bluuebunny/crossref_metadata_2025_split huggingface dataset:
Template switching in DNA replication can create and maintain RNA hairpins
Authors: Mönttinen Heli , Löytynoja Ari 
Published: April 2021

AbstractThe evolutionary origin of ribonucleic acid (RNA) stem structures and the preservation of their base-pairing under a spontaneous and random mutation process have puzzled theoretical evolutionary biologists. DNA replication-related template switching is a mutation mechanism that creates reverse-complement copies of sequence regions within a genome by replicating briefly either along the complementary or nascent DNA strand. Depending on the relative positions and context of the four switch points, this process may produce a reverse-complement repeat capable of forming the stem of a perfect DNA hairpin, or fix the base-pairing of an existing stem. Template switching is typically thought to trigger large structural changes and its possible role in the origin and evolution of RNA genes has not been studied. Here we show that the reconstructed ancestral histories of RNA genes contain mutation patterns consistent with the DNA replication-related template switching. In addition to multi-base compensatory mutations, the mechanism can explain complex sequence changes, though mutations breaking the structure rarely get fixed in evolution. Our results suggest a solution for the longstanding dilemma of RNA gene evolution and demonstrate how template switching can both create perfect stems with a single mutation event and help maintaining the stem structure over time. Interestingly, template switching also provides an elegant explanation for the asymmetric base-pair frequencies within RNA stems.
Genome-scale modeling ofPseudomonas aeruginosaPA14 unveils its broad metabolic capabilities and role of metabolism in drug potentiation
Authors: Dahal Sanjeev , Renz Alina , Dräger Andreas , Yang Laurence 
Published: April 2021

AbstractP. aeruginosais an opportunistic human pathogen that is one of the leading causes of hospital-acquired infections. We have developed an updated genome-scale model (GEM) ofPseudomonas aeruginosaPA14 for systems-study of the pathogen. We used both automated and semi-manual approaches to reconstruct and curate the model. After an extensive literature research, we added organism-specific reactions (e.g., phenazine transport and redox metabolism, cofactor metabolism, carnitine metabolism, oxalate production, etc.) to the model. This effort led to a highly curated, three-compartment, and mass-and-charge balanced BiGG model of PA14 that contains 1509 genes, 1779 metabolic reactions and 1151 unique metabolites. The model (iSD1509) has the largest genome coverage ofP. aeruginosaPA14 to date with 424 more genes than the previous model (iPau1129). It is also the most accurate with prediction accuracies as high as 92.4% (for gene essentiality) and 93.5% (for substrate utilization). The model simulates growth in both aerobic and anaerobic conditions. It predicts the biosynthesis of the virulence factor phenazine as a process for the pathogen to grow in low-oxygen environment. Further, a mechanism for the overproduction of a drug susceptibility biomarker (gluconate) can be elucidated by the principles of optimal growth. Finally, the model also simulates drug activity potentiation and protection by fumarate and glyoxylate, respectively, and provides mechanistic explanations for these processes. Overall,iSD1509 can be utilized to decipher the metabolic mechanisms associated with virulence and antibiotic susceptibility ofP. aeruginosaPA14 to aid in the development of effective intervention strategies.
Opposing roles of the dorsolateral and dorsomedial striatum in the acquisition of skilled action sequencing in rats
Authors: Turner Karly M. , Svegborn Anna , Langguth Mia , McKenzie Colin , Robbins Trevor W. 
Published: April 2021

ABSTRACTThe shift in control from dorsomedial to dorsolateral striatum during skill and habit formation has been well established, but whether striatal subregions orchestrate this shift co-operatively or competitively remains unclear. Cortical inputs have also been implicated in the shift towards automaticity, but it is unknown if they mirror their downstream striatal targets across this transition. We addressed these questions using a five-step heterogeneous action sequencing task in rats that is optimally performed by automated chains of actions. By optimising automatic habitual responding, we discovered that loss of function in the dorsomedial striatum accelerated sequence acquisition. In contrast, loss of function in the dorsolateral striatum impeded acquisition of sequencing, demonstrating functional opposition within the striatum. Unexpectedly the medial prefrontal cortex was not involved, however the lateral orbitofrontal cortex was critical. These results shift current theories about striatal control of behavior to a model of competitive opposition, where the dorsomedial striatum acts in a gating role to inhibit dorsolateral-striatum driven behavior.
The neural bases of program comprehension: a coordinate-based fMRI meta-analysis
Authors: Ikutani Yoshiharu , Itoh Takeshi D. , Kubo Takatomi 
Published: April 2021

