bluuebunny/crossref_metadata_2025_split huggingface dataset:
Altered composition of the γδ T cell pool in lymph nodes during ageing enhances tumour growth
Authors: Chen Hung-Chang , Eling Nils , Martinez-Jimenez Celia Pilar , O’Brien Louise McNeill , Marioni John C. , Odom Duncan T. , la Roche Maike de 
Published: November 2018

ABSTRACTHow age-associated decline of immune function leads to increased cancer incidence is poorly understood. Here, we have characterized the cellular composition of the γδ T cell pool in peripheral lymph nodes (pLNs) upon ageing. We found that ageing has minimal cell-intrinsic effects on function and global gene expression of γδ T cells, and TCRγδ diversity remained stable. However, ageing altered TCRδ chain usage and clonal structure of γδ T cell subsets. Importantly, IL-17-producing γδ17 T cells dominated the γδ T cell pool of aged mice - mainly due to the selective expansion of Vγ6+γδ17 T cells and augmented γδ17-polarisation of Vγ4+ T cells. Expansion of the γδ17 T cell compartment was supported by increased Interleukin-7 expression in the T cell zone of old mice. In a Lewis lung cancer model, pro-tumourigenic Vγ6+γδ17 T cells were exclusively activated in the tumour-draining LN and their infiltration into the tumour correlated with increased tumour size in aged mice. Thus, upon ageing, substantial compositional changes of γδ T cell pool in a dysregulated pLN microenvironment promote tumour growth.
FAM83D directs protein kinase CK1α to the mitotic spindle for proper spindle positioning
Authors: Fulcher Luke J. , He Zhengcheng , Mei Lin , Macartney Thomas J. , Wood Nicola T. , Prescott Alan R. , Whigham Arlene J. , Varghese Joby , Gourlay Robert , Ball Graeme , Clarke Rosemary , Campbell David G. , Maxwell Christopher A. , Sapkota Gopal P. 
Published: November 2018

SummaryThe concerted action of many protein kinases helps orchestrate the error-free progression through mitosis of mammalian cells. The roles and regulation of some prominent mitotic kinases, such as cyclin-dependent kinases, are well-established. However, these and other known mitotic kinases alone cannot account for the extent of protein phosphorylation that has been reported during mammalian mitosis. Here we demonstrate that CK1α, of the casein kinase 1 family of protein kinases, localises to the spindle and is required for proper spindle-positioning and timely cell division. CK1α is recruited to the spindle by FAM83D, and cells devoid ofFAM83D, or those harbouring CK1α-binding-deficientFAM83DF283A/F283Aknockin mutation, display pronounced spindle-positioning defects, and a prolonged mitosis. RestoringFAM83Dat the endogenous locus inFAM83D-/-cells, or artificially delivering CK1α to the spindle inFAM83DF283A/F283Acells, rescues these defects. These findings implicate CK1α as new mitotic kinase that orchestrates the kinetics and orientation of cell division.
The Range of Cooperativity Modulates Actin Binding Protein Cluster Size Density and Dynamics
Authors: Goff T. Le , Michelot A. 
Published: November 2018

ABSTRACTThe actin cytoskeleton is composed of multiple networks which are specialized for several processes such as cell motility or cell division. Each of these networks are composed of organized actin microfilaments which are decorated with specific sets of actin binding proteins (ABPs). The molecular mechanisms guiding ABPs to specific actin networks are still poorly understood, but cooperativity, the mechanism by which the binding of an ABP is positively influenced by proximal bound ABPs, plays a crucial role in generating locally dense stretches of ABPs. Cooperative binding is characterized by its amplitude, but also by the range at which its effects are propagated along an actin filament through long-range allosteric interactions. The range of these allosteric effects is still debated, but is likely to be significant at the lengthscale of actin filaments in cells. Here, we investigated how cooperativity influences the clustering of ABPs, using a stochastic computational model of binding of ABPs to actin filaments. The model reproduces the formation of ABP clusters observed experimentally at the single filament scale, and provides a theoretical estimation of the range of cooperativity for proteins such as ADF/cofilin. We found that both the amplitude and the spatial range of cooperativity dramatically impact the properties of clustering. However, the parameters of cooperativity modulate differently the rate of assembly, size and dynamics of the ABP clusters, suggesting that cooperativity is an efficient mechanism to regulate precisely the recruitment of ABPs in cells. This work provides a more general framework for future understanding of how actin networks acquire distinct and specific protein compositions from a common cytoplasm.
Neural circuit robustness to acute, global physiological perturbations
Authors: Ratliff Jacob , Marder Eve , O’Leary Timothy 
Published: November 2018

AbstractNeural function depends on underlying physiological processes that are highly sensitive to physical variables such as temperature. However, some robustness to perturbations in these variables manifests at the circuit level, suggesting that circuit properties are organized to tolerate consistent changes in underlying parameters. We show that a crustacean pacemaker circuit is robust to two global perturbations - temperature and pH - that differentially alter circuit properties. Consistent with high variability in underlying circuit parameters, we find that the critical temperatures and pH values where circuit activity breaks down vary widely across animals. Despite variability in critical points the network state transitions at these critical points are consistent, implying that qualitative circuit dynamics are preserved across animals, in spite of high quantitative parameter variability. Surprisingly, robustness perturbations in pH only moderately affect temperature robustness. Thus, robustness to a global perturbation does not necessarily imply sensitivity to other global perturbations.
Ergodicity analysis and antithetic integral control of a class of stochastic reaction networks with delays
Authors: Briat Corentin , Khammash Mustafa 
Published: November 2018

AbstractDelays are important phenomena arising in a wide variety of real world systems, including biological ones, because of diffusion/propagation effects or as simplifying modeling elements. We propose here to consider delayed stochastic reaction networks, a class of networks that has been relatively few studied until now. The difficulty in analyzing them resides in the fact that their state-space is infinite-dimensional. We demonstrate here that by restricting the delays to be phase-type distributed, one can represent the associated delayed reaction network as a reaction network with finite-dimensional state-space. This can be achieved by suitably adding chemical species and reactions to the delay-free network following a simple algorithm which is fully characterized. Since phase-type distributions are dense in the set of probability distributions, they can approximate any distribution arbitrarily closely and this makes their consideration only a bit restrictive. As the state-space remains finite-dimensional, usual tools developed for non-delayed reaction network directly apply. In particular, we prove, for unimolecular mass-action reaction networks, that the delayed stochastic reaction network is ergodic if and only if the delay-free network is ergodic as well. Bimolecular reactions are more difficult to consider but slightly stronger analogous results are nevertheless obtained. These results demonstrate that delays have little to no harm to the ergodicity property of reaction networks as long as the delays are phase-type distributed, and this holds regardless the complexity of their distribution. We also prove that the presence of those delays adds convolution terms in the moment equation but does not change the value of the stationary means compared to the delay-free case. The covariance, however, is influenced by the presence of the delays. Finally, the control of a certain class of delayed stochastic reaction network using a delayed antithetic integral controller is considered. It is proven that this controller achieves its goal provided that the delay-free network satisfy the conditions of ergodicity and output-controllability.
Intracellular pH controls Wnt signaling downstream of glycolysis in the vertebrate embryo
Authors: Oginuma Masayuki , Harima Yukiko , Xiong Fengzhu , Pourquié Olivier 
Published: November 2018

AbstractFormation of the body of vertebrate embryos proceeds sequentially by posterior addition of tissues. While this process depends on aerobic glycolysis acting upstream of Wnt signaling in tail bud cells, the molecular details of this regulation are unknown. Here we used chicken embryos and human tail bud-like cells differentiatedin vitrofrom iPS cells to show that glycolysis acts by increasing the intracellular pH (pHi) of tail bud cells. This promotes β-catenin acetylation leading to Wnt signaling activation and the choice of a mesodermal fate at the expense of the neural fate in tail bud precursors. Our data suggest that by increasing the pHi of tail bud cells, aerobic glycolysis creates a favorable chemical environment for non-enzymatic acetylation of β-catenin, ultimately triggering Wnt signaling.
Defining developmental diversification of diencephalon neurons through single-cell gene expression profiling
Authors: Guo Qiuxia , Li James Y. H. 
Published: November 2018

