bluuebunny/crossref_metadata_2025_split huggingface dataset:
Small molecule inhibition of PIKFYVE kinase rescues gain- and loss-of-functionC9ORF72ALS/FTD disease processesin vivo
Authors: Staats K. A. , Seah C. , Sahimi A. , Wang Y. , Koutsodendris N. , Lin S. , Kim D. , Chang W-H. , Gray K. A. , Shi Y. , Li Y. , Chateau M. , Vangoor V. R. , Senthilkumar K. , Pasterkamp R. J. , Cannon P. , Zlokovic B.V. , Ichida J. K. 
Published: June 2019

AbstractThe most common known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is a hexanucleotide repeat expansion (HRE) inC9ORF72that contributes to neurodegeneration by both loss-of-function (decreased C9ORF72 protein levels) and gain-of-function (e.g. dipeptide repeat protein production) mechanisms. Although therapeutics targeting the gain-of-function mechanisms are in clinical development, it is unclear if these will be efficacious given the contribution of C9ORF72 loss-of-function processes to neurodegeneration. Moreover, there is a lack of therapeutic strategies forC9ORF72ALS/FTD with demonstrated efficacyin vivo. Here, we show that small molecule inhibition of PIKFYVE kinase rescues both loss- and gain-of-function C9ORF72 disease mechanismsin vivo. We find that the reduction of C9ORF72 in mouse motor neurons leads to a decrease in early endosomes. In contrast, treatment with the PIKFYVE inhibitor apilimod increases the number of endosomes and lysosomes. We show that reduced C9ORF72 levels increases glutamate receptor levels in hippocampal neurons in mice, and that apilimod treatment rescues this excitotoxicity-related phenotypein vivo. Finally, we show that apilimod also alleviates the gain-of-function pathology induced by theC9ORF72HRE by decreasing levels of dipeptide repeat proteins derived from both sense and antisenseC9ORF72transcripts in hippocampal neuronsin vivo. Our data demonstrate the neuroprotective effect of PIKFYVE kinase inhibition in both gain- and loss-of-function murine models ofC9ORF72ALS/FTD.
Functional clusters of neurons in layer 6 of macaque V1
Authors: Hawken Michael J , Shapley Robert M , Disney Anita A , Garcia-Marin Virginia , Henrie JA , Henry Christopher A , Johnson Elizabeth M , Joshi Siddartha , Kelly Jenna G , Ringach Dario L , Xing Dajun 
Published: June 2019

AbstracLayer 6 appears to perform a very important role in the function of macaque primary visual cortex, V1, but not enough is understood about the functional characteristics of neurons in the layer 6 population. It is unclear to what extent the population is homogeneous with respect to their visual properties or if one can identify distinct sub-populations. Here we performed a cluster analysis based on measurements of the responses of single neurons in layer 6 of primary visual cortex to achromatic grating stimuli that varied in orientation, direction of motion, spatial and temporal frequency, and contrast. The visual stimuli were presented in a stimulus window that was also varied in size. Using the responses to parametric variation in these stimulus variables we extracted a number of tuning response measures and used them in the cluster analysis. Six main clusters emerged along with some smaller clusters. Additionally we asked whether parameter distributions from each of the clusters were statistically different. There were clear separations of parameters between some of the clusters, particularly for f1/f0 ratio, direction selectivity, and temporal frequency bandwidth but other dimensions also showed differences between clusters. Our data suggest that in layer 6, across the spatial extent of a single cortical hypercolumn, there are multiple parallel circuits that provide information about different aspects of the visual stimulus.
Expansion of apical extracellular matrix underlies the morphogenesis of a recently evolved structure
Authors: Smith Sarah Jacquelyn , Davidson Lance A. , Rebeiz Mark 
Published: June 2019

