bluuebunny/crossref_metadata_2025_split huggingface dataset:
Blood-based untargeted metabolomics in Relapsing-Remitting Multiple Sclerosis revealed the testable therapeutic target
Authors: Zahoor Insha , Suhail Hamid , Datta Indrani , Ahmed Mohammad Ejaz , Poisson Laila M , Waters Jeffrey , Bin Rui , Singh Jaspreet , Cerghet Mirela , Kumar Ashok , Hoda Md Nasrul , Rattan Ramandeep , Mangalam Ashutosh K , Giri Shailendra 
Published: September 2021

SUMMARYMetabolic aberrations impact the pathogenesis of multiple sclerosis (MS) and possibly can provide clues for new treatment strategies. Using untargeted metabolomics, we measured serum metabolites from 35 relapsing-remitting patients and 14 healthy age-matched controls. Out of 632 known metabolites detected, 60 were significantly altered in relapsing-remitting MS (RRMS). Bioinformatics analysis identified an altered “metabotype” in RRMS patients, represented by 4 changed metabolic pathways of glycerophospholipid, citrate cycle, sphingolipid, and pyruvate metabolism. Interestingly, the common upstream metabolic pathway feeding these 4 pathways is the glycolysis pathway. Real-time bioenergetic analysis of the patient derived peripheral blood mononuclear cells, showed enhanced glycolysis, supporting the altered metabolic state of immune cells. Experimental autoimmune encephalomyelitis mice treated with the glycolytic inhibitor, 2-deoxy-D-glucose ameliorated the disease progression and inhibited the disease pathology significantly by promoting the anti-inflammatory phenotype of monocytes/macrophage in the central nervous system. Our study suggests that targeting glycolysis offers a potential target for MS.
Multiphase Organization Is a Second Phase Transition Within Multi-Component Biomolecular Condensates
Authors: Mazarakos Konstantinos , Zhou Huan-Xiang 
Published: September 2021

ABSTRACTWe present a mean-field theory for the multiphase organization of multi-component biomolecular condensates and validate the theory by molecular dynamics simulations of model mixtures. A first phase transition results in the separation of the dense phase from the bulk phase. In a second phase transition, the components in the dense phase demix to localize in separate regions that attach to each other. The second phase transition occurs when the strength of cross-species attraction goes below the mean strength of the self-attraction of the individual species and reaches a critical value. At a given strength of cross-species attraction, both of the phase transitions can be observed by decreasing temperature, leading first to phase separation and then to demixing of the dense phase. The theory and simulations establish the disparity in strength between self and cross-species attraction as a main driver for the multiphase organization of multi-component biomolecular condensates.TOC GRAPHICS
Active sensing in bees through antennal movements is independent of odor molecule
Authors: Claverie Nicolas , Buvat Pierrick , Casas Jérôme 
Published: September 2021

AbstractWhen sampling odors, many insects are moving their antennae in a complex but repeatable fashion. Previous works with bees have tracked antennal movements in only two dimensions, with a low sampling rate and with relatively few odorants. A detailed characterization of the multimodal antennal movement patterns as function of olfactory stimuli is thus wanting. The aim of this study is to test for a relationship between the scanning movements and the properties of the odor molecule.We tracked several key locations on the antennae of 21 bumblebees at high frequency (up to 1200 fps) and in three dimensions while submitting them to puffs of 11 common odorants released in a low-speed continuous flow. To cover the range of diffusivity and molecule size of most odors sampled by bees, compounds as different as butanol and farnesene were chosen, with variations of 200% in molar masses. Water and paraffin were used as negative controls. Movement analysis was done on the tip, the scape and the base of the antennae tracked with the neural network Deeplabcut.Bees use a stereotypical motion of their antennae when smelling odors, similar across all bees, independently of the identity of the odors and hence their diffusivity. The variability in the movement amplitude among odors is as large as between individuals. The first oscillation mode at low frequencies and large amplitude (ca. 1-3 Hz, ca. 100°) is triggered by the presence of an odor and is in line with previous work, as is the speed of movement. The second oscillation mode at higher frequencies and smaller amplitude (40 Hz, ca. 0.1°) is constantly present. Antennae are quickly deployed when a stimulus is perceived, decorrelate their movement trajectories rapidly and oscillate vertically with a large amplitude and laterally with a smaller one. The cone of air space thus sampled was identified through the 3D understanding of the motion patterns.The amplitude and speed of antennal scanning movements seem to be function of the internal state of the animal, rather than determined by the odorant. Still, bees display an active olfaction strategy. First, they deploy their antennae when perceiving an odor rather than let them passively encounter it. Second, fast vertical scanning movements further increase the flow speed experienced by an antenna and hence the odorant capture rate. Finally, lateral movements might enhance the likelihood to locate the source of odor, similarly to the lateral scanning movement of insects at odor plume boundaries. Definitive proofs of this function will require the simultaneous 3D recordings of antennal movements with both the air flow and odor fields.
Convergent transcriptomic targets of propranolol and primidone identify potential biomarkers for essential tremor
Authors: Castonguay Charles-Etienne , Liao Calwing , Khayachi Anouar , Houle Gabrielle , Ross Jay P , Dion Patrick A , Rouleau Guy A 
Published: September 2021

ABSTRACTEssential tremor (ET) is one of the most common movement disorders, affecting nearly 5% of individuals over 65 years old. Despite its high heritability, few genetic risk loci for ET have been identified. Recent advances in pharmacogenomics have generated a wealth of data that led to the identification of molecular signatures in response to hundreds of chemical compounds. Among the different forms of data, gene expression has proven to be quite successful for the inference of drug response in cell models. We sought to leverage this approach in the context of ET where many patients are responsive two drugs: propranolol and primidone. Propranolol- and primidone-specific transcriptomic drug targets, as well as convergent gene targets across both drugs, could provide insights into the pathogenesis of ET and identify possible targets of interest for future treatments. In this study, cerebellar DAOY and neural progenitor cells were treated for 5 days with clinical concentrations of propranolol and primidone, after which RNA-sequencing was used to identify differentially expressed genes. The expression of genes previously implicated in genetic and transcriptomic studies of ET and other movement disorders, such as TRAPPC11, were significantly upregulated by propranolol. Pathway enrichment analysis identified multiple terms related to calcium signalling, endosomal sorting, axon guidance, and neuronal morphology. Convergent differentially expressed genes across all treatments and cell types were also found to be significantly more mutationally constrained, implying that they might harbour rare deleterious variants implicated in disease. Furthermore, these genes were enriched within cell types having high expression of ET related genes in both cortical and cerebellar tissues. Altogether, our results highlight potential cellular and molecular mechanisms associated with tremor reduction and identify relevant genetic biomarkers for drug-responsiveness in ET.
Development of anin-situprinting system with human platelet lysate-based bio-adhesive to treat corneal perforation
Authors: You Jingjing , Frazer Hannah , Sayyar Sepidar , Chen Zhi , Liu Xiao , Taylor Adam , Filippi Benjamin , Beirne Stephen , Wise Innes , Hodge Chris , Wallace Gordon , Sutton Gerard 
Published: September 2021

