bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fides: Reliable Trust-Region Optimization for Parameter Estimation of Ordinary Differential Equation Models
Authors: Fröhlich Fabian , Sorger Peter K. 
Published: May 2021

Ordinary differential equation (ODE) models are widely used to describe biochemical processes, since they effectively represent mass action kinetics. Optimization-based calibration of ODE models on experimental data can be challenging, even for low-dimensional problems. However, reliable model calibration is a prerequisite for uncertainty analysis, model comparison, and biological interpretation. Multiple hypotheses have been advanced to explain why optimization based calibration of biochemical models is challenging, but there are few comprehensive studies that test these hypotheses, likely because tools for performing such studies are also lacking.We implemented an established trust-region method as a modular Python framework (fides) to enable systematic comparison of different approaches to ODE model calibration involving various Hessian approximation schemes. We evaluatedfideson a set of benchmark problems for which real experimental data are available. Unexpectedly, we observed high variability in optimizer performance among different implementations of the same algorithm. Overall,fidesperformed most reliably and efficiently. Our investigation of possible sources of poor optimizer performance identified drawbacks in the widely used Gauss-Newton, BFGS and SR1 Hessian approximations. We address these drawbacks by proposing a novel hybrid Hessian approximation scheme that enhances optimizer performance and outperforms existing hybrid approaches. We expectfidesto be broadly useful for ODE constrained optimization problems and to enable future methods development.Availabilityfidesis published under the permissive BSD-3-Clause license with source code publicly available athttps://github.com/fides-dev/fides. Citeable releases are archived on Zenodo. Code to reproduce results presented in this manuscript is available athttps://github.com/fides-dev/fides-benchmark.
Understanding the complexity of Epimorphic Regeneration in zebrafish: A Transcriptomic and Proteomic approach
Authors: Banu Sarena , Gaur Namami , Nair Sowmya , Ravikrishnan Tanuja , Khan Shahida , Mani Sandhya , Bharathi Swarna , Mandal Komal , Kuram Naga Anusha , Vuppaladadium Sowmya , N. Murthy Ch. Lakshmi , Quoseena Mir , Babu Nukala Sarath , Idris Mohammed M 
Published: May 2021

AbstractGenomic and Proteomic changes play a crucial role in perpetuating regeneration of complex tissues through differentiation and growth. The complex Epimorphic regeneration of zebrafish caudal fin tissue is hasty and absolute. This study was executed to understand the role of various genes/proteins involved in the regeneration of zebrafish caudal fin tissue through differential expression analysis. High throughput transcriptomics analysis involving Next Generation Sequencing approach and iTRAQ based quantitative proteomics analyses were performed on the regenerating tissue samples for various regenerating time points. Based on our study 1408 genes and 661 proteins were found differentially regulated in the regenerating caudal fin tissue for having at least 1-log fold change in their expression at 12hpa, 1, 2, 3 and 7dpa stages against control non-regenerating tissue. Interleukin, SLC, PRMT, HOX, neurotransmitter and several novel genes were found to be associated with regeneration for its differential regulation during the mechanism. Based on the network and pathway analysis the differentially regulated genes and proteins were found allied with activation of cell proliferation, cell viability, cell survival & cell movement and inactivation of organismal death, morbidity, necrosis, death of embryo & cell death. Network pathways such as Cancer & development disorder, Cell signaling molecular transport, organismal injury & abnormalities and Cellular development, growth & proliferation were found most significantly associated with the zebrafish caudal fin regeneration mechanism. This study has mapped a detailed insight of the genes/proteins expression associated with the epimorphic regeneration more profoundly.
Development and Application of Cas13a-based Diagnostic Assay for Neisseria Gonorrhoeae Detection and Identification of Azithromycin Resistance
Authors: Luo Hao , Chen Wentao , Mai Zhida , Lin Xiaomian , Yang Jianjiang , Zeng Lihong , Pan Yuying , Xie Qinghui , Xu Qingqing , Li Xiaoxiao , Liao Yiwen , Feng Zhanqin , Ou Jiangli , Qin Xiaolin , Zheng Heping 
Published: May 2021

