bluuebunny/crossref_metadata_2025_split huggingface dataset:
Recalibrating the Epigenetic Clock: Implications for Assessing Biological Age in the Human Cortex
Authors: Shireby Gemma L , Davies Jonathan P , Francis Paul T , Burrage Joe , Walker Emma M , Neilson Grant W A , Dahir Aisha , Thomas Alan J , Love Seth , Smith Rebecca G , Lunnon Katie , Kumari Meena , Schalkwyk Leonard C , Morgan Kevin , Brookes Keeley , Hannon Eilis J , Mill Jonathan 
Published: April 2020

AbstractHuman DNA-methylation data have been used to develop biomarkers of ageing - referred to ‘epigenetic clocks’ - that have been widely used to identify differences between chronological age and biological age in health and disease including neurodegeneration, dementia and other brain phenotypes. Existing DNA methylation clocks are highly accurate in blood but are less precise when used in older samples or on brain tissue. We aimed to develop a novel epigenetic clock that performs optimally in human cortex tissue and has the potential to identify phenotypes associated with biological ageing in the brain. We generated an extensive dataset of human cortex DNA methylation data spanning the life-course (n = 1,397, ages = 1 to 104 years). This dataset was split into ‘training’ and ‘testing’ samples (training: n = 1,047; testing: n = 350). DNA methylation age estimators were derived using a transformed version of chronological age on DNA methylation at specific sites using elastic net regression, a supervised machine learning method. The cortical clock was subsequently validated in a novel human cortex dataset (n = 1,221, ages = 41 to 104 years) and tested for specificity in a large whole blood dataset (n = 1,175, ages = 28 to 98 years). We identified a set of 347 DNA methylation sites that, in combination optimally predict age in the human cortex. The sum of DNA methylation levels at these sites weighted by their regression coefficients provide the cortical DNA methylation clock age estimate. The novel clock dramatically out-performed previously reported clocks in additional cortical datasets. Our findings suggest that previous associations between predicted DNA methylation age and neurodegenerative phenotypes might represent false positives resulting from clocks not robustly calibrated to the tissue being tested and for phenotypes that become manifest in older ages. The age distribution and tissue type of samples included in training datasets need to be considered when building and applying epigenetic clock algorithms to human epidemiological or disease cohorts.
Metabolic exchange and energetic coupling between nutritionally stressed bacterial species, the possible role of QS molecules
Authors: Ranava David , Backes Cassandra , Karthikeyan Ganesan , Ouari Olivier , Soric Audrey , Guiral Marianne , Cárdenas María Luz , Giudici-Orticoni Marie Thérèse 
Published: April 2020

AbstractTo clarify the principles controlling inter-species interactions, we previously developed a co-culture model with two anaerobic bacteria, Clostridium acetobutylicum and Desulfovibrio vulgaris Hildenborough, in which nutritional stress for D. vulgaris induced tight cell-cell inter-species interaction. Here we show that exchange of metabolites produced by C. acetobutylicum allows D. vulgaris to duplicate its DNA, and to be energetically viable even without its substrates. Physical interaction between C. acetobutylicum and D. vulgaris (or Escherichia coli and D. vulgaris) is linked to the quorum-sensing molecule AI-2, produced by C. acetobutylicum and E. coli. With nutrients D. vulgaris produces a small molecule that inhibits in vitro the AI-2 activity, and could act as an antagonist in vivo. Sensing of AI-2 by D. vulgaris could induce formation of an intercellular structure that allows directly or indirectly metabolic exchange and energetic coupling between the two bacteria.
Alternative phage-host interaction inLactococcus lactis: the carrier state drives rapid evolution of phages
Authors: Marcelli Barbara , de Jong Anne , Janzen Thomas , Kok Jan , Kuipers Oscar P. 
Published: April 2020

AbstractLactococcus lactisis a lactic acid bacterium widely used as starter culture for the manufacture of fermented milk products like quark, buttermilk and cheese. Bacteriophage infection of starter cultures is one of the biggest causes of fermentation failure and, therefore, lactococcal phages have received great attention from the scientific community in the past decades. In this work we present evidence for the establishment of a carrier state life cycle (CSLC) by a bacteriophage belonging to the c2 species, in the model laboratory strainL. lactisMG1363. Our results show that infection ofL. lactisMG1363 with a second, dissimilar, c2 bacteriophage can induce the CSLC phage to enter an active lytic life cycle. The viral progeny obtained after this infection is a mixed population of phages with differences in their genome sequences and host ranges, indicative of an extremely rapid evolution process. We discuss the possible implications of this phage-host interaction, both with respect to bacteriophage evolution and phage adaptation to different hosts.IMPORTANCEOur results broaden the current know-how on the yet poorly investigated phage-host interaction mechanism of CSLC, propose a new bacteriophage evolution mechanism, and demonstrate that the outcome of phage infections is possibly more intricate than presently acknowledged.
MOSAIC: A Joint Modeling Methodology for Combined Circadian and Non-Circadian Analysis of Multi-Omics Data
Authors: De los Santos Hannah , Bennett Kristin P. , Hurley Jennifer M. 
Published: April 2020

AbstractMotivationCircadian rhythms are approximately 24 hour endogenous cycles that control many biological functions. To identify these rhythms, biological samples are taken over circadian time and analyzed using a single omics type, such as transcriptomics or proteomics. By comparing data from these single omics approaches, it has been shown that transcriptional rhythms are not necessarily conserved at the protein level, implying extensive circadian post-transcriptional regulation. However, as proteomics methods are known to be noisier than transcriptomic methods, this suggests that previously identified arrhythmic proteins with rhythmic transcripts could have been missed due to noise and may not be due to post-transcriptional regulation.ResultsTo determine if one can use information from less-noisy transcriptomic data to inform rhythms in more-noisy proteomic data, and thus more accurately identify rhythms in the proteome, we have created the MOSAIC (Multi-Omics Selection with Amplitude Independent Criteria) application. MOSAIC combines model selection and joint modeling of multiple omics types to recover significant circadian and non-circadian trends. Using both synthetic data and proteomic data fromNeurospora crassa, we showed that MOSAIC accurately recovers circadian rhythms at higher rates in not only the proteome but the transcriptome as well, outperforming existing methods for rhythm identification. In addition, by quantifying non-circadian trends in addition to circadian trends in data, our methodology allowed for the recognition of the diversity of circadian regulation as compared to non-circadian regulation.AvailabilityMOSAIC’s full interface is available athttps://github.com/delosh653/MOSAIC.Contacthurlej2@rpi.eduSupplementary informationSupplementary data are available.atBioinformaticsonline.
Transcriptome Sequencing Reveals Sex Differences in Human Meniscal Cell Response to Estrogen Based on Dosing Kinetics
Authors: Knewtson Kelsey E. , Gonzalez Flores Jesus G. , Pacicca Donna M. , Robinson Jennifer L. 
Published: April 2020

ABSTRACTOsteoarthritis is a disease marked by progressive and irreversible hyaline cartilage and fibrocartilage breakdown that affects the lives of millions of patients worldwide. Female sex and menopause are both risk factors for knee osteoarthritis, indicating that estrogen could play a role in this disease. In this study, RNA sequencing was used to determine the effects of estrogen treatment on human meniscal cells. Differences in the number and type of differentially expressed genes were seen based on donor sex, estrogen dose, and dosing kinetics. Significantly more differentially expressed genes were seen from male meniscal cells in response to all dosing conditions compared to female cells. Importantly, more genes were differentially expressed in cells treated with continuous dosing of estrogen, which has been shown to stimulate genomic estrogen signaling, as compared to pulsed dosing. Additionally, functional enrichment analysis revealed that many genes of the extracellular matrix, which is important for joint health and injury repair, were differentially expressed. Overall, this initial study lays the groundwork for future avenues to pursue the effect of estrogen delivery on regenerative pathways. This critical analysis will then inform the design and implementation of estrogen replacement therapies to promote meniscal health and reduce the onset of osteoarthritis.
A conserved neuropeptide system links head and body motor circuits to enable adaptive behavior
Authors: Ramachandran Shankar , Banerjee Navonil , Bhattacharya Raja , Lemons Michele L , Florman Jeremy , Lambert Christopher M. , Touroutine Denis , Alexander Kellianne , Schoofs Liliane , Alkema Mark J , Beets Isabel , Francis Michael M. 
Published: April 2020

