Arzanol, a prenylated heterodimeric phloroglucinyl pyrone, inhibits eicosanoid biosynthesis and exhibits anti-inflammatory efficacy in vivo.

Based on its capacity to inhibit in vitro HIV-1 replication in T cells and the release of pro-inflammatory cytokines in monocytes, the prenylated heterodimeric phloroglucinyl α-pyrone arzanol was identified as the major anti-inflammatory and anti-viral constituent from Helichrysum italicum. We have now investigated the activity of arzanol on the biosynthesis of pro-inflammatory eicosanoids, evaluating its anti-inflammatory efficacy in vitro and in vivo. Arzanol inhibited 5-lipoxygenase (EC 7.13.11.34) activity and related leukotriene formation in neutrophils, as well as the activity of cyclooxygenase (COX)-1 (EC 1.14.99.1) and the formation of COX-2-derived prostaglandin (PG)E(2)in vitro (IC(50)=2.3-9μM). Detailed studies revealed that arzanol primarily inhibits microsomal PGE(2) synthase (mPGES)-1 (EC 5.3.99.3, IC(50)=0.4μM) rather than COX-2. In fact, arzanol could block COX-2/mPGES-1-mediated PGE(2) biosynthesis in lipopolysaccharide-stimulated human monocytes and human whole blood, but not the concomitant COX-2-derived biosynthesis of thromboxane B(2) or of 6-keto PGF(1α), and the expression of COX-2 or mPGES-1 protein was not affected. Arzanol potently suppressed the inflammatory response of the carrageenan-induced pleurisy in rats (3.6mg/kg, i.p.), with significantly reduced levels of PGE(2) in the pleural exudates. Taken together, our data show that arzanol potently inhibits the biosynthesis of pro-inflammatory lipid mediators like PGE(2)in vitro and in vivo, providing a mechanistic rationale for the anti-inflammatory activity of H. italicum, and a rationale for further pre-clinical evaluation of this novel anti-inflammatory lead

The Ecocruiser

Electronic resources on environmental topics

Understanding response to rituximab treatment in rheumatoid arthritis through immune fingerprinting of T and B cells

Despite the great research advances in dissecting the mechanisms underlying rheumatoid arthritis onset and development, the exact pathophysiology of this disease remains unsolved. In the past years, the introduction of biologicals, and in particular of therapeutic monoclonal antibodies (mAb), has constituted a major breakthrough in the clinical management of the disease. Although these new drugs have proven effective, in some patients, remission or low disease activity is only partially or temporally achieved. Understanding the mechanism behind this incomplete response might lead to improved therapies and in ultimately to improved quality of life for patients. This thesis describes our efforts to elucidate the mechanisms behind response to B-cell depletion therapy using rituximab in rheumatoid arthritis. We evaluated how both direct and indirect effects can influence clinical response to the treatment. To achieve this we applied AIRR sequencing or Adaptive Immune Receptor Repertoire sequencing, which allows to identify and quantify all T- and B-cell receptors within an individual. This methodology allowed us to fingerprint and monitor ongoing immune responses in cohorts of rheumatoid arthritis patients undergoing rituximab treatment

The prospectivity of a potential shale gas play: An example from the southern Pennine Basin (central England, UK)

During the Serpukhovian (late Mississippian) Stage, the Pennine Basin, now underlying much of northern England, consisted of a series of interlinked sub-basins that developed in response to the crustal extension north of the Hercynic orogenic zone. For the current study, mudstone samples of the Morridge Formation from two sub-basins located in the south-eastern part of the Pennine Basin were collected from the Carsington Dam Reconstruction C3 Borehole (Widmerpool Gulf sub-basin) and the Karenight 1 Borehole (Edale Gulf sub-basin). Detailed palynological analyses indicate that aside from the dominant (often 90% or more) heterogeneous amorphous organic matter (AOM), variable abundances of homogeneous AOM and phytoclasts are present. To complement the palynological dataset, a suite of geochemical and mineralogical techniques were applied to evaluate the prospectivity of these potentially important source rocks. Changes in the carbon isotope composition of the bulk organic fraction (δ13COM) suggest that the lower part (Biozone E2a) of Carsington DR C3 is markedly more influenced by terrigenous kerogen than the upper part of the core (Biozones E2a3–E2b1). The Karenight 1 core yielded more marine kerogen in the lower part (Marine Bands E1–E2b) than the upper part (Marine Band E2b). Present day Rock-Eval™ Total Organic Carbon (TOC) surpasses 2% in most samples from both cores, a proportion suggested by Jarvie (2012) that defines prospective shale gas reservoirs. However, when the pyrolysable component that reflects the generative kerogen fraction is considered, very few samples reach this threshold. The kerogen typing permits for the first time the calculation of an original hydrogen index (HIo) and original total organic carbon (TOCo) for Carboniferous mudstones of the Pennine Basin. The most prospective part of Carsington DR C3 (marine bands E2b1–E2a3) has an average TOCo of 3.2% and an average HIo of 465 mg/g TOCo. The most prospective part of Karenight 1 (242.80–251.89 m) is characterized by an average TOCo of 9.3% and an average HIo of 504 mg/g TOCo. Lastly, X-ray diffraction (XRD) analysis confirms that the siliceous to argillaceous mudstones contain a highly variable carbonate content. The palynological, geochemical and mineralogical proxies combined indicate that marine sediments were continuously being deposited throughout the sampled intervals and were punctuated by episodic turbiditic events. The terrestrial material, originating from the Wales-Brabant High to the south of the Pennine Basin, was principally deposited in the Widmerpool Gulf, with much less terrigenous organic matter reaching the Edale Gulf. As a consequence, the prospective intervals are relatively thin, decimetre-to meter-scale, and further high resolution characterization of these intervals is required to understand variability in prospectivitiy over these limited intervals

