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Abstract The full data set of the Daya Bay reactor neutrino experiment is used to probe the effect of the charged current non-standard interactions (CC-NSI) on neutrino oscillation experiments. Two different approaches are applied and constraints on the corresponding CC-NSI parameters are obtained with the neutrino flux taken from the Huber-Mueller model with a 5% uncertainty. For the quantum mechanics-based approach (QM-NSI), the constraints on the CC-NSI parameters ϵ eα and ϵ eα s $$ {\epsilon}_{e\alpha}^s $$ are extracted with and without the assumption that the effects of the new physics are the same in the production and detection processes, respectively. The approach based on the weak effective field theory (WEFT-NSI) deals with four types of CC-NSI represented by the parameters [ε X ] eα . For both approaches, the results for the CC-NSI parameters are shown for cases with various fixed values of the CC-NSI and the Dirac CP-violating phases, and when they are allowed to vary freely. We find that constraints on the QM-NSI parameters ϵ eα and ϵ eα s $$ {\epsilon}_{e\alpha}^s $$ from the Daya Bay experiment alone can reach the order O $$ \mathcal{O} $$ (0.01) for the former and O $$ \mathcal{O} $$ (0.1) for the latter, while for WEFT-NSI parameters [ε X ] eα , we obtain O $$ \mathcal{O} $$ (0.1) for both cases.

Abstract The significance of the Gallium Anomaly, from the BEST, GALLEX, and SAGE radioactive source experiments, is quantified using different theoretical calculations of the neutrino detection cross section, and its explanation due to neutrino oscillations is compared with the bounds from the analyses of reactor rate and spectral ratio data, β-decay data, and solar neutrino data. In the 3+1 active-sterile neutrino mixing scheme, the Gallium Anomaly is in strong tension with the individual and combined bounds of these data sets. In the combined scenario with all available data, the parameter goodness of fit is below 0.042%, corresponding to a severe tension of 4–5σ, or stronger. Therefore, we conclude that one should pursue other possible solutions beyond short-baseline oscillations for the Gallium Anomaly. We also present a new global fit of ν e and ν ¯ e $$ {\overline{\nu}}_e $$ disappearance data, showing that there is a 2.6–3.3σ preference in favor of short-baseline oscillations, which is driven by an updated analysis of reactor spectral ratio data.

Abstract Coherent elastic neutrino-nucleus scattering (CEνNS) represents a powerful tool to investigate key electroweak physics parameters and neutrino properties since its first observation in 2017 by the COHERENT experiment exploiting the spallation neutron source at Oak Ridge National Laboratory. In light of the recent detection of such a process with antineutrinos produced by the Dresden-II reactor scattering off a germanium detector, we revisit the limits so far set on the neutrino magnetic moments, charge radii and millicharges as well as on the weak mixing angle. In order to do so, we also include the contribution of elastic neutrino-electron scattering, whose effect becomes non negligible in some beyond the Standard Model theories. By using different hypotheses for the germanium quenching factor and the reactor antineutrino flux, we provide a measurement of the weak mixing angle at the low-energy scale of the Dresden-II reactor experiment and, thanks to a combined analysis with the latest cesium iodide and argon data set released by the COHERENT Collaboration, we deliver updated limits for the neutrino electromagnetic properties. Interestingly, we are able to set a new best upper limit on the electron neutrino charge radius and significantly improve the other CEνNS-related limits on the neutrino electric charge and magnetic moment.

Abstract Background SP140 is a bromodomain-containing protein expressed predominantly in immune cells. Genetic polymorphisms and epigenetic modifications in the SP140 locus have been linked to Crohn’s disease (CD), suggesting a role in inflammation. Results We report the development of the first small molecule SP140 inhibitor (GSK761) and utilize this to elucidate SP140 function in macrophages. We show that SP140 is highly expressed in CD mucosal macrophages and in in vitro-generated inflammatory macrophages. SP140 inhibition through GSK761 reduced monocyte-to-inflammatory macrophage differentiation and lipopolysaccharide (LPS)-induced inflammatory activation, while inducing the generation of CD206+ regulatory macrophages that were shown to associate with a therapeutic response to anti-TNF in CD patients. SP140 preferentially occupies transcriptional start sites in inflammatory macrophages, with enrichment at gene loci encoding pro-inflammatory cytokines/chemokines and inflammatory pathways. GSK761 specifically reduces SP140 chromatin binding and thereby expression of SP140-regulated genes. GSK761 inhibits the expression of cytokines, including TNF, by CD14+ macrophages isolated from CD intestinal mucosa. Conclusions This study identifies SP140 as a druggable epigenetic therapeutic target for CD.

