bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adjusting non-pharmaceutical interventions based on hospital bed capacity using a multi-operator differential evolution
Authors: Mendoza Victoria May P. , Mendoza Renier , Lee Jongmin , Jung Eunok 
Published: July 2022

AbstractWithout vaccines and medicine, non-pharmaceutical interventions (NPIs) such as social distancing, have been the main strategy in controlling the spread of COVID-19. Strict social distancing policies may lead to heavy economic losses, while relaxed social distancing policies can threaten public health systems. We formulate an optimization problem that minimizes the stringency of NPIs during the prevaccination and vaccination phases and guarantees that cases requiring hospitalization will not exceed the number of available hospital beds. The approach utilizes an SEIQR model that separates mild from severe cases and includes a parameter µ that quantifies NPIs. Payoff constraints ensure that daily cases are decreasing at the end of the prevaccination phase and cases are minimal at the end of the vaccination phase. Using the penalty method, the constrained minimization is transformed into a non-convex, multi-modal unconstrained optimization problem, which is solved using a metaheuristic algorithm called the improved multi-operator differential evolution. We apply the framework to determine optimal social distancing strategies in the Republic of Korea given different amounts and types of antiviral drugs. The model considers variants, booster shots, and waning of immunity. The optimal µ values show that fast administration of vaccines is as important as using highly effective vaccines. The initial number of infections and daily imported cases should be kept minimum especially if the severe bed capacity is low. In Korea, a gradual easing of NPIs without exceeding the severe bed capacity is possible if there are at least seven million antiviral drugs and the effectiveness of the drug in reducing disease severity is at least 86%. Model parameters can be adapted to a specific region or country, or other infectious disease. The framework can also be used as a decision support tool in planning practical and economic policies, especially in countries with limited healthcare resources.Mathematics Subject Classification34A55, 34H05, 90C26, 92-10
α-synucleinopathy associated calcium overload and autophagy failure is regulated by gain-of-function of Tousled-like kinase
Authors: Gong Fangyan , Chen Hao , Xiong Ying , Cai Rong , Zhang Jing , Wang Ningli , Liu Lei 
Published: July 2022

AbstractAs a pathological hallmark in Parkinson’s disease (PD), α-synucleinopathy causes multiple cellular damages, including calcium overload, mitochondrial and autophagic dysfunction, and eventually dopamine neuron death. However, the hierarchy of these detrimental events is unclear. InDrosophila, we confirmed that overexpression of α-synuclein could induce all these cytotoxic events. To determine the specific cytotoxic events induced by calcium overload, we established a calcium overload model inDrosophilaand performed genetic screens. We found that calcium overload caused mitochondrial damage and autophagy failure and cell death, and these cytotoxic processes could be strongly rescued by loss of Tousled-like kinase (TLK). Interestingly, loss of TLK also rescued defects induced by α-synuclein overexpression inDrosophila. This suggests that calcium overload acts as the crucial event upstream of mitochondrial and autophagy dysfunction. For TLK regulation of autophagy, our data indicated that a transcriptional factor REPTOR, which regulated the expression of several lysosomal genes, functioned downstream of TLK. In mammalian cells and mice, TLK2 (the homolog ofDrosophilaTLK) was phosphorylated under calcium overload. Upon phosphorylation, TLK2 increased its kinase activity. In addition, TLK2 could phosphorylate CREBRF (the human homolog of REPTOR) to cause its loss of transcription on the lysosomal genes. Moreover, TLK2 knockout mice rescued multi-aspect cytotoxicity induced by calcium overload and α-synuclein overexpression. Our research demonstrates that TLK2 acts as a key regulator to mediate cell death and dysfunctions of mitochondria and autophagy downstream of calcium overload.
An autoregulatory feedback loop converging on H2A ubiquitination drives synovial sarcoma
Authors: Benabdallah Nezha S. , Dalal Vineet , Sotiriou Afroditi , Scott R. Wilder , Kommoss Felix K.F. , Pejkovska Anastasija , Gaspar Ludmila , Wagner Lena , Sánchez-Rivera Francisco J. , Ta Monica , Thornton Shelby , Nielsen Torsten O. , Underhill T. Michael , Banito Ana 
Published: July 2022

