bluuebunny/crossref_metadata_2025_split huggingface dataset:
DCATS: differential composition analysis for complex single-cell experimental designs
Authors: Lin Xinyi , Chau Chuen , Huang Yuanhua , Ho Joshua W.K. 
Published: March 2022

AbstractDifferential composition analysis – the identification of cell types that have statistically significantly change in abundance between multiple experimental conditions – is one of the most common tasks in single cell omic data analysis. However, it remains challenging to perform differential composition analysis in the presence of complex experimental designs and uncertainty in cell type assignment. Here, we introduce a statistical model and an open source R package, DCATS, for differential composition analysis based on a beta-binomial regression framework that addresses these challenges. Our empirical evaluation shows that DCATS consistently maintain high sensitively and specificity compared to state-of-the-art methods.
Persistence of rareSalmonellaTyphi genotypes susceptible to first-line antibiotics in the remote islands of Samoa
Authors: Sikorski Michael J. , Hazen Tracy H. , Desai Sachin N. , Nimarota-Brown Susana , Tupua Siaosi , Sialeipata Michelle , Rambocus Savitra , Ingle Danielle J. , Duchene Sebastian , Ballard Susan A. , Valcanis Mary , Zufan Sara , Ma Jianguo , Sahl Jason W. , Maes Mailis , Dougan Gordon , Thomsen Robert E. , Robins-Browne Roy M. , Howden Benjamin P. , Naseri Take K. , Levine Myron M. , Rasko David A. 
Published: March 2022

ABSTRACTFor decades, the remote island nation of Samoa (pop. ~200,000) has faced endemic typhoid fever despite improvements in water quality, sanitation, and economic development. We recently described the epidemiology of typhoid fever in Samoa from 2008-2019 by person, place, and time; however, the localSalmonella entericaserovar Typhi (S.Typhi) population structure, evolutionary origins, and genomic features remained unknown. Herein, we report whole genome sequence analyses of 306S.Typhi isolates from Samoa collected between 1983 and 2020. Phylogenetics revealed a dominant population of rare genotypes 3.5.4 and 3.5.3, together comprising 292/306 (95.4%) of Samoan versus 2/4934 (0.04%) globalS.Typhi isolates. Three distinct 3.5.4 genomic sub-lineages were identified and their defining polymorphisms were determined. These dominant Samoan genotypes, which likely emerged in the 1970s, share ancestry with other clade 3.5 isolates from South America, Southeast Asia, and Oceania. Additionally, a 106-kb pHCM2 phenotypically-cryptic plasmid, detected earliest in a 1992 SamoanS.Typhi isolate, was identified in 106/306 (34.6%) of Samoan isolates; this is more than double the observed proportion of pHCM2-containing isolates in the global collection. In stark contrast with globalS.Typhi trends, resistance-conferring polymorphisms were detected in only 15/306 (4.9%) of SamoanS.Typhi, indicating overwhelming susceptibility to antibiotics that are no longer effective in most of South and Southeast Asia. This country-level genomic framework can help local health authorities in their ongoing typhoid surveillance and control efforts, as well as to fill a critical knowledge gap inS.Typhi genomic data from Oceania.IMPORTANCEIn this study we used whole genome sequencing and comparative genomics analyses to characterize the population structure, evolutionary origins, and genomic features ofS.Typhi associated with decades of endemic typhoid fever in Samoa. Our analyses of Samoan isolates from 1983 to 2020 identified a rareS.Typhi population in Samoa that likely emerged around the early 1970s and evolved into sub-lineages that presently dominate. The dominance and persistence of these endemic genotypes in Samoa are not readily explained by any apparent genomic competitive advantage or widespread acquisition of antimicrobial resistance. These data establish the necessary framework for future genomic surveillance ofS.Typhi in Samoa for public health benefit.
Ventricular and Atrial Pressure-Volume Loops: Analysis of the Effects Induced by Right Centrifugal Pump Assistance
Authors: De Lazzari Beatrice , Iacovoni Attilio , Capoccia Massimo , Papa Silvia , Badagliacca Roberto , Vizza Carmine Dario , De Lazzari Claudio 
Published: March 2022

ABSTRACTBackground and ObjectiveThe main indications for right ventricular assist device (RVAD) support are right heart failure after implantation of a left ventricular assist device (LVAD) or early graft failure following heart transplantation. About 30-40% of patients will need RVAD support after LVAD implantation. Pulmonary hypertension is also an indication for right heart assistance. Several types of RVAD generating pulsatile or continuous flow are available on the market. These assist devices can be connected to the cardiovascular system in different ways. We sought to analyse the effects induced by different RVAD connections when right ventricular elastance is modified using a numerical simulator. The analysis was based on the behaviour of both left and right ventricular and atrial loops in the pressure-volume plane.MethodsNew modules of the cardiovascular network and a right ventricular centrifugal pump were implemented in CARDIOSIM© software simulator platform. The numerical pump model generated continuous flow when connected in series or parallel to the right ventricle. When the RVAD was connected in series (parallel), the pump removed blood from the right ventricle (atrium) and ejected it into the pulmonary artery. In our study, we analysed the effects induced by RVAD support on left/right ventricular/atrial loops when right ventricular elastance slope (EesRIGHT) changed from 0.3 to 0.8 mmHg/ml with the pump connected either in series or parallel. The effect of low and high rotational pump speed was also addressed.ResultsPercentage changes up to 60% were observed for left ventricular pressure-volume area and external work during in-parallel RVAD support at 4000 rpm with EesRIGHT = 0.3mmHg/ml. The same pump setting and connection type led to percentage variation up to 20% for left ventricular ESV and up to 25% for left ventricular EDV with EesRIGHT = 0.3mmHg/ml. Again the same pump setting and connection generated up to 50% change in left atrial pressure-volume loop area (PVLAL-A) and only 3% change in right atrial pressure-volume loop area (PVLAR-A) when EesRIGHT = 0.3mmHg/ml. Percentage variation was lower when EesRIGHT was increased up to 0.8 mmHg/ml.ConclusionEarly recognition of right ventricular failure followed by aggressive treatment is desirable to achieve a more favourable outcome. RVAD support remains an option for advanced right ventricular failure although onset of major adverse events may preclude its use.
Single cell Transcriptome and T cell Repertoire Mapping of the Mechanistic Signatures and T cell Trajectories Contributing to Vascular and Dermal Manifestations of Behcet’s Disease
Authors: Chang Ling , Zheng Zihan , Zou Qinghua , Zhong Bing , Chen Chengshun , Cheng Xian , Ni Qingshan , Che Tiantian , Zhao Zhihua , Cao Chunhao , Zhou Yiwen , Tang Xiangyu , Zhai Zhifang , Zhao Jing , Zhang Junying , Wang Liting , Wan Ying , Chen Guangxing , Li Jingyi , Zou Liyun , Wu Yuzhang 
Published: March 2022

AbstractBehcet’s disease (BD) is a form of vasculitis characterized by complex multi-organ manifestations that may frequently recur and induce major tissue damage. Although genetic association studies have identified a number of risk factors, the etiology of BD and its tissue manifestations remains unknown, and the landscape of immune responses in BD is opaque, particularly in terms of inflammatory recurrence. In this study, we mapped the transcriptomes of the immune cell compartment in BD at single-cell resolution, sampling both circulation and affected skin in order to chart the immune interplay driving pathogenesis. Through comprehensive expression and communication analysis of the twenty major cell types identified, we observe striking mechanistic differences in immune response between BD skin lesions and peripheral circulation involving TNF signaling and T cell migration. Through integrated TCR sequencing, we further discover a pattern of clonal sharing between circulating and skin CD8+T cell populations along a trajectory defined by the acquisition of tissue-residential properties. In addition, we also identify a population of expanded CD4+ Tregs with the propensity to produce IL-32. Instead of suppressing effector T cell proliferation and function, IL-32 triggers increased expression of CD97, and may thus encourage prolonged local T cell activity in the skin. Collectively, our data serve to advance understandings of contributions of varying immune cell types to BD pathogenesis in the vasculature and skin, as well as the lifecycle patterns of T cells clones in this context. These data may also assist in further investigations of the mechanisms contributing to Treg dysfunction in systemic autoimmunity, while generating a conceptual model of T cell function contributing to BD recurrence.
scMAGS: Marker gene selection from scRNA-seq data for spatial transcriptomics studies
Authors: Baran Yusuf , Doğan Berat 
Published: March 2022

