bluuebunny/crossref_metadata_2025_split huggingface dataset:
Spatial distribution and cognitive impact of cerebrovascular risk-related white matter hyperintensities
Authors: Veldsman Michele , Kindalova Petya , Husain Masud , Kosmidis Ioannis , Nichols Thomas E. 
Published: June 2020

AbstractObjectivesWhite matter hyperintensities (WMHs) are considered macroscale markers of cerebrovascular burden and are associated with increased risk of vascular cognitive impairment and dementia. However, the spatial location of WMHs has typically been considered in broad categories of periventricular versus deep white matter. The spatial distribution of WHMs associated with individual cerebrovascular risk factors (CVR), controlling for frequently comorbid risk factors, has not been systematically investigated at the population level in a healthy ageing cohort. Furthermore, there is an inconsistent relationship between total white matter hyperintensity load and cognition, which may be due to the confounding of several simultaneous risk factors in models based on smaller cohorts.MethodsWe examined trends in individual CVR factors on total WMH burden in 13,680 individuals (aged 45-80) using data from the UK Biobank. We estimated the spatial distribution of white matter hyperintensities associated with each risk factor and their contribution to explaining total WMH load using voxel-wise probit regression and univariate linear regression. Finally, we explored the impact of CVR-related WMHs on speed of processing using regression and mediation analysis.ResultsContrary to the assumed dominance of hypertension as the biggest predictor of WMH burden, we show associations with a number of risk factors including diabetes, heavy smoking, APOEε4/ε4 status and high waist-to-hip ratio of similar, or greater magnitude to hypertension. The spatial distribution of WMHs varied considerably with individual cerebrovascular risk factors. There were independent effects of visceral adiposity, as measured by waist-to-hip ratio, and carriage of the APOEε4 allele in terms of the unique spatial distribution of CVR-related WMHs. Importantly, the relationship between total WMH load and speed of processing was mediated by waist-to-hip ratio suggesting cognitive consequences to WMHs associated with excessive visceral fat deposition.ConclusionWaist-to-hip ratio, diabetes, heavy smoking, hypercholesterolemia and homozygous APOEε4 status are important risk factors, beyond hypertension, associated with WMH total burden and warrant careful control across ageing. The spatial distribution associated with different risk factors may provide important clues as to the pathogenesis and cognitive consequences of WMHs. High waist-to-hip ratio is a key risk factor associated with slowing in speed of processing. With global obesity levels rising, focused management of visceral adiposity may present a useful strategy for the mitigation of cognitive decline in ageing.
SalivaryAsHPX12influence pre-blood meal associated behavioral properties in the mosquitoAnopheles stephensi
Authors: Kumari Seena , De Tanwee Das , Chauhan Charu , Rani Jyoti , Tevatiya Sanjay , Sharma Punita , Pandey Kailash C , Pande Veena , Dixit Rajnikant 
Published: June 2020

AbstractIn the adult female mosquito, successful blood meal acquisition is accomplished by salivary glands, which releases a cocktail of proteins to counteract vertebrate host’s immune-homeostasis. However, the biological relevance of many salivary proteins remains unknown. Here, we characterize a salivary specific Heme peroxidase family member HPX12, originally identified fromPlasmodium vivaxinfected salivary RNAseq data of the mosquitoAnopheles stephensi. We demonstrate that dsRNA silencing mediated mRNA depletion of salivaryAsHPX12(80-90%), causes enhanced host attraction but reduced blood-meal acquisition abilities, by increasing probing propensity (31%), as well as probing time (100–200s,P<0.0001) as compared to control (35-90s) mosquitoes group. Altered expression of the salivary secretory and antennal proteins may account for an unusual fast release of salivary cocktail proteins, but the slowing acquisition of blood meal, possibly due to salivary homeostasis disruption ofAsHPX12silenced mosquitoes. A parallel transcriptional modulation in response to blood feeding andP. vivaxinfection, further establish a possible functional correlation ofAsHPX12role in salivary immune-physiology andPlasmodiumsporozoites survival/transmission. We propose that salivary HPX12 may have a vital role in the management of ‘pre- and post’-blood meal associated physiological-homeostasis and parasite transmission.Graphical abstractFigure 1:Schematic representation of mosquito’s blood meal acquisition and upshot on blood-feeding after silencing of salivary gland HPX-12.(A)After landing over host skin, mosquito mouthparts (proboscis) actively engaged to search, probe, and pierce the skin followed by a rapid release of the pre-synthesized salivary cocktail, which counteracts the host homeostasis, inflammation, and immune responses, during blood meal uptake.(B)Silencing of HPX-12 disrupts salivary gland homeostasis, enhancing mosquito attraction, possibly by up-regulating odorant-binding proteins genes-OBP-7,10 and OBP-20 expression in the Olfactory System. However, HPX-12 disruption may also cause significant effects on pre-blood meal associated probing abilities, which may be due to fast down-regulation of salivary cocktail proteins such as Anopheline, Apyrase, D7L proteins.
Persistence of quantal synaptic vesicle recycling following dynamin depletion
Authors: Afuwape Olusoji A.T. , Chanaday Natali L. , Kasap Merve , Monteggia Lisa M. , Kavalali Ege T. 
Published: June 2020

