bluuebunny/crossref_metadata_2025_split huggingface dataset:
FORUM: Building a Knowledge Graph from public databases and scientific literature to extract associations between chemicals and diseases
Authors: Delmas M. , Filangi O. , Paulhe N. , Vinson F. , Duperier C. , Garrier W. , Saunier P.-E. , Pitarch Y. , Jourdan F. , Giacomoni F. , Frainay C. 
Published: February 2021

AbstractMetabolomics studies aim at reporting a metabolic signature (list of metabolites) related to a particular experimental condition. These signatures are instrumental in the identification of biomarkers or classification of individuals, however their biological and physiological interpretation remains a challenge. Overcoming this challenge is critical when aiming to associate metabolic signatures with potential pathological outcomes. To support this task, we introduce FORUM: a Knowledge Graph (KG) providing a semantic representation of relations between chemicals and biomedical concepts, built from a federation of life science databases and scientific literature repositories. An important number of scientific articles discuss relations between chemical compounds and biomedical concepts in various contexts, from biomarkers to therapeutic uses. The extraction of these statements and their interconnection in a graph structure can thus allow us to identify and explore relations strongly supported in the scientific literature.The use of a Semantic Web framework on biological data allows us to apply ontological based reasoning to infer new relations between entities. We show that these new relations provide different levels of abstraction and could open the path to new hypotheses. We estimate the statistical relevance of each extracted relation, explicit or inferred, using an enrichment analysis, and instantiate them as new knowledge in the KG to support results interpretation/further inquiries. Beyond this result, FORUM can also provide insights into complex biological questions and the extracted information could then be used for further developments.Containing more than 8 billion triples and providing more than 8 million relations, FORUM leverages the increasing availability of linked datasets in life science and is built in agreement with FAIR principles. A web interface to browse and download the extracted relations, as well as a SPARQL endpoint to directly probe the whole FORUM knowledge graph, are available athttps://forum-webapp.semantic-metabolomics.fr. The code needed to reproduce the triplestore is available athttps://github.com/eMetaboHUB/Forum-DiseasesChem.
Structural origins of protein conformational entropy
Authors: Caro José A. , Valentine Kathleen G. , Wand A. Joshua 
Published: February 2021

AbstractThe thermodynamics of molecular recognition by proteins is a central determinant of complex biochemistry. For over a half-century detailed cryogenic structures have provided deep insight into the energetic contributions to ligand binding by proteins1. More recently, a dynamical proxy based on NMR-relaxation methods has revealed an unexpected richness in the contributions of conformational entropy to the thermodynamics of ligand binding2,3,4,5. There remains, however, a discomforting absence of an understanding of the structural origins of fast internal motion and the conformational entropy that this motion represents. Here we report the pressure-dependence of fast internal motion within the ribonuclease barnase and its complex with the protein barstar. Distinctive clustering of the pressure sensitivity correlates with the presence of small packing defects or voids surrounding affected side chains. Prompted by this observation, we performed an analysis of the voids surrounding over 2,500 methyl-bearing side chains having experimentally determined order parameters. We find that changes in unoccupied volume as small as a single water molecule surrounding buried side chains greatly affects motion on the subnanosecond timescale. The discovered relationship begins to permit construction of a united view of the relationship between changes in the internal energy, as exposed by detailed structural analysis, and the conformational entropy, as represented by fast internal motion, in the thermodynamics of protein function.
Environmental enrichment mitigates stroke-induced change in sharp-wave associated ripple characteristics
Authors: Ip Zachary , Rabiller Gratianne , He Ji-Wei , Chavan Shivalika , Nishijima Yasuo , Akamatsu Yosuke , Liu Jialing , Yazdan-Shahmorad Azadeh 
Published: February 2021

AbstractCognitive and memory impairments are common sequelae after stroke, yet how middle cerebral artery (MCA) stroke chronically affects the neural activity of the hippocampus, a brain region critical for memory but remote from the stroke epicenter, is poorly understood. Environmental enrichment (EE) improves cognition following stroke; however, the electrophysiology that underlies this behavioral intervention is still elusive. We recorded local field potentials simultaneously from sensorimotor cortex and hippocampus in rats following MCA occlusion and subsequent EE treatment. We found that MCA stroke significantly impacted the electrophysiology in the hippocampus, in particular it disrupted characteristics of sharp-wave associated ripples (SPW-Rs) which are known correlates of memory and cognition. Importantly, we show that EE mitigates stroke-induced changes to SPW-R characteristics. These results begin to uncover the complex interaction between cognitive deficit following stroke and EE treatment, providing a testbed to assess different strategies for therapeutics following stroke.
Rapid evolution of complete dosage compensation inPoecilia
Authors: Metzger David C.H. , Sandkam Benjamin A. , Darolti Iulia , Mank Judith E. 
Published: February 2021

ABSTRACTDosage compensation balances gene expression between the sexes in systems with diverged heterogametic sex chromosomes. Theory predicts that dosage compensation should rapidly evolve in parallel with the divergence of sex chromosomes to prevent the deleterious effects of dosage imbalances that occur as a result of sex chromosome divergence. Examples of complete dosage compensation, where gene expression of the entire sex chromosome is compensated, are rare and have only been found in relatively ancient sex chromosome systems. Consequently, very little is known about the evolutionary dynamics of complete dosage compensation systems. We recently found the first example of complete dosage compensation in a fish,Poecilia picta. We also found that the Y chromosome degraded substantially in the common ancestor ofP. pictaand their close relativePoecilia parae. In this study we find thatP. paraealso have complete dosage compensation, thus complete dosage compensation likely evolved in the short (∼3.7 my) interval after the split of the ancestor of these two species fromP. reticulata, but before they diverged from each other. These data suggest that novel dosage compensation mechanisms can evolve rapidly, thus supporting the longstanding theoretical prediction that such mechanisms arise in parallel with rapidly diverging sex chromosomes.SIGNIFICANCE STATEMENTIn species with XY sex chromosomes, females (XX) have as many copies of X-linked genes compared to males (XY), leading to unbalanced expression between the sexes. Theory predicts that dosage compensation mechanisms should evolve rapidly as X and Y chromosomes diverge, but examples of complete dosage compensation in recently diverged sex chromosomes are scarce, making this theory difficult to test. Across Poeciliid species the X and Y chromosomes have recently diversified. Here we find complete dosage compensation evolved rapidly as the X and Y diverged in the common ancestor ofPoecilia paraeandP. picta, supporting that novel dosage compensation mechanisms can evolve rapidly in tandem with diverging sex chromosomes. These data confirm longstanding theoretical predictions of sex chromosome evolution.
Remarked Suppression of Aβ42 Protomer-Protomer Dissociation Reaction Elucidated by Molecular Dynamics Simulation
Authors: Kurisaki Ikuo , Tanaka Shigenori 
Published: February 2021

AbstractMultimeric protein complexes are molecular apparatuses to regulate biological systems and often determine their fate. Among proteins forming such molecular assemblies, amyloid proteins have drawn attention over a half-century since amyloid fibril formation of these proteins is supposed to be a common pathogenic cause for neurodegenerative diseases. This process is triggered by the accumulation of fibril-like aggregates, while the microscopic mechanisms are mostly elusive due to technical limitation of experimental methodologies in individually observing each of diverse aggregate species in the aqueous solution. We then addressed this problem by employing atomistic molecular dynamics simulations for the paradigmatic amyloid protein, amyloid-β (1-42) (Aβ42). Seven different dimeric forms of oligomeric Aβ42 fibril-like aggregate in aqueous solution, ranging from tetramer to decamer, were considered. We found additive effects of the size of these fibril-like aggregates on their thermodynamic stability and have clarified kinetic suppression of protomer-protomer dissociation reactions at and beyond the point of pentamer dimer formation. This observation was obtained from the specific combination of the Aβ42 protomer structure and the physicochemical condition that we here examined, while it is worthwhile to recall that several amyloid fibrils take dimeric forms of their protomers. We could thus conclude that the stable formation of fibril-like protomer dimer should be involved in a turning point where rapid growth of amyloid fibrils is triggered.
PolyA: a tool for adjudicating competing annotations of biological sequences
Authors: Carey Kaitlin M. , Hubley Robert , Lesica George T. , Olson Daniel , Roddy Jack W. , Rosen Jeb , Shingleton Audrey , Smit Arian F. , Wheeler Travis J. 
Published: February 2021

