bluuebunny/crossref_metadata_2025 huggingface dataset:
Setting Standards to Promote Artificial Intelligence in Colon Mass Endoscopic Sampling
Authors: Zheng Yueping , Su Ruizhang , Wang Wangyue , Meng Sijun , Xiao Hang , Zhang Wen , Xu Haineng , Bu Yemei , Zhong Yuhuan , Zhang Yi , Qiu Hesong , Qin Wenjuan , Zhang Yongxiu , Xu Wen , Chen Hong , Zhang Changhua , Wu Siqi , Han Zhaofang , Zheng Xiaofang , Zhu Huafen , Wu Shuisheng , Pan Wensheng , He Yulong , Hu Yiqun
Published: October 2019

Objective

Artificial intelligence (AI) has undeniable values in detection, characterization, and monitoring of tumors during cancer imaging. However, major AI explorations in digestive endoscopy have not been systematically planned, and more important, most AI productions are based on Single-center Studies (ScSs). ScSs result in data scarcity, redundancy as well as island effects, which leads to some limitations in applying it on endoscopy. We investigate the disadvantages of picture processing which may effect the AI detection, and make improvements in AI detection and image recognition accuracy.

Design

Current investigation aggregates a total of 2,500 gastroenteroscopy samples from various hospitals in multiple regions and carries out deep learning.

Results

It is found that factors inconducive to AI recognition are common such as: (a) the gastrointestinal tract is not cleaned up completely; (b) shooting angle (from left to right and the top of polyp are unexposed clearly), shooting distance (too close or too far to shoot causes the lump to be unclear), shooting light (insufficient light source or overexposed light source in mass) and unstable shooting lead to poor quality of pictures.

Conclusion

We set standards for a multicenter cooperation involving three-level medical institutions from the provincial, municipal and county to improve the recognition accuracy as well as the diagnosis and treatment efficiency meanwhile.
Towards a brain signature of chronic pain using cerebral blood flow spatial covariance analysis in people with chronic knee pain
Authors: Iwabuchi Sarina J. , Xing Yue , Cottam William J. , Drabek Marianne M. , Tadjibaev Arman , Fernandes Gwen S. , Petersen Kristian K , Arendt-Nielsen Lars , Graven-Nielsen Thomas , Valdes Ana M. , Zhang Weiya , Doherty Michael , Walsh David , Auer Dorothee P.
Published: October 2019

Chronic musculoskeletal pain is a common problem globally. Current evidence suggests that maladaptive modulation of central pain pathways is associated with pain chronicity following e.g. chronic post-operative pain after knee replacement. Other factors such as low mood, anxiety and tendency to catastrophize seem to also be important contributors. We aimed to identify a chronic pain brain signature that discriminates chronic pain from pain-free conditions using cerebral blood flow (CBF) measures, and explore how this signature relates to the chronic pain experience. In 44 chronic knee pain patients and 29 pain-free controls, we acquired CBF data (using arterial spin labelling) and T1-weighted images. Participants completed a series of questionnaires related to affective processes, and pressure and cuff algometry to assess pain sensitization. Two factor scores were extracted from these scores representing negative affect and pain sensitization, respectively. A spatial covariance principal components analysis of CBF identified five components that significantly discriminated chronic pain patients from controls, with the unified network achieving 0.83 discriminatory accuracy (area under the curve). In chronic knee pain, significant patterns of relative hypo-perfusion were evident in anterior regions of the default mode and salience network hubs, while hyperperfusion was seen in posterior default mode regions, the thalamus, and sensory regions. One component was positively correlated to the pain sensitization score (r=.43,p=.006), suggesting that this CBF pattern reflects the neural activity changes encoding pain sensitization. Here, we report the first chronic knee pain-related brain signature, pointing to a brain signature underpinning the central aspects of pain sensitisation.
Bayesian Linear Mixed Models for Motif Activity Analysis
Authors: Lederer Simone , Heskes Tom , van Heeringen Simon J. , Albers Cornelis A.
Published: October 2019

Motivation

Cellular identity and behavior is controlled by complex gene regulatory networks. Transcription factors (TFs) bind to specific DNA sequences to regulate the transcription of their target genes. On the basis of these TF motifs in cis-regulatory elements we can model the influence of TFs on gene expression. In such models of TF motif activity the data is usually modeled assuming a linear relationship between the motif activity and the gene expression level. A commonly used method to model motif influence is based on Ridge Regression. One important assumption of linear regression is the independence between samples. However, if samples are generated from the same cell line, tissue, or other biological source, this assumption may be invalid. This same assumption of independence is also applied to different, yet similar, experimental conditions, which may also be inappropriate. In theory, the independence assumption between samples could lead to loss in signal detection. Here we investigate whether a Bayesian model that allows for correlations results in more accurate inference of motif activities.

Results

We extend the Ridge Regression to a Bayesian Linear Mixed Model, which allows us to model dependence between different samples. In a simulation study, we in-vestigate the differences between the two model assumptions. We show that our Bayesian Linear Mixed Model implementation outperforms Ridge Regression in a simulation scenario where the noise, the signal that can not be explained by TF motifs, is uncorrelated. However, we demonstrate that there is no such gain in performance if the noise has a similar covariance structure over samples as the signal that can be explained by motifs. We give a mathematical explanation to why this is the case. Using two representative real data sets we show that at most∼40% of the signal is explained by motifs using the linear model. With these data there is no advantage to using the Bayesian Linear Mixed Model, due to the similarity of the covariance structure.

Availability & Implementation

The project implementation is available athttps://github.com/Sim19/SimGEXPwMotifs.
PlasClass improves plasmid sequence classification
Authors: Pellow David , Mizrahi Itzik , Shamir Ron
Published: October 2019

Background

Many bacteria contain plasmids, but separating between contigs that originate on the plasmid and those that are part of the bacterial genome can be difficult. This is especially true in metagenomic assembly, which yields many contigs of unknown origin. Existing tools for classifying sequences of plasmid origin give less reliable results for shorter sequences, are trained using a fraction of the known plasmids, and can be difficult to use in practice.

Results

We present PlasClass, a new plasmid classifier. It uses a set of standard classifiers trained on the most current set of known plasmid sequences for different sequence lengths. PlasClass outperforms the state-of-the-art plasmid classification tool on shorter sequences, which constitute the majority of assembly contigs, while using less time and memory.

Conclusions

PlasClass can be used to easily classify plasmid and bacterial genome sequences in metagenomic or isolate assemblies. It is available from: https://github.com/Shamir-Lab/PlasClass
GiniClust3: a fast and memory-efficient tool for rare cell type identification
Authors: Dong Rui , Yuan Guo-Cheng
Published: October 2019

Motivation

With the rapid development of single-cell RNA sequencing technology, it is possible to dissect cell-type composition at high resolution. A number of methods have been developed with the purpose to identify rare cell types. However, existing methods are still not scalable to large datasets, limiting their utility. To overcome this limitation, we present a new software package, called GiniClust3, which is an extension of GiniClust2 and significantly faster and memory-efficient than previous versions.

Results

Using GiniClust3, it only takes about 7 hours to identify both common and rare cell clusters from a dataset that contains more than one million cells. Cell type mapping and perturbation analyses show that GiniClust3 could robustly identify cell clusters.

Availability

GiniCluster3 is implemented in the open-source python package, with source code freely available through the Github (https://github.com/rdong08/GiniClust3).

Contact

gcyuan@jimmy.harvard.edu

Supplementary information

Supplementary data are available at Bioinformatics online.
Globins in the marine Annelid Platynereis dumerilii shed new light on hemoglobin evolution in Bilaterians
Authors: Song Solène , Starunov Viktor , Bailly Xavier , Ruta Christine , Kerner Pierre , Cornelissen Annemiek J.M. , Balavoine Guillaume
Published: October 2019

Background

How vascular systems and their respiratory pigments evolved is still debated. While many animals present a vascular system, hemoglobin exists as a blood pigment only in a few groups (Vertebrates, Annelids, a few Arthropod and Mollusk species). Hemoglobins are formed of globin sub-units, belonging to multigene families, in various multimeric assemblages. It was so far unclear whether hemoglobin families from different Bilaterian groups had a common origin.

Results

To unravel globin evolution in Bilaterians, we studied the marine Annelid Platynereis dumerilii, a species with a slow evolving genome. Platynereis exhibits a closed vascular system filled with extracellular hemoglobin. Platynereis genome and transcriptomes reveal a family of 19 globins, nine of which are predicted to be extracellular. Extracellular globins are produced by specialized cells lining the vessels of the segmental appendages of the worm, serving as gills, and thus likely participate in the assembly of the giant hexagonal bilayer hemoglobin of the worm. Extracellular globin mRNAs are absent in smaller juvenile, accumulate considerably in growing and more active worms and peak in swarming adults, as the need for O2 culminates. Next, we conducted a Metazoan-wide phylogenetic analysis of globins using data from complete genomes. We establish that five globin genes (stem globins) were present in the last common ancestor of Bilaterians. Based on these results, we propose a new nomenclature of globins, with five clades. All five ancestral stem-globin clades are retained in some Spiralians, while some clades disappeared early in Deuterostome and Ecdysozoan evolution. All known Bilaterian blood globin families are grouped in a single clade (clade I) together with intracellular globins of Bilaterians devoid of red blood.

Conclusions

We uncover a complex “pre-blood” evolution of globins, with an early gene radiation in ancestral Bilaterians. Circulating hemoglobins in various bilaterian groups evolved convergently, presumably in correlation with animal size and activity. However, all hemoglobins derive from a clade I globin, or cytoglobin, probably involved in intracellular O2 transit and regulation (clade I). The Annelid Platynereis is remarkable in having a large family of extracellular blood globins, while retaining all clades of ancestral Bilaterian globins.
Fine-scale position effects shape the distribution of inversion breakpoints inDrosophila melanogaster
Authors: McBroome Jakob , Liang David , Corbett-Detig Russell
Published: October 2019

Chromosomal inversions are among the primary drivers of genome structure evolution in a wide range of natural populations. While there is an impressive array of theory and empirical analyses that has identified conditions under which inversions can be positively selected, comparatively little data is available on the fitness impacts of these genome structural rearrangements themselves. Because inversion breakpoints can interrupt functional elements and alter chromatin domains, each rearrangement may in itself have strong effects on fitness. Here, we compared the fine-scale distribution of low frequency inversion breakpoints with those of high frequency inversions and inversions that have fixed betweenDrosophilaspecies. We identified important differences that may influence inversion fitness. In particular, proximity to insulator elements, large tandem duplications adjacent to the breakpoints, and minimal impacts on gene coding spans are more prevalent in high frequency and fixed inversions than in rare inversions. The data suggest that natural selection acts both to preserve both genes and larger cis-regulatory networks in the occurrence and spread of rearrangements. These factors may act to limit the availability of high fitness arrangements when suppressed recombination is favorable.
ProteoClade: a taxonomic toolkit for multi-species and metaproteomic analysis
Authors: Mooradian Arshag D. , van der Post Sjoerd , Naegle Kristen M. , Held Jason M.
Published: October 2019

We present ProteoClade, a Python toolkit that performs taxa-specific peptide assignment, protein inference, and quantitation for multi-species proteomics experiments. ProteoClade scales to hundreds of millions of protein sequences, requires minimal computational resources, and is open source, multi-platform, and accessible to non-programmers. We demonstrate its utility for processing quantitative proteomic data derived from patient-derived xenografts and its speed and scalability enable a novel de novo proteomic workflow for complex microbiota samples.
A polyclonal allelic expression assay for detecting regulatory effects of transcript variants
Authors: Brandt Margot , Gokden Alper , Ziosi Marcello , Lappalainen Tuuli
Published: October 2019

We present an assay to experimentally test regulatory effects of genetic variants within transcripts using CRISPR/Cas9 followed by targeted sequencing. We applied the assay to 35 premature stop-gained variants across the genome and in two Mendelian disease genes, 33 putative causal variants of eQTLs and 65 control variants. We detected significant effects generally in the expected direction, demonstrating the ability of the assay to capture regulatory effects of eQTL variants and nonsense-mediated decay triggered by premature stop-gained variants. The results suggest a utility for validating transcript-level effects of genetic variants.
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

Lyme 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

Model 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.

