Possible role of 18-kDa translocator protein (TSPO) in etifoxine-induced reduction of direct twitch responses in isolated rat nerve-skeletal muscle preparations

Purpose: To determine the effects of etifoxine on directly-elicited twitch tension of isolated rat nerveskeletal muscle preparations and to propose a possible explanation of the mechanism of the observed effect.Methods: Striated muscles contractile activity was elicited by electrical field stimulation. The effects of etifoxine and nifedipine on direct single twitch response were studied.Results: The results demonstrate that the effect of etifoxine on skeletal muscle depends on the concentrations: low concentrations (10-8 М and 10-7 М) have little effect on twitch tension, whereas higher concentrations (10-6 М and 10-5 М) induced a significant decrease in the direct single twitch response in comparison to controls. The mean IC50 (reduction of directly-elicited twitch tension) of etifoxine was 0.85 x 10-6 M. The selective L-type calcium channel blocker nifedipine (10-5 М) induced a greater decrease in the muscle force than 10-6 М etifoxine. The different abilities of etifoxine and nifedipine to reduce direct single twitch response may be related to their distinct mechanisms of action. The observed effect of etifoxine could be more complex. Probably etifoxine acts as a non-selective agent not only on L-type calcium channels Cav1.1 localized in sarcolemma but also on 18-kDa translocator protein (TSPO) in skeletal muscle.Conclusion: Etifoxine-induced reduction of direct twitch responses could be attributed to an effect on TSPO and Cav1.1. Knowledge of the effects of TSPO ligands on the contraction of skeletal muscle might explain the role of TSPO in muscle contractility.Keywords: Etifoxine, TSPO, Calcium channels, Direct single twitch response, Striated muscl

Amorpha fruticosa invasibility of different habitats in lower Danube

Abstract. Danube River plays a role of major corridor for plant invasions. Downstream is expected to be more strongly affected by such invasions. There were scarce data about alien plants dispersion by habitats in Bulgarian part of Danube. Sampling sites were selected on the river banks and on several islands and Amorpha fruticosa cover together with number of alien plants were sampled. Four habitat types were recognized. Most affected by indigo bush were poplar plantations while natural forests due to their closed structure and biodiversity remain less influenced

Assessing Autophagy in Archived Tissue or How to Capture Autophagic Flux from a Tissue Snapshot

Este artículo pertenece a un número especial: Autophagy in CancerAutophagy is a highly conserved degradation mechanism that is essential for maintaining cellular homeostasis. In human disease, autophagy pathways are frequently deregulated and there is immense interest in targeting autophagy for therapeutic approaches. Accordingly, there is a need to determine autophagic activity in human tissues, an endeavor that is hampered by the fact that autophagy is characterized by the flux of substrates whereas histology informs only about amounts and localization of substrates and regulators at a single timepoint. Despite this challenging task, considerable progress in establishing markers of autophagy has been made in recent years. The importance of establishing clear-cut autophagy markers that can be used for tissue analysis cannot be underestimated. In this review, we attempt to summarize known techniques to quantify autophagy in human tissue and their drawbacks. Furthermore, we provide some recommendations that should be taken into consideration to improve the reliability and the interpretation of autophagy biomarkers in human tissue samplesInstitute de Salud Carlos III (ISCIII) y Fondos FEDER de la UE PI14/01085 y PI17/00093Ministerio de Ciencia, Innovación y Universidades RTI2018-096748-B-100 to N.A.Ministerio de Ciencia, Innovación y Universidades FPU17/00026Consejería de Igualdad, Salud y Políticas Sociales PI-0198-2016Fondos FEDER de la UE NORTE-01-0145-FEDER-000013 y los proyectos POCI-01-0145-FEDER-028159 y POCI-01-0145-FEDER-03078

IL-33 expression in response to SARS-CoV-2 correlates with seropositivity in COVID-19 convalescent individuals

Our understanding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still developing. We perform an observational study to investigate seroprevalence and immune responses in subjects professionally exposed to SARS-CoV-2 and their family members (155 individuals; ages 5-79 years). Seropositivity for SARS-CoV-2 Spike glycoprotein aligns with PCR results that confirm the previous infection. Anti-Spike IgG/IgM titers remain high 60 days post-infection and do not strongly associate with symptoms, except for fever. We analyze PBMCs from a subset of seropositive and seronegative adults. TLR7 agonist-activation reveals an increased population of IL-6+TNF-IL-1β+ monocytes, while SARS-CoV-2 peptide stimulation elicits IL-33, IL-6, IFNa2, and IL-23 expression in seropositive individuals. IL-33 correlates with CD4+ T cell activation in PBMCs from convalescent subjects and is likely due to T cell-mediated effects on IL-33-producing cells. IL-33 is associated with pulmonary infection and chronic diseases like asthma and COPD, but its role in COVID-19 is unknown. Analysis of published scRNAseq data of bronchoalveolar lavage fluid (BALF) from patients with mild to severe COVID-19 reveals a population of IL-33-producing cells that increases with the disease. Together these findings show that IL-33 production is linked to SARS-CoV-2 infection and warrant further investigation of IL-33 in COVID-19 pathogenesis and immunity

Deletions of Immunoglobulin heavy chain and T cell receptor gene regions are uniquely associated with lymphoid blast transformation of chronic myeloid leukemia