AbstractThe understanding of brain activity during program comprehension have advanced thanks to noninvasive neuroimaging techniques, such as functional magnetic resonance imaging (fMRI). However, individual neuroimaging studies of program comprehension often provided inconsistent results and made it difficult to identify the neural bases. To identify the essential brain regions, this study performed a small meta-analysis on recent fMRI studies of program comprehension using multilevel kernel density analysis (MKDA). Our analysis identified a set of brain regions consistently activated in various program comprehension tasks. These regions consisted of three clusters, each of which centered at the left inferior frontal gyrus pars triangularis (IFG Tri), posterior part of middle temporal gyrus (pMTG), and right middle frontal gyrus (MFG). Additionally, subsequent analyses revealed relationships among the activation patterns in the previous studies and multiple cognitive functions. These findings suggest that program comprehension mainly recycles the language-related networks and partially employs other domain-general resources in the human brain.
Accumulation-depuration data collection in support of toxicokinetic modelling
Authors: Ratier Aude , Charles Sandrine 
Published: April 2021

ABSTRACTRegulatory bodies requires evaluation of bioaccumulation of chemicals within organisms with the objective to better assess risks linked to the toxicity of active substances. To this end, toxicokinetic (TK) data are particularly useful to relate the chemical exposure concentration to the accumulation and depuration processes happening within organisms. The bioaccumulative property of substances is quantified by bioaccumulation metrics obtained by fitting TK models to data collected from bioaccumulation tests. The internal concentrations of the studied substances are measured within organisms at regular time points during both accumulation and depuration phases, and their time course is captured by TK models thus providing bioaccumulation metrics. Still today, raw TK data remain difficult to access, as most of the time provided within papers in plots only. To increase accessibility to TK data, we present in this paper a wide collection of raw data sets extracted from the scientific literature in support of TK modelling to be performed with the MOSAICbioaccweb application (https://mosaic.univ-lyon1.fr/bioacc/).
Genetic mapping of sex and self-incompatibility determinants in the androdioecious plantPhillyrea angustifolia
Authors: Carré Amélie , Gallina Sophie , Santoni Sylvain , Vernet Philippe , Godé Cécile , Castric Vincent , Saumitou-Laprade Pierre 
Published: April 2021

AbstractThe diversity of mating and sexual systems in angiosperms is spectacular, but the factors driving their evolution remain poorly understood. In plants of the Oleaceae family, an unusual self-incompatibility (SI) system has been discovered recently, whereby only two distinct homomorphic SI specificities segregate stably. To understand the role of this peculiar SI system in preventing or promoting the diversity of sexual phenotypes observed across the family, an essential first step is to characterize the genetic architecture of these two traits. Here, we developed a high-density genetic map of the androdioecious shrubP. angustifoliabased on a F1 cross between a hermaphrodite and a male parent with distinct SI genotypes. Using a double restriction-site associated digestion (ddRAD) sequencing approach, we obtained reliable genotypes for 196 offspring and their two parents at 10,388 markers. The resulting map comprises 23 linkage groups totaling 1,855.13 cM on the sex-averaged map. We found strong signals of association for the sex and SI phenotypes, that were each associated with a unique set of markers on linkage group 12 and 18 respectively, demonstrating inheritance of these traits as single, independent, mendelian factors. TheP. angustifolialinkage map shows robust synteny to the olive tree genome overall. Two of the six markers strictly associated with SI inP. angustifoliahave strong similarity with a recently identified 741kb chromosomal region fully linked to the SI phenotype on chromosome 18 of the olive tree genome, providing strong cross-validation support. The SI locus stands out as being markedly rearranged, while the sex locus has remained relatively more collinear between the two species. ThisP. angustifolialinkage map will be a useful resource to investigate the various ways by which the sex and SI determination systems have co-evolved in the broader phylogenetic context of the Oleaceae family.
Studies of Salt and Stress Sensitivity on Arterial Pressure in Renin-b Deficient Mice
Authors: Nakagawa Pablo , Gomez Javier , Lu Ko-Ting , Grobe Justin L. , Sigmund Curt D. 
Published: April 2021

