bluuebunny/crossref_metadata_2025_split huggingface dataset:
Schizophrenia-related cognitive dysfunction in the Cyclin-D2 knockout mouse model of ventral hippocampal hyperactivity
Authors: Grimm Christina M. , Aksamaz Sonat , Schulz Stefanie , Teutsch Jasper , Sicinski Piotr , Liss Birgit , Kätzel Dennis 
Published: October 2018

AbstractElevated activity at the output stage of the anterior hippocampus has been described as a physiological endophenotype of schizophrenia, and its development maps onto the transition from the prodromal to the psychotic state. Interventions that halt the spreading glutamatergic over-activity in this region and thereby the development of overt schizophrenia could be promising therapies. However, animal models with high construct validity to support such pre-clinical development are scarce. The Cyclin-D2 knockout (CD2-KO) mouse model shows a hippocampal parvalbumin-interneuron dysfunction, and its pattern of hippocampal over-activity shares similarities with that seen in prodromal patients. Conducting a comprehensive phenotyping of CD2-KO mice, we found that they displayed novelty-induced hyperlocomotion (a rodent correlate of positive symptoms of schizophrenia), that was largely resistant against D1- and D2-dopamine-receptor antagonism, but responsive to the mGluR2/3-agonist LY379268. In the negative symptom domain, CD2-KO mice showed transiently reduced sucrose-preference (anhedonia), but enhanced interaction with novel mice and objects, as well as normal nest building and incentive motivation. Also, unconditioned anxiety, perseveration, and motor-impulsivity were unaltered. However, in the cognitive domain, CD2-knockouts showed reduced executive function in assays of rule-shift and rule-reversal learning, and also an impairment in working memory, that was resistant against LY379268-treatment. In contrast, sustained attention and forms of spatial and object-related memory that are mediated by short-term habituation of stimulus-specific attention were intact. Our results suggest that CD2-KO mice are a valuable model in translational research targeted at the pharmacoresistant cognitive symptom domain in causal relation to hippocampal over-activity in the prodrome-to-psychosis transition.
Nitazoxanide, an antiprotozoal drug, inhibits late-stage autophagy and promotes ING1-induced cell cycle arrest in glioblastoma
Authors: Wang Xiaoxiong , Shen Chen , Liu Zhendong , Peng Fei , Chen Xin , Yang Guang , Zhang Daming , Yin Zhiqin , Ma Jichao , Zheng Zhixing , Zhao Boxian , Liu Huailei , Wang Ligang , Wu Jianing , Han Dayong , Wang Kaikai , Zhong Chen , Hou Xu , Zhao Wenyang , Shu Mengting , Wang Xinzhuang , Zhao Shiguang 
Published: October 2018

AbstractGlioblastoma is the most common and aggressive primary brain tumor in adults. New drug design and development is still a major challenge for glioma treatment. Increasing evidence has shown that nitazoxanide, an antiprotozoal drug, has a novel antitumor role in various tumors and exhibits multiple molecular functions, especially autophagic regulation. However, whether nitazoxanide-associated autophagy has an antineoplastic effect in glioma remains unclear. Here, we aimed to explore the underlying molecular mechanism of nitazoxanide in glioblastoma. Our results showed that nitazoxanide suppressed cell growth and induced cell cycle arrest in glioblastoma by upregulating ING1 expression with a favorable toxicity profile. Nitazoxanide inhibited autophagy through blockage of late-stage lysosome acidification, resulting in decreased cleavage of ING1. A combination with chloroquine or Torin1 enhanced or impaired the chemotherapeutic effect of nitazoxanide in glioblastoma cells. Taken together, these findings indicate that nitazoxanide as an autophagy inhibitor induces cell cycle arrest in glioblastoma via upregulated ING1 due to increased transcription and decreased post-translational degradation by late-stage autophagic inhibition.
Automated quantification of bioluminescence images
Authors: Klose Alexander D. , Paragas Neal 
Published: October 2018

AbstractWe developed a computer-aided analysis tool for quantitatively determining bioluminescent reporter distributions inside small animals. The core innovations are a body-fitting animal shuttle and a statistical mouse atlas, both of which are spatially aligned and scaled according to the animal’s weight, and hence provide data congruency across animals of varying size and pose. In conjunction with a multispectral bioluminescence tomography technique capitalizing on the spatial framework of the shuttle, the in vivo biodistribution of luminescent reporters can rapidly be calculated and, thus, enables operator-independent and computer-driven data analysis. We demonstrate its functionality by quantitatively monitoring a bacterial infection, where the bacterial organ burden was determined and validated with the established serial-plating method. In addition, the statistical mouse atlas was validated and compared to existing techniques providing an anatomical reference. The proposed data analysis tool promises to increase data throughput and data reproducibility and accelerate human disease modeling in mice.
Complex virome in feces from Amerindian children in isolated Amazonian villages
Authors: Siqueira Juliana D. , Dominguez-Bello Maria Gloria , Contreras Monica , Lander Orlana , Caballero-Arias Hortensia , Xutao Deng , Noya-Alarcon Oscar , Delwart Eric 
Published: October 2018

AbstractThe number of viruses circulating in small isolated human populations may be reduced by viral extinctions and rare introductions. Here we used viral metagenomics to characterize the eukaryotic virome in feces from healthy children from a large urban center and from three Amerindian villages with minimal outside contact. Numerous human enteric viruses, mainly from the Picornaviridae and Caliciviridae families, were sequenced from each of the sites. Multiple children from the same villages shed closely related viruses reflecting frequent transmission clusters. Feces of isolated villagers also contained multiple viral genomes of unknown cellular origin from the Picornavirales order and CRESS-DNA group and higher levels of nematode and protozoan DNA. Despite cultural and geographic isolation, the diversity of enteric human viruses was therefore not reduced in these Amazonian villages. Frequent viral introductions and/or increased susceptibility to enteric infections may account for the complex fecal virome of Amerindian children in isolated villages.
SHQ1 regulation of RNA splicing is required for T-lymphoblastic leukemia cell survival
Authors: Su Hexiu , Hu Juncheng , Huang Liang , Yang Yang , Thenoz Morgan , Kuchmiy Anna , Hu Yufeng , Li Peng , Feng Hui , Zhou Yu , Taghon Tom , Van Vlierberghe Pieter , Qing Guoliang , Chen Zhichao , Liu Hudan 
Published: October 2018

AbstractT-acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy with complicated heterogeneity. Although expression profiling reveals common elevated genes in distinct T-ALL subtypes, little is known about their functional role(s) and regulatory mechanism(s). We here show that SHQ1, an H/ACA snoRNP assembly factor involved in snRNA pseudouridylation, is highly expressed in T-ALL. Mechanistically, oncogenic NOTCH1 directly binds to the SHQ1 promoter and activates its transcription. SHQ1 depletion induces T-ALL cell death in vitro and prolongs animal survival in murine T-ALL models. RNA-Seq reveals that SHQ1 depletion impairs widespread RNA splicing, and MYC is one of the most prominently downregulated genes due to inefficient splicing. MYC overexpression significantly rescues T-ALL cell death resulted from SHQ1 inactivation. We herein report a mechanism of NOTCH1–SHQ1–MYC axis in T-cell leukemogenesis. These findings not only shed light on the role of SHQ1 in RNA splicing and tumorigenesis, but also provide additional insight into MYC regulation.
Rats adopt the optimal timescale for evidence integration in a dynamic environment
Authors: Piet Alex T. , El Hady Ahmed , Brody Carlos D. 
Published: October 2018

AbstractDecision making in dynamic environments requires discounting old evidence that may no longer inform the current state of the world. Previous work found that humans discount old evidence in a dynamic environment, but do not discount at the optimal rate. Here we investigated whether rats can optimally discount evidence in a dynamic environment by adapting the timescale over which they accumulate evidence. Using discrete evidence pulses, we exactly compute the optimal inference process. We show that the optimal timescale for evidence discounting depends on both the stimulus statistics and noise in sensory processing. When both of these components are taken into account, rats accumulate and discount evidence with the optimal timescale. Finally, by changing the volatility of the environment, we demonstrate experimental control over the rats’ accumulation timescale. The mechanisms supporting integration are a subject of extensive study, and experimental control over these timescales may open new avenues of investigation.
HIV-1 Tat interactions with cellular 7SK and viral TAR RNAs identifies dual structural mimicry
Authors: Pham Vincent V. , Salguero Carolina , Khan Shamsun Nahar , Meagher Jennifer L. , Brown W. Clay , Humbert Nicolas , de Rocquigny Hugues , Smith Janet L. , D’Souza Victoria M. 
Published: October 2018

AbstractThe HIV Tat protein competes with the 7SK:HEXIM interaction to hijack pTEFb from 7SK snRNP and recruit it to the TAR motif on stalled viral transcripts. Here we solve structures of 7SK stemloop-1 and TAR in complex with Tat’s RNA binding domain (RBD) to gain insights into this process. We find that 7SK is peppered with arginine sandwich motifs (ASM)—three classical and one with a pseudo configuration. Despite having similar RBDs, the presence of an additional arginine, R52, confers Tat the ability to remodel the pseudo configuration, required for HEXIM binding, into a classical sandwich, thus displacing HEXIM. Tat also uses R52 to remodel the TAR bulge into an ASM whose structure is identical to that of the remodeled ASM in 7SK. Together, our structures reveal a dual structural mimicry wherein viral Tat and TAR have co-opted structural motifs present in cellular HEXIM and 7SK for productive transcription of its genome.
The olfactory epithelium as a port of entry in neonatal neurolisteriosis
Authors: Pägelow Dennis , Chhatbar Chintan , Beineke Andreas , Liu Xiaokun , Nerlich Andreas , van Vorst Kira , Rohde Manfred , Kalinke Ulrich , Förster Reinhold , Halle Stephan , Valentin-Weigand Peter , Hornef Mathias W. , Fulde Marcus 
Published: October 2018

AbstractBacterial infections of the central nervous system (CNS) remain a major cause of mortality in the neonatal population. Commonly used parenteral infection models, however, do not reflect the early course of the disease leaving this critical step of the pathogenesis largely unexplored. Here, we analyzed nasal exposure of 1-day-old newborn mice to Listeria monocytogenes (Lm). We found that nasal, but not intragastric administration, led to early CNS infection in neonate mice. In particular, upon bacterial invasion of the olfactory epithelium, Lm subsequently spread along the sensory neurons entering the brain tissue at the cribriform plate and causing a significant influx of monocytes and neutrophils. CNS infection required listeriolysin for penetration of the olfactory epithelium and ActA, a mediator of intracellular mobility, for translocation into the brain tissue. Taken together, we propose an alternative port of entry and route of infection for neonatal neurolisteriosis and present a novel infection model to mimic the clinical features of late-onset disease in human neonates.
Modulation of AMPA receptor surface diffusion restores hippocampal plasticity and memory in Huntington’s disease models
Authors: Zhang Hongyu , Zhang Chunlei , Vincent Jean , Zala Diana , Benstaali Caroline , Sainlos Matthieu , Grillo-Bosch Dolors , Daburon Sophie , Coussen Françoise , Cho Yoon , David Denis J. , Saudou Frederic , Humeau Yann , Choquet Daniel 
Published: October 2018

AbstractImpaired hippocampal synaptic plasticity contributes to cognitive impairment in Huntington’s disease (HD). However, the molecular basis of such synaptic plasticity defects is not fully understood. Combining live-cell nanoparticle tracking and super-resolution imaging, we show that AMPAR surface diffusion, a key player in synaptic plasticity, is disturbed in various rodent models of HD. We demonstrate that defects in the brain-derived neurotrophic factor (BDNF)–tyrosine receptor kinase B (TrkB) signaling pathway contribute to the deregulated AMPAR trafficking by reducing the interaction between transmembrane AMPA receptor regulatory proteins (TARPs) and the PDZ-domain scaffold protein PSD95. The disturbed AMPAR surface diffusion is rescued by the antidepressant drug tianeptine via the BDNF signaling pathway. Tianeptine also restores the impaired LTP and hippocampus-dependent memory in different HD mouse models. These findings unravel a mechanism underlying hippocampal synaptic and memory dysfunction in HD, and highlight AMPAR surface diffusion as a promising therapeutic target.
Tridimensional infiltration of DNA viruses into the host genome shows preferential contact with active chromatin
Authors: Moreau Pierrick , Cournac Axel , Palumbo Gianna Aurora , Marbouty Martial , Mortaza Shogofa , Thierry Agnes , Cairo Stefano , Lavigne Marc , Koszul Romain , Neuveut Christine 
Published: October 2018

AbstractWhether non-integrated viral DNAs distribute randomly or target specific positions within the higher-order architecture of mammalian genomes remains largely unknown. Here we use Hi-C and viral DNA capture (CHi-C) in primary human hepatocytes infected by either hepatitis B virus (HBV) or adenovirus type 5 (Ad5) virus to show that they adopt different strategies in their respective positioning at active chromatin. HBV contacts preferentially CpG islands (CGIs) enriched in Cfp1 a factor required for its transcription. These CGIs are often associated with highly expressed genes (HEG) and genes deregulated during infection. Ad5 DNA interacts preferentially with transcription start sites (TSSs) and enhancers of HEG, as well as genes upregulated during infection. These results show that DNA viruses use different strategies to infiltrate genomic 3D networks and target specific regions. This targeting may facilitate the recruitment of transcription factors necessary for their own replication and contribute to the deregulation of cellular gene expression.
Genome-wide identification of geographical segregated genetic markers in Salmonella enterica serovar Typhimurium variant 4,[5],12:i:-
Authors: Palma Federica , Manfreda Gerardo , Silva Mickael , Parisi Antonio , Barker Dillon O. R. , Taboada Eduardo N. , Pasquali Frédérique , Rossi Mirko 
Published: October 2018

AbstractSalmonella enterica ser. Typhimurium monophasic variant 4,[5],12:i:- has been associated with food-borne epidemics worldwide and swine appeared to be the main reservoir in most of the countries of isolation. However, the monomorphic nature of this serovar has, so far, hindered identification of the source due to expansion of clonal lineages in multiple hosts and food producing systems. Since geographically structured genetic signals can shape bacterial populations, identification of biogeographical markers in S. 1,4,[5],12:i:- genomes can contribute to improving source attribution. In this study, the phylogeographical structure of 148 geographically and temporally related Italian S. 1,4,[5],12:i:- has been investigated. The Italian isolates belong to a large population of clonal S. Typhimurium/1,4,[5],12:i:- isolates collected worldwide in two decades showing up to 2.5% of allele differences. Phylogenetic reconstruction revealed that isolates from the same geographical origin form highly supported monophyletic groups, suggesting discrete geographical segregation. These monophyletic groups are characterized by the gene content of a large sopE-containing prophage. Within this prophage, genome-wide comparison identified several genes overrepresented in strains of Italian origin. This suggests that certain lineages may be characterized by the acquisition of specific accessory genetic markers useful for improving identification of the source in ongoing epidemics.
Prenatal exposure to incubation calls affects song learning in the zebra finch
Authors: Katsis Andrew C. , Davies Mzuri H. , Buchanan Katherine L. , Kleindorfer Sonia , Hauber Mark E. , Mariette Mylene M. 
Published: October 2018

AbstractSongbirds are important models for understanding the mechanisms and fitness consequences of imitative vocal learning. Although the effects of early-life environmental and social conditions on song learning are well-established, the impact of early sound exposure has received surprisingly little attention. Yet recent evidence hints at auditory sensitivity in songbird embryos, including in the zebra finch (Taeniopygia guttata), a classic model species for song learning. Here, we tested whether prenatal exposure to incubation calls—highly rhythmic parental vocalisations produced on the nest—affected song learning in zebra finches. Embryos were exposed in the egg to either incubation (treatment) or contact (control) calls, and after hatching were reared in a large colony. The playback treatment did not affect song complexity nor the accuracy of song copying from the social father, but instead increased learning of non-paternal song syllables. This, in turn, improved males’ mounting success in mating trials. These effects may be attributable to changes in juvenile social behaviours, as playback also influenced male behaviour during mating trials. Our study provides the first experimental evidence that prenatal acoustic environment affects song learning and courtship behaviour in songbirds, thereby raising interesting questions on the role of innate versus acquired biases for vocal learning.
Recurrent Neural Network for Predicting Transcription Factor Binding Sites
Authors: Shen Zhen , Bao Wenzheng , Huang De-Shuang 
Published: October 2018

AbstractIt is well known that DNA sequence contains a certain amount of transcription factors (TF) binding sites, and only part of them are identified through biological experiments. However, these experiments are expensive and time-consuming. To overcome these problems, some computational methods, based on k-mer features or convolutional neural networks, have been proposed to identify TF binding sites from DNA sequences. Although these methods have good performance, the context information that relates to TF binding sites is still lacking. Research indicates that standard recurrent neural networks (RNN) and its variants have better performance in time-series data compared with other models. In this study, we propose a model, named KEGRU, to identify TF binding sites by combining Bidirectional Gated Recurrent Unit (GRU) network with k-mer embedding. Firstly, DNA sequences are divided into k-mer sequences with a specified length and stride window. And then, we treat each k-mer as a word and pre-trained word representation model though word2vec algorithm. Thirdly, we construct a deep bidirectional GRU model for feature learning and classification. Experimental results have shown that our method has better performance compared with some state-of-the-art methods. Additional experiments about embedding strategy show that k-mer embedding will be helpful to enhance model performance. The robustness of KEGRU is proved by experiments with different k-mer length, stride window and embedding vector dimension.
The dissipation of thiamethoxam and its main metabolite clothianidin during strawberry growth and jam-making process
Authors: Liu Na , Pan Xinglu , Yang Qingxi , Ji Mingshan , Zhang Zhihong 
Published: October 2018

AbstractFew studies focused on the residue of thiamethoxam and its metabolite clothianidin on strawberry where it is widely used, despite this is essential to assess the potential food risk of thiamethoxam and its main metabolite clothianidin. In this study, the dissipation of thiamethoxam and its metabolite clothianidin during strawberry growth and jam-making process were assessed. The strawberry was sprayed with thiamethoxam based on the field application to investigate the dissipation of thiamethoxam as well as clothianidin formation. The half-life of thiamethoxam in strawberry was 9.0 days and the concentration of clothianidin in strawberry gradually increased from 0.55 to 11 μg/kg within 30 days. In addition, the amount of thiamethoxam decreased by 51.7% and clothianidin decreased by 40.2% during the homogenization process. The processing factor values of whole processing all less than 1 except simmering. This results from this study will not only help to understand the dissipation kinetics of thiamethoxam and clothianidin in the strawberry, but also facilitate to make more accurate risk assessments of them during strawberry jam making process.
A change of perspective in network centrality
Authors: Sciarra Carla , Chiarotti Guido , Laio Francesco , Ridolfi Luca 
Published: October 2018

AbstractTyping “Yesterday” into the search-bar of your browser provides a long list of websites with, in top places, a link to a video by The Beatles. The order your browser shows its search results is a notable example of the use of network centrality. Centrality measures the importance of the nodes in a network and it plays a crucial role in several fields, ranging from sociology to engineering, and from biology to economics. Many centrality metrics are available. However, these measures are generally based on ad hoc assumptions, and there is no commonly accepted way to compare the effectiveness and reliability of different metrics. Here we propose a new perspective where centrality definition arises naturally from the most basic feature of a network, its adjacency matrix. Following this perspective, different centrality measures naturally emerge, including degree, eigenvector, and hub-authority centrality. Within this theoretical framework, the effectiveness of different metrics is evaluated and compared. Tests on a large set of networks show that the standard centrality metrics perform unsatisfactorily, highlighting intrinsic limitations for describing the centrality of nodes in complex networks. More informative multi-component centrality metrics are proposed as the natural extension of standard metrics.
Evidence for a direct link between PAD4-mediated citrullination and the oxidative burst in human neutrophils
Authors: Zhou Yebin , An Ling-Ling , Chaerkady Raghothama , Mittereder Nanette , Clarke Lori , Cohen Taylor S. , Chen Bo , Hess Sonja , Sims Gary P. , Mustelin Tomas 
Published: October 2018

AbstractNeutrophils are critical for the defense against pathogens, in part through the extrusion of extracellular DNA traps, phagocytosis, and the production of reactive oxygen species. Neutrophils may also play an important role in the pathogenesis of rheumatoid arthritis (RA) through the activation of protein arginine deiminases (PADs) that citrullinate proteins that subsequently act as autoantigens. We report that PAD4 is physically associated with the cytosolic subunits of the oxidative burst machinery, p47phox (also known as neutrophil cytosol factor 1, NCF1) and p67phox (NCF2). Activation of PAD4 by membranolytic insults that result in high levels of intracellular calcium (higher than physiological neutrophil activation) leads to rapid citrullination of p47phox/NCF1 and p67phox/NCF2, as well as their dissociation from PAD4. This dissociation prevents the assembly of an active NADPH oxidase complex and an oxidative burst in neutrophils stimulated by phorbol-ester or immune complexes. In further support of a substrate-to-inactive enzyme interaction, small-molecule PAD inhibitors also disrupt the PAD4-NCF complex and reduce oxidase activation and phagocytic killing of Staphylococcus aureus. This novel role of PAD4 in the regulation of neutrophil physiology suggests that targeting PAD4 with active site inhibitors for the treatment of RA may have a broader impact on neutrophil biology than just inhibition of citrullination.