bluuebunny/crossref_metadata_2025 huggingface dataset:
nPIST: A Novel Actin Binding Protein of trans-Golgi Network
Authors: Das Swagata , Dutta Priyanka , Mazumder Mohit , Seal Soma , Duraivelan Kheerthana , Samanta Dibyendu , Gourinath Samudrala , Maiti Sankar
Published: February 2018

npist is the neuronal isoform of PIST, a trans-golgi associated protein involved in major modulation of vesicular trafficking. nPIST interacts with glutamate delta2 receptor (GluRδ2) in Purkinje cells. Our study shows nPIST as a novel actin binding protein. Our structure based sequence analysis shows nPIST contains one WH2-like domain. Further our experimental analysis illustrates that fragment of nPIST consisting of WH2-like domain binds to actin. Moreover it was found that nPIST contains several regions involved in interaction with actin. The binding of nPIST to actin through multiple actin binding regions facilitated actin filament stabilization in vitro. In vivo, nPIST localized actin in perinuclear region as a blotch when ectopically expressed.
Network hubs in root-associated fungal metacommunities
Authors: Toju Hirokazu , Tanabe Akifumi S. , Sato Hirotoshi
Published: February 2018

Background

Although a number of recent studies have uncovered remarkable diversity of microbes associated with plants, understanding and managing dynamics of plant microbiomes remain major scientific challenges. In this respect, network analytical methods have provided a basis for exploring “hub” microbial species, which potentially organize community-scale processes of plant-microbe interactions.

Methods

By compiling Illumina sequencing data of root-associated fungi in eight forest ecosystems across the Japanese Archipelago, we explored hubs within “metacommunity-scale” networks of plant-fungus associations. In total, the metadata included 8,080 fungal operational taxonomic units (OTUs) detected from 227 local populations of 150 plant species/taxa.

Results

Few fungal OTUs were common across all the eight forests. However, in each metacommunity-scale network representing northern four localities or southern four localities, diverse mycorrhizal, endophytic, and pathogenic fungi were classified as “metacommunity hubs”, which were detected from diverse host plant taxa throughout a climatic region. Specifically,Mortierella(Mortierellales),Cladophialophora(Chaetothyriales),Ilyonectria(Hypocreales),Pezicula(Helotiales), andCadophora(incertae sedis) had broad geographic and host ranges across the northern (cool-temperate) region, whileSaitozyma/Cryptococcus(Tremellales/Trichosporonales) andMortierellaas well as some arbuscular mycorrhizal fungi were placed at the central positions of the metacommunity-scale network representing warm-temperate and subtropical forests in southern Japan.

Conclusions

The network theoretical framework presented in this study will help us explore prospective fungi and bacteria, which have high potentials for agricultural application to diverse plant species within each climatic region. As some of those fungal taxa with broad geographic and host ranges have been known to increase the growth and pathogen resistance of host plants, further studies elucidating their functional roles are awaited.
Bi-clustering interpretation and prediction of correlation between gene expression and protein abundance
Authors: Wang Xiaojun , Teng Lin , Zhang Haicang , Zhou Qian , Su Xiaoquan , Cui Xinping , Bu Dongbo , Gong Xinqi , Poetsch Ansgar , Ning Kang
Published: February 2018

Most organisms’ transcript and protein level only moderately correlate for various reasons, such as regulation of transcription and protein degradation. Better prediction and understanding the correlation between gene expression and protein abundance has been possible by harnessing the matching RNA/protein datasets produced by modern high-throughput RNA-Seq and mass spectrometry methods. In this work, we have utilized some well-studied matching RNA/protein datasets, and explored for the first time a bi-clustering method to cluster genes that have consistent correlation patterns between gene expression and protein abundance. The clustering results have been interpreted from the perspective of both transcriptomic and proteomic features, which show that mRNA half-life, protein half-life and protein structure in concert significantly affect the correlation of gene expression and protein abundance. With these and other carefully selected features, a prediction model based on individual clusters, called Cluster-based Linear prediction Model (CLM), was built and tested on mouse liver mitochondrial, mouse brainstem mitochondrial, Saccharomyces cerevisiae and Danio rerio datasets. CLM could find genes for which protein abundance can be predicted from mRNA data. In summary, based on bi-clustering, feature selection and CLM model, we have established a new and valuable cluster-based protein abundance prediction method.
The fungal ligand chitin directly binds and signals inflammation dependent on oligomer size and TLR2
Authors: Fuchs Katharina , Gloria Yamel Cardona , Wolz Olaf-Oliver , Herster Franziska , Sharma Lokesh , Dillen Carly , Täumer Christoph , Dickhöfer Sabine , Bittner Zsofia , Dang Truong-Minh , Singh Anurag , Haischer Daniel , Schlöffel Maria A. , Koymans Kirsten J. , Sanmuganantham Tharmila , Krach Milena , Schilling Nadine A. , Frauhammer Felix , Miller Lloyd , Nürnberger Thorsten , LeibundGut-Landmann Salomé , Gust Andrea A. , Macek Boris , Frank Martin , Gouttefangeas Cécile , Dela Cruz Charles S. , Hartl Dominik , Weber Alexander N.R.
Published: February 2018