AbstractOne of the fundamental gaps in our knowledge of the evolution of novel structures is understanding how the morphogenetic processes that form these structures arise. Here, we traced the cellular development of a morphological novelty, the posterior lobe ofD. melanogaster. We found that this genital outgrowth forms through an extreme increase in cell height. By examining the apical extracellular matrix (aECM), we uncovered a vast network associated with the developing genitalia of lobed and non-lobed species. We observed that cells which will form the posterior lobe show expanded expression of the aECM protein Dumpy which connects them to the ancestral aECM network. Further analysis demonstrated a required role for Dumpy in cell height increase during development. We propose that the aECM presents a rich reservoir for generating morphological novelty, in addition to highlighting a yet unseen role for aECM in regulating extreme cell height.
Functional conservation of lncRNAJPXdespite sequence and structural divergence
Authors: Karner Heather M. , Webb Chiu-Ho , Carmona Sarah , Liu Yu , Lin Benjamin , Erhard Micaela , Chan Dalen , Baldi Pierre , Spitale Robert C. , Sun Sha 
Published: June 2019

SummaryLong noncoding RNAs (lncRNAs) have been identified in all eukaryotes and are most abundant in the human genome. However, the functional importance and mechanisms of action for human lncRNAs are largely unknown. Using comparative sequence, structural, and functional analyses, we characterize the evolution and molecular function of human lncRNAJPX. We find that humanJPXand its mouse homolog, lncRNAJpx, have deep divergence in their nucleotide sequences and RNA secondary structures. Despite such differences, both lncRNAs demonstrate robust binding to CTCF, a protein that is central toJpx’s role in X chromosome inactivation. In addition, our functional rescue experiment usingJpx-deletion mutant cells, shows that humanJPXcan functionally complement the loss ofJpxin mouse embryonic stem cells. Our findings support a model for functional conservation of lncRNAs independent from sequence and structural changes. The study provides mechanistic insight into the evolution of lncRNA function.
Loci specific epigenetic drug sensitivity
Authors: Zhang Thanutra , Pilko Anna , Wollman Roy 
Published: June 2019

AbstractTherapeutic targeting of epigenetic modulators offers a novel approach to the treatment of several diseases including cancer, heart diseases and AIDS. The cellular consequences of chemical compounds that target epigenetic regulators (epi-drugs) are complex. Epi-drugs affect global cellular phenotypes and cause local changes to gene expression due to alteration of a gene chromatin environment. Despite increasing use in the clinic, the mechanisms responsible for cellular changes are unclear. Specifically, to what degree the effects are a result of cell-wide changes or disease related locus specific effects is unknown. Here we developed a platform to systematically and simultaneously investigate the sensitivity of epi-drugs at hundreds of genomic locations by combining DNA barcoding, unique split-pool encoding and single cell expression measurements. Internal controls are used to isolate locus specific effects separately from any global consequences these drugs have. Using this platform we discovered wide-spread loci specific sensitivities to epi-drugs for three distinct epi-drugs that target histone deacetylase, DNA methylation and bromodomain proteins. By leveraging ENCODE data on chromatin modification, we identified features of chromatin environments that are most likely to be affected by epi-drugs. The measurements of loci specific epi-drugs sensitivities will pave the way to the development of targeted therapy for personalized medicine.
Microstructural Abnormalities of Substantia Nigra in Parkinson’s disease: A Neuromelanin Sensitive MRI Atlas Based Study
Authors: Safai Apoorva , Prasad Shweta , Saini Jitender , Pal Pramod Kumar , Ingalhalikar Madhura 
Published: June 2019

AbstractMicrostructural changes associated with degeneration of dopaminergic neurons of the substantia nigra pars compacta (SNc) in Parkinson’s disease (PD) have been studied using Diffusion Tensor Imaging (DTI). However, these studies show inconsistent results, mainly due to methodological variations in delineation of SNc. To mitigate this, our work aims to construct a probabilistic atlas of SNc based on a Neuromelanin sensitive MRI (NMS-MRI) sequence and demonstrate its applicability to investigate microstructural changes on a large dataset of PD. Using manual segmentation and deformable registrations, we create a novel SNc atlas in the MNI space using NMS-MRI sequences of 27 healthy controls (HC). We employ this atlas to evaluate the diffusivity and anisotropy measures, derived from diffusion MRI in the SNc of 135 patients with PD and 99 HCs. Our observations of significantly increased diffusivity measures provide evidence of microstructural abnormalities in PD. However, no changes in the anisotropy were observed. Moreover, the asymmetry in abnormalities is prominent as the left SNc showed significant increase in diffusivity, and a reduction in FA when compared to the right SNc. Further the diffusivity and FA values also demonstrated a trend when correlated with the PD severity scores. Overall, from this work we establish a normative baseline for the SNc region of interest using NMS-MRI while the application on PD data emphasizes on the contribution of diffusivity measures rather than anisotropy of white matter in PD.
Draft genome assemblies using sequencing reads from Oxford Nanopore Technology and Illumina platforms for four species of North American killifish from the Fundulus genus
Authors: Johnson Lisa K. , Sahasrabudhe Ruta , Gill Tony , Roach Jennifer , Froenicke Lutz , Brown C. Titus , Whitehead Andrew 
Published: June 2019

