bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transoceanic voyages of drywood termites (Isoptera: Kalotermitidae) inferred from extant and extinct species
Authors: Buček A. , Wang M. , Šobotník J. , Sillam-Dussès D , Mizumoto N. , Stiblík P. , Clitheroe C. , Lu T. , González Plaza J. J. , Mohagan A. , Rafanomezantsoa J. J. , Fisher B. , Engel M. S , Roisin Y. , Evans T. A. , Scheffrahn R. , Bourguignon T. 
Published: September 2021

ABSTRACTTermites are major decomposers of organic matter in terrestrial ecosystems and the second most diverse lineage of social insects. The Kalotermitidae, the second-largest termite family, are widely distributed across tropical and subtropical ecosystems, where they typically live in small colonies confined to single wood items inhabited by individuals with no foraging abilities. How the Kalotermitidae have acquired their global distribution patterns remains unresolved. Similarly, it is unclear whether foraging is ancestral to Kalotermitidae or was secondarily acquired in a few species. These questions can be addressed in a phylogenetic framework. We inferred time-calibrated phylogenetic trees of Kalotermitidae using mitochondrial genomes and nuclear ribosomal RNA genes of ∼120 species, about 27% of kalotermitid diversity, including representatives of 22 of the 23 kalotermitid genera. We found that extant kalotermitids shared a common ancestor 81 Mya (72–91 Mya 95% HPD), indicating that a few disjunctions among early-diverging kalotermitid lineages may predate Gondwana breakup. However, most of the ∼40 disjunctions among biogeographic realms were dated at less than 50 Mya, indicating that transoceanic dispersals, and more recently human-mediated dispersals, have been the major drivers of the global distribution of Kalotermitidae. Our phylogeny also revealed that the capacity to forage is often found in early-diverging kalotermitid lineages, implying that the ancestors of Kalotermitidae were able to forage among multiple wood pieces. Our phylogenetic estimates provide a platform for a critical taxonomic revision of the family and for future comparative analyses of Kalotermitidae.
SyNPL: Synthetic Notch pluripotent cell lines to monitor and manipulate cell interactionsin vitroandin vivo
Authors: Malaguti Mattias , Migueles Rosa Portero , Annoh Jennifer , Sadurska Daina , Blin Guillaume , Lowell Sally 
Published: September 2021

ABSTRACTCell-cell interactions govern differentiation and cell competition in pluripotent cells during early development, but the investigation of such processes is hindered by a lack of efficient analysis tools. Here we introduce SyNPL: clonal pluripotent stem cell lines which employ optimised Synthetic Notch (SynNotch) technology to report cell-cell interactions between engineered “sender” and “receiver” cells in cultured pluripotent cells and chimaeric mouse embryos. A modular design makes it straightforward to adapt the system for programming differentiation decisions non-cell-autonomously in receiver cells in response to direct contact with sender cells. We demonstrate the utility of this system by enforcing neuronal differentiation at the boundary between two cell populations. In summary, we provide a new tool which could be used to identify cell interactions and to profile changes in gene or protein expression that result from direct cell-cell contact with defined cell populations in culture and in early embryos, and which can be adapted to generate synthetic patterning of cell fate decisions.SUMMARY STATEMENTOptimised Synthetic Notch circuitry in mouse pluripotent stem cells provides a modular tool to monitor cell-cell interactions and program synthetic patterning of cell fates in culture and in embryos.
Reconstitution and use of highly active human CDK1:Cyclin-B:CKS1 complexes
Authors: Huis in ’t Veld Pim J. , Wohlgemuth Sabine , Koerner Carolin , Mueller Franziska , Janning Petra , Musacchio Andrea 
Published: September 2021

