bluuebunny/crossref_metadata_2025 huggingface dataset:
Functional genomics of a symbiotic community: shared traits in the olive fruit fly gut microbiota
Authors: Blow Frances , Gioti Anastasia , Goodhead Ian B. , Kalyva Maria , Kampouraki Anastasia , Vontas John , Darby Alistair C.
Published: March 2019

The olive fruit flyBactroceraoleae is a major pest of olives worldwide and houses a specialized gut microbiota dominated by the obligate symbiont “CandidatusErwinia dacicola”.Ca. E. dacicola is thought to supplement dietary nitrogen to the host, with only indirect evidence for this hypothesis so far. Here, we sought to investigate the contribution of the symbiosis to insect fitness and explore the ecology of the insect gut. For this purpose, we examined the composition of bacterial communities associated with Cretan olive fruit fly populations, and inspected several genome and transcriptome assemblies. We identified, and reconstructed the genome of, a novel component of the gut microbiota,Tatumellasp. TA1, which is stably associated with Mediterranean olive fruit fly populations. We also reconstructed a number of pathways related to nitrogen assimilation and interaction with the host. The results show that, despite variation in taxa composition of the gut microbial community, core functions related to the symbiosis are maintained. Functional redundancy between different microbial taxa was observed for genes allowing urea hydrolysis. The latter is encoded in the obligate symbiont genome by a conserved urease operon, likely acquired by horizontal gene transfer, based on phylogenetic evidence. A potential underlying mechanism is the action of mobile elements, especially abundant in theCa. E. dacicola genome. This finding, along with the identification, in the studied genomes, of extracellular surface structure components that may mediate interactions within the gut community, suggest that ongoing and past genetic exchanges between microbes may have shaped the symbiosis.
A Robust Model for Circadian Redox Oscillations
Authors: Olmo Marta del , Kramer Achim , Herzel Hanspeter
Published: March 2019

The circadian clock is an endogenous oscillator that controls daily rhythms in metabolism, physiology and behavior. Although the timekeeping components differ among species, a common design principle is a transcription-translation negative feedback loop. However, it is becoming clear that other mechanisms can contribute to the generation of 24 h rhythms. In mammalian adrenal gland, heart and brown adipose tissue, peroxiredoxins (Prx) exhibit 24 h rhythms in their redox state. Such rhythms are generated as a result of an inactivating hyperoxidation reaction that is reduced by coordinated import of the sulfiredoxin (Srx) into the mitochondria. However, a quantitative description of the Prx/Srx oscillating system is still missing. We investigate the basic principles that generate mitochondrial Prx/Srx rhythms using computational modeling. We observe that the previously described delay in mitochondrial Srx import, in combination with an appropriate separation of fast and slow reactions is sufficient to generate robust self-sustained relaxation-like oscillations. We find that our conceptual model can be regarded as a series of three consecutive phases and two temporal switches, highlighting the importance of delayed negative feedback and switches in the generation of oscillations.
Cultivatingin situtriggers growth of previously uncultivated microorganisms via a growth initiation factor in nature
Authors: Jung Dawoon , Machida Koshi , Nakao Yoichi , Kindaichi Tomonori , Ohashi Akiyoshi , Aoi Yoshiteru
Published: March 2019

Most microorganisms resist cultivation under standard laboratory conditions. On the other hand, to cultivate microbes in a membrane-bound device incubated in nature (in situcultivation) is an effective approach. In the present study, we appliedin situcultivation to isolate diverse previously uncultivated marine sponge-associated microbes and comparatively analyzed this method’s efficiencies with those of the conventional method. Then, we attempted to clarify the key and unknown mechanism ofin situcultivation by focusing on growth triggering via growth initiation factor. We hypothesized that majority of environmental microorganisms are in nongrowing state and requiring “growth initiation factor” for the recovery and that can be provided from environments. Consequently, significantly more novel and diverse microbial types were isolated viain situcultivation than by standard direct plating (SDP). Next, the effect of the sponge extract on starvation recovery was compared between strains derived fromin situand SDP cultivation. Adding small amounts of the sponge extracts to the medium elevated the colony-formation efficiencies of thein situstrains at the starvation recovery step, while it showed no positive effect on that of SDP strains. Conversely, specific growth rates or carrying capacities of all tested strains were not positively affected. These results indicate that, 1) the sponge extract contains chemical compounds that facilitate starvation recovery, these substances selectively worked on thein situstrains, and 2) growth initiation factor in the sponge extract did not continuously promote growth activity but worked as triggers for regrowth (resuscitation from dormancy).

Importance

Most microbial species resist cultivation under laboratory condition. This is critical impediment for both academic and applied microbiology, and thus clarification of the mechanism of microbial uncultivability is highly demanded. Several evidences have been reported that to cultivate microbes in a membrane-bound device incubated in nature (in situcultivation) is an effective approach. However, the mechanism behind this approach has not been clarified. The present study shows the evidence that 1) initiating growth is a key for cultivating previously uncultivated microbes rather than simple growth promotion, and 2) growth initiation factor (signaling-like compounds) in natural environments stimulate microbial resuscitation from a nongrowing state. Since no study has focused on growth initiation for cultivation of previously uncultivated microorganisms, the discovery shown in the present study provides a new insight into microorganisms previously considered uncultivable and a microbial growth controlling system in nature.
Minimisation of surface energy drives apical epithelial organisation and gives rise to Lewis’ law
Authors: Kokic Marco , Iannini Antonella , Villa-Fombuena Gema , Casares Fernando , Iber Dagmar
Published: March 2019

The packing of cells in epithelia exhibits striking regularities, regardless of the organism and organ. One of these regularities is expressed in Lewis’ law, which states that the average apical cell area is linearly related to the number of neighbours, such that cells with larger apical area have on average more neighbours. The driving forces behind the almost 100-year old Lewis’ law have remained elusive. We now provide evidence that the observed apical epithelial packing minimizes surface energy at the intercellular apical adhesion belt. Lewis’ law emerges because the apical cell surfaces then assume the most regular polygonal shapes within a contiguous lattice, thus minimising the average perimeter per cell, and thereby surface energy. We predict that the linear Lewis’ law generalizes to a quadratic law if the variability in apical areas is increased beyond what is normally found in epithelia. We confirm this prediction experimentally by generating heterogeneity in cell growth inDrosophilaepithelia. Our discovery provides a link between epithelial organisation, cell division and growth and has implications for the general understanding of epithelial dynamics.
Enhancer-promoter association determines Sox2 transcription regulation in mouse pluripotent cells
Authors: Huang Lei , Li Qing , Huang Qitong , Kong Siyuan , Zhu Xiusheng , Peng Yanling , Zhang Yubo
Published: March 2019

Distal enhancer-promoter associations are essential for transcription control and emerging as a common epigenetic way to determine gene expression in eukaryotes. However, it remains as an uncultivated land on how their diversity influences gene transcription during development. In this study, we select three defined Sox2 associated enhancers (E1, E2 and E3), representing different distal interaction categories, to further explore their biological effects. We construct three enhancer-knockout cells via CRISPR/Cas9 system in mouse embryonic stem cells. Results show that these associations carry out various biological features. Embryonic stem cell specific association (E1) speeds up cell cycle and involves in cardiac development, which has been validated in vivo. In contrast, the indirect one (E2) restrains nerve differentiation and has potential effect on lipid metabolism. The common one (E3) promotes nerve differentiation and inhibits oxidation-reduction process. Together, these different associations determine Sox2 transcription and function specificity in mouse embryonic stem cells. Our study will enable a way for exploring miscellaneous spatiotemporal gene transcription control and advancing quantitative knowledge by utilizing three-dimensional genomic information.

Summary statement

Sox2 transcription is complicated in mouse embryonic stem cells. It involves in heavily enhancer-promoter associations, which might make it a suitable model for phase-separation study. To decompose this cooperative regulation, diverse interactions are investigated. The biological effects have been explored in multiple perspectives. This may represent a quantitative way to explore and a potential new strategy to transcription control study.
Substantial genetic mixing among sexual and androgenetic lineages within the clam genus Corbicula
Authors: Martin Vastrade , Emilie Etoundi , Thibaut Bournonville , Mathilde Colinet , Nicolas Debortoli , Hedtke Shannon M. , Emilien Nicolas , Lise-Marie Pigneur , Julie Virgo , Jean-François Flot , Jonathan Marescaux , Karine Van Doninck
Published: March 2019

Abstract

“Occasional” sexuality occurs when a species combines clonal reproduction and genetic mixing. This strategy is predicted to combine the advantages of both asexuality and sexuality, but its actual consequences on the genetic diversity and species longevity are poorly understood. Androgenesis, a reproductive mode in which the offspring inherits its entire nuclear genome from the father, is often reported as a strictly clonal reproductive mode. Androgenesis is the predominant reproductive mode within the hermaphroditic, invasive lineages of the mollusk genus Corbicula. Their ability to reproduce clonally through androgenesis has been determinant in their invasive success, having colonized during the 20th century American and European freshwater systems, where they became notorious invaders with a widespread, global distribution. However, in androgenetic Corbicula clams, occasional genetic mixing between distinct lineages has also been observed when the sperm of one lineage fertilizes the oocyte of another one. Because of these occasional introgressions, the genetic relationships between Corbicula species remained unclear, and the biogeographic origins of the invasive androgenetic lineages have been challenging to identify. To address these issues, we analyzed the patterns of allele sharing for several nuclear and mitochondrial molecular markers among Corbicula individuals collected across both the native and invasive range. Our results show the occurrence of an allelic pool encompassing all Corbicula freshwater species worldwide, including sexual and androgenetic ones, which highlights the substantial genetic mixing within this genus. However, the differences in allele sharing patterns between invasive lineages, and the low diversity within each lineage, suggest recent, distinct biogeographic origins of invasive Corbicula androgenetic lineages. Finally, the polyploidy, high heterozygosity, and hybrid phenotypes and genotypes found in our study probably originated from hybridization events following egg parasitism between distinct Corbicula lineages. This extensive cross-lineage mixing found in Corbicula may generate nuclear diversity in an otherwise asexually reproducing species.
Short term memory properties of sensory neural architectures
Authors: Dubreuil Alexis M.
Published: March 2019

A functional role of the cerebral cortex is to form and hold representations of the sensory world for behavioral purposes. This is achieved by a sheet of neurons, organized in modules called cortical columns, that receives inputs in a peculiar manner, with only a few neurons driven by sensory inputs through thalamic projections, and a vast majority of neurons receiving mainly cortical inputs. How should cortical modules be organized, with respect to sensory inputs, in order for the cortex to efficiently hold sensory representations in memory? To address this question we investigate the memory performance of trees of recurrent networks (TRN) that are composed of recurrent networks, modeling cortical columns, connected with each others through a tree-shaped feed-forward backbone of connections, with sensory stimuli injected at the root of the tree. On these sensory architectures two types of short-term memory (STM) mechanisms can be implemented, STM via transient dynamics on the feed-forward tree, and STM via reverberating activity on the recurrent connectivity inside modules. We derive equations describing the dynamics of such networks, which allow us to thoroughly explore the space of possible architectures and quantify their memory performance. By varying the divergence ratio of the tree, we show that serial architectures, where sensory inputs are successively processed in different modules, are better suited to implement STM via transient dynamics, while parallel architectures, where sensory inputs are simultaneously processed by all modules, are better suited to implement STM via reverberating dynamics.
PrankWeb: web server for ligand binding-site prediction and visualization
Authors: Jendele Lukas , Krivak Radoslav , Skoda Petr , Novotny Marian , Hoksza David
Published: March 2019

PrankWeb is an online resource providing an interface to P2Rank, a state-of-the-art ligand binding site prediction method. P2Rank is a template-free machine learning method which is based on the prediction of ligandability of local chemical neighborhoods centered on points placed on a solvent accessible surface of a protein. Points with high ligandability score are then clustered to form the resulting ligand binding sites. On top of that, PrankWeb then provides a web interface enabling users to easily carry out the prediction and visually inspect the predicted binding sites via an integrated sequence-structure view. Moreover, PrankWeb can determine sequence conservation for the input molecule and use it in both the prediction and results visualization steps. Alongside its online visualization options, PrankWeb also offers the possibility to export the results as a PyMOL script for offline visualization. The web frontend communicates with the serer side via a REST API. Therefore, in high-throughput scenarios users can utilize the server API directly, bypassing the need for a webbased front end or installation of the P2Rank application. PrankWeb is available at http://prankweb.cz/. The source code of the web application and the P2Rank method can be accessed at https://github.com/jendelel/PrankWebApp and https://github.com/rdk/p2rank, respectively.
Rapid and iterative genome editing in the zoonotic malaria parasitePlasmodium knowlesi: New tools forP. vivaxresearch
Authors: Mohring Franziska , Hart Melissa N. , Rawlinson Thomas A. , Henrici Ryan , Charleston James A. , Benavente Ernest Diez , Patel Avnish , Hall Joanna , Almond Neil , Campino Susana , Clark Taane G. , Sutherland Colin J. , Baker David A. , Draper Simon J. , Moon Robert W.
Published: March 2019

Tackling relapsingPlasmodium vivaxand zoonoticPlasmodium knowlesiinfections is critical to reducing malaria incidence and mortality worldwide. Understanding the biology of these important and related parasites was previously constrained by the lack of robust molecular and genetic approaches. Here, we establish CRISPR-Cas9 genome editing in a culture-adaptedP. knowlesistrain and define parameters for optimal homology-driven repair. We establish a scalable protocol for the production of repair templates by PCR and demonstrate the flexibility of the system by tagging proteins with distinct cellular localisations. Using iterative rounds of genome-editing we generate a transgenic line expressingP. vivaxDuffy binding protein (PvDBP), a lead vaccine candidate. We demonstrate that PvDBP plays no role in reticulocyte restriction but can alter the macaque/human host cell tropism ofP. knowlesi. Critically, antibodies raised against theP. vivaxantigen potently inhibit proliferation of this strain, providing an invaluable tool to support vaccine development.
MASST: A Web-based Basic Mass Spectrometry Search Tool for Molecules to Search Public Data
Authors: Wang Mingxun , Jarmusch Alan K. , Vargas Fernando , Aksenov Alexander A. , Gauglitz Julia M. , Weldon Kelly , Petras Daniel , Silva Ricardo da , Quinn Robby , Melnik Alexey V. , van der Hooft Justin J.J. , Caraballo Rodríguez Andrés Mauricio , Nothias Louis Felix , Aceves Christine M. , Panitchpakdi Morgan , Brown Elizabeth , Di Ottavio Francesca , Sikora Nicole , Elijah Emmanuel O. , Labarta-Bajo Lara , Gentry Emily C. , Shalapour Shabnam , Kyle Kathleen E. , Puckett Sara P. , Watrous Jeramie D. , Carpenter Carolina S. , Bouslimani Amina , Ernst Madeleine , Swafford Austin D. , Zúñiga Elina I. , Balunas Marcy J. , Klassen Jonathan L. , Loomba Rohit , Knight Rob , Bandeira Nuno , Dorrestein Pieter C.
Published: March 2019

Correspondence

We introduce a web-enabled small-molecule mass spectrometry (MS) search engine. To date, no tool can query all the public small-molecule tandem MS data in metabolomics repositories, greatly limiting the utility of these resources in clinical, environmental and natural product applications. Therefore, we introduce aMassSpectrometrySearchTool (MASST) (https://proteosafe-extensions.ucsd.edu/masst/), that enables the discovery of molecular relationships among accessible public metabolomics and natural product tandem mass spectrometry data (MS/MS).
Fingerprinting CANDO: Increased Accuracy with Structure and Ligand Based Shotgun Drug Repurposing
Authors: Schuler James , Samudrala Ram
Published: March 2019

We have upgraded our Computational Analysis of Novel Drug Opportunities (CANDO) platform for shotgun drug repurposing to include ligand-based, data fusion, and decision tree pipelines. The first version of CANDO implemented a structure-based pipeline that modeled interactions between compounds and proteins on a large scale, generating compoundproteome interaction signatures used to infer similarity of drug behavior; the new pipelines accomplish this by incorporating molecular fingerprints and the Tanimoto coefficient. We obtain improved benchmarking performance with the new pipelines across all three evaluation metrics used: average indication accuracy, pairwise accuracy, and coverage. The best performing pipeline achieves an average indication accuracy of 19.0% at the top10 cutoff, compared to 11.7% for v1, and 2.2% for a random control. Our results demonstrate that the CANDO drug recovery accuracy is substantially improved by integrating multiple pipelines, thereby enhancing our ability to generate putative therapeutic repurposing candidates, and increasing drug discovery efficiency.
Differential Expression of the T cell Inhibitor TIGIT in Glioblastoma and Multiple Sclerosis
Authors: Lucca Liliana E. , Lerner Benjamin A. , DeBartolo Danielle , Park Calvin , Ponath Gerald , Raddassi Khadir , Hafler David A. , Pitt David
Published: March 2019

To identify co-inhibitory immune pathways important in the brain, we hypothesized that comparison of T cells in lesions from patients with MS with tumor infiltrating T cells (TILs) from patients with GBM may reveal novel targets for immunotherapy. Focusing on PD-1 and TIGIT, we found that TIGIT and its ligand CD155 were highly expressed on GBM TILs but were near-absent in MS lesions, while lymphocytic expression of PD-1/PDL-1 was comparable. TIGIT was also upregulated in peripheral lymphocytes in GBM, suggesting recirculation of TILs. These data raise the possibility that anti-TIGIT therapy may be beneficial for patients with glioblastoma.
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

Genome-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

With 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

The 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

Multicenter 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

Although 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 summary

In 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

Introduction

Japanese 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.

Methods

More 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.

Results

More 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.

Conclusion

G1 is the main genotype of JEV circulating in nature in China. Some G3 and G5 were found, but no G2 or G4.

Author summary

Japanese 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

Background

Diverse 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.

Methods

The 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.

Results

Behaviour 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.

Conclusions

Diverse 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

Quantitative 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

Binocular 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

The 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

The 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

Psychrotolerant 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

We 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.
Monovision and the Misperception of Motion
Authors: Burge Johannes , Rodriguez-Lopez Victor , Dorronsoro Carlos
Published: March 2019

Monovision corrections are a common treatment for presbyopia. Each eye is fit with a lens that sharply focuses light from a different distance, causing the image in one eye to be blurrier than the other. Millions of people in the United States and Europe have monovision corrections, but little is known about how differential blur affects motion perception. We investigated by measuring the Pulfrich effect, a stereo-motion phenomenon first reported nearly 100 years ago. When a moving target is viewed with unequal retinal illuminance or contrast in the two eyes, the target appears to be closer or further in depth than it actually is, depending on its frontoparallel direction. The effect occurs because the image with lower illuminance or contrast is processed more slowly. The mismatch in processing speed causes a neural disparity, which results in the illusory motion in depth. What happens with differential blur? Remarkably, differential blur causes a reverse Pulfrich effect, an apparent paradox. Blur reduces contrast and should therefore cause processing delays. But the reverse Pulfrich effect implies that the blurry image is processed more quickly. The paradox is resolved by recognizing that: i) blur reduces the contrast of high-frequency image components more than low-frequency image components, and ii) high spatial frequencies are processed more slowly than low spatial frequencies, all else equal. Thus, this new illusion—the reverse Pulfrich effect—can be explained by known properties of the early visual system. A quantitative analysis shows that the associated misperceptions are large enough to impact public safety.
Exploration of interaction scoring criteria in the CANDO platform
Authors: Falls Zackary , Mangione William , Schuler James , Samudrala Ram
Published: March 2019

Background

Drug discovery is an arduous process that requires many years and billions of dollars before approval for patient use. However, there are a number of drugs and human ingestibles approved for a variety of indications/diseases that can be potentially repurposed as new treatments for others, decreasing the time and cost required.

Methods

CANDO (Computational Analysis of Novel Drug Opportunities) is a platform for shotgun, multitarget drug discovery and repurposing. The CANDO platform scores interactions between 46,784 proteins structures and 3,733 human use compounds using a bioinformatic docking protocol to generate compound-proteome interaction signatures that are then compared to identify candidates for repurposing. Benchmarking of the platform is accomplished by comparing the compound-proteome interaction signatures and determining whether signatures corresponding to pairs of drugs approved for the same indication fall within particular cutoffs.

Results

We have altered the scoring function of bioinformatic docking protocol in the newest version of our platform (v1.5) to use the best OBscore for each compound-protein interaction, resulting in an increased benchmarking accuracy from 11.7% in v1 to 12.8% in v1.5 for the top10 cutoff, the most stringent one used, and correspondingly from 24.9% to 31.2% for the top100 cutoff.

Conclusions

The change in the interaction scoring and other bug fixes in CANDO v1.5 have resulted in improved benchmarking performance, making the platform more effective at predicting novel, therapeutic drug-indication pairs.