bluuebunny/crossref_metadata_2025_split huggingface dataset:
Flow-independent accumulation of motor-competent non-muscle myosin II in the contractile ring is essential for cytokinesis
Authors: Osorio DS , Chan FY , Saramago J , Leite J , Silva AM , Sobral AF , Gassmann R , Carvalho AX 
Published: May 2018

AbstractCytokinesis in animal cells requires the assembly of a contractile actomyosin ring, whose subsequent constriction physically separates the two daughter cells. Non-muscle myosin II (myosin) is essential for cytokinesis, but the role of its motor activity remains poorly defined. Here, we examine cytokinesis inC. elegansone-cell embryos expressing myosin motor mutants generated by genome editing. Motor-dead myosin, which is capable of binding F-actin, does not support cytokinesis, and embryos co-expressing motor-dead and wild-type myosin are delayed in cytokinesis. Partially motor-impaired myosin also delays cytokinesis and renders contractile rings more sensitive to reduced myosin levels. Thus, myosin motor activity, rather than its ability to cross-link actin filaments, drives contractile ring assembly and constriction. We further demonstrate that myosin motor activity is required for long-range cortical actin flows, but that flowsper seplay a minor role in contractile ring assembly. Our results suggest that flow-independent recruitment of motor-competent myosin to the cell equator is both essential and rate-limiting for cytokinesis.
The role of gene flow in rapid and repeated evolution of cave related traits in Mexican tetra,Astyanax mexicanus
Authors: Herman Adam , Brandvain Yaniv , Weagley James , Jeffery William R. , Keene Alex C. , Kono Thomas J. Y. , Bilandžija Helena , Borowsky Richard , Espinasa Luis , O’Quin Kelly , Ornelas-García Claudia P. , Yoshizawa Masato , Carlson Brian , Maldonado Ernesto , Gross Joshua B. , Cartwright Reed A. , Rohner Nicolas , Warren Wesley C. , McGaugh Suzanne E. 
Published: May 2018

ABSTRACTUnderstanding the molecular basis of repeated evolved phenotypes can yield key insights into the evolutionary process. Quantifying the amount of gene flow between populations is especially important in interpreting mechanisms of repeated phenotypic evolution, and genomic analyses have revealed that admixture is more common between diverging lineages than previously thought. In this study, we resequenced and analyzed nearly 50 whole genomes of the Mexican tetra from three blind cave populations, two surface populations, and outgroup samples. We confirmed that cave populations are polyphyletic and twoAstyanax mexicanuslineages are present in our dataset. The two lineages likely diverged ∼257k generations ago, which, assuming 1 generation per year, is substantially younger than previous mitochondrial estimates of 5-7mya. Divergence of cave populations from their phylogenetically closest surface population likely occurred between ∼161k - 191k generations ago. The favored demographic model for most population pairs accounts for divergence with secondary contact and heterogeneous gene flow across the genome, and we rigorously identified abundant gene flow between cave and surface fish, between caves, and between separate lineages of cave and surface fish. Therefore, the evolution of cave-related traits occurred more rapidly than previously thought, and trogolomorphic traits are maintained despite substantial gene flow with surface populations. After incorporating these new demographic estimates, our models support that selection may drive the evolution of cave-derived traits, as opposed to the classic hypothesis of disuse and drift. Finally, we show that a key QTL is enriched for genomic regions with very low divergence between caves, suggesting that regions important for cave phenotypes may be transferred between caves via gene flow. In sum, our study shows that shared evolutionary history via gene flow must be considered in studies of independent, repeated trait evolution.
Hepatitis C virus NS5A inhibitor daclatasvir allosterically impairs NS4B-involved protein-protein interactions within the viral replicase and disrupts the replicase quaternary structure in a replicase assembly surrogate system
Authors: Zhang Yang , Zou Jingyi , Zhao Xiaomin , Yuan Zhenghong , Yi Zhigang 
Published: May 2018

AbstractDaclatasvir (DCV) is a highly potent direct-acting antiviral that targets the non-structural protein 5A (NS5A) of hepatitis C virus (HCV) and has achieved great clinical successes. Previous studies demonstrate its impact on the viral replication complex assembly. However the precise mechanism by which DCV impairs the replication complex assembly remains elusive. In this study, by using HCV subgenomic replicons and a viral replicase assembly surrogate system that expresses the HCV NS3-5B polyprotein to mimic the viral replicase assembly, we dissected the impacts of DCV on aggregation and tertiary structure of NS5A, the protein-protein interactions within the viral replicase and the quaternary structure of the viral replicase. We found that DCV didn’t affect aggregation and tertiary structure of NS5A. DCV induced a quaternary structural change of the viral replicase, evidenced by selectively increasing of the NS4B’s sensitivity to proteinase K digestion. Mechanically, DCV impaired the NS4B-involved protein-protein interactions within the viral replicase. The DCV-resistant mutant Y93H was refractory to the DCV-induced reduction of the NS4B-invoved protein interactions and the quaternary structural change of the viral replicase. In addition, Y93H reduced NS4B-involed protein-protein interactions within the viral replicase and attenuated viral replication. We propose that DCV may induce a position change of NS5A, which allosterically affects the protein interactions within the replicase components and disrupts the replicase assembly.ImportanceThe development of the direct-acting antivirals (DAA) has resulted in great clinical achievements for Hepatitis C Virus (HCV) treatment. Daclatasvir (DCV) is an inhibitor targeting the non-enzymatic NS5A, with the 50% effective concentration values in the picomolar range. Accumulated data suggest that DCV blocks the biogenesis of the HCV replication complex. However the mechanistic actions of DCV are still largely unknown. Insights into the action mechanism of DCV on the viral replication complex assembly of HCV may enlighten the development of next generation of DAAs and new anti-viral strategies for other positive-strand RNA viruses for which there are a scarcity of DAAs. Herein, using HCV subgenomic replicons and a viral replicase assembly surrogate system, we dissected the mechanistic actions of DCV on the viral replicase assembly. We found that DCV allosterically impairs NS4B-involved protein-protein interactions within the viral replicase and disrupts the quaternary structure of the viral replicase.
A capsular polysaccharide-expressing live vaccine suppresses streptococcal toxic shock-like syndrome and provides sequence type-independent protection during Streptococcus suis infection
Authors: Li Zhiwei , Chang Peixi , Xu Jiali , Tan Chen , Wang Xiaohong , Bei Weicheng , Li Jinquan 
Published: May 2018

AbstractStreptococcus suis (S. suis) is an encapsulated zoonotic pathogen, which is responsible for bacterial meningitis and streptococcal toxic shock-like syndrome (STSLS). Despite many attempts to develop an effective vaccine, none is currently available. Here, a capsular polysaccharide (CPS)-expressing attenuated mutant 2015033 was constructed by deleting five virulence-associated factors (sly, scpA, ssnA, fhb, and ssads) in an outbreak S. suis strain SC19. Genes mentioned above are associated with either innate immunity-evading or tissue barrier-invading. Deletion of these genes did not impact the growth ability and CPS generation of 2015033, and the mutant exhibited no hemolytic activity to erythrocytes and no cytotoxicity to different epithelial or endothelial cells. In addition, 2015033 was more easily eliminated by whole human blood in vitro and by mouse blood in vivo. In addition, 2015033 showed a diminished invasive ability in different mouse organs (brain, lung, and liver) and avirulent properties in mice associated with weak inflammation-inducing ability. Immunization with 2015033 triggered T cell-dependent immunity and this immunity suppressed STSLS during SC19 infection by inhibiting excessive proinflammatory responses. In addition, immunization with 2015033 successfully conferred sequence type (STs)-independent protection to mice during heterogeneous infections (ST1, ST7, and ST658). This study presents the feasibility of the strategy of multi-gene deletion for the development of promising live vaccines against invasive encapsulated pathogens.IMPORTANCES. suis is a traditional zoonotic agent causing human meningitis and STSLS, which is also a neglected emerging food-borne pathogen. Increasing antimicrobial resistance invokes reduction of preventative use of antibiotics in livestock creating an urgent need for effective vaccines. Given the expression of CPS is the basis for promising vaccines against encapsulated pathogens, and in order to find an effective and economical strategy for CPS-based vaccine development, multi-gene deletion was introduced into the design of a S. suis vaccine for the first time. From our results, CPS-expressing attenuated mutant 2015033 exhibited diminished evasive ability against the innate immune system and reduced invasive properties against different host barriers. To our knowledge, 2015033 is the first STSLS-suppressing S. suis vaccine to provide STs-independent protection during heterogeneous infections.
Systematic Review on Barriers and Facilitators for Access to Diabetic Retinopathy Screening Services
Authors: Prabhath Nishantha Piyasena M.M. , Murthy Gudlavalleti Venkata S. , Yip Jennifer L.Y. , Gilbert Clare , Zuurmond Maria , Peto Tunde , Gordon Iris , Hewage Suwin , Kamalakannan Sureshkumar 
Published: May 2018

