bluuebunny/crossref_metadata_2025_split huggingface dataset:
Therapeutic genetic variation revealed in diverse Hsp104 homologs
Authors: March Zachary M. , Sweeney Katelyn , Kim Hanna , Yan Xiaohui , Castellano Laura M. , Jackrel Meredith E. , Chuang Edward , Gomes Edward , Michalska Karolina , Jedrzejczak Robert , Joachimiak Andrzej , Caldwell Kim A. , Caldwell Guy A. , Shalem Ophir , Shorter James 
Published: March 2020

ABSTRACTThe AAA+ protein disaggregase, Hsp104, increases fitness under stress by reversing stress-induced protein aggregation. We have engineered potentiated Hsp104 variants to antagonize proteotoxic misfolding linked to human neurodegenerative diseases. However, these Hsp104 variants can exhibit off-target toxicity, which may limit their therapeutic utility. Hsp104 is conserved among all nonmetazoan eukaryotes, which raises the possibility that natural variants might exist with enhanced, selective activity against neurodegenerative disease substrates. To assess this possibility, we screened a cross-kingdom collection of Hsp104 homologs in several yeast proteotoxicity models. We uncovered therapeutic genetic variation among several Hsp104 homologs that specifically antagonize TDP-43 orα-synuclein condensate formation and toxicity in yeast, human cells, andC. elegans. Surprisingly, this variation manifested as increased passive chaperone activity, distinct from disaggregase activity, which neutralizes proteotoxicity of specific substrates. Thus, by exploring natural tuning of passive chaperone activity we elucidated enhanced, substrate-specific agents to counter proteotoxicity underlying neurodegenerative disease.
Regulation of caveolae through cholesterol-depletion dependent tubulation by PACSIN2/Syndapin II
Authors: Amir Aini Gusmira , Takemura Kazuhiro , Hanawa-Suetsugu Kyoko , Oono-Yakura Kayoko , Yasuhara Kazuma , Kitao Akio , Suetsugu Shiro 
Published: March 2020

AbstractThe membrane shaping ability of PACSIN2 via its FCH-BAR (F-BAR) domain has been shown to be essential for caveolar morphogenesis, presumably through the shaping of the caveolar neck. Caveolar membrane contains abundant levels of cholesterol. However, the role of cholesterol in PACSIN2-mediated membrane deformation remains unclear. We show that the binding of PACSIN2 to the membrane could be negatively regulated by the amount of cholesterol in the membrane. We prepared a reconstituted membrane based on the lipid composition of caveolae. The reconstituted membrane with cholesterol had a weaker affinity to the F-BAR domain of PACSIN2 than the membrane without cholesterol, presumably due to a decrease in electrostatic charge density. Consistently, the acute depletion of cholesterol from the plasma membrane resulted in the appearance of PACSIN2-localized tubules with caveolin-1 at their tips, suggesting that the presence of cholesterol inhibited the prominent membrane tubulation by PACSIN2. The tubules induced by PACSIN2 were suggested to be an intermediate of caveolae endocytosis. Consistently, the removal of caveolae from the plasma membrane upon cholesterol depletion was diminished in the cells deficient in PACSIN2. These data suggested that PACSIN2 mediated the caveolae internalization dependently on the amount of cholesterol at the plasma membrane, providing a possible mechanism for the cholesterol-dependent regulation of caveolae.
Differences in post-mating transcriptional responses between conspecific and heterospecific matings inDrosophila
Authors: Ahmed-Braimah Yasir H. , Wolfner Mariana F. , Clark Andrew G. 
Published: March 2020