ABSTRACTThe SS18-SSX fusion drives oncogenic transformation in synovial sarcoma by bridging SS18, a member of mSWI/SNF complex, to Polycomb repressive complex 1 (PRC1) target genes. Here we show that the SSX C-terminus, via its SSXRD domain, directs SS18-SSX chromatin binding independently of SS18. SSXRD specific targeting is mediated by interaction with mono ubiquitinated H2A (H2AK119ub1) and histone MacroH2A with which the fusion overlaps genome wide. Variant Polycomb Repressive Complex 1.1 (PRC1.1) acts as the main depositor of H2AK119ub1 and is therefore required for SS18-SSX occupancy. Importantly, the SSX C-terminus not only depends on H2AK119ub1 for localization but also further increases it by promoting PRC1.1 complex stability. Consequently, high H2AK119ub1 levels are a feature of murine and human synovial sarcomas. These results reveal an SSX/PRC1 autoregulatory feedback loop that reinforces fusion chromatin binding and therefore its oncogenic activity, and could play a role in a wider range of cancers and physiological settings where SSX proteins are overexpressed.
Discovering host protein interactions specific for SARS-CoV-2 RNA genome
Authors: Giambruno Roberto , Zacco Elsa , Ugolini Camilla , Vandelli Andrea , Mulroney Logan , D’Onghia Manfredi , Giuliani Bianca , Criscuolo Elena , Castelli Matteo , Clementi Nicola , Clementi Massimo , Mancini Nicasio , Bonaldi Tiziana , Gustincich Stefano , Leonardi Tommaso , Tartaglia Gian Gaetano , Nicassio Francesco 
Published: July 2022

ABSTRACTSARS-CoV-2, a positive single-stranded RNA virus, interacts with host cell proteins throughout its life cycle. These interactions are necessary for the host to recognize and hinder the replication of SARS-CoV-2. For the virus, to translate, transcribe and replicate its genetic material. However, many details of these interactions are still missing. We focused on the proteins binding to the highly structured 5’ and 3’ end regions of SARS-CoV-2 RNA that were predicted by thecatRAPID algorithm to attract numerous proteins, exploiting RNA-Protein Interaction Detection coupled with Mass Spectrometry (RaPID-MS) technology. The validated interactors, which agreed with our predictions, include pseudouridine synthase PUS7 that binds to both ends of the viral RNA. Nanopore direct-RNA sequencing confirmed that the RNA virus is heavily modified, and PUS7 consensus regions were found in both SARS-CoV-2 RNA end regions. Notably, a modified site was detected in the viral Transcription Regulatory Sequence - Leader (TRS-L) and can influence the viral RNA structure and interaction propensity. Overall, our data map host protein interactions within SARS-CoV-2 UTR regions, pinpointing to a potential role of pseudouridine synthases and post-transcriptional modifications in the viral life cycle. These findings contribute to understanding virus-host dynamics and may guide the development of targeted therapies.
Rounding up the annual ryegrass genome: high-quality reference genome of Lolium rigidum
Authors: Paril Jefferson , Pandey Gunjan , Barnett Emma B. , Rane Rahul V. , Court Leon , Walsh Thomas , Fournier-Level Alexandre 
Published: July 2022

AbstractThe genome of the major agricultural weed species, annual ryegrass (Lolium rigidum) was assembled, annotated and analysed. Annual ryegrass is a major weed in wheat cropping, and has the remarkable capacity to evolve resistance to herbicides with various modes of action. The chromosome-level assembly was achieved using short- and long-read sequencing in combination with Hi-C mapping. The assembly size is 2.44Gb with N50=361.79Mb across 1,764 scaffolds where the seven longest sequences correspond to the seven chromosomes. Genome completeness assessed through BUSCO returned a 99.8% score for complete (unique and duplicated) and fragmented genes using the Viridiplantae set. We found evidence for the expansion of herbicide resistance-related gene families including detoxification genes. The reference genome assembly of L. rigidum is pivotal for the management of this highly problematic weed species which leverages genomic tools to devise new control options.
Unveiling hidden eukaryotes: diversity of Endomyxa (Rhizaria) in coastal marine habitats
Authors: Berney Cédric , Ciaghi Stefan , Romac Sarah , Mahé Frédéric , de Vargas Colomban , Jaillon Olivier , Kirchmair Martin , Bass David , Neuhauser Sigrid 
Published: July 2022

