bluuebunny/crossref_metadata_2025_split huggingface dataset:
Variation in a pleiotropic hub gene drives morphological evolution: Insights from interspecific differences in head shape and eye size inDrosophila
Authors: Buchberger Elisa , Bilen Anıl , Ayaz Sanem , Salamanca David , Matas de las Heras Cristina , Niksic Armin , Almudi Isabel , Torres-Oliva Montserrat , Casares Fernando , Posnien Nico 
Published: January 2020

AbstractRevealing the mechanisms underlying the breath-taking morphological diversity observed in nature is a major challenge in Biology. It has been established that recurrent mutations in hotspot genes cause the repeated evolution of rather simple morphological traits, such as body pigmentation or the gain and loss of structures. To date, however, it remains elusive whether hotspot genes contribute to natural variation in complex morphological traits, such as the size and shape of organs. Since natural variation in head morphology is pervasive inDrosophila, we studied the molecular and developmental basis of differences in compound eye size and head shape in two closely relatedDrosophilaspecies. We show that differences in both traits are established late during head development and we applied comparative transcriptomics and chromatin accessibility data to identify the GATA transcription factor Pannier (Pnr) as central factor regulating these differences. Although the genetic manipulation of Pnr affected multiple aspects of dorsal head development, the effect of natural variation is restricted to a subset of the phenotypic space. We present data suggesting that this developmental constraint is caused by the co-evolution of expression ofpnrand its co-factoru-shaped (ush). We propose that natural variation in highly connected developmental regulators with pleiotropic functions is a major driver for morphological evolution and we discuss implications on gene regulatory network evolution. In comparison to previous findings, our data strongly suggests that evolutionary hotspots do not contribute to the repeated evolution of eye size and head shape inDrosophila.
Linking endoplasmic reticulum stress to polyploidy in ovarian cancer cells
Authors: Yart Lucile , Bastida-Ruiz Daniel , Wuillemin Christine , Ribaux Pascale , Allard Mathilde , Dietrich Pierre-Yves , Petignat Patrick , Cohen Marie 
Published: January 2020

AbstractPolyploid giant cancer cells (PGCCs) have been observed in epithelial ovarian tumors and have the ability to survive to antimitotic drugs. Their appearance can result from paclitaxel treatment or hypoxia, two conditions known to induce unfolded protein response (UPR) activation. PGCCs produced under hypoxia may be formed by cell fusion and can contribute by bursting and budding to the generation of cancer stem-like cells which have a more aggressive phenotype than the parental cells. Despite the fact that PGCCs may contribute to tumor maintenance and recurrence, they were poorly studied. Here, we confirmed that PGCCs could derive, at least in part, from cell fusion. We also observed that PGCCs nuclei were able to fuse. The resulting cells were able to proliferate by mitosis and were more invasive than the parental cancer cells. Using two different ovarian cancer cell lines (COV318 and SKOV3), we showed that UPR activation with chemical inducers increased cell fusion and PGCCs appearance. Down-regulation of the UPR-associated protein PERK expression partially reversed the UPR-induced PGCCs formation, suggesting that the PERK arm of the UPR is involved in ovarian PGCCs onset.
Msps Governs Acentrosomal Microtubule Assembly and Reactivation of Quiescent Neural Stem Cells
Authors: Deng Qiannan , Tan Ye Sing , Chew Liang Yuh , Wang Hongyan 
Published: January 2020

SUMMARYThe ability of stem cells to switch between quiescence and proliferation is crucial for tissue homeostasis and regeneration.Drosophilaquiescent neural stem cells (NSCs) extend a primary cellular protrusion from the cell body prior to their reactivation. However, the structure and function of this protrusion are not well established. In this study, we show that in the primary protrusion of quiescent NSCs microtubules are predominantly acentrosomal and oriented plus-end-out, distal to the cell body. We have identified Mini Spindles (Msps)/XMAP215 as a key regulator of NSC reactivation and acentrosomal microtubule assembly in quiescent NSCs. We show that E-cadherin, a cell adhesion molecule, is localized to NSC-neuropil contact points, in a Msps-dependent manner, and is intrinsically required for NSC reactivation. Our study demonstrates a novel mechanism by which Msps-dependent microtubule assembly in the primary protrusion of quiescent NSCs targets E-cadherin to NSC-neuropil contact sites to promote NSC reactivation. We propose that the neuropil functions as a new niche for promoting NSC reactivation, which may be a general paradigm in mammalian systems.
Single molecule imaging reveals the collective and independent search mechanisms of cFos and cJun on DNA
Authors: Leech James T. , Brennan Andrew , Don Nicola A. , Mason Jody M. , Kad Neil M. 
Published: January 2020