AbstractIn many animal species, females undergo physiological and behavioral changes after mating. Some of these changes are driven by male-derived seminal fluid proteins, and are critical for fertilization success. Unfortunately, our understanding of the molecular interplay between female and male reproductive proteins remains superficial. Here we analyze the post-mating response in aDrosophilaspecies that has evolved strong gametic incompatibility with its sister species;D. novamexicanafemales produce only 1% fertilized eggs in crosses withD. americanamales, compared to ~98% produced in within-species crosses. This incompatibility is likely caused by mismatched male and female reproductive molecules. In this study we use short-read RNA sequencing to examine the evolutionary dynamics of female reproductive genes and the post-mating transcriptome response in crosses within and between species. First, we found that most female reproductive tract genes are slow-evolving compared to the genome average. Second, post-mating responses in con- and heterospecific matings are largely congruent, but heterospecific mating induces expression of additional stress-response genes. Some of those are immunity genes that are activated by the Imd pathway. We also identify several genes in the JAK/STAT signaling pathway that are induced in heterospecific, but not conspecific mating. While this immune response was most pronounced in the female reproductive tract, we also detect it in the female head and ovaries. Our results show that the female’s post-mating transcriptome-level response is determined in part by the genotype of the male, and that divergence in male reproductive genes and/or traits can have immunogenic effects on females.
FRET-based Tau seeding assay does not represent prion-like templated assembly of Tau fibers
Authors: Kaniyappan Senthilvelrajan , Tepper Katharina , Biernat Jacek , Chandupatla Ram Reddy , Hübschmann Sabrina , Irsen Stephan , Bicher Sandra , Klatt Christoph , Mandelkow Eva-Maria , Mandelkow Eckhard 
Published: March 2020

AbstractTau aggregation into amyloid fibers based on the cross-beta structure is a hallmark of several Tauopathies, including Alzheimer Disease (AD). Trans-cellular propagation of Tau with pathological conformation has been suggested as a key disease mechanism. This is thought to cause the spreading of Tau pathology in AD by templated conversion of naive Tau in recipient cells into a pathological state, followed by assembly of pathological Tau fibers, similar to the mechanism proposed for prion pathogenesis. In cell cultures, the process is usually monitored by a FRET assay where the recipient cell expresses the Tau repeat domain (TauRD, with pro-aggregant mutation, e.g., ΔK280 or P301L, ∼13.5 kDa) fused to GFP-based FRET pairs (YFP or CFP, ∼28 kD). Since the diameter of the reporter GFP (∼3 nm) is ∼6.5 times larger than the β-strand distance (0.47nm), this points to a potential steric clash. Hence, we investigated the influence of GFP tagged (N- or C-terminally) TauRDand TauFL(full-length Tau) on their aggregation behavior in vitro. Using biophysical methods (light scattering, atomic force microscopy (AFM), and scanning-transmission electron microscopy (STEM)), we found that the assembly of TauRDΔK-GFP was severely inhibited, even in the presence of nucleation enhancers (heparin and/or pre-formed PHFs from TauRDΔK). Some rare fiber-like particles had a very different subunit packing from proper PHFs, as judged by STEM. The mass per length (MPL) values of TauRDΔKfibrils are equivalent to 4.45 molecules/nm, close to the expected value for a paired-helical fiber with 2 protofilaments and cross-β structure. By contrast, the elongated particles formed by TauRDΔK-GFP have MPL values around ∼2, less than half of the values expected for PHFs, indicating that the subunit packing is distinct. Thus, both kinetic and structural observations are incompatible with a model whereby external Tau can form a template for PHF assembly of Tau-GFP in recipient cells. As a consequence, the observed local increase of FRET in recipient cells must be caused by other signalling processes.
Cryo-EM structure of coronavirus-HKU1 haemagglutinin esterase reveals architectural changes arising from prolonged circulation in humans
Authors: Hurdiss Daniel L. , Drulyte Ieva , Lang Yifei , Shamorkina Tatiana M. , Pronker Matti F. , van Kuppeveld Frank J.M. , Snijder Joost , de Groot Raoul J. 
Published: March 2020

AbstractThe human betacoronaviruses HKU1 and OC43 (subgenusEmbecovirus)arose from separate zoonotic introductions, OC43 relatively recently and HKU1 apparently much longer ago. Embecovirus particles are studded with two types of surface projections called S (for spike) and HE (for haemagglutinin-esterase), with S mediating receptor-binding and membrane fusion and HE acting as a receptor-destroying enzyme. Together, they promote dynamic virion attachment to glycan-based receptors with 9-O-acetylated sialic acid as main constituent. We recently showed that adaptation of HKU1 and OC43 to replication in the human respiratory tract involved loss-of-function mutations in the lectin domain of HE. Here we present the cryo-EM structure of the ∼80 kDa, heavily glycosylated HKU1 HE at a global resolution of 3.4 Å. Comparison to existing HE structures reveals a drastically truncated lectin domain, incompatible with sialic acid binding, but with the structure and function of the HE esterase domain left intact. Our cryo-EM structure, in combination with mass spectrometry analysis, also describes the extent of glycosylation on the now redundant lectin domain, which forms a putative glycan shield. The findings further our insight into the evolution and host adaptation of human embecoviruses and also demonstrate the utility of cryo-EM for studying small, heavily glycosylated proteins which are intractable to X-ray crystallography.
Nexus of knowledge-oriented leadership, knowledge management, innovation and organizational performance in higher education
Authors: Rehman Ubaid Ur , Iqbal Amjad 
Published: March 2020