AbstractDraft de novo reference genome assemblies were obtained from four North American killifish species (Fundulus xenicus, Fundulus catenatus, Fundulus nottii, and Fundulus olivaceus) using sequence reads from Illumina and Oxford Nanopore Technologies’ PromethION platforms. For each species, the PromethION platform was used to generate 30-45x sequence coverage, and the Illumina platform was used to generate 50-160x sequence coverage. Contig N50 values ranged from 0.4 Mb to 2.7 Mb, and BUSCO scores were consistently above 90% complete using the Eukaryota database. Draft assemblies and raw sequencing data are available for public use. We encourage use and re-use of these data for assembly benchmarking and external analyses.
Streptolysin production and activity is central toin vivopathotype and disease outcome in GAS infections
Authors: Clarke Jenny , Baltazar Murielle , Alsahag Mansoor , Panagiotou Stavros , Pouget Marion , Paxton William A , Pollakis Georgios , Everett Dean , French Neil , Kadioglu Aras 
Published: June 2019

AbstractStreptococcus pyogenes (GAS) is among the most diverse of all human pathogens, responsible for a range of clinical manifestations, from mild superficial infections such as pharyngitis to serious invasive infections such as necrotising fasciitis and sepsis. The drivers of these different disease phenotypes are not known. The GAS cholesterol-dependent cytolysin, streptolysin O (SLO), has well established cell and tissue destructive activity. We investigated the role of SLO in determining disease outcomein vivo, by using two different clinical lineages; the recently emerged hypervirulent outbreakemmtype 32.2 strains, which result in sepsis, and theemmtype 1.0 strains which cause septic arthritis. Using clinically relevantin vivomouse models of sepsis and a novel septic arthritis model, we demonstrated that the amount and activity of SLO is vital in determining the pathotype of infection. Theemm32.2 strain produced large quantities of highly haemolytic SLO that resulted in rapid development of sepsis. By contrast, the lower levels and haemolytic activity ofemm1.0 SLO led to translocation of bacteria to joints. Importantly, sepsis associated strains that were attenuated by deletion or inhibition of SLO also translocated to the joint, confirming the key role of SLO in determining infection niche. Our findings demonstrate that SLO is key toin vivopathotype and disease outcome. Careful consideration should be given to novel therapy or vaccination strategies that target SLO. Whilst neutralising SLO activity may reduce severe invasive disease, it has the potential to promote chronic inflammatory conditions such as septic arthritis.
Enhanced inference of ecological networks by parameterizing ensembles of population dynamics models constrained with prior knowledge
Authors: Liao Chen , Xavier Joao B. , Zhu Zhenduo 
Published: June 2019

AbstractBackgroundAccurate network models of species interaction could be used to predict population dynamics and be applied to manage real world ecosystems. Most relevant models are nonlinear, however, and data available from real world ecosystems are too noisy and sparsely sampled for common inference approaches. Here we improved the inference of generalized Lotka-Volterra (gLV) ecological networks by using a new optimization algorithm to constrain parameter signs with prior knowledge and a perturbation-based ensemble method.ResultsWe applied the new inference to long-term species abundance data from the freshwater fish community in the Illinois River, United States. We constructed an ensemble of 668 gLV models that explained 79% of the data on average. The models indicated (at a 70% level of confidence) a strong positive interaction from emerald shiner (Notropis atherinoides) to channel catfish (Ictalurus punctatus), which we could validate using data from a nearby observation site, and predicted that the relative abundances of most fish species will continue to fluctuate temporally and concordantly in the near future. The network shows that the invasive silver carp (Hypophthalmichthys molitrix) has much stronger impacts on native predators than on prey, supporting the notion that the invader perturbs the native food chain by replacing the diets of predators.ConclusionsEnsemble approaches constrained by prior knowledge can improve inference and produce networks from noisy and sparsely sampled time series data to fill knowledge gaps on real world ecosystems. Such network models could aid efforts to conserve ecosystems such as the Illinois River, which is threatened by the invasion of the silver carp.
Automated characterization of noise distributions in diffusion MRI data
Authors: St-Jean Samuel , De Luca Alberto , Tax Chantal M. W. , Viergever Max A. , Leemans Alexander 
Published: June 2019

