bluuebunny/crossref_metadata_2025_split huggingface dataset:
Getting Personal with Epigenetics: Towards Machine-Learning-Assisted Precision Epigenomics
Authors: Hawkins-Hooker Alex , Visonà Giovanni , Narendra Tanmayee , Rojas-Carulla Mateo , Schölkopf Bernhard , Schweikert Gabriele 
Published: February 2022

AbstractEpigenetic modifications are dynamic control mechanisms involved in the regulation of gene expression. Unlike the DNA sequence itself, they vary not only between individuals but also between different cell types of the same individual. Exposure to environmental factors, somatic mutations, and ageing contribute to epigenomic changes over time, which may constitute early hallmarks or causal factors of disease. Epigenetic changes are reversible and, therefore, promising therapeutic targets. However, mapping efforts to determine an individual’s cell-type-specific epigenome are constrained by experimental costs. We developed eDICE, an attention-based deep learning model, to impute epigenomic tracks. eDICE achieves improved overall performance compared to previous models on the reference Roadmap epigenomes. Furthermore, we present a proof of concept for the imputation of personalised epigenomic measurements on the ENTEx dataset, where eDICE correctly predicts individual- and cell-type-specific epigenetic patterns. This case study constitutes an important step towards robustly employing machine-learning-based approaches for personalised epigenomics.
In-vivo estimation of axonal morphology from MRI and EEG data
Authors: Oliveira Rita , Pelentritou Andria , Domenicantonio Giulia Di , De Lucia Marzia , Lutti Antoine 
Published: February 2022

AbstractPurposeWe present a novel approach that allows the estimation of morphological features of axonal fibers from data acquired in-vivo in humans. This approach allows the assessment of white matter microscopic properties non-invasively with improved specificity.TheoryThe proposed approach is based on a biophysical model of Magnetic Resonance Imaging (MRI) data and of axonal conduction velocity estimates obtained with Electroencephalography (EEG). In a white matter tract of interest, these data depend on 1) the distribution of axonal radius – P(r)– and 2) the g-ratio of the individual axons that compose this tract – g(r). P(r)is assumed to follow a Gamma distribution with mode and scale parameters, M and θ, and g(r) is described by a power-law with parameters α and β.MethodsMRI and EEG data were recorded from 14 healthy volunteers. MRI data were collected with a 3T scanner. MRI g-ratio maps were computed and sampled along the visual transcallosal tract. EEG data were recorded using a 128-lead system with a visual Poffenberg paradigm. The interhemispheric transfer time and axonal conduction velocity were computed from the EEG current density at the group level. Using the MRI and EEG measures and the proposed model, we estimated morphological properties of axons in the visual transcallosal tract.ResultsThe estimated interhemispheric transfer time was 11.72±2.87 ms, leading to an average conduction velocity across subjects of 13.22±1.18 m/s. Out of the 4 free parameters of the proposed model, we estimated θ – the width of the right tail of the axonal radius distribution and β – the scaling factor of the axonal g-ratio, a measure of fiber myelination. Across subjects, the parameter θ was 0.40±0.07 µm and the parameter β was 0.67±0.02 µm−α.ConclusionsThe estimates of axonal radius and myelination are consistent with histological findings, illustrating the feasibility of this approach. The proposed method allows the measurement of the distribution of axonal radius and myelination within a white matter tract, opening new avenues for the combined study of brain structure and function, and for in-vivo histological studies of the human brain.
Intercontinental movement of H5 2.3.4.4 Highly Pathogenic Avian Influenza A(H5N1) to the United States, 2021
Authors: Bevins Sarah N. , Shriner Susan A. , Cumbee James C. , Dilione Krista E. , Douglass Kelly E. , Ellis Jeremy W. , Killian Mary Lea , Torchetti Mia K. , Lenoch Julianna B. 
Published: February 2022

AbstractEurasian-origin highly pathogenic avian influenza A(H5N1) belonging to the Gs/GD lineage, clade 2.3.4.4b, was detected in two Atlantic states in wild waterfowl in the United States in January 2022. Bird banding data show widespread movement of waterfowl both within the Atlantic Flyway and between neighboring flyways and northern breeding grounds.
Discovery of Flaviviridae-derived endogenous viral elements in shrew genomes provide novel insights into Pestivirus ancient history
Authors: Li YQ , Bletsa M , Zisi Z , Boonen I , Gryseels S , Kafetzopoulou L , Webster JP , Catalano S , Pybus OG , Van de Perre F , Li HT , Li YY , Li YC , Abramov A , Lymberakis P , Lemey P , Lequime S 
Published: February 2022

