Toscana virus (TOSV) (Bunyavirales, Phenuiviridae, Phlebovirus, Toscana phlebovirus) and other related human pathogenic arboviruses are transmitted by phlebotomine sand flies. TOSV has been reported in nations bordering the Mediterranean Sea among other regions. Infection can result in febrile illness as well as meningitis and encephalitis. Understanding vector-arbovirus interactions is crucial to improving our knowledge of how arboviruses spread, and in this context, immune responses that control viral replication play a significant role. Extensive research has been conducted on mosquito vector immunity against arboviruses, with RNA interference (RNAi) and specifically the exogenous siRNA (exo-siRNA) pathway playing a critical role. However, the antiviral immunity of phlebotomine sand flies is less well understood. Here we were able to show that the exo-siRNA pathway is active in a Phlebotomus papatasi-derived cell line. Following TOSV infection, distinctive 21 nucleotide virus-derived small interfering RNAs (vsiRNAs) were detected. We also identified the exo-siRNA effector Ago2 in this cell line, and silencing its expression rendered the exo-siRNA pathway largely inactive. Thus, our data show that this pathway is active as an antiviral response against a sand fly transmitted bunyavirus, TOSV.
- MeSH
- arboviry * genetika MeSH
- lidé MeSH
- malá interferující RNA genetika MeSH
- Phlebotomus * genetika MeSH
- Phlebovirus * genetika MeSH
- Psychodidae * genetika MeSH
- RNA interference MeSH
- virus horečky pappataci * genetika MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
INTRODUCTION: Treatment with biologics for severe asthma is informed by international and national guidelines and defined by national regulating bodies, but how these drugs are used in real-life is unknown. MATERIALS AND METHODS: The European Respiratory Society (ERS) SHARP Clinical Research Collaboration conducted a three-step survey collecting information on asthma biologics use in Europe. Five geographically distant countries defined the survey questions, focusing on seven end-points: biologics availability and financial issues, prescription and administration modalities, inclusion criteria, continuation criteria, switching biologics, combining biologics and evaluation of corticosteroid toxicity. The survey was then sent to SHARP National Leads of 28 European countries. Finally, selected questions were submitted to a broad group of 263 asthma experts identified by national societies. RESULTS: Availability of biologics varied between countries, with 17 out of 28 countries having all five existing biologics. Authorised prescribers (pulmonologists and other specialists) also differed. In-hospital administration was the preferred deliverance modality. While exacerbation rate was used as an inclusion criterion in all countries, forced expiratory volume in 1 s was used in 46%. Blood eosinophils were an inclusion criterion in all countries for interleukin-5 (IL-5)-targeted and IL-4/IL-13-targeted biologics, with varying thresholds. There were no formally established criteria for continuing biologics. Reduction in exacerbations represented the most important benchmark, followed by improvement in asthma control and quality of life. Only 73% (191 out of 263) of surveyed clinicians assessed their patients for corticosteroid-induced toxicity. CONCLUSION: Our study reveals important heterogeneity in the use of asthma biologics across Europe. To what extent this impacts on clinical outcomes relevant to patients and healthcare services needs further investigation.
- Publikační typ
- časopisecké články MeSH
Inflammation, structural, and functional abnormalities within the airways are key features of asthma. Although these processes are well documented, their expression varies across the heterogeneous spectrum of asthma. Type 2 inflammatory responses are characterized by increased levels of eosinophils, FeNO, and type 2 cytokines in blood and/or airways. Presently, type 2 asthma is the best-defined endotype, typically found in patients with allergic asthma, but surprisingly also in nonallergic patients with (severe) asthma. The etiology of asthma with non-type 2 inflammation is less clear. During the past decade, targeted therapies, including biologicals and small molecules, have been increasingly integrated into treatment strategies of severe asthma. These treatments block specific inflammatory pathways or single mediators. Single or composite biomarkers help to identify patients who will benefit from these treatments. So far, only a few inflammatory biomarkers have been validated for clinical application. The European Academy of Allergy & Clinical Immunology Task Force on Biomarkers in Asthma was initiated to review different biomarker sampling methods and to investigate clinical applicability of new and existing inflammatory biomarkers (point-of-care) to support diagnosis, targeted treatment, and monitoring of severe asthma. Subsequently, we discuss existing and novel targeted therapies for asthma as well as applicable biomarkers.
- MeSH
- biologické markery * MeSH
- bronchiální astma diagnóza etiologie terapie MeSH
- cílená molekulární terapie MeSH
- cytokiny metabolismus MeSH
- dýchací soustava imunologie metabolismus patologie MeSH
- fenotyp MeSH
- kombinovaná terapie MeSH
- kritické cesty * MeSH
- lidé MeSH
- management nemoci MeSH
- mediátory zánětu metabolismus MeSH
- náchylnost k nemoci MeSH
- remodelace dýchacích cest MeSH
- T-lymfocyty - podskupiny imunologie metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
The allosteric influence of adenosine triphosphate (ATP) on the binding effectiveness of a series of peptide inhibitors with the catalytic subunit of 3'5'-cyclic adenosine monophosphate dependent protein kinase was investigated, and the dependence of this effect on peptide structure was analyzed. The allosteric effect was calculated as ratio of peptide binding effectiveness with the enzyme-ATP complex and with the free enzyme, quantified by the competitive inhibition of the enzyme in the presence of ATP excess, and by the enzyme-peptide complex denaturation assay, respectively It was found that the principle "better binding-stronger allostery" holds for interactions of the studied peptides with the enzyme, indicating that allostery and peptide binding with the free enzyme are governed by the same specificity pattern. This means that the allosteric regulation does not include new ligand-protein interactions, but changes the intensity (strength) of the interatomic forces that govern the complex formation in the case of each individual ligand. We propose that the allosteric regulation can be explained by the alteration of the intrinsic dynamics of the protein by ligand binding, and that this phenomenon, in turn, modulates the ligand off-rate from its binding site as well as the binding affinity. The positive allostery could therefore be induced by a reduction in the enzyme's overall intrinsic dynamics.
- MeSH
- 2-naftylamin analogy a deriváty chemie MeSH
- adenosintrifosfát chemie metabolismus MeSH
- alosterická regulace MeSH
- alosterické místo MeSH
- AMP cyklický chemie metabolismus MeSH
- barvení a značení metody MeSH
- fluorescenční barviva chemie MeSH
- inhibitory proteinkinas chemie metabolismus MeSH
- katalytická doména MeSH
- kinetika MeSH
- lidé MeSH
- ligandy MeSH
- peptidy chemie metabolismus MeSH
- proteinkinasy závislé na cyklickém AMP chemie metabolismus MeSH
- sekvence aminokyselin MeSH
- termodynamika MeSH
- vazba proteinů MeSH
- vazebná místa MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
