bluuebunny/crossref_metadata_2025 huggingface dataset:
Dyella solisilvae sp. nov., isolated from mixed pine and broad-leaved forest soil
Authors: Gao Zeng-hong , Yang Zi , Chen Mei-hong , Huang Zhi-jie , Qiu Li-hong
Published: January 2019

A Gram-stain-negative, aerobic, motile, yellow-pigmented, rod-shaped with a single polar flagellum bacterial strain, designated strain DHG54T, was isolated from a forest soil sample of Dinghushan Biosphere Reserve, Guangdong Province, China. Strain DHG54T grew at 12–37 °C (optimum, 28 °C), pH 4.5–8.0 (optimum, pH 6.0–7.0) and in the presence of 0–3.0 % (w/v) NaCl (optimum, 0–1.5 %, w/v). Based on 16S rRNA gene sequence analysis, strain DHG54T formed a clade with the members of the genus

Dyella

and showed highest sequence similarities of 98.2 % to

Dyella japonica

DSM 16301T and

Dyella terrae

KACC 12748T. This was also supported by phylogenetic analysis based on the concatenated partial gyrB, lepA and recA housekeeping gene sequences. DNA–DNA hybridization results between strain DHG54T and closely related

Dyella

species were all lower than 70 %. Ubiquinone-8 was the only respiratory quinone, and iso-C15 : 0, iso-C17 : 0 and iso-C17 : 1
 ω9c were major fatty acids. The DNA G+C content of strain DHG54T was 65.4 mol%. The major polar lipids were phosphatidylethanolamine, phosphatidylglycerol and diphosphatidylglycerol. On the basis of the polyphasic characterization results presented here, strain DHG54T represents a novel species of the genus

Dyella

, for which the name

Dyella
solisilvae sp. nov. (type strain DHG54T=GDMCC 1.1187T = LMG 30091T) is proposed.
Discovery of New Classes of Glycine transporter 2 (GlyT2) Inhibitors and Study of GlyT2 Selectivity by Combination of Novel Structural Based Virtual Screening Approach and Free Energy Perturbation (FEP+) Calculations
Authors: Fratev Filip , Miranda-Arango Manuel , Padilla Elvia , Sirimulla Suman
Published: January 2019

In recent years, the mammalian GlyT2 transporter have emerged as a promising target for the development of anti-chronic pain agents. In our current work, we discovered a new set of promising hits that inhibit the glycine transport at nano and micromolar activity and have excellent selectivity over GlyT1 (as shown by in vitro studies), using a newly designed virtual screening (VS) protocol that combines a structure-based pharmacophore and docking screens. Furthermore, the free energy perturbation (FEP+ protocol) calculations and molecular dynamics (MD) studies revealed the GlyT2 amino acid residues critical for the binding and selectivity of both Glycine and our Lead1 compound. The FEP+ results well-matched available literature mutational data proving the quality of generated GlyT2 structure. Based on these calculations we propose that Lead1 may also be a strong inhibitor of the neutral and basic amino acid transporter B (0+) (SLC6A14). Thus, the subsequent lead optimization and characterization of refined compounds may lead to both chronic pain and pancreatic cancer agents addressing an unmet and challenging clinical needs.
Genomics and transcriptomics to unravel sex determination pathway and its evolution in sand flies
Authors: Petrella Valeria , Aceto Serena , Colonna Vincenza , Saccone Giuseppe , Sanges Remo , Polanska Nikola , Volf Petr , Gradoni Luigi , Bongiorno Gioia , Salvemini Marco
Published: January 2019

Background

Phlebotomine sand flies (Diptera, Nematocera) are important vectors of several pathogens, includingLeishmaniaparasites, causing serious diseases of humans and dogs. Despite their importance as disease vectors, most aspects of sand fly biology remain unknown including the molecular bases of their reproduction and sex determination, aspects also relevant for the development of novel vector control strategies.

Results

Using a comparative genomics/transcriptomics approach, we identified the sex determining genes in phlebotomine sand flies and proposed the first model for the sex determination cascade of these insects. For all the genes identified, we produced manually curated gene models, developmental gene expression profile and performed evolutionary molecular analysis. We identified and characterized, for the first time in a Nematocera species, thetransformer(tra) homolog which exhibits both conserved and novel features. The analysis of thetralocus in sand flies and its expression pattern suggest that this gene is able to autoregulate its own splicing, as observed in the fruit flyCeratitis capitataand several other insect species.

Conclusions

Our results permit to fill the gap about sex determination in sand flies, contribute to a better understanding of this developmental pathway in Nematocera and open the way for the identification of sex determining orthologs in other species of this important Diptera sub-order. Furthermore, the sex determination genes identified in our work also provide the opportunity of future biotech applications to control natural population of sand flies, reducing their impact on public health.
Nod2 protects remote small intestinal sites in case of colonic inflammation
Authors: Nabhani Ziad Al , Berrebi Dominique , Martinez-Vinson Christine , Montcuquet Nicolas , Dietrich Gilles , Singh Gurminder , Turner Jerrold R. , Madre Chrystele , Roy Maryline , Ogier-Denis Eric , Dussaillant Monique , Cerf-Bensussan Nadine , Zouali Habib , Jung Camille , Daniel Fanny , Barreau Frédérick , Hugot Jean-Pierre
Published: January 2019

