bluuebunny/crossref_metadata_2025_split huggingface dataset:
Radiotherapy induces specific miRNA expression profiles in glioblastoma exosomes
Authors: Boukredine Axel , Saada Sofiane , Durand Stéphanie , Nivet Alexandre , Bessette Barbara , Rehailia Amel , Clavère Pierre , Jauberteau Marie-Odile , Deluche Elise , Lalloué Fabrice 
Published: September 2021

AbstractBackgroundGlioblastoma (GBM) is the most aggressive and frequent primary brain tumor during adulthood. One of the major treatments is the association of surgery and a combination of chemo and radiotherapies. Despite its immediate efficiency, it fails to prevent the cancer recurrence in the irradiated area due to radioresistance mechanisms.MicroRNAs (miRNAs or miR) are small non-coding, single strand RNA molecules encoding to various specific genes and able to regulate their expression and induce the tumor cell survival leading to radioresistance. Small extracellular vesicles (EVs), or exosomes released by tumor cells in tumor microenvironment and blood circulation are able to transport and diffuse miRNAs and affect the microenvironment by spreading the miRNAs, which drive radioresistance.AimsTo identify the variations of miRNAs expression induced by irradiation in human glioblastoma U87-MG cells and their secreted exosomes collected in supernatants.To analyze the miRNAs variations in EVs-derived from the plasma of patients during radiotherapy, in order to identify a miRNA signature induced by radiotherapy in a liquid biopsy.Materiel and methodsU87-MG cells were cultured on plates and exposed to irradiation. miRNAs analyzes were performed in cells and in EVs isolated from cell supernatants to determine miRNAs expressions both in cells and in secreted exosomes before and after irradiation.Plasma-derived EVs were collected from 4 glioblastoma patients before and after surgery and radiotherapy treatments.ConclusionThe analysis of miRNAs expression profiles in both GBM cells and their derived EVs revealed that miR profile changes after irradiation. However, the number of similar miR between cells or EVs, following cell irradiation, was restricted to 3 miRs alone suggesting that the irradiation-induced changes in the miR profile in the cells and their EVs are not closely linked. In this context, the miR profile in EVs from patients plasma was investigated to establish a potential link with the miRNAs profile observed in EVs from irradiated cells and to assess its relationship with the response to radiotherapy. Three miRs (different from those identified in cells) were common between EVs derived from cells and patients derived-exosomes. These miRs detected in circulating EVs could provide a specific and reliable signature in response to ionizing radiation, which could be useful for monitoring the effectiveness of radiotherapy. Further experiments on a larger patients population with clinical data could also help to define whether this signature might have a prognostic value on the response to radiotherapy.
Spatiotemporal coordination at the maternal-fetal interface promotes trophoblast invasion and vascular remodeling in the first half of human pregnancy
Authors: Greenbaum Shirley , Averbukh Inna , Soon Erin , Rizzuto Gabrielle , Baranski Alex , Greenwald Noah F. , Kagel Adam , Bosse Marc , Jaswa Eleni G. , Khair Zumana , Kwok Shirley , Warshawsky Shiri , Piyadasa Hadeesha , Miller Geneva , Schwartz Morgan , Graf Will , Van Valen David , Winn Virginia D. , Hollmann Travis , Keren Leeat , van de Rijn Matt , Angelo Michael 
Published: September 2021