AbstractObjectivesThe aim of this systematic review is to identify the barriers/enablers for the people with diabetes (PwDM) in accessing DRS services (DRSS) and challenges/facilitators for the providers.BackgroundDiabetic retinopathy (DR) can lead to visual impairment and blindness if not detected and treated in time. Achievement of an acceptable level of screening coverage is a challenge in any setting. Both patient-related and provider-related factors affect provision of DR screening (DRS) and uptake of services.MethodsWe searched MEDLINE, Embase, CENTRAL in the Cochrane Library from the databases start date to September 2016. We included the studies reported on barriers and enablers to access DRS by PwDM and studies which have assessed barriers or facilitators experienced by the providers in provision of DRSS. We identified and classified the studies that used quantitative or qualitative methods for data collection and analysis in reporting themes of barriers and enablers.Main ResultsWe included 63 studies primarily describing the barriers and enablers. The findings of these studies were based on PwDM from different socio-economic backgrounds and different levels of income settings. Most of the studies were from high income settings (48/63, 76.2%) and cross sectional in design (49/63, 77.8%). From the perspectives of users, lack of knowledge, attitude, awareness and motivation were identified as major barriers to access DRSS. The enablers to access DRSS were fear of blindness, proximity of screening facility, experiences of vision loss and being concerned of eye complications. Providers often mentioned that lack of awareness and knowledge among the PwDM was the main barrier to access. In their perspective lack of skilled human resources, training programs and infrastructure of retinal imaging and cost of services were the main obstacles in provision of screening services.ConclusionKnowing the barriers to access DRS is a pre-requisite in development of a successful screening program. The awareness, knowledge and attitude of the consumers, availability of skilled human resources and infrastructure emerged as the major barriers to access to DRS in any income setting.
Large-scale docking predicts that sORF-encoded peptides may function through protein-peptide interactions in Arabidopsis thaliana
Authors: Hazarika Rashmi R. , Sostaric Nikolina , Sun Yifeng , van Noort Vera 
Published: May 2018

AbstractSeveral recent studies indicate that small Open Reading Frames (sORFs) embedded within multiple eukaryotic non-coding RNAs can be translated into bioactive peptides of up to 100 amino acids in size. However, the functional roles of the 607 Stress Induced Peptides (SIPs) previously identified from 189 Transcriptionally Active Regions (TARs) inArabidopsis thalianaremain unclear. To provide a starting point for function annotation of these peptides, we performed a large-scale prediction of peptide binding sites on protein surfaces using and coarse-grained peptide docking. The docked models were subjected to further atomistic refinement and binding energy calculations. A total of 530 peptide-protein pairs were successfully docked. In cases where a peptide encoded by a TAR is predicted to bind at a known ligand or cofactor-binding site within the protein, it can be assumed that the peptide modulates the ligand or cofactor-binding. Moreover, we predict that several peptides bind at protein-protein interfaces, which could therefore regulate the formation of the respective complexes. Protein-peptide binding analysis further revealed that peptides employ both their backbone and side chain atoms when binding to the protein, forming predominantly hydrophobic interactions and hydrogen bonds. In this study, we have generated novel predictions on the potential protein-peptide interactions inA. thaliana, which will help in further experimental validation.Author summaryDue to their small size, short peptides are difficult to find and have been ignored in genome annotations. Only recently, we have realized that these short peptides of less than 100 amino acids may actually play an important role in the cell. Currently, there are no high-throughput methods to find out what the functions of these peptides are in contrast with efforts that exist for ‘normal’proteins. In this work, we try to fill this gap by predicting with which larger proteins, the short peptides might interact to exert their function. We find that many peptides bind to pockets where normally other proteins or molecules bind. We thus think that these peptides that are induced by stress, may regulate protein-protein and protein-molecule binding. We make this information available through our database ARA-PEPs so that individual predictions can be followed up.
Complexity of ABA signaling for stomatal development and aperture regulation
Authors: Jalakas Pirko , Merilo Ebe , Kollist Hannes , Brosché Mikael 
Published: May 2018

