bluuebunny/crossref_metadata_2025_split huggingface dataset:
Age-related intrinsic functional connectivity changes of locus coeruleus from childhood to older adults
Authors: Song Inuk , Neal Joshua , Lee Tae-Ho 
Published: October 2021

ABSTRACTThe locus coeruleus is critical for selective information processing by modulating brain’s connectivity configuration. Increasingly studies have suggested that LC controls sensory inputs at the sensory gating stage. Furthermore, accumulating evidence has examined that young children and older adults are more prone to distraction and filter out irrelevant information less efficiently, possibly due to the impaired LC connectivity. However, the LC connectivity pattern across the life span is not fully examined yet, hampering our ability to understand the relationship between LC development and the distractibility. In this study, we examined the intrinsic network connectivity of the LC using resting-state fMRI from the enhanced NKI dataset with wide-range age samples. Based on LC-seed functional connectivity maps, we examined the age-related variation in the LC connectivity with a quadratic model. The analyses revealed two connectivity patterns explicitly. The sensory-related brain regions showed a positive quadratic age effect (u-shape), and the frontal regions for the cognitive control showed a negative quadratic age effect (inverted u-shape). Our results imply that such age-related distractibility is possibly due to the impaired sensory gating by the LC and the insufficient top-down controls by the frontal regions. We discuss the underlying neural mechanisms and limitations of our study.
Assessing The Repeatability of Multi-Frequency Multi-Layer Brain Network Topologies Across Alternative Researcher’s Choice Paths
Authors: Dimitriadis Stavros I. 
Published: October 2021

AbstractThere is a growing interest in the neuroscience community on the advantages of multilayer functional brain networks. Researchers usually treated different frequencies separately at distinct functional brain networks. However, there is strong evidence that these networks share complementary information while their interdependencies could reveal novel findings. For this purpose, neuroscientists adopt multilayer networks, which can be described mathematically as an extension of trivial single-layer networks. Multilayer networks have become popular in neuroscience due to their advantage to integrate different sources of information. Here, we will focus on the multi-frequency multilayer functional connectivity analysis on resting-state fMRI recordings. However, constructing a multilayer network depends on selecting multiple pre-processing steps that can affect the final network topology. Here, I analyzed the fMRI dataset from a single human performing scanning over a period of 18 months (84 scans in total), and the second dataset of 25 subjects with 3 repeat scans. I focused on assessing the reproducibility of multi-frequency multilayer topologies exploring the effect of two filtering methods for extracting frequencies from BOLD activity, three connectivity estimators, with or without a topological filtering scheme, and two spatial scales. Finally, I untangled specific combinations of researchers’ choices that yield consistently brain networks with repeatable topologies, giving us the chance to recommend best practices over consistent topologies.
Extracellular Fluid Flow Induces Shallow Quiescence through Physical and Biochemical Cues
Authors: Liu Bi , Wang Xia , Jiang Linan , Xu Jianhua , Zohar Yitshak , Yao Guang 
Published: October 2021

ABSTRACTThe balance between cell quiescence and proliferation is fundamental to tissue physiology and homeostasis. Recent studies have shown that quiescence is not a passive and homogeneous state but actively maintained and heterogeneous. These cellular characteristics associated with quiescence were observed primarily in cultured cells under a static medium. However, cells in vivo face different microenvironmental conditions, particularly, under interstitial fluid flows distributed through extracellular matrices. Interstitial fluid flow exerts shear stress on cells and matrix strain, and results in continuous replacement of extracellular factors. In this study, by analyzing individual cells under varying fluid flow rates in microfluidic devices, we found that extracellular fluid flow alters cellular quiescence depth through flow-induced physical and biochemical cues. Specifically, increasing the flow rate drives cells to shallower quiescence and become more likely to reenter the cell cycle upon growth stimulation. Furthermore, we found that increasing shear stress or extracellular factor replacement individually, without altering other parameters, also results in shallow quiescence. We integrated the experimental results into a mathematical model to gain insight and predict the effects of varying extracellular fluid flow conditions on cellular quiescence depth. Our findings uncover a previously unappreciated mechanism that likely underlies the heterogeneous responses of quiescent cells for tissue repair and regeneration in physiological tissue microenvironments.
Feasibility conditions of ecological models: Unfolding links between model parameters
Authors: AlAdwani Mohammad , Saavedra Serguei 
Published: October 2021

AbstractOver more than 100 years, ecological research has been striving to derive internal and external conditions compatible with the coexistence of a given group of interacting species. To address this challenge, numerous studies have focused on developing ecological models and deriving the necessary conditions for species coexistence under equilibrium dynamics, namely feasibility. However, due to mathematical limitations, it has been impossible to derive analytic expressions if the isocline equations have five or more roots, which can be easily reached even in 2-species models. Here, we propose a general formalism to obtain the set of analytical conditions of feasibility for any polynomial population dynamics model of any dimension without the need to solve for the equilibrium locations. We additionally illustrate the application of our methodology by showing how it is possible to derive mathematical relationships between model parameters, while maintaining feasibility in modified Lotka-Volterra models with functional responses and higher-order interactions (model systems with at least five equilibrium points)—a task that is impossible to do with simulations. This work unlocks the opportunity to increase our systematic understanding of species coexistence.
Losses and gains of fallows impact farmland bird populations over three funding periods of the EU Common Agricultural Policy
Authors: Hertzog Lionel R. , Röder Norbert , Frank Claudia , Böhner Hannah G. S. , Kamp Johannes , Klimek Sebastian 
Published: October 2021

AbstractFallow land provides habitat for threatened and declining farmland biodiversity. Policy change under the EU’s Common Agricultural Policy (CAP) has been driving the area of fallows over the past decades and influenced trends in farmland biodiversity.We analyzed the relationships between fallow land area across Germany over three CAP funding periods and species richness and abundance of farmland birds. We examined whether the strength of the relationships with fallow land area were moderated by species habitat preferences and landscape configurational complexity (edge density). We combined spatial data on fallow land area from three agricultural censuses in Germany (2007, 2010 and 2016) with country-wide farmland bird monitoring data.Farmland bird species richness and the abundance of the majority of the studied farmland bird species were positively related to increases in fallows across three CAP funding periods. The relationship of fallows with bird richness was strongest at intermediate levels of edge density. There was generally little support for a moderating effect of edge density on the relations between fallows and bird abundance.We conclude that the loss of fallows in the period 2007 to 2016 resulted in strong declines of farmland birds. We predict that a future increase of the proportion of fallow land to 4% of the arable land, as envisaged in the German 2023-2027 CAP strategic plans, or to 10%, as foreseen in the EU Biodiversity Strategy, will lead to increases in farmland bird species richness and abundance depending on the landscape context and species-specific habitat preferences.Policy implicationsIncreasing the proportion of fallow land will likely be a key lever to stabilize and revert negative farmland bird population trends. An increase of fallow area in all but the least complex landscapes will boost farmland bird richness and abundance. Increasing the proportion of fallow land to 4% should bring farmland bird richness and abundance back to the levels observed in 2007 acknowledging that farmland bird populations were already severely depleted in 2007. A more ambitious expansion of fallow land towards 10% should be targeted towards areas that experienced the strongest loss of fallows and towards landscapes with intermediate levels of edge density.
HIF1α-AS1 is a DNA:DNA:RNA triplex-forming lncRNA interacting with the HUSH complex
Authors: Leisegang Matthias S. , Bains Jasleen Kaur , Seredinski Sandra , Oo James A. , Krause Nina M. , Kuo Chao-Chung , Günther Stefan , Cetin Nevcin Sentürk , Warwick Timothy , Cao Can , Boos Frederike , Ponce Judit Izquierdo , Bednarz Rebecca , Valasarajan Chanil , Fuhrmann Dominik , Preussner Jens , Looso Mario , Pullamsetti Soni S. , Schulz Marcel H. , Rezende Flávia , Gilsbach Ralf , Pflüger-Müller Beatrice , Wittig Ilka , Grummt Ingrid , Ribarska Teodora , Costa Ivan G. , Schwalbe Harald , Brandes Ralf P. 
Published: October 2021

