bluuebunny/crossref_metadata_2025_split huggingface dataset:
Conserved cell-lineage controlled epigenetic regulation in human and mouse glioblastoma stem cells determines functionally distinct subgroups
Authors: Lu Xi , Maturi Naga Prathyusha , Jarvius Malin , Zhao Linxuan , Xie Yuan , Tan E-Jean , Xing Pengwei , Fryknäs Mårten , Uhrbom Lene , Chen Xingqi 
Published: February 2021

AbstractThere is ample support for developmental regulation of glioblastoma stem cells (GSCs). To examine how cell lineage controls GSC function we have performed a cross-species epigenome analysis of mouse and human GSC cultures. We have analyzed and compared the chromatin-accessibility landscape of nine mouse GSC cultures of defined cell of origin and 60 patient-derived GSC cultures by assay for transposase-accessible chromatin using sequencing (ATAC-seq). This uncovered a variability of both mouse and human GSC cultures that was different from transcriptome analysis and better at predicting functional subgroups. In both species the chromatin accessibility-guided clusters were predominantly determined by distal regulatory element (DRE) regions, displayed contrasting sets of transcription factor binding motifs, and exhibited different functional and drug-response properties. Cross-species analysis of DRE regions in accessible chromatin revealed conserved epigenetic regulation of mouse and human GSCs. Human ATAC-seq data produced three distinct clusters with significant overlap to our previous mouse cell of origin- based stratification, where two of the clusters displayed significantly different patient survival. We conclude that epigenetic regulation of GSCs primarily is dictated by developmental origin which controls key GSC properties and affects therapeutic response.
Previously uncharacterized interactions between the folded and intrinsically disordered domains impart asymmetric effects on UBQLN2 phase separation
Authors: Zheng Tongyin , Castañeda Carlos A. 
Published: February 2021

AbstractShuttle protein UBQLN2 functions in protein quality control (PQC) by binding to proteasomal receptors and ubiquitinated substrates via its N-terminal ubiquitin-like (UBL) and C-terminal ubiquitin-associated (UBA) domains, respectively. Between these two folded domains are intrinsically disordered STI1-I and STI1-II regions, connected by disordered linkers. The STI1 regions bind other components, such as HSP70, that are important to the PQC functions of UBQLN2. We recently determined that the STI1-II region enables UBQLN2 to undergo liquid-liquid phase separation (LLPS) to form liquid dropletsin vitroand biomolecular condensates in cells. However, how the interplay between the folded (UBL/UBA) domains and the intrinsically-disordered regions mediates phase separation is largely unknown. Using engineered domain deletion constructs, we found that removing the UBA domain inhibits UBQLN2 LLPS while removing the UBL domain enhances LLPS, suggesting that UBA and UBL domains contribute asymmetrically in modulating UBQLN2 LLPS. To explain these differential effects, we interrogated the interactions that involve the UBA and UBL domains across the entire UBQLN2 molecule using NMR spectroscopy. To our surprise, aside from well-studied canonical UBL:UBA interactions, there also exist moderate and weak interactions between the UBL and STI1-I/STI1-II domains, and between the UBA domain and the linker connecting the two STI1 regions, respectively. Our findings are essential for the understanding of both the molecular driving forces of UBQLN2 LLPS and the effects of ligand binding to UBL, UBA, or STI1 domains on the phase behavior and physiological functions of UBQLN2.Impact of Work StatementZheng and Castañeda show that interplay between the folded domains and intrinsically disordered regions regulates liquid-liquid phase separation behavior of UBQLN2, a protein quality control (PQC) shuttle protein. Despite their similar size, the folded UBL and UBA domains inhibit and promote phase separation, respectively, due to their previously uncharacterized, asymmetric interactions with the middle intrinsically-disordered region. These results strongly suggest that PQC components, including proteasomal receptors, are likely to modulate UBQLN2 phase separation behavior in cells.
Human immunodeficiency reveals GIMAP5 as lymphocyte-specific regulator of senescence
Authors: Park Ann Y. , Leney-Greene Michael , Lynberg Matthew , Xu Xijin , Zheng Lixin , Zhang Yu , Matthews Helen , Chao Brittany , Morawski Aaron , Jiang Ping , Aluri Jahnavi , Aydiner Elif Karakoc , Kiykim Ayca , Pascall John , Barlan Isil , Sari Sinan , Butcher Geoff , Rao V. Koneti , Lifton Richard , Baris Safa , Ozen Ahmet , Vilarinho Silvia , Su Helen , Lenardo Michael J. 
Published: February 2021