ABSTRACTThe embryonic diencephalon gives rise to diverse neuronal cell types, which form complex integration centers and intricate relay stations of the vertebrate forebrain. Prior anecdotal gene expression studies suggest several developmental compartments within the developing diencephalon. In the current study, we utilized single-cell RNA sequencing to profile transcriptomes of dissociated cells from the diencephalon of E12.5 mouse embryos. Through analysis of unbiased transcriptional data, we identified the divergence of different progenitors, intermediate progenitors, and emerging neuronal cell types. After mapping the identified cell groups to their spatial origins, we were able to characterize the molecular features across different cell types and cell states, arising from various diencephalic compartments. Furthermore, we reconstructed the developmental trajectory of different cell lineages within the diencephalon. This allowed the identification of the genetic cascades and gene regulatory networks underlying the progression of the cell cycle, neurogenesis, and cellular diversification. The analysis provides new insights into the molecular mechanism underlying the specification and amplification of thalamic progenitor cells. In addition, the single-cell-resolved trajectories not only confirm a close relationship between the rostral thalamus and prethalamus, but also uncover an unexpected close relationship between the caudal thalamus, epithalamus and rostral pretectum. Our data provide a useful resource for the systematic study of cell heterogeneity and differentiation kinetics within the developing diencephalon.
Ribozyme-Mediated, Multiplex CRISPR Gene Editing and CRISPRi in Plasmodium yoelii
Authors: Walker Michael P. , Lindner Scott E. 
Published: November 2018

AbstractFunctional characterization of genes in Plasmodium parasites often relies on genetic manipulations to disrupt or modify a gene-of-interest. However, these approaches are limited by the time required to generate transgenic parasites for P. falciparum and the availability of a single drug selectable marker for P. yoelii. In both cases, there remains a risk of disrupting native gene regulatory elements with the introduction of exogenous sequences. To address these limitations, we have developed CRISPR-RGR, a SpCas9-based gene editing system for Plasmodium that utilizes a Ribozyme-Guide-Ribozyme (RGR) sgRNA expression strategy. Using this system with P. yoelii, we demonstrate that both gene disruptions and coding sequence insertions are efficiently generated, producing marker-free and scar-free parasites with homology arms as short as 80-100bp. Moreover, we find that the common practice of using one sgRNA can produce both unintended plasmid integration and the desired locus replacement editing events, while the use of two sgRNAs results in only locus replacement editing. Lastly, we show that CRISPR-RGR can be used for CRISPR interference (CRISPRi) by binding dCas9 to targets in the gene control region of a gene-of-interest, resulting in a modest reduction in gene expression. This robust and flexible system should open the door for in-depth and efficient genetic characterizations in both rodent- and human-infectious Plasmodium species.ImportancePlasmodium parasites, the causative agent of malaria, still pose an enormous threat to public health worldwide. Gaining additional insight into the biology of the parasite is essential for generating an effective vaccine and identifying novel drug targets. To this end, CRISPR/Cas9 tools have been developed to more efficiently interrogate the Plasmodium genome than is possible with conventional reverse genetics approaches. Here, we describe CRISPR-RGR as an addition to the CRISPR/Cas9 toolbox for the rodent-infectious Plasmodium parasites. By using multiple ribozyme-flanked single guide RNAs expressed from RNA polymerase II promoters, transgenic parasites can be rapidly generated as designed without leaving selectable markers. Moreover, CRISPR-RGR can be adapted for use as a CRISPR interference (CRISPRi) system to alter gene expression without genome modification. Together, CRISPR-RGR for gene editing and CRISPRi application can hasten investigations into the biology and vulnerabilities of the malaria parasite.
Beat-Relevant Signals in Auditory Cortical Responses to Musical Excerpts
Authors: Rajendran Vani G. , Harper Nicol S. , Schnupp Jan W. H. 
Published: November 2018

AbstractMusical beat perception is widely regarded as a high-level ability involving widespread coordination across brain areas, but how low-level auditory processing must necessarily shape these dynamics, and therefore perception, remains unexplored. Previous cross-species work suggested that beat perception in simple rhythmic noise bursts is shaped by neural transients in the ascending sensory pathway. Here, we found that low-level processes even substantially explain the emergence of beat in real music. Firing rates in the rat auditory cortex in response to twenty musical excerpts were on average higher on the beat than off the beat tapped by human listeners. This “neural emphasis” distinguished the perceived beat from alternative interpretations, was predictive of the degree of consensus across listeners, and was accounted for by a spectrotemporal receptive field model. These findings indicate that low-level auditory processing may have a stronger influence on the location and clarity of the beat in music than previously thought.
Single-Trial Decoding of Scalp EEG Under Natural Conditions
Authors: Tuckute Greta , Hansen Sofie Therese , Pedersen Nicolai , Steenstrup Dea , Hansen Lars Kai 
Published: November 2018

