bluuebunny/crossref_metadata_2025_split huggingface dataset:
BAC Transgenic Expression of Human TREM2-R47H Remodels Amyloid Plaques but Unable to Reprogram Plaque-associated Microglial Reactivity in 5xFAD Mice
Authors: Lee C.Y. Daniel , De La Rocha Amberlene J. , Inouye Kellie , Langfelder Peter , Daggett Anthony , Gu Xiaofeng , Jiang Lu-Lin , Pamonag Zoe , Vaca Raymond G. , Richman Jeffrey , Kawaguchi Riki , Gao Fuying , Xu Huaxi , Yang X. William 
Published: August 2023

ABSTRACTBackgroundGenetic study of late-onset Alzheimer’s disease (AD) reveals that a rare Arginine-to-Histamine mutation at amino acid residue 47 (R47H) in Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) results in increased disease risk. TREM2 plays critical roles in regulating microglial response to amyloid plaques in AD, leading to their clustering and activation surrounding the plaques. We previously showed that increasing humanTREM2gene dosage exerts neuroprotective effects against AD-related deficits in amyloid depositing mouse models of AD. However, thein vivoeffects of the R47H mutation on human TREM2-mediated microglial reprogramming and neuroprotection remains poorly understood.MethodHere we created a BAC transgenic mouse model expressing human TREM2 with the R47H mutation in its cognate genomic context (BAC-TREM2-R47H). Importantly, the BAC used in this study was engineered to delete critical exons of other TREM-like genes on the BAC to prevent confounding effects of overexpressing multiple TREM-like genes. We crossed BAC-TREM2- R47H mice with 5xFAD [1], an amyloid depositing mouse model of AD, to evaluate amyloid pathologies and microglial phenotypes, transcriptomics andin situexpression of keyTREM2-dosage dependent genes. We also compared the key findings in 5xFAD/BAC-TREM2-R47H to those observed in 5xFAD/BAC-TREM2 mice.ResultBoth BAC-TREM2 and BAC-TREM2-R47H showed proper expression of three splicing isoforms ofTREM2that are normally found in human. In 5xFAD background, elevated TREM2-R47H gene dosages significantly reduced the plaque burden, especially the filamentous type. The results were consistent with enhanced phagocytosis and altered NLRP3 inflammasome activation in BAC- TREM2-R47H microglia in vitro. However, unlike TREM2 overexpression, elevated TREM2- R47H in 5xFAD failed to ameliorate cognitive and transcriptomic deficits.In situanalysis of keyTREM2-dosage dependent genes and microglial morphology uncovered that TREM2-R47H showed a loss-of-function phenotype in reprogramming of plaque-associated microglial reactivity and gene expression in 5xFAD.ConclusionOur study demonstrated that the AD-risk variant has a previously unknown, mixture of partial and full loss of TREM2 functions in modulating microglial response in AD mouse brains. Together, our new BAC-TREM2-R47H model and prior BAC-TREM2 mice are invaluable resource to facilitate the therapeutic discovery that target human TREM2 and its R47H variant to ameliorate AD and other neurodegenerative disorders.
A Multi-Centre, Tolerability Study of a Cannabidiol-enriched Cannabis Herbal Extract for Chronic Headaches in Adolescents: the CAN-CHA Protocol
Authors: Chhabra Manik , Lewis Evan C. , Balshaw Robert , Stewart Breanne , Zaslawski Zina , Lowthian Trinity , Alidina Zahra , Chesick-Gordis Melila , Xie Wenli , Drögemöller Britt I. , Wright Galen E.B. , Birnie Kathryn A , Boerner Katelynn E , Tsang Vivian W. L. , Irwin Samantha Lee , Pohl Daniela , Weil Alexander G , Sell Erick , Penz Erika , MacKay Amy Robson- , Mbabaali Sophia , Blackman Stephanie , Gordon Shanlea , Alcorn Jane , Huntsman Richard J. , Oberlander Tim F , Finley G Allen , Kelly Lauren E 
Published: August 2023