AbstractElucidating the molecular basis of immunodeficiency diseases is a powerful approach to discovering new immunoregulatory pathways in humans. Here we report 10 affected individuals from 4 families with a new immunodeficiency disease comprising of severe progressive lymphopenia, autoimmunity, immunodeficiency, and liver disease due to recessive loss of function variants in“GTPase of immunity-associated proteins” protein 5 (GIMAP5). We show that the disease involves the progressive loss of naïve T lymphocytes and a corresponding increase in antigen-experienced, but poorly functional and replicatively senescent T cells. In vivo treatment of Gimap5-deficient mice with rapamycin (an inhibitor of mTORC1) significantly restores the fraction of naïve T lymphocytes. Furthermore, a GIMAP5-deficient human patient who was treated with rapamycin (sirolimus) showed a remarkable reduction in spleen/lymph node size. Together, these observations reveal that GIMAP5 plays a critical role in lymphocyte metabolism which is essential for senescence prevention and immune competence, suggesting that an inhibitor of mTORC1 could be a valuable clinical intervention in treating patients deficient for GIMAP5.
Dependency of Lower Limb Joint Reaction Forces on Femoral Anteversion
Authors: Modenese Luca , Barzan Martina , Carty Christopher P 
Published: February 2021

AbstractBackgroundMusculoskeletal (MSK) models based on literature data are meant to represent a generic anatomy and are a popular tool employed by biomechanists to estimate the internal loads occurring in the lower limb joints, such as joint reaction forces (JRFs). However, since these models are normally just linearly scaled to an individual’s anthropometry, it is unclear how their estimations would be affected by the personalization of key features of the MSK anatomy, one of which is the femoral anteversion angle.Research QuestionHow are the lower limb JRF magnitudes computed through a generic MSK model affected by changes in the femoral anteversion?MethodsWe developed a bone-deformation tool in MATLAB (https://simtk.org/projects/bone_deformity) and used it to create a set of seven OpenSim models spanning from 2° femoral retroversion to 40° anteversion. We used these models to simulate the gait of an elderly individual with an instrumented prosthesis implanted at their knee joint (5thGrand Challenge dataset) and quantified both the changes in JRFs magnitude due to varying the skeletal anatomy and their accuracy against the correspondent in vivo measurements at the knee joint.ResultsHip and knee JRF magnitudes were affected by the femoral anteversion with variations from the unmodified generic model up to 11.7±5.5% at the hip and 42.6±31.0% at the knee joint. The ankle joint was unaffected by the femoral geometry. The MSK models providing the most accurate knee JRFs (root mean squared error: 0.370±0.069 body weight, coefficient of determination: 0.764±0.104, largest peak error: 0.36±0.16 body weight) were those with the femoral anteversion angle closer to that measured on the segmented bone of the individual.SignificanceFemoral anteversion substantially affects hip and knee JRFs estimated with generic MSK models, suggesting that personalizing key MSK anatomical features might be necessary for accurate estimation of JRFs with these models.
Gradients of receptor expression in the macaque cortex
Authors: Froudist-Walsh Sean , Xu Ting , Niu Meiqi , Rapan Lucija , Margulies Daniel S. , Zilles Karl , Wang Xiao-Jing , Palomero-Gallagher Nicola 
Published: February 2021

AbstractDynamics and functions of neural circuits depend on synaptic interactions mediated by receptors. Therefore, a comprehensive map of receptor organization is needed to understand how different functions may emerge across distinct cortical regions. Here we usein-vitroreceptor autoradiography to measure the density of 14 neurotransmitter receptor types in 109 areas of macaque cortex. We integrate the receptor data with other anatomical, genetic and functional connectivity data into a common cortical space. We uncovered a principal gradient of increasing receptor expression per neuron aligned with cortical hierarchy from early sensory cortex to higher cognitive areas. A second gradient, primarily driven by 5-HT1Areceptors, peaks in the anterior and subcallosal cingulate, suggesting that the macaque may be a promising animal model for major depressive disorder. The receptor gradients may enable rapid, reliable information processing in sensory cortical areas and slow, flexible integration of information in higher cognitive areas.
Expression of CD49f defines subsets of human regulatory T cells with divergent transcriptional landscape and function that correlate with ulcerative colitis disease activity
Authors: Weerakoon Harshi , Straube Jasmin , Lineburg Katie , Cooper Leanne , Lane Steven , Smith Corey , Alabbas Saleh , Begun Jakob , Miles John J , Hill Michelle M , Lepletier Ailin 
Published: February 2021

