bluuebunny/crossref_metadata_2025_split huggingface dataset:
Altered fibrin clot structure contributes to thrombosis risk in severe COVID-19
Authors: Wygrecka Malgorzata , Birnhuber Anna , Seeliger Benjamin , Michalick Laura , Pak Oleg , Schultz Astrid-Solveig , Schramm Fabian , Zacharias Martin , Gorkiewicz Gregor , David Sascha , Welte Tobias , Schmidt Julius J. , Weissmann Norbert , Schermuly Ralph T. , Barreto Guillermo , Schaefer Liliana , Markart Philipp , Brack Markus C. , Hippenstiel Stefan , Kurth Florian , Sander Leif E. , Witzenrath Martin , Kuebler Wolfgang M. , Kwapiszewska Grazyna , Preissner Klaus T. 
Published: September 2021

AbstractThe high incidence of thrombotic events suggests a possible role of the contact system pathway in COVID-19 pathology. Here, we demonstrate altered levels of factor XII (FXII) and its activation products in two independent cohorts of critically ill COVID-19 patients in comparison to patients suffering from severe acute respiratory distress syndrome due to influenza virus (ARDS-influenza). Compatible with this data, we report rapid consumption of FXII in COVID-19, but not in ARDS-influenza, plasma. Interestingly, the kaolin clotting time was not prolonged in COVID-19 as compared to ARDS-influenza. Using confocal and electron microscopy, we show that increased FXII activation rate, in conjunction with elevated fibrinogen levels, triggers formation of fibrinolysis-resistant, compact clots with thin fibers and small pores in COVID-19. Accordingly, we observed clot lysis in 30% of COVID-19 patients and 84% of ARDS-influenza subjects. Analysis of lung tissue sections revealed wide-spread extra- and intra-vascular compact fibrin deposits in COVID-19. Together, our results indicate that elevated fibrinogen levels and increased FXII activation rate promote thrombosis and thrombolysis resistance via enhanced thrombus formation and stability in COVID-19.
Legionella pneumophila modulates host energy metabolism by ADP-ribosylation of ADP/ATP translocases
Authors: Fu Jiaqi , Zhou Mowei , Gritsenko Marina A. , Nakayasu Ernesto S. , Song Lei , Luo Zhao-Qing 
Published: September 2021

AbstractThe intracellular pathogen Legionella pneumophila delivers more than 330 effectors into host cells by its Dot/Icm secretion system. Those effectors direct the biogenesis of the Legionella-containing vacuole (LCV) that permits its intracellular survival and replication. It has long been documented that the LCV is associated with mitochondria and a number of Dot/Icm effectors have been shown to target to this organelle. Yet, the biochemical function and host cell target of most of these effectors remain unknown. Here, we found that the Dot/Icm substrate Ceg3 (Lpg0080) is a mono-ADP-ribosyltransferase that localizes to the mitochondria in host cells where it attacks ADP/ATP translocases by ADP-ribosylation, and blunts their ADP/ATP exchange activity. The modification occurs on the second arginine residue in the -RRRMMM- element, which is conserved among all known ADP/ATP carriers from different organisms. Our results reveal modulation of host energy metabolism as a virulence mechanism for L. pneumophila.
Mapping pontocerebellar connectivity with diffusion MRI
Authors: Rousseau Paul-Noel , Chakravarty M. Mallar , Steele Christopher J. 
Published: September 2021

AbstractThe cerebellum’s involvement in cognitive, affective and motor functions is mediated by connections to different regions of the cerebral cortex. A distinctive feature of cortico-cerebellar loops that has been demonstrated in the animal work is a topographic organization that is preserved across its different components. Here we used tractography derived from diffusion imaging data to characterize the connections between the pons and the individual lobules of the cerebellum, and generate a classification of the pons based on its pattern of connectivity. We identified a rostral to caudal gradient in the pons, similar to that observed in the animal work, such that rostral regions were preferentially connected to cerebellar lobules involved in non-motor, and caudal regions with motor regions. These findings advance our fundamental understanding of the cerebellum, and the classifications we generated provide context for future research into the pontocerebellar tract’s involvement in health and disease.
Therapeutic role of Filarial HSP70 in murine models of polymicrobial sepsis and H1N1 Influenza
Authors: Patel Paresh , Siddappa Shilpa , Ravindran Balachandran , Saiyed Taslimarif 
Published: September 2021

