- Klíčová slova
- ruxolitinib, studie COMFORT-I, studie COMFORT-II,
- MeSH
- analýza přežití MeSH
- Janus kinasa 1 antagonisté a inhibitory MeSH
- Janus kinasa 2 * antagonisté a inhibitory MeSH
- klinické zkoušky, fáze III jako téma MeSH
- lidé MeSH
- primární myelofibróza * farmakoterapie MeSH
- protokoly protinádorové léčby MeSH
- pyrazoly * aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- randomizované kontrolované studie jako téma MeSH
- slezina účinky léků MeSH
- Check Tag
- lidé MeSH
The spleen is a large and highly vascularized secondary lymphatic organ. Spleen injuries are among the most frequent trauma-related injuries in the abdominal region. The aims of the study were to assess the volume fractions of the main splenic tissue components (red pulp, white pulp, trabeculae and reticular fibres) and to determine the severity of splenic injury due to the experimental impact test. Porcine spleens (n = 17) were compressed by 6.22 kg wooden plate using a drop tower technique from three impact heights (50, 100 and 150 mm corresponding to velocities 0.79, 1.24 and 1.58 m/s). The pressure was measured via catheters placed in the splenic vein. The impact velocity was measured using lasers. The severity of induced injuries was analysed on the macroscopic level. The volume fractions of splenic components were assessed microscopically using stereology. The volume fraction of the red pulp was 76.4%, white pulp 21.3% and trabeculae 2.7% respectively. All impact tests, even with the low impact velocities, led to injuries that occurred mostly in the dorsal extremity of the spleen, and were accompanied by bleeding, capsule rupture and parenchyma crushing. Higher impact height (impact velocity and impact energy) caused more severe injury. Porcine spleen had the same volume fraction of tissue components as human spleen, therefore we concluded that the porcine spleen was a suitable organ model for mechanical experiments. Based on our observations, regions around hilum and the diaphragmatic surface of the dorsal extremity, that contained fissures and notches, were the most prone to injury and required considerable attention during splenic examination after injury. The primary mechanical data are now available for the researchers focused on the splenic trauma modelling.
- MeSH
- lidé MeSH
- nemoci prasat * MeSH
- prasata MeSH
- slezina MeSH
- tupá poranění * veterinární MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The calcium release activated calcium channel is activated by the endoplasmic reticulum-resident calcium sensor protein STIM1. On activation, STIM1 C terminus changes from an inactive, tight to an active, extended conformation. A coiled-coil clamp involving the CC1 and CC3 domains is essential in controlling STIM1 activation, with CC1 as the key entity. The nuclear magnetic resonance-derived solution structure of the CC1 domain represents a three-helix bundle stabilized by interhelical contacts, which are absent in the Stormorken disease-related STIM1 R304W mutant. Two interhelical sites between the CC1α1 and CC1α2 helices are key in controlling STIM1 activation, affecting the balance between tight and extended conformations. Nuclear magnetic resonance-directed mutations within these interhelical interactions restore the physiological, store-dependent activation behavior of the gain-of-function STIM1 R304W mutant. This study reveals the functional impact of interhelical interactions within the CC1 domain for modifying the CC1-CC3 clamp strength to control the activation of STIM1.
- MeSH
- abnormální erytrocyty MeSH
- dyslexie genetika MeSH
- HEK293 buňky MeSH
- ichtyóza genetika MeSH
- kanály aktivované uvolněním vápníku metabolismus MeSH
- klonování DNA MeSH
- konformace nukleové kyseliny MeSH
- lidé MeSH
- magnetická rezonanční spektroskopie MeSH
- metoda terčíkového zámku MeSH
- migréna genetika MeSH
- mióza genetika MeSH
- molekulární modely MeSH
- mutace genetika MeSH
- nádorové proteiny genetika MeSH
- protein ORAI1 genetika MeSH
- protein STIM1 genetika MeSH
- slezina abnormality MeSH
- svalová únava genetika MeSH
- trombocytopatie genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The Gram-negative, obligate intracellular tick-transmitted pathogen Anaplasma phagocytophilum can cause acute febrile diseases in humans and domestic animals. The expansion of the tick Ixodes ricinus (Linnaeus, 1758) in northern Europe due to climate change is of serious concern for animal and human health. The aim of the present study was to investigate the impact of A. phagocytophilum infection in moose Alces alces (Linnaeus) calves by evaluating the carcass weights of infected and non-infected animals and examining animal tissues samples for co-infections with either species of Babesia Starcovici, 1893 or bacteria of the genus Bartonella. The carcasses of 68 free-ranging moose calves were weighed by hunters during the hunting seasons from 2014 to 2017 in two regions in southern Norway and spleen samples were collected. Anaplasma phagocytophilum was detected in moose sampled from locations infected with ticks with a prevalence of 82% (n = 46). The carcass weights of A. phagocytophilum-infected calves (n = 46) and non-infected (n = 22) calves were compared. Although the average weight of infected calves (45.6 kg) was lower than that of non-infected calves (46.5 kg), the difference was not statistically significant. Three different variants of the bacterium 16S rRNA gene were identified. The average weight of animals infected with variant I was 49.9 kg, whereas that of animals infected with variant III was 42.0 kg, but the difference was not statistically significant (p = 0.077). Co-infections of A. phagocytophilum with Bartonella spp. or with Babesia spp. were found in 20 and two calves, respectively. A triple infection was found in two calves. Sequence analysis of the 18S rRNA gene of Babesia-positive samples revealed the presence of Babesia cf. odocoilei (Emerson et Wright, 1970). Strains of Bartonella closely related to Bartonella bovis (Bermond, Boulouis, Heller, Laere, Monteil, Chomel, Sander, Dehio et Piemont, 2002) were identified based on phylogenetic analysis of the gltA and rpoB genes. The loss of body mass in moose calves in the tick-infected site was probably influenced by multiple factors.
- MeSH
- Anaplasma phagocytophilum * klasifikace genetika izolace a purifikace MeSH
- Babesia genetika MeSH
- Bartonella genetika MeSH
- DNA bakterií chemie genetika izolace a purifikace MeSH
- ehrlichióza komplikace epidemiologie patologie veterinární MeSH
- fylogeneze MeSH
- oligonukleotidy chemie MeSH
- polymerázová řetězová reakce veterinární MeSH
- sekvence nukleotidů MeSH
- slezina mikrobiologie patologie MeSH
- tělesná hmotnost MeSH
- vysoká zvěř * MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Norsko MeSH
Erythropoietin (EPO) downregulates hepcidin expression to increase the availability of iron; the downregulation of hepcidin is mediated by erythroferrone (ERFE) secreted by erythroblasts. Erythroblasts also express transferrin receptor 2 (TFR2); however, the possible role of TFR2 in hepcidin downregulation is unclear. The purpose of the study was to correlate liver expression of hepcidin with the expression of ERFE and TFR2 in murine bone marrow and spleen at 4, 16, 24, 48, 72 and 96 h following administration of a single dose of EPO. Splenic Fam132b expression increased 4 h after EPO injection; liver hepcidin mRNA was decreased at 16 h. In the spleen, expression of TFR2 and transferrin receptor (TFR1) proteins increased by an order of magnitude at 48 and 72 h after EPO treatment. The EPO-induced increase in splenic TFR2 and TFR1 was associated with an increase in the number of Tfr2- and Tfr1-expressing erythroblasts. Plasma exosomes prepared from EPO-treated mice displayed increased amount of TFR1 protein; however, no exosomal TFR2 was detected. Overall, the results confirm the importance of ERFE in stress erythropoiesis, support the role of TFR2 in erythroid cell development, and highlight possible differences in the removal of TFR2 and TFR1 from erythroid cell membranes.
- MeSH
- cytokiny genetika metabolismus MeSH
- erythropoetin farmakologie MeSH
- erytroblasty účinky léků metabolismus MeSH
- exozómy metabolismus MeSH
- hepcidiny genetika metabolismus MeSH
- játra metabolismus MeSH
- kultivované buňky MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- receptory transferinu genetika metabolismus MeSH
- slezina metabolismus MeSH
- svalové proteiny genetika metabolismus MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Matriptase-2, a serine protease expressed in hepatocytes, is a negative regulator of hepcidin expression. The purpose of the study was to investigate the interaction of matriptase-2 with hemojuvelin protein in vivo. Mice lacking the matriptase-2 proteolytic activity (mask mice) display decreased content of hemojuvelin protein. Vice versa, the absence of hemojuvelin results in decreased liver content of matriptase-2, indicating that the two proteins interact. To further characterize the role of matriptase-2, we investigated iron metabolism in mask mice fed experimental diets. Administration of iron-enriched diet increased liver iron stores as well as hepcidin expression. Treatment of iron-overloaded mask mice with erythropoietin increased hemoglobin and hematocrit, indicating that the response to erythropoietin is intact in mask mice. Feeding of an iron-deficient diet to mask mice significantly increased spleen weight as well as the splenic content of erythroferrone and transferrin receptor proteins, indicating stress erythropoiesis. Liver hepcidin expression was decreased; expression of Id1 was not changed. Overall, the results suggest a complex interaction between matriptase-2 and hemojuvelin, and demonstrate that hepcidin can to some extent be regulated even in the absence of matriptase-2 proteolytic activity.
- MeSH
- dietní železo farmakologie MeSH
- erythropoetin farmakologie MeSH
- GPI-vázané proteiny biosyntéza nedostatek genetika fyziologie MeSH
- hepcidiny biosyntéza genetika MeSH
- inhibitor diferenciace 1 biosyntéza genetika MeSH
- játra metabolismus MeSH
- kostní morfogenetický protein 6 biosyntéza genetika MeSH
- membránové proteiny nedostatek genetika fyziologie MeSH
- myši inbrední C57BL MeSH
- myši knockoutované MeSH
- myši MeSH
- orgánová specificita MeSH
- přetížení železem metabolismus MeSH
- promotorové oblasti (genetika) genetika MeSH
- protein hemochromatózy biosyntéza nedostatek genetika fyziologie MeSH
- proteinové domény MeSH
- regulace genové exprese účinky léků MeSH
- rekombinantní proteiny metabolismus MeSH
- serinové endopeptidasy nedostatek genetika fyziologie MeSH
- slezina metabolismus MeSH
- železo nedostatek MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Tick saliva is a rich source of pharmacologically and immunologically active molecules. These salivary components are indispensable for successful blood feeding on vertebrate hosts and are believed to facilitate the transmission of tick-borne pathogens. Here we present the functional and structural characterization of Iripin-3, a protein expressed in the salivary glands of the tick Ixodes ricinus, a European vector of tick-borne encephalitis and Lyme disease. Belonging to the serpin superfamily of protease inhibitors, Iripin-3 strongly inhibited the proteolytic activity of serine proteases kallikrein and matriptase. In an in vitro setup, Iripin-3 was capable of modulating the adaptive immune response as evidenced by reduced survival of mouse splenocytes, impaired proliferation of CD4+ T lymphocytes, suppression of the T helper type 1 immune response, and induction of regulatory T cell differentiation. Apart from altering acquired immunity, Iripin-3 also inhibited the extrinsic blood coagulation pathway and reduced the production of pro-inflammatory cytokine interleukin-6 by lipopolysaccharide-stimulated bone marrow-derived macrophages. In addition to its functional characterization, we present the crystal structure of cleaved Iripin-3 at 1.95 Å resolution. Iripin-3 proved to be a pluripotent salivary serpin with immunomodulatory and anti-hemostatic properties that could facilitate tick feeding via the suppression of host anti-tick defenses. Physiological relevance of Iripin-3 activities observed in vitro needs to be supported by appropriate in vivo experiments.
- MeSH
- adaptivní imunita účinky léků MeSH
- aktivace lymfocytů účinky léků MeSH
- antikoagulancia izolace a purifikace farmakologie MeSH
- cytokiny metabolismus MeSH
- hemokoagulace účinky léků MeSH
- hmyzí proteiny izolace a purifikace farmakologie MeSH
- imunologické faktory izolace a purifikace farmakologie MeSH
- inhibitory proteas izolace a purifikace farmakologie MeSH
- klíště metabolismus MeSH
- králíci MeSH
- kultivované buňky MeSH
- lidé MeSH
- lymfocyty účinky léků imunologie metabolismus MeSH
- morčata MeSH
- myši inbrední C3H MeSH
- myši inbrední C57BL MeSH
- myši transgenní MeSH
- proliferace buněk účinky léků MeSH
- slezina účinky léků imunologie metabolismus MeSH
- slinné proteiny a peptidy izolace a purifikace farmakologie MeSH
- sliny metabolismus MeSH
- zvířata MeSH
- Check Tag
- králíci MeSH
- lidé MeSH
- morčata MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- anamnéza MeSH
- diferenciální diagnóza MeSH
- dítě MeSH
- dospělí MeSH
- erytém etiologie MeSH
- fatální výsledek MeSH
- Gaucherova nemoc diagnóza farmakoterapie MeSH
- histiocytóza z Langerhansových buněk diagnóza farmakoterapie MeSH
- klinické rozhodování MeSH
- komorbidita MeSH
- kostní dřeň patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mutace MeSH
- myeloidní leukemie diagnóza terapie MeSH
- Niemannova-Pickova nemoc diagnóza MeSH
- novorozenec MeSH
- ruptura sleziny chirurgie diagnóza etiologie MeSH
- senioři MeSH
- sfingomyelinfosfodiesterasa nedostatek MeSH
- slezina patologie MeSH
- splenektomie MeSH
- transplantace kmenových buněk MeSH
- trombocytopenie * diagnóza etiologie terapie MeSH
- vemurafenib aplikace a dávkování MeSH
- vyšetřování kostní dřeně MeSH
- výsledek terapie MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- novorozenec MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