AbstractAnnotation of a biological sequence is usually performed by aligning that sequence to a database of known sequence elements. When that database contains elements that are highly similar to each other, the proper annotation may be ambiguous, because several entries in the database produce high-scoring alignments. Typical annotation methods work by assigning a label based on the candidate annotation with the highest alignment score; this can overstate annotation certainty, mislabel boundaries, and fails to identify large scale rearrangements or insertions within the annotated sequence. Here, we present a new software tool, PolyA, that adjudicates between competing alignment-based annotations by computing estimates of annotation confidence, identifying a trace with maximal confidence, and recursively splicing/stitching inserted elements. PolyA communicates annotation certainty, identifies large scale rearrangements, and detects boundaries between neighboring elements.
Clinically Validated Model Predicts the Effect of Intratumoral Heterogeneity on Overall Survival for Non-Small Cell Lung Cancer (NSCLC) Patients
Authors: Ghaderi Nima , Jung Joseph H. , Odde David J. , Peacock Jeffrey 
Published: February 2021

AbstractPurposeWe demonstrate the importance of considering intratumoral heterogeneity and the development of resistance during fractionated radiotherapy when the same dose of radiation is delivered for all fractions (Fractional Equivalent Dosing FED).Materials and MethodsA mathematical model was developed with the following parameters: a starting population of 1011non-small cell lung cancer (NSCLC) tumor cells, 48-hour doubling time, and cell death per the linear-quadratic (LQ) model with α and β values derived from RSIα/β, in a previously described gene expression based model that estimates α and β. To incorporate both inter- and intratumor radiation sensitivity, RSIα/β output for each patient sample is assumed to represent an average value in a gamma distribution with the bounds set to -50% and +50% of RSIα/b. Therefore, we assume that within a given tumor there are subpopulations that have varying radiation sensitivity parameters that are distinct from other tumor samples with a different mean RSIα/β. A simulation cohort (SC) comprised of 100 lung cancer patients with available RSIα/β (patient specific α and β values) was used to investigate 60Gy in 30 fractions with fractionally equivalent dosing (FED). A separate validation cohort (VC) of 57 lung cancer patients treated with radiation with available local control (LC), overall survival (OS), and tumor gene expression was used to clinically validate the model. Cox regression was used to test for significance to predict clinical outcomes as a continuous variable in multivariate analysis (MVA). Finally, the VC was used to compare FED schedules with various altered fractionation schema utilizing a Kruskal-Wallis test. This was examined using the end points of end of treatment log cell count (LCC) and by a parameter described as mean log kill efficiency (LKE) defined as:ResultsCox regression analysis on LCC for the VC demonstrates that, after incorporation of intratumoral heterogeneity, LCC has a linear correlation with local control (p = 0.002) and overall survival (p =< 0.001). Other suggested treatment schedules labeled as High Intensity Treatment (HIT) with a total 60Gy delivered over 6 weeks have a lower mean LCC and an increased LKE compared to standard of care 60Gy delivered in FED in the VC.ConclusionWe find that LCC is a clinically relevant metric that is correlated with local control and overall survival in NSCLC. We conclude that 60Gy delivered over 6 weeks with altered HIT fractionation leads to an enhancement in tumor control compared to FED when intratumoral heterogeneity is considered.
Nano-hydroxyapatite coating synthesized on quasi-fibrillar superstructures of collagen hydrolysate leads to superior osteoblast proliferation when compared to nano-hydroxyapatite synthesized on collagen fibrils
Authors: Banerjee Pradipta , Bajaj Mayur , Bhat Chetna , Geethika Y , Irle Hemanth 
Published: February 2021