AbstractNematodes characteristically modulate effector immune responses by synthesizing and releasing both anti-inflammatory as well as proinflammatory molecules in infected hosts. Pre-clinical studies suggest that immuno-modulatory molecules and synthetic small molecules that mimic parasite products could have therapeutic value to ameliorate tissue damage found in inflammatory diseases. We report here identification of a glycoprotein from filarial parasite, a homologue of mammalian Heat Shock Protein 70 with immunostimulatory attributes. The purified native glycoprotein designated as FHSP70 and its recombinant protein moiety, WFL were found to be TLR2 and TLR4 agonists in vitro in human myeloid cells and induce systemic inflammatory cytokines in vivo. Cecal ligation and puncture (CLP) performed in mice which leads to onset of poly microbial sepsis and mortality could be treated by therapeutic administration of a single dose of FHSP70, along with antibiotics, suggesting its potential as a immunotherapeutic adjuvant for clinical management of Sepsis. Intra-nasal administration of WFL to mice followed by challenge with virulent human Influenza-A virus resulted in decreased viral growth as well as improved survival. The protective effect was demonstrable by both prophylactic as well as therapeutic intranasal administration of WFL. Further, therapeutic administration of WFL by intraperitoneal route 5 days post viral challenge also resulted in significant decrease in viral load in the respiratory tract.One sentence SummarySystemic administration of a Filarial HSP70 acts as an adjuvant therapy, through immuno-modulation, for improved survival against murine Polymicrobial Sepsis and Viral Infection while its intra nasal administration protects mice prophylactically as well as therapeutically against H1N1 Influenza viral challenge.
COMPARISON OF WOODY SPECIES DIVERSITY AND POPULATION STRUCTURE STATUS ACROSS DIFFERENT MANAGEMENT PRACTICE IN THE GOLA NATURAL VEGETATION, EASTER HARARGHE, OROMIA OF ETHIOPIA
Authors: Hussein Abdulbasit , Temesgen Tasisa 
Published: September 2021

AbstractThe research was carried out at Gola natural vegetation eastern Ethiopia, to identify and Woody species' diversity, richness, evenness, and population structural status will be documented, as well as their diversity, richness, evenness, and population structural status will be analyzed. Using systematic sampling procedures, the woody species diversity and population structure of species were examined in 73 quadrats, each measuring 20 m × 20 m for trees and 5 m × 5 m for shrubs and climbers, within three land use systems: farm land (FL), grazing land (GL), and protected area (PA). The diameter at breast height (DBH), richness, evenness, and density of woody species were all measured in the vegetation. The Shannon Weiner Diversity Index was used to examine the diversity of vegetation. A total of 52 woody species belonging to 33 genera, and there were 24 families found. in Gola natural vegetation. Fabaceae was represented by the highest number of species comprising 8 (18.18 %), 9 (25.00 %) and 8 (32%) of the total number of plant species found in PA, GL, and FL. The PA site had significantly highest population density of vegetation, followed by the GL site, while the FL site had the lowest. The total basal area of PA, GL and FL were 43.73, 31.68 and 22.62 m2/ha, respectively. PA site had significantly (P= 0.042) highest Shannon’s diversity index value with mean (3.53) than the others two land use system. This result suggests significance of anthropological disturbance like grazing and farming on woody species diversity and natural forest ecosystem appeared to be adverse dependent on the category and severity of the anthropogenic disturbances.
Effects of early life adversity on meningeal mast cells and proinflammatory gene expression in male and female Mus musculus
Authors: Duque-Wilckens Natalia , Sarno Erika , Teis Robby E. , Stoelting Frauke , Khalid Sonia , Dairi Zakaria , Douma Alex , Maradiaga Nidia , Thelen Kyan , Robison A.J. , Moeser Adam J. 
Published: September 2021

