bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Primeval Mechanism of Tolerance to Desiccation Based on Glycolic Acid Saves Neurons from Ischemia in Mammals by Reducing Intracellular Calcium-Mediated Excitotoxicity
Authors: Chovsepian Alexandra , Berchtold Daniel , Winek Katarzyna , Mamrak Uta , Álvarez Inés Ramirez , Dening Yanina , Golubczyk Dominika , Weitbrecht Luis , Dames Claudia , Aillery Marine , Fernandez-Sanz Celia , Gajewski Zdzislaw , Dieterich Marianne , Janowski Miroslaw , Falkai Peter , Walczak Piotr , Plesnila Nikolaus , Meisel Andreas , Pan-Montojo Francisco 
Published: November 2020

ABSTRACTStroke is the second leading cause of death and disability worldwide. Current treatments, such as pharmacological thrombolysis or mechanical thrombectomy, re-open occluded arteries but do not protect against ischemia-induced damage that has already occurred before reperfusion or ischemia/reperfusion-induced neuronal damage. It has been shown that disrupting the conversion of glyoxal to glycolic acid (GA) results in a decreased tolerance to anhydrobiosis inC. elegans, dauer larva, while GA itself can rescue this phenotype. During the process of desiccation/rehydration, a metabolic stop/start similar to the one observed during ischemia/reperfusion occurs. In this study, we tested the protective effect of GA in different ischemia models, including commonly used stroke models in mice and swine. Our results show that GA, given during reperfusion, strongly protects against ischemic damage and improves the functional outcome. We provide evidence that GA exerts its effect by counteracting the glutamate-dependent increase in intracellular calcium during excitotoxicity. These results suggest that GA treatment has the potential to reduce the mortality and disability caused by stroke in patients.
Longitudinal white matter changes associated with cognitive training
Authors: Nichols E.S. , Erez J. , Stojanoski B. , Lyons K.M. , Witt S.T. , Mace C.A. , Khalid S. , Owen A.M. 
Published: November 2020

AbstractImprovements in behaviour are known to be accompanied by both structural and functional changes in the brain. However whether those changes lead to more general improvements, beyond the behaviour being trained, remains a contentious issue. We investigated whether training on one of two cognitive tasks would lead to either near transfer (that is, improvements on a quantifiably similar task) or far transfer (that is, improvements on a quantifiably different task), and furthermore, if such changes did occur, what the underlying neural mechanisms might be. Participants trained on either a verbal inhibitory control task or a visuospatial working memory task for four weeks, over the course of which they received five diffusion tensor imaging scans. Two additional tasks, a test of verbal reasoning and a test of spatial span, served as measures of near transfer for the inhibitory control task and spatial working memory task, respectively. These two tasks also served as measures of far transfer for the alternate training task. Behaviourally, participants improved on the task that they trained on, but did not improve on cognitively similar tests (near transfer), nor cognitively dissimilar tests (far transfer). Extensive changes to white matter microstructure were observed, with verbal inhibitory control training leading to changes in a left-lateralized network of fronto-temporal and occipito-frontal tracts, and visuospatial working memory training leading to changes in right-lateralized fronto-parietal tracts. Very little overlap was observed in changes between the two training groups. On the basis of these results, we suggest that near and far transfer were not observed because the changes in white matter tracts associated with training on each task are almost entirely non-overlapping with, and therefore afford no advantages for, the untrained tasks.
Heterochiasmy facilitated the establishment ofgsdfas a novel sex determining gene in Atlantic halibut
Authors: Edvardsen R.B. , Wallerman O. , Furmanek T. , Kleppe L. , Jern P. , Wallberg A. , Kjærner-Semb E. , Mæhle S. , Olausson S. K. , Sundström E. , Harboe T. , Mangor-Jensen R. , Møgster M. , Perrichon P. , Norberg B. , Rubin C-J 
Published: November 2020