Abstract Background Vagus nerve stimulation has been suggested to affect immune responses, partly through a neuronal circuit requiring sympathetic innervation of the splenic nerve bundle and norepinephrine (NE) release. Molecular and cellular mechanisms of action remain elusive. Here, we investigated the therapeutic value of this neuromodulation in inflammatory bowel disease (IBD) by applying electrical splenic nerve bundle stimulation (SpNS) in mice with dextran sulfate sodium (DSS)-induced colitis. Methods Cuff electrodes were implanted around the splenic nerve bundle in mice, whereupon mice received SpNS or sham stimulation. Stimulation was applied 6 times daily for 12 days during DSS-induced colitis. Colonic and splenic tissues were collected for transcriptional analyses by qPCR and RNA-sequencing (RNA-seq). In addition, murine and human splenocytes were stimulated with lipopolysaccharide (LPS) in the absence or presence of NE. Single-cell RNA-seq data from publicly available data sets were analyzed for expression of β-adrenergic receptors (β-ARs). Results Colitic mice undergoing SpNS displayed reduced colon weight/length ratios and showed improved Disease Activity Index scores with reduced Tumor Necrosis Factor α mRNA expression in the colon compared with sham stimulated mice. Analyses of splenocytes from SpNS mice using RNA-seq demonstrated specific immune metabolism transcriptome profile changes in myeloid cells. Splenocytes showed expression of β-ARs in myeloid and T cells. Cytokine production was reduced by NE in mouse and human LPS-stimulated splenocytes. Conclusions Together, our results demonstrate that SpNS reduces clinical features of colonic inflammation in mice with DSS-induced colitis possibly by inhibiting splenic myeloid cell activation. Our data further support exploration of the clinical use of SpNS for patients with IBD.

Abstract We present the constraints on the parameters of several light boson mediator models obtained from the analysis of the current data of the COHERENT CEνNS experiment. We consider a variety of vector boson mediator models: the so-called universal, the B − L and other anomaly-free U(1)′ gauge models with direct couplings of the new vector boson with neutrinos and quarks, and the anomaly-free L e − L μ , L e − L τ , and L μ − L τ gauge models where the coupling of the new vector boson with the quarks is generated by kinetic mixing with the photon at the one-loop level. We consider also a model with a new light scalar boson mediator that is assumed, for simplicity, to have universal coupling with quarks and leptons. Since the COHERENT CEνNS data are well-fitted with the cross section predicted by the Standard Model, the analysis of the data yields constraints for the mass and coupling of the new boson mediator that depend on the charges of quarks and neutrinos in each model under consideration. We compare these constraints with the limits obtained in other experiments and with the values that can explain the muon g − 2 anomaly in the models where the muon couples to the new boson mediator.

A laser-driven time-limited light-sail acceleration scheme for proton tumor radiotherapy is proposed, where a whole spread-out Bragg peak (SOBP) dose delivery to the tumor region can be achieved with a single laser shot. By using a proper match of laser and ultrathin foil target parameters, proton light-sail acceleration terminates immaturely before the transverse instability grows up, resulting in the production of a proton beam with the required highly peaked energy spectrum and sufficiently large particle number. A self-consistent combination of three-dimensional particle-in-cell simulations and geant4 microdosimetry simulations in a water phantom model demonstrates that our scheme is able to deliver a single-shot SOBP dose up to 1.76 Gy to cubic-centimeter-scale volumes on a nanosecond timescale for shallow-seated tumors and around 0.56 Gy for deep-seated tumors, where the deviations of dose equivalent in the flat SOBP region are both within the clinically acceptable range.

Introduction Predictive biomarkers for treatment efficacy of ulcerative colitis [UC] treatments are lacking. Here, we performed a longitudinal study investigating the association and potential predictive power of genome-wide peripheral blood [PB] DNA methylation signatures and response to tofacitinib treatment in UC. Methods We recruited moderate-to-severe UC patients starting tofacitinib treatment, and measured PB DNA methylation profiles at baseline [T1], after 8 weeks [T2], and in a subset [ n = 8] after a median of 20 weeks [T3] using the Illumina Infinium HumanMethylation EPIC BeadChip. After 8 weeks, we distinguished responders [R] from non-responders [NR] based on a centrally read endoscopic response [decrease in endoscopic Mayo score ≥1 or Ulcerative Colitis Endoscopic Index of Severity ≥2] combined with corticosteroid-free clinical and/or biochemical response. T1 PB samples were used for biomarker identification, and T2 and publicly available intraclass correlation [ICC] data were used for stability analyses. RNA-sequencing was performed to understand the downstream effects of the predictor CpG loci. Results In total, 16 R and 15 NR patients, with a median disease duration of 7 [4–12] years and overall comparable patient characteristics at baseline, were analysed. We identified a panel of 53 differentially methylated positions [DMPs] associated with response to tofacitinib [AUROC 0.74]. Most DMPs [77%] demonstrated both short- and long-term hyperstability [ICC ≥0.90], irrespective of inflammatory status. Gene expression analysis showed lower FGFR2 [ p BH = 0.011] and LRPAP1 [ p BH = 0.020], and higher OR2L13 [pBH = 0.016] expression at T1 in R compared with NR. Conclusion Our observations demonstrate the utility of genome-wide PB DNA methylation signatures to predict response to tofacitinib. [ABSTRACT FROM AUTHOR]

Fetal alcohol spectrum disorder (FASD) encompasses neurodevelopmental disabilities and physical birth defects associated with prenatal alcohol exposure. Previously, we attempted to identify epigenetic biomarkers for FASD by investigating the genome-wide DNA methylation (DNAm) profiles of individuals with FASD compared to healthy controls. In this study, we generated additional gene expression profiles in a subset of our previous FASD cohort, encompassing the most severely affected individuals, to examine the functional integrative effects of altered DNAm status on gene expression. We identified six differentially methylated regions (annotated to the SEC61G, REEP3, ZNF577, HNRNPF, MSC, and SDHAF1 genes) associated with changes in gene expression (p-value < 0.05). To the best of our knowledge, this study is the first to assess whole blood gene expression and DNAm-gene expression associations in FASD. Our results present novel insights into the molecular footprint of FASD in whole blood and opens opportunities for future research into multi-omics biomarkers for the diagnosis of FASD.