Significance

The 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

Background

Over 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.

Results

We 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.

Conclusions

With 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

One 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.

Significance

We 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

The 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

Changes 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

Segmented 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

When 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 PARAGRAPH

The 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

The 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

Disturbance 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.
Understanding the factors influencing citizens’ willingness-to-accept the use of insects to feed poultry, cattle, pig and fish in Brazil
Authors: de Faria Domingues Carla Heloisa , Borges João Augusto Rossi , Ruviaro Clandio Favarini , Guidolin Diego Gomes Freire , Carrijo Juliana Rosa Mauad
Published: October 2019

The increase in world’s population will cause a high demand of animal-sourced food, which will require a boost in the production of protein, because protein is an important component of animal feed. A higher production of protein, however, might contribute for the depletion of environmental resources. In this scenario, the use of insects as an alternative source of protein to feed animals could be a solution. However, citizens’ willingness-to-accept insect as a source of protein to feed animals is unknown, particularly in developing countries, such as Brazil. The aim of this study was to investigate the factors influencing citizens’ willingness-to-accept the use of insects to feed poultry, cattle, pig and fish. To reach this aim, we conducted an online survey with Brazilian citizens. We analyzed the data using descriptive statistics and four logistic regression models. In each of logistic models, the dependent variable was citizens’ willingness-to-accept the use of insects to feed either poultry, or cattle, or pig or fish. A set of independent variables including socio-demographic characteristics, attitudes, perceived benefits, perceived risks, and perceived concerns were used to explain citizens' willingness-to-accept the use of insect to feed animals. Results showed that most citizens would accept that poultry, pig, and fish receive insect-based diets, and half of the citizens would accept and half would not accept that cattle receive such diet. Results of the logistic regression models showed that citizens who had a positive attitude about using insects to feed animals were more willing-to-accept the use of insect to feed poultry, cattle, pig, and fish compared to those who had a negative attitude. Citizens who perceived the benefits of using insect to feed animals were less willing-to-accept the use of insects to feed poultry compared to those who didn’t perceive the benefits. Citizens who perceived the benefits of using insects to feed animals were more willing-to-accept the use of insect to feed fish compared to those who didn’t perceive the benefits. Citizens who were more concerned about using insect to feed animals were more willing-to-accept the use of insects to feed poultry compared to those who were less concerned. Finally, citizens who were more concerned about using insects to feed animals were less willing-to-accept the use of insect to feed pigs compared to those who were less concerned. These results revealed important insights that can be used to design strategies to increase the acceptance of the use of insects to feed poultry, cattle, pig, and fish.
Early conservation benefits of a de facto marine protected area at San Clemente Island, California
Authors: Esgro Michael W. , Lindholm James , Nickols Kerry J. , Bredvik Jessica
Published: October 2019

De facto marine protected areas (DFMPAs) are regions of the ocean where human activity is restricted for reasons other than conservation. Although DFMPAs are widespread globally, their potential role in the protection of marine habitats, species, and ecosystems has not been well studied. In 2012 and 2013, we conducted remotely operated vehicle (ROV) surveys of marine communities at a military DFMPA and an adjacent fished reference site at San Clemente Island, the southernmost of California’s Channel Islands. We used data extracted from ROV imagery to compare density and biomass of focal species, as well as biodiversity and community composition, between the two sites. Generalized linear modeling indicated that both density and biomass of California sheephead (Semicossyphus pulcher) were significantly higher inside the DFMPA. Biomass of ocean whitefish (Caulolatilus princeps) was also significantly higher inside the DFMPA. However, species richness and Shannon-Weaver diversity were not significantly higher inside the DFMPA, and overall fish community composition did not differ significantly between sites. Demonstrable differences between the DFMPA and fished site for two highly sought-after species hint at early potential benefits of protection, though the lack of differences in the broader community suggests that a longer trajectory of recovery may be required for other species. A more comprehensive understanding of the potential conservation benefits of DFMPAs is important in the context of marine spatial planning and global marine conservation objectives.
Microscaled Proteogenomic Methods for Precision Oncology
Authors: Satpathy Shankha , Jaehnig Eric J. , Krug Karsten , Kim Beom-Jun , Saltzman Alexander B. , Chan Doug , Holloway Kimberly R. , Anurag Meenakshi , Huang Chen , Singh Purba , Gao Ari , Namai Noel , Dou Yongchao , Wen Bo , Vasaikar Suhas , Mutch David , Watson Mark , Ma Cynthia , Ademuyiwa Foluso O. , Rimawi Mothaffar , Hoog Jeremy , Jacobs Samuel , Malovannaya Anna , Hyslop Terry , Clauser Karl C. , Mani D. R. , Perou Charles , Miles George , Zhang Bing , Gillette Michael A. , Carr Steven A. , Ellis Matthew J.
Published: October 2019

