bluuebunny/crossref_metadata_2025_split huggingface dataset:
Robust Harmonization of Microbiome Studies by Phylogenetic Scaffolding with MaLiAmPi
Authors: Minot Samuel S , Garb Bailey , Roldan Alennie , Tang Alice , Oskotsky Tomiko , Rosenthal Christopher , Hoffman Noah G , Sirota Marina , Golob Jonathan L 
Published: July 2022

AbstractMicrobiome science is difficult to translate back to patients due to an inability to harmonize 16S rRNA gene-based microbiome data, as differences in the technique will result in different amplicon sequence variants (ASV) from the same microbe. Here we demonstrate that placement of ASV onto a common phylogenetic tree of full-length 16S rRNA alleles can harmonize microbiome studies. Using in silico data approximating 100 healthy human stool microbiomes we demonstrated that phylogenetic placement of ASV can recapitulate the true relationships between communities as compared closed-OTU based approaches (Spearman R 0.8 vs 0.2). Using real data from thousands of human gut and vaginal microbiota, we demonstrate phylogenetic placement, but not closed OTUs, were able to group communities by origin (stool vs vaginal) without being confounded by technique and integrate new data into existing ordination/clustering models for precision medicine. This enables meta-analysis of microbiome studies and the microbiome as a biomarker.
Hepatic lipid overload potentiates biliary epithelial cell activation via E2Fs
Authors: Yildiz Ece , Alam Gaby El , Perino Alessia , Jalil Antoine , Denechaud Pierre-Damien , Huber Katharina , Fajas Lluis , Auwerx Johan , Sorrentino Giovanni , Schoonjans Kristina 
Published: July 2022

AbstractDuring severe or chronic hepatic injury, biliary epithelial cells (BECs), also known as cholangiocytes, undergo rapid reprogramming and proliferation, a process known as ductular reaction (DR), and allow liver regeneration by differentiating into both functional cholangiocytes and hepatocytes. While DR is a hallmark of chronic liver diseases, including advanced stages of non-alcoholic fatty liver disease (NAFLD), the early events underlying BEC activation are largely unknown. Here, we demonstrate that BECs readily accumulate lipids upon fatty acid (FA) treatment in BEC-derived organoids, and during high-fat diet feeding in mice. Lipid overload induces a metabolic rewiring to support the conversion of adult cholangiocytes into active BECs. Mechanistically, we found that lipid overload unleashes the activation of the E2F transcription factors in BECs, which drives cell cycle progression while promoting glycolytic metabolism. These findings demonstrate that fat overload is sufficient to initiate a DR, without epithelial damage, and provide new insights into the mechanistic basis of BEC activation, revealing unexpected connections between lipid metabolism, stemness, and regeneration.
Dysfunction of the Polycomb protein RYBP and of 5-methylcytosine oxidases leads to widespread CpG island hypermethylation and cell transformation
Authors: Cui Wei , Huang Zhijun , Jin Seung-Gi , Johnson Jennifer , Hostetter Galen , Pfeifer Gerd P. 
Published: July 2022

ABSTRACTDNA hypermethylation is a hallmark of cancer and predominantly affects CpG island regions. Although this phenomenon was first described more than three decades ago, its mechanisms have remained unknown. Since CpG island hypermethylation is strongly biased towards Polycomb target genes, we reasoned that dysfunction of Polycomb repression complexes (PRCs) may underlie CpG island hypermethylation. We observed that a few genes coding for components of the PRC1 complex are downregulated in many cancer types. We focused on RYBP, a key activator of variant PRC1 complexes responsible for H2AK119 monoubiquitylation. We inactivated RYBP in nontumorigenic bronchial epithelial cells and observed a limited extent of DNA hypermethylation. Considering that tumors are deficient in 5-methylcytosine oxidase (TET protein) function as documented by substantially reduced levels of 5-hydroxymethylcytosine in all solid tumors, we then inactivated TET1, TET2, and TET3 in bronchial cells, individually and in combination. Using quadruple knockouts of RYBP and all three TET proteins, we observed widespread hypermethylation of H2AK119Ub1-marked CpG islands affecting almost 4,000 target genes. This hypermethylation closely mirrored the DNA hypermethylation landscape observed in human lung tumors. These cells showed aberrant methylation and dysregulation of several cancer-relevant pathways including cell cycle control genes, defects in the Hippo pathway and overexpression of AP-1 transcription factor genes. As a result, the quadruple knockout bronchial cells acquired properties of a transformed phenotype, including efficient growth in soft agar and formation of squamous cell carcinomas in immune-compromised mice. Our data provide a long- sought mechanism for DNA hypermethylation in cancer and explain how such hypermethylation leads to cell transformation. Cancer formation, therefore, is achievable by misregulation of two epigenetic pathways without introduction of cancer driver mutations.
Sunscreen redox status in a multicellular cyanobacterium visualized by Raman scattering spectral microscope
Authors: Tamamizu Kouto , Sakamoto Toshio , Kurashige Yuki , Nozue Shuho , Kumazaki Shigeichi 
Published: July 2022

AbstractUV radiation, desiccation, and starvation induce some cyanobacteria to produce a UVA-absorbing pigment, scytonemin, at extracellular sheaths. Although the accumulation of scytonemin is recognizable as dark sheaths through optical microscopes, it has been nontrivial to identify its redox status and obtain its subcellular distribution in response to physiological conditions. Here, we show that a spontaneous Raman scattering spectral microscopy based on an excitation-laser-line-scanning method unveil 3D subcellular distributions of non-UV-induced scytonemins with distinct redox statuses in a filamentous cyanobacterium with a single nitrogen-fixing cell at the basal end. Cellular differentiations and scytonemin redox conditions were simultaneously visualized with an excitation wavelength at 1064 nm that is virtually free from the optical screening by the dark sheaths. The molecular imaging results give insights into not only secretion mechanisms of the sunscreen pigment but also interdependence between photosynthesis, nitrogen fixation, and redox homeostasis in one of the simplest forms of multicellular organisms.
Brain structural covariances in the ageing brain in the UK Biobank
Authors: Dong Chao , Thalamuthu Anbupalam , Jiang Jiyang , Mather Karen A. , Sachdev Perminder S. , Wen Wei 
Published: July 2022

AbstractBrain structural covariances or pairwise correlations describe how morphologic properties of brain regions are related to one another across individuals. Although it is reported that brain structural covariance changes during brain development, it is not clear how structural covariance relates to the ageing process. Here we investigated the human brain structural covariances of cortical thickness and subcortical volumes in the ageing brain and their associations with age, cognition, and longevity polygenic risk score (longevity-PRS) by using cross-sectional data from the UK Biobank (N = 42075, aged 45-83 years, M/F=19752 /22323). The sample of participants was divided into 84 non-overlapping groups based on their age. The older the age group, the greater the variability in the whole brain structural covariance. However, there was a differential rate of age-related increase of variance between males and females. The variance of females started lower than those of males and then increased with age with a greater gradient than that of males. There was a consistent and significant enrichment of pairwise correlations within the occipital lobe in ageing process. The cortical thickness and subcortical covariances in older groups were significantly different from those in the youngest group. Sixty-two of the total 528 pairs of cortical thickness correlations and 10 of the total 21 pairs of subcortical volume correlations were significantly associated with age after Bonferroni correction. Specifically, with an increasing age, most decreased cortical thickness correlations were found between the regions within the frontal lobe as well as between the frontal lobe regions and regions in other lobes, while pairwise correlations within occipital lobe regions were all strengthening. Most of these correlations were also associated with global cognition and weakly associated with longevity-PRS. These findings revealed that the structural covariance was not stable during ageing. Given the thinning of the cortex and the volumetric reduction of subcortical structures seen in the ageing process, an increased pairwise correlation between the brain regions in the older brain suggested a strengthened coordinated decline between the brain regions involved. However, some of the brain regions demonstrated a differentiated rate of decline which was shown as the inversed or reduced pairwise correlations between these regions.
Effect of Single Nucleotide Polymorphisms on the structure of long noncoding RNAs and their interaction with RNA Binding Proteins
Authors: Singh Mandakini , Kumar Santosh 
Published: July 2022

AbstractLong non-coding RNAs (lncRNA) are emerging as a new class of regulatory RNAs with remarkable potential to be utilized as therapeutic targets against many human diseases. Several genome-wide association studies (GWAS) have catalogued Single Nucleotide Polymorphisms (SNPs) present in the noncoding regions of the genome, transcribing lncRNAs. In this study, we have selected 67 lncRNAs with GWAS-tagged SNPs and have also investigated their role in affecting the local secondary structures. The majority of the SNPs lead to changes in the secondary structure of lncRNA to a different extent by altering the base pairing patterns. These structural changes in lncRNA are also manifested in form of alteration in the binding site for RNA binding proteins (RBPs) along with affecting their binding efficacies. Ultimately, these structural modifications may influence the transcriptional and post-transcriptional pathways of these RNAs, leading to the causation of diseases. Hence, it is important to understand the possible underlying mechanism of RBPs in association with GWAS-tagged SNPs in human diseases.
Environmental Stability of Enveloped Viruses is Impacted by the Initial Volume and Evaporation Kinetics of Droplets
Authors: French Andrea J. , Longest Alexandra K. , Pan Jin , Vikesland Peter J. , Duggal Nisha K. , Lakdawala Seema S. , Marr Linsey C. 
Published: July 2022

AbstractEfficient spread of respiratory viruses requires the virus to maintain infectivity in the environment. Environmental stability of viruses can be influenced by many factors, including temperature and humidity. Our study measured the impact of initial droplet volume (50, 5, and 1 µL) and relative humidity (RH: 40%, 65%, and 85%) on the stability of influenza A virus, bacteriophage, Phi6, a common surrogate for enveloped viruses, and SARS-CoV-2 under a limited set of conditions. Our data suggest that the drying time required for the droplets to reach quasi-equilibrium (i.e. a plateau in mass) varied with RH and initial droplet volume. The macroscale physical characteristics of the droplets at quasi-equilibrium varied with RH but not with initial droplet volume. We observed more rapid virus decay when the droplets were still wet and undergoing evaporation, and slower decay after the droplets had dried. Initial droplet volume had a major effect on virus viability over the first few hours; whereby the decay rate of influenza virus was faster in smaller droplets. In general, influenza virus and SARS-CoV-2 decayed similarly. Overall, this study suggests that virus decay in media is closely correlated with the extent of droplet evaporation, which is controlled by RH. Taken together, these data suggest that decay of different viruses is more similar at higher RH and in smaller droplets and is distinct at lower RH and in larger droplets. Importantly, accurate assessment of transmission risk requires use of physiologically relevant droplet volumes and careful consideration of the use of surrogates.FundingNational Institute of Allergy and Infectious Diseases, National Institute of Neurological Disorders and Stroke, National Institutes of Health; Department of Health and Human Services; Flu Lab.ImportanceDuring the COVID-19 pandemic, policy decisions were being driven by virus stability experiments involving SARS-CoV-2 applied to surfaces in large droplets at various humidity conditions. The results of our study indicate that determination of half-lives for emerging pathogens in large droplets likely over-estimates transmission risk for contaminated surfaces, as occurred during the COVID-19 pandemic. Our study implicates the need for the use of physiologically relevant droplet sizes with use of relevant surrogates in addition to what is already known about the importance of physiologically relevant media for risk assessment of future emerging pathogens.
Long-term effects of early postnatal stress on Sertoli cells functions
Authors: Thumfart Kristina M. , Lazzeri Samuel , Manuella Francesca , Mansuy Isabelle M. 
Published: July 2022

