bluuebunny/crossref_metadata_2025_split huggingface dataset:
No evidence for social genetic effects or genetic similarity among friends beyond that due to population stratification: a reappraisal of Domingue et al (2018)
Authors: Yengo Loic , Sidari Morgan , Verweij Karin J. H. , Visscher Peter M. , Keller Matthew C. , Zietsch Brendan P. 
Published: May 2019

AbstractUsing data from 5,500 adolescents from the National Longitudinal Study of Adolescent to Adult Health, Domingue et al. (2018) claimed to show that friends are genetically more similar to one another than randomly selected peers, beyond the confounding effects of population stratification by ancestry. The authors also claimed to show ‘social-genetic’ effects, whereby individuals’ educational attainment (EA) is influenced by their friends’ genes. Neither claim is justified by the data. Mathematically we show that 1) although similarity at causal variants is expected under assortment, the genome-wide relationship between friends (and similarly between mates) is extremely small (an effect that could be explained by subtle population stratification) and 2) significant association between individuals’ EA and their friends’ polygenic score for EA is expected under homophily with no socio-genetic effects.
A terminal selector prevents a Hox transcriptional switch to safeguard motor neuron identity throughout life
Authors: Feng Weidong , Li Yinan , Dao Pauline , Aburas Jihad , Islam Priota , Elbaz Benayahu , Kolarzyk Anna , Brown André E.X. , Kratsios Paschalis 
Published: May 2019

ABSTRACTNervous system function critically relies on continuous expression of neuron type-specific terminal identity features, such as neurotransmitter receptors, ion channels and neuropeptides. How individual neuron types select such features during development and maintain them throughout life is poorly understood. Here, we report an unconventional mechanism that enables cholinergic motor neurons (MNs) in theC. elegansventral nerve cord to select and maintain their distinct terminal identity features. The conserved terminal selector UNC-3 (Collier/Ebf) UNC-3 is continuously required not only to promote cholinergic MN features, but also to prevent expression of “unwanted” terminal identity features normally reserved for other neuron types. Mechanistically, this dual function is achieved by the ability of UNC-3 to prevent a switch in the transcriptional targets of the Hox protein LIN-39 (Scr/Dfd/Hox4-5). The strategy of a terminal selector preventing a Hox transcriptional switch may constitute a general principle for safeguarding neuronal terminal identity features throughout life.
Software Toolkit for Fast High-Resolution TMS Modeling
Authors: Makarov Sergey N. , Noetscher Gregory M. , Burnham Edward H. , Pham Dung Ngoc , Htet Aung Thu , de Lara Lucia Navarro , Raij Tommi , Nummenmaa Aapo 
Published: May 2019

AbstractComputational modeling of Transcranial Magnetic Stimulation (TMS) is a tradeoff between computational speed vs. spatial precision. In this study, we introduce a software toolkit for high-resolution TMS modeling, which may offer the best of both. The toolkit employs the recently developed boundary element fast multipole method (BEM-FMM) with accurate solution computations close to tissue interfaces. It operates within the MATLAB platform and is designed for a broad, medically-oriented computational research community. To enable easy, subject-specific operation, the package is compatible with human head models generated with automated tools such as SimNIBS and FreeSurfer.Both coil design in free space as well as efficacy and focality of TMS for a specific subject could be modeled by the package, including optional user-defined parametric loops. Detailed and widely used coil models, generated in both CAD and wire formats, may include several hundred thousand elementary current elements and observation spaces with approximately 1 M field points; the corresponding computational times are on the order of 1 sec. Detailed head models with approximately 1 M triangular facets and a mesh resolution of 0.6 points per mm2 are simulated in approximately 1.5 min which is arguably the fastest time to date. Further reduction of computational times is foreseen. The toolkit is augmented with a population of 16 ready-to-use head models for performing simulations for computational studies that do not involve MRI data collection. The toolkit is also augmented with a coil geometry generator capable of creating accurate coil models.
Transcriptomic analysis of bone and fibrous tissue morphogenesis during digit tip regeneration in the adult mouse
Authors: Qu Feini , Palte Ilan C. , Gontarz Paul M. , Zhang Bo , Guilak Farshid 
Published: May 2019

