bluuebunny/crossref_metadata_2025_split huggingface dataset:
The relationship between ageing and changes in the human blood and brain methylomes
Authors: Bryant Patrick , Elofsson Arne 
Published: January 2021

AbstractChanges in DNA methylation have been found to be strongly correlated with age, enabling the creation of “epigenetic clocks”. Previously, studies on the relationship between ageing and DNA methylation have assumed a linear relationship, but no study has shown this always to be the case. We show that the relationships between significant methylation changes and ageing are different in different tissues, and that these changes show variable rates across life. Further, we observe a tendency for saturation as ageing proceeds. We provide a straightforward method of assessing all methylation-age relationships and cluster them according to their relative change rates based on fold change. Less than 13% of the significant markers selected here are used in the most common epigenetic clocks. When the significant markers display largely non-linear relationships, our fold change selection outperforms the most common epigenetic clocks in predicting age. We also show that the saturation observed at older ages explains the earlier observations that the epigenetic clock consistently underestimates the age in older samples. The findings imply that markers selected from linear adjustments or correlations do not represent the most meaningful biological changes.
Youthful and age-related matreotypes predict drugs promoting longevity
Authors: Statzer Cyril , Jongsma Elisabeth , Liu Sean X. , Dakhovnik Alexander , Wandrey Franziska , Mozharovskyi Pavlo , Zülli Fred , Ewald Collin Y. 
Published: January 2021

AbstractThe identification and validation of drugs that promote health during aging (‘geroprotectors’) is key to the retardation or prevention of chronic age-related diseases. Here we found that most of the established pro-longevity compounds shown to extend lifespan in model organisms also alter extracellular matrix gene expression (i.e.,matrisome) in human cell lines. To harness this novel observation, we used age-stratified human transcriptomes to define the age-related matreotype, which represents the matrisome gene expression pattern associated with age. Using a ‘youthful’ matreotype, we screenedin silicofor geroprotective drug candidates. To validate drug candidates, we developed a novel tool using prolonged collagen expression as a non-invasive andin-vivosurrogate marker forC. eleganslongevity. With this reporter, we were able to eliminate false positive drug candidates and determine the appropriate dose for extending the lifespan ofC. elegans. We improved drug uptake for one of our predicted compounds, genistein, and reconciled previous contradictory reports of its effects on longevity. We identified and validated new compounds, tretinoin, chondroitin sulfate, and hyaluronic acid, for their ability to restore age-related decline of collagen homeostasis and increase lifespan. Thus, our innovative drug screening approach - employing extracellular matrix homeostasis - facilitates the discovery of pharmacological interventions promoting healthy aging.HighlightsMany geroprotective drugs alter extracellular matrix gene expressionDefined young and old human matreotype signatures can identify novel potential geroprotective compoundsProlonged collagen homeostasis as a surrogate marker for longevity
Local protein synthesis of mtIF3 regulates mitochondrial translation for axonal development
Authors: Lee Soyeon , Park Dongkeun , Lim Chunghun , Kim Jae-Ick , Min Kyung-Tai 
Published: January 2021

AbstractMitochondrial initiation factor 3 (mtIF3) binds to and dissociates mitochondrial ribosomes. The mtIF3-small subunit complex then recruits mtIF2, mRNA, and N-formylmethionine-tRNA to initiate mitochondrial translation. Intriguingly, transcripts of the nuclear-encoded mtIF3 gene have been shown present in axonal growth cones; however, the biological function of this compartmentalization remains largely unknown. Here, we demonstrate that brain-derived neurotrophic factor (BDNF) induces local translation of mtIF3 mRNA in axonal growth cones. Subsequently, mtIF3 protein is translocated into axonal mitochondria and promotes mitochondrial translation as assessed by our newly developed bimolecular fluorescence complementation sensor for the assembly of mitochondrial ribosomes. We further show that BDNF-induced axonal growth requires mtIF3-dependent mitochondrial translation in axons. These findings provide new insight into how neurons adaptively control mitochondrial physiology and axonal development via local mtIF3 translation.
Note: Updating the metadata of four misidentified samples in the DrosRTEC dataset
Authors: Nunez Joaquin C. B. , Paris Margot , Machado Heather , Bogaerts Maria , Gonzalez Josefa , Flatt Thomas , Coronado Marta , Kapun Martin , Schmidt Paul , Petrov Dmitri , Bergland Alan 
Published: January 2021