AbstractExcessive sodium intake is known to increase the risk for hypertension, heart disease, and stroke. Individuals who are more susceptible to the effects of high salt are at higher risk for cardiovascular diseases even independent of their blood pressure status. Local activation of the renin-angiotensin system (RAS) in the brain, among other mechanisms, has been hypothesized to play a key role in contributing to salt balance. We have previously shown that deletion of the alternative renin isoform termed renin-b disinhibits the classical renin-a encoding preprorenin in the brain resulting in elevated brain RAS activity. Thus, we hypothesized that renin-b deficiency results in higher susceptibility to salt-induced elevation in blood pressure. Telemetry implanted Ren-bNulland wildtype littermate mice were first offered a low salt diet for a week and subsequently a high salt diet for another week. A high salt diet induced a mild blood pressure elevation in both Ren-bNulland wildtype mice, but mice lacking renin-b did not exhibit an exaggerated pressor response. When renin-b deficient mice were exposed to a high salt diet for a longer duration (4 weeks), was a trend for increased myocardial enlargement in Ren-bNullmice when compared with control mice. Multiple studies have also demonstrated the association of chronic and acute environmental stress with hypertension. Activation of the RAS in the rostral ventrolateral medulla and the hypothalamus is required for stress-induced hypertension. Thus, we next questioned whether the lack of renin-b would result in exacerbated response to an acute restraint-stress. Wildtype and Ren-bNullmice equally exhibited elevated blood pressure in response to restraint-stress, which was similar in mice fed either a low or high salt diet. These studies highlight a complex mechanism that masks/unmasks roles for renin-b in cardiovascular physiology.
Development and comparison of Loop-Mediated Isothermal Amplification with Quantitative PCR for the specific detection ofSaprolegniaspp
Authors: Ghosh Satyaki , Straus David L. , Good Christopher , Phuntumart Vipaporn 
Published: April 2021

AbstractSaprolegniasis is an important disease in freshwater aquaculture, and is associated with oomycete pathogens in the genusSaprolegnia. Early detection of significant levels ofSaprolegniaspp. pathogens would allow informed decisions for treatment which could significantly reduce losses. This study is the first to report the development of loop-mediated isothermal amplification (LAMP) for the detection ofSaprolegniaspp. and compares it with quantitative PCR (qPCR). The developed protocols targeted the internal transcribed spacer (ITS) region of ribosomal DNA and the cytochrome C oxidase subunit 1 (CoxI) gene and was shown to be specific only toSaprolegniagenus. This LAMP method can detect as low as 10 fg ofS. salmonisDNA while the qPCR method has a detection limit of 2 pg ofS. salmonisDNA, indicating the superior sensitivity of LAMP compared to qPCR. When applied to detect the pathogen in water samples, both methods could detect the pathogen when only one zoospore ofSaprolegniawas present. We propose LAMP as a quick (about 20-60 minutes) and sensitive molecular diagnostic tool for the detection ofSaprolegniaspp. suitable for on-site applications.
The dopamine circuit as a reward-taxis navigation system
Authors: Karin Omer , Alon Uri 
Published: April 2021