AbstractAs dividing cells transition into mitosis, hundreds of proteins are phosphorylated by a complex of cyclin-dependent kinase 1 (CDK1) and Cyclin-B, often at multiple sites. CDK1:Cyclin-B phosphorylation patterns alter conformations, interaction partners, and enzymatic activities and need to be recapitulated in vitro for the structural and functional characterization of the mitotic protein machinery. This requires a pure and active recombinant kinase complex. The kinase activity of CDK1 critically depends on the phosphorylation of a Threonine residue in its activation loop by a CDK1 activating kinase (CAK). We developed protocols to activate CDK1:Cyclin-B either in vitro with purified CDK1 activating kinases (CAK) or in insect cells through CDK-CAK co-expression. To boost kinase processivity, we reconstituted a tripartite complex consisting of CDK1, Cyclin-B, and CKS1. In this work, we provide and compare detailed protocols to obtain and use highly active CDK1:Cyclin-B (CC) and CDK1:Cyclin-B:CKS1 (CCC).
Artificial neural networks enable genome-scale simulations of intracellular signaling
Authors: Nilsson Avlant , Peters Joshua M. , Bryson Bryan , Lauffenburger Douglas A. 
Published: September 2021

AbstractMammalian cells adapt their functional state in response to external signals in form of ligands that bind receptors on the cell-surface. Mechanistically, this involves signal-processing through a complex network of molecular interactions that govern transcription factor (TF) activity patterns. Computer simulations of the information flow through this network could help predict cellular responses in health and disease. Here we develop a recurrent neural network constrained by prior knowledge of the signaling network with ligand concentrations as input, TF activity as output and signaling molecules as hidden nodes. Simulations are assumed to reach steady state, and we regularize the parameters to enforce this. Using synthetic data, we train models that generalize to unseen data and predict the effects of gene knockouts. We also fit models to a small experimental data set from literature and confirm the predictions using cross validation. This demonstrates the feasibility of simulating intracellular signaling at the genome-scale.
Conserved structural elements specialize ATAD1 as a membrane protein extraction machine
Authors: Wang Lan , Toutkoushian Hannah , Belyy Vladislav , Kokontis Claire , Walter Peter 
Published: September 2021

AbstractThe mitochondrial AAA protein ATAD1 (in humans; Msp1 in yeast) removes mislocalized membrane proteins, as well as stuck import substrates from the mitochondrial outer membrane, facilitating their re-insertion into their cognate organelles and maintaining mitochondria’s protein import capacity. In doing so, it helps to maintain proteostasis in mitochondria. How ATAD1 tackles the energetic challenge to extract hydrophobic membrane proteins from the lipid bilayer and what structural features adapt ATAD1 for its particular function has remained a mystery. Previously, we determined the structure of Msp1 in complex with a peptide substrate (Wang et al., 2020). The structure showed that Msp1’s mechanism follows the general principle established for AAA proteins while adopting several structural features that specialize it for its function. We used the yeast growth assay to test the function of key amino acids within these structural elements. In this work, we determined the cryo-EM structures of the human ATAD1 in complex with a peptide substrate at near atomic resolution. The structures show that phylogenetically conserved structural elements adapt ATAD1 for its function while generally adopting a conserved mechanism shared by many AAA proteins. ATAD1’s distinguishing features include an abundance of aromatic amino acids that line the central pore proposed to give ATAD1 a firm grip on its substrate and a short α-helix at the C-terminus that strongly facilitates ATAD1’s oligomerization. We also developed a microscopy-based assay reporting on protein mislocalization, with which we directly assessed ATAD1’s activity in live cells.
A lack of repeatability creates the illusion of a trade-off between basal and plastic cold tolerance
Authors: O’Neill Erica , Davis Hannah E. , MacMillan Heath A. 
Published: September 2021

AbstractThe thermotolerance-plasticity trade-off hypothesis predicts that ectotherms with greater basal thermal tolerance have a lower acclimation capacity. This hypothesis has been tested at both high and low temperatures but the results often conflict. If basal tolerance constrains plasticity (e.g. through shared mechanisms that create physiological constraints), it should be evident at the level of the individual, provided the trait measured is repeatable. Here, we used chill-coma onset temperature and chill-coma recovery time (CCO and CCRT; non-lethal thermal limits) to quantify cold tolerance of Drosophila melanogaster across two trials (pre- and post-acclimation). Cold acclimation improved cold tolerance, as expected, but individual measurements of CCO and CCRT in non-acclimated flies were not (or only slightly) repeatable. Surprisingly, however, there was still a strong correlation between basal tolerance and plasticity in cold-acclimated flies. We argue that this relationship is a statistical artefact (specifically, a manifestation of regression to the mean; RTM) and does not reflect a true trade-off or physiological constraint. Thermal tolerance trade-off patterns in previous studies that used similar methodology are thus likely to be impacted by RTM. Moving forward, controlling and/or correcting for RTM effects is critical to determining whether such a trade-off or physiological constraint truly exists.
RNA helicase DDX6 in P-bodies is essential for the assembly of stress granules
Authors: Majerciak Vladimir , Zhou Tongqing , Zheng Zhi-Ming 
Published: September 2021