AbstractGonorrhea caused by Neisseria gonorrhoeae has spread world-wide. Antimicrobial-resistant strains have emerged to an alarming level to most antibiotics including to the ceftriaxone-azithromycin combination, currently recommended as first-line dual therapy. Rapid testing for antimicrobial resistance will contribute to clinical decision-making for rational drug use and will slow this trend. Herein, we developed a Cas13a-based assay for N. gonorrhoeae detection (porA target) and azithromycin resistance identification (A2059G and C2611T point mutations). We evaluated the sensitivity and specificity of this method, and 10 copies per reaction can be achieved in porA detection and C2611T identification, with no cross-reactions. Comparison of the Cas13a-based assay (porA target) with Roche Cobas 4800 assay (n=23 urine samples) revealed 100% concordance. Isolated N. gonorrhoeae strains were used to validate the identification of A2059G and C2611T resistance mutations. All tested strains (8 A2059G strains, 8 C2611T strains, and 8 wild-type strains) were successfully distinguished by our assay and verified by testing MIC for azithromycin and sequencing the 23S rRNA gene. We adopted lateral flow for the SHERLOCK assay readout, which showed a visible difference between test group and NC group results. To further evaluate the capability of our assay, we tested 27 urethral swabs from patients with urethritis for N. gonorrhoeae detection and azithromycin-resistance identification. Of these, 62.96% (17/27) strains were detected with no mutant strains and confirmed by sequencing. In conclusion, the novel Cas13a-based assay for rapid and accurate N. gonorrhoeae detection combined with azithromycin drug resistance testing is a promising assay for application in clinical practice.
Repurposing of the tamoxifen metabolites to treat methicillin-resistant Staphylococcus epidermidis and vancomycin-resistant Enterococcus faecalis infections
Authors: Miró-Canturri Andrea , Vila-Domínguez Andrea , Ayerbe-Algaba Rafael , Pachón J , Jiménez-Mejías Manuel E. , Smani Younes 
Published: May 2021

AbstractRepurposing drugs provides a new approach to the fight against multidrug-resistant (MDR) bacteria. We have reported that three major tamoxifen metabolites, N-desmethyltamoxifen (DTAM), 4-hydroxytamoxifen (HTAM) and endoxifen (ENDX), presented bactericidal activity against Acinetobacter baumannii and Escherichia coli. Here, we aimed to analyse the activity of a mixture of the three tamoxifen metabolites against methicillin-resistant Staphylococcus epidermidis (MRSE) and Enterococcus spp.MRSE (n=17) and Enterococcus spp. (E. faecalis n=8, and E. faecium n=10) strains were used. MIC of the mixture of DTAM, HTAM and ENDX, and vancomycin were determined by microdilution assay. The bactericidal activity of the three metabolites together and vancomycin against MRSE (SE385 and SE742) and vancomycin-resistant E. faecalis (EVR1 and EVR2) strains was determined by time-kill curve assays. Finally, changes in membrane permeability of SE742 and EVR1 strains were analyzed using fluorescence assays.MIC50 and MIC90 of tamoxifen metabolites were 1 mg/L for MRSE strains and 2 mg/L for Enterococcus spp. strains. In the time-killing assays, tamoxifen metabolites mixture showed bactericidal activity at 2x and 4xMIC for MRSE (SE385 and SE742) and E. faecalis (EVR1 and EVR2) strains. This antimicrobial activity of tamoxifen metabolites paralleled an increased membrane permeability of SE385 and EVR2 strains.Altogether, these results showed that tamoxifen metabolites presented antibacterial activity against MRSE and vancomycin-resistant E. faecalis, suggesting that tamoxifen metabolites might increase the arsenal of drugs treatment against these bacterial pathogens.
TheUrtica DioicaAgglutinin Prevents Rabies Virus Infection in a Muscle Explant Model
Authors: Wang Xinyu , Terrie Lisanne , Wu Guanghui , Van Damme Els J.M. , Fooks Anthony R , Banyard Ashley C , Thorrez Lieven , Jochmans Dirk , Neyts Johan 
Published: May 2021