AbstractAtlantic Halibut (Hippoglossus hippoglossus) has a X/Y genetic sex determination system, but the sex determining factor is not known. We produced a high-quality genome assembly and identified parts of chromosome 13 as the Y chromosome due to sequence divergence between sexes and segregation of sex genotypes in pedigrees. Linkage analysis revealed that all chromosomes exhibit heterochiasmy, i.e. male- and female restricted meiotic recombination intervals (MRR/FRR). We show that FRR/MRR intervals differ in nucleotide diversity and repeat class content and that this is true also for other Pleuronectidae species. We further show that remnants of a Gypsy-like transposable element insertion on chr13 promotes early male specific expression of gonadal somatic cell derived factor (gsdf). Less than 4 MYA, this male-determining element evolved on an autosomal FRR segment featuring pre-existing male meiotic recombination barriers, thereby creating a Y chromosome. We propose that heterochiasmy may facilitate the evolution of genetic sex determination systems.
Increased Colonic Expression of ACE2 Associates with Poor Prognosis in Crohn’s disease
Authors: Toyonaga Takahiko , Araba Kenza C. , Kennedy Meaghan M. , Keith Benjamin P. , Wolber Elisabeth A. , Beasley Caroline , Steinbach Erin C. , Schaner Matthew R. , Jain Animesh , Long Millie D. , Barnes Edward L. , Herfarth Hans H. , Isaacs Kim L. , Hansen Jonathan J. , Kapadia Muneera , Gaston Guillem José , Koruda Mark J. , Rahbar Reza , Sadiq Tim , Gulati Ajay S. , Sethupathy Praveen , Furey Terrence S. , Ehre Camille , Sheikh Shehzad Z. 
Published: November 2020

AbstractBackground and AimsThe host receptor for SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2), is highly expressed in small intestine. Our aim was to study colonic ACE2 expression in Crohn’s disease (CD) and non-inflammatory bowel disease (non-IBD) controls. We hypothesized that the colonic expression levels of ACE2 impacts CD course.MethodsWe examined the expression of colonACE2using RNA-seq and quantitative (q) RT-PCR from 69 adult CD and 14 NIBD control patients. In a subset of this cohort we validated ACE2 protein expression and localization in formalin-fixed, paraffin-embedded matched colon and ileal tissues using immunohistochemistry. The impact of increasedACE2expression in CD for the risk of surgery was evaluated by a multivariate regression analysis and a Kaplan-Meier estimator. To provide critical support for the generality of our findings, we analyzed previously published RNA-seq data from two large independent cohorts of CD patients.ResultsColonicACE2expression was significantly higher in a subset of adult CD patients (ACE2-high CD). IHC in a sampling of ACE2-high CD patients confirmed high ACE2 protein expression in the colon and ileum compared to ACE2-low CD and NIBD patients. Notably, we found that ACE2-high CD patients are significantly more likely to undergo surgery within 5 years of diagnosis, with a Cox regression analysis finding that highACE2levels is an independent risk factor (OR 2.18; 95%CI, 1.05-4.55; p=0.037).ConclusionIncreased intestinal expression of ACE2 is associated with deteriorated clinical outcomes in CD patients. These data point to the need for molecular stratification that may impact CD disease-related outcomes.
SUN-MKL1 crosstalk regulates nuclear deformation and fast motility of breast carcinoma cells in fibrillar ECM micro-environment
Authors: Sharma Ved P , Williams James , Leung Edison , Sanders Joe , Eddy Robert , Castracane James , Oktay Maja H , Entenberg David , Condeelis John S 
Published: November 2020