ABSTRACTThere is significant current interest in decoding mental states from electro-encephalography (EEG) recordings. EEG signals are subject-specific, sensitive to disturbances, and have a low signal-to-noise ratio, which has been mitigated by the use of laboratory-grade EEG acquisition equipment under highly controlled conditions. In the present study, we investigate single-trial decoding of natural, complex stimuli based on scalp EEG acquired with a portable, 32 dry-electrode sensor system in a typical office setting. We probe generalizability by a leave-one-subject-out cross-validation approach. We demonstrate that Support Vector Machine (SVM) classifiers trained on a relatively small set of de-noised (averaged) pseudo-trials perform on par with classifiers trained on a large set of noisy single-trial samples. For visualization of EEG signatures exploited by SVM classifiers, we propose a novel method for computing sensitivity maps of EEG-based SVM classifiers. Moreover, we apply the NPAIRS resampling framework for estimation of map uncertainty and show that effect sizes of sensitivity maps for classifiers trained on small samples of de-noised data and large samples of noisy data are similar. Finally, we demonstrate that the average pseudo-trial classifier can successfully predict the class of single trials from withheld subjects, which allows for fast classifier training, parameter optimization and unbiased performance evaluation in machine learning approaches for brain decoding.
Activity or Connectivity? Evaluating neurofeedback training in Huntington’s disease
Authors: Papoutsi Marina , Magerkurth Joerg , Josephs Oliver , Pépés Sophia E , Ibitoye Temi , Reilmann Ralf , Hunt Nigel , Payne Edwin , Weiskopf Nikolaus , Langbehn Douglas , Rees Geraint , Tabrizi Sarah J 
Published: November 2018

AbstractNon-invasive methods, such as neurofeedback training (NFT), could support cognitive symptom management in Huntington’s disease (HD) by targeting brain regions whose function is impaired. The aim of our single-blind, sham-controlled study was to collect rigorous evidence regarding the feasibility of NFT in HD by examining two different methods, activity and connectivity real-time fMRI NFT. Thirty-two HD gene-carriers completed 16 runs of NFT training, using an optimized real-time fMRI protocol. Participants were randomized into four groups, two treatment groups, one receiving neurofeedback derived from the activity of the Supplementary Motor Area (SMA), and another receiving neurofeedback based on the correlation of SMA and left striatum activity (connectivity NFT), and two sham control groups, matched to each of the treatment groups. We examined differences between the groups during NFT training sessions and after training at follow-up sessions. Transfer of training was measured by measuring the participants’ ability to upregulate NFT target levels without feedback (near transfer), as well as by examining change in objective, a-priori defined, behavioural measures of cognitive and psychomotor function (far transfer) before and at 2 months after training. We found that the treatment group had significantly higher NFT target levels during the training sessions compared to the control group. However, we did not find robust evidence of better transfer in the treatment group compared to controls, or a difference between the two NFT methods. We also did not find evidence in support of a relationship between change in cognitive and psychomotor function and NFT learning success. We conclude that although there is evidence that NFT can be used to guide participants to regulate the activity and connectivity of specific regions in the brain, evidence regarding transfer of learning and clinical benefit was not robust. Although the intervention is non-invasive, given the costs and absence of reliable evidence of clinical benefit, we cannot recommend real-time fMRI NFT as a potential intervention in HD.
Vernonia Amygdalina Del (Bitter Leaf) extract ameliorates isoniazid (INH) induced liver injury in Swiss Albino Mice
Authors: Tilaye Gebreselassie Addisu , Zerihun Muluken Fekadie , Chuffa Kasaw Adane , Arayaselassie Mahelet , Seifu Daniel 
Published: November 2018

