bluuebunny/crossref_metadata_2025_split huggingface dataset:
Learning orientation-invariant representations enables accurate and robust morphologic profiling of cells and organelles
Authors: Burgess James , Nirschl Jeffrey J. , Zanellati Maria-Clara , Cohen Sarah , Yeung Serena 
Published: December 2022

ABSTRACTCell and organelle morphology are driven by diverse genetic and environmental factors and thus accurate quantification of cellular phenotypes is essential to experimental cell biology. Representation learning methods for phenotypic profiling map images to feature vectors that form anembedding spaceof morphological variation useful for clustering, dimensionality reduction, outlier detection, and supervised learning problems. Morphology properties do not change with orientation, and thus we argue that representation learning methods should encode this orientation invariance. We show that prior methods are sensitive to orientation, which can lead to suboptimal clustering. To address this issue, we develop O2-VAE, an unsupervised learning method that learns robust, orientation-invariant representations. We use O2-VAE to discover novel morphology subgroups in segmented cells and mitochondria, detect outlier cells, and rapidly characterise cellular shape and texture in large datasets, including in a newly generated synthetic benchmark.
Sensory evaluations of a novel iron and zinc-enriched powder for the potential treatment and prevention of iron deficiency in women of reproductive age
Authors: Miller Clara H , Sheyholislami Hauna , Burns Jessie L , Connor Kristin L 
Published: December 2022

AbstractIron deficiency (ID) and iron deficiency with anaemia (IDA) are serious global health problems that disproportionately affect women aged 15-49 years. Although food fortification is one of the most effective and sustainable ways to combat nutritional deficiencies, iron remains one of the most difficult micronutrients to fortify, given its tendency to react strongly with food constituents. Therefore, it is important to assess the sensory properties of foods fortified with iron to determine the acceptability and palatability in target populations. We aimed to determine the palatability and acceptability of a novel iron and zinc enriched powder fortified in tap water by conducting sensory evaluations in 35 women of reproductive age using a 9-point hedonic scale, where participants rated the sensory properties of six samples containing different amounts of the active or placebo. We found significant differences between samples reconstituted at 1g/L, 2g/L, and 3g/L for sensory properties, including overall taste. Participants were found to be more willing to drink the mineral-enriched powder when prepared at the lowest concentration (1g/L) compared to higher concentrations. Our results provide important insight on sensory qualities of a novel formulation of an iron and zinc -enriched powder for at-home fortification, and indicate consumer acceptability in reproductive aged women, a key group at risk for ID/IDA. If found to improve iron status, novel treatments like this product will contribute to global efforts to develop safe, acceptable and sustainable interventions for ID and IDA.
Brain cross-omics integration in Alzheimer’s disease
Authors: Eteleeb Abdallah M. , Novotny Brenna C. , Tarraga Carolina Soriano , Sohn Christopher , Dhungel Eliza , Brase Logan , Nallapu Aasritha , Buss Jared , Farias Fabiana , Bergmann Kristy , Bradley Joseph , Norton Joanne , Gentsch Jen , Wang Fengxian , Davis Albert A. , Morris John C. , Karch Celeste M. , Perrin Richard J. , Benitez Bruno A. , Harari Oscar 
Published: December 2022

AbstractUnbiased data-driven omic approaches are revealing the molecular heterogeneity of Alzheimer disease. Here, we used machine learning approaches to integrate high-throughput bulk and single-nucleus transcriptomic, proteomic, metabolomic, and lipidomic profiles with clinical and neuropathological data from multiple AD cohorts. We discovered four unique multimodal molecular profiles, one showing signs of poor cognitive function, a faster pace of disease progression, shorter survival with the disease, severe neurodegeneration and astrogliosis, and reduced levels of metabolomic profiles. This profile shows similar cellular and molecular profiles in multiple affected cortical regions associated with higher Braak tau scores and significant dysregulation of synapse-related genes and endocytosis, phagosome, mTOR signaling pathways altered in AD early and late stages. The multimodal clusters uncovered cerebrospinal fluid biomarkers to monitor AD progression. AD cross-omics data integration with transcriptomic data from an SNCA mouse model revealed an overlapping signature. Our cross-omics analyses provide novel critical molecular insights into AD.
Identification of genomic signatures and multiple lineage markers from the second and third wave samples of COVID-19 in Western Rajasthan, India
Authors: Bokolia Naveen Prakash , Gadepalli Ravisekhar 
Published: December 2022