AbstractHumans have limited regenerative potential of musculoskeletal tissues following limb or digit loss. The murine digit has been used to study mammalian regeneration, where stem/progenitor cells (the ‘blastema’) regrow the digit tip after distal, but not proximal, amputation. However, the molecular mechanisms responsible for this response remain to be determined. We hypothesized that regeneration is initiated and maintained by a gene regulatory network that recapitulates aspects of limb development, whereas a non-regenerative response exhibits fibrotic wound healing and minimal bone remodeling. To test these hypotheses, we evaluated the spatiotemporal formation of bone and fibrous tissues after level-dependent amputation of the murine terminal phalanx and quantified the transcriptome of the repair tissue. We show that digit regeneration is a level-dependent and spatiotemporally controlled process, with distal and proximal amputations showing significant differences in gene expression and tissue regrowth over time. Regeneration is characterized by the transient upregulation of genes that direct skeletal system development and limb morphogenesis, including distal Hox genes. By identifying the molecular pathways regulating regeneration, this work will lead to novel therapies that restore complex tissues after injury.Summary StatementMurine digit tip regeneration after distal amputation is orchestrated through a transient, limb-specific gene network by blastema cells. Proximal amputation activates an alternate transcriptional program that results in scar formation.
Mitochondrial morphology provides a mechanism for energy buffering at synapses
Authors: Garcia Guadalupe C. , Bartol Thomas M. , Phan Sébastien , Bushong Eric A. , Perkins Guy , Sejnowski Terrence J. , Ellisman Mark H. , Skupin Alexander 
Published: May 2019

AbstractMitochondria as the main energy suppliers of eukaryotic cells are highly dynamic organelles that fuse, divide and are transported along the cytoskeleton to ensure cellular energy homeostasis. While these processes are well established, substantial evidence indicates that the internal structure is also highly variable in dependence on metabolic conditions. However, a quantitative mechanistic understanding of how mitochondrial morphology affects energetic states is still elusive. To address this question, we here present an agent-based dynamic model using three-dimensional morphologies from electron microscopy tomography which considers the molecular dynamics of the main ATP production components. We apply our modeling approach to mitochondria at the synapse which is the largest energy consumer within the brain. Interestingly, comparing the spatiotemporal simulations with a corresponding space-independent approach, we find minor space dependence when the system relaxes toward equilibrium but a qualitative difference in fluctuating environments. These results suggest that internal mitochondrial morphology is not only optimized for ATP production but also provides a mechanism for energy buffering and may represent a mechanism for cellular robustness.
Entropic regulation of dynamical metabolic processes
Authors: Adler Stephan O. , Klipp Edda 
Published: May 2019

AbstractLife depends on the input of energy, either directly provided by sunlight or in form of high-energy matter. The rules and conditions for the conversion of chemical or electromagnetic energy into living structure and all the processes related with life are governed by the laws of thermodynamics. Hence, to understand the potential and the limitations of cell growth and metabolism, it is unavoidable to take these laws into account. During the last years, systems biology has developed many mathematical models aiming to describe steady states and dynamic behavior of cellular processes in qualitative and quantitative terms. The validity of the model predictions depends strongly on whether the model formulation is in agreement with the laws of physics, chemistry, and, specifically, thermodynamics.Here, we review basic principles of thermodynamics for equilibrium and non-equilibrium processes as well as for closed and open systems as far as they concern metabolic processes, especially in their dynamics. We illustrate the application of thermodynamic laws for some practical cases that are currently intensively studied in systems and computational biology. Specifically, we will discuss the concept of entropy production and energy dissipation for isolated and open systems and its interpretation for the feasibility of biological processes, especially metabolism. We demonstrate that steady states of metabolic systems cannot show energy dissipation, while in dynamical modes entropy of the system can be both increased or decreased, depending on the type of perturbation and the kinetics of the reaction system. These findings are very important for biotechnological processes where energy dissipation should be limited, but also for analysis of healthy and diseased cellular metabolism.
Fast, Efficient, and Precise Gene Editing in the MossPhyscomitrella patens
Authors: Yi Peishan , Goshima Gohta 
Published: May 2019