Differences in frequencies of blood cell subpopulations were reported to influence the course of infections, atopic and autoimmune diseases, and cancer. We have discovered a unique mouse strain B10.O20 containing extremely high frequency of myeloid-derived cells (MDC) in spleen. B10.O20 carries 3.6% of genes of the strain O20 on the C57BL/10 genetic background. It contains much higher frequency of CD11b+Gr1+ cells in spleen than both its parents. B10.O20 carries O20-derived segments on chromosomes 1, 15, 17, and 18. Their linkage with frequencies of blood cell subpopulations in spleen was tested in F2 hybrids between B10.O20 and C57BL/10. We found 3 novel loci controlling MDC frequencies: Mydc1, 2, and 3 on chromosomes 1, 15, and 17, respectively, and a locus controlling relative spleen weight (Rsw1) that co-localizes with Mydc3 and also influences proportion of white and red pulp in spleen. Mydc1 controls numbers of CD11b+Gr1+ cells. Interaction of Mydc2 and Mydc3 regulates frequency of CD11b+Gr1+ cells and neutrophils (Gr1+Siglec-F- cells from CD11b+ cells). Interestingly, Mydc3/Rsw1 is orthologous with human segment 6q21 that was shown previously to determine counts of white blood cells. Bioinformatics analysis of genomic sequence of the chromosomal segments bearing these loci revealed polymorphisms between O20 and C57BL/10 that change RNA stability and genes' functions, and we examined expression of relevant genes. This identified potential candidate genes Smap1, Vps52, Tnxb, and Rab44. Definition of genetic control of MDC can help to personalize therapy of diseases influenced by these cells.
- MeSH
- chromozomy genetika MeSH
- genetická vazba genetika MeSH
- genetické lokusy genetika MeSH
- lidé MeSH
- myeloidní buňky fyziologie MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- neutrofily fyziologie MeSH
- polymorfismus genetický genetika MeSH
- slezina fyziologie MeSH
- stabilita RNA genetika MeSH
- výpočetní biologie metody MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Species of Hepatozoon Miller, 1908 are vector-borne parasites that infect domestic and wild animals worldwide. Hepatozoon ursi Kubo, Uni, Agatsuma, Nagataki, Panciera et al., 2008 was reported from bears (Ursidae) in Japan and India. The present study represents the first report of infection with H. ursi in Turkish brown bears (Ursus arctos Linnaeus) by microscopic and molecular analysis. Two dead brown bears were found in Uzundere and Pasinler districts of Erzurum. Blood and visceral organ (spleen and liver) samples were delivered to laboratory by the Nature Conservation and National Parks officers. Detected gamonts were evaluated based on morphological features and confirmed as gamonts of H. ursi. The size of gamonts and parasitemia were 8.2 × 3.5 μm (6.9-8.7 × 3.0-3.9 μm; n = 12) and 0.6% (6/1000 leukocytes), respectively. The blood and visceral organ samples were positive for species of Hepatozoon by PCR targeting partial sequence of 18S rDNA. Sequence analysis of newly obtained sequences of H. ursi showed 98.8-100% identity with previously sequenced isolates of H. ursi. Sequences of H. ursi from Erzurum were identical to each other and showed 100% identity with isolates of H. ursi from ticks Ixodes ricinus (Linnaeus), Rhipicephalus turanicus Pomerantzev and Hyalomma marginatum Koch collected from two brown bears in Turkey (GenBank accession numbers MN463021, MN463022, MN905023). Analysis of partial sequences of the 18S rRNA gene of H. ursi showed that Turkish isolates differ in NT substitutions found at three different positions [72 (A→G), 537 (A→G) and 570 (A→T)]. This study provides morphological and molecular data of H. ursi infection in brown bears from two districts of Erzurum, Turkey. Further studies are needed to elucidate whether brown bears have any eco-epidemiologic importance in the life cycle of H. ursi in wildlife.
- MeSH
- Eucoccidiida * genetika izolace a purifikace MeSH
- fylogeneze MeSH
- játra parazitologie MeSH
- klíšťata parazitologie MeSH
- klíště parazitologie MeSH
- krev parazitologie MeSH
- medvědovití * parazitologie MeSH
- RNA ribozomální 18S genetika MeSH
- slezina parazitologie MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Turecko MeSH