bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inferring time-lagged causality using the derivative of single-cell expression
Authors: Wei Huan-Huan , Lu Hui , Zhao Hongyu 
Published: February 2021

AbstractMany computational methods have been developed for inferring causality among genes using cross-sectional gene expression data, such as single-cell RNA sequencing (scRNA-seq) data. However, due to the limitations of scRNA-seq technologies, time-lagged causal relationships may be missed by existing methods. In this work, we propose a method, called causal inference with time-lagged information (CITL), to infer time-lagged causal relationships from scRNA-seq data by assessing conditional independence between the changing and current expression levels of genes. CITL estimates the changing expression levels of genes by “RNA velocity”. We demonstrate the accuracy and stability of CITL for inferring time-lagged causality on simulation data against other leading approaches. We have applied CITL to real scRNA data and inferred 878 pairs of time-lagged causal relationships, with many of these inferred results supported by the literature.Author summaryComputational causal inference is a promising way to survey causal relationships between genes efficiently. Though many causal inference methods have been applied to gene expression data, none considers the time-lagged causal relationship, which means that some genes may take some time to affect their target genes with several reactions. If relationships between genes are time-lagged, the existing methods’ assumptions will be violated. The relationships will be challenging to recognize. We demonstrate that this is indeed the case through simulation. Therefore, we develop a method for inferring time-lagged causal relationships of single-cell gene expression data. We assume that a time-lagged causal relationship should present a strong association between the cause and the effect’s changing. To calculate such correlation, we first estimate the derivative of gene expression using the information from unspliced transcripts. Then, we use conditional independent tests to search gene pairs satisfying our assumption. Our results suggest that we could accurately infer time-lagged causal gene pairs validated by published literature. This method may complement gene regulatory analysis and provide candidate gene pairs for further controlled experiments.
Selection of stimulus parameters for enhancing slow wave sleep events with a Neural-field theory thalamocortical computational model
Authors: Torres Felipe A. , Orio Patricio , Escobar María-José 
Published: February 2021

AbstractSlow-wave sleep cortical brain activity, conformed by slow-oscillations and sleep spindles, plays a key role in memory consolidation. The increase of the power of the slow-wave events, obtained by auditory sensory stimulation, positively correlates to memory consolidation performance. However, little is known about the experimental protocol maximizing this effect, which could be induced by the power of slow-oscillation, the number of sleep spindles, or the timing of both events’ co-occurrence. Using a mean-field model of thalamocortical activity, we studied the effect of several stimulation protocols, varying the pulse shape, duration, amplitude, and frequency, as well as a target-phase using a closed-loop approach. We evaluated the effect of these parameters on slow-oscillations (SO) and sleep-spindles (SP), considering: (i) the power at the frequency bands of interest, (ii) the number of SO and SP, (iii) co-occurrences between SO and SP, and (iv) synchronization of SP with the up-peak of the SO. The first three targets are maximized using a decreasing ramp pulse with a pulse duration of 50 ms. Also, we observed a reduction in the number of SO when increasing the stimulus energy by rising its amplitude. To assess the target-phase parameter, we applied closed-loop stimulation at 0º, 45º, and 90º of the phase of the narrow-band filtered ongoing activity, at 0.85 Hz as central frequency. The 0º stimulation produces better results in the power and number of SO and SP than the rhythmic or aleatory stimulation. On the other hand, stimulating at 45º or 90º change the timing distribution of spindles centers but with fewer co-occurrences than rhythmic and 0º phase. Finally, we propose the application of closed-loop stimulation at the rising zero-cross point using pulses with a decreasing ramp shape and 50 ms of duration for future experimental work.Author summaryDuring the non-REM (NREM) phase of sleep, events that are known as slow oscillations (SO) and spindles (SP) can be detected by EEG. These events have been associated with the consolidation of declarative memories and learning. Thus, there is an ongoing interest in promoting them during sleep by non-invasive manipulations such as sensory stimulation. In this paper, we used a computational model of brain activity that generates SO and SP, to investigate which type of sensory stimulus –shape, amplitude, duration, periodicity– would be optimal for increasing the events’ frequency and their co-occurrence. We found that a decreasing ramp of 50 ms duration is the most effective. The effectiveness increases when the stimulus pulse is delivered in a closed-loop configuration triggering the pulse at a target phase of the ongoing SO activity. A desirable secondary effect is to promote SPs at the rising phase of the SO oscillation.
Variation in predicted COVID-19 risk among lemurs and lorises
Authors: Melin Amanda D. , Orkin Joseph D. , Janiak Mareike C. , Valenzuela Alejandro , Kuderna Lukas , Marrone Frank , Ramangason Hasinala , Horvath Julie E. , Roos Christian , Kitchener Andrew C. , Khor Chiea Chuen , Lim Weng Khong , Lee Jessica G. H. , Tan Patrick , Umapathy Govindhaswamy , Raveendran Muthuswamy , Harris R. Alan , Gut Ivo , Gut Marta , Lizano Esther , Nadler Tilo , Zinner Dietmar , Johnson Steig E. , Jarvis Erich D. , Fedrigo Olivier , Wu Dongdong , Zhang Guojie , Farh Kyle Kai-How , Rogers Jeffrey , Marques-Bonet Tomas , Navarro Arcadi , Juan David , Arora Paramjit S. , Higham James P. 
Published: February 2021

AbstractThe novel coronavirus SARS-CoV-2, which in humans leads to the disease COVID-19, has caused global disruption and more than 1.5 million fatalities since it first emerged in late 2019. As we write, infection rates are currently at their highest point globally and are rising extremely rapidly in some areas due to more infectious variants. The primary viral target is the cellular receptor angiotensin-converting enzyme-2 (ACE2). Recent sequence analyses of theACE2gene predicts that many nonhuman primates are also likely to be highly susceptible to infection. However, the anticipated risk is not equal across the Order. Furthermore, some taxonomic groups show high ACE2 amino acid conservation, while others exhibit high variability at this locus. As an example of the latter, analyses of strepsirrhine primateACE2sequences to date indicate large variation among lemurs and lorises compared to other primate clades despite low sampling effort. Here, we reportACE2gene and protein sequences for 71 individual strepsirrhines, spanning 51 species and 19 genera. Our study reinforces previous results and finds additional variability in other strepsirrhine species, and suggests several clades of lemurs have high potential susceptibility to SARS-CoV-2 infection. Troublingly, some species, including the rare and Endangered aye-aye (Daubentonia madagascariensis), as well as those in the generaAvahiandPropithecus, may be at high risk. Given that lemurs are endemic to Madagascar and among the primates at highest risk of extinction globally, further understanding of the potential threat of COVID-19 to their health should be a conservation priority. All feasible actions should be taken to limit their exposure to SARS-CoV-2.
Using population-specific add-on polymorphisms to improve genotype imputation in underrepresented populations
Authors: Xu Zhi Ming , Rüeger Sina , Zwyer Michaela , Brites Daniela , Hiza Hellen , Reinhard Miriam , Borrell Sonia , Isihaka Faima , Temba Hosiana , Maroa Thomas , Naftari Rastard , Hella Jerry , Sasamalo Mohamed , Reither Klaus , Portevin Damien , Gagneux Sebastien , Fellay Jacques 
Published: February 2021

AbstractGenome-wide association studies rely on the statistical inference of untyped variants, called imputation, to increase the coverage of genotyping arrays. However, the results are often suboptimal in populations underrepresented in existing reference panels and array designs, since the selected single nucleotide polymorphisms (SNPs) may fail to capture population-specific haplotype structures, hence the full extent of common genetic variation. Here, we propose to sequence the full genome of a small subset of an underrepresented study cohort to inform the selection of population-specific add-on SNPs, such that the remaining array-genotyped cohort could be more accurately imputed. Using a Tanzania-based cohort as a proof-of-concept, we demonstrate the validity of our approach by showing improvements in imputation accuracy after the addition of our designed addon SNPs to the base H3Africa array.
RAD51 nuclear recruitment and inhibition towards innovative strategies against pancreatic cancer
Authors: Schipani Fabrizio , Manerba Marcella , Marotta Roberto , Gennari Arianna , Rinaldi Francesco , Armirotti Andrea , Roberti Marinella , Di Stefano Giuseppina , Rocchia Walter , Tirelli Nicola , Girotto Stefania , Cavalli Andrea 
Published: February 2021

AbstractRAD51, a key player in the homologous recombination (HR) mechanism, is a critical protein to preserve genomic stability. BRCA2, upon DNA damage, promotes RAD51 fibrils disassembly and its nuclear recruitment.Here, we use BRC4, a peptide derived from the fourth BRC repeat of BRCA2; BRC4 induces RAD51 defibrillation through a ‘domino’ effect, eroding fibrils from their termini, and yielding monomeric RAD51. The congruence among several techniques (static and dynamic light scattering, negative staining transmission electron microscopy (TEM), and microscale thermophoresis) allows an accurate estimation of the kinetic and thermodynamic parameters of this process. BRC4 lacks, however, a nuclear localization sequence; therefore, it cannot transport RAD51 into the nucleus, thus behaving as a RAD51 inhibitor. Cellular assays (BxPC-3, pancreatic cancer cells) indeed show that BRC4 efficiently inhibits HR and enhances the cytotoxic effect of cisplatin, a DNA-damaging drug.The present study sheds further light on the complexity of the HR pathway, paving the way for designing peptide and small organic molecule inhibitors of RAD51 as innovative anticancer and chemo/radiosensitizer compounds.
SplicingFactory – Splicing diversity analysis for transcriptome data
Authors: Dankó Benedek , Szikora Péter , Pór Tamás , Szeifert Alexa , Sebestyén Endre 
Published: February 2021

AbstractMotivationAlternative splicing contributes to the diversity of RNA found in biological samples. Current tools investigating patterns of alternative splicing check for coordinated changes in the expression or relative ratio of RNA isoforms where specific isoforms are up- or downregulated in a condition. However, the molecular process of splicing is stochastic and changes in RNA isoform diversity for a gene might arise between samples or conditions. A specific condition can be dominated by a single isoform, while multiple isoforms with similar expression levels can be present in a different condition. These changes might be the result of mutations, drug treatments or differences in the cellular or tissue environment. Here, we present a tool for the characterization and analysis of RNA isoform diversity using isoform level expression measurements.ResultsWe developed an R package called SplicingFactory, to calculate various RNA isoform diversity metrics, and compare them across conditions. Using the package, we tested the effect of RNA-seq quantification tools, quantification uncertainty, gene expression levels, and isoform numbers on the isoform diversity calculation. We analyzed a set of CD34+ hematopoietic stem cells and myelodysplastic syndrome samples and found a set of genes whose isoform diversity change is associated withSF3B1mutations.Availability and implementationThe SplicingFactory package is freely available under the GPL-3.0 license from Bioconductor for the Windows, MacOS and Linux operating systems (https://www.bioconductor.org/packages/release/bioc/html/SplicingFactory.html).Contactsebestyen.endre@med.semmelweis-univ.huSupplementary informationSupplementary data are available at Bioinformatics online.
Mechanically induced localization of SECONDARY WALL INTERACTING bZIP is associated with thigmomorphogenic and secondary cell wall gene expression
Authors: Coomey Joshua H. , MacKinnon Kirk J.-M. , McCahill Ian W. , Khahani Bahman , Handakumbura Pubudu P. , Trabucco Gina M. , Mazzola Jessica , Leblanc Nicole A. , Kheam Rithany , Hernandez-Romero Miriam , Barry Kerrie , Liu Lifeng , Lee Ji E. , Vogel John P. , O’Malley Ronan C. , Chambers James J. , Hazen Samuel P. 
Published: February 2021

AbstractPlant growth requires the integration of internal and external cues, perceived and transduced into a developmental program of cell division, elongation, and wall thickening. Mechanical forces contribute to this regulation, and thigmomorphogenesis typically includes reducing stem height, increasing stem diameter, and a canonical transcriptomic response. We present data on a bZIP transcription factor involved in this process in grasses.Brachypodium distachyonSECONDARY WALL INTERACTING bZIP (SWIZ) protein translocated into the nucleus following mechanostimulation. Classical touch responsive genes were upregulated inB. distachyonroots following touch, including significant induction of the glycoside hydrolase 17 family, which may be unique to grass thigmomorphogenesis. SWIZ protein binding to an E-box variant in exons and introns was associated with immediate activation followed by repression of gene expression.SWIZoverexpression resulted in plants with reduced stem and root elongation. These data further define plant touch-responsive transcriptomics and physiology, offering insights to grass mechanotranduction dynamics.
S-acylation targets ORAI1 channels to lipid rafts for efficient Ca2+ signaling by T cell receptors at the immune synapse
Authors: Carreras-Sureda Amado , Abrami Laurence , Kim Ji-Hee , Frieden Maud , Didier Monica , Van der Goot F. Gisou , Demaurex Nicolas 
Published: February 2021