Chitin is a highly abundant polysaccharide and linked to fungal infection and asthma. Unfortunately, its polymeric structure has hampered the identification of immune receptors directly binding chitin and signaling immune activation and inflammation, because purity, molecular structure and molarity are not well definable for a polymer typically extracted from biomass. Therefore, by using defined chitin (N-acetyl-glucosamine) oligomers, we identified six subunit long chitin chains as the smallest immunologically active motif and the innate immune receptor Toll-like receptor (TLR) 2 as the primary fungal chitin receptor on human and murine immune cells. Chitin oligomers directly bound TLR2 with nanomolar affinity and showed both overlapping and distinct signaling outcomes compared to known mycobacterial TLR2 ligands. Conversely, chitin oligomers shorter than 6 subunits were inactive or showed antagonistic effects on chitin/TLR2-mediated signaling, hinting to a size-dependent sensing/activation system unexpectedly conserved in plants and humans. Since blocking the chitin-TLR2 interaction effectively prevented chitin-mediated inflammation in vitro and in vivo, our study highlights the chitin TLR2 interaction as a potential target for developing novel therapies in chitin-related pathologies and fungal disease.
SMuRF: Portable and accurate ensemble-based somatic variant calling
Authors: Huang Weitai , Guo Yu Amanda , Muthukumar Karthik , Baruah Probhonjon , Chang Meimei , Skanderup Anders Jacobsen
Published: February 2018

ABSTARCT

SMuRF is an ensemble method for prediction of somatic point mutations (SNVs) and small insertions/deletions (indels) in cancer genomes. The method integrates predictions and auxiliary features from different somatic mutation callers using a Random Forest machine learning approach. SMuRF is trained on community-curated tumor whole genome sequencing data, is robust across cancer types, and achieves improved accuracy for both SNV and indel predictions of genome and exome-level data. The software is user-friendly and portable by design, operating as an add-on to the community-developed bcbio-nextgen somatic variant calling pipeline.

Contact

skanderupamj@gis.a-star.edu.sg
Quantitative solid-phase assay to measure deoxynucleoside triphosphate pools
Authors: Landoni Juan Cruz , Wang Liya , Suomalainen Anu
Published: February 2018

Deoxyribonucleoside triphosphates (dNTPs) are the reduced nucleotides used as the building blocks and energy source for DNA replication and maintenance in all living systems. They are present in highly regulated amounts and ratios in the cell, and their balance has been implicated in the most important cell processes, from determining the fidelity of DNA replication to affecting cell fate. Furthermore, many cancer drugs target biosynthetic enzymes in dNTP metabolism, and mutations in genes directly or indirectly affecting these pathways are the cause of devastating diseases. The accurate and systematic measurement of these pools is key to understand the mechanisms behind these diseases and their treatment. We present a new method for measuring dNTP pools from biological samples, utilising the current state-of-the-art polymerase method, modified to a solid-phase setting and optimised for larger scale measurements.
Amino acid stylization: a new approach for representing protein sequences and scoring protein alignments
Authors: Marino Stefano M.
Published: February 2018

Synopsis

The amino acids (AA) stylization, introduced in this work, is a mean to obtain a qualitative and quantitative description of different AA; the goal is to allow, via a chemically meaningful representation, the analysis of protein similarity in multiple alignments, without any statistical and evolutionary information involved. The AA Stylization Matrix Method (aSMM) has been tested positively with different data sets, in line with most common statistically based approaches (e.g. BLOSUM62), while allowing the exploitation of some unique capabilities, e.g. to be rapidly configured for specific properties that can be (over-, or under-) weighted. Overall, applying ad hoc parameterization aSMM permits a tailored investigation to account for different types of substitutions in protein alignments.
Integrin signaling downregulates filopodia in muscle-tendon attachment
Authors: Richier Benjamin , Inoue Yoshiko , Dobramysl Ulrich , Friedlander Jonathan , Brown Nicholas H. , Gallop Jennifer L.
Published: February 2018

Cells in developing tissues need to sense their environment for their accurate targeting to specific destinations. This occurs in developing muscles, which need to attach to their respective tendon cell before muscle contractions can begin. Elongating myotube tips form filopodia, which are presumed to have sensory roles, and are later suppressed upon building the attachment site. Here, we use live imaging and quantitative image analysis of lateral transverse (LT) myotubes inDrosophilato show that filopodia suppression occurs as a result of integrin signaling. Loss of the integrin subunits αPS2 and βPS increased filopodia number and length at stages when they are normally suppressed. Conversely, inducing integrin signaling, achieved by expression of constitutively dimerised βPS cytoplasmic domain (diβ), prematurely suppressed filopodia. We discovered that the integrin signal is transmitted through the ArfGAP and scaffolding protein Git (G-protein receptor coupled interacting protein) and its downstream kinase Pak (p21-activated kinase). Absence of these proteins causes profuse filopodia formation and prevents filopodial inhibition by diβ. Thus, integrin signaling switches off the exploratory behaviour of myotubes seeking tendons, enabling the actin machinery to focus on forming a strong attachment and assembling the contractile apparatus.
Parentage assignment with genotyping-by-sequencing data
Authors: Whalen Andrew , Gorjanc Gregor , Hickey John M
Published: February 2018

