bluuebunny/crossref_metadata_2025_split huggingface dataset:
eQTL mapping in fetal-like pancreatic progenitor cells reveals early developmental insights into diabetes risk
Authors: Nguyen Jennifer P. , Arthur Timothy D. , Fujita Kyohei , Salgado Bianca M. , Donovan Margaret K.R. ,   iPSCORE Consortium, Matsui Hiroko , Kim Ji Hyun , D’Antonio-Chronowska Agnieszka , D’Antonio Matteo , Frazer Kelly A. 
Published: March 2021

AbstractThe impact of genetic regulatory variation active in early pancreatic development on adult pancreatic disease and traits is not well understood. Here, we generate a panel of 107 fetal-like iPSC-derived pancreatic progenitor cells (iPSC-PPCs) from whole genome-sequenced individuals and identify 4,065 genes and 4,016 isoforms whose expression and/or alternative splicing are affected by regulatory variation. We integrate eQTLs identified in adult islets and whole pancreas samples, which reveal 1,805 eQTL associations that are unique to the fetal-like iPSC-PPCs and 1,043 eQTLs that exhibit regulatory plasticity across the fetal-like and adult pancreas tissues. Colocalization with GWAS risk loci for pancreatic diseases and traits show that some putative causal regulatory variants are active only in the fetal-like iPSC-PPCs and likely influence disease by modulating expression of disease-associated genes in early development, while others with regulatory plasticity likely exert their effects in both the fetal and adult pancreas by modulating expression of different disease genes in the two developmental stages.
Direct phosphorylation and stabilization of HIF-1α by PIM1 kinase drives angiogenesis in solid tumors
Authors: Casillas Andrea L. , Chauhan Shailender S. , Toth Rachel K. , Sainz Alva G. , Clements Amber N. , Jensen Corbin C. , Langlais Paul R. , Miranti Cindy K. , Cress Anne E. , Warfel Noel A. 
Published: March 2021

SummaryAngiogenesis is essential for sustained growth of solid tumors. Hypoxia-inducible factor 1 (HIF-1) is a master regulator of angiogenesis and constitutive activation of HIF-1 is frequently observed in human cancers. Thus, understanding mechanisms governing the activation of HIF-1 is critical for successful therapeutic targeting of tumor angiogenesis. Herein, we establish a new regulatory mechanism responsible for the constitutive activation of HIF-1α in cancer, irrespective of oxygen tension. PIM1 kinase directly phosphorylates HIF-1α at threonine 455, a previously uncharacterized site within its oxygen-dependent degradation domain. This phosphorylation event disrupts the ability of prolyl hydroxylases (PHDs) to bind and hydroxylate HIF-1α, interrupting its canonical degradation pathway and promoting constitutive transcription of HIF-1 target genes. Overexpression of PIM1 is sufficient to stabilize HIF-1α in normoxia and stimulate angiogenesis in a HIF-1-dependent mannerin vivo. CRISPR mutants of HIF-1α (Thr455D) showed increased tumor growth, proliferation and angiogenesis. Moreover, T455D xenograft tumors were refractory to the anti-angiogenic and cytotoxic effects of PIM inhibitors. These data identify a new signaling axis responsible for hypoxia-independent activation of HIF-1 and expand our understanding of the tumorigenic role of PIM1 in solid tumors.
A comparison of the Mouse Song Analyzer and DeepSqueak ultrasonic vocalization analysis systems in C57BL/6J, FVB.129, and FVB mice
Authors: Binder Matthew S. , Pranske Zachary P. , Lugo Joaquin N. 
Published: March 2021

AbstractVocal communication is an essential behavior in mammals and is relevant to human neurodevelopmental conditions. Mice produce communicative vocalizations, known as ultrasonic vocalizations (USVs), that can be recorded with various programs. The Mouse Song Analyzer is an automated analysis system, while DeepSqueak is a semi-automated system. We used data from C57BL/6J, FVB.129, and FVB mice to compare whether the DeepSqueak and Mouse Song Analyzer systems measure a similar total number, duration, and fundamental frequency of USVs. We found that the two systems detected a similar quantity of USVs for FVB.129 mice (r= .90,p< .001), but displayed lower correlations for C57BL/6J (r= .76,p< .001) and FVB mice (r= .60,p< .001). We also found that DeepSqueak detected significantly more USVs for C57BL/6J mice than the Mouse Song Analyzer. The two systems detected a similar duration of USVs for C57BL/6J (r= .82,p< .001), but lower correlations for FVB.129 (r= .13,p< .001) and FVB mice (r= .51,p< .01) were found, with DeepSqueak detecting significantly more USVs per each strain. We found lower than acceptable correlations for fundamental frequency in C57BL/6J (r= .54,p< .01), FVB.129 (r= .76,p< .001), and FVB mice (r= .07,p= .76), with the Mouse Song Analyzer detecting a significantly higher fundamental frequency for FVB.129 mice. These findings demonstrate that the strain of mouse used significantly affects the number, duration, and fundamental frequency of USVs that are detected between programs. Overall, we found that DeepSqueak is more accurate than the Mouse Song Analyzer.
Membrane Hydrophobicity Determines the Activation Free Energy of Passive Lipid Transport
Authors: Rogers Julia R. , Garcia Gustavo Espinoza , Geissler Phillip L. 
Published: March 2021

