IL-17+ CD8+ T cell suppression by dimethyl fumarate associates with clinical response in multiple sclerosis

IL-17-producing CD8+ (Tc17) cells are enriched in active lesions of patients with multiple sclerosis (MS), suggesting a role in the pathogenesis of autoimmunity. Here we show that amelioration of MS by dimethyl fumarate (DMF), a mechanistically elusive drug, associates with suppression of Tc17 cells. DMF treatment results in reduced frequency of Tc17, contrary to Th17 cells, and in a decreased ratio of the regulators RORC-to-TBX21, along with a shift towards cytotoxic T lymphocyte gene expression signature in CD8+ T cells from MS patients. Mechanistically, DMF potentiates the PI3K-AKT-FOXO1-T-BET pathway, thereby limiting IL-17 and RORγt expression as well as STAT5-signaling in a glutathione-dependent manner. This results in chromatin remodeling at the Il17 locus. Consequently, T-BET-deficiency in mice or inhibition of PI3K-AKT, STAT5 or reactive oxygen species prevents DMF-mediated Tc17 suppression. Overall, our data disclose a DMF-AKT-T-BET driven immune modulation and suggest putative therapy targets in MS and beyond

Prunella vulgaris: A comprehensive review of chemical constituents, pharmacological effects and clinical applications.

Prunella vulgaris (PV) is a perennial herb belonging to the Labiate family and is widely distributed in northeastern Asian countries such as Korea, Japan, and China. It is reported to display diverse biological activities including anti-microbial, anti-cancer, and anti-inflammation as determined by in vitro or in vivo studies. So far, about 200 compounds have been isolated from PV plant and majority of these have been characterized mainly as triterpenoids, sterols and flavonoids, followed by coumarins, phenylpropanoids, polysaccharides and volatile oils. This review summarizes and analyzes the current knowledge on the chemical constituents, pharmacological activities, mechanisms of action and clinical applications of the PV plant including its potential as a future medicinal plant. Although some of the chemical constituents of the PV plant and their mechanism of action have been investigated the biological activities of many of these remain unknown and further clinical trials are required to further enhance its reputation as a medicinal plant

The Physics of the B Factories

This work is on the Physics of the B Factories. Part A of this book contains a brief description of the SLAC and KEK B Factories as well as their detectors, BaBar and Belle, and data taking related issues. Part B discusses tools and methods used by the experiments in order to obtain results. The results themselves can be found in Part C

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field

The evaluation of risk for obstructive sleep apnea in patients with type 2 diabetes

Cilj istraživanja je procijeniti rizik za opstrukcijsku apneju tijekom spavanja (engl. Obstructive sleep apnea, OSA) u bolesnika sa šećernom bolešću tipa 2, s pomoću STOP upitnika (engl. Snoring, Tiredness, Observed, Pressure; STOP). S pomoću Epworthove ljestvice pospanosti (ESS) procijenjena je prekomjerna dnevna pospanost i ispitana povezanost pospanosti i rizika za OSA-u u bolesnika sa šećernom bolešću tipa 2. Dosadašnja istraživanja pokazala su da oštećena tolerancije glukoze i šećerna bolest tipa 2 predstavljaju čimbenik rizika za OSA-u, ali i da OSA predstavlja čimbenik rizika za šećernu bolest tipa 2. U našem istraživanju sudjelovala su 252 ispitanika sa šećernom bolešću tipa 2, koji su bili anketirani za vrijeme redovitih pregleda u Kliničkom bolničkom centru Split. Rezultati našeg istraživanja pokazali su da je 156 ispitanika (61,9%) imalo povećan rizik za OSA-u prema rezultatima STOP upitnika. Nadalje, ispitanici koji su imali povećani rizik u odnosu na ispitanike koji nisu imali rizik za OSA-u bili su stariji (65 vs. 61 godina, p < 0,05), imali viši indeks tjelesne mase (28,6 ± 5,1 vs. 26,5 ± 4,1, p < 0,001), veći opseg vrata (41,5 ± 4,7 vs. 39,6 ± 6,2, p < 0,009) i bili pospaniji prema rezultatima ESS (5,3 ± 3,1 vs. 3,9 ± 2,5, p < 0,001). Uz šećernu bolest, većina ispitanika imala je i pridružene bolesti: arterijska hipertenzija (46%), gastroezofagealna refluksna bolest (28%), depresija (10%) i astma (8%). OSA je dio širokoga spektra poremećaja disanja tijekom spavanja koja se dovodi u vezu s metaboličkim poremećajima poput šećerne bolesti tipa 2, a epidemiološki podaci o zastupljenosti OSA u Hrvatskoj su nedostatni. Ovo istraživanje ukazuje na potrebu provođenja probira za OSA u bolesnika sa šećernom bolešću tipa 2, koristeći STOP upitnik.The aim of this study was to evaluate the risk for obstructive sleep apnea (OSA) in patients with type 2 diabetes using the STOP questionnaire (Snoring, Tiredness, Observed, Pressure; STOP). Excessive daytime sleepiness was evaluated with the Epworth sleepiness scale (ESS). Previous studies support the idea that glucose intolerance and type 2 diabetes might represent risk factors for OSA, as well as the idea of OSA being the risk factor for type 2 diabetes. A total of 252 patients with type 2 diabetes were surveyed during the regular follow-up in the Regional Centre for Diabetes, Endocrinology and Metabolic Diseases of Split University Hospital. The results of our study indicate that 156 patients (61.9%) had increased risk for OSA according to STOP questionnaire score. In addition, those at high risk for OSA were older (65 vs. 61 years of age, p < 0.05), had higher body mass index (BMI, 28.6 ± 5.1 vs. 26.5 ± 4.1, p < 0.001), higher neck circumference (41.5 ± 4.7 vs. 39.6 ± 6.2, p < 0.009), and had excessive daytime sleepiness according to the ESS score (5.3 ± 3.1 vs. 3.9 ± 2.5, p < 0.001). Individuals with type 2 diabetes reported to have comorbidities, mainly hypertension (46%), gastroesophageal reflux disease (28%), depression (10%), and asthma (8%). Based on current evidence from literature, OSA could be related to clinical conditions such as diabetes and essential hypertension. More epidemiological data are needed to establish the prevalence of OSA in Croatian patients with type 2 diabetes. Our findings indicate the relevance of STOP questionnaire use as a screening tool for obstructive sleep apnea in patients with type 2 diabetes in Croatia

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe