bluuebunny/crossref_metadata_2025_split huggingface dataset:
ROS induction as a strategy to target persister cancer cells with low metabolic activity in NRAS mutated melanoma
Authors: Eichhoff Ossia M. , Stoffel Corinne I. , Käsler Jan , Briker Luzia , Turko Patrick , Karsai Gergely , Zila Nina , Paulitschke Verena , Cheng Phil F. , Leitner Alexander , Bileck Andrea , Zamboni Nicola , Irmisch Anja , Balazs Zsolt , Tastanova Aizhan , Pascoal Susana , Johansen Pål , Wegmann Rebekka , Mena Julien , Othman Alaa , Viswanathan Vasanthi S. , Wenzina Judith , Aloia Andrea , Saltari Annalisa , Dzung Andreas ,   TuPro Consortium, Krauthammer Michael , Schreiber Stuart L. , Hornemann Thorsten , Distel Martin , Snijder Berend , Dummer Reinhard , Levesque Mitchell P. 
Published: October 2022

AbstractMetabolic reprogramming is an emerging hallmark of resistance to cancer therapy but may generate vulnerabilities that can be targeted with small molecules. Multi-omics analysis revealed that NRAS-mutated melanoma cells with a mesenchymal transcriptional profile adopt a quiescent metabolic program to resist cellular stress response induced by MEK-inhibitor resistance. However, as a result of elevated baseline ROS levels, these cells become highly sensitive to ROS induction.In vivoxenograft experiments and single-cell RNA sequencing demonstrated that intra-tumor heterogeneity requires the combination of a ROS-inducer and a MEK-inhibitor to target both tumor growth and metastasis. Byex vivopharmacoscopy of 62 human metastatic melanomas, we found that MEK-inhibitor resistant tumors significantly benefitted from the combination therapy.Finally, we profiled 486 cancer cell lines and revealed that oxidative stress responses and translational suppression are biomarkers of ROS-inducer sensitivity, independent of cancer indication. These findings link transcriptional plasticity to a metabolic phenotype that can be inhibited by ROS-inducers in melanoma and other cancers.Statement of SignificanceTargeted-therapy resistance in cancer arises from genetic selection and both transcriptional and metabolic adaptation. We show that metabolic reprogramming sensitizes resistant cells to ROS-induction in combination with pathway inhibitors. Predictive biomarkers of metabolic sensitivity to ROS-inducing agents were identified in many cancer entities, highlighting the generalizability of this treatment approach.Graphical summary
High-resolution promoter interaction analysis in Type 3 Innate Lymphoid Cells implicates Batten Disease geneCLN3in Crohn’s Disease aetiology
Authors: Malysheva Valeriya , Ray-Jones Helen , Cazares Tareian A. , Clay Owen , Ohayon David , Artemov Pavel , Wayman Joseph A. , Rosa Monica Della , Petitjean Carmen , Booth Clarissa , Ellaway Joseph I.J. , Orchard William R. , Chen Xiaoting , Parameswaran Sreeja , Nagano Takashi , Fraser Peter , Schoenfelder Stefan , Weirauch Matthew T. , Kottyan Leah C. , Smith David F. , Powell Nick , Weimer Jill M. , Wallace Chris , Miraldi Emily R. , Waggoner Stephen , Spivakov Mikhail 
Published: October 2022

AbstractInnate lymphoid cells (ILCs) are rare tissue-resident “helper” lymphocytes that do not express diversified antigen receptors. Type 3 ILCs (ILC3s) are an important class of these cells enriched in the respiratory and intestinal mucosa, where they regulate inflammation and mucosal homeostasis. To gain insight into the cis-regulatory circuitries underlying ILC3 function, we used high-resolution Capture Hi-C to profile promoter-anchored chromosomal contacts in human primary ILC3s. Combining significant interaction detection with the Activity-By-Contact approach adapted to Capture Hi-C, we reveal a multitude of contacts between promoters and distal regulatory elements and obtain evidence for distinct regulatory wiring of alternative promoters. We find that promoter-interacting regions in ILC3s are enriched for genetic variants associated with multiple immune diseases. Focusing on Crohn’s disease (CD), in which ILC3s are established mediators, we devised a Bayesian approach that incorporates multivariate fine-mapping to link CD-associated genetic variants with putative target genes. We identify known and previously unimplicated genes in conferring genetic risk of CD through activity in ILC3s. This includes the CLN3gene that is mutated in most cases of the neurodegenerative disorder Batten disease. UsingCln3mutant mice, we show that CLN3 is a putative negative regulator of IL-17 production in an inflammatory subset of ILC3s. This finding suggests a functional role for CLN3 in ILC3 biology, with mechanistic implications for Crohn’s and Batten diseases.
Thermally Reversible Pattern Formation in Arrays of Molecular Rotors
Authors: DeLuca Marcello , Pfeifer Wolfgang G. , Randoing Benjamin , Huang Chao-Min , Poirier Michael G. , Castro Carlos E. , Arya Gaurav 
Published: October 2022