AbstractNucleic acid based studies of marine biodiversity often focus on Kingdom-level diversity. Such approaches often largely miss diversity of less studied groups, likely to harbour many unknown lineages which are likely playing significant ecological roles. Among these elusive groups are Endomyxa (Rhizaria), a ubiquitous, but understudied lineage comprising parasites (e.g. Ascetosporea, Phytomyxea), free-living amoebae (e.g. Vampyrellida, Gromia, Filoreta), flagellates (e.g. Tremula, Aquavolon), and unknown environmental lineages. Using Endomyxa-biased primers targeting the hypervariable region V4 of the 18S rRNA gene, we explored the diversity of Endomyxa in marine samples from European coastal sites and compared it to that found in pan-eukaryote V4 libraries of the same samples. In total 458 endomyxan OTUs were identified, of which 38% were only detected by the specific primers. Most are distinct from published sequences, and include novel diversity within known clades, and putative novel lineages. The data revealed variations in endomyxan assemblages related to habitat (benthic vs. pelagic, sampling site), mode of nutrition (parasitic vs. free-living) and nucleic acid type (DNA vs. RNA). Overall, the vast majority of endomyxan diversity occurs in sediments (including Vampyrellida, Reticulosida, and the environmental “Novel Clade 12”) where they form diverse and active communities including many uncharacterised lineages.
An automated workflow for multi-omics screening of microbial model organisms
Authors: Donati Stefano , Mattanovich Matthias , Hjort Pernille , Jacobsen Simo Abdessamad Baallal , Blomquist Sarah Dina , Mangaard Drude , Gurdo Nicolas , Pastor Felix Pacheco , Maury Jérôme , Hanke Rene , Herrgård Markus J. , Wulff Tune , Jakočiūnas Tadas , Nielsen Lars Keld , McCloskey Douglas 
Published: July 2022

AbstractMulti-omics datasets are becoming of key importance to drive discovery in fundamental research as much as generating knowledge for applied biotechnology. However, the construction of such large datasets is usually time-consuming and expensive. Automation is needed to overcome these issues by streamlining workflows from sample generation to data analysis. Here, we describe the construction of a complex workflow for the generation of high-throughput microbial multi-omics datasets. The workflow comprises a custom-built platform for automated cultivation and sampling of microbes, sample preparation protocols, analytical methods for sample analysis and automated scripts for raw data processing. We demonstrate possibilities and limitations of such workflow in generating data for three biotechnologically relevant model organisms, namely Escherichia coli, Saccharomyces cerevisiae, and Pseudomonas putida.
Comprehensive analysis of kill switch toxins in plant-beneficial Pseudomonas fluorescens reveals drivers of lethality, stability, and escape
Authors: Halvorsen Tiffany M. , Ricci Dante P. , Park Dan M. , Jiao Yongqin , Yung Mimi C. 
Published: July 2022

AbstractKill switches provide a biocontainment strategy in which unwanted growth of an engineered microorganism is prevented by expression of a toxin gene. A major challenge in kill switch engineering is balancing evolutionary stability with robust cell killing activity in application relevant host strains. Understanding host-specific containment dynamics and modes of failure helps to develop potent yet stable kill switches. To guide the design of robust kill switches in the agriculturally relevant strain Pseudomonas fluorescens SBW25, we present a comparison of lethality, stability, and genetic escape of eight different toxic effectors in the presence of their cognate inactivators (i.e., toxin-antitoxin modules, polymorphic exotoxin-immunity systems, restriction endonuclease-methyltransferase pair). We find that cell killing capacity and evolutionary stability are inversely correlated and dependent on the level of protection provided by the inactivator gene. Decreasing the proteolytic stability of the inactivator protein can increase cell killing capacity, but at the cost of long-term circuit stability. By comparing toxins within the same genetic context, we determine that modes of genetic escape increase with circuit complexity and are driven by toxin activity, the protective capacity of the inactivator, and the presence of mutation-prone sequences within the circuit. Collectively, our study reveals that circuit complexity, toxin choice, inactivator stability, and DNA sequence design are powerful drivers of kill switch stability and valuable targets for optimization of biocontainment systems.
Taxanes act as vascular disrupting agents and increase rate of metastasis when combined with anti-angiogenic therapy
Authors: Nandigama Rajender , Kallius Mathias , Hemmen Katharina , Das Shaoli , Pinnecker Jürgen , Ascheid David , Burkhard Verena , Ali Hla , Rainer Johannes , Scheld Daniela , Herterich Sabine , Zernecke-Madsen Alma , Penack Olaf , Diller Stefan , Camphausen Kevin , Ergün Süleyman , Shankavaram Uma , Heinze Katrin , Escorcia Freddy E. , Henke Erik 
Published: July 2022

