bluuebunny/crossref_metadata_2025_split huggingface dataset:
Isolating the key factors defining the magnitude of hippocampal neurogenesis’ effects on anxiety, memory and pattern separation
Authors: França Thiago F. A. 
Published: March 2019

AbstractIn this paper, I analyze the hypothesis that hippocampal neurogenesis (HN) exerts its effects on behavior via activation of inhibitory circuits in the hippocampus. Using a very simple mathematical model (half-borrowed from biochemistry) to aid the reasoning, I show that the key factors determining the magnitude of HN’s effects on behavior are: the baseline levels of HN in the animal, the efficiency of the animal’s inhibitory circuits, the strength/intensity of the stimulus presented to the animal and how much accuracy the behavioral task requires from the information contained in the hippocampal representations. Taken together, those factors can help explain patterns observed in the behavioral results for memory, pattern separation and anxiety. The conclusions of the analysis suggest that HN’s effects on inhibitory circuits can explain the impact of neurogenesis in both emotion and cognition and provide a framework to interpret future studies with rodents and possibly with other species as well.
Slide-seq: A Scalable Technology for Measuring Genome-Wide Expression at High Spatial Resolution
Authors: Rodriques Samuel G. , Stickels Robert R. , Goeva Aleksandrina , Martin Carly A. , Murray Evan , Vanderburg Charles R. , Welch Joshua , Chen Linlin M. , Chen Fei , Macosko Evan Z. 
Published: March 2019

AbstractThe spatial organization of cells in tissue has a profound influence on their function, yet a high-throughput, genome-wide readout of gene expression with cellular resolution is lacking. Here, we introduce Slide-seq, a highly scalable method that enables facile generation of large volumes of unbiased spatial transcriptomes with 10 µm spatial resolution, comparable to the size of individual cells. In Slide-seq, RNA is transferred from freshly frozen tissue sections onto a surface covered in DNA-barcoded beads with known positions, allowing the spatial locations of the RNA to be inferred by sequencing. To demonstrate Slide-seq’s utility, we localized cell types identified by large-scale scRNA-seq datasets within the cerebellum and hippocampus. We next systematically characterized spatial gene expression patterns in the Purkinje layer of mouse cerebellum, identifying new axes of variation across Purkinje cell compartments. Finally, we used Slide-seq to define the temporal evolution of cell-type-specific responses in a mouse model of traumatic brain injury. Slide-seq will accelerate biological discovery by enabling routine, high-resolution spatial mapping of gene expression.One Sentence SummarySlide-seq measures genome-wide expression in complex tissues at 10-micron resolution.
Theta phase synchrony is sensitive to corollary discharge abnormalities in early illness schizophrenia but not in the clinical high-risk syndrome
Authors: Ford Judith M. , Roach Brian J. , Loewy Rachel L. , Stuart Barbara K. , Ford Judith M. , Mathalon Daniel H. 
Published: March 2019

ABSTRACTBackgroundAcross the animal kingdom, responses in auditory cortex are dampened during vocalizing compared to passive listening, reflecting the action of the corollary discharge mechanism. In humans, it is seen as suppression of the EEG-based N1 event-related potential, with less N1-suppression seen in people with schizophrenia and those at clinical high risk (CHR) for psychosis. Because N1 is an admixture of theta (4-7Hz) power and phase synchrony, we asked which is responsible for N1 effects and if they outperform the sensitivity of N1 to corollary discharge and schizophrenia.MethodsTheta phase and power values were extracted from EEG data acquired from CHR youth (n=71), early illness schizophrenia patients (ESZ; n=84), and healthy controls (HC; n=103) as they said /ah/ (Talk) and then listened to the sounds played back (Listen). A principal components analysis extracted theta inter-trial coherence (ITC; phase consistency) and event related spectral power, peaking in the N1 latency range.ResultsTheta ITC-suppression (Cohen d=1.46) was greater than N1-suppression in HC (Cohen d=.63). Both were both reduced in ESZ, but only N1-suppression was reduced in CHR. When deprived of the variance shared with theta-ITC suppression, N1-suppression was no longer sensitive to HC vs. ESZ or HC vs. CHR group differences. Deficits in theta ITC-suppression were correlated with delusions (p=.007) in ESZ. Suppression of theta power was not affected by Group.ConclusionsTheta ITC-suppression may provide a simpler assay of the corollary discharge mechanism than N1-suppression. Deficits in circuits that generate low frequency oscillations may be an important component of schizophrenia.
Dissection of the Hydrogen Metabolism of the EnterobacteriumTrabulsiella guamensis: Identification of a Formate-Dependent and Essential Formate Hydrogenlyase Complex Exhibiting Phylogenetic Similarity to Complex I
Authors: Lindenstrauß Ute , Pinske Constanze 
Published: March 2019

AbstractTrabulsiella guamensisis a non-pathogenic enterobacterium that was isolated from a vacuum cleaner on the island of Guam. It has one H2-oxidizing Hyd-2-type hydrogenase (Hyd), and encodes a H2-evolving Hyd that is most similar to the uncharacterizedEscherichia coliformate hydrogenlyase (FHL-2Ec) complex. The FHL-2Tgcomplex is predicted to have 5 membrane-integral and between 4-5 cytoplasmic subunits. We could show that FHL-2Tgcomplex catalyses the disproportionation of formate to CO2and H2. FHL-2Tghas an activity similar to theE. coliFHL-1Eccomplex in H2-evolution from formate, but the complex appears more labile upon cell lysis. Cloning of the entire 13 kbp FHL-2Tgoperon in the heterologousE. colihost has now enabled us to prove FHL-2Tgactivity unambiguously and allowed us to characterize the FHL-2Tgcomplex biochemically. Although the formate dehydrogenase (FdhH) genefdhFis not encoded in the operon, the FdhH is part of the complex and FHL-2Tgactivity was dependent on the presence ofE. coliFdhH. Also, in contrast toE. coli, T. guamensiscan ferment the alternative carbon source cellobiose, and we further investigated the participation of both the H2-oxidizing Hyd-2Tgand the H2-forming FHL-2Tgunder these conditions.ImportanceBiological H2-production presents an attractive alternative for fossil fuels. But in order to compete with conventional H2-production methods, the process requires our understanding on the molecular level. FHL complexes are efficient H2-producers and the prototype FHL-1Eccomplex inE. coliis well studied. This paper presents the first biochemical characterisation of an FHL-2-type complex. The data presented here will enable us to solve the long-standing mystery of the FHL-2Eccomplex, allow a first biochemical characterisation ofT. guamensis’s fermentative metabolism and establish this enterobacterium as model organism for FHL-dependent energy conservation.
Parasite histones mediate leak and coagulopathy in cerebral malaria
Authors: Moxon Christopher A , Alhamdi Yasir , Storm Janet , Toh Julien MH , Ko Joo Yeon , Murphy George , Taylor Terrie E , Seydel Karl B , Kampondeni Sam , Potchen Michael , O’Donnell James S. , O’Regan Niamh , Wang Guozheng , García-Cardeña Guillermo , Molyneux Malcolm , Craig Alister , Abrams Simon T , Toh Cheng-Hock 
Published: March 2019

AbstractCoagulopathy and leak, specific to the brain vasculature, are central pathogenetic components of cerebral malaria (CM). It is unclear how the parasite, Plasmodium falciparum, triggers these processes. Extracellular histones, released from damaged host cells, bind to cell membranes and cause coagulation activation, platelet aggregation and vascular leak in diverse critical illnesses. In CM patients with P. falciparum, serum histones correlate with fibrin formation, thrombocytopenia, and endothelial activation and predict brain swelling on magnetic resonance imaging and fatal outcome. Post-mortem, histones bind to the luminal vascular surface, co-localizing with P. falciparum-infected erythrocytes (IE), and with thrombosis and leak. Purified P. falciparum histones cause toxicity and barrier disruption in cultured human brain microvascular endothelial cells, as does serum from CM patients, reversed by anti-histone antibodies and non-anticoagulant heparin. These data implicate parasite histones as a key trigger of fatal brain swelling in CM. Neutralizing histones with agents such as non-anticoagulant heparin warrant exploration to prevent brain swelling and improve outcome.
Gene expression noise produces cell-to-cell heterogeneity in eukaryotic homologous recombination rate
Authors: Liu Jian , François Jean-Marie , Capp Jean-Pascal 
Published: March 2019

AbstractVariation in gene expression among genetically identical individual cells (called gene expression noise) directly contributes to phenotypic diversity. Whether such variation can impact genome stability and lead to variation in genotype remains poorly explored. We addressed this question by investigating whether noise in the expression of genes affecting homologous recombination (HR) activity either directly (RAD52) or indirectly (RAD27) confers cell-to-cell heterogeneity in HR rate inSaccharomyces cerevisiae. Using cell sorting to isolate subpopulations with various expression levels, we show that spontaneous HR rate is highly heterogeneous from cell-to-cell in clonal populations depending on the cellular amount of proteins affecting HR activity. Phleomycin-induced HR is even more heterogeneous, showing thatRAD27expression noise strongly affects the rate of recombination from cell-to-cell. Strong variations in HR rate between subpopulations are not correlated to strong changes in cell cycle stage. Moreover, this heterogeneity occurs even when simultaneously sorting cells at equal expression level of another gene involved in DNA damage response (BMH1) that is upregulated by DNA damage, showing that the initiating DNA damage is not responsible for the observed heterogeneity in HR rate. Thus gene expression noise seems mainly responsible for this phenomenon. Finally, HR rate non-linearly scales with Rad27 levels showing that total amount of HR cannot be explained solely by the time- or population-averaged Rad27 expression. Altogether, our data reveal interplay between heterogeneity at the gene expression and genetic levels in the production of phenotypic diversity with evolutionary consequences from microbial to cancer cell populations.
Biodiversity lost: The phylogenetic relationships of a complete mitochondrial DNA genome sequenced from the extinct wolf population of Sicily
Authors: Reale Stefano , Randi Ettore , Bonanno Floriana , Cumbo Valentina , Sammarco Ignazio , Spinnato Antonio , Seminara Salvatore 
Published: March 2019

AbstractUsing next-generation sequencing, we obtained for the first time a complete mitochondrial DNA genome from a museum specimen of the extinct wolf (Canis lupus) population of the island of Sicily (Italy). Phylogenetic analyses showed that this genome, which was aligned with a number of historical and extant complete wolf and dog mtDNAs sampled worldwide, was closely related to an Italian wolf mtDNA genome (TN93 andp-distances = 0.0012), five to seven times shorter than divergence among Sicilian and any other known wolf mtDNA genomes (distance range = 0.0050 – 0.0070). Sicilian and Italian haplotypes joined a basal clade belonging to the mtDNA haplogroup-2 of ancient western European wolf populations (Pilot et al. 2010). Bayesian calibration of divergence times indicated that this clade coalesced at MRCA = 13.400 years (with 95% HPD = 4000 – 21.230 years). These mtDNA findings suggest that wolves probably colonized Sicily from southern Italy towards the end of the last Pleistocene glacial maximum, when the Strait of Messina was almost totally dry. Additional mtDNA and genomic data will further clarify the origin and population dynamics before the extinction of wolves in Sicily.
Joint modelling of diffusion MRI and microscopy
Authors: Howard Amy FD , Mollink Jeroen , Kleinnijenhuis Michiel , Pallebage-Gamarallage Menuka , Bastiani Matteo , Cottaar Michiel , Miller Karla L , Jbabdi Saad 
Published: March 2019

AbstractThe combination of diffusion MRI with microscopy provides unique opportunities to study microstructural features of tissue, particularly when acquired in the same sample. Microscopy is frequently used to validate diffusion MRI microstructure models, addressing the indirect nature of dMRI signals. Typically, these modalities are analysed separately, and microscopy is taken as a gold standard against which dMRI-derived parameters are validated. Here we propose an alternative approach in which we combine diffusion MRI and microscopy data obtained from the same tissue sample to drive a single, joint model. This simultaneous analysis allows us to take advantage of the breadth of information provided by complementary data acquired from different modalities. By applying this framework to a spherical-deconvolution analysis, we are able to overcome a known degeneracy between fibre dispersion and radial diffusion. Spherical-deconvolution based approaches typically estimate a global fibre response function to determine the fibre orientation distribution in each voxel. However, the assumption of a ‘brain-wide’ fibre response function may be challenged if the diffusion characteristics of white matter vary across the brain. Using a generative joint dMRI-histology model, we demonstrate that the fibre response function is dependent on local anatomy, and that current spherical-deconvolution based models may be overestimating dispersion and underestimating the number of distinct fibre populations per voxel.
Cancer-type specific aneuploidies hard-wire chromosome-wide gene expression patterns of their tissue of origin
Authors: Auslander Noam , Heselmeyer-Haddad Kerstin , Patkar Sushant , Hirsch Daniela , Camps Jordi , Brown Markus , Bronder Daniel , Chen Wei-Dong , Lokanga Rachel , Wangsa Darawalee , Wangsa Danny , Hu Yue , Lischka Annette , Braun Rüdiger , Emons Georg , Ghadimi B. Michael , Gaedcke Jochen , Grade Marian , Montagna Cristina , Lazebnik Yuri , Difilippantonio Michael J. , Habermann Jens K. , Auer Gert , Ruppin Eytan , Ried Thomas 
Published: March 2019