AbstractDynamins are GTPases required for pinching vesicles off the plasma membrane once a critical curvature is reached during endocytosis. Here, we probed dynamin function in central synapses by depleting all three dynamin isoforms in postnatal hippocampal neurons. We found a decrease in the propensity of evoked neurotransmission as well as a reduction in synaptic vesicle numbers. Using the fluorescent reporter vGluT1-pHluorin, we observed that compensatory endocytosis after 20 Hz stimulation was arrested in ~40% of presynaptic boutons, while remaining synapses showed only a modest effect suggesting the existence of a dynamin-independent endocytic pathway in central synapses. Surprisingly, we found that the retrieval of single synaptic vesicles, after either evoked or spontaneous fusion, was largely impervious to disruption of dynamins. Overall, our results suggest that classical dynamin-dependent endocytosis is not essential for retrieval of synaptic vesicle proteins after quantal single synaptic vesicle fusion.
Flanking sequence preference modulatesde novoDNA methylation in the mouse genome
Authors: Mallona Izaskun , Ilie Ioana Mariuca , Manzo Massimiliano , Caflisch Amedeo , Baubec Tuncay 
Published: June 2020

AbstractMammaliande novoDNA methyltransferases (DNMT) are responsible for the establishment of cell-type-specific DNA methylation in healthy and diseased tissues. Through genome-wide analysis ofde novomethylation activity in murine stem cells we uncover that DNMT3A prefers to methylate CpGs followed by cytosines or thymines, while DNMT3B predominantly methylates CpGs followed by guanines or adenines. These signatures are further observed at non-CpG sites, resembling methylation context observed in specialised cell types, including neurons and oocytes. We further show that these preferences are not mediated by the differential recruitment of the twode novoDNMTs to the genome but are resulting from structural differences in their catalytic domains. Molecular dynamics simulations suggest that, in case of DNMT3A, the preference is due to favourable polar interactions between the flexible Arg836 side chain and the guanine that base-pairs with the cytosine following the CpG. This context-dependentde novoDNA methylation provides additional insights into the complex regulation of methylation patterns in different cell types.
Bypassing juvenility, first report of functional flowering and fruiting in six months old seedlings ofCordia myxa L.(lasuda)
Authors: Guleria Vipan 
Published: June 2020

ABSTRACTCordia myxaL. is a medium-sized broad-leaved deciduous tree of flowering plant belongs to Boraginaceae. It grows naturally from dry desert India up to hills of Himalayas in India up to 1400 m elevation above mean sea level. Fruits are mostly used for pickle making and dried for its use in local off season vegetable recipes since long time. The ripe fruits are full of vitamins and its regular use is supposed to be helpful in good growth of hair. Lasuda preparations are, thus, good for people whose constitution might have tendency to go bald. In addition to fruit, Lasuda bark and roots are also very effective as a local remedy against cough, cold and various other ailments connected with indigestion and throat problems. At regional research laboratory of Dr. Y. S. Parmar University of Horticulture and Forestry, Nauni (India) we are working for the last 12 years on various aspects like propagation and development of promising strains ofCordia myxa. Grafting/budding techniques have been standardized to produce true to type precocious plants which bear flower and fruits in two to three years. However, flowering and fruiting has been observed in six months old seedling of seed origin, which can be ascribed to biochemical or cellular changes. Early flowering and fruiting is a rare phenomenon in tree seedlings of the species which otherwise flower at the age of 7-8 years. This could be very useful for manipulating the species at gene as well as physiological level in future to get early fruits and breeding of the species.
MSCs from syndecan-3 null mice exhibit enhanced adhesion to collagen type I, hyperactivation of the AKT pathway and increased efficacy in inflammatory arthritis
Authors: Jones Fiona K , Stefan Andrei , Kay Alasdair G , Hyland Mairead , Morgan Rebecca , Forsyth Nicholas R , Pisconti Addolorata , Kehoe Oksana 
Published: June 2020

