Proton pump inhibitors (PPIs) have been recognized as a primary treatment of eosinophilic esophagitis (EoE), an allergic inflammatory disease of the esophageal mucosa. The mechanisms underlying ...esophageal epithelial responses to PPIs remain poorly understood.
We hypothesized that PPIs can counteract IL-13–mediated esophageal epithelial responses that are germane for EoE pathogenesis.
Transcriptional responses of human esophageal cells to IL-13 and the PPIs omeprazole and esomeprazole were assessed by RT-PCR and RNA sequencing. Cytokine secretion was measured by multiplex analysis and ELISA.
Human esophageal epithelial cells robustly responded to PPI stimulation by inducing a set of 479 core genes common between omeprazole and esomeprazole treatments. The transcriptional response to PPIs was partially mediated through the aryl hydrocarbon receptor signaling pathway, as the aryl hydrocarbon receptor antagonist GNF-351 modified approximately 200 genes, particularly those enriched in metabolic processes and regulation of cell death. PPI treatment reversed approximately 20% of the IL-13 transcriptome. Functional analysis of the PPI-responsive, upregulated genes revealed enrichment in metabolic and oxidation processes, and the unfolded protein response. In contrast, downregulated genes were overrepresented in functional terms related to cell division and cytoskeletal organization, which were also enriched for the genes in the EoE transcriptome reversed by PPIs. Furthermore, PPI treatment decreased the IL-13–induced proliferative response of esophageal epithelial cells.
These results demonstrate broad effects of PPIs on esophageal epithelium, including their ability to curtail transcriptomic processes involved in cellular proliferation and IL-13–induced responses, and they highlight the importance of AHR signaling in mediating these responses.
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The host cell serine protease TMPRSS2 is an attractive therapeutic target for COVID-19 drug discovery. This protease activates the Spike protein of severe acute respiratory syndrome coronavirus 2 ...(SARS-CoV-2) and of other coronaviruses and is essential for viral spread in the lung. Utilizing rational structure-based drug design (SBDD) coupled to substrate specificity screening of TMPRSS2, we have discovered covalent small-molecule ketobenzothiazole (kbt) TMPRSS2 inhibitors which are structurally distinct from and have significantly improved activity over the existing known inhibitors Camostat and Nafamostat. Lead compound MM3122 (4) has an IC
(half-maximal inhibitory concentration) of 340 pM against recombinant full-length TMPRSS2 protein, an EC
(half-maximal effective concentration) of 430 pM in blocking host cell entry into Calu-3 human lung epithelial cells of a newly developed VSV-SARS-CoV-2 chimeric virus, and an EC
of 74 nM in inhibiting cytopathic effects induced by SARS-CoV-2 virus in Calu-3 cells. Further, MM3122 blocks Middle East respiratory syndrome coronavirus (MERS-CoV) cell entry with an EC
of 870 pM. MM3122 has excellent metabolic stability, safety, and pharmacokinetics in mice, with a half-life of 8.6 h in plasma and 7.5 h in lung tissue, making it suitable for in vivo efficacy evaluation and a promising drug candidate for COVID-19 treatment.
Host proteases have been suggested to be crucial for dissemination of MERS, SARS-CoV, and SARS-CoV-2 coronaviruses, but the relative contribution of membrane versus intracellular proteases remains ...controversial. Transmembrane serine protease 2 (TMPRSS2) is regarded as one of the main proteases implicated in the coronavirus S protein priming, an important step for binding of the S protein to the angiotensin-converting enzyme 2 (ACE2) receptor before cell entry.
We developed a cell-based assay to identify TMPRSS2 inhibitors. Inhibitory activity was established in SARS-CoV-2 viral load systems.
We identified the human extracellular serine protease inhibitor (serpin) alpha 1 anti-trypsin (A1AT) as a novel TMPRSS2 inhibitor. Structural modeling revealed that A1AT docked to an extracellular domain of TMPRSS2 in a conformation that is suitable for catalysis, resembling similar serine protease inhibitor complexes. Inhibitory activity of A1AT was established in a SARS-CoV-2 viral load system. Notably, plasma A1AT levels were associated with COVID-19 disease severity.
Our data support the key role of extracellular serine proteases in SARS CoV-2 infections and indicate that treatment with serpins, particularly the FDA-approved drug A1AT, may be effective in limiting SARS-CoV-2 dissemination by affecting the surface of the host cells.
ABSTRACT
The Neil Gehrels Swift Observatory followed up 18 gravitational wave (GW) triggers from the LIGO/Virgo collaboration during the O3 observing run in 2019/2020, performing approximately 6500 ...pointings in total. Of these events, four were finally classified (if real) as binary black hole (BH) triggers, six as binary neutron star (NS) events, two each of NSBH and Mass Gap triggers, one an unmodelled (Burst) trigger, and the remaining three were subsequently retracted. Thus far, four of these O3 triggers have been formally confirmed as real gravitational wave events. While no likely electromagnetic counterparts to any of these GW events have been identified in the X-ray data (to an average upper limit of 3.60 × 10−12 erg cm−2 s−1 over 0.3–10 keV), or at other wavelengths, we present a summary of all the Swift-XRT observations performed during O3, together with typical upper limits for each trigger observed. The majority of X-ray sources detected during O3 were previously uncatalogued; while some of these will be new (transient) sources, others are simply too faint to have been detected by earlier survey missions such as ROSAT. The all-sky survey currently being performed by eROSITA will be a very useful comparison for future observing runs, reducing the number of apparent candidate X-ray counterparts by up to 95 per cent.
Abstract Objective To investigate utility and limitations of 3-Tesla diffusion-weighted (DW) magnetic resonance imaging (MRI) for differentiation of benign versus malignant renal lesions and renal ...cell carcinoma (RCC) subtypes. Materials and methods Sixty patients with 71 renal lesions underwent 3 Tesla DW-MRI of the kidney before diagnostic tissue confirmation. The images were retrospectively evaluated blinded to histology. Single-shot echo-planar imaging was used as the DW imaging technique. Apparent diffusion coefficient (ADC) values were measured and compared with histopathological characteristics. Results There were 54 malignant and 17 benign lesions, 46 lesions being small renal masses ≤4 cm. Papillary RCC lesions had lower ADC values ( p = 0.029) than other RCC subtypes (clear cell or chromophobe). Diagnostic accuracy of DW-MRI for differentiation of papillary from non-papillary RCC was 70.3% resulting in a sensitivity and specificity of 64.3% (95% CI, 35.1–87.2) and 77.1 (95% CI, 59.9–89.6%). Accuracy increased to 83.7% in small renal masses (≤4 cm diameter) and sensitivity and specificity were 75.0% and 88.5%, respectively. The ADC values did not differ significantly between benign and malignant renal lesions ( p = 0.45). Conclusions DW-MRI seems to distinguish between papillary and other subtypes of RCCs especially in small renal masses but could not differentiate between benign and malignant renal lesions. Therefore, the use of DW-MRI for preoperative differentiation of renal lesions is limited.
Forests are key components of European multifunctional landscapes and supply numerous forest ecosystem services (FES) fundamental to human well-being. The sustainable provision of FES has the ...potential to provide responses to major societal challenges, such as climate change, biodiversity loss, or rural development. To identify suitable strategies for the future sustenance of FES, we performed a solution scanning exercise with a group of transdisciplinary forest and FES experts from different European regions. We identified and prioritized fifteen major challenges hindering the balanced provision of multiple FES and identified a series of potential solutions to tackle each of them. The most prominent challenges referred to the increased frequency and impacts of extreme weather events and the normative mindset regarding forest management. The respective solutions pointed to the promotion of forest resilience via climate-smart forestry and mainstreaming FES-oriented management through a threefold strategy focusing on education, awareness raising, and networking. In a subsequent survey, most solutions were assessed as highly effective, transferable, monitorable, and with potential for being economically efficient. The implementation of the solutions could have synergistic effects when applying the notion of leverage points. Seven emerging pathways towards the sustainable supply of FES have been identified. These pathways build on each other and are organized based on their potential for transformation: (1) shifting forest management paradigms towards pluralistic ecosystem valuation; (2) using integrated landscape approaches; (3) increasing forest resilience; (4) coordinating actions between forest-related actors; (5) increasing participation in forest planning and management; (6) continuous, open, and transparent knowledge integration; and (7) using incentive-based instruments to support regulating and cultural FES. These pathways can contribute to the implementation of the new EU Forestry Strategy to support the balanced supply of multiple FES.
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ABSTRACT
In this paper, we report on the observational performance of the Swift Ultra-violet/Optical Telescope (UVOT) in response to the gravitational wave (GW) alerts announced by the Advanced Laser ...Interferometer Gravitational Wave Observatory and the Advanced Virgo detector during the O3 period. We provide the observational strategy for follow-up of GW alerts and provide an overview of the processing and analysis of candidate optical/UV sources. For the O3 period, we also provide a statistical overview and report on serendipitous sources discovered by Swift/UVOT. Swift followed 18 GW candidate alerts, with UVOT observing a total of 424 deg2. We found 27 sources that changed in magnitude at the 3σ level compared with archival u- or g-band catalogued values. Swift/UVOT also followed up a further 13 sources reported by other facilities during the O3 period. Using catalogue information, we divided these 40 sources into five initial classifications: 11 candidate active galactic nuclei (AGNs)/quasars, three cataclysmic variables (CVs), nine supernovae, 11 unidentified sources that had archival photometry, and six uncatalogued sources for which no archival photometry was available. We have no strong evidence to identify any of these transients as counterparts to the GW events. The 17 unclassified sources are likely a mix of AGN and a class of fast-evolving transient, and one source may be a CV.
On 2020 February 24, during their third observing run ("O3"), the Laser Interferometer Gravitational-wave Observatory and Virgo Collaboration detected S200224ca: a candidate gravitational wave (GW) ...event produced by a binary black hole (BBH) merger. This event was one of the best-localized compact binary coalescences detected in O3 (with 50%/90% error regions of 13/72 deg2), and so the Neil Gehrels Swift Observatory performed rapid near-UV/X-ray follow-up observations. Swift-XRT and UVOT covered approximately 79.2% and 62.4% (respectively) of the GW error region, making S200224ca the BBH event most thoroughly followed-up in near-UV (u-band) and X-ray to date. No likely EM counterparts to the GW event were found by the Swift BAT, XRT, or UVOT, nor by other observatories. Here, we report on the results of our searches for an EM counterpart, both in the BAT data near the time of the merger, and in follow-up UVOT/XRT observations. We also discuss the upper limits we can place on EM radiation from S200224ca, as well as the implications these limits have on the physics of BBH mergers. Namely, we place a shallow upper limit on the dimensionless BH charge, , and an upper limit on the isotropic-equivalent energy of a blast wave E < 4.1 × 1051 erg (assuming typical GRB parameters).
The Neil Gehrels Swift Observatory carried out prompt searches for gravitational-wave (GW) events detected by the LIGO/Virgo Collaboration (LVC) during the second observing run ("O2"). Swift ...performed extensive tiling of eight LVC triggers, two of which had very low false-alarm rates (GW170814 and the epochal GW170817), indicating a high confidence of being astrophysical in origin; the latter was the first GW event to have an electromagnetic counterpart detected. In this paper we describe the follow-up performed during O2 and the results of our searches. No GW electromagnetic counterparts were detected; this result is expected, as GW170817 remained the only astrophysical event containing at least one neutron star after LVC's later retraction of some events. A number of X-ray sources were detected, with the majority of identified sources being active galactic nuclei. We discuss the detection rate of transient X-ray sources and their implications in the O2 tiling searches. Finally, we describe the lessons learned during O2 and how these are being used to improve the Swift follow-up of GW events. In particular, we simulate a population of gamma-ray burst afterglows to evaluate our source ranking system's ability to differentiate them from unrelated and uncataloged X-ray sources. We find that 60%-70% of afterglows whose jets are oriented toward Earth will be given high rank (i.e., "interesting" designation) by the completion of our second follow-up phase (assuming that their location in the sky was observed), but that this fraction can be increased to nearly 100% by performing a third follow-up observation of sources exhibiting fading behavior.
It was hypothesized that subjects with metabolic syndrome (hypertension, obesity, hyperlipidemia, diabetes mellitus): (1) develop measurable peripheral edema at moderate altitude and (2) might show ...differences on erythropoiesis, iron status and vascular endothelial growth factor (VEGF) in comparison to healthy subjects during and after a long-term stay (3-week exposure) at moderate altitude (congruent with 1700 m). Twenty-two male subjects with metabolic syndrome were selected. Baseline investigations (t1) were performed in Innsbruck (500 m). All participants were transferred by bus to 1700 m (Alps) and remained there for 3 weeks with examinations on day 1 (after the first night at altitude, t2), day 4 (t3), day 9 (t4) and day 19 (t5). After returning to Innsbruck, post-altitude examinations were conducted after 7-10 days (t6) and 6-7 weeks (t7), respectively. Body mass was decreased from t1 to t7 (P<0.01). Total body water was decreased at t2 (P<0.01), returned to control level (t3, t4), and was found elevated at t7 (P<0.01). Lean body mass did not change, but body fat decreased during the study (P<0.01). Tissue thickness at the forehead decreased during and after altitude exposure (P<0.01), whereas tissue thickness at the tibia did not alter. Erythropoietin (EPO) was elevated as early as t2 and remained increased until t5. Reticulocyte count was increased at t3 and remained above pre-altitude values. VEGF levels were unchanged. After a 3-week exposure to moderate altitude, patients with metabolic syndrome had reduced their body mass, mainly because of a reduction in body fat. The moderate altitude was found to stimulate erythropoiesis in these patients but this was not sufficient to increase serum VEGF concentration.
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