ABSTRACTMost of the mutations occurred in SARS-CoV-2 are either relatively neutral or swiftly purged. However, some mutations have altered the functional aspects in terms of infectivity and transmission, host-viral interactions, disease severity and immune or vaccine escape. There are emerging evidence that certain mutations are jeopardizing the immune based therapies. The present research report is focused on the identification of genomic signatures of SARS-CoV-2 variant that caused mortality during second and third wave of COVID-19 in Western Rajasthan, India. We identified that Delta clade of SARS-CoV-2 is the predominant cause of mortality during second wave and even third wave in Western Rajasthan, India. Importantly, this study also revealed the unique and common substitution mutations within the spike domain, those are present in mortality and survived persons during the second and third wave of COVID-19 in India. In addition, this study also revealed the multiple lineage markers (Delta and Omicron), that would update with insightful understanding in the clade development of SARS-CoV-2.
Dynamical nonequilibrium molecular dynamics simulations identify allosteric sites and positions associated with drug resistance in the SARS-CoV-2 main protease
Authors: Chan H. T. Henry , F. Oliveira A. Sofia , Schofield Christopher J. , Mulholland Adrian J. , Duarte Fernanda 
Published: December 2022

AbstractThe SARS-CoV-2 main protease (Mpro) plays an essential role in the coronavirus lifecycle by catalysing hydrolysis of the viral polyproteins at specific sites. Mprois the target of drugs, such as nirmatrelvir, though resistant mutants have emerged that threaten drug efficacy. Despite its importance, questions remain on the mechanism of how Mprobinds its substrates. Here, we apply dynamical nonequilibrium molecular dynamics (D-NEMD) simulations to evaluate structural and dynamical responses of Mproto the presence and absence of a substrate. The results highlight communication between the Mprodimer subunits and identify networks, including some far from the active site, that link the active site with a known allosteric inhibition site, or which are associated with nirmatrelvir resistance. They imply that some mutations enable resistance by altering the allosteric behaviour of Mpro. More generally, the results show the utility of the D-NEMD technique for identifying functionally relevant allosteric sites and networks including those relevant to resistance.
Priority effects in herbivore communities vary in effect on plant development and reproduction in four Brassicaceae plant species
Authors: Mertens Daan , Douma Jacob C. , Kamps Bram B. J. , Zhu Yunsheng , Zwartsenberg Sophie A. , Poelman Erik H. 
Published: December 2022

AbstractInsect herbivores can directly affect plant reproduction by feeding on reproductive tissues, or indirectly by feeding on vegetative tissues for which plants are unable to compensate. Additionally, early arriving herbivores may have cascading effects on plant fitness by altering the richness and abundance of the later arriving community.Studies are divided on whether herbivory early in the development of plants can impact plant fitness and whether these effects are predominantly mediated through changes in plant development or subsequent herbivory. Obtaining insight into the generality and consistency of mediated effects on plant reproduction induced by early-season herbivory requires a comparative approach across plant species and environmental conditions.By excluding the herbivore community in an exclosure experiment and by manipulating early-season herbivory in a common garden experiment replicated across four Brassicaceae species and two years, we tested whether early-season herbivory could affect plant development, reproduction, and the herbivore communities associated with individual plants. In addition, we tested a causal hypothesis to disentangle the direct effect of herbivory on plant reproduction, and their indirect effect through changes in the development of plants.Early-season herbivory affected plant development and reproduction, but effects were highly dependent on the plant species, the inducing herbivore species, and the biotic and abiotic environment. The exploratory path analysis indicated that plant reproduction was best predicted by variation in plant development, explaining up to 90.88% of the total effect on seed production. Even though the richness and abundance of the subsequent herbivore community were conditionally affected by the initial colonising herbivore, herbivore pressure is predicted to have only minor effects on reproduction. Importantly, the effects of herbivore pressure on seed set were not direct but were mediated by changes in plant development.Synthesis:Early-season herbivory has the potential to affect plant reproduction through changes in the development of plants and, less strongly, through effects mediated by the plant-associated herbivore community. However, as plants are often able to compensate and attenuate the effects induced by herbivory, the detection, sign, and strength of effects are highly dependent on the plant species and environment.
Safety and Immunogenicity of Omicron BA.4/BA.5 Bivalent Vaccine Against Covid-19
Authors: Chalkias Spyros , Whatley Jordan , Eder Frank , Essink Brandon , Khetan Shishir , Bradley Paul , Brosz Adam , McGhee Nichole , Tomassini Joanne E. , Chen Xing , Zhao Xiaoping , Sutherland Andrea , Shen Xiaoying , Girard Bethany , Edwards Darin K. , Feng Jing , Zhou Honghong , Walsh Stephen , Montefiori David C. , Baden Lindsey R. , Miller Jacqueline M. , Das Rituparna 
Published: December 2022