SummaryTwo prominent cytoplasmic RNA granules, ubiquitous RNA-processing bodies (PB) and inducible stress granules (SG), regulate storage of translationally arrested mRNAs and are intimately related. In this study, we found the dependence of SG formation on PB in the cells under arsenite (ARS) stress, but not the other way around. GW182, 4E-T and DDX6 essential for PB formation differentially affect SG formation in the cells under ARS stress, with DDX6 being the most prominent. The cells with DDX6 deficiency display irregular shape of SG which could be rescued by ectopic wt DDX6, but not its helicase mutant E247A DDX6, which induces SG in the cells without stress, indicating that DDX6 helicase activity is essential for PB, but suppressive for SG. DDX6’s dual roles are independent of DDX6 interactors EDC3, CNOT1, and PAT1B. This study provides a conceptual advance of how DDX6 involves in the biogenesis of PB and SG.HighlightsPB act as the seeds for SG nucleationPB components colocalize with SGDDX6 plays a critical role in biogenesis of both PB and SGDDX6 helicase activity prevents SG formation in normal cells
Endothelial PHD2 Deficiency Induces Nitrative Stress via Suppression of Caveolin-1 in Pulmonary Arterial Hypertension
Authors: Liu Bin , Peng Yi , Yi Dan , Dai Jingbo , Vanderpool Rebecca , Zhu Maggie M. , Dai Zhiyu , Zhao You-Yang 
Published: September 2021

AbstractNitrative stress is a characteristic feature of the pathology of human pulmonary arterial hypertension (PAH). However, the role of nitrative stress in the pathogenesis of obliterative vascular remolding and severe PAH remains largely unclear. Our recent studies identified a novel mouse model (Egln1Tie2Cre, Egln1 encoding prolyl hydroxylase 2 [PHD2]) with obliterative vascular remodeling and right heart failure, which provides us an excellent model to study the role of nitrative stress in obliterative vascular remodeling. Here we show that nitrative stress was markedly elevated whereas endothelial Caveolin-1 (Cav1) expression was suppressed in the lungs of Egln1Tie2Cre mice. Treatment with a superoxide dismutase mimetic, manganese (III) tetrakis (1-methyl-4-pyridyl) porphyrin pentachloride (MnTmPyP, also known as a peroxynitrite scavenger) treatment inhibited obliterative pulmonary vascular remodeling and attenuated severe PAH in Egln1Tie2Cre mice. Genetic restoration of endothelial Cav1 expression in Egln1Tie2Cre mice normalized nitrative stress, reduced PAH and improved right heart function. These data suggest that suppression of endothelial Cav1 expression secondary to PHD2 deficiency augments nitrative stress, which contributes to obliterative vascular remodeling and severe PAH. Thus, reactive oxygen/nitrogen species scavenger might have great therapeutic potential for the inhibition of obliterative vascular remodeling and severe PAH.
Structure insights of the human peroxisomal ABC transporter ALDP
Authors: Jia Yutian , Zhang Yanming , Lei Jianlin , Yang Guanghui 
Published: September 2021

AbstractAdrenoleukodystrophy protein (ALDP) is responsible for the transport of free very-long-chain fatty acids (VLCFAs) and corresponding CoA-esters across the peroxisomal membrane. ALDP belongs to the ATP-binding cassette sub-family D, which is also named as ABCD1. Dysfunction of ALDP leads to peroxisomal metabolic disorder exemplified by X-linked adrenoleukodystrophy (ALD). Hundreds of ALD-causing mutations are identified on ALDP. However, the pathogenic mechanisms of these mutations are restricted to clinical description due to limited structural information. Furthermore, ALDP plays a role in myelin maintenance, which is tightly associated with axon regeneration. Here we report the cryo-electron microscopy (cryo-EM) structure of human ALDP with nominal resolution of 3.4 Å in nucleotide free state. The structure of ALDP exhibits a typical assembly of ABC transporters. The nucleotide binding domains (NBDs) displays a ligand free state. ALDP exhibits an inward-open conformation to the cytosol. A short helix is located at the peroxisomal side, which is different from other three members of ABCD transporters. The two transmembrane domains (TMDs) of ALDP form a cavity, in which two lipid-like densities can be recognized as the head group of an coenzyme-A ester of a lipid. This structure provides a framework for understanding the working mechanism of ALDP and classification of the disease-causing mutations.
DHODH is an independent prognostic marker and potent therapeutic target in neuroblastoma
Authors: Olsen Thale Kristin , Dyberg Cecilia , Embaie Bethel , Alchahin Adele , Milosevic Jelena , Otte Jörg , Tümmler Conny , Myrberg Ida Hed , Westerhout Ellen M. , Koster Jan , Versteeg Rogier , Kogner Per , Johnsen John Inge , Sykes David B. , Baryawno Ninib 
Published: September 2021

ABSTRACTDespite intensive therapy, children with high-risk neuroblastoma are at risk of treatment failure. We applied a pan-cancer, multi-omic system approach to evaluate metabolic vulnerabilities in human neuroblastoma. By combining metabolomics, CRISPR screen and gene expression data from more than 700 solid tumor cell lines, we identified DHODH, a critical enzyme in pyrimidine synthesis, as a potential novel treatment target in neuroblastoma. Of note, DHODH inhibition is currently under clinical investigation in patients with hematologic malignancies. In neuroblastoma, DHODH expression was identified as an independent risk factor for aggressive disease, and high DHODH levels correlated to worse overall and event-free survival. A subset of high-risk neuroblastoma tumors with the highest DHODH expression was associated with a dismal prognosis, with a 5-year survival of less than 10%. In neuroblastoma cell lines, DHODH gene dependency was found to correlate with MYCN dependency, rendering these cell lines highly sensitive to DHODH inhibition in vitro. In xenograft and transgenic neuroblastoma mouse models, tumor growth was dramatically reduced, and survival extended following treatment with the DHODH inhibitor brequinar. A combination of brequinar and temozolomide cured the majority of transgenic TH-MYCN neuroblastoma mice, indicating a highly active clinical combination therapy with curative potential. Overall, DHODH inhibition combined with temozolomde has clear therapeutic potential in neuroblastoma and we propose this combination as a candidate for clinical testing.
LIGHTHOUSE illuminates therapeutics for a variety of diseases including COVID-19
Authors: Shimizu Hideyuki , Kodama Manabu , Matsumoto Masaki , Orba Yasuko , Sasaki Michihito , Sato Akihiko , Sawa Hirofumi , Nakayama Keiichi I. 
Published: September 2021

AbstractOne of the bottlenecks in the application of basic research findings to patients is the enormous cost, time, and effort required for high-throughput screening of potential drugs for given therapeutic targets. Here we have developed LIGHTHOUSE, a graph-based deep learning approach for discovery of the hidden principles underlying the association of small-molecule compounds with target proteins. Without any 3D structural information for proteins or chemicals, LIGHTHOUSE estimates protein-compound scores that incorporate known evolutionary relations and available experimental data. It identified novel therapeutics for cancer, lifestyle-related disease, and bacterial infection. Moreover, LIGHTHOUSE predicted ethoxzolamide as a therapeutic for coronavirus disease 2019 (COVID-19), and this agent was indeed effective against alpha, beta, gamma, and delta variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that are rampant worldwide. We envision that LIGHTHOUSE will bring about a paradigm shift in translational medicine, providing a bridge from bench side to bedside.
Overlap of anxiety, depression, irritability and aggressiveness in autism spectrum disorder: an exploratory study using cluster analysis
Authors: Jean Francois A.M. , Jouni Ali , Bouvard Manuel P. , Camelot Guillaume , Beggiato Anita , Scheid Isabelle , Gaman Alexandru , Bouquet Celine , Ly-Le Moal Myryam , Houenou Josselin , Delorme Richard , Leboyer Marion , Amestoy Anouck 
Published: September 2021

Purpose
This study aims to explore the overlap between symptoms of depression, anxiety, irritability and aggressiveness in autism spectrum disorder (ASD), to measure specific and idiosyncratic emotional responses.