AbstractTaxanes are known to have a profound effect on endothelial cells and the vasculature even at low doses. Here, we show that taxanes, rather than being anti-angiogenic, function more as vascular disrupting agents (VDAs), although they exert a different mechanism of vascular permeabilization when compared to traditional VDAs such as combretastatins. In the tumor context, this VDA-effect leads to a rapid vascular collapse and acute hypoxia. Concomitant treatment with anti-VEGF drugs aggravates hypoxia by blocking vasculogenic rescue mechanisms. While this results in a strong growth-suppressing effect on the tumor, it also increases its invasiveness and metastatic potential. We demonstrate that combination of anti-angiogenic drugs with taxanes blocks tumor reperfusion, intensifies intravasation of circulating tumor cells (CTCs) and strongly increases metastasis. Anti-VEGF drugs are commonly applied in combination with cytotoxic drugs including taxanes. Our findings have significant implications for the clinical use of this drug combination.
The Implicit Assumptions of Classic Functional Responses and Their Multi-Species Extensions
Authors: Palamara Gian Marco , Capitán José A. , Alonso David 
Published: July 2022

AbstractFunctional responses are central to describe consumer-resource interactions. Defined as the per capita average feeding rate of consumers, since Holling’s seminal papers, they have been widely used in ecology. Holling’s central observation was that they often saturate as resource density increases. If the interference between consumers is strong, they also decrease with consumer density. Here we emphasize the stochastic nature of the individual feeding processes and the associated probability distributions of the different behavioral types and show how they control population-averaged feeding rates. We do so by revisiting a classic approach based on the formulation of feeding interactions in terms of individual-based reaction schemes. We highlight the common assumptions underlying the different functional forms and discover a new predator-dependent functional response that should be considered the natural extension of the Holling type II functional response when consumers interference is considered. Our work has clear implications, on the one hand, for both model selection and parameter inference from feeding experiments, and, on the other, for the use of multi-species extensions of these functional responses in population-level food-web dynamic models.
Hidden Markov Modeling of Molecular Orientations and Structures from High-Speed Atomic Force Microscopy Time-Series Images
Authors: Ogane Tomonori , Noshiro Daisuke , Ando Toshio , Yamashita Atsuko , Sugita Yuji , Matsunaga Yasuhiro 
Published: July 2022

AbstractHigh-speed atomic force microscopy (HS-AFM) is a powerful technique for capturing the time-resolved behavior of biomolecules. However, structural information in HS-AFM images is limited to the surface geometry of a sample molecule. Inferring latent three-dimensional structures from the surface geometry is thus important for getting more insights into conformational dynamics of a target biomolecule. Existing methods for estimating the structures are based on the rigid-body fitting of candidate structures to each frame of HS-AFM images. Here, we extend the existing frame-by-frame rigid-body fitting analysis to multiple frames to exploit orientational correlations of a sample molecule between adjacent frames in HS-AFM data due to the interaction with the stage. In the method, we treat HS-AFM data as time-series data, and they are analyzed with the hidden Markov modeling. Using simulated HS-AFM images of the taste receptor type 1 as a test case, the proposed method shows a more robust estimation of molecular orientations than the frame-by-frame analysis. The method is widely applicable in integrative modeling of conformational dynamics using real experimental HS-AFM data.Author summaryBiomolecules dynamically change their structures in cells and perform various functions that are important for life. It is difficult to observe such dynamic structural changes using conventional experimental techniques, such as X-ray crystallography, that mainly observe static atomic structures. Alternative approach is the atomic force microscopy (AFM), a technique to measure the surface geometry of a sample molecule by scanning with an acute tip. Recently, by increasing the imaging rate of the AFM, it has become possible to observe the dynamics of biomolecules at work. However, the information measured with AFM is limited to the surface geometry of a molecule, so it is important to extract three-dimensional structural information from those data. In this study, we develop a method to estimate structural information with higher accuracy.
Haplotype based testing for a better understanding of the selective architecture
Authors: Chen Haoyu , Pelizzola Marta , Futschik Andreas 
Published: July 2022