AbstractIntroductionCannabis products have been used in the management of headaches in adults and may play a role in pediatric chronic pain. Canadian pediatricians report increasing use of cannabis for the management of chronic headaches, despite no well-controlled studies to inform its dosing, safety, and effectiveness. The aim of our clinical trial is to determine the dosing and safety of a Cannabidiol (CBD)-enriched Cannabis Herbal Extract (CHE) for the treatment of chronic headaches in adolescents.Methods and analysisYouth, parents and an expert steering committee co-designed this tolerability study. Twenty adolescents (aged 14 to 17 years), with a chronic migraine diagnosis for more than 6 months that has not responded to other therapies, will be enrolled into an open label, dose escalation study across three Canadian sites. Study participants will receive escalating doses of a CBD-enriched CHE (MPL-001 with a THC:CBD of 1:25), starting at 0.2-0.4 mg/kg of CBD per day escalating monthly up to 0.8-1.0 mg/kg of CBD per day. The primary objective of this study is to determine the safety and tolerability of CBD-enriched CHE in adolescents with chronic migraine. Secondary objectives of this study will inform the development of subsequent randomized controlled trials and include investigating the relationship between the dose escalation and change in the frequency of headache, impact and intensity of pain, changes in sleep, mood, function, and quality of life. Exploratory outcomes include investigating steady-state trough plasma levels of bioactive cannabinoids and investigating how pharmacogenetic profiles affect cannabinoid metabolism among adolescents receiving CBD-enriched CHE.DiscussionThis protocol was co-designed with youth and describes a tolerability clinical trial of CBD-enriched CHE in adolescents with chronic headaches that have not responded to conventional therapies. This study is the first clinical trial on cannabis products in adolescents with chronic headaches and will inform the development of future comparative effectiveness clinical trials.Trial registration:CAN-CHA trial is registered with ClinicalTrials.gov with a number of registerNCT05337033.
Detecting co-selection through excess linkage disequilibrium in bacterial genomes
Authors: Mallawaarachchi Sudaraka , Tonkin-Hill Gerry , Pöntinen Anna K. , Calland Jessica K. , Gladstone Rebecca A. , Arredondo-Alonso Sergio , MacAlasdair Neil , Thorpe Harry A. , Top Janetta , Sheppard Samuel K. , Balding David , Croucher Nicholas J. , Corander Jukka 
Published: August 2023

AbstractPopulation genomics has revolutionised our ability to study bacterial evolution by enabling data-driven discovery of the genetic architecture of trait variation. Genome-wide association studies (GWAS) have more recently become accompanied by genome-wide epistasis and co-selection (GWES) analysis, which offers a phenotype-free approach to generating hypotheses about selective processes that simultaneously impact multiple loci across the genome. However, existing GWES methods only consider associations between distant pairs of loci within the genome due to the strong impact of linkage-disequilibrium (LD) over short distances. Based on the general functional organisation of genomes it is nevertheless expected that the majority of co-selection and epistasis will act within relatively short genomic proximity, on co-variation occurring within genes and their promoter regions, and within operons. Here we introduce LDWeaver, which enables an exhaustive GWES across both short- and long-range LD, to disentangle likely neutral co-variation from selection. We demonstrate the ability of LDWeaver to efficiently generate hypotheses about co-selection using large genomic surveys of multiple major human bacterial pathogen species and validate several findings using functional annotation and phenotypic measurements. Our approach will facilitate the study of bacterial evolution in the light of rapidly expanding population genomic data.
Neuromelanin accumulation drives endogenous synucleinopathy in non-human primates
Authors: Chocarro Julia , Rico Alberto J. , Ariznabarreta Goiaz , Roda Elvira , Honrubia Adriana , Collantes María , Peñuelas Iván , Vázquez Alfonso , Rodríguez-Pérez Ana I. , Labandeira-García José L. , Vila Miquel , Lanciego José L. 
Published: August 2023

AbstractAlthough neuromelanin (NMel) is a dark pigment characteristic of dopaminergic neurons in the human substantia nigra pars compacta (SNpc), its potential role in the pathogenesis of Parkinson’s disease (PD) has often been neglected since most commonly used laboratory animals lack NMel. Here we took advantage of adeno-associated viral vectors encoding the human tyrosinase gene for triggering a time-dependent NMel accumulation within SNpc dopaminergic neurons in macaques up to similar levels of pigmentation as observed in elderly humans. Furthermore, NMel accumulation induced an endogenous synucleinopathy mimicking intracellular inclusions typically observed in PD together with a progressive degeneration of NMel-expressing dopaminergic neurons. Moreover, Lewy body-like intracellular inclusions were observed in cortical areas of the frontal lobe receiving dopaminergic innervation, supporting a circuit-specific anterograde spread of endogenous synucleinopathy by permissive trans-synaptic templating. In summary, the conducted strategy resulted in the development and characterization of a new macaque model of PD matching the known neuropathology of this disorder with unprecedented accuracy. Most importantly, evidence is provided showing that intracellular aggregation of endogenous alpha-synuclein is triggered by NMel accumulation, therefore any therapeutic approach intended to decrease NMel levels may provide appealing choices for the successful implementation of novel PD therapeutics.
PoxiPred: An artificial intelligence-based method for the prediction of potential antigens and epitopes to accelerate vaccine development efforts against poxviruses
Authors: Martinez Gustavo Sganzerla , Dutt Mansi , Kumar Anuj , Kelvin David J. 
Published: August 2023

