bluuebunny/crossref_metadata_2025_split huggingface dataset:
Using Watershed Characteristics for Improving Fecal Source Identification
Authors: Hart John J. , Jamison Megan N. , McNair James N. , Woznicki Sean A. , Jordan Ben , Rediske Richard 
Published: June 2022

AbstractFecal pollution is one of the most prevalent forms of pollution affecting waterbodies worldwide, threatening public health, and negatively impacting aquatic environments. Microbial source tracking (MST) applies polymerase chain reaction (PCR) technology to help identify the source of fecal pollution. In this study, we combine spatial data for two watersheds with general and host-specific MST markers to target human, bovine, and general ruminant sources. Two different PCR technologies were applied for quantifying the targets: quantitative PCR (qPCR) and droplet digital PCR (ddPCR). We found that ddPCR had a higher detection rate (75%) of quantifiable samples compared to qPCR (27%), indicating that ddPCR is more sensitive than qPCR. The three host-specific markers were detected at all sites (n=25), suggesting that humans, cows, and ruminants are contributing to fecal contamination in these watersheds. MST results, combined with watershed characteristics, suggest that streams draining areas with low-infiltration soil groups, high septic system prevalence, and high agricultural land use are at an increased risk for fecal contamination. Microbial source tracking has been applied in numerous studies to aid in identifying the sources of fecal contamination, however these studies usually lack information on the involvement of watershed characteristics. Our study combined watershed characteristics with MST results, applying more sensitive PCR techniques, in addition to watershed characteristics to provide more comprehensive insight into the factors that influence fecal contamination in order to implement the most effective best management practices.Abstract FigureHighlightsddPCR provided higher sensitivity over qPCR when analyzing environmental samplesHuman markers had an association with the number of septic systems in a watershedEvery site had positive detections for all FIB markersBoth ruminant markers were associated with low infiltration hydrologic soil groupsCombining watershed characteristics with MST testing improved source identification
Engineered protein nanocages for concurrent RNA and protein packagingin vivo
Authors: Kwon Seokmu , Giessen Tobias W. 
Published: June 2022

AbstractProtein nanocages have emerged as an important engineering platform for biotechnological and biomedical applications. Among naturally occurring protein cages, encapsulin nanocompartments have recently gained prominence due to their favorable physico-chemical properties, ease of shell modification, and highly efficient and selective intrinsic protein packaging capabilities. Here, we expand encapsulin function by designing and characterizing encapsulins for concurrent RNA and protein encapsulationin vivo. Our strategy is based on modifying encapsulin shells with nucleic acid binding peptides without disrupting the native protein packaging mechanism. We show that our engineered encapsulins reliably self-assembleinvivo, are capable of efficient size-selectivein vivoRNA packaging, can simultaneously load multiple functional RNAs, and can be used for concurrentin vivopackaging of RNA and protein. Our engineered encapsulation platform has potential for co-delivery of therapeutic RNAs and proteins to elicit synergistic effects, and as a modular tool for other biotechnological applications.
Towards A More Informative Representation of the Fetal-Neonatal Brain Connectome using Variational Autoencoder
Authors: Kim Jung-Hoon , De Asis-Cruz Josepheen , Krishnamurthy Dhineshvikram , Limperopoulos Catherine 
Published: June 2022

AbstractRecent advances in functional magnetic resonance imaging (fMRI) have helped elucidate previously inaccessible trajectories of early-life prenatal and neonatal brain development. To date, the interpretation of fetal-neonatal fMRI data has relied on linear analytic models, akin to adult neuroimaging data. However, unlike the adult brain, the fetal and newborn brain develops extraordinarily rapidly, far outpacing any other brain development period across the lifespan. Consequently, conventional linear computational models may not adequately capture these accelerated and complex neurodevelopmental trajectories during this critical period of brain development along the prenatal-neonatal continuum. To obtain a nuanced understanding of fetal-neonatal brain development, including non-linear growth, for the first time, we developed quantitative, systems-wide representations of neuronal circuitry in a large sample (>700) of fetuses, preterm, and full-term neonates using an unsupervised deep generative model called Variational Autoencoder (VAE), a model previously shown to be superior to linear models in representing complex resting state data in healthy adults. Here, we demonstrated that non-linear brain features, i.e., latent variables, derived with the VAE, carried important individual neural signatures, leading to improved representation of prenatal-neonatal brain maturational patterns and more accurate and stable age prediction compared to linear models. Using the VAE decoder, we also revealed distinct functional brain networks spanning the sensory and default mode networks. Using the VAE, we are able to reliably capture and quantify complex, non-linear fetal-neonatal functional neural connectivity. This will lay the critical foundation for detailed mapping of healthy and aberrant functional brain signatures that have their origins in fetal life.
Combined transcriptome and metabolome analysis of a new species of microalgae from Tibetan plateau and its response to sewage treatment
Authors: Jinhu Wang , Qiangying Zhang , Junyu Chen , Jinna Zhou , Jing Li , Yanli Wei , Duo Bu 
Published: June 2022

AbstractMicroalgae are pivotal in maintaining water quality in the lakes and rivers of Qinghai-Tibet plateau. The optimum sewage treatment conditions for Desmodesmus sp. are, temperature: 20–25°C, light intensity: 3000–8000 lx, and pH: 7.0–7.5, identified based on orthogonal experiments. The maximum removal rate of total nitrogen, total phosphorus, and chemical oxygen demand was more than 95% in the actual sewage treatment. The sewage treatment capacity of Desmodesmus sp. from plateau is higher than that from plains under the same treatment conditions. To identify the differentially expressed genes and metabolites in Desmodesmus sp. in response to sewage treatment, a combination of metabolomics and transcriptomics was employed to the microalgae with and without sewage treatment. The results showed that the oxidative phosphorylation, photosynthesis, and propanoate metabolism pathways were the most significantly enriched pathways in sewage treatment. Further, the metabolism of adenosine diphosphate, 2-oxobutanoate, and succinate were significantly upregulated, downregulated, and both upregulated and downregulated, respectively, as shown by the combined transcriptome and metabolome analysis. Additionally, we found that sewage treatment could also induce numerous changes in the primary metabolism, such as carbohydrate, fatty acid biosynthesis, and amino acid metabolism when compared with control. Overall, our results should improve fundamental knowledge of molecular responses to Desmodesmus sp. in sewage treatment and contribute to the design of strategies in microalgae response to sewage treatment.
Targeting Chromatin Effector Pygo2 to Enhance Immunotherapy in Prostate Cancer
Authors: Zhu Yini , Zhao Yun , Wen Jiling , Liu Sheng , Huang Tianhe , Hatial Ishita , Peng Xiaoxia , Janabi Hawraa Al , Huang Gang , Mittlesteadt Jackson , Cheng Michael , Bhardwaj Atul , Ashfeld Brandon L. , Kao Kenneth R. , Maeda Dean Y. , Dai Xing , Wiest Olaf , Blagg Brian S.J. , Lu Xuemin , Cheng Liang , Wan Jun , Lu Xin 
Published: June 2022

ABSTRACTThe noninflamed microenvironment in prostate cancer represents a barrier to immunotherapy. Genetic alterations underlying cancer cell-intrinsic oncogenic signaling have emerging roles in shaping the immune landscape. Recently, we identified Pygopus 2 (PYGO2) as the driver oncogene for the amplicon at 1q21.3. Here, using transgenic mouse models of metastatic prostate adenocarcinoma, we found that Pygo2 deletion decelerated tumor progression, diminished metastases, and extended survival. Pygo2 loss augmented the infiltration of cytotoxic T lymphocytes (CTLs) and sensitized tumor cells to T cell killing. Mechanistically, Pygo2 orchestrated a p53/Sp1/Kit/Ido1 signaling network to foster a microenvironment hostile to CTLs. Genetic or pharmacological inhibition of Pygo2 enhanced the anti-tumor efficacy of immunotherapies using immune checkpoint blockade, adoptive cell transfer, or myeloid-derived suppressor cell inhibitors. In human prostate cancer samples, Pygo2 expression was inversely correlated with CD8+ T cells. Our results highlight a promising path to improving immunotherapy with targeted therapy for lethal prostate cancer.
Enhancement of the Activity of the Antimicrobial Peptides HNP1 and LL-37 by Bovine Pancreatic Ribonuclease A
Authors: Ericksen Bryan 
Published: June 2022