AbstractDNA:DNA:RNA triplexes that are formed through Hoogsteen base-pairing have been observed in vitro, but the extent to which these interactions occur in cells and how they impact cellular functions remains elusive. Using a combination of bioinformatic techniques, RNA/DNA pulldown and biophysical studies, we set out to identify functionally important DNA:DNA:RNA triplex-forming long non-coding RNAs (lncRNA) in human endothelial cells. The lncRNA HIF1α-AS1 was retrieved as a top hit. Endogenous HIF1α-AS1 reduced the expression of numerous genes, including EPH Receptor A2 and Adrenomedullin through DNA:DNA:RNA triplex formation by acting as an adapter for the repressive human silencing hub complex (HUSH). Moreover, the oxygen-sensitive HIF1α-AS1 was down-regulated in pulmonary hypertension and loss-of-function approaches not only resulted in gene de-repression but also enhanced angiogenic capacity. As exemplified here with HIF1α-AS1, DNA:DNA:RNA triplex formation is a functionally important mechanism of trans-acting gene expression control.
Neuronal Dot1l is a broad mitochondrial gene-repressor associated with human brain aging via H3K79 hypermethylation
Authors: Van Heesbeen H.J , Von Oerthel L , De Vries P.M , Wagemans M.R.J , Smidt M.P. 
Published: October 2021

AbstractMethylation of histone 3 at lysine 79 (H3K79) and its catalyst, disrupter of telomeric silencing (Dot1l), have been coupled to multiple forms of stress like bioenergetic and ER challenges. However, studies on H3K79 methylation and Dot1l in the aging brain and neurons are very limited. This together with increasing evidence of a dynamic neuroepigenome made us wonder if H3K79 methylation and Dot1l could play unknown roles in brain aging and associated disorders. In aged humans, we found strong and consistent hypermethylation of H3K79 in neurons that accumulate lipofuscine, while neuronal Dot1l transcript abundance reacts to bioenergenic and oxidative challenges. Indeed, in dopaminergic neurons we found rapid global H3K79me turnover (<12h). While shortly after reduction of H3K79 methylation, synaptic transcripts decreased while mitochondrial genes, particularly respiratory chain transcripts increased. Strikingly, 6 months after reduction of Dot1l levels, almost solely a variety of mitochondrial genes linked to aging and Parkinsons disease remained increased. These profiles are in much detail inverse to those described in hallmark PD and aging studies and associate Dot1l and H3K79me with neuronal stress in the aging brain while putting Dot1l forward as dynamic master regulator of mitochondrial transcription in dopamine neurons.
Linking intrinsic scales of ecological processes to characteristic scales of biodiversity and functioning patterns
Authors: Zelnik Yuval R. , Barbier Matthieu , Shanafelt David W. , Loreau Michel , Germain Rachel M. 
Published: October 2021

AbstractEcology is a science of scale, which guides our description of both ecological processes and patterns, but we lack a systematic understanding of how process scale and pattern scale are connected. Recent calls for a synthesis between population ecology, community ecology, and ecosystem ecology motivate the integration of phenomena at multiple levels of organization. Furthermore, many studies leave out the scaling of a critical process: species interactions, which may be non-local through movement or foraging and must be distinguished from dispersal scales. Here, we use simulations to explore the consequences of three different process scales (species interactions, dispersal, and the environment) on emergent patterns of biodiversity, ecosystem functioning, and their relationship, in a spatially-explicit landscape and stable equilibrium setting. A major result of our study is that the spatial scales of dispersal and species interactions have opposite effects: a larger dispersal scale homogenizes spatial biomass patterns, while a larger interaction scale amplifies their heterogeneity. Interestingly, the specific scale at which dispersal and interaction scales begin to influence landscape patterns depends on the scale of environmental heterogeneity – in other words, the scale of one process allows important scales to emerge in other processes. This interplay between process scales, i.e., a situation where no single process dominates, can only occur when the environment is heterogeneous and the scale of dispersal small. Finally, contrary to our expectations, we observe that the spatial scale of ecological processes is more clearly reflected in landscape patterns (i.e., distribution of local outcomes) than in global patterns such as Species-Area Relationships or large-scale biodiversity-functioning relationships. Overall we conclude that long-range interactions often act differently and even in opposite ways to dispersal, and that the landscape patterns that emerge from the interplay of long-ranged interactions, dispersal and environmental heterogeneity are not well captured by often-used metrics like the Species-Area Relationship.
Catestatin selects for the colonization of antimicrobial-resistant gut bacterial communities
Authors: González-Dávila Pamela , Schwalbe Markus , Danewalia Arpit , Dalile Boushra , Verbeke Kristin , Mahata Sushil K , El Aidy Sahar 
Published: October 2021

AbstractThe gut microbiota is in continuous interaction with the innermost layer of the gut, namely the epithelium. One of the various functions of the gut epithelium, is to keep the microbes at bay to avoid overstimulation of the underlying mucosa immune cells. To do so, the gut epithelia secrete a variety of antimicrobial peptides, such as chromogranin A (CgA) peptide catestatin (CST: hCgA352-372). As a defense mechanism, gut microbes have evolved antimicrobial resistance mechanisms to counteract the killing effect of the secreted peptides. To this end, we treated wild-type mice and CST knockout (CST-KO) mice (where only the 63 nucleotides encoding CST have been deleted) with CST for 15 consecutive days. CST treatment was associated with a shift in the diversity and composition of the microbiota in the CST-KO mice. This effect was less prominent in WT mice. Levels of the microbiota-produced short-chain fatty acids, in particular, butyrate and acetate were significantly increased in CST-treated CST-KO mice but not the WT group. Both CST-treated CST-KO and WT mice showed a significant increase in microbiota-harboring phosphoethanolamine transferase-encoding genes, which facilitate their antimicrobial resistance. Finally, we show that CST was degraded by Escherichia coli via an omptin-protease and that the abundance of this gene was significantly higher in metagenomic datasets collected from patients with Crohn’s disease but not with ulcerative colitis. Overall, this study illustrates how the endogenous antimicrobial peptide, CST, shapes the microbiota composition in the gut and primes further research to uncover the role of bacterial resistance to CST in disease states such as inflammatory bowel disease.
Towards a machine-learning assisted diagnosis of psychiatric disorders and their operationalization in preclinical research: evidence from studies on addiction-like behaviour in individual rats
Authors: Jadhav Kshitij S , Jamot Benjamin Boury , Deroche-Gamonet Veronique , Belin David , Boutrel Benjamin 
Published: October 2021

AbstractBackgroundOver the last few decades there is a progressive transition from a categorical to a dimensional approach to psychiatric disorders. Especially in case of substance use disorders, the increased interest in the individual vulnerability to transition from controlled to compulsive drug seeking and taking warrants the development of novel dimension-based objective diagnostic or stratification tools. Here we drew on a multidimensional preclinical model of addiction, namely the 3-criteria model, previously developed to identify the neurobehavioural basis of the individual vulnerability to switch from control to compulsive drug taking, to test the potential interest of a machine-learning assisted classifier objectively to identify individual subjects as vulnerable or resistant to addiction.MethodsLarge behavioural datasets from several of our previous studies on addiction-like behaviour for cocaine or alcohol were fed to a variety of machine-learning algorithms (each consisting of an unsupervised-clustering method combined with a supervised-prediction algorithm) to develop a classifier that identifies resilient and vulnerable rats with high precision and reproducibility irrespective of the cohort to which they belong.ResultsA classifier based on K-median or K-mean-clustering (for cocaine or alcohol, respectively) followed by Artificial Neural Networks emerged as a highly reliable and accurate tool to predict if a single rat is vulnerable or resilient to addiction. Thus, each of the rats previously characterized as displaying 0 criterion (i.e., resilient) or 3 criteria (i.e., vulnerable) in individual cohorts were correctly labelled by this classifier.ConclusionThe present machine-learning-based classifier objectively labels single individuals as resilient or vulnerable to develop addiction-like behaviour in multisymptomatic preclinical models of cocaine or alcohol addiction-like behaviour in rats. This novel dimension-based classifier thereby increases the heuristic value and generalizability of these preclinical models while providing proof of principle for the deployment of similar tools for the future of diagnosis of psychiatric disorders.
Subcellular localization of mutant P23H rhodopsin in an RFP fusion knockin mouse model of retinitis pigmentosa
Authors: Robichaux Michael A. , Nguyen Vy , Chan Fung , Kailasam Lavanya , He Feng , Wilson John H. , Wensel Theodore G. 
Published: October 2021

AbstractThe P23H mutation in rhodopsin (Rho), the visual pigment protein in rod photoreceptor neurons, is the most common genetic cause of autosomal dominant retinitis pigmentosa (adRP), a retinal disease that causes blindness. Despite multiple studies in animal models, the subcellular details of the fate of misfolded mutant Rho in rod photoreceptors have not been completely defined. We generated a new mouse model of adRP, in which the P23H-Rho mutant allele is fused to the fluorescent protein Tag-RFP-T (P23HhRhoRFP). In heterozygotes, outer segments formed, and WT rhodopsin was properly localized there, but mutant P23H-Rho protein was specifically mislocalized in the inner segments of rods. Despite this cellular phenotype, the P23HhRhoRFP heterozygous mice exhibited only slowly progressing retinal degeneration; in ERG recordings, scotopic a-wave amplitudes were reduced by 24% and 26% at 30 days and 90 days respectively, and the corresponding scotopic b-waves by 18% and 24%. Outer nuclear layer thickness was still 80% of WT at 90 days, but at 364 days had declined to 40% of WT. Transmission electron microscopy revealed greatly expanded membrane lamellae in the inner segment, and by fluorescence imaging, we determined that the mislocalized P23HhRhoRFP was contained in greatly expanded endoplasmic reticulum (ER) membranes. TUNEL staining revealed a slow pace of cell death involving chromosomal endonucleolytic degradation. Quantification of mRNA for markers of ER stress and the unfolded protein response revealed little or no increases in levels of messages encoding the proteins BiP, CHOP, ATF6, XBP1, PERK, Eif2α and Derlin-1, but a decreased level of total Rhodopsin (mouse + human) mRNA levels. The decline in the rate of cell death after an initial burst suggests that P23HhRhoRFP mutant rods undergo an adaptative process that prolongs survival despite gross P23HhRhoRFP protein accumulation in the ER. Because of its slowly progressing nature, and easy visualization of the mutant protein, the P23H-Rho-RFP mouse may represent a useful tool for the future study of the pathology and treatment of P23H-Rho and adRP.
Loss of TBK1 activity leads to TDP-43 proteinopathy through lysosomal dysfunction in human motor neurons
Authors: Hao Jin , Wells Michael F. , Niu Gengle , San Juan Irune Guerra , Limone Francesco , Fukuda Atsushi , Leyton-Jaimes Marcel F , Joseph Brian , Qian Menglu , Mordes Daniel A. , Budnik Bogdan , Dou Zhixun , Eggan Kevin 
Published: October 2021

AbstractAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron loss accompanied by cytoplasmic localization of TDP-43 proteins and their insoluble accumulations. Haploinsufficiency of TBK1 has been found to associate with or cause ALS. However, the cell-autonomous mechanisms by which reduced TBK1 activity contributes to human motor neuron pathology remain elusive. Here, we generated a human cellular model harboring loss-of-function mutations of TBK1 by gene editing and found that TBK1 deficiency was sufficient to cause TDP-43 pathology in human motor neurons. In addition to its functions in autophagy, we found that TBK1 interacted with endosomes and was required for normal endosomal maturation and subsequent lysosomal acidification. Surprisingly, TDP-43 pathology resulted more from the dysfunctional endo-lysosomal pathway than the previously recognized autophagy inhibition mechanism. Restoring TBK1 levels ameliorated lysosomal dysfunction and TDP-43 pathology and maintained normal motor neuron homeostasis. Notably, using patient-derived motor neurons, we found that haploinsufficiency of TBK1 sensitized neurons to lysosomal stress, and chemical regulators of endosomal maturation rescued the neurodegenerative process. Together, our results revealed the mechanism of TBK1 in maintaining TDP-43 and motor neuron homeostasis and suggested that modulating endosomal maturation was able to rescue neurodegenerative disease phenotypes caused by TBK1 deficiency.