ABSTRACTObjectiveAdoptive regulatory T cell (Treg) therapy is being trialled for treatment of different autoimmune disorders, including inflammatory bowel diseases (IBD). In-depth understanding of the biological variability of Treg in the human blood may be required to improve IBD immune monitoring and treatment strategies.MethodsThrough a combination of quantitative proteomic, multiparametric flow cytometry, RNA-sequencing data analysis and functional assays on Treg enriched from the blood of ulcerative colitis (UC) patients and healthy controls, we investigated the association between CD49f expression, Treg phenotype and function, and UC disease activity.ResultsHigh-dimensional analysis and filtering defined two distinct subsets of human Treg based on the presence or absence of CD49f with divergent transcriptional landscape and functional activities. CD49f negative Treg are enriched for functional Treg markers and present significantly increased suppressive capacity. In contrast, CD49f high Treg display a pro-inflammatory Th17-like phenotype and accumulate in the blood of UC patients. Dysregulation on CD49f Treg subsets in UC patients correlate with disease activity.ConclusionOverall our findings uncover the importance of CD49f expression on Treg in physiological immunity and in pathological autoimmunity.
Protein-protein docking with large-scale backbone flexibility using coarse-grained Monte-Carlo simulations
Authors: Kurcinski Mateusz , Kmiecik Sebastian , Zalewski Mateusz , Kolinski Andrzej 
Published: February 2021

AbstractMost of the protein-protein docking methods treat proteins as almost rigid objects. Only the side-chains flexibility is usually taken into account. The few approaches enabling docking with a flexible backbone typically work in two steps, in which the search for protein-protein orientations and structure flexibility are simulated separately. In this work, we propose a new straightforward approach for docking sampling. It consists of a single simulation step during which a protein undergoes large-scale backbone rearrangements, rotations, and translations. Simultaneously, the other protein exhibits small backbone fluctuations. Such extensive sampling was possible using the CABS coarse-grained protein model and Replica Exchange Monte Carlo dynamics at a reasonable computational cost. In our proof-of-concept simulations of 62 protein-protein complexes, we obtained acceptable quality models for a significant number of cases.
Targeting CoV-2 Spike RBD and ACE-2 Interaction with Flavonoids of Anatolian Propolis byin silicoandin vitroStudies in terms of possible COVID-19 therapeutics
Authors: Guler Halil Ibrahim , Ay Sal Fulya , Can Zehra , Kara Yakup , Yildiz Oktay , Belduz Ali Osman , Çanakci Sabriye , Kolayli Sevgi 
Published: February 2021

ABSTRACTPropolis is a multi-functional bee product with a rich in polyphenols. In this study, the inhibition effect of Anatolian propolis against SARS coronavirus-2 (SARS CoV-2) was investigated asin vitroandin silico. Raw and commercial of propolis samples were used in the study and it was found that both of were rich in caffeic acid, p-coumaric acid, ferulic acid, t-cinnamic acid, hesperetin, chrysin, pinocembrin and caffeic acid phenethyl ester (CAPE) by HPLC-UV analysis. The ethanolic propolis extracts (EPE) were used in the screening ELISA test against the spike S1 protein (SARS Cov-2): ACE-2 inhibition KIT forin vitrostudy. Binding energy constants of these polyphenols to the CoV-2 Spike S1 RBD and ACE-2proteinwere calculated separately as molecular docking study using AutoDock 4.2 molecular docking software. In addition, pharmacokinetics and drug-likeness properties of these eight polyphenols were calculated according to the SwissADME tool. Binding energy constant of pinocembrin was the highest for both of the receptors, followed by chrysin, CAPE and hesperetin.In silicoADME behavior of the eight polyphenols were found potential ability to work effectively as novel drugs. The findings of both studies showed that propolis has a high inhibitory potential against Covid-19 virus. However, further studies are needed.
Kynurenine pathway in post-mortem prefrontal cortex and cerebellum in schizophrenia: relationship with monoamines and symptomatology
Authors: Afia Amira Ben , Vila Èlia , MacDowell Karina S. , Ormazabal Aida , Leza Juan Carlos , Haro Josep Maria , Artuch Rafael , Ramos Belén , Garcia-Bueno Borja 
Published: February 2021