AbstractBackgroundHNP1, LL-37, and HBD1 are antimicrobial against Escherichia coli ATCC 25922 at the standard inoculum but less active at higher inocula.MethodsThe virtual colony count (VCC) microbiological assay was adapted for high inocula and the addition of yeast tRNA and bovine pancreatic ribonuclease A (RNase). 96-well plates were read for 12 hours in a Tecan Infinite M1000 plate reader and photographed under 10x magnification.ResultsAdding tRNA 1:1 to HNP1 at the standard inoculum almost completely abrogated activity. Adding RNase 1:1 to HNP1 at the standard inoculum of 5x105 CFU/mL did not enhance activity. Increasing the inoculum to 6.25x107 CFU/mL almost abrogated HNP1 activity. However, adding RNase 25:1 to HNP1 enhanced activity. Adding both tRNA and RNase resulted in enhanced activity, indicating that the enhancement effect of RNase overwhelms the inhibiting effect of tRNA when both are present. HBD1 activity at the standard inoculum was almost completely abrogated by the addition of tRNA, but LL-37 activity was only slightly inhibited by tRNA. At the high inoculum, LL-37 activity was enhanced by RNase. HBD1 activity was not enhanced by RNase. RNase was not antimicrobial in the absence of antimicrobial peptides. Cell clumps were observed at the high inoculum in the presence of all three antimicrobial peptides and at the standard inoculum in the presence of HNP1+tRNA.ConclusionsAntimicrobial peptide-ribonuclease combinations have the potential to be active against high cell concentrations and biofilms, conditions where the antimicrobial agent alone is relatively ineffective.
Chromatin-immunoprecipitation reveals the PnPf2 transcriptional network controlling effector-mediated virulence in a fungal pathogen of wheat
Authors: John Evan , Singh Karam B. , Oliver Richard P. , Soyer Jessica L. , Muria-Gonzalez Jordi , Soo Daniel , Jacques Silke , Tan Kar-Chun 
Published: June 2022

AbstractThe regulation of virulence in plant-pathogenic fungi has emerged as a key area of importance underlying host infections. Recent work has highlighted the role of transcription factors (TFs) that mediate the expression of virulence-associated genes. A prominent example is Pf2, a member of the Zn2Cys6 family of fungal TFs, where orthologues regulate the expression of genes linked to parasitism in several plant-pathogen lineages. These include PnPf2 which controls effector-gene expression in Parastagonospora nodorum, thereby determining the outcome of effector-triggered susceptibility on its host, wheat. PnPf2 is a promising target for disease suppression but the genomic targets, or whether other are regulators involved, remain unknown. This study used chromatin immunoprecipitation (ChIP-seq) and a mutagenesis analysis to investigate these components. Two distinct binding motifs connected to positive gene-regulation were characterised and genes directly targeted by PnPf2 were identified. These included genes encoding major effectors and other components associated with the P. nodorum pathogenic lifestyle, such as carbohydrate-active enzymes and nutrient assimilators. This supports a direct involvement of PnPf2 in coordinating virulence on wheat. Other TFs were also prominent PnPf2 targets, suggesting it also operates within a transcriptional network. Several TFs were therefore functionally investigated in connection to fungal virulence. Distinct metabolic and developmental roles were evident for the newly characterised PnPro1, PnAda1, PnEbr1 and the carbon-catabolite repressor PnCreA. Overall, the results uphold PnPf2 as the central transcriptional regulator orchestrating genes that contribute to virulence on wheat and provide mechanistic insight into how this occurs.ImportanceFungal pathogens cause large crop losses worldwide and consequently much attention has focused on improving host genetic resistance to diseases. These pathogens use effectors, which require coordinated expression at specific stages of the pathogenic lifecycle, to manipulate the host plant metabolism in favour of infection. However, our understanding of the underlying regulatory network in coordination with other genes involved in fungal pathogenicity is lacking. The Pf2 TF orthologues are key players underpinning virulence and effector gene expression in several fungal phytopathogens, including P. nodorum. This study provided significant insight into the DNA-binding regulatory mechanisms of P. nodorum PnPf2, as well as further evidence that it is central to the coordination of virulence. In the context of crop protection, the Pf2 taxonomic orthologues present opportune targets in major fungal pathogens that can be perturbed to reduce the impact of effector triggered-susceptibility and improve disease resistance.
“It hurts your heart”: frontline healthcare worker experiences of moral injury during the COVID-19 pandemic
Authors: Hegarty Siobhan , Lamb Danni , Stevelink Sharon A. M. , Bhundia Rupa , Raine Rosalind , Doherty Mary Jane , Scott Hannah R. , Marie Anne , Williamson Victoria , Dorrington Sarah , Hotopf Matthew , Razavi Reza , Greenberg Neil , Wessely Simon 
Published: June 2022