ABSTRACTExposure to early life adversity (ELA) in the form of physical and/or psychological abuse or neglect increases the risk of developing psychiatric and inflammatory disorders later in life. It has been hypothesized that exposure to ELA results in persistent, low grade inflammation that leads to increased disease susceptibility by amplifying the crosstalk between stress-processing brain networks and the immune system, but the mechanisms remain largely unexplored. The meninges, a layer of three overlapping membranes that surround the central nervous system (CNS)- duramater, arachnoid, and piamater – possess unique features that allow them to play a key role in coordinating immune trafficking between the brain and the peripheral immune system. These include a network of lymphatic vessels that carry cerebrospinal fluid from the brain to the deep cervical lymph nodes, fenestrated blood vessels that allow the passage of molecules from blood to the CNS, and a rich population of resident mast cells, master regulators of the immune system. Using a mouse model of ELA consisting of neonatal maternal separation plus early weaning (NMSEW), we sought to explore the effects of ELA on duramater mast cell histology and expression of inflammatory markers in male and female C57Bl/6 mice. We found that mast cell number, activation level, and relative expression of pseudopodia differ across duramater regions, and that NMSEW exerts region-specific effects on mast cells in males and females. Using gene expression analyses, we next found that NMSEW increases the expression of inflammatory markers in the duramater of females but not males, and that this is prevented by pharmacological inhibition of mast cells with ketotifen. Together, our results show that ELA drives sex-specific, long-lasting effects on the duramater mast cell population and immune-related gene expression, suggesting that the long-lasting effects of ELA on disease susceptibility could be partly mediated by meningeal function.
Two common and distinct forms of variation in human functional brain networks
Authors: Dworetsky Ally , Seitzman Benjamin A. , Adeyemo Babatunde , Nielsen Ashley N. , Hatoum Alexander S. , Smith Derek M. , Nichols Thomas E. , Neta Maital , Petersen Steven E. , Gratton Caterina 
Published: September 2021

AbstractThe cortex has a characteristic layout with specialized functional areas forming distributed large-scale networks. However, substantial work shows striking variation in this organization across people, which relates to differences in behavior. While most prior work treats all individual differences as equivalent and primarily linked to boundary shifts between the borders of regions, here we show that cortical ‘variants’ actually occur in two different forms. In addition to border shifts, variants also occur at a distance from their typical position, forming ectopic intrusions. Both forms of variants are common across individuals, but the forms differ in their location, network associations, and activations during tasks, patterns that replicate across datasets and methods of definition. Border shift variants also track significantly more with shared genetics than ectopic variants, suggesting a closer link between ectopic variants and environmental influences. Further, variant properties are categorically different between subgroups of individuals. Exploratory evidence suggests that variants can predict individual differences in behavior, but the two forms differ in which behavioral phenotypes they predict. This work argues that individual differences in brain organization commonly occur in two dissociable forms – border shifts and ectopic intrusions – suggesting that these types of variation are indexing distinct forms of cortical variation that must be separately accounted for in the analysis of cortical systems across people. This work expands our knowledge of cortical variation in humans and helps reconceptualize the discussion of how cortical systems variability arises and links to individual differences in cognition and behavior.
Darwin’s finches - an adaptive radiation constructed from ancestral genetic modules
Authors: Rubin Carl-Johan , Enbody Erik D. , Dobreva Mariya P. , Abzhanov Arhat , Davis Brian W. , Lamichhaney Sangeet , Pettersson Mats , Sprehn C. Grace , Valle Carlos A. , Vasco Karla , Wallerman Ola , Grant B. Rosemary , Grant Peter R. , Andersson Leif 
Published: September 2021