AbstractStomata, small pores on the surfaces of leaves formed by a pair of guard cells, adapt rapidly to changes in the environment by adjusting the aperture width. As a long term response, the number of stomata is regulated during stomatal development. The hormone abscisic acid (ABA) regulates both processes. In ABA mediated guard cell signaling the protein kinase OPEN STOMATA1 (OST1) has a central role, as stomatal closure in the ost1 mutant is impaired in response to ABA and to different environmental stimuli. We aimed to dissect the contribution of different ABA-related regulatory mechanisms in determining stomatal conductance, a combination of stomatal density and aperture width, and crossed the ost1 mutant with mutants that either decreased (aba3) or increased (cyp707a1/a3) the concentration of ABA in plants. The double mutant ost1 aba3 had higher stomatal conductance than either parent due to a combination of increased stomatal aperture width and higher stomatal density. In the triple mutant ost1 cyp707a1/a3 stomatal conductance was significantly lower compared to ost1-3 due to lower stomatal density. Further characterization of the single, double and triple mutants showed that responses to treatments that lead to stomatal closure were impaired in ost1 as well as ost1 aba3 and ost1 cyp707a1/a3 mutants, supporting a critical role for OST1 in stomatal aperture regulation. Based on our results, we suggest that there are two signaling pathways to regulate water flux from leaves i.e. stomatal conductance: an ABA-dependent pathway that determines stomatal density independent of OST1; and an OST1-dependent pathway that regulates rapid changes in stomatal aperture.
Thermostabilization and purification of the human dopamine transporter (hDAT) in an inhibitor and allosteric ligand bound conformation
Authors: Navratna Vikas , Tosh Dilip K. , Jacobson Kenneth A. , Gouaux Eric 
Published: May 2018

AbstractThe human dopamine transporter(hDAT) plays a major role in dopamine homeostasis and regulation of neurotransmission by clearing dopamine from the extracellular space using secondary active transport. Dopamine is an essential monoamine chemical messenger that regulates reward seeking behavior, motor control, hormonal release, and emotional response in humans. Psychostimulants such as cocaine primarily target the central binding site of hDAT and lock the transporter in an outward-facing conformation, thereby inhibiting dopamine reuptake. The inhibition of dopamine reuptake leads to accumulation of dopamine in the synapse causing heightened signaling. In addition, hDAT is implicated in various neurological disorders and disease-associated neurodegeneration. Despite its significance, the molecular architecture of hDAT and its various conformational states are poorly understood. Instability of hDAT in detergent micelles has been a limiting factor in its successful biochemical, biophysical, and structural characterization. To overcome this hurdle, first we identified ligands that stabilize hDAT in detergent micelles. Then, we screened ∼200 single residue mutants of hDAT using high-throughput scintillation proximity assay, and identified a thermostable variant(I248Y). Here we report a robust strategy to overexpress and successfully purify a thermostable variant of hDAT in an inhibitor and allosteric ligand bound conformation.
Age-related macular degeneration affects the optic radiation white matter projecting to locations of retinal damage
Authors: Yoshimine Shoyo , Ogawa Shumpei , Horiguchi Hiroshi , Terao Masahiko , Miyazaki Atsushi , Matsumoto Kenji , Tsuneoka Hiroshi , Nakano Tadashi , Masuda Yoichiro , Pestilli Franco 
Published: May 2018

