bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hoslundia oppositaand other Nigerian plants inhibit sickle hemoglobin polymerization and prevent erythrocyte sickling: a virtual screening-guided identification of bioactive plants
Authors: Olori Eric O. , Olubiyi Olujide O. , Babalola Chinedum P. 
Published: July 2021

AbstractIn sickle cell disease, a hereditary hemoglobinopathy, clinically observed disease presentations are the endpoint of a point mutation involving the substitution of glutamic acid with valine at the position 6 of the beta globin chain. With about 4.4 million people globally being affected, and another 43 million people bearing the sickle cell trait, several research efforts have been made to discover new and affordable treatment and possibly cure for the disease. Africa is endowed with a large flora population and traditional healers and citizens have over time depended on the use of herbs in folkloric medicine for different ailments including sickle cell disease (SCD). Such native knowledge has often formed the basis for different research exploration into the anti-sickling activities of selected African plants. These plants that have been so far investigated for their anti-sickling properties represent about 0.05 % of the 45,000 plant species enriching the flora landscape in Sub-Saharan Africa. Some of these have yielded potent anti-sickling profiles. In the current work we seek to achieve a more extensive search of the African plant diversity with anti-sickling properties: for this we have adopted a hybrid computational-cum-experimental protocol that employed computer-aided drug design (CADD) means for identifying plants with at least one constituent capable of interacting with the sickle hemoglobin, followed by extractive procedures and anti-sickling experiments for validating the predictions. Over two thousand (or 2,000) African natural products, representing over 200 plant species, were first virtually screened against the crystal structure of the dimerized human sickle hemoglobin. The natural products with the best computed sickle hemoglobin interaction energetics were found to belong to five plant species includingCatharanthus roseus, Rauvolfia vomitoria, Hoslundia opposita, Lantana camara and Euphorbia hirta. The leaves of these plants were each collected subsequently and subjected to standard processing and extraction procedures. Using both HbSS polymerization inhibition and sickling reversal tests significant reductions in polymerization of erythrocyte hemolysate of the HbSS genotype were observed with the methanolic extracts of the plants, as well as sickling reversal levels of up to 68.50 % (H. opposita) was observed.
Artificial Intelligence Resolves Kinetic Pathways of Magnesium Binding to RNA
Authors: Neumann Jan , Schwierz Nadine 
Published: July 2021

AbstractMagnesium is an indispensable cofactor in countless vital processes. In order to understand its functional role, the characterization of the binding pathways to biomolecules such as RNA is crucial. Despite the importance, a molecular description is still lacking since the transition from the water-mediated outer-sphere to the direct inner-sphere conformation is on the millisecond timescale and therefore out of reach for conventional simulation techniques. To fill this gap, we use transition path sampling to resolve the binding pathways and to elucidate the role of the solvent in the reaction. The results reveal that the molecular void provoked by the leaving phosphate oxygen of the RNA is immediately filled by an entering water molecule. In addition, water molecules from the first and second hydration shell couple to the concerted exchange. To capture the intimate solute-solvent coupling, we perform a committor analysis as basis for a machine learning algorithm that derives the optimal deep learning model from thousands of scanned architectures using hyperparameter tuning. The results reveal that the properly optimized deep network architecture recognizes the important solvent structures, extracts the relevant information and predicts the commitment probability with high accuracy. Our results provide a quantitative description of solute-solvent coupling which is ubiquitous for kosmotropic ions and governs a large variety of biochemical reactions in aqueous solutions.
Specialized subsets of innate-like T cells and dendritic cells protect from lethal pneumococcal infection in the lung
Authors: Murray Mallory Paynich , Crosby Catherine M. , Marcovecchio Paola , Hartmann Nadine , Chandra Shilpi , Zhao Meng , Khurana Archana , Zahner Sonja P. , Clausen Björn E. , Coleman Fadie T. , Mizgerd Joseph P. , Mikulski Zbigniew , Kronenberg Mitchell 
Published: July 2021

