bluuebunny/crossref_metadata_2025_split huggingface dataset:
Myogenetic oligodeoxynucleotides as anti-nucleolin aptamers inhibit the growth of embryonal rhabdomyosarcoma cells
Authors: Nohira Naoki , Shinji Sayaka , Nakamura Shunichi , Nihashi Yuma , Shimosato Takeshi , Takaya Tomohide 
Published: October 2021

AbstractBackgroundEmbryonal rhabdomyosarcoma (ERMS) is the muscle-derived tumor retaining myogenic ability. iSN04 and AS1411, which are myogenetic oligodeoxynucleotides (myoDNs) serving as anti-nucleolin aptamers, have been reported to inhibit the proliferation and induce the differentiation of myoblasts. The present study investigated the effects of iSN04 and AS1411 on the growth of multiple ERMS1 cell lines in vitro.MethodsThree patient-derived ERMS cell lines, ERMS1, KYM1, and RD, were used. Nucleolin expression and localization in these cells was confirmed by immunostaining. The effects of iSN04 or AS1411 on the growth of ERMS cells were examined by cell counting, EdU staining, quantitative RT-PCR (qPCR), and three-dimensional culture of tumorspheres.ResultsIn all ERMS cell lines, nucleolin was abundantly expressed, and localized and concentrated in nucleoli, similar to myoblasts. Both iSN04 and AS1411 (10-30 μM) significantly decreased the number of all ERMS cells; however, their optimal conditions were different among the cell lines. iSN04 (10 μM) markedly reduced the ratio of EdU+cells, indicating the inhibition of cell proliferation. qPCR demonstrated that iSN04 suppressed the cell cycle, partially promoted myogenesis, but did not induce apoptosis. Finally, both iSN04 and AS1411 (10-30 μM) disrupted the formation and outgrowth of RD tumorspheres mimicking in vivo tumorigenesis.ConclusionsERMS cells expressed nucleolin, and their growth was inhibited by the anti-nucleolin aptamers, iSN04 and AS1411. The present study provides the first evidence that anti-nucleolin aptamers can be used as nucleic acid drugs for chemotherapy against ERMS.
Genomic identification, annotation, and comparative analysis of Vacuolar-type ATP synthase subunits in Diaphorina citri
Authors: Grace Rebecca , Massimino Crissy , Shippy Teresa D. , Tank Will , Hosmani Prashant S. , Flores-Gonzalez Mirella , Mueller Lukas A. , Hunter Wayne B. , Benoit Joshua B. , Brown Susan J. , D’Elia Tom , Saha Surya 
Published: October 2021

AbstractDetailed annotation and comparative analysis were performed on the Asian citrus psyllid (ACP), Diaphorina citri, vacuolar-type ATP synthase (V-ATPase) to support the biological understanding and development of novel therapeutics to manage psyllid vectors. D. citri is a hemipteran insect that vectors the causative agent, the bacteria Candidatus Liberibacter asiaticus (CLas), of the citrus greening disease, Huanglongbing (HLB). Millions of citrus trees have been destroyed by citrus greening and every grove in Florida has been directly impacted. In eukaryotic organisms, V-ATPase is an abundant heterodimeric enzyme that serves the cell with essential compartment acidification through the active processes that transport protons across the membrane. Manual curation was completed on 15 putative V-ATPase genes in the D. citri genome. Comparative genomic analysis reveals that the D. citri V-ATPase subunits share domains and motifs with other insects, including the V-ATPase-A superfamily domain from the V-ATPase catalytic subunit A, which shares a 92% identity with Acyrthosiphon pisum. Phylogenetic analysis separates D. citri V-ATPase subunits into expected clades with orthologous sequences. Based on the results of annotation and comparative genomic analysis, RNAi therapies targeting D. citri V-ATPase genes, which have been successfully utilized in related hemipterans, are being pursued. Annotation of the D. citri genome is a critical step towards the development of directed-pest management that will lead to the reduced spread of the pathogens causing HLB throughout the citrus industry.
Heptanol-mediated phase separation determines phase preference of molecules in live cell membranes
Authors: Gupta Anjali , Lu Danqin , Balasubramanian Harikrushnan , Chi Zhang , Wohland Thorsten 
Published: October 2021