PurposeThe purpose of this research is to investigate the effect of knowledge-oriented leadership on organizational performance of higher education institutions (HEIs) and examine the neglected mediating role of knowledge management (KM) processes and innovation.Design/methodology/approachFollowing the quantitative and cross-sectional research design, data were collected through self-administered questionnaire from 312 faculty members of HEIs of Pakistan. The partial least squares structural equation modelling data analysis technique was applied to test the hypothesized relationships.FindingsThe results indicate that knowledge-oriented leadership has direct and positive effect on organizational performance. Moreover, the findings reveal that KM processes and innovation partially mediate the effect of knowledge-oriented leadership on organizational performance.Practical implicationsThis study underscores the imrportant role of knowledge-oriented leadership in HEIs. Findings of this research suggest that by exhibiting knowledge-oriented behaviours, managers of HEIs can effectively manage their knowledge assets, ensure successful implementation of KM processes and augment product and process innovation leading towards superior organizational performance.Originality/valueThis is amongst one of the first studies that proposes an integrated research model and examines interrelationships amongst knowledge-oriented leadership, KM processes, innovation and organizational performance in the context of HEIs.
Analysis of a wind farm with SCIG integrated into a high power system
Authors: Malamov Dian , Hadzhiev Ivan , Zlatanova Vasilina , Terzieva Snejana , Georgiev Aleksandar 
Published: March 2020

Purpose
The aim of this paper is a steady-state analysis of the basic electrical characteristics of a wind farm with squirrel-cage induction generators (SCIG), integrated into a high power system. The SCIG are connected to the system by means of a step-up substation 21/115 kV, realized by cable lines.

Design/methodology/approach
The analyses have been done with the help of a computer model, developed in MATLAB/Simulink.

Findings
Results have been obtained, concerning the influence of the SCIG on the active and reactive power, on the power factor and the voltage deviation in the cases of only one generator operating, all generators operating and disabled generators.

Practical implications
The analysis has been carried out for an operating wind farm in the power system. The obtained results are applicable for optimizing and managing the modes of operation of the wind farm.

Originality/value
A mathematical model for studying the electrical parameters of an SCIG integrated into a high power system has been described. A computer model in MATLAB/Simulink has been synthesized. Numerical results have been obtained, concerning the dependence of the active power, the reactive power, the power factor and the voltage deviation on the shaft torque of the wind farms with SCIG.
Employees' experiences of participating in a workplace-supported weight management service: a qualitative inquiry
Authors: Staniford Leanne Jane , Radley Duncan , Gately Paul , Blackshaw Jamie , Thompson Lisa , Coulton Vickie 
Published: March 2020

PurposeThe purpose of this study is to explore public health employees' experiences of participating in a commercial weight management programme supported by their employers over a 12-week period.Design/methodology/approachSemi-structured interviews were conducted with 28 employees who had participated in the programme (group-based or online).FindingsThe main motivators for enquiring about and attending the programme were: the offer to attend the programme free of charge, the opportunity to kick start their weight loss efforts, to take part in an academic research study and the opportunity for “shared experiences” with their colleagues.Research limitations/implicationsThis study did not allow us to explore the reasons why some employees opted not to take up the opportunity for weight management support through their workplace. Further qualitative research with non-engagers would allow us to inquire about why employees might not engage with WM support and offer alternative strategies.Practical implicationsEmployers should facilitate their employees' efforts to lead a healthier lifestyle in the long-term creating employer health and safety policies that actively encourage healthy living and weight management. Improving employee health can contribute to increasing productivity, reducing stress and absenteeism.Originality/valueThis paper presents a novel approach to facilitating employees' weight management. Employees perceived their employer-supported participation in a commercial weight management programme outside of their work setting as a positive experience that assisted their weight management efforts suggesting the acceptability and feasibility of this approach to addressing weight in the workplace.
Competition, R&D and innovation in Chilean firms
Authors: Montégu José Pablo , Calvo Carolina , Pertuze Julio A. 
Published: March 2020