AbstractRecent years, the bryophyte mossPhyscomitrella patenshas become an emerging model organism for studying conserved signaling pathways and developmental processes during plant evolution. Its short life cycle, ease of cultivation, and high rate of homologous recombination have made it an ideal system for genetic analysis. However, the presence of highly redundant genes and the difficulty of isolating hypomorphic mutants have limited its broader use. Here we developed a simple, fast, and efficient method to generate customized mutants inP. patens.We show that transient cotransformation of CRISPR/Cas9 and oligonucleotide templates enables microindel knock-in with high efficiency and accuracy. Using this method, we generated strains carrying various types of mutations, including amino acid substitution, out-of-frame deletion/insertion, splice site alteration, and small tag integration. We also demonstrate that multiplex gene editing can be efficiently achieved to generate putative null and hypomorphic mutants of redundant genes in one step. Thus our method will not only simplify multiple-gene knockout, but also allows the generation of hypomorphic mutants of genes of interest, especially those that are essential for viability.
NEAT1 involves Alzheimer’s Disease (AD) progression via regulation of glycolysis and P-tau
Authors: Zhao Yiwan , Wang Ziqiang , Mao Yunhao , Li Bing , Zhu Yuanchang , Zhang Shikuan , Wang Songmao , Jiang Yuyang , Xu Naihan , Xie Yizhen , Xie Weidong , Zhang Yaou 
Published: May 2019

AbstractNuclear paraspeckles assembly transcript 1 (NEAT1) is a well-known long noncoding RNA (LncRNA) with unclear mechanism in Alzheimer’s disease (AD) progression. Here, we found that NEAT1 down-regulates in the early stage of AD patients and APPswe/PS1dE9 mouse. Moreover, knockdown of NEAT1 induced de-polymerization of microtubule (MT) and axonal retraction of nerve cells by dysregulation of the FZD3/GSK3β/p-tau signaling pathway. Histone acetylation analysis at the Frizzled Class Receptor 3 (FZD3) promoter shows a marked decreased in the levels of the H3K27 acetylation (H3K27Ac) after NEAT1 knockdown. Our data demonstrates that P300/CBP recruited by NEAT1 to the FZD3 promoter and induced its transcription via histone acetylation. In recent years a growing number of evidences have shown an abnormal brain glucose homeostasis in AD. In the present study we also observed an abnormal brain glucose homeostasis and enhanced sirtuin1 (SIRT1) activity after knockdown of NEAT similarly as in AD. Our results provided insight into the role of NEAT1 in the maintenance of MT stability and its effect on glucose metabolism during early stages of AD.
Characterising the balance between short-interval intracortical inhibition and short-interval intracortical facilitation in younger and older adults
Authors: Rurak B.K. , Hammond G.R , Fujiyama H. , Vallence A.M. 
Published: May 2019

News and noteworthyMeasures of short-interval intracortical inhibition (SICI) and facilitation (SICF) reflect a balance between the excitability of inhibitory and facilitatory circuits in the motor cortex.SICI stimulus-response functions, measured with a range of conditioning stimulus intensities and two intervals (first peak and trough of the SICF function), were similar between younger and older adults, except at the shift from net inhibition to facilitation.Relationships between SICI and SICF and manual dexterity show that an inhibition-facilitation balance favouring inhibition is associated with better manual dexterity and a balance favouring facilitation is associated with poorer manual dexterity.AbstractResearch investigating age-related differences in intracortical inhibition acting within the primary motor cortex (M1) reports inconsistent results. Age-related changes in the balance of inhibition and facilitation acting within M1 might underlie the inconsistent findings. Here, paired-pulse TMS was used to examine the balance between short-interval intracortical inhibition (SICI) and short-interval intracortical facilitation (SICF) in younger (n=26) and older (n=21) adults. First, the inter-stimulus intervals (ISIs) that produced maximal and minimal SICF at the first peak and trough were identified for each individual. Second, SICI stimulus-response functions (conditioning stimulus (CS): 50–110% resting motor threshold) were determined at ISIs that produced maximal and minimal facilitation for each individual. When SICI was measured with the ISI that produced maximal facilitation, the shift from net inhibition to net facilitation occurred at a lower CS intensity in older than younger adults. When SICI was measured with the ISI that produced minimal facilitation, older adults showed a persistent net inhibition at the highest CS intensity, whereas younger adults showed a shift from net inhibition to net facilitation at high CS intensities. Relationships between SICI and SICF and manual dexterity were evident across all measures of the inhibition-facilitation balance, whereby a balance favouring inhibition is associated with better manual dexterity and a balance favouring facilitation is associated with poorer manual dexterity. These findings contribute to our understanding of age-related differences in intracortical inhibitory and facilitatory processes, as well as highlight the importance of considering the balance between inhibitory and facilitatory processes when measuring SICI and SICF.
Can we assume the gene expression profile as a proxy for signaling network activity?
Authors: Piran Mehran , Karbalaei Reza , Piran Mehrdad , Aldahdooh Jehad , Mirzaie Mehdi , Ansari-Pour Naser , Tang Jing , Jafari Mohieddin 
Published: May 2019