AbstractAP-1 proteins are members of the basic leucine zipper (bZIP) family of dimeric transcription factors, which facilitate a multitude of cellular processes, but are primarily known for their oncogenic potential in several cancer types. The oncogenic transcription factor AP-1 binds a specific DNA target site (5’TCA[G/C]TGA), however the physical mechanism of how this is achieved has not been determined. The archetypal AP-1 complex is formed by cFos and cJun, which heterodimerize via their leucine zipper domains. We investigated the DNA-binding bZIP domains of AP-1 interacting with DNA tightropes using real-time single molecule fluorescence imagingin vitro. We find that AP-1 bZIP domains comprising cFos:cJun and cJun:cJun rapidly scan DNA using a 1D diffusional search with average diffusion constants of 0.14 μm2s−1and 0.26 μm2s−1respectively. We also report for the first time that cFos is able to bind to and diffuse on DNA (0.29 μm2s−1) as a mixed population of monomers and homodimers, despite previous studies suggesting that it is incapable of independent DNA binding. Additionally, we note increased pause lifetimes for the cFos:cJun heterodimer compared to the cJun:cJun homodimer, and were able to detect distinct pausing behaviours within diffusion data. Understanding how cFos:cJun and other transcription factors identify their targets is highly relevant to the development of new therapeutics which target DNA binding proteins using these search mechanisms.
Definition of the fibroblast adhesome using multiplexed proximity biotinylation
Authors: Chastney Megan R. , Lawless Craig , Humphries Jonathan D. , Warwood Stacey , Jones Matthew C. , Knight David , Jorgensen Claus , Humphries Martin J. 
Published: January 2020

AbstractIntegrin adhesion complexes (IACs) bridge the extracellular matrix to the actin cytoskeleton and transduce signals in response to both chemical and mechanical cues. The composition, interactions, stoichiometry and topological organisation of proteins within IACs are not fully understood. To address this gap, we used multiplexed proximity biotinylation (BioID) to generate anin situ,proximity-dependent adhesome in mouse pancreatic fibroblasts. Integration of the interactomes of 16 IAC-associated baits revealed a network of 147 proteins with 361 proximity interactions. Candidates with underappreciated roles in adhesion were identified, in addition to established IAC components. Bioinformatic analysis revealed five clusters of IAC baits that link to common groups of prey, and which therefore may represent functional modules. The five clusters, and their spatial associations, are consistent with current models of IAC interaction networks and stratification. This study provides a resource to examine proximal relationships within IACs at a global level.
Crystal structure of the Tof1-Csm3 (Timeless-Tipin) fork protection complex
Authors: Grabarczyk Daniel B. 
Published: January 2020

AbstractThe Tof1-Csm3 fork protection complex has a central role in the replisome – it promotes the progression of DNA replication forks and protects them when they stall, while also enabling cohesion establishment and checkpoint responses. Here, I present the crystal structure of the Tof1-Csm3 complex fromChaetomium thermophilumat 3.1 Å resolution. The structure reveals that Tof1 is an extended alpha-helical repeat protein which is capped at its C-terminal end by Csm3, a small helical bundle protein. I also characterize the DNA binding properties of the complex and a cancer-associated peptide-binding site. This study provides the molecular basis for understanding the functions of the Tof1-Csm3 complex, its human orthologue the Timeless-Tipin complex and additionally the Drosophila circadian rhythm protein Timeless.
Sequential combinations of chemotherapeutic agents with BH3 mimetics to treat rhabdomyosarcoma and avoid resistance
Authors: Alcon Clara , Manzano-Muñoz Albert , Prada Estela , Mora Jaume , Soriano Aroa , Guillén Gabriela , Gallego Soledad , Roma Josep , Samitier Josep , Villanueva Alberto , Montero Joan 
Published: January 2020

AbstractRhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood and adolescence. Refractory/relapsed RMS patients present a bad prognosis that combined with the lack of specific biomarkers difficult the development of new therapies. We here utilize dynamic BH3 Profiling (DBP), a functional predictive biomarker that measures net changes in mitochondrial apoptotic signaling, to identify anti-apoptotic adaptations upon treatment. We use this information to guide the use of BH3 mimetics to specifically inhibit BCL-2 pro-survival proteins, defeat resistance and avoid relapse to therapy. Indeed, we found that BH3 mimetics that selectively target BCL-xL and MCL-1 synergistically enhance the effect of the clinically used chemotherapeutic agents vincristine and doxorubicin in RMS cells. We validated this strategy in vivo using a RMS patient-derived xenograft (PDX) model and observed a reduction on tumor growth with a tendency to its stabilization with the sequential combination of vincristine and the MCL-1 inhibitor S63845. Finally, we identified the molecular mechanism by which RMS cells acquire resistance to vincristine: through the anti-apoptotic protein MCL-1 for which we observed an enhanced binding between MCL-1 and BID after drug exposure, which is suppressed by the sequential addition of S63845. In conclusion, our findings validate the use of DBP as a functional assay to predict treatment effectiveness in RMS and provide a rationale for BH3 mimetic combination with chemotherapeutic agents to avoid tumor resistance, improve treatment efficiency and decrease undesired secondary effects.
Combining feature selection and shape analysis uncovers precise rules for miRNA regulation in Huntington’s disease mice
Authors: Mégret Lucile , Nair Satish Sasidharan , Dancourt Julia , Aaronson Jeff , Rosinski Jim , Neri Christian 
Published: January 2020

AbstractBackgroundMicroRNA (miRNA) regulation is associated with several diseases, including neurodegenerative diseases. Several approaches can be used for modeling miRNA regulation. However, their precision may be limited for analyzing multidimensional data. Here, we addressed this question by integrating shape analysis and feature selection into miRAMINT, a methodology that we used for analyzing multidimensional RNA-seq and proteomic data from a knock-in mouse model (Hdh mice) of Huntington’s disease (HD), a disease caused by CAG repeat expansion in huntingtin (htt). This dataset covers 6 CAG repeat alleles and 3 age points in the striatum and cortex of Hdh mice.ResultsRemarkably, compared to previous analyzes of this multidimensional dataset, the miRAMINT approach retained only 31 explanatory striatal miRNA-mRNA pairs that are precisely associated with the shape of CAG repeat dependence over time, among which 5 pairs with a strong change of target expression levels. Several of these pairs were previously associated with neuronal homeostasis or HD pathogenesis, or both. Such miRNA-mRNA pairs were not detected in cortex.ConclusionsThese data suggest that miRNA regulation has a limited global role in HD while providing accurately-selected miRNA-target pairs to study how the brain may compute molecular responses to HD over time. These data also provide a methodological framework for researchers to explore how shape analysis can enhance multidimensional data analytics in biology and disease.
Cardiomyocyte-specific ACSL1 Deficiency Prevents Cardiac Lipotoxicity and Alleviates Heart Dysfunction in theob/obModel of Obesity
Authors: Pascual Florencia , Grevengoed Trisha J. , Zhao Liyang , Willis Monte S. , Coleman Rosalind A. 
Published: January 2020

AbstractCardiac lipotoxicity is associated with structural remodeling and functional changes that are features of obesity-related cardiomyopathy. Both high fat diet and theob/obmutation lead to increased fatty acid (FA) uptake, elevated triacylglycerol (TAG) content, hypertrophy, and systolic and diastolic dysfunction in murine hearts. Cardiomyocyte-specific long-chain acyl-CoA synthetase 1 (ACSL1) deficiency (Acsl1H-/-) results in a 90% reduction in FA activation, suggesting thatAcsl1ablation might alleviate obesity-associated myocardial dysfunction. Double knockoutob-Acsl1H-/-andob-Acsl1flox/floxcontrol mice were treated with tamoxifen at 20 weeks of age; heart function, TAG content, and relevant gene expression were assessed immediately before and 2 and 5 weeks after treatment. Heart weights initially increased in lean and obeseAcsl1H-/-mice, but normalized inob-Acsl1H-/-mice by 5 weeks. Ventricular TAG content was decreased by 51% and 61% inob-Acsl1H-/-mice 2 and 5 weeks afterAcsl1knockout induction, respectively. Moreover, ACSL1 knockout resulted in increased survival ofob/obmice, suggesting that lack of ACSL1 protected obese hearts subjected to stress. Our results indicate that partial knockdown of cardiac ACSL1 is sufficient to reverse cardiac TAG accumulation and to ameliorate heart dysfunction even in the context of established obesity-related cardiomyopathy.
Macrophages Promote Aortic Valve Cell Calcification Through STAT3 Splicing
Authors: Raddatz Michael A. , Huffstater Tessa M. , Bersi Matthew R. , Reinfeld Bradley I. , Madden Matthew Z. , Booton Sabrina E. , Rathmell W. Kimryn , Rathmell Jeffrey C. , Lindman Brian R. , Madhur Meena S. , Merryman W. David 
Published: January 2020