AbstractRecent adaptive radiations are models for investigating mechanisms contributing to the evolution of biodiversity. An unresolved question is the relative importance of new mutations, ancestral variants, and introgressive hybridization for phenotypic evolution and speciation. Here we address this issue using Darwin’s finches, which vary in size from an 8g warbler finch with a pointed beak to a 40g large ground finch with a massive blunt beak. We present a highly contiguous genome assembly for one of the species and investigate the genomic architecture underlying phenotypic diversity in the entire radiation. Admixture mapping for beak and body size in the small, medium and large ground finches revealed 28 loci showing strong genetic differentiation. These loci represent ancestral haplotype blocks with origins as old as the Darwin’s finch phylogeny (1-2 million years). Genes expressed in the developing beak are overrepresented in these genomic regions. Frequencies of allelic variants at the 28 loci covary with phenotypic similarities in body and beak size across the Darwin’s finch phylogeny. These ancestral haplotypes constitute genetic modules for selection, and act as key determinants of the exceptional phenotypic diversity of Darwin’s finches. Such ancestral haplotype blocks can be critical for how species adapt to environmental variability and change.
Interplay between Brownian motion and cross-linking kinetics controls bundling dynamics in actin networks
Authors: Maxian Ondrej , Donev Aleksandar , Mogilner Alex 
Published: September 2021

AbstractMorphology changes in cross-linked actin networks are important in cell motility, division, and cargo transport. Here we study the transition from a weakly cross-linked network of actin filaments to a heavily cross-linked network of actin bundles through microscopic Brownian dynamics simulations. We show that this transition occurs in two stages: first, a composite bundle network of small and highly aligned bundles evolves from cross linking of individual filaments; second, small bundles coalesce into the clustered bundle state. We demonstrate that Brownian motion speeds up the first stage of this process at a faster rate than the second. We quantify the time to reach the composite bundle state and show that it is a strong function of mesh size only when the concentration of cross links is small, and that it remains roughly constant if we decrease the relative ratio of cross linkers as we increase the actin concentration. Finally, we examine the dependence of the bundling timescale on filament length, finding that shorter filaments bundle faster because they diffuse faster.
The response of a metapopulation to a changing environment
Authors: Barton Nick , Olusanya Oluwafunmilola 
Published: September 2021

AbstractA species distributed across diverse environments may adapt to local conditions. We ask how quickly such a species changes its range in response to changed conditions. Szep et al (Evolution, 2021) used the infinite island model to find the stationary distribution of allele frequencies and deme sizes. We extend this to find how a metapopulation responds to changes in carrying capacity, selection strength, or migration rate when deme sizes are fixed. We further develop a “fixed-state” approximation. Under this approximation, polymorphism is only possible for a narrow range of habitat proportions when selection is weak compared to drift, but for a much wider range otherwise. When rates of selection or migration relative to drift change in a single deme of the metapopulation, the population takes a time of order 1/m to reach the new equilibrium. However, even with many loci, there can be substantial fluctuations in net adaptation, because at each locus, alleles randomly get lost or fixed. Thus, in a finite metapopulation, variation may gradually be lost by chance, even if it would persist in an infinite metapopulation. When conditions change across the whole metapopulation, there can be rapid change, which is predicted well by the fixed-state approximation.
SGLT2 inhibitors therapy protects glucotoxicity-induced β-cell failure in a mouse model of human KATP-induced diabetes trough mitigation of oxidative and ER stress
Authors: Shyr Zeenat A. , Yan Zihan , Ustione Alessandro , Egan Erin M. , Remedi Maria S. 
Published: September 2021

