bluuebunny/crossref_metadata_2025_split huggingface dataset:
Predicting biological age based on the BBMRI-NL 1H-NMR metabolomics repository
Authors: van den Akker E.B. , Trompet S. , Wolf J.J.H. Barkey , Beekman M. , Suchiman H.E.D. , Deelen J. , Asselbergs F.W. ,   BBMRI-NL, Boersma E. , Cats D. , Elders P.M. , Geleijnse J.M. , Ikram M.A. , Kloppenburg M. , Mei H. , Meulenbelt I. , Mooijaart S.P. , Nelissen R.G.H.H. , Netea M.G. , Penninx B.W.J.H. , Slofstra M. , Stehouwer C.D.A. , Swertz M.A. , Teunissen C.E. , Terwindt G.M. , ‘t Hart L.M. , van den Maagdenberg A.M.J.M. , van der Harst P. , van der Horst I.C.C. , van der Kallen C.J.H. , van Greevenbroek M.M.J. , van Spil W.E. , Wijmenga C. , Zhernakova A. , Zwinderman A.H. , Sattar N. , Jukema J.W. , van Duijn C.M. , Boomsma D.I. , Reinders M.J.T. , Slagboom P. Eline 
Published: May 2019

ABSTRACTThe blood metabolome incorporates cues from the environment as well as the host’s genetic background, potentially offering a holistic view of an individual’s health status. We have compiled a vast resource of 1H-NMR metabolomics and phenotypic data encompassing over 25,000 samples derived from 26 community and hospital-based cohorts. Using this resource, we constructed a metabolomics-based age predictor (metaboAge) to calculate an individual’s biological age. Exploration in independent cohorts demonstrates that being judged older by one’s metabolome, as compared to one’s chronological age, confers an increased risk on future cardiovascular disease, mortality and functionality in older individuals. A web-based tool for calculating metaboAge (metaboage.researchlumc.nl) allows easy incorporation in other epidemiological studies. Access to data can be requested at bbmri.nl/samples-images-data. In summary, we present a vast resource of metabolomics data and illustrate its merit by constructing a metabolomics-based score for biological age that captures aspects of current and future cardio-metabolic health.
Role of Triose Phosphate Utilization in photosynthetic response of rice to variable carbon dioxide levels and plant source-sink relations
Authors: Fabre Denis , Yin Xinyou , Dingkuhn Michael , Clément-Vidal Anne , Roques Sandrine , Rouan Lauriane , Soutiras Armelle , Luquet Delphine 
Published: May 2019

AbstractThis study aimed to understand the physiological bases of rice photosynthesis response to C source-sink imbalances, with focus on dynamics of the photosynthetic parameter TPU (Triose Phosphate Utilization). A dedicated experiment was replicated twice on IR64 indica rice cultivar in controlled environments. Plants were grown under the current ambient CO2 concentration until heading, thereafter, two CO2 treatments (400 and 800 μmol mol−1) were compared in the presence and absence of a panicle pruning treatment modifying the C sink. At two weeks after heading, photosynthetic parameters derived from CO2 response curves, and nonstructural carbohydrate content of flag leaf and internodes were measured 3-4 times of day. Spikelet number per panicle and flag leaf area on the main culm were recorded. Net C assimilation and TPU decreased progressively after midday in panicle-pruned plants, especially under 800 μmol mol−1. This TPU reduction was explained by sucrose accumulation in the flag leaf resulting from the sink limitation. It is suggested that TPU is involved in rice photosynthesis regulation under elevated CO2 conditions, and that sink limitation effects should be considered in crop models.HighlightThis study provide new insights in the effect of C source-sink relationships on rice photosynthesis. TPU should be considered in photosynthesis studies under severe source-sink imbalance at elevated CO2.
A labeled-line for cold from the periphery to the parabrachial nucleus
Authors: Hachisuka Junichi , Koerber H. Richard , Ross Sarah E. 
Published: May 2019