Abstract We present new constraints on three different models, the so-called universal, B − L and L μ − L τ models, involving a yet to be observed light vector Z′ mediator, by exploiting the recent observation of coherent elastic neutrino-nucleus scattering (CEνNS) in argon and cesium-iodide performed by the COHERENT Collaboration. We compare the results obtained from a combination of the above data sets with the limits derived from searches in fixed target, accelerator, solar neutrino and reactor CEνNS experiments, and with the parameter region that could explain the anomalous magnetic moment of the muon. We show that for the universal and the B − L models, the COHERENT data allow us to put stringent limits in the light vector mediator mass, M Z′, and coupling, g Z′, parameter space.

Anthocyanin and peroxidase (POD) are important active compounds in Chinese red radish (Raphanus sativus L.). The effects of exogenous sucrose, mixture of fructose and glucose (F/G 1:1), and mannose on anthocyanin accumulation and POD activity were investigated in hypocotyls and roots of red radish seedlings. Sucrose was most effective in inducing anthocyanin accumulation and POD activity in both organs, followed by F/G; mannose caused only a little increase of anthocyanin content and POD activity in hypocotyls, but a decrease in roots. The distribution of anthocyanin accumulation was different between hypocotyls and roots in the presence or absence of sucrose. Anthocyanin was clearly induced in root tips and cortex under exogenous sucrose. Accumulation of anthocyanin was closely correlated to the increase of endogenous sucrose content rather than glucose or fructose content. Sucrose significantly induced the expressions of late anthocyanin biosynthetic genes by up-regulating Raphanus sativus myeloblastosis 1 and Raphanus sativus transparent testa 8 in both organs. The POD activity significantly increased following the remarkable accumulation of anthocyanin in hypocotyls under exogenous sucrose, which may be partially required for anthocyanin oxidation. In roots, the high POD activity might lead to a low anthocyanin content by degrading anthocyanin and diverting the metabolic flux to lignin synthesis.

Abstract Background Recent evidence demonstrated that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) propagates in intestinal epithelial cells expressing Angiotensin-Converting Enzyme 2 (ACE2), implying that these cells represent an important entry site for the viral infection. Nicotinic receptors (nAChRs) have been put forward as potential regulators of inflammation and of ACE2 expression. As vagus nerve stimulation (VNS) activates nAChRs, we aimed to investigate whether VNS can be instrumental in affecting intestinal epithelial ACE2 expression. Methods By using publicly available datasets we qualified epithelial ACE2 expression in human intestine, and assessed gene co-expression of ACE2 and SARS-CoV-2 priming Transmembrane Serine Protease 2 (TMPRSS2) with nAChRs in intestinal epithelial cells. Next, we investigated mouse and human ACE2 expression in intestinal tissues after chronic VNS via implanted devices. Results We show co-expression of ACE2 and TMPRSS2 with nAChRs and α7 nAChR in particular in intestinal stem cells, goblet cells, and enterocytes. However, VNS did not affect ACE2 expression in murine or human intestinal tissue, albeit in colitis setting. Conclusions ACE2 and TMPRSS2 are specifically expressed in epithelial cells of human intestine, and both are co-expressed with nAChRs. However, no evidence for regulation of ACE2 expression through VNS could be found. Hence, a therapeutic value of VNS with respect to SARS-CoV-2 infection risk through ACE2 receptor modulation in intestinal epithelia could not be established.

BackgroundPrimary sclerosing cholangitis (PSC) is a chronic inflammatory liver disease affecting the intra- and extrahepatic bile ducts, and is strongly associated with ulcerative colitis (UC). In this study, we explored the peripheral blood DNA methylome and its immune cell composition in patients with PSC-UC, UC, and healthy controls (HC) with the aim to develop a predictive assay in distinguishing patients with PSC-UC from those with UC alone.MethodsThe peripheral blood DNA methylome of male patients with PSC and concomitant UC, UC and HCs was profiled using the Illumina HumanMethylation Infinium EPIC BeadChip (850K) array. Differentially methylated CpG position (DMP) and region (DMR) analyses were performed alongside gradient boosting classification analyses to discern PSC-UC from UC patients. As observed differences in the DNA methylome could be the result of differences in cellular populations, we additionally employed mass cytometry (CyTOF) to characterize the immune cell compositions.ResultsGenome wide methylation analysis did not reveal large differences between PSC-UC and UC patients nor HCs. Nonetheless, using gradient boosting we were capable of discerning PSC-UC from UC with an area under the receiver operator curve (AUROC) of 0.80. Four CpG sites annotated to the NINJ2 gene were found to strongly contribute to the predictive performance. While CyTOF analyses corroborated the largely similar blood cell composition among patients with PSC-UC, UC and HC, a higher abundance of myeloid cells was observed in UC compared to PSC-UC patients.ConclusionDNA methylation enables discerning PSC-UC from UC patients, with a potential for biomarker development.