AbstractSertoli cells are somatic cells in testes essential for spermatogenesis, as they support the development, maturation, and differentiation of germ cells. Sertoli cells are metabolically highly active and physiologically regulated by external signals, particularly factors in the blood stream. In disease conditions, circulating pathological signals may affect Sertoli cells and consequentially, alter germ cells and fertility. While the effects of stress on reproductive cells have been well studied, how Sertoli cells respond to stress remains poorly characterized. Therefore, we used a mouse model of early postnatal stress to assess the effects of stress on Sertoli cells. We developed an improved enrichment strategy based on intracellular stainings and obtained enriched preparations of adult Sertoli cells from exposed males. We show that adult Sertoli cells have impaired electron transport chain (ETC) pathways and that several components of ETC complexes I, III, and IV are persistently affected. We identify the circulation as a potential mediator of the effects of stress, since treatment of primary Sertoli cells with serum from stressed males induces similar ETC alterations. These results newly highlight Sertoli cells as cellular targets of early life stress, and suggest that they may contribute to the negative effects of stress on fertility.HighlightsWe present an improved method to obtain enriched preparations of Sertoli cells from adult mouse testis for molecular analysesSertoli cells from adult males exposed to stress during early postnatal life have altered electron transport chain (ETC) expression, suggesting persistent effects of early life stress on Sertoli cells physiologySerum from adult males exposed to early postnatal stress reproduces ETC gene dysregulation in cultured Sertoli cells.Graphical abstract
Segmented MS/MS acquisition of a1 ion-based strategy for in-depth proteome quantitation
Authors: Wang Zhiting , Liu Chao , Wang Songduo , Hou Xinhang , Gong Pengyun , Li Xiao , Liang Zhen , Liu Jianhui , Zhang Lihua , Zhang Yukui 
Published: July 2022

ABSTRACTIn-depth proteome quantitation is of great significance for understanding protein functions, advancing biological, medical, environmental and metabolic engineering research. Herein, benefiting from the high formation efficiencies and intensities of dimethyl-labeled a1 ions for accurate quantitation, we developed an in-depth a1 ion-based proteome quantitation method, named deep-APQ, by a sequential MS/MS acquisition of the high mass range for identification and the low mass range for a1 ion intensity extraction to increase quantitative protein number and sequence coverage. By the analysis of HeLa protein digests, our developed method showed deeper quantitative coverage than our previously reported a1 ion-based quantitation method without mass range segmentation and lower missing values than widely-used label-free quantitation method. It also exhibited excellent accuracy and precision within a 20-fold dynamic range. We further integrated a workflow combining the deep-APQ method with highly efficient sample preparation, high-pH and low-pH reversed-phase separation and high-field asymmetric waveform ion mobility spectrometry (FAIMS) to study E. coli proteome responses under the nutritional conditions of glucose and acetate. A total of 3447 proteins were quantified, representing 82% of protein-coding genes, with the average sequence coverage up to 40%, demonstrating the high coverage of quantitation results. We found that most of the quantified proteins related to chemotaxis were differentially expressed, including the low-abundance proteins such as trg, fliL, and cheA, indicating that chemotaxis would play an important role for E. coli cell to survive from acetate toxicity. The above results demonstrated that the deep-APQ method is of great promising to achieve the deep-coverage proteome quantitation with high confidence.GRAPHICAL ABSTRACT
TCR-pMHC complex formation triggers CD3 dynamics
Authors: van Eerden Floris J. , Sherif Aalaa Alrahman , Llamas-Covarrubias Mara Anais , Millius Arthur , Lu Xiuyuan , Ishizuka Shigenari , Yamasaki Sho , Standley Daron M. 
Published: July 2022

AbstractIn this study, we present an allosteric mechanism for T cell receptor (TCR) triggering upon binding a peptide-MHC complex (pMHC), in which a conformational change in the TCR upon pMHC binding controls the mobility of the CD3 proteins. We found that the TCRβ FG loop serves as a gatekeeper, preventing accidental triggering, while the connecting peptide acts as a hinge for essential conformational changes in the TCR. Atomistic simulations and cell-based experiments with genetically modified connecting peptides demonstrate that rigidified hinge residues result in excessive CD3 dynamics and hypersensitivity to pMHC binding. Our model thus provides a clear connection between extracellular TCR-pMHC binding and changes in CD3 dynamic that propagate from outside to inside the cell.
COVID19-vaccination affects breath methane dynamics
Authors: Polag Daniela , Keppler Frank 
Published: July 2022