AbstractBackgroundthe cortico-cerebellar-thalamic-cortical circuit has been implicated in the emergence of psychotic symptoms in schizophrenia (SZ). The kynurenine pathway (KP) has been linked to alterations in glutamatergic and monoaminergic neurotransmission and to SZ symptomatology through the production of the metabolites quinolinic acid (QA) and kynurenic acid (KYNA).Methodsthis work describes alterations in KP in the post-mortem prefrontal cortex (PFC) and cerebellum (CB) of 15 chronic SZ patients and 14 control subjects in PFC and 13 control subjects in CB using immunoblot for protein levels and ELISA for interleukins and QA and KYNA determinations. Monoamine metabolites were analysed by High Performance Liquid Chromatography and SZ symptomatology was assessed by Positive and Negative Syndrome Scale (PANSS). The association of KP with inflammatory mediators, monoamine metabolism and SZ symptomatology was explored.Resultsin the PFC, the presence of the anti-inflammatory cytokine IL-10 together with IDO2 and KATII enzymes decreased in SZ, while TDO and KMO enzymes expression increased. A network interaction analysis showed that in the PFC IL-10 was coupled to the QA branch of the kynurenine pathway (TDO-KMO-QA), whereas IL-10 associated with KMO in CB. KYNA in the CB inversely correlated with negative and general PANSS psychopathology. Although there were no changes in monoamine metabolites content in the PFC in SZ, a network interaction analysis showed associations between dopamine and methoxyhydroxyphenylglycol degradation metabolite. Direct correlations were found between general PANSS psychopathology and the serotonin degradation metabolite, 5-hydroxyindoleacetic acid. Interestingly, KYNA in the CB inversely correlated with 5-hydroxyindoleacetic acid in the PFC.Conclusionsthus, this work found alterations in KP in two brain areas belonging to the cortico-cerebellar-thalamic-cortical circuit associated with SZ symptomatology, with a possible impact across areas in 5-HT degradation.
Modeling SARS-CoV-2 infection and its individual differences with ACE2-expressing human iPS cells
Authors: Sano Emi , Sakamoto Ayaka , Mimura Natsumi , Hirabayashi Ai , Muramoto Yukiko , Noda Takeshi , Yamamoto Takuya , Takayama Kazuo 
Published: February 2021

AbstractGenetic differences are a primary reason for differences in the susceptibility and severity of coronavirus disease 2019 (COVID-19). Because induced pluripotent stem (iPS) cells maintain the genetic information of the donor, they can be used to model individual differences in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infectionin vitro. Notably, undifferentiated human iPS cells themselves cannot be infected bySARS-CoV-2. Using adenovirus vectors, here we found that human iPS cells expressing the SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) (ACE2-iPS cells) can be infected with SARS-CoV-2. In infected ACE2-iPS cells, the expression of SARS-CoV-2 nucleocapsid protein, the budding of viral particles, the production of progeny virus, double membrane spherules, and double-membrane vesicles were confirmed. We also evaluated COVID-19 therapeutic drugs in ACE2-iPS cells and confirmed the strong antiviral effects of Remdesivir, EIDD-2801, and interferon-beta. In addition, we performed SARS-CoV-2 infection experiments on ACE2-iPS/ES cells from 8 individuals. Male iPS/ES cells were more capable of producing the virus as compared with female iPS/ES cells. These findings suggest that ACE2-iPS cells can not only reproduce individual differences in SARS-CoV-2 infectionin vitro, but they are also a useful resource to clarify the causes of individual differences in COVID-19 due to genetic differences.Graphical Abstract
The Role of Interspecies recombinations in the evolution of antibiotic-resistant pneumococci
Authors: D’Aeth Joshua C. , van der Linden Mark P.G. , McGee Lesley , Lencastre Herminia De , Turner Paul , Song Jae-Hoon , Lo Stephanie W. , Gladstone Rebecca A. , Sá-Leão Raquel , Ko Kwan Soo , Hanage William P. , Beall Bernard , Bentley Stephen D. , Croucher Nicholas J. ,   The GPS Consortium
Published: February 2021

