bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cilia stimulatory and antibacterial activities of bitter receptor agonist diphenhydramine: insights into potential complimentary strategies for CF nasal infections
Authors: Kuek L. E. , McMahon D.B. , Ma R.Z. , Miller Z.A. , Jolivert J.F. , Adappa N.D. , Palmer J.N. , Lee R.J 
Published: February 2022

ABSTRACTBACKGROUNDBitter compounds increase ciliary beating and nitric oxide (NO) production in nasal epithelial cells through T2Rs in motile cilia. We examined expression of cilia T2Rs and both host and bacterial responses to T2R14 agonist diphenhydramine.METHODUsing cultured human nasal epithelial cells grown at air liquid interface, we measured expression of T2Rs via qPCR. We measured effects of diphenhydramine on ciliary beat frequency via high-speed imaging and nitric oxide production via fluorescent dye DAF-FM. We measured effects of diphenhydramine on growth of lab and clinical strains of Pseudomonas aeruginosa. We measured biofilm formation of P. aeruginosa using crystal violet staining and surface attachment of P. aeruginosa to cystic fibrosis bronchial epithelial (CBFE41o-) cells using CFU counting.RESULTST2R expression increased with mucocilliary differentiation and did not vary between CF and non-CF ALIs. Treatment with P. aeruginosa flagellin decreased expression of diphenhydramine-responsive T2R14 and 40, among other isoforms. Diphenhydramine increased both NO and CBF. Increases in CBF were disrupted after flagellin treatment. Diphenhydramine impaired growth, biofilm production, and surface attachment of P. aeruginosa.CONCLUSIONST2R expression is similar between normal and CF cells but decreases with flagellin treatment. Utilizing T2R agonists as therapeutics within the context of CF, P. aeruginosa infections may require co-treatment with anti-inflammatories to prevent the reduction of T2R expression with TLR activation. T2R agonist diphenhydramine increases NO production and CBF while also decreasing bacterial growth and biofilm production, and thus diphenhydramine or derivate compounds may have potential clinical usefulness in CF infections as a topical therapy.HIGHLIGHTST2R14 agonist diphenhydramine increases nitric oxide production and cilia beatingFlagellin decreases T2R14 expression in primary airway epithelial cellsT2R14 agonist Diphenhydramine inhibits Pseudomonas growth and biofilm formation
Toward Atomistic Models of Intact SARS-CoV-2 via Martini Coarse-Grained Molecular Dynamics Simulations
Authors: Wang Dali , Li Jiaxuan , Wang Lei , Cao Yipeng , Li Sai , Song Chen 
Published: February 2022

AbstractThe causative pathogen of Coronavirus disease 2019 (COVID-19), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is an enveloped virus assembled by a lipid envelope and multiple structural proteins. In this study, by integrating experimental data, structural modeling, and coarse-grained molecular dynamics simulations, we constructed multiscale models of SARS-CoV-2. Our 500-ns coarse-grained simulation of the intact virion allowed us to investigate the dynamic behavior of the membrane-embedded proteins and the surrounding lipid moleculesin situ. Our results indicated that the membrane-embedded proteins are highly dynamic, and certain types of lipids exhibit various binding preferences to specific sites of the membrane-embedded proteins. The equilibrated virion model was transformed into atomic resolution, which provided a 3D structure for scientific demonstration and can serve as a framework for future exascale all-atom MD simulations.
Transcription Factor-Centric Approach to Identify Non-Recurring Putative Regulatory Drivers in Cancer
Authors: Zhao Jingkang , Martin Vincentius , Gordân Raluca 
Published: February 2022

ABSTRACTRecent efforts to sequence the genomes of thousands of matched normal-tumor samples have led to the identification of millions of somatic mutations, the majority of which are non-coding. Most of these mutations are believed to be passengers, but a small number of non-coding mutations could contribute to tumor initiation or progression, e.g. by leading to dysregulation of gene expression. Efforts to identify putative regulatory drivers rely primarily on information about the recurrence of mutations across tumor samples. However, in regulatory regions of the genome, individual mutations are rarely seen in more than one donor. Instead of using recurrence information, here we present a method to identify putative regulatory driver mutations based on the magnitude of their effects on transcription factor-DNA binding. For each gene, we integrate the effects of mutations across all its regulatory regions, and we ask whether these effects are larger than expected by chance, given the mutation spectra observed in regulatory DNA in the cohort of interest. We applied our approach to analyze mutations in a liver cancer data set with ample somatic mutation and gene expression data available. By combining the effects of mutations across all regulatory regions of each gene, we identified dozens of genes whose regulation in tumor cells is likely to be significantly perturbed by non-coding mutations. Overall, our results show that focusing on the functional effects of non-coding mutations, rather than their recurrence, has the potential to identify putative regulatory drivers and the genes they dysregulate in tumor cells.
A New Classification Method Based on Dynamic Ensemble Selection and its Application to Predict Variance Patterns in HIV-1 Env
Authors: Fili Mohammad , Hu Guiping , Han Changze , Kort Alexa , Trettin John , Haim Hillel 
Published: February 2022