AbstractStudying relationships among gene-products by gene expression profile analysis is a common approach in systems biology. Many studies have generalized the outcomes to the different levels of central dogma information flow and assumed correlation of transcript and protein expression levels. All these efforts partook in the current understanding of signaling network models and expanded the signaling databases. In fact, due to the unavailability or high-cost of the experiments, most of the studies do not usually look for direct interactions, and some parts of these networks are contradictory. Besides, it is now a standard step to accomplish enrichment analysis on biological annotations, to make claims about the potentially implicated biological pathways in any perturbation. Explicitly, upon identifying differentially expressed genes, they are spontaneously presumed the corresponding dysregulated pathways. Then, molecular mechanistic insights are proposed for disease etiology and drug discovery based on statistically enriched biological processes. In this study, using four common and comprehensive databases, we extracted all relevant gene expression data and all relationships among directly linked gene pairs. We aimed to evaluate the ratio of coherency or sign consistency between the expression level and the causal relationships among the gene pairs. We illustrated that the signaling network was not more consistent or coherent with the recorded expression profile compared to the random relationships. Finally, we provided the pieces of evidence and concluded that gene-product expression data, especially at the transcript level, are not reliable or at least insufficient to infer causal biological relationships among genes and in turn, describe cellular behavior.
Pericytes regulate vascular immune homeostasis in the CNS
Authors: Török Orsolya , Schreiner Bettina , Tsai Hsing-Chuan , Utz Sebastian , Schaffenrath Johanna , Nassiri Sina , Delorenzi Mauro , Aguzzi Adriano , Han May H. , Greter Melanie , Becher Burkhard , Keller Annika 
Published: May 2019

AbstractBrain endothelium possesses several organ-specific features collectively known as the blood-brain barrier (BBB). In addition, trafficking of immune cells in the healthy central nervous system (CNS) is tightly regulated by CNS vasculature. In CNS autoimmune diseases such as multiple sclerosis (MS), these homeostatic mechanisms are overcome by autoreactive lymphocyte entry into the CNS causing inflammatory demyelinating immunopathology. Previous studies have shown that pericytes regulate the development of organ-specific characteristics of brain vasculature such as the BBB and astrocytic end-feet. Whether pericytes are involved in the control of leukocyte trafficking remains elusive. Using adult, pericyte-deficient mice (Pdgfbret/ret), we show here that brain vasculature devoid of pericytes shows increased expression of VCAM-1 and ICAM-1, which is accompanied by increased leukocyte infiltration of dendritic cells, monocytes and T cells into the brain, but not spinal cord parenchyma. Regional differences enabling leukocyte trafficking into the brain as opposed to the spinal cord inversely correlate with the pericyte coverage of blood vessels. Upon induction of experimental autoimmune encephalitomyelitis (EAE), pericyte-deficient mice succumb to severe neurological impairment. Treatment with first line MS therapy - fingolimod significantly reverses EAE, indicating that the observed phenotype is due to the massive influx of immune cells into the brain. Furthermore, pericyte-deficiency in mice that express myelin oligodendrocyte glycoprotein peptide (MOG35-55) specific T cell receptor (Pdgfbret/ret; 2D2Tg) leads to the development of spontaneous neurological symptoms paralleled by massive influx of leukocytes into the brain, suggesting altered brain vascular immune quiescence as a prime cause of exaggerated neuroinflammation. Thus, we show that pericytes indirectly restrict immune cell transmigration into the CNS under homeostatic conditions and during autoimmune-driven neuroinflammation by inducing immune quiescence of brain endothelial cells.
Inheritance of Chromatin Proteins in Budding Yeast: metabolic gene regulators TUP1, FPR4 and Rpd3L are retained in the mother cell
Authors: Vasseur Pauline , Tonazzini Saphia , Castro Francesc Rubert , Sučec Iva , Fall Arame , Koulali Khadija El , Urbach Serge , Radman-Livaja Marta 
Published: May 2019