AbstractBeginning in the first trimester, fetally derived extravillous trophoblasts (EVTs) invade the uterus and remodel its spiral arteries, transforming them into large, dilated blood vessels left with a thin, discontinuous smooth muscle layer and partially lined with EVTs. Several mechanisms have been proposed to explain how EVTs coordinate with the maternal decidua to promote a tissue microenvironment conducive to spiral artery remodeling (SAR). However, it remains a matter of debate which immune and stromal cell types participate in these interactions and how this process evolves with respect to gestational age. Here, we used a multiomic approach that combined the strengths of spatial proteomics and transcriptomics to construct the first spatiotemporal atlas of the human maternal-fetal interface in the first half of pregnancy. We used multiplexed ion beam imaging by time of flight (MIBI-TOF) and a 37-plex antibody panel to analyze ∼500,000 cells and 588 spiral arteries within intact decidua from 66 patients between 6-20 weeks of gestation, integrating this with coregistered transcriptomic profiles. Gestational age substantially influenced the frequency of many maternal immune and stromal cells, with tolerogenic subsets expressing CD206, CD163, TIM-3, Galectin-9, and IDO-1 increasingly enriched and colocalized at later time points. In contrast, SAR progression preferentially correlated with EVT invasion and was transcriptionally defined by 78 gene ontology pathways exhibiting unique monotonic and biphasic trends. Lastly, we developed an integrated model of SAR supporting an intravasation mechanism where invasion is accompanied by upregulation of pro-angiogenic, immunoregulatory EVT programs that promote interactions with vascular endothelium while avoiding activation of immune cells in circulating maternal blood. Taken together, these results support a coordinated model of decidualization in which increasing gestational age drives a transition in maternal decidua towards a tolerogenic niche conducive to locally regulated, EVT-dependent SAR.
scBasset: Sequence-based modeling of single cell ATAC-seq using convolutional neural networks
Authors: Yuan Han , Kelley David R 
Published: September 2021

1AbstractSingle cell ATAC-seq (scATAC) shows great promise for studying cellular heterogeneity in epigenetic landscapes, but there remain significant challenges in the analysis of scATAC data due to the inherent high dimensionality and sparsity. Here we introduce scBasset, a sequence-based convolutional neural network method to model scATAC data. We show that by leveraging the DNA sequence information underlying accessibility peaks and the expressiveness of a neural network model, scBasset achieves state-of-the-art performance across a variety of tasks on scATAC and single cell multiome datasets, including cell type identification, scATAC profile denoising, data integration across assays, and transcription factor activity inference.
Myelination deficits in the auditory brainstem of a mouse model of Fragile X Syndrome, a possible mechanism for auditory phenotypes
Authors: Lucas Alexandra , Poleg Shani , Klug Achim , McCullagh Elizabeth 
Published: September 2021

1AbstractAuditory symptoms are one of the most frequent sensory issues described in people with Fragile X Syndrome (FXS), the most common genetic form of intellectual disability. However, the mechanisms that lead to these symptoms are under explored. In this study, we examined whether alterations in myelination in auditory brainstem circuitry contribute to auditory impairments in FXS mice. Specifically, we studied myelinated fibers that terminate in the Calyx of Held, which encode temporally precise sound arrival time, and are some of the most heavily myelinated axons in the brain. We measured anatomical myelination characteristics using coherent anti-stokes Raman spectroscopy (CARS) and electron microscopy (EM) in a FXS mouse model in the medial nucleus of the trapezoid body (MNTB) where the Calyx of Held synapses. We measured number of mature oligodendrocytes (OL) and oligodendrocyte precursor cells (OPCs) to determine if changes in myelination were due to changes in the number of myelinating or immature glial cells. The two microscopy techniques (EM and CARS) showed a decrease in fiber diameter in FXS mice. Additionally, EM results indicated reductions in myelin thickness and axon diameter, and an increase in g-ratio, a measure of structural and functional myelination. Lastly, we showed an increase in both OL and OPCs in MNTB sections of FXS mice suggesting that the myelination phenotype is not due to an overall decrease in number of myelinating OLs. This is the first study to show that a potential myelination mechanism can explain alterations seen in FXS at the level of the auditory brainstem.
Characterization of apicomplexan amino acid transporters (ApiATs) in the malaria parasite Plasmodium falciparum
Authors: Wichers Jan Stephan , van Gelder Carolina , Fuchs Gwendolin , Ruge Julia Mareike , Pietsch Emma , Ferreira Josie L. , Safavi Soraya , von Thien Heidrun , Burda Paul-Christian , Mesén-Ramirez Paolo , Spielmann Tobias , Strauss Jan , Gilberger Tim-Wolf , Bachmann Anna 
Published: September 2021