AbstractResearch on certain circuits in simple organisms, such as bacterial chemotaxis, has enabled the formulation of mathematical design principles, leading to ever more precise experimental tests, catalyzing quantitative understanding. It would be important to map these principles to the far more complex case of a vertebrate behavioral circuit. Here, we provide such a mapping for the midbrain dopamine system. Dopamine transmission plays a key role in learning, motivation, and movement, but its systems-level function is not fully understood. We develop a minimal mechanistic model of the dopamine circuit based on physiological and behavioral data, and show that it can be mapped mathematically to the bacterial chemotaxis circuit. Just as chemotaxis robustly climbs attractant gradients, the dopamine circuit performs ‘reward-taxis’ where the attractant is the expected value of reward. The reward-taxis mechanism is based on a circuit feature called fold-change detection, where the circuit outputs the temporal logarithmic derivative of expected reward. The model can explain the general matching law, in which the ratio of responses to concurrent rewards goes as the reward ratio to the power β. It provides an accurate mechanistic value for β as the average gain/baseline ratio of the dopaminergic neurons. Reward-taxis provides testable etiologies for specific dopamine-related disorders.
GeneCodis 4: Expanding the modular enrichment analysis to regulatory elements
Authors: García-Moreno A. , López-Domínguez R. , Ramirez-Mena A. , Pascual-Montano A. , Aparicio-Puerta E. , Hackenberg M. , Carmona-Saez P. 
Published: April 2021

ABSTRACTGeneCodis is a web-based tool for functional enrichment analysis that allows researchers to integrate different sources of annotations. It extracts sets of significant concurrent annotations and assigns a statistical score to evaluate those that are significantly enriched in the input list. Since its first release in 2007, it has been widely employed to analyze lists of genes in order to interpret the underlying biological mechanisms. Here we present GeneCodis 4, a new release that expands the functional analysis provided by the application, to accept regulatory elements, including lists of, transcription factors, CpG sites and miRNAs. It also incorporates new annotation databases and improved interactive visualizations functionalities to explore results. GeneCodis 4 is freely available athttps://genecodis.genyo.es.
Development of Microbiome Biomarkers for IgA: a Joint Modeling Approach
Authors: Sengupta Rudradev , Owokotomo Olajumoke Evangelina , Shkedy Ziv 
Published: April 2021

AbstractOur aim in this study is to develop predictive microbiome biomarkers for intestinal IgA levels. In this article, a operational taxonomic units(OTU)-specific (family-specific) and time-specific joint model is presented as a tool to model the association between OTU (or family) and biological response (measured by IgA level) taking into account the treatment group (Control or PAT) of the subjects. The model allows detecting OTUs (families) that are associated with the IgA; for some OTUs (families), the association is driven by the treatment while for others the association reflects the correlation between the OTUs (families) and IgA.The results of the analysis reveal that: (1) the observed diversity of S24-7 family can be used as a biomarker to classify samples according to treatment group for days 6 and 12; (2) the treatment effect induces the corrlelation between the S24-7 diversity and the IgA level at day 20; (3) The OTUs that are identified to be significantly differentially abundant (FDR level of 0.05) between the two treatment groups for days 12 and 20 are all part of the S24-7 family, although most of the differentially abundant ones at day 1 are from the Lactobacillaceae family; (4) only the Lachnospiraceae family diversity at day 6, and 20 can be used as predictive biomarker for the IgA level at day 20; (5) New.ReferenceOTU513, correlated with the IgA level at day 20, since day 12, belongs to the Lachnospiraceae family and all other OTUs among the top 10 significantly associated OTUs at day 20 are from the S24-7 family; (6) the observed alpha diversity at day 6 is significantly differentially abundant and can be used as predictive biomarker for IgA level at day 20.
Mitochondrial genomes of two parasiticCuscutaspecies lack clear evidence of horizontal gene transfer and retain unusually fragmentedccmFCgenes
Authors: Anderson Benjamin M , Krause Kirsten , Petersen Gitte 
Published: April 2021

