bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Novel Machine Learning Approach Uncovers New and Distinctive Inhibitors for Cyclin-Dependent Kinase 9
Authors: Assmann Mariana , Bal Matthias , Craig Michael , D’Oyley Jarryl , Phillips Lawrence , Triendl Hagen , Bates Paul A. , Bashir Usman , Ruprah Parminder , Shaker Noor , Stojevic Vid 
Published: March 2020

AbstractWe present a novel combination of generative and predictive machine learning models for discovering unique protein inhibitors. The new method is assessed on its ability to generate unique inhibitors for the cancer associated protein kinase, CDK9. We validate our method by performing biochemical assays, attaining a hit rate of more than 10%, demonstrating the method to be a notable improvement upon a more standard, and somewhat naive approach. Moreover, we imposed the additional challenge of finding inhibitors that are readily synthesized. Importantly, two new inhibitors are found, with one being distinct from reported CDK9 inhibitors. We discuss the results in the context of modern machine learning principles and the desire expressed by the rational drug design community to secure molecules that are structurally different, yet with high binding affinities, to structurally determined protein targets.
A Combinatorial Approach of Biparental QTL Mapping and Genome-Wide Association Analysis Identifies Candidate Genes for Phytophthora Blight Resistance in Sesame
Authors: Sovetgul Asekova , Oh Eunyoung , Kulkarni Krishnanand P. , Lee Myoung Hee , In Kim Jung , Pae Suk-Bok , Kim Minsu , Oh Ki-Won , Cho Kwang-Soo , Kim Sungup 
Published: March 2020

SummaryPhytophthora blight, caused by pathogenPhytophthora nicotianae, is responsible for a huge reduction in sesame (Sesamum indicumL.) crop yields. In this study, we utilized a combinatorial approach involving biparental QTL mapping and genome-wide association (GWAS) analysis to identify genes associated with Phytophthora blight resistance in sesame. Evaluation of resistant of the parental varieties (Goenbaek, Osan and Milsung) and the RILs of both the populations in greenhouse conditions suggested the qualitative nature of the trait.. The genetic map comprised thirteen LGs covering a total map length of 887.49 cM with an average inter-marker distance of 4.69 cM. Significant QTLs explaining phenotypic variation in the range of 2.25% to 69.24% were identified on chromosomes 10 and 13 (Chr10 and Chr13). A resistance locus detected on Chr10 was found to be highly significant. The association of this locus to PBR was also identified through BSA and single marker analysis in Goenbaek × Milsung cross and through genome-wide association mapping of 87 sesame accessions. The GWAS analysis identified 44 SNP loci significantly associated with Phytophthora disease-resistant traits on Chr10. Further, the haplotype block analysis conducted in order to find whether the SNPs associated with resistance in this study showed that the SNPs are in high LD with the resistance QTL. We obtained a total of 68 candidate genes, which included a number of defense-relatedRgenes. One of the genes,SIN_1019016(At1g58390)showed high expression in the resistant parent. The results from this study would be highly useful in identifying genetic and molecular factors associated with Phytophthora blight resistance in sesame.
Variability within rare cell states enables multiple paths towards drug resistance
Authors: Emert Benjamin L. , Cote Christopher , Torre Eduardo A. , Dardani Ian P. , Jiang Connie L. , Jain Naveen , Shaffer Sydney M. , Raj Arjun 
Published: March 2020

AbstractMolecular differences between individual cells can lead to dramatic differences in cell fate, such as death versus survival of cancer cells upon drug treatment. These originating differences remain largely hidden due to difficulties in determining precisely what variable molecular features lead to which cellular fates. Thus, we developed Rewind, a methodology that combines genetic barcoding with RNA FISH to directly capture rare cells that give rise to cellular behaviors of interest. Applied to BRAFV600Emelanoma, we trace drug-resistant cell fates back to single-cell gene expression differences in their drug-naive precursors (initial frequency of ∼1:1000-1:10,000 cells) and relative persistence of MAP-kinase signaling soon after drug treatment. Within this rare subpopulation, we uncover a rich substructure in which molecular differences between several distinct subpopulations predict future differences in phenotypic behavior, such as proliferative capacity of distinct resistant clones following drug treatment. Similarly, we show that treatments that modify the frequency of resistance can allow otherwise non-resistant cells in the drug-naive population to become resistant, and that these new populations are marked by the variable expression of distinct genes. Together, our results reveal the presence of hidden, rare-cell variability that can underlie a range of latent phenotypic outcomes upon drug exposure.
Trpm8modulates thermogenesis in a sex-dependent manner without influencing cold-induced bone loss
Authors: Carvalho Adriana Lelis , Treyball Annika , Brooks Daniel J. , Costa Samantha , Neilson Ryan J. , Reagan Michaela R. , Bouxsein Mary L. , Motyl Katherine J. 
Published: March 2020