ABSTRACTDuring the symptomatic human blood phase, malaria parasites replicate within red blood cells. Parasite proliferation relies on the uptake of nutrients, such as amino acids, from the host cell and the blood plasma, requiring transport across multiple membranes. Amino acids are delivered to the parasite through the parasite surrounding vacuolar compartment by specialized nutrient-permeable channels of the erythrocyte membrane and the parasitophorous vacuole membrane (PVM). However, further transport of amino acid across the parasite plasma membrane (PPM) is currently not well characterized. In this study, we focused on a family of Apicomplexan amino acid transporters (ApiATs) that comprises five members in Plasmodium falciparum. First, we localized four of the PfApiATs at the PPM using endogenous GFP-tagging. Next, we applied reverse genetic approaches to probe into their essentiality during asexual replication and gametocytogenesis. Upon inducible knockdown and targeted gene disruption a reduced asexual parasite proliferation was detected for PfApiAT2 and PfApiAT4. Functional inactivation of individual PfApiATs targeted in this study had no effect on gametocyte development. Our data suggest that individual PfApiATs are partially redundant during asexual in vitro proliferation and fully redundant during gametocytogenesis of P. falciparum parasites.IMPORTANCEMalaria parasites live and multiply inside cells. To facilitate their extremely fast intracellular proliferation they hijack and transform their host cells. This also requires the active uptake of nutrients, such as amino acids, from the host cell and the surrounding environment through various membranes that are the consequence of the parasite’s intracellular lifestyle. In this manuscript we focus on a family of putative amino acid transporters termed ApiAT. We show expression and localization of four transporters in the parasite plasma membrane of Plasmodium falciparum-infected erythrocytes that represent one interface of the pathogen to its host cell. We probed into the impact of functional inactivation of individual transporters on parasite growth in asexual and sexual blood stages of P. falciparum and reveal that only two of them show a modest but significant reduction in parasite proliferation but no impact on gametocytogenesis pointing towards redundancy within this transporter family.
How do inter-organisational electronic health records affect hospital physician and pharmacist decisions? A scoping review
Authors: Scott Philip , Nakkas Haythem , Roderick Paul 
Published: September 2021

AbstractObjectiveTo provide an overview of the effects of inter-organisational electronic health records on inpatient diagnosis and treatment decisions by hospital physicians and pharmacists.Materials and MethodsFive-stage scoping review, using distributed cognition and the information value chain as guiding conceptual models. Eligibility criteria: empirical studies addressing how shared health records were used in inpatient clinical decision-making, published 2008-18. Sources: Healthcare Databases Advanced Search, covering nine sources including PubMed. Charting methods: data extraction form completed by one author, with inter-rater reliability assessment at title and abstract review.ResultsQuantitative studies (n=14) often reported relatively low usage of shared records (6.8% to 37.1% of cases). Usage is associated with reduction in diagnostic testing and readmission and variable effects on admissions and overall costs. Qualitative studies (n=6) reported avoidance of duplicate diagnostics, changing clinical decisions, the value of historical laboratory results and optimising the timeliness of care. We found no explicit use of explanatory theoretical models, but there is implicit evidence of an information value chain. We found only one study specifically about pharmacists.DiscussionRelatively low usage is due to clinical judgement whether “extra” data is needed, given current knowledge of the presenting condition and relative complexity. We suggest that extensive EHRs need recommender systems to highlight (sometimes unexpected) relevant content, in parallel with professional guidance on indications for consulting shared records.ConclusionsClinicians only consult shared health records when they must. Mixed effects on process outcomes are due to the hidden variables of patient complexity, clinician judgement and organisational context.
Re-evaluating the role of nucleosomal bivalency in early development
Authors: Shah Rohan N. , Grzybowski Adrian T. , Elias Jimmy , Chen Zhonglei , Hattori Takamitsu , Lechner Carolin C. , Lewis Peter W. , Koide Shohei , Fierz Beat , Ruthenburg Alexander J. 
Published: September 2021

