bluuebunny/crossref_metadata_2025_split huggingface dataset:
A potential cortical precursor of visual word form recognition in untrained monkeys
Authors: Rajalingham Rishi , Kar Kohitij , Sanghavi Sachi , Dehaene Stanislas , DiCarlo James J. 
Published: August 2019

AbstractSkilled human readers can readily recognize written letters and letter strings. This domain of visual recognition, known as orthographic processing, is foundational to human reading, but it is unclear how it is supported by neural populations in the human brain. Behavioral research has shown that non-human primates (baboons) can learn to distinguish written English words from pseudo-words (lexical decision), successfully generalize that behavior to novel strings, and exhibit behavioral error patterns that are consistent with humans. Thus, non-human primate models, while not capturing the entirety of human reading abilities, may provide a unique opportunity to investigate the neuronal mechanisms underlying orthographic processing. Here, we investigated the neuronal representation of letters and letter strings in the ventral visual stream of naive macaque monkeys, and asked to what extent these representations could support visual word recognition. We recorded the activity of hundreds of neurons at the top two levels of the ventral visual form processing pathway (V4 and IT) while monkeys passively viewed images of letters, English words, and non-word letter strings. Linear decoders were used to probe whether those neural responses could support a battery of orthographic processing tasks such as invariant letter identification and lexical decision. We found that IT-based decoders achieved baboon-level performance on these tasks, with a pattern of errors highly correlated to the previously reported primate behavior. This capacity to support orthographic processing tasks was also present in the high-layer units of state-of-the-art artificial neural network models of the ventral stream, but not in the low-layer representations of those models. Taken together, these results show that the IT cortex of untrained monkeys contains a reservoir of precursor features from which downstream brain regions could, with some supervised instruction, learn to support the visual recognition of written words. This suggests that the acquisition of reading in humans did not require a full rebuild of visual processing, but rather the recycling of a brain network evolved for other visual functions.
A supervised learning framework for chromatin loop detection in genome-wide contact maps
Authors: Salameh Tarik J. , Wang Xiaotao , Song Fan , Zhang Bo , Wright Sage M. , Khunsriraksakul Chachrit , Yue Feng 
Published: August 2019

ABSTRACTAccurately predicting chromatin loops from genome-wide interaction matrices such as Hi-C data is critical to deepen our understanding of proper gene regulation events. Current approaches are mainly focused on searching for statistically enriched dots on a genome-wide map. However, given the availability of a wide variety of orthogonal data types such as ChIA-PET, GAM, SPRITE, and high-throughput imaging, a supervised learning approach could facilitate the discovery of a comprehensive set of chromatin interactions. Here we present Peakachu, a Random Forest classification framework that predicts chromatin loops from genome-wide contact maps. Compared with current enrichment-based approaches, Peakachu identified more meaningful short-range interactions. We show that our models perform well in different platforms such as Hi-C, Micro-C, and DNA SPRITE, across different sequencing depths, and across different species. We applied this framework to systematically predict chromatin loops in 56 Hi-C datasets, and the results are available at the 3D Genome Browser (www.3dgenome.org).
Analysis of the effectiveness of sub-sensory electrical noise stimulation during visuomotor adaptations in different visual feedback conditions
Authors: Castronovo Anna Margherita , Giles Doran Ciara , Holden Méabh , Severini Giacomo 
Published: August 2019

AbstractSub-sensory electrical noise stimulation has been shown to improve motor performance in tasks that rely principally on proprioceptive feedback. During the generation of movements such as reaching, proprioceptive feedback combines dynamically with visual feedback. It is still unclear whether boosting proprioceptive information in tasks where proprioception mixes with vision can influence motor performance at all, either by improving or worsening it. To better understand this point, we tested the effect of electrical noise stimulation applied superficially to the muscle spindles during four different experiments consisting of isometric reaching tasks under different visual feedback conditions. The first experiment (n=40) consisted of a reach-and-hold task where subjects had to hold a cursor on a target for 30 seconds and had visual feedback removed 10 seconds into the task. Subjects performed 30 repetitions of this task with different stimulation levels, including no stimulation. We observed that trials in which the stimulation was present, displayed smaller movement variability. Moreover, we observed a positive correlation between the level of stimulation and task performance. The other experiments consisted of three versions of an isometric visuomotor adaptation task where subjects were asked to reach to random targets in less than 1.5 seconds (otherwise incurring in negative feedback) while overcoming a 45° clockwise rotation in the mapping between the force exerted and the movement of the cursor. The three experiments differed in the visual feedback presented to the subjects, with one group (n=20) performing the experiment with full visual feedback, one (n=10) with visual feedback restricted only to the beginning of the trajectory and one (n=10) without visual feedback of the trajectory. All subjects performed their experiment twice, with and without stimulation. We did not observe substantial effects of the stimulation when visual feedback was present (either completely or partially). We observed a limited effect of the stimulation in the absence of visual feedback consisting in a significant smaller number of negative-feedback trials in the first block of the adaptation phase. Our results suggest that sub-sensory stimulation can be beneficial when proprioception is the main feedback modality but mostly ineffective in tasks where visual feedback is actively employed.
Structural basis for Rab8a GTPase recruitment of RILPL2 via LRRK2 phosphorylation of switch 2
Authors: Waschbüsch Dieter , Purlyte Elena , Pal Prosenjit , McGrath Emma , Alessi Dario R. , Khan Amir R. 
Published: August 2019

AbstractRab8a GTPase is associated with the dynamic regulation of membrane protrusions in polarized cells. Rab8a is one of several Rab-family GTPases that are substrates of leucine-rich repeat kinase 2 (LRRK2), a serine/threonine kinase that is linked to inherited Parkinson’s disease. Rab8a is phosphorylated at T72 (pT72) in its switch 2 helix and the post-translational modification facilitates phospho-Rab8a (pRab8a) interactions with RILPL2, which subsequently regulates ciliogenesis. Here we report the crystal structure of pRab8a in complex with the phospho-Rab binding domain of RILPL2. The complex is a heterotetramer with RILPL2 forming a central α-helical dimer that bridges two pRab8a molecules. The N-termini of the α-helices cross over to form an X-shaped cap (X-cap) that enables electrostatic interactions between Arg residues from RILPL2 and the phosphate moiety from pT72. RILPL2 residues in the X-cap that are critical for pRab8a binding are conserved in the RILP family of effector proteins. We find that JIP3 and JIP4 also interact specifically with LRRK2-phosphorylated Rab10, suggesting a general mode of recognition for phosphorylated Rab GTPases by phospho-specific effectors.
Salient images: Evidence for a component process architecture for visual imagination
Authors: Murphy Charlotte , Ping Ho Nerissa Siu , Bernhardt Boris , Macrae C. Neil , Sormaz Mladen , Vatansever Deniz , Jefferies Elizabeth , Smallwood Jonathan 
Published: August 2019

AbstractThe ability to visualise different people and places in imagination is a core element of human cognition. Contemporary neuroimaging research highlights regions of primary visual cortex as important in instantiating images in the mind’s eye. Here we combine task-based functional magnetic resonance imaging with measures of intrinsic brain organisation to show the ventral attention, or salience, network, also plays an important role in visual imagination. In a task-based study we replicated prior observations of regions of medial occipital cortex, including Brodmann Area 17, showing greater neural activity during imagination than when perceiving similar stimuli. In addition, we found regions of the ventral attention network, and in particular right dorsolateral prefrontal cortex (BA 9/46), were activated by the same acts of imagination. In a subsequent resting-state study, we demonstrated medial occipital cortex regions form a functional network with regions of the ventral attention network that were also active during imagination. Furthermore, this pattern was maximised in an overlapping region of right dorsolateral prefrontal cortex for individuals whose self-reported imagery had stronger negative affect. Together these data suggest visual imagination relies on functional interactions between regions of primary visual cortex with the ventral attention system, and in particular, with a region of right dorsolateral prefrontal cortex.
Use of short-term high energy dietary for estimating transcriptional profiling of liver tissues in sheep
Authors: Yang Shaohua , Guo Yunxia , He Chengshi , Liu Yueqin , Zhang Yingjie 
Published: August 2019

ABSTRACTThis study aimed to evaluate if short-term high energy dietary has any stimulatory effects on liver function and metabolic status in sheep. The experiment was carried out using 30 Dorset×Han crossbred ewes (age, 9 ± 0.6 months; weight, 36.58 ± 2.56kg) allocated into two treatments, the control group (DE 11.72 MJ/d; DP 79.71 g/d) and the high energy group (DE18.75 MJ/d; DP 108.44 g/d), respectively. Experiment lasted 20 days, including 10 d for adaption. Blood samples of these ewes were collected to detect the concentrations of glucose, insulin, leptin, and cholesterol, respectively. Then, animals were sacrificed and optimal liver samples subjected to explore the genome-wide transcriptome analysis. Results showed that the weight gain was significantly increased in the high energy group, compared with those in the control group (p< 0.01). The concentrations of glucose, insulin, leptin, and cholesterol were also influenced by short-term nutritional supplementation at different levels. Subsequently, 622 differentially expressed genes were identified by pairwise comparison. Of these, 271 genes were down regulated while 351 genes were up regulated. qRT-PCR analysis of 10 randomly selected genes were consistent with the sequencing results. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways revealed 12 DEGs (includingPDK4, ABCA9, ALDH6A1, SLC45A3, G0S2, PPARGC1, GHRHR, GHR, DGKI, SOCS2, LPIN1andCSKMT) were significantly enriched in cellular carbohydrate catabolic and metabolic process, phosphorelay sensor and phosphotransferase kinase activity, generation of precursor metabolites and energy, lipid metabolic and transport process, positive regulation of cellular metabolic process, acyl-CoA desaturase activity and monosaccharide metabolic process. Additionally, we concluded an interaction network related to energy metabolism, which might be contributed to elucidate the precise molecular mechanisms of related genes associated with energy metabolism in the liver tissues of sheep.
Proteomic profiling ofMycobacterium tuberculosisculture filtrate identifies novel O-glycosylated proteins
Authors: Tucci Paula , Portela Madelón , Chetto Carlos Rivas , González-Sapienza Gualberto , Marín Mónica 
Published: August 2019

AbstractDespite being the subject of intensive research, tuberculosis, caused byMycobacterium tuberculosis, remains at present the leading cause of death from an infectious agent. Secreted and cell wall proteins interact with the host and play important roles in pathogenicity. These proteins have been explored as candidate diagnostic markers, potential drug targets or vaccine antigens, and special attention has been given to the role of their post-translational modifications. With the purpose of contributing to the proteomic characterization of this important pathogen including an O-glycosylation profile analysis, we performed a shotgun analysis of culture filtrate proteins ofM. tuberculosisbased on a liquid nano-HPLC tandem mass spectrometry and a label-free spectral counting normalization approach for protein quantification. We identified 1314M. tuberculosisproteins in culture filtrate and found that the most abundant proteins belong to the extracellular region or cell wall compartment, and that the functional categories with higher protein abundance factor were virulence, detoxification and adaptation, and cell wall and cell processes. In culture filtrate, 140 proteins were predicted to contain one of the three types of bacterial N-terminal signal peptides. Besides, various proteins belonging to the ESX secretion systems, and to the PE and PPE families, secreted by the type VII secretion system using nonclassical secretion signals, were also identified. O-glycosylation was identified as a frequent modification, being present in 108 proteins, principally lipoproteins and secreted immunogenic antigens. We could identify a group of proteins consistently detected in previous studies, most of which were highly abundant proteins. Interestingly, we also provide proteomic evidence for 62 novel O-glycosylated proteins, aiding to the glycoproteomic characterization of relevant antigenic membrane and exported proteins.
Acute characterization of tissue and functional deficits in a clinically translatable pig model of ischemic stroke
Authors: Kaiser Erin E. , Waters Elizabeth S. , Fagan Madison M. , Scheulin Kelly M. , Platt Simon R. , Jeon Julie H. , Fang Xi , Kinder Holly A. , Shin Soo K. , Duberstein Kylee J. , Park Hea J. , West Franklin D. 
Published: August 2019

