bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeted cancer therapy induces APOBEC fuelling the evolution of drug resistance
Authors: Mayekar Manasi K. , Caswell Deborah R. , Vokes Natalie I. , Law Emily K. , Wu Wei , Hill William , Gronroos Eva , Rowan Andrew , Al Bakir Maise , McCoach Caroline E. , Blakely Collin M. , Temiz Nuri Alpay , Nagano Ai , Kerr D. Lucas , Rotow Julia K. , Haderk Franziska , Dietzen Michelle , Ruiz Carlos Martinez , Almeida Bruna , Cech Lauren , Gini Beatrice , Przewrocka Joanna , Moore Chris , Murillo Miguel , Bakker Bjorn , Rule Brandon , Durfee Cameron , Nanjo Shigeki , Tan Lisa , Larson Lindsay K. , Argyris Prokopios P. , Brown William L. , Yu Johnny , Gomez Carlos , Gui Philippe , Vogel Rachel I. , Yu Elizabeth A. , Thomas Nicholas J. , Venkatesan Subramanian , Hobor Sebastijan , Chew Su Kit , Kanu Nnennaya , McGranahan Nicholas , Van Allen Eliezer M. , Downward Julian , Harris Reuben S. , Bivona Trever G. , Swanton Charles 
Published: December 2020

Introductory paragraphThe clinical success of targeted cancer therapy is limited by drug resistance that renders cancers lethal in patients1-4. Human tumours can evolve therapy resistance by acquiringde novogenetic alterations and increased heterogeneity via mechanisms that remain incompletely understood1. Here, through parallel analysis of human clinical samples, tumour xenograft and cell line models and murine model systems, we uncover an unanticipated mechanism of therapy-induced adaptation that fuels the evolution of drug resistance. Targeted therapy directed against EGFR and ALK oncoproteins in lung cancer induced adaptations favoring apolipoprotein B mRNA-editing enzyme, catalytic polypeptide (APOBEC)-mediated genome mutagenesis. In human oncogenicEGFR-driven andALK-driven lung cancers and preclinical models, EGFR or ALK inhibitor treatment induced the expression and DNA mutagenic activity ofAPOBEC3Bvia therapy-mediated activation of NF-κB signaling. Moreover, targeted therapy also mediated downregulation of certain DNA repair enzymes such as UNG2, which normally counteracts APOBEC-catalyzed DNA deamination events. In mutantEGFR-driven lung cancer mouse models, APOBEC3B was detrimental to tumour initiation and yet advantageous to tumour progression during EGFR targeted therapy, consistent with TRACERx data demonstrating subclonal enrichment of APOBEC-mediated mutagenesis. This study reveals how cancers adapt and drive genetic diversity in response to targeted therapy and identifies APOBEC deaminases as future targets for eliciting more durable clinical benefit to targeted cancer therapy.
Functional idiosyncrasy has a shared topography with group-level connectivity alterations in autism
Authors: Benkarim Oualid , Paquola Casey , Park Bo-yong , Hong Seok-Jun , Royer Jessica , de Wael Reinder Vos , Lariviere Sara , Valk Sofie , Bzdok Danilo , Mottron Laurent , Bernhardt Boris 
Published: December 2020

ABSTRACTAutism spectrum disorder (ASD) is commonly understood as a network disorder, yet case-control analyses against typically-developing controls (TD) have yielded somewhat inconsistent patterns of results. The current work was centered on a novel approach to profile functional network idiosyncrasy, the inter-individual variability in the association between functional network organization and brain anatomy, and we tested the hypothesis that idiosyncrasy contributes to connectivity alterations in ASD. Studying functional network idiosyncrasy in a multi-centric dataset with 157 ASD and 172 TD, our approach revealed higher idiosyncrasy in ASD in the default mode, somatomotor and attention networks together with reduced idiosyncrasy in the lateral temporal lobe. Idiosyncrasy was found to increase with age in both ASD and TD, and was significantly correlated with symptom severity in the former group. Association analysis with structural and molecular brain features indicated that patterns of functional network idiosyncrasy were not correlated with ASD-related cortical thickness alterations, but closely with the spatial expression patterns of intracortical ASD risk genes. In line with our main hypothesis, we could demonstrate that idiosyncrasy indeed plays a strong role in the manifestation of connectivity alterations that are measurable with conventional case-control designs and may, thus, be a principal driver of inconsistency in the autism connectomics literature. These findings support important interactions between the heterogeneity of individuals with an autism diagnosis and group-level functional signatures, and help to consolidate prior research findings on the highly variable nature of the functional connectome in ASD. Our study promotes idiosyncrasy as a potential individualized diagnostic marker of atypical brain network development.
A phenotypic screen identifies a compound series that induces differentiation of acute myeloid leukemia cellsin vitroand shows anti-tumour effectsin vivo
Authors: Josa-Culleré Laia , Madden Katrina S. , Cogswell Thomas J. , Jackson Thomas R. , Carter Tom S. , Zhang Douzi , Trevitt Graham , Davies Stephen G. , Vyas Paresh , Wynne Graham M. , Milne Thomas A. , Russell Angela J. 
Published: December 2020

