bluuebunny/crossref_metadata_2025_split huggingface dataset:
Unscheduled origin building in S-phase upon tight CDK1 inhibition suppresses CFS instability
Authors: Brison Olivier , Gnan Stefano , Azar Dana , Schmidt Mélanie , Koundrioukoff Stéphane , El-Hilali Sami , Jaszczyszyn Yan , Lachages Anne-Marie , Thermes Claude , Chen Chun-Long , Debatisse Michelle 
Published: November 2020

SummaryGenome integrity requires replication to be completed before chromosome segregation. This coordination essentially relies on replication-dependent activation of a dedicated checkpoint that inhibits CDK1, delaying mitotic onset. Under-replication of Common Fragile Sites (CFSs) however escapes surveillance, which triggers chromosome breakage. Using human cells, we asked here whether such leakage results from insufficient CDK1 inhibition under modest stresses used to destabilize CFSs. We found that tight CDK1 inhibition suppresses CFS instability. Repli-Seq and molecular combing analyses consistently showed a burst of replication initiations in mid S phase across large origin-poor domains shaped by transcription, including CFSs. Strikingly, CDC6 or CDT1 depletion or CDC7-DBF4 inhibition during the S phase prevented both extra-initiations and CFS rescue, showing that CDK1 inhibition promotes targeted and mistimed building of functional extra-origins. In addition to delay mitotic onset, checkpoint activation therefore advances replication completion of chromosome domains at risk of under-replication, two complementary roles preserving genome stability.
Mechanistic modeling suggests that low-intensity focused ultrasound can selectively recruit myelinated or unmyelinated nerve fibers
Authors: Lemaire Théo , Vicari Elena , Neufeld Esra , Kuster Niels , Micera Silvestro 
Published: November 2020

AbstractLow-Intensity Focused Ultrasound Stimulation (LIFUS) holds promise for the remote modulation of neuronal activity, but an incomplete mechanistic characterization hinders its clinical maturation. Here, we developed a computational framework to model intramembrane cavitation in multi-compartmental, morphologically-realistic neuronal representations, and used it to investigate ultrasound neuromodulation of peripheral nerves by spatially-varying pressure fields. Our findings show that LIFUS offers distinct parametric sub-spaces to selectively recruit myelinated or unmyelinated axons and modulate their spiking activity over physiologically relevant regimes and within safe exposure limits. This singular feature, explained by fiber-specific differences in membrane electromechanical coupling, consistently explains recent empirical findings and suggests that LIFUS can preferentially target nociceptive and sensory fibers to enable peripheral therapeutic applications not addressable by electric stimulation. These results open up new opportunities for the development of more selective and effective peripheral neuroprostheses. Our framework can be readily applied to other neural targets to establish application-specific LIFUS protocols.
Adipose Triglyceride Lipase protects the endocytosis of renal cells on a high fat diet inDrosophila
Authors: Lubojemska Aleksandra , Stefana M. Irina , Lampe Lena , Yoshimura Azumi , Burrell Alana , Collinson Lucy , Gould Alex P. 
Published: November 2020

AbstractObesity-related renal lipotoxicity and chronic kidney disease (CKD) are prevalent pathologies with complex aetiologies. One hallmark of renal lipotoxicity is the ectopic accumulation of lipid droplets in kidney podocytes and in proximal tubule cells. Renal lipid droplets are observed in human CKD patients and in high-fat diet rodent models but their precise role remains unclear. Here, we establish a high-fat diet model inDrosophilathat recapitulates renal lipid droplets and several other aspects of mammalian CKD. Cell-type specific genetic manipulations show that lipid can overflow from adipose tissue and is taken up by renal cells called nephrocytes. A high-fat diet drives nephrocyte lipid uptake via the multiligand receptor Cubilin, leading to the ectopic accumulation of lipid droplets. These nephrocyte lipid droplets correlate with ER and mitochondrial deficits, as well as with impaired macromolecular endocytosis, a key conserved function of renal cells. Nephrocyte knockdown of diglyceride acyltransferase 1 (DGAT1), overexpression of adipose triglyceride lipase (ATGL) and epistasis tests together reveal that fatty acid flux through the lipid droplet triglyceride compartment protects the ER, mitochondria and endocytosis of renal cells. Strikingly, boosting nephrocyte expression of the lipid droplet resident enzyme ATGL is sufficient to rescue high-fat diet induced defects in renal endocytosis. Moreover, endocytic rescue requires a conserved mitochondrial regulator, peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC1α). This study demonstrates that lipid droplet lipolysis counteracts the harmful effects of a high-fat diet via a mitochondrial pathway that protects renal endocytosis. It also provides a genetic strategy for determining whether lipid droplets in different biological contexts function primarily to release beneficial or to sequester toxic lipids.
EcDNA hubs drive cooperative intermolecular oncogene expression
Authors: Hung King L. , Yost Kathryn E. , Xie Liangqi , Wu Sihan , Lange Joshua T. , Duffy Connor V. , Kraft Katerina , Tang Jun , Shi Quanming , Rose John C. , Corces M. Ryan , Granja Jeffrey M. , Li Rui , Rajkumar Utkrisht , Tjian Robert , Bafna Vineet , Mischel Paul S. , Liu Zhe , Chang Howard Y. 
Published: November 2020

ABSTRACTExtrachromosomal DNAs (ecDNAs) are prevalent in human cancers and mediate high oncogene expression through elevated copy number and altered gene regulation1. Gene expression typically involves distal enhancer DNA elements that contact and activate genes on the same chromosome2,3. Here we show that ecDNA hubs, comprised of ~10-100 ecDNAs clustered in the nucleus of interphase cells, drive intermolecular enhancer input for amplified oncogene expression. Single-molecule sequencing, single-cell multiome, and 3D enhancer connectome reveal subspecies ofMYC-PVT1ecDNAs lacking enhancers that access intermolecular and ectopic enhancer-promoter interactions in ecDNA hubs. ecDNA hubs persist without transcription and are tethered by BET protein BRD4. BET inhibitor JQ1 disperses ecDNA hubs, preferentially inhibits ecDNA oncogene transcription, and kills ecDNA+ cancer cells. Two amplified oncogenesMYCandFGFR2intermix in ecDNA hubs, engage in intermolecular enhancer-promoter interactions, and transcription is uniformly sensitive to JQ1. Thus, ecDNA hubs are nuclear bodies of many ecDNAs tethered by proteins and platforms for cooperative transcription, leveraging the power of oncogene diversification and combinatorial DNA interactions. We suggest ecDNA hubs, rather than individual ecDNAs, as units of oncogene function, cooperative evolution, and new targets for cancer therapy.
piNET: An Automated Proliferation Index Calculator Framework for Ki67 Breast Cancer Images
Authors: Geread Rokshana Stephny , Sivanandarajah Abishika , Brouwer Emily , Wood Geoffrey A. , Androutsos Dimitrios , Faragalla Hala , Khademi April 
Published: November 2020

AbstractIn this work, a novel proliferation index (PI) calculator for Ki67 images called piNET is proposed. It is successfully tested on four datasets, from three scanners comprised of patches, tissue microarrays (TMAs) and wholeslide images (WSI), representing a diverse multicentre dataset for evaluating Ki67 quantification. Compared to state-of-the-art methods, piNET consistently performs the best over all datasets with an average PI difference of 5.603%, PI accuracy rate of 86% and correlation coefficient R = 0.927. The success of the system can be attributed to a number of innovations. Firstly, this tool is built based on deep learning, which can adapt to wide variability of medical images – and it was posed as a detection problem to mimic pathologists’ workflow which improves accuracy and efficiency. Secondly, the system is trained purely on tumour cells, which reduces false positives from non-tumour cells without needing the usual pre-requisite tumour segmentation step for Ki67 quantification. Thirdly, the concept of learning background regions through weak supervision is introduced, by providing the system with ideal and non-ideal (artifact) patches that further reduces false positives. Lastly, a novel hotspot analysis is proposed to allow automated methods to score patches from WSI that contain “significant” activity.
Intra-individual variability in task performance after cognitive training is associated with long-term outcomes in children
Authors: Cubillo A , Hermes H , Berger E , Winkel K , Schunk D , Fehr E , Hare T. A. 
Published: November 2020

