bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enhanced metabolic potentials and functional gene interactions of microbial stress response towards high elevation in freshwater lakes
Authors: Li Huabing , Zeng Jin , Ren Lijuan , Yan Qingyun , Wu Qinglong L. 
Published: July 2020

ABSTRACTElevation has strong influence on microbial community composition, but its influence on aquatic microbial functional genes remains unclear. Here, we compared the functional gene structure of microbial communities in surface water between two low-elevation lakes (LELs, with elevation of ca. 530 meters) and two high-elevation lakes (HELs, with elevation of ca. 4,600 meters) by using a metagenomic approach of Geo Chip-based functional gene arrays. We found significant differences in composition but not in richness of the microbial functional genes between the HELs and the LELs. In the HELs, the microbial communities had higher functional capacities in stress responses than those in LELs, which include cold shock, oxygen limitation, osmotic stress, nitrogen limitation, phosphate limitation, glucose limitation, radiation stress, heat shock, protein stress, and sigma factors genes. We also observed higher metabolic potentials in the degradation of aromatic, chitin, cellulose and hemicellulose in HELs than in LELs. By performing network analyses, we found enhanced interactions and complexity among the co-occurring functional genes in the HELs than those in the LELs in terms of network size, links, connectivity, and clustering coefficients. Notably, more functional genes of stress response played module-hub roles in the network of HELs. Overall, we observed contrasting patterns of microbial metabolic potentials and functional gene interactions in different elevational freshwater lakes, and found that the microbial communities developed functional strategies to cope with the harsh conditions at the high elevational lakes.IMPORTANCEElevational patterns of biodiversity have attracted scientific interest in the fields of microbial ecology and biogeography. The influence of elevation on aquatic microbial functional gene structure and their metabolic potentials remains unclear. We compared the functional gene structure of microbial communities in surface water between two low-elevation lakes and two high-elevation lakes with a more than 4,000-meter difference in elevation along a mountainside by using GeoChip 5.0, which covered in total 144,000 gene sequences from 393 functional gene families. We found apparent differences in functional gene structures in lakes between the two different elevations. We also found enhanced metabolic potentials and functional gene interactions for microbial stress response with increasing elevation in freshwater lakes. These results highlighted that limnetic microbial communities could develop functional strategies to cope with harsh conditions towards high elevations.
The contribution of rehabilitation settings to the cost of integrated continuum-care episodes for hip fracture: a retrospective cohort study
Authors: Golinelli Davide , Boetto Erik , Mazzotti Antonio , Rosa Simona , Rucci Paola , Berti Elena , Ugolini Cristina , Fantini Maria Pia 
Published: July 2020

ABSTRACTBackgroundHip fracture (HF) requires an intensive healthcare resources utilization. Long-term morbidity related to poor fracture management is associated with a significant increase in healthcare costs. Many factors may affect the costs and outcomes in patients with HF. Using a definition of integrated Continuum-Care Episode (CCE) that encompasses the hospital phase and the post-acute rehabilitation after a surgical procedure for HF, we investigated the costs of CCEs for HF and their determinants, with particular regard to the contribution of different rehabilitation settings.MethodsWe conducted a retrospective observational cohort study using data extracted from administrative databases of 5094 consecutive patients hospitalized for HF in 2017, aged ≥65 years, and resident in Emilia Romagna, Italy. To evaluate the overall costs of the CCE, we calculated the acute and post-acute costs from the date of the first hospital admission to the end of the integrated CCE. The determinants of costs were investigated using generalized linear regression models.ResultsAfter adjusting for demographic and clinical characteristics, type of surgery (b=-0.340, p<0.001), and hospital bed-based rehabilitation in public or private healthcare facilities either followed by rehabilitation in a community hospital/temporary nursing home beds (b=0.372, p<0.001) or not (b=0.313, p<0.001) were the strongest determinants of costs, while rehabilitation in intermediate care facilities alone was associated with lower costs (0.163, p<0.001).ConclusionsOur findings suggest that CCE cost and its variability is mainly related to the rehabilitation settings. Cost-wise, intermediate care resulted to be an appropriate setting for providing post-acute rehabilitation for HF, representing the one associated with the lower cost of the overall CCE. Therefore, intermediate care settings should be privileged when planning HF rehabilitation pathways.
DIPPER: a spatiotemporal proteomics atlas of human intervertebral discs for exploring ageing and degeneration dynamics
Authors: Tam Vivian , Chen Peikai , Yee Anita , Solis Nestor , Klein Theo , Kudelko Mateusz , Sharma Rakesh , Chan Wilson CW , Overall Christopher M. , Haglund Lisbet , Sham Pak C , Cheah Kathryn SE , Chan Danny 
Published: July 2020

AbstractThe spatiotemporal proteome of the intervertebral disc (IVD) underpins its integrity and function. We present DIPPER, a deep and comprehensive IVD proteomic resource comprising 94 genomewide profiles from 17 individuals. To begin with, protein modules defining key directional trends spanning the lateral and anteroposterior axes were derived from high-resolution spatial proteomes of intact young cadaveric lumbar IVDs. They revealed novel region-specific profiles of regulatory activities, and displayed potential paths of deconstruction in the level- and location-matched aged cadaveric discs. Machine learning methods predicted a “hydration matrisome” that connects extracellular matrix with MRI intensity. Importantly, the static proteome used as point-references can be integrated with dynamic proteome (SILAC/degradome) and transcriptome data from multiple clinical samples, enhancing robustness and clinical relevance. The data, findings and methodology, available on a web interface, will be valuable references in the field of IVD biology and proteomic analytics.
Plasticity in prefrontal cortex induced by coordinated nucleus reuniens and hippocampal synaptic transmission
Authors: Banks Paul J , Warburton E Clea , Bashir Zafar I 
Published: July 2020

AbstractThe nucleus reuniens of the thalamus (NRe) is reciprocally connected to a range of higher order cortices including hippocampus (HPC) and medial prefrontal cortex (mPFC). The physiological function of NRe is well predicted by requirement for interactions between mPFC and HPC, including associative recognition memory, spatial navigation and working memory. Although anatomical and electrophysiological evidence suggests NRe makes excitatory synapses in mPFC there is little data on the physiological properties of these projections, or whether NRe and HPC target overlapping cell populations and, if so, how they interact. We demonstrate inex vivomPFC slices that NRe and HPC afferent inputs converge onto more than two-thirds of layer 5 pyramidal neurons, show that NRe, but not HPC, undergoes marked short-term plasticity at theta, and that HPC, but not NRe, afferents are subject to neuromodulation by acetylcholine acting via muscarinic receptor M2. Finally, we demonstrate that pairing HPC followed by NRe (but not pairing NRe followed by HPC) at theta frequency induces associative, NMDA receptor dependent synaptic plasticity in both inputs to mPFC. These data provide vital physiological phenotypes of the synapses of this circuit and provide a novel mechanism for HPC-NRe-mPFC encoding.
Acute changes in systemic glycaemia gate access and action of GLP-1R agonist on brain structures controlling energy homeostasis
Authors: Bakker Wineke , Salinas Casper Gravesen , Imbernon Monica , Chao Daniela Herrera Moro , Hassouna Rim , Morel Chloe , Martin Claire , Gangarossa Giuseppe , Denis Raphael GP , Castel Julien , Peter Andreas , Heni Martin , Maetzler Walter , Nielsen Heidi Solvang , Duquenne Manon , Secher Anna , Hecksher-Sørensen Jacob , Åskov Pedersen Thomas , Prevot Vincent , Luquet Serge 
Published: July 2020