AbstractLiver plays a central role in the metabolism of drugs. Drug clearance and transformation exposes liver to toxic injury. Antitubercular drugs have been found to be hepatotoxic and potentially lead to drug-induced liver injury. Isoniazid is one of the most hepatotoxic first line antitubercular drugs. Conventional drugs used in the treatment of liver disease are often inadequate and a search for supplementation or alternative drugs for the treatment of hepatic damage is indispensible. Therefore our study aims to investigate the hepatoprotective potential of Vernonia Amygdalina Del (bitter leaf) extract against Isoniazid-induced liver injury in Swiss Albino Mice. Treatment of Mice orally with Vernonia Amygdalina Del extract at dose of 250mg/kg and 375 mg/kg significantly lowered (P<0.05) the serum level of liver enzymes in Isoniazid pretreated mice. The hepatoptotective activity of the extract found to be comparable with the standard drug, Silymarin (100 mg/kg, P.o.). Moreover, treatment with the extract significantly alleviated Isoniazid induced hepatic injury as supported by the photomicrographs of liver section of mice. The data shows aqueous Vernonia Amygdalina Del extract has a very promising hepatoprotective potential against isoniazid-induced liver injury.
Hi-C detects novel structural variants in HL-60 and HL-60/S4 cell lines
Authors: Jacobson Elsie C. , Grand Ralph S. , Perry Jo K. , Vickers Mark H. , Olins Ada L. , Olins Donald E. , O’Sullivan Justin M. 
Published: November 2018

AbstractCancer cell lines often have large structural variants (SVs) that evolve over time. There are many reported differences in large scale SVs between HL-60 and HL-60/S4, two cell lines derived from the same acute myeloid leukemia sample. However, the stability and variability of inter- and intra-chromosomal structural variants between different sources of the same cell line is unknown. Here, we used Hi-C and RNA-seq to identify and compare large SVs in HL-60 and HL-60/S4 cell lines. Comparisons with previously published karyotypes identified novel SVs in both cell lines. Hi-C was used to characterize the known expansion centered on the MYC locus. The MYC expansion was integrated into known locations in HL-60/S4, and a novel location (chr4) in HL-60. The HL-60 cell line has more within-line structural variation than the HL-60/S4 derivative cell line. Collectively we demonstrate the usefulness of Hi-C and with RNA-seq data for the identification and characterization of SVs.
Identification of common molecular biomarker signatures in blood and brain of Alzheimer’s disease
Authors: Rahman Md. Rezanur , Islam Tania , Shahjaman Md. , Quinn Julian M.W. , Holsinger R. M. Damian , Moni Mohammad Ali 
Published: November 2018

AbstractBackgroundAlzheimers disease (AD) is a progressive neurodegenerative disease characterized by memory loss and confusion. Neuroimaging and cerebrospinal fluid-based early detection is limited in sensitivity and specificity as well as by cost. Therefore, detecting AD from blood cell analysis could improve early diagnosis and treatment of the disease. The present study aimed to identify blood cell transcripts that reflect brain expression levels of factors linked to AD progression.MethodsWe analyzed blood cell and brain microarray gene expression datasets from NCBI-GEO for AD association and expression in blood and brain. We also used eQTL and epigenetics data to identify AD-related genes that were regulated similarly in blood and brain.ResultsWe identified 9 differentially expressed genes (DEG; AD versus controls) common to blood cells and brain (CNBD1, SUCLG2-AS1, CCDC65, PDE4D, MTMR1, C3, SLC6A15, LINC01806, and FRG1JP) and 18 genes (HSD17B1, GAS5, RPS5, VKORC1, GLE1, WDR1, RPL12, MORN1, RAD52, SDR39U1, NPHP4, MT1E, SORD, LINC00638, MCM3AP-AS1, GSDMD, RPS9, and GNL2) that were commonly dysregulated between AD blood and brain tissues using SNP and cis-eQTL data. This data revealed significant neurodegeneration-associated molecular pathways in the ribosomal and complement systems. Integration of these different analyses revealed dys-regulation of hub transcription factors (SREBF2, NR1H2, NR1H3, PRDM1, XBP1) and microRNAs (miR-518e, miR-518a-3p, miR-518b, miR-518c, miR-518d-3p and miR-518f) in AD. Several significant histone modification sites in DEGs were also identified.ConclusionWe have identified new putative links between pathological processes in brain and transcripts in blood cells in AD subjects that may enable the use of blood to diagnose and monitor AD onset and progression.