ABSTRACTBackgroundInformation on the safety and immunogenicity of the omicron BA.4/BA.5-containing bivalent booster mRNA-1273.222 are needed.MethodsIn this ongoing, phase 2/3 trial, 50-μg mRNA-1273.222 (25-μg each ancestral Wuhan-Hu-1 and omicron BA.4/BA.5 spike mRNAs) is compared to 50-μg mRNA-1273, administered as second boosters in adults who previously received a 2-injection (100-μg) primary series and first booster (50-μg) dose of mRNA-1273. The primary objectives were safety and immunogenicity 28 days post-boost.ResultsParticipants received 50-μg of mRNA-1273 (n=376) or mRNA-1273.222 (n=511) as second booster doses. Omicron BA.4/BA.5 and ancestral SARS-CoV-2 D614G neutralizing antibody geometric mean titers (GMTs [95% confidence interval]) after mRNA-1273.222 (2324.6 [1921.2-2812.7] and 7322.4 [6386.2-8395.7]) were significantly higher than mRNA-1273 (488.5 [427.4-558.4] and 5651.4 (5055.7-6317.3) respectively, at day 29 post-boost in participants with no prior SARS-CoV-2-infection. A randomly selected subgroup (N=60) of participants in the mRNA-1273.222 group also exhibited cross-neutralization against the emerging omicron variants BQ.1.1 and XBB.1. No new safety concerns were identified with mRNA-1273.222.Vaccine effectiveness was not assessed in this study; in an exploratory analysis 1.6% (8/511) of mRNA-1273.222 recipients had Covid-19 post-boost.ConclusionThe bivalent omicron BA.4/BA.5-containing vaccine mRNA-1273.222 elicited superior neutralizing antibody responses against BA.4/BA.5 compared to mRNA-1273, with no safety concerns identified.(Supported by Moderna;ClinicalTrials.govIdentifier:NCT04927065)
Sequencing-free Tissue-wide Spatial Profiling of Post-transcriptional Regulations
Authors: Ji Xianglin , Fang Peilin , Zhao Xi , Xiong Chuanyin , Yang Qi , Wan Youyang , Do Richard Yan , Wang Zixun , Qi Lin , Huang Linfeng , Zhang Wenjun , Wang Xin , Shi Peng 
Published: December 2022

AbstractThe importance of genetic or epi-genetic heterogeneity has been increasingly recognized, but it has been challenging to profile intracellular post-transcriptional targets with sufficient throughput and resolution at across large-scale tissue samples. This study describes a technique, Spectrum-FISH, for high-throughput, sequencing-free, and tissue-wide spatial profiling of various post-transcriptional targets in acute tissue sections with subcellular resolution. The platform uses a biochip with an array of vertically aligned nanoprobes to effectively extract intracellular molecules for downstream analysis in the coordinates of the large-scale of cells within a tissue slice. As a proof-of-concept, the Spectrum-FISH is used to profile the spatial dynamics of 24 miRNAs and 9 m6A-modified messenger RNAs (m6A-mRNA) in acute olfactory bulb (OB) slices of millimeter scale. The results showed potentially multiomics spatial heterogeneity for the examined post-transcriptional regulations in rodent OB, especially in the outer plexiform layer and granule layer, where highly correlated miRNAs and m6A-mRNAs groups were identified, indicating a potential cooperative involvement of different post-transcriptional regulations at these OB regions.
A single protein to multiple peptides: Investigation of protein-peptide relationship using targeted alpha-2-macroglobulin analysis
Authors: Yildiz Pelin , Ozcan Sureyya 
Published: December 2022