ABSTRACTThe control of body weight and glucose homeostasis are the bedrock of type 2 diabetes medication. Therapies based on co-administration of glucagon-like peptide-1 (GLP-1) long-acting analogues and insulin are becoming popular in the treatment of T2D. Both insulin and GLP-1 receptors (InsR and GLP1-R, respectively) are expressed in brain regions critically involved in the regulation of energy homeostasis, suggesting a possible cooperative action. However, the mechanisms underlying the synergistic action of insulin and GLP-1R agonists on body weight loss and glucose homeostasis remain largely under-investigated. In this study, we provide evidence that peripheral insulin administration modulates the action of GLP-1R agonists onto fatty acids oxidation. Taking advantage of fluorescently labeled insulin and GLP-1R agonists, we found that glucoprivic condition, either achieved by insulin or by 2-deoxyglucose (2-DG), acts as a permissive signal on the blood-brain barrier (BBB) at circumventricular organs, including the median eminence (ME) and the area postrema (AP), enhancing the passage and action of GLP-1-R agonists. Mechanistically, this phenomenon relied on the release of tanycyctic vascular endothelial growth factor A (VEGF-A) and it was selectively impaired after calorie-rich diet exposure. Finally, we found that in human subjects, low blood glucose also correlates with enhanced blood-to-brain passage of insulin suggesting that changes in glycaemia also affect passage of peptide hormones into the brain in humans.In conclusion, we describe a yet unappreciated mechanism by which acute variations of glycaemia gate the entry and action of circulating energy-related signals in the brain. This phenomenon has physiological and clinical relevance implying that glycemic control is critical to harnessing the full benefit of GLP-1R agonist co-treatment in body weight loss therapy.
Anxiety makes time pass quicker: neural correlates
Authors: Sarigiannidis I , Kieslich K , Grillon C , Ernst M , Roiser JP , Robinson OJ 
Published: July 2020

AbstractAnxiety can be an adaptive process that promotes harm avoidance. It is accompanied by shifts in cognitive processing, but the precise nature of these changes and the neural mechanisms that underlie them are not fully understood. One theory is that anxiety impairs concurrent (non-harm related) cognitive processing by commandeering finite neurocognitive resources. For example, we have previously shown that anxiety reliably ‘speeds up time’, promoting temporal underestimation, possibly due to loss of temporal information. Whether this is due anxiety ‘overloading’ neurocognitive processing of time is unknown. We therefore set out to understand the neural correlates of this effect, examining whether anxiety and time processing overlap, particularly in regions of the cingulate cortex. Across two studies (an exploratory Study 1, N=13, followed by a pre-registered Study 2, N=29) we combined a well-established anxiety manipulation (threat of shock) with a temporal bisection task while participants were scanned using functional magnetic resonance imaging. Consistent with our previous work, time was perceived to pass more quickly under induced anxiety. Anxiety induction led to widespread activation in cingulate cortex, while the perception of longer intervals was associated with more circumscribed activation in a mid-cingulate area. Importantly, conjunction analysis identified convergence between anxiety and time processing in the insula and mid-cingulate cortex. These results provide tentative support for the hypothesis that anxiety impacts cognitive processing by overloading already-in-use neural resources. In particular, overloading mid-cingulate cortex capacity may drive emotion-related changes in temporal perception, consistent with the hypothesised role of this region in mediating cognitive affective and behavioural responses to anxiety.
Agonal factors distort gene-expression patterns in human postmortem brains
Authors: Dai Jiacheng , Chen Yu , Chen Chao , Liu Chunyu 
Published: July 2020

AbstractAgonal factors, the conditions that occur just prior to death, can impact the molecular quality of postmortem brains, influencing gene expression results. Nevertheless, study designs using postmortem brain tissue rarely, if ever, account for these factors, and previous studies had not documented nor adjusted for agonal factors. Our study used gene expression data of 262 samples from ROSMAP with the following terminal states recorded for each donor: surgery, fever, infection, unconsciousness, difficulty breathing, and mechanical ventilation. Performed differential gene expression and weighted gene co-expression network analyses (WGCNA), fever and infection were the primary contributors to brain gene expression changes. Fever and infection also contributed to brain cell-type specific gene expression and cell proportion changes. Furthermore, the gene expression patterns implicated in fever and infection were unique to other agonal factors. We also found that previous studies of gene expression in postmortem brains were confounded by variables of hypoxia or oxygen level pathways. Therefore, correction for agonal factors through probabilistic estimation of expression residuals (PEER) or surrogate variable analysis (SVA) is recommended to control for unknown agonal factors. Our analyses revealed fever and infection contributing to gene expression changes in postmortem brains and emphasized the necessity of study designs that document and account for agonal factors.
The Contribution of Environmental Enrichment to Phenotypic Variation in Mice and Rats
Authors: Kentner Amanda C. , Speno Amanda V. , Doucette Joanne , Roderick Ryland C. 
Published: July 2020