AbstractThis study had a two-fold objective: To utilize collagen hydrolysate for synthesizing a nanoscale Hydroxyapatite (HA) coating that would act as a superior osteoblast adhesion/proliferation agent compared to collagen-derived HA (C/HA) and to comprehend the significant role played by structural constraints on HA nucleation. Collagen was extracted from pacu skin with a high yield of 65.3% (w/w of tissue). It was digested by collagenase and the hydrolysate (CH) was purified with a high yield of 0.68g/g of collagen. The CH peptides had a mass of 6kDa, a predominant PP-II conformation and formed self-assembling hierarchical structures at physiological pH with dimensions of 842.2±229nm. The HA synthesized on CH (CH/HA) displayed higher yield when compared to C/HA. Structural analysis of CH/HA revealed that the PP-II peptides coiled to form mimic-helical moieties with reduced intermolecular packing distance of 0.9nm. The mimic helices cross-linked to form a vast quasi-fibrillar network that was comparatively smaller than collagen fibrils but exhibited enhanced stability and greater dynamicity. CH/HA displayed intense calcium-carboxyl interactions, sharper diffraction planes, smaller size of 48±6.2nm and a Ca/P ratio closer to 1.69 when compared to C/HA along with displaying serrated edge blooming crystals. Because of the small size, the CH/HA nanocrystals displayed significantly better osteoblast adhesion than C/HA and reduced the doubling time of cells. Overall, the results indicated that CH based nanocomposites displayed suitable morphological characteristics and cellular response for potential application as implant and bone graft coating material.Graphical abstract
Genomes of gut bacteria fromNasoniawasps shed light on phylosymbiosis and microbe-assisted hybrid breakdown
Authors: Cross Karissa L. , Leigh Brittany A. , Hatmaker E. Anne , Mikaelyan Aram , Miller Asia K. , Bordenstein Seth R. 
Published: February 2021

ABSTRACTPhylosymbiosis is a cross-system trend whereby microbial community relationships recapitulate the host phylogeny. InNasoniaparasitoid wasps, phylosymbiosis occurs throughout development, is distinguishable between sexes, and benefits host development and survival. Moreover, the microbiome shifts in hybrids as a rareProteusbacteria in the microbiome becomes dominant. The larval hybrids then catastrophically succumb to bacterial-assisted lethality and reproductive isolation between the species. Two important questions for understanding phylosymbiosis and bacterial-assisted lethality in hybrids are: (i) Do theNasoniabacterial genomes differ from other animal isolates and (ii) Are the hybrid bacterial genomes the same as those in the parental species? Here we report the cultivation, whole genome sequencing, and comparative analyses of the most abundant gut bacteria inNasonialarvae,Providencia rettgeriandProteus mirabilis. Characterization of new isolates showsProteus mirabilisforms a more robust biofilm thanProvidencia rettgeriand when grown in co-culture,Proteus mirabilissignificantly outcompetesProvidencia rettgeri. Providencia rettgerigenomes fromNasoniaare similar to each other and more divergent to pathogenic, human-associates strains.Proteus mirabilisfromN. vitripennis, N. giraulti, and their hybrid offspring are nearly identical and relatively distinct from human isolates. These results indicate that members of the larval gut microbiome withinNasoniaare most similar to each other, and the strain of the dominantProteus mirabilisin hybrids is resident in parental species. Holobiont interactions between shared, resident members of the wasp microbiome and the host underpin phylosymbiosis and hybrid breakdown.IMPORTANCEAnimal and plant hosts often establish intimate relationships with their microbiomes. In varied environments, closely-related host species share more similar microbiomes, a pattern termed phylosymbiosis. When phylosymbiosis is functionally significant and beneficial, microbial transplants between host species or host hybridization can have detrimental consequences on host biology. In theNasoniaparasitoid wasp genus that contains a phylosymbiotic gut community, both effects occur and provide evidence for selective pressures on the holobiont. Here, we show that bacterial genomes inNasoniadiffer from other environments and harbor genes with unique functions that may regulate phylosymbiotic relationships. Furthermore, the bacteria in hybrids are identical to parental species, thus supporting a hologenomic tenet that the same members of the microbiome and the host genome impact phylosymbiosis, hybrid breakdown, and speciation.
Suppression ofPlasmodiumMIF-CD74 Signaling Protects Against Severe Malaria
Authors: Garcia Alvaro Baeza , Siu Edwin , Du Xin , Leng Lin , Franke-Fayard Blandine , Janse Chris J , Howland Shanshan W , Rénia Laurent , Lolis Elias , Bucala Richard 
Published: February 2021

AbstractMalaria begins when mosquito-bornePlasmodiumsporozoites invade hepatocytes and usurp host pathways to support the differentiation and multiplication of erythrocyte-infective merozoite progeny. The deadliest complication of infection, cerebral malaria, accounts for the majority of malarial fatalities. Although our understanding of the cellular and molecular mechanisms underlying the pathology remains incomplete, recent studies support the contribution of systemic and neuroinflammation as the cause of cerebral edema and blood-brain barrier (BBB) dysfunction. AllPlasmodiumspecies encode an orthologue of the innate cytokine, Macrophage Migration Inhibitory Factor (MIF), which functions in mammalian biology to regulate innate responses.PlasmodiumMIF (PMIF) similarly signals through the host MIF receptor CD74, leading to an enhanced inflammatory response. We investigated the PMIF-CD74 interaction in the onset of experimental cerebral malaria (ECM) using CD74 deficient (Cd74−/−) mice, which were found to be protected from ECM. The protection was associated with the inability of brain microvessels fromCd74−/−hosts to present parasite antigen to sequesteredPlasmodium-specific CD8+T cells. Infection of mice with PMIF-deficient sporozoites (PbAmif-) also protected mice from ECM, highlighting the pivotal role of PMIF in the pre-erythrocytic stage of the infection. A novel pharmacologic PMIF-selective antagonist reduced PMIF/CD74 signaling and fully protected mice from ECM. These findings reveal a conserved mechanism forPlasmodiumusurpation of host CD74 signaling and suggest a tractable approach for new pharmacologic intervention.
Aggregation-induced emission dots assisted non-invasive fluorescence hysterography in near-infrared IIb window
Authors: Yu Xiaoming , Ying Yanyun , Feng Zhe , Qi Ji , Zheng Junyan , Zhang Yuhuang , Liu Juan , Qian Jun , Tang Ben Zhong , Zhang Dan 
Published: February 2021

AbstractUterine diseases seriously threaten the physical and mental health of women. The main principle, when clinicians adopt examinations, is to achieve efficient diagnosis without negative effect on the physical function including fertility. Hysterography in near-infrared (NIR) IIb window (1500-1700 nm) presents perceptibly enhanced signal to background ratio (SBR) and higher penetration capability compared with those beyond 1000 nm and 1300 nm, but lays down high requirements for the biosafety of fluorophores at the same time. Assisted by the biologically excretable aggregation-induced emission (AIE) dots, non-invasive NIR-IIb fluorescence hysterography visualized typical Y-shaped uteruses, real-time uterine peristalsis or the uterine lesions (mimetic disease statuses in clinic) in mouse models. Significantly, after intrauterine perfusion, the reproductive capacity was unimpaired via fertility assessment and histological analysis. This work could inspire some new ideas for non-invasive clinical diagnosis of uterine diseases and effectively promote the clinical translation of AIE dots.
Mutation N501Y in RBD of Spike Protein Strengthens the Interaction between COVID-19 and its Receptor ACE2
Authors: Tian Fang , Tong Bei , Sun Liang , Shi Shengchao , Zheng Bin , Wang Zibin , Dong Xianchi , Zheng Peng 
Published: February 2021

ABSTRACTSARS-CoV-2 is spreading around the world for the past year. Enormous efforts have been taken to understand its mechanism of transmission. It is well established now that the receptor-binding domain (RBD) of the spike protein binds to the human angiotensin-converting enzyme 2 (ACE2) as its first step of entry. Being a single-stranded RNA virus, SARS-CoV-2 is evolving rapidly. Recently, several variants such as B.1.1.7, B.1.351, and P.1, with a key mutation N501Y on the RBD, appear to be more infectious to humans. To understand its mechanism, we combined cell surface binding assay, kinetics study, single-molecule technique, and computational method to investigate the interaction between these RBD (mutations) and ACE2. Remarkably, RBD with the N501Y mutation exhibited a considerably stronger interaction characterized from all these methodologies, while the other two mutations from B.1.351 contributed to a less effect. Fluorescence-activated cell scan (FACS) assays found that RBD N501Y mutations are of higher binding affinity to ACE2 than the wild type. Surface plasmon resonance further indicated that N501Y mutation had a faster association rate and slower dissociation rate. Consistent with the kinetics study, atomic force microscopy-based single-molecule force microscopy quantify their strength on living cells, showing a higher binding probability and unbinding force for the mutation. Finally, Steered Molecular Dynamics (SMD) simulations on the dissociation of RBD-ACE2 complexes revealed that the N501Y introduced additional π-π and π-cation interaction for the higher force/interaction. Taken together, we suggested that the reinforced interaction from N501Y mutation in RBD should play an essential role in the higher transmission of COVID-19 variants.