AbstractBackgroundMoral injury is defined as the strong emotional and cognitive reactions following events which clash with someone’s moral code, values or expectations. During the COVID-19 pandemic, increased exposure to potentially morally injurious events (PMIEs) has placed healthcare workers (HCWs) at risk of moral injury. Yet little is known about the lived experience of cumulative PMIE exposure and how NHS staff respond to this.ObjectiveWe sought to rectify this knowledge gap by qualitatively exploring the lived experiences and perspectives of clinical frontline NHS staff who responded to COVID-19.MethodsWe recruited a diverse sample of 30 clinical frontline HCWs from the NHS CHECK study cohort, for single time point qualitative interviews. All participants endorsed at least one item on the 9-item Moral Injury Events Scale (MIES) (Nash et al., 2013) at six month follow up. Interviews followed a semi-structured guide and were analysed using reflexive thematic analysis.ResultsHCWs described being routinely exposed to ethical conflicts, created by exacerbations of pre-existing systemic issues including inadequate staffing and resourcing. We found that HCWs experienced a range of mental health symptoms primarily related to perceptions of institutional betrayal as well as feeling unable to fulfil their duty of care towards patients.ConclusionThese results suggest that a multi-facetted organisational strategy is warranted to prepare for PMIE exposure, promote opportunities for resolution of symptoms associated with moral injury and prevent organisational disengagement.HighlightsClinical frontline healthcare workers (HCWs) have been exposed to an accumulation of potentially morally injurious events (PMIEs) throughout the COVID-19 pandemic, including feeling betrayed by both government and NHS leaders as well as feeling unable to provide duty of care to patientsHCWs described the significant adverse impact of this exposure on their mental health, including increased anxiety and depression symptoms and sleep disturbanceMost HCWs interviewed believed that organisational change within the NHS was necessary to prevent excess PMIE exposure and promote resolution of moral distress
A multi-omics approach identifies a blood-based miRNA signature of cognitive decline in two large observational trials
Authors: Sadlon Angélique , Takousis Petros , Evangelou Evangelos , Prokopenko Inga , Alexopoulos Panagiotis , Udeh-Momoh Chinedu T , Price Geraint , Middleton Lefkos , Perneczky Robert ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: June 2022

AbstractIdentifying individuals before the onset of overt symptoms is a key prerequisite for the prevention of Alzheimer’s disease (AD). A wealth of data reports dysregulated microRNA (miRNA) expression in the blood of individuals with AD, but evidence in individuals at subclinical stages is sparse. In this study, a qPCR analysis of a prioritised set of 38 candidate miRNAs in the blood of 830 healthy individuals from the CHARIOT PRO cohort (West London, UK) was undertaken. Here, we identified six differentially expressed miRNAs (hsa-miR-128-3p, hsa-miR-144-5p, hsa-miR-146a-5p, hsa-miR-26a-5p, hsa-miR-29c-3p and hsa-miR-363-3p) in the blood of individuals with low cognitive performance on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). A pathway enrichment analysis for the six miRNAs indicated involvement of apoptosis and inflammation, relevant in early AD stages. Subsequently, we used whole genome sequencing (WGS) data from 750 individuals from the AD Neuroimaging Initiative (ADNI) to perform a genetic association analysis for polymorphisms within the significant miRNAs’ genes and CSF concentrations of phosphorylated-tau, total-tau, amyloid-β42 and soluble-TREM2 and BACE1 activity. Our analysis revealed 24 SNPs withinMIR29Cto be associated with CSF levels of amyloid-β42 and soluble-TREM2 and BACE1 activity. Our study shows the potential of a six-miRNA set as diagnostic blood biomarker of subclinical cognitive deficits in AD. Polymorphisms withinMIR29Csuggest a possible interplay between the amyloid cascade and microglial activation at preclinical stages of AD.
Neurochemistry-enriched dynamic causal models of magnetoencephalography, using magnetic resonance spectroscopy
Authors: Jafarian Amirhossein , Hughes Laura E , Adams Natalie E , Lanskey Juliette , Naessens Michelle , Rouse Matthew A , Murley Alexander G , Friston Karl J , Rowe James B 
Published: June 2022