AbstractMethane (CH4) is well known as a component in the exhaled breath of humans. It has been assumed for a long time that formation of CH4 in humans occurs exclusively by anaerobic microbial activity (methanogenesis) in the gastrointestinal tract. A fraction of the produced CH4 is excreted via the lungs and can then be detected in the breath. However, recent studies challenge this view by showing that CH4 might also be produced endogenously in cells by oxidative-reductive stress reactions. Thus, an increased and fluctuating level of breath CH4 compared to the base level of an individual might also indicate enhanced oxidative stress levels. Thus, monitoring breath CH4 levels might have great potential for ‘in vivo’ diagnostics.Generally, vaccines generate a strong immune response including the production of pro-inflammatory cytokines. To evaluate the effect from current vaccines against COVID-19 on breath CH4 dynamics, breath CH4 was monitored from 12 subjects prior and after the injection of several COVID-vaccines. Prior to COVID-19 vaccination the concentration of breath CH4 was frequently measured by gas chromatograph flame ionization detection (GC-FID, with analytical precision better than 10 parts per billion, ppbv) to obtain the individual variation range of breath CH4 for each subject. Following vaccination, CH4 breath samples were collected at high frequency for a period of 14 days.All subjects monitored showed a strong response in breath CH4 release within 1 to 72 hours after vaccination including shifts and high fluctuations with maximum peaks showing a factor of up to ±100 compared to base values. Thus, it is highly likely that the observed changes in breath CH4 are coupled to immune responses following Covid-19 vaccination. These preliminary results strongly support the hypothesis that non-microbial methane liberation and utilisation in the human body might be also linked to cellular processes and stress responses independent of classical microbial methanogenesis. Thus, CH4 might be used as a breath biomarker for specific immune responses and individual immune states.
Phenotypic extremes or extreme phenotypes? On the use of large and small-bodied “phenocopied” Drosophila melanogaster males in studies of sexual selection and conflict
Authors: Schang Kyle , Garant Renée , Long Tristan A.F. 
Published: July 2022

AbstractIn the fruit fly, Drosophila melanogaster, variation in body size is influenced by a number of different factors and may be strongly associated with individual condition, performance and success in reproductive competitions. Consequently, intra-sexual variation in size in this model species has been frequently explored in order to better understand how sexual selection and sexual conflict may operate and shape evolutionary trajectories. However, measuring individual flies can often be logistically complicated and inefficient, which can result in limited sample sizes. Instead, many experiments use large and/or small body sizes that are created by manipulating the developmental conditions experienced during the larval stages, resulting in “phenocopied” flies whose phenotypes resemble what is seen at the extremes of a population’s size distribution. While this practice is fairly common, there has been remarkedly few direct tests to empirically compare the behaviour or performance of phenocopied flies to similarly-sized individuals that grew up under typical developmental conditions. Contrary to assumptions that phenocopied flies are reasonable approximations, we found that both large and small-bodied phenocopied males frequently differed from their standard development equivalents in their mating frequencies, their lifetime reproductive successes, and in their effects on the fecundity of the females they interacted with. Our results highlight the complicated contributions of environment and genotype to the expression of body size phenotypes and lead us to strongly urge caution in the interpretation of studies solely replying upon phenocopied individuals.
Global fMRI signal topography differs systematically across the lifespan
Authors: Nomi Jason S. , Bzdok Danilo , Li Jingwei , Bolt Taylor , Chang Catie , Kornfeld Salome , Goodman Zachary T. , Yeo B.T. Thomas , Spreng R. Nathan , Uddin Lucina Q. 
Published: July 2022

AbstractThe global signal (GS) in resting-state fMRI, known to contain artifacts and non-neuronal physiological signals, also contains important neural information related to individual state and trait characteristics. Here we show distinct linear and curvilinear lifespan patterns of GS topography in a cross-sectional lifespan sample, demonstrating its importance for consideration in studies of development and aging. Subcortical brain regions such as the thalamus and putamen show linear associations with the GS across the lifespan. The thalamus has stronger coupling in older-age individuals compared with younger-aged individuals, while the putamen has stronger coupling in younger individuals compared with older individuals. The subcortical nucleus basalis shows a u-shaped pattern similar to cortical regions within the lateral frontoparietal network and dorsal attention network, where coupling with the GS is stronger at early and old age, with weaker coupling in middle age. This differentiation in coupling strength between subcortical and cortical brain activity across the lifespan supports a dual-layer model of GS composition, where subcortical aspects of the GS are differentiated from cortical aspects of the GS. We find that these subcortical-cortical contributions to the GS depend strongly on the lifespan stage of individuals. Our findings demonstrate how neurobiological information within the GS differs across development and highlight the need to carefully consider whether or not to remove this signal when investigating age-related functional differences in the brain.