In this paper we evaluate using genotype-by-sequencing (GBS) data to perform parentage assignment in lieu of traditional array data. The use of GBS data raises two issues: First, for low-coverage GBS data, it may not be possible to call the genotype at many loci, a critical first step for detecting opposing homozygous markers. Second, the amount of sequencing coverage may vary across individuals, making it challenging to directly compare the likelihood scores between putative parents. To address these issues we extend the probabilistic framework of Huisman (2017) and evaluate putative parents by comparing their (potentially noisy) genotypes to a series of proposal distributions. These distributions describe the expected genotype probabilities for the relatives of an individual. We assign putative parents as a parent if they are classified as a parent (as opposed to e.g., an unrelated individual), and if the assignment score passes a threshold. We evaluated this method on simulated data and found that (1) high-coverage GBS data performs similarly to array data and requires only a small number of markers to correctly assign parents and (2) low-coverage GBS data (as low as 0.1x) can also be used, provided that it is obtained across a large number of markers. When analysing the low-coverage GBS data, we also found a high number of false positives if the true parent is not contained within the list of candidate parents, but that this false positive rate can be greatly reduced by hand tuning the assignment threshold. We provide this parentage assignment method as a standalone program called AlphaAssign.
Quantifying genetic, environmental and individual stochastic variability inPlantago lanceolata
Authors: Steiner Ulrich K. , Tuljapurkar Shripad , Roach Deborah A.
Published: February 2018

Predicting ecological and evolutionary population dynamics requires understanding how genetic and environmental parameters influence variation in survival and reproduction among individuals. However such a focus often neglects the stochastic events that individuals experience throughout their lives that also influence survival and reproduction. With an illustrative example, we quantify and illustrate the influence of such non-selective demographic variability on population dynamics using size-structured matrix models of an experimental population ofPlantago lanceolata. Our analysis shows that variation in survival and reproduction among individuals explained by environment, genes, and their interaction was modest compared to the stochastic variation in lifespan and reproduction. We illustrate how expectations on population growth, based on expected lifetime reproduction and generation time, can be misleading when variance in reproduction among individuals of the same genotype (full sibs) was large. Such large within genotype variance can lower population growth, fitness. Our results accompany recent investigations that call for more focus on stochastic variation in survival and reproduction, rather than dismissal of this variation as uninformative noise.
Amplification and Suppression of Distinct Brain-wide Activity Patterns by Catecholamines
Authors: van den Brink RL , Nieuwenhuis S , Donner TH
Published: February 2018

The widely projecting catecholaminergic (norepinephrine and dopamine) neurotransmitter systems profoundly shape the state of neuronal networks in the forebrain. Current models posit that the effects of catecholaminergic modulation on network dynamics are homogenous across the brain. However, the brain is equipped with a variety of catecholamine receptors with distinct functional effects and heterogeneous density across brain regions. Consequently, catecholaminergic effects on brain-wide network dynamics might be more spatially specific than assumed. We tested this idea through the analysis of functional magnetic resonance imaging (fMRI) measurements performed in humans (19 females, 5 males) at ‘rest’ under pharmacological (atomoxetine-induced) elevation of catecholamine levels. We used a linear decomposition technique to identify spatial patterns of correlated fMRI signal fluctuations that were either increased or decreased by atomoxetine. This yielded two distinct spatial patterns, each expressing reliable and specific drug effects. The spatial structure of both fluctuation patterns resembled the spatial distribution of the expression of catecholamine receptor genes: α1 norepinephrine receptors (for the fluctuation pattern: placebo > atomoxetine), ‘D2-like’ dopamine receptors (pattern: atomoxetine > placebo), and β norepinephrine receptors (for both patterns, with correlations of opposite sign). We conclude that catecholaminergic effects on the forebrain are spatially more structured than traditionally assumed and at least in part explained by the heterogeneous distribution of various catecholamine receptors. Our findings link catecholaminergic effects on large-scale brain networks to low-level characteristics of the underlying neurotransmitter systems. They also provide key constraints for the development of realistic models of neuromodulatory effects on large-scale brain network dynamics.

SIGNIFICANCE STATEMENT

The catecholamines norepinephrine and dopamine are an important class of modulatory neurotransmitters. Because of the widespread and diffuse release of these neuromodulators, it has commonly been assumed that their effects on neural interactions are homogenous across the brain. Here, we present results from the human brain that challenge this view. We pharmacologically increased catecholamine levels and imaged the effects on the spontaneous covariations between brain-wide fMRI signals at ‘rest’. We identified two distinct spatial patterns of covariations: one that was amplified and another that was suppressed by catecholamines. Each pattern was associated with the heterogeneous spatial distribution of the expression of distinct catecholamine receptor genes. Our results provide novel insights into the catecholaminergic modulation of large-scale human brain dynamics.
Loss of embryonic neural crest cardiomyocytes causes adult hypertrophic cardiomyopathy
Authors: Abdul-Wajid Sarah , Demarest Bradley L , Yost H Joseph
Published: February 2018