Background: Myeloid cells are critical determinants of the sustained inflammation in Crohn’s Disease (CD). Targeting such cells may be an effective therapeutic approach for refractory CD patients. Bromodomain and extra-terminal domain protein inhibitors (iBET) are potent anti-inflammatory agents; however, they also possess wide-ranging toxicities. In the current study, we make use of a BET inhibitor containing an esterase sensitive motif (ESM-iBET), which is cleaved by carboxylesterase-1 (CES1), a highly expressed esterase in mononuclear myeloid cells. Methods: We profiled CES1 protein expression in the intestinal biopsies, peripheral blood, and CD fistula tract (fCD) cells of CD patients using mass cytometry. The anti-inflammatory effect of ESM-iBET or its control (iBET) were evaluated in healthy donor CD14+ monocytes and fCD cells, using cytometric beads assay or RNA-sequencing. Results: CES1 was specifically expressed in monocyte, macrophage, and dendritic cell populations in the intestinal tissue, peripheral blood, and fCD cells of CD patients. ESM-iBET inhibited IL1β, IL6, and TNFα secretion from healthy donor CD14+ monocytes and fCD immune cells, with 10- to 26-fold more potency over iBET in isolated CD14+ monocytes. Transcriptomic analysis revealed that ESM-iBET inhibited multiple inflammatory pathways, including TNF, JAK-STAT, NF-kB, NOD2, and AKT signaling, with superior potency over iBET. Conclusions: We demonstrate specific CES1 expression in mononuclear myeloid cell subsets in peripheral blood and inflamed tissues of CD patients. We report that low dose ESM-iBET accumulates in CES1-expressing cells and exerts robust anti-inflammatory effects, which could be beneficial in refractory CD patients.

Prediction of endoscopic post-operative recurrence (POR) in Crohn’s disease (CD) patients following ileocolonic resection (ICR) using clinical risk factors alone has thus far been inadequate. While peripheral blood leukocyte (PBL) DNA methylation has shown promise as a tool for predicting recurrence in cancer, no data in CD patients exists. Therefore, this study explored the association and predictive value of PBL DNA methylation in CD patients following ICR. From a cohort of 117 CD patients undergoing ICR, epigenome-wide PBL methylation profiles from 25 carefully selected patients presenting either clear endoscopic remission (n = 12) or severe recurrence (n = 13) were assessed using the Illumina MethylationEPIC (850K) array. No statistically significant differentially methylated positions (DMPs) or regions (DMRs) associated with endoscopic POR were identified (FDR p ≤ 0.05), further evidenced by the low accuracy (0.625) following elastic net classification analysis. Nonetheless, interrogating the most significant differences in methylation suggested POR-associated hypermethylation in the MBNL1, RAB29 and LEPR genes, respectively, which are involved in intestinal fibrosis, inflammation and wound healing. Notably, we observed a higher estimated proportion of monocytes in endoscopic POR compared to remission. Altogether, we observed limited differences in the genome-wide DNA methylome among CD patients with and without endoscopic POR. We therefore conclude that PBL DNA methylation is not a feasible predictive tool in post-operative CD.

In this study, we sought to characterize synovial tissue obtained from individuals with arthralgia and disease-specific auto-antibodies and patients with established rheumatoid arthritis (RA), by applying an integrative multi-omics approach where we investigated differences at the level of DNA methylation and gene expression in relation to disease pathogenesis. We performed concurrent whole-genome bisulphite sequencing and RNA-Sequencing on synovial tissue obtained from the knee and ankle from 4 auto-antibody positive arthralgia patients and thirteen RA patients. Through multi-omics factor analysis we observed that the latent factor explaining the variance in gene expression and DNA methylation was associated with Swollen Joint Count 66 (SJC66), with patients with SJC66 of 9 or more displaying separation from the rest. Interrogating these observed differences revealed activation of the immune response as well as dysregulation of cell adhesion pathways at the level of both DNA methylation and gene expression. We observed differences for 59 genes in particular at the level of both transcript expression and DNA methylation. Our results highlight the utility of genome-wide multi-omics profiling of synovial samples for improved understanding of changes associated with disease spread in arthralgia and RA patients, and point to novel candidate targets for the treatment of the disease.

