bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of a Mitofusin specificity region that confers unique activities to Mfn1 and Mfn2
Authors: Sloat SR , Whitley BN , Engelhart EA , Hoppins S 
Published: May 2019

ABSTRACTMitochondrial structure can be maintained at steady state or modified in response to changes in cellular physiology. This is achieved by the coordinated regulation of dynamic properties including mitochondrial fusion, division and transport. Disease states, including neurodegeneration, are associated with defects in these processes. In vertebrates, two Mitofusin paralogs, Mfn1 and Mfn2, are required for efficient mitochondrial fusion. The Mitofusins share a high degree of homology and have very similar domain architecture, including an amino terminal GTPase domain and two extended helical bundles that are connected by flexible regions. Mfn1 and Mfn2 are non-redundant and are both required for mitochondrial outer membrane fusion. However, the molecular features that make these proteins functionally distinct are poorly defined. By engineering chimeric proteins composed of Mfn1 and Mfn2, we discovered a region that contributes to isoform-specific function (Mitofusin IsoformSpecificRegion – MISR). MISR confers unique fusion activity and Mitofusin specific nucleotide-dependent assembly properties. We propose that MISR functions in higher order oligomerization either directly, as an interaction interface, or indirectly through conformational changes.
Dock5 is a new regulator of microtubule dynamic instability through GSK3β inhibition in osteoclasts
Authors: Guimbal Sarah , Guérit David , Chardon Manon , Blangy Anne , Vives Virginie 
Published: May 2019

AbstractBackground informationOsteoclast resorption is dependent on a podosome-rich structure, called sealing zone, which is stabilized by acetylated microtubules. It tightly attaches the osteoclast to the bone creating a favorable acidic microenvironment for bone degradation. We already established that Rac activation by Dock5 is necessary for osteoclast resorption. Indeed, inhibition of Dock5 in osteoclasts results in Rac1 decreased activity associated to impaired podosome assembly into sealing zones and resorbing activity.ResultsIn this report, we show that Dock5 knockout osteoclasts also present a reduced acetylated tubulin level leading to a decreased length and duration of microtubule growth phases whereas their growth speed remains unaffected. Dock5 does not act by direct interaction with the polymerized tubulin but through inhibition of the microtubules destabilizing kinase GSK3β downstream of Akt activation. Interestingly, we ruled out the implication of Rac1 in this process using specific inhibitors.ConclusionOur data involve Dock5 as a new regulator of microtubule dynamic instability in osteoclast.SignificanceThe fact that Dock5 is a regulator of both actin cytoskeleton and microtubule dynamics makes it an interesting therapeutic target for osteolytic pathologies because of its dual role on sealing zone formation and stabilization.
SigProfilerMatrixGenerator: a tool for visualizing and exploring patterns of small mutational events
Authors: Bergstrom Erik N. , Huang Mi Ni , Mahto Uma , Barnes Mark , Stratton Michael R. , Rozen Steven G. , Alexandrov Ludmil B. 
Published: May 2019

ABSTRACTBackgroundCancer genomes are peppered with somatic mutations imprinted by different mutational processes. The mutational pattern of a cancer genome can be used to identify and understand the etiology of the underlying mutational processes. A plethora of prior research has focused on examining mutational signatures and mutational patterns from single base substitutions and their immediate sequencing context. We recently demonstrated that further classification of small mutational events (including substitutions, insertions, deletions, and doublet substitutions) can be used to provide a deeper understanding of the mutational processes that have molded a cancer genome. However, there has been no standard tool that allows fast, accurate, and comprehensive classification for all types of small mutational eventsResultsHere, we present SigProfilerMatrixGenerator, a computational tool designed for optimized exploration and visualization of mutational patterns for all types of small mutational events. SigProfilerMatrixGenerator is written in Python with an R wrapper package provided for users that prefer working in an R environment. SigProfilerMatrixGenerator produces fourteen distinct matrices by considering transcriptional strand bias of individual events and by incorporating distinct classifications for single base substitutions, doublet base substitutions, and small insertions and deletions. While the tool provides a comprehensive classification of mutations, SigProfilerMatrixGenerator is also faster and more memory efficient than existing tools that generate only a single matrix.ConclusionsSigProfilerMatrixGenerator provides a standardized method for classifying small mutational events that is both efficient and scalable to large datasets. In addition to extending the classification of single base substitutions, the tool is the first to provide support for classifying doublet base substitutions and small insertions and deletions. SigProfilerMatrixGenerator is freely available athttps://github.com/AlexandrovLab/SigProfilerMatrixGeneratorwith an extensive documentation athttps://osf.io/s93d5/wiki/home/.
A novel effect of the antigenic peptides position for presentation upon MHC class I
Authors: Imai Jun , Otani Mayu , Koike Eri , Yokoyama Yuuki , Maruya Mikako , Koyasu Shigeo , Sakai Takahiro 
Published: May 2019

