bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tximeta: reference sequence checksums for provenance identification in RNA-seq
Authors: Love Michael I. , Soneson Charlotte , Hickey Peter F. , Johnson Lisa K. , Pierce N. Tessa , Shepherd Lori , Morgan Martin , Patro Rob 
Published: September 2019

AbstractCorrect annotation metadata is critical for reproducible and accurate RNA-seq analysis. When files are shared publicly or among collaborators with incorrect or missing annotation metadata, it becomes difficult or impossible to reproduce bioinformatic analyses from raw data. It also makes it more difficult to locate the transcriptomic features, such as transcripts or genes, in their proper genomic context, which is necessary for overlapping expression data with other datasets. We provide a solution in the form of an R/Bioconductor package tximeta that performs numerous annotation and metadata gathering tasks automatically on behalf of users during the import of transcript quantification files. The correct reference transcriptome is identified via a hashed checksum stored in the quantification output, and key transcript databases are downloaded and cached locally. The computational paradigm of automatically adding annotation metadata based on reference sequence checksums can greatly facilitate genomic workflows, by helping to reduce overhead during bioinformatic analyses, preventing costly bioinformatic mistakes, and promoting computational reproducibility. The tximeta package is available athttps://bioconductor.org/packages/tximeta.
UVB mutagenesis differs in NRAS- and BRAF-mutant mouse models of melanoma
Authors: Bowman Robert L. , Hennessey Rebecca C. , Tallman David A. , Weiss Tirzah J. , Crawford Emma R. , Murphy Brandon M. , Webb Amy , Zhang Souhui , La Perle Krista M. D. , Burd Craig J. , Levine Ross L. , Shain A. Hunter , Burd Christin E. 
Published: September 2019

ABSTRACTBRAF-mutant melanomas are more likely than NRAS-mutant melanomas to arise in anatomical locations protected from chronic sun damage. We hypothesized that this discrepancy in tumor location is a consequence of the differential sensitivity of BRAF and NRAS-mutant melanocytes to ultraviolet light (UV)-mediated carcinogenesis. We tested this hypothesis by comparing the mutagenic consequences of a single, narrow band ultraviolet-A (UVA; 320-400nm) or ultraviolet-B (UVB; 280-320nm) exposure in mouse models predisposed to Braf- or Nras-mutant melanoma. Exposures approximated the amount of UVA or UVB energy contained in ~40 minutes of summer sunlight. Tumor onset was accelerated in all UVB-, but only half of UVA- irradiated mice as compared to unirradiated controls. Melanomas from both mouse models, harbored recurrent mutations affecting the RING domain of MAP3K1 and Actin-binding domain of Filamin A irrespective of UV status. Melanomas from UVB-irradiated, Braf-mutant mice averaged twice as many SNVs (1,025 vs. 435) and five times as many dipyrimidine variants (33.3 vs. 5.7) than tumors from similarly irradiated Nras-mutant mice. We identified a mutational signature enriched in UVB-accelerated tumors which mirrored COSMIC signatures associated with human skin cancer. Notably, this signature was enriched to a greater extent in Braf- than Nras-mutant murine melanomas. These data suggest that oncogenic BRAF may enhance UVB carcinogenesis to promote melanoma formation at anatomic sites with low or intermittent sun exposure.
Structural insights into the mammalian late-stage initiation complexes
Authors: Simonetti Angelita , Guca Ewelina , Bochler Anthony , Kuhn Lauriane , Hashem Yaser 
Published: September 2019

SUMMARYIn higher eukaryotes, the mRNA sequence in direct vicinity of the start codon, called the Kozak sequence (CRCCaugG, where R is a purine), is known to influence the rate of the initiation process. However, the molecular basis underlying its role remains poorly understood. Here, we present the cryo-electron microscopy (cryo-EM) structures of mammalian late-stage 48S initiation complexes (LS48S IC) in the presence of two different native mRNA sequences, β-globin and histone 4 (H4) at overall resolution of 3Å and 3.5Å, respectively. Our high-resolution structures unravel key interactions from the mRNA to eukaryotic initiation factors (eIF): 1A, 2, 3, 18S rRNA, and several 40S ribosomal proteins. In addition, we were able to study the structural role of ABCE1 in the formation of native 48S ICs. Our results reveal a comprehensive map of the ribosome/eIFs –mRNA and –tRNA interactions and suggest the impact of mRNA sequence on the structure of the LS48S IC.
Gene duplications trace mitochondria to the onset of eukaryote complexity
Authors: Tria Fernando D. K. , Brückner Julia , Skejo Josip , Xavier Joana C. , Zimorski Verena , Gould Sven B. , Garg Sriram G. , Martin William F. 
Published: September 2019

AbstractThe last eukaryote common ancestor (LECA) lived 1.6 billion years ago1,2. It possessed nuclei, sex, an endomembrane system, mitochondria, and all key traits that make eukaryotic cells more complex than their prokaryotic ancestors2–6. The closest known relatives of the host lineage that acquired the mitochondrion are, however, small obligately symbiotic archaea that lack any semblance of eukaryotic cell complexity7. Although the steep evolutionary grade separating prokaryotes from eukaryotes increasingly implicates mitochondrial symbiosis at eukaryote origin4,7, the timing and evolutionary significance of mitochondrial origin remains debated. Gradualist theories contend that eukaryotes arose from archaea by slow accumulation of eukaryotic traits8–10 with mitochondria arriving late11, while symbiotic theories have it that mitochondria initiated the onset of eukaryote complexity in a non-nucleated archaeal host7 by gene transfers from the organelle4,12–14. The evolutionary process leading to LECA should be recorded in its gene duplications. Among 163,545 duplications in 24,571 gene trees spanning 150 sequenced eukaryotic genomes we identified 713 gene duplication events that occurred in LECA. LECA’s bacterially derived genes were duplicated more frequently than archaeal derived or eukaryote specific genes, reflecting the serial copying15,16 of genes from the mitochondrial endosymbiont to the archaeal host’s chromosomes prior to the onset of eukaryote genome complexity. Bacterial derived genes for mitochondrial functions, lipid synthesis, biosynthesis, as well as core carbon and energy metabolism in LECA were duplicated more often than archaeal derived genes and even more often than eukaryote-specific inventions for endomembrane, cytoskeletal or cell cycle functions. Gene duplications record the sequence of events at LECA’s origin and indicate that recurrent gene transfer from a resident mitochondrial endosymbiont preceded the onset of eukaryotic cellular complexity.
Massive gene presence/absence variation in the mussel genome as an adaptive strategy: first evidence of a pan-genome in Metazoa
Authors: Gerdol Marco , Moreira Rebeca , Cruz Fernando , Gómez-Garrido Jessica , Vlasova Anna , Rosani Umberto , Venier Paola , Naranjo-Ortiz Miguel A. , Murgarella Maria , Balseiro Pablo , Corvelo André , Frias Leonor , Gut Marta , Gabaldón Toni , Pallavicini Alberto , Canchaya Carlos , Novoa Beatriz , Alioto Tyler S. , Posada David , Figueras Antonio 
Published: September 2019

AbstractMussels are ecologically and economically relevant edible marine bivalves, highly invasive and resilient to biotic and abiotic stressors causing recurrent massive mortalities in other species. Here we show that the Mediterranean mussel Mytilus galloprovincialis has a complex pan-genomic architecture, which includes a core set of 45,000 genes shared by all individuals plus a surprisingly high number of dispensable genes (∼15,000). The latter are subject to presence/absence variation (PAV), i.e., they may be entirely missing in a given individual and, when present, they are frequently found as a single copy. The enrichment of dispensable genes in survival functions suggests an adaptive value for PAV, which might be the key to explain the extraordinary capabilities of adaptation and invasiveness of this species. Our study underpins a unique metazoan pan-genome architecture only previously described in prokaryotes and in a few non-metazoan eukaryotes, but that might also characterize other marine invertebrates.Significance statementIn animals, intraspecific genomic diversity is generally thought to derive from relatively small-scale variants, such as single nucleotide polymorphisms, small indels, duplications, inversions and translocations. On the other hand, large-scale structural variations which involve the loss of genomic regions encoding protein-coding genes in some individuals (i.e. presence/absence variation, PAV) have been so far only described in bacteria and, occasionally, in plants and fungi. Here we report the first evidence of a pan-genome in the animal kingdom, revealing that 25% of the genes of the Mediterranean mussel are subject to PAV. We show that this unique feature might have an adaptive value, due to the involvement of dispensable genes in functions related with defense and survival.
Mechanism underlying starvation-dependent modulation of olfactory behavior in Drosophila larva
Authors: Slankster Eryn , Kollala Sai , Baria Dominique , Dailey-Krempel Brianna , Jain Roshni , Odell Seth R. , Mathew Dennis 
Published: September 2019

ABSTRACTStarvation enhances olfactory sensitivity that encourage animals to search for food. The molecular mechanisms that enable sensory neurons to remain flexible and adapt to a particular internal state remain poorly understood. Here, we study the roles of GABA and insulin signaling in starvation-dependent modulation of olfactory sensory neuron (OSN) function in the Drosophila larva. We show that GABAB-receptor and insulin-receptor are necessary for OSN modulation. Using a novel OSN-specific gene expression analysis, we explore downstream targets of insulin signaling in OSNs. Our results strongly suggest that insulin and GABA signaling pathways interact within OSNs and modulate OSN function by impacting olfactory information processing and neurotransmission. We further show that manipulating these signaling pathways specifically in the OSNs impact larval feeding behavior and its body weight. These results challenge the prevailing model of OSN modulation and highlight opportunities to better understand OSN modulation mechanisms and their relationship to animal physiology.
A Non-genetic Mechanism for Chemoresistance in Lung Cancer: The Role of Integrin β4/Paxillin Axis
Authors: Mohanty Atish , Nam Arin , Pozhitkov Alex , Bhattacharya Supriyo , Yang Lu , Nathan Anusha , Wu Xiwei , Srivastava Saumya , Mambetsariev Isa , Nelson Michael , Pangeni Rajendra , Raz Dan , Chen Yihong , He Yanan , Orban John , Subbalakshmi A. R. , Guo Linlin , Nasser Mohd W. , Koczywas Marianna , Batra Surinder K. , Jolly Mohit Kumar , Kulkarni Prakash , Massarelli Erminia , Salgia Ravi 
Published: September 2019

SummaryTumor heterogeneity and cisplatin resistance are a major cause of tumor relapse and poor survival. Here we show that in lung adenocarcinoma (LUAD), paxillin (PXN) and integrin beta 4 (ITGB4) are associated with tumor progression, and cisplatin resistance. Silencing PXN and ITGB4 render cisplatin tolerant cells sensitive, and immunologically neutralizing ITGB4 improves sensitivity. The N-terminal half of PXN is intrinsically disordered and interacts with ITGB4 to regulate expression of USP1 and VDAC1 which are required for maintaining genomic stability and mitochondrial function in LUAD. By virtual screening an FDA-approved compound library, we identified compounds that interact with PXNin silicoand attenuate cisplatin resistance in LUAD cells. RNAseq analysis identified a double negative feedback loop between ITGB4 and microRNA miR-1-3p, suggesting that bistability could lead to stochastic switching between cisplatin-sensitive and resistant states in these cells. The data highlight an alternate, non-genetic, mechanism underlying chemoresistance in lung cancer.
H3K9me2 protects lifespan against the transgenerational burden of germline transcription in C. elegans
Authors: Lee Teresa W. , David Heidi S. , Engstrom Amanda K. , Carpenter Brandon S. , Katz David J. 
Published: September 2019

ABSTRACTDuring active transcription, the COMPASS complex methylates histone H3 at lysine 4 (H3K4me). In Caenorhabditis elegans, mutations in COMPASS subunits, including WDR-5, extend lifespan and enable the inheritance of increased lifespan in wild-type descendants. Here we show that the increased lifespan of wdr-5 mutants is itself a transgenerational trait that manifests after eighteen generations and correlates with changes in the heterochromatin factor H3K9me2. Additionally, we find that wdr-5 mutant longevity and its inheritance requires the H3K9me2 methyltransferase MET-2 and can be recapitulated by a mutation in the putative H3K9me2 demethylase JHDM-1. These data suggest that lifespan is constrained by reduced H3K9me2 due to transcription-coupled H3K4me. wdr-5 mutants alleviate this burden, extending lifespan and enabling the inheritance of increased lifespan. Thus, H3K9me2 functions in the epigenetic establishment and inheritance of a complex trait. Based on this model, we propose that lifespan is limited by the germline in part because germline transcription reduces heterochromatin.
Mechanosensitive regulation of FGFR1 through the MRTF-SRF pathway
Authors: Zonderland Jip , Rezzola Silvia , Moroni Lorenzo 
Published: September 2019

AbstractControlling basic fibroblast growth factor (bFGF) signaling is important for both tissue-engineering purposes, controlling proliferation and differentiation potential, and for cancer biology, influencing tumor progression and metastasis. Here, we observed that human mesenchymal stromal cells (hMSCs) no longer responded to soluble or covalently bound bFGF when cultured on microfibrillar substrates, while fibroblasts did. This correlated with a downregulation of FGF receptor 1 (FGFR1) expression of hMSCs on microfibrillar substrates, compared to hMSCs on conventional tissue culture plastic (TCP). hMSCs also expressed less SRF on ESP scaffolds, compared to TCP, while fibroblasts maintained high FGFR1 and SRF expression. Inhibition of actin-myosin tension or the MRTF/SRF pathway decreased FGFR1 expression in hMSCs, fibroblasts and MG63 osteosarcoma cells. This downregulation was functional, as hMSCs became irresponsive to bFGF in the presence of MRTF/SRF inhibitor. Together, our data show that hMSCs, but not fibroblasts, are irresponsive to bFGF when cultured on microfibrillar susbtrates by downregulation of FGFR1 through the MRTF/SRF pathway. This is the first time FGFR1 expression has been shown to be mechanosensitive and adds to the sparse literature on FGFR1 regulation. These results could open up new targets for cancer treatments and could aid designing tissue engineering constructs that better control cell proliferation.
Learning with naturalistic odor representations in a dynamic model of the Drosophila olfactory system
Authors: Kennedy Ann 
Published: September 2019

AbstractMany odor receptors in the insect olfactory system are broadly tuned, yet insects can form associative memories that are odor-specific. The key site of associative olfactory learning in insects, the mushroom body, contains a population of Kenyon Cells (KCs) that form sparse representations of odor identity and enable associative learning of odors by mushroom body output neurons (MBONs). This architecture is well suited to odor-specific associative learning if KC responses to odors are uncorrelated with each other, however it is unclear whether this hold for actual KC representations of natural odors. We introduce a dynamic model of the Drosophila olfactory system that predicts the responses of KCs to a panel of 110 natural and monomolecular odors, and examine the generalization properties of associative learning in model MBONs. While model KC representations of odors are often quite correlated, we identify mechanisms by which odor-specific associative learning is still possible.
Assessment of enzyme active site positioning and tests of catalytic mechanisms through X-ray-derived conformational ensembles
Authors: Yabukarski Filip , Biel Justin T , Pinney Margaux M , Doukov Tzanko , Powers Alexander S , Fraser James S , Herschlag Daniel 
Published: September 2019

AbstractHow enzymes achieve their enormous rate enhancements remains a central question in biology, and our understanding to date has impacted drug development, influenced enzyme design, and deepened our appreciation of evolutionary processes. While enzymes position catalytic and reactant groups in active sites, physics requires that atoms undergo constant motion. Numerous proposals have invoked positioning or motions as central for enzyme function, but a scarcity of experimental data has limited our understanding of positioning and motion, their relative importance, and their changes through the enzyme’s reaction cycle. To examine positioning and motions and test catalytic proposals, we collected “room temperature” X-ray crystallography data forP. putidaketosteroid isomerase (KSI), and we obtained conformational ensembles for this and a homologous KSI from multiple PDB crystal structures. Ensemble analyses indicated limited change through KSI’s reaction cycle. Active site positioning was on the 1-1.5 Å scale, and was not exceptional compared to non-catalytic groups. The KSI ensembles provided evidence against catalytic proposals invoking oxyanion hole geometric discrimination between the ground state and transition state or highly precise general base positioning. Instead, increasingordecreasing positioning of KSI’s general base reduced catalysis, suggesting optimized Ångstrom-scale conformational heterogeneity that allows KSI to efficiently catalyze multiple reaction steps. Ensemble analyses of surrounding groups for WT and mutant KSIs provided insights into the forces and interactions that allow and limit active site motions. Most generally, this ensemble perspective extends traditional structure–function relationships, providing the basis for a new era of “ensemble–function” interrogation of enzymes.
A pentylenetetrazole-induced kindling zebrafish larval model for evoked recurrent seizures
Authors: Sun Sha , Zhu Chenyanwen , Ma Manxiu , Ni Bing , Chen Lin , Zhu Hongwei , Zuxiang Liu 
Published: September 2019