Peatlands are a large source of methane (CH4) to the atmosphere, yet the uncertainty around the estimates of CH4 flux from peatlands is large. To better understand the spatial heterogeneity in temperate peatland CH4 emissions and their response to physical and biological drivers, we studied CH4 dynamics throughout the growing seasons of 2017 and 2018 in Flatiron Lake Bog, a kettle-hole peat bog in Ohio. The site is composed of six different hydro-biological zones: an open water zone, four concentric vegetation zones surrounding the open water, and a restored zone connected to the main bog by a narrow channel. At each of these locations, we monitored water level (WL), CH4 pore-water concentration at different peat depths, CH4 fluxes from the ground and from representative plant species using chambers, and microbial community composition with a focus here on known methanogens and methanotrophs. Integrated CH4 emissions for the growing season were estimated as 315.4±166 mgCH4m-2d-1 in 2017 and 362.3±687 mgCH4m-2d-1 in 2018. Median CH4 emission was highest in the open water, then it decreased and became more variable through the concentric vegetation zones as the WL dropped, with extreme emission hotspots observed in the tamarack mixed woodlands (Tamarack) and low emissions in the restored zone (18.8–30.3 mgCH4m-2d-1). Generally, CH4 flux from above-ground vegetation was negligible compared to ground flux ( %), although blueberry plants were a small CH4 sink. Pore-water CH4 concentrations varied significantly among zones, with the highest values in the Tamarack zone, close to saturation, and the lowest values in the restored zone. While the CH4 fluxes and pore-water concentrations were not correlated with methanogen relative abundance, the ratio of methanogens to methanotrophs in the upper portion of the peat was significantly correlated to CH4 transfer velocity (the CH4 flux divided by the difference in CH4 pore-water concentration between the top of the peat profile and the concentration in equilibrium with the atmosphere). Since ebullition and plant-mediated transport were not important sources of CH4 and the peat structure and porosity were similar across the different zones in the bog, we conclude that the differences in CH4 transfer velocities, and thus the flux, are driven by the ratio of methanogen to methanotroph relative abundance close to the surface. This study illustrates the importance of the interactions between water-level and microbial composition to better understand CH4 fluxes from bogs and wetlands in general.

Accumulating evidence shows that microbes with their theater of activity residing within the human intestinal tract (i.e., the gut microbiome) influence host metabolism. Some of the strongest results come from recent fecal microbial transplant (FMT) studies that relate changes in intestinal microbiota to various markers of metabolism as well as the pathophysiology of insulin resistance. Despite these developments, there is still a limited understanding of the multitude of effects associated with FMT on the general physiology of the host, beyond changes in gut microbiome composition. We examined the effect of either allogenic (lean donor) or autologous FMTs on the gut microbiome, plasma metabolome, and epigenomic (DNA methylation) reprogramming in peripheral blood mononuclear cells in individuals with metabolic syndrome measured at baseline (pre-FMT) and after 6 weeks (post-FMT). Insulin sensitivity was determined with a stable isotope-based 2 step hyperinsulinemic clamp and multivariate machine learning methodology was used to uncover discriminative microbes, metabolites, and DNA methylation loci. A larger gut microbiota shift was associated with an allogenic than with autologous FMT. Furthemore, the data results of the the allogenic FMT group data indicates that the introduction of new species can potentially modulate the plasma metabolome and (as a result) the epigenome. Most notably, the introduction of Prevotella ASVs directly correlated with methylation of AFAP1, a gene involved in mitochondrial function, insulin sensitivity, and peripheral insulin resistance (Rd, rate of glucose disappearance). FMT was found to have notable effects on the gut microbiome but also on the host plasma metabolome and the epigenome of immune cells providing new avenues of inquiry in the context of metabolic syndrome treatment for the manipulation of host physiology to achieve improved insulin sensitivity.

Histone deacetylases (HDACs) are a group of enzymes that control histone deacetylation and bear potential to direct expression of large gene sets. We determined the effect of HDAC inhibitors (HDACi) on human monocytes and macrophages, with respect to their polarization, activation, and their capabilities of inducing endotoxin tolerance. To address the role for HDACs in macrophage polarization, we treated monocytes with HDAC3i, HDAC6i or pan-HDACi prior to polarization into M1 or M2 macrophages using IFNγ or IL-4 respectively. To study the HDAC inhibition effect on cytokine expression, macrophages were treated with HDACi prior to LPS-stimulation. TNFα, IL-6, and p40 were measured with ELISA, whereas modifications of Histone 3 and STAT1 were assessed using western blot. To address the role for HDAC3 in repeated LPS challenge induction, HDAC3i or HDAC3 siRNA was added to monocytes prior to incubation with IFNγ, which were then repeatedly challenged with LPS and analyzed by means of protein analyses and transcriptional profiling. Pan-HDACi and HDAC3i reduced cytokine secretion in monocytes and M1 macrophages, whereas HDAC6i yielded no such effect. Notably, neither pan-HDACi nor HDAC3i reduced cytokine secretion in M2 macrophages. In contrast to previous reports in mouse macrophages, HDAC3i did not affect macrophage polarization in human cells. Likewise, HDAC3 was not required for IFNγ signaling or IFNβ secretion. Cytokine and gene expression analyses confirmed that IFNγ-treated macrophages consistently develop a cytokine response after LPS repeated challenge, but pretreatment with HDAC3i or HDAC3 siRNA reinstates a state of tolerance reflected by general suppression of tolerizable genes, possibly through decreasing TLRs expression, and particularly TLR4/CD14. The development of endotoxin tolerance in macrophages is important to reduce exacerbated immune response and limit tissue damage. We conclude that HDAC3 is an attractive protein target to mediate macrophage reactivity and tolerance induction in inflammatory macrophages.