AbstractNucleosomes, composed of DNA and histone proteins, represent the fundamental repeating unit of the eukaryotic genome1; posttranslational modifications of these histone proteins influence the activity of the associated genomic regions to regulate cell identity2–4. Traditionally, trimethylation of histone 3-lysine 4 (H3K4me3) is associated with transcriptional initiation5–10, whereas trimethylation of H3K27 (H3K27me3) is considered transcriptionally repressive11–15. The apparent juxtaposition of these opposing marks, termed “bivalent domains”16–18, was proposed to specifically demarcate of small set transcriptionally-poised lineage-commitment genes that resolve to one constituent modification through differentiation, thereby determining transcriptional status19–22. Since then, many thousands of studies have canonized the bivalency model as a chromatin hallmark of development in many cell types. However, these conclusions are largely based on chromatin immunoprecipitations (ChIP) with significant methodological problems hampering their interpretation. Absent direct quantitative measurements, it has been difficult to evaluate the strength of the bivalency model. Here, we present reICeChIP, a calibrated sequential ChIP method to quantitatively measure H3K4me3/H3K27me3 bivalency genome-wide, addressing the limitations of prior measurements. With reICeChIP, we profile bivalency through the differentiation paradigm that first established this model16,18: from naïve mouse embryonic stem cells (mESCs) into neuronal progenitor cells (NPCs). Our results cast doubt on every aspect of the bivalency model; in this context, we find that bivalency is widespread, does not resolve with differentiation, and is neither sensitive nor specific for identifying poised developmental genes or gene expression status more broadly. Our findings caution against interpreting bivalent domains as specific markers of developmentally poised genes.
Phomoarcherin B as a novel HIV-1 reverse transcriptase RNase H activity inhibitor: conclusions from comprehensive computational analysis
Authors: Abdul Ghafoor Naeem , Baysal Ömür , Süzek Barış Ethem , Silme Ragıp Soner 
Published: September 2021

AbstractThe HIV epidemic has claimed more than 32.7 million live since its emergence in 1981, while many ART and HAART therapies are available and provide relief and control for patients, most of these therapeutics come with long-term side effects, resistance, socio-economical barriers, and other obstacles. In this study, genomic analysis was performed on 98 HIV-1 genomes to determine the most coherent target that could be utilized to restrict and cease the viral replication, the reverse transcriptase enzyme. Following the identification of the target protein, the RNase H activity of the reverse transcriptase was nominated as the potent target given the limited research associated with it. A library of 94 thousand small molecule inhibitors was generated and virtual screening was performed to identify hits, based on the reproducibility of the screening results, 4 compounds with the best scores were considered and their interaction within the active site was analyzed. Subsequently, all-atom molecular dynamics simulations and MM-PBSA was performed to validate the stability and binding free energy of the hits within the RNase H active. In silico ADMET assays were performed on the hit compounds to analyze their drug-likeness, physicochemical and pharmacological properties. Phomoarcherin B, a pentacyclic aromatic sesquiterpene naturally found in the endophytic fungus Phomopsis archeri, known for its anticancer properties scored the best in all the experiments and was nominated as a potential inhibitor of the HIV-1 reverse transcriptase RNase H activity.Author SummaryThe Human immunodeficiency virus 1 (HIV-1) has remained a global public health issue for the past 4 decades with millions of patients around the globe affected. Long years of research in the field of anti-viral therapies had introduced several drugs to combat the viral infection, however, most of these drugs come with their shortcomings. In this study, computational drug discovery approaches were utilized to research novel drugs that could be used as anti-viral agents against the former virus, the results had revealed Phomoarcherin B, a natural compound from an endophytic fungus to hold promising therapeutic potentials.
Spectral Separation of Evoked and Background Cortical Activity – Application to Short Latency Median Nerve Evoked Potentials
Authors: Fischer G. , Baumgarten D. , Kofler M. 
Published: September 2021