ABSTRACTThis note details the consortium’s rationale behind its decision to modify the metadata for putatively misidentified European samples in the DrosRTEC dataset. In brief, we use PCA on published datasets from North America and Europe to generate phylogeographic clusters reflective of worldwideD. melanogasterdemography. We used this PCA to train a DAPC model in order the predict the group membership. Our results indicate that 4 out of 73 samples were misclassified and the metadata was updated accordingly. These samples are a spring-fall pair from Spain and Austria.
Human stem cell model ofHNF1Adeficiency shows uncoupled insulin to C-peptide secretion with accumulation of abnormal insulin granules
Authors: González Bryan J. , Zhao Haoquan , Niu Jacqueline , Williams Damian J. , Lee Jaeyop , Goulbourne Chris N. , Xing Yuan , Wang Yong , Oberholzer Jose , Chen Xiaojuan , LeDuc Charles A. , Chung Wendy K. , Colecraft Henry M. , Gromada Jesper , Shen Yufeng , Goland Robin S. , Leibel Rudolph L. , Egli Dieter 
Published: January 2021

AbstractMutations inHNF1Acause Maturity Onset Diabetes of the Young type 3 (MODY3), the most prevalent form of monogenic diabetes. We generated stem cell-derived pancreatic endocrine cells from human embryonic stem cells (hESCs) with induced hypomorphic mutations inHNF1A. Using these cells, we show thatHNF1Aorchestrates a transcriptional program required for distinct aspects of β-cell fate and function. During islet cell differentiation,HNF1Adeficiency biases islet endocrine cells towards anα-cell fate associated withPAX4down-regulation.HNF1A-deficient β-cells display impaired basal and glucose stimulated-insulin secretion in association with a reduction inCACNA1Aand intracellular calcium levels, and impaired insulin granule exocytosis in association withSYT13down-regulation. Knockout ofPAX4,CACNA1AandSYT13reproduce the relevant phenotypes. Reduction of insulin secretion is associated with accumulation of enlarged secretory granules, and altered stoichiometry of secreted insulin to C-peptide. InHNF1Adeficient β-cells, glibenclamide, a sulfonylurea drug used in the treatment of MODY3 patients, increases intracellular calcium to levels beyond those achieved by glucose, and restores C-peptide and insulin secretion to a normal stoichiometric ratio. To studyHNF1Adeficiency in the context of a human disease model, we also generated stem cell-derived pancreatic endocrine cells from two MODY3 patient’s induced pluripotent stem cells (iPSCs). While insulin secretion defects are constitutive in cells with completeHNF1Aloss of function, β-cells heterozygous for hypomorphicHNF1Amutations are initially normal, but lose the ability to secrete insulin and acquire abnormal stoichiometric secretion ratios. Importantly, the defects observed in these stem cell models are also seen in circulating proportions of insulin:C-peptide in nine MODY3 patients.One sentence of summaryDeficiency of the transcription factorHNF1Abiases islet endocrine cell fate towardsα-cells, impairs intracellular calcium homeostasis and insulin exocytosis, alters the stoichiometry of insulin to C-peptide release, and leads to an accumulation of abnormal insulin secretory granules in β-cells.
Disentangling adaptation from drift in bottlenecked and reintroduced populations of Alpine ibex
Authors: Leigh D.M. , Lischer H.E.L. , Guillaume F. , Grossen C. , Günther T. 
Published: January 2021