AbstractEfficient immune responses require Ca2+ fluxes across ORAI1 channels during engagement of T cell receptors (TCR) at the immune synapse (IS) between T cells and antigen presenting cells. Here, we show that ZDHHC20-mediated S-acylation of the ORAI1 channel at residue Cys143 is required for TCR assembly and signaling at the IS. Cys143 mutations reduced ORAI1 currents and store-operated Ca2+ entry in HEK-293 cells and nearly abrogated long-lasting Ca2+ elevations, NFATC1 translocation, and IL-2 secretion evoked by TCR engagement in Jurkat T cells. The acylation-deficient channel had reduced mobility in lipids, accumulated in cholesterol-poor domains, formed tiny clusters, failed to reach the IS and unexpectedly also prevented TCR recruitment to the IS. Our results establish S-acylation as a critical regulator of ORAI1 channel assembly and function at the IS and reveal that local Ca2+ fluxes are required for TCR recruitment to the synapse.
Individuals at risk for developing rheumatoid arthritis harbor differential intestinal bacteriophage communities with distinct metabolic potential
Authors: Mangalea Mihnea R. , Paez-Espino David , Kieft Kristopher , Chatterjee Anushila , Seifert Jennifer A. , Feser Marie L. , Demoruelle M. Kristen , Chriswell Meagan E. , Sakatos Alexandra , Anantharaman Karthik , Deane Kevin D. , Kuhn Kristine A. , Holers V. Michael , Duerkop Breck A. 
Published: February 2021

SUMMARYRheumatoid arthritis (RA) is an autoimmune disease characterized in seropositive individuals by the presence of anti-cyclic citrullinated protein (CCP) antibodies. RA is linked to the intestinal microbiota, yet the association of microbes with CCP serology and their contribution to RA is unclear. We describe intestinal phage communities of individuals at risk for developing RA, with or without anti-CCP antibodies, whose first degree relatives have been diagnosed with RA. We show that at-risk individuals harbor intestinal phage compositions that diverge based on CCP serology, are dominated by Lachnospiraceae phages, and originate from disparate ecosystems. These phages encode unique repertoires of auxiliary metabolic genes (AMGs) which associate with anti-CCP status, suggesting that these phages directly influence the metabolic and immunomodulatory capability of the microbiota. This work sets the stage for the use of phages as preclinical biomarkers and provides insight into a possible microbial-based causation of RA disease development.
Does colour impact attention towards 2D images in geckos?
Authors: Katlein Nathan , Ray Miranda , Wilkinson Anna , Claude Julien , Kiskowski Maria , Wang Bin , Glaberman Scott , Chiari Ylenia 
Published: February 2021

AbstractAnimals are exposed to different visual stimuli that influence how they perceive and interact with their environment. Visual information such as shape and colour can help the animal detect, discriminate and make appropriate behavioural decisions for mate selection, communication, camouflage, and foraging. In all major vertebrate groups, it has been shown that certain species can discriminate and prefer certain colours and that colours may increase the response to a stimulus. However, because colour is often studied together with other potentially confounding factors, it is still unclear to what extent colour discrimination plays a crucial role in the perception of and attention towards biologically relevant and irrelevant stimuli. To address these questions in reptiles, we assessed the response of three gecko speciesCorrelophus ciliatus, Eublepharis macularius, andPhelsuma laticaudato familiar and novel 2D images in colour or grayscale. We found that while all species responded more often to the novel than to the familiar images, colour information did not influence object discrimination. We also found that the duration of interaction with images was significantly longer for the diurnal species,P. laticauda, than for the two nocturnal species, but this was independent from colouration. Finally, no differences among sexes were observed within or across species. Our results indicate that geckos discriminate between 2D images of different content independent of colouration, suggesting that colouration does not increase detectability or intensity of the response. These results are essential for uncovering which visual stimuli produce a response in animals and furthering our understanding of how animals use colouration and colour vision.
Photosynthesis dynamics and regulation sensed in the frequency domain
Authors: Nedbal Ladislav , Lazár Dušan 
Published: February 2021

