bluuebunny/crossref_metadata_2025 huggingface dataset:
Multi-ancestry genome-wide analysis identifies common genetic variants for self-reported sleep duration and shared genetic effects
Authors: Scammell Ben H , Song Yanwei , Tchio Cynthia , Nishiyama Takeshi , Louie Tin L , Dashti Hassan S , Nakatochi Masahiro , Zee Phyllis C , Daghlas Iyas , Momozawa Yukihide , Cai Jianwen , Ollila Hanna M. , Redline Susan , Wakai Kenji , Sofer Tamar , Suzuki Sadao , Lane Jacqueline M , Saxena Richa
Published: February 2022

Both short and long sleep duration are associated with increased risk of chronic diseases, but the genetic determinants of sleep duration are largely unknown outside of European populations. Here we report transferability of a polygenic score of 78 European ancestry sleep duration SNPs to an African (n=7,288; p=0.003), a South Asian (n=7,485; p=0.025), and a Japanese (n=13,618; p=6x10-4) cohort, but not to a cohort of Hispanic/Latino (n- XXX; p=0.71) participants. Furthermore, in a pan-ancestry (N = 483,235) meta-analysis of genome-wide association studies (GWAS) for habitual sleep duration, 5 novel and 68 known loci are associated with genome-wide significance. For the novel loci, sleep duration signals colocalize with expression-QTLs for PRR12 and COG5 in brain tissues, and pleiotropic associations are observed with cardiovascular and neuropsychiatric traits. Overall, our results suggest that the genetic basis of sleep duration is at least partially shared across diverse ancestry groups.
Dissecting the Genetic Architecture of Carbon Partitioning in Sorghum using Multiscale Phenotypes
Authors: Boatwright J. Lucas , Sapkota Sirjan , Myers Matthew , Kumar Neeraj , Cox Alex , Kresovich Stephen
Published: February 2022

Carbon partitioning in plants may be viewed as a dynamic process composed of the many interactions between sources and sinks. The accumulation and distribution of fixed carbon is not dictated simply by the sink strength and number but is dependent upon the source, pathways, and interactions of the system. As such, the study of carbon partitioning through perturbations to the system or through focus on individual traits may fail to produce actionable developments or a comprehensive understanding of the mechanisms underlying this complex process. Using the recently published sorghum carbon-partitioning panel, we collected both macroscale phenotypic characteristics such as plant height, above-ground biomass, and dry weight along with microscale compositional traits to deconvolute the carbon-partitioning pathways in this multipurpose crop. Multivariate analyses of traits resulted in the identification of numerous loci associated with several distinct carbon-partitioning traits, which putatively regulate sugar content, manganese homeostasis, and nitrate transportation. Using a multivariate adaptive shrinkage approach, we identified several loci associated with multiple traits suggesting that pleiotropic and/or interactive effects may positively influence multiple carbon-partitioning traits, or these overlaps may represent molecular switches mediating basal carbon allocating or partitioning networks. Conversely, we also identify a carbon tradeoff where reduced lignin content is associated with increased sugar content. The results presented here support previous studies demonstrating the convoluted nature of carbon partitioning in sorghum and emphasize the importance of taking a holistic approach to the study of carbon partitioning by utilizing multiscale phenotypes.
Rapid motor adaptation to bounce perturbations in online Pong game is independent from the visual tilt of the bouncing surface
Authors: Mikula Laura , ’t Hart Bernard Marius , Henriques Denise Y. P.
Published: February 2022

Motor adaptation describes the ability of the motor system to counteract repeated perturbations in order to reduce movement errors. Most research in the field investigated adaptation in response to perturbations affecting the moving hand. Fewer studies looked at the effect of a perturbation applied to the movement target, however they used simplistic visual stimuli. In this study, we examined motor adaptation to perturbations affecting the motion of dynamic targets. In addition, we asked whether external visual cues in the environment could facilitate this process. To do so, participants were asked to play an online version of the Pong game in which they intercepted a ball bouncing off a wall using a paddle. A perturbation was applied to alter the post-bounce trajectory of the ball and the wall orientation was manipulated to be consistent or not with the ball trajectory. The “trained tilt” group (n = 34) adapted to the consistent condition and the “trained horizontal” group (n = 36) adapted to the inconsistent condition. In case participants optimally integrate external visual cues, the “trained tilt” group is expected to exhibit faster and/or more complete adaptation than the “trained horizontal” group. We found that the perturbation reduced interception accuracy. Participants showed large interception errors when the perturbation was introduced, followed by rapid error decrease and aftereffects (errors in the opposite direction) once the perturbation was removed. Although both experimental groups showed these typical markers of motor adaptation, we did not find differences in interception success rates or errors between the “trained tilt” and “trained horizontal” groups. Our results demonstrate that participants quickly adapted to the dynamics of the pong ball. However, the visual tilt of the bouncing surface did not enhance their performance. The present study highlights the ability of the motor system to adapt to external perturbations applied to a moving target in a more dynamical environment and in online settings. These findings underline the prospects of further research on sensorimotor adaptation to unexpected changes in the environment using more naturalistic and complex real-world or virtual reality tasks as well as gamified paradigms.
C. difficilemay be overdiagnosed in adults and is a prevalent commensal in infants
Authors: Ferretti Pamela , Wirbel Jakob , Maistrenko Oleksandr M , Van Rossum Thea , Alves Renato , Fullam Anthony , Akanni Wasiu , Schudoma Christian , Schwarz Anna , Thielemann Roman , Thomas Leonie , Kandels Stefanie , Hercog Rajna , Telzerow Anja , Letunic Ivica , Kuhn Michael , Zeller Georg , Schmidt Thomas SB , Bork Peer
Published: February 2022

Clostridioides difficileis an urgent threat in hospital-acquired infections world-wide, yet the microbial composition associated withC. difficile, in particular inC. difficileinfection (CDI) cases, remains poorly characterised. To investigate the gut microbiome composition in CDI patients, we analysed 534 metagenomes from 10 publicly available CDI study populations. We then trackedC. difficileon a global scale, screening 42,900 metagenomes from 253 public studies. Among the CDI cohorts, we detectedC. difficilein only 30% of the stool samples from CDI patients. However, we found that multiple other toxigenic species capable of inducing CDI-like symptomatology were prevalent. In addition, the majority of the investigated studies did not adhere to the recommended guidelines for a correct CDI diagnosis.

In the global survey, we found thatC. difficileprevalence, abundance and biotic context were age-dependent.C. difficileis a rare taxon associated with reduced diversity in healthy adults, but common and associated with increased diversity in infants. We identified a group of species co-occurring withC. difficileexclusively in healthy infants, enriched in obligate anaerobes and in species typical of the healthy adult gut microbiome.C. difficilein healthy infants was therefore associated with multiple indicators of healthy gut microbiome maturation.

Our analysis raises concerns about potential CDI overdiagnosis and suggests thatC. difficileis an important commensal in infants and that its asymptomatic carriage in adults depends on microbial context.
Identification of Mebendazole as an ethylene signaling activator reveals a role of ethylene signaling in the regulation of lateral root angles
Authors: He Wenrong , Truong Hai An , Zhang Ling , Cao Min , Arakawa Neal , Xiao Yao , Zhong Kaizhen , Hou Yingnan , Busch Wolfgang
Published: February 2022

The lateral root angle or gravitropic set-point angle (GSA) is an important trait for root system architecture (RSA) that determines the radial expansion of the root system. The GSA therefore plays a crucial role for the ability of plants to access nutrients and water in the soil. Despite its importance, only few regulatory pathways and mechanisms that determine GSA are known, and these mostly relate to auxin and cytokinin pathways. Here, we report the identification of a small molecule, Mebendazole (MBZ) that modulates GSA inArabidopsis thalianaroots and acts via the activation of ethylene signaling. We uncover that MBZ directly acts on the serine/threonine protein kinase CTR1, which is a negative regulator of ethylene signaling. Our study not only reveals that the ethylene signaling pathway is essential for GSA regulation, but it also identifies a small molecular modulator of RSA and the first small molecule that acts downstream of ethylene receptors and that directly activates ethylene signaling.

In brief

Heet al. identify a small molecule that regulates lateral root angle. They show that the compound increases lateral root angle by inhibiting CTR1 kinase activity, which in turn activates ethylene signaling. Therefore, they uncover that the ethylene pathway is involved in lateral root angle regulation.

Highlights

MBZ increases lateral root angle

MBZ regulates lateral root angle by activating ethylene signaling

MBZ inhibits CTR1 kinase activity

The ethylene pathway is involved in lateral root angle regulation
cLD: Rare-variant disequilibrium between genomic regions identifies novel genomic interactions
Authors: Wang Dinghao , He Jingni , Perera Deshan , Cao Chen , Kossinna Pathum , Li Qing , Zhang William , Guo Xingyi , Platt Alexander , Wu Jingjing , Zhang Qingrun
Published: February 2022

Linkage disequilibrium (LD) is a fundamental concept in genetics; critical for studying genetic associations and molecular evolution. However, LD measurements are only reliable for common genetic variants, leaving low-frequency variants unanalyzed. In this work, we introduce cumulative LD (cLD), a stable statistic that captures the rare-variant LD between genetic regions, which reflects more biological interactions between variants, in addition to lack of recombination. We derived the theoretical variance of cLD using delta methods to demonstrate its higher stability than LD for rare variants. This property is also verified by bootstrapped simulations using real data. In application, we find cLD reveals an increased genetic association between genes in 3D chromatin interactions, a phenomenon recently reported negatively by calculating standard LD between common variants. Additionally, we show that cLD is higher between gene pairs reported in interaction databases, identifies unreported protein-protein interactions, and reveals interacting genes distinguishing case/control samples in association studies.
Brain signatures for neuropsychological and everyday memory achieve high replicability and explanatory power in two data cohorts
Authors: Fletcher Evan , Farias Sarah , DeCarli Charles , Gavett Brandon , Widaman Keith , De Leon Fransia , Mungas Dan
Published: February 2022

Background

The “brain signature of cognition” concept has garnered interest as a data-driven, exploratory approach to better understand key brain regions involved in specific cognitive functions, with the potential to maximally characterize brain substrates of clinical outcomes. However, to be a robust brain phenotype, the signature approach requires a statistical foundation showing that model performance replicates across a variety of cohorts. Here, we outline a procedure that provides this foundation for a signature models of two memory-related behavioral domains.