NOD2 mutations are key risk factors for Crohn’s disease (CD). NOD2 contributes to intestinal homeostasis by regulating innate and adaptive immunity together with intestinal epithelial function. However, the roles of NOD2 during gut inflammation is not known. We initially observed that NOD2 expression was increased in epithelial cells remote from inflamed areas in CD patients. To explore this finding, Nod2 mRNA expression, inflammation and gut permeability were examined in the small bowel of wild-type (WT), Nod2 knockout and Nod2 mutant mice after rectal instillation of 2,4,6-trinitrobenzene sulfonic acid (TNBS). In WT mice, Nod2 upregulation remote to rectal injury was associated with pro-inflammatory cytokine expression, recirculating CD4+ T-cells, increased paracellular permeability and myosin like chain kinase activity. Nod2 knockout or mutation led to duodenitis and ileitis demonstrating the remote protective role of Nod2. Bone morrow stem cell (BMSC) transplantations indicated that the small intestinal inflammation was due to NOD2 loss in both hematopoietic and non-hematopoietic compartments. As a whole, WT but not mutant NOD2 prevents disease extension at sites remote from the initial intestinal injury.
Cannabinoids modulate associative cerebellar learning via alterations in behavioral state
Authors: Albergaria Catarina , Silva N. Tatiana , Darmohray Dana , Carey Megan R.
Published: January 2019

Cannabinoids are notorious and profound modulators of behavioral state. In the brain, endocannabinoids act via Type 1-cannabinoid receptors (CB1) to modulate synaptic transmission and mediate multiple forms of synaptic plasticity. CB1 knockout (CB1KO) mice display a range of behavioral phenotypes, in particular hypoactivity and various deficits in learning and memory, including cerebellumdependent delay eyeblink conditioning. Here we find that the apparent effects of CB1 deletion on cerebellar learning are not due to direct effects on CB1-dependent plasticity, but rather, arise as a secondary consequence of altered behavioral state. Hypoactivity of CB1KO mice accounts for their impaired eyeblink conditioning across both animals and trials. Moreover, learning in these mutants is rescued by walking on a motorized treadmill during training. Finally, cerebellar granule cell-specific CB1KOs exhibit normal eyeblink conditioning, and both global and granule cell-specific CB1KOs display normal cerebellum-dependent locomotor coordination and learning. These findings highlight the modulation of behavioral state as a powerful independent means through which individual genes contribute to complex behaviors.
Associations between vascular risk factors and brain MRI indices in UK Biobank
Authors: Cox SR , Lyall DM , Ritchie SJ , Bastin ME , Harris MA , Buchanan CR , Fawns-Ritchie C , Barbu MC , de Nooij L , Reus LM , Alloza C , Shen X , Neilson E , Alderson HL , Hunter S , Liewald DC , Whalley HC , McIntosh AM , Lawrie SJ , Pell JP , Tucker-Drob EM , Wardlaw JM , Gale CR , Deary IJ
Published: January 2019

Aims

Several factors are known to increase risk for cerebrovascular disease and dementia, but there is limited evidence on associations between multiple vascular risk factors (VRFs) and detailed aspects of brain macro- and microstructure in large community-dwelling populations across middle- and older age.

Methods and Results

Associations between VRFs (smoking, hypertension, pulse pressure, diabetes, hypercholersterolaemia, BMI, and waist-hip ratio) and both global and regional brain structural and diffusion MRI markers were examined in UK Biobank (N = 9722, age range 44-77 years). A larger number of VRFs was associated with greater brain atrophy, lower grey matter volume, and poorer white matter health. Effect sizes were small (brain structural R2 ≤ 1.8%). Higher aggregate vascular risk was related to multiple regional MRI hallmarks associated with dementia risk: lower frontal and temporal cortical volumes, lower subcortical volumes, higher white matter hyperintensity volumes, and poorer white matter microstructure in association and thalamic pathways. Smoking pack years, hypertension and diabetes showed the most consistent associations across all brain measures. Hypercholesterolaemia was not uniquely associated with any MRI marker.

Conclusion

Higher levels of VRFs were associated with poorer brain health across grey and white matter macro- and microstructure. Effects are mainly additive, converging upon frontal and temporal cortex, subcortical structures, and specific classes of white matter fibres. Though effect sizes were small, these results emphasise the vulnerability of brain health to vascular factors even in relatively healthy middle and older age, and the potential to partly ameliorate cognitive decline by addressing these malleable risk factors.
Combining 3D-MOT with motor and perceptual decision-making tasks: conception of a life-sized virtual perceptual-cognitive training paradigm
Authors: Romeas Thomas , Chaumillon Romain , Labbé David , Faubert Jocelyn
Published: January 2019

The present study introduces a virtual life-sized perceptual-cognitive paradigm combining three dimensional multiple object tracking (3D-MOT) with motor (Experiment 1) or perceptual (Experiment 2) decision-making tasks. The objectives were to assess the impact of training on task performance and to determine the best training conditions for improvement and learning.

Seventy-one participants were randomly trained under one of four training conditions (isolated 3D-MOT task, 3D-MOT simultaneously combined with a decision-making task, consolidated 3D-MOT and decision-making task, isolated decision-making task). Task performance was evaluated using speed thresholds, decision accuracy (%) and reaction time (s).

Findings showed that the dual-task paradigm allowed satisfactory degrees of performance on both tasks despite an important dual-task cost. Interestingly, the results seemed to favor consolidated over simultaneous training for dual-task performance when 3D-MOT was combined with a motor task. The amount of attentional shared resources in regards to the nature of the additional task was discussed.
Structure and function of a 9.6 megadalton bacterial iron storage compartment
Authors: Giessen T. W. , Orlando B. J. , Verdegaal A. A. , Chambers M. G. , Gardener J. , Bell D. C. , Birrane G. , Liao M. , Silver P. A.
Published: January 2019

Iron storage proteins are essential for maintaining intracellular iron homeostasis and redox balance. Iron is generally stored in a soluble and bioavailable form inside ferritin protein compartments. However, some organisms do not encode ferritins and thus rely on alternative storage strategies. Encapsulins, a class of protein-based organelles, have recently been implicated in microbial iron and redox metabolism. Here, we report the structural and mechanistic characterization of a 42 nm two-component encapsulin-based iron storage compartment fromQuasibacillus thermotolerans. Using cryo-electron microscopy and x-ray crystallography, we reveal the assembly principles of a thermostable T = 4 shell topology and its catalytic ferroxidase cargo. We show that the cargo-loaded compartment has an exceptionally large iron storage capacity storing over 23,000 iron atoms. These results form the basis for understanding alternate microbial strategies for dealing with the essential element iron.
Selection and characterization of a reovirus mutant with improved thermostability
Authors: Snyder Anthony J. , Danthi Pranav
Published: January 2019

The environment represents a significant barrier to infection. Physical stressors (heat) or chemical agents (ethanol and sodium dodecyl sulfate) can render virions noninfectious. As such, discrete proteins are necessary to stabilize the dual layered structure of mammalian orthoreovirus (reovirus). The outer capsid participates in cell entry: (i) σ3 is degraded to generate the infectious subviral particle and (ii) μ1 facilitates membrane penetration and subsequent core delivery. μ1-σ3 interactions also prevent inactivation; however, this activity is not fully characterized. Using forward and reverse genetic approaches, we identified two mutations (μ1 M258I and σ3 S344P) within heat resistant strains. σ3 S344P was sufficient to enhance capsid integrity and to reduce protease sensitivity. Moreover, these changes impaired replicative fitness in a reassortant background. This work reveals new details regarding the determinants of reovirus stability.

SIGNIFICANCE

Nonenveloped viruses rely on protein-protein interactions to shield their genomes from the environment. The capsid, or protective shell, must also disassemble during cell entry. In this work, we identified a determinant within mammalian orthoreovirus that regulates heat resistance, disassembly kinetics, and replicative fitness. Together, capsid function is balanced for optimal replication and for spread to a new host.
WDR76 promotes MLL-rearranged leukemia via selective recognition of 5-hydroxymethylcytosine in DNA
Authors: Malecek Kathryn E. , Weng Hengyou , Sullivan Matthew A. , Kokontis Claire Y. , Werner Michael S. , Chen Jianjun , Ruthenburg Alexander J.
Published: January 2019

Although rare, the distribution of the 5-hydroxymethylcytosine (hmC) modification in mammalian DNA is tissue- and gene-specific, yet distinct from its transcriptionally-repressive methylcytosine (mC) precursor, suggesting unique signaling potential. To examine this possibility, we fractionated mammalian brain extracts to discover binding partners specific for oxidized states of mC. We demonstrate that one such factor, WDR76, is a highly hmC-specific binding protein that modulates gene expression within chromosomal regions enriched in hmC where it binds. We demonstrate direct transcriptional activation of several target genes in mouse embryonic stem cells as a function of hmC levels and contingent upon WDR76. In human cell lines and mouse models, WDR76 recruitment by hmC is critical for the initiation and maintenance of MLL-rearranged leukemias. Beyond its canonical role as an intermediate in mC remediation, we show that hmC can be an epigenetic mark whose recognition drives leukemogenesis, portending analogous signaling pathways for other rare DNA modifications.
Cytoplasmic volume and limiting nucleoplasmin scale nuclear size duringXenopus laevisdevelopment
Authors: Chen Pan , Tomschik Miroslav , Nelson Katherine , Oakey John , Gatlin J. C. , Levy Daniel L.
Published: January 2019

How nuclear size is regulated relative to cell size is a fundamental cell biological question. Reductions in both cell and nuclear sizes duringXenopus laevisembryogenesis provide a robust scaling system to study mechanisms of nuclear size regulation. To test if the volume of embryonic cytoplasm is limiting for nuclear growth, we encapsulated gastrula stage embryonic cytoplasm and nuclei in droplets of defined volume using microfluidics. Nuclei grew and reached new steady-state sizes as a function of cytoplasmic volume, supporting a limiting component mechanism of nuclear size control. Through biochemical fractionation, we identified the histone chaperone nucleoplasmin (Npm2) as a putative nuclear size-scaling factor. Cellular amounts of Npm2 decrease over development, and nuclear size was sensitive to Npm2 levels both in vitro and in vivo, affecting nuclear histone levels and chromatin organization. Thus, reductions in cell volume with concomitant decreases in Npm2 amounts represent a developmental mechanism of nuclear size-scaling that may also be relevant to cancers with increased nuclear size.
ABC transporters confer multidrug resistance to Drosophila intestinal stem cells
Authors: Dayton Hannah , DiRusso Jonathan , Kolbert Kristopher , Williamson Olivia , Balciunaite Aiste , D’Souza Edridge , Becker Kelly , Hosage Elizaveta , Issa Muneera , Liu Victoria , Viswanatha Raghuvir , Kondo Shu , Markstein Michele
Published: January 2019

Adult stem cells can survive a wide variety of insults from ionizing radiation to toxic chemicals1–3. To date, the multidrug resistant features of stem cells have been characterized only in vertebrates, where there is a critical need to understand how cancer stem cells thwart chemotherapy drugs4–6. These studies reveal that the ability of both normal and cancer stem cells to survive toxins hinges on their high levels of expression of ABC transporters, transmembrane pumps that efflux lipophilic compounds out of cells7,8. This has been observed across a wide spectrum of vertebrate stem cells including breast, blood, intestine, liver, and skin, suggesting that high efflux ability and multidrug resistance may be general features of stem cells that distinguish them from their differentiated daughter cells. Here we show that these previously described vertebrate stem cell features are conserved in Drosophila intestinal stem cells. Using a novel in vivo efflux assay and multiple drug challenges, we show that stem cells in the fly intestine depend on two ABC transporters—one constitutively expressed and the other induced—for efflux and multidrug resistance. These results suggest that stem cell multidrug resistance by ABC transporters is a general stem cell feature conserved over 500 million years of evolution.
Divergence in gut microbial communities mirrors a social group fission event in a black-and-white colobus monkey (Colobus vellerosus)
Authors: Goodfellow Claire K. , Whitney Tabor , Christie Diana M. , Sicotte Pascale , Wikberg Eva C. , Ting Nelson
Published: January 2019

Host behavior and social factors have increasingly been implicated in structuring the composition of gut microbial communities. In social animals, distinct microbial communities characterize different social groups across a variety of taxa, although little longitudinal research has been conducted that demonstrates how this divergence occurs. Our study addresses this question by characterizing the gut microbial composition of an African Old World monkey, the black-and-white colobus (Colobus vellerosus), prior to and after a social group fission event. Gut microbial taxonomic composition of these monkeys was profiled using the V-4 hypervariable region of the bacterial 16s rRNA gene, and pairwise-relatedness values were calculated for all individuals using 17 STR loci and partial pedigree information. The two social groups in this study were found to harbor distinct microbial signatures after the fission event from which they emerged, while these communities were not divergent in the same individuals prior to this event. Three genera were found to differ in abundance between the two new social groups: Parabacteroides, Coprococcus, and Porphyromonadaceae. Additionally, although this fission happened partially along lines of relatedness, relatedness did not structure the differences that we found. Taken together, this study suggests that distinct gut microbial profiles can emerge in social groups in less than one year and recommends further work into more finely mapping the timescales, causes, and potentially adaptive effects of this recurring trend toward distinct group microbial signatures.

Research highlights

Distinct gut microbial profiles emerge in two social groups of C. vellerosus less than nine months after a fission event.

Three genera differ in abundance between the two new social groups.

Relatedness does not structure differences in microbial composition between the groups.
A Hybrid Deep Clustering Approach for Robust Cell Type Profiling Using Single-cell RNA-seq Data
Authors: Srinivasan Suhas , Johnson Nathan T. , Korkin Dmitry
Published: January 2019

Single-cell RNA sequencing (scRNA-seq) is a recent technology that enables fine-grained discovery of cellular subtypes and specific cell states. It routinely uses machine learning methods, such as feature learning, clustering, and classification, to assist in uncovering novel information from scRNA-seq data. However, current methods are not well suited to deal with the substantial amounts of noise that is created by the experiments or the variation that occurs due to differences in the cells of the same type. Here, we develop a new hybrid approach, Deep Unsupervised Single-cell Clustering (DUSC), that integrates feature generation based on a deep learning architecture with a model-based clustering algorithm, to find a compact and informative representation of the single-cell transcriptomic data generating robust clusters. We also include a technique to estimate an efficient number of latent features in the deep learning model. Our method outperforms both classical and state-of-the-art feature learning and clustering methods, approaching the accuracy of supervised learning. The method is freely available to the community and will hopefully facilitate our understanding of the cellular atlas of living organisms as well as provide the means to improve patient diagnostics and treatment.
Setting off the Alarms:Candida albicansElicits Pro-Inflammatory Differential Gene Expression in Intestinal Peyer’s Patches
Authors: Singh Navjot , Kim Heather C. , Song Renjie , Dhinsa Jaskiran K. , Torres Steven R. , Jesus Magdia De
Published: January 2019

Candida albicanshas been associated with a number of human diseases that pertain to the gastrointestinal (GI) tract. However, the details of how gut-associated lymphoid tissues (GALT) such as Peyer’s patches (PPs) in the small intestine play a role in immune surveillance and microbial differentiation, and what mechanisms PP use to protect the mucosal barrier in response to fungal organisms such asC. albicans, are still unclear. We particularly focus on PPs as they are the immune sensors and inductive sites of the gut that influence inflammation and tolerance. We have previously demonstrated that CD11c+phagocytes located in the sub-epithelial dome (SED) within PPs sampleC. albicans. To gain insight on how specific cells within PPs sense and respond to the sampling of fungi, we gavaged mice withC. albicansstrains ATCC 18804 and SC5314 as well asSaccharomyces cerevisiae. We measured the differential gene expression of sorted CD45+B220+B-cells, CD3+T-cells, and CD11c+DCs within the first 24 hrs post-gavage using nanostring nCounter® technology. The results reveal that at 24 hrs, PP phagocytes were the cell type that displayed differential gene expression. These phagocytes were both able to sampleC. albicansand able to discriminate between strains. In particular, strain ATCC 18804 upregulated fungal specific pro-inflammatory genes in CD11c+phagocytes pertaining to innate and adaptive immune responses. Interestingly, PP CD11c+phagocytes differentially expressed genes in response toC. albicansthat were important in the protection of the mucosal barrier. These results highlight that the mucosal barrier not only responds toC. albicans, but also aids in the protection of the host.

Importance

The specific gene expression changes within PPs that send the warning signals when encountering fungi, and how PPs can discriminate between innocuousS. cerevisiaeor different strains ofC. albicansduring early stages of sampling, have not been elucidated. Here we show that within the first 24 hours of sampling, CD11c+phagocytes were not only important in sampling, but they were the cell type that exhibited clear differential gene expression. These differentially expressed genes play important dual roles in inflammation, chemotaxis, and fungal specific recognition, as well as maintaining homeostasis and protection of the mucosal barrier. Using nanostring technology, we were also able to demonstrate that PPs can distinguish between different strains ofC. albicansand can “set off the alarms” when necessary.
Identifying small proteins by ribosome profiling with stalled initiation complexes
Authors: Weaver Jeremy , Mohammad Fuad , Buskirk Allen R. , Storz Gisela
Published: January 2019

Small proteins consisting of 50 or fewer amino acids have been identified as regulators of larger proteins in bacteria and eukaryotes. Despite the importance of these molecules, the true prevalence of small proteins remains unknown because conventional annotation pipelines usually exclude small open reading frames (smORFs). We previously identified several dozen small proteins in the model organismEscherichia coliusing theoretical bioinformatic approaches based on sequence conservation and matches to canonical ribosome binding sites. Here, we present an empirical approach for discovering new proteins, taking advantage of recent advances in ribosome profiling in which antibiotics are used to trap newly-initiated 70S ribosomes at start codons. This approach led to the identification of many novel initiation sites in intergenic regions inE. coli. We tagged 41 smORFs on the chromosome and detected protein synthesis for all but three. The corresponding genes are not only intergenic, but are also found antisense to other genes, in operons, and overlapping other open reading frames (ORFs), some impacting the translation of larger downstream genes. These results demonstrate the utility of this method for identifying new genes, regardless of their genomic context.

IMPORTANCE

Proteins comprised of 50 or fewer amino acids have been shown to interact with and modulate the function of larger proteins in a range of organisms. Despite the possible importance of small proteins, the true prevalence and capabilities of these regulators remain unknown as the small size of the proteins places serious limitations on their identification, purification and characterization. Here, we present a ribosome profiling approach with stalled initiation complexes that led to the identification of 38 new small proteins.
Effects of phenotypic robustness on adaptive evolutionary dynamics
Authors: Rigato Emanuele , Fusco Giuseppe
Published: January 2019

Theoretical and experimental studies have provided evidence for a positive role of phenotype resistance to genetic mutation in enhancing long-term adaptation to novel environments. With the aim of contributing to an understanding of the origin and evolution of phenotypic robustness to genetic mutations in organismal systems, we adopted a theoretical approach, elaborating on a classical mathematical formalizations of evolutionary dynamics, the quasispecies model. We show that a certain level of phenotypic robustness is not only a favourable condition for adaptation to occur, but that it is also a necessary condition for short-term adaptation in most real organismal systems. This appears as a threshold effect, i.e. as a minimum level of phenotypic robustness (critical robustness) below which evolutionary adaptation cannot consistently occur or be maintained, even in the case of sizably selection coefficients and in the absence of any drift effect. These results, are in agreement with the observed pervasiveness of robustness at different levels of biological organization, from molecules to whole organisms.
Coupling water fluxes with cell wall mechanics in a multicellular model of plant development
Authors: Cheddadi Ibrahim , Génard Michel , Bertin Nadia , Godin Christophe
Published: January 2019

The growth of plant organs is a complex process powered by osmosis that attracts water inside the cells; this influx induces simultaneously an elastic extension of the walls and pressure in the cells, called turgor pressure; above a threshold, the walls yield and the cells grow. Based on Lockhart’s seminal work, various models of plant morphogenesis have been proposed, either for single cells, or focusing on the wall mechanical properties. However, the synergistic coupling of fluxes and wall mechanics has not yet been fully addressed in a multicellular model. This work lays the foundations of such a model, by simplifying as much as possible each process and putting emphasis on the coupling itself. Its emergent properties are rich and can help to understand plant morphogenesis. In particular, we show that the model can display a new type of lateral inhibitory mechanism that could contribute to the amplification of growth heterogeneities, essential for shape differentiation.