AbstractThe reproducibility and translation of neuroscience research is assumed to be undermined by introducing environmental complexity and heterogeneity. Rearing laboratory animals with minimal (if any) environmental stimulation is thought to control for biological variability but may not adequately test the robustness of our animal models. Standard laboratory housing is associated with reduced demonstrations of species typical behaviors and changes in neurophysiology that may impact the translation of research results. Modest increases in environmental enrichment (EE), mitigate against insults used to induce animal models of disease, directly calling into question the translatability of our work. This may in part underlie the disconnect between preclinical and clinical research findings. Enhancing environmental stimulation for our model organisms promotes ethological natural behaviors but may simultaneously increase phenotypic trait variability. To test this assumption, we conducted a systematic review and evaluated coefficients of variation between EE and standard housed mice and rats. Given findings of suboptimal reporting of animal laboratory housing conditions, we also developed a methodological reporting table for enrichment use in neuroscience research. Our data show that animals housed in environmental enrichment were not more variable than those in standard housing. Therefore, environmental heterogeneity introduced into the laboratory, in the form of enrichment, does not compromise data integrity. Overall, human life is complicated and by embracing such nuanced complexity into our laboratories we may paradoxically improve upon the rigor and reproducibility of our research.Significance StatementEnvironmental complexity is thought to increase phenotypic variability, undermining research translation. We conducted a systematic review and compared coefficients of variation between environmentally enriched and standard housed laboratory animals. Despite there being no differences in variability across several phenotypic traits, there are stark contrasts in the display of ethological natural behaviors between these housing conditions. Environmental enrichment is recognized as being beneficial for animal welfare and mitigates against insults used to induce animal models of disease. In contrast, standard laboratory cages are recognized as being impoverished and ‘unnatural’. From these observations, it is apparent that our current “gold standard” caging system is not a true control condition as it does not adequately test the robustness of our animal models.
Hematopoietic Stem and Progenitor Cell Aging is Initiated at Middle Age Through Decline in Local Insulin-Like Growth Factor 1 (IGF1)
Authors: Young Kira , Eudy Elizabeth , Bell Rebecca , Loberg Matthew , Stearns Tim , Velten Lars , Haas Simon , Trowbridge Jennifer J. 
Published: July 2020

AbstractHematopoietic stem cells (HSCs) are responsible for lifelong maintenance and regeneration of the blood system. With aging, loss of HSC function is a major contributor to decline in overall hematopoietic function, leading to increased rate of infection, poor vaccination response, clonal hematopoiesis, and increased risk of hematologic malignancies. While cellular and molecular hallmarks of HSC aging have been defined1–3, the lack of understanding of the nature and timing of the initiating events that cause HSC aging is a barrier to achieving the goal of extending healthy hematopoietic function into older age. Here we discover that hallmarks of HSC aging and myeloid-biased hematopoiesis accumulate by middle age in mice, and that the bone marrow (BM) microenvironment at middle age induces and is indispensable for hematopoietic aging phenotypes. Using unbiased transcriptome-based approaches, we identify decreased production of IGF1 by cells in the middle-aged BM microenvironment as a factor causing hematopoietic stem and progenitor cell aging and show that direct stimulation with IGF1 rescues hallmarks of hematopoietic aging. Declining IGF1 in the BM microenvironment at middle age represents a compelling target for intervention using prophylactic therapies to effectively extend healthspan and to prevent functional decline during aging.
Bayesian Markov models improve the prediction of binding motifs beyond first order
Authors: Ge Wanwan , Meier Markus , Roth Christian , Söding Johannes 
Published: July 2020