ABSTRACTPlasma membranes contain diverse nanoscale assemblies of lipid and protein domains. Specific localization of lipids and proteins in these domains is often essential for membrane function and integrity. Due to the nanoscale size and dynamic nature of membrane domains, identification of molecules residing in domains either is not possible with modern imaging techniques or requires advanced methods with high spatiotemporal resolution. Such methods need expensive equipment making these approaches inaccessible and thus difficult to implement at large scale. Here, we present a novel membrane fluidizer-induced clustering (MFIC) approach to identify the phase-preference of molecules in intact cell membranes. Experiments in phase-separated bilayers and live cells on molecules with known phase preference demonstrate that heptanol hyperfluidizes the membrane and stabilizes phase separation in cell membranes. The domain stabilization results in a transition of nano-to micron-sized clusters of associated molecules and allows identification of molecules localized in domains using routine microscopy techniques. This assay can be carried out on both genetically and extrinsically labelled molecules in live cell membranes, does not require any invasive sample preparation and can be carried out in 10-15 minutes. This inexpensive and easy to implement assay can be conducted at large-scale and will allow easy identification of molecules partitioning into domains.
Photosynthetic induction upon transfer from low to high light is affected by leaf nitrogen content in tomato
Authors: Sun Hu , Zhang Yu-Qi , Zhang Shi-Bao , Huang Wei 
Published: October 2021

AbstractThe response of photosynthetic CO2 assimilation to changes of illumination affects plant growth and crop productivity under natural fluctuating light conditions. However, the effects of nitrogen (N) supply on photosynthetic physiology after transition from low to high light are seldom studied. To elucidate this, we measured gas exchange and chlorophyll fluorescence under fluctuating light in tomato (Solanum lycopersicum) seedlings grown with different N conditions. After transition from low to high light, the induction speeds of net CO2 assimilation (AN), stomatal conductance (gs) and mesophyll conductance (gm) delayed with the decline in leaf N content. The times to reach 90% of maximum AN, gs and gm were negatively correlated to leaf N content. This delayed photosynthetic induction in plants grown under low N concentration was mainly caused by the slow induction response of gm rather than that of gs. Furthermore, the photosynthetic induction upon transfer from low to high light was hardly limited by photosynthetic electron flow. These results indicate that decreased leaf N content declines carbon gain under fluctuating light in tomato. Increasing the induction kinetics of gm has the potential to enhance the carbon gain of field crops grown in infertile soil.
Deep learning-based detection and segmentation of diffusion abnormalities in acute ischemic stroke
Authors: Liu Chin-Fu , Hsu Johnny , Xu Xin , Ramachandran Sandhya , Wang Victor , Miller Michael I. , Hillis Argye E. , Faria Andreia V. ,   the STIR and VISTA Imaging investigators
Published: October 2021

ABSTRACTBackgroundAccessible tools to efficiently detect and segment diffusion abnormalities in acute strokes are highly anticipated by the clinical and research communities.MethodsWe developed a tool with deep learning networks trained and tested on a large dataset of 2,348 clinical diffusion weighted MRIs of patients with acute and sub-acute ischemic strokes, and further tested for generalization on 280 MRIs of an external dataset (STIR).ResultsOur proposed model outperforms generic networks and DeepMedic, particularly in small lesions, with lower false positive rate, balanced precision and sensitivity, and robustness to data perturbs (e.g., artefacts, low resolution, technical heterogeneity). The agreement with human delineation rivals the inter-evaluator agreement; the automated lesion quantification of volume and contrast has virtually total agreement with human quantification.ConclusionOur tool is fast, public, accessible to non-experts, with minimal computational requirements, to detect and segment lesions via a single command line. Therefore, it fulfills the conditions to perform large scale, reliable and reproducible clinical and translational research.Plain Language SummaryQuantifying the volume and location of lesions caused by acute ischemic strokes is crucial for therapeutics and prognostic assessment. Research wise, it can be a window to observe relationships between anatomy and function. The definition of such lesions, mostly made by humans, is time- and work-consuming and uses subjective criteria. We used artificial intelligence in a large database of MRIs of patients with ischemic stroke to create an automated tool to detect and segment lesions derived from acute stroke. It outputs the lesion volumes and 3D segmentation maps. Our tool is fast, public, accessible to non-experts, run in local computers, with minimal computational requirements, fulfilling the conditions to perform large scale, reliable and reproducible clinical and translational research.
Metabolic Dysfunction Related Liver Disease as a Risk Factor for Cancer
Authors: Taylor Alasdair , Siddiqui Moneeza K , Ambery Philip , Armisen Javier , Challis Benjamin G. , Haefliger Carolina , Pearson Ewan R. , Doney Alex S.F. , Dillon John F. , Palmer Colin N.A. 
Published: October 2021