AbstractThe benefits and mechanistic effects of working memory training in children are the subject of much research and debate. The cumulative evidence indicates that training can alter brain structure and function in the short term and have lasting effects on behaviour. We show that five weeks of working memory training led to greater activity in prefrontal and striatal brain regions, better accuracy, and reduced intra-individual variability in response times. The reduction in intra-individual variability can be explained by changes to the evidence accumulation rates and thresholds in a sequential sampling decision model. Critically, intra-individual variability was more closely associated with academic skills and mental health 6-12 months after the end of training than task accuracy. These results indicate that intra-individual variability may be a useful way to quantify the immediate impact of cognitive training interventions and predict the future emergence of academic and socioemotional skills.
CD28 costimulatory domain protects against tonic signaling-induced functional impairment in CAR-Tregs
Authors: Lamarthée Baptiste , Marchal Armance , Charbonnier Soëli , Blein Tifanie , Martin Emmanuel , Vogt Katrin , Titeux Matthias , Delville Marianne , Vinçon Hélène , Six Emmanuelle , Pallet Nicolas , Anglicheau Dany , Legendre Christophe , Taupin Jean-Luc , Sawitzki Birgit , Latour Sylvain , Cavazzana Marina , André Isabelle , Zuber Julien 
Published: November 2020

ABSTRACTThe use of chimeric antigen receptor (CAR)-engineered regulatory T cells (Tregs) has emerged as a promising strategy to promote immune tolerance in transplantation. However, in conventional T cells (Tconvs), CAR expression is often associated with tonic signaling resulting from ligand-independent baseline activation. Tonic signaling may cause CAR-T cell dysfunction, especially when the CAR structure incorporates the CD28 costimulatory domain (CSD) rather than the 4-1BB CSD.Here, we explored the impact of tonic signaling on human CAR-Tregs according to the type of CSD. Compared to CD28-CAR-Tregs, 4-1BB-CAR-Tregs showed enhanced proliferation and greater activation of MAP kinase and mTOR pathways but exhibited decreased lineage stability and reduced abilities to produce IL-10 and be restimulated through the CAR. Although both CAR-Treg populations were suppressivein vivo,cell tracking with bioluminescence imaging found longer persistence for CD28-CAR-Tregs than for 4-1BB-CAR-Tregs. This study demonstrates that CD28-CAR best preserves Treg function and survival in the context of tonic signaling, in contrast with previous findings for Tconvs.SUMMARYLamarthée et al investigated the impact of chimeric antigen receptor (CAR) tonic signaling on CAR-engineered Tregs according to the incorporated costimulatory domain (either CD28 or 4-1BB). CD28 ameliorated Treg stability, long-term survival and function compared to 4-1BB.
Frontoparietal pattern similarity analyses of cognitive control in monozygotic twins
Authors: Tang Rongxiang , Etzel Joset A. , Kizhner Alexander , Braver Todd S. 
Published: November 2020

AbstractThe ability to flexibly adapt thoughts and actions in a goal-directed manner appears to rely on cognitive control mechanisms that are strongly impacted by individual differences. A powerful research strategy for investigating the nature of individual variation is to study monozygotic (identical) twins. Evidence of twin effects have been observed in prior behavioral and neuroimaging studies, yet within the domain of cognitive control, it remains to be demonstrated that the neural underpinnings of such effects are specific and reliable. Here, we utilize a multi-task, within-subjects event-related neuroimaging design with functional magnetic resonance imaging to investigate twin effects through multivariate pattern similarity analyses. We focus on fronto-parietal brain regions exhibiting consistently increased activation associated with cognitive control demands across four task domains: selective attention, context processing, multi-tasking, and working memory. Healthy young adult monozygotic twin pairs exhibited increased similarity of within- and cross-task activation patterns in these fronto-parietal regions, relative to unrelated pairs. Twin activation pattern similarity effects were clearest under high control demands, were not present in a set of task-unrelated parcels or due to anatomic similarity, and were primarily observed during the within-trial timepoints in which the control demands peaked. Together, these results indicate that twin similarity in the neural representation of cognitive control may be domain-general but also functionally and temporally specific in relation to the level of control demand. The findings suggest a genetic and/or environmental basis for individual variation in cognitive control function, and highlight the potential of twin-based neuroimaging designs for exploring heritability questions within this domain.
Peroxisome import stress impairs ribosome biogenesis and induces integrative stress response through eIF2α phosphorylation
Authors: Huang Kerui , Kim Jinoh , Vo Pham , Miao Ting , Bai Hua 
Published: November 2020