Macrophages are heterogeneous leukocytes regulated in a tissue- and disease-specific context. While in vitro macrophage models have been used to study diseases empirically, a systematic analysis of the transcriptome thereof is lacking. Here, we acquired gene expression data from eight commonly-used in vitro macrophage models to perform a meta-analysis. Specifically, we obtained gene expression data from unstimulated macrophages (M0) and macrophages stimulated with lipopolysaccharides (LPS) for 2–4 h (M-LPSearly), LPS for 24 h (M-LPSlate), LPS and interferon-γ (M-LPS+IFNγ), IFNγ (M-IFNγ), interleukin-4 (M-IL4), interleukin-10 (M-IL10), and dexamethasone (M-dex). Our meta-analysis identified consistently differentially expressed genes that have been implicated in inflammatory and metabolic processes. In addition, we built macIDR, a robust classifier capable of distinguishing macrophage activation states with high accuracy (>0.95). We classified in vivo macrophages with macIDR to define their tissue- and disease-specific characteristics. We demonstrate that alveolar macrophages display high resemblance to IL10 activation, but show a drop in IFNγ signature in chronic obstructive pulmonary disease patients. Adipose tissue-derived macrophages were classified as unstimulated macrophages, but acquired LPS-activation features in diabetic-obese patients. Rheumatoid arthritis synovial macrophages exhibit characteristics of IL10- or IFNγ-stimulation. Altogether, we defined consensus transcriptional profiles for the eight in vitro macrophage activation states, built a classification model, and demonstrated the utility of the latter for in vivo macrophages.

Precisely controlled growth of oxide interfaces at the atomic layer level is critical for device applications but quite challenging. Here Sun et al. show real time monitoring and control of the surface composition of epitaxial strontium titanate perovskite films by analysing the Kikuchi lines.

The miR171 is a conserved microRNA (miRNA) family and has been shown to participate in plant growth and development. However, the precise function of miR171 in Pinus densata remains largely unclear. Mature miR171 sequence comparison reveals high similarity between Arabidopsis thaliana and P. densata and the pre-miR171 could fold into a characteristic stem-loop hairpin structure. Genes encoding GRAS (GAI-RGA-SCR) family transcription factors and actin binding protein were identified as targets of pde-miR171 using a modified RNA ligase mediated 5' rapid amplification of cDNA ends (RLM-RACE). Furthermore, the interaction between pde-miR171 and Arabidopsis SCL6 (SCARECROW-LIKE6) was further validated through transient co-expression of both genes in Nicotiana benthamiana leaves. Next, results of real-time quantitative PCR demonstrated that the expression of pde-miR171 was significantly up-regulated in miR171-overexpressing plants than in wild-type plants, which was inversely correlated with the expression of Arabidopsis SCL6 genes. In addition, overexpression of pde-miR171 in Arabidopsis induced larger leaves and earlier flowering under long-day conditions compared with the wild type. The findings presented here suggest that miR171 derived from a P. densata precursor together with its target gene SCL6 may play important roles in the regulation of primary root growth, leaf shape, and flowering time in plants.

For an aerostatic circular thrust bearing with a single pocketed orifice-type restrictor, the flow field in the bearing clearance is analyzed numerically, and the formation mechanism of the bearing micro-vibration is investigated. Through flow field analysis, the flow structures in the bearing clearance are discussed and classified. The formed vortex flow in flow field is analyzed, and the influence of the vortex flow on bearing dynamic stability related to micro-vibration is discussed. For each flow structure, the vortex flow always exists and induces the bearing micro-vibration. The Reynolds number is used to represent the degree of bearing micro-vibration and the rationality is verified. Based on the flow analysis results, the maximum Reynolds number in the bearing clearance flow field is taken as the optimization objective to reduce the micro-vibration amplitude, the approximate model for design optimization is established by using the radial basis functions method and the optimization methodology is illustrated. Several cases of optimization are carried out with different given bearing loads. Through optimization, the maximum Reynolds number is reduced greatly, which means the enhancement of the bearing dynamic stability. The optimization results show that in order to suppress the micro-vibration, the air supply pressure should be kept as small as possible, the small air pocket diameter and orifice diameter are also needed.

Abstract We analyzed the evolution data of the Daya Bay reactor neutrino experiment in terms of short-baseline active-sterile neutrino oscillations taking into account the theoretical uncertainties of the reactor antineutrino fluxes. We found that oscillations are disfavored at 2.6σ with respect to a suppression of the 235U reactor antineutrino flux and at 2.5σ with respect to variations of the 235U and 239Pu fluxes. On the other hand, the analysis of the rates of the short-baseline reactor neutrino experiments favor active-sterile neutrino oscillations and disfavor the suppression of the 235U flux at 3.1σ and variations of the 235U and 239Pu fluxes at 2.8σ. We also found that both the Daya Bay evolution data and the global rate data are well-fitted with composite hypotheses including variations of the 235U or 239Pu fluxes in addition to active-sterile neutrino oscillations. A combined analysis of the Daya Bay evolution data and the global rate data shows a slight preference for oscillations with respect to variations of the 235U and 239Pu fluxes. However, the best fits of the combined data are given by the composite models, with a preference for the model with an enhancement of the 239Pu flux and relatively large oscillations.