AbstractBackgroundTransient pentylenetetrazol (PTZ) treatment on zebrafish larvae has been widely accepted a promising animal model for human epilepsy. However, this model is not ideal due to its acuteness and lack of recurrent seizures, which are the key feature of epilepsy in human disease. It is important to develop a more sensitive zebrafish model for epilepsy with well-controlled, predictable, recurrent seizures.New MethodThe new method includes an experimental setup and a treatment protocol. The setup tracks the locomotion activity of up to 48 larvae simultaneously, while a visual stimulus can be presented to each of the 48 animals individually. The protocol treated the larvae through a water bath in 5 mM PTZ while being stimulated with rotating grating stimuli for 1 hour/day from 5 to 7 days postfertilization.ResultsThe setup captured the locomotion activity of zebrafish larvae during visual stimulation. The new protocol generated recurrent responses after flashing lights 4 hours post PTZ treatment. The effects could be suppressed by the anti-epileptic drug valproic acid. The characteristics of the visual stimulus play a major role in this kindling model.Comparisons with Existing MethodsWe compared the proposed method with the transient PTZ model and confirmed that the flashing-light-evoked recurrent seizure is a new feature in addition to the transient changes.ConclusionsThe new method generated non-drug-triggered predictable recurrent seizures in response to intermittent photic stimulation in zebrafish larvae and may serve as a sensitive method for anti-epileptic drug screening or a new research protocol in epilepsy research.
A novel constrained optimization-build method for precision assembly of aircraft engine
Authors: Sun Chuanzhi , Chen Danyang , Li Chengtian , Liu Yongmeng , Liu Zewei , Hu Ming , Tan Jiubin 
Published: September 2019

Purpose
This paper aims to provide a precision assembly method to improve the aircraft engine quality of initial unbalance with the purpose of founding the process for mass eccentricity propagation and demonstration of assembly process. The proposed method can be used for assembly guidance, tolerance allocation and so on, especially for the assembly with a large number of rotors and the assembly requirements of initial unbalance and coaxiality in high precision.

Design/methodology/approach
This paper proposes a constrained optimization-build method to minimize initial unbalance of aircraft engine assembly, which takes amount of unbalance and concentricity of each rotor into account. A constrained nonlinear programming model is extracted by choosing the initial unbalance as the objective function, and choosing the coaxiality and assembly orientations as the nonlinear constraints. The initial unbalance is reduced stage-by-stage by controlling the assembly angle of each rotor.

Findings
The validity and accuracy of the proposed method is verified by the multistage rotors assembly through experiments run with the measuring instruments. Compared with the direct-build method, the initial unbalance of final assembly using proposed method is reduced by 22.2% in four rotors assembly.

Originality/value
Different from the geometric eccentricity propagation control methods to reduce the initial unbalance indirectly, this paper establishes mass eccentric propagation model in multistage rotors assembly of aircraft engine for the first time. It provides a new idea to establish the relationship between the amount of unbalance of each rotor and the initial unbalance of multistage rotors.
Leveraging service design as a multidisciplinary approach to service innovation
Authors: Prestes Joly Maíra , Teixeira Jorge Grenha , Patrício Lia , Sangiorgi Daniela 
Published: September 2019

PurposeService design is a multidisciplinary approach that plays a key role in fostering service innovation. However, the lack of a comprehensive understanding of its multiple perspectives hampers this potential to be realized. Through an activity theory lens, the purpose of this paper is to examine core areas that inform service design, identifying shared concerns and complementary contributions.Design/methodology/approachThe study involved a literature review in two stages, followed by a qualitative study based on selected focus groups. The first literature review identified core areas that contribute to service design. Based on this identification, the second literature review examined 135 references suggested by 13 world-leading researchers in this field. These references were qualitatively analyzed using the NVivo software. Results were validated and complemented by six multidisciplinary focus groups with service research centers in five countries.FindingsSix core areas were identified and characterized as contributing to service design: service research, design, marketing, operations management, information systems and interaction design. Data analysis shows the various goals, objects, approaches and outcomes that multidisciplinary perspectives bring to service design, supporting them to enable service innovation.Practical implicationsThis paper supports service design teams to better communicate and collaborate by providing an in-depth understanding of the multiple contributions they can integrate to create the conditions for new service.Originality/valueThis paper identifies and examines the core areas that inform service design, their shared concerns, complementarities and how they contribute to foster new forms of value co-creation, building a common ground to advance this approach and leverage its impact on service innovation.