Neural crest cells migrate to the embryonic heart and transform into a small number of cardiomyocytes, but their functions in the developing and adult heart are unknown. Here, we map the fates of neural crest derived cardiomyocytes (NC-Cms) and genetically ablate them in embryogenesis in zebrafish. Specific NC-Cm ablation results in aberrant trabeculation patterns and altered Notch signaling, but is not detrimental to the development of the fish or early heart function. Strikingly, embryonic NC-Cm ablation results in adult fish that show severely hypertrabeculated hearts, altered cardiomyocyte size, diminished adult heart capacity and consequently poor physiological response to cardiac stress tests. Thus, we identify a novel developmental mechanism and genetic pathway that predisposes adults to hypertrophic cardiomyopathy and provides the first zebrafish model of adult-onset heart failure.
Improved protein model quality assessments by changing the target function
Authors: Uziela Karolis , Menéndez Hurtado David , Shu Nanjiang , Wallner Björn , Elofsson Arne
Published: February 2018

Protein modeling quality is an important part of protein structure prediction. We have for more than a decade developed a set of methods for this problem. We have used various types of description of the protein and different machine learning methodologies. However, common to all these methods has been the target function used for training. The target function in ProQ describes the local quality of a residue in a protein model. In all versions of ProQ the target function has been the S-score. However, other quality estimation functions also exist, which can be divided into superposition- and contact-based methods. The superposition-based methods, such as S-score, are based on a rigid body superposition of a protein model and the native structure, while the contact-based methods compare the local environment of each residue. Here, we examine the effects of retraining our latest predictor, ProQ3D, using identical inputs but different target functions. We find that the c ntact-based methods are easier to predict and that predictors trained on these measures provide some advantages when it comes to identifying the best model. One possible reason for this is that contact based methods are better at estimating the quality of multi-domain targets. However, training on the S-score gives the best correlation with the GDT_TS score, which is commonly used in CASP to score the global model quality. To take the advantage of both of these features we provide an updated version of ProQ3D that predicts local and global model quality estimates based on different quality estimates.
Why do eukaryotic proteins contain more intrinsically disordered regions?
Authors: Basile Walter , Salvatore Marco , Bassot Claudio , Elofsson Arne
Published: February 2018

Intrinsic disorder is much more abundant in eukaryotic than in prokaryotic proteins. However, the reason behind this is unclear. It has been proposed that the disordered regions are functionally important for regulation in eukaryotes, but it has also been proposed that the difference is a result of lower selective pressure in eukaryotes. Almost all studies intrinsic disorder is predicted from the amino acid sequence of a protein. Therefore, there should exist an underlying difference in the amino acid distributions between eukaryotic and prokaryotic proteins causing the predicted difference in intrinsic disorder. To obtain a better understanding of why eukaryotic proteins contain more intrinsically disordered regions we compare proteins from complete eukaryotic and prokaryotic proteomes.

Here, we show that the difference in intrinsic disorder origin from differences in the linker regions. Eukaryotic proteins have more extended linker regions and, in particular, the eukaryotic linker regions are more disordered. The average eukaryotic protein is about 500 residues long; it contains 250 residues in linker regions, of which 80 are disordered. In comparison, prokaryotic proteins are about 350 residues long and only have 100-110 residues in linker regions, and less than 10 of these are intrinsically disordered.

Further, we show that there is no systematic increase in the frequency of disorder-promoting residues in eukaryotic linker regions. Instead, the difference in frequency of only three amino acids seems to lie behind the difference. The most significant difference is that eukaryotic linkers contain about 9% serine, while prokaryotic linkers have roughly 6.5%. Eukaryotic linkers also contain about 2% more proline and 2-3% fewer isoleucine residues. The reason why primarily these amino acids vary in frequency is not apparent, but it cannot be excluded that the difference is serine is related to the increased need for regulation through phosphorylation and that the proline difference is related to increase of eukaryotic specific repeats.
Hedgehog signaling activates a heterochronic gene regulatory network to control differentiation timing across lineages
Authors: Rowton Megan , Perez-Cervantes Carlos , Rydeen Ariel , Hur Suzy , Jacobs-Li Jessica , Deng Nikita , Lu Emery , Guzzetta Alexander , Steimle Jeffrey D. , Hoffmann Andrew , Lazarevic Sonja , Yang Xinan Holly , Kim Chul , Yu Shuhan , Eckart Heather , Iddir Sabrina , Koska Mervenaz , Hanson Erika , Chan Sunny Sun-Kin , Garry Daniel J. , Kyba Michael , Basu Anindita , Ikegami Kohta , Pott Sebastian , Moskowitz Ivan P.
Published: February 2018

Heterochrony, defined as differences in the timing of developmental processes, impacts organ development, homeostasis, and regeneration. The molecular basis of heterochrony in mammalian tissues is poorly understood. We report that Hedgehog signaling activates a heterochronic pathway that controls differentiation timing in multiple lineages. A differentiation trajectory from second heart field cardiac progenitors to first heart field cardiomyocytes was identified by single-cell transcriptional profiling in mouse embryos. A survey of developmental signaling pathways revealed specific enrichment for Hedgehog signaling targets in cardiac progenitors. Removal of Hh signaling caused loss of progenitor and precocious cardiomyocyte differentiation gene expression in the second heart fieldin vivo. Introduction of active Hh signaling to mESC-derived progenitors, modelled by transient expression of the Hh-dependent transcription factor GLI1, delayed differentiation in cardiac and neural lineagesin vitro. A shared GLI1-dependent network in both cardiac and neural progenitors was enriched with FOX family transcription factors. FOXF1, a GLI1 target, was sufficient to delay onset of the cardiomyocyte differentiation program in progenitors, by epigenetic repression of cardiomyocyte-specific enhancers. Removal of active Hh signaling orFoxf1expression from second heart field progenitors caused precocious cardiac differentiationin vivo, establishing a mechanism for resultant Congenital Heart Disease. Together, these studies suggest that Hedgehog signaling directly activates a gene regulatory network that functions as a heterochronic switch to control differentiation timing across developmental lineages.
Brainstem control of urethral sphincter relaxation and scent marking behavior
Authors: Keller Jason , Chen Jingyi , Simpson Sierra , Wang Eric Hou-Jen , Lilascharoen Varoth , George Olivier , Lim Byung Kook , Stowers Lisa
Published: February 2018

Urination may occur either reflexively in response to a full bladder or deliberately irrespective of immediate need. Voluntary control is desired because it ensures that waste is expelled when consciously desired and socially appropriate1,2. Urine release requires two primary components: bladder pressure and urethral relaxation1–3. Although the bladder contracts during urination, its slow smooth muscle is not under direct voluntary control and its contraction alone is not sufficient for voiding. The decisive action of urination is at the urethral sphincter, where striated muscle permits fast control. This sphincter is normally constricted, but relaxes to enable urine flow. Barrington’s nucleus (Bar, or pontine micturition center) in the brainstem is known to be essential for the switch from urine storage to elimination4–7, and a subset of Bar neurons expressing corticotropin releasing hormone (BarCRH) have recently been shown to promote bladder contraction8–10. However, Bar neurons that relax the urethral sphincter to enable urination behavior have not been identified. Here we describe novel brainstem neurons that control the external urethral sphincter. We find that scent marking behavior in male mice depends upon a subpopulation of spatially clustered Bar neurons that express high levels of estrogen receptor 1 (BarESR1). These neurons are glutamatergic, project to urinary nuclei in the spinal cord with a bias towards sphincter-inhibiting interneurons, and their activity correlates with natural urination. Optogenetic stimulation of BarESR1 neurons rapidly initiates sphincter bursting and efficient voiding in absence of sensory cues in anesthetized and behaving animals. Conversely, inhibiting the activity of these neurons prevents olfactory cues from promoting scent marking behavior. The identification of BarESR1 cells provides an expanded model for the supraspinal control of urination and its dysfunction.
Epigenomic convergence of genetic and immune risk factors in neurodevelopmental disorder cortex
Authors: A. Vogel Ciernia , B.I. Laufer , K.W. Dunaway , H. Hwang , C.E. Mordaunt , R.L. Coulson , D.H. Yasui , J.M. LaSalle
Published: February 2018

Neurodevelopmental disorders (NDDs) impact 7% to 14% of all children in developed countries and are one of the leading causes of lifelong disability. Epigenetic modifications are poised at the interface between genes and environment and are predicted to reveal insight into the gene networks, cell types, and developmental timing of NDD etiology. Whole-genome bisulfite sequencing was used to examine DNA methylation in 49 human cortex samples from three different NDDs (autism spectrum disorder, Rett syndrome, and Dup15q syndrome) and matched controls. Integration of methylation differences across NDDs with relevant genomic and genetic datasets revealed differentially methylated regions (DMRs) unique to each type of NDD but with shared regulatory functions in neurons and microglia. DMRs were significantly enriched for known NDD genetic risk factors, including both common inherited and rare de novo variants. Weighted region co-methylation network analysis revealed a module related to NDD diagnosis and enriched for microglial regulatory regions. Together, these results demonstrate an epigenomic signature of NDDs in human cortex shared with known genetic and immune etiological risk. Epigenomic insights into cell types and gene regulatory regions will aid in defining therapeutic targets and early biomarkers at the interface of genetic and environmental NDD risk factors.
SAMHD1 Impairs HIV-1 Gene Expression and Reactivation of Viral Latency in CD4+ T-cells
Authors: Antonucci Jenna M. , Kim Sun Hee , St. Gelais Corine , Bonifati Serena , Buzovetsky Olga , Knecht Kirsten M. , Duchon Alice A. , Xiong Yong , Musier-Forsyth Karin , Wu Li
Published: February 2018