AbstractObjectiveMacrophages have been described in calcific aortic valve disease, but it is unclear if they promote or counteract calcification. We aimed to determine how macrophages are involved in calcification using theNotch1+/-model of calcific aortic valve disease.Approach and ResultsMacrophages in wild-type andNotch1+/-murine aortic valves were characterized by flow cytometry. Macrophages inNotch1+/-aortic valves had increased expression of MHCII. We then used bone marrow transplants to test if differences inNotch1+/-macrophages drive disease.Notch1+/-mice had increased valve thickness, macrophage infiltration, and M1-like macrophage polarization regardless of transplanted bone marrow genotype.In vitroapproaches confirm thatNotch1+/-aortic valve cells promote macrophage invasion as quantified by migration index and M1-like polarization quantified by Ly6C and CCR2 positivity regardless of macrophage genotype. Finally, we found that macrophage interaction with aortic valve cells promotes osteogenic, but not dystrophic, calcification by decreasing abundance of the STAT3β isoform.ConclusionsThis study reveals thatNotch1+/-aortic valve disease involves increased macrophage recruitment and polarization driven by altered aortic valve cell secretion, and that increased macrophage recruitment promotes osteogenic calcification through STAT3 splicing changes. Further investigation of STAT3 and macrophage-driven inflammation as therapeutic targets in calcific aortic valve disease is warranted.Graphical Abstract
Structure-based inhibitors reveal roles for the clathrin terminal domain and its W-box binding site in CME
Authors: Chen Zhiming , Mino Rosa , Mettlen Marcel , Michaely Peter , Bhave Madhura , Reed Dana Kim , Schmid Sandra L. 
Published: January 2020

AbstractClathrin-mediated endocytosis (CME) occurs via the formation of clathrin-coated vesicles from clathrin-coated pits (CCPs). Clathrin is recruited to CCPs through interactions between the AP2 complex and its N-terminal domain (TD), which in turn recruits endocytic accessory proteins. Inhibitors of CME that interfere with clathrin function have been described, but their specificity and mechanisms of action are unclear. Here we show that overexpression of the TD with or without the distal leg specifically inhibits CME and CCP dynamics by perturbing clathrin interactions with AP2 and SNX9. We designed small membrane-penetrating peptides that mimic the four known binding sites on the TD. A peptide, Wbox2, designed to mimic to the W-box motif binding surface on TD binds to SNX9 and AP2, and potently and acutely inhibits CME, while not perturbing AP1-dependent lysosomal trafficking from the Golgi or bulk, fluid phase endocytosis.SummaryChen et al define the role the N-terminal domain (TD) of clathrin heavy chain in early and late stages of clathrin-mediated endocytosis, and guided by its structure, design a membrane-penetrating peptide, Wbox2, that acutely and potently inhibits CME.
Under-the-radar dengue virus infections in natural populations ofAedes aegyptimosquitoes
Authors: Boyles Sean M. , Mavian Carla N. , Finol Esteban , Ukhanova Maria , Stephenson Caroline J. , Hamerlinck Gabriela , Kang Seokyoung , Baumgartner Caleb , Geesey Mary , Stinton Israel , Williams Kate , Mathias Derrick K. , Prosperi Mattia , Mai Volker , Salemi Marco , Buckner Eva A. , Lednicky John A. , Rivers Adam R. , Dinglasan Rhoel R. 
Published: January 2020