AbstractAs viral genomic imprints in host genomes, endogenous viral elements (EVEs) shed light on the deep evolutionary history of viruses, ancestral host ranges, and ancient viral-host interactions. In addition, they may provide crucial information for calibrating viral evolutionary timescales. In this study, we conducted a comprehensive in silico screening of a large dataset of available mammalian genomes for EVEs deriving from members of the viral family Flaviviridae, an important group of viruses including well-known human pathogens. We identified two novel pestivirus-like EVEs in the reference genome of the Indochinese shrew (Crocidura indochinensis). Homologs of these novel EVEs were subsequently detected in vivo by molecular detection and sequencing in 27 shrew species, including 26 species representing a wide distribution within the Crocidurinae subfamily and one in the Soricinae subfamily. Based on this wide distribution, we estimate that the integration event occurred before the last common ancestor of the subfamily, about 10.8 million years ago, attesting to an ancient origin of pestiviruses and Flaviviridae in general. Moreover, we provide the first description of Flaviviridae-derived EVEs in mammals even though the family encompasses numerous mammal-infecting members, including major human pathogens such as Zika, dengue, or hepatitis C viruses. This also suggests that shrews were past and perhaps also current natural reservoirs of pestiviruses. Taken together, our results expand the current known Pestivirus host range and provide novel insight into the ancient evolutionary history of pestiviruses and the Flaviviridae family in general.
Cryo-EM structures reveal ubiquinone-10 binding to mitochondrial complex I and conformational transitions associated with Q-site occupancy
Authors: Chung Injae , Wright John J. , Bridges Hannah R. , Ivanov Bozhidar S. , Biner Olivier , Pereira Caroline S. , Arantes Guilherme M. , Hirst Judy 
Published: February 2022

AbstractMitochondrial complex I is a central metabolic enzyme that uses the reducing potential of NADH to reduce ubiquinone-10 (Q10) and drive four protons across the inner mitochondrial membrane, powering oxidative phosphorylation. Although many complex I structures are now available, structures of Q10-bound states have remained elusive. Here, we reconstitute mammalian complex I into phospholipid nanodiscs with exogenous Q10. Using cryo-EM, we reveal a Q10 molecule occupying the full length of the Q-binding site in the ‘active’ (ready-to-go) resting state (plus a matching substrate-free structure) and apply molecular dynamics simulations to propose how the charge states of key residues influence the Q10 binding pose. By comparing ligand-bound and ligand-free forms of the ‘deactive’ resting state (that require reactivating to catalyse), we begin to define how substrate binding restructures the deactive Q-binding site, providing insights into its physiological and mechanistic relevance.
Functional characterization of Atlantic salmon (Salmo salar L.) PepT2 transporters
Authors: Vacca Francesca , Gomes Ana S. , Murashita Koji , Cinquetti Raffella , Roseti Cristina , Barca Amilcare , Rønnestad Ivar , Verri Tiziano , Bossi Elena 
Published: February 2022