Abstract We present the results of an updated fit of short-baseline neutrino oscillation data in the framework of 3+1 active-sterile neutrino mixing. We first consider ν e and ν ¯ e $$ {\overline{\nu}}_e $$ disappearance in the light of the Gallium and reactor anomalies. We discuss the implications of the recent measurement of the reactor ν ¯ e $$ {\overline{\nu}}_e $$ spectrum in the NEOS experiment, which shifts the allowed regions of the parameter space towards smaller values of |U e4|2. The β-decay constraints of the Mainz and Troitsk experiments allow us to limit the oscillation length between about 2 cm and 7 m at 3σ for neutrinos with an energy of 1 MeV. The corresponding oscillations can be discovered in a model-independent way in ongoing reactor and source experiments by measuring ν e and ν ¯ e $$ {\overline{\nu}}_e $$ disappearance as a function of distance. We then consider the global fit of the data on short-baseline ν μ − → ν e − $$ {}_{\nu_{\mu}}^{\left(-\right)}{\to}_{\nu_e}^{\left(-\right)} $$ transitions in the light of the LSND anomaly, taking into account the constraints from ν e − $$ {}_{\nu_e}^{\left(-\right)} $$ and ν μ − $$ {}_{\nu_{\mu}}^{\left(-\right)} $$ disappearance experiments, including the recent data of the MINOS and IceCube experiments. The combination of the NEOS constraints on |U e4|2 and the MINOS and IceCube constraints on |U μ4|2 lead to an unacceptable appearance-disappearance tension which becomes tolerable only in a pragmatic fit which neglects the MiniBooNE low-energy anomaly. The minimization of the global χ 2 in the space of the four mixing parameters Δm 41 2 , |U e4|2, |U μ4|2, and |U τ4|2 leads to three allowed regions with narrow Δm 41 2 widths at Δm 41 2 ≈ 1.7 (best-fit), 1.3 (at 2σ), 2.4 (at 3σ) eV2. The effective amplitude of short-baseline ν μ − → ν e − $$ {}_{\nu_{\mu}}^{\left(-\right)}{\to}_{\nu_e}^{\left(-\right)} $$ oscillations is limited by 0.00048 ≲ sin2 2ϑ eμ ≲ 0.0020 at 3σ. The restrictions of the allowed regions of the mixing parameters with respect to our previous global fits are mainly due to the NEOS constraints. We present a comparison of the allowed regions of the mixing parameters with the sensitivities of ongoing experiments, which show that it is likely that these experiments will determine in a definitive way if the reactor, Gallium and LSND anomalies are due to active-sterile neutrino oscillations or not.

The overflow of the flame plume from the window is the main cause of the vertical spread of the fire on the facade of the building. This paper considers the geometry of the window by taking measures to prevent the flame from propagating along the vertical wall. In this paper, a residential building is taken as an example to evaluate the flame plume characteristics through experimental tests and numerical simulations. The objective of the present study is to study the flame plume characteristics under the air blow on the outer window side of the building. The theoretical equations of the flame tilt angle, non-dimensional temperature and non-dimensional velocity are derived. A series of experimental tests were carried out in a reduced-scale building model corresponding to the changes of lateral blow ventilation velocity. Reduced scale numerical simulations were conducted to verify the experiments. Results showed that the flame tilt angle increases with ventilation velocity increases. Meanwhile, the experimental results were compared with the reduced-scale tests and numerical simulations. These showed a good agreement between experimental results and numerical simulations. All these findings provide theoretical basis for building fire prevention outside window.

To improve the coercivity of the Nd-Fe-B sintered magnets, the Cu29.8Al70.2 (at.%) powders with low melting point were introduced into the Nd-Fe-B magnets. The magnetic properties, microstructure, thermal stability and corrosion behavior of the sintered magnets with different amount of Cu29.8Al70.2 (0,0.25,0.50,0.75,1.0 wt.%) were investigated. When the amount of doped Cu29.8Al70.2 was less than 0.75 wt.%, the coercivity was improved, especially that of the magnets with 0.25 wt.% Cu29.8Al70.2, markedly increased to 13.97 kOe from 12.67 kOe (without CuAl). The improvement of magnetic properties could be attributed to enhanced wettability between Nd2Fe14B phase and Nd-rich phase and decreased exchange coupling between grains, which depended on the optimization of grain boundary microstructure and their distribution by codoping Cu and Al. With the addition of 0-1.0 wt.% Cu29.8Al70.2 powders, the reversible temperature coefficients of remanence and coercivity of the magnets could be also improved. The corrosion resistances was also found to be improved through small addition of Cu29.8Al70.2 powder in 3.5 wt.% NaCl solution by electrochemical and immersion tests, which could be due to the enhancement of the Nd-rich intergranular phase by addition Cu29.8Al70.2.