AbstractTrpm8(transient receptor potential cation channel, subfamily M, member 8) is expressed by sensory neurons, and it is involved in the detection of cold temperatures. Increased TRPM8 activity triggers an increase in uncoupling protein 1 (Ucp1)-dependent brown adipose tissue (BAT) thermogenesis. Bone density and marrow adipose tissue are regulated by rodent housing temperature and brown adipose tissue, suggesting one mediator of this effect may be TRPM8. In order to test whether TRPM8 was involved in the co-regulation of thermogenesis and bone homeostasis, we examined the bone phenotypes of one-year-oldTrpm8knockout mice (Trpm8-KO) and then exposed them to a 4-week cold temperature challenge. MaleTrpm8-KOmice had lower bone mineral density than WT, with smaller bone size (femur length and cross-sectional area) being the most striking finding, and exhibited a delayed cold acclimation with increased BAT expression ofUcp1, Dio2andCideaat the end of the study. In contrast to males, femaleTrpm8-KOmice had low vertebral bone microarchitectural parameters, but no genotype-specific alterations in body temperature. Interestingly,Trpm8was not required for cold-induced trabecular bone loss in either sex, but may be required for cold-induced changes in marrow adiposity in males. Furthermore, bone marrow adipose tissue accumulation in females was significantly blunted byTrpm8deletion. In summary, we identified sex differences in the role of TRPM8 in maintaining body temperature, bone density and marrow adipose tissue. Identifying mechanisms through which cold temperature and brown adipose tissue influence bone could help to ameliorate potential bone side effects of obesity treatments designed to stimulate thermogenesis.
APOL1 variant-expressing endothelial cells exhibit autophagic dysfunction and mitochondrial stress
Authors: Blazer Ashira , Qian Yingzhi , Schlegel Martin Paul , Buyon Jill P. , Cadwell Ken , Cammer Michael , Heffron Sean P. , Liang Feng-Xia , Mehta-Lee Shilpi , Niewold Timothy , Rasmussen Sara E. , Clancy Robert M. 
Published: March 2020

AbstractApolipoprotein L1 (APOL1) gene risk variants (RV) associate with renal and cardiovascular disease particularly in SLE. We hypothesized that in RV-carrying human umbilical vein endothelial cells (HUVECs) cytokine-induced APOL1 expression compromises mitochondrial respiration, lysosome integrity, and autophagic flux. HUVEC cultures of each APOL1 genotype were generated. APOL1 was expressed using IFNɣ; HUVEC mitochondrial function, lysosome integrity, and autophagic flux were measured. IFNɣ increased APOL1 expression across all genotypes 20-fold (p=0.001). Compared to the homozygous G0 (ancestral) allele (0RV), high risk (2RV) HUVECs showed both depressed baseline and maximum mitochondrial oxygen consumption (p<0.01), and impaired mitochondrial networking on MitoTracker assays. These cells also demonstrated a contracted lysosome compartment (p<0.001), and an accumulation of autophagosomes suggesting a defect in autophagic flux. Treatment of 0RV HUVECs with a non-selective lysosome inhibitor, hydroxychloroquine, produced autophagosome accumulations similar to the 2RV cells, thus implicating lysosome dysfunction in blocking autophagy. Compared to 0RV and 2RV HUVECs, 1 RV cells demonstrated an intermediate autophagy defect which was exacerbated by IFNɣ. Our findings implicate dysfunction of mitochondrial respiration, lysosome, and autophagy in APOL1 RV-mediated endothelial cytotoxicity. IFNɣ amplified this phenotype even in variant heterozygous cells–a potential underpin of the APOL1/inflammation interaction. This is the first description of APOL1 pathobiology in variant heterozygous cell cultures.
Orchard layout and plant traits influence fruit yield more strongly than pollinator behaviour and density in a dioecious crop
Authors: Peace Angela , Pattermore David , Broussard Melissa , Fonseka Dilini , Tomer Nathan , Bosque-Pérez Nilsa A. , Crowder David , Shaw Allison K. , Jesson Linley , Howlett Brad , Jochym Mateusz , Li Jing 
Published: March 2020