AbstractKnowledge of the noise distribution in magnitude diffusion MRI images is the centerpiece to quantify uncertainties arising from the acquisition process. The use of parallel imaging methods, the number of receiver coils and imaging filters applied by the scanner, amongst other factors, dictate the resulting signal distribution. Accurate estimation beyond textbook Rician or noncentral chi distributions often requires information about the acquisition process (e.g., coils sensitivity maps or reconstruction coeffcients), which is usually not available. We introduce two new automated methods using the moments and maximum likelihood equations of the Gamma distribution to estimate noise distributions as they explicitly depend on the number of coils, making it possible to estimate all unknown parameters using only the magnitude data. A rejection step is used to make the framework automatic and robust to artifacts. Simulations using stationary and spatially varying noncentral chi noise distributions were created for two diffusion weightings with SENSE or GRAPPA reconstruction and 8, 12 or 32 receiver coils. Furthermore, MRI data of a water phantom with different combinations of parallel imaging were acquired on a 3T Philips scanner along with noise-only measurements. Finally, experiments on freely available datasets from a single subject acquired on a 3T GE scanner are used to assess reproducibility when limited information about the acquisition protocol is available. Additionally, we demonstrated the applicability of the proposed methods for a bias correction and denoising task on an in vivo dataset acquired on a 3T Siemens scanner. A generalized version of the bias correction framework for non integer degrees of freedom is also introduced. The proposed framework is compared with three other algorithms with datasets from three vendors, employing different reconstruction methods. Simulations showed that assuming a Rician distribution can lead to misestimation of the noise distribution in parallel imaging. Results on the acquired datasets showed that signal leakage in multiband can also lead to a misestimation of the noise distribution. Repeated acquisitions of in vivo datasets show that the estimated parameters are stable and have lower variability than compared methods. Results for the bias correction and denoising task show that the proposed methods reduce the appearance of noise at high b-value. The proposed algorithms herein can estimate both parameters of the noise distribution automatically, are robust to signal leakage artifacts and perform best when used on acquired noise maps.
The intracellular symbiont Wolbachia enhances recombination in a dose-dependent manner
Authors: Bryant Kaeli N. , Newton Irene L.G. 
Published: June 2019

AbstractWolbachia pipientis is an intracellular alphaproteobacterium that infects 40-60% of insect species and is well known for host reproductive manipulations. Although Wolbachia are primarily maternally transmitted, evidence of horizontal transmission can be found in incongruent host-symbiont phylogenies and recent acquisitions of the same Wolbachia strain by distantly related species. Parasitoids and predator-prey interactions may indeed facilitate the transfer of Wolbachia between insect lineages but it is likely that Wolbachia are acquired via introgression in many cases. Many hypotheses exist as to explain Wolbachia prevalence and penetrance such as nutritional supplementation, protection from parasites, protection from viruses, or straight up reproductive parasitism. Using classical genetics we show that Wolbachia increase recombination in infected lineages across two genomic intervals. This increase in recombination is titer dependent as the wMelPop variant, which infects at higher load in Drosophila melanogaster, increases recombination 5% more than the wMel variant. In addition, we also show that Spiroplasma poulsonii, the other bacterial intracellular symbiont of Drosophila melanogaster, does not induce an increase in recombination. Our results suggest that Wolbachia infection specifically alters host recombination landscape in a dose dependent manner.Article SummaryThe ubiquitous bacterial symbiont Wolbachia is known to alter host reproduction through manipulation of host cell biology, protect from pathogens, and supplement host nutrition. In this work we show that Wolbachia specifically increases host recombination in a dose dependent manner. Flies harboring Wolbachia exhibit elevated rates of recombination across the 2nd and X chromosomes and this increase is proportional to their Wolbachia load. In contrast, another intracellular symbiont, Spiroplasma, does not lead to an increase in recombination across the intervals tested. Our results point to a specific effect of Wolbachia infection that may have a significant effect on infected insect populations.
Classification of human physical activity based on the raw accelerometry data via spherical coordinate transformation
Authors: Kos Michał , Bogdan Małgorzata , Glynn Nancy W. , Harezlak Jaroslaw 
Published: June 2019

