bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Non-Synonymous SHARPIN Variant is Associated with Limbic Degeneration and Family History of Alzheimer’s Disease
Authors: Soheili-Nezhad Sourena , Jahanshad Neda , Guelfi Sebastian , Khosrowabadi Reza , Saykin Andrew J. , Thompson Paul M. , Beckmann Christian F. , Sprooten Emma , Zarei Mojtaba ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: October 2017

AbstractPharmacological progress, basic science and medical practice can benefit from objective biomarkers that assist in early diagnosis and prognostic stratification of diseases. In the field of Alzheimer’s disease (AD), the clinical presentation of early stage dementia may not fulfill any diagnostic criteria for years, and quantifying structural brain changes by magnetic resonance imaging (MRI) has shown promise in the discovery of sensitive biomarkers. Although hippocampal atrophy is often used as an in vivo measure of AD, data-driven neuroimaging has revealed complex patterns of regional brain vulnerability that may not perfectly map to anatomical boundaries. In addition to aiding diagnosis, decoding genetic influences on neuroimaging measures of the disease can enlighten molecular mechanisms of the underlying pathology in living patients and guide the therapeutic design.Here, we aimed to extract a data-driven MRI feature of brain atrophy in AD by decomposing structural neuroimages using independent component analysis (ICA), a method for performing unbiased computational search in high dimensional data spaces. Our study of the AD Neuroimaging Initiative dataset (n=1,100 subjects) revealed a disease-vulnerable feature with a network-like topology, comprising amygdala, hippocampus, fornix and the inter-connecting white-matter tracts of the limbic system. Whole-genome sequencing identified a nonsynonymous variant (rs34173062) in SHARPIN, a gene coding for a synaptic protein, as a significant modifier of this new MRI feature (p=2.1×10−10). The risk variant was brought to replication in the UK Biobank dataset (n=8,428 subjects), where it was associated with reduced cortical thickness in areas co-localizing with those of the discovery sample (left entorhinal cortex p=0.002, right entorhinal cortex p=8.6×10−4; same direction), as well as with the history of AD in both parents (p=2.3×10−6; same direction).In conclusion, our study shows that ICA can transform voxel-wise volumetric measures of the brain into a data-driven feature of neurodegeneration in AD. Structure of the limbic system, as the most vulnerable focus of brain atrophy in AD, is affected by genetic variability of SHARPIN. The elevated risk of dementia in carriers of the minor allele supports engagement of SHARPIN in the disease pathways, and its role in neurotransmitter receptor scaffolding and integrin signaling may inform on new molecular mechanisms of AD pathophysiology.AbbreviationsAlzheimer’s disease (AD), genome-wide association study (GWAS), independent component analysis (ICA), mild cognitive impairment (MCI), medial temporal circuit (MTC), single-nucleotide polymorphism (SNP), tensor-based morphometry (TBM)
Multiphoton minimal inertia scanning for fast acquisition of neural activity signals
Authors: Schuck Renaud , Go Mary Ann , Garasto Stefania , Reynolds Stephanie , Dragotti Pier Luigi , Schultz Simon R. 
Published: October 2017

AbstractMulti-photon laser scanning microscopy provides a powerful tool for monitoring the spatiotemporal dynamics of neural circuit activity. It is, however, intrinsically a point scanning technique. Standard raster scanning enables imaging at subcellular resolution; however, acquisition rates are limited by the size of the field of view to be scanned. Recently developed scanning strategies such as Travelling Salesman Scanning (TSS) have been developed to maximize cellular sampling rate by scanning only regions of interest in the field of view corresponding to locations of interest such as somata. However, such strategies are not optimized for the mechanical properties of galvanometric scanners. We describe here the Adaptive Spiral Scanning (SSA) algorithm, which fits a set of near-circular trajectories to the cellular distribution to avoid inertial drifts of galvanometer position. We compare its performance to raster scanning and TSS in terms of cellular sampling frequency and signal-to-noise ratio (SNR). Using surrogate neuron spatial position data, we show that SSA acquisition rates are an order of magnitude higher than those for raster scanning and generally exceed those achieved by TSS for neural densities comparable with those found in the cortex. We show that this result also holds true forin vitrohippocampal mouse brain slices bath loaded with the synthetic calcium dye Cal-520 AM. The ability of TSS to ”park” the laser on each neuron along the scanning trajectory, however, enables higher SNR than SSA when all targets are precisely scanned. Raster scanning has the highest SNR but at a substantial cost in number of cells scanned. To understand the impact of sampling rate and SNR on functional calcium imaging, we used the Cramér-Rao Bound on evoked calcium traces recorded simultaneously with electrophysiology traces to calculate the lower bound estimate of the spike timing occurrence. The results show that TSS and SSA achieve comparable accuracy in spike time estimates compared to raster scanning despite their lower SNR. SSA is an easily implementable way for standard multi-photon laser scanning systems to gain temporal precision in the detection of action potentials while scanning hundreds of active cells.
Conflict between heterozygote advantage and hybrid incompatibility in haplodiploids (and sex chromosomes)
Authors: Ghenu Ana-Hermina , Blanckaert Alexandre , Butlin Roger K. , Kulmuni Jonna , Bank Claudia 
Published: October 2017