AbstractProgressive loss of pancreatic β-cell functional mass and anti-diabetic drug responsivity are classic findings in diabetes, frequently attributed to compensatory insulin hypersecretion and β-cell exhaustion. However, loss of β-cell mass and identity still occurs in mouse models of human KATP-gain-of-function induced Neonatal Diabetes Mellitus (NDM), in the absence of insulin secretion. Here we studied the mechanisms underlying and temporal progression of glucotoxicity-induced loss of functional β-cell mass in NDM mice, and the effects of sodium-glucose transporter 2 inhibitors (SGLT2i) therapy. Upon tamoxifen induction of transgene expression, NDM mice developed severe diabetes followed by an unexpected loss of insulin content, decreased proinsulin processing and proinsulin accumulation at 2-weeks of diabetes. This was accompanied by a marked increase in β-cell oxidative and ER stress, without changes in islet cell identity. Strikingly, early treatment with the SGLT2 inhibitor dapagliflozin restored insulin content, decreased proinsulin:insulin ratio and reduced oxidative and ER stress. However, despite reduction of blood glucose, dapagliflozin therapy was ineffective in restoring β-cell function in NDM mice when tit was initiated at >40 days of diabetes, when loss of β-cell mass and identity had already occurred. These results have important clinical implications as they demonstrate that: i) hyperglycemia per se, and not insulin hypersecretion, drives β-cell failure in diabetes, ii) recovery of β-cell function by SGLT2 inhibitors is through reduction of oxidative and ER stress, iii) SGLT2 inhibitors revert/prevent β-cell failure when used in early stages of diabetes, but not when loss of β-cell mass/identity already occurred, iv) common execution pathways underlie loss and recovery of β-cell function in different forms of diabetes.
Dual regulation of spine-specific and synapse-to-nucleus signaling by PKCδ during plasticity
Authors: Colgan Lesley A. , Parra-Bueno Paula , Holman Heather L. , Calubag Mariah F. , Misler Jaime A. , Tu Xun , Yasuda Ryohei 
Published: September 2021

AbstractThe activity-dependent plasticity of synapses is believed to be the cellular basis of learning. These synaptic changes are mediated through the coordination of local biochemical reactions in synapses and changes in gene transcription in the nucleus to modulate neuronal circuits and behavior. The protein kinase C (PKC) family of isozymes has long been established as critical for synaptic plasticity. However, due to a lack of suitable isozyme-specific tools, the role of the novel subfamily of PKC isozymes is largely unknown. Here, through the development of FLIM-FRET activity sensors, we investigate novel PKC isozymes in synaptic plasticity in mouse CA1 pyramidal neurons. We find that PKCδ is activated downstream of TrkB and that the spatiotemporal nature of its activation depends on the plasticity stimulation. In response to single spine plasticity, PKCδ is activated primarily in the stimulated spine and is required for local expression of plasticity. However, in response to multi-spine stimulation, a long-lasting and spreading activation of PKCδ scales with the number of spines stimulated and, by regulating CREB activity, couples spine plasticity to transcription in the nucleus. Thus, PKCδ plays a dual functional role in facilitating synaptic plasticity.
A p53-Phosphoinositide Signalosome Regulates Nuclear Akt Activation
Authors: Chen Mo , Choi Suyong , Wen Tianmu , Chen Changliang , Thapa Narendra , Cryns Vincent L. , Anderson Richard A. 
Published: September 2021

AbstractThe tumor suppressor p53 and the phosphoinositide 3-kinase (PI3K)-Akt pathway have fundamental roles in regulating cell growth, apoptosis and are frequently mutated in cancer. Here, we show that genotoxic stress induces nuclear Akt activation by a p53-dependent mechanism that is independent from the canonical membrane-localized PI3K-Akt pathway. Upon genotoxic stress a nuclear p53-PI3,4,5P3 complex is generated in regions devoid of membranes by a nuclear PI3K, and this complex recruits all the kinases required to activate Akt and phosphorylate FOXOs, inhibiting DNA damage-induced apoptosis. Wild-type p53 activates nuclear Akt in an on/off fashion upon stress, whereas mutant p53 stimulates high basal Akt activity, indicating a fundamental difference. The nuclear p53-phosphoinositide signalosome is distinct from the canonical membrane-localized pathway and insensitive to PI3K inhibitors currently in the clinic, underscoring its therapeutic relevance.In briefp53 assembles a PI3K-Akt pathway that regulates nuclear Akt activation independent of the canonical pathway on membranes.