AbstractMotivationPoxviridaeis a family of large, complex, enveloped, and double-stranded DNA viruses. Members of this family are ubiquitous and well known to cause contagious diseases in humans and other types of animals as well. Despite significant progress in Artificial intelligence (AI) based methods, limited methods are available to predict the epitopes. In this study, we have proposed a unique method to predict the potential antigens and T-cell epitopes for multiple poxviruses.ResultsWith PoxiPred, we developed an AI-based tool that was trained and tested with antigens and epitopes ofPoxviruses. Our tool was able to locate 1,675 antigen proteins from 25 distinctpoxviruses. From these antigenic proteins, PoxiPred also located 6,579 T-cell epitopes. PoxiPred is able to, on a single run, identify antigens and T-cell epitopes for poxviruses with one single input, i.e., the proteome file of any poxvirus.AvailabilityThe code that implements PoxiPred and the predicted antigens/T-cell epitopes is publicly available athttps://github.com/gustavsganzerla/poxipred.
Measuring phase-amplitude coupling opposition in neurophysiological signals with the Mean Opposition Vector Index (MOVI)
Authors: Saint-Amour di Chanaz Ludovico , Pérez-Bellido Alexis , Fuentemilla Lluís 
Published: August 2023

AbstractBackgroundThe phase–amplitude coupling (PAC) opposition between distinct neural oscillations is critical to understanding brain functions. Available methods to assess phase-preference differences between conditions rely on density of occurrences. Other methods like the Kullback-Leibler Divergence (DKL) assess the distance between two conditions by transforming neurophysiological data into probabilistic distributions of phase-preference and assessing the distance between them. However, these methods have limitations such as susceptibility to noise and bias.New MethodWe propose the “Mean Opposition Vector Index” (MOVI), a parameter-free, data-driven algorithm for unbiased estimation of PAC opposition. MOVI establishes a unified framework that integrates the strength of PAC to account for reliable unimodal differences in phase-specific amplitude coupling between neurophysiological datasets.ResultsWe found that MOVI accurately detected phase opposition, was resistant to noise and gave consistent results with low or asymmetrical number of trials, therefore in conditions more similar to experimental studies.Comparison with existing methodsMOVI outperformed Jensen-Shannon Divergence (JSD), an adaptation of the DKL, in terms of sensitivity, specificity, and accuracy to detect phase opposition.ConclusionsMOVI provides a novel and useful approach to study of phase-preference opposition in neurophysiological datasets.
Genome and transcriptome mining revealed evolutionary insights and tissue-specific expression patterns of Cytochrome P450 superfamily inAquilaria sinensis
Authors: Das Ankur , Begum Khaleda , Ahmed Raja , Akhtar Suraiya , Banu Sofia 
Published: August 2023

AbstractThe Cytochrome P450 (CYPs) enzyme superfamily has evolved and expanded in plants to play a significant role in the biosynthesis of valuable secondary metabolites. InAquilariaplant, the process of wounding and fungal infection results in the accumulation of distinct aromatic metabolites which contribute to the formation of resinous agarwood. The members of CYPs in plants genomes have diversified to catalyze a wide array of fragrant metabolites. Therefore, this study aimed to identify and provide insights into the evolution and expansion of the CYP superfamily members inAquilaria sinensisand elucidate their tissue-specific functional role through mapping and expression analyses. In total, 179 AsCYPs were identified and subsequently classified into 8 clans and 42 families which were found to be dispersed in the 8 chromosomes. Duplication analysis highlights slow segmental events as a major force, coupled with negative selection pressure, behind the expansion of theAsCYPs. We observed their participation in the biosynthesis of various secondary metabolites, particularly sesquiterpenoids. Expression analysis showed variation in the expression pattern of the genes in different tissues, revealing that the diversification of the AsCYP superfamily occurred to carry out tissue-specific functional role. Additionally, molecular docking of a sesquiterpene oxidase which is specifically expressed in wounded wood, indicated its potential to generate sesquiterpenoids derivatives in agarwood. This study sheds light on the evolution and expansion of theAsCYPsin the genome ofA. sinensisand highlights their crucial role in the biosynthesis of various secondary metabolites found in different parts of the plant. Further functional exploration may pave the way for advancements in the field ofAquilaria-based fragrance development and natural product synthesis.
Decoding Glycomics: Differential Expression Reimagined
Authors: Lundstrøm Jon , Urban James , Bojar Daniel 
Published: August 2023