Where Are You, Congress?: Silence Rings in Congress as Juvenile Offenders Remain in Prison for Life

Over the last decade, Supreme Court precedent has changed the way courts have sentenced juveniles in the United States. It has failed, however, to clearly establish the proper handling of cases in which juveniles are sentenced to extended periods of time in prison that equate to a de facto sentence of life in prison without parole. Congress has also remained noticeably silent on the issue. Children are not considered mature enough to vote, to drink alcohol, to serve on a jury, and yet, courts treat juvenile offenders as mature enough to pay for their crimes for the remainder of their lives. Without a clear remedy in sight, juvenile offenders face uncertain fates and unequal treatment in the justice system, both on the state and federal level. Therefore, despite residing in the same circuit, a juvenile in New Jersey, for example, will face different sentencing consequences than a juvenile in Pennsylvania for similar crimes. This note proposes a solution for Congress to start the trend by banning de facto LWOP to fully establish that children are, in fact, treated differently than adults in the United States

Understanding response to rituximab treatment in rheumatoid arthritis through immune fingerprinting of T and B cells

Despite the great research advances in dissecting the mechanisms underlying rheumatoid arthritis onset and development, the exact pathophysiology of this disease remains unsolved. In the past years, the introduction of biologicals, and in particular of therapeutic monoclonal antibodies (mAb), has constituted a major breakthrough in the clinical management of the disease. Although these new drugs have proven effective, in some patients, remission or low disease activity is only partially or temporally achieved. Understanding the mechanism behind this incomplete response might lead to improved therapies and in ultimately to improved quality of life for patients. This thesis describes our efforts to elucidate the mechanisms behind response to B-cell depletion therapy using rituximab in rheumatoid arthritis. We evaluated how both direct and indirect effects can influence clinical response to the treatment. To achieve this we applied AIRR sequencing or Adaptive Immune Receptor Repertoire sequencing, which allows to identify and quantify all T- and B-cell receptors within an individual. This methodology allowed us to fingerprint and monitor ongoing immune responses in cohorts of rheumatoid arthritis patients undergoing rituximab treatment

Quantitative results for fractional overdetermined problems in exterior and annular sets

We consider overdetermined problems related to the fractional capacity. In particular we study s-harmonic functions defined in unbounded exterior sets or in bounded annular sets, and having a level set parallel to the boundary. We first classify the solutions of the overdetermined problems, by proving that the domain and the solution itself are radially symmetric. Then we prove a quantitative stability counterpart of the symmetry results: we assume that the overdetermined condition is slightly perturbed and we measure, in a quantitative way, how much the domain is close to a symmetric set. (c) 2023 Elsevier Inc. All rights reserved

SincVAE: a New Approach to Improve Anomaly Detection on EEG Data Using SincNet and Variational Autoencoder

Over the past few decades, electroencephalography (EEG) monitoring has become a pivotal tool for diagnosing neurological disorders, particularly for detecting seizures. Epilepsy, one of the most prevalent neurological diseases worldwide, affects approximately the 1 \% of the population. These patients face significant risks, underscoring the need for reliable, continuous seizure monitoring in daily life. Most of the techniques discussed in the literature rely on supervised Machine Learning (ML) methods. However, the challenge of accurately labeling variations in epileptic EEG waveforms complicates the use of these approaches. Additionally, the rarity of ictal events introduces an high imbalancing within the data, which could lead to poor prediction performance in supervised learning approaches. Instead, a semi-supervised approach allows to train the model only on data not containing seizures, thus avoiding the issues related to the data imbalancing. This work proposes a semi-supervised approach for detecting epileptic seizures from EEG data, utilizing a novel Deep Learning-based method called SincVAE. This proposal incorporates the learning of an ad-hoc array of bandpass filter as a first layer of a Variational Autoencoder (VAE), potentially eliminating the preprocessing stage where informative band frequencies are identified and isolated. Results indicate that SincVAE improves seizure detection in EEG data and is capable of identifying early seizures during the preictal stage as well as monitoring patients throughout the postictal stage