ABSTRACTAligned collagen fibers provide topography for the rapid migration of single tumor cells (streaming migration) to invade the surrounding stroma, move within tumor nests towards blood vessels to intravasate and form distant metastases. Mechanisms of tumor cell motility have been studied extensively in the 2D context, but the mechanistic understanding of rapid single tumor cell motility in thein vivocontext is still lacking. Here, we show that streaming tumor cellsin vivouse collagen fibers with diameters below 3 μm. Employing 1D migration assays with matchingin vivofiber dimensions, we found a dependence of tumor cell motility on 1D substrate width, with cells moving the fastest and the most persistently on the narrowest 1D fibers (700 nm – 2.5 μm). Interestingly, we also observed nuclear deformation in the absence of restricting extracellular matrix pores during high speed carcinoma cell migration in 1D, similar to the nuclear deformation observed in tumor cellsin vivo. Further, we found that actomyosin machinery is aligned along the 1D axis and actomyosin contractility synchronously regulates cell motility and nuclear deformation. To further investigate the link between cell speed and nuclear deformation, we focused on the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex proteins and SRF-MKL1 signaling, key regulators of mechanotransduction, actomyosin contractility and actin-based cell motility. Analysis of The Cancer Genome Atlas dataset showed a dramatic decrease in the LINC complex proteins SUN1 and SUN2 in primary tumor compared to the normal tissue. Disruption of LINC complex by SUN1+2 KD led to multi-lobular elongated nuclei, increased tumor cell motility and concomitant increase in F-actin, without affecting Lamin proteins. Mechanistically, we found that MKL1, an effector of changes in cellular G-actin to F-actin ratio, is required for increased 1D motility seen in SUN1+2 KD cells. Thus, we demonstrate a previously unrecognized crosstalk between SUN proteins and MKL1 transcription factor in modulating nuclear shape and carcinoma cell motility in anin vivorelevant 1D microenvironment.
Time-resolved structured illumination microscopy reveals key principles of Xist RNA spreading
Authors: Rodermund Lisa , Coker Heather , Oldenkamp Roel , Wei Guifeng , Bowness Joseph , Rajkumar Bramman , Nesterova Tatyana , Pinto David , Schermelleh Lothar , Brockdorff Neil 
Published: November 2020

AbstractXist RNA directs the process of X-chromosome inactivation in mammals by spreadingin cisalong the chromosome from which it is transcribed and recruiting chromatin modifiers to silence gene transcription. To elucidate mechanisms of Xist RNAcis-confinement, we established a sequential dual color labeling, super-resolution imaging approach to trace individual Xist RNA molecules over time, enabling us to define fundamental parameters of spreading. We demonstrate a feedback mechanism linking Xist RNA synthesis and degradation, and an unexpected physical coupling between preceding and newly synthesized Xist RNA molecules. Additionally, we show that the protein SPEN, a key factor for Xist-mediated gene-silencing, has a distinct function in Xist RNA localization, stability and in coupling behavior. Our results provide important insights towards understanding the unique dynamic properties of Xist RNA.One Sentence SummaryVisualizing Xist RNA dynamics in single cells during X chromosome inactivation
Crystal structure of chloroplastic thioredoxin z defines a novel type-specific target recognition
Authors: Le Moigne Théo , Gurrieri Libero , Crozet Pierre , Marchand Christophe H. , Zaffagnini Mirko , Sparla Francesca , Lemaire Stéphane D. , Henri Julien 
Published: November 2020

AbstractThioredoxins (TRXs) are ubiquitous disulfide oxidoreductases structured according to a highly conserved fold. TRXs are involved in a myriad of different processes through a common chemical mechanism. Plant thioredoxins evolved into seven types with diverse subcellular localization and distinct protein targets selectivity. Five TRX types coexist in the chloroplast, with yet scarcely described specificities. We solved the first crystal structure of a chloroplastic z-type TRX, revealing a conserved TRX fold with an original electrostatic surface potential surrounding the redox site. This recognition surface is distinct from all other known TRX types from plant and non-plant sources and is exclusively conserved in plant z-type TRXs. We show that this electronegative surface endows TRXz with a capacity to activate the photosynthetic Calvin-Benson cycle enzyme phosphoribulokinase. TRXz distinct electronegative surface thereby extends the repertoire of TRX-target recognitions.
Ovarian carcinosarcoma genomics and pre-clinical models highlight the N-MYC pathway as a key driver and susceptibility to EMT-targeting therapy
Authors: Ho Gwo Yaw , Kyran Elizabeth L. , Bedo Justin , Wakefield Matthew J. , Ennis Darren P. , Mirza Hasan B. , Lieschke Elizabeth , Vandenberg Cassandra J. , Kondrashova Olga , Upstill-Goddard Rosie , Bailey Ulla-Maja , Dowson Suzanne. , Roxburgh Patricia , Glasspool Rosalind M. , Bryson Gareth , Biankin Andrew V. , Cooke Susanna L. , Ratnayake Gayanie , McNally Orla , Traficante Nadia ,   Australian Ovarian Cancer Study, DeFazio Anna , Weroha John , Bowtell David D. , McNeish Iain A. , Papenfuss Anthony T. , Scott Clare L. , Barker Holly E. 
Published: November 2020

AbstractOvarian carcinosarcoma (OCS) is an aggressive and rare tumour type with limited treatment options. OCS is hypothesised to develop via the combination theory from a single progenitor, resulting in carcinomatous and sarcomatous components, or alternatively via the conversion theory, with the sarcomatous component developing from the carcinomatous component through epithelial-to-mesenchymal transition (EMT). We show OCS from 18 women to be monoclonal through analysis of DNA variants from isolated carcinoma and sarcoma components. RNA sequencing indicated the carcinoma components were more mesenchymal when compared with pure ovarian carcinomas, supporting the conversion theory. We used pre-clinical OCS models to test the efficacy of microtubule-targeting drugs, including eribulin, which has been shown to reverse EMT characteristics. We demonstrated that microtubule inhibitors, vinorelbine and eribulin, were more effective than standard-of-care platinum-based chemotherapy. Eribulin reduced mesenchymal characteristics, N-MYC expression and cholesterol biosynthesis. Finally, eribulin induced a strong immune response, supporting immunotherapy combinations in the clinic.
The structural connectome constrains fast brain dynamics
Authors: Sorrentino P , Seguin C , Rucco R , Liparoti M , Troisi Lopez E , Bonavita S , Quarantelli M , Sorrentino G , Jirsa V , Zalesky A 
Published: November 2020

AbstractBrain activity during rest displays complex, rapidly evolving patterns in space and time. Structural connections comprising the human connectome are hypothesized to impose constraints on the dynamics of this activity. Here, we use magnetoencephalography (MEG) to quantify the extent to which fast neural dynamics in the human brain are constrained by structural connections inferred from diffusion MRI tractography. We characterize the spatio-temporal unfolding of whole-brain activity at the millisecond scale from source-reconstructed MEG data, estimating the probability that any two brain regions will significantly deviate from baseline activity in consecutive time epochs. We find that the structural connectome relates to, and likely affects, the rapid spreading of neuronal avalanches, evidenced by a significant association between these transition probabilities and structural connectivity strengths (r=0.37, p<0.0001). This finding opens new avenues to study the relationship between brain structure and neural dynamics.
An Ultra-Stable and Dense Single-Molecule Click Platform for Sensing Protein-DNA Interactions
Authors: Visser Emiel W. A. , Miladinovic Jovana , Milstein Joshua N. 
Published: November 2020

AbstractWe demonstrate an ultra-stable, highly dense single-molecule assay ideal for observing protein-DNA interactions. Stable click Tethered Particle Motion (scTPM) leverages next generation click-chemistry to achieve an ultrahigh density of surface tethered reporter particles, has a high antifouling resistance, is stable at elevated temperatures to at least 45 °C, and is compatible with Mg2+, an important ionic component of many regulatory protein-DNA interactions. Prepared samples remain stable, with little degradation, for > 6 months in physiological buffers. These improvements enabled us to study previously inaccessible sequence and temperature dependent effects on DNA binding by the bacterial protein H-NS, a global transcriptional regulator found in E. Coli. This greatly improved assay can directly be translated to accelerate existing tethered particle based, single-molecule biosensing applications.
Deciphering the LRRK code: LRRK1 and LRRK2 phosphorylate distinct Rab proteins and are regulated by diverse mechanisms
Authors: Malik Asad U. , Karapetsas Athanasios , Nirujogi Raja S. , Mathea Sebastian , Pal Prosenjit , Lis Pawel , Taylor Matthew , Purlyte Elena , Gourlay Robert , Dorward Mark , Weidlich Simone , Toth Rachel , Polinski Nicole K. , Knapp Stefan , Tonelli Francesca , Alessi Dario R 
Published: November 2020