PurposeThe purpose of this paper is to analyze the effect of competition on both innovation inputs and outputs in Chilean firms. More specifically, the authors investigate whether there is an inverted-U relationship at different stages of the innovation process.Design/methodology/approachThe sample covers 1,347 firms that responded to both the 4th Chilean Longitudinal Enterprise Survey and the 10th Chilean Innovation Survey. The CDM model (Crépon et al., 1998) is applied to correct for selectivity bias and endogeneity. Competition is proxied by measures of market concentration. The robustness of the results is checked using four alternative indicators.FindingsThe results strongly suggest that competition and both R&D and innovation intensities are linked by an inverted U-shaped curve. The estimated effects of competition on innovation output and labor productivity are rather ambiguous. Thus, market structure would be influencing the firms’ incentives to innovate, but not necessarily their innovation performance.Research limitations/implicationsThe model is based on cross-sectional data, hampering the possibility to control for unobserved heterogeneity. Competitive pressures from potential entrants and foreign markets are not captured in the analysis.Practical implicationsModerate levels of competition would be the optimal market structure in terms of promoting more business R&D and innovation spending.Originality/valueA previously unutilized data set covering the whole economy is used. Estimations are executed at three different stages of the innovation process. Two types of innovation input and four types of innovation output are taken into account.
Industry perspectives on Malaysian hotel minimum wage issues
Authors: Balasingam Ann Selvaranee , Hussain Kashif , Manaf Alwie 
Published: March 2020

Purpose
The purpose of this paper is to investigate and compare the impact of the minimum wage order from the perspectives of two different stakeholders, namely, hotel managers and employees, in the Malaysian hotel industry.

Design/methodology/approach
For the study, qualitative data were collected through semi-structured interviews from three managers and three employees from hotels in West Malaysia.

Findings
From the managers’ perspective, minimum wage implementation has resulted in managers adopting the best payment structure to reduce labour costs for the operators, deciding to reduce the service charge allocation to employees and having to deal with minimal improvement in employee productivity and motivation. In contrast, the positive impact from the managers’ perspective is lower turnover intentions and social justice for foreign workers. From the employees’ perspective, there is a rather negative impact – minimum wage policy has resulted in a minimal increase in the salary. From a positive perspective, employees said that they have experienced an improvement in living standards.

Originality/value
This research presents current responses from hotel participants regarding the latest wage increase impact, some six years after its implementation.
Core–periphery dynamics in a plant–pollinator network
Authors: Miele Vincent , Ramos‐Jiliberto Rodrigo , Vázquez Diego P. 
Published: March 2020

Abstract

Mutualistic networks are highly dynamic, characterized by high temporal turnover of species and interactions. Yet, we have a limited understanding of how the internal structure of these networks and the roles species play in them vary through time.

We used 6 years of observation data and a novel statistical method (dynamic stochastic block models) to assess how network structure and species' structural position within the network change throughout subseasons of the flowering season and across years in a quantitative plant–pollinator network from a dryland ecosystem in Argentina.

Our analyses revealed a core–periphery structure persistent through subseasons and years. Yet, species structural position as core or peripheral was highly dynamic: virtually all species that were at the core in some subseasons were also peripheral in other subseasons, while many other species always remained peripheral.

Our results illuminate our understanding of the dynamics of mutualistic networks and have important implications for ecosystem management and conservation.
Oncogenic pseudogene DUXAP10 knockdown suppresses proliferation and invasion and induces apoptosis of papillary thyroid carcinoma cells by inhibition of Akt/mTOR pathway
Authors: Li Jian , Jiang Li , Liu Zhu , Li Yanguo , Xu Yang , Liu Hongwei 
Published: March 2020