AbstractSingle-Cell RNA sequencing (scRNA-seq) has provided unprecedented opportunities for exploring gene expression and thus uncovering regulatory relationships between genes at the single cell level. However, scRNA-seq relies on isolating cells from tissues. Thus, the spatial context of the regulatory processes is lost. A recent technological innovation, spatial transcriptomics, allows to measure gene expression while preserving spatial information. A first step in the spatial transcriptomic analysis is to identify the cell type which requires a careful selection of cell-specific marker genes. For this purpose, currently scRNA-seq data is used to select limited number of marker genes from among all genes that distinguish cell types from each other. This study proposes scMAGS (single-cell MArker Gene Selection), a new approach for marker gene selection from scRNA-seq data for spatial transcriptomics studies. scMAGS uses a filtering step in which the candidate genes are extracted prior to the marker gene selection step. For the selection of marker genes, cluster validity indices, Silhouette index or Calinski-Harabasz index (for large datasets) are utilized. Experimental results showed that, in comparison to the existing methods, scMAGS is scalable, fast and accurate. Even for the large datasets with millions of cells, scMAGS could find the required number of marker genes in a reasonable amount of time with less memory requirements.
Density-dependent attributes of schooling in small pelagic fishes
Authors: Furuichi Sho , Kamimura Yasuhiro , Suzuki Masahiro , Yukami Ryuji 
Published: March 2022

AbstractMany small pelagic fishes obligately form schools; some of these schools attain a remarkable size. Although the school is a fundamental and important ecological unit and is the site of biological interactions such as competition and predation, information on schooling processes in the field remains scarce. Here, we examined the quantitative relationships between population density and school size, the number of schools, and other school characteristics (i.e., packing density, volume, and cross-sectional area) in three species of small pelagic fishes: Japanese anchovyEngraulis japonicus, Japanese sardineSardinops melanostictus, and chub mackerelScomber japonicus. We found that school size increased almost linearly with population density, whereas the number of schools and other characteristics increased non-linearly with population density, whereby the rate of increase slowed radically as population density increased. These results indicate that, at low population densities, an increase in density causes an increase in both school size and the number of schools, whereas at higher population densities, an increase in density triggers the formation of larger schools rather than more schools. Furthermore, we found that the shapes of the relationships of all school characteristics with population density differed among species. Our results indicate that the schooling behaviour of small pelagic fishes is density-dependent, and responses to changes in density are species-specific. Our results provide insight into how biological interactions such as intra- and inter-specific competition and predator-prey interactions mediate the density-dependent processes that underlie the population dynamics and community structure of small pelagic fishes in marine ecosystems.
Occurrence and quantities of DNA modifications across the tree of life
Authors: Varma Sreejith Jayasree , Calvani Enrica , Grüning Nana-Maria , Messner Christoph , Grayson Nicholas , Capuano Floriana , Mülleder Michael , Ralser Markus 
Published: March 2022

AbstractEnzymatic DNA modifications like methylcytosine (5mdC), methyladenine (N6mdA), or hydroxymethylcytosine (5hmdC) are key for chromatin function, gene expression regulation, and antiviral defense, but they remain understudied in non-model organisms. We established a mass spectrometric method for the sensitive and accurate quantification of enzymatic DNA modifications, and analyzed 85 bacterial genomes, 19 plant samples, 41 tissues from 12 animal species, 6 yeast species, and two archaeal species. We report no or only very low concentrations of DNA modifications in yeast and insects, but find DNA modifications universal to both bacteria and higher eukaryotes. Specifically for prokaryotes, our dataset indicates that evolutionary relationships and host–pathogen interactions, but not the ecological niche in general, select for a similar degree of DNA modification. In higher eukaryotes, largest concentration differences between tissues are detected for 5hmdC. Our dataset further reveals unique biological cases that warrant attention in the study of DNA modifications. For instance, while our data shows that most species contain just one dominating DNA modification, we detect all dominianting DNA modifications (5mdC, N6mdA, and 5hmdC) to exist in parallel in Raphanus sativus. Other plant species, like onion, sunflower, or the grass big bluestem, can have more than 35% of cytosines methylated. Finally, 5hmdC, so far mostly studied in the vertebrate central nervous system, was identified to reach a concentration of up to 8% of all cytosines in the Oman garra brain, and was also detected in several plants, like Lepidium sativum. The present study underscores the exploitation of biological diversity for studying DNA modifications.
Strain design optimization using reinforcement learning
Authors: Sabzevari Maryam , Szedmak Sandor , Penttilä Merja , Jouhten Paula , Rousu Juho 
Published: March 2022

AbstractEngineered microbial cells present a sustainable alternative to fossil-based synthesis of chemicals and fuels. Cellular synthesis routes are readily assembled and introduced into microbial strains using state-of-the-art synthetic biology tools. However, the optimization of the strains required to reach industrially feasible production levels is far less efficient. It typically relies on trial-and-error leading into high uncertainty in total duration and cost. New techniques that can cope with the complexity and limited mechanistic knowledge of the cellular regulation are called for guiding the strain optimization.In this paper, we put forward a multi-agent reinforcement learning (MARL) approach that learns from experiments to tune the metabolic enzyme levels so that the production is improved. Our method is model-free and does not assume prior knowledge of the microbe’s metabolic network or its regulation. The multi-agent approach is well-suited to make use of parallel experiments such as multi-well plates commonly used for screening microbial strains.We demonstrate the method’s capabilities using the genome-scale kinetic model of Escherichia coli, k-ecoli457, as a surrogate for an in vivo cell behaviour in cultivation experiments. We investigate the method’s performance relevant for practical applicability in strain engineering i.e. the speed of convergence towards the optimum response, noise tolerance, and the statistical stability of the solutions found. We further evaluate the proposed MARL approach in improving L-tryptophan production by yeast Saccharomyces cerevisiae, using publicly available experimental data on the performance of a combinatorial strain library.Overall, our results show that multi-agent reinforcement learning is a promising approach for guiding the strain optimization beyond mechanistic knowledge, with the goal of faster and more reliably obtaining industrially attractive production levels.Author summaryEngineered microbial cells offer a sustainable alternative solution to chemical production from fossil resources. However, to make the chemical production using microbial cells economically feasible, they need to be substantially optimized. Due to the biological complexity, this optimization to reach sufficiently high production is typically a costly trial and error process.This paper presents an Artificial Intelligence (AI) approach to guide this task. Our tool learns a model from previous experiments and uses the model to suggest improvements to the engineering design, until a satisfactory production performance is reached. This paper evaluates the behaviour of the proposed AI method from several angles, including the amount of experiments needed, the tolerance to noise as well as the stability of the proposed designs.
Phenology of plant reproduction, foliar infection, and herbivory change along an urbanization gradient
Authors: Fox Quinn N. , Bugay Mahal J. , Grant Eleanor , Shaw Olivia , Farah Keiko , Penczykowski Rachel M. 
Published: March 2022

AbstractUrbanization involves numerous environmental changes that may affect the timing of plant reproduction and foliar damage by pathogens, herbivores, and human activities. Yet such relationships have not been examined simultaneously in plant populations across levels of urbanization.We conducted monthly surveys of 22 populations ofPlantago lanceolataandP. rugeliiin parks spanning an urbanization gradient. We quantified plant reproductive development and prevalence of powdery mildew infection, insect herbivory, and mowing damage. Additionally, we placed potted “sentinel” plants into field populations to directly measure infection and herbivory rates.Urbanization was associated with earlier flowering and more seed production forP. rugelii, but less seed maturation forP. lanceolata. Mildew epidemics onP. rugeliistarted earlier and achieved greater prevalence in more urban sites. Correspondingly, sentinels only became infected in suburban and urban sites. There was less infection onP. lanceolata, including sentinels, suggesting low availability of pathogen genotypes able to infect this species. Early-summer herbivory on both plant species was accelerated in urban sites.Urbanization has species-specific associations with reproductive phenology and is associated with increased early-summer herbivory, larger epidemics of a foliar pathogen, and more mowing damage on two weedy herbs
Modulation of the DA1 pathway in maize shows that translatability of information from Arabidopsis to crops is complex
Authors: Gong Pan , Demuynck Kirin , De Block Jolien , Aesaert Stijn , Coussens Griet , Pauwels Laurens , Inzé Dirk , Nelissen Hilde 
Published: March 2022