Significance Statement

Plant cells are surrounded by a rigid wall that prevents cell displacements and rearrangements as in animal tissues. Therefore, plant morphogenesis relies only on cell divisions, shape changes, and local modulation of growth rate. It has long been recognized that cell growth relies on the competition between osmosis that tends to attract water into the cells and wall mechanics that resists to it, but this interplay has never been fully explored in a multicellular model. The goal of this work is to analyze the theoretical consequences of this coupling. We show that the emergent behavior is rich and complex: among other findings, pressure and growth rate heterogeneities are predicted without any ad-hoc assumption; furthermore the model can display a new type of lateral inhibition based on fluxes that could complement and strengthen the efficiency of already known mechanisms.
Interaction of HelQ helicase with RPA modulates RPA-DNA binding and stimulates HelQ to unwind DNA through a protein roadblock
Authors: Northall Sarah J. , Jenkins Tabitha , Ptchelkine Denis , Taresco Vincenzo , Cooper Christopher D. O. , Soultanas Panos , Bolt Edward L.
Published: January 2019

Cells reactivate compromised DNA replication forks using enzymes that include DNA helicases for separating DNA strands and remodelling protein-DNA complexes. HelQ helicase promotes replication-coupled DNA repair in mammals in a network of interactions with other proteins. We report newly identified HelQ helicase activities, when acting alone and when interacting with RPA. HelQ helicase was strongly inhibited by a DNA-protein barrier (BamHIE111A), and by an abasic site in the translocating DNA strand. Interaction of HelQ with RPA activated DNA unwinding through the protein barrier, but not through the abasic site. Activation was lost when RPA was replaced with bacterial SSB or DNA binding-defective RPA, RPAARO1. We observed stable HelQ-RPA-DNA ternary complex formation, and present evidence that an intrinsically disordered N-terminal region of HelQ (N-HelQ) interacts with RPA, destabilising RPA-DNA binding. Additionally, SEC-MALS showed that HelQ multimers are converted into catalytically active dimers when ATP-Mg2+is bound. HelQ and RPA are proposed to jointly promote replication fork recovery by helicase-catalysed displacement of DNA-bound proteins, after HelQ gains access to ssDNA through its N-terminal domain interaction with RPA.
Controlling noisy expression through auto regulation of burst frequency and protein stability
Authors: Bokes Pavol , Singh Abhyudai
Published: January 2019

Protein levels can be controlled by regulating protein synthesis or half life. The aim of this paper is to investigate how introducing feedback in burst frequency or protein decay rate affects the stochastic distribution of protein level. Using a tractable hybrid mathematical framework, we show that the two feedback pathways lead to the same mean and noise predictions in the small-noise regime. Away from the small-noise regime, feedback in decay rate outperforms feedback in burst frequency in terms of noise control. The difference is particularly conspicuous in the strong-feedback regime. We also formulate a fine-grained discrete model which reduces to the hybrid model in the large system-size limit. We show how to approximate the discrete protein copy-number distribution and its Fano factor using hybrid theory. We also demonstrate that the hybrid model reduces to an ordinary differential equation in the limit of small noise. Our study thus contains a comparative evaluation of feedback in burst frequency and decay rate, and provides additional results on model reduction and approximation.
Somatic mutation landscape reveals differential variability of cell-of-origin for primary liver cancer
Authors: Ha Kyungsik , Fujita Masashi , Karlić Rosa , Yang Sungmin , Hoshida Yujin , Polak Paz , Nakagawa Hidewaki , Kim Hong-Gee , Lee Hwajin
Published: January 2019

Background

Primary liver tissue cancers display consistent increase in global disease burden and mortality. Identification of cell-of-origins for primary liver cancers would be a necessity to expand options for designing relevant therapeutics and preventive medicine for these cancer types. Previous reports on cell-of-origin for primary liver cancers was mainly from animal studies, and integrative research utilizing human specimen data was poorly established.

Methods

We analyzed a whole-genome sequencing data set for a total of 363 tumor and progenitor tissues along with 423 normal tissue epigenomic marks to predict the cell-of-origin for primary liver cancer subtypes.

Results

Despite the mixed histological features, the predicted cell-of-origin for mixed hepatocellular carcinoma / intrahepatic cholangiocarcinoma were uniformly predicted as a hepatocytic origin. Individual sample-level prediction revealed differential level of cell-of-origin heterogeneity depending on the primary liver cancer types, with more heterogeneity observed in intrahepatic cholangiocarcinomas. Additional analyses on the whole genome sequencing data of hepatic progenitor cells suggest these progenitor cells might not a direct cell-of-origin for liver cancers.

Conclusions

These results provide novel insights on the heterogeneous nature and potential contributors of cell-of-origin predictions for primary liver cancers.
Functional Near-Infrared Spectroscopy (fNIRS) informed neurofeedback: regional-specific modulation of lateral orbitofrontal activation and cognitive flexibility
Authors: Li Keshuang , Jiang Yihan , Gong Yilong , Zhao Weihua , Zhao Zhiying , Liu Xiaolong , Kendrick Keith M. , Zhu Chaozhe , Becker Benjamin
Published: January 2019