ABSTRACTControl over the mesoscale to microscale patterning of materials is of great interest to the soft matter community. Inspired by DNA origami rotors, we introduce a 2D nearest-neighbor lattice of spinning rotors that exhibit discrete orientational states and interactions with their neighbors. Monte Carlo simulations of rotor lattices reveal that they exhibit a variety of interesting ordering behaviors and morphologies that can be modulated through rotor design parameters. The rotor arrays exhibit diverse patterns including closed loops, radiating loops, and bricklayer structures in their ordered states. They exhibit specific heat peaks at very low temperatures for small system sizes, and some systems exhibit multiple order-disorder transitions depending on inter-rotor interaction design. We devise an energy-based order parameter and showviaumbrella sampling and histogram reweighting that this order parameter captures well the order-disorder transitions occurring in these systems. We fabricate real DNA origami rotors which themselves can orderviaprogrammable DNA base-pairing interactions and demonstrate both ordered and disordered phases, illustrating how rotor lattices may be realized experimentally and used for responsive organization. This work establishes the feasibility of realizing structural nanomaterials that exhibit locally mediated microscale patterns which could have applications in sensing and precision surface patterning.
Effect ofF. mosseaeon the expression of genes and proteins about sulfur nutrition in the continuous crop soybean roots
Authors: Zhang Xueqi , Lu Chengcheng , Liu Ronglin , Sun Zixin , Cai Baiyan 
Published: October 2022

ABSTRACTSoybean is a sulfur-loving oilseed crop, and continuous cropping can lead to soil sulfur deficiency, which can inhibit the growth and quality of soybean. This experiment used transcriptomic and proteomic sequencing techniques to analyse the changes in the expression of functional genes and related proteins in the root system of continuously cropped soybean and to reveal the molecular mechanism ofF. mosseaeinoculation on the soybean root system in response to sulfur nutrient supply at the molecular level. It was thus demonstrated thatF. mosseaecould enhance the uptake and transport of soil sulfur in continuously cropped soybean. This study, therefore, provides a theoretical basis for the application ofF. mosseaeas a biofertilizer in soybean production on sulfur-deficient soils.One-sentence summaryF. mosseaeaffects soybean genes and proteins at the transcriptome and proteome levels.
ComprehensiveSMN1andSMN2profiling for spinal muscular atrophy analysis using long-read PacBio HiFi sequencing
Authors: Chen Xiao , Harting John , Farrow Emily , Thiffault Isabelle , Kasperaviciute Dalia ,   Genomics England Research Consortium, Hoischen Alexander , Gilissen Christian , Pastinen Tomi , Eberle Michael A 
Published: October 2022

AbstractSpinal muscular atrophy, a leading cause of early infant death, is caused by biallelic mutations of theSMN1gene. Sequence analysis ofSMN1is challenging due to high sequence similarity with its paralogSMN2. Both genes have variable copy numbers across populations. Furthermore, without pedigree information, it is impossible to identify silent carriers (2+0) with two copies ofSMN1on one chromosome and zero copies on the other. We developed Paraphase, an informatics method that identifies full-lengthSMN1andSMN2haplotypes, determines the gene copy numbers and calls phased variants using long-read PacBio HiFi data. TheSMN1andSMN2copy number calls by Paraphase are highly concordant with orthogonal methods (99.2% forSMN1and 100% forSMN2). We applied Paraphase to 438 samples across five ethnic populations to conduct a population-wide haplotype analysis of these highly homologous genes. We identified majorSMN1andSMN2haplogroups and characterized their co-segregation through pedigree-based analyses. We identified twoSMN1haplotypes that form a common two-copySMN1allele in African populations. Testing positive for these two haplotypes in an individual with two copies ofSMN1gives a silent carrier risk of 88.5%, which is significantly higher than the currently used marker (1.7-3.0%). Extending beyond simple copy number testing, Paraphase can detect pathogenic variants and enable potential haplotype-based screening of silent carriers through statistical phasing of haplotypes into alleles. Future analysis of larger population data will allow identification of more diverse haplotypes and genetic markers for silent carriers.
Evolutionary blocks to anthocyanin accumulation and the loss of an anthocyanin carrier protein in betalain-pigmented Caryophyllales
Authors: Pucker Boas , Walker-Hale Nathanael , Yim Won C. , Cushman John , Crum Alexandra , Yang Ya , Brockington Samuel 
Published: October 2022