Design/methodology/approach
A total of 42 high functioning adolescents and adults, between 12 and 39 years old, meeting the diagnostic and statistical manual of mental disorders – 5 criteria for ASD were selected from the InFoR Autism cohort. Data were analyzed in an exploratory way using Hill and Smith and K-medoids cluster analysis.

Findings
The authors found an aggregation of anxiety, depression, aggressive behaviors and irritability. Cluster analysis was maximized for two groups with 17 and 25 participants, respectively. The first group was characterized by high levels of symptoms of irritability, aggressiveness, hyperactivity and intermediate levels of anxiety and depression. In the first group, participants had significantly higher levels of autistic symptoms considering the social responsiveness scale and repetitive behavior scale-revised scales (relatives’ reports) suggesting that a particular group of subjects with a high level of ASD specific symptoms may express anxiety and depression in a specific way based on externalizing behaviors in addition to the common mood and anxiety symptoms.

Research limitations/implications
Improved understanding of the aggregation of externalized symptoms with symptoms of anxiety and mood disorders in ASD should lead to a better understanding of the underlying mechanisms related to emotion dysregulation in ASD.

Practical implications
Improved knowledge of the symptoms could lead to enhanced detection of psychiatric comorbidities in ASD.

Originality/value
The study was based on a transdiagnostic approach of psychiatric symptoms in individuals with ASD. Aggregation and clustering analysis was used to explore naive patterns of these psychiatric symptoms.
Journey of customers in this digital era: Understanding the role of artificial intelligence technologies in user engagement and conversion
Authors: Bag Surajit , Srivastava Gautam , Bashir Md Mamoon Al , Kumari Sushma , Giannakis Mihalis , Chowdhury Abdul Hannan 
Published: September 2021

PurposeThe first research objective is to understand the role of digital [artificial intelligence (AI)] technologies on user engagement and conversion that has resulted in high online activities and increased online sales in current times in India. In addition, combined with changes such as social distancing and lockdown due to the COVID-19 pandemic, digital disruption has largely impacted the old ways of communication both at the individual and organizational levels, ultimately resulting in prominent social change. While interacting in the virtual world, this change is more noticeable. Therefore, the second research objective is to examine if a satisfying experience during online shopping leads to repurchase intention.Design/methodology/approachUsing primary data collected from consumers in a developing economy (India), we tested the theoretical model to further extend the theoretical debate in consumer research.FindingsThis study empirically tests and further establishes that deploying AI technologies have a positive relationship with user engagement and conversion. Further, conversion leads to satisfying user experience. Finally, the relationship between satisfying user experience and repurchase intention is also found to be significant.Originality/valueThe uniqueness of this study is that it tests few key relationships related to user engagement during this uncertain period (COVID-19 pandemic) and examines the underlying mechanism which leads to increase in online sales.
Labor lawsuits and debt maturity
Authors: Unsal Omer 
Published: September 2021

PurposeThis paper aims to investigate how firms’ relationships with employees define their debt maturity. The authors empirically test the role of employee litigations in influencing firms’ choice of short-term versus long-term debt. The authors study employee relations by analyzing the importance of the workplace environment on capital structure.Design/methodology/approachThe author’s test hypotheses using a sample of US publicly traded firms between 2000 and 2017, including 3,056 unique firms with 4,256 unique chief executive officer, adopting the fixed effect panel model.FindingsThe authors document that employee litigations have a significant negative effect on the use of short-term debt and a significant positive affect on long-term debt. Employee litigations, along with legal fees, outcomes and charging parties, matter the most in explaining debt maturity. In addition, frequently sued firms abandon the short-term debt market and use less shareholders’ equity to finance their operations while relying more on the longer debt market.Originality/valueTo the best of the authors’ knowledge, this is the first study to examine the role of employee mistreatment in debt maturity choice. The study extends the lawsuit and finance literature by examining unique, hand-collected data sets of employee lawsuits, allegations, violations, settlements, charging parties, case outcomes and case durations.