Cognitive flexibility and reward processing critically rely on the orbitofrontal cortex. Dysregulations in these domains and orbitofrontal activation have been reported in major psychiatric disorders. Haemodynamic brain imaging informed neurofeedback allows regional-specific control over brain activation and thus may represent an innovative intervention to regulate orbitofrontal dysfunctions. Against this background the present proof-of-concept study evaluated the feasibility and behavioral relevance of functional Near-Infrared Spectroscopy (fNIRS) assisted neurofeedback training of the lateral orbitofrontal cortex (lOFC). In a randomized sham-controlled between-subject design 60 healthy participants underwent four subsequent runs of training to enhance lOFC activation. Training-induced changes in the lOFC, attentional set shifting performance and reward experience served as primary outcomes. Feedback from the target channel significantly increased regional-specific lOFC activation over the four training runs in comparison with sham feedback. The experimental group demonstrated a trend for faster responses during set shifting relative to the sham group. Within the experimental group stronger training-induced lOFC increases were associated with higher reward experience. The present results demonstrate that fNIRS-informed neurofeedback allows regional-specific regulation of lOFC activation and may have the potential to modulate associated behavioral domains. As such fNIRS-informed neurofeedback may represent a promising strategy to regulate OFC dysfunctions in psychiatric disorders.
BMP4 patterns Smad activity and generates stereotyped cell fate organisation in spinal organoids
Authors: Duval Nathalie , Vaslin Célia , Barata Tiago , Nédélec Stéphane , Ribes Vanessa
Published: January 2019

Bone Morphogenetic Proteins (BMP) are secreted regulators of cell fate in several developing tissues. In the embryonic spinal cord, they control the emergence of the neural crest, roof plate and distinct subsets of dorsal interneurons. Although a gradient of BMP activity has been proposed to determine cell type identity invivo, whether this is sufficient for pattern formation invitrois unclear. Here, we demonstrate that exposure to BMP4 initiates distinct spatial dynamics of BMP signalling within the self-emerging epithelia of both mouse and human pluripotent stem cells derived spinal organoids. The pattern of BMP signalling results in the stereotyped spatial arrangement of dorsal neural tube cell types and concentration, timing and duration of BMP4 exposure modulate these patterns. Moreover, differences in the duration of competence time-windows between mouse and human account for the species specific tempo of neural differentiation. Together the study describes efficient methods to generate patterned subsets of dorsal interneurons in spinal organoids and supports the conclusion that graded BMP activity orchestrates the spatial organization of the dorsal neural tube cellular diversity in mouse and human.
Dynamics of bacterial cell proliferation inhibited by specific proteins for effective horizontal transmission of the integrative and conjugative element ICEclc
Authors: Takano Sotaro , Koto Akiko , Miyazaki Ryo
Published: January 2019

The integrative and conjugative element ICEclc, a prevalent mobile element in proteobacteria, is one of the experimental models for horizontal gene transfer. ICEclc is usually retained in a bacterial chromosome, but can be excised and transferred from the donor to other bacterial lineages. The horizontal transmission is accomplished by developing specialized transfer competent (tc) cells in the donor population. The tc cells entirely dedicate to the ICE transmission by sacrificing their proliferation, which results in an increase in the transfer frequency. The cell growth impairment is mediated by two specific genes, parA and shi, on ICEclc, but its mechanistic details and cellular dynamics are still unknown. We here developed fluorescence reporter strains to monitor intracellular behavior of ParA and Shi proteins as well as host cellular proliferation at the single-cell level. Superresolution imaging revealed that ParA colocalized with the host nucleoid while Shi diffused in cytoplasm during the growth impairment. Mutations in the Walker A motif of ParA diminished the inhibitory effect. Combining quantitative time-lapse microscopy and numerical simulations using mathematical models, we found that ParA and Shi initially blocked cell division and then, as time elapsed, inhibited cellular elongation. The parA-shi locus is highly conserved in other ICEs, and the ParA-Shi-mediated growth inhibition was still observed in different proteobacterial species, suggesting that the ICEs have evolved the system to efficiently distribute themselves in the niche. The results of our study provide mechanistic insight into the novel and unique system on ICEs and help to understand such epistatic interaction between ICE genes and host physiology that entails efficient horizontal gene transfer.

Author summary

Horizontal gene transfer is a major diving force for bacterial evolution, which is frequently mediated by mobile DNA vectors, such as plasmids and bacteriophages. Integrative and conjugative elements (ICEs) are a relatively new class of mobile vectors, which normally integrate in a host chromosome but under certain conditions can be excised and transferred from the host to a new recipient cell via conjugation. Recent genomic studies estimated that ICEs are more abundant than plasmids among bacteria. Why so prevalent? One of the characteristics of ICEclc, an ICE model in proteobacteria, is that it develops specialized cells which entirely dedicate to the ICE horizontal transmission by repressing their proliferation. Here, we qualitatively and quantitatively describe two proteins, which are expressed from ICEclc when it transfers, and how they actually inhibit the host cell growth. Our results suggest that the system has evolved for the efficient horizontal transmission and is widely conserved in the ICE family.
Molecular basis of P[6] and P[8] major human rotavirus VP8* domain interactions with histo-blood group antigens
Authors: Xu Shenyuan , Liu Yang , Tan Ming , Zhong Weiming , Zhao Dandan , Jiang Xi , Kennedy Michael A.
Published: January 2019