AbstractBackgroundThe intimate association between parasitic plants and their hosts favours the exchange of genetic material, potentially leading to horizontal gene transfer (HGT) between plants. With the recent publication of several parasitic plant nuclear genomes, there has been considerable focus on such non-sexual exchange of genes. To enhance the picture on HGT events in a widely distributed parasitic genus,Cuscuta(dodders), we assembled and analyzed the organellar genomes of two recently sequenced species,C. australisandC. campestris, making this the first account of complete mitochondrial genomes (mitogenomes) for this genus.ResultsThe mitogenomes are 265,696 and 275,898 bp in length and contain a typical set of mitochondrial genes, with ten missing or pseudogenized genes often lost from angiosperm mitogenomes. Each mitogenome also possesses a structurally unusualccmFCgene, which exhibits splitting of one exon and a shift to trans-splicing of its intron. Based on phylogenetic analysis of mitochondrial genes from across angiosperms and similarity-based searches, there is little to no indication of HGT into theCuscutamitogenomes. A few candidate regions for plastome-to-mitogenome transfer were identified, with one suggestive of possible HGT.ConclusionsThe lack of HGT is surprising given examples from the nuclear genomes, and may be due in part to the relatively small size of theCuscutamitogenomes, limiting the capacity to integrate foreign sequences.
Machine learning sequence prioritization for cell type-specific enhancer design
Authors: Lawler Alyssa J , Ramamurthy Easwaran , Brown Ashley R , Shin Naomi , Kim Yeonju , Toong Noelle , Kaplow Irene M , Wirthlin Morgan , Zhang Xiaoyu , Fox Grant , Pfenning Andreas R 
Published: April 2021

AbstractRecent discoveries of extreme cellular diversity in the brain warrant rapid development of technologies to access specific cell populations, enabling characterization of their roles in behavior and in disease states. Available approaches for engineering targeted technologies for new neuron subtypes are low-yield, involving intensive transgenic strain or virus screening. Here, we introduce SNAIL (Specific Nuclear-Anchored Independent Labeling), a new virus-based strategy for cell labeling and nuclear isolation from heterogeneous tissue. SNAIL works by leveraging machine learning and other computational approaches to identify DNA sequence features that confer cell type-specific gene activation and using them to make a probe that drives an affinity purification-compatible reporter gene. As a proof of concept, we designed and validated two novel SNAIL probes that target parvalbumin-expressing (PV) neurons. Furthermore, we show that nuclear isolation using SNAIL in wild type mice is sufficient to capture characteristic open chromatin features of PV neurons in the cortex, striatum, and external globus pallidus. Expansion of this technology has broad applications in cell type-specific observation, manipulation, and therapeutics across species and disease models.
Single-cell antigen-specific activation landscape of CAR T infusion product identifies determinants of CD19 positive relapse in patients with ALL
Authors: Bai Zhiliang , Woodhouse Steven , Kim Dongjoo , Lundh Stefan , Sun Hongxing , Deng Yanxiang , Xiao Yang , Barrett David M. , Myers Regina M. , Grupp Stephan A. , June Carl H. , Melenhorst J. Joseph , Camara Pablo G. , Fan Rong 
Published: April 2021

AbstractChimeric antigen receptor-modified (CAR) T cells targeting CD19 have mediated dramatic responses in relapsed/refractory acute lymphoblastic leukemia (ALL), yet a notable number of patients have CD19-positive relapse within one year of treatment. It remains unclear if the long-term response is associated with the characteristics of CAR T cells in infusion products, hindering the identification of biomarkers to predict therapeutic outcomes prior to treatment. Herein we present 101,326 single cell transcriptomes and surface protein landscape from the CAR T infusion products of 12 pediatric ALL patients upon CAR antigen-specific stimulation in comparison with TCR-mediated activation and controls. We observed substantial heterogeneity in the antigen-specific activation states, among which a deficiency of Th2 function was associated with CD19-positive relapsed patients (median remission 9.6 months) compared with very durable responders (remission>54 months). Proteomic profiles also revealed that the frequency of early memory T cell subsets, rather than activation or co-inhibitory signatures could distinguish CD19-positive relapse. Additionally, a deficit of type 1 helper and cytotoxic effector function and an enrichment for terminally differentiated CD8+ T cells exhibiting low cytokine polyfunctionality was associated with initial non-responders. By contrast, the single-cell transcriptomic data of unstimulated or TCR-activated CAR T cells failed to predict clinical responses. In aggregate, our results dissect the landscape of CAR-specific activation states in infusion products that can identify patients who do not develop a durable response to the therapy, and unveil the molecular mechanisms that may inform strategies to boost specific T cell function to maintain long term remission.