AbstractThe acute stroke phase is a critical time frame used to evaluate stroke severity, therapeutic options, and prognosis while also serving as a major target for the development of diagnostics. To better understand stroke pathophysiology and to enhance the development of treatments, our group developed a translational pig ischemic stroke model. In this study, the evolution of acute ischemic stroke tissue damage, immune response, and functional deficits were further characterized in the pig model. Stroke was induced by middle cerebral artery occlusion in Landrace pigs. At 24 hours post-stroke, magnetic resonance imaging revealed a decrease in ipsilateral diffusivity and an increase in hemispheric swelling and intracranial hemorrhage resulting in notable midline shift. Stroke negatively impacted white matter integrity leading to decreased fractional anisotropy. Similar to acute clinical patients, stroked pigs showed a reduction in circulating lymphocytes and a surge in neutrophils and band cells. Functional responses corresponded with structural changes with reduced exploration in open field testing and impairments in spatiotemporal gait parameters. This novel, acute ischemia characterization provides important insights into tissue and functional level changes in a pig model that can be used to identify treatment targets and future testing of therapeutics and diagnostics.
Successes of artemisinin elicitation in low-artemisinin producing Artemisia annua cell cultures constrained by repression of biosynthetic genes
Authors: Yee Melissa Kam Yit , Ping Winnie Yap Soo 
Published: August 2019

AbstractThe sesquiterpene phytolactone derived from Artemisia annua, artemisinin is associated with a variety of novel biological properties, such as immunoregulatory and anticancer effects, and therapeutic applications, apart from its main function as an antimalarial drug. Emerging from the fact that artemisinin production in planta occurs in trace amounts and its compartmentalized synthesis, the irregular agricultural supply often results in market fluctuations and reductions in artemisinin inventory. Further improvement in artemisinin production calls for approaches that act in a supplementary manner, filling the agricultural production gap. Here we investigated the elicitation efficiency of ultraviolet B (UV-B) and dimethyl sulfoxide (DMSO) independently on a low-artemisinin producing (LAP) chemotype of the species A. annua. The exposure of cell suspension cultures to short-term UV-B radiation and DMSO treatment did not result in significant changes in artemisinin yield. The lack of stimulation has been associated with: (i) the general lack of cytodifferentiation of cell cultures; (ii) negative feedback regulation of artemisinin biosynthesis; and (iii) artemisinin sequestration by cellular detoxification. Further molecular analysis revealed the repression of key genes ADS, DBR2 and ALDH1 which affected artemisinin synthesis. This study provides insights into the complexity of stress-induced responses of A. annua cell suspension cultures in relation to metabolic processes (transportation, accumulation and degradation of secondary products) which are important for artemisinin formation.
Cep97 Is Required For Centriole Structural Integrity And Cilia Formation In Drosophila
Authors: Dobbelaere Jeroen , Schmidt-Cernohorska Marketa , Huranova Martina , Slade Dea , Dammermann Alexander 
Published: August 2019

SUMMARYCentrioles are highly elaborate microtubule-based structures responsible for the formation of centrosomes and cilia. Despite considerable variation across species and tissues, within any given tissue their size is essentially constant [1, 2]. While the diameter of the centriole cylinder is set by the dimensions of the inner scaffolding structure of the cartwheel [3], how centriole length is set so precisely and stably maintained over many cell divisions is not well understood. Cep97 and CP110 are conserved proteins that localize to the distal end of centrioles and have been reported to limit centriole elongation in vertebrates [4, 5]. Here, we examine Cep97 function in Drosophila melanogaster. We show that Cep97 is essential for formation of full-length centrioles in multiple tissues of the fly. We further identify the microtubule deacetylase Sirt2 as a Cep97 proximity interactor. Deletion of Sirt2 likewise affects centriole size. Interestingly, so does deletion of the acetylase Atat1, indicating that loss of stabilizing acetyl marks impairs centriole integrity. Cep97 and CP110 were originally identified as inhibitors of cilia formation in vertebrate cultured cells [6] and loss of CP110 is a widely used marker of basal body maturation. In contrast, in Drosophila Cep97 is only transiently removed from basal bodies and loss of Cep97 strongly impairs ciliogenesis. Collectively, our results support a model whereby Cep97 functions as part of a protective cap that acts together with the microtubule acetylation machinery to maintain centriole stability, essential for proper function in cilium biogenesis.
Extent of N-terminus exposure by altered long-range interactions of monomeric alpha-synuclein determines its aggregation propensity
Authors: Stephens Amberley D. , Zacharopoulou Maria , Moons Rani , Fusco Giuliana , Seetaloo Neeleema , Chiki Anass , Hooper Philippa J. , Mela Ioanna , Lashuel Hilal A. , Phillips Jonathan J , Simone Alfonso De , Sobott Frank , Schierle Gabriele S. Kaminski 
Published: August 2019

AbstractAs an intrinsically disordered protein, monomeric alpha synuclein (aSyn) constantly reconfigures and probes the conformational space. Long-range interactions across the protein maintain its solubility and mediate this dynamic flexibility, but also provide residual structure. Certain conformations lead to aggregation prone and non-aggregation prone intermediates, but identifying these within the dynamic ensemble of monomeric conformations is difficult. Herein, we used the biologically relevant calcium ion to investigate the conformation of monomeric aSyn in relation to its aggregation propensity. By using calcium to perturb the conformational ensemble, we observe differences in structure and intra-molecular dynamics between two aSyn C-terminal variants, D121A and pS129, and the aSyn familial disease mutants, A30P, E46K, H50Q, G51D, A53T and A53E, compared to wild-type (WT) aSyn. We observe that the more exposed the N-terminus and the beginning of the NAC region are, the more aggregation prone monomeric aSyn conformations become. N-terminus exposure occurs upon release of C-terminus interactions when calcium binds, but the level of exposure is specific to the aSyn mutation present. There was no correlation between single charge alterations, calcium affinity, or the number of ions bound on aSyn’s aggregation propensity, indicating that sequence or post-translation modification (PTM)-specific conformational differences between the N- and C-termini and the specific local environment mediate aggregation propensity instead. Understanding aggregation prone conformations of monomeric aSyn and the environmental conditions they form under will allow us to design new therapeutics targeted to the monomeric protein, to stabilise aSyn in non-aggregation prone conformations, by either preserving long-range interactions between the N- and C-termini or by protecting the N-terminus from exposure.
Therapeutically actionable PAK4 is amplified, overexpressed and involved in bladder cancer progression
Authors: Chandrashekar Darshan S. , Chakravarthi Balabhadrapatruni V. S. K. , Robinson Alyncia D. , Anderson Joshua C. , Agarwal Sumit , Hodigere Balasubramanya Sai Akshaya , Eich Marie-Lisa , Bajpai Akhilesh Kumar , Davuluri Sravanthi , Guru Maya S. , Guru Arjun S. , Naik Gurudatta , Della Manna Deborah L. , Acharya Kshitish K. , Carskadon Shannon , Manne Upender , Crossman David K. , Ferguson James E. , Grizzle William E. , Palanisamy Nallasivam , Willey Christopher D. , Crowley Michael R. , Netto George J , Yang Eddy S. , Varambally Sooryanarayana , Sonpavde Guru 
Published: August 2019

AbstractMuscle-invasive bladder carcinomas (MIBCs) are aggressive genitourinary malignancies. Disease incidence and survival rates vary based on aggressiveness and treatment options. Metastatic urothelial carcinoma of the bladder is generally incurable by current chemotherapy and leads to early mortality. For a minority (∼20%) of patients, T-cell checkpoint inhibitors provide durable benefits following prior platinum therapy. Recent studies have identified molecular subtypes of MIBCs with different sensitivities to frontline therapy, suggesting heterogeneity in these tumors and pointing to the importance of molecular characterization of MIBCs to provide effective treatment. We have performed multi-omic profiling of the kinome to identify therapeutic targets that are overexpressed in a subset of BLCAs. Our analyses revealed amplification and overexpression of P21 (RAC1) activated kinase 4 (PAK4) in a subset of BLCAs. For these tumors, multiplex kinase assay profiling identified corresponding PAK4 target substrates. By performing experiments using cultured bladder cancer cells, we confirmed the role of PAK4 in BLCA cell proliferation and invasion. Furthermore, our studies showed that a PAK4 inhibitor was effective in curtailing growth of BLCA cells. Transcriptomic analyses identified elevated expression of another kinase, Protein Tyrosine Kinase 6 (PTK6), upon treatment with a PAK4 inhibitor. Similarly, RNA interference of PAK4 led to elevated expression of PTK6. Treatment with a combination of kinase inhibitors (vandetanib and dasatinib) showed enhanced sensitivity compared to either drug alone. Thus, PAK4 may be therapeutically actionable for a subset of MIBC patients with amplified and/or overexpressed PAK4 in their tumors. Our results also indicate that combined inhibition of PAK4 and PTK6 may overcome resistance to PAK4. These observations warrant clinical investigations with selected BLCA patients.