1AbstractRheumatoid arthritis (RA) is a debilitating and painful inflammatory autoimmune disease characterised by the accumulation of leukocytes in the synovium, cartilage destruction and bone erosion. The immunomodulatory effects of bone marrow derived mesenchymal stem cells (MSCs) has been widely studied and the recent observations that syndecan-3 (SDC3) is selectively pro-inflammatory in the joint led us to hypothesise that SDC3 might play an important role in MSC biology. MSCs isolated from bone marrow of wild type and Sdc3−/−mice were used to assess immunophenotype, differentiation, adhesion and migration properties and cell signalling pathways. While both cell types show similar differentiation potential and forward scatter values, the cell complexity in wild type MSCs was significantly higher than in Sdc3−/−cells and was accompanied by lower spread surface area. Moreover, Sdc3−/−MSCs adhered more rapidly to collagen type I and showed a dramatic increase in AKT phosphorylation, accompanied by a decrease in ERK1/2 phosphorylation compared with control cells. In a mouse model of antigen-induced inflammatory arthritis, intraarticular injection of Sdc3−/−MSCs yielded enhanced recovery compared to injection of wild type MSCs. In conclusion, our data suggest that syndecan-3 regulates MSC adhesion and efficacy in inflammatory arthritis, likely via induction of the AKT pathway.
BUB-1 targets PP2A:B56 to regulate chromosome congression during meiosis I inC. elegansoocytes
Authors: Borja Laura Bel , Soubigou Flavie , Taylor Samuel J.P. , Bringas Conchita Fraguas , Budrewicz Jacqueline , Lara-Gonzalez Pablo , Turpin Christopher G. Sorensen , Bembenek Joshua N. , Cheerambathur Dhanya K. , Pelisch Federico 
Published: June 2020

ABSTRACTProtein Phosphatase 2A (PP2A) is an heterotrimer composed of scaffolding (A), catalytic (C), and regulatory (B) subunits with various key roles during cell division. While A and C subunits form the core enzyme, the diversity generated by interchangeable B subunits dictates substrate specificity. Within the B subunits, B56-type subunits play important roles during meiosis in yeast and mice by protecting centromeric cohesion and stabilising the kinetochore-microtubule attachments. These functions are achieved through targeting of B56 subunits to centromere and kinetochore by Shugoshin and BUBR1. In the nematodeCaenorhabditis elegans(C. elegans)the closest BUBR1 ortholog lacks the B56 interaction domain and the Shugoshin orthologue is not required for normal segregation during oocyte meiosis. Therefore, the role of PP2A inC. elegansfemale meiosis is not known. Here, we report that PP2A is essential for meiotic spindle assembly and chromosome dynamics duringC. elegansfemale meiosis. Specifically, B56 subunits PPTR-1 and PPTR-2 associate with chromosomes during prometaphase I and regulate chromosome congression. The chromosome localization of B56 subunits does not require shugoshin orthologue SGO-1. Instead we have identified the kinase BUB-1 as the key B56 targeting factor to the chromosomes during meiosis. PP2A BUB-1 recruits PP2A:B56 to the chromosomes via dual mechanism: 1) PPTR-1/2 interacts with the newly identified LxxIxE short linear motif (SLiM) within a disordered region in BUB-1 in a phosphorylation-dependent manner; and 2) PPTR-2 can also be recruited to chromosomes in a BUB-1 kinase domain-dependent manner. Our results highlight a novel, BUB-1-dependent mechanism for B56 recruitment, essential for recruiting a pool of PP2A required for proper chromosome congression during meiosis I.
ALX1-related Frontonasal Dysplasia Results From Defective Neural Crest Cell Development and Migration
Authors: Pini Jonathan , Kueper Janina , Hu Yiyuan David , Kawasaki Kenta , Yeung Pan , Tsimbal Casey , Yoon Baul , Carmichael Nikkola , Maas Richard L. , Cotney Justin , Grinblat Yevgenya , Liao Eric C. 
Published: June 2020