AbstractInduction of differentiation is a promising therapeutic strategy against acute myeloid leukemia. However, current differentiation therapies are effective only to specific patient populations. To identify novel differentiation agents with wider efficacy, we developed a phenotypic high-throughput screen with a range of genetically diverse cell lines. From the resulting hits, one chemical scaffold was optimised in terms of activity and physicochemical properties to yield OXS007417, which was also able to decrease tumour volume in a murine in vivo xenograft model.
WNT11 is a novel ligand for ROR2 in human breast cancer
Authors: Menck Kerstin , Heinrichs Saskia , Wlochowitz Darius , Sitte Maren , Noeding Helen , Janshoff Andreas , Treiber Hannes , Ruhwedel Torben , Schatlo Bawarjan , von der Brelie Christian , Wiemann Stefan , Pukrop Tobias , Beißbarth Tim , Binder Claudia , Bleckmann Annalen 
Published: December 2020

ABSTRACTBreast cancer has been associated with activation of the WNT signaling pathway, although the underlying molecular mechanisms are still unclear. Here, we found the WNT receptor ROR2 to be highly expressed in aggressive breast tumors and associated with worse metastasis-free survival. In order to understand the molecular basis of these observations, we overexpressed ROR2 in human breast cancer cell lines, inducing a BRCAness-like phenotype and rendering them resistant to PARP inhibition. High levels of ROR2 were associated with defects in cell morphology and cell-cell-contacts leading to increased tumor invasiveness. Using gene expression analysis we demonstrated an upregulation of several non-canonical WNT ligands in ROR2-overexpressing breast cancer cells, in particular WNT11. Co-immunoprecipitation confirmed that WNT11 is indeed a novel ligand for ROR2 that interacts with its cysteine-rich domain and triggers the invasion-promoting signaling via RHO/ROCK. Knockdown of WNT11 reversed the pro-invasive phenotype and the cellular changes in ROR2-overexpressing cells. Taken together, our studies revealed a novel auto-stimulatory loop in which ROR2 triggers the expression of its own ligand, WNT11, resulting in enhanced tumor invasion associated with breast cancer metastasis.
Previous motor actions outweigh sensory information in sensorimotor learning
Authors: Feulner Barbara , Postin Danilo , Schwiedrzik Caspar M. , Pooresmaeili Arezoo 
Published: December 2020

AbstractHumans can use their previous experience in form of statistical priors to improve decisions. It is however unclear how such priors are learned and represented. Importantly, it has remained elusive whether prior learning is independent of the sensorimotor system involved in the learning process or not, as both modality-specific and modality-general learning have been reported in the past. Here, we used a saccadic eye movement task to probe the learning and representation of a spatial prior across a few trials. In this task, learning occurs in an unsupervised manner and through encountering trial-by-trial visual hints drawn from a distribution centered on the target location. Using a model-comparison approach, we found that participants’ prior knowledge is largely represented in the form of their previous motor actions, with minimal influence from the previously seen visual hints. By using two different motor contexts for response (looking either at the estimated target location, or exactly opposite to it), we could further compare whether prior experience obtained in one motor context can be transferred to the other. Although learning curves were highly similar, and participants seemed to use the same strategy for both response types, they could not transfer their knowledge between contexts, as performance and confidence ratings dropped to naïve levels after a switch of the required response. Together, our results suggest that humans preferably use the internal representations of their previous motor actions, rather than past incoming sensory information, to form statistical sensorimotor priors on the timescale of a few trials.
Origin and evolution of the cannabinoid oxidocyclase gene family
Authors: van Velzen Robin , Schranz M. Eric 
Published: December 2020