AbstractThe high-affinity/low-capacity system Slc15a2 (PepT2) is responsible for the reuptake of di/tripeptides from the renal proximal tubule, but it also operates in many other tissues/organs. Information regarding PepT2 in teleost fish is limited and to date functional data are available from the zebrafish (Danio rerio) only. Here, we report the identification of two slc15a2 genes in the Atlantic salmon (Salmo salar) genome, namely slc15a2a and slc15a2b. The two encoded PepT2 proteins share 87% identity and resemble both structurally and functionally to the canonical vertebrate PepT2 system. The mRNA tissue distribution analyses reveal a widespread distribution of slc15a2a transcripts, being more abundant in the brain and gills, while slc15a2b transcripts are mainly expressed in kidney and distal part of gastrointestinal tract. The function of the two transporters was investigated by heterologous expression in Xenopus laevis oocytes and two- electrode voltage-clamp recordings of transport and presteady-state currents. Both PepT2a and PepT2b in the presence of Gly-Gln elicit pH-dependent and Na+ independent inward currents. The biophysical and kinetic analysis of the recorded currents defined the transport properties, confirming that the two Atlantic salmon PepT2 proteins behave as high-affinity/low-capacity transporters. The recent structures and the previous kinetic schemes of rat and human PepT2 qualitatively account for the characteristics of the two Atlantic salmon proteins. This study is the first to report on the functional expression of two PepT2-type transporters that operate in the same vertebrate organism as a result of (a) gene duplication process(es).Key points summaryTwo slc15a2-type genes, slc15a2a and slc15a2b coding for PepT2-type peptide transporters were found in the Atlantic salmon.slc15a2a transcripts, widely distributed in the fish tissues, are abundant in brain and gills, while slc15a2b transcripts are mainly expressed in kidney and distal gastrointestinal tract.Amino acids involved in vertebrate Slc15 transport function are conserved in PepT2a and PepT2b proteins.Detailed kinetic analysis indicates that both PepT2a and PepT2b operate as high-affinity transporters.The kinetic schemes and structures proposed for the mammalian models of PepT2 are suitable to explain the function of the two Atlantic salmon transporters.
Conifer leaves have a peroxisomal oxidative decarboxylation path in the photorespiratory pathway
Authors: Miyazawa Shin-Ichi , Miyama Takafumi , Tahara Ko , Ujino-Ihara Tokuko , Tobita Hiroyuki , Suzuki Yuji , Nishiguchi Mitsuru 
Published: February 2022

AbstractThe photorespiratory pathway consists of enzymes operating in chloroplasts, mitochondria, and peroxisomes. Conifer leaves lack one of them, chloroplastic Gln synthetase, which questioned the current belief that the photorespiratory mechanism is identical between angiosperm C3 species and conifers. A photorespiratory-metabolite analysis of the leaves of 13 conifer and 14 angiosperm tree species revealed significant differences in the mean metabolite concentrations between the two taxonomic groups: the glycerate content on chlorophyll basis in conifer leaves was <1/10 that detected in angiosperm leaves, whereas the glycolate content was 1.6 times higher in conifer leaves. Glycerate is produced from Ser through an intermediate, hydroxypyruvate. To investigate the lower glycerate levels observed in conifer leaves, we performed experiments of 13C-labeled Ser feeding to the detached shoots of a conifer (Cryptomeria japonica) via the transpiration stream, and compared the labeling patterns of photorespiratory metabolites with those of an angiosperm (Populus nigra). Glycerate was most labeled in P. nigra, whereas glycolate was more labeled than glycerate in C. japonica. The photorespiration pathway involves H2O2-scavenging and H2O2-generating enzymes, catalase (CAT) and glycolate oxidase (GLO), respectively, which are the peroxisomal targeting enzymes in angiosperms. In contrast, database analyses of the peroxisomal targeting signal motifs and analyses of the peroxisomal fractions isolated from C. japonica leaves indicated that the conifer peroxisomes were not a major localization of CAT. These results suggest that the conifer photorespiration pathway has a bypass from Ser to glycolate via the decarboxylation of hydroxypyruvate, because of an imbalance between CAT and GLO activities in peroxisomes.One sentence summaryConifer peroxisome is not a major localization of catalase and yields a unique oxidative decarboxylation path in the photorespiratory pathway.
WlzWarp: An Open-Source Tool for Complex Alignment of Spatial Data
Authors: Hill Bill , Husz Zsolt , Armit Chris , Davidson Duncan R. , Murphy Paula , Baldock Richard A. 
Published: February 2022