AbstractMHC-I molecules are expressed on the cell surface complexed with oligopeptides, most of which are generated from intracellular proteins by the ubiquitin-proteasome pathways and would be roughly proportional to the relative abundance of proteins and their rate of degradation. Thus MHC-I together with peptides function as immunological self-markers to exhibit the information about the repertoire of proteins expressed in a given cell to the immune system, and this process is called antigen (Ag) direct-presentation. Herein, we report a novel rule for the preference of peptides selected for the direct presentation; the N-terminally located antigenic peptides are more efficiently complexed with MHC-I than the C-terminally located peptides on the same protein. The superiority is largely dependent uponde novoproteins synthesis, degradation by proteasomes, and less dependent upon stabilities of proteins, indicating that this difference derived from rapidly degraded newly synthesized proteins such as defective ribosomal products (DRiPs). The effects of those N-terminal predominance was comparable with the enhanced MHC-I presentation by IFN-γ suggesting that they might play important roles in the adaptive immunity.
Extra-cellular matrix induced by steroids through a G-protein coupled receptor in a Drosophila model of renal fibrosis
Authors: Zheng Wenjing , Ocorr Karen , Tatar Marc 
Published: May 2019

AbstractAldosterone is produced by the mammalian adrenal cortex to modulate blood pressure and fluid balance, however excessive, prolonged aldosterone production promotes fibrosis and kidney failure. How aldosterone triggers disease may involve actions that are independent of its canonical mineralocorticoid receptor. Here we present aDrosophilamodel of renal pathology caused by excess extra-cellular matrix formation, stimulated by exogenous aldosterone and insect ecdysone steroids. Chronic administration of aldosterone or ecdysone induces expression and accumulation of collagen-like pericardin at adult nephrocytes – podocyte-like cells that filter circulating hemolymph. Excess pericardin deposition disrupts nephrocyte (glomerular) filtration and causes proteinuria in Drosophila, hallmarks of mammalian kidney failure. Steroid-induced pericardin arises from cardiomyocytes associated with nephrocytes, reflecting an analogous role of mammalian myofibroblasts in fibrotic disease. Remarkably, the canonical ecdysteroid nuclear hormone receptor, ecdysone receptor EcR, is not required for aldosterone or ecdysone to stimulate pericardin production or associated renal pathology. Instead, these hormones require a cardiomyocyte-associated G-protein coupled receptor, dopamine-EcR (dopEcR), a membrane-associated receptor previously characterized in the fly brain as affecting behavior. ThisDrosophilarenal disease model reveals a novel signaling pathway through which steroids may potentially modulate human fibrosis through proposed orthologs of dopEcR.Significance StatementAldosterone regulates salt and fluid homeostasis, yet excess aldosterone contributes to renal fibrosis. Aldosterone acts through a nuclear hormone receptor, but an elusive, G-protein coupled receptor (GPCR) is thought to also mediate the hormone’s pathology. Here we introduce a Drosophila model of renal fibrosis. Flies treated with human aldosterone produce excess extra-cellular matrix and that causes kidney pathology. Flies treated with the insect steroid ecdysone produce similar pathology, and from this analogous response we identify an alternative receptor through which steroids mediate renal fibrosis -- the GPCR dopamine-Ecdysone Receptor (dopEcR). dopEcR functions in heart muscle cells associated with nephrocytes, analogous to the role of myofibroblasts in human fibrosis. This finding opens avenues to identify mammalian GPCR homologs of dopEcR through which aldosterone mediates renal fibrosis.
Hydrogel platform for in vitro three-dimensional assembly of human stem cell-derived β cells and endothelial cells
Authors: Augsornworawat Punn , Velazco-Cruz Leonardo , Song Jiwon , Millman Jeffrey R. 
Published: May 2019