Sterile alpha motif and HD domain-containing protein 1 (SAMHD1) restricts human immunodeficiency virus type 1 (HIV-1) replication in non-dividing cells by degrading intracellular deoxynucleoside triphosphates (dNTPs). SAMHD1 is highly expressed in resting CD4+ T-cells that are important for the HIV-1 reservoir and viral latency; however, whether SAMHD1 affects HIV-1 latency is unknown. Recombinant SAMHD1 binds HIV-1 DNA or RNA fragments in vitro, but the function of this binding remains unclear. Here we investigate the effect of SAMHD1 on HIV-1 gene expression and reactivation of viral latency. We found that endogenous SAMHD1 impaired HIV-1 LTR activity in monocytic THP-1 cells and HIV-1 reactivation in latently infected primary CD4+ T-cells. Overexpression of wild-type (WT) SAMHD1 suppressed HIV-1 long terminal repeat (LTR)-driven gene expression at the level of transcription. SAMHD1 overexpression also suppressed LTR activity from human T-cell leukemia virus type 1 (HTLV-1), but not from murine leukemia virus (MLV), suggesting specific suppression of retroviral LTR-driven gene expression. WT SAMHD1 bound to proviral DNA and impaired reactivation of HIV-1 gene expression in latently infected J-Lat cells. In contrast, a nonphosphorylated mutant (T592A) and a dNTP triphosphohydrolase (dNTPase) inactive mutant (H206D/R207N, or HD/RN) of SAMHD1 failed to efficiently suppress HIV-1 LTR-driven gene expression and reactivation of latent virus. Purified recombinant WT SAMHD1, but not T592A and HD/RN mutants, bound to fragments of the HIV-1 LTR in vitro. These findings suggest that SAMHD1-mediated suppression of HIV-1 LTR-driven gene expression contributes to regulation of viral latency in CD4+ T-cells.

IMPORTANCE

A critical barrier to developing a cure for HIV-1 infection is the long-lived viral reservoir that exists in resting CD4+ T-cells, the main targets of HIV-1. The viral reservoir is maintained through a variety of mechanisms, including regulation of the HIV-1 LTR promoter. The host protein SAMHD1 restricts HIV-1 replication in non-dividing cells, but its role in HIV-1 latency remains unknown. Here we report a new function of SAMHD1 in regulating HIV-1 latency. We found that SAMHD1 suppressed HIV-1 LTR promoter-driven gene expression and reactivation of viral latency in cell lines and primary CD4+ T-cells. Furthermore, SAMHD1 bound to the HIV-1 LTR in vitro and in a latently infected CD4+ T-cell line, suggesting that the binding may negatively modulate reactivation of HIV-1 latency. Our findings indicate a novel role for SAMHD1 in regulating HIV-1 latency, which enhances our understanding of the mechanisms regulating proviral gene expression in CD4+ T-cells.
Probing the network structure of health deficits in human aging
Authors: Farrell Spencer G. , Mitnitski Arnold B. , Theou Olga , Rockwood Kenneth , Rutenberg Andrew D.
Published: February 2018

Human aging leads to the stochastic accumulation of damage. We model an aging population using a stochastic network model. Individuals are modeled as a network of interacting nodes, representing health attributes. Nodes in the network stochastically damage and repair, with rates dependent on the state of their neighbors. Damaged nodes represent health deficits. The Frailty Index (FI) assesses age-related damage as the proportion of health deficits an individual has accumulated, from a selection of attributes. Here, we use computational, information-theoretic, and mean-field approaches to show that the degree distribution and degree correlations of the underlying network are important to the model’s ability to recover the behavior of observational health data. We use different measures of damage in the network to probe the structure of the network. We find that the behavior of different classes of observational health deficits (laboratory or clinical) is similar to the behavior of nodes of low or high degree in the model, respectively. This explains how damage can propagate within the network, leading towards individual mortality.
Characterization of convergent thickening, a major convergence force producing morphogenic movement in amphibians
Authors: Shook David , Wen Jason , Rolo Ana , Francica Brian , Dobins Destiny , Skoglund Paul , DeSimone Doug , Winklbauer Rudolf , Keller Ray
Published: February 2018

We characterize the morphogenic process of convergent thickening (CT), which occurs in the involuting marginal zone (IMZ) during gastrulation ofXenopus, the African clawed frog. CT was described previously as the tendency of explants of the ventral IMZ ofXenopusto converge their circumblastoporal dimension and thicken their radial dimension (Keller and Danilchik 1988). Here we show that CT occurs from the onset of gastrulation, initially throughout the pre-involution IMZ. We suggest that CT is driven by an increase in the interfacial tension between the deep IMZ and its epithelium, resulting in cells of the deep IMZ tending to minimize their surface area. In explants, this results in a progressive shortening (convergence) of the IMZ along its longer mediolateral axis and thickening in the orthogonal planes, and can generate tensile force (Shook et al. 2018). In vivo, convergence of the annular IMZ generates circumferential tension, closing the blastopore. These results provide the first clear example of a tensile morphogenic force from a Holtfreterian/Steinbergian change in tissue affinity.
Enhancer RNAs predict enhancer-gene regulatory links and are critical for enhancer function in neuronal systems
Authors: Carullo Nancy V. N. , Phillips Robert A. , Simon Rhiana C. , Roman Soto Salomon A. , Hinds Jenna E. , Salisbury Aaron J. , Revanna Jasmin S. , Bunner Kendra D. , Ianov Lara , Sultan Faraz A. , Savell Katherine E. , Gersbach Charles A. , Day Jeremy J.
Published: February 2018