ABSTRACTPurposeWe investigated the impact of age-related macular degeneration (AMD) on visual acuity and the visual white matter.MethodsWe combined an adaptive cortical atlas and diffusion-weighted magnetic resonance imaging (dMRI) and tractography to separate optic radiation (OR) projections to different retinal eccentricities in human primary visual cortex. We exploited the known anatomical organization of the OR and clinically relevant data to segment the OR into three primary components projecting to fovea, mid- and far-periphery. We measured white matter tissue properties – (fractional anisotropy, linearity, planarity, sphericity) along the aforementioned three components of the optic radiation to compare AMD patients and controls.ResultsWe found differences in white matter properties specific to OR white matter fascicles projecting to primary visual cortex locations corresponding to the location of retinal damage (fovea). Additionally, we show that the magnitude of white matter properties in AMD patients’ correlates with visual acuity. In sum, we demonstrate a specific relation between visual loss, anatomical location of retinal damage and white matter damage in AMD patients. Importantly, we demonstrate that these changes are so profound that can be detected using magnetic resonance imaging data with clinical resolution. The conserved mapping between retinal and white matter damage suggests that retinal neurodegeneration might be a primary cause of white matter degeneration in AMD patients.ConclusionsThe results highlight the impact of eye disease on brain tissue, a process that may become an important target to monitor during the course of treatment.
Relationship-focused or deal-focused? Building interpersonal bonds within B2B relationships
Authors: Glinska-Newes Aldona , Escher Iwona , Brzustewicz Pawel , Szostek Dawid , Petrykowska Joanna 
Published: May 2018

Purpose
There is a research gap regarding frameworks identifying the specific activities and resources used by companies to build and enhance social ties between them and business actors. The purpose of this paper is to identify those activities and resources and propose a model of them for referring to successive stages of business relationship-building.

Design/methodology/approach
Qualitative research was conducted in the form of 16 semi-structured in-depth individual interviews in four companies operating in Poland, representing the construction, chemical, alcoholic beverages and automotive industries.

Findings
Resources and activities used by companies to build and strengthen interpersonal bonds within business relationships may be categorised according to the dimension of relationship-focused (RF) vs deal-focused (DF) approach. In the companies analysed, the RF approach appeared dominant, while some symptoms of changes towards a DF approach were observed.

Research limitations/implications
The proposed model of resources and activities used in companies at successive stages of business relationship-building extends the understanding of how high-quality relationships are built. The study is exploratory in nature and aims to inspire further in-depth analyses, including cross-cultural comparisons.

Practical implications
The paper helps managers in their day-to-day management of B2B relationships. It provides particular guidelines for business people seeking a potential business partner in Poland and other countries with a communist past.

Originality/value
The paper’s originality results from combining the behavioural approach to B2B relationships with the concept of the RF vs DF approach. The latter concept is based on the experience and observations of its author and, as such, has so far received limited attention in the literature.
The influence of political risk, inertia and imitative behavior on the location choice of Chinese multinational enterprises
Authors: Quer Diego , Claver Enrique , Rienda Laura 
Published: May 2018

PurposeDrawing on the institutional perspective, the purpose of this paper is to investigate how state ownership moderates the relationships between political risk, inertia and mimetic behavior, and the location choice of Chinese multinational enterprises (MNEs).Design/methodology/approachThe authors argue that state ownership leads Chinese firms to behave toward political risk in an unconventional way, and that government support makes them less dependent on their own and other Chinese firms’ prior host country experience. The authors tested the hypotheses using data on outward foreign direct investment (OFDI) decisions made by 186 Chinese firms in 93 countries.FindingsThe authors found that Chinese state-owned enterprises (SOEs), compared to non-SOEs, are more likely to move into countries with high political risk, and that they are less likely to be inertial and mimetic.Originality/valueBuilding on the distinction between macro- and micro-political risk, The authors contribute to the political risk literature by developing several arguments that explains why political risk varies across investing firms in a given host country. Moreover, this is one of the first studies of its kind to investigate the moderating effect of state ownership on the relationship between inertial and mimetic behavior, and the location choice of Chinese MNEs.