Method

In each of two independent data cohorts, we derived regional brain gray matter thickness associations for neuropsychological and everyday cognition memory, testing for replicability. In each cohort we computed regional association to outcome in 40 randomly selected “discovery subsets” of size N = 400; we generated spatial overlap frequency maps and selected high-frequency regions as “consensus” signature masks for each cohort. We tested replicability by comparing cohort-based consensus model fits in all discovery sets. We tested explanatory power in each full cohort, compare signature model fits with competing “standard” models of each outcome.

Result

Spatial replications produced strongly convergent consensus signature regions derived from UCD and ADNI. Consensus model fits were highly correlated in 40 random subsets of each cohort indicating high replicability. In comparisons over each full cohort, signature models outperformed other models with one exception.

Conclusion

Multiple random model generations, followed by consensus selection of regional brain substrates, produced signature models that replicated model fits to outcome and outperformed other commonly used measures. Robust biomarkers of cognition and everyday function may be achievable by this method.

Funding

This project was funded by R01 AG052132 (NIH/NIA)
Bioframe: Operations on Genomic Intervals in Pandas Dataframes
Authors:   Open2C, Abdennur Nezar , Fudenberg Geoffrey , Flyamer Ilya , Galitsyna Aleksandra A. , Goloborodko Anton , Imakaev Maxim , Venev Sergey V.
Published: February 2022

Motivation

Genomic intervals are one of the most prevalent data structures in computational genome biology, and used to represent features ranging from genes, to DNA binding sites, to disease variants. Operations on genomic intervals provide a language for asking questions about relationships between features. While there are excellent interval arithmetic tools for the command line, they are not smoothly integrated into Python, one of the most popular general-purpose computational and visualization environments.

Results

Bioframeis a library to enable flexible and performant operations on genomic interval dataframes in Python.Bioframeextends the Python data science stack to use cases for computational genome biology by building directly on top of two of the most commonly-used Python libraries,numpyandpandas. ThebioframeAPI enables flexible name and column orders, and decouples operations from data formats to avoid unnecessary conversions, a common scourge for bioinformaticians. Bioframe achieves these goals while maintaining high performance and a rich set of features.

Availability and implementation

Bioframeis open-source under MIT license, cross-platform, and can be installed from the Python package index. The source code is maintained by Open2C on Github athttps://github.com/open2c/bioframe.
A Model-Based Clustering via Mixture of Bayesian Hierarchical Models with Covariate Adjustment for Detecting Differentially Expressed Genes from Paired Design
Authors: Zhang Yixin , Liu Wei , Qiu Weiliang
Published: February 2022

The causes of many complex human diseases are still largely unknown. Genetics plays an important role in uncovering the molecular mechanisms of complex human diseases. A key step to characterize the genetics of a complex human disease is to unbiasedly identify disease-associated gene transcripts in whole-genome scale. Confounding factors could cause false positives. Paired design, such as measuring gene expression before and after treatment for the same subject, can reduce the effect of known confounding factors. Model-based clustering, such as mixtures of Bayesian hierarchical models, has been proposed to detect gene transcripts differentially expressed between paired samples. However, not all known confounding factors can be controlled in a paired/match design. To the best of our knowledge, no clustering methods have the capacity to adjust for the effects of covariates yet. In this article, we proposed a novel mixture of Bayesian hierarchical models with covariate adjustment in identifying differentially expressed transcripts using high-throughput whole-genome data from paired design. Both simulation study and real data analysis show the good performance of the proposed method
Notch signaling in tumor vasculature programs cancer-associated fibroblasts to suppress anti-tumor immunity
Authors: Zhu Yu , Xiang Menglan , Brulois Kevin F. , Lazarus Nicole H. , Pan Junliang , Butcher Eugene C.
Published: February 2022

Scarcity of tumor-infiltrating T cells poses significant challenges to cancer treatment, but mechanisms that regulate T cell recruitment into the tumor microenvironment are unclear. Here we ask if the endothelial lining of tumor vasculature suppresses T cell infiltration. Using mouse pancreatic ductal adenocarcinoma models, we found that Notch signaling in endothelial cells (ECs) inhibits the pro-inflammatory functions of cancer-associated fibroblasts (CAFs) and prevents CAFs from secreting CXCL10, a chemokine that recruits anti-tumor T cells via its receptor CXCR3. Abrogation of canonical Notch signaling in ECs reprogrammed the phenotype of CAFs from myofibroblasts into pro-inflammatory fibroblasts, unleashed interferon gamma (IFNγ) responses in the tumor, and stimulated CXCL10/CXCR3-mediated recruitment of T cells to inhibit tumor growth. Collectively, these data uncover an important role of endothelial Notch signaling in shaping the tumor immune microenvironment, and suggest the potential of targeting EC-CAF crosstalk as an approach to enhance anti-tumor immunity in immunologically cold tumors.

In brief

How blood vasculature shapes the tumor immune microenvironment is poorly defined. This study demonstrates that tumor endothelial cells reprogram cancer-associated fibroblasts to limit anti-tumor T cell recruitment, and suggests the potential of targeting endothelium-fibroblast crosstalk to overcome T cell scarcity in “cold” tumors and enhance anti-tumor immunity.
Identification of biological processes and signaling pathways in lactate-treated cancer cells
Authors: Qian Zhiwen , Gu Hanming , Chang Tingxiang
Published: February 2022

Cancer is a complex disease that involves the alterations of metabolic pathways and tumor microenvironment. Lactate in the tumor microenvironment leads to cancer proliferation, metastasis, and angiogenesis. However, the effect of lactate on prostate cancer cells is still unclear. Here, our objective is to identify the significant molecules and biological processes by analyzing the RNA-seq data. The GSE195639 was produced by the Illumina NextSeq 500 (Homo sapiens). The KEGG and GO analyses show that Herpes simplex virus 1 infection and Rap1 signaling pathway are considered major pathways during the lactate-treated cancer cells. Furthermore, we identified the top ten essential molecules including IL6, CASP3, JUN, MAPK3, BRCA1, PIK3R1, CCNA2, TPI1, APOE, and EXO1. Therefore, our study may provide novel insights into the mechanism of prostate cancers.
Read depth correction for somatic mutations
Authors: Anaya Jordan , Baras Alexander S.
Published: February 2022

The ability to accurately detect mutations is a function of read depth and variant allele frequency (VAF). While the read depth distribution of a sample is observable, the true VAF distribution of all mutations in a sample is uncertain when there is low coverage depth. We propose to estimate the VAF distributions that would be observed with high-depth sequencing for samples with low sequencing depth by grouping samples with similar clonality and purity and using the VAF distributions observed with the high-depth mutations that are available. With these estimated high-depth VAF distributions we then calculate what the expected VAF distributions would be at a given depth and compare against the observed VAF distributions at that depth. Using this procedure we estimate that The Cancer Genome Atlas (TCGA) MC3 dataset only reports on average 83% of the mutations in a sample which would have been detected with high-depth sequencing. These results have important implications for comparing tumor mutational burden (TMB) estimates when samples are sequenced at different depths and for modeling high-depth, gene panel-based sequencing from the TCGA MC3 dataset.
Comprehensive dissection of immune microenvironment in the progression of early gastric cancer at spatial and single-cell resolution
Authors: Du Tiantian , Gao Huiru , Wu Honglei , Li Juan , Li Peilong , Gao Jie , Qi Qiuchen , Liu Xiaoyan , Du Lutao , Wang Yunshan , Wang Chuanxin
Published: February 2022

While the changes of tumor immune microenvironment (TME) have critical implications for most tumor progression, works that could reveal the compositions and immunity features of TME are needed. Profiling gastric malignant cells at single-cells resolution has shown the transcriptional heterogeneity is represented at different states of gastric cancer, implying that diverse cell states may exist, including immune cells, and all components in TME make some balances in early gastric cancer (EGC) progression. However, it remains unclear how immune cells contributing malignancy of gastritis, constituting general characteristics of gastric TME. Furthermore, the role of specific interactions among cells in gastric TME remains to be illustrated. Here, we performed spatial transcriptomes and single-cell RNA-seq analysis across 18 gastric samples, identifying 17 celltypes and reconstructing their location information. We found that immune cells represented different degree of dysregulations during the progression from non-atrophic gastritis (NAG), atrophic gastritis (AG) to EGC, including imbalance of cytotoxic and inhibitory effects in T cells, maturation inhibition in B cells and malignant genes up-regulated obviously in myeloid cells. Besides, pathway activities showed that hypoxia, reactive oxygen species and fatty metabolism signaling were activated from AG stage, which may accelerate progression of EGC. Moreover, cellular interactions further identified the roles of hypoxia in gastric TME. Overall, the multi-omics data presented in this study offer a comprehensive view of immune cell types, states changes and locations within the gastric tissues during the progression from NAG, AG to EGC, advancing our understanding of the composition and immunity of different gastric states, offering diagnostic and preventive thoughts for EGC.
Inhibition of the tuft cell/ILC2 axis reduces gastric tumor development in mice
Authors: O’Keefe Ryan N , Carli Annalisa LE , Baloyan David , Afshar-Sterle Shoukat , Eissmann Moritz F , Poh Ashleigh R , Seillet Cyril , Locksley Richard M , Ernst Matthias , Buchert Michael
Published: February 2022

Although gastric cancer is a leading cause of cancer-related deaths, systemic treatment strategies remain scarce. Here we explore a metabolite-triggered circuit between epithelial tuft cells and innate lymphoid type 2 cells (ILC2) that is evolutionarily optimized for intestinal remodeling in response to helminth infection. We demonstrate that tuft cell-derived interleukin 25 (IL25) acts as an alarmin on ILC2s to induce the release of IL13 as a growth factor for tuft cells, and propose that this model drives early metaplastic remodeling and gastric tumor formation. Genetic ablation of tuft cells, ILC2s or antibody-mediated neutralization of IL13 or IL25 reduces the growth of established tumors. Thus, the tuft cell/ILC2 axis provides an opportunity to therapeutically inhibit preneoplastic lesions and early-stage gastric cancer through repurposing of antibody-mediated therapies.

One-Sentence Summary

Tuft cells and type 2 innate lymphoid cells offer a new therapeutic target in gastric disease.
CRISPR-Detector: Fast and Accurate Detection, Visualization, and Annotation of Genome-Wide Mutations Induced by Gene Editing Events
Authors: Huang Lei , Wang Dan , Chen Haodong , Hu Jinnan , Dai Xuechen , Liu Chuan , Li Anduo , Shen Xuechun , Qi Chen , Sun Haixi , Zhang Dengwei , Chen Tong , Jiang Yuan
Published: February 2022

The leading edge of genome editing, driven by CRISPR/Cas technology, is revolutionizing biotechnologies. In pace with the burst of novel genome editing methods, bioinformatic tools to monitor the on/off-target events need to be more evolved as well. Existing tools suffer from limitations in speed and scalability, and they especially struggle with whole genome sequencing (WGS) data analysis which has the potential to detect off-target mutations at a genome-wide level via an unbiased manner. Here, we introduce our CRISPR-detector tool, which is a web-hosted or locally deployable pipeline with five key innovations: 1) optimized scalability allowing for WGS data analysis beyond BED (Browser Extensible Data) file-defined regions; 2) improved accuracy benefiting from haplotype-based variant calling to handle sequencing errors; 3) treated and control sample co-analysis to remove background variants existing prior to genome editing; 4) integrated structural variation (SV) calling; and 5) functional and clinical annotation of editing-induced mutations.
Prey size spectra and predator to prey size ratios of southern ocean salps
Authors: Fender Christian K. , Décima Moira , Gutiérrez-Rodríguez Andres , Selph Karen E. , Yingling Natalia , Stukel Michael R.
Published: February 2022

Salp grazing is important in shaping planktonic food-web structure. However, little is known about the size ranges of their prey in the field or how grazing impacts size structure. This study investigated the feeding habits of 7 different species of salps, representing a variety of sizes and life stages across subtropical and subantarctic waters east of New Zealand. Scanning electron microscopy was used to examine the gut contents of 58 salps, which were then compared to water column plankton communities characterized via epifluorescence microscopy, FlowCam, and flow cytometry. While most of the gut contents resembled ambient waters, substantial differences were found amongst some co-occurring species, such as increased retention of submicron bacteria amongst smaller salps likeThalia democratica. We found that even for those salps capable of feeding on bacteria efficiently, nanoplankton and small microplankton still made up the majority of gut biomass. Larger microplankton were rarer in the guts than in the water column, potentially suggesting an upper size-threshold in addition to the lower size-threshold that has been the focus of most previous work. Salp carbon-weighted predator to prey size ratios were variable, with the majority falling between 1,000:1 and 10,000:1 depending largely on the size of the salp. Taken together our results indicate that despite being able to feed on submicron particles, picoplankton make up at most 26.4% (mean = 6.4%) of salp gut carbon and are relatively unimportant to the energetics of most salps in this region compared to nanoplankton such as small dinoflagellates and diatoms.
Assessing base-resolution DNA mechanics on the genome scale
Authors: Jiang Wen-Jie , Hu Congcong , Yi Xinyao , Xu Qianyi , Lou Tianai , Wang Haojie , Zhou Jialu , Zhu Hanwen , Li Yong , Wen Yilin , Fan Ruiqi , Shen Jing , Wong Catherine C.L. , Zhen Xiaoqi , Wu Hua-Jun
Published: February 2022

Intrinsic DNA properties such as bending play a crucial role in diverse biological systems. A recent advantage in the high-throughput method called loop-seq makes it possible to determine bendability of hundred thousand 50-bp DNA duplexes in one experiment. However, it’s still infeasible to assess whole sequence bendability in large genomes such as human, which needs thousands of loop-seq experiments. Here we introduce ‘BendNet’ – a neural network to accurately predict the intrinsic DNA bending at base-resolution by only given DNA sequences. BendNet can increase the resolution of experimental results, and can predict DNA bendability for any new given sequences in high accuracy. We applied BendNet to the human genome and observed high-stiffness regions located at both transcriptional start sites and transcriptional end sites. Such stiffness patterns are different for coding and non-coding genes, which matches distinct nucleosome occupancy patterns. As expected, most transcription factors (TFs) bind in DNA of low bendability. In contrast, we observed an unusually high bendability within binding elements of specific TFs such as EBF1 and regulators of genome folding such as CTCF. These factors either co-bind or compete with nucleosomes to carry out their functions. More interestingly, CTCF binding regions exhibit the highest bendability than other DNA elements, implying their potential role in trapping and holding the CTCF in the exact locations to make sure CTCF as stable anchor in loop extrusion process. Our work provides a tool to assess DNA bendability for large-scale DNA sequences and expands our understanding on DNA mechanics in chromatin regulation and genome folding.
DGMP: Identifying Cancer Driver Genes by Jointing DGCN and MLP from Multi-Omics Genomic Data
Authors: Zhang Shao-Wu , Xu Jing-Yu , Zhang Tong
Published: February 2022