AbstractPurposeCorneal perforation is a clinical emergency. Tissue glue to seal the perforation, and supplementary topical medication represents existing standard treatment. Previously, our group developed a transparent human platelet lysate (hPL)-based biomaterial that showed good cell compatibility and accelerated corneal epithelial cells healingin-vitro.This study aims to develop a novel treatment method for corneal perforation using this biomaterial.MethodsRheometry was used to measure the hPL-based biomaterial behaviour at room and corneal surface temperatures. Its adhesiveness to porcine skin and burst pressure limit were also measured. Based on rheological behaviour, a hand-held biopen was developed to extrude it onto the cornea. An animal trial (5 New Zealand white rabbits) to compare impact of the biomaterial and cyanoacrylate glue (control group) on a 2mm perforation was conducted to evaluate safety and efficacy.ResultsThe hPL-based biomaterial showed higher adhesiveness compared to commercial fibrin glue and withstood burst pressure approximately 6.4× higher than routine intraocular pressure. Treatment rabbits had lower pain scores and faster recovery, despite generating similar scar-forming structure compared to controls. No secondary corneal ulcer was generated in rabbits treated with the bio-adhesive.ConclusionsThis study reports a novelin-situprinting system capable of delivering a hPL-based, transparent bio-adhesive and successfully treating small corneal perforations. Bio-adhesive-treated rabbits recovered faster and required no additional analgesia. Both groups showed scarred corneal tissue after healing, however no infection and inflammation was observed by 3 weeks. The delivery system was easy to use and may represent an alternative treatment for corneal perforation.HighlightsThis study presents a novelin situprinting system to treat corneal perforationThe system is comprised of a human platelet lysate-based bio-adhesive and a pen-like hand held delivery systemMechanical tests showed our transparent bio-adhesive has a higher adhesiveness compared to existing treatments and burst pressure threshold approximately 6.4 times higher than normal intraocular pressure.In vivo rabbit trial showed that compared to cyanoacrylate glue, the bio-adhesive was safer, faster healing and led to less pain in rabbits.
Performance of the sea turtleLepidochelys olivaceahatchlings from a hatchery on the Pacific coast of Guatemala
Authors: Morales-Mérida B. Alejandra , Contreras-Mérida María Renee , Cortés-Gómez Adriana , Godfrey Matthew H. , Girondot Marc 
Published: September 2021

AbstractSea turtles are marine species that are generally in danger of extinction. The conservation strategies in the different countries are attempting to preserve these species and should be constantly updating their policies according to research results taking place on site. The most abundant and frequent species of sea turtle that nest in the Pacific Coast of Guatemala isLepidochelys olivacea(Eschscholtz, 1829), therefore human predation has been historically high. The solution to this predation, since the 1970s, as a conservation strategy was to place eggs in enclosed protected spaces called hatcheries, where collectors must give 20% of the nest as a conservation quota. Since this program leads to no natural nests (in situ) remaining on the beaches, the good functioning of the hatcheries plays a fundamental role in the conservation process to work. To understand and predict the fitness of the hatchlings being produced in Guatemalan hatcheries, crawling performance and self-righting performance were measured in 210 hatchlings of the Multiple Uses Area of Hawaii, in the Pacific Coast of Guatemala. The results of the performance were contrasted with incubation conditions to provide an insight into how the management may influence it. We found that self-righting may be a more meaningful measure of variable behavior than crawling performance, showing that there was little variation due to the homogeneous environment of the hatcheries. We can conclude that a greater number of eggs result in faster self-righting, while deeper nests produce hatchlings with slower rates of self-righting.Summary statementWhen hatcheries are the only sea turtle conservation strategy, and their well-functioning is vital to achieve this purpose, performance can provide information of hatchlings’ fitness in response to management conditions.
Optimization of long-term human iPSC-derived spinal motor neuron culture using a dendritic polyglycerol amine-based substrate
Authors: Thiry Louise , Clément Jean-Pierre , Haag Rainer , Kennedy Timothy E , Stifani Stefano 
Published: September 2021

AbstractHuman induced pluripotent stem cells (h-iPSCs) derived from healthy and diseased individuals can give rise to many cell types, facilitating the study of mechanisms of development, human disease modeling, and early drug target validation. In this context, experimental model systems based on h-iPSC-derived motor neurons (MNs) have been used to study MN diseases such as spinal muscular atrophy and amyotrophic lateral sclerosis. Modeling MN disease using h-iPSC-based approaches requires culture conditions that can recapitulate in a dish the events underlying differentiation, maturation, aging, and death of MNs. Current h-iPSC-derived MN-based applications are often hampered by limitations in our ability to monitor MN morphology, survival, and other functional properties over a prolonged timeframe, underscoring the need for improved long-term culture conditions. Here we describe a cytocompatible dendritic polyglycerol amine (dPGA) substrate-based method for prolonged culture of h-iPSC-derived MNs. We provide evidence that MNs cultured on dPGA-coated dishes are more amenable to long-term study of cell viability, molecular identity, and spontaneous network electrophysiological activity. The present study has the potential to improve iPSC-based studies of human MN biology and disease.
EROS is a selective chaperone regulating the phagocyte NADPH oxidase and purinergic signalling
Authors: Randzavola Lyra O. , Mortimer Paige M. , Garside Emma , Dufficy Elizabeth R. , Schejtman Andrea , Roumelioti Georgia , Yu Lu , Pardo Mercedes , Spirohn Kerstin , Tolley Charlotte , Brandt Cordelia , Harcourt Katherine , Nichols Esme , Nahorski Mike , Woods Geoff , Williamson James C. , Suresh Shreehari , Sowerby John M. , Matsumoto Misaki , Santos Celio X.C. , Kiar Cher Shen , Mukhopadhyay Subhankar , Rae Will M. , Dougan Gordon J. , Grainger John , Lehner Paul J. , Calderwood Michael , Choudhary Jyoti , Clare Simon , Speak Anneliese , Santilli Giorgia , Bateman Alex , Smith Kenneth G. C. , Magnani Francesca , Thomas David C. 
Published: September 2021