AbstractWe present a hierarchical and empirical Bayesian framework for testing hypotheses about synaptic neurotransmission, based on the integration of ultra-high field magnetic resonance spectroscopy (7T-MRS) and magnetoencephalography data (MEG). A first level dynamic causal modelling of cortical microcircuits is used to infer the connectivity parameters of a generative model of individuals’ neurophysiological observations. At the second level, individuals’ 7T-MRS estimates of regional neurotransmitter concentration supply empirical priors on synaptic connectivity. We compare the group-wise evidence for alternative empirical priors, defined by monotonic functions of spectroscopic estimates, on subsets of synaptic connections. For efficiency and reproducibility, we used Bayesian model reduction (BMR), parametric empirical Bayes and variational Bayesian inversion. In particular, we used Bayesian model reduction to compare models of how spectroscopic neurotransmitter measures inform estimates of synaptic connectivity. This identifies the subset of synaptic connections that are influenced by neurotransmitter levels, as measured by 7T-MRS. We demonstrate the method using resting-state MEG (i.e., task-free recording) and 7T-MRS data from healthy adults. We perform cross-validation using split-sampling of the MEG dataset. Our results confirm the hypotheses that GABA concentration influences local recurrent inhibitory intrinsic connectivity in deep and superficial cortical layers, while glutamate influences the excitatory connections between superficial and deep layers and connections from superficial to inhibitory interneurons. The method is suitable for applications with magnetoencephalography or electroencephalography, and is well-suited to reveal the mechanisms of neurological and psychiatric disorders, including responses to psychopharmacological interventions.
De novoannotation of lncRNAHOTAIRtranscripts by long-read RNA capture-seq reveals a differentiation-driven isoform switch
Authors: Potolitsyna Evdokiia , Pickering Sarah Hazell , Tooming-Klunderud Ave , Collas Philippe , Briand Nolwenn 
Published: June 2022

AbstractBackgroundLncRNAs are tissue-specific and emerge as important regulators of various biological processes and as disease biomarkers.HOTAIRis a well-established pro-oncogenic lncRNA which has been attributed a variety of functions in cancer and native contexts. However, a lack of an exhaustive, cell type-specific annotation questions whetherHOTAIRfunctions are supported by the expression of multiple isoforms.ResultsUsing a capture long-read sequencing approach, we characterizeHOTAIRisoforms expressed in human primary adipose stem cells. We identify a highly cell type-specificHOTAIRisoform and uncover a shift in theHOTAIRisoform balance at differentiation onset. Composition of theHOTAIRisoform pool is regulated by distinct promoter usage and is under control of hormonal and nutrient-sensing pathways.ConclusionOur results highlight the complexity and cell type-specificity ofHOTAIRisoforms and open perspectives on functional implications of these variants and their balance to key cellular processes.
Group AStreptococcusInduces Lysosomal Dysfunction in THP-1 Macrophages
Authors: Nishioka Scott T. , Snipper Joshua , Lee Jimin , Schapiro Joshua , Zhang Robert Z. , Abe Hyewon , Till Andreas , Okumura Cheryl Y.M. 
Published: June 2022

AbstractThe human-specific bacterial pathogen Group AStreptococcus(GAS) is a significant cause of morbidity and mortality. Macrophages are important to control GAS infection, but previous data indicate that GAS can persist in macrophages. In this study, we detail the molecular mechanisms by which GAS survives in THP-1 macrophages. Our fluorescence microscopy studies demonstrate that GAS are readily phagocytosed by macrophages, but persist within phagolysosomes. These phagolysosomes are not acidified, which is in agreement with our findings that GAS cannot survive in low pH environments. We find that the secreted pore-forming toxin Streptolysin O (SLO) perforates the phagolysosomal membrane, allowing leakage of not only protons, but large proteins including the lysosomal protease cathepsin B. Additionally, GAS blocks the activity of vacuolar ATPase (v-ATPase) to prevent acidification of the phagolysosome. Thus, while GAS does not inhibit fusion of the lysosome with the phagosome, it has multiple mechanisms to prevent proper phagolysosome function, allowing for persistence of the bacteria within the macrophage. This has important implications for not only the initial response but the overall functionality of the macrophages, which may lead to the resulting pathologies in GAS infection. Our data suggests that therapies aimed at improving macrophage function may positively impact patient outcomes in GAS infection.