bluuebunny/crossref_metadata_2025 huggingface dataset:
Redundant and specific roles of cohesin STAG subunits in chromatin looping and transcription control
Authors: Casa Valentina , Gines Macarena Moronta , Gusmao Eduardo Gade , Slotman Johann A. , Zirkel Anne , Josipovic Natasa , Oole Edwin , van IJcken Wilfred F.J. , Houtsmuller Adriaan B. , Papantonis Argyris , Wendt Kerstin S.
Published: May 2019

Cohesin is a ring-shaped multiprotein complex that is crucial for 3D genome organization and transcriptional regulation during differentiation and development. It also confers sister chromatid cohesion and facilitates DNA damage repair. Besides its core subunits SMC3, SMC1A and RAD21, cohesin contains in somatic cells one of two orthologous STAG subunits, SA1 or SA2. How these variable subunits affect the function of the cohesin complex is still unclear. SA1- and SA2-cohesin were initially proposed to organize cohesion at telomeres and centromeres, respectively. Here, we uncover redundant and specific roles of SA1 and SA2 in gene regulation and chromatin looping using HCT116 cells with an auxin-inducible degron (AID) tag fused to either SA1 or SA2. Following rapid depletion of either subunit, we perform high resolution Hi-C, RNA-sequencing and sequential ChIP studies to show that SA1 and SA2 do not co-occupy individual binding sites and have distinct ways how they affect looping and gene expression. These findings are supported at the single cell level by single-molecule localizations via dSTORM super-resolution imaging. Since somatic and congenital mutations of the SA subunits are associated with cancer (SA2) and intellectual disability syndromes with congenital abnormalities (SA1 and SA2), we verified SA1-/SA2-dependencies using human neural stem cells, hence highlighting their importance for understanding particular disease contexts.
Acute inflammation alters energy metabolism in mice and humans: Role in sickness-induced hypoactivity, impaired cognition and delirium
Authors: Kealy John , Murray Carol , Griffin Eadaoin W. , Lopez-Rodriguez Ana Belen , Healy Dáire , Tortorelli Lucas Silva , Lowry John P. , Watne Leiv Otto , Cunningham Colm
Published: May 2019

Systemic infection triggers a spectrum of metabolic and behavioral changes, collectively termed sickness behavior, that while adaptive for the organism, can affect mood and cognition. In vulnerable individuals, acute illness can also produce profound, maladaptive, cognitive dysfunction including delirium, but our understanding of delirium pathophysiology remains limited. Here we used bacterial lipopolysaccharide (LPS) in C57BL/6J mice and acute hip fracture in humans to address whether disrupted energy metabolism contributes to inflammation-induced behavioral and cognitive changes. LPS (250 μg/kg) induced hypoglycemia, which was mimicked by IL-1β (25 μg/kg) but not prevented in IL-1RI-/-mice, nor by IL-1RA (10 mg/kg). LPS suppression of locomotor activity correlated with blood glucose concentration, was mitigated by exogenous glucose (2 g/kg) and was exacerbated by 2-deoxyglucose glycolytic inhibition, which prevented IL-1β synthesis. Using the ME7 model of chronic neurodegeneration, to examine vulnerability of the diseased brain to acute stressors, we showed that LPS (100 μg/kg) produced acute cognitive dysfunction, selectively in those animals. These acute cognitive impairments were mimicked by insulin (11.5 IU/kg) and mitigated by glucose, demonstrating that acutely reduced glucose metabolism impairs cognition in the vulnerable brain. To test whether these acute changes might predict altered carbohydrate metabolism during delirium, we assessed glycolytic metabolite levels in cerebrospinal fluid (CSF) in humans during delirium, triggered by acute inflammatory trauma. Hip fracture patients showed elevated CSF lactate and pyruvate during delirium, consistent with altered brain energy metabolism. Collectively the data suggest that disruption of energy metabolism drives behavioral and cognitive consequences of acute systemic inflammation.
Single-cell RNA-seq analysis reveals the crucial role of Collagen Triplex Helix Repeat Containing 1 (CTHRC1) cardiac fibroblasts for ventricular remodeling after myocardial infarction
Authors: Ruiz-Villalba Adrian , Romero Juan P. , Hernandez Silvia C. , Vilas-Zornoza Amaia , Fortelny Nikolaus , Castro Laura , Martin-Uriz Patxi San , Lorenzo-Vivas Erika , García-Olloqui Paula , Palacios Marcel , Gavira Juan José , Bastarrika Gorka , Janssens Stefan , Iglesias Elena , Abizanda Gloria , de Morentin Xabier Martinez , Bock Christoph , Alignani Diego , Medal Gema , Gomez-Cabrero David , Prudovsky Igor , Jin Yong-Ri , Ryzhov Sergey , Yin Haifeng , Pelacho Beatriz , Lindner Volkhard , Lara-Astiaso David , Prósper Felipe
Published: May 2019