ABSTRACTRecent advances in proteomics technologies have enabled analysis of thousands of proteins in a high-throughput manner. Mass Spectrometry (MS) based proteomics, uses a peptide centric approach where biological samples undergo a specific proteolytic digestion and then only unique peptides are used for protein identification and quantification. Considering the fact that a single protein may have multiple unique peptides and a number of different forms, it becomes essential to understand dynamic protein-peptide relationship to ensure robust and reliable peptide centric protein analysis. In this study, we investigated the correlation between protein concentration and corresponding unique peptide responses under conventional proteolytic digestion conditions. Protein-peptide correlation, digestion efficiency, matrix-effect, and concentration-effect were evaluated. Twelve unique alpha-2-macroglobulin (A2MG) peptides were monitored using a targeted MS approach to acquire insights into protein-peptide dynamics. Although the peptide responses were reproducible between replicates, protein-peptide correlation was moderate in protein standards and low in complex matrices. The results suggest that reproducible peptide signal could be misleading in clinical studies and a peptide selection could dramatically change the outcome at protein level. This is the first study investigating quantitative protein-peptide correlations in biological samples using all unique peptides representing the same protein and opens a discussion on peptide-based proteomics.
Bio-psycho-social factors’ associations with brain age: a large-scale UK Biobank diffusion study of 35,749 participants
Authors: Korbmacher Max , Gurholt Tiril P. , de Lange Ann Marie , van der Meer Dennis , Beck Dani , Eikefjord Eli , Lundervold Arvid , Andreassen Ole A. , Westlye Lars T. , Maximov Ivan I. 
Published: December 2022

AbstractBrain age refers to age predicted by brain features. Brain age has previously been associated with various health and disease outcomes and suggested as a potential biomarker of general health. Few previous studies have systematically assessed brain age variability derived from single and multi-shell diffusion magnetic resonance imaging data. Here, we present multivariate models of brain age derived from various diffusion approaches and how they relate to bio-psycho-social variables within the domains of sociodemographic, cognitive, life-satisfaction, as well as health and lifestyle factors in midlife to old age (N= 35,749, 44.6 to 82.8 years of age). Bio-psycho-social factors could uniquely explain a small proportion of the brain age variance, in a similar pattern across diffusion approaches: cognitve scores, life satisfaction, health and lifestyle factors adding to the variance explained, but not socio-demographics. Consistent brain age associations across models were found for waist-to-hip ratio, diabetes, hypertension, smoking, matrix puzzles solving, and job and health satisfaction and perception. Furthermore, we found large variability in sex and ethnicity group differences in brain age. Our results show that brain age cannot be sufficiently explained by bio-psycho-social variables alone. However, the observed associations suggest to adjust for sex, ethnicity, cognitive factors, as well as health and lifestyle factors, and to observe bio-psycho-social factor interactions’ influence on brain age in future studies.
Evolution of lineage-specific trafficking proteins and a novel post-Golgi trafficking pathway in Apicomplexa
Authors: Klinger Christen M. , Jimenez-Ruiz Elena , Mourier Tobias , Klingl Andreas , Lemgruber Leandro , Pain Arnab , Dacks Joel B. , Meissner Markus 
Published: December 2022

AbstractThe Organelle Paralogy Hypothesis (OPH) posits a mechanism to explain the evolution of non-endosymbiotically derived organelles, predicting that lineage-specific pathways organelles should result when identity-encoding membrane trafficking components duplicate and co-evolve. Here we investigate the presence of such lineage-specific membrane-trafficking machinery paralogs in the globally important lineage of parasites, the Apicomplexa. Using a new phylogenetic workflow, we are able to identify 18 novel paralogs of known membrane-trafficking machinery, the emergence of several of which correlate with the presence of new endomembrane organelles in apicomplexans or their larger lineage. Gene coregulation analysis of a large set of membrane-trafficking proteins in Toxoplasma both corroborate known molecular cell biological interactions between characterized machinery and suggest involvement of many of these new components into established pathways for biogenesis of or trafficking to the microneme and rhoptry invasion organelles. Moreover, focused molecular parasitological analysis of the apicomplexan Arf-like small GTPases, and the ArlX3 protein specifically, revealed a novel post-Golgi trafficking pathways involved in delivery of proteins to micronemes and rhoptries, with knock down demonstrating reduced invasion capacity. The totality of our data has identified an unforeseen post-Golgi trafficking pathway in apicomplexans and is consistent with the OPH mechanism acting to produce novel endomembrane pathways or organelles at various evolutionary stages across the Alveolate lineage.Significance statementThe mechanism of non-endosymbiotic organelle evolution has been relatively poorly explored and yet is relevant to many eukaryotic compartments, including the endomembrane system. The Organelle Paralogy Hypothesis predicts novel lineage-specific paralogs evolutionarily concurrent with emergence of new endomembrane organelles or pathways. By investigating this phenomenon in the apicomplexan parasites and their relatives, we identify and profile over a dozen new trafficking factors, several correlating with emergence of lineage-specific organelles. Cell biological study of one such factor demonstrates the existence of a novel post-Golgi trafficking pathway for components to the invasion organelles in the parasiteToxoplasma gondii. This work reveals how non-endosymbiotic organelle evolution has shaped cellular novelty in this lineage, relevant both to global health and fundamental evolutionary biology.
Multimodal Mapping of Human Lymphopoiesis Reveals B and T/NK/ILC Lineages are Subjected to Cell-IntrinsicversusFlt3L-Dependent Regulation
Authors: Alhaj Hussen Kutaiba , Chabaane Emna , Nelson Elisabeth , Lekiashvili Shalva , Diop Samuel , Keita Seydou , Evrard Bertrand , Lardenois Aurélie , Delord Marc , Verhoeyen Els , Cornils Kerstin , Kasraian Zeinab , Macintyre Elizabeth A. , Cumano Ana , Garrick David , Goodhardt Michele , Andrieu Guillaume P. , Asnafi Vahid , Chalmel Frederic , Canque Bruno 
Published: December 2022