SUMMARYNeuromodulators promote adaptive behaviors that are often complex and involve concerted activity changes across circuits that are often not physically connected. It is not well understood how neuromodulatory systems accomplish these tasks. Here we show that theC. elegansNLP-12 neuropeptide system shapes responses to food availability by modulating the activity of head and body wall motor neurons through alternate G-protein coupled receptor (GPCR) targets, CKR-1 and CKR-2. We showckr-2deletion reduces body bend depth during movement under basal conditions. We demonstrate CKR-1 is a functional NLP-12 receptor and define its expression in the nervous system. In contrast to basal locomotion, biased CKR-1 GPCR stimulation of head motor neurons promotes turning during local searching. Deletion ofckr-1reduces head neuron activity and diminishes turning while specificckr-1overexpression or head neuron activation promote turning. Thus, our studies suggest locomotor responses to changing food availability are regulated through conditional NLP-12 stimulation of head or body wall motor circuits.Impact statementInvestigation of neuromodulatory control of ethologically conserved area-restricted food search behavior shows that NLP-12 stimulation of the head motor circuit promotes food searching through the previously uncharacterized CKR-1 GPCR.
Universal NicE-seq for high resolution accessible chromatin profiling for formaldehyde fixed and FFPE tissues
Authors: Chin Hang Gyeong , Sun Zhiyi , Vishnu Udayakumar S. , Hao Christina , Cejas Paloma , Spracklin George , Estève Pierre-Olivier , Xu Shuang-yong , Long Henry W. , Pradhan Sriharsa 
Published: April 2020

AbstractAccessible chromatin plays a central role in gene expression and chromatin architecture. Current accessible chromatin approaches depend on limited digestion/cutting and pasting adaptors at the accessible DNA, thus requiring additional materials and time for optimization. Universal NicE-seq (UniNicE-seq) is an improved accessible chromatin profiling method that negate the optimization step and is suited to a variety of mammalian cells and tissues. Addition of 5-methyldeoxycytidine triphosphate during accessible chromatin labeling and an on-bead library making step substantially improved the signal to noise ratio while protecting the accessible regions from repeated nicking in cell lines, mouse T cells, mouse kidney, and human frozen tissue sections. We also demonstrate one tube UniNicE-seq for FFPE tissue section for direct NGS library preparation without sonication and DNA purification steps. These refinements allowed reliable mapping of accessible chromatin for high resolution genomic feature studies.
Age-Related Changes in Chimpanzee (Pan troglodytes) Cognition: Cross-Sectional and Longitudinal Analyses
Authors: Hopkins William D , Mareno Mary Catherine , Webb Sarah J Neal , Schapiro Steve J , Raghanti Mary Ann , Sherwood Chet C 
Published: April 2020

AbstractChimpanzees are the species most closely related to humans yet age-related changes in brain and cognition remain poorly understood. The lack of studies on age-related changes in cognition in chimpanzees is particularly unfortunate in light of the recent evidence demonstrating that this species naturally develops Alzheimer’s disease (AD) neuropathology. Here, we tested 213 young, middle-aged, and elderly chimpanzees on the Primate Cognitive Test Battery (PCTB), a set of 13 tasks that assess physical and social cognition in nonhuman primates. A subset of these chimpanzees (n=146) were tested a second time on a portion of the PCTB tasks as a means of evaluating longitudinal changes in cognition. Cross-sectional analyses revealed a significant quadratic association between age and cognition with younger and older chimpanzees performing more poorly than middle-aged individuals. Longitudinal analyses showed that, while young chimpanzees’ performance improved from test 1 to test 2, middle-aged and elderly chimpanzees’ performance showed significant decline over time. The collective data show that chimpanzees, like other nonhuman primates, show age-related decline in cognition. Further investigations into whether the observed cognitive decline is associated with AD pathologies in chimpanzees would be invaluable in understanding the comparative biology of aging and neuropathology in primates.
Adaptive synaptic plasticity maintains CRH neuron output during chronic glucocorticoid exposure
Authors: Rasiah Neilen , Rosenegger David , Daviu Nuria , Füzesi Tamás , Muir Jessie , Sterley Toni-Lee , Bains Jaideep S. 
Published: April 2020