Cardiac fibroblasts have a central role during the ventricular remodeling process associated with different types of cardiac injury. Recent studies have shown that fibroblasts do not respond homogeneously to heart damage, suggesting that the adult myocardium may contain specialized fibroblast subgroups with specific functions. Due to the limited set ofbona fidefibroblast markers, a proper characterization of fibroblast population dynamics in response to cardiac damage is still missing. Using single-cell RNA-seq, we identified and characterized a fibroblast subpopulation that emerges in response to myocardial infarction (MI) in a murine model. These activated fibroblasts exhibit a clear pro-fibrotic signature, express high levels of the hormone CTHRC1 and of the immunomodulatory co-receptor CD200 and localize to the injured myocardium. Combining epigenomic profiling with functional assays, we showSox9and the non-canonical TGF-β signaling as important regulators mediating their response to cardiac damage. We show that the absence of CTHRC1, in this activated fibroblast subpopulation, results in pronounced lethality due to ventricular rupture in a mouse model of myocardial infarction. Finally, we find evidence for the existence of similar mechanisms in a pig pre-clinical model of MI and establish a correlation betweenCTHRC1levels and cardiac function after MI.
Gli3 regulates vomeronasal neurogenesis, olfactory ensheathing cell formation and GnRH-1 neuronal migration
Authors: Taroc Ed Zandro M. , Naik Ankana , Lin Jennifer M. , Peterson Nicolas B. , Keefe David L. , Genis Elizabet , Fuchs Gabriele , Balasubramanian Ravikumar , Forni Paolo E.
Published: May 2019

During mammalian development, gonadotropin-releasing-hormone-1 neurons (GnRH-1ns) migrate from the developing vomeronasal organ (VNO) into the brain asserting control of pubertal onset and fertility. Recent data suggest that correct development of the olfactory ensheathing cells (OEC) is imperative for normal GnRH-1 neuronal migration. However, the full ensemble of molecular pathways that regulate OEC development remains to be fully deciphered. Loss-of-function of the transcription factor Gli3 is known to disrupt olfactory development, however, if Gli3 plays a role in GnRH-1 neuronal development is unclear. By analyzing Gli3 extra-toe mutants (Gli3Xt/Xt), we found that Gli3 loss-of-function compromises the onset of achaete-scute family bHLH transcription factor 1 (Ascl-1) positive vomeronasal progenitors and the formation of OEC in the nasal mucosa. Surprisingly, GnRH-1 neurogenesis was intact in Gli3Xt/Xtmice but they displayed significant defects in GnRH-1 neuronal migration. In contrast, Ascl-1nullmutants showed reduced neurogenesis for both vomeronasal and GnRH-1ns but less severe defects in OEC development. These observations suggest that Gli3 is critical for OEC development in the nasal mucosa and subsequent GnRH-1 neuronal migration. However, the non-overlapping phenotypes between Ascl-1 and Gli3 mutants indicate that Ascl-1, while crucial for GnRH-1 neurogenesis, is not required for normal OEC development. Since Kallmann syndrome (KS) is characterized by abnormal GnRH migration, we examined whole exome sequencing data from KS subjects. We identified and validated aGLI3loss-of-function variant in a KS individual. These findings provide new insights into GnRH-1 and OECs development and demonstrate that humanGLI3mutations contribute to KS etiology.