AbstractFoundations of photosynthesis research have been established mainly by studying the response of plants to changing light, typically to sudden exposure to a constant light intensity after a dark acclimation or light flashes. This approach remains valid and powerful, but can be limited by requiring dark acclimation before time-domain measurements and often assumes that rate constants determining the photosynthetic response do not change between the dark- and light-acclimation.We present experimental data and mathematical models demonstrating that these limits can be overcome by measuring plant responses to sinusoidally modulated light of varying frequency. By its nature, such frequency-domain characterization is performed in light-acclimated plants with no need for prior dark acclimation. Amplitudes, phase shifts, and upper harmonic modulation extracted from the data for a wide range of frequencies can target different kinetic domains and regulatory feedbacks. The occurrence of upper harmonic modulation reflects non-linear phenomena, including photosynthetic regulation. To support these claims, we present a frequency- and time-domain response in chlorophyll fluorescence emission of the green algaChlorella sorokinianain the frequency range 1000 – 0.001 Hz. Based on these experimental data and numerical as well as analytical mathematical models, we propose that frequency-domain measurements can become a versatile new tool in plant sensing.One sentence summaryIt is proposed to characterize photosynthesis in the frequency domain without the need for dark adaptation and, thus, without assumptions about the dark-to-light transition.
Extending the Near Infrared Emission Range of Indium Phosphide Quantum Dots for MultiplexedIn VivoImaging
Authors: Saeboe Alexander M. , Nikiforov Alexey Y. , Toufanian Reyhaneh , Kays Joshua C. , Chern Margaret , Casas J. Paolo , Han Keyi , Piryatinski Andrei , Jones Dennis , Dennis Allison M. 
Published: February 2021

AbstractThis report of the reddest emitting indium phosphide quantum dots (InP QDs) to date demonstrates tunable, near infrared (NIR) photoluminescence and fluorescence multiplexing in the first optical tissue window with a material that avoids toxic constituents. This synthesis overcomes the InP synthesis “growth bottleneck” and extends the emission peak of InP QDs deeper into the first optical tissue window using an inverted QD heterostructure. The ZnSe/InP/ZnS core/shell/shell structure is designed to produce emission from excitons with heavy holes confined in InP shells wrapped around larger-bandgap ZnSe cores and protected by a second shell of ZnS. The InP QDs exhibit InP shell thickness-dependent tunable emission with peaks ranging from 515 – 845 nm. The high absorptivity of InP leads to effective absorbance and photoexcitation of the QDs with UV, visible, and NIR wavelengths in particles with diameters of eight nanometers or less. These nanoparticles extend the range of tunable direct-bandgap emission from InP-based nanostructures, effectively overcoming a synthetic barrier that has prevented InP-based QDs from reaching their full potential as NIR imaging agents. Multiplexed lymph node imaging in a mouse model shows the potential of the NIR-emitting InP particles forin vivoimaging.
The biochemical resolving power of fluorescence lifetime imaging: untangling the roles of the instrument response function and photon-statistics
Authors: Trinh Andrew L. , Esposito Alessandro 
Published: February 2021

AbstractA deeper understanding of spatial resolution has led to innovations in microscopy and the disruption of biomedical research, as with super-resolution microscopy. To foster similar advances in time-resolved and spectral imaging, we have previously introduced the concept of ‘biochemical resolving power’ in fluorescence microscopy. Here, we apply those concepts to investigate how the instrument response function (IRF), sampling conditions, and photon-statistics limit the biochemical resolution of fluorescence lifetime microscopy. Using Fisher information analysis and Monte Carlo simulations, we reveal the complex dependencies between photon-statistics and the IRF, permitting us to quantify resolution limits that have been poorly understood (e.g., the minimum resolvable decay time for a given width of the IRF and photon-statistics) or previously underappreciated (e.g., optimization of the IRF for biochemical detection). With this work, we unravel common misunderstandings on the role of the IRF and provide theoretical insights with significant practical implications on the design and use of time-resolved instrumentation.