AbstractIn many diploid species the sex chromosomes play a special role in mediating reproductive isolation. In haplodiploids, where females are diploid and males haploid, the whole genome behaves similarly to the X/Z chromosomes of diploids. Therefore, haplodiploid systems can serve as a model for the role of sex chromosomes in speciation and hybridization. A previously described population of FinnishFormicawood ants displays genome-wide signs of ploidally and sexually antagonistic selection resulting from hybridization. Here, hybrid females have increased survivorship but hybrid males are inviable. To understand how the unusual hybrid population may be maintained, we developed a mathematical model with hybrid incompatibility, female heterozygote advantage, recombination, and assortative mating. The rugged fitness landscape resulting from the co-occurrence of heterozygote advantage and hybrid incompatibility results in a sexual conflict in haplodiploids, which is caused by the ploidy difference. Thus, whereas heterozygote advantage always promotes long-term polymorphism in diploids, we find various outcomes in haplodiploids in which the population stabilizes either in favor of males, females, or via maximizing the number of introgressed individuals. We discuss these outcomes with respect to the potential long-term fate of the Finnish wood ant population, and provide approximations for the extension of the model to multiple incompatibilities. Moreover, we highlight the general implications of our results for speciation and hybridization in haplodiploids versus diploids, and how the described fitness relationships could contribute to the outstanding role of sex chromosomes as hotspots of sexual antagonism and genes involved in speciation.
JIP2 haploinsufficiency contributes to neurodevelopmental abnormalities in human pluripotent stem cell-derived neural progenitors and cortical neurons
Authors: Roessler Reinhard , Goldmann Johanna , Shivalila Chikdu , Jaenisch Rudolf 
Published: October 2017

AbstractPhelan-McDermid syndrome (also known as 22q13 deletion syndrome) is a syndromic form of autism spectrum disorder and currently thought to be caused by heterozygous loss of SHANK3. However, patients most frequently present with large chromosomal deletions affecting several additional genes. We used human pluripotent stem cell technology and genome editing to further dissect molecular and cellular mechanisms. We found that loss of JIP2 (MAPK8IP2) may contribute to a distinct neurodevelopmental phenotype in neural progenitors (NPCs) affecting neuronal maturation. This is most likely due to simultaneous misregulation of JNK proteins, leading to impaired generation of mature neurons. Furthermore, semaphorin signaling is compromised in patient NPCs and neurons. Pharmacological stimulation of neuropilin receptor 1 (NRP1) rescued impaired semaphorin pathway activity and JNK expression in patient neurons. Our results suggest a novel disease-specific mechanism involving the JIP/JNK complex and identify NRP1 as potential therapeutic target.
Modeling the Role of the Striatum in Non-Stationary Bandit Tasks
Authors: Shivkumar Sabyasachi , Srinivasa Chakravarthy V. , Rougier Nicolas P. 
Published: October 2017

AbstractDecision making in non-stationary and stochastic environments can be interpreted as a variant of non-stationary multi armed bandit task where the optimal decision requires identification of the current context. We formalize the problem using a Bayesian approach taking biological constraints into account (limited memory) that allow us to define a sub-optimal theoretical model. From this theoretical model, we derive a biological model of the striatum based on its micro-anatomy that is able to learn state and action representations. We show that this model matches the theoretical model for low stochasticity in the environment and could be considered as a neural implementation of the theoretical model. Both models are tested on non-stationary multi-armed bandit task and compared to animal performances.Author SummaryDecision making in changing environments requires knowledge of the current context in order to adapt the response to the environment. Such context identification is based on the recent history of actions and their outcome: when some action used to be rewarded but is not anymore, it might be a sign of a context change. An ideal observer with infinite memory could optimally estimate the current context and act accordingly. Taking biological constraint into account, we show that a model of the striatum, which is the largest nucleus of the basal ganglia, can solve the task in a sub-optimal way as it has been shown to be the case in rats in a T-maze task.
Modulation of high frequency by low-frequency Oscillations in the basal ganglia
Authors: Nouri D. , Ebrahimpour R. , Mirzaei A. 
Published: October 2017

AbstractModulation of beta band fioscillatory activity (15-30 Hz) by delta band oscillatory activity (1-3 Hz) in the cortico-basal ganglia loop is important for normal basal ganglia functions. However, the neural mechanisms underlying this modulation are poorly understood. To understand the mechanisms underlying such frequency modulations in the basal ganglia, we use large scale subthalamo-pallidal network model stimulated via a delta-frequency input signal. We show that inhibition of external Globus Pallidus (GPe) and excitation of the Subthalamic nucleus (STN) using the delta-band stimulation leads to the same delta-beta interactions in the network model as the experimental results observed in healthy basal ganglia. In addition, we show that pathological beta oscillations in the network model decorrelates the delta-beta link in the network model. In general, using our simulation results, we propose that striato-pallidal inhibition and cortico-subthalamic excitation are the potential sources of the delta-beta link observed in the intact basal ganglia.
A LaeA- and BrlA-dependent cellular network governs tissue-specific secondary metabolism in the human pathogenAspergillus fumigatus
Authors: Lind Abigail L. , Lim Fang Yun , Soukup Alexandra A. , Keller Nancy P. , Rokas Antonis 
Published: October 2017

AbstractBiosynthesis of many ecologically important secondary metabolites (SMs) in filamentous fungi is controlled by several global transcriptional regulators, like the chromatin modifier LaeA, and tied to both development and vegetative growth. InAspergillusmolds, asexual development is regulated by the BrlA>AbaA>WetA transcriptional cascade. To elucidate BrlA pathway involvement in SM regulation, we examined the transcriptional and metabolic profiles of ΔbrlA, ΔabaA, ΔwetAand wild-type strains of the human pathogenAspergillus fumigatus. We find that BrlA, in addition to regulating production of developmental SMs, regulates vegetative SMs and the SrbA-regulated hypoxia stress response in a concordant fashion to LaeA. We further show that the transcriptional and metabolic equivalence of ΔbrlAand ΔlaeAis mediated by a LaeA requirement preventing heterochromatic marks in thebrlApromoter. These results provide a framework for the cellular network regulating not only fungal SMs but diverse cellular processes linked to virulence of this pathogen.
Membrane Proteins Significantly Restrict Exosome Mobility
Authors: Skliar Mikhail , Chernyshev Vasiliy S. , Belnap David M. , Al-Hakami Samer M. , Stijleman Inge J. , Rachamadugu Rakesh , Bernard Philip S. 
Published: October 2017

ABSTRACTExosomes are membrane nanovesicles that intermediate cell-to-cell signaling through the transfer of their molecular cargo. The exosomes’ small size facilitates rapid migration through the extracellular matrix and into and out of circulation. Here we report that the mobility of the exosomes is much lower than would be expected from the size of their membrane vesicles. The difference is broadly distributed and caused by surface proteins, which significantly impede exosome migration. The observed wide range in the mobility implies that a subpopulation of hydrodynamically small exosomes is more likely to participate in signaling. The extracellular environment amplifies the size-dependent hindrance to the exosomes migration. The significant contribution of surface proteins to the transport resistance make the exosome mobility a dynamic property that changes with the extracellular environment which affects the membrane protein conformation, glycosylation, specific, and non-specific surface adsorption.
Scopoletin 8-hydroxylase: a novel enzyme involved in coumarin biosynthesis and iron-deficiency responses in Arabidopsis
Authors: Siwinska Joanna , Wcisla Kinga , Olry Alexandre , Grosjean Jeremy , Hehn Alain , Bourgaud Frederic , Meharg Andrew A. , Carey Manus , Lojkowska Ewa , Ihnatowicz Anna 
Published: October 2017

HighlightA strongly iron-responsive gene of previously unknown function, At3g12900, encodes a scopoletin 8-hydroxylase involved in coumarin biosynthesis and plays an important role in the iron uptake strategy in Arabidopsis.AbstractIron (Fe) deficiency represents a serious agricultural problem, particularly in alkaline soils. Secretion of coumarins byArabidopsis thalianaroots is induced under Fe-deficiency. An essential enzyme for the biosynthesis of major Arabidopsis coumarins, scopoletin and its derivatives, is Feruloyl-CoA 6’-Hydroxylase1 (F6′H1) that belongs to a large enzyme family of the 2-oxoglutarate and Fe(II)-dependent dioxygenases. Another member of this family that is a close homologue of F6’H1 and is encoded by a strongly Fe-responsive gene, At3g12900, is functionally characterized in the presented work. We purified the At3g12900 protein heterologously expressed inEscherichia coliand demonstrated that it is involved in the conversion of scopoletin into fraxetinviahydroxylation at the C8-position. Consequently, it was named scopoletin 8-hydroxylase (S8H). Its function in plant cells was confirmed by the transient expression of S8H protein inNicotiana benthamianaleaves followed by the metabolite profiling and the biochemical and ionomic characterization of Arabidopsiss8hknockout lines grown under various regimes of Fe availability. Our results indicate that S8H is involved in coumarin biosynthesis as part of the Fe acquisition machinery.
Immune-active microenvironment in small cell carcinoma of the ovary, hypercalcemic type: rationale for immune checkpoint blockade
Authors: Jelinic Petar , Ricca Jacob , Oudenhove Elke Van , Olvera Narciso , Merghoub Taha , Levine Douglas A. , Zamarin Dmitriy 
Published: October 2017

AbstractSmall cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a highly aggressive monogenic cancer driven bySMARCA4mutations. Here, we report responses to anti-PD1 immunotherapy in four patients and characterize the immune landscape of SCCOHT tumors using quantitative immunofluorescence and gene expression profiling. Unexpectedly for a low mutation burden cancer, the majority of the tumors demonstrated PD-L1 expression with strong associated T cell infiltration. PD-L1 expression was detected in both tumor and stromal cells, with macrophages being the most abundant PD-L1 positive cells in some tumors. Transcriptional profiling revealed increased expression of genes related to Th1 and cytotoxic cell function in PD-L1 high tumors, suggesting that PD-L1 acts as a pathway of adaptive immune resistance in SCCOHT. These findings suggest that although SCCOHT are low-mutational-burden tumors, their immunogenic microenvironment that resembles the landscape of tumors that respond well to treatment with PD-1/PD-L1 blockade.
The interface of malignant and immunologic clonal dynamics in high-grade serous ovarian cancer
Authors: Zhang Allen W. , McPherson Andrew , Milne Katy , Kroeger David R. , Hamilton Phineas T. , Miranda Alex , Funnell Tyler , Laan Sonya , Cochrane Dawn R. , Lim Jamie L.P. , Yang Winnie , Roth Andrew , Smith Maia A. , de Souza Camila , Ho Julie , Tse Kane , Zeng Thomas , Shlafman Inna , Mayo Michael R. , Moore Richard , Failmezger Henrik , Heindl Andreas , Wang Yi Kan , Bashashati Ali , Brown Scott D. , Lai Daniel , Wan Adrian N. C. , Nielsen Cydney B. , Bouchard-Côté Alexandre , Yuan Yinyin , Wasserman Wyeth W. , Gilks C. Blake , Karnezis Anthony N. , Aparicio Samuel , McAlpine Jessica N. , Huntsman David G. , Holt Robert A. , Nelson Brad H. , Shah Sohrab P. 
Published: October 2017

SummaryHigh-grade serous ovarian cancer exhibits extensive intratumoral heterogeneity coupled with widespread intraperitoneal disease. Despite this, metastatic spread of tumor clones is non-random, implying the existence of local microenvironmental factors that shape tumor progression. We interrogated the molecular interface between tumor-infiltrating lymphocytes (TIL) and cancer cells in 143 samples from 21 patients using whole-genome sequencing, immunohistochemistry, histologic image analysis, gene expression profiling, and T- and B-cell receptor sequencing. We identify 3 immunologic response categories, which frequently co-exist within individual patients. Furthermore, epithelial CD8+ TIL were inversely associated with malignant cell diversity, evidenced by subclonal neoepitope elimination and spatial tracking between tumor and T-cell clones. Intersecting mutational signatures and immune analysis showed that foldback inversion genomic aberrations lead to worse outcomes even in the presence of cytotoxic TIL (n=433). Thus, regional variation in immune contexture mirrors the pattern of intraperitoneal malignant spread, provoking new perspectives for treatment of this challenging disease.
A Single Mechanosensitive Channel ProtectsFrancisella tularensissubsp.holarcticafrom Hypoosmotic Shock and Promotes Survival in the Aquatic Environment
Authors: Williamson David R. , Dewan Kalyan K. , Patel Tanmay , Wastella Catherine M. , Ning Gang , Kirimanjeswara Girish S. 
Published: October 2017

AbstractFrancisella tularensissubspeciesholarcticais found throughout the northern hemisphere and causes the disease tularemia in humans and animals. An aquatic cycle has been described for this subspecies, which has caused water-borne outbreaks of tularemia in at least 10 countries. In this study, we sought to identify mechanosensitive channel(s) required for the bacterium to survive the transition from mammalian hosts to freshwater, which is likely essential for transmission of the bacterium between susceptible hosts. A singlemechanosensitivechannel MscS (FTL_1753), among the smallest members of the mechanosensitive channel superfamily, was found to protect subsp.holarctiafrom hypoosmotic shock. Deletion of this channel did not affect virulence within the mammalian host, howevermscSwas required to survive the transition from the host niche to fresh water. Deletion ofmscSdid not alter the sensitivity ofF. tularensissubspeciesholarcticato detergents, H2O2, or antibiotics, suggesting that the role of MscS is specific to protection from hypoosmotic shock. Interestingly, deletion ofmscSalso led to reduced average cell size without altering gross cell morphology. The small mechanosensitive channel identified and characterized in this study likely contributes to the transmission of tularemia between hosts by allowing the bacterium to survive the transition from mammalian hosts to fresh water.
A subcortical circuit linking the cerebellum to the basal ganglia engaged in vocal learning
Authors: Pidoux Ludivine , Leblanc Pascale , Leblois Arthur 
Published: October 2017

AbstractSpeech is a complex sensorimotor skill, and vocal learning involves both the basal ganglia and the cerebellum. These subcortical structures interact indirectly through their respective loops with thalamo-cortical and brainstem networks, and directly via subcortical pathways, but the role of their interaction during sensorimotor learning remains undetermined. While songbirds and their song-dedicated basal ganglia-thalamo-cortical circuitry offer a unique opportunity to study subcortical circuits involved in vocal learning, the cerebellar contribution to avian song learning remains unknown. We demonstrate that the cerebellum provides a strong input to the song-related basal ganglia nucleus in zebra finches. Cerebellar signals are transmitted to the basal ganglia via a disynaptic connection through the thalamus and then conveyed to their cortical target and to the premotor nucleus controlling song production. Finally, cerebellar lesions impair juvenile song learning, opening new opportunities to investigate how subcortical interactions between the cerebellum and basal ganglia contribute to sensorimotor learning.
Temporal profiling of redox-dependent heterogeneity in single cells
Authors: Radzinski Meytal , Fasler Rosi , Yogev Ohad , Breuer William , Shai Nadav , Gutin Jenia , Ravid Tommer , Friedman Nir , Schuldiner Maya , Reichmann Dana 
Published: October 2017

AbstractCellular redox status affects diverse cellular functions, including proliferation, protein homeostasis, and aging. Thus, individual differences in redox status can give rise to distinct sub-populations even among cells with identical genetic backgrounds. Here, we have created a novel methodology to track redox status at single cell resolution using the redox-sensitive probe roGFP. Our method allows identification and sorting of sub-populations with different oxidation levels in either the cytosol, mitochondria or peroxisomes. Using this approach we defined redox-dependent heterogeneity of yeast cells, and characterized growth, as well as proteomic and transcriptomic profiles of subpopulations of cells that differ in their redox status, but are similar in age. We report that, starting in late logarithmic growth, cells of the same age have a bi-modal distribution of oxidation status. A comparative proteomic analysis between these populations identified three key proteins, Hsp30, Dhh1, and Pnc1, which affect basal oxidation levels and may serve as first line of defense proteins in redox homeostasis.