AbstractThe evolutionary histories of the antibiotic-resistantStreptococcus pneumoniaelineages PMEN3 and PMEN9 were reconstructed using global collections of genomes. In PMEN3, one resistant clade spread worldwide, and underwent 25 serotype switches, enabling evasion of vaccine-induced immunity. In PMEN9, only 9 switches were detected, and multiple resistant lineages emerged independently and circulated locally. In Germany, PMEN9’s expansion correlated significantly with the macrolide:penicillin consumption ratio. These isolates were penicillin sensitive but macrolide resistant, through a homologous recombination that integrated Tn1207.1into a competence gene, preventing further diversification via transformation. Analysis of a species-wide dataset found 183 acquisitions of macrolide resistance, and multiple gains of the tetracycline-resistant transposon Tn916, through homologous recombination, often originating in other streptococcal species. Consequently, antibiotic selection preserves atypical recom- bination events that cause sequence divergence and structural variation throughout theS. pneumoniaechromosome. These events reveal the genetic exchanges between species normally counter-selected until perturbed by clinical interventions.
Monitoring oxidative inflammatory processes in live cells and tissue with Hypocrates, a genetically encoded biosensor for hypochlorite
Authors: Kostyuk Alexander I. , Tossounian Maria-Armineh , Panova Anastasiya S. , Thauvin Marion , Wahni Khadija , Van Molle Inge , Raevskii Roman I. , Baranov Mikhail S. , Vriz Sophie , Messens Joris , Bilan Dmitry S. , Belousov Vsevolod V. 
Published: February 2021

AbstractHypochlorous acid, an aggressive oxidant, is important in immune defense against pathogens. The current lack of tools to monitor the dynamics of hypochlorous acid in live cells and tissue hinders a better understanding of inflammatory processes. We engineered a genetically encoded biosensor, Hypocrates, for the visualization of hypochlorous acid. Hypocrates consists of a circularly permuted yellow fluorescent protein integrated into the structure of the transcription repressor NemR fromE. coli. We determined sensitivity, selectivity, reaction rates, and the X-ray structure of this ratiometric redox biosensor, and tested the response of Hypocrates in HeLa Kyoto cells at varying hypochlorite concentrations. By combining Hypocrates with the biosensor HyperRed, we visualized the dynamics of hypochlorous acid and hydrogen peroxide in a zebrafish tail fin injury model.
Beneficial cumulative effects of old parental age on offspring fitness
Authors: Travers Laura. M. , Carlsson Hanne , Lind Martin I. , Maklakov Alexei A. 
Published: February 2021

AbstractOld parental age is commonly associated with negative effects on offspring life-history traits. Such parental effect senescence is predicted to have a cumulative detrimental effect over successive generations. However, old parents may benefit from producing high-quality offspring when these compete for seasonal resources. Thus, old parents may choose to increase investment in their offspring, thereby producing fewer but larger and more competitive progeny. We show thatCaenorhabditis eleganshermaphrodites increase parental investment with advancing age, resulting in fitter offspring who reach their reproductive peak earlier. Remarkably, these effects increased over six successive generations of breeding from old parents and were subsequently reversed following a single generation of breeding from a young parent. These results contradict the theory that old parents transfer a cumulative detrimental “ageing factor” to their offspring. Instead, our findings support the hypothesis that offspring of old parents receive more resources and convert them into increasingly faster life-histories.
pyControl: Open source, Python based, hardware and software for controlling behavioural neuroscience experiments
Authors: Akam Thomas , Lustig Andy , Rowland James , Kapanaiah Sampath K.T. , Esteve-Agraz Joan , Panniello Mariangela , Marquez Cristina , Kohl Michael , Kätzel Dennis , Costa Rui M. , Walton Mark 
Published: February 2021

AbstractLaboratory behavioural tasks are an essential research tool. As questions asked of behaviour and brain activity become more sophisticated, the ability to specify and run richly structured tasks becomes more important. An increasing focus on reproducibility also necessitates accurate communication of task logic to other researchers. To these ends we developed pyControl, a system of open source hardware and software for controlling behavioural experiments comprising; a simple yet flexible Python-based syntax for specifying tasks as extended state machines, hardware modules for building behavioural setups, and a graphical user interface designed for efficiently running high throughput experiments on many setups in parallel, all with extensive online documentation. These tools make it quicker, easier and cheaper to implement rich behavioural tasks at scale. As important, pyControl facilitates communication and reproducibility of behavioural experiments through a highly readable task definition syntax and self-documenting features.ResourcesDocumentation:https://pycontrol.readthedocs.ioRepositories:https://github.com/pyControlUser support:https://groups.google.com/g/pycontrol