ABSTRACTA pedigree of subjects with frontonasal dysplasia (FND) presented with bilateral oblique facial clefts and ocular phenotypes. Genome sequencing and analysis identified a L165F missense variant in the homeodomain of the transcription factorALX1which was imputed to be pathogenic. Induced pluripotent stem cells (iPSC) were derived from the subjects and differentiated to neural crest cells (NCC). NCC derived from ALX1L165F/L165FiPSC were more sensitive to apoptosis, showed an elevated expression of several neural crest progenitor state markers, and exhibited impaired migration compared to wild type controls. NCC migration was also evaluatedin vivousing lineage tracing in a zebrafish model, which revealed defective migration of the anterior NCC stream that contributes to the median portion of the anterior neurocranium, phenocopying the clinical presentation. Analysis of human NCC culture media revealed a change in the level of bone morphogenic proteins (BMP), with a low-level of BMP2 and a high level of BMP9. Soluble BMP2 and BMP9 antagonist treatments were able to rescue the defective migration phenotype. Taken together, these results demonstrate a mechanistic requirement ofALX1in NCC development and migration.
Competition NMR for Detection of Hit/Lead Inhibitors of Protein-Protein Interactions
Authors: Musielak Bogdan , Janczyk Weronika , Rodriguez Ismael , Plewka Jacek , Sala Dominik , Magiera-Mularz Katarzyna , Holak Tad A. 
Published: June 2020

ABSTRACTScreening for small-molecule fragments that can lead to potent inhibitors of protein-protein interactions (PPIs) is often a laborious step as the fragments cannot dissociate the targeted PPI due to their low μM-mM affinities. Here, we describe an NMR competition assay - called w-AIDA-NMR (weak-Antagonist Induced Dissociation Assay-NMR) - that is sensitive to weak μM-mM ligand-protein interactions and which can be used in initial fragment screening campaigns. By introducing point mutations in the complex’s protein that is not targeted by the inhibitor, we lower the effective affinity of the complex allowing for short fragments to dissociate the complex. We illustrate the method with the compounds that block the Mdm2/X-p53 and PD-1/PD-L1 oncogenic interactions. Targeting the PD-/PD-L1 PPI has profoundly advanced the treatment of different types of cancers.
Anatomical Plasticity of the Distal Forelimb Projection of the Ventral Premotor Cortex Four weeks After Primary Motor Cortex Injury
Authors: McNeal David W. , Barbay Scott , Frost Shawn B. , Taylor Michael , Guggenmos David J. , Nudo Randolph J. 
Published: June 2020

AbstractBrain injury affecting the isocortical frontal cortex is a common pathological occurrence. Many patients report severe deficits to functions of daily living. However, there is a variable degree of motor recovery that occurs with some individuals recovering astounding degrees of motor recovery while others have not. This variability has led researchers into investigating the possible mechanisms for this variability. Recently, several non-human primate studies have shed light on the possibility of spared, ipsilesional motor area taken over the lost function to the damaged cortex. Unfortunately, these studies have focused on long-term adaption ranging from 5months to one year post injury. In this present study, we are the first use rigorous stereological quantification to show that significant neuroplastic changes in the form of changes to neuroanatomical connections between distant cortical area occurs at a very early time point of 4 weeks post injury. Much like the Dancause study in 2005, we found that ishemic damage to the distal forelimb area (DFL) of the primary motor cortex (M1) induced plastic changes between the DFL of the ventral premotor cortex (PMv) and area 1/2 of the somatosensory cortex. Indeed, we found a nearly 2 fold increase in the number of boutons between PMV and area 1/2. Additionally, labeled fibers from PMv change direction from their normal termination within M1 and traveled in a ventral posterior direction toward the somatosensory cortex. Also of interest, several labeled fibers actually traveled through the glial scar of M1 toward the somatosensory cortex. These data demonstrate that a massive neuroplastic response has occurred following an ischemic insult to the DFL of M1. These data may suggest that the brain may be undergoing an attempt to re-establish a degree of motor and or sensory control to compensate for the lost function due to the injury.
Effect of Elbow Flexion Angle on Cortical Voluntary Activation of the Non-Impaired Biceps: A 3 Days Repeated Sessions Study
Authors: Roumengous Thibault , Howell Paul A. , Peterson Carrie L. 
Published: June 2020

ABSTRACTMeasurement of cortical voluntary activation (VA) with transcranial magnetic stimulation (TMS) is limited by technical challenges. One challenge is the difficulty in preferential stimulation of cortical neurons projecting to the target muscle and minimal stimulation of cortical neurons projecting to antagonists. Thus, the motor evoked potential (MEP) response to TMS in the target muscle compared to its primary antagonist may be an important parameter in the assessment of cortical VA. Modulating isometric elbow angle alters the magnitude of MEPs at rest. The purpose of this study was to evaluate the effect of isometric elbow flexion-extension angle on: 1) the ratio of biceps MEP relative to the triceps MEP amplitude across a range of voluntary efforts, and 2) cortical VA. Ten non-impaired participants completed three sessions wherein VA was determined using TMS at 45°, 90° and 120° of isometric elbow flexion, and peripheral electrical stimulation at 90° of elbow flexion. The biceps/triceps MEP ratio was greater in the more flexed elbow angle (120° flexion) compared to 90° during contractions of 50% and 75% of maximum voluntary contraction. Cortical VA assessed in the more extended elbow angle (45° flexion) was lower relative to 90° elbow flexion; this effect was dependent on the biceps/triceps MEP ratio. Cortical VA was sensitive to small changes in the linearity of the voluntary torque and superimposed twitch relationship, regardless of the elbow angle. Peripheral and cortical VA measures at 90° of elbow flexion were repeatable across three days. In conclusion, although the biceps/triceps MEP ratio was increased at a more flexed elbow angle relative to 90°, there was not a corresponding difference in cortical VA. Thus, increasing the MEP ratio via elbow angle did not affect estimation of cortical VA.
Regeneration of a Full-Thickness Defect in Rotator Cuff Tendon with Umbilical Cord-Derived Mesenchymal Stem Cells in a Rat Model
Authors: Yea Ji-Hye , Kim InJa , Sym Gayoung , Park Jin-Kyung , Lee Ah-Young , Cho Byeong Chan , Bae Tae Soo , Kim Byoung Jae , Jo Chris Hyunchul 
Published: June 2020

AbstractAlthough rotator cuff disease is a common cause of shoulder pain, there is still no treatment method that could halt or reveres its development and progression. The purpose of this study was to investigate the efficacy of umbilical cord-derived mesenchymal stem cells (UC MSCs) on the regeneration of a full-thickness rotator cuff defect (FTD) in a rat model. We injected either UC MSCs or saline to the FTD and investigated macroscopic, histological and biomechanical results and cell trafficking. Treatment with UC MSCs improved macroscopic appearance in terms of tendon thickness at two weeks, and inflammation, defect size, swelling/redness and connection surrounding tissue and slidability at four weeks compared to the saline group. Histologically, UC MSCs induced the tendon matrix formation recovering collagen organization, nuclear aspect ratio and orientation angle of fibroblast as well as suppressing cartilage-related glycosaminoglycan compared to saline group at four weeks. The UC MSCs group also improved ultimate failure load by 25.0% and 19.0% and ultimate stress by 27.3% and 26.8% at two and four weeks compared to saline group. UC MSCs labeled with PKH26 exhibited 5.3% survival at four weeks compared to three hours after injection. This study demonstrated that UC MSCs regenerated the FTD with tendon tissue similar properties to the normal tendon in terms of macroscopic, histological and biomechanical characteristics in a rat model.
Interactions of SARS-CoV-2 infection with chronic obesity inflammation: a complex network phenomenon
Authors: Favero Giovani Marino , Gomes Mascarenhas Luis Paulo , Furmann Meirielly , Berton Juliana , Miranda Pedro Jeferson 
Published: June 2020

AbstractObesity is one of the biggest public health problems in the world, and its pathophysiological characteristics include chronic inflammation with an increase in various circulating inflammatory markers, such as acute inflammatory cytokines. Complications in the respiratory tract are related to bodily problems, which lead to a restriction of lung function due to reduced volume, inducing an increase in respiratory work. SARS-CoV-2 has a high potential for contamination by respiratory secretions and, therefore, obesity is one of the main risk factors for complications due to the association established between obesity, chronic inflammation and respiratory infection. The objective was to analyze the complex relationships between obesity and COVID-19 in a meta-analysis study using complex network modeling and the theoretical knockouts technique. Here, we identify and justify through a mathematical analysis the relationships between all the immunological agents added to the proposed immunological networks, considered as a simple evident interaction, relationship, influence, response, activation, based on our quantifiers. They performed the knockouts of all 52 vertices in the COVID-19 network and obesity - regardless of the environment, which would result in nonsense - and the COVID-19 infection network without considering obesity. The stationary flow vector (flow profile), for some knockouts of immunological interest in COVID-19 infections, was chosen IFNα, IL-6, IL-10, IL-17 and TNFα. This initial study pointed out the importance of chronic inflammation in the obese individual as an important factor in potentiating the disease caused by covid-19 and, in particular, the importance on IL-17.