Novel and potential future therapeutic options in systemic autoimmune diseases.

Autoimmune inflammation is caused by the loss of tolerance to specific self-antigens and can result in organ-specific or systemic disorders. Systemic autoimmune diseases affect a significant portion of the population with an increasing rate of incidence, which means that is essential to have effective therapies to control these chronic disorders. Unfortunately, several patients with systemic autoimmune diseases do not respond at all or just partially respond to available conventional synthetic disease-modifying antirheumatic drugs and targeted therapies. However, during the past few years, some new medications have been approved and can be used in real-life clinical settings. Meanwhile, several new candidates appeared and can offer promising novel treatment options in the future. Here, we summarize the newly available medications and the most encouraging drug candidates in the treatment of systemic lupus erythematosus, rheumatoid arthritis, Sjögren's disease, systemic sclerosis, systemic vasculitis, and autoimmune myositis.

The selective inhibition of the Syk tyrosine kinase ameliorates experimental autoimmune arthritis.

Autoimmune arthritis - such as rheumatoid arthritis - affect a significant proportion of the population, which can cause everyday joint pain, decreased mobility and reduced quality of life. Despite having more and more therapeutic options available, there are still a lot of patients who cannot reach remission or low disease activity by current therapies. This causes an urgent need for the development of new treatment options. The Syk tyrosine kinase plays an essential role in B cell receptor, Fc receptor and integrin signaling. It has been shown that the hematopoietic cell-specific deletion of Syk resulted in a complete protection against autoantibody-induced experimental arthritis. This prompted us to test the effect of entospletinib, a second generation, Syk-selective inhibitor, which has a tolerable safety profile according to hematological clinical trials, in experimental autoimmune arthritis. We found that entospletinib dose-dependently decreased the macroscopic signs of joint inflammation, while it did not affect the health status of the animals. In line with these findings, local neutrophil accumulation and cytokine levels were reduced compared to the vehicle-treated group, while macrophage accumulation and synovial fibroblast numbers were not significantly altered. Meanwhile, entospletinib dose-dependently decreased the cell responses of immune complex- or integrin ligand-activated neutrophils. Overall, we found that selective Syk inhibition by entospletinib reduced the activity of autoantibody-induced experimental arthritis, which seems to be based mainly on the effect of the inhibitor on neutrophil functions. Our data raise the possibility that entospletinib could be a good drug candidate in the treatment of human autoimmune arthritis.

[The benefits of a hybrid operation room in neurosurgery.] / A hibrid muto elonyei idegsebészeti mutétek során.

INTRODUCTION: The hybrid operation room - with a robotic arm equipped angiographic device - started its operation in November 2019 at the Department of Neurosurgery, Szeged, Hungary. OBJECTIVE: We report the benefits of the hybrid operation room in the neurosurgery practice based on our results and experiences of the last 1.5 years. METHOD: 576 operations took place between 15. 11. 2019 and 01. 03. 2021, which include 332 neurointerventions amd 244 skull-brain and spine surgeries. By using Siemens ARTIS pheno®, we performed purely catheter only interventions or surgical only interventions, but combined treatments were also performed in several cases (catheter and surgical intervention). Thanks to ARTIS pheno® versatility, it is used as a modern imaging system in preoperative examination or as navigation system in spine surgery and control imaging for intra- and postoperative examinations. DISCUSSION: We created three categories based on the results of the last months according to the need of using the hybrid operation room for the given operation: (1) strongly recommended, (2) recommended, (3) advantageous. Strongly recommended: if the two teams (surgical and interventional team) have to work together during the operation. Recommended: if the two teams are not participating together in the operation, but the other team is on standby and may join the operation if necessary. Advantageous: this category means the possibility of performing control imaging before the wound closure. CONCLUSION: Based on our experience, the hybrid operation room provides significant help in neurosurgery. It has become part of our daily care, and we think it is indispensable in the work of a neurosurgery center. Orv Hetil. 2023; 164(43): 1701-1711.