AbstractPeroxisome biogenesis diseases (PBDs) are characterized by global defects in peroxisomal function and can result in severe brain, liver, kidney, and bone malfunctions. PBDs are due to mutations in peroxisome biogenesis factors (PEX genes) that are responsible for peroxisome assembly and function. Increasing evidence suggests that peroxisome import functions decline during aging. However, the transcriptome profiling of peroxisome import defects and how they affect disease development are still lacking.PEX5encodes the cytoplasmic receptors for peroxisome-targeting signal types 1. We generate knock-in human HEK293 cells mutant using CRISPR to transiently expressPEX5cysteine 11 to alanine mutant (PEX5C11A), which blocks PEX5 recycling and exerts dominant negative effect onPEX5mediated peroxisome import. To identify conserved responses, we perform transcriptomic analysis onDrosophilaoenocyte-specific Pex1, Pex12 and Pex5 knockdowns and on human cells with impaired peroxisome import (PEX5C11Aand PEX5 siRNA respectively). PEX5C11Ainduction triggers vast transcriptomic changes, including decreased oxidative phosphorylation, increased MAPK signaling and HIPPO signaling. PEX5 siRNA specifically decreases spliceosome activity and increases cholesterol metabolism. Using gene set enrichment analysis (GSEA), we identify protein processing in endoplasmic reticulum pathway, specifically ER-associated protein degradation (ERAD) pathway is induced in all PEX knockdowns inDrosophila. Peroxisome dysfunction elevates eIF2α phosphorylation in bothDrosophilaand human cell culture independent ofXBP1activation, suggesting increased integrative stress response (ISR). Moreover, peroxisome stress decreases ribosome biogenesis genes and impairs ribosome biogenesis in flies and human cells. Specifically, peroxisome stress impairs the 5’-ETS cleavage activity during the ribosome biogenesis and dampens 40S small ribosomal export in both flies and human. Our results suggest that reduced ribosome biogenesis and elevated ISR could be conserved cellular response to peroxisome import stress.
Disentangling genetic feature selection and aggregation in transcriptome-wide association studies
Authors: Cao Chen , Kwok Devin , Li Qing , He Jingni , Guo Xingyi , Zhang Qingrun , Long Quan 
Published: November 2020

ABSTRACTThe success of transcriptome-wide association studies (TWAS) has led to substantial research towards improving its core component of genetically regulated expression (GReX). GReX links expression information with phenotype by serving as both the outcome of genotype-based expression models and the predictor for downstream association testing. In this work, we demonstrate that current linear models of GReX inadvertently combine two separable steps of machine learning - feature selection and aggregation - which can be independently replaced to improve overall power. We show that the monolithic approach of GReX limits the adaptability of TWAS methodology and practice, especially given low expression heritability.
Supporting Student Learning and Experiences in the Lab: (How) Should We Design Their Groups?
Authors: Tan Tanya Y. , Barker Megan K. 
Published: November 2020