Genomic enhancer elements regulate gene expression programs important for neuronal fate and function and are implicated in brain disease states. Enhancers undergo bidirectional transcription to generate non-coding enhancer RNAs (eRNAs). However, eRNA function remains controversial. Here, we combined ATAC-Seq and RNA-Seq datasets from three distinct neuronal culture systems in two activity states, enabling genome-wide enhancer identification and prediction of putative enhancer-gene pairs based on correlation of transcriptional output. Notably, stimulus-dependent enhancer transcription preceded mRNA induction, and CRISPR- based activation of eRNA synthesis increased mRNA at paired genes, functionally validating enhancer-gene predictions. Focusing on enhancers surrounding the Fos gene, we report that targeted eRNA manipulation bidirectionally modulates Fos mRNA, and that Fos eRNAs directly interact with the histone acetyltransferase domain of the enhancer-linked transcriptional co-activator CBP. Together, these results highlight the unique role of eRNAs in neuronal gene regulation and demonstrate that eRNAs can be used to identify putative target genes.
Classification of breast tumours into molecular apocrine, luminal and basal groups based on an explicit biological model
Authors: Iggo Richard
Published: February 2018

The gene expression profiles of human breast tumours fall into three main groups that have been called luminal, basal and either HER2-enriched or molecular apocrine. To escape from the circularity of descriptive classifications based purely on gene signatures I describe a biological classification based on a model of the mammary lineage. In this model I propose that the third group is a tumour derived from a mammary hormone-sensing cell that has undergone apocrine metaplasia. I first split tumours into hormone sensing and milk secreting cells based on the expression of transcription factors linked to cell identity (the luminal progenitor split), then split the hormone sensing group into luminal and apocrine groups based on oestrogen receptor activity (the luminal-apocrine split). I show that the luminal-apocrine-basal (LAB) approach can be applied to microarray data (186 tumours) from an EORTC trial and to RNA-seq data from TCGA (674 tumours), and compare results obtained with the LAB and PAM50 approaches. Unlike pure signature-based approaches, classification based on an explicit biological model has the advantage that it is both refutable and capable of meaningful improvement as biological understanding of mammary tumorigenesis improves.
Forming of thin-walled profiles made of FML in autoclave process
Authors: Jakubczak Patryk Adam , Bienias Jaroslaw , Mania Radoslaw , Majerski Krzysztof
Published: February 2018

Purpose

The purpose of the study was to develop the forming methodology for FML laminates with complex shapes, based on aluminium and epoxy-glass composite.

Design/methodology/approach

The subject of research encompassed Al/GFRP fibre metal laminates. Autoclave process has been selected for FML profiles production. The manufacturing process was followed by quality analysis for laminates produced.

Findings

The achievement of high stability and dimensional tolerance of thin-walled FML laminates is ensured by developed technology. The values of selected sections angles are significantly limited as a result of forming of FML laminates through the components performing. Failure to adhere to technological recommendations and to high regime of developer technology may lead to the occurrence of defects in FML.

Practical implications

Thin-walled composite structures could be applied in light-weight constructions, such as aircraft structures, which must meet rigorous requirements with regard to operation under complex load. The development of this type of technology may contribute to increased importance of FML sections in research area and finally to increased scope of their applications.

Originality/value

The production of thin-walled FML profiles with complex geometry, which would be characterized by dimensional stability and repeatable structural quality free of defects, is associated with many problems. No studies have been published so far on an effective forming process for FML laminates with complex shapes. Developed methodology has been verified through quality evaluation of produced profiles by means of non-destructive and destructive methods. The development of this type of technology may contribute to increased importance of FML, e.g. in aerospace technology.
An invariant-based performance-oriented procedure for preliminary design of composite structures
Authors: Danzi Francesco , Frulla Giacomo , Romeo Giulio
Published: February 2018

Purpose

This paper aims to present a systematic performance-oriented procedure to predict structural responses of composite layered structures. The procedure has a direct application in the preliminary design of aerospace composite structures evaluating the right and most effective material.

Design/methodology/approach

The aforementioned procedure is based upon the definition of stiffness invariants. In the paper, the authors briefly recall the definition and the physical explanation of the invariants, i.e. the trace; then they present the scaling procedure for the selection of the best material for a fixed geometrical shape.

Findings

The authors report the basic principles of the scaling procedure and several examples pertaining typical responses sought in the preliminary design of aeronautic structures

Research limitations/implications

Typically, during early stages, engineers had to perform the daunting task of balancing among functional requirements and constraints and give the optimum solution in terms of structural concept and material selection. Moreover, preliminary design activities require evaluating different responses as a function of as less as possible parameters, ensuring medium to high fidelity. The importance of incorporating as much physics and understanding of the problem as early as possible in the preliminary design stages is therefore fundamental. A robust and systematic procedure is necessary.

Practical implications

The time/effort reduction in the preliminary design of composite structures can increase the overall quality of the configuration chosen.

Social implications

Reduction in design costs and time.