AbstractThe aim of this study was to investigate the association with obesity, diabetes and related liver dysfunction and the incidence of cancer.This study was conducted with health record data available from the National Health Service in Tayside and Fife. GoDARTS, SHARE and Tayside and Fife diabetics, three Scottish cohorts of 13,695, 62,438, and 16,312 patients respectively were analysed in this study. Participants in GoDARTS were a volunteer sample, with half having T2DM. SHARE were a volunteer sample. Tayside and Fife diabetics was a population level cohort. Metabolic dysfunction-related liver disease (MDLD) was defined using ALT measurements, and individuals with alternative causes of liver disease (alcohol abuse, viruses etc) were excluded from the analysis. Other indicators of liver disease were analysed including the Fatty Liver Index, Fibrosis Score(FIB-4) and hospital admissions for NASH. The main outcomes were cancer incidence and cancer death.MDLD associated with increased cancer incidence with a hazard ratio of 1.31 in a cox proportional hazards model adjusted for sex, type 2 diabetes, BMI, and smoking status (95% CI = 1.27 – 1.35, p < 0.0001). This was replicated in two further cohorts, and similar associations with cancer incidence were found for Fatty Liver Index (FLI), FIB-4 and NASH. Homozygous carriers of the common NAFLD risk variant PNPLA3 rs738409 had increased risk of cancer. (HR = 1.27 (1.02-1.58), p = 3.1×10−2). BMI was not independently associated with cancer incidence when MDLD was included as a covariate. MDLD was associated with increased risk of cancer death (HR = 1.40, 95% CI =1.33 - 1.47, p < 0.0001).MDLD, FLI, FIB-4 and NASH associated with increased risk of cancer incidence and death. Further, we found evidence of a causal association between NAFLD and cancer using the established causal risk allele of PNPLA3 as a genetic instrument. NAFLD may be a major component of the relationship between obesity and cancer incidence.Lay SummaryWe found that individuals with metabolic dysfunction-related liver disease (MDLD) have higher overall cancer risk than healthy individuals, as well as increased risk of specific cancers such as colon, breast and lung. We also show that when MDLD is accounted for, obesity does not significantly increase overall cancer risk.
Mutations on non-structural proteins of SARS-CoV-2 are possibly responsible for adverse clinical outcomes
Authors: Ichikawa Takaya , Torii Shiho , Suzuki Hikoyu , Takada Akio , Suzuki Satoshi , Nakajima Masahide , Tampo Akihito , Kakinoki Yasutaka 
Published: October 2021

AbstractAmong a cluster of COVID-19 cases from the end of March through April 2021 in Asahikawa, we experienced the cases in which patients manifested severe clinical symptoms compared to patients who were infected before that. A hundred three patients (age range: 65 to 89 years old) enrolled in this study were divided into two groups, group A: the patients infected from November 2020 to March 2021, and group B: the patients in this cluster population. The mortality rates were 6.1% in group A and 16.2% in group B (OR: 2.97, 95%CI: 0.65-15.38). For the severity of disease, the patients in group B required higher oxygen flow rate in early course of admission (mild; p=0.892, moderate; p=0.117, severe; p=0.029). Whole viral genome sequences revealed five non-synonymous mutations by comparison of the isolates with each group. Of these, four were on non-structural proteins (NSPs) including nsp3, 6 and 15, and one was on S protein located near the C-terminus, suggesting that the mutations on NSPs could be responsible for adverse clinical outcomes in COVID-19 patients.
Modeling remdesivir antiviral efficacy in COVID-19 hospitalized patients of the randomized, controlled, open-label DisCoVeRy trial
Authors: Lingas Guillaume , Néant Nadège , Gaymard Alexandre , Belhadi Drifa , Peytavin Gilles , Hites Maya , Staub Thérèse , Greil Richard , Paiva Jose-Artur , Poissy Julien , Peiffer-Smadja Nathan , Costagliola Dominique , Yazdanpanah Yazdan , Wallet Florent , Gagneux-Brunon Amandine , Mentré France , Ader Florence , Burdet Charles , Guedj Jérémie , Bouscambert-Duchamp Maude ,   the DisCoVeRy study group
Published: October 2021