AbstractAsymmetric division is a prerequisite for cellular differentiation. Phenotypic transformation during differentiation is a poorly understood epigenetic phenomenon, in which chromatin theoretically plays a role. The assumption that chromatin components segregate asymmetrically in asymmetric divisions has however not been systematically tested. We have developed a live cell imaging method to measure how 18 chromatin proteins are inherited in asymmetric divisions of budding yeast. We show that abundant and moderately abundant maternal proteins segregate stochastically and symmetrically between the two cells with the exception of Rxt3, Fpr4 and Tup1, which are retained in the mother. Mother retention seems to be the norm for low abundance proteins with the exception of Sir2 and the linker histone H1. Our in vivo analysis of chromatin protein behavior in single cells highlights general trends in protein biology during the cell cycle such as coupled protein synthesis and decay, and a correlation between half-lives and cell cycle duration.
A “Human-in-the-Loop” Approach for Semi-automated Image Restoration in Electron Microscopy
Authors: Roels Joris , Vernaillen Frank , Kremer Anna , Gonçalves Amanda , Aelterman Jan , Luong Hiêp Q. , Goossens Bart , Philips Wilfried , Lippens Saskia , Saeys Yvan 
Published: May 2019

ABSTRACTThe recent advent of 3D in Electron Microscopy (EM) has allowed for detection of detailed sub-cellular nanometer resolution structures. While being a scientific breakthrough, this has also caused an explosion in dataset size, necessitating the development of automated workflows. Automated workflows typically benefit reproducibility and throughput compared to manual analysis. The risk of automation is that it ignores the expertise of the microscopy user that comes with manual analysis. To mitigate this risk, this paper presents a hybrid paradigm. We propose a ‘human-in-the-loop’ (HITL) approach that combines expert microscopy knowledge with the power of large-scale parallel computing to improve EM image quality through advanced image restoration algorithms. An interactive graphical user interface, publicly available as an ImageJ plugin, was developed to allow biologists to use our framework in an intuitive and user-friendly fashion. We show that this plugin improves visualization of EM ultrastructure and subsequent (semi-)automated segmentation and image analysis.
Jointly embedding multiple single-cell omics measurements
Authors: Liu Jie , Huang Yuanhao , Singh Ritambhara , Vert Jean-Philippe , Noble William Stafford 
Published: May 2019

AbstractMany single-cell sequencing technologies are now available, but it is still difficult to apply multiple sequencing technologies to the same single cell. In this paper, we propose an unsupervised manifold alignment algorithm, MMD-MA, for integrating multiple measurements carried out on disjoint aliquots of a given population of cells. Effectively, MMD-MA performs an in silico co-assay by embedding cells measured in different ways into a learned latent space. In the MMD-MA algorithm, single-cell data points from multiple domains are aligned by optimizing an objective function with three components: (1) a maximum mean discrepancy (MMD) term to encourage the differently measured points to have similar distributions in the latent space, (2) a distortion term to preserve the structure of the data between the input space and the latent space, and (3) a penalty term to avoid collapse to a trivial solution. Notably, MMD-MA does not require any correspondence information across data modalities, either between the cells or between the features. Furthermore, MMD-MA’s weak distributional requirements for the domains to be aligned allow the algorithm to integrate heterogeneous types of single cell measures, such as gene expression, DNA accessibility, chromatin organization, methylation, and imaging data. We demonstrate the utility of MMD-MA in simulation experiments and using a real data set involving single-cell gene expression and methylation data.