Originality/value

In spite of the well-known invariant properties of composites, the application and extension to the preliminary design of composite structures by means of a scaling rule is new and original.
Lumped parameter modelling for the thermal analysis of the launch vehicle Vega C
Authors: Olivero Mattia , Ferrai Matteo , Pantaleone Piero , Perkovic Ivan , D’Amato Antonella , Moroni David , Perugini Pierluigi , Tirelli Matteo
Published: February 2018

Purpose

This activity dealt with the thermal analysis of the launch vehicle Vega C through a lumped parameter model. The Vega C is the upgrade of the actual launch vehicle Vega within the Vega Consolidation and Evolution Program, whose objective is to develop a consolidated – hence the C – version of the Vega by 2020. The main aim of the study was verifying the thickness of the external thermal protection of the launch vehicle, such that the structure and equipment temperatures were kept within their operating ranges.

Design/methodology/approach

The analysis has been performed by means of ESATAN–TMS during a time-frame that included the stand-by on ground phase and a flight phase up to the separation of the second stage from the third one. Two operating conditions have been considered, i.e. the worst hot and worst cold cases. The study has been divided as follows: geometry definition through spatial discretization; application of materials and optical properties; application of thermal loads; thermal analysis; and post-processing of the results in ThermNV.

Findings

It was concluded that the calculated temperatures were within the supposed project specifications, while their trends reflected the expected behavior.

Originality/value

During the flight phase, the mutual separation of the investigated stages has been explicitly modelled through a routine specifically developed for this purpose. Therefore, the submodels of each stage have been disabled at the correct instant according to the known time-sheet.
Design of inoffensive sUAS for humanitarian missions
Authors: Novaro Mascarello Laura , Quagliotti Fulvia
Published: February 2018

Purpose

The purpose of this study is to define configuration requirements needed to define “harmless” small unmanned aerial systems (sUAS) by taking into account mathematical models and ballistic approaches, already defined for small projectiles and now modified, with appropriate assumptions. These safety requirements are related to structures, materials, weight and dimensions, such as the radius of curvature.

Design/methodology/approach

In this paper, the state-of-the-art forensic and ballistic physics models are presented, and then safety requirements are defined for sUAS. This big challenge is due to a lack of regulation because each country and each regulatory authority have published their own regulations, where the imposed requirements are different because the mathematical models, and the related assumptions, are different from one country to another. Therefore, proper assumptions are introduced in these models to obtain safety requirements to define harmless final configuration.

Findings

If the final configuration meets the requirements defined in the methodology, there are no severe injuries on the human body, in case of impact with the sUAS. In other words, the inoffensive configuration can also be used in overcrowded areas without risks for the human life.

Originality/value

The final configuration proposed in this paper has some design features substantially modified, compared to the conventional configuration, and in particular, the sUAS could be the first harmless multicopter certified in Italy.
A study of a new screw press forging process for producing aircraft drop forgings made of magnesium alloy AZ61A
Authors: Gontarz Andrzej , Drozdowski Krzysztof , Dziubinska Anna , Winiarski Grzegorz
Published: February 2018

Purpose

The aim of this study is to develop a die forging process for producing aircraft components made of magnesium alloy AZ61A using a screw press.

Design/methodology/approach

The proposed forging technique has been developed based on the results of a numerical and experimental research. The required forging temperature has been determined by upsetting cylindrical specimens on a screw press to examine both plasticity of the alloy and the quality of its microstructure. The next stage involved performing numerical simulations of the designed forging processes for producing forgings of a door handle and a bracket, both made of magnesium alloy AZ61A. The finite element method based on simulation programme, Deform 3D has been used for numerical modelling. The numerical results revealed that the forgings are free from material overheating and shape defects. In addition to this, the results have also helped determine the regions that are the most prone to cracking. The final stage of the research involved performing forging tests on a screw press under industrial conditions. The forgings of door handles and brackets were made, and then these were tested for their mechanical and structural properties. The results served as a basis for assessing both the viability of the designed technique and the quality of the produced parts.

Findings

The experimental results demonstrate that aircraft components made of magnesium alloy AZ61A can be produced by die forging on screw presses. The results have been used to determine the fundamental parameters of the process such as the optimum forging temperature, the method of tool heating, the way of cooling parts after the forging process, and the method of thermal treatment. The results of the mechanical and structural tests confirm that the products meet the required quality standards.

Practical implications

The developed forging technique for alloy AZ61A has been implemented by the forging plant ZOP Co. Ltd in Swidnik (Poland), which specializes in the manufacturing of aircraft components made of non-ferrous metal alloys.

Originality/value

Currently, the global tendency is to forge magnesium alloys (including alloy AZ61A) on free hydraulic presses using expensive die-heating systems. For this reason, the production efficiency of such forging processes is low, while the manufacturing costs are high. The proposed forging technique for alloy AZ61A is an innovative method for producing forgings using relatively fast and efficient machines (screw presses). The proposed forging method can be implemented by forging plants equipped with standard stocks of tools, which increases the range of potential manufacturers of magnesium alloy products. In addition, this technology is highly efficient and ensures reduced manufacturing costs.