AbstractHuman health is strongly associated with person’s lifestyle and levels of physical activity. Therefore, characterization of daily human activity is an important task. Accelerometers have been used to obtain precise measurements of body acceleration. Wearable accelerometers collect data as a three-dimensional time series with frequencies up to 100Hz. Using such accelerometry signal, we are able to classify different types of physical activity.In our work, we present a novel procedure for physical activity classification based on the raw accelerometry signal. Our proposal is based on the spherical representation of the data. We classify four activity types: resting, upper body activities (sitting), upper body activities (standing) and lower body activities. The classifier is constructed using decision trees with extracted features consisting of spherical coordinates summary statistics, moving averages of the radius and the angles, radius variance and spherical variance.The classification accuracy of our method has been tested on data collected on a sample of 47 elderly individuals who performed a series of activities in laboratory settings. The achieved classification accuracy is over 90% when the subject-specific data are used and 84% when the group data are used. Main contributor to the classification accuracy is the angular part of the collected signal, especially spherical variance. To the best of our knowledge, spherical variance has never been previously used in the analysis of the raw accelerometry data. Its major advantage over other angular measures is its invariance to the accelerometer location shifts.
Analysis of DNM3 and VAMP4 as genetic modifiers of LRRK2 Parkinson’s disease
Authors: Brown EE , Blauwendraat C , Trinh J , Rizig M , Nalls MA , Leveille E , Ruskey JA , Jonvik H , Tan MMX , Bandres-Ciga S , Hassin-Baer S , Brockmann K , Infante J , Tolosa E , Ezquerra M , Benromdhan S , Benmahdjoub M , Hardy J , Singleton AB , Alcalay RN , Gasser T , Grosset D , Williams NM , Pittman A , Gan-Or Z , Fernandez-Santiago R , Brice A , Lesage S , Farrer M , Wood N , Morris HR ,   on behalf of the International Parkinson Disease Genomics Consortium (IPDGC)
Published: June 2019

AbstractObjectiveTo assess genetic modifiers of Parkinson’s disease (PD) age at onset (AAO) penetrance in individuals carrying common and rare LRRK2 risk allelesMethodsWe analysed reported genetic modifier DNM3 rs2421947 in 724 LRRK2 p.G2019S heterozygotes using linear regression of AAO. We meta-analysed our data with previously published data (n=754). VAMP4 is in close proximity to DNM3 and is associated with PD. We analysed the effect of the rs11578699 VAMP4 variant on pG2019S penetrance in 786 LRRK2 p.G2019S heterozygotes. We also evaluated the impact of VAMP4 variants using AAO regression in 4882 patients with PD carrying a common LRRK2 risk variant (rs10878226).ResultsThere was no evidence for linkage disequilibrium between DNM3 rs2421947 and VAMP4 rs11578699. Our linear regression AAO of 724 p.G2019S carriers showed no relationship between DNM3 rs2421947 and AAO (beta = −1.19, p = 0.55, n =708). Meta-analysis with previously published data did not indicate a significant effect on AAO (beta = −2.21, p = 0.083, n = 1304), but there was significant heterogeneity in the analyses of new and previously published data. VAMP4 rs11578699 was nominally associated with AAO in patients dichotomized by the common LRRK2 risk variant rs10878226 (beta=1.68, se=0.81 p=0.037).InterpretationAnalysis of DNM3 in previously unpublished data does not show an interaction between DNM3 and LRRK2 G2019S for AAO, however the inter-study heterogeneity may indicate ethnic-specific effects of DNM3 rs2421947. Analysis of sporadic PD patients stratified by the PD risk variant rs10878226 indicates a possible interaction between LRRK2 and VAMP4.