Identification of cancer driver genes plays an important role in precision oncology research, which is helpful to understand the cancer initiation and progression. However, most of existing computational methods mainly used the protein-protein interaction networks (PPIs), or treated the directed gene regulatory networks (GRNs) as the undirected gene-gene association networks to identify the cancer driver genes, which will lose the unique structure regulatory information in the directed GRNs, and then affect the outcome of the cancer driver genes identification. Here, based on the multi-omics pan-cancer data (i.e., gene expression, mutation, copy number variation and DNA methylation), we proposed a novel method (called DGMP) to identify cancer driver genes by jointing Directed Graph Convolution Network (DGCN) and Multilayer Perceptron (MLP). DGMP learns the multi-omics features of genes as well as the topological structure features in GRN with DGCN model, and uses MLP to weight more on gene features for mitigating the bias toward the graph topological features in DGCN learning process. The results on three gene regulation networks show that DGMP outperforms other existing state-of-the-art methods. It can not only identify highly mutated cancer driver genes but also the driver genes harboring other kinds of alterations (e.g., differential expression, aberrant DNA methylation) or genes involved in GRNs with other cancer genes. The source code of DGMP can be freely downloaded fromhttps://github.com/NWPU-903PR/DGMP.
Population structure and inbreeding in wild house mice (Mus musculus) at different geographic scales
Authors: Morgan Andrew P , Hughes Jonathan J , Didion John P , Jolley Wesley J , Campbell Karl J , Threadgill David W , Bonhomme Francois , Searle Jeremy B , de Villena Fernando Pardo-Manuel
Published: February 2022

House mice (Mus musculus) have spread globally as a result of their commensal relationship with humans. In the form of laboratory strains, both inbred and outbred, they are also among the most widely-used model organisms in biomedical research. Although the general outlines of house mouse dispersal and population structure are well known, details have been obscured by either limited sample size or small numbers of markers. Here we examine ancestry, population structure and inbreeding using SNP microarray genotypes in a cohort of 814 wild mice spanning five continents and all major subspecies of Mus, with a focus on M. m. domesticus. We find that the major axis of genetic variation in M. m. domesticus is a south-to-north gradient within Europe and the Mediterranean. The dominant ancestry component in North America, Australia, New Zealand and various small offshore islands is of northern European origin. Next we show that inbreeding is surprisingly pervasive and highly variable, even between nearby populations. By inspecting the length distribution of homozygous segments in individual genomes, we find that inbreeding in commensal populations is mostly due to consanguinity. Our results offer new insight into the natural history of an important model organism for medicine and evolutionary biology.
Call count surveys as a tool to monitor habitats occupied by Cheer Pheasants (Catreus wallichii) in Shimla, Himachal Pradesh
Authors: Tiwari Samakshi , Ranganathan Lakshminarasimha , Kumar Sanjeev , Sharma Rajesh
Published: February 2022

The vulnerable Cheer Pheasant (Catreus wallichii) is found in the western Himalayas. It prefers successional grasslands which are maintained by residents near villages. Therefore, it is prone to anthropogenic pressures which have led to local extinctions and a decline in population. We conducted five call count surveys at dusk and dawn from 15 April – 15 May 2020 in grasslands of Dharbhog panchayat, Shimla, Himachal Pradesh to assess presence of Cheer Pheasants in different habitat types. We used frequency of occurrence (number of encounters / number of visits) to determine presence or absence of Cheer Pheasant in an area of 10.5 km2 with ten established call count stations. We encountered Cheer Pheasants at six call count stations and the frequency of occurrence of the species ranged from 0 – 0.60. This survey provides an index of occupancy of the species and can be used to assess the change in habitat occupied by the species with time. The local forest department can also use these results to regulate over grazing and burning of grasslands during the breeding season in areas where we recorded the species.
Transkingdom mechanism of MAMP generation by chitotriosidase (CHIT1) feeds oligomeric chitin from fungal pathogens and allergens into TLR2-mediated innate immune sensing
Authors: Chang Tzu-Hsuan , Gloria Yamel Cardona , Hellmann Margareta J. , Greve Carsten Leo , Le Roy Didier , Roger Thierry , Bork Francesca , Bugl Stefanie , Jakob Johanna , Kasper Lydia , Hube Bernhard , Pusch Stefan , Gow Neil , Sørlie Morten , Tøndervik Anne , Moerschbacher Bruno M. , Weber Alexander N.R.
Published: February 2022

Chitin is a highly abundant polysaccharide in nature and linked to immune recognition of fungal infections and asthma in humans. Ubiquitous in fungi and insects, chitin is absent in mammals and plants and, thus, represents a microbe-associated molecular pattern (MAMP). However, the highly polymeric chitin is insoluble, which potentially hampers recognition by host immune sensors. In plants, secreted chitinases degrade polymeric chitin into diffusible oligomers, which are ‘fed to’ innate immune receptors and co-receptors. In human and murine immune cells, a similar enzymatic activity was shown for human chitotriosidase (CHIT1) and oligomeric chitin is sensed via an innate immune receptor, Toll-like receptor (TLR) 2. However, a complete system of generating MAMPs from chitin and feeding them into a specific receptor/co-receptor-aided sensing mechanism has remained unknown in mammals. Here, we show that the secreted chitinolytic host enzyme, CHIT1, converts inert polymeric chitin into diffusible oligomers that can be sensed by TLR1-TLR2 co-receptor/receptor heterodimers, a process promoted by the lipopolysaccharide binding protein (LBP) and CD14. Furthermore, we observed thatChit1is induced via the β-glucan receptor Dectin-1 upon direct contact of immortalized human macrophages to the fungal pathogenCandida albicans, whereas the defined fungal secreted aspartyl proteases, Sap2 and Sap6, fromC. albicanswere able to degrade CHIT1 in vitro. Our study shows the existence of an inducible system of MAMP generation in the human host that enables contact-independent immune activation by diffusible MAMP ligands with striking similarity to the plant kingdom. Moreover, this study highlights CHIT1 as a potential therapeutic target for TLR2-mediated inflammatory processes that are fueled by oligomeric chitin.
Development of a Novel Peptide Aptamer that Interacts with the eIF4E Capped-mRNA Binding Site using Peptide Epitope Linker Evolution (PELE)
Authors: Frosi Yuri , Ng Simon , Lin Yen-Chu , Jiang Shimin , Ramlan Siti Radhiah , Lama Dilraj , Verma Chandra S , Asial Ignacio , Brown Christopher J
Published: February 2022