SUMMARY◻The order Caryophyllales exhibits complex pigment evolution, with mutual exclusion of anthocyanin and betalain pigments. Given recent evidence for multiple shifts to betalain pigmentation, we re-evaluated potential mechanisms underpinning the exclusion of anthocyanins from betalain-pigmented lineages.◻We examined the evolution of the flavonoid pathway using transcriptomic and genomic datasets covering 309 species in 31 families. Orthologs and paralogs of known flavonoid synthesis genes were identified by sequence similarity, with gene duplication and gene loss inferred by phylogenetic and syntenic analysis. Relative transcript abundances were assessed to reveal broad-scale gene expression changes between betalain- and anthocyanin-pigmented lineages.◻Most flavonoid genes are retained and transcribed in betalain-pigmented lineages, and many also show evidence of extensive gene duplication within betalain-pigmented lineages. However, expression of several flavonoid genes is reduced in betalain-pigmented lineages, especially the late-stage genes dihydroflavonol 4-reductase (DFR) and anthocyanidin synthase (ANS). Notably flavonoid 3′,5′-hydroxylase (F3′5′H) homologs have been repeatedly lost in belatain-pigmented lineages, and Anthocyanin9 (AN9) homologs are undetectable in any betalain-pigmented lineages.◻Down-regulation ofANSandDFRhomolog expression (limiting synthesis) and reiterative loss ofAN9homologs (limiting transport), coincident with multiple shifts to betalain pigmentation, are likely crucial the loss of anthocyanins in betalain-pigmented Caryophyllales.
Prediction and scanning of IL-5 inducing peptides using alignment-free and alignment-based method
Authors: Devi Naorem Leimarembi , Sharma Neelam , Raghava Gajendra P. S. 
Published: October 2022

AbstractInterleukin-5 (IL-5) is the key cytokine produced by T-helper, eosinophils, mast and basophils cells. It can act as an enticing therapeutic target due to its pivotal role in several eosinophil-mediated diseases. Though numerous methods have been developed to predict HLA binders and cytokines-inducing peptides, no method was developed for predicting IL-5 inducing peptides. All models in this study have been trained, tested and validated on experimentally validated 1907 IL-5 inducing and 7759 non-IL-5 inducing peptides obtained from IEDB. First, alignment-based methods have been developed using similarity and motif search. These alignment-based methods provide high precision but poor coverage. In order to overcome this limitation, we developed machine learning-based models for predicting IL-5 inducing peptides using a wide range of peptide features. Our random-forest model developed using selected 250 dipeptides achieved the highest performance among alignment-free methods with AUC 0.75 and MCC 0.29 on validation dataset. In order to improve the performance, we developed an ensemble or hybrid method that combined alignment-based and alignment-free methods. Our hybrid method achieved AUC 0.94 with MCC 0.60 on validation/ independent dataset. The best model developed in this study has been incorporated in the web server IL5pred (https://webs.iiitd.edu.in/raghava/il5pred/).Key PointsIL-5 is a regulatory cytokine that plays a vital role in eosinophil-mediated diseasesBLAST-based similarity search against IL-5 inducing peptides was employedA hybrid approach combines alignment-based and alignment-free methodsAlignment-free models are based on machine learning techniquesA web server ‘IL5pred’ and its standalone software have been developedAuthors’ BiographyDr. Naorem Leimarembi Devi is currently working as a DBT-Research Associate in Department of Computational Biology, Indraprastha Institute of Information Technology, New Delhi, India.Neelam Sharma is pursuing her Ph.D. in Computational Biology from the Department of Computational Biology, Indraprastha Institute of Information Technology, New Delhi, India.Prof. G.P.S. Raghava is currently working as Professor and Head of Department of Computational Biology, Indraprastha Institute of Information Technology, New Delhi, India.
Antimicrobial resistance ofEnterococcus cecorum: ECOFF determination
Authors: Laurentie Jeanne , Mourand Gwenaelle , Grippon Pauline , Furlan Sylviane , Chauvin Claire , Jouy Eric , Serror Pascale , Kempf Isabelle 
Published: October 2022

ABSTRACTEnterococcus cecorum, a commensal Gram-positive bacterium of the chicken gut, has emerged as a worldwide cause of lameness in poultry, particularly in fast-growing broilers. It is responsible for osteomyelitis, spondylitis and femoral head necrosis, causing animal suffering, mortality and antimicrobial use. Research on the antimicrobial resistance ofE. cecorumclinical isolates in France is scarce, and epidemiological cut-off (ECOFF) values unknown. To determine tentative ECOFF (COWT) values forE. cecorumand to investigate the antimicrobial resistance patterns of isolates from mainly French broilers, we tested the susceptibility of a collection of commensal and clinical isolates (n=208) to 29 antimicrobials by the disc diffusion (DD) method. We also determined the minimum inhibitory concentrations (MICs) of 23 antimicrobials by the broth micro-dilution method. To detect chromosomal mutations conferring antimicrobial resistance, we investigated the genomes of 118E. cecorumisolates mainly obtained from infectious sites and previously described in the literature. We determined the COWTvalues for more than 20 antimicrobials and identified two chromosomal mutations explaining fluoroquinolone resistance. The DD method appears better suited for detectingE. cecorumantimicrobial resistance. Although tetracycline and erythromycin resistances were persistent in clinical and non-clinical isolates, we found little or no resistance to medically important antimicrobials.
A new method for a priori practical identifiability
Authors: Thompson Peter , Andersson Benjamin Jan , Sundqvist Nicolas , Cedersund Gunnar 
Published: October 2022

AbstractBackground and objectivePractical identifiability analysis – to determine whether a model property can be determined from given data – is central to model-based data analysis in biomedicine. The main approaches used today all require that the coverage of the parameter space be exhaustive, which is usually not possible. An attractive alternative could be to use structural identifiability methods, since they do not need such a parameter coverage. However, current structural methods are unsuited for practical identifiability analysis, since they assume that all higher-order derivatives of the measured variables are available, and we do not know the implications of this assumption. Herein, we provide new definitions and methods that allow for this assumption to be relaxed.MethodsThe new methods and definitions are valid for ordinary differential equations, and use a combination of differential algebra and modulus calculus, implemented in Maple.ResultsWe introduce the concept of (ν1, …, νm)-identifiability, which differs from previous definitions in that it assumes that only the first νiderivatives of the measurement signalyiare available. This new type of identifiability can be determined using our new algorithm, as is demonstrated by applications to various published biomedical models. Our methods allow for identifiability of not only parameters, but of any model property, i.e. observability. These new results provide further strengthening of conclusions made in previous analysis of these models. Importantly, our analysis can for the first time quantify the impact of the assumption that all derivatives are available in specific examples. If one e.g. assumes that only up to third order derivatives, instead of all derivatives, are available, the number of identifiable parameters drops from 17 to 1 for a Drosophila model, and from 21 to 6 for an NF-κB model. In both these models, the previously obtained identifiability is present only if at least 20 derivatives of all measurement signals are available.ConclusionsOur results demonstrate that the assumption regarding availability of derivatives done in traditional structural identifiability analysis causes a big overestimation regarding the number of parameters that can be estimated. Our new methods and algorithms allow for this assumption to be relaxed, which moves structural identifiability methodology one step closer to practical identifiability analysis.
Linking prokaryotic genome size variation to metabolic potential and environment
Authors: Rodríguez-Gijón Alejandro , Buck Moritz , Andersson Anders F. , Izabel-Shen Dandan , Nascimento Francisco J. A. , Garcia Sarahi L. 
Published: October 2022

ABSTRACTWhile theories and models have appeared to explain genome size as a result of evolutionary processes, little work has shown that genome sizes carry ecological signatures. Our work delves into the ecological implications of microbial genome size variation in benthic and pelagic habitats across environmental gradients of the brackish Baltic Sea. While depth is significantly associated with genome size in benthic and pelagic brackish metagenomes, salinity is only correlated to genome size in benthic metagenomes. Overall, we confirm that prokaryotic genome sizes in Baltic sediments (3.47 Mbp) are significantly bigger than in the water column (2.96 Mbp). While benthic genomes have a higher number of functions than pelagic genomes, the smallest genomes coded for a higher number of module steps per Mbp for most of the functions irrespective of their environment. Some examples of this functions are amino acid metabolism and central carbohydrate metabolism. However, we observed that nitrogen metabolism was almost absent in pelagic genomes and was mostly present in benthic genomes. Finally, we also show that Bacteria inhabiting Baltic sediments and water column not only differ in taxonomy, but also in their metabolic potential, such as the Wood-Ljungdahl pathway or the presence of different hydrogenases. Our work shows how microbial genome size is linked to abiotic factors in the environment, metabolic potential and taxonomic identity of Bacteria and Archaea within aquatic ecosystems.
Progressive decline in the levels of six miRNAs from parents to children in autism
Authors: Rassoulzadegan Minoo , Mehmetbeyoglu Ecmel , Yilmaz Zeynep , Taheri Serpil , Ozkul Yusuf 
Published: October 2022

SummaryThe growing burden of a gradual increase in births of children with autism has placed it at the center of the concerns of major laboratories. We have previously detected a decrease in the levels of six miRNAs (miR-19a-3p, miR-361-5p, miR-3613-3p, miR-150-5p, miR-126-3p, and miR-499a-5p) in parents and their children inherited at a lower level. Here, we suggest that down-regulation of each of these six miRNAs inherited from parents contributes to the development of children with autism. We compare their levels of distribution in each family between the autistic child and siblings. We find that the distribution of levels of these miRNAs in siblings (undiagnosed as autism) is not always higher than in autistic children, but it is at varying levels. These data support a model in which autistic behavior relies on low levels of the six miRNAs expressed in children potentially associated with autistic syndrome (ASD). The intimate link between miRNAs levels and behavioral characteristics suggests possibilities for understanding the basic circuitry involved in autism and thus advancing partial knowledge of brain functions. An early diagnosis of autism helps provide children an environment conducive to their development.Graphical abstract
The male mouse meiotic cilium emanates from the mother centriole at zygotene prior to centrosome duplication
Authors: López-Jiménez P , Pérez-Martín S , Hidalgo I , Garcia-Gonzalo FR , Page J , Gómez R 
Published: October 2022

ABSTRACTCilia are hair-like projections of the plasma membrane with an inner microtubule skeleton known as axoneme. Motile cilia and flagella beat to displace extracellular fluids, playing important roles in the airways and reproductive system, among others. Instead, primary cilia function as cell type-dependent sensory organelles, detecting chemical, mechanical or optical signals from the extracellular environment. Cilia dysfunction is associated with genetic diseases called ciliopathies, and with some types of cancer.Cilia have been recently identified in zebrafish gametogenesis as an important regulator of thebouquetconformation and recombination. However, there is very little information about the structure and functions of cilia in mammalian meiosis. Here we describe the presence of cilia in male mouse meiotic cells. These solitary cilia form transiently in 20% of zygotene spermatocytes and reach considerable lengths (up to 15 μm). CEP164 and CETN3 localization studies indicate that these cilia emanate from the mother centriole, prior to centrosome duplication. In addition, the study of telomeric TFR2 suggests that these cilia are not directly related to thebouquetconformation during early male mouse meiosis. Instead, based on TEX14 labeling of intercellular bridges in spermatocyte cysts, we suggest that mouse meiotic cilia may have sensory roles affecting cyst function during prophase I.
The Network Basis for the Structural Thermostability and the Functional Thermoactivity of Aldolase B
Authors: Wang Guangyu 
Published: October 2022

AbstractThermostability is important for thermoactivity of proteins including enzymes. However, it is still challenging to pinpoint the specific structural factors for different temperature thresholds to initiate their specific structural and functional perturbations. Here, graph theory was used to investigate how the temperature-dependent noncovalent interactions as identified in the structures of aldolase B and its prevalent A149P mutant could form a systematic fluidic grid-like mesh network with topological grids to regulate the structural thermostability and the functional thermoactivity. The results showed that the biggest grid may determine the temperature thresholds for the changes in their secondary and tertiary structures and specific catalytic activities. Further, a highly conserved thermostable grid may serve as an anchor to secure the flexible active site to achieve the specific thermoactivity. Finally, higher grid-based systematic thermal instability may disfavor the thermoactivity. Thus, this computational study may provide critical clues for the structural thermostability and the functional thermoactivity of proteins including enzymes.