AbstractDifferentiation of stem cells into functional replacement cells and tissues is a major goal of the regenerative medicine field. However, one limitation has been organization of differentiated cells into multi-cellular, three-dimensional assemblies. The islets of Langerhans contain many endocrine and non-endocrine cell types, such as insulin-producing β cells and endothelial cells. Transplantation of exogenous islets into diabetic patients can serve as a cell replacement therapy, replacing the need for patients to inject themselves with insulin, but the number of available islets from cadaveric donors is low. We have developed a strategy of assembling human embryonic stem cell-derived β cells with endothelial cells into three-dimensional aggregates on a hydrogel. The resulting islet organoids express β cell markers and are functional, capable of undergoing glucose-stimulated insulin secretion. These results provide a platform for evaluating the effects of the islet tissue microenvironment on human embryonic stem cell-derived β cells and other islet endocrine cells to develop tissue engineered islets.
On the Reliability of Chronically Implanted Thin-Film Electrodes in Human Arm Nerves for Neuroprosthetic Applications
Authors: Čvančara P. , Valle G. , Müller M. , Guiho T. , Hiairrassary A. , Petrini F. , Raspopovic S. , Strauss I. , Granata G. , Fernandez E. , Rossini P. M. , Barbaro M. , Yoshida K. , Jensen W. , Divoux J.-L. , Guiraud D. , Micera S. , Stieglitz T. 
Published: May 2019

AbstractDirect stimulation of peripheral nerves can successfully provide sensory feedback to amputees while using hand prostheses. Recent clinical studies have addressed this important limitation of current prostheses solutions using different implantable electrode concepts. Longevity of the electrodes is key to success. We have improved the long-term stability of the polyimide-based transverse intrafascicular multichannel electrode (TIME) that showed promising performance in clinical trials by integration of silicon carbide adhesion layers. The TIMEs were implanted in the median and ulnar nerves of three trans-radial amputees for up to six months. Here, we present the characterization of the electrical properties of the thin-film metallization as well as material status post explantationem for the first time. The TIMEs showed reliable performance in terms of eliciting sensation and stayed within the electrochemical safe limits maintaining a good working range with respect to amplitude modulation. After termination of the trials and explantation of the probes, no signs of corrosion or morphological change to the thin-film metallization was observed by means of electrochemical and optical analysis. Damage to the metallization was assigned exclusively to mechanical impacts during explantation and handling. The results indicate that thin-film metallization on polymer substrates is applicable in permanent implant system.
Membrane integration and topology of RIFIN and STEVOR proteins of thePlasmodium falciparumparasite
Authors: Andersson Annika , Kudva Renuka , Magoulopoulou Anastasia , Lejarre Quentin , Lara Patricia , Xu Peibo , Goel Suchi , Pissi Jennifer , Ru Xing , Hessa Tara , Wahlgren Mats , von Heijne Gunnar , Nilsson IngMarie , Tellgren-Roth Åsa 
Published: May 2019