SummaryGlycomics, the comprehensive study of all glycan structures in a sample, is a rapidly expanding field with substantial relevance for understanding physiology and disease mechanisms. However, the complexity of glycan structures and glycomics data interpretation present significant challenges, especially when it comes to differential expression analysis. Here, we present a novel computational framework for differential glycomics expression analysis. Our methodology encompasses specialized and domain-informed methods for data normalization and imputation, glycan motif extraction and quantification, differential expression analysis, motif enrichment analysis, time series analysis, and meta-analytic capabilities, allowing for synthesizing results across multiple studies. All methods are integrated into our open-source glycowork package, facilitating performant workflows and user-friendly access. We demonstrate these methods using dedicated simulations and various glycomics datasets. Our rigorous approach allows for more robust, reliable, and comprehensive differential expression analyses in glycomics, contributing to the advancement of glycomics research and its translation to clinical and diagnostic applications.
Transitions in sex determination mechanisms through parental antagonism
Authors: Schenkel Martijn A. 
Published: August 2023

AbstractParental antagonism (PA) occurs when the fitness effects of a gene depend on the parent from which it is inherited. Such genes may become enriched on sex chromosomes, due to their biased inheritance patterns. Although various sex determination (SD) genes exhibit parent-of-origin effects themselves, and between-parent conflict over offspring sex may affect SD, PA itself has not been considered as a driver of SD transitions. Here, I present a model to investigate the scope for transitions in SD mechanisms through PA. My model assumes an ancestral SD locus linked to a PA gene, as well as an autosomal PA gene in whose vicinity a novel SD gene arises. Transitions between functionally-homologous genes are found to depend on the fitness effects of both PA genes and their linkage to nearby SD genes. Transitions between male and female heterogamety by the invasion of a dominant SD gene are however nearly unconstrained. This also allows for back-and-forth dynamics where the ancestral SD and novel SD genes constantly evolve to be dominant over each other. These results further underline the malleability of SD mechanisms, and the need to consider parent-of-origin effects in driving transitions in SD, through proximate and/or ultimate means.
Low prevalence of HLA-G antibodies in lung transplant patients detected by MAIPA adapted protocol
Authors: Pedini Pascal , Hubert Lucas , Carlini Federico , Baudey Jean Baptiste , Tous Audrey , Jordier Francois , Basire Agnès , Bagnis Claude , Reynaud-Gaubert Martine , Coiffard Benjamin , Chiaroni Jacques , Silvy Monique , Picard Christophe 
Published: August 2023

AbstractLung transplantation is often complicated by acute and/or chronic rejection leading to graft function loss. In addition to the HLA donor-specific antibodies (HLA-DSA), a few autoantibodies are correlated with the occurrence of these complications. Recently, antibodies directed against non-classical HLA molecules, HLA-G, -E, and -F have been detected in autoimmune diseases, like systemic lupus erythematosus. Non-classical HLA molecules are crucial in the immunological acceptance of the lung graft, and some of their isoforms, like HLA-G*01:04 and -G*01:06, are associated with a negative clinical outcome. The aim of this study is to determine the frequency of detection of HLA-G antibodies in lung transplant recipients (LTRs) and their impact on the occurrence of clinical complications. After incubating the cell lines SPI-801, with and without 3 different HLA-G isoforms expression, with sera from 90 healthy blood donors and 35 LTRs (before and after transplantation), HLA-G reactivity was revealed by using reagents from commercial monoclonal antibody immobilization of platelet antigen assay (MAIPA ApDIA®). Only one serum from one blood donor had specific reactivity against the HLA-G transduced lines. Non-specific reactivity in many sera from LTRs was observed with transduced and wild type cell lines, which may suggest recognition of an autoantigen expressed by the SPI-801 cell line. In conclusion, this study allowed the development of a specific detection tool for non-denatured HLA-G antibodies. These antibodies seem uncommon, both in healthy subjects and in complicated LTRs. This study should be extended to patients suffering from autoimmune diseases as well as kidney and heart transplant recipients.
Induction of antiviral Interferon-Stimulated Genes (ISGs) by neuronal STING promotes the resolution of pain
Authors: Defaye Manon , Bradaia Amyaouch , Abdullah Nasser S. , Agosti Francina , Iftinca Mircea , Soubeyre Vanessa , Svendsen Kristofer , Gill Gurveer , Cuménal Mélissa , Gheziel Nadine , Martin Jérémy , Poulen Gaetan , Lonjon Nicolas , Vachiery-Lahaye Florence , Bauchet Luc , Basso Lilian , Bourinet Emmanuel , Chiu Isaac M. , Altier Christophe 
Published: August 2023