ABSTRACTThe collective behavior of lipids with diverse chemical and physical features determines a membrane’s thermodynamic properties. Yet, the influence of lipid physicochemical properties on lipid dynamics, in particular interbilayer transport, remains underexplored. Here, we systematically investigate how the activation free energy of passive lipid transport depends on lipid chemistry and membrane phase. Through all-atom molecular dynamics simulations of 11 chemically distinct glycerophos-pholipids, we determine how lipid acyl chain length, unsaturation, and headgroup influence the free energy barriers for two elementary steps of lipid transport, lipid desorption, which is rate-limiting, and lipid insertion into a membrane. Consistent with previous experimental measurements, we find that lipids with longer, saturated acyl chains have increased activation free energies compared to lipids with shorter, unsaturated chains. Lipids with different headgroups exhibit a range of activation free energies; however, no clear trend based solely on chemical structure can be identified, mirroring difficulties in the interpretation of previous experimental results. Compared to liquid-crystalline phase membranes, gel phase membranes exhibit substantially increased free energy barriers. Overall, we find that the activation free energy depends on a lipid’s local hydrophobic environment in a membrane and that the free energy barrier for lipid insertion depends on a membrane’s interfacial hydrophobicity. Both of these properties can be altered through changes in lipid acyl chain length, lipid headgroup, and membrane phase. Thus, the rate of lipid transport can be tuned through subtle changes in local membrane composition and order, suggesting an unappreciated role for nanoscale membrane domains in regulating cellular lipid dynamics.SIGNIFICANCECell homeostasis requires spatiotemporal regulation of heterogeneous membrane compositions, in part, through non-vesicular transport of individual lipids between membranes. By systematically investigating how the chemical diversity present in glycerophospholipidomes and variations in membrane order influence the free energy barriers for passive lipid transport, we discover a correlation between the activation free energy and membrane hydrophobicity. By demonstrating how membrane hydrophobicity is modulated by local changes in membrane composition and order, we solidify the link between membrane physicochemical properties and lipid transport rates. Our results suggest that variations in cell membrane hydrophobicity may be exploited to direct non-vesicular lipid traffic.
Gold nanocluster mediated delivery of siRNA to intact plant cells for efficient gene knockdown
Authors: Zhang Huan , Cao Yuhong , Xu Dawei , Goh Natalie S. , Demirer Gozde S. , Chen Yuan , Landry Markita P. , Yang Peidong 
Published: March 2021

AbstractRNA interference (RNAi), which involves the delivery of small interfering RNA molecules (siRNA), has been used to validate target genes in plants, to understand and control cellular metabolic pathways, and as a ‘green’ alternative for crop pest tolerance. Conventional siRNA delivery methods such as viruses andAgrobacterium-mediated delivery exhibit limitations in host plant species range and their use can result in uncontrolled DNA integration into the plant host genome. Here, we synthesize polyethyleneimine functionalized gold nanoclusters (PEI-AuNCs) to mediate siRNA delivery into intact plant cells and show these constructs enable efficient gene knockdown. We demonstrate that functionalized AuNCs protect siRNA from RNase degradation and are small enough (~2 nm) to bypass the plant cell wall which exhibits a size exclusion limit of 5-20 nm. These AuNCs in turn enable up to 76.5 ± 5.9% GFP mRNA knockdown efficiency with no cellular toxicity. Our data suggest this simple and biocompatible platform for passive delivery of siRNA into intact plant cells could have broad applications in plant biotechnology.
Establishment and Resilience of Transplanted Gut Microbiota in Aged Mice
Authors: Wang Ying , Tang Jinhui , Lv Qingqing , Tan Yuxiang , Dong Xiaoxiao , Liu Hongbin , Zhao Nannan , He Zhen , Kou Yan , Tan Yan , Liu Xin-an , Wang Liping , Liu Yang-Yu , Dai Lei 
Published: March 2021