Initial cell attachment of rotavirus (RV) to specific cell surface glycans, which is the essential first step in RV infection, is mediated by the VP8* domain of the spike protein VP4. Recently, human histo-blood group antigens (HBGAs) have been identified as ligands or receptors for human RV strains. RV strains in the P[4] and P[8] genotypes of the P[II] genogroup share common recognition of the Lewis b and H type 1 antigens, while P[6], which is one of the other genotypes in P[II], only recognizes the H type 1 antigen. The molecular basis of receptor recognition by the major human P[8] RVs remains unknown due to lack of experimental structural information. Here, we used nuclear magnetic resonance (NMR) titration experiments and NMR-derived high ambiguity driven docking (HADDOCK) methods to elucidate the molecular basis for P[8] VP8* recognition of the Leband type 1 HBGAs and for P[6] recognition of H type 1 HBGAs. Unlike P[6] VP8* that recognizes H type 1 HGBAs in a binding surface composed of an α-helix and a β-sheet, referred as “βα binding domain”, the P[8] VP8* binds the type 1 HBGAs requiring the presence of the Lewis epitope in a previously undescribed pocket formed by two β-sheets, referred as “ββ binding domain”. The observation that P[6] and P[8] VP8* domains recognize different glycan structures at distinct binding sites supports the hypothesis that RV evolution is driven, at least in part, by selective pressure driven adaptation to HBGA structural diversity of their natural hosts living in the world. Recognition of the role that HBGAs play in driving RV evolution is essential to understanding RV diversity, host ranges, disease burden and zoonosis and to developing strategies to improve vaccines against RV infections.

Author summary

Rotaviruses (RV)s are the main cause of severe diarrhea in humans and animals. Significant advances in understanding RV diversity, evolution and epidemiology have been made after discovering that RVs recognize histo-blood group antigens (HBGAs) as host cell receptors. While different RV strains are known to have distinct binding preferences for HBGA receptors, the molecular basis in controlling strain-specific host ranges remains unclear. In this study, we used solution nuclear magnetic resonance to determine the molecular level details for interactions of the human P[8] and P[6] RV VP8* domains with their HBGA receptors. The distinct binding patterns observed between these major human RVs and their respective receptor ligands provides insight into the evolutionary relationships between different P[II] genotypes that ultimately determine host ranges, disease burden, zoonosis and epidemiology, which may impact future strategies for vaccine development against RVs.
Kinome-wide activity classification of small molecules by deep learning
Authors: Allen Bryce K , Ayad Nagi G , Schürer Stephan C
Published: January 2019

Deep learning is a machine learning technique that attempts to model high-level abstractions in data by utilizing a graph composed of multiple processing layers that experience various linear and non-linear transformations. This technique has been shown to perform well for applications in drug discovery, utilizing structural features of small molecules to predict activity. However, the application of deep learning to discriminating features of kinase inhibitors has not been well explored. Small molecule kinase inhibitors are an important class of anti-cancer agents and have demonstrated impressive clinical efficacy in several different diseases. However, resistance is often observed mediated by adaptive Kinome reprogramming or subpopulation diversity. Therefore, polypharmacology and combination therapies offer potential therapeutic strategies for patients with resistant disease. Their development would benefit from more comprehensive and dense knowledge of small-molecule inhibition across the human Kinome. Because such data is not publicly available, we evaluated multiple machine learning methods to predict small molecule inhibition of 342 kinases using over 650K aggregated bioactivity annotations for over 300K small molecules curated from ChEMBL and the Kinase Knowledge Base (KKB). Our results demonstrated that multi-task deep neural networks outperform classical single-task methods, offering potential towards predicting activity profiles and filling gaps in the available data.
Crystal structure, Hirshfeld surface analysis and electrostatic potential study of naturally occurring cassane-type diterpenoid Pulcherrimin C monohydrate at 100 K
Authors: Kumar Rajesh , Ogbeide K. Osahon , Mujeeb-Ur-Rehman  , Owolabi Bodunde , Falodun Abiodun , Choudhary M. Iqbal , Yousuf Sammer
Published: January 2019

The title cassane-type diterpenoid known as pulcherrimin C, C34H36O8·H2O, systematic name 5,6-bis(benzoyloxy)-4a-hydroxy-4,7,11b-trimethyl-1,2,3,4,4a,5,6,6a,7,11,11a,11b-dodecahydrophenanthro[3,2-b]furan-4-carboxylic acid monohydrate, was isolated as a monohydrate from the medicinally important plant Caesalpinia pulcherrima, found in the tropical regions of south and south-east Asia. The molecule is composed of three trans-fused six-membered rings having chair, chair and half-chair conformations, and a five-membered planar furan ring. In the crystal, O—H...O hydrogen bonds link molecules into chains parallel to the b axis. Weak C—H...π interactions are also observed. Hirshfeld surface analysis indicates that the contribution of O...H interactions towards the total generated Hirshfeld surface is 21.5%.
The crystal structure of 1-(2-iodobenzoyl)-4-(pyrimidin-2-yl)piperazine: a three-dimensional hydrogen-bonded framework, augmented by π–π stacking interactions and I...N halogen bonds
Authors: Mahesha Ninganayaka , Yathirajan Hemmige S. , Furuya Tetsundo , Akitsu Takashiro , Glidewell Christopher
Published: January 2019

In 1-(2-iodobenzoyl)-4-(pyrimidin-2-yl)piperazine, C15H15IN4O, the central piperazine ring adopts an almost perfect chair conformation with the pyrimidine substituent in an equatorial site. The planar amide unit makes a dihedral angle of 80.44 (7)° with the phenyl ring. A combination of C—H...O and C—H...π(arene) hydrogen bonds links the molecules into a complex three-dimensional network structure, augmented by a π–π stacking interaction and an I...N halogen bond, all involving different pairs of inversion-related molecules. Comparisons are made with the structures of a number of related compounds.