Astaxanthin (AST) is a beneficial dietary supplement in shrimp farming. However, the different effects of synthetic AST (S-Ast) and natural AST (N-Ast) on the postlarvae is unclear. These effects were compared by supplementation with a gradient of AST (0, 50, 70, 90, 140 ppm) for 35 days. Growth parameters including weight and length gain, carotenoid content, AST content and isomer composition, antioxidant capacity (superoxide dismutase, catalase, glutathione peroxidase), survival rate and mRNA expression levels for antioxidant enzymes in Litopenaeus vannamei postlarvae were measured. The results indicated that postlarvae given N-Ast had significantly higher growth performance and AST content. Although there were different ratios of AST optical isomers in the diets, there was a similar optical isomer content in juvenile shrimp. The cis/trans AST ratio and antioxidant enzyme (SOD and GPx) activities in N-Ast90 were the highest among all groups. Cumulative mortality in N-Ast90, N-Ast140 and S-Ast70 were significantly lower than in the control and N-AST50. The mRNA expression levels for the antioxidant enzymes (cMnSOD and GPx) also increased for N-Ast90-fed shrimp under stress conditions. These results suggest that an epimerase may exist in vivo and that an appropriate level of botanical AST in diets was approximately 90 ppm for L. vannamei postlarvae.

BackgroundThe chronic remitting and relapsing intestinal inflammation characteristic of Crohn's disease frequently leads to fibrosis and subsequent stenosis of the inflamed region. Approximately a third of all Crohn's disease patients require resection at some stage in their disease course. As the pathogenesis of Crohn's disease associated fibrosis is largely unknown, a strong necessity exists to better understand the pathophysiology thereof.MethodsIn this study, we investigated changes of the DNA methylome and transcriptome of ileum-derived fibroblasts associated to the occurrence of Crohn's disease associated fibrosis. Eighteen samples were included in a DNA methylation array and twenty-one samples were used for RNA sequencing.ResultsMost differentially methylated regions and differentially expressed genes were observed when comparing stenotic with non-inflamed samples. By contrast, few differences were observed when comparing Crohn's disease with non-Crohn's disease, or inflamed with non-inflamed tissue. Integrative methylation and gene expression analyses revealed dysregulation of genes associated to the PRKACA and E2F1 network, which is involved in cell cycle progression, angiogenesis, epithelial to mesenchymal transition, and bile metabolism.ConclusionOur research provides evidence that the methylome and the transcriptome are systematically dysregulated in stenosis-associated fibroblasts.

Gas/particle (G/P) partitioning of semi-volatile organic compounds (SVOCs) is an important process that primarily governs their atmospheric fate, long-range atmospheric transport, and their routes of entering the human body. All previous studies on this issue are hypothetically based on equilibrium conditions, the results of which do not predict results from monitoring studies well in most cases. In this study, a steady-state model instead of an equilibrium-state model for the investigation of the G/P partitioning behavior of polybrominated diphenyl ethers (PBDEs) was established, and an equation for calculating the partition coefficients under steady state (KPS) of PBDEs (log KPS = log KPE + logα) was developed in which an equilibrium term (log KPE = log KOA + logfOM −11.91 where fOM is organic matter content of the particles) and a non-equilibrium term (log α, caused by dry and wet depositions of particles), both being functions of log KOA (octanol–air partition coefficient), are included. It was found that the equilibrium is a special case of steady state when the non-equilibrium term equals zero. A criterion to classify the equilibrium and non-equilibrium status of PBDEs was also established using two threshold values of log KOA, log KOA1, and log KOA2, which divide the range of log KOA into three domains: equilibrium, non-equilibrium, and maximum partition domain. Accordingly, two threshold values of temperature t, tTH1 when log KOA = log KOA1 and tTH2 when log KOA = log KOA2, were identified, which divide the range of temperature also into the same three domains for each PBDE congener. We predicted the existence of the maximum partition domain (the values of log KPS reach a maximum constant of −1.53) that every PBDE congener can reach when log KOA ≥ log KOA2, or t ≤ tTH2. The novel equation developed in this study was applied to predict the G/P partition coefficients of PBDEs for our Chinese persistent organic pollutants (POPs) Soil and Air Monitoring Program, Phase 2 (China-SAMP-II) program and other monitoring programs worldwide, including in Asia, Europe, North America, and the Arctic, and the results matched well with all the monitoring data, except those obtained at e-waste sites due to the unpredictable PBDE emissions at these sites. This study provided evidence that the newly developed steady-state-based equation is superior to the equilibrium-state-based equation that has been used in describing the G/P partitioning behavior over decades. We suggest that the investigation on G/P partitioning behavior for PBDEs should be based onsteady-state, not equilibrium state, and equilibrium is just a special case of steady-state when non-equilibrium factors can be ignored. We also believe that our new equation provides a useful tool for environmental scientists in both monitoring and modeling research on G/P partitioning of PBDEs and can be extended to predict G/P partitioning behavior for other SVOCs as well.