AbstractInfection with the rabies virus (RABV) results, once symptoms develop, in a 100% lethal neurological disease. Post-exposure prophylaxis (PEP), consists of a combination of vaccination and anti-rabies immunoglobulins (RIGs); it is 100% effective if administered early after infection. Because of the limited availability, alternatives for RIGs are needed. To that end we evaluated a panel of 33 different lectins for their effect on RABV infection in cell culture. Several lectins, with either mannose or GlcNAc specificity elicited anti-RABV activity of which the GlcNAc specificUrtica dioicaAgglutinin (UDA) was selected for further studies. UDA was found to prevent entry of the virus into the host cell. To further assess the potential of UDA, a physiologically relevant RABV infection muscle explant model was developed. Strips of dissected swine skeletal muscle that were kept in culture medium could be productively infected with the RABV. When the infection of the muscle strips was carried out in the presence of UDA, RABV replication was completely prevented. We thus developed a physiologically relevant RABV muscle infection model. UDA (i) may serve as a reference for further studies and (ii) holds promise as a cheap and simple to produce alternative for RIGs in PEP.
Fission yeast polycystin Pkd2p promotes the cell expansion and antagonizes the Hippo pathway SIN
Authors: Sinha Debatrayee , Ivan Denisa , Gibbs Ellie , Chetluru Madhurya , Goss John , Chen Qian 
Published: May 2021

AbstractPolycystins are conserved mechanosensitive channels whose mutations lead to the common human renal disorder ADPKD. Previously we discovered that the plasma membrane-localized fission yeast homologue Pkd2p is an essential protein required for cytokinesis, but the mechanism remains unclear. Here, we isolated a novel temperature-sensitive mutant pkd2-B42. Among its strong growth defects, the most unique was that many mutant cells often lost significant portion of their volume in just 5 minutes followed by a gradual recovery, a process that we termed Deflation. Unlike cell lysis, deflation did not result in the plasma membrane rupture and it occurred independently from the cell cycle progression. The tip extension of pkd2-B42 cells was 80% slower than the wild type and their turgor pressure was 50% lower. Both pkd2-B42 and the other mutant pkd2-81KD partially rescued the mutants of the yeast Hippo signaling pathway Septation Initiation Network, by preventing cell lysis, enhancing septum formation, and doubling the number of Sid2/Mob1 molecules at the spindle pole bodies. We conclude that Pkd2p promotes cell size expansion during interphase by regulating turgor pressure and antagonizes SIN during cytokinesis.Summary statementMutations of polycystins lead to human genetic disorder ADPKD. We discovered that the fission yeast homologue Pkd2p promotes the cell expansion during interphase growth and antagonizes the Hippo pathway SIN during cytokinesis.
An Integrative Apoptotic Reaction Model for extrinsic and intrinsic stimuli
Authors: Corbat Agustin A. , Silberberg Mauro , Grecco Hernán E. 
Published: May 2021

AbstractApoptosis, a form of programmed cell death central to all multicellular organisms, plays a key role during organism development and is often misregulated in cancer. Devising a single model applicable to distinct stimuli and conditions has been limited by lack of robust observables. Indeed, previous numerical models have been tailored to fit experimental datasets in restricted scenarios, failing to predict response to different stimuli. We quantified the activity of three caspases simultaneously upon intrinsic or extrinsic stimulation to assemble a comprehensive dataset. We measured and modeled the time between maximum activity of intrinsic, extrinsic and effector caspases, a robust observable of network dynamics, to create the first integrated Apoptotic Reaction Model (ARM). Observing how effector caspases reach maximum activity first irrespective of stimuli used, led us to identify and incorporate a missing feedback into a successful model for extrinsic stimulation. By simulating different recently performed experiments, we corroborated that ARM adequately describes them. This integrated model provides further insight into the indispensable feedback from effector caspase to initiator caspases.
Personality profiling may help select better cleaner fish for sea-lice control in salmon farming
Authors: Whittaker Benjamin Alexander , Consuegra Sofia , de Leaniz Carlos Garcia 
Published: May 2021

AbstractLumpfish (Cyclopterus lumpus) are increasingly being used as cleaner fish to control parasitic sea-lice in salmon farming, but cleaning rates are very variable and not all individuals eat sea-lice, which increases the risk of emaciation and has ethical and practical implications. Selecting good cleaners is a priority to make the industry more sustainable, but there is little information on what behaviours make cleaner fish effective under a commercial setting. We examined variation in lumpfish personalities according to the five-factor personality model that takes into account differences in activity, anxiety (shelter use, thigmotaxis), aggression, sociality, and boldness (neophobia). We then quantified how variation in lumpfish personalities influenced interactions with naïve Atlantic salmon (Salmo salar), without the confounding effects of variation in sea-lice loads. Variation in activity, sociality, aggression and neophobia, but not in anxiety, was repeatable, which is consistent with a heritable basis. Neophilic, non-aggressive lumpfish spent more time inspecting salmon than neophobic and aggressive individuals, but salmon fled in the presence of the most active and social individuals, suggesting there may be an optimal cleaner fish personality amenable to artificial selection. The personality screening protocols developed in this study could inform a more efficient use of cleaner fish in salmon farming and reduce the number of individuals required to control sea-lice.
Genetic isolation by distance underlies color pattern divergence in red-eyed treefrogs (Agalychnis callidryas)
Authors: Clark Meaghan I. , Bradburd Gideon S. , Akopyan Maria , Vega Andres , Rosenblum Erica Bree , Robertson Jeanne M. 
Published: May 2021