ABSTRACTThe malarial parasitePlasmodium, infects red blood cells by remodeling them and transporting its own proteins to their cell surface. These proteins trigger adhesion of infected cells to uninfected cells (rosetting), and to the vascular endothelium, obstructing blood flow and contributing to pathogenesis. RIFINs (P. falciparum-encoded repetitive interspersed families of polypeptides) and STEVORs (subtelomeric variable open reading frame), are two classes of proteins that are involved in rosetting. Here we study the membrane insertion and topology of three RIFIN and two STEVOR proteins, employing a well-established assay that uses N-linked glycosylation of sites within the protein as a measure to assess the topology a protein adopts when inserted into the ER membrane. Our results indicate that all the proteins tested assume an overall topology of Ncyt-Ccyt, with predicted transmembrane helices TM1 and TM3 integrated into the ER membrane. We also show that the segments predicted as TM2 do not reside in the membrane. Our conclusions are consistent with other recent topology studies on RIFIN and STEVOR proteins.
Frequency and Distribution of Corneal Astigmatism and Keratometry Features: Methodology and Findings of the UK Biobank Study
Authors: Pontikos Nikolas , Chua Sharon , Foster Paul J , Tuft Stephen J , Day Alexander C ,   UK Biobank Eye and Vision Consortium
Published: May 2019

AbstractPurposeTo describe corneal astigmatism in the UK Biobank population, to look for associations with other biometric variables and socio-demographic factors, and to report the proportion with abnormal keratometry and irregular astigmatism suggestive of pathological corneal ectasias such as keratoconus.MethodsCross-sectional data were obtained from UK Biobank (www.ukbiobank.ac.uk/). A subsample of 107,452 participants from UK communities had undergone an enhanced ophthalmic examination including autorefractor keratometry (Tomey RC 5000, Tomey Corp., Nagoya, Japan). After quality control and applying relevant exclusions, data on corneal astigmatism on 83,751 participants was available for analysis. Potential associations were tested through univariable regression and significant parameters carried forward for multivariable analysis.ResultsIn a univariable analysis, the characteristics significantly protective against corneal astigmatism were gender (male), older age, darker skin colour and increased alcohol intake (all p<0.001). The parameters significantly associated with increased corneal astigmatism were older age at completion of full time education, use of UV protection and lower corrected visual acuity. After inclusion in the multivariable analysis, age, gender, age at completion of full time education, corrected visual acuity and skin colour remained significant (all p<0.001). Increased corneal astigmatism was also found to be significantly associated with amblyopia or strabismus. No individuals with abnormal keratometry or irregular astigmatism were reported.ConclusionsThis analysis of associations with astigmatism in a large cohort of volunteers confirms previous associations including adverse associations with younger age and female gender, and identified novel associations including darker skin colour and frequency of alcohol intake. The highest risk group for corneal astigmatism were younger females of lighter skin colour, having completed full time education later, with higher logMAR corrected visual acuity. We also confirmed that corneal astigmatism is a high risk factor for amblyopia and strabismus. Finally since no cases of keratoconus were identified, this would suggest that simple keratometry indices may not be sufficient for population screening of keratoconus.
RFQAmodel: Random Forest Quality Assessment to identify a predicted protein structure in the correct fold
Authors: West Clare E. , Oliveira Saulo H. P. de , Deane Charlotte M. 
Published: May 2019

AbstractWhile template-free protein structure prediction protocols now produce good quality models for many targets, modelling failure remains common. For these methods to be useful it is important that users can both choose the best model from the hundreds to thousands of models that are commonly generated for a target, and determine whether this model is likely to be correct. We have developed Random Forest Quality Assessment (RFQAmodel), which assesses whether models produced by a protein structure prediction pipeline have the correct fold. RFQAmodel uses a combination of existing quality assessment scores with two predicted contact map alignment scores. These alignment scores are able to identify correct models for targets that are not otherwise captured. Our classifier was trained on a large set of protein domains that are structurally diverse and evenly balanced in terms of protein features known to have an effect on modelling success, and then tested on a second set of 244 protein domains with a similar spread of properties. When models for each target in this second set were ranked according to the RFQAmodel score, the highest-ranking model had a high-confidence RFQAmodel score for 67 modelling targets, of which 52 had the correct fold. At the other end of the scale RFQAmodel correctly predicted that for 59 targets the highest-ranked model was incorrect. In comparisons to other methods we found that RFQAmodel is better able to identify correct models for targets where only a few of the models are correct. We found that RFQAmodel achieved a similar performance on the model sets for CASP12 and CASP13 free-modelling targets. Finally, by iteratively generating models and running RFQAmodel until a model is produced that is predicted to be correct with high confidence, we demonstrate how such a protocol can be used to focus computational efforts on difficult modelling targets.
AVDM: Angular Velocity Decoding Model Accounting for Visually Guided Flight Behaviours of the Bee
Authors: Wang Huatian , Fu Qinbing , Wang Hongxin , Baxter Paul , Peng Jigen , Yue Shigang 
Published: May 2019