AbstractTranscription factors (TFs) regulate gene expression by binding to specific DNA motifs. Accurate models for predicting binding affinities are crucial for quantitatively understanding transcriptional regulation. Motifs are commonly described by position weight matrices, which assume that each position contributes independently to the binding energy. Models that can learn dependencies between positions, for instance, induced by DNA structure preferences, have yielded markedly improved predictions for most TFs onin vivodata. However, they are more prone to overfit the data and to learn patterns merely correlated with rather than directly involved in TF binding. We present an improved, faster version of our Bayesian Markov model software, BaMMmotif2. We tested it with state-of-the-art motif discovery tools on a large collection of ChIP-seq and HT-SELEX datasets. BaMMmotif2 models of fifth-order achieved a median false-discovery-rate-averaged recall 13.6% and 12.2% higher than the next best tool on 427 ChIP-seq datasets and 164 HT-SELEX datasets, respectively, while being 8 to 1000 times faster. BaMMmotif2 models showed no signs of overtraining in cross-cell line and cross-platform tests, with similar improvements on the next-best tool. These results demonstrate that dependencies beyond first order clearly improve binding models for most TFs.
Generating Ensembles of Gene Regulatory Networks to Assess Robustness of Disease Modules
Authors: Lim James T. , Chen Chen , Grant Adam D. , Padi Megha 
Published: July 2020

AbstractThe use of biological networks such as protein-protein interaction and transcriptional regulatory networks is becoming an integral part of biological research in the genomics era. However, these networks are not static, and during phenotypic transitions like disease onset, they can acquire new “communities” of genes that carry out key cellular processes. Changes in community structure can be detected by maximizing a modularity-based score, but because biological systems and network inference algorithms are inherently noisy, it remains a challenge to determine whether these changes represent real cellular responses or whether they appeared by random chance. Here, we introduce Constrained Random Alteration of Network Edges (CRANE), a computational method that samples networks with fixed node strengths to identify a null distribution and assess the robustness of observed changes in network structure. In contrast with other approaches, such as consensus clustering or established network generative models, CRANE produces more biologically realistic results and performs better in simulations. When applied to breast and ovarian cancer networks, CRANE improves the recovery of cancer-relevant GO terms while reducing the signal from non-specific housekeeping processes. CRANE is a general tool that can be applied in tandem with a variety of stochastic community detection methods to evaluate the veracity of their results.
Chromatin topology and the timing of enhancer function at thehoxdlocus
Authors: Rodríguez-Carballo Eddie , Lopez-Delisle Lucille , Willemin Andréa , Beccari Leonardo , Gitto Sandra , Mascrez Bénédicte , Duboule Denis 
Published: July 2020

ABSTRACTTheHoxDgene cluster is critical for proper limb formation in tetrapods. In the emerging limb buds, different sub-groups ofHoxdgenes respond first to a proximal regulatory signal, then to a distal signal that organizes digits. These two regulations are exclusive from one another and emanate from two distinct TADs flankingHoxD, both containing a range of appropriate enhancer sequences. The telomeric TAD (T-DOM) contains several enhancers active in presumptive forearm cells and is divided into two sub-TADs separated by a CTCF-rich boundary, which defines two regulatory sub-modules. To understand the importance of this particular regulatory topology to controlHoxdgene transcription in time and space, we either deleted or inverted this sub-TAD boundary, eliminated the CTCF binding sites or inverted the entire T-DOM to exchange the respective positions of the two sub-TADs. The effects of such perturbations on the transcriptional regulation ofHoxdgenes illustrate the requirement of this regulatory topology for the precise timing of gene activation. However, the spatial distribution of transcripts was eventually resumed, showing that the presence of enhancers sequences, rather than either their exact topology or a particular chromatin architecture, is the key factor. We also show that the affinity of enhancers to find their natural target genes can overcome the presence of both a strong TAD border and an unfavourable orientation of CTCF sites.SIGNIFICANCE STATEMENTMany genes important for vertebrate development are surrounded by series of remote enhancer sequences. Such regulatory landscapes and their target genes are usually located within the same chromatin domains, which appears to constrain the action of these regulatory sequences and hence to facilitate enhancer-promoter recognition and gene expression. We used theHoxDlocus to assess the impact of modifying the regulatory topology upon gene activation in space and time. A series of chromosomal re-arrangements involving deletions and inversions reveals that the enhancer topology plays a role in the timing of gene activation. However, gene expression was often recovered, subsequently, illustrating the intrinsic capacity of some enhancers to find their target promoters despite an apparently adverse chromatin topology.