AbstractAn increase in circulating glucocorticoids (CORT) is an essential part of the response to stress. Sustained elevations of CORT, however, have dramatic consequences on behavior, endocrine systems and peripheral organs. Critically, they dampen the endocrine response to acute challenges and decrease intrinsic excitability of corticotropin-releasing hormone neurons in the paraventricular nucleus (CRHPVN), suggesting key circuits may be less responsive to stress. Here, we make the surprising discovery that CRHPVNneurons harness a form of adaptive synaptic scaling to escape the persistent negative feedback pressure from CORT and maintain stable outputin vivo. Specifically, there is an increase in glutamatergic drive to these cells that is mediated by a postsynaptic, multiplicative increase in synaptic strength. These findings suggest that dysfunctions associated with chronic stress may not be due to the primary actions of CORT, but instead reflect the emergence of synaptic adaptations as networks seek to re-establish intrinsic activity setpoints.
Nano-positioning and tubuline conformation determine transport of mitochondria along microtubules
Authors: Van Steenbergen V. , Lavoie-Cardinal F. , Kazwiny Y. , Decet M. , Martens T. , Verstreken P. , Boesmans W. , De Koninck P. , Berghe P. Vanden 
Published: April 2020

AbstractCorrect spatiotemporal distribution of organelles and vesicles is crucial for healthy cell functioning and is regulated by intracellular transport mechanisms. Controlled transport of bulky mitochondria is especially important in polarized cells such as neurons that rely on these organelles to locally produce energy and buffer calcium. Mitochondrial transport requires and depends on microtubules which fill much of the available axonal space. How mitochondrial transport is affected by their position within the microtubule bundles is not known. Here, we found that anterograde transport, driven by kinesin motors, is susceptible to the molecular conformation of tubulin bothin vitroandin vivo. Anterograde velocities negatively correlate with the density of elongated tubulin dimers, similar to GTP-tubulin, that are more straight and rigid. The impact of the tubulin conformation depends primarily on where a mitochondrion is positioned, either within or at the rim of microtubule bundle. Increasing elongated tubulin levels lowers the number of motile anterograde mitochondria within the microtubule bundle and increases anterograde transport speed at the microtubule bundle rim. We demonstrate that the increased kinesin step processivity on microtubules consisting of elongated dimers underlies increased mitochondrial dynamics. Our work indicates that the molecular conformation of tubulin controls mitochondrial motility and as such locally regulates the distribution of mitochondria along axons.
Engineering Highly Homogenous Tetravalent IgGs with Enhanced Sperm Agglutination Potency
Authors: Shrestha Bhawana , Schaefer Alison , Chavez Elizabeth C. , Kopp Alexander J. , Jacobs Timothy M. , Moench Thomas R. , Lai Samuel K. 
Published: April 2020

AbstractMillions of women avoid using available contraceptives and risk unintended pregnancies every year, due to perceived and/or real side-effects associated with the use of exogenous hormones. Naturally occurring anti-sperm antibodies can prevent fertilization in immune infertile women by limiting sperm permeation through mucus, particularly multivalent antibodies such as sIgA that offers robust agglutination potencies. Unfortunately, sIgA remains challenging to produce in large quantities and easily aggregates. Here, we designed two tetravalent anti-sperm IgGs with a Fab domain previously isolated from an immune infertile woman. Both constructs possess at least 4-fold greater agglutination potency and induced much more rapid sperm agglutination than the parent IgG while exhibiting comparable production yields and identical thermostability as the parent IgG. These tetravalent IgGs offer promise for non-hormonal contraception and underscore the multimerization of IgG as a promising strategy to improve existing mAb therapeutics.
In silicoCharacterization of Class II Plant Defensins fromArabidopsis thaliana
Authors: Costa Laura S.M. , Pires Állan S. , Damaceno Neila B. , Rigueiras Pietra O. , Maximiano Mariana R. , Franco Octavio L. , Porto William F. 
Published: April 2020

