bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractProtein 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

AbstractIntrinsic 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

SUMMARYHeterochrony, 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.
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

AbstractNeurodevelopmental 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

ABSTRACTSterile 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.IMPORTANCEA 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.
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

SUMMARYWe 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.
Classification of breast tumours into molecular apocrine, luminal and basal groups based on an explicit biological model
Authors: Iggo Richard 
Published: February 2018

ABSTRACTThe 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

PurposeThe 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/approachIn 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.FindingsIf 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/valueThe 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.