ABSTRACTSpinal projection neurons are a major pathway through which somatic stimuli are conveyed to the brain. However, the manner in which this information is coded is poorly understood. Here, we report the identification of a modality-selective spinoparabrachial (SPB) neuron subtype with unique properties. Specifically, we find that cold-selective SPB neurons are differentiated by selective afferent input, reduced neuropeptide sensitivity, distinct physiological properties, small soma size, and low basal drive. In addition, optogenetic experiments reveal that cold-selective SPB neurons are distinctive with respect to their connectivity, with little to no input from either Pdyn or Nos1 inhibitory interneurons. Together, these data define a neural substrate supporting a labeled-line for cold from the periphery to the brain.
Single-cell transcriptomes of the aging human skin reveal loss of fibroblast priming
Authors: Solé-Boldo Llorenç , Raddatz Günter , Schütz Sabrina , Mallm Jan-Philipp , Rippe Karsten , Lonsdorf Anke S. , Rodríguez-Paredes Manuel , Lyko Frank 
Published: May 2019

SummaryFibroblasts are the main dermal cell type and are essential for the architecture and function of human skin. Important differences have been described between fibroblasts localized in distinct dermal layers, and these cells are also known to perform varied functions. However, this phenomenon has not been analyzed comprehensively yet. Here we have used single-cell RNA sequencing to analyze >15,000 cells from a sun-protected area in young and old donors. Our results define four main fibroblast subpopulations that can be spatially localized and functionally distinguished. Importantly, intrinsic aging reduces this fibroblast ‘priming’, generates distinct expression patterns of skin aging-associated genes, and substantially reduces the interactions of dermal fibroblasts with other skin cell types. Our work thus provides comprehensive evidence for a functional specialization of human dermal fibroblasts and suggests that the age-related loss of fibroblast priming contributes to human skin aging.
CRISPR interference at the FAAH-OUT genomic region reduces FAAH expression
Authors: Mikaeili Hajar , Yeung Charlix , Habib Abdella M , Wood John N , Okorokov Andrei L , Cox James J 
Published: May 2019

AbstractFAAH-OUT encodes a putative long non-coding RNA which is located next to the FAAH gene on human chromosome 1. Recently an ~8 kb microdeletion, that removes upstream regulatory elements and the first 2 exons of FAAH-OUT, was reported in a pain insensitive patient (PFS) with additional clinical symptoms including a happy, non-anxious disposition, fast wound healing, fear and memory deficits, and significant post-operative nausea and vomiting induced by morphine. PFS also carries a hypomorphic SNP in FAAH that significantly reduces the activity of the encoded fatty-acid amide hydrolase enzyme. The FAAH and FAAH-OUT mutations identified in PFS result in elevated levels of anandamide (AEA), palmitoylethanolamide (PEA) and oleoylethanolamine (OEA) measured in peripheral blood. These bioactive lipids, which are normally degraded by FAAH, have diverse biological functions including known roles in pain pathways.Here we report the first mechanistic insights into how the FAAH-OUT microdeletion affects FAAH function. Gene editing in a human cell line to mimic the FAAH-OUT microdeletion observed in PFS results in reduced expression of FAAH. Furthermore, CRISPRi experiments targeting the promoter region of FAAH-OUT or a short highly evolutionarily conserved element in the first intron of FAAH-OUT also result in reduced expression of FAAH. These experiments confirm the importance of FAAH-OUT and specific genomic elements within the ~8 kb microdeleted sequence to normal FAAH expression. Our results also highlight the potential of CRISPRi and gene editing strategies that target the FAAH-OUT region for the development of novel FAAH-based analgesic and anxiolytic therapies.
Oral bacteriophages are maintained at high levels for months in individuals but infrequently transmitted between mothers and infants
Authors: Beall Clifford J. , Sulyanto Rosalyn M. , Griffen Ann L. , Leys Eugene J. 
Published: May 2019

ABSTRACTIn this work, we exploit recent advances in metagenomic assembly and bacteriophage identification to describe the phage content of saliva from 5 mother-baby pairs sampled twice 7 - 11 months apart during the first year of the babies’ lives. We identify 25 phage genomes that are comprised of one to 71 contigs, with 16 having a single contig. At the detectable level, phage were sparsely distributed with the most common one being present in 4 of the 20 samples, derived from two mothers and one baby. However, if they were present in the early time point sample from an individual, they were also present in the later sample from the same person more frequently than expected by chance. The nucleotide diversity (π) in phage from the same sample or the same person was much lower than between different individuals, indicating dominance of one strain in each person. This was different from bacterial genomes, which had higher diversity indicating the presence of multiple strains within an individual. We identify likely bacterial hosts for 16 of the 25 phage, including an apparent inovirus that is capable of integrating in the dif site ofHaemophilusspecies. It appears that phage in the oral cavity are sparsely distributed, but can be maintained for months once acquired.
Improving short and long term genetic gain by accounting for within family variance in optimal cross selection
Authors: Allier Antoine , Lehermeier Christina , Charcosset Alain , Moreau Laurence , Teyssèdre Simon 
Published: May 2019