AbstractThe identification of genomic regions affected by selection is one of the most important goals in population genetics. If temporal data are available, allele frequency changes at SNP positions are often used for this purpose. Here we provide a new testing approach that uses haplotype frequencies instead of allele frequencies. With this approach, less multiple testing correction is needed, which leads to tests with higher power, especially when the number of candidate haplotypes is small or moderate. Another advantage is that haplotype frequencies can often be recovered with less noise than SNP frequencies, especially under pool sequencing. For a larger number of haplotypes, we investigate methods to combine them to a moderate number of haplotype subsets. The use of haplotypes also permits a better understanding of selective signatures. For this purpose, we propose post hoc tests for the selected haplotypes and differences between their selection coefficients. Using both simulated and real data sets, we illustrate the performance and benefits of our proposed test statistics.
Neuronal selectivity for multiple features in the primary visual cortex
Authors: Wei Wenqing , Merkt Benjamin , Rotter Stefan 
Published: July 2022

AbstractNeurons in rodent primary visual cortex are simultaneously tuned to several stimulus features, including orientation and spatial frequency of moving gratings used in experiments. Light-induced signals emitted by retinal ganglion cells (RGC) are relayed to the primary visual cortex (V1) via cells in the dorsal lateral geniculate nucleus (dLGN). However, there is currently no agreement on which thalamocortical transformation leads to the neuronal tuning curves observed in experiments. Here, we outline a model that explains the emergence of feature-specific neural responses as the result of a two-step integration process: First, the compound input to cortical neurons comes from a set of retinal sensors randomly placed in the receptive field. Second, the cortical responses to the combined input are shaped by the rectification caused by the spike threshold of the neurons. We performed numerical simulations of a thalamocortical network stimulated by moving gratings and found that simultaneous tuning to orientation and spatial frequency results from this spatio-temporal integration process. We also show how this tuning is related to the complex structure of the receptive fields that reflect the input. We conclude that different types of feature selectivity arise naturally from random thalamocortical projections. Moreover, we describe in detail the underlying neural mechanism.
Enhanced cell viscosity: a new phenotype associated with lamin A/C alterations
Authors: Jebane Cécile , Varlet Alice-Anaïs , Karnat Marc , Hernandez-Cedillo Lucero M. , Lecchi Amélie , Bedu Frédéric , Desgrouas Camille , Vigouroux Corinne , Vantyghem Marie-Christine , Viallat Annie , Rupprecht Jean-François , Helfer Emmanuèle , Badens Catherine 
Published: July 2022

AbstractLamin A/C is a well-established key contributor to nuclear stiffness and its role in nucleus mechanical properties has been extensively studied. However, its impact on whole cell mechanics has been poorly addressed, even less so in terms of measurable physical parameters. In the present study, microfluidic experiments combined with theoretical analyses were performed to provide a quantitative estimation of the whole cell mechanical properties. This allowed the characterization of mechanical cell changes induced by lamin A/C alterations resulting from Atazanavir treatment or lipodystrophy-associated LMNA R482W pathogenic variant. Results unveil an increase in the long-time viscosity as a signature of cells affected by lamin A/C alterations. In addition, they show that the whole cell response to mechanical stress is driven not only by the nucleus but also by the nucleo-cytoskeleton links and the microtubule network. This enhanced cell viscosity assessed by our microfluidic device could represent a useful diagnosis marker for lamin-related diseases.