AbstractEROS (Essential for Reactive Oxygen Species) protein is indispensable for expression of gp91phox, the catalytic core of the phagocyte NADPH oxidase. EROS deficiency in humans is a novel cause of the severe immunodeficiency, chronic granulomatous disease (CGD), but its mechanism of action was unknown until now. We elucidate the role of EROS, showing it acts at the earliest stages of gp91phox maturation. It binds the immature 58kDa gp91phox directly, preventing gp91phox degradation and allowing glycosylation via the oligosaccharyltransferase (OST) machinery and the incorporation of the heme prosthetic groups essential for catalysis. EROS also regulates the purine receptors P2X7 and P2X1 through direct interactions and P2X7 is almost absent in EROS deficient mouse and human primary cells. Accordingly, lack of EROS results in markedly abnormal P2X7 signalling, inflammasome activation and T cell responses. The loss of both ROS and P2X7 signalling leads to resistance to influenza infection. Our work identifies EROS as a highly selective chaperone for key proteins in innate and adaptive immunity and a rheostat for immunity to infection. It has profound implications for our understanding of immune physiology, ROS dysregulation and possibly gene therapy.
ToxoNet: A high confidence map of protein-protein interactions inToxoplasma gondiireveals novel virulence factors implicated in host cell invasion
Authors: Swapna Lakshmipuram S. , Stevens Grant C. , da Silva Aline Sardinha , Hu Lucas Zhongming , Brand Verena , Fusca Daniel D. , Xiong Xuejian , Boyle Jon P. , Grigg Michael E. , Emili Andrew , Parkinson John 
Published: September 2021

ABSTRACTThe apicomplexan intracellular parasiteToxoplasma gondiiis a major food borne pathogen with significant impact in children and during pregnancy. The majority of theT. gondiiproteome remains uncharacterized and the organization of proteins into complexes is unclear. To overcome this knowledge gap, we utilize a biochemical fractionation strategy coupled with mass spectrometry to predict interactions by correlation profiling. Key to this approach is the integration of additional datasets based on gene co-expression as well as phylogenetic profiles that eliminate poorly supported interactions and reduce the number of false positive interactions. In addition to a supervised machine learning strategy, we employed an unsupervised approach in data integration, based on similarity network fusion, to overcome the deficit of high-quality training data in non-model organisms. The resulting high confidence network, we term ToxoNet, comprises 2,063 interactions connecting 652 proteins. Clustering of this network identifies 93 protein complexes, predicting both novel complexes as well as new components for previously known complexes. In particular, we identified clusters enriched in mitochondrial machinery that include previously uncharacterized proteins that likely represent novel adaptations to oxidative phosphorylation. Furthermore, complexes enriched in proteins localized to secretory organelles and the inner membrane complex, predict additional novel components representing novel targets for detailed functional characterization. We present ToxoNet as a publicly available resource with the expectation that it will help drive future hypotheses within the research community.
Interpreting sensory and cognitive signals in the cortical reading network
Authors: Lerma-Usabiaga Garikoitz , Le Rosemary , Gafni Chen , Ben-Shachar Michal , Wandell Brian 
Published: September 2021

