Water in the terrestrial planet-forming zone of the PDS 70 disk.

Terrestrial and sub-Neptune planets are expected to form in the inner (less than 10 AU) regions of protoplanetary disks1. Water plays a key role in their formation2-4, although it is yet unclear whether water molecules are formed in situ or transported from the outer disk5,6. So far Spitzer Space Telescope observations have only provided water luminosity upper limits for dust-depleted inner disks7, similar to PDS 70, the first system with direct confirmation of protoplanet presence8,9. Here we report JWST observations of PDS 70, a benchmark target to search for water in a disk hosting a large (approximately 54 AU) planet-carved gap separating an inner and outer disk10,11. Our findings show water in the inner disk of PDS 70. This implies that potential terrestrial planets forming therein have access to a water reservoir. The column densities of water vapour suggest in-situ formation via a reaction sequence involving O, H2 and/or OH, and survival through water self-shielding5. This is also supported by the presence of CO2 emission, another molecule sensitive to ultraviolet photodissociation. Dust shielding, and replenishment of both gas and small dust from the outer disk, may also play a role in sustaining the water reservoir12. Our observations also reveal a strong variability of the mid-infrared spectral energy distribution, pointing to a change of inner disk geometry.

Using long-read CAGE sequencing to profile cryptic-promoter-derived transcripts and their contribution to the immunopeptidome.

Recent studies have shown that the noncoding genome can produce unannotated proteins as antigens that induce immune response. One major source of this activity is the aberrant epigenetic reactivation of transposable elements (TEs). In tumors, TEs often provide cryptic or alternate promoters, which can generate transcripts that encode tumor-specific unannotated proteins. Thus, TE-derived transcripts (TE transcripts) have the potential to produce tumor-specific, but recurrent, antigens shared among many tumors. Identification of TE-derived tumor antigens holds the promise to improve cancer immunotherapy approaches; however, current genomics and computational tools are not optimized for their detection. Here we combined CAGE technology with full-length long-read transcriptome sequencing (long-read CAGE, or LRCAGE) and developed a suite of computational tools to significantly improve immunopeptidome detection by incorporating TE and other tumor transcripts into the proteome database. By applying our methods to human lung cancer cell line H1299 data, we show that long-read technology significantly improves mapping of promoters with low mappability scores and that LRCAGE guarantees accurate construction of uncharacterized 5' transcript structure. Augmenting a reference proteome database with newly characterized transcripts enabled us to detect noncanonical antigens from HLA-pulldown LC-MS/MS data. Lastly, we show that epigenetic treatment increased the number of noncanonical antigens, particularly those encoded by TE transcripts, which might expand the pool of targetable antigens for cancers with low mutational burden.

Efficient activation of hundreds of LTR12C elements reveals cis-regulatory function determined by distinct epigenetic mechanisms.

Long terminal repeats (LTRs), which often contain promoter and enhancer sequences of intact endogenous retroviruses (ERVs), are known to be co-opted as cis-regulatory elements for fine-tuning host-coding gene expression. Since LTRs are mainly silenced by the deposition of repressive epigenetic marks, substantial activation of LTRs has been found in human cells after treatment with epigenetic inhibitors. Although the LTR12C family makes up the majority of ERVs activated by epigenetic inhibitors, how these epigenetically and transcriptionally activated LTR12C elements can regulate the host-coding gene expression remains unclear due to genome-wide alteration of transcriptional changes after epigenetic inhibitor treatments. Here, we specifically transactivated >600 LTR12C elements by using single guide RNA-based dCas9-SunTag-VP64, a site-specific targeting CRISPR activation (CRISPRa) system, with minimal off-target events. Interestingly, most of the transactivated LTR12C elements acquired the H3K27ac-marked enhancer feature, while only 20% were co-marked with promoter-associated H3K4me3 modifications. The enrichment of the H3K4me3 signal was intricately associated with downstream regions of LTR12C, such as internal regions of intact ERV9 or other types of retrotransposons. Here, we leverage an optimized CRISPRa system to identify two distinct epigenetic signatures that define LTR12C transcriptional activation, which modulate the expression of proximal protein-coding genes.

Skeletal stem cell fate defects caused by Pdgfrb activating mutation.

Autosomal dominant PDGFRß gain-of-function mutations in mice and humans cause a spectrum of wasting and overgrowth disorders afflicting the skeleton and other connective tissues, but the cellular origin of these disorders remains unknown. We demonstrate that skeletal stem cells (SSCs) isolated from mice with a gain-of-function D849V point mutation in PDGFRß exhibit colony formation defects that parallel the wasting or overgrowth phenotypes of the mice. Single-cell RNA transcriptomics with SSC-derived polyclonal colonies demonstrates alterations in osteogenic and chondrogenic precursors caused by PDGFRßD849V. Mutant cells undergo poor osteogenesis in vitro with increased expression of Sox9 and other chondrogenic markers. Mice with PDGFRßD849V exhibit osteopenia. Increased STAT5 phosphorylation and overexpression of Igf1 and Socs2 in PDGFRßD849V cells suggests that overgrowth in mice involves PDGFRßD849V activating the STAT5-IGF1 axis locally in the skeleton. Our study establishes that PDGFRßD849V causes osteopenic skeletal phenotypes that are associated with intrinsic changes in SSCs, promoting chondrogenesis over osteogenesis.

Determinants of Meal-Induced Changes in Circulating FFA Epoxides, Diols, and Diol-to-Epoxide Ratios as Indices of Soluble Epoxide Hydrolase Activity.

Soluble epoxide hydrolase (sEH) is an important enzyme for metabolic and cardiovascular health. sEH converts FFA epoxides (EpFAs), many of which are regulators of various cellular processes, to biologically less active diols. In human studies, diol (sEH product) to EpFA (sEH substrate) ratios in plasma or serum have been used as indices of sEH activity. We previously showed these ratios profoundly decreased in rats during acute feeding, possibly reflecting decreases in tissue sEH activities. The present study was designed to test which tissue(s) these measurements in the blood represent and if factors other than sEH activity, such as renal excretion or dietary intake of EpFAs and diols, significantly alter plasma EpFAs, diols, and/or their ratios. The results show that postprandial changes in EpFAs and diols and their ratios in plasma were very similar to those observed in the liver but not in other tissues, suggesting that the liver is largely responsible for these changes in plasma levels. EpFAs and diols were excreted into the urine, but their levels were not significantly altered by feeding, suggesting that renal excretion of EpFAs and diols may not play a major role in postprandial changes in circulating EpFAs, diols, or their ratios. Diet intake had significant impacts on circulating EpFA and diol levels but not on diol-to-EpFA (D-to-E) ratios, suggesting that these ratios, reflecting sEH activities, may not be significantly affected by the availability of sEH substrates (i.e., EpFAs). In conclusion, changes in FFA D-to-E ratios in plasma may reflect those in the liver, which may in turn represent sEH activities in the liver, and they may not be significantly affected by renal excretion or the dietary intake of EpFAs and diols.

Effects of Individual Circulating FFAs on Plasma and Hepatic FFA Epoxides, Diols, and Epoxide-Diol Ratios as Indices of Soluble Epoxide Hydrolase Activity.

Oxylipins, oxidation products of unsaturated free fatty acids (FFAs), are involved in various cellular signaling systems. Among these oxylipins, FFA epoxides are associated with beneficial effects in metabolic and cardiovascular health. FFA epoxides are metabolized to diols, which are usually biologically less active, by soluble epoxide hydrolase (sEH). Plasma epoxide-diol ratios have been used as indirect measures of sEH activity. This study was designed to examine the effects of acute elevation of individual plasma FFAs on a variety of oxylipins, particularly epoxides, diols, and their ratios. We tested if FFA epoxide-diol ratios are altered by circulating FFA levels (i.e., substrate availability) independent of sEH activity. Wistar rats received a constant intravenous infusion of olive (70% oleic acid (OA)), safflower seed (72% linoleic acid (LA)), and fish oils (rich in ω-3 FFAs) as emulsions to selectively raise OA, LA, and ω-3 FFAs (eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)), respectively. As expected, olive, safflower seed, and fish oil infusions selectively raised plasma OA (57%), LA (87%), EPA (70%), and DHA (54%), respectively (p < 0.05 for all). Raising plasma FFAs exerted substrate effects to increase hepatic and plasma epoxide and diol levels. These increases in epoxides and diols occurred to similar extents, resulting in no significant changes in epoxide-diol ratios. These data suggest that epoxide-diol ratios, often used as indices of sEH activity, are not affected by substrate availability or altered plasma FFA levels and that epoxide-diol ratios may be used to compare sEH activity between conditions of different circulating FFA levels.

Optimization of spray drying process of Japanese apricot (Prunus mume Sieb. et Zucc.) juice powder using nondigestible maltodextrin by response surface methodology (RSM).

The optimal spray-drying conditions for manufacturing Japanese apricot (Prunus mume Sieb. et Zucc.) juice powder (JAJP) using response surface methodology (RSM) were investigated. The optimization was performed using two independent factors, which are inlet air temperature (130-180 °C) and different concentrations of nondigestible maltodextrin (NMD) as a carrier agent (10-30%). Responses such as drying yield, moisture content, water solubility index (WSI), bulk density, color, pH, and antioxidant activities of JAJP were investigated. Moisture content, vitamin C content, color, antioxidant activity, pH and bulk density were greatly influenced by inlet air temperature, but dry yield and WSI were only significantly affected by NMD concentration. The optimum spray drying conditions were determined as 14.7% NMD concentration and 154.5 °C inlet air temperature, respectively. At these optimum conditions, a drying yield of 55.73%, 4.84% moisture content, 90.98% WSI, 0.59 g/mL of bulk density, and 169.87 mg/g vitamin C content in JAJP were measured. Therefore, JAJP with the desirable physicochemical properties could be produced.

Estimating in vivo potassium distribution and fluxes with stable potassium isotopes.

Extracellular potassium (K+) homeostasis is achieved by a concerted effort of multiple organs and tissues. A limitation in studies of K+ homeostasis is inadequate techniques to quantify K+ fluxes into and out of organs and tissues in vivo. The goal of the present study was to test the feasibility of a novel approach to estimate K+ distribution and fluxes in vivo using stable K+ isotopes. 41K was infused as KCl into rats consuming control or K+-deficient chow (n = 4 each), 41K-to-39K ratios in plasma and red blood cells (RBCs) were measured by inductively coupled plasma mass spectrometry, and results were subjected to compartmental modeling. The plasma 41K/39K increased during 41K infusion and decreased upon infusion cessation, without altering plasma total K+ concentration ([K+], i.e., 41K + 39K). The time course of changes was analyzed with a two-compartmental model of K+ distribution and elimination. Model parameters, representing transport into and out of the intracellular pool and renal excretion, were identified in each rat, accurately predicting decreased renal K+ excretion in rats fed K+-deficient vs. control diet (P < 0.05). To estimate rate constants of K+ transport into and out of RBCs, 41K/39K were subjected to a simple model, indicating no effects of the K+-deficient diet. The findings support the feasibility of the novel stable isotope approach to quantify K+ fluxes in vivo and sets a foundation for experimental protocols using more complex models to identify heterogeneous intracellular K+ pools and to answer questions pertaining to K+ homeostatic mechanisms in vivo.

Altered distributions in circulating follicular helper and follicular regulatory T cells accountable for imbalanced cytokine production in multiple sclerosis.

Follicular T helper (Tfh) and regulatory (Tfr) cells are distinct subsets of CD4+ T lymphocytes, regulating humoral immune responses in the germinal center. It is widely accepted that dysregulated Tfh and Tfr cells are associated with autoimmunity. In this study, we evaluated the frequencies of circulating chemokine receptor (CXCR)5+ programmed cell death 1 (PD-1+ ) Tfh (cTfh) and CXCR5+ PD-1+ forkhead box protein 3 (FoxP3+ ) CD25+ Tfr (cTfr) cells, and their corresponding cytokines from the peripheral blood mononuclear cells of 28 patients with relapsing-remitting multiple sclerosis (MS) and 16 age- and sex-matched healthy controls (HC). Subsets of cTfh cells by Th1- and Th17-related surface markers (CXCR3 and CCR6) were also evaluated. We found that the frequency of cTfh cells was significantly higher in MS patients compared to that of HC. Conversely, the frequency of cTfr cells was lower in MS patients than that of HC. Interleukin (IL)-21-producing cTfh cells were significantly increased in MS patients, while IL-10-secreting cTfr cells were lower in MS patients compared to levels in HC. Among cTfh cells, cTfh17.1 cells were the major subtypes that were significantly increased in MS patients compared to HC, with the frequency of IL-21-secreting cells being the highest. These results suggest that an imbalanced distribution of cTfh and cTfr exist in MS patients, which contributes to the reciprocally altered IL-21 and IL-10 production.

Role of α- and ß-adrenergic signaling in phenotypic targeting: significance in benign and malignant urologic disease.

The urinary tract is highly innervated by autonomic nerves which are essential in urinary tract development, the production of growth factors, and the control of homeostasis. These neural signals may become dysregulated in several genitourinary (GU) disease states, both benign and malignant. Accordingly, the autonomic nervous system is a therapeutic target for several genitourinary pathologies including cancer, voiding dysfunction, and obstructing nephrolithiasis. Adrenergic receptors (adrenoceptors) are G-Protein coupled-receptors that are distributed throughout the body. The major function of α1-adrenoceptors is signaling smooth muscle contractions through GPCR and intracellular calcium influx. Pharmacologic intervention of α-and ß-adrenoceptors is routinely and successfully implemented in the treatment of benign urologic illnesses, through the use of α-adrenoceptor antagonists. Furthermore, cell-based evidence recently established the antitumor effect of α1-adrenoceptor antagonists in prostate, bladder and renal tumors by reducing neovascularity and impairing growth within the tumor microenvironment via regulation of the phenotypic epithelial-mesenchymal transition (EMT). There has been a significant focus on repurposing the routinely used, Food and Drug Administration-approved α1-adrenoceptor antagonists to inhibit GU tumor growth and angiogenesis in patients with advanced prostate, bladder, and renal cancer. In this review we discuss the current evidence on (a) the signaling events of the autonomic nervous system mediated by its cognate α- and ß-adrenoceptors in regulating the phenotypic landscape (EMT) of genitourinary organs; and (b) the therapeutic significance of targeting this signaling pathway in benign and malignant urologic disease. Video abstract.

Optimal application of compressive palatal stents following mesiodens removal in pediatric patients: A Randomized Controlled Trial.

BACKGROUND: There is no scientific evidence supporting the choice of a palatal stent in patients who underwent removal of an impacted supernumerary tooth. We aimed to investigate the effects of palatal stents in patients who underwent supernumerary tooth removal through a palatal approach and to suggest the optimal stent thickness and material. MATERIAL AND METHODS: We recruited 144 patients who underwent extraction of a supernumerary tooth between the maxillary anterior teeth. Subjects were assigned to a control group (CG) or one of four compressive palatal stent groups (CPSGs) classified by the thickness and material of the thermoplastic acrylic stent used. Palatal gingival swelling and objective indices (healing, oral hygiene, gingival, and plaque) were evaluated before surgery and on postoperative days (PODs) 3, 7, and 14; pain/discomfort and the Child Oral Health Impact Profile (COHIP) were assessed as subjective indices of the effects of the stent. RESULTS: The CPSGs showed faster healing than did the CG on PODs 7 (P<0.001) and 14 (P=0.043); swelling was measured by 1.64±0.88 mm and 4.52±0.39 mm, respectively. Although swelling was least in the 4-mm hard group (0.92±0.33 mm), the difference compared with that in the 2-mm hard group (1.01±0.18 mm) was not significant (P=0.077). The CPSGs showed better COHIP (P<0.001-0.036) and pain scores (P<0.001) than did the CG on PODs 1-3. CONCLUSIONS: Compressive palatal stents reduce discomfort by decreasing pain and alleviating swelling. Although a stent is effective regardless of its thickness and material, 2-mm hard stents maximized such positive effects with minimal discomfort.

Search for Sub-eV Sterile Neutrinos at RENO.

We report a search result for a light sterile neutrino oscillation with roughly 2200 live days of data in the RENO experiment. The search is performed by electron antineutrino (ν[over ¯]_{e}) disappearance taking place between six 2.8 GW_{th} reactors and two identical detectors located at 294 m (near) and 1383 m (far) from the center of the reactor array. A spectral comparison between near and far detectors can explore reactor ν[over ¯]_{e} oscillations to a light sterile neutrino. An observed spectral difference is found to be consistent with that of the three-flavor oscillation model. This yields limits on sin^{2}2θ_{14} in the 10^{-4}≲|Δm_{41}^{2}|≲0.5 eV^{2} region, free from reactor ν[over ¯]_{e} flux and spectrum uncertainties. The RENO result provides the most stringent limits on sterile neutrino mixing at |Δm_{41}^{2}|≲0.002 eV^{2} using the ν[over ¯]_{e} disappearance channel.

Outcome of pregnancies after onset of the neuromyelitis optica spectrum disorder.

BACKGROUND AND PURPOSE: Data on the pregnancy outcome of neuromyelitis optica spectrum disorder (NMOSD) remain limited, especially for woman who had received immunosuppressive treatment before becoming pregnant. The aim was to evaluate the outcome of pregnancy amongst patients with NMOSD who attempted to become pregnant after NMOSD onset and to identify risk factors that predict pregnancy-related attack. METHODS: Medical records from 29 patients who attempted to become pregnant after NMOSD onset were retrospectively evaluated and the patients were interviewed for pregnancy outcomes. Pregnancy-related attack was defined as an attack that occurred during pregnancy or within 1 year of delivery. RESULTS: Amongst the 29 patients, 26 had 33 pregnancies after NMOSD symptom onset. The 33 pregnancies after NMOSD onset resulted in 24 live births (healthy neonates except one with low birth weight), six miscarriages and three elective abortions. Pregnancy-related attack occurred in nine (75%) of 12 pregnancies before initiation of immunosuppressive therapy, but in only five (24%) of 21 pregnancies after initiation of immunosuppressive therapy (P = 0.009). Multivariable analysis indicated that pregnancy-related attack was negatively associated with pregnancy after initiation of rituximab (odds ratio 0.048, 95% confidence interval 0.004-0.546). CONCLUSION: Successful pregnancy without maternal and neonatal complications may be feasible in patients with NMOSD. Rituximab treatment before pregnancy might help to prevent pregnancy-related attack in patients with NMOSD.

Hearing loss is associated with cortical thinning in cognitively normal older adults.

BACKGROUND AND PURPOSE: Hearing loss (HL) is one of the most influential risk factors of dementia in older adults. However, its potential association with neurodegeneration is not well established. The association between HL and cortical thickness in cognitively normal older adults was evaluated. METHODS: In all, 982 cognitively normal older adults (age ≥65 years) were identified from the Health Promotion Center at the Samsung Medical Center from September 2008 to December 2014. The participants underwent pure-tone audiometry and brain magnetic resonance imaging. HL was evaluated according to a four-frequency (0.5, 1, 2, 4 kHz) pure-tone average. Participants were divided into three groups according to pure-tone average (normal hearing ≤15 dB, minimal HL 16-25 dB, mild-to-severe HL >25 dB). Cortical thickness in the HL groups was compared with that of the normal hearing group. RESULTS: In women, right ear HL was associated with cortical thinning: the minimal HL group showed cortical thinning in the left frontal and bilateral occipital areas and the mild-to-severe HL group showed cortical thinning in the bilateral frontal, right temporal and bilateral occipital areas compared to the normal hearing group. In men, there was no significant association between HL on either side and cortical thickness. CONCLUSION: In older women, right ear HL is associated with neurodegeneration even in a cognitively normal state. Therefore, managing HL especially in older women may be an effective strategy for dementia prevention.

Assessment of soluble epoxide hydrolase activity in vivo: A metabolomic approach.

Soluble epoxide hydrolase (sEH) converts several FFA epoxides to corresponding diols. As many as 15 FFA epoxide-diol ratios are measured to infer sEH activity from their ratios. Using previous data, we assessed if individual epoxide-diol ratios all behave similarly to reflect changes in sEH activity, and whether analyzing these ratios together increases the power to detect changes in in-vivo sEH activity. We demonstrated that epoxide-diol ratios correlated strongly with each other (P < 0.05), suggesting these ratios all reflect changes in sEH activity. Furthermore, we developed a modeling approach to analyze all epoxide-diol ratios simultaneously to infer global sEH activity, named SAMI (Simultaneous Analysis of Multiple Indices). SAMI improved power in detecting changes in sEH activity in animals and humans when compared to individual ratio estimates. Thus, we introduce a new powerful method to infer sEH activity by combining metabolomic determination and simultaneous analysis of all measurable epoxide-diol pairs.

Lack of association between early menopause and non-alcoholic fatty liver disease in postmenopausal women.

Background: The possibility of an association between early menopause and the risk of non-alcoholic fatty liver disease (NAFLD) is as yet unclear.Methods: The subjects consisted of 4354 postmenopausal women who participated in the 2010-2012 Korea National Health and Nutrition Examination Survey. Early, normal, and late menopause were defined as age at menopause <45 years, 45-54 years, and ≥55 years, respectively. NAFLD was defined by a hepatic steatosis index of >36.Results: When compared with normal menopausal women, early or late menopausal women had no significant differences in the odds ratios (ORs) of NAFLD: OR = 1.05, 95% confidence interval (CI), 0.83-1.32 and OR = 1.02, 95% CI, 0.75-1.39, respectively. These results remained similar after adjustment for known risk factors for NAFLD, reproductive factors, and comorbidities. The OR for NAFLD per 1-year increase in age at menopause was 1.01 (95% CI, 0.99-1.03; p = 0.329). The prevalence of advanced fibrosis was 2.1% (95% CI, 0.7-6.4%), 2.2% (95% CI, 1.3-3.8%), and 3.9% (95% CI, 1.2-12.2%) in early, normal, and late menopausal women, respectively.Conclusions: This study provides no evidence for an association of early menopause with NAFLD risk. However, NAFLD-related advanced fibrosis is highly prevalent in postmenopausal women.

Microbial communities of a variety of cheeses and comparison between core and rind region of cheeses.

Understanding the microbial community of cheese is important in the dairy industry, as the microbiota contributes to the safety, quality, and physicochemical and sensory properties of cheese. In this study, the microbial compositions of different cheeses (Cheddar, provolone, and Swiss cheese) and cheese locations (core, rind, and mixed) collected from the Arbuthnot Dairy Center at Oregon State University were analyzed using 16S rRNA gene amplicon sequencing with the Illumina MiSeq platform (Illumina, San Diego, CA). A total of 225 operational taxonomic units were identified from the 4,675,187 sequencing reads generated. Streptococcus was observed to be the most abundant organism in provolone (72 to 85%) and Swiss (60 to 67%), whereas Lactococcus spp. were found to dominate Cheddar cheese (27 to 76%). Species richness varied significantly by cheese. According to alpha diversity analysis, porter-soaked Cheddar cheese exhibited the highest microbial richness, whereas smoked provolone cheese showed the lowest. Rind regions of each cheese changed color through smoking and soaking for the beverage process. In addition, the microbial diversity of the rind region was higher than the core region because smoking and soaking processes directly contacted the rind region of each cheese. The microbial communities of the samples clustered by cheese, indicated that, within a given type of cheese, microbial compositions were very similar. Moreover, 34 operational taxonomic units were identified as biomarkers for different types of cheese through the linear discriminant analysis effect size method. Last, both carbohydrate and AA metabolites comprised more than 40% of the total functional annotated genes from 9 varieties of cheese samples. This study provides insight into the microbial composition of different types of cheese, as well as various locations within a cheese, which is applicable to its safety and sensory quality.

Role of transient receptor potential vanilloid type 1 in the trigeminal ganglion and brain stem following dental pulp inflammation.

AIM: To verify whether experimentally induced pulpitis activates the expression of transient receptor potential vanilloid type 1 (TRPV1) and c-Fos, both peripherally and centrally. METHODOLOGY: Acute pulpitis was induced in Sprague-Dawley rats via pulp exposure and application of complete Freund's adjuvant (CFA; n = 13). Saline-treated (n = 13) rats and rats that did not undergo tooth preparation (n = 13) served as control groups. Three days post-CFA or post-saline application, face grooming activity was recorded, and the rats were then euthanized to allow for immunohistochemical analysis of the trigeminal ganglion (TG) and spinal trigeminal nucleus. anova with Student's t-test for post-hoc analysis was used to quantify the differences in behavioural tests and immunohistochemical labelling (c-Fos and TRPV1) in TG amongst groups. Kruskal-Wallis test with Dunnett's test for post-hoc analysis was used to compare immunohistochemical labelling (c-Fos and TRPV1) in the brainstem amongst groups. RESULTS: Histological evidence of severe pulp inflammation was found, and there was a significant increase in pain-like behaviour (P < 0.05) in CFA-treated animals. C-Fos labelling and TRPV1 immunoreactivity in the TG were significantly higher (both P < 0.05) in the CFA group than in the control groups. In the spinal trigeminal nucleus, the immunoreactivity for c-Fos was absent in the intermediate region (trigeminal subnucleus interpolaris) in all animals, with comparable expression of TRPV1 amongst all groups. In contrast, neurons in the trigeminal subnucleus caudalis (TSC) exhibited significant c-Fos immunoreactivity in the CFA group (P = 0.0063). The expression of TRPV1 did not differ amongst the three groups, but the superficial laminae of the TSC exhibited significantly greater expression of TRPV1 than did the deep layers (P = 0.0014). CONCLUSIONS: Following acute pulp inflammation, the TRPV1 channel was significantly involved in nociceptive signal processing in the peripheral nervous system, but not in the CNS. Because pulpitis induced some neuronal activation at the brainstem levels, further studies are needed to identify additional transducers that mediate signal transmission from pulpal afferents to their central targets.

Fuel-Composition Dependent Reactor Antineutrino Yield at RENO.

We report a fuel-dependent reactor electron antineutrino (ν[over ¯]_{e}) yield using six 2.8 GW_{th} reactors in the Hanbit nuclear power plant complex, Yonggwang, Korea. The analysis uses 850 666 ν[over ¯]_{e} candidate events with a background fraction of 2.0% acquired through inverse beta decay (IBD) interactions in the near detector for 1807.9 live days from August 2011 to February 2018. Based on multiple fuel cycles, we observe a fuel ^{235}U dependent variation of measured IBD yields with a slope of (1.51±0.23)×10^{-43} cm^{2}/fission and measure a total average IBD yield of (5.84±0.13)×10^{-43} cm^{2}/fission. The hypothesis of no fuel-dependent IBD yield is ruled out at 6.6σ. The observed IBD yield variation over ^{235}U isotope fraction does not show significant deviation from the Huber-Mueller (HM) prediction at 1.3 σ. The measured fuel-dependent variation determines IBD yields of (6.15±0.19)×10^{-43} and (4.18±0.26)×10^{-43} cm^{2}/fission for two dominant fuel isotopes ^{235}U and ^{239}Pu, respectively. The measured IBD yield per ^{235}U fission shows the largest deficit relative to the HM prediction. Reevaluation of the ^{235}U IBD yield per fission may mostly solve the reactor antineutrino anomaly (RAA) while ^{239}Pu is not completely ruled out as a possible contributor to the anomaly. We also report a 2.9 σ correlation between the fractional change of the 5 MeV excess and the reactor fuel isotope fraction of ^{235}U.

Repurposing auranofin to combat uropathogenic Escherichia coli biofilms.

AIMS: The aim of this study was to assess anti-biofilm and antimicrobial effects of auranofin, an anti-rheumatic agent, on uropathogenic Escherichia coli (UPEC) biofilm formation. METHODS AND RESULTS: The minimum inhibitory concentration and biofilm inhibition concentration of auranofin against UPEC ranged from 24 to 32 µg ml-1 . Biofilm eradication concentration and XTT reduction concentration of auranofin were found to be at 112 µg ml-1 . Confocal laser scanning microscopy results confirmed that biofilm was inhibited by auranofin. These results indicate that auranofin possesses potent anti-biofilm and antimicrobial activities against UPEC. Effects of auranofin on type 1 fimbriae gene (fimH) and response regulator gene (rpoS) to stress were explored using quantitative real time-polymerase chain reaction. In addition, combination of auranofin and tetracycline showed synergistic effect. CONCLUSIONS: These data indicate that auranofin has inhibitory effect on biofilm formation and synergistic effect on UPEC infection when it is combined with tetracycline. SIGNIFICANCE AND IMPACT OF THE STUDY: Our study strongly suggest that auranofin is a promising alternative anti-biofilm and antimicrobial agent to prevent UPEC biofilm formation in UTIs. Auranofin already approved for human use have the advantage of being able to be put into clinical use relatively quickly.