AbstractInvestigating the spatial distribution of genetic and phenotypic variation can provide insights into the evolutionary processes that shape diversity in natural systems. We characterized patterns of genetic and phenotypic diversity to learn about drivers of color-pattern diversification in red-eyed treefrogs (Agalychnis callidryas) in Costa Rica. Along the Pacific coast, red-eyed treefrogs have conspicuous leg color patterning that transitions from orange in the north to purple in the south. We measured phenotypic variation of frogs, with increased sampling at sites where the orange-to-purple transition occurs. At the transition zone, we discovered the co-occurrence of multiple color-pattern morphs. To explore possible causes of this variation, we generated a SNP dataset to analyze population genetic structure, measure genetic diversity, and infer the processes that mediate genotype-phenotype dynamics. We investigated how patterns of genetic relatedness correspond with individual measures of color pattern along the coast, including testing for the role of hybridization in geographic regions where orange and purple phenotypic groups co-occur. We found no evidence that color-pattern polymorphism in the transition zone arose through recent hybridization. Instead, a strong pattern of genetic isolation by distance (IBD) indicates that color-pattern variation was either retained through other processes such as ancestral color polymorphisms or ancient secondary contact, or else it was generated by novel mutations. We found that phenotype changes along the Pacific coast more than would be expected based on genetic divergence and geographic distance alone. Combined, our results suggest the possibility of selective pressures acting on color pattern at a small geographic scale.
Assessing and removing the effect of unwanted technical variations in microbiome data
Authors: Fachrul Muhamad , Méric Guillaume , Inouye Michael , Pamp Sünje Johanna , Salim Agus 
Published: May 2021

AbstractVarying technologies and experimental approaches used in microbiome studies often lead to irreproducible results due to unwanted technical variations. Such variations, often unaccounted for and of unknown source, may interfere with true biological signals, resulting in misleading biological conclusions. In this work, we aim to characterize the major sources of technical variations in microbiome data and demonstrate how a state-of-the art approach can minimize their impact on downstream analyses. We analyzed 184 pig faecal metagenomes encompassing 21 specific combinations of deliberately introduced factors of technical and biological variations. We identify several known experimental factors, specifically storage conditions and freeze-thaw cycles, as a likely major source of unwanted variation in metagenomes. We also observed that these unwanted technical variations do not affect taxa uniformly, with freezing samples affecting taxa of class Bacteroidia the most, for example. Additionally, we benchmarked the performance of a novel batch correcting tool used in this study, RUV-III-NB (https://github.com/limfuxing/ruvIIInb/), to other popular batch correction methods, including ComBat, ComBat-seq, RUVg, and RUVs. While RUV-III-NB performed consistently robustly across our sensitivity and specificity metrics, most other methods did not remove unwanted variations optimally, with RUVg even overcorrecting and removing some of the true biological signals from the samples. Our analyses suggests that a careful consideration of possible technical confounders is critical in the experimental design of microbiome studies to ensure accurate biological reading of microbial taxa of interest, and that the inclusion of technical replicates is necessary to efficiently remove unwanted variations computationally.
A barley gene cluster for the biosynthesis of diterpenoid phytoalexins
Authors: Liu Yaming , Balcke Gerd U. , Porzel Andrea , Mahdi Lisa , Scherr-Henning Anja , Bathe Ulschan , Zuccaro Alga , Tissier Alain 
Published: May 2021