AbstractIdentifying local adaptation in bottlenecked species is essential for effective conservation management. Selection detection methods are often applied to bottlenecked species and have an important role in species management plans, assessments of the species’ adaptive capacity, and looking for responses to major threats like climate change. Yet, the allele frequency changes driven by selection and exploited in selection detection methods, are similar to those caused by the strong neutral genetic drift expected during a bottleneck. Consequently, it is often unclear what accuracy selection detection methods may offer within bottlenecked populations. In this study, we used simulations to explore if signals of selection could be confidently distinguished from genetic drift across 23 bottlenecked and reintroduced populations of Alpine ibex (Capra ibex). We used the meticulously recorded demographic history of the Alpine ibex to generate a comprehensive simulated SNP data. The simulated SNPs were then used to benchmark the confidence we could place in putative outliers identified through selection scans on empirical Alpine ibex SNP data. Within the simulated dataset, the false positive rates were high for all selection detection methods but fell substantially when two or more selection detection methods were combined. However, the true positive rates were consistently low and became essentially negligible after this increased stringency. Despite the detection of many putative outlier loci in the empirical Alpine ibex RADseq data, none met the threshold needed to distinguish them from genetic drift-driven false positives. Unfortunately, the low true positive rate also creates a paradox, by preventing the exclusion of recent local adaptation within the Alpine ibex.
Fibroblast State Reversal By MBNL1-Dependent Transcriptome Modification Regulates Cardiac Repair
Authors: Bugg Darrian , Bretherton Ross , Beach Kylie , Reese Anna , Gunaje Jagadambika , Flint Galina , DeForest Cole A. , Stempien-Otero April , Davis Jennifer 
Published: January 2021

SUMMARYDynamic fibroblast state transitions are responsible for the heart’s fibrotic response to injury, raising the possibility that tactical control of these transitions could alter maladaptive fibrotic outcomes. Transcriptome maturation by the RNA binding protein Muscleblind Like 1 (MBNL1) has emerged as a potential driver of differentiated cell states. Here genetic lineage tracing of myofibroblasts in the injured heart demonstrated that gains in MBNL1 function corresponded to profibrotic fibroblast states. Similarly, in mice cardiac fibroblast specific MBNL1 overexpression induced a transcriptional myofibroblast profile in healthy cardiac fibroblasts that prevented the fibroproliferative phase of cardiac wound healing. By contrast loss of MBNL1 reverted cardiac fibroblasts to a pro-proliferative epicardial progenitor state that limited cardiac fibrosis following myocardial infarction. This progenitor state transition was associated with an MBNL1-dependent destabilization of the mesenchymal transition gene,Sox9.These findings suggest that MBNL1 regulation of the fibroblast transcriptome drives state transitions underlying cardiac fibrosis and repair.
High-order areas and auditory cortex both represent the high-level event structure of music
Authors: Williams Jamal A. , Margulis Elizabeth H. , Nastase Samuel A. , Chen Janice , Hasson Uri , Norman Kenneth A. , Baldassano Christopher 
Published: January 2021

AbstractRecent fMRI studies of event segmentation have found that default mode regions represent high-level event structure during movie watching. In these regions, neural patterns are relatively stable during events and shift at event boundaries. Music, like narratives, contains hierarchical event structure (e.g., sections are composed of phrases). Here, we tested the hypothesis that brain activity patterns in default mode regions reflect the high-level event structure of music. We used fMRI to record brain activity from 25 participants (male and female) as they listened to a continuous playlist of 16 musical excerpts, and additionally collected annotations for these excerpts by asking a separate group of participants to mark when meaningful changes occurred in each one. We then identified temporal boundaries between stable patterns of brain activity using a hidden Markov model and compared the location of the model boundaries to the location of the human annotations. We identified multiple brain regions with significant matches to the observer-identified boundaries, including auditory cortex, medial prefrontal cortex, parietal cortex, and angular gyrus. From these results, we conclude that both higher-order and sensory areas contain information relating to the high-level event structure of music. Moreover, the higher-order areas in this study overlap with areas found in previous studies of event perception in movies and audio narratives, including regions in the default mode network.Significance StatementListening to music requires the brain to track dynamics at multiple hierarchical timescales. In our study, we had fMRI participants listen to real-world music (classical and jazz pieces) and then used an unsupervised learning algorithm (a hidden Markov model) to model the high-level event structure of music within participants’ brain data. This approach revealed that default mode brain regions involved in representing the high-level event structure of narratives are also involved in representing the high-level event structure of music. These findings provide converging support for the hypothesis that these regions play a domain-general role in processing events occurring over long timescales.
Identification and Classification of Reverse Transcriptases in Bacterial Genomes and Metagenomes
Authors: Sharifi Fatemeh , Ye Yuzhen 
Published: January 2021