AbstractThe implementation of genomic selection in recurrent breeding programs raised several concerns, especially that a higher inbreeding rate could compromise the long term genetic gain. An optimized mating strategy that maximizes the performance in progeny and maintains diversity for long term genetic gain on current and yet unknown future targets is essential. The optimal cross selection approach aims at identifying the optimal set of crosses maximizing the expected genetic value in the progeny under a constraint on diversity in the progeny. Usually, optimal cross selection does not account for within family selection, i.e. the fact that only a selected fraction of each family serves as candidate parents of the next generation. In this study, we consider within family variance accounting for linkage disequilibrium between quantitative trait loci to predict the expected mean performance and the expected genetic diversity in the selected progeny of a set of crosses. These predictions rely on the method called usefulness criterion parental contribution (UCPC). We compared UCPC based optimal cross selection and optimal cross selection in a long term simulated recurrent genomic selection breeding program considering overlapping generations. UCPC based optimal cross selection proved to be more efficient to convert the genetic diversity into short and long term genetic gains than optimal cross selection. We also showed that using the UCPC based optimal cross selection, the long term genetic gain can be increased with only limited reduction of the short term commercial genetic gain.
Machine learning and mechanistic modeling for prediction of metastatic relapse in early-stage breast cancer
Authors: Nicolò C. , Périer C. , Prague M. , Bellera C. , MacGrogan G. , Saut O. , Benzekry S. 
Published: May 2019

AbstractPurposeFor patients with early-stage breast cancer, prediction of the risk of metastatic relapse is of crucial importance. Existing predictive models rely on agnostic survival analysis statistical tools (e.g. Cox regression). Here we define and evaluate the predictive ability of a mechanistic model for the time to metastatic relapse.MethodsThe data consisted of 642 patients with 21 clinicopathological variables. A mechanistic model was developed on the basis of two intrinsic mechanisms of metastatic progression: growth (parameterα) and dissemination (parameterμ). Population statistical distributions of the parameters were inferred using mixed-effects modeling. A random survival forest analysis was used to select a minimal set of 5 covariates with best predictive power. These were further considered to individually predict the model parameters, by using a backward selection approach. Predictive performances were compared to classical Cox regression and machine learning algorithms.ResultsThe mechanistic model was able to accurately fit the data. Covariate analysis revealed statistically significant association ofKi67expression withα(p=0.001) andEGFRwithμ(p=0.009). Achieving a c-index of 0.65 (0.60-0.71), the model had similar predictive performance as the random survival forest (c-index 0.66-0.69) and Cox regression (c-index 0.62 - 0.67), as well as machine learning classification algorithms.ConclusionBy providing informative estimates of the invisible metastatic burden at the time of diagnosis and forward simulations of metastatic growth, the proposed model could be used as a personalized prediction tool of help for routine management of breast cancer patients.
A nemertean excitatory peptide/CCHamide regulates ciliary swimming in the larvae of Lineus longissimus
Authors: Thiel Daniel , Bauknecht Philipp , Jékely Gáspár , Hejnol Andreas 
Published: May 2019

AbstractBackgroundThe trochozoan excitatory peptide (EP) and its ortholog, the arthropod CCHamide, are neuropeptides that are only investigated in very few animal species. Previous studies on different trochozoan species focused on their physiological effect in adult specimens, demonstrating a myo-excitatory effect, often on tissues of the digestive system. The function of EP in the planktonic larvae of trochozoans has not yet been studied.ResultsWe surveyed transcriptomes from species of various spiralian (Orthonectia, Nemertea, Brachiopoda, Entoprocta, Rotifera) and ecdysozoan taxa (Tardigrada, Onychophora, Priapulida, Loricifera, Nematomorpha) to investigate the evolution of EPs/CCHamides in protostomes. We found that the EPs of several pilidiophoran nemerteans show a characteristic difference in their C-terminus. Deorphanization of a pilidiophoran EP receptor showed, that the two isoforms of the nemertean Lineus longissimus EP activate a single receptor. We investigated the expression of EP in L. longissimus larvae and juveniles with customized antibodies and found that EP-positive nerves in larvae project from the apical organ to the ciliary band and that EP is expressed more broadly in juveniles in the neuropil and the prominent longitudinal nerve cords. While exposing juvenile L. longissimus specimens to synthetic excitatory peptides did not show any obvious effect, exposure of larvae to either of the two EPs increased the beat frequency of their locomotory cilia and shifted their vertical swimming distribution in a water column upwards.ConclusionOur results show that EP/CCHamide peptides are broadly conserved in protostomes. We show that the EP increases the ciliary beat frequency of L. longissimus larvae, which shifts their vertical distribution in a water column upwards. Endogenous EP may be released at the ciliary band from the projections of apical organ EP-positive neurons to regulate ciliary beating. A locomotory function of EP in L. longissimus larvae, compared to the association of EP/CCHamides with the digestive system in other animals suggests a dynamic integration of orthologous neuropeptides into different functions during evolution.
Characterization of the Golgi c10orf76-PI4KB complex, and its necessity for Golgi PI4P levels and enterovirus replication
Authors: McPhail J.A. , Lyoo H.R. , Pemberton J.G. , Hoffmann R.M. , van Elst W. , Strating J.R.P.M. , Jenkins M.L. , Stariha J.T.B. , van Kuppeveld F.J.M. , Balla T. , Burke J.E. 
Published: May 2019

SummaryThe lipid kinase PI4KB, which generates phosphatidylinositol 4-phosphate (PI4P), is a key enzyme in regulating membrane transport and is also hijacked by multiple picornaviruses to mediate viral replication. PI4KB can interact with multiple protein binding partners, which are differentially manipulated by picornaviruses to facilitate replication. The protein c10orf76 is a PI4KB-associated protein that increases PI4P levels at the Golgi, and is essential for the viral replication of specific enteroviruses. We used hydrogen deuterium exchange mass spectrometry to characterize the c10orf76-PI4KB complex and reveal that binding is mediated by the kinase linker of PI4KB, with formation of the heterodimeric complex modulated by PKA-dependent phosphorylation. Complex-disrupting mutations demonstrate that PI4KB is required for membrane recruitment of c10orf76 to the Golgi, and that an intact c10orf76-PI4KB complex is required for the replication of c10orf76-dependent enteroviruses. Intriguingly, c10orf76 was also required for proper Arf1 activation at the Golgi, providing a putative mechanism for the c10orf76-dependent increase in PI4P levels at the Golgi.Highlightsc10orf76 forms a direct complex with PI4KB, with the interface formed by a disorder-to-order transition in the kinase linker of PI4KBThe c10orf76 binding site of PI4KB can be phosphorylated by PKA, with phosphorylation leading to decreased affinity for c10orf76Complex-disrupting mutants of PI4KB and c10orf76 reveal that PI4KB recruits c10orf76 to the Golgi/TGNDepletion of c10orf76 leads to decreases in both active Arf1 and Golgi PI4P levelsEnteroviruses that rely on c10orf76 for replication depend on formation of the c10orf76-PI4KB complex
A simple and sensitive SYBR Gold-based assay to quantify DNA-protein interactions
Authors: Schreier Spencer , Petla Bhanu Prakash , Lin Tao , Chakravarty Suvobrata , Subramanian Senthil 
Published: May 2019