A Nature-Inspired Antioxidant Strategy based on Porphyrin for Aromatic Hydrocarbon Containing Fuel Cell Membranes.

The use of hydrocarbon-based proton conducting membranes in fuel cells is currently hampered by the insufficient durability of the material in the device. Membrane aging is triggered by the presence of reactive intermediates, such as HO⋅, which attack the polymer and eventually lead to chain breakdown and membrane failure. An adequate antioxidant strategy tailored towards hydrocarbon-based ionomers is therefore imperative to improve membrane lifetime. In this work, we perform studies on reaction kinetics using pulse radiolysis and γ-radiolysis as well as fuel cell experiments to demonstrate the feasibility of increasing the stability of hydrocarbon-based membranes against oxidative attack by implementing a Nature-inspired antioxidant strategy. We found that metalated-porphyrins are suitable for damage transfer and can be used in the fuel cell membrane to reduce membrane aging with a low impact on fuel cell performance.

Plastocerus angulosus (Germar, 1844) (Coleoptera: Elateridae: Dendrometrinae): an enigmatic click beetle with a convoluted taxonomic history.

Plastocerus angulosus (Germar, 1844) is one of the only two species of genus Plastocerus Schaum, 1852 within the monogeneric click beetle tribe Plastocerini. It is distributed in the area comprising Greece, Turkey, Syria, Israel, and Lebanon (first record for Lebanon published here). Due to the slightly modified morphology of P. angulosus, this taxon has a convoluted taxonomic history and was earlier classified in various families and even superfamilies. However, recent phylogenies place it in Elateridae: Dendrometrinae. In this study, we review the morphology, intraspecific morphological and genetic variability, sexual dimorphism, systematics, bibliography, and distribution of P. angulosus. Our results show rather low morphological and relatively high genetic variability in this species. Females, which are larger than males and differ mainly in the antennae and abdominal ventrites, are not so rare as previously thought. Further field research should focus on the discovery of immature stages to describe their morphology and understand their biology and ecology.

Water-Soluble Gd(III)-Porphyrin Complexes Capable of Both Photosensitization and Relaxation Enhancement.

With the aim of developing more stable Gd(III)-porphyrin complexes, two types of ligands 1 and 2 with carboxylic acid anchors were synthesized. Due to the N-substituted pyridyl cation attached to the porphyrin core, these porphyrin ligands were highly water-soluble and formed the corresponding Gd(III) chelates, Gd-1 and Gd-2. Gd-1 was sufficiently stable in neutral buffer, presumably due to the preferred conformation of the carboxylate-terminated anchors connected to nitrogen in the meta position of the pyridyl group helping to stabilize Gd(III) complexation by the porphyrin center. 1H NMRD (nuclear magnetic relaxation dispersion) measurements on Gd-1 revealed high longitudinal water proton relaxivity (r1 = 21.2 mM-1 s-1 at 60 MHz and 25 °C), which originates from slow rotational motion resulting from aggregation in aqueous solution. Under visible light irradiation, Gd-1 showed extensive photoinduced DNA cleavage in line with efficient photoinduced singlet oxygen generation. Cell-based assays revealed no significant dark cytotoxicity of Gd-1, while it showed sufficient photocytotoxicity on cancer cell lines under visible light irradiation. These results indicate the potential of this Gd(III)-porphyrin complex (Gd-1) as a core for the development of bifunctional systems acting as an efficient photodynamic therapy photosensitizer (PDT-PS) with magnetic resonance imaging (MRI) detection capabilities.

Myeloid Src-family kinases are critical for neutrophil-mediated autoinflammation in gout and motheaten models.

Autoinflammatory diseases include a number of monogenic systemic inflammatory diseases, as well as acquired autoinflammatory diseases such as gout. Here, we show that the myeloid Src-family kinases Hck, Fgr, and Lyