bluuebunny/crossref_metadata_2025 huggingface dataset:
Phosphodiesterase-induced cAMP degradation restricts hepatitis B virus infection
Authors: Evripioti Antonia Alexandra , Ortega-Prieto Ana Maria , Skelton Jessica Katy , Bazot Quentin , Dorner Marcus
Published: April 2019

Hepatitis B virus (HBV) entry into hepatocytes is mediated via a high-affinity interaction between the preS1 glycoprotein and sodium/bile acid cotransporting polypeptide (NTCP). To date,
in vitro
model systems rely on high multiplicities of infection to achieve infection of cell lines overexpressing human NTCP. This study investigates a novel regulatory pathway for NTCP trafficking to the cell surface, induced by DMSO-mediated cellular differentiation. DMSO rapidly induces high cell surface expression of NTCP and results in increased susceptibility of cells to HBV infection. Additionally, DMSO treatment induces actin, as well as Tubulin reshaping within the cells. We show that direct disruption of the actin and Tubulin network directly enhances NTCP expression and the subsequent susceptibility of cells to HBV infection. DMSO induces these changes via alterations in the levels of cyclic (c)AMP, which participates in the observed actin rearrangements. Blocking of phosphodiesterases (PDEs), which degrade accumulated cAMP, had the same effect as DMSO differentiation and demonstrates that DMSO prevents phosphodiesterase-mediated cAMP degradation. This identifies adenylate cyclase as a novel target for blocking the entry of HBV via targeting the cell surface accumulation of NTCP.

This article is part of the theme issue ‘Silent cancer agents: multi-disciplinary modelling of human DNA oncoviruses’.
Capturing multiple-type interactions into practical predictors of type replacement following human papillomavirus vaccination
Authors: Man Irene , Auranen Kari , Wallinga Jacco , Bogaards Johannes A.
Published: April 2019

Current HPV vaccines target a subset of the oncogenic human papillomavirus (HPV) types. If HPV types compete during infection, vaccination may trigger replacement by the non-targeted types. Existing approaches to assess the risk of type replacement have focused on detecting competitive interactions between pairs of vaccine and non-vaccine types. However, methods to translate any inferred pairwise interactions into predictors of replacement have been lacking. In this paper, we develop practical predictors of type replacement in a multi-type setting, readily estimable from pre-vaccination longitudinal or cross-sectional prevalence data. The predictors we propose for replacement by individual non-targeted types take the form of weighted cross-hazard ratios of acquisition versus clearance, or aggregate odds ratios of coinfection with the vaccine types. We elucidate how the hazard-based predictors incorporate potentially heterogeneous direct and indirect type interactions by appropriately weighting type-specific hazards and show when they are equivalent to the odds-based predictors. Additionally, pooling type-specific predictors proves to be useful for predicting increase in the overall non-vaccine-type prevalence. Using simulations, we demonstrate good performance of the predictors under different interaction structures. We discuss potential applications and limitations of the proposed methodology in predicting type replacement, as compared to existing approaches.

This article is part of the theme issue ‘Silent cancer agents: multi-disciplinary modelling of human DNA oncoviruses’.
Modelling the evolution of viral oncogenesis
Authors: Murall Carmen Lía , Alizon Samuel
Published: April 2019

Most human oncogenic viruses share several characteristics, such as being DNA viruses, having long (co)evolutionary histories with their hosts and causing either latent or chronic infections. They can reach high prevalences while causing relatively low case mortality, which makes them quite fit according to virulence evolution theory. After analysing the life histories of DNA oncoviruses, we use a mathematical modelling approach to investigate how the virus life cycle may generate selective pressures favouring or acting against oncogenesis at the within-host or at the between-host level. In particular, we focus on two oncoprotein activities, namely extending cell life expectancy and increasing cell proliferation rate. These have immediate benefits (increasing viral population size) but can be associated with fitness costs at the epidemiological level (increasing recovery rate or risk of cancer) thus creating evolutionary trade-offs. We interpret the results of our nested model in light of the biological features and identify future perspectives for modelling oncovirus dynamics and evolution.

This article is part of the theme issue ‘Silent cancer agents: multi-disciplinary modelling of human DNA oncoviruses’.
Function and clinical relevance of RHAMM isoforms in pancreatic tumor progression
Authors: Choi Soyoung , Wang Dunrui , Chen Xiang , Tang Laura H. , Verma Akanksha , Chen Zhengming , Kim Bu Jung , Selesner Leigh , Robzyk Kenneth , Zhang George , Pang Sharon , Han Teng , Chan Chang S. , Fahey Thomas J. , Elemento Olivier , Du Yi-Chieh Nancy
Published: April 2019