AbstractModern agriculture is struggling to meet the increasing food, silage and raw material demands due to the rapid growth of population and climate change. In Arabidopsis, DA1 and DAR1 are proteases that negatively regulate cell proliferation and control organ size. DA1 and DAR1 are activated by ubiquitination catalyzed by the E3 ligase BIG BROTHER (BB). Here, we characterized the DA1, DAR 1 and BB gene families in maize and analyzed whether perturbation of these genes regulates organ size similar to what was observed in Arabidopsis. We generated da1_dar1a_dar1b triple CRISPR maize mutants and bb1_bb2 double mutants. Detailed phenotypic analysis showed that the size of leaf, stem, cob, and seed was not consistently enlarged in these mutants. Also overexpression of a dominant-negative DA1R333K allele, resembling the da1-1 allele of Arabidopsis which has larger leaves and seeds, did not alter the maize phenotype. The mild negative effects on plant height of the DA1R333K_bb1_bb2 mutant indicate that the genes in the DA1 pathway may control organ size in maize, albeit less obvious than in Arabidopsis.
An Orobanche cernua x Orobanche cumana segregating population provides insight into the regulation of germination specificity in a parasitic plant
Authors: Larose Hailey , Plakhine Dina , Wycoff Nathan , Zhang Na , Conn Caitlin , Nelson David C. , Eizenberg Hanan , Joel Daniel M. , Tadmor Yaakov , Westwood James H. 
Published: March 2022

SummaryGermination of seeds of Orobanche species requires specific chemicals exuded by host roots. A family of “divergent” KARRIKIN INSENSITIVE2 (KAI2d) genes encode proteins that recognize strigolactone (SL) class germination simulants. We explored specificity of germination stimulant detection by analyzing interspecific segregants of a cross between Orobanche cernua and O. cumana, closely related species that differ in stimulant response. O. cernua parasitizes tomato and germinates in response to the SL orobanchol, while O. cumana parasitizes sunflower and responds to dehydrocostus lactone (DCL). KAI2d genes were catalogued in parents and in segregants that showed stimulant specificity. KAI2d genes were also functionally assayed in the Arabidopsis kai2 mutant background. We identified five full-length KAI2d genes in O. cernua and eight in O. cumana. The O. cernua KAI2d2, as well as its ortholog in O. cumana, are associated with SL perception. A cluster of O. cumana KAI2d genes was genetically linked to DCL perception, although no specific receptor gene was identified by heterologous complementation. These findings support the KAI2d-mediated perception of SLs, but fall short of explaining how O. cumana perceives DCL. The ability of some O. cumana KAI2d genes to detect SLs points to the involvement of additional factors in regulating stimulant specificity.
Recovering false negatives in CRISPR fitness screens with JLOE
Authors: Dede Merve , Hart Traver 
Published: March 2022

AbstractIt is widely accepted that pooled library CRISPR knockout screens offer greater sensitivity and specificity than prior technologies in detecting genes whose disruption leads to fitness defects, a critical step in identifying candidate cancer targets. However, the assumption that CRISPR screens are saturating has been largely untested. Through integrated analysis of screen data in cancer cell lines generated by the Cancer Dependency Map, we show that a typical CRISPR screen has a ∼20% false negative rate, in addition to library-specific false negatives. Replicability falls sharply as gene expression decreases, while cancer subtype-specific genes within a tissue show distinct profiles compared to false negatives. Cumulative analyses across tissues improves our understanding of core essential genes and suggest only a small number of lineage-specific essential genes, enriched for transcription factors that define pathways of tissue differentiation. To recover false negatives, we introduce a method, Joint Log Odds of Essentiality (JLOE), which builds on our prior work with BAGEL to selectively rescue the false negatives without an increased false discovery rate.