AbstractCannabisis an ancient crop representing a rapidly increasing legal market, especially for medicinal purposes. Medicinal and psychoactive effects ofCannabisrely on specific terpenophenolic ligands named cannabinoids. Recent whole-genome sequencing efforts have uncovered variation in multiple genes encoding the final steps in cannabinoid biosynthesis. However, the origin, evolution, and phylogenetic relationships of these cannabinoid oxidocyclase genes remain unclear. To elucidate these aspects we performed comparative genomic analyses ofCannabis, related genera within the Cannabaceae family, and selected outgroup species. Results show that cannabinoid oxidocyclase genes originated in theCannabislineage from within a larger gene expansion in the Cannabaceae family. Localization and divergence of oxidocyclase genes in theCannabisgenome revealed two main syntenic blocks, each comprising tandemly repeated cannabinoid oxidocyclase genes. By comparing these blocks with those in genomes from closely related species we propose an evolutionary model for the origin, neofunctionalization, duplication, and diversification of cannabinoid oxidocycloase genes. Based on phylogenetic meta-analyses, we propose a comprehensive classification of three main clades and seven subclades that is intended to aid unequivocal referencing and identification of cannabinoid oxidocyclase genes. Our data suggest that cannabinoid oxidocyclase gene copy number variation may have less functional relevance than previously thought. Instead, we propose that cannabinoid phenotype is primarily determined by presence/absence of single-copy genes. Increased sampling acrossCannabis’native geographic range is likely to uncover additional cannabinoid oxidocyclase gene sequence variation.Significance statementCannabisgenome sequencing efforts have revealed extensive cannabinoid oxidocyclase gene variation. However, phylogenetic relationships and evolution of these genes remains unclear. Our meta analysis of currently available data reveals that these genes comprise three main clades and seven subclades that originated throughCannabis-specific gene duplication and divergence. Our new conceptual and evolutionary framework serves as a reference for future description and functional analyses of cannabinoid oxidocyclases.
Leveraging selective hippocampal vulnerability among Alzheimer’s disease subtypes reveals a novel tau binding partner SERPINA5
Authors: Crist Angela M. , Hinkle Kelly M. , Wang Xue , Moloney Christina M. , Matchett Billie J. , Labuzan Sydney A. , Frankenhauser Isabelle , Azu Nkem O. , Liesinger Amanda M. , Lesser Elizabeth R. , Serie Daniel J. , Quicksall Zachary S. , Patel Tulsi A. , Carnwath Troy P. , DeTure Michael , Tang Xiaojia , Petersen Ronald C. , Duara Ranjan , Graff-Radford Neill R. , Allen Mariet , Carrasquillo Minerva M. , Li Hu , Ross Owen A. , Ertekin-Taner Nilufer , Dickson Dennis W. , Asmann Yan W. , Carter Rickey E. , Murray Melissa E. 
Published: December 2020

SummarySelective vulnerability is a central concept to the myriad of devastating neurodegenerative disorders. Although hippocampus and cortex are selectively vulnerable in Alzheimer’s disease (AD), the degree of involvement lies along a spectrum that we previously defined as AD subtypes revealing distinct clinical correlates. To operationalize heterogeneity of disease spectrum, we classified corticolimbic patterns of neurofibrillary tangles to capture extreme and representative phenotypes. We combined bulk RNA sequencing with digital pathology to examine hippocampal vulnerability in AD. Using a multidisciplinary approach, we uncovered disease-relevant hippocampal gene expression changes. Biological relevance was prioritized using machine learning and several levels of human validation. This resulted in five genes highly predictive of neuropathologically diagnosed AD:SERPINA5, RYBP, SLC38A2, FEM1B, andPYDC1. Deeper investigation revealed SERPINA5 to be a novel tau binding partner that may represent a “tipping point” in the dynamic maturity of neurofibrillary tangles. Our study highlights the importance of embracing heterogeneity of the human brain to yield promising gene candidates as exampled bySERPINA5.
Sensitive detection of DNA contamination in tumor samples via microhaplotypes
Authors: Whitty Brett , Thompson John F. 
Published: December 2020