AbstractWe present a new angular velocity estimation model for explaining the honeybee’s flight behaviours of tunnel centring and terrain following, capable of reproducing observations of the large independence to the spatial frequency and contrast of the gratings in visually guide flights of honeybees. The model combines both temporal and texture information to decode the angular velocity well. The angular velocity estimation of the model is little affected by the spatial frequency and contrast in synthetic grating experiments. The model is also tested behaviourally in Unity with the tunnel centring and terrain following paradigms. Together with the proposed angular velocity based control algorithms, the virtual bee navigates well in a patterned tunnel and can keep a certain distance from undulating ground with gratings in a series of controlled trials. The results coincide with both neuron spike recordings and behavioural path recordings of honeybees, demonstrating that the model can explain how visual motion is detected in the bee brain.Author summaryBoth behavioural and electro-physiological experiments indicate that honeybees can estimate the angular velocity of image motion in their retinas to control their flights, while the neural mechanism behind has not been fully understood. In this paper, we present a new model based on previous experiments and models aiming to reproduce similar behaviours as real honeybees in tunnel centring and terrain following simulations. The model shows a large spatial frequency independence which outperforms the previous model, and our model generally reproduces the wanted behaviours in simulations.
Construction productivity revisited: towards measuring performance of construction output
Authors: Haugbølle Kim , Larsen Jacob Norvig , Nielsen Jørgen 
Published: May 2019

Purpose
Construction is repeatedly criticised for its low productivity based on statistical data that do not represent the output of construction adequately. The purpose of this paper is to improve the understanding of construction output – being the numerator in construction productivity calculations – by focussing on changes in quantity of the products, product characteristics and composition of the aggregate rather than as changes in price.

Design/methodology/approach
The research design of this study applies statistical data from the national accounts along with data from four paradigmatic case studies of social housing projects covering a period of 50 years.

Findings
The results indicate that while construction output prices have increased threefold over the past 50 years, improvements in performance can only explain approximately 20 per cent.

Research limitations/implications
The developed four-step method has demonstrated its value as a means to measure changes in the characteristics of the product, but more studies on the actual figures and results over time and regions are required before solid conclusions can be drawn.

Social implications
This study has added new knowledge of construction output that supports the development of a more accurate construction statistics, which in turn can assist the design of more effective and evidence-based policies for improving construction productivity.

Originality/value
This paper describes and demonstrates a novel performance-based methodology for addressing changes in the characteristics of the products in a longitudinally perspective, which can potentially provide a better understanding of changes in productivity.
Effect of trapezoidal heater on natural convection heat transfer and fluid flow inside a cubical cavity
Authors: Gibanov Nikita , Sheremet Mikhail A. 
Published: May 2019

Purpose
The purpose of this paper is to investigate natural convective heat transfer in a cubical cavity with the heat source of a trapezoidal form having a constant temperature.

Design/methodology/approach
The domain of interest is a cubical cavity with two isothermal opposite vertical walls, while other walls are adiabatic. A discrete heater of a trapezoidal shape is located at the bottom wall of the cavity. Governing equations formulated in dimensionless vector potential functions, vorticity vector and temperature with corresponding initial and boundary conditions have been solved numerically using a developed computational code based on the finite difference method.

Findings
The results show that the variation of geometric parameters, such as height, length and size of the local heater, significantly influences the evolution of a temperature field and fluid flow inside the enclosure. The effects of Rayleigh number and time on streamlines, isotherms and average Nusselt number have been studied.

Originality/value
The originality of this work is to explore three-dimensional (3D) natural convection in a cubical cavity with a local heat source of trapezoidal shape, to analyze the effects of heater geometric parameters and to compare obtained 3D data with two-dimensional results.