AbstractMutualistic plant-pollinator interactions are critical for the functioning of both non-managed and agricultural systems. Mathematical models of plant-pollinator interactions can help understand key determinants in pollination success. However, most previous models have not addressed pollinator behavior and plant biology combined. Information generated from such a model can inform optimal design of crop orchards and effective utilization of managed pollinators like honey bees, and help generate hypotheses about the effects of management practices and cultivar selection. We expect that honey bee density per flower and male to female flower ratio will influence fruit yield. To test the relative importance of these effects, both singly and simultaneously, we utilized a delay differential equation model combined with Latin hypercube sampling for sensitivity analysis. Empirical data obtained from historical records and collected in kiwifruit orchards in New Zealand were used to parameterize the model. We found that, at realistic bee densities, the optimal orchard had 65-75% female flowers, and the most benefit was gained from the first 6-8 bees/1000 flowers, with diminishing returns thereafter. While bee density significantly impacted fruit production, plant-based parameters-flower density and male:female flower ratio-were the most influential. The predictive model provides strategies for improving crop management.
Erosion of human X chromosome inactivation causes major remodelling of the iPSC proteome
Authors: Brenes Alejandro J. , Yoshikawa Harunori , Bensaddek Dalila , Mirauta Bogdan , Seaton Daniel , Hukelmann Jens L. , Jiang Hao , Stegle Oliver , Lamond Angus I. 
Published: March 2020

SummaryX chromosome inactivation (XCI) is a dosage compensation mechanism in female mammals whereby genes from one X chromosome are repressed. Analysis of human induced pluripotent stem cell (iPSC) lines using proteomics, RNAseq and polysome profiling showed a major change in the proteome upon XCI erosion. This resulted in amplified RNA and protein expression from X-linked genes. However, increased protein expression was also detected from autosomal genes without a corresponding mRNA increase, altering the protein-RNA correlation between genes on the X chromosome and autosomes. Eroded iPSC lines display ~13% increase in cell protein content, along with increased expression of ribosomal proteins, ribosome biogenesis and translation factors. They also showed significantly increased levels of active polysomes within the eroded lines. We conclude that erosion of XCI causes a major remodelling of the proteome, with translational mechanisms affecting the expression of a much wider range of proteins and disease-linked loci than previously realised.
Lipid metabolic stress in development defines which genetically-susceptible DYT-TOR1Amice develop disease
Authors: Cascalho Ana , Foroozandeh Joyce , Rous Stef , Martínez Vizcaíno Natalia , Gallego Sandra F. , Goodchild Rose E. 
Published: March 2020

SummaryThere has been enormous progress defining the genetic landscape of disease. However, genotypes rarely fully predict neurological phenotypes, and we rarely understand why.TOR1A+/Δgag that causes dystonia with ~30% penetrance is a classic case. Here we show, in inbred mice, that +/Δgag affects embryonic brain lipid metabolism with sex-skewed reduced penetrance. Penetrance is affected by environmental context, including maternal diet. The lipid metabolic defect resolves during post-natal development. Nevertheless, we discover dystonia-like symptoms in ~30% of juvenile femaleTor1a+/Δgagmice, and prevent these symptoms by genetically suppressing abnormal lipid metabolism. We conclude thatTor1a+/Δgagembryos poorly buffer metabolic stressin utero, resulting in a period of abnormal metabolism that hardwires the brain for dystonia in later life. The data show unexpected and profound impacts of sex, and thus highlight the importance of examining male and female animal models of disease.Significance StatementThe genetic landscape of neurological disease is relatively well mapped. However, we typically cannot explain why some mutations only cause disease in a subset of individuals. A classic case is DYT-TOR1Adystonia that only develops in 30% ofTOR1A+/Δgagcarriers. We now find that ~30% of inbred femaleTor1a+/Δgagmice develop abnormal brain lipid metabolism as embryos, while males are spared. The percentage is affected by maternal diet. Further, this period of abnormal lipid metabolism causes dystonia-like symptoms in juvenile mice. These data show how an environmentally-sensitive event of development defines which genetically-susceptible individuals develop disease in later life. They also highlight the importance of examining male and female animal models of disease.
EMU: reconfigurable graphical user interfaces for Micro-Manager
Authors: Deschamps Joran , Ries Jonas 
Published: March 2020

Advanced light microscopy methods are becoming increasingly popular in biological research. Their ease of use depends, besides experimental aspects, on intuitive user interfaces. The open-source software Micro-Manager offers a universal interface for microscope control but requires implementing plugins to further tailor it to specific systems. Since even similar devices can have different Micro-Manager properties (such as power percentage versus absolute power), transferring user interfaces to other systems is usually very restricted.We developed Easier Micro-Manager User interface (EMU), a Micro-Manager plugin, to simplify building flexible and reconfigurable user interfaces. EMU offers a choice of interfaces that are rapidly ready to use thanks to an intuitive configuration menu. In particular, the configuration menu allows mapping device properties to the various functions of the interface in a few clicks. Exchanging or adding new devices to the microscope no longer requires rewriting code. The EMU framework also simplifies implementing a new interface by providing the configuration and device interaction mechanisms. The user interface can be built by using a drag-and-drop tool in one’s favorite Java development environment and writing a few lines of code for compatibility with EMU.Micro-Manager users now have a powerful tool to improve the user experience on their instruments. EMU interfaces can be easily transferred to new microscopes and shared with other research groups. In the future, newly developed interfaces will be added to EMU to benefit the whole community.
Auxin Regulation andMdPINExpression during Adventitious Root Initiation in Apple Cuttings
Authors: Guan Ling , Li Yingjun , Huang Kaihui , Cheng Zong-Ming (Max) 
Published: March 2020

AbstractAdventitious root (AR) formation is critical for the efficient propagation of elite horticultural and forestry crops. Despite decades of research, the cellular processes and molecular mechanisms underlying AR induction in woody plants remains obscure. We examined the details of AR formation in the apple (Malus domestica) M.9 rootstock, the most widely used dwarf rootstock for intensive production, and investigated the role of polar auxin transport in post-embryonic organogenesis. AR formation begins with a series of founder cell divisions and elongation of interfascicular cambium adjacent to vascular tissues. This process was associated with a relatively high indole acetic acid (IAA) content and hydrolysis of starch grains. Exogenous auxin treatment promoted cell division, as well as the proliferation and reorganization of the endoplasmic reticulum and Golgi membrane. By contrast, treatment with the auxin transport inhibitorN-1-naphthylphthalamic acid (NPA) inhibited cell division in the basal region of the cutting and resulted in abnormal cell divisions during early AR formation. In addition, PIN-FORMED (PIN) transcripts were expressed differentially throughout the whole AR development process, with the up-regulation ofMdPIN8andMdPIN10during induction, an up-regulation ofMdPIN4,MdPIN5andMdPIN8during extension, and an up-regulation of allMdPINsduring AR initiation. This research provides a deeper understanding of the cellular and molecular underpinnings of the AR process in woody plants.
Corporate governance and underpricing of small and medium enterprises IPOs in India
Authors: Arora Nischay , Singh Balwinder 
Published: March 2020

PurposeThe purpose of the paper is to examine the impact of corporate governance mechanisms, i.e. board structure and ownership structure on the underpricing of small and medium enterprises (SME) IPOs in India.Design/methodology/approachMost of the extant empirical research studies have either pivoted on mainstream IPOs or SMEs IPOs in developed economies, but the present study examines 200 SME IPOs issued during Feb 2012 to April 2017. Multiple regressions have been used to examine the impact of the corporate governance mechanisms on raw return (RR). Furthermore, robustness of the results has been verified through the employment of market-adjusted excess return (MAER) as an additional proxy of underpricing.FindingsThe results highlight that board size, inverse of board committees, board independence, board age, board directorships positively, and top ten shareholding negatively influence RR. Further, direction of promoter ownership variable indicates curvilinear relationship with underpricing. Other explanatory variables used in model lack statistical validity. Similar results have been obtained when variables were regressed against MAER with related board members being additionally significant in model.Practical implicationsThe findings suggest that Indian investors do take cues from board structure and ownership patterns for making investment decisions in small- and medium-sized firms. Further, the results are also helpful to top management in structuring their boards.Originality/valueThe present research enriches SME IPOs underpricing literature because the impact of corporate governance mechanisms on unadjusted returns is relatively under explored particularly within the context of small- and medium-sized firms.
Product development in Islamic finance and banking in secular economies
Authors: Dinc Yusuf 
Published: March 2020