AbstractThe incidence of locally acquired dengue infections increased during the last decade in the United States, compelling a sustained research effort on the dengue mosquito vector,Aedes aegypti,and its microbiome, which has been shown to influence virus transmission success. We examined the ‘metavirome’ of four populations ofAe. aegyptimosquitoes collected in 2016-2017 from Manatee County, Florida. Unexpectedly, we discovered that dengue virus serotype 4 (DENV4) was circulating in these mosquito populations, representing the first documented case of such a phenomenon in the absence of a local DENV4 human case in this county over a two-year period. We confirmed that all of the mosquito populations carried the same DENV4 strain, assembled its full genome, validated infection orthogonally by reverse transcriptase PCR, traced the virus origin, estimated the time period of its introduction to the Caribbean region, as well as explored the viral genetic signatures and mosquito-specific virome associations that potentially mediated DENV4 persistence in mosquitoes. We discuss the significance of prolonged maintenance of these DENV4 infections inAe. aegyptithat occurred in the absence of a DENV4 human index case in Manatee County with respect to the inability of current surveillance paradigms to detect mosquito vector infections prior to a potential local outbreak.ImportanceSince 1999, dengue outbreaks in the continental United States (U.S.) involving local transmission have occurred episodically and only in Florida and Texas. In Florida, these episodes appear to be coincident with increased introductions of dengue virus into the region through human travel and migration from endemic countries. To date, the U.S. public health response to dengue outbreaks is largely reactive, and implementation of comprehensive arbovirus surveillance in advance of predictable transmission seasons, which would enable proactive preventative efforts, remains unsupported. The significance of our finding is that it is the first documented report of non-outbreak DENV4 transmission and maintenance within a local mosquito vector population in the continental U.S.in the absence of a human case during a two-year time period. Our data suggest that molecular surveillance of mosquito populations in high-risk, high tourism areas of the U.S., may allow for proactive, targeted vector control before potential arbovirus outbreaks.
The end of plastic bags: strategic dilemma of INAPOL
Authors: Peña Ramírez Camilo , Briones Maira Fernanda , Paredes Fernanda Valentina , Diaz Javiera Constanza , Vásquez María José 
Published: January 2020

Learning outcomes
Learning outcomes of this study are as follows: formulate an external analysis of INAPOL; and develop a strategic analysis to identify strategic alternatives.

Case overview/synopsis
INAPOL is a manufacturing company dedicated to the production of polyethylene sleeves and the manufacture of plastic bags, which faced a crisis because of the new environmental regulations in Chile. This rule prohibits the delivery of plastic bags in commerce, which leads directly to a decrease in the demand for bags by its main customers. This is why it is necessary to conduct a strategic analysis and reformulate a development plan. The reader is expected to be able to identify the external factors that limit the company and the internal factors that affect the company. In addition, the reader is expected to develop strategic analysis tools such as PESTEL and SWOT and identify background information to propose strategic alternatives.

Complexity academic level
The present case study presents a low complexity and can be applied in introductory courses of strategy or management for undergraduate students in administration.

Supplementary materials
Teaching Notes are available for educators only.

Subject code
CSS 11: Strategy.
Estimation of technical efficiency and output growth decomposition for small-scale rice farmers in Eastern India
Authors: Wu Wei 
Published: January 2020

Purpose
The purpose of this paper is to estimate the degree of technical efficiency, determinants of technical inefficiencies and driving forces behind the production growth for a panel data set collected during the 1998/1999 and 2004/2006 Kharif cropping season, from 452 small-scale rice farming households in the Giridih and Purulia districts of Eastern India.

Design/methodology/approach
The estimations of technical efficiency utilize stochastic frontier production function with a sub-model of inefficiency effects at both aggregated farm level and disaggregated plot level where traditional varieties (TVs) and high-yielding varieties (HYVs) are differentiated. The output growth decomposition analysis identifies the main contributor to the total rice production growth.

Findings
The results indicate that the sampled farms are operated at moderate levels of technical efficiency. The production of HYV rice is associated with higher technical efficiency compared to TV rice. Farming experience, education attainment, landholding size, the share of non-agricultural income and the share of land in the lower terraces account for the differences in technical inefficiencies across the sampled farms. The decomposition analysis suggests that as technical efficiency decreased, technical change is the main source of production growth during the survey period.

Research limitations/implications
The small sample size applied in the analysis will result in an insufficient representativeness of the study area.

Originality/value
This paper fills the literature gap as estimations of technical efficiency that account for subtle differences in adopted rice varieties are still rare in India.