AbstractDefensins comprise a polyphyletic group of multifunctional defense peptides. Cis-defensins, also known as cysteine stabilized αβ (CSαβ) defensins, are one of the most ancient defense peptide families. In plants, these peptides have been divided into two classes, according to their precursor organization. Class I defensins are composed of the signal peptide and the mature sequence, while class II defensins have an additional C-terminal prodomain, which is proteolytically cleaved. Class II defensins have been described in Solanaceae and Poaceae species, indicating this class could be spread among all flowering plants. Here, a search by regular expression (RegEx) was applied to theArabidopsis thalianaproteome, a model plant with more than 300 predicted defensin genes. Two sequences were identified, A7REG2 and A7REG4, which have a typical plant defensin structure and an additional C-terminal prodomain. TraVA database indicated they are expressed in flower, ovules and seeds, and being duplicated genes, this indicates they could be a result of a subfunctionalization process. The presence of class II defensin sequences in Brassicaceae and Solanaceae and evolutionary distance between them suggest class II defensins may be present in other eudicots. Discovery of class II defensins in other plants could shed some light on flower, ovules and seed physiology, as this class is expressed in these locations.
Prevalence of asymptomatic glioma and implications for survival
Authors: Warren Paula Province , Lobbous Mina , Peeri Noah C. , Thompson Zachary J. , Thompson Reid C. , Olson Jeffrey J. , LaRocca Renato V. , Chowdhary Sajeel A. , Anderson Mark D. , Vogelbaum Michael A. , Markert James M. , Nabors Louis B. , Egan Kathleen M. 
Published: April 2020

AbstractBackgroundBrain tumors can present as focal neurologic deficits (reflecting the tumor location) or generalized symptoms due to increased intracranial pressure. Occasionally, brain tumors can be found incidentally in asymptomatic patients or in patients with unrelated symptoms who undergo brain imaging. The term incidentaloma is used to refer to these imaging abnormalities.ObjectiveThe object of this study was to examine the prevalence and correlates of asymptomatic glioma in a large epidemiological study of brain tumors.MethodsThe analysis was based on a large series of patients with glioma (N = 1989) enrolled in a multicenter clinic-based epidemiologic study between 2005 and 2017. Patients were considered asymptomatic from the tumor, and thus as having an incidentally detected glioma (IDG), if the tumor was diagnosed during workup of injury or unrelated medical condition.ResultsA total of 32 of 1989 (1.6%) patients were asymptomatic at diagnosis. The leading indication for brain imaging in IDG was non-workplace injuries followed by medical workup for unrelated conditions. IDG was more prevalent in patients younger than 50 years of age (2.6% vs 1.0%). IDG was also more common in patients with low grade gliomas (4.7% for WHO grade II and 1.5% for WHO grade III) vs glioblastomas (0.6% in WHO grade IV).ConclusionThe present data suggest that gliomas may be found incidentally, especially among low grade gliomas. Studies of IDG may be useful as a proxy for early detection of tumor as a means to improve patient survival.
Functional data analysis techniques to improve the generalizability of near-infrared spectral data for monitoring mosquito populations
Authors: Esperança Pedro M. , Da Dari F. , Lambert Ben , Dabiré Roch K. , Churcher Thomas S. 
Published: April 2020

AbstractNear infrared spectroscopy is increasingly being used as an economical method to monitor mosquito vector populations in support of disease control. Despite this rise in popularity, strong geographical variation in spectra has proven an issue for generalising predictions from one location to another. Here, we use a functional data analysis approach—which models spectra as smooth curves rather than as a discrete set of points—to develop a method that is robust to geographic heterogeneity. Specifically, we use a penalised generalised linear modelling framework which includes efficient functional representation of spectra, spectral smoothing and regularisation. To ensure better generalisation of model predictions from one training set to another, we use cross-validation procedures favouring smoother representation of spectra. To illustrate the performance of our approach, we collected spectra for field-caught specimens ofAnopheles gambiaecomplex mosquitoes – the most epidemiologically important vector species on the planet – in two sites in Burkina Faso. Using these spectra, we show how models trained on data from one site can successfully classify morphologically identical sibling species in another site, over 250km away. Whilst we apply our framework to species prediction, our unified statistical framework can, alternatively, handle regression analysis (for example, to determine mosquito age) and other types of multinomial classification (for example, to determine infection status). To make our methods readily available for field entomologists, we have created an open-source R packagemlevcm. All data used is publicly also available.