SUMMARYMost carcinomas have characteristic chromosomal aneuploidies specific to the tissue of tumor origin. The reason for this specificity is unknown. As aneuploidies directly affect gene expression, we hypothesized that cancer-type specific aneuploidies, which emerge at early stages of tumor evolution, confer adaptive advantages to the physiological requirements of the tissue of origin. To test this hypothesis, we compared chromosomal aneuploidies reported in the TCGA database to chromosome arm-wide gene expression levels of normal tissues from the GTEx database. We find that cancer-type specific chromosomal aneuploidies mirror differential gene expression levels specific to the respective normal tissues which cannot be explained by copy number alterations of resident cancer driver genes. We propose that cancer-type specific aneuploidies “hard-wire” chromosome arm-wide gene expression levels present in normal tissues, favoring clonal expansion and tumorigenesis.One sentence summaryThe clonal evolution of cancer is initiated by tissue-specific transcriptional requirements
Human-level recognition of blast cells in acute myeloid leukemia with convolutional neural networks
Authors: Matek Christian , Schwarz Simone , Spiekermann Karsten , Marr Carsten 
Published: March 2019

AbstractReliable recognition of malignant white blood cells is a key step in the diagnosis of hematologic malignancies such as Acute Myeloid Leukemia. Microscopic morphological examination of blood cells is usually performed by trained human examiners, making the process tedious, time-consuming and hard to standardise.We compile an annotated image dataset of over 18,000 white blood cells, use it to train a convolutional neural network for leukocyte classification, and evaluate the network’s performance. The network classifies the most important cell types with high accuracy. It also allows us to decide two clinically relevant questions with human-level performance, namely (i) if a given cell has blast character, and (ii) if it belongs to the cell types normally present in non-pathological blood smears.Our approach holds the potential to be used as a classification aid for examining much larger numbers of cells in a smear than can usually be done by a human expert. This will allow clinicians to recognize malignant cell populations with lower prevalence at an earlier stage of the disease.
μECoG Recordings Through a Thinned Skull
Authors: Brodnick Sarah K. , Ness Jared P. , Richner Thomas J. , Thongpang Sanitta , Novello Joseph , Hayat Mohammed , Cheng Kevin P , Krugner-Higby Lisa , Suminski Aaron J. , Ludwig Kip A. , Williams Justin C. 
Published: March 2019

AbstractThe studies described in this paper for the first time characterize the acute and chronic performance of optically transparent thin-film µECoG grids implanted on a thinned skull as both an electrophysiological complement to existing thinned skull preparation for optical recordings/manipulations, and a less invasive alternative to epidural or subdurally placed µECoG arrays. In a longitudinal chronic study, µECoG grids placed on top of a thinned skull maintain impedances comparable to epidurally placed µECoG grids that are stable for periods of at least one month. Optogenetic activation of cortex is also reliably demonstrated through the optically transparent ECoG grids acutely placed on the thinned skull. Finally, spatially distinct electrophysiological recordings were evident on µECoG electrodes placed on a thinned skull separated by 500-750µm, as assessed by stimulation evoked responses using optogenetic activation of cortex as well as invasive and epidermal stimulation of the sciatic and median nerve at chronic time points. Neural signals were collected through a thinned skull in multiple species, demonstrating potential utility in neuroscience research applications such as in vivo imaging, optogenetics, calcium imaging, and neurovascular coupling.
Multi-omics Integrative Analysis of Acute and Relapsing Malaria in a Non-Human Primate Model ofP. vivaxinfection
Authors: Tang Yan , Joyner Chester J , Cordy Regina J ,   Malaria Host-Pathogen Interaction Center (MaHPIC), Galinski Mary R , Lamb Tracey J , Styczynski Mark P. 
Published: March 2019

SummarySystems-scale analysis of multiple layers of molecular and cellular data has significant potential for providing novel insights into malaria pathology and immunity. We present here a unique longitudinal multi-omics dataset encompassingMacaca mulattablood and bone marrow responses to infection byPlasmodium cynomolgi, a non-human primate (NHP) parasite species used to modelP. vivaxmalaria acute and relapsing infections in humans. We analyzed relationships across multiple biological layers using a mutual information-based machine learning approach to integrate heterogeneous longitudinal datasets and constructed an atlas of multi-omics relatedness networks (MORNs). Using this technique, we were able to detect signatures that defined both acute and relapsing infections. Importantly, relapse infections could be distinguished from both acutely-infected and uninfected NHP, suggesting that the host-parasite interactions during relapses are unique compared to acutePlasmodiuminfections. To our knowledge, this is the first report of large-scale, longitudinal multi-omics analysis of malaria in any system. This dataset, along with the method used to analyze it, provides a unique resource for the malaria research community and demonstrates the power of longitudinal infection study designs, NHP model systems and integrative multi-omics analyses.
mTORC1 In the Orbitofrontal Cortex Promotes Habitual Alcohol Seeking
Authors: Morisot Nadege , Berger Anthony L. , Phamluong Khanhky , Laguesse Sophie , Moffat Jeffrey J. , Ron Dorit 
Published: March 2019

AbstractThe mammalian target of rapamycin complex 1 (mTORCl) plays an important role in dendritic translation, synaptic plasticity, and learning and memory. We previously showed that heavy alcohol use activates mTORC1 in the orbitofrontal cortex (OFC) of rodents. Here, we set out to determine the consequences of alcohol-dependent mTORC1 activation in the OFC. We found that although inhibition of mTORC1 in the OFC does not alter rat alcohol intake per se, it attenuates alcohol seeking. We then tested whether mTORC1 in the OFC is required for goal-directed or habitual alcohol seeking. To do so, rats were trained self-administer alcohol under a random ratio (RR) or a random interval (RI) schedule of reinforcement, which biases toward goal-directed or habitual responding, respectively, and tested whether mTORC1 inhibition alters lever presses following alcohol devaluation. We found that pharmacological inhibition of mTORC1 or knockdown of the adaptor protein, Raptor, did not affect goal-directed alcohol responding but restored sensitivity to devaluation in RI-trained rats. In contrast, habitual responding for sucrose was unaltered by mTORC1 inhibition. These data suggest that mTORC1 in the OFC drives alcohol habit. We then elucidate the mechanism by which mTORC1 is activated by alcohol, and found that the recruitment of GluN2B during alcohol withdrawal stimulates mTORC1 in OFC cFos-positive neurons. Finally, we show that inhibition of GluN2B in the OFC attenuates both alcohol seeking and habitual responding for alcohol. Together, our data suggest that alcohol withdrawal promotes an NMDAR-dependent activation of mTORC1 which in turn drives habitual alcohol seeking.
Longshot: accurate variant calling in diploid genomes using single-molecule long read sequencing
Authors: Edge Peter , Bansal Vikas 
Published: March 2019

AbstractShort-read sequencing technologies such as Illumina enable the accurate detection of single nucleotide variants (SNVs) and short insertion/deletion variants in human genomes but are unable to provide information about haplotypes and variants in repetitive regions of the genome. Single-molecule sequencing technologies such as Pacific Biosciences and Oxford Nanopore generate long reads (≥ 10 kb in length) that can potentially address these limitations of short reads. However, the high error rate of SMS reads makes it challenging to detect small-scale variants in diploid genomes. We introduce a variant calling method, Longshot, that leverages the haplotype information present in SMS reads to enable the accurate detection and phasing of single nucleotide variants in diploid genomes. Using whole-genome Pacific Biosciences data for multiple human individuals, we demonstrate that Longshot achieves very high accuracy for SNV detection (precision ≥0.992 and recall ≥0.96) that is significantly better than existing variant calling methods. Longshot can also call SNVs with good accuracy using whole-genome Oxford Nanopore data. Finally, we demonstrate that it enables the discovery of variants in duplicated regions of the genome that cannot be mapped using short reads. Longshot is freely available at https://github.com/pjedge/longshot.