<p>Abstract</p> <p>Background</p> <p>Chronic myelogenous leukemia (CML) results from the neoplastic transformation of a haematopoietic stem cell. The hallmark genetic abnormality of CML is a chimeric <it>BCR/ABL1 </it>fusion gene resulting from the Philadelphia chromosome rearrangement t(9;22)(q34;q11). Clinical and laboratory studies indicate that the <it>BCR/ABL1 </it>fusion protein is essential for initiation, maintenance and progression of CML, yet the event(s) driving the transformation from chronic phase to blast phase are poorly understood.</p> <p>Results</p> <p>Here we report multiple genome aberrations in a collection of 78 CML and 14 control samples by oligonucleotide array comparative genomic hybridization. We found a unique signature of genome deletions within the immunoglobulin heavy chain (<it>IGH</it>) and T cell receptor regions (<it>TCR</it>), frequently accompanied by concomitant loss of sequences within the short arm regions of chromosomes 7 and 9, including <it>IKZF1</it>, <it>HOXA7</it>, <it>CDKN2A/2B</it>, <it>MLLT3</it>, <it>IFNA/B</it>, <it>RNF38</it>, <it>PAX5</it>, <it>JMJD2C </it>and <it>PDCD1LG2 </it>genes.</p> <p>Conclusions</p> <p>None of these genome losses were detected in any of the CML samples with myeloid transformation, chronic phase or controls, indicating that their presence is obligatory for the development of a malignant clone with a lymphoid phenotype. Notably, the coincidental deletions at <it>IGH </it>and <it>TCR </it>regions appear to precede the loss of <it>IKZF1 </it>and/or <it>p16 </it>genes in CML indicating a possible involvement of RAG in these deletions.</p

Using exomarkers to assess mitochondrial reactive species in vivo

Background: The ability to measure the concentrations of small damaging and signalling molecules such as reactive oxygen species (ROS) in vivo is essential to understanding their biological roles. While a range of methods can be applied to in vitro systems, measuring the levels and relative changes in reactive species in vivo is challenging. Scope of review: One approach towards achieving this goal is the use of exomarkers. In this, exogenous probe compounds are administered to the intact organism and are then transformed by the reactive molecules in vivo to produce a diagnostic exomarker. The exomarker and the precursor probe can be analysed ex vivo to infer the identity and amounts of the reactive species present in vivo. This is akin to the measurement of biomarkers produced by the interaction of reactive species with endogenous biomolecules. Major conclusions and general significance: Our laboratories have developed mitochondria-targeted probes that generate exomarkers that can be analysed ex vivo by mass spectrometry to assess levels of reactive species within mitochondria in vivo. We have used one of these compounds, MitoB, to infer the levels of mitochondrial hydrogen peroxide within flies and mice. Here we describe the development of MitoB and expand on this example to discuss how better probes and exomarkers can be developed. This article is part of a Special Issue entitled Current methods to study reactive oxygen species - pros and cons and biophysics of membrane proteins. Guest Editor: Christine Winterbourn. Abbreviations: EPR, electron paramagnetic resonance; GFP, green fluorescent protein; 4-HNE, 4-hydroxynonenal; MitoB, 3-(dihydroxyboronyl)benzyltriphenylphosphonium bromide; MitoP, (3-hydroxybenzyl)triphenylphosphonium bromide; ROS, reactive oxygen species; SOD, superoxide dismutase; TPMP, methyltriphenylphosphonium; TPP, triphenylphosphonium catio

Novel verbal fluency scores and structural brain imaging for prediction of cognitive outcome in mild cognitive impairment

AbstractIntroductionThe objective of this study was to assess the utility of novel verbal fluency scores for predicting conversion from mild cognitive impairment (MCI) to clinical Alzheimer's disease (AD).MethodVerbal fluency lists (animals, vegetables, F, A, and S) from 107 MCI patients and 51 cognitively normal controls were transcribed into electronic text files and automatically scored with traditional raw scores and five types of novel scores computed using methods from machine learning and natural language processing. Additional scores were derived from structural MRI scans: region of interest measures of hippocampal and ventricular volumes and gray matter scores derived from performing ICA on measures of cortical thickness. Over 4 years of follow-up, 24 MCI patients converted to AD. Using conversion as the outcome variable, ensemble classifiers were constructed by training classifiers on the individual groups of scores and then entering predictions from the primary classifiers into regularized logistic regression models. Receiver operating characteristic curves were plotted, and the area under the curve (AUC) was measured for classifiers trained with five groups of available variables.ResultsClassifiers trained with novel scores outperformed those trained with raw scores (AUC 0.872 vs 0.735; P < .05 by DeLong test). Addition of structural brain measurements did not improve performance based on novel scores alone.ConclusionThe brevity and cost profile of verbal fluency tasks recommends their use for clinical decision making. The word lists generated are a rich source of information for predicting outcomes in MCI. Further work is needed to assess the utility of verbal fluency for early AD

CSF and Brain Structural Imaging Markers of the Alzheimer's Pathological Cascade

10.1371/journal.pone.0047406PLoS ONE712

Fusion Techniques in Biomedical Information Retrieval

For difficult cases clinicians usually use their experience and also the information found in textbooks to determine a diagnosis. Computer tools can help them supply the relevant information now that much medical knowledge is available in digital form. A biomedical search system such as developed in the Khresmoi project (that this chapter partially reuses) has the goal to fulfil information needs of physicians. This chapter concentrates on information needs for medical cases that contain a large variety of data, from free text, structured data to images. Fusion techniques will be compared to combine the various information sources to supply cases similar to an example case given. This can supply physicians with answers to problems similar to the one they are analyzing and can help in diagnosis and treatment planning