AbstractMuch attention has focused on LRRK2, as autosomal dominant missense mutations that enhance its kinase activity cause inherited Parkinson’s disease. LRRK2 regulates biology by phosphorylating a subset of Rab GTPases including Rab8A and Rab10 within its effector binding motif. In this study we explore whether LRRK1, a less studied homologue of LRRK2 that regulates growth factor receptor trafficking and osteoclast biology might also phosphorylate Rab proteins. Using mass spectrometry, we found that the endogenous Rab7A protein, phosphorylated at Ser72 was most impacted by LRRK1 knock-out. This residue is not phosphorylated by LRRK2 but lies at the equivalent site targeted by LRRK2 on Rab8A and Rab10. Accordingly, recombinant LRRK1 efficiently phosphorylated Rab7A at Ser72, but not Rab8A or Rab10. Employing a novel phospho-specific antibody, we found that phorbol ester stimulation of mouse embryonic fibroblasts markedly enhanced phosphorylation of Rab7A at Ser72 via LRRK1. We identify two LRRK1 mutations (K746G and I1412T), equivalent to the LRRK2 R1441G and I2020T Parkinson’s mutations, that enhance LRRK1 mediated phosphorylation of Rab7A. We demonstrate that two regulators of LRRK2 namely Rab29 and VPS35[D620N], do not influence LRRK1. Widely used LRRK2 inhibitors do not inhibit LRRK1, but we identify a promiscuous Type-2 tyrosine kinase inhibitor termed GZD-824 that inhibits both LRRK1 and LRRK2. Finally, we show that interaction of Rab7A with its effector RILP is not affected by high stoichiometry LRRK1 phosphorylation. Altogether, these finding reinforce the idea that the LRRK enzymes have evolved as major regulators of Rab biology.
Synergistic CDK control pathways maintain cell size homeostasis
Authors: Patterson James O. , Basu Souradeep , Rees Paul , Nurse Paul 
Published: November 2020

AbstractTo coordinate cell size with cell division, cell size must be computed by the cyclin-CDK control network to trigger division appropriately. Here we dissect determinants of cyclin-CDK activity using a novel high-throughput single-cell in vivo system. We show that inhibitory phosphorylation of CDK encodes cell size information and works synergistically with PP2A to prevent division in smaller cells. However, even in the absence of all canonical regulators of cyclin-CDK, small cells with high cyclin-CDK levels are restricted from dividing. We find that diploid cells of equivalent size to haploid cells exhibit lower CDK activity in response to equal cyclin-CDK enzyme concentrations, suggesting that CDK activity is reduced by DNA concentration. Thus, multiple pathways directly regulate cyclin-CDK activity to maintain robust cell size homeostasis.
Effect of volatility of foreign direct investment inflows on corporate income tax revenue volatility
Authors: Gnangnon Sena Kimm 
Published: November 2020

PurposeThis paper aims to examine how the volatility of foreign direct investment (FDI) inflows affects the volatility of corporate income tax revenue.Design/methodology/approachThe study has used an unbalanced panel data set of 129 countries over the period 1981–2016 and the two-step system generalized methods of moment approach to perform the empirical analysis.FindingsThe main findings are that FDI volatility enhances the volatility of corporate income tax revenue in less advanced economies, but reduces it in relatively advanced countries. The positive corporate income tax revenue volatility effect of FDI inflows is far higher in non-tax haven countries than in tax haven countries. Additionally, FDI volatility exerts a higher positive effect on corporate income tax revenue volatility as countries experience greater dependence on natural resources. Finally, the positive effect of FDI volatility on corporate income tax revenue volatility is further amplified by higher FDI volatility.Research limitations/implicationsOne important limitation of the present analysis is the use of aggregate FDI inflows because of the lack of data over a long period on greenfield FDI inflows and cross-border mergers and acquisitions FDI inflows. Therefore, an avenue for future research could be to explore separately the effect of the volatility greenfield FDI inflows and the volatility of cross-border mergers and acquisitions FDI inflows on the volatility of corporate income tax revenue, when long-time series data (covering many countries) would be available.Practical implicationsThese outcomes particularly shed light on the role of FDI volatility on the volatility of corporate income tax revenue, particularly in countries that are highly dependent on natural resources. Foreign capital flows, notably FDI flows, play an essential role for countries’ economic development through, inter alia, technology transfer, jobs creation and economic growth. Policymakers should aim to attract FDI, while also reducing their volatility, by designing and implementing policies and measures (such as those in favor of business environment improvement, property rights enforcement and political stability) that would assure foreign investors of the continuous high returns of their investments.Originality/valueTo the best of the author’s knowledge, this is the first time this topic is being addressed empirically in the literature.