AbstractBackgroundSpectral analysis of repeatedly evoked potentials (EPs) is challenging since recordings contain a superposition of evoked signals and background activity. We developed a novel approach, N-interval Fourier Transform Analysis (N-FTA), which allows for reliable separation and accurate assessment of evoked and background spectral components. We applied this approach to spectral analysis of median nerve short latency EPs for identifying spectral bands of clinical relevance.MethodsWe performed right median nerve stimulation in two volunteers at 2.46 Hz and 3.95 Hz stimulation rate (600 and 1000 repetitions respectively). We applied N-FTA for splitting the periodically repeated evoked components from irregular background activity and investigated spectral components in the low, medium and high frequency (LF-, MF-, HF-) bands. We present a signal processing approach, which allows for accurately extracting diagnostically relevant features (signal morphology, latency and amplitude) using an 18 Hz to 240 Hz bandwidth.ResultsIn the LF-band < 10 Hz, evoked-to-background ratio (EBR) was below −15 dB due to the high level near DC background activity (1/f-activity, eye blinks, θ-band). Highest EBR was near −5 dB and obtained at a few tens of Hz. Relatively broad continuous segments of evoked activity were detected in the MF band. These frequencies of a few hundred Hz were linked to the signal segment between the N20 and P25 peaks in the time domain. High frequency oscillations (HFOs) near 600 Hz were approximately −25 dB below the background level and near the limit of the sensitivity of N-FTA. By subtracting stimulation artifacts and applying zero-phase filters it was possible to extract diagnostically relevant short latency EP features (signal morphology, latency and amplitude) only from the MF-band with a similar accuracy as a routinely used broad-band setting. HFOs displayed amplitudes of a few tenths of µV.SummaryN-FTA allows for accurate, simultaneous spectral analysis of evoked and background activity in individual trials. The approach allowed for identifying target frequency bands of high evoked activity and for tailoring signal processing such, that morphology and latency can be obtained at a significantly reduced bandwidth. This should allow for development of more robust and faster recording techniques in the near future.
Spontaneous alpha-band oscillations bias subjective contrast perception
Authors: Balestrieri Elio , Busch Niko A. 
Published: September 2021

AbstractPerceptual decisions depend both on the features of the incoming stimulus and on the ongoing brain activity at the moment the stimulus is received. Specifically, trial-to-trial fluctuations in cortical excitability have been linked to fluctuations in the amplitude of pre-stimulus alpha oscillations (≈8-13 Hz), which are in turn are associated with fluctuations in subjects’ tendency to report the detection of a stimulus. It is currently unknown whether alpha oscillations bias post-perceptual decision making, or even bias subjective perception itself. To answer this question, we used a contrast discrimination task in which subjects reported which of two gratings – one in each hemifield – was perceived as having a stronger contrast. Our EEG analysis showed that subjective contrast was reduced for the stimulus in the hemifield represented in the hemisphere with relatively stronger pre-stimulus alpha amplitude, reflecting reduced cortical excitability. Furthermore, the strength of this spontaneous hemispheric lateralization was strongly correlated with the magnitude of individual subjects’ biases, suggesting that the spontaneous patterns of alpha lateralization play a role in explaining the intersubject variability in contrast perception. These results indicate that spontaneous fluctuations in cortical excitability, indicted by patterns of pre-stimulus alpha amplitude, affect perceptual decisions by altering the phenomenological perception of the visual world.Significance StatementOur moment to moment perception of the world is shaped by the features of the environment surrounding us, as much as by the constantly evolving states that characterize our brain activity. Previous research showed how the ongoing electrical activity of the brain can influence whether a stimulus has accessed conscious perception. However, evidence is currently missing on whether these electrical brain states can be associated to the subjective experience of a sensory input. Here we show that local changes in patterns of electrical brain activity preceding visual stimulation can bias our phenomenological perception. Importantly, we show that the strength of these variations can help explaining the great inter-individual variability in how we perceive the visual environment surrounding us.
Evolutionary transition from a single RNA replicator to a multiple replicator network
Authors: Mizuuchi Ryo , Furubayashi Taro , Ichihashi Norikazu 
Published: September 2021

AbstractIn prebiotic evolution, self-replicating molecules are believed to have evolved into complex living systems by expanding their information and functions open-endedly. Theoretically, such evolutionary complexification could occur through successive appearance of novel replicators that interact with one another to form replication networks. Here we performed long-term evolution experiments using an RNA that replicates by a self-encoded RNA replicase. The RNA diversified into multiple coexisting host and parasite lineages, whose frequencies in the population initially fluctuated and gradually stabilized. The final population, comprising five RNA lineages, forms a replicator network with diverse interactions, including cooperation to help the replication of all other members. These results support the capability of molecular replicators to spontaneously develop complexity through Darwinian evolution, a critical step for the emergence of life.