AbstractVoxels in the visual cortex contain neurons that are responsive to small regions of the visual field; these regions can be quantified using population receptive field (pRF) analysis. We measured pRFs using several types of patterns: words, visually matched false-fonts, and visually dissimilar checker patterns. In visual field maps pRF estimates using words and false-fonts are similar, but pRF estimates using checkers differ substantially. The pattern of results in the contiguous ventral occipito-temporal reading circuitry is different: word pRF estimates differ from false-fonts and checkers. These findings were replicated at two research sites. We explain these results with a qualitative model, where the response differences in the visual field maps arise from sensory signals, and the differences in the reading circuitry arise from the integration of sensory and cognitive signals.
The future impact of climate and land-use changes on Anatolian ground squirrels under different scenarios
Authors: Gür Hakan 
Published: September 2021

ABSTRACTClimate and land-use changes are among the most important drivers of biodiversity loss and, moreover, their impacts on biodiversity are expected to increase further in the 21st century. In this study, the future impact of climate and land-use changes on Anatolian ground squirrels was assessed. Accordingly, a hierarchical approach with two steps was used. First, ecological niche modelling was used to assess the impact of climate change in areas accessible to Anatolian ground squirrels through dispersal (i.e. the impact of climate change). Second, based on the habitat preferences of ground squirrels, land-use data were used to assess the impact of land-use change in suitable bioclimatic areas for Anatolian ground squirrels under present and future conditions (i.e. the combined impact of both changes). Also, priority areas for the conservation of Anatolian ground squirrels were identified based onin-situclimate change refugia. This study represents a first attempt to combine niche modelling and land-use data for a species in Anatolia, one of the most vulnerable regions to the drivers of biodiversity loss, because it is the region where three of biodiversity hotspots meet, and interact. Habitat availability (i.e. suitable habitats across suitable bioclimatic areas) was projected to decline by 19-69% in the future (depending on the scenario), mainly due to the loss of suitable bioclimatic areas (47-77%, depending on the scenario) at lower elevations and in the western part of the central Anatolia and in the eastern Anatolia, suggesting that Anatolian ground squirrels will contract their range in the future, mainly due to climate change. Thus,in-situclimate change refugia were projected mainly in the eastern and southeastern parts of the central Anatolia, suggesting these regions as priority areas for the conservation of Anatolian ground squirrels.
Four layer multi-omics reveals molecular responses to aneuploidy in Leishmania
Authors: Cuypers B. , Meysman P. , Erb I. , Bittremieux W. , Valkenborg D. , Baggerman G. , Mertens I. , Sundar Shyam , Khanal Basudha , Notredame C. , Dujardin J-C. , Domagalska M.A. , Laukens K. 
Published: September 2021

AbstractAneuploidy causes system-wide disruptions in the stochiometric balances of transcripts, proteins, and metabolites, often resulting in detrimental effects for the organism. The protozoan parasite Leishmania has an unusually high tolerance for aneuploidy, but the molecular and functional consequences for the pathogen remain poorly understood. Here, we addressed this question in vitro and present the first integrated analysis of the genome, transcriptome, proteome, and metabolome of highly aneuploid Leishmania donovani strains. Our analyses unambiguously establish that aneuploidy in Leishmania proportionally impacts the average transcript- and protein abundance levels of affected chromosomes, ultimately correlating with the degree of metabolic differences between strains. This proportionality was present in both proliferative and non-proliferative in vitro promastigotes. However, protein complex subunits and non-cytoplasmic proteins, showed dosage compensation, responding less or even not at all to aneuploidy-induced dosage changes. In contrast to other Eukaryotes, we did not observe the widespread regulation at the transcript level that typically modulates some of the negative effects of aneuploidy. Further, the majority of differentially expressed proteins between aneuploid strains were encoded by non-aneuploid chromosomes and were not driven by a significant underlying transcript change, suggesting that aneuploidy is accompanied by extensive post-transcriptional protein-level modulation. This makes Leishmania a unique Eukaryotic model for elucidating post-transcriptional protein-abundance modulation in the context of aneuploidy.