream translation initiation, sNSVs can expand still further the coding potential of their extremely compact RNA genomes.
Intra-individual behavioural variability: a trait under genetic control
Authors: Henriksen Rie , Hoeglund Andrey , Fogelholm Jesper , Abbey-Lee Robin , Johnsson Martin , Dingemanse Niels , Wright Dominic 
Published: October 2019

AbstractWhen individuals are measured more than once in the same context they do not behave in exactly the same way each time. The degree of predictability differs between individuals, with some individuals showing low levels of variation around their behavioural mean while others show high levels of variation. This intra-individual variation in behaviour has received much less attention than between-individual variance in behaviour and very little is known about the underlying mechanisms that affect this potentially large but understudied component of behavioural variation. In this study, we combine standardized behavioural tests to estimate intra-individual behavioural variance with a large-scale genetical genomics analysis to identify genes affecting intra-individual variability in an avian population. Our study shows that within-individual variance in behaviour has a direct genetic basis which is largely unique compared to the genetic architecture for the standard behavioural measures they are based on. We identify six candidate genes underlying variation in intra-individual behavioural variability many of which have previously been linked to behaviour and mental health. These findings demonstrate that within-individual variability in behavioural is a heritable trait in and of itself on which evolution can act.
Large scale genome-wide association study in a Japanese population identified 45 novel susceptibility loci for 22 diseases
Authors: Ishigaki Kazuyoshi , Akiyama Masato , Kanai Masahiro , Takahashi Atsushi , Kawakami Eiryo , Sugishita Hiroki , Sakaue Saori , Matoba Nana , Low Siew-Kee , Okada Yukinori , Terao Chikashi , Amariuta Tiffany , Gazal Steven , Kochi Yuta , Horikoshi Momoko , Suzuki Ken , Ito Kaoru , Momozawa Yukihide , Hirata Makoto , Matsuda Koichi , Ikeda Masashi , Iwata Nakao , Ikegawa Shiro , Kou Ikuyo , Tanaka Toshihiro , Nakagawa Hidewaki , Suzuki Akari , Hirota Tomomitsu , Tamari Mayumi , Chayama Kazuaki , Miki Daiki , Mori Masaki , Nagayama Satoshi , Daigo Yataro , Miki Yoshio , Katagiri Toyomasa , Ogawa Osamu , Obara Wataru , Ito Hidemi , Yoshida Teruhiko , Imoto Issei , Takahashi Takashi , Tanikawa Chizu , Suzuki Takao , Sinozaki Nobuaki , Minami Shiro , Yamaguchi Hiroki , Asai Satoshi , Takahashi Yasuo , Yamaji Ken , Takahashi Kazuhisa , Fujioka Tomoaki , Takata Ryo , Yanai Hideki , Masumoto Akihide , Koretsune Yukihiro , Kutsumi Hiromu , Higashiyama Masahiko , Murayama Shigeo , Minegishi Naoko , Suzuki Kichiya , Tanno Kozo , Shimizu Atsushi , Yamaji Taiki , Iwasaki Motoki , Sawada Norie , Uemura Hirokazu , Tanaka Keitaro , Naito Mariko , Sasaki Makoto , Wakai Kenji , Tsugane Shoichiro , Yamamoto Masayuki , Yamamoto Kazuhiko , Murakami Yoshinori , Nakamura Yusuke , Raychaudhuri Soumya , Inazawa Johji , Yamauchi Toshimasa , Kadowaki Takashi , Kubo Michiaki , Kamatani Yoichiro 
Published: October 2019