Significance statement

The transcription factor Gli3 is necessary for correct development of the olfactory system. However, if Gli3 plays a role in controlling GnRH-1 neuronal development has not been addressed. We found that Gli3 loss-of-function compromises the onset of Ascl1+ vomeronasal progenitors, formation of olfactory ensheathing cells in the nasal mucosa and impairs GnRH-1 neuronal migration to the brain. By analyzing Ascl1 null mutants we dissociated the neurogenic defects observed in Gli3 mutants from lack of olfactory ensheathing cells in the nasal mucosa, moreover, we discovered that Ascl1 is necessary for GnRH-1 ontogeny. Analyzing human whole exome sequencing data, we identified aGLI3loss-of-function variant in a KS individual. Our data suggest thatGLI3is a candidate gene contributing to KS etiology.
Multiplexed measurement of protein biomarkers in high-frequency longitudinal dried blood spot (DBS) samples: characterization of inflammatory responses
Authors: Anderson N. Leigh , Razavi Morteza , Pope Matthew E. , Yip Richard , Pearson Terry W.
Published: May 2019

A detailed understanding of changes in blood protein biomarkers occuring in individuals over time would enable truly personalized approaches to health and disease monitoring. Such measurements could reveal smaller, earlier departures from normal baseline levels of biomarkers thus allowing better disease detection and treatment monitoring. Current practice, however, generally involves infrequent, sporadic biomarker testing, and this undersampling likely fails to capture important biological phenomena. Here we report the use of a robust multiplex immuno-mass spectrometric method (SISCAPA) to measure a panel of clinically-relevant proteins in a unique collection of 1,522 dried blood spots collected longitudinally by 8 individuals over periods of up to 9 years, with daily sampling during some intervals. Analytical workflow CVs of 2-6% for most assays were achieved by normalizing DBS plasma volume using a set of 3 minimally varying proteins, facilitating temporal analysis of both high- and low-amplitude biomarker changes compared to personalized baselines. The biomarkers included a panel of 9 positive and 5 negative acute phase response (inflammatory) proteins, allowing longitudinal analysis of inflammation markers associated with major and minor infections, influenza vaccination, recovery from hip-replacement surgery and Crohn’s disease. The results illustrate complex time-dependent “biomarker trajectories” on multiple timescales and provide a basis for detailed personalized models of inflammation dynamics. The striking stability of most biomarker protein levels over time, combined with the convenience of self-sampling and low cost of multiplexed measurements using mass spectrometry, provide a new window into the temporal dynamics of disease processes. The extensive results obtained using this high throughput approach offer a new source of precision biomarker ‘big data’ amenable to machine learning approaches and application to more personalized health monitoring.
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

Using 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

Nervous 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

Computational 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

Humans 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 Statement

Murine 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

Mitochondria 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

Life 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

Recent 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

Nuclear 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 noteworthy

Measures 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.

Research 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

Studying 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

Brain 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

Asymmetric 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

The 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

Many 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.
Anterior Insula Reflects Inferential Errors in Value-Based Decision-making and Perception
Authors: Loued-Khenissi Leyla , Pfeuffer Adrien , Einhäuser Wolfgang , Preuschoff Kerstin
Published: May 2019

The process of inference is theorized to underlie neural processes, including value-based decision-making and perception. Value-based decision-making commonly involves deliberation, a time-consuming process that requires conscious consideration of decision variables. Perception, by contrast, is thought to be automatic and effortless. To determine if inference characterizes both perception and value-based decision-making, we directly compared uncertainty signals in visual perception and an economic task using fMRI. We presented the same individuals with different versions of a bi-stable figure (Necker’s cube) and with a gambling task during fMRI acquisition. To track the inferential process assumed in both tasks, we experimentally varied uncertainty, either on perceptual state or financial outcome. We found that inferential errors captured by surprise in the gambling task yielded BOLD responses in the anterior insula, in line with earlier findings. Moreover, we found perceptual risk and surprise in the Necker Cube task yielded similar responses in the anterior insula. These results suggest that uncertainty, irrespective of domain, correlates to a common brain region, the anterior insula. These findings provide empirical evidence that the brain interacts with its environment through inferential processes.
Yap suppresses T cell function and infiltration in the tumor microenvironment
Authors: Stampouloglou Eleni , Federico Anthony , Slaby Emily , Monti Stefano , Szeto Gregory L. , Varelas Xaralabos
Published: May 2019

A major challenge for cancer immunotherapy is sustaining T cell activation and recruitment in immunosuppressive solid tumors. Here we report that Yap levels are sharply induced upon activation of CD4+and CD8+T cells and that Yap functions as an immunosuppressive factor and inhibitor of effector differentiation. Loss of Yap in T cells results in enhanced T cell activation, differentiation and function, which translatesin vivoto an improved ability for T cells to infiltrate and repress tumors. Gene expression analyses of tumor-infiltrating T cells following Yap deletion implicates Yap as a mediator of global T cell responses in the tumor microenvironment and as a key negative regulator of T cell tumor infiltration and patient survival in diverse human cancers. Collectively, our results indicate that Yap plays critical roles in T cell biology, and suggest that inhibiting Yap activity improves T cell responses in cancer.
Comparison of IL-33 and IL-5 Family Mediated Activation of Human Eosinophils
Authors: Angulo Evelyn L. , McKernan Elizabeth M. , Fichtinger Paul S. , Mathur Sameer K.
Published: May 2019