AbstractBackgroundThe spatio-temporal organisation of many biological processes such as gene-expression and neuronal activity is critical to understanding the overall biological behaviour, phenotype and disease. This is especially true during embryonic development. During development spatial patterns of gene expression are key to segmentation, tissue differentiation and organ development. In situ techniques can reveal the activity of genes and the presence of proteins to a very high sub-cellular resolution but typically at high resolution only a few probes can be used on any sample therefore to compare many such patterns requires mapping of image-based data to a standard spatial framework. Once mapped those data can be collated, queried and analysed in purely spatial terms to reveal unknown combinatorial gene-activity that could not be discovered any other way. Mapping spatial data to image domains with systematic variation in shape and pose, such as embryos or elongated organs, presents special problems. Automated techniques available for more constrained systems can not deliver the mapping fidelity required to analyse these data therefore we have developed a manual editing tool, WlzWarp, for mapping 3D image data using the constrained distance transform (CDT) which uniquely can deliver the complex transforms required.ResultsWe have implemented a fully open-source tool (available on GitHub), WlzWarp to provide interactive complex spatial mapping of 3D image data. We have applied WlzWarp to map a set of gene-expression patterns in the developing mouse embryo that could not be mapped by any other technique. The transform procedure was tested by using multiple images of the same gene from independent samples and thereby testing the full end-to-end mapping process. WlzWarp is implemented in C++ using open-source packages Qt, Coin and SIMVoleon for cross-architecture compatibility. It has been developed under Linux but also tested on Mac OSX and MS Windows.ConclusionsWlzWarp is a freely available software tool for non-linear registration and alignment of complex 2D & 3D spatial patterns from one image to another or to an atlas model. It has been tested in the context of embryo data but can be used for any 3D or 2D image registration problem.
Characterization of the Interaction of Nanobubble Ultrasound Contrast Agents with Human Blood Components
Authors: Cooley Michaela B. , Abenojar Eric C. , Wegierak Dana , Gupta Anirban Sen , Kolios Michael C. , Exner Agata A. 
Published: February 2022

AbstractNanoscale ultrasound contrast agents, or nanobubbles, are being explored in preclinical applications ranging from vascular and cardiac imaging to targeted drug delivery in cancer. These sub-micron particles are approximately 10x smaller than clinically available microbubbles. This allows them to effectively traverse compromised physiological barriers and circulate for extended periods of time. While various aspects of nanobubble behavior have been previously examined, their behavior in human whole blood has not yet been explored. Accordingly, herein we examined, for the first time, the short and long-term effects of blood components on nanobubble acoustic response. We observed differences in the kinetics of backscatter from nanobubble suspensions in whole blood compared to bubbles in phosphate buffered saline (PBS), plasma, or red blood cell solutions (RBCs). Specifically, after introducing nanobubbles to fresh human whole blood, signal enhancement gradually increased by 22.8 ± 13.1% throughout our experiment, with peak intensity reached within 145 seconds. In contrast, nanobubbles in PBS had a stable signal with negligible change in intensity (−1.7 ± 3.2%) over 8 minutes. Under the same conditions, microbubbles made with the same lipid formulation showed a −56.8 ± 6.1% decrease in enhancement. Subsequent confocal, fluorescent, and scanning electron microscopy analysis revealed attachment of the nanobubbles to the surface of RBCs, suggesting that direct interactions, or hitchhiking, of nanobubbles on RBCs in the presence of plasma may be a possible mechanism for the observed effects. This phenomenon could be key to extending nanobubble circulation time and has broad implications in drug delivery, where RBC interaction with nanoparticles could be exploited to improve delivery efficiency.
Neurophysiological Measures of Auditory Sensory Processing are Associated with Adaptive Behavior in Children with Autism Spectrum Disorder
Authors: Cotter Mairin , Tikir Seydanur , Francisco Ana Alves , Oakes Leona , Crosse Michael J. , Foxe John J. , Molholm Sophie 
Published: February 2022

ABSTRACTBackgroundAtypical auditory cortical processing is consistently found in scalp electrophysiological and magnetoencephalographic studies of Autism Spectrum Disorder (ASD), and may provide a marker of neuropathological brain development. However, the relationship between atypical cortical processing of auditory information and adaptive behavior in ASD is not yet well understood.MethodsWe sought to test the hypothesis that early auditory processing in ASD is related to everyday adaptive behavior through the examination of auditory event-related potentials (AEPs) in response to simple tones and Vineland Adaptive Behavior Scales in a large cohort of children with ASD (N=89), aged 6-17, and in age- and IQ-matched neurotypically (NT) developing controls (N=120).ResultsStatistical analyses revealed significant group differences in early AEPs over temporal scalp regions. Whereas the expected rightward lateralization of the AEP to tonal stimuli occurred in both groups, lateralization of the AEP was only significantly associated with adaptive functioning, in the domains of communication and daily living, in the ASD group.ConclusionsThese results lend support to the hypothesis that atypical processing of sensory information is related to everyday adaptive behavior in autism.
Vaccine-elicitation of cross-group neutralizing protective antibodies to influenza A viruses
Authors: Moin Syed M. , Boyington Jeffrey C. , Boyoglu-Barnum Seyhan , Gillespie Rebecca A. , Cerutti Gabriele , Cheung Crystal Sao-Fong , Cagigi Alberto , Gallagher John R. , Brand Joshua , Prabhakaran Madhu , Tsybovsky Yaroslav , Stephens Tyler , Fisher Brian E. , Creanga Adrian , Ataca Sila , Rawi Reda , Corbett Kizzmekia S. , Crank Michelle C. , Gorman Jason , McDermott Adrian B. , Harris Audray K. , Zhou Tongqing , Kwong Peter D. , Shapiro Lawrence , Mascola John R. , Graham Barney S. , Kanekiyo Masaru 
Published: February 2022