AbstractFecal microbiota transplantation (FMT), a procedure in which fecal material is transferred from a donor to a recipient, has been increasingly used as a treatment to restore healthy gut microbiota. There is a substantial difference in the composition of gut microbiota between young and aged hosts, but little is known about whether age matching between the FMT donor and recipient affects microbiota restoration and long-term maintenance. In the present investigation, we aimed to study the establishment and resilience of transplanted gut microbiota in aged recipients. We treated naturally aged mice (20 months old) with a broad-spectrum antibiotic cocktail and monitored the restoration of gut microbiota over 8 weeks. The diversity of gut microbiota in aged mice failed to reach the baseline level via spontaneous recovery; in contrast, FMT from either (age-)matched or unmatched donors facilitated the recovery of gut microbiota diversity. The microbiota transplanted from different donors successfully established in the aged recipients and had long-term effects on the gene expression profiles of the host colon. Finally, we evaluated the long-term maintenance of transplanted microbiota via intentional disruption of gut homeostasis. We found that lack of age matching between FMT donors and recipients may decrease the resilience of transplanted gut microbiota against colonic inflammation. The results from our study systematically examining the effects of FMT on the gut homeostasis of aged hosts suggest that the compatibility between donors and recipients should be taken into account when implementing FMT.
Time-lagged Independent Component Analysis of Random Walks and Protein Dynamics
Authors: Schultze Steffen , Grubmüller Helmut 
Published: March 2021

AbstractTime-lagged independent component analysis (tICA) is a widely used dimension reduction method for the analysis of molecular dynamics (MD) trajectories and has proven particularly useful for the construction of protein dynamics Markov models. It identifies those ‘slow’ collective degrees of freedom onto which the projections of a given trajectory show maximal autocorrelation for a given lag time. Here we ask how much information on the actual protein dynamics and, in particular, the free energy landscape that governs these dynamics the tICA-projections of MD-trajectories contain, as opposed to noise due to the inherently stochastic nature of each trajectory. To answer this question, we have analyzed the tICA-projections of high dimensional random walks using a combination of analytical and numerical methods. We find that the projections resemble cosine functions and strongly depend on the lag time, exhibiting strikingly complex behaviour. In particular, and contrary to previous studies of principal component projections, the projections change non-continuously with increasing lag time. The tICA-projections of selected 1μs protein trajectories and those of random walks are strikingly similar, particularly for larger proteins, suggesting that these trajectories contain only little information on the energy landscape that governs the actual protein dynamics. Further the tICA-projections of random walks show clusters very similar to those observed for the protein trajectories, suggesting that clusters in the tICA-projections of protein trajectories do not necessarily reflect local minima in the free energy landscape. We also conclude that, in addition to the previous finding that certain ensemble properties of non-converged protein trajectories resemble those of random walks, this is also true for their time correlations. Due to the higher complexity of the latter, this result also suggests tICA analyses as a more sensitive tool to test MD simulations for proper convergence.
PySTACHIO: Python Single-molecule TrAcking stoiCHiometry Intensity and simulatiOn, a flexible, extensible, beginner-friendly and optimized program for analysis of single-molecule microscopy data
Authors: Shepherd Jack W , Higgins Ed J , Wollman Adam J M , Leake Mark C 
Published: March 2021

AbstractAs camera pixel arrays have grown larger and faster, and optical microscopy techniques ever more refined, there has been an explosion in the quantity of data acquired during routine light microcopy. At the single-molecule level, analysis involves multiple steps and can rapidly become computationally expensive, in some cases intractable on office workstations. Complex bespoke software can present high activation barriers to entry for new users. Here, we redevelop our quantitative single-molecule analysis routines into an optimized and extensible Python program, with GUI and command-line implementations to facilitate use on local machines and remote clusters, by beginners and advanced users alike. We demonstrate that its performance is on par with previous MATLAB implementations but runs an order of magnitude faster. We tested it against challenge data and demonstrate its performance is comparable to state-of-the-art analysis platforms. We show the code can extract fluorescence intensity values for single reporter dye molecules and, using these, estimate molecular stoichiometries and cellular copy numbers of fluorescently-labeled biomolecules. It can evaluate 2D diffusion coefficients for the characteristically short single-particle tracking data. To facilitate benchmarking we include data simulation routines to compare different analysis programs. Finally, we show that it works with 2-color data and enables colocalization analysis based on overlap integration, to infer interactions between differently labelled biomolecules. By making this freely available we aim to make complex light microscopy single-molecule analysis more democratized.HighlightsWe present PySTACHIO, a refined version of our spot tracking algorithmWe demonstrate highly improved performance over previous MATLAB versionsPySTACHIO can accurately estimate stoichiometries and 2D diffusion coefficientsPerformance is comparable to state-of-the-art packages on challenge dataPySTACHIO has both GUI and command line interfaces and can be hosted as a web appGraphical abstract
Project buffer sizing and dynamic buffer consumption algorithm in power generation construction
Authors: Zohrehvandi Shakib , Khalilzadeh Mohammad , Amiri Maghsoud , Shadrokh Shahram 
Published: March 2021