SummaryInnate-like T cells, including invariant natural killer T (iNKT) cells, mucosal-associated invariant T (MAIT) cells and γδ T cells, are present in various barrier tissues, including the lung. They carry out protective responses during infections, but the mechanisms for protection are not completely understood. Here, we investigated their roles during pulmonary infection with Streptococcus pneumoniae. Following infection, innate-like T cells rapidly increased in lung tissue, in part through recruitment, but TCR activation and cytokine production occurred mostly in IL-17-producing NKT17 and γδ T cells. NKT17 cells were preferentially located outside the vasculature prior to infection, as were CD103+ dendritic cells (cDC1), which were important both for antigen presentation to NKT17 cells and γδ T cell activation. Whereas IL-17A-producing γδ T cells also were numerous, GM-CSF was exclusive to NKT17 cells and contributed to iNKT cell-mediated protection. These studies demonstrate how particular cellular interactions and responses of functional subsets of innate-like T cells contribute to protection from pathogenic lung infection.
Supra-physiological levels of gibberellins/DELLAs modify the root cell size/number and the root architecture in root tips of A. thaliana seedlings. Connections to the root hair patterning and abundance
Authors: McCarthy-Suárez Iva 
Published: July 2021

ABSTRACTA previous study (McCarthy-Suárez, 2021) showed that growing A. thaliana seedlings for 5 days under excessive levels of gibberellins (GAs)/DELLAs altered the arrangement, shape and frequency of root hairs in root tips. Because no changes in the distribution or number of root hairs occurred when the gai-1 (gibberellin-insensitive-1) DELLA was over-expressed at the root epidermis, it was concluded that the GAs/DELLAs might regulate the root hair patterning and abundance in A. thaliana seedlings by acting from the root sub-epidermal tissues. In the present study, microscopy analyses showed that excessive levels of GAs/DELLAs also modified the size and number of root tip cells in A. thaliana seedlings. While excessive DELLAs shortened and widened the root epidermal, cortical, endodermal and pericycle cells, excessive GAs, excepting the epidermal cells, generally narrowed them. However, no changes of root cell size occurred when gai-1 was over-expressed at the root epidermis. In addition, high levels of DELLAs often induced extra cells at the root epidermis, cortex, endodermis and pericycle, whereas high levels of GAs sometimes induced extra cells at the root cortex and pericycle. On the other hand, excessive levels of DELLAs enhanced the outgrowth of lateral roots in root tips, unlike excessive levels of GAs. Thus, the results of this study suggest that supra-physiological levels of GAs/DELLAs might modify the size/number of root tip cells by acting from the root sub-epidermal tissues. This, in turn, might impact on the patterning and abundance of root hairs and on the root architecture.
First record ofTemnothorax convexus(Forel, 1894) in Portugal (Hymenoptera: Formicidae) with an updated checklist of ants from the country
Authors: Arcos Javier , Chaves Diogo , Alarcón Paco , Rosado Ángel 
Published: July 2021

AbstractThe arboreal antTemnothorax convexus(Forel, 1894) is reported for the first time in Portugal. A single colony was found nesting inside an abandoned gall near Lisbon. A full morphometric evaluation of the specimens is provided, including a small sample from the recently discovered population in South Iberia. High-definition photographs of the worker caste are given, together with a comparison with the most similar species in Iberia and an update of the Portuguese ant checklist.
Opposing roles of blood-borne monocytes and tissue-resident macrophages in limbal stem cell damage after ocular injury
Authors: Zhou Chengxin , Lei Fengyang , Mittermaier Mirja , Ksander Bruce , Dana Reza , Dohlman Claes H. , Vavvas Demetrios G. , Chodosh James , Paschalis Eleftherios I. 
Published: July 2021