ABSTRACTReverse Transcriptases (RTs) are found in different systems including group II introns, Diversity Generating Retroelements (DGRs), retrons, CRISPR-Cas systems, and Abortive Infection (Abi) systems in prokaryotes. Different classes of RTs can play different roles, such as template switching and mobility in group II introns, spacer acquisition in CRISPR-Cas systems, mutagenic retrohoming in DGRs, programmed cell suicide in Abi systems, and recently discovered phage defense in retrons. While some classes of RTs have been studied extensively, others remain to be characterized. There is a lack of computational tools for identifying and characterizing various classes of RTs. In this study, we built a tool (called myRT) for identification and classification of prokaryotic RTs. In addition, our tool provides information about the genomic neighborhood of each RT, providing potential functional clues. We applied our tool to predict and classify RTs in all complete and draft bacterial genomes, and created a collection that can be used for exploration of putative RTs. Application of myRT to gut metagenomes showed that gut metagenomes encode proportionally more RTs related to DGRs, outnumbering retron-related RTs, as compared to the collection of reference genomes. MyRT is both available as a standalone software and also through a website.
40 minutes RT-qPCR Assay for Screening Spike N501Y and HV69-70del Mutations
Authors: Korukluoglu Gulay , Kolukirik Mustafa , Bayrakdar Fatma , Ozgumus Gozde Girgin , Altas Ayse Basak , Cosgun Yasemin , Ketre Kolukirik Canan Zohre 
Published: January 2021

ABSTRACTA one-step reverse transcription and real-time PCR (RT-qPCR) test was developed for rapid screening (40 minutes) of the Spike N501Y and HV69-70del mutations in SARS-CoV-2 positive samples. The test also targets a conserved region of SARS-CoV-2 Orf1ab as an internal control. The samples containing both the N501Y and HV69-70del mutations are concluded as VOC-202012/01 positive. Samples suspected to be positive for B.1.351 or P.1 are the N501Y positive and HV69-70del negative cases. Limit of detection (LOD) of the kit for Orf1ab target is 500 copies/mL, while that of the N501, Y501 and HV69-70del targets are 5000 copies/mL. The developed assay was applied to 165 clinical samples containing SARS-CoV-2 from 32 different lineages. The SARS-CoV-2 lineages were determined via the next-generation sequencing (NGS). The RT-qPCR results were in 100% agreement with the NGS results that 19 samples were N501Y and HV69-70del positive, 10 samples were N501Y positive and HV69-70del negative, 1 sample was N501Y negative and HV69-70del positive, and 135 samples were N501Y and HV69-70del negative. All the VOC-202012/01 positive samples were detected in people who have traveled from England to Turkey. The RT-qPCR test and the Sanger sequencing was further applied to 1000 SARS-CoV-2 positive clinical samples collected in Jan2021 from the 81 different provinces of Turkey. The RT-qPCR results were in 100% agreement with the Sanger sequencing results that 32 samples were N501Y positive and HV69-70del negative, 4 samples were N501Y negative and HV69-70del positive, 964 samples were N501Y and HV69-70del negative. The specificity of the 40 minutes RT-qPCR assay relative to the sequencing-based technologies is 100%. The developed assay is an advantageous tool for timely and representative estimation of the N501Y positive variants’ prevalence because it allows testing a much higher portion of the SARS-CoV-2 positives in much lower time compared to the sequencing-based technologies.
Application of the SMALP technology to the isolation of GPCRs from low-yielding cell lines
Authors: Tedesco Daniele , Maj Maciej , Malarczyk Paulina , Cingolani Andrea , Zaffagnini Mirko , Wnorowski Artur , Benelli Tiziana , Mazzoni Rita , Bartolini Manuela , Jóźwiak Krzysztof 
Published: January 2021