Purpose
As the global paradigm in economics shifts, Islamic economics is attracting more attention as an alternative sector. The most common and most active institutional structure of Islamic economics is in the form of Islamic finance and banking. Islamic finance and banking have been the centre of innovation in many economies in recent years. In this regard, product development is a vital element in driving the success of Islamic financial institutions (IFIs). The product development of IFIs is one of the key elements of their overall economic performance. This study aims to fill the gap in the literature concerning the product development process of IFIs in secular economies.

Design/methodology/approach
Verily, product development is a complex process; it is likely that introducing specific models will be useful for expanding the activities of IFIs. In this study, contemporary source materials are used to develop this conceptual research.

Findings
It suggests two separate methodologies for the product development process of IFIs in secular economies to overhaul two criticised product-based problems. To the best of the author’s knowledge, it is the first attempt to model the product development process for IFIs in a secular economic setup.

Originality/value
Recently, this study is the first attempt for modelling product development in IFIs under secular economies. Advances in the field of Shari’ah-compliant product development is important for researchers and professional.
Shopping value, trust, and online shopping well-being: a duality approach
Authors: Nghia Ho Trong , Olsen Svein Ottar , Trang Nguyen Thi Mai 
Published: March 2020

PurposeBased on a duality approach, this study examines the path from utilitarian value via cognitive trust versus hedonic value via affective trust in online shopping well-being. This study also explores the moderating role of extraversion in the relationships between shopping value and trust.Design/methodology/approachA data set collected from 648 online consumers in Vietnam was used to validate the measures employing confirmatory factor analysis (CFA) and to test the hypotheses using structural equation modelling (SEM).FindingsThe results show that online shopping well-being is determined hedonically and affectively rather than in an utilitarian manner and cognitively. Affective trust positively contributes to online shopping well-being, but cognitive trust does not. The dual-process associations between utilitarian shopping value and cognitive trust and between hedonic shopping value and cognitive trust were also confirmed. Finally, extraversion moderates the cognitive and affective associations between shopping values and trust.Originality/valueThis study contributes to the literature on online shopping by applying a dual perspective to confirm the role of hedonic shopping value and affective trust in positively determining online shopping well-being. As a result, this study provides a deeper understanding about if and why online shopping well-being is affect-based, instead of cognition-based.
A novel dimethylsulfoxide reductase family of molybdenum enzyme, Idr, is involved in iodate respiration by Pseudomonas sp. SCT
Authors: Yamazaki Chihiro , Kashiwa Sumie , Horiuchi Ayaka , Kasahara Yasuhiro , Yamamura Shigeki , Amachi Seigo 
Published: March 2020

SummaryPseudomonas sp. strain SCT is capable of using iodate (IO3−) as a terminal electron acceptor for anaerobic respiration. A possible key enzyme, periplasmic iodate reductase (Idr), was visualized by active staining on non‐denaturing gel electrophoresis. Liquid chromatography–tandem mass spectrometry analysis revealed that at least four proteins, designated as IdrA, IdrB, IdrP1, and IdrP2, were involved in Idr. IdrA and IdrB were homologues of catalytic and electron transfer subunits of respiratory arsenite oxidase (Aio); however, IdrA defined a novel clade within the dimethylsulfoxide (DMSO) reductase family. IdrP1 and IdrP2 were closely related to each other and distantly related to cytochrome c peroxidase. The idr genes (idrABP
1P
2) formed an operon‐like structure, and their transcription was upregulated under iodate‐respiring conditions. Comparative proteomic analysis also revealed that Idr proteins and high affinity terminal oxidases (Cbb3 and Cyd), various H2O2 scavengers, and chlorite (ClO2−) dismutase‐like proteins were expressed specifically or abundantly under iodate‐respiring conditions. These results suggest that Idr is a respiratory iodate reductase, and that both O2 and H2O2 are formed as by‐products of iodate respiration. We propose an electron transport chain model of strain SCT, in which iodate, H2O2, and O2 are used as terminal electron acceptors.