Eosinophils are the prominent inflammatory cell involved in allergic asthma, atopic dermatitis, eosinophilic esophagitis, and hypereosinophilic syndrome and are found in high numbers in local tissue and/or circulating blood of affected patients. There is recent interest in a family of alarmins, including TSLP, IL-25 and IL-33, that are epithelial-derived and released upon stimulation of epithelial cells. Several genome wide association studies have found SNPs in genes encoding IL-33 to be risk factors for asthma. In two studies examining the direct role of IL-33 in eosinophils, there were differences in eosinophil responses. We sought to further characterize activation of eosinophils with IL-33 compared to activation by other cytokines and chemokines. We assessed IL-33 stimulated adhesion, degranulation, chemotaxis and cell surface protein expression in comparison to IL-3, IL-5, and eotaxin-1 on human eosinophils. Our results demonstrate that IL-33 can produce as potent or more eosinophil activation than IL-3, IL-5 and eotaxin-1. Thus, when considering specific cytokine targeting strategies, IL-33 will be important to consider for modulating eosinophil function.
Energy balance; choices between energy spend on migration and mating influences the life cycle of the pond bat (Myotis dasycneme)
Authors: Haarsma Anne-Jifke , Lina Peter H.C. , Voûte Aldo M. , Glas Gerhard H. , Siepel Henk
Published: May 2019

During autumn in the temperate zone, insectivorous male bats face a profound energetic challenge, as in the same period they have to make energy choices related to hibernation, mating and migration. We found evidence by looking at biometric measurements that male pond bats (Myotis dasycneme) are pre-occupied with mating and lose weight, while simultaneously females are accumulating fat. Our purpose was to characterize the known hibernacula in terms of male or female bias, and subsequently compare their population trend during two study periods, between 1930-1980 and 1980-2015. Our findings include evidence of colonisation of winter roosts in formerly unoccupied areas and consequently a change in the migration patterns of the male population of this species. As male bats do not assist to raise their offspring, males have abundant time to restore their energy balance after hibernation. Our results suggest that choosing a hibernacula closer to the summer habitat not only decreases energy cost needed for migration, it also lengthens the mating season and presumably also has the additional advantage of increased paternity. Additionally, these findings have important conservation implications, as male and female biased hibernation assemblages may differ critically in terms of microclimate preferences.
Agricultural and geographic factors shaped the North American 2015 highly pathogenic avian influenza H5N2 outbreak
Authors: Hicks Joseph T. , Lee Dong-Hun , Duvuuri Venkata R. , Torchetti Mia Kim , Swayne David E , Bahl Justin
Published: May 2019

The 2014 – 2015 highly pathogenic avian influenza (HPAI) H5NX outbreak represents the largest and most expensive HPAI outbreak in the United States to date. Despite extensive traditional and molecular epidemiological studies, factors associated with the spread of HPAI among midwestern poultry premises remain unclear. To better understand the dynamics of this outbreak, 182 full genome HPAI H5N2 sequences isolated from commercial layer chicken and turkey production premises were analyzed using evolutionary models modified to incorporate epidemiological and geographic information. Epidemiological compartmental models constructed in a phylogenetic framework provided evidence that poultry type acted as a barrier to the transmission of virus among midwestern poultry farms. Furthermore, after initial introduction, a continuous external source of virus was not needed to explain the propagation of HPAI cases within the commercial poultry industries. Discrete trait diffusion models indicated that within state viral transitions occurred more frequently than inter-state transitions. Distance, road density and proportion of water coverage were all supported as associated with viral transition between county groups (Bayes Factor > 3.0). Together these findings indicate that the midwestern poultry industries were not a single homogenous population, but rather, the outbreak was shaped by poultry sectors and geographic factors.