AbstractLow levels of sample contamination with other human DNAs can have disastrous effects on the accurate identification of somatic variation in tumor samples. Detection of sample contamination in DNA is often based on low frequency variants that indicate if more than a single source of DNA is present. This strategy works with standard DNA samples but can be problematic in solid tumor FFPE samples because there are often huge variations in allele frequency (AF) due to copy number changes arising from gains and losses across the genome. The variable AFs make detection of contamination challenging. To avoid this, we counted microhaplotypes to assess sample contamination. Microhaplotypes are sets of variants on the same sequencing read that can be unambiguously phased. Instead of measuring AF, the number of microhaplotypes is determined. Contamination detection becomes based on fundamental genomic properties, linkage disequilibrium (LD) and the diploid nature of human DNA, rather than variant frequencies. We optimized microhaplotype panel content and selected 164 SNV sets located in regions already being sequenced within a cancer panel. Thus, contamination detection uses existing sequence data. LD data from the 1000 Genomes Project is used to make the panel ancestry agnostic, providing the same sensitivity for contamination detection with samples from individuals of African, East Asian, and European ancestry. Detection of 1% contamination with no matching normal sample is possible. The methods described here can also be extended to other DNA mixtures such as forensic and non-invasive prenatal testing samples where DNA mixes can be similarly detected. The microhaplotype method allows sensitive detection of DNA contamination in FFPE tumor and other samples when deep coverage with Illumina or other high accuracy NGS is used.
A versatile toolkit for molecular QTL mapping and meta-analysis at scale
Authors: Quick Corbin , Guan Li , Li Zilin , Li Xihao , Dey Rounak , Liu Yaowu , Scott Laura , Lin Xihong 
Published: December 2020

AbstractMolecular QTLs (xQTLs) are widely studied to identify functional variation and possible mechanisms underlying genetic associations with diseases. Larger xQTL sample sizes are critical to help identify causal variants, improve predictive models, and increase power to detect rare associations. This will require scalable and accurate methods for analysis of tens of thousands of molecular traits in large cohorts, and/or from summary statistics in meta-analysis, both of which are currently lacking. We developed APEX (All-in-one Package for Efficient Xqtl analysis), an efficient toolkit for xQTL mapping and meta-analysis that provides (a) highly optimized linear mixed models to account for relatedness and shared variation across molecular traits; (b) rapid factor analysis to infer latent technical and biological variables from molecular trait data; (c) fast and accurate trait-level omnibus tests that incorporate prior functional weights to increase statistical power; and (d) compact summary data files for flexible and accurate joint analysis of multiple variants (e.g., joint/conditional regression or Bayesian finemapping) without individual-level data in meta-analysis. We applied the methods to data from three LCL eQTL studies and the UK Biobank. APEX is open source:https://corbinq.github.io/apex.
Paternal leakage of organelles can improve adaptation to changing environments
Authors: Radzvilavicius Arunas , Johnston Iain G. 
Published: December 2020

AbstractSexual eukaryotes have diverse mechanisms preventing the biparental inheritance of mitochondria and plastids, and reducing the coexistence of dissimilar organelle DNA (heteroplasmy). Nevertheless, paternal leakage often occurs in plants, fungi, protists and animals, and this leaves the possibility that heteroplasmy can in some contexts be advantageous. Theoretical models developed in the past revealed that maternal inheritance improves selection against deleterious mitochondrial mutations, but none of them have explained the observed variation in the extent of paternal leakage. Here we show that paternal leakage regulated by nuclear loci can evolve to maintain advantageous organelle diversity in fluctuating environments. Strict maternal inheritance reduces organelle variance within the cell, but this loss of diversity can be detrimental when environments are shifting rapidly. Our model reveals that high levels of paternal leakage can evolve in these types of rapidly changing environments and that strict maternal inheritance evolves only when the environment is changing slowly.DataMatlab/Octave implementation of the model is available atHttps://github.com/StochasticBiology/PaternalLeakageEvolution.
Apoptosis is a generator of Wnt-dependent regeneration and homeostatic cell renewal in the ascidianCiona
Authors: Jeffery William R. , Goricki Spela 
Published: December 2020

AbstractBody regeneration is unilateral in the ascidianCiona intestinalis: severed basal body parts can regenerate distal structures, such as the siphons and neural complex, but severed distal body parts do not replace basal structures. Regeneration involves the activity of adult stem cells in vasculature of the branchial sac, which are induced to proliferate and produce migratory progenitor cells for the replacement of missing tissues and organs. Branchial sac-derived stem cells also replenish continuously recycling cells lining the pharyngeal fissures during homeostatic growth. Apoptosis at injury sites is an early and transient event of regeneration and occurs continuously in the pharyngeal fissures during homeostatic growth. Treatment of amputated animals with caspase 1 inhibitor, caspase 3 inhibitor, or the pan-caspase inhibitor Z-VAD-FMK blocked apoptosis, prevented regeneration, and suppressed the growth and function of the branchial sac. A pharmacological screen and inhibitory siRNA treatments indicated that regeneration and homeostatic growth require canonical Wnt signaling. Furthermore, exogenously supplied recombinant Wnt3a protein rescued both caspase-blocked regeneration and normal branchial sac growth. As determined by EdU pulse-chase studies, inhibition of apoptosis did not affect branchial sac stem cell proliferation but instead prevented the survival of progenitor cells. After bisection across the mid-body, apoptosis at the injury site occurred in the regenerating basal fragments, but not in the non-regenerating distal fragments, although both fragments contain a large portion of the branchial sac, suggesting that apoptosis is unilateral at the wound site and the presence of branchial sac stem cells is insufficient for regeneration. The results show that apoptosis-dependent Wnt signaling mediates regeneration and homeostatic growth by promoting progenitor cell survival inCiona.
Task specificity in mouse parietal cortex
Authors: Lee Julie J , Krumin Michael , Harris Kenneth D , Carandini Matteo 
Published: December 2020

SummaryParietal cortex is implicated in a variety of behavioral processes, but it is unknown whether and how individual neurons participate in multiple tasks. We trained head-fixed mice to perform two visual decision tasks involving a steering wheel or a virtual T-maze, and recorded from the same parietal neurons during the two. Neurons that were active during the T-maze task were typically inactive during the steering-wheel task, and vice versa. Recording from the same neurons in the same apparatus without task stimuli yielded the same specificity as in the task, suggesting that task specificity depends on physical context. To confirm this, we trained some mice in a third task combining the steering wheel with the visual environment of the T-maze. This hybrid task engaged the same neurons as the steering-wheel task. Thus, participation by neurons in mouse parietal cortex is task-specific, and this specificity is determined by physical context.
A robust and automated algorithm that uses single-channel spike sorting to label multi-channel Neuropixels data
Authors: Zhang Zheng , Constandinou Timothy G. 
Published: December 2020

AbstractThis paper describes preliminary work towards an automated algorithm for labelling Neuropixel data that exploits the fact that adjacent recording sites are spatially oversampled. This is achieved by combining classical single channel spike sorting with spatial spike grouping, resulting in an improvement in both accuracy and robustness. This is additionally complemented by an automated method for channel selection that determines which channels contain high quality data. The algorithm has been applied to a freely accessible dataset, produced by Cortex Lab, UCL. This has been evaluated to have a accuracy of over 77% compared to a manually curated ground truth.
The molecular framework of heterophylly inCallitriche palustrisL. differs from that in other amphibious plants
Authors: Koga Hiroyuki , Kojima Mikiko , Takebayashi Yumiko , Sakakibara Hitoshi , Tsukaya Hirokazu 
Published: December 2020

AbstractHeterophylly refers to the development of different leaf forms in a single plant depending on the environmental conditions. It is often observed in amphibious aquatic plants that can grow under aerial and submerged conditions. Although heterophylly is well recognized in aquatic plants, the associated developmental mechanisms and the molecular basis remain unclear. In this study, we analyzed heterophyllous leaf formation in an aquatic plant,Callitriche palustris, to clarify the underlying developmental and molecular mechanisms. Morphological analyses revealed extensive cell elongation and the rearrangement of cortical microtubules in the elongated submerged leaves ofC. palustris. Our observations also suggested that gibberellin, ethylene, and abscisic acid regulate the formation of submerged leaves. However, the perturbation of one or more of the hormones was insufficient to induce the formation of submerged leaves under aerial conditions. Finally, we analyzed gene expression changes during aerial and submerged leaf development and narrowed down the candidate genes controlling heterophylly via transcriptomic comparisons, including a comparison with a closely related terrestrial species. We revealed that the molecular mechanism regulating heterophylly inC.palustrisis associated with hormonal changes and diverse transcription factor gene expression profiles, suggesting differences from the corresponding mechanisms in previously investigated amphibious plants.