AbstractLimbal stem cell (LSC) deficiency is a frequent and severe complication after chemical injury to the eye. Previous studies have assumed that this is mediated directly by the caustic agent. Here we show that LSC damage occurs through immune cell mediators, even without direct injury to LSCs. In particular, pH elevation in the anterior chamber (AC) causes acute uveal stress, release of inflammatory cytokines at the basal limbal tissue, and subsequent LSC loss. Peripheral CCR2+ CX3CR1- monocytes are the key mediators of LSC damage, through the upregulation of tumor necrosis factor alpha (TNF-α) at the limbus. In contrast to peripherally-derived monocytes, CX3CR1+ CCR2- tissue-resident macrophages have a protective role and their depletion prior to injury exacerbates LSC loss and increases LSC vulnerability to TNF-α-mediated apoptosis independently of CCR2+ cell infiltration into the tissue. Consistently, repopulation of the tissue by new resident macrophages not only restores the protective M2-like phenotype of macrophages but also suppresses LSC loss after exposure to inflammatory signals. These findings may have clinical implication in patient with chemical burns.SignificanceLimbal stem cell (LSC) loss after chemical burn is a significant clinical problem that has long been thought to be the result of direct chemical injury. This study demonstrates the existence of competing inflammatory mechanism responsible for LSC death, mediated by infiltrating peripheral monocytes that antagonize and overcome the protective role of tissue-resident macrophages. Thus, enhancing the role of tissue-resident macrophages while suppressing that of infiltrating monocytes could be a novel therapeutic strategy for LSC survival.
Eukaryotic genomes from a global metagenomic dataset illuminate trophic modes and biogeography of ocean plankton
Authors: Alexander Harriet , Hu Sarah K. , Krinos Arianna I. , Pachiadaki Maria , Tully Benjamin J. , Neely Christopher J. , Reiter Taylor 
Published: July 2021

AbstractMetagenomics is a powerful method for interpreting the ecological roles and physiological capabilities of mixed microbial communities. Yet, many tools for processing metagenomic data are not designed to consider eukaryotes, nor are they built for an increasing amount of sequence data. EukHeist is an automated pipeline to retrieve eukaryotic and prokaryotic metagenome assembled genomes (MAGs) from large-scale metagenomic datasets. We developed the EukHeist workflow to specifically process large amounts of both metagenomic and/or metatranscriptomic sequence data in an automated and reproducible fashion. Here, we applied EukHeist to the large-size fraction data (0.8-2000µm) fromTaraOceans to recover both eukaryotic and prokaryotic MAGs, which we refer to as TOPAZ (TaraOceans Particle-Associated MAGs). The TOPAZ MAGs consisted of >900 environmentally-relevant eukaryotic MAGs and >4,000 bacterial and archaeal MAGs. The bacterial and archaeal TOPAZ MAGs expand the known marine phylogenetic diversity through the increase in coverage of likely particle- and host-associated taxa. We also demonstrate an approach to infer the putative functional mode of the recovered eukaryotic MAGs. A global survey of the TOPAZ MAGs enabled the identification of ecological cohorts, driven by specific environmental factors, and putative host-microbe associations.ImportanceDespite the ecological importance of single-celled eukaryotic organisms in marine environments, the majority are difficult to cultivate in the lab. Sequencing genetic material extracted from environmental samples enables researchers to document naturally-occurring protistan communities. However, conventional sequencing methodologies cannot separate out the genomes of individual organisms. To more completely capture the entire genomic content of mixed protistan community, we can create bins of sequences that represent the same organism. We developed a pipeline that enables scientists to bin individual organisms out of metagenomic reads, and show results that provide exciting insights into what protistan communities are present in the ocean and what roles they play in the ecosystem. Here, a global survey of both eukaryotic and prokaryotic MAGs enabled the identification of ecological cohorts, driven by specific environmental factors, and putative host-microbe associations. Accessible and scalable computational tools, such as EukHeist, are likely to accelerate the identification of meaningful genetic signatures from large datasets, ultimately expanding the eukaryotic tree of life.
Intermittent hypoxia enhances the expression of HIF1A by increasing the quantity and catalytic activity of KDM4A-C and demethylating H3K9me3 at the HIF1A locus
Authors: Martinez Chloe-Anne , Bal Neha , Cistulli Peter A , Cook Kristina M 
Published: July 2021