Cancer proteogenomics integrates genomics, transcriptomics and mass spectrometry (MS)-based proteomics to gain insights into cancer biology and treatment efficacy. A proteogenomics approach was therefore developed for frozen core biopsies using tissue-sparing specimen processing with a “microscaled” proteomics workflow. For technical proof-of-principle, biopsies from ERBB2 positive breast cancers before and 48-72 hours after the first dose of neoadjuvant trastuzumab-based chemotherapy were analyzed. ERBB2 protein and phosphosite levels, as well as mTOR target phosphosites, were significantly more suppressed upon treatment in cases associated with pathological complete response, suggesting MS-based pharmacodynamics is achievable. Furthermore, integrated analyses indicated potential causes of treatment resistance including the absence of ERBB2 amplification (false-ERBB2 positive) and insufficient ERBB2 activity for therapeutic sensitivity despite ERBB2 amplification (pseudo-ERBB2 positive). Candidate resistance features in true-ERBB2+ cases, including androgen receptor signaling, mucin expression and an inactive immune microenvironment were observed. Thus, proteogenomic analysis of needle core biopsies is feasible and clinical utility should be investigated.
Discovery and Optimization of Inhibitors for the Pup Proteasome System in Mycobacterium tuberculosis
Authors: Janssen Guido V. , Zhang Susan , Merkx Remco , Schiesswohl Christa , Chatterjee Champak , Darwin K. Heran , Ovaa Huib
Published: October 2019

Tuberculosis is a global health problem with the existence and spreading of multidrug resistant and extensive drug resistant strains. The development of new drugs for tuberculosis that inhibit different activities than the current drugs is thus urgent. The prokaryotic ubiquitin like protein proteasome system is an attractive target for the development of new drugs. Using a Pup-based fluorogenic substrate, we screened for inhibitors of Dop, a depupylase, and identified I-OMe-Tyrphostin AG538 (1) and Tyrphostin AG53 (2). The hits were validated and determined to be fast reversible non-ATP competitive inhibitors. The SAR was established by testing 27 synthesized analogs of 1 and 2. Several of the synthesized compounds also inhibited the depupylation of a native substrate, FabD∼Pup. Importantly, the pupylation and depupylation activities of PafA, the sole Pup ligase in M. tuberculosis, was also inhibited by some of these compounds. With the identification of the first described lead compounds for Dop and PafA inhibition, this study shows that high throughput screening can be a successful strategy for this purpose.
Multicentric tracking of multiple agents by anterior cingulate cortex during pursuit and evasion
Authors: Yoo Seng Bum Michael , Tu Jiaxin Cindy , Hayden Benjamin Yost
Published: October 2019

Successful pursuit and evasion require rapid and precise coordination of navigation with adaptive motor control. We hypothesized that the dorsal anterior cingulate cortex (dACC), which communicates bidirectionally with both the hippocampal complex and premotor/motor areas, would serve a mapping role in this process. We recorded responses of dACC ensembles in two macaques performing a joystick-controlled continuous pursuit/evasion task. We found that dACC multiplexes two sets of signals, (1) world-centric variables that together form a representation of the position and velocity of all relevant agents (self, prey, and predator) in the virtual world, and (2) avatar-centric variables, i.e. self-prey distance and angle. Both sets of variables are multiplexed within an overlapping set of neurons. Our results suggest that dACC may contribute to pursuit and evasion by computing and continuously updating a multicentric representation of the unfolding task state, and support the hypothesis that it plays a high-level abstract role in the control of behavior.