AbstractDespite several clinical studies, the antiviral efficacy of remdesivir in COVID-19 hospitalized patients remains controversial. We analyzed nasopharyngeal normalized viral loads collected in the 29 days following randomization from 665 hospitalized patients included in the DisCoVeRy trial, allocated to either standard of care (SoC, N=329) or SoC + remdesivir for 10 days (N=336). We used a mathematical model to reconstruct viral kinetic profiles and estimate the antiviral efficacy of remdesivir in reducing viral production. To identify factors associated with viral kinetics, additional analyses were conducted stratified either on time of treatment initiation (≤ or > 7 days since symptom onset) or viral load at randomization (< or ≥ 3.5 log10 copies/104 cells). In our model, remdesivir reduced viral production by 2-fold on average (95%CI: 1.5-3.2). Using the estimated parameter of the model, simulations predict that remdesivir reduces time to viral clearance by 0.7 day compared to SoC, with large inter-individual variabilities (Inter-Quartile Range, IQR: 0.0-1.3 days). Exploratory analyses suggest that remdesivir had a larger impact in patients with a high viral load at randomization, reducing viral production by 5-fold on average (95%CI: 2.8-25), leading to a predicted median reduction in the time to viral clearance of 2.4 days (IQR: 0.9-4.5 days).In summary, our model shows that remdesivir reduces viral production from infected cells by a factor 2, leading to a median reduction of 0.7 days in the time to viral clearance compared to SoC. The efficacy was larger in patients with high level of viral load at treatment initiation.One sentence summaryRemdesivir reduces the time to SARS-CoV-2 clearance by 1 day in hospitalized patients, and up to 3 days in those with high viral load at admission.
Opposing subclasses of Drosophila ellipsoid body neurons promote and suppress sleep
Authors: Aleman Abigail , Omoto Jaison Jiro , Singh Prabhjit , Nguyen Bao-Chau , Kandimalla Pratyush , Hartenstein Volker , Donlea Jeffrey M. 
Published: October 2021

SummaryRecent work in Drosophila has uncovered several neighboring classes of sleep-regulatory neurons within the central complex. However, the logic of connectivity and network motifs remains limited by the incomplete examination of relevant cell types. Using a recent genetic-anatomical classification of ellipsoid body ring neurons, we conducted a thermogenetic screen to assess sleep/wake behavior and discovered two opposing populations: sleep-promoting R3m and wake-promoting R3d neurons. Activation of these neurons influences sleep duration and architecture by prolonging or shortening sleep bouts, suggesting a key role in sleep maintenance. R3m and R3d neurons are GABAergic and require GABA synthesis for their effects on sleep. Finally, we use a fluorescent reporter for putative synaptic partners to embed these neurons within the known sleep-regulatory network; R3m and R3d neurons lay downstream of wake-active Helicon cells, and R3m neurons likely inhibit R3d neurons. Together, the data presented herein suggest a neural mechanism by which previously uncharacterized circuit elements operate within the sleep homeostat to stabilize sleep-wake states.
Periodic and Aperiodic Neural Activity Displays Age-Dependent Changes Across Early-to-Middle Childhood
Authors: Hill Aron T. , Clark Gillian M. , Bigelow Felicity J. , Lum Jarrad A. G. , Enticott Peter G. 
Published: October 2021

AbstractThe neurodevelopmental period spanning early-to-middle childhood represents a time of significant growth and reorganisation throughout the cortex. Such changes are critical for the emergence and maturation of a range of social and cognitive processes. Here, we utilised both eyes open and eyes closed resting-state electroencephalography (EEG) to examine maturational changes in both oscillatory (i.e., periodic) and non-oscillatory (aperiodic, ‘1/f-like’) activity in a large cohort of participants ranging from 4-to-12 years of age (N=139, average age=9.41 years, SD=1.95). The EEG signal was parameterised into aperiodic and periodic components, and linear regression models were used to evaluate if chronological age could predict aperiodic exponent and offset, as well as well as peak frequency and power within the alpha and beta ranges. Exponent and offset were found to both decrease with age, while aperiodic-adjusted alpha peak frequency increased with age; however, there was no association between age and peak frequency for the beta band. Age was also unrelated to aperiodic-adjusted spectral power within either the alpha or beta bands, despite both frequency ranges being correlated with the aperiodic signal. Overall, these results highlight the capacity for both periodic and aperiodic features of the EEG to elucidate age-related functional changes within the developing brain.
Dynamic proton-dependent motors power Type IX secretion and gliding adhesin movement inFlavobacterium
Authors: Vincent Maxence S. , Hervada Caterina Comas , Sebban-Kreuzer Corinne , Guenno Hugo Le , Chabalier Maïalène , Kosta Artemis , Guerlesquin Françoise , Mignot Tâm , McBride Mark , Cascales Eric , Doan Thierry 
Published: October 2021