SUMMARYThe developmental cartography of human lymphopoiesis remains incompletely understood. Here, we establish a multimodal map that extends the current view of lymphoid development. Our results demonstrate that lymphoid specification follows independent direct or stepwise differentiation pathways converging toward the emergence of CD117lomulti-lymphoid progenitors (MLPs) that undergo a proliferation arrest before entering the CD127-(T/NK/ILC) or CD127+(B) lymphoid pathways. While the emergence of CD127-early lymphoid progenitors is driven by Flt3 signaling, differentiation of their CD127+counterparts is regulated cell-intrinsically and depends exclusively on the divisional history of their precursors. Single-cell mapping of lymphoid differentiation trajectories reveals that a dissociation between proliferation and differentiation phases allows amplification of the precursor pools prior to the onset of antigen receptor rearrangement. Besides demonstrating that B and T/NK/ILC lineages are subjected to differential cell-autonomousversusFlt3-inducible regulation, our results go a long way to reconciling human and mouse models of lymphoid architecture.
AUTS2 expression within mammalian lineage: a predictor of neural networks involved in Autism Spectrum Disorders
Authors: Lepagnol-Bestel Aude-Marie , Loe-Mie Yann , Bensaid Mounia , Simonneau Michel 
Published: December 2022

AbstractAutism susceptibility gene 2 (AUTS2) is a neurodevelopmental regulator associated with an autosomal dominant neurological syndrome with ASD-like (Autism Spectrum Disorder-like) features. TheAUTS2syndrome phenotype includes borderline to severe intellectual disability (ID), microcephaly and mild dysmorphic traits. Specific ASD-like features, including obsessive or ritualistic behaviours, are frequently displayed, although sociability is largely unaffected. Syndrome severity is worse when mutations are present in the 3’ region (exons 9-19) of theAUTS2gene.AUTS2is also associated with alcohol consumption, heroin dependence, schizophrenia and dyslexia, using GWAS studies. Our working hypothesis is thatAUTS2expression during mammalian evolution can be instrumental to predict phenotypes linked to the disease. For that, we studied brain In Situ Hybridization (ISH) data in mouse, marmoset, human embryo and fetuses and sequences data of Neanderthal, Denisovan and modern humans. Developmental mouse brain expression is found in neocortex, hippocampus, thalamus, tegmentum and cerebellum suggesting a link linked with cognition, stereotypies and perseverative behaviors. Expression in amygdala and claustrum found in marmoset extend these phenotypes to anxiety and higher-order cognitive processes. In human embryos (8 weeks) and fetuses (15- and 19-weeks), we foundAUTS2expression in similar regions but also in medial, lateral and caudal ganglionic eminence, that are involved in the diversity of interneurons found in neocortex, hippocampus and striatum. Sequence comparison ofAUTS2locus in Neanderthal, Denisova and modern human reveals novel sites in regulatory regions ofAUTS2. Altogether, these results suggest that ISH distribution along mammals is a novel phenotype-related biomarker useful for translational research.