Identifying new binding sites and poses that modify biological function are an important step towards drug discovery. We have identified a novel disulphide constrained peptide that interacts with the cap-binding site of eIF4E, an attractive therapeutic target that is commonly overexpressed in many cancers and plays a significant role in initiating a cancer specific protein synthesis program though binding the 5’cap (7’methyl-guanoisine) moiety found on mammalian mRNAs. The use of disulphide constrained peptides to explore intracellular biological targets is limited by their lack of cell permeability and the instability of the disulphide bond in the reducing environment of the cell, loss of which results in abrogation of binding. To overcome these challenges, the cap-binding site interaction motif was placed in a hypervariable loop on an VH domain, and then selections performed to select a molecule that could recapitulate the interaction of the peptide with the target of interest in a process termed Peptide Epitope Linker Evolution (PELE). A novel VH domain was identified that interacted with the eIF4E cap binding site with a nanomolar affinity and that could be intracellularly expressed in mammalian cells. Additionally, it was demonstrated to specifically modulate eIF4E function by decreasing cap-dependent translation and cyclin D1 expression, common effects of eIF4F complex disruption.
Babesia divergensegress from host cells is orchestrated by essential and druggable kinases and proteases
Authors: Elsworth Brendan , Keroack Caroline D. , Rezvani Yasaman , Tennessen Jacob A. , Sack Samantha A. , Paul Aditya S. , Moreira Cristina K. , Gubbels Marc-Jan , Zarringhalam Kourosh , Duraisingh Manoj T.
Published: February 2022

A unique aspect of apicomplexan biology is the requirement for egress from and invasion into host red blood cells (RBCs). The cellular mechanisms and molecular mediators of RBC egress and invasion remain poorly characterized inBabesiaspp., a group of parasites of veterinary importance and emerging cause of zoonotic disease. Through the use of video microscopy, transcriptomics, and chemical genetics we have implicated signaling, proteases and gliding motility in egress and/or invasion byBabesia divergens. We developed CRISPR/Cas9 and two inducible knockdown systems to perform a genetic screen of putative mediators of egress. We found that proteases ASP2 and ASP3 are required for invasion, and the latter is also required for egress. Strikingly, parasites continue to replicate intracellularly in the absence of the protein kinases, PKG or CDPK4, indicating that they are required for exit from the replication cycle and egress. These essential molecules present druggable targets forBabesia spp. All together we have established a molecular framework for the spread of infection through host RBCs, with egress ofB. divergensmore closely resemblingT. gondiithan the more evolutionarily relatedPlasmodiumspp.

Highlights

Egress inBabesia divergensrequires host cell lysis and parasite motility

Transcriptomics can be used to identify egress and invasion proteins

Knockdown of the proteases, ASP2 and ASP3, inhibit egress and invasion

Inhibition of PKG or CDPK4 signaling results in continued intracellular replication
Photo-Electrochemical Stimulation of Neurons with Organic Donor-Acceptor Heterojunctions
Authors: Savva Achilleas , Hama Adel , Herrera-López Gabriel , Gasparini Nicola , Migliaccio Ludovico , Kawan Malak , Steiner Nadia , McCulloch Iain , Baran Derya , Fiumelli Hubert , Magistretti Pierre , Głowacki Eric D. , Inal Sahika
Published: February 2022

Recent advancements in light-responsive materials enabled the development of devices to artificially activate tissue with light, and show great potential for use in different types of therapy. Photo-stimulation based on organic semiconductors has recently attracted interest due to their unique set of properties such as biocompatibility, better mechanical match with human tissue, and strong absorption of light in the visible spectrum. Here we show the development of solution processed organic heterojunctions that are able to control the activity of primary neurons in vitro with light. The p-type polymer semiconductor PDCBT and the n-type polymer semiconductor ITIC (also known as non-fullerene acceptor) are simply spin coated on glass substrates forming a bilayer p-n junction with high photo-sensitivity in aqueous electrolytes. Photo-electrochemical measurements reveal that high photo-voltage and photo-current is produced, as a result of a charge transfer between the polymers and oxygen in the electrolyte. The biocompatibility of the proposed materials is addressed with live/dead assays on both primary mouse cortical neurons and human cell lines that are cultured on their surface. We have found that light of low intensity (i.e. 40 mW/cm2) is absorbed, and converted into a cue that triggers action potential on primary cortical neurons directly cultured on glass/PDCBT/ITIC interfaces as proven by patch clamp measurements. The activation of neurons is most likely due to photochemical reactions at the polymer/electrolyte interface that result in hydrogen peroxide, which might lead to modulation of specific ion channels on neurons membrane. Photo-thermal effects are excluded with controlled patch clamp measurements on neurons cultured on plain glass and on photoresist thin films. The profound advantages of low intensity light stimulation, simplified fabrication, and wireless operation pave the way for the integration of these interfaces in multiplex bioelectronic devices for the development of novel light therapy concepts and powerful neuroscience research tools.
Modularity in temporal co-occurrence networks at a stopover site reveals strong co-migration fidelity in African-European migratory landbirds over time
Authors: Bellisario Bruno , Cardinale Massimiliano , Maggini Ivan , Fusani Leonida , Carere Claudio
Published: February 2022