AbstractPhytoalexins are specialized metabolites that are induced upon pathogen infection and contribute to the defense arsenal of plants. Maize and rice produce multiple diterpenoid phytoalexins and there is evidence from genomic sequences that other monocots may also produce diterpenoid phytoalexins. Here we report on the identification and characterization of a gene cluster in barley (Hordeum vulgare cv. Golden Promise) that is involved in the production of a set of labdane-related diterpenoids upon infection of roots by the fungal pathogen Bipolaris sorokiniana. The cluster is localized on chromosome 2, covers over 600 kb and comprises genes coding for a (+)-copalyl diphosphate synthase (HvCPS2), a kaurene synthase like (HvKSL4) and several cytochrome P450 oxygenases (CYPs). Expression of HvCPS2 and HvKSL4 in yeast and Nicotiana benthamiana resulted in the production of a single major product, whose structure was determined to be of the cleistanthane type and was named hordediene. Co-expression of HvCPS2, HvKSL4 and one of the CYPs from the cluster (CYP89E31) afforded two additional products, hordetriene and 11-hydroxy-hordetriene. Both of these compounds could be detected in extracts of barley roots infected by B. sorokiniana, validating the function of these genes in planta. Furthermore, diterpenoids with multiple oxidations and with molecular masses of 316, 318 and 332 were induced in infected barley roots and secreted in the medium, indicating that additional oxidases, possibly from the same genomic cluster are involved in the production of these phytoalexins. Our results provide the basis for further investigation of the role of this gene cluster in the defense of barley against pathogens and more generally in the interaction with the microbiome.
Automated Pipeline for Infants Continuous EEG (APICE): a flexible pipeline for developmental studies
Authors: Fló Ana , Gennari Giulia , Benjamin Lucas , Dehaene-Lambertz Ghislaine 
Published: May 2021

AbstractInfant electroencephalography (EEG) presents several challenges compared with adult data. Recordings are typically short. Motion artifacts heavily contaminate the data. The EEG neural signal and the artifacts change throughout development. Traditional data preprocessing pipelines have been developed mainly for event-related potentials analyses, and they required manual steps, or use fixed thresholds for rejecting epochs. However, larger datasets make the use of manual steps infeasible, and new analytical approaches may have different preprocessing requirements. Here we propose an Automated Pipeline for Infants Continuous EEG (APICE). APICE is fully automated, flexible, and modular. Artifacts are detected using multiple algorithms and adaptive thresholds, making it suitable to different age groups and testing procedures without redefining parameters. Artifacts detection and correction of transient artifacts is performed on continuous data, allowing for better data recovery and providing flexibility (i.e., the same preprocessing is usable for different analyses). Here we describe APICE and validate it using two infant datasets of different ages tested in different experimental paradigms. We also tested the combination of APICE with common data cleaning methods such as Independent Component Analysis and Denoising Source Separation. APICE uses EEGLAB and compatible custom functions. It is freely available athttps://github.com/neurokidslab/eeg_preprocessing, together with example scripts.
Identification of a novel lineage bat SARS-related coronaviruses that use bat ACE2 receptor
Authors: Guo Hua , Hu Ben , Si Hao-rui , Zhu Yan , Zhang Wei , Li Bei , Li Ang , Geng Rong , Lin Hao-Feng , Yang Xing-Lou , Zhou Peng , Shi Zheng-Li 
Published: May 2021

AbstractSevere respiratory disease coronavirus-2 (SARS-CoV-2) causes the most devastating disease, COVID-19, of the recent century. One of the unsolved scientific questions around SARS-CoV-2 is the animal origin of this virus. Bats and pangolins are recognized as the most probable reservoir hosts that harbor the highly similar SARS-CoV-2 related viruses (SARSr-CoV-2). Here, we report the identification of a novel lineage of SARSr-CoVs, including RaTG15 and seven other viruses, from bats at the same location where we found RaTG13 in 2015. Although RaTG15 and the related viruses share 97.2% amino acid sequence identities to SARS-CoV-2 in the conserved ORF1b region, but only show less than 77.6% to all known SARSr-CoVs in genome level, thus forms a distinct lineage in theSarbecovirusphylogenetic tree. We then found that RaTG15 receptor binding domain (RBD) can bind to and useRhinolophus affinisbat ACE2 (RaACE2) but not human ACE2 as entry receptor, although which contains a short deletion and has different key residues responsible for ACE2 binding. In addition, we show that none of the known viruses in bat SARSr-CoV-2 lineage or the novel lineage discovered so far use human ACE2 efficiently compared to SARSr-CoV-2 from pangolin or some of the SARSr-CoV-1 lineage viruses. Collectively, we suggest more systematic and longitudinal work in bats to prevent future spillover events caused by SARSr-CoVs or to better understand the origin of SARS-CoV-2.