ABSTRACTTherapeutics that target the envelope glycoproteins (Envs) of human immunodeficiency virus type 1 (HIV-1) effectively reduce virus levels in patients. However, due to mutations, new Env variants are frequently generated, which may be resistant to the treatments. The appearance of such sequence variance at any Env position is seemingly random. A better understanding of the spatiotemporal patterns of variance across Env may lead to the development of new therapeutic strategies. We hypothesized that, at any time point in a patient, positions with sequence variance are clustered on the three-dimensional structure of Env. To test this hypothesis, we examined whether variance at any Env position can be predicted by the variance measured at adjacent positions. Sequences from 300 HIV-infected patients were applied to a new algorithm we developed. The k-best classifiers (KBC) method is a dynamic ensemble selection technique that identifies the best classifier(s) within the neighborhood of a new observation. It applies bootstrap resampling to generate out-of-bag samples that are used with the resampled set to evaluate each classifier. For many positions of Env, primarily in the CD4-binding site, KBC accurately predicted variance based on the variance at their adjacent positions. KBC improved performance compared to the initial learners, static ensemble, and other baseline models. KBC also outperformed other algorithms for predicting variance at multi-position footprints of therapeutics on Env. These understandings can be applied to refine models that predict future changes in HIV-1 Env. More generally, we propose KBC as a new high-performance dynamic ensemble selection technique.
Generating spatiotemporal patterns of linearly polarised light at high frame rates for insect vision research
Authors: Supple Jack A. , Varennes-Phillit Léandre , Gajjar-Reid Dexter , Cerkvenik Uroš , Belušič Gregor , Krapp Holger G. 
Published: February 2022

AbstractPolarisation vision is commonplace among invertebrates; however, most experiments focus on determining behavioural and/or neurophysiological responses to static polarised light sources rather than moving patterns of polarised light. To this end, we designed a polarisation stimulation device based on superimposing polarised and non-polarised images from two projectors, which can display moving patterns at frame rates exceeding invertebrate flicker fusion frequencies. A linear polariser fitted to one projector enables moving patterns of polarised light to be displayed, whilst the other projector contributes arbitrary intensities of non-polarised light to yield moving patterns with a defined polarisation and intensity contrast. To test the device, we measured receptive fields of polarisation sensitive Argynnis paphia butterfly photoreceptors for both non-polarised and polarised light. We then measured local motion sensitivities of the optic flow-sensitive lobula plate tangential cell H1 in Calliphora vicina blowflies under both polarised and non-polarised light, finding no polarisation sensitivity in this neuron.
Proteomics and Functional Analysis Revealed TaGSTU6/TaCBSX3 Enhances Wheat Resistance to Powdery Mildew
Authors: Wang Qiao , Guo Jia , Jin Pengfei , Ying Guo Meng , Guo Jun , Peng Cheng , Li Qiang , Wang Baotong 
Published: February 2022

