bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regulatory sites for known and novel splicing in human basal ganglia are enriched for disease-relevant information
Authors: Guelfi Sebastian , D’Sa Karishma , Botía Juan , Vandrovcova Jana , Reynolds Regina H. , Zhang David , Trabzuni Daniah , Collado-Torres Leonoardo , Thomason Andrew , Leyton Pedro Quijada , Gagliano Sarah A. , Nalls Mike A. ,   UK Brain Expression Consortium, Small Kerrin S. , Smith Colin , Ramasamy Adaikalavan , Hardy John , Weale Michael E. , Ryten Mina 
Published: March 2019

AbstractGenome-wide association studies have generated an increasing number of common genetic variants that affect neurological and psychiatric disease risk. Given that many causal variants are likely to operate by regulating gene expression, an improved understanding of the genetic control of gene expression in human brain is vital. However, the difficulties of sampling human brain, and its complexity, has meant that brain-related expression quantitative trait loci (eQTL) and allele specific expression (ASE) signals have been more limited in their explanatory power than might otherwise be expected. To address this, we use paired genomic and transcriptomic data from putamen and substantia nigra dissected from 117 brains, combined with a comprehensive set of analyses, to interrogate regulation at different stages of RNA processing and uncover novel transcripts. We identify disease-relevant regulatory loci and reveal the types of analyses and regulatory positions yielding the most disease-specific information. We find that splicing eQTLs are enriched for neuron-specific regulatory information; that ASE analyses provide highly cell-specific regulatory information; and that incomplete annotation of the brain transcriptome limits the interpretation of risk loci for neuropsychiatric disease. We release this rich resource of regulatory data through a searchable webserver, http://braineacv2.inf.um.es/.
Viral infection overcomes ineffectiveness of anti-tumoral CD8+ T cell mediated cytotoxicity
Authors: Zhou Fan , Kardash Justa , Bhat Hilal , Duhan Vikas , Friedrich Sarah-Kim , Bezgovsek Judith , Kalkavan Halime , Bergerhausen Michael , Schiller Max , Machlah Yara , Brandenburg Tim , Hardt Cornelia , Krolik Michal , Flatz Lukas , Lang Philipp A. , Lang Karl S. 
Published: March 2019

AbstractWith the integration of PD-1 and CTLA-4 targeting immune checkpoint blockade into cancer treatment regimes, the anti-tumoral cytotoxicity of tumor-specific CD8+T cells is well established. However, while the unresponsiveness of CD8+T cells against big tumors is mainly explained by T cell exhaustion, other factors contributing to CD8+T cell failure remain not well studied. Here we used a mouse melanoma model to study the interaction of growing tumor cells, innate immunity and CD8+T cell responses induced by viral replication. Mouse model of melanoma (B16F10-OVA) and infections with arenaviruses. Growing B16F10-OVA cells did not induce systemic ablation of tumor specific CD8+T cells. However, despite the presence of tumor-infiltrating CD8+T cells, the anti-tumoral immune response was very limited. T cell anergy against the tumor was accompanied with a strong down-regulation of MHC-I on advanced tumors. LCMV infection restored the MHC class I expression, enhanced T cell function and lead to tumor regression. This study shows that tumor progression does not necessary lead to systemic exhaustion of the anti-tumoral CD8+T cell response. Lack of innate signals is an additional reason for limited CD8+T cell mediated cytotoxicity against the tumor.
Intermolecular interactions play a role in the distribution and transport of charged contrast agents in a cartilage model
Authors: Algotsson Jenny , Jönsson Peter , Forsman Jan , Topgaard Daniel , Söderman Olle 
Published: March 2019

AbstractThe transport and distribution of charged molecules in polyelectrolyte solutions are of both fundamental and practical importance. A practical example, which is the specific subject addressed in the present paper, is the transport and distribution of charged species into cartilage. The charged species could be a contrast agent or a drug molecule involved in diagnosis or treatment of the widespread degenerative disease osteoarthritis, which leads to degradation of articular cartilage. Associated scientific issues include the rate of transport and the equilibrium concentrations of the charged species in the cartilage and the synovial fluid. To address these questions, we present results from magnetic resonance micro-imaging experiments on a model system of articular cartilage. The experiments yield temporally and spatially resolved data on the transport of a negatively charged contrast agent (charge = −2), used in medical examinations of cartilage, into a polyelectrolyte solution, which is designed to capture the electrostatic interactions in cartilage. Also presented is a theoretical analysis of the transport where the relevant differential equations are solved using finite element techniques as well as treated with approximate analytical expressions. In the analysis, non-ideal effects are included in the treatment of the mobile species in the system. This is made possible by using results from previous Monte Carlo simulations. The results demonstrate the importance of taking non-idealities into account when data from measurements of transport of charged solutes in a system with fixed charges from biological polyelectrolytes are analyzed.
Multicenter preclinical studies as an innovative method to enhance translation: a systematic review of published studies
Authors: Hunniford Victoria T. , Grudniewicz Agnes , Fergusson Dean A. , Grigor Emma , Lansdell Casey , Lalu Manoj M. ,   on behalf of the Canadian Critical Care Translational Biology Group
Published: March 2019

AbstractMulticenter preclinical studies have been suggested as a method to improve reproducibility, generalizability and potential clinical translation of preclinical work. In these studies, multiple independent laboratories collaboratively conduct a research experiment using a shared protocol. The use of a multicenter design in preclinical experimentation is a recent approach and only a handful of preclinical multicenter studies have been published. Here, we systematically identify, assess and synthesize published preclinical multicenter studies investigating interventions using in vivo models. Synthesized data included study methods/design, basic characteristics, outcomes, and barriers and facilitators. Study risk of bias, completeness of reporting and the degree of collaboration were evaluated using established methods. The database searches identified 3095 citations and 12 studies met inclusion criteria. The multicenter study design was applied across a diverse range of diseases including stroke, heart attack, traumatic brain injury, and diabetes. The median number of centers was 4 (range 2-6) and the median sample size was 135 (range 23-384). Most studies had lower risk of bias and higher completeness of reporting than typically seen in single-centered studies. Only four of the twelve studies produced results consistent with previous single-center studies, highlighting a central concern of preclinical research: irreproducibility and poor generalizability of findings from single laboratories. Our review suggests that multicenter preclinical studies may provide a method to robustly assess therapies prior to considering clinical translation. Registered with PROSPERO CRD42018093986.
M. leprae infects human keratinocytes via the interaction of laminin-5 with α-dystroglycan, integrin-β1, or -β4
Authors: Jin Song-Hyo , Kim Se-Kon , Lee Seong-Beom 
Published: March 2019

AbstractAlthough Mycobacterium leprae (M. leprae) is usually found in macrophages and nerves of the dermis of patients with multibacillary leprosy, it is also present in all layers of the epidermis, basal, suprabasal, prickle cells, and keratin layers. However, the mechanism by which M.leprae invades the dermis remains unknown, whereas the underlying mechanism by which M.leprae invades peripheral nerves, especially Schwann cells, is well defined. M. leprae binds to the α-dystroglycan (DG) of Schwann cells via the interaction of α-DG and laminin (LN)-α2 in the basal lamina, thus permitting it to become attached to and invade peripheral nerves. In the current study, we investigated the issue of how M.leprae infects keratinocytes. LN-5 is the predominant form of laminin in the epidermis and allows the epidermis to be stably attached to the dermis via its interaction with α/β-DG as well as integrins that are produced by keratinocytes. We therefore focused on the role of LN-5 in when M. leprae invades keratinocytes. Our results show that M.leprae preferentially binds to LN-5-coated slides and this binding to LN-5 enhances its binding to human epidermal keratinocytes, neonatal (HEKn). The findings also show that pre-treatment with an antibody against α-DG, integrin-β1, or -β4 inhibited the binding of LN-5-coated M.leprae to HEKn cells. These results suggest that M. leprae infects keratinocytes by taking advantage of the interaction of LN-5 in the basal lamina of the epidermis and a surface receptor of keratinocytes, such as α-DG, integrin-β1, or -β4.Author summaryIn the current study, we investigated the issue of how M.leprae infects keratinocytes. We focused on the role of LN-5, a predominant form of laminin of the epidermis, in the invasion of M. leprae in keratinocytes. Our results show that M. leprae preferentially binds to LN-5-coated slides and coating M.leprae with LN-5 enhanced its binding to human epidermal keratinocytes, neonatal (HEKn). In addition, a pre-treatment with an antibody against α-DG, integrin-β1 or -β4 inhibited the binding of LN-5-coated M. leprae to HEKn cells. These results suggest that M. leprae invades keratinocytes by taking advantage of the interaction of LN-5 in the basal lamina of the epidermis and a surface receptor of keratinocytes, such as α-DG, integrin-β1, or -β4
Genotype 1 Japanese encephalitis virus predominates in nature in China
Authors: Shao Nan , Fu Shihong , Li Fan , Zhang Weijia , Wang Qianying , Lei Wenwen , He Ying , Cao Yuxi , Liang Guodong , Wang Huanyu 
Published: March 2019

AbstractIntroductionJapanese encephalitis virus (JEV), in the genusFlavivirus, familyFlaviviridae, is the leading cause of viral encephalitis in the Asian-Pacific region. JEV has a wide range of vector hosts, including mosquitoes, swine, and wading birds.Culexspecies, especiallyCulex tritaeniorhynchus, are the main vectors for JEV transmission. JEV has been classified into five genotypes (G1–G5). JEV G1, G3, and G5 isolates have been found in China.MethodsMore than 200,000 mosquitoes collected in 14 provinces in China from 2004 to 2016 were examined for JEV using a TaqMan real-time RT-PCR assay. The JEV envelope (E) gene was sequenced from positive pools. The nucleic acid sequences were analyzed and aligned using ClustalX ver. 2.0. Representative JEV envelope (E) gene sequences were downloaded from GenBank and compared with the newly obtained JEV sequences. MEGA 5.05 was used to generate a phylogenetic tree based on the JEV sequences.ResultsMore than 200,000 mosquitoes were divided into 3107 pools to test for JEV. Of the pools, 9.04% (281/3107) were positive. The JEV obtained from mosquitoes included three genotypes (G1, G3, and G5). JEV G1 was detected from different provinces during 2004–2016. G1 was the dominant genotype circulating in nature, comprising 98.93% (278/281). JEV G3 was detected in Yunnan and Chongqing Provinces before 2010; JEV G5 was detected only in Tibet. No pools were positive for JEV G2 and G4.C.tritaeniorhynchuswas the major mosquito species and the principal vector for transmitting JEV in China. The results of the TaqMan real-time RT-PCR assay and phylogenetic analysis consistently indicated that all 50 newly identified JEV sequences belonged to JEV G1.ConclusionG1 is the main genotype of JEV circulating in nature in China. Some G3 and G5 were found, but no G2 or G4.Author summaryJapanese encephalitis virus (JEV) is a member of the genusFlavivirus, familyFlaviviridaeand is the major pathogen agent of Japanese encephalitis (JE) in the Asian-Pacific region. The fatality rate of JE is 20–30%. JEV consists of five genotypes (G1-G5). The predominant genotype was G3 before the 20thcentury. G1 and G3 co-circulated in China at the end of the 20thand early 21stcentury. JEV G1 is the youngest genotype and has gradually been found in many areas worldwide. Using a sensitive TaqMan real-time RT-PCR assay, this study examined 3107 pools of mosquito. The main genotype of Japanese encephalitis virus in China was G1, with some G3 and G5, but no G2 or G4.C.tritaeniorhynchuswas the major mosquito species and the principal vector for transmitting JEV in China. TaqMan real-time RT-PCR assay and phylogenetic analysis consistently indicated that all 50 newly identified JEV sequences belonged to JEV G1.
Thepfactor: Genetic analyses support a general dimension of psychopathology in childhood and adolescence
Authors: Allegrini A.G. , Cheesman R. , Rimfeld K. , Selzam S. , Pingault JB. , Eley T.C. , Plomin R. 
Published: March 2019

AbstractBackgroundDiverse behaviour problems in childhood correlate phenotypically, suggesting a general dimension of psychopathology that has been called the p factor. The shared genetic architecture between childhood psychopathology traits also supports a genetic p. This study systematically investigates the manifestation of this common dimension across self-, parent- and teacher-rated measures in childhood and adolescence.MethodsThe sample included 7,026 twin pairs from the Twins Early Development Study (TEDS). First, we employed multivariate twin models to estimate common genetic and environmental influences on p based on diverse measures of behaviour problems rated by children, parents and teachers at ages 7, 9, 12 and 16 (depressive symptoms, emotional problems, peer problems, autistic symptoms, hyperactivity, antisocial, conduct and psychopathic symptoms). Second, to assess the stability of genetic and environmental influences on p across time, we conducted longitudinal twin modelling of the first phenotypic principal components of childhood psychopathological measures across each of the four ages. Third, we created a genetic p factor in 7,026 unrelated genotyped individuals based on eight polygenic scores for adult psychiatric disorders to estimate how a general polygenic predisposition to adult psychiatric disorders relates to childhood p.ResultsBehaviour problems were consistently correlated phenotypically and genetically across ages and raters. The p factor is substantially heritable (50-60%), and manifests consistently across diverse ages and raters. Genetic correlations of p components across childhood and adolescence suggest stability over time (49-78%). A polygenic general psychopathology factor, derived from studies of adult psychiatric disorders consistently predicted a general phenotypic p factor across development.ConclusionsDiverse forms of psychopathology consistently load on a common p factor, which is highly heritable. There are substantial genetic influences on the stability of p across childhood. Our analyses indicate genetic overlap between general risk for psychiatric disorders in adulthood and p in childhood, even as young as age 7. The p factor has far-reaching implications for genomic research and, eventually, for diagnosis and treatment of behaviour problems.
A systematic evaluation of interneuron morphology representations for cell type discrimination
Authors: Laturnus Sophie , Kobak Dmitry , Berens Philipp 
Published: March 2019

AbstractQuantitative analysis of neuronal morphologies usually begins with choosing a particular feature representation in order to make individual morphologies amenable to standard statistics tools and machine learning algorithms. Many different feature representations have been suggested in the literature, ranging from density maps to intersection profiles, but they have never been compared side by side. Here we performed a systematic comparison of various representations, measuring how well they were able to capture the difference between known morphological cell types. For our benchmarking effort, we used several curated data sets consisting of mouse retinal bipolar cells and cortical inhibitory neurons. We found that the best performing feature representations were two-dimensional density maps closely followed by morphometric statistics, which both continued to perform well even when neurons were only partially traced. The same representations performed well in an unsupervised setting, implying that they can be suitable for dimensionality reduction or clustering.
Area-specific mapping of binocular disparity across mouse visual cortex
Authors: La Chioma Alessandro , Bonhoeffer Tobias , Hübener Mark 
Published: March 2019

SummaryBinocular disparity, the difference between left and right eye images, is a powerful cue for depth perception. Many neurons in the visual cortex of higher mammals are sensitive to binocular disparity, with distinct disparity tuning properties across primary and higher visual areas. Mouse primary visual cortex (V1) has been shown to contain disparity-tuned neurons, but it is unknown how these signals are processed beyond V1. We find that disparity signals are prominent in higher areas of mouse visual cortex. Preferred disparities markedly differ among visual areas, with area RL encoding visual stimuli very close to the mouse. Moreover, disparity preference is systematically related to visual field elevation, such that neurons with receptive fields in the lower visual field are overall tuned to near disparities, likely reflecting an adaptation to natural image statistics. Our results reveal ecologically relevant areal specializations for binocular disparity processing across mouse visual cortex.
Rule-governed Dynamic Stochastic Equilibration of Multicellular MotionIn VivoDuring Olfactory Neurogenesis
Authors: Warrier Vijay , Cluzeau Celine , Chen Bi-Chang , Green-Saxena Abigail , Bergey Dani E. , Betzig Eric , Saxena Ankur 
Published: March 2019

SummaryThe complexity of patterning during organ-wide stem cell migration and differentiation can be challenging to interpret quantitatively. Here, we track neural crest (NC) and ectodermal placode-derived progenitor movementsin vivo, for hundreds of cells, implement unbiased algorithmic approaches to extract biologically meaningful information, and discover cell-cell and lineage-lineage coordination between progenitors that form olfactory sensory neurons (OSNs) during zebrafish embryogenesis. Our approach discriminates between NC- and placode-derived contributions and segregates ingressing NC cells into two previously unidentified subtypes termed ‘trend’ and ‘dispersed’ lineages. Our analyses indicate that NC and placodal progenitor migration and intercalation are coordinated by at least two types of collective behavior: spatiotemporal exclusion and elastic tethering, akin to a push-pull mechanism. A stochastic equilibrium model accurately represents the interactions of NC and placode-derived lineages. Our approach provides insights into the coordination of dual-origin lineages during vertebrate olfactory neurogenesis and offers an algorithmic toolkit for probing multicellular coordinationin vivo.Graphical Abstract
Thermodynamic impacts of combinatorial mutagenesis on protein conformational stability: precise, high-throughput measurement by Thermofluor
Authors: Weinreb Violetta , Weinreb Gabriel , Chandrasekaran Srinivas Niranj , Das Jhuma , Dokholyan Nikolay V. , Carter Charles W. 
Published: March 2019

ABSTRACTThe D1 switch is a packing motif, broadly distributed in the proteome, that couples tryptophanyl-tRNA synthetase (TrpRS) domain movement to catalysis and specificity, thereby creating an escapement mechanism essential to free-energy transduction. The escapement mechanism arose from analysis of an extensive set of combinatorial mutations to this motif, which allowed us to relate mutant-induced changes quantitatively to both kinetic and computational parameters during catalysis. To further characterize the origins of this escapement mechanism in differential TrpRS conformational stabilities, we use high-throughput Thermofluor measurements for the 16 variants to extend analysis of the mutated residues to their impact on unliganded TrpRS stability. Aggregation of denatured proteins complicates thermodynamic interpretations of denaturation experiments. The free energy landscape of a liganded TrpRS complex, carried out for different purposes, closely matches the volume, helix content, and transition temperatures of Thermoflour and CD melting profiles. Regression analysis using the combinatorial design matrix accounts for >90% of the variance in Tms of both Thermofluor and CD melting profiles. We argue that the agreement of experimental melting temperatures with both computational free energy landscape and with Regression modeling means that experimental melting profiles can be used to analyze the thermodynamic impact of combinatorial mutations. Tertiary packing and aromatic stacking of Phenylalanine 37 exerts a dominant stabilizing effect on both native and molten globular states. The TrpRS Urzyme structure remains essentially intact at the highest temperatures explored by the simulations.
Characterization of novelChrysosporium morrisgordoniisp. nov., from bat white-nose syndrome (WNS) affected mines, northeastern United States
Authors: Zhang Tao , Ren Ping , Li XiaoJiang , Chaturvedi Sudha , Chaturvedi Vishnu 
Published: March 2019

AbstractPsychrotolerant hyphomycetes including unrecognized taxon are commonly found in bat hibernation sites in Upstate New York. During a mycobiome survey, a new fungal species,Chrysosporium morrisgordoniisp. nov., was isolated from bat White-nose syndrome (WNS) afflicted Graphite mine in Warren County, New York. This taxon was distinguished by its ability to grow at low temperature spectra from 6°C to 25°C. Conidia were tuberculate and thick-walled, globose to subglobose, unicellular, 3.5-4.6 µm ×3.5-4.6 µm, sessile or borne on narrow stalks. The stalks occurred at right angles to the hypha. Intercalary aleuroconidia were also observed; the hyphae were septate, hyaline, smooth-walled, 1-3 µm wide, straight or branched. The ITS1-5.8S-ITS2 sequence ofC. morrisgordoniidiffered from the closest match toC. speluncarumby 37 nucleotides (94% identity); the Neighbor-joining phylogenetic tree confirmed thatC. morrisgordoniiwas placed in a well-supported monophyletic group withC. speluncarum. LSU and ITS phylogenetic trees further indicated thatC. morrisgordonii, C. speluncarum, Renispora flavissima, Neogymnomyces virgineus and Gymnoascus demonbreuniiformed a distinct group in theOnygenales.
Addressable, “Packet-Based” Intercellular Communication through Plasmid Conjugation
Authors: Marken John P. , Murray Richard M. 
Published: March 2019

AbstractWe develop a system for implementing “packet-based” intercellular communication in an engineered bacterial population via conjugation. Our system uses gRNA-based identification markers that allow messages to be addressed to specific strains via Cas9-mediated cleavage of messages sent to the wrong recipient, which we show reduces plasmid transfer by four orders of magnitude. Integrase-mediated editing of the address on the message plasmid allows cells to dynamically update the message’s recipients in vivo. As a proof-of-concept demonstration of our system, we propose a linear path scheme that would propagate a message sequentially through the strains of a population in a defined order.