AbstractInflammation and pain are intertwined responses to injury, infection, or chronic diseases. While acute inflammation is essential in determining pain resolution and opioid analgesia, maladaptive processes occurring during resolution can lead to the transition to chronic pain. Here we found that inflammation activates the cytosolic DNA-sensing protein Stimulator of Interferon Genes (STING) in DRG nociceptors. Neuronal activation of STING promotes signaling through TANK-binding kinase 1 (TBK1) and triggers an interferon-beta (IFNβ) response that mediates pain resolution. Notably, we found that mice expressing a nociceptor-specific gain-of-function mutation in STING exhibited an IFN gene signature that reduced nociceptor excitability and inflammatory hyperalgesia through a KChIP1-Kv4.3 regulation. Our findings reveal a role of IFN-regulated genes (IRGs) and KChIP1 downstream of STING, in the resolution of inflammatory pain.
Leach’s Storm-Petrels fledge on the full moon and throughout the lunar cycle
Authors: Collins Sydney M. , Hedd April , Montevecchi William A. , Burt Tori , Wilson David R. , Fifield David A. 
Published: August 2023

AbstractMany seabirds are attracted to anthropogenic light, and the risk is greater for recent fledglings. Lunar phase predicts the probability of stranding, but it remains uncertain whether lunar phase is associated with when young seabirds fledge. Fledging behaviour of nocturnal, burrowing seabirds can be difficult to monitor using traditional methods but can provide insight into environmental factors that influence the risk of stranding. We used passive integrated transponder tags to monitor the fledging dates and times of Leach’s Storm-Petrel chicks from four breeding seasons at a major colony in Newfoundland and Labrador, Canada. We also assessed whether lunar phase associated with fledging date. The median fledge time was 2.4 h after sunset (1.4 - 12.4 h). The median fledge date was 10 October, and fledging dates ranged from 13 September to 13 November. Most importantly, Leach’s Storm-Petrels chicks did fledge during the full moon. These results provide insight into why storm-petrels are less attracted to anthropogenic light during high levels of natural illumination and can be used to inform periods of higher risk for stranding, thus allowing better concentration of conservation efforts.
PDBe CCDUtils: an RDKit-based toolkit for handling and analysing small molecules in the Protein Data Bank
Authors: Kunnakkattu Ibrahim Roshan , Choudhary Preeti , Pravda Lukas , Nadzirin Nurul , Smart Oliver S. , Yuan Qi , Anyango Stephen , Nair Sreenath , Varadi Mihaly , Velankar Sameer 
Published: August 2023

AbstractWhile the Protein Data Bank (PDB) contains a wealth of structural information on ligands bound to macromolecules, their analysis can be challenging due to the large amount and diversity of data. Here, we present PDBe CCDUtils, a versatile toolkit for processing and analysing small molecules from the PDB in PDBx/mmCIF format.PDBe CCDUtils provides streamlined access to all the metadata for small molecules in the PDB and offers a set of convenient methods to compute various properties using RDKit, such as 2D depictions, 3D conformers, physicochemical properties, scaffolds, common fragments and cross-references to small molecule databases using UniChem. The toolkit also provides methods for identifying all the covalently attached chemical components in a macromolecular structure and calculating similarity among small molecules. By providing a broad range of functionality, PDBe CCDUtils caters to the needs of researchers in cheminformatics, structural biology, bioinformatics and computational chemistry.