AbstractA simple, accessible, and inexpensive assay to quantify the strength of DNA-protein interactions was developed. The assay relies on capturing DNA-protein complexes using an affinity resin that binds tagged, recombinant proteins. Sequential washes with filtration spin cups and centrifugation remove non-specific interactions in a gentle, uniform manner and a final elution isolates specific DNA-protein complexes. SYBR Gold nucleic acid stain is added to the eluted product and the fluorescence intensity accurately quantifies the amount of captured DNA, ultimately illustrating the relative strength of the DNA-protein interaction. The major utility of the assay resides in the versatility and quantitative nature of the SYBR Gold:nucleic acid interaction, eliminating the need for customized or labeled oligos and permitting relatively inexpensive quantification of binding capacity. The assay also employs DNA-protein complex capture by the very common purification tag, 6xHis, but other tags could likely be utilized. Further, SYBR Gold fluorescence is compatible with a wide variety of instruments, including UV transilluminators, a staple to any molecular biology laboratory. This assay was used to compare the binding capacities of different Auxin Response Factor (ARF) transcription factors to various dsDNA targets, including the classical AuxRE motif and several divergent sequences. Results from dose-response assays suggest that different ARF proteins might show distinct comparative affinities for AuxRE variants, emphasizing that specific ARF-AuxRE binding strengths likely contribute to the complex and fine-tuned cellular auxin response.
Separation of hemodynamic signals from GCaMP fluorescence measured with widefield imaging
Authors: Valley M.T. , Moore M.G. , Zhuang J , Mesa N , Castelli D , Sullivan D , Reimers M , Waters J 
Published: May 2019

ABSTRACTWidefield calcium imaging is often used to measure brain dynamics in behaving mice. With a large field of view and a high sampling rate, widefield imaging can monitor activity from several distant cortical areas simultaneously, revealing cortical interactions. Interpretation of widefield images is complicated, however, by the absorption of light by hemoglobin, which can substantially affect the measured fluorescence. One approach to separating hemodynamics and calcium signals is to use multi-wavelength backscatter recordings to measure light absorption by hemoglobin. Following this approach, we develop a spatially-detailed regression-based method to estimate hemodynamics. The spatially-detailed model is based on a linear form of the Beer-Lambert relationship, but is fit at every pixel in the image and does not rely on the estimation of physical parameters. In awake mice of three transgenic lines, the Spatial Model offers improved separation of hemodynamics and changes in GCaMP fluorescence. The improvement is pronounced near blood vessels and, in contrast with other models based on regression or the Beer-Lambert law, can remove vascular artifacts along the sagittal midline. Compared to other separation approaches, the spatially-detailed model permits more accurate fluorescence-based determination of neuronal activity across the cortex.NEW & NOTEWORTHYThis manuscript addresses a well-known and strong source of contamination in widefield calcium imaging data: hemodynamics. To guide researchers towards the best method to separate calcium signals from hemodynamics, we compare the performance of several commonly used methods in three commonly-used Cre-driver lines, and we present a novel regression model that out-performs the other techniques we consider.
Simulating groundcover community assembly in a frequently burned ecosystem using a simple neutral model
Authors: Loudermilk E. Louise , Dyer Lee , Pokswinski Scott , Hudak Andrew T. , Hornsby Benjamin , Richards Lora , Dell Jane , Goodrick Scott L. , Hiers J. Kevin , O’Brien Joseph J. 
Published: May 2019

AbstractFire is a global process that drives patterns of biodiversity. In frequently burned fire-dependent ecosystems, surface fire regimes allow for the coexistence of high plant diversity at fine-scales even where soils are uniform. The mechanisms on how fire impacts groundcover community dynamics are however, poorly understood. Because fire can act as a stochastic agent of mortality, we hypothesized that a neutral mechanism might be responsible for maintaining plant diversity. We used the demographic parameters of the Unified Neutral Theory of Biodiversity (UNTB) as a foundation to model groundcover species richness, using a southeastern U.S. pine woodland as an example. We followed the fate of over 7,000 individuals of 123 plant species for four years and two prescribed burns in frequently burned Pinus palustris sites in NW FL, USA. Using these empirical data and UNTB-based assumptions, we developed two parsimonious autonomous agent models, which were distinct by spatially explicit and implicit local recruitment processes. Using a parameter sensitivity test, we examined how empirical estimates, input species frequency distributions, and community size affected output species richness. We found that dispersal limitation was the most influential parameter, followed by mortality and birth, and that these parameters varied based on scale of the frequency distributions. Overall, these nominal parameters were useful for simulating fine-scale groundcover communities, although further empirical analysis of richness patterns, particularly related to fine-scale burn severity is needed. This modeling framework can be utilized to examine our premise that localized groundcover assemblages are neutral communities at high fire frequencies, as well as examine the extent to which niche-based dynamics determine community dynamics when fire frequency is altered and spatial fire intensity patterns differ.