AbstractUndergraduate science students spend a substantial amount of time working in their laboratory groups, and instructors want to make evidence-based decisions on how to best set up these groups. Despite several studies on group composition, the evidence appears to be quite context-specific, and very little has been published about lab groups. Further, many studies focus solely on conceptual learning; however, the lab is an important venue for also supporting non-content outcomes such as confidence, process skills, team skills, and attitudes. Thus, in our introductory course on molecules, cells, and physiology we were interested in the impact of group composition, on a spread of student outcomes. Students were either placed into groups by the instructor, or self-selected into groups. To assess the impact of group composition on student outcome, we collected pre/post data from >500 students over 2 semesters. Our measures assess conceptual knowledge, confidence in lab skills, attitudes toward group learning, lab grades, gender, year of study, and (via open-ended questions) student perspectives. Using a multiple regression approach, we established models that predict student outcomes based on their individual attributes and on their lab group attributes. Surprisingly, the hetero/homogeneity of the initial group, and whether the groups were student- or instructor-selected, did not affect student outcomes in these models. Further MANCOVA analysis demonstrated that student interaction outside of the lab time was the strongest predictor of positive student attitudes toward group learning. Student perspectives on group formation are mixed, and suggest that a simple and flexible choice approach may best support our students. Overall, these findings have clear implications for our course design and instructional choices: we should focus our efforts to promote positive student interactions, rather than worrying about initial composition.
An Adhesive-Based Fabrication Technique for Culture of Lung Airway Epithelial Cells with Applications in Microfluidics and Lung-on-a-Chip
Authors: Tiessen Nicholas , Dabaghi Mohammadhossein , Cao Quynh , Chandiramohan Abiram , Selvaganapathy P. Ravi , Hirota Jeremy A. 
Published: November 2020

1AbstractThis work describes a versatile and cost-effective cell culture method for growing adherent cells on a porous membrane using pressure-sensitive double-sided adhesives. This technique allows cell culture using conventional methods and easy transfer to microfluidic chip devices. To support the viability of our system, we evaluate the toxicity effect of four different adhesives on two distinct airway epithelial cell lines and show functional applications for microfluidic cell culture chip fabrication. We showed that cells could be grown and expanded on a “floating” membrane, which can be transferred upon cell confluency to a microfluidic chip for further analysis. The viability of cells and their inflammatory responses to IL-1β stimulation was investigated. Such a technique would be useful to culture cells in a conventional fashion, which is more convenient and faster, and stimulate cells in an advanced model with perfusion when needed.
Impact of Chrysin on Vitamin D and Bone Health - Preclinical Studies
Authors: Kasarla Siva Swapna , Dodoala Sujatha , Sampathi Sunitha , Talluri Narendra Kumar 
Published: November 2020

AbstractVitamin D deficiency is an endemic problem existing worldwide. Although several strategies were established to enhance vitamin D3levels, studies specifically focussing inhibition of vitamin D metabolism which may prolong the availability of active vitamin D in pathological conditions are less explored. Studies also suggest that higher doses of vitamin D3fail to achieve optimum vitamin D levels. In this context, we focussed on the enzyme CYP3A4 which promotes inactivation of active vitamin D. The current study was aimed to decipher the impact of chrysin, a proven CYP3A4 inhibitor as an intervention and its effects in combination with low dose vitamin D3(40 IU) and bone health in vitamin D deficiency condition. Thein-vivoactivity of chrysin was evaluated on female Wistar albino rats fed with a vitamin D deficient diet to attain vitamin D deficiency for 28 days. Chrysin was given alone and in combination with calcium carbonate (CaCO3) and/or vitamin D3. All the therapeutic interventions were assessed for serum 25-OH-D3 by LC-MS, biochemical, urinary, and bone parameters. Animals treated with chrysin alone and in combination with low dose vitamin D3and/or CaCO3showed an eminent rise in serum 25-OH-D3 levels along with increased serum biochemical parameters. On contrary, a significant decrease in the urinary parameters followed by beneficial effects on bone parameters was noticed in contrast with the vitamin D deficient diet group. Our findings revealed that although chrysin alone showed a notable effect on 25-OH-D3 and osseous tissue, comparatively it showed intensified therapeutic effect in combination with vitamin D3and CaCO3which can be employed as a cost-effective option to improve bone health.Graphical Abstract