Migratory species are changing the timing of departures from wintering areas and arrival to breeding sites (i.e., migration phenology), as response to climate change to exploit maximum food availability at higher latitudes and improve their fitness. Despite the impact of changing migration phenology on migratory connectivity at population and community level, the extent to which such individual and species-specific response affects associations among co-migrating species has been seldom explored. By applying temporal co-occurrence network models on 15 years of standardized bird ringing data at a spring stopover site, we show that African-European migratory landbirds tend to migrate in well-defined groups of species with high temporal overlap. Such ‘co-migration fidelity’ is significantly increasing over the years and higher in trans-Saharan than North-African migrants. Our findings suggest non-random patterns of associations in co-migrating species, possibly related to the existence of regulatory mechanisms associated with changing climate conditions and different uses of stopover sites by migrants, ultimately influencing the global migration economy of landbirds in the Palearctic-African migration system.
Inhibiting Runx1 protects heart function after myocardial infarction
Authors: Martin Tamara P , MacDonald Eilidh A , Bradley Ashley , Watson Holly , Saxena Priyanka , Rog-Zielinska Eva A. , Fisher Simon , Elbassioni Ali Ali Mohamed , Almuzaini Ohood , Booth Catriona , Campbell Morna , Herzyk Pawel , Blyth Karen , Nixon Colin , Zentilin Lorena , Berry Colin , Braun Thomas , Giacca Mauro , McBride Martin W , Nicklin Stuart A , Cameron Ewan R , Loughrey Christopher M
Published: February 2022

Myocardial infarction is a major cause of death worldwide. Effective treatments are required that limit adverse cardiac remodelling and preserve cardiac contractility following myocardial infarction, with the aim of improving patient outcomes and preventing progression to heart failure. The perfused but hypocontractile myocardium bordering a newly created infarct is functionally distinct from the remote surviving myocardium; it is also a major determinant of adverse cardiac remodelling and whole heart contractility. Expression of the transcription factor RUNX1 is increased in the border zone at 1 day after myocardial infarction, suggesting potential for targeted therapeutic intervention. Here we demonstrate that RUNX1 drives reductions in cardiomyocyte contractility, sarcoplasmic reticulum-mediated calcium release, mitochondrial density, and the expression of genes important for oxidative phosphorylation.

Antagonising RUNX1 expression via short-hairpin RNA interference preserved cardiac contractile function following myocardial infarction when delivered either via direct adenoviral delivery into the border zone or via an adeno-associated virus vector administered intravenously. Equivalent effects were obtained with a small molecule inhibitor (Ro5-3335) that reduces RUNX1 function by blocking its interaction with the essential co-factor CBFβ. Both tamoxifen-inducible Runx1-deficient and Cbfβ-deficient cardiomyocyte-specific mouse models demonstrated that antagonising RUNX1 function preserves the expression of genes important for oxidative phosphorylation following myocardial infarction. Our results confirm the translational potential of RUNX1 as a novel therapeutic target in myocardial infarction, with wider opportunities for use across a range of cardiac diseases where RUNX1 drives adverse cardiac remodelling.
Dense satellite data reveals landscape connectivity decline in the Andes-Amazon region
Authors: Murillo-Sandoval Paulo J. , Clerici Nicola , Correa-Ayram Camilo
Published: February 2022

There is a complex interplay of criminal groups’ control over land, illicit activities, and forest cover change in the Colombian Andes-Amazon region. This area is dealing with diverse forms of conflict andpeace,directly impacting landscape connectivity. While many studies have documented rapid deforestation after the peace agreement in 2016, we know little about the effect of these socio-political changes on the state of landscape connectivity. We disentanglehabitatfromconnected habitatin forest ecosystems using the Landsat archive and landscape connectivity indices. We find that in the Andes-Amazon region during 2000-2020,connected habitatloss reached 18%, whilehabitatloss was 13%. This result is worrisome, because it indicates that well-connected patches are more fragmented and isolated, affecting the natural connections between the Andes and Amazon biogeographical regions and the movement ability of species. The Colombian government should conduct a strategicpeacebuildingprocess incorporating structural changes that prevent the increase of large-scale extractive activities that are often illegal in the region. While finding a balance between extractive activities and conservation remains a big challenge, legal land tenure, census/taxation, and specific agreements with local actors can initially prevent deforestation. We discourage localized military actions and the return of aerial fumigation of coca fields, which rather than stop deforestation might exacerbate land cover change deeper into pristine forests.