INTRODUCTORY PARAGRAPHThe overwhelming majority of participants in current genetic studies are of European ancestry1–3, limiting our genetic understanding of complex disease in non-European populations. To address this, we aimed to elucidate polygenic disease biology in the East Asian population by conducting a genome-wide association study (GWAS) with 212,453 Japanese individuals across 42 diseases. We detected 383 independent signals in 331 loci for 30 diseases, among which 45 loci were novel (P< 5 × 10−8). Compared with known variants, novel variants have lower frequency in European populations but comparable frequency in East Asian populations, suggesting the advantage of this study in discovering these novel variants. Three novel signals were in linkage disequilibrium (r2> 0.6) with missense variants which are monomorphic in European populations (1000 Genomes Project) including rs11235604(p.R220W ofATG16L2, a autophagy-related gene) associated with coronary artery disease. We further investigated enrichment of heritability within 2,868 annotations of genome-wide transcription factor occupancy, andidentified 378 significant enrichments across nine diseases (FDR < 0.05) (e.g. NF-κB for immune-related diseases). This large-scale GWAS in a Japanese population provides insights into the etiology of common complex diseases and highlights the importance of performing GWAS in non-European populations.
Phosphoproteomics of CD2 signaling reveals an AMPK-dependent regulation of lytic granule polarization in cytotoxic T cells
Authors: Zurli Vanessa , Montecchi Tommaso , Heilig Raphael , Poschke Isabel , Volkmar Michael , Wimmer Giuliana , Boncompagni Gioia , Turacchio Gabriele , D’Elios Mario Milco , Campoccia Giuseppe , Resta Nicoletta , Offringa Rienk , Fischer Roman , Acuto Oreste , Baldari Cosima Tatiana , Kabanova Anna 
Published: October 2019

SummaryThe in-depth analysis of costimulatory signaling enhancing the activity of cytotoxic T cells (CTLs) represents a major approach towards immunotherapy development. Here we report that CD2 costimulation plays a critical role in killing by freshly isolated human CTLs, which represent a challenging but valuable study model to gain insight into CTL biology. We show that CD2 triggering critically aids signaling by the T cell receptor in the formation of functional immune synapses by promoting the polarization of lytic granules towards the microtubule-organizing center (MTOC). To gain insight into the underlying elusive mechanism, we explored the CD2 signaling network by phosphoproteomics, which revealed 616 CD2-regulated phosphorylation events in 373 proteins implicated in the regulation of vesicular trafficking, cytoskeleton organization, autophagy and metabolism. Strikingly, signaling by the master metabolic regulator AMP-activated protein kinase (AMPK) represents a functionally critical node of the CD2 network which regulates granule polarization towards the MTOC in CTLs. Granule trafficking is driven by active AMPK enriched on adjacent lysosomes, illustrating a novel signaling cross-talk between vesicular compartments in CTLs. Our results thus establish CD2 signaling as key for regulating cytotoxic killing and granule polarization in freshly isolated CTLs and strengthens the rationale to choose CD2 and AMPK as therapeutic targets to boost CTL activity.
Exploring Disturbance as a Force for Good in Motor Learning
Authors: Brookes Jack , Mushtaq Faisal , Jamieson Earle , Fath Aaron J. , Bingham Geoffrey P. , Culmer Peter , Wilkie Richard M. , Mon-Williams Mark A. 
Published: October 2019

AbstractDisturbance forces facilitate motor learning, but theoretical explanations for this counterintuitive phenomenon are lacking. Smooth arm movements require predictions (inference) about the force-field associated with a workspace. The Free Energy Principle (FEP) suggests that such ‘active inference’ is driven by ‘surprise’. We used these insights to create a formal model that explains why disturbance helps learning. In two experiments, participants undertook a continuous tracking task where they learned how to move their arm in different directions through a novel 3D force field. We compared baseline performance before and after exposure to the novel field to quantify learning. In Experiment 1, the exposure phases (but not the baseline measures) were delivered under three different conditions: (i) robot haptic assistance; (ii) no guidance; (iii) robot haptic disturbance. The disturbance group showed the best learning as our model predicted. Experiment 2 further tested our FEP inspired model. Assistive and/or disturbance forces were applied as a function of performance (low surprise), and compared to a random error manipulation (high surprise). The random group showed the most improvement as predicted by the model. Thus, motor learning can be conceptualised as a process of entropy reduction. Short term motor strategies (e.g. global impedance) can mitigate unexpected perturbations, but continuous movements require active inference about external force-fields in order to create accurate internal models of the external world (motor learning). Our findings reconcile research on the relationship between noise, variability, and motor learning, and show that information is the currency of motor learning.