AbstractMotile bacteria usually rely on external apparatus like flagella for swimming or pili for twitching. By contrast, gliding bacteria do not rely on obvious surface appendages to move on solid surfaces.Flavobacterium johnsoniaeand other bacteria in the Bacteroidetes phylum use adhesins whose movement on the cell surface supports motility. InF. johnsoniae, secretion and helicoidal motion of the main adhesin SprB are intimately linked and depend on the type IX secretion system (T9SS). Both processes necessitate the proton motive force (PMF), which is thought to fuel a molecular motor that comprises the GldL and GldM cytoplasmic membrane proteins. Here we show thatF. johnsoniaegliding motility is powered by the pH gradient component of the PMF. We further delineate the interaction network between the GldLM transmembrane helices (TMH) and show that conserved glutamate residues in GldL TMH are essential for gliding motility, although having distinct roles in SprB secretion and motion. We then demonstrate that the PMF and GldL trigger conformational changes in the GldM periplasmic domain. We finally show that multiple GldLM complexes are distributed in the membrane suggesting that a network of motors may be present to move SprB along a helical path on the cell surface. Altogether, our results provide evidence that GldL and GldM assemble dynamic membrane channels that use the proton gradient to power both T9SS-dependent secretion of SprB and its motion at the cell surface.
Cyclooxygenase production of PGE2 promotes phagocyte control of A. fumigatus hyphal growth in larval zebrafish
Authors: Thrikawala Savini , Niu Mengyao , Keller Nancy P. , Rosowski Emily E. 
Published: October 2021

AbstractInvasive aspergillosis is a common opportunistic infection, causing >50% mortality in infected immunocompromised patients. The specific molecular mechanisms of the innate immune system that prevent pathogenesis of invasive aspergillosis in immunocompetent individuals are not fully understood. Here, we used a zebrafish larva-Aspergillus infection model to identify cyclooxygenase (COX) enzyme signaling as one mechanism that promotes host survival. Larvae exposed to the pan-COX inhibitor indomethacin succumb to infection at a significantly higher rate than control larvae. COX signaling is both macrophage- and neutrophil-mediated. However, indomethacin treatment has no effect on phagocyte recruitment. Instead, COX signaling promotes phagocyte-mediated inhibition of germination and invasive hyphal growth. Protective COX-mediated signaling requires the receptor EP2 and exogenous prostaglandin E2 (PGE2) rescues indomethacin-induced decreased immune control of fungal growth. Collectively, we find that COX signaling activates the PGE2-EP2 pathway to increase control A. fumigatus hyphal growth by phagocytes in zebrafish larvae.Author SummaryInvasive aspergillosis causes mortality in >50% of infected patients. It is caused by a free-living fungus Aspergillus fumigatus which releases thousands of airborne spores. While healthy individuals clear inhaled spores efficiently, in immunocompromised individuals these spores grow into filamentous hyphae and destroy lungs and other tissues causing invasive aspergillosis. The immune mechanisms that control this fungal growth in healthy people are still largely unknown. Here, we used a larval zebrafish model of A. fumigatus infection to determine that cyclooxygenase enzymes, which are the target of non-steroidal anti-inflammatory drugs such as aspirin and ibuprofen, are important to control the fungus. Innate immune cells use cyclooxygenase signaling to prevent hyphal growth and tissue destruction. Our study provides new insights into the mechanisms that immune cells deploy to stop invasive growth of A. fumigatus and inform development of future strategies to combat invasive aspergillosis.
Mechanical coupling of supracellular stress amplification and tissue fluidization during exit from quiescence
Authors: Lång Emma , Pedersen Christian , Lång Anna , Blicher Pernille , Klungland Arne , Carlson Andreas , Bøe Stig Ove 
Published: October 2021

AbstractCellular quiescence is a state of reversible cell cycle arrest that is associated with tissue dormancy. Timely regulated entry into and exit from quiescence is important for processes such as tissue homeostasis, tissue repair, stem cell maintenance, developmental processes and immunity. Here we show that quiescent human keratinocyte monolayers contain an actinomyosin-based system that facilitates global viscoelastic flow upon serum-stimulated exit from quiescence. Mechanistically, serum exposure causes rapid amplification of pre-existing contractile sites leading to a burst in monolayer stress that subsequently drives monolayer fluidization. The stress magnitude after quiescence exit correlates with quiescence depth, and a critical stress level must be reached to overcome the cell sheet displacement barrier. The study shows that static quiescent cell monolayers are mechanically poised for motility and identifies global stress amplification as a mechanism for tissue fluidization.