AbstractCellular oxygen-sensing pathways are primarily regulated by hypoxia inducible factor-1 (HIF-1) in chronic hypoxia and are well studied. Intermittent hypoxia also occurs in many pathological conditions, yet little is known about its biological effects. In this study, we investigated how two proposed cellular oxygen sensing systems, HIF-1 and KDM4A-C, respond to cells exposed to intermittent hypoxia and compared to chronic hypoxia. We found that intermittent hypoxia increases HIF-1 activity through a pathway distinct from chronic hypoxia, involving the KDM4A, -B and -C histone lysine demethylases. Intermittent hypoxia increases the quantity and activity of KDM4A-C resulting in a decrease in H3K9 methylation. This contrasts with chronic hypoxia, which decreases KDM4A-C activity, leading to hypermethylation of H3K9. Demethylation of histones bound to the HIF1A gene in intermittent hypoxia increases HIF1A mRNA expression, which has the downstream effect of increasing overall HIF-1 activity and expression of HIF target genes. This study highlights how multiple oxygen-sensing pathways can interact to regulate and fine tune the cellular hypoxic response depending on the period and length of hypoxia.
Understanding associative false memories in aging using multivariate analyses
Authors: Dennis Nancy A. , Overman Amy A. , Carpenter Catherine M. , Gerver Courtney R. 
Published: July 2021

ABSTRACTAge-related declines in associative memory are ubiquitous, having been observed across a wide array of stimuli and experimental paradigms. Research further shows that such decreases in behavioral discriminability arise from increases in false memories for recombined lures. The current study examined the underlying neural basis of associative false memories by using representational similarity analyses to examine both age differences in the reactivation of encoded representations during retrieval and the neural overlap in the similarity of neural patterns underlying targets and related lures during retrieval. Behaviorally, we observed an age-related reduction in d’, which was shown to be driven by increased false alarms in the older adults. While we found no age difference in the relationship between patterns of neural activity underlying hits across memory phases (as measured by ERS), the similarity of neural patterns underlying targets and lures was affected by age. Specifically, while younger and older adults exhibited overall higher pattern similarity between hits and CRs compared to hits and FAs (as measured by RSA), this difference was reduced in older adults within occipital cortices. Additionally, greater Hit-FA representational similarity correlated with increases in associative FAs across occipital, frontal, and parietal cortices. Results suggest that while neural representations underlying targets may not differ across age, greater pattern similarity between the neural representation of targets and lures may reflect reduced distinctiveness of the information encoded in memory, such that old and new items are more difficult to discriminate, leading to more false alarms.
Inhibition of striatal SEZ6 by miR-3594-5p is a drug-specific marker for late-stage heroin intake escalation
Authors: Lenoir Magalie , Bondi Isabella , Clemenceau Loïc , Nondier Isabelle , Ballé Margaux , Jacques Sébastien , Duché Angéline , Canestrelli Corinne , Martin-Lannerée Séverine , Mouillet-Richard Sophie , Gunnersen Jenny M. , Ahmed Serge H. , Marie Nicolas , Noble Florence 
Published: July 2021

SUMMARYEscalation of drug use is a hallmark stage in the transition to addiction and uncovering its underlying brain molecular mechanisms constitutes a considerable challenge. Here, we report in rats with extended access to heroin for self-administration that miR-3594-5p was upregulated in the dorsal striatum at late, but not early, stages during escalation when excessive heroin intake plateaued. Striatal miR-3594-5p bound directly to the 3’UTR region ofSez6transcript and inhibited its expression, thereby decreasing the mature form of the translated SEZ6 protein. This miR-3594-5p/Sez6interaction was specific to heroin, as it was not observed with cocaine, and correlated with the severity of heroin intake escalation. Our findings reveal that miRNA alterations during escalation of drug self-administration are spatially and temporally regulated and drug-specific.
LAMP2A regulates the loading of proteins into exosomes
Authors: Ferreira João Vasco , da Rosa Soares Ana , Ramalho José , Carvalho Catarina Máximo , Cardoso Maria Helena , Pintado Petra , Carvalho Ana Sofia , Beck Hans Christian , Matthiesen Rune , Zuzarte Mónica , Girão Henrique , van Niel Guillaume , Pereira Paulo 
Published: July 2021