AbstractWheat stripe rust and powdery mildew are important worldwide diseases of wheat (Triticum aestivum). The wheat cultivar Xingmin318 (XM318) is resistant to both wheat stripe rust and powdery mildew, which are caused byPuccinia striiformisf. sp.tritici(Pst) andBlumeria graminisf. sp.tritici(Bgt), respectively. To explore the molecular mechanisms of wheat defenses againstPstandBgt, quantitative proteomic analyses of XM318 inoculated withPstandBgt,respectively, were performed using tandem mass tags (TMT) technology. A total of 741 proteins were identified as differentially accumulated proteins (DAPs). Bioinformatics analyses indicated that some functional categories, including antioxidant activity, exhibited obvious differences betweenPstandBgtinfections. Intriguingly, only 42 DAPs responded to bothPstandBgtinfections. Twelve DAPs were randomly selected for RT-qPCR analysis, and the mRNA expression levels of eleven were consistent with their protein expression. Furthermore, gene silencing using the virus-induced gene silencing system indicated that glutathione S-transferase (TaGSTU6) has an important role in resistance toBgtbut not toPst. TaGSTU6 was shown to interact with the cystathionine beta-synthase (CBS) domain-containing protein (TaCBSX3). Knockdown ofTaCBSX3expression only reduced wheat resistance toBgtinfection. Overexpression ofTaGSTU6andTaCBSX3in Arabidopsis (Arabidopsis thaliana) promoted plant resistance toPseudomonas syringaepv.tomatoDC3000 (PstDC3000). Our results indicated that the TaGSTU6 interacting with TaCBSX3 only confers wheat resistance toBgt, suggesting that wheat has different response mechanisms toPstandBgtstress.One-sentence summaryProteomics revealed a difference in the wheat resistance response toPstandBgt, and the TaGSTU6/TaCBSX3 interaction plays an important role only in wheat resistance toBgt.
Genetic mapping of flowering time and plant height in a maize Stiff Stalk MAGIC population
Authors: Michel Kathryn J. , Lima Dayane C. , Hundley Hope , Singan Vasanth , Yoshinaga Yuko , Daum Chris , Barry Kerrie , Broman Karl W. , Robin Buell C. , de Leon Natalia , Kaeppler Shawn M. 
Published: February 2022

ABSTRACTThe Stiff Stalk heterotic pool is a foundation of US maize seed parent germplasm and has been heavily utilized by both public and private maize breeders since its inception in the 1930’s. Flowering time and plant height are critical characteristics for both inbred parents and their test crossed hybrid progeny. To study these traits, a six parent multiparent advanced generation intercross (MAGIC) population was developed including maize inbred lines B73, B84, PHB47 (B37 type), LH145 (B14 type), PHJ40 (novel early Stiff Stalk), and NKH8431 (B73/B14 type). A set of 779 doubled haploid lines were evaluated for flowering time and plant height in two field replicates in 2016 and 2017, and a subset of 689 and 561 doubled haploid lines were crossed to two testers, respectively, and evaluated as hybrids in two locations in 2018 and 2019 using an incomplete block design. Markers were derived from a Practical Haplotype Graph built from the founder whole genome assemblies and genotype-by-sequencing and exome capture-based sequencing of the population. Genetic mapping utilizing an update to R/qtl2 revealed differing profiles of significant loci for both traits between 636 of the DH lines and two sets of 571 and 472 derived hybrids. Genomic prediction was used to test the feasibility of predicting hybrid phenotypes based on theper sedata. Predictive abilities were highest on direct models trained using the data they would predict (0.55 to 0.63), and indirect models trained usingper sedata to predict hybrid traits had slightly lower predictive abilities (0.49 to 0.55). Overall, this finding is consistent with the overlapping and non-overlapping significant QTL found within theper seand hybrid populations and suggests that selections for phenology traits can be made effectively on doubled haploid lines before hybrid data is available.Core IdeasA multi-parent advanced generation intercross (MAGIC) mapping population was developed from six founder Stiff Stalk maize inbreds with commercial relevance. Genetic mapping utilizing an update to R/qtl2 was demonstrated for flowering and plant height traits.Genetic mapping using maize inbred and hybrid information was compared and provided insight into trait expression in inbreds relative to heterotic testcross hybrids.
Injectable hydrogels with phase-separated structures that can encapsulate live cells
Authors: Ishikawa Shohei , Yoshikawa Yuki , Kamata Hiroyuki , Chung Ung-il , Sakai Takamasa 
Published: February 2022

AbstractInjectable hydrogels are biomaterials that can be administered minimally invasively in liquid form, and are considered promising artificial extracellular matrix (ECM) materials. However, ordinary injectable hydrogels are synthesized from water-soluble molecules to ensure injectability, resulting in nonphase-separated structures, making them structurally different from natural ECMs with phase-separated insoluble structural proteins, such as collagen and elastin. Here, we propose a simple material design approach to impart phase-separated structures to injectable hydrogels by adding inorganic salts. Injecting a gelling solution of mutually crosslinkable tetra-arm poly(ethylene glycol)s with potassium sulfate at optimal concentrations results in the formation of a hydrogel with phase-separated structures in situ. These phase-separated structures provide up to an 8-fold increase in fracture toughness while allowing the encapsulation of live mouse chondrogenic cells without compromising their proliferative activity. Our findings highlight that the concentration of inorganic salts is an important design parameter in injectable hydrogels for artificial ECMs.
Associations between brain imaging and polygenic scores of mental health and educational attainment in children aged 9-11
Authors: Fernandez-Cabello Sara , Alnæs Dag , van der Meer Dennis , Dahl Andreas , Holm Madelene , Kjelkenes Rikka , Maximov Ivan I. , Norbom Linn B. , Pedersen Mads L. , Voldsbekk Irene , Andreassen Ole A. , Westlye Lars T. 
Published: February 2022

AbstractPsychiatric disorders are highly heritable and polygenic, and many have their peak onset in late childhood and adolescence, a period of tremendous changes. Although the neurodevelopmental antecedents of mental illness are widely acknowledged, research in youth population cohorts is still scarce, preventing our progress towards the early characterization of these disorders. We included 7,124 children (9-11 years old) from the Adolescent Brain and Cognitive Development Study to map the associations of structural and diffusion brain imaging with common genetic variants and polygenic scores for psychiatric disorders and educational attainment. We used principal component analysis to derive imaging components, and calculated their heritability. We then assessed the relationship of imaging components with genetic and clinical psychiatric risk with univariate models and Canonical correlation analysis (CCA). Most imaging components had moderate heritability. Univariate models showed limited evidence and small associations of polygenic scores with brain structure at this age. CCA revealed two significant modes of covariation. The first mode linked higher polygenic scores for educational attainment with less externalizing problems and larger surface area. The second mode related higher polygenic scores for schizophrenia, bipolar disorder, and autism spectrum disorder to higher global cortical thickness, smaller white matter volumes of the fornix and cingulum, larger medial occipital surface area and smaller surface area of lateral and medial temporal regions. While cross-validation suggested limited generalizability, our results highlight the potential of multivariate models to better understand the transdiagnostic and distributed relationships between mental health and brain structure in late childhood.
Protection by 4th dose of BNT162b2 against Omicron in Israel
Authors: Bar-On Yinon M. , Goldberg Yair , Mandel Micha , Bodenheimer Omri , Amir Ofra , Freedman Laurence , Alroy-Preis Sharon , Ash Nachman , Huppert Amit , Milo Ron 
Published: February 2022

AbstractBACKGROUNDOn January 2, 2022, Israel began administering a fourth dose of BNT162b2 vaccine (Pfizer-BioNTech) to people aged over 60 years and at-risk populations, who had received a third dose of vaccine at least 4 months earlier. The effect of the fourth dose on confirmed coronavirus 2019 disease (Covid-19) and severe illness are still unclear.METHODSWe extracted data for the Omicron-dominated period January 15 through January 27, 2022, from the Israeli Ministry of Health database regarding 1,138,681 persons aged over 60 years and eligible for the fourth dose. We compared the rate of confirmed Covid-19 and severe illness between those who had received a fourth dose at least 12 days earlier, those who had received only three doses, and those 3 to 7 days after receiving the fourth dose. We used Poisson regression after adjusting for possible confounding factors.RESULTSThe rate of confirmed infection was lower in people 12 or more days after their fourth dose than among those who received only three doses and those 3 to 7 days after vaccination by factors of 2.0 (95% confidence interval [CI], 2.0 to 2.1) and 1.9 (95% CI, 1.8 to 2.0), respectively. The rate of severe illness was lower by factors of 4.3 (95% CI, 2.4 to 7.6) and 4.0 (95% CI, 2.2 to 7.5).CONCLUSIONSRates of confirmed Covid-19 and severe illness were lower following a fourth dose compared to only three doses.
Ethiopian Healthcare Workers’ Experiences During the COVID-19 Pandemic
Authors: Chakrabarti Averi , Memirie Solomon Tessema , Bekele Delayehu , Kiros Mizan , Meyer Christina L. , Pham Phuong N. , Vinck Patrick , Verguet Stéphane 
Published: February 2022