PurposeThe aim of this research is to propose a buffer sizing and buffer controlling algorithm (BSCA) as a heuristic algorithm for calculating project buffer and feeding buffers as well as dynamic controlling of buffer consumption in different phases of a wind power plant project in order to achieve a more realistic project duration.Design/methodology/approachThe BSCA algorithm has two main phases of planning and buffer sizing and construction and buffer consumption. Project buffer and feeding buffers are determined in the planning and buffer sizing phase, and their consumption is controlled in the construction and buffer consumption phase. The heuristic algorithm was coded and run in MATLAB software. The sensitivity analysis was conducted to show the BSCA influence on project implementation. Then, to evaluate the BSCA algorithm, inputs from this project were run through several algorithms recently presented by researchers. Finally, the data of 20 projects previously accomplished by the company were applied to compare the proposed algorithm.FindingsThe results show that BSCA heuristic algorithm outperformed the other algorithms as it shortened the projects' durations. The average project completion time using the BSCA algorithm was reduced by about 15% compared to the previous average project completion time.Originality/valueThe proposed BSCA algorithm determines both the project buffer and feeding buffers and simultaneously controls their consumption in a dynamic way.
Barriers to employment for refugees seeking work in the Australian construction industry: an exploratory study
Authors: Loosemore Martin , Alkilani Suhair Z. , Hammad Ahmed W.A. 
Published: March 2021

PurposeIn Australia, as in many other countries, refugees are over-represented in the ranks of the unemployed, under-employed and precariously employed and often become frustrated in their attempts to secure work. Despite the construction industry being a major potential source of employment for refugees, there has been a surprising lack of research into their experiences of securing work in the industry. Addressing this gap and also the general lack of voice for refugees in construction research, the aim of this paper is to explore the barriers refugees face in securing employment in the construction industry.Design/methodology/approachThis paper reports a survey of refugees who have worked or attempted to seek work in the Australian construction industry.FindingsResults show that the main barriers to securing employment in construction are: lack of local work experience; employer discrimination; employer failure to recognise previous qualifications, skills and experience and employers not understanding the challenges they face. Government employment agencies and systems are also perceived to be of limited value and overly complex, in contrast to the activities of not-for-profit support agencies.Research limitations/implicationsWhile the research is limited to Australia, the findings contribute an important and missing refugee dimension to the emerging body of research on construction social procurement. They also contribute unique sector-specific insights into the broader debate about refugee resettlement and employment. Further research is needed in other national contexts.Practical implicationsRecommendations are made to address the barriers to employment identified including: initiatives to provide refugees with work experience in the industry; education to break-down negative stereotypes of refugees among employers; greater support for not-for-profits supporting refugees and reform of government and employment agency systems and procedures.Social implicationsBy enhancing understanding of the barriers to employment for refugees in construction and proposing solutions to reduce those barriers, this research contributes new insights into a growing global challenge of how we better integrate growing numbers of refugees into harmonious and prosperous societies.Originality/valueThe findings are important in facilitating the smoother integration of refugees into society. Beyond the moral imperative, there are significant social, cultural and economic benefits which successful refugee integration brings to host countries and industries like construction which in many countries are now being required to employ refugees in their workforce as a condition of public sector contracts.
High-frequency forecasting from mobile devices’ bigdata: an application to tourism destinations’ crowdedness
Authors: Ramos Vicente , Yamaka Woraphon , Alorda Bartomeu , Sriboonchitta Songsak 
Published: March 2021

PurposeThis paper aims to illustrate the potential of high-frequency data for tourism and hospitality analysis, through two research objectives: First, this study describes and test a novel high-frequency forecasting methodology applied on big data characterized by fine-grained time and spatial resolution; Second, this paper elaborates on those estimates’ usefulness for visitors and tourism public and private stakeholders, whose decisions are increasingly focusing on short-time horizons.Design/methodology/approachThis study uses the technical communications between mobile devices and WiFi networks to build a high frequency and precise geolocation of big data. The empirical section compares the forecasting accuracy of several artificial intelligence and time series models.FindingsThe results robustly indicate the long short-term memory networks model superiority, both for in-sample and out-of-sample forecasting. Hence, the proposed methodology provides estimates which are remarkably better than making short-time decision considering the current number of residents and visitors (Naïve I model).Practical implicationsA discussion section exemplifies how high-frequency forecasts can be incorporated into tourism information and management tools to improve visitors’ experience and tourism stakeholders’ decision-making. Particularly, the paper details its applicability to managing overtourism and Covid-19 mitigating measures.Originality/valueHigh-frequency forecast is new in tourism studies and the discussion sheds light on the relevance of this time horizon for dealing with some current tourism challenges. For many tourism-related issues, what to do next is not anymore what to do tomorrow or the next week.Plain Language SummaryThis research initiates high-frequency forecasting in tourism and hospitality studies. Additionally, we detail several examples of how anticipating urban crowdedness requires high-frequency data and can improve visitors’ experience and public and private decision-making.