AUTHOR SUMMARY

The highly pathogenic avian influenza outbreak among poultry farms in the midwestern United States appears to be influenced by agricultural and geographic factors. After initial introduction of the virus into the poultry industries, no further introductions (such as from a wild bird reservoir) were necessary to explain the continuation of the outbreak from March to June 2015. Additionally, evidence suggests that proximity increases the chances of viral movement between two locations. While many hypotheses have been proposed to explain the transmission of virus among poultry farms, the support for road density as an important driver of viral movement suggests human-mediated viral transportation played a key role in the spread of the highly pathogenic H5N2 outbreak in North America.
High-numerical-aperture macroscope optics for time-resolved experiments
Authors: Bührer Minna , Stampanoni Marco , Rochet Xavier , Büchi Felix , Eller Jens , Marone Federica
Published: May 2019

A novel high-quality custom-made macroscope optics, dedicated to high-resolution time-resolved X-ray tomographic microscopy at the TOMCAT beamline at the Swiss Light Source (Paul Scherrer Institut, Switzerland), is introduced. The macroscope offers 4× magnification, has a very high numerical aperture of 0.35 and it is modular and highly flexible. It can be mounted both in a horizontal and vertical configuration, enabling imaging of tall samples close to the scintillator, to avoid edge-enhancement artefacts. The macroscope performance was characterized and compared with two existing in-house imaging setups, one dedicated to high spatial and one to high temporal resolution. The novel macroscope shows superior performance for both imaging settings compared with the previous systems. For the time-resolved setup, the macroscope is 4 times more efficient than the previous system and, at the same time, the spatial resolution is also increased by a factor of 6. For the high-spatial-resolution setup, the macroscope is up to 8.5 times more efficient with a moderate spatial resolution improvement (factor of 1.5). This high efficiency, increased spatial resolution and very high image quality offered by the novel macroscope optics will make 10–20 Hz high-resolution tomographic studies routinely possible, unlocking unprecedented possibilities for the tomographic investigations of dynamic processes and radiation-sensitive samples.
Dodecan-1-aminium sulfate trihydrate
Authors: Liu Jiapan , Di Youying , Chen Fengying
Published: May 2019

The asymmetric unit of the title salt, 2C12H28N+·SO4
2−·3H2O, contains two n-dodecylammonium cations, one sulfate anion and three water molecules. In the crystal, N—H...O hydrogen bonds link the cations and anions into layers parallel to (100). These layers are further connected through O—H...O hydrogen-bonding interactions involving the sulfate ions and the isolated water molecules. The three-dimensional structure can also be considered as the superposition of thin inorganic layers of SO4
2− anions and thick layers of alkylammonium cations perpendicular to the c axis.
Organizational learning and job satisfaction of trainee auditors: a case study of Chinese CPA firms
Authors: Liu Guangyou , Ren Hong
Published: May 2019

Purpose

This study aims to investigate the organizational learning of trainee auditors who represent the young generation of new entry-level professionals in CPA firms, and examines the possible associations between organizational learning and job satisfaction.

Design/methodology/approach

A questionnaire survey is administered among the target group of trainee auditors to explore possible approaches to their organizational learning in CPA firms. The results are used to generate organizational learning variables, which enable us to empirically test the research hypotheses regarding the association between organizational learning and job satisfaction.

Findings

The authors conclude that there are three main dimensions of organizational learning for new entry-level professionals in CPA firms, namely: workplace interactions, supervising and monitoring and supportive informational systems. The authors also find that workplace interactions and supportive information systems are significantly associated with job satisfaction. The authors show that the females and males prefer different approaches to organizational learning in CPA firms. The authors also find that trainee auditors who work for bigger CPA firms enjoy more job satisfaction than those working for smaller CPA firms, and that male trainee auditors are more easily satisfied with audit jobs than female trainees.

Research limitations/implications

This study is limited in that its sample is composed of trainee auditors, who are used to proxy for entry-level professionals in CPA firms. Future studies can include a direct focus on the organizational learning of junior auditors in CPA firms. Future studies can also investigate organizational learning in the firm-wide context in which CPA firms and their employees are considered as part of a larger situational process of organizational learning.

Practical implications

The conclusions can help to improve practice management and human resource policies in CPA firms. The findings highlight the importance of establishing an effective organizational learning culture, and suggest how this can be achieved by providing friendly and instructive workplace interactions, helpful supervisory and mentoring relationships, and better information support.

Originality/value

This study contributes to the audit literature by identifying the three dimensions of organizational learning for entry-level professionals in CPA firms. The authors substantiate the argument that mentor-protégé relationships in CPA firms have different effects on job satisfaction for female and male trainee auditors.