AbstractThe ability of styrene–maleic acid (SMAc) co-polymers to spontaneously insert into biological membranes can be exploited to extract G protein-coupled receptors (GPCRs) embedded in styrene–maleic acid lipid particles (SMALPs), preserving the native environment around the protein and thus enhancing the feasibility of functional studies. So far, the SMALP technology has been primarily employed on non-mammalian cells and protocols are not optimized for adherent human cell lines, which cannot be harvested in large amounts. In this work, a fine investigation of key parameters affecting the formation of SMALPs was undertaken with the purpose of maximizing the yield of extraction of a recombinant form of human β2-adrenergic receptor (rhβ2AR) from HEK293T cells. The study highlighted an important influence of ionic strength on the membrane solubilization efficiency and GPCR purification yield of SMAc co-polymers: by lowering the salt concentration of all buffers used in previously published SMALP protocols, the water solubility and extraction efficiency of the selected SMAc co-polymer (commercially supplied as a potassium salt) were enhanced. In-line combination of size-exclusion chromatography (SEC) with immobilized metal affinity chromatography (IMAC) allowed further improvement of the final rhβ2AR yield by reducing the loss of SMALP-embedded GPCRs during the fractionation and purification of SMALPs. The overall findings of this study show that the available SMALP protocols can be significantly optimized in several aspects in order to increase the efficiency of GPCR solubilization and isolation from low-yielding expression systems.HighlightsThe SMALP technology enables a direct solubilization of GPCRs from cell membranes.The isolation of GPCRs from mammalian cells is usually a low-yield procedure.SMALPs embedding the β2-adrenergic receptor were prepared from a HEK293T cell line.The ionic strength of buffers plays a key role in SMALP formation and isolation.Standard SMALP protocols can be finely optimized to increase purification yields.Graphical abstract
Infant gut strain persistence is associated with maternal origin, phylogeny, and functional potential including surface adhesion and iron acquisition
Authors: Lou Yue Clare , Olm Matthew R. , Diamond Spencer , Crits-Christoph Alexander , Firek Brian A. , Baker Robyn , Morowitz Michael J. , Banfield Jillian F. 
Published: January 2021

SUMMARYGut microbiome succession impacts infant development. However, it remains unclear what factors promote persistence of initial bacterial colonists in the developing gut. Here, we performed strain-resolved metagenomic analyses to compare gut colonization of preterm and full-term infants throughout the first year of life and evaluated links between strain persistence and strain origin as well as genetic potential. Analysis of 206 fecal metagenomes collected from full-term and preterm infants and their mothers revealed that infants’ initially distinct microbial communities converged by age one. Approximately 11% of early colonists, primarilyBacteroidesandBifidobacterium, persisted during the first year of life, and these were more prevalent in full-term compared to preterm infants. Gut-associated strains from mothers were significantly more likely to persist in the infant gut than other strains. Enrichment in genes for surface adhesion, iron acquisition and carbohydrate degradation may explain persistence of some strains through the first year of life.
Age, Origin, and Biogeography: Unveiling the Factors Behind the Diversification of Dung Beetles
Authors: Schwery Orlando , O’Meara Brian C. 
Published: January 2021

AbstractThe remarkable diversity and global distribution of dung beetles has long attracted the interest of researchers. However, there is still an ongoing debate on their origin, the reasons behind their diversity, and their path to global distribution. The two most prominent hypotheses regarding their origin and biogeographic history involve either vicariance events after the breakup of Gondwana, or an African origin and subsequent dispersal. One of the key reasons why the question is still disputed is a dependence on knowing the age of the dung beetles – a Mesozoic origin would favor the scenario of Gondwanan vicariance, a Cenozoic origin would suggest the out-of-Africa scenario. To help settle this longstanding question, we provide a taxonomically expanded phylogeny, with divergence times estimated under two calibration schemes suggesting an older or younger origin respectively. Using model-based inference, we estimate the ancestral area of the group and test for the influence of ranges on diversification rates. Our results support the hypothesis of an old age for Scarabaeinae and Gondwanan origin but remain ambiguous about the exact relation of range on lineage diversification.