AbstractPseudogenes, another novel group of non‐coding segments without protein‐coding capacity, are closely associated with tumourigenesis and cancer progression. Double homeoboxA pseudogene 10 (DUXAP10) is reported to be robustly expressed in thyroid carcinoma. However, the functional role and underlying mechanism of DUXAP10 in papillary thyroid carcinoma (PTC) progression remain undefined. DUXAP10 expression in PTC cells was detected by qRT‐PCR. Cell proliferation and invasion were determined using 3‐(4,5‐dimethyl‐2‐thiazolyl)‐2,5‐diphenyl‐2‐H‐tetrazolium bromide (MTT) and Transwell invasion assay, respectively. Apoptosis was evaluated using flow cytometry. Protein expression of matrix metalloproteinase (MMP)‐2, MMP‐9, protein kinase B (Akt), phosphorylated Akt, mammalian target of rapamycin (mTOR), and phosphorylated mTOR was examined by western blot. Results showed that DUXAP10 was significantly overexpressed in PTC cells compared with normal thyroid follicular epithelium cells. DUXAP10 silencing suppressed cell proliferation and invasive ability, reduced the expression of MMP‐2 and MMP‐9, and increased apoptotic rate and caspase‐3 activity in PTC cells. Additionally, the Akt/mTOR pathway was inhibited following DUXAP10 knockdown in PTC cells. Activation of the Akt/mTOR pathway by 740Y‐P and MHY1485 attenuated DUXAP10 knockdown‐induced proliferation reduction, invasion suppression and apoptosis in PTC cells. In conclusion, DUXAP10 knockdown suppressed proliferation and invasion and induced apoptosis in PTC cells at least partially by inhibition of the Akt/mTOR pathway.
The JAK2 inhibitor AG490 regulates the Treg/Th17 balance and alleviates DSS‐induced intestinal damage in IBD rats
Authors: Guo Jing , Wang Li‐yun , Wu Jie , Xu Ling‐fen , Sun Mei 
Published: March 2020

AbstractThe pathogenesis of inflammatory bowel disease (IBD) remains unclear, and it is currently believed that an imbalance in regulatory T (Treg) cells/T helper 17 cells (Th17 cells) is related to the occurrence and development of IBD. Recently, the JAK2 inhibitor AG490 has been used in animal models such as rheumatoid arthritis and bronchial asthma models and shown to exert immunoregulatory functions that improve disorder in the Treg/Th17 cell balance. This study aimed to evaluate the effect of AG490 on the intestinal inflammatory process in an IBD rat model. A dextran sulfate sodium (DSS)‐induced IBD rat model was established, and disease activity index (DAI) scores were calculated. The histopathological damage score was determined by haematoxylin‐eosin (H&E) staining. Treg/Th17 cells in the spleen were detected by flow cytometry. The levels of interleukin (IL)‐10, IL‐6 and IL‐17A were detected by enzyme‐linked immunosorbent assay (ELISA). AG490 attenuated DSS‐induced IBD injury by regulating the Treg/Th17 balance and related cytokine secretion to reduce the DAI and colonic tissue damage. Thus, AG490 may be a new method for effective treatment of IBD.
Distinct assembly mechanisms underlie similar biogeographical patterns of rare and abundant bacteria in Tibetan Plateau grassland soils
Authors: Ji Mukan , Kong Weidong , Stegen James , Yue Linyan , Wang Fei , Dong Xiaobin , Cowan Don A , Ferrari Belinda C 
Published: March 2020

SummaryRare biosphere represents the majority of Earth's biodiversity and performs vital ecological functions, yet little is known about its biogeographical patterns and community assembly processes in terrestrial ecosystems. Herein, we investigated the community composition and phylogeny of rare (relative abundance <0.1%) and abundant (>1%) bacteria in dryland grassland soils on the Tibetan Plateau. Results revealed similar biogeographical patterns of rare and abundant bacteria at both compositional and phylogenetic levels, but rare subcommunity was more heavily influenced by stochasticity (72%) than the abundant (57%). The compositional variation of rare bacteria was less explained by environmental factors (41%) than that of the abundant (80%), while the phylogeny of rare bacteria (36%) was more explained than that of the abundant (29%). The phylogeny of rare bacteria was equally explained by local factors (soil and vegetation) and geospatial distance (11.5% and 11.9% respectively), while that of the abundant was more explained by geospatial distance (22.1%) than local factors (11.3%). Furthermore, a substantially tighter connection between the community phylogeny and composition was observed in rare (R2 = 0.65) than in abundant bacteria (R2 = 0.08). Our study provides novel insights into the assembly processes and biographical patterns of rare and abundant bacteria in dryland soils.