AbstractExosomes are extracellular vesicles of endosomal origin released by virtually all cell types across metazoans. Exosomes are active vehicles of intercellular communication and can transfer lipids, RNAs and proteins between different cells, tissues or organs. However, the mechanisms that regulate the selective loading of cytosolic proteins into these vesicles are still largely unknow. Here we describe a mechanism whereby proteins containing a pentapeptide sequence, biochemically related to the KFERQ-motif, are loaded into a subpopulation of exosomes in a process that is dependent on the membrane protein LAMP2A. Moreover, this mechanism is independent of the ESCRT machinery components TSG101 and VPS4b and dependent on HSC70, CD63, Alix, Syntenin-1, Rab31 and ceramides. The transcription factor and master regulator of hypoxia HIF1A is loaded into exosomes by this mechanism to transport hypoxia signaling to normoxic cells. Additionally, by tagging fluorescent proteins with KFERQ-like sequences we were able to follow inter-organ transfer of exosomes in zebrafish larvae. Our findings identify LAMP2A as a key component in exosome biogenesis while opening new avenues for exosome engineering by allowing the loading of bioactive proteins by tagging them with KFERQ-like motifs.
ABlooper: Fast accurate antibody CDR loop structure prediction with accuracy estimation
Authors: Abanades Brennan , Georges Guy , Bujotzek Alexander , Deane Charlotte M. 
Published: July 2021

AbstractAntibodies are a key component of the immune system and have been extensively used as biotherapeutics. Accurate knowledge of their structure is central to understanding their antigen binding function. The key area for antigen binding and the main area of structural variation in antibodies is concentrated in the six complementarity determining regions (CDRs), with the most important for binding and most variable being the CDR-H3 loop. The sequence and structural variability of CDR-H3 make it particularly challenging to model. Recently deep learning methods have offered a step change in our ability to predict protein structures. In this work we present ABlooper, an end-to-end equivariant deep-learning based CDR loop structure prediction tool. ABlooper rapidly predicts the structure of CDR loops with high accuracy and provides a confidence estimate for each of its predictions. On the models of the Rosetta Antibody Benchmark, ABlooper makes predictions with an average CDR-H3 RMSD of 2.49Å, which drops to 2.05Å when considering only its 76% most confident predictions.
Impact of neurite alignment on organelle motion
Authors: Mytiliniou Maria , Wondergem Joeri A. J. , Schmidt Thomas , Heinrich Doris 
Published: July 2021

AbstractIntracellular transport is pivotal for cell growth and survival. Malfunctions in this process have been associated with devastating neurodegenerative diseases, posing a need for deeper understanding of the involved mechanisms. Here, we used an experimental methodology that lead neurites of differentiated PC12 cells in either of two configurations: an one-dimensional, where the neurites align along lines, or a two-dimensional configuration, where the neurites adopt a random orientation and shape on a fiat substrate. We subsequently monitored the motion of functional organelles, the lysosomes, inside the neurites. Implementing a time-resolved analysis of the mean-squared displacement, we quantitatively characterized distinct motion modes of the lysosomes. Our results indicate that neurite alignment gives rise to faster diffusive and super-diffusive lysosomal motion in comparison to the situation where the neurites are randomly oriented. After inducing lysosome swelling through an osmotic challenge by sucrose, we confirmed the predicted slowdown in diffusive mobility. Surprisingly we found that the swelling-induced mobility change affected each of the (sub-/super-) diffusive motion modes differently and depended on the alignment configuration of the neurites. Our findings imply that intracellular transport is significantly and robustly dependent on cell morphology, which might be in part controlled by the extracellular matrix.
A highly conserved host lipase deacylates oxidized phospholipids and ameliorates acute lung injury
Authors: Zou Benkun , Goodwin Michael , Saleem Danial , Jiang Wei , Tang Jianguo , Chu Yiwei , Munford Robert , Lu Mingfang 
Published: July 2021

AbstractOxidized phospholipids have diverse biological activities, many of which can be pathological, yet how they are inactivatedin vivois not fully understood. Here we present evidence that a previously unsuspected host lipase, acyloxyacyl hydrolase (AOAH), can play a significant role in reducing the pro-inflammatory activities of two prominent products of phospholipid oxidation, 1-palmitoyl-2-glutaryl-sn-glycero-3- phosphocholine (PGPC) and 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC). AOAH removed the sn-2 and sn-1 acyl chains from both lipids and reduced their ability to induce macrophage inflammasome activation and cell deathin vitroand acute lung injuryin vivo. In addition to transforming Gram-negative bacterial lipopolysaccharide from stimulus to inhibitor, its most studied activity, AOAH can inactivate these important danger-associated molecular pattern (DAMP) molecules and reduce tissue inflammation and cell death.