The receptor for hyaluronic acid-mediated motility (RHAMM) is upregulated in various cancers. We previously screened genes upregulated in human hepatocellular carcinomas for their metastatic function in a mouse model of pancreatic neuroendocrine tumor (PNET) and identified that humanRHAMMBpromoted liver metastasis. It was unknown whetherRHAMMBis upregulated in pancreatic cancer or contributes to its progression. In this study, we found that RHAMM protein was frequently upregulated in human PNETs. We investigated alternative splicing isoforms,RHAMMAandRHAMMB, by RNA-Seq analysis of primary PNETs and liver metastases.RHAMMB, but notRHAMMA, was significantly upregulated in liver metastases. RHAMMBwas crucial forin vivometastatic capacity of mouse and human PNETs. RHAMMA, carrying an extra 15-amino acid-stretch, did not promote metastasis in spontaneous and experimental metastasis mouse models. Moreover,RHAMMBwas substantially higher thanRHAMMAin pancreatic ductal adenocarcinoma (PDAC).RHAMMB, but notRHAMMA, correlated with both higherEGFRexpression and poorer survival of PDAC patients. Knockdown of EGFR abolished RHAMMB-driven PNET metastasis. Altogether, our findings suggest a clinically relevant function ofRHAMMB, but notRHAMMA, in promoting PNET metastasis in part through EGFR signaling.RHAMMBcan thus serve as a prognostic factor for pancreatic cancer.
Unexpected termite inquilines in nests of Constrictotermes cyphergaster (Silvestri, 1901) (Blattodea: Isoptera)
Authors: Costa Diogo , Marins Alessandra , DeSouza Og
Published: April 2019

The heterospecific termite-termite cohabitation in a single termitarium, so called in-quilinism, is a common event whose basal mechanisms remain hypothetical. While some termite hosts have plenty of inquilines, others house only a few. Among these, Constrictotermes cyphergaster are frequently found cohabiting with a single obligate inquiline species but have been unknown to house any facultative inquilines. Here we present the first record of facultative inquilines (Embiratermes festivellus, Nasutitermes kemneri, Obitusitermes bacchanalis and Subulitermes) to this host, evidencing that this was unlikely to have happened fortuitously. In an attempt to pose hypotheses on the mechanisms behind such invasions, we explored likely connections between the settlement of obligate and facultative inquilines and nest wall’s physical traits. We found that nests bearing atypical external walls (moist, eroded, and partially covered by mosses) held higher richness of facultative inquilines than nests presenting walls void of such traits (χ2 = 8.3965, 1 df, n = 17, P = 0.0038). The presence of healthy host colonies in all nests, including the atypical ones, reinforces the hypothesis that the settlement of these facultative inquilines depends less on host colonies biotic status and more on abiotic features associated to the nest. In addition, the presence of obligate inquilines was not affected by the nest wall status (χ2 = 8.3965, 1 df, n = 17, P = 0.0038), implying that invasion by facultative and obligate inquilines in these nests would obey distinct restrictions. While warning that these hypotheses require further testing, we suggest that their understanding could shed light on the determinants of cohabitation not only in C. cyphergaster but in termites in general. cohabitation interspecific interaction nest invasion barriers
Solart: A Structure-Based Method To Predict Protein Solubility And Aggregation
Authors: Hou Q. , Kwasigroch J. M. , Rooman M. , Pucci F.
Published: April 2019

Motivation

The solubility of a protein is often decisive for its proper functioning. Lack of solubility is a major bottleneck in high-throughput structural genomic studies and in high-concentration protein production, and the formation of protein aggregates causes a wide variety of diseases. Since solubility measurements are time-consuming and expensive, there is a strong need for solubility prediction tools.

Results

We have recently introduced solubility-dependent distance potentials that are able to unravel the role of residue-residue interactions in promoting or decreasing protein solubility. Here, we extended their construction by defining solubility-dependent potentials based on backbone torsion angles and solvent accessibility, and integrated them, together with other structure- and sequence-based features, into a random forest model trained on a set of E. coli proteins with experimental structures and solubility values. We thus obtained the SOLart protein solubility predictor, whose most informative features turned out to be folding free energy differences computed from our solubility-dependent statistical potentials. SOLart performances are very good, with a Pearson correlation coefficient between experimental and predicted solubility values of 0.7 both in the training dataset and on an independent set of S. Cerevisiae proteins. On test sets of modeled structures, only a limited drop in performance is observed. SOLart can thus be used with both high-resolution and low-resolution structures, and clearly outperforms state-of-art solubility predictors. It is available through a user-friendly webserver, which is easy to use by non-expert scientists.

Availability

The SOLart webserver is freely available at babylone.ulb.ac.be/SOLART/
Systematics, biogeography and diversification ofScytalopustapaculos (Rhinocryptidae), an enigmatic radiation of Neotropical montane birds
Authors: Cadena Carlos Daniel , Cuervo Andrés M. , Céspedes Laura N. , Bravo Gustavo A. , Krabbe Niels , Schulenberg Thomas S. , Derryberry Graham E. , Silveira Luis Fabio , Derryberry Elizabeth P. , Brumfield Robb T. , Fjeldså Jon
Published: April 2019

We studied the phylogeny, biogeography and diversification of suboscine birds in the genusScytalopus(Rhinocryptidae), a widespread, speciose, and taxonomically challenging group of Neotropical birds. We analyzed nuclear (exons, regions flanking ultraconserved elements) and mitochondrial (ND2) DNA sequence data for a taxonomically and geographically comprehensive sample of specimens collected from Costa Rica to Patagonia and eastern Brazil. We found thatScytalopusis a monophyletic group sister toEugralla, and consists of three main clades roughly distributed in (1) the Southern Andes, (2) eastern Brazil, and (3) the Tropical Andes and Central America. The clades from the Southern Andes and Eastern Brazil are sister to each other. Despite their confusing overall uniformity in plumage coloration, body shape and overall appearance, rates of species accumulation through time inScytalopussince the origin of the clade in the Late Miocene are unusually high compared to those of other birds, suggesting rapid non-adaptive diversification in the group which we attribute to their limited dispersal abilities making them speciation-prone and their occurrence in a complex landscape with numerous barriers promoting allopatric differentiation. Divergence times among species and downturns in species accumulation rates in recent times suggest that most speciation events inScytalopuspredate climatic oscillations of the Pleistocene. Our analyses identified various cases of strong genetic structure within species and lack of monophyly of taxa, flagging populations which likely merit additional study to establish their taxonomic status. In particular, detailed analyses of species limits are due inS. parvirostris, S. latrans, S. speluncae, theS. atratuscomplex, and the Southern Andes clade.
Consistent bacterial responses to land use change across the tropics
Authors: Petersen Ian AB , Meyer Kyle M , Bohannan Brendan JM
Published: April 2019

Bacterial communities are a major component of global diversity and are intimately involved in most terrestrial biogeochemical processes. Despite their importance, we know far less about the response of bacteria to human-induced environmental change than we do about other organisms. Understanding the response of organisms to land use change is especially pressing for tropical rainforests, which are being altered at a higher rate than any other ecosystem. Here, we conduct a meta-analysis of studies performed in each of the major tropical rainforest regions to ask whether there are consistent responses of belowground bacterial communities to the conversion of tropical rainforest to agriculture. Remarkably, we find common responses despite wide variation across studies in the types of agriculture practiced and the research methodology used to study land use change. These responses include changes in the relative abundance of phyla, most notably decreases in Acidobacteria and Proteobacteria and increases in Actinobacteria, Chloroflexi and Firmicutes. We also find that alpha diversity (at the scale of single soil cores), consistently increases with ecosystem conversion. These consistent responses suggest that, while there is great diversity in agricultural practices across the tropics, common features such as the use of slash-and-burn tactics have the potential to alter bacterial community composition and diversity belowground.
Targeting Age-Related Differences in Brain and Cognition with Multimodal Imaging and Connectome Topography Profiling
Authors: Lowe Alexander J. , Paquola Casey , Vos de Wael Reinder , Girn Manesh , Lariviere Sara , Tavakol Shahin , Caldairou Benoit , Royer Jessica , Schrader Dewi V. , Bernasconi Andrea , Bernasconi Neda , Spreng R. Nathan , Bernhardt Boris C.
Published: April 2019

I.

Abstract

Aging is characterised by accumulation of structural and metabolic changes in the brain. Recent studies suggest transmodal brain networks are especially sensitive to aging, which, we hypothesise, may be due to their apical position in the cortical hierarchy. Studying an open-access healthy cohort (n=102, age range = 30-89 years) with MRI and Aβ PET data, we estimated age-related cortical thinning, hippocampal atrophy and Aβ deposition. In addition to carrying out surface-based morphological and metabolic mapping, we stratified effects along neocortical and hippocampal resting-state functional connectome gradients derived from independent datasets. The cortical gradient depicts an axis of functional differentiation from sensory-motor regions to transmodal regions, whereas the hippocampal gradient recapitulates its long-axis. While age-related thinning and increased Aβ deposition occurred across the entire cortical topography, increased Aβ deposition was especially pronounced towards higher-order transmodal regions. Age-related atrophy was greater towards the posterior end of the hippocampal long-axis. No significant effect of age on Aβ deposition in the hippocampus was observed. Imaging markers correlated with behavioural measures of fluid intelligence and episodic memory in a topography-specific manner. Our results strengthen existing evidence of structural and metabolic change in the aging brain and support the use of connectivity gradients as a compact framework to analyse and conceptualize brain-based biomarkers of aging.
xml2jupyter: Mapping parameters between XML and Jupyter widgets
Authors: Heiland Randy , Mishler Daniel , Zhang Tyler , Bower Eric , Macklin Paul
Published: April 2019

Jupyter Notebooks [4, 6] provide executable documents (in a variety of programming languages) that can be run in a web browser. When a notebook contains graphical widgets, it becomes an easy-to-use graphical user interface (GUI). Many scientific simulation packages use text-based configuration files to provide parameter values and run at the command line without a graphical interface. Manually editing these files to explore how different values affect a simulation can be burdensome for technical users, and impossible to use for those with other scientific backgrounds. xml2jupyter is a Python package that addresses these scientific bottlenecks. It provides a mapping between configuration files, formatted in the Extensible Markup Language (XML), and Jupyter widgets. Widgets are automatically generated from the XML file and these can, optionally, be incorporated into a larger GUI for a simulation package, and optionally hosted on cloud resources. Users modify parameter values via the widgets, and the values are written to the XML configuration file which is input to the simulation’s command-line interface. xml2jupyter has been tested using PhysiCell [1], an open source, agent-based simulator for biology, and it is being used by students for classroom and research projects. In addition, we use xml2jupyter to help create Jupyter GUIs for PhysiCell-related applications running on nanoHUB [5].
An integrative analysis of GWAS and intermediate molecular trait data reveals common molecular mechanisms supporting genetic similarity between seemingly unrelated complex traits
Authors: Gu Jialiang , Fuller Chris , Zheng Jiashun , Li Hao
Published: April 2019

The rapid accumulation of Genome Wide Association Studies (GWAS) and association studies of intermediate molecular traits provides new opportunities for comparative analysis of the genetic basis of complex human phenotypes. Using a newly developed statistical framework called Sherlock-II that integrates GWAS with eQTL (expression Quantitative Trait Loci) and metabolite-QTL data, we systematically analyzed 445 GWAS datasets, and identified 1371 significant gene-phenotype associations and 308 metabolites-phenotype associations (passing a Q value cutoff of 1/3). This integrative analysis allows us to translate SNP-phenotype associations into functionally informative gene-phenotype association profiles. Genetic similarity analyses based on these profiles clustered phenotypes into sub-trees that reveal both expected and unexpected relationships. We employed a statistical approach to delineate sets of functionally related genes that contribute to the similarity between their association profiles. This approach suggested common molecular mechanisms that connect the phenotypes in a subtree. For example, we found that fasting insulin, fasting glucose, breast cancer, prostate cancer, and lung cancer clustered into a subtree, and identified cyclic AMP/GMP signaling that connects breast cancer and insulin, NAPDH oxidase/ROS generation that connects the three cancers, and apoptosis that connects all five phenotypes. Our approach can be used to assess genetic similarity and suggest mechanistic connections between phenotypes. It has the potential to improve the diagnosis and treatment of a disease by mapping mechanistic insights from one phenotype onto others based on common molecular underpinnings.
Synergistic interactions of quercetin with antibiotics against biofilm associated clinical isolates ofPseudomonas aeruginosa in vitro
Authors: Vipin C. , Mujeeburahiman M. , Saptami K. , Arun A.B. , Rekha P.D.
Published: April 2019

Development of extreme resistance to multiple antibiotics is the major concern in infections due to biofilm formingPseudomonas aeruginosa.The existing antibiotics have become ineffective against biofilm associated infections and hence, in this study, the combinatorial efficacy of antibiotics with a quorum sensing inhibitor (quercetin) was tested against biofilm formingP. aeruginosaisolates. The effect of drug combinations was studied by the checkerboard method. The fractional inhibitory concentration index (FICI) was calculated for determining the synergistic effect. Additionally, biofilm cell viability, time-kill and live-dead assays were performed to study the combinatorial effect. MIC of quercetin against all theP. aeruginosastrains was 500 μg/mL. However, quercetin at 125 μg/mL showed synergistic effect with ½ × MIC or ¼ × MIC of all the antibiotics against all the strains. Quercetin (125 μg/mL) with ½ MIC of levofloxacin and tobramycin combinations were highly effective with ≥80% killing of biofilm associated cells. Increasing the concentration to 250 μg/mL with ½ × MIC antibiotics could completely inhibit the biofilm cell viability in quercetin combination with amikacin and tobramycin. The findings show that quercetin combinations can enhance the treatment outcome againstP. aeruginosainfection and this approach may reduce antibiotic overuse and selection pressure.

Graphical abstract
Genome-wide analyses indirectly implicate miRNA regulatory mechanisms in Obsessive-compulsive Disorder psychopathology
Authors: McGregor NW , O’Connell KS ,   TS/ OCD PGC Workgroup, Davis L , Mathews CA , Lochner C , Stein DJ
Published: April 2019

Background

MiRNAs are small, noncoding RNAs possessing the potential to modulate gene expression upon binding to their target messenger RNA (mRNA) constructs, and are known to play a role in the pathogenesis of a range of psychiatric disorders. To date, little work has focused on the role of miRNAs in obsessive-compulsive disorder (OCD). The aim of this study was to assess the potential involvement of miRNAs in OCD psychopathology.

Methods

The most significant variants (p ≤ 1×10−4) from the Psychiatric Genomics Consortium (PGC) TS/OCD Workgroup OCD meta-analysis were selected and investigated using miRBASE, TargetScan and SNPnexus to determine whether they influence miRNA- mediated regulation in the clinical manifestation of OCD.

Results

Two-hundred and forty SNPs were identified from the PGC OCD summarystatistics, of which none were found to directly alter miRNA-related gene regulation usingin silicoanalyses. Enrichment analyses identified several potential indirect miRNA-mediated targets associated with both increased (ITPR3: mir-124A) and decreased risk (GPR109A: mir-520A, and mir-525;CGNL1: mir-98 and mir-219).

Conclusion

miRNA-mediated regulation was indirectly implicated in the psychopathology of OCD. Enrichment analyses implicates intracellular calcium and immune dysregulation in the clinical manifestation of the disorder and warrants further investigation of the role the immune system may play in the manifestation of disease.
Demonstration of a fast and easy sample-to-answer protocol forMycobacterium tuberculosisdiagnosis in point-of-care settings
Authors: Ali Nasir , Bello Graziele Lima , Rossetti Maria Lúcia Rosa , Costa Alexandre Dias Tavares , Krieger Marco Aurelio
Published: April 2019

Background

Tuberculosis (TB) is currently the ninth leading cause of death worldwide and the leading cause from a single infectious agent, ranking above HIV/AIDS. Point of care diagnosis is one of the diagnostic aspects in the health care system that might have the potential to mitigate this worldwide epidemic. Although several qPCR tests are available, most cannot be taken to the field. Therefore, their use in POC settings is limited. Smooth sample preparation and streamlined DNA extraction constitute the biggest challenges for this limitation.

Methods

SeventeenM. tuberculosissamples which were already previously analyzed by GeneXpert or culture technique were subjected to our in-house protocol. Of these samples, ten were positive and seven negatives when tested by GeneXpert, while seven were positive and ten negatives when analyzed by culturing.

Results

Here we present a “proof of concept” protocol for sputum liquefaction and disinfection, followed by FTA card DNA extraction. The resulting DNA is rapidly amplified andMycobacterium tuberculosis(MTB) DNA is detected with the use of a portable qPCR instrument. Our protocol is able to linearly identify down to 2 CFU/mL of MTB, showing great sensitivity on artificial samples. The protocol was challenged with patient samples, and showed excellent agreement with the gold-standard molecular protocol, allowing the detection of 9/10 positive samples (90%, or 10% of false negatives) and 7/7 of the negative (100%, no false positives). When compared to culture, 7/7 culture-positive samples were also found positive (100%, no false negatives), while 2/10 culture-negative were found positive by the present method (20% of false positives).

Conclusion

The proposed sample preparation protocol provides a rapid and easy procedure with a small number of reagents and steps, as well as minimal use of equipments, resulting in an easy-to-use tool forM. tuberculosisdiagnosis in POC settings.
Additive genetic variance for lifetime fitness and the capacity for adaptation in an annual plant
Authors: Kulbaba Mason W. , Sheth Seema N. , Pain Rachel E. , Eckhart Vince M. , Shaw Ruth G.
Published: April 2019

The immediate capacity for adaptation under current environmental conditions is directly proportional to the additive genetic variance for fitness, VA(W). Mean absolute fitness,, is predicted to change at the rate, according to Fisher’s Fundamental Theorem of Natural Selection. Despite ample research evaluating degree of local adaptation, direct assessment of VA(W) and the capacity for ongoing adaptation is exceedingly rare. We estimated VA(W) andin three pedigreed populations of annualChamaecrista fasciculata,over three years in the wild. Contrasting with common expectations, we found significant VA(W) in all populations and years, predicting increased mean fitness in subsequent generations (0.83 to 6.12 seeds per individual). Further, we detected two cases predicting “evolutionary rescue”, where selection on standing VA(W) was expected to increase fitness of declining populations (< 1.0) to levels consistent with population sustainability and growth. Within populations, interannual differences in genetic expression of fitness were striking. Significant genotype-by-year interactions reflected modest correlations between breeding values across years (allr< 0.490), indicating temporally variable selection at the genotypic level; that could contribute to maintaining VA(W). By directly estimating VA(W) and total lifetime, our study presents an experimental approach for studies of adaptive capacity in the wild.
Grain Protein Content QTLs Identified in a Durum × Wild Emmer Wheat Mapping Population Tested in Five Environments
Authors: Fatiukha Andrii , Lupo Itamar , Lidzbarsky Gabriel , Klymiuk Valentina , Korol Abraham B. , Pozniak Curtis , Fahima Tzion , Krugman Tamar
Published: April 2019

Wild emmer wheat (Triticum turgidumssp.dicoccoides, WEW) was shown to exhibit high grain protein content (GPC) and therefore, possess a great potential for improvement of cultivated wheat nutritional value. A recombinant inbred line (RIL) population derived from a cross betweenT. durumvar. Svevo and WEW acc. Y12-3 was used for construction of a high-density genetic map and genetic dissection of GPC. Genotyping of 208 F6RILs with 15K wheat SNP array yielded 4,166 polymorphic SNP markers, of which 1,510 were designated as skeleton markers. A total map length of 2,169 cM was obtained with an average distance of 1.5 cM between SNPs. A total of 12 GPC QTLs with LOD score range of 2.7-35.9, and PEV of 2.6-26.6% were identified under five environments. Major QTLs with favorable alleles from WEW were identified on chromosomes 4BS, 5AS, 6BS and 7BL. The QTL region on 6BS coincided with the physical position of the previously cloned QTL,Gpc-B1. Comparisons of the physical intervals of the GPC QTLs described here with the results previously reported in other durum×WEW RIL population led to the identification of four common and two homoeologous QTLs. Exploration of the large genetic variation within WEW accessions is a precondition for discovery of exotic beneficial alleles, as we have demonstrated here, by the identification of seven novel GPC QTLs. Therefore, our research emphasizes the importance of GPC QTL dissection in diverse WEW accessions as a source of novel alleles for improvement of GPC in cultivated wheat.

Key message

Genetic dissection of GPC in tetraploid durum × WEW RIL population, based on high-density SNP genetic map, revealed 12 QTLs, with favorable WEW allele for 11 QTLs.
Continuous theta burst TMS of area MT+ impairs attentive motion tracking
Authors: Chakraborty Arijit , Tran Tiffany T. , Silva Andrew E. , Giaschi Deborah , Thompson Benjamin
Published: April 2019

Attentive motion tracking deficits, measured using multiple object tracking (MOT) tasks, have been identified in a number of visual and neurodevelopmental disorders such as amblyopia and autism. These deficits are often attributed to the abnormal development of high-level attentional networks. However, neuroimaging evidence from amblyopia suggests that reduced MOT performance can be explained by impaired function in motion sensitive area MT+ alone. To test the hypothesis that MT+ plays an important role in MOT, we assessed whether modulation of MT+ activity using continuous theta burst stimulation (cTBS) influenced MOT performance in participants with normal vision. An additional experiment involving numerosity judgements of MOT stimulus elements was conducted to control for non-specific effects of MT+ cTBS on psychophysical task performance. The MOT stimulus consisted of 4 target and 4 distractor dots and was presented at 10° eccentricity in the right or left hemifield. Functional MRI-guided cTBS was applied to left MT+. Participants (n = 13, age:27 ± 3) attended separate active and sham cTBS sessions where the MOT task was completed before, 5 mins post and 30 mins post cTBS. Active cTBS significantly impaired MOT task accuracy relative to baseline for the right (stimulated) hemifield 5 mins (10 ± 2% reduction; t12= 1.95, p = 0.03) and 30 mins (14 ± 3% reduction; t12= 2.96, p = 0.01) post stimulation. No impairment occurred within the left (control) hemifield after active cTBS or for either hemifield after sham cTBS. Numerosity task performance was unaffected by cTBS. These results highlight the importance of lower-level motion processing for MOT and suggest that abnormal function of MT+ alone is sufficient to cause a deficit in MOT task performance.
Chromatin-lamin B1 interaction promotes genomic compartmentalization and constrains chromatin dynamics
Authors: Chang Lei , Li Mengfan , Shao Shipeng , Xue Boxin , Hou Yingping , Zhang Yiwen , Li Ruifeng , Li Cheng , Sun Yujie
Published: April 2019

The eukaryotic genome is folded into higher-order conformation accompanied with constrained dynamics for coordinated genome functions. However, the molecular machinery underlying these hierarchically organized chromatin architecture and dynamics remains poorly understood. Here by combining imaging and Hi-C sequencing, we studied the role of lamin B1 in chromatin architecture and dynamics. We found that lamin B1 depletion leads to chromatin redistribution and decompaction. Consequently, the inter-chromosomal interactions and overlap between chromosome territories are increased. Moreover, Hi-C data revealed that lamin B1 is required for the integrity and segregation of chromatin compartments but not for the topologically associating domains (TADs). We further proved that depletion of lamin B1 leads to increased chromatin dynamics, owing to chromatin decompaction and redistribution toward nuclear interior. Taken together, our data suggest that chromatin-lamin B1 interactions promote chromosomal territory segregation and genomic compartmentalization, and confine chromatin dynamics, supporting its crucial role in chromatin higher-order structure and dynamics.
Native molecule sequencing by nano-ID reveals synthesis and stability of RNA isoforms
Authors: Maier Kerstin C. , Gressel Saskia , Cramer Patrick , Schwalb Björn
Published: April 2019

Eukaryotic genes often generate a variety of RNA isoforms that can lead to functionally distinct protein variants. The synthesis and stability of RNA isoforms is however poorly characterized. The reason for this is that current methods to quantify RNA metabolism use ‘short-read’ sequencing that cannot detect RNA isoforms. Here we present nanopore sequencing-based Isoform Dynamics (nano-ID), a method that detects newly synthesized RNA isoforms and monitors isoform metabolism. nano-ID combines metabolic RNA labeling, ‘long-read’ nanopore sequencing of native RNA molecules and machine learning. Application of nano-ID to the heat shock response in human cells reveals that many RNA isoforms change their synthesis rate, stability, and splicing pattern. nano-ID also shows that the metabolism of individual RNA isoforms differs strongly from that estimated for the combined RNA signal at a specific gene locus. And although combined RNA stability correlates with poly(A)-tail length, individual RNA isoforms can deviate significantly. nano-ID enables studies of RNA metabolism on the level of single RNA molecules and isoforms in different cell states and conditions.
Spectral tilt underlies mathematical problem solving
Authors: Randazzo Michael J. , Ezzyat Youssef , Kahana Michael J.
Published: April 2019

Neural activity associated with successful cognition appears as a tilt in the power spectrum of the local field potential, wherein increases in high-frequency power accompany decreases in low frequency power. Whereas this pattern has been shown in a wide range of memory tasks, it is unknown whether this increased spectral tilt reflects underlying memory-specific processes or rather a domain-general index of task engagement. To address the question of whether increased spectral tilt reflects increased attention to a cognitive task, we collected intracranial recordings from three hundred thirty neurosurgical patients as they performed a mathematical problem solving task. We used a mathematical problem solving task, because it allowed us to decouple task-specific processes with domain-general attention in a novel way. Using a statistical model to control for inherent problem complexity, we classified individual math problems based on whether a subject performed faster than predicted (high-attention orfast) or slower than predicted (low-attention, orslow) based on residual response times. In contrast to the domain-general attentional account, problems that took longer than predicted produced stronger evidence for the spectral tilt: widespread increases in high frequency (31–180 Hz) power and decreases in low frequency (3–17 Hz) power across frontal, temporal, and parietal cortices. The pattern emerged early within each trial and was sustained throughout the response period but was not observed in the medial temporal lobe. The data show that engaging in mathematical problem solving leads to a distributed spectral tilt pattern, even when accounting for variability in performance driven by the arithmetic demands of the problems themselves, and suggest that broadband changes in the power spectrum reflect an index of information processing in the brain beyond simple attention to the cognitive task.
Megaplasmids on the Rise: Combining Sequencing Approaches to Fully Resolve a Carbapenemase-Encoding Plasmid in a Proposed NovelPseudomonasSpecies
Authors: Botelho João , Lood Cédric , Partridge Sally R. , van Noort Vera , Lavigne Rob , Grosso Filipa , Peixe Luísa
Published: April 2019

Horizontal transfer of plasmids plays a pivotal role in the dissemination of antibiotic resistance genes and emergence of multidrug-resistant bacteria. Sequencing of plasmids is thus paramount for the success of accurate epidemiological tracking strategies in the hospital setting and routine surveillance. Here, we combine Nanopore and Illumina sequencing to fully assemble a carbapenemase-encoding megaplasmid carried by a clinical isolate belonging to a putative novelPseudomonasspecies. FFUP_PS_41 has a multidrug resistance phenotype and was initially identified asPseudomonas putida, but an average nucleotide identity below the cut-off for species delineation suggests a new species related to theP. putidaphylogenetic group. FFUP_PS_41 harbors a 498,516-bp untypable megaplasmid (pJBCL41) with low similarity compared with publicly available plasmids. pJBCL41 contains a full set of genes for self-transmission and genes predicted to be responsible for plasmid replication, partitioning, maintenance and heavy metal resistance. pJBCL41 carries a class 1 integron with the |aacA7|blaVIM-2|aacA4| cassette array (In103) located within a defective Tn402-like transposon that forms part of a 50,273-bp mosaic region bound by 38-bp inverted repeats typical of the Tn3family and flanked by 5-bp direct repeats. This region is composed of different elements, including additional transposon fragments, five insertion sequences and a Tn3-Derived Inverted-Repeat Miniature Element. The hybrid Nanopore/Illumina approach resulted in contiguous assemblies and allowed us to fully resolve a carbapenemase-encoding megaplasmid fromPseudomonasspp. The identification of novel megaplasmids will shed a new light on the evolutionary effects of gene transfer and the selective forces driving AR.
Generation of human hepatic progenitor cells with regenerative and metabolic capacities from primary hepatocytes
Authors: Katsuda Takeshi , Matsuzaki Juntaro , Yamaguchi Tomoko , Yamada Yasuhiro , Hosaka Kazunori , Takeuchi Atsuko , Saito Yoshimasa , Ochiya Takahiro
Published: April 2019

Hepatocytes are regarded as the only effective cell source for cell transplantation to treat liver diseases; however, their availability is limited due to a donor shortage. Thus, a novel cell source must be developed. We recently reported that mature rodent hepatocytes can be reprogrammed into progenitor-like cells with a repopulative capacity using small molecule inhibitors. Here, we demonstrate that hepatic progenitor cells can be obtained from human infant hepatocytes using the same strategy. These cells, named human chemically induced liver progenitors (hCLiPs), had a significant repopulative capacity in injured mouse livers following transplantation. hCLiPs redifferentiated into mature hepatocytes in vitro upon treatment with hepatic maturation-inducing factors. These redifferentiated cells exhibited cytochrome P450 (CYP) enzymatic activities in response to CYP-inducing molecules and these activities were comparable with those in primary human hepatocytes. These findings will facilitate liver cell transplantation therapy and drug discovery studies.
PBS3 and EPS1 complete salicylic acid biosynthesis from isochorismate in Arabidopsis
Authors: Torrens-Spence Michael P. , Bobokalonova Anastassia , Carballo Valentina , Glinkerman Christopher M. , Pluskal Tomáš , Shen Amber , Weng Jing-Ke
Published: April 2019

Salicylic acid (SA) is an important phytohormone mediating both local and systemic defense responses in plants. Despite over half a century of research, how plants biosynthesize SA remains unresolved. In Arabidopsis, a major part of SA is derived from isochorismate, a key intermediate produced by the isochorismate synthase (ICS), which is reminiscent of SA biosynthesis in bacteria. Whereas bacteria employ an isochorismate pyruvate lyase (IPL) that catalyzes the turnover of isochorismate to pyruvate and SA, plants do not contain an IPL ortholog and generate SA from isochorismate through an unknown mechanism. Combining genetic and biochemical approaches, we delineated the SA biosynthetic pathway downstream of isochorismate in Arabidopsis. We show that PBS3, a GH3 acyl adenylase-family enzyme important for SA accumulation, catalyzes ATP- and Mg2+-dependent conjugation of L-glutamate primarily to the 8-carboxyl of isochorismate and yields the key SA biosynthetic intermediate isochorismoyl-glutamate A. Moreover, EPS1, a BAHD acyltransferase-family protein with previously implicated role in SA accumulation upon pathogen attack, harbors a noncanonical active site and an unprecedented isochorismoyl-glutamate A pyruvoyl-glutamate lyase (IPGL) activity that produces SA from the isochorismoyl-glutamate A substrate. Together, PBS3 and EPS1 form a two-step metabolic pathway to produce SA from isochorismate in Arabidopsis, which is distinct from how SA is biosynthesized in bacteria. This study closes a major knowledge gap in plant SA metabolism and would help develop new strategies for engineering disease resistance in crop plants.
Solid State High Throughput Screening Microscopy
Authors: Ashraf M. , Mohanan S. , Sim B , Tam A. , Brousseau D. , Thibault S. , Corbett A. , Bub G.
Published: April 2019

We introduce a solid state high throughput screening (ssHTS) imaging modality that uses a novel Newtonian telescope design to image multiple spatially separated samples without moving parts or robotics. Conventional high-throughput imaging modalities either require movement of the sample to the focal plane of the imaging system1–3 or movement of the imaging system itself4,5, or use a wide-field approach to capture several samples in one frame. Schemes which move the sample or the imaging system can be mechanically complex and are inherently slow, while wide-field imaging systems have poor light collection efficiency and resolution compared to systems that image a single sample at a given time point. Our proposed ssHTS system uses a large parabolic reflector and an imaging lenses positioned at their focal distances above each sample. A fast LED array sequentially illuminate samples to generate images that are captured with a single camera placed at the focal point of the reflector. This optical configuration allows each sample to completely fill a sensors field of view. Since each LED illuminates a single sample and LED switch times are very fast, images from spatially separated samples can be captured at rates limited only by the camera’s frame rate. The system is demonstrated by imaging cardiac monolayer and Caenorhabditis elegans (C. elegans) preparations.
Odor-background segregation of unknown odorants based on stimulus onset asynchrony in honey bees
Authors: Sehdev Aarti , Szyszka Paul
Published: April 2019

Animals use olfaction to search for distant objects. Unlike vision, where objects are spaced out, olfactory information mixes when it reaches olfactory organs. Therefore, efficient olfactory search requires segregating odors that are mixed with background odors. Animals can segregate known target odors by detecting short differences in the arrival of odorants from different sources (stimulus onset asynchrony). However, it is unclear whether animals can also use stimulus onset asynchrony to segregate previously unknown odorants that have no innate or learned relevance. Using behavioral experiments in honey bees, we here show that stimulus onset asynchrony also improves odor-background segregation of unknown odorants. The stimulus onset asynchrony necessary to behaviorally segregate unknown odorants is in the range of seconds, which is two orders of magnitude larger than the previously reported stimulus asynchrony sufficient for segregating known odorants. We propose that for unknown odorants, odor-background segregation requires sensory adaptation to the background stimulus.
A Network Architecture for Bidirectional Neurovascular Coupling in Rat Whisker Barrel Cortex
Authors: Kumar Bhadra S. , Khot Aditi , Chakravarthy Srinivasa V , Pushpavanam S
Published: April 2019

The neurovascular coupling is mostly considered as a master-slave relationship between the neurons and the cerebral vessels: the neurons demand energy which the vessels supply in the form of glucose and oxygen. In the recent past both theoretical and experimental studies have suggested that the neurovascular coupling is a bidirectional system, a loop that includes a feedback signal from the vessels influencing neural firing and plasticity. An integrated model of bidirectionally connected neural network and vascular network is hence required to understand the relationship between the informational and metabolic aspects of neural dynamics. In this study, we present a computational model of the bidirectional neurovascular system in the whisker barrel cortex and study the effect of such coupling on neural activity and plasticity as manifest in the map formation. In this model, a biologically plausible self-organizing network model of rate coded, dynamic neurons is nourished by a network of vessels modeled using the biophysical properties of blood vessels. The neural layer which is designed to simulate the whisker barrel cortex of rat transmits the vasodilatory signals to the vessels. The feedback from the vessels is in the form of available oxygen for oxidative metabolism whose end result is the ATP necessary to fuel neural firing. The model captures the effect of the feedback from the vascular network on the neuronal map formation in the whisker barrel model under normal and pathological (Hypoxia and Hypoxia-Ischemia) conditions.

Author Summary

Although neurovascular coupling is typically depicted as a unidirectional influence originating from the neurons and acting on the cerebral vessels, in reality it forms a bidirectional system, consisting of neuronal energy demand signals transmitted to the vessels, and a feedback of metabolic substrates from the vessels, that influence the neural firing and plasticity. We present a computational model of the bidirectional neurovascular coupling in the whisker barrel cortex of rats and study the effect of such coupling on neural activity and plasticity as manifest in the map formation. The model consists of a biologically plausible self-organizing dynamic, neural network model and a biophysical vascular network model that nourishes the neural network in the form of oxygen necessary for neural oxidative metabolism. The model reproduces the spatio-temporal hemodynamic responses observed in rat whisker barrel cortex. It also demonstrates the essentiality of the vascular feedback on the whisker barrel map formation under normal and pathological conditions.