AbstractBackgroundThe COVID-19 pandemic has caused widespread health and socioeconomic disruptions around the world. Understanding the impact that this crisis has had on health workers and the delivery of routine health care services within countries provides evidence on pandemic preparedness and response. Here, we conduct an investigation into these factors for the Ethiopian context.Methods and findingsWe conducted an online cross-sectional survey with Ethiopian health care professionals between August 27 and October 10, 2020 via existing research networks. The variables of interest were confidence in COVID-19 related knowledge, training and experience, the adoption of precautionary health practices, risk perceptions, and respondent concerns. The majority of surveyed health care professionals in Ethiopia reported seeing fewer patients than usual during the COVID-19 crisis, gaps in pandemic training, inadequate access to personal protective equipment (PPE) and barriers to accessing COVID-19 testing. Most health care professionals were also deeply concerned and worried about their own COVID-19 risks and the likelihood that they would transmit the disease to others.ConclusionsOur study findings point to a possible reduction in routine health care services during the COVID-19 pandemic and gaps in pandemic preparedness in Ethiopia. The ministry of health and other stakeholders should work towards improving access to PPE and testing, and identify approaches to ensure that essential healthcare provision (such as immunizations) is not disrupted during crises akin to the COVID-19 outbreak.
Humoral response, associated symptoms and profile of patients infected by SARS-CoV-2 with taste or smell disorders in the SAPRIS multicohort study
Authors: Ramillon Julien , de Lamballerie Xavier , Robineau Olivier , Blanché Helene , Severi Gianluca , Touvier Mathilde , Zins Marie , Carrat Fabrice , Lapidus Nathanaël ,   the SAPRIS-SERO study group
Published: February 2022

AbstractObjectivesTaste or smell disorders have been reported as strongly associated with COVID-19 diagnosis. We aimed to identify subject characteristics, symptom associations, and humoral response intensity associated with taste or smell disorders.Patients and methodsWe used data from SAPRIS, a study based on a consortium of five prospective cohorts gathering 279,478 participants in the French general population. In the analysis, we selected participants who were presumably infected by SARS-CoV-2 during the first epidemic wave.ResultsThe analysis included 3,439 patients with a positive ELISA-Spike. Sex (OR = 1.28 [95% CI 1.05-1.58] for women), smoking (OR = 1.54 [95% CI 1.13-2.07]), consumption of more than 2 drinks of alcohol a day (OR = 1.37 [95% CI 1.06-1.76]) were associated with a higher probability of taste or smell disorders. The relationship between age and taste or smell disorders was non-linear. Serological titers were associated with taste or smell disorders: OR = 1.31 [95% CI 1.26-1.36], OR = 1.37 [95% CI 1.33-1.42] and OR = 1.34 [95% CI 1.29-1.39] for ELISA-Spike, ELISA-Nucleocapsid and seroneutralization, respectively. Among participants with taste or smell disorders, 90% reported a wide variety of other symptoms whereas 10% reported no other symptom or only rhinorrhea.ConclusionAmong patients with a positive ELISA-Spike test, women, smokers and people drinking more than 2 drinks a day were more likely to develop taste or smell disorders. This symptom was strongly associated with a humoral response. The overwhelming majority of patients with taste or smell disorders experienced a wide variety of symptoms.
Activity and state-dependent modulation of salt taste behavior via pharyngeal neurons inDrosophila melanogaster
Authors: Kaushik Shivam , Kumar Rahul , Kumar Sachin , Sanghi Srishti , Tanimura Teiichi , Rincon-Limas Diego E. , Kain Pinky 
Published: February 2022

AbstractSodium present in NaCl is a fundamental nutrient required for many physiological processes. In animals, includingDrosophila,low-salt concentrations induce attraction and high-salt concentrations evoke aversive behavior. Although the cellular basis of low and high salt taste detection has been described, the mechanisms regulating high salt consumption and salt taste modulation in animals remain elusive. Thus, we investigated the neural mechanisms behind high NaCl consumption in adultDrosophila, focusing on how flies adjust their acceptance of high salt based on their diet. Our findings show that long-term exposure to high salt increases the taste sensitivity of pharyngeal LSO neurons, which, in turn, enhances high salt intake. Exposing flies to a high NaCl diet for three days shows a decline in high salt aversion under starvation. Our results suggest that this modulation requires active LSO neurons and a starvation state or dopamine as genetic suppression of LSO pharyngeal neuronal activity in high NaCl-fed flies inhibit excessive salt intake. We also found that several independent taste receptor neurons and pathways are involved in such a modulation. Silencing any one of multiple LSO neuronal types inhibits excessive salt intake. Our study suggests that flies can adapt to the amount of salt ingested over several days, indicating the presence of a critical mechanism that resets the salt appetite and related neural circuits.