ABSTRACTCurrent influenza vaccines predominantly induce immunity to the hypervariable viral hemagglutinin (HA) head, requiring frequent vaccine reformulation. Conversely, antigenic sites on the conserved HA stem are subdominant and harbor a supersite which is targeted by broadly neutralizing antibodies (bnAbs), making it a prime target for universal vaccines. Here, we show that co-immunization of two stem immunogens derived from influenza A group 1 and 2 HAs elicits cross-group protective immunity and neutralizing antibody responses in mice, ferrets, and nonhuman primates (NHPs). Immunized mice were protected from multiple group 1 and 2 viruses, and all animal models showed broad serum neutralizing activity. A bnAb isolated from an immunized NHP broadly neutralized and conferred protection from viruses including H5N1 and H7N9. Genetic and structural analyses revealed a remarkable convergent evolution between macaque and human bnAbs, illustrating the biophysical constraints for acquiring immunoglobulins with cross-group specificity. Co-immunization of stem immunogens elicits not only group-specific protective immunity, but also cross-group bnAb responses, and represents a step towards broadly protective influenza vaccines.
An optimized method to infer relatedness up to the 5th degree from low coverage ancient human genomes
Authors: Nyerki Emil , Kalmár Tibor , Schütz Oszkár , Lima Rui M. , Neparáczki Endre , Török Tibor , Maróti Zoltán 
Published: February 2022

AbstractBackgroundCurrent state of art kinship analysis is capable to infer relatedness up to the 5-6th degree from deeply sequenced DNA if the proper reference population is known. Low coverage, partially genotyped, degraded archaic (or forensic) DNA and often unavailable or unknown reference population poses additional challenges, hence kinship analysis from low coverage archaic sequences so far has been possible up to the second degree with large uncertainties.ResultsWe performed extensive simulations to identify and correct the main factors of bias in kinship analysis from low coverage data. As a result, we introduce a new metric for correction and offer a guideline, which overcomes the difficulties associated with low coverage samples. We validated our methodology on experimental modern and archaic data with widely different genome coverages (0.12x-11.9x) using samples with known family relations and known or unknown population structure. Out of 2526 ancient individuals from the REICH data set we confirmed all 96 indicated, and identified 303 new relatives additionally.ConclusionWith the proposed workflow we provide the necessary additional tools to calculate the corrected kinship coefficient from the commonly used genome data formats. Our methodology allows to reliably identify relatedness up to the 4-5th degree from variable/low coverage archaic (or badly degraded forensic) WGS genome data.
Sequence-Dependent Backbone Dynamics of Intrinsically Disordered Proteins
Authors: Dey Souvik , MacAinsh Matthew , Zhou Huan-Xiang 
Published: February 2022

AbstractFor intrinsically disordered proteins (IDPs), a pressing question is how sequence codes for function. Dynamics serves as a crucial link, reminiscent of the role of structure in sequence-function relations of structured proteins. To define general rules governing sequence-dependent backbone dynamics, we carried out long molecular dynamics simulations of eight IDPs. Blocks of residues exhibiting large amplitudes in slow dynamics are rigidified by local inter-residue interactions or secondary structures. A long region or an entire IDP can be slowed down by long-range contacts or secondary- structure packing. On the other hand, glycines promote fast dynamics and either demarcate rigid blocks or facilitate multiple modes of local and long-range inter-residue interactions. The sequence-dependent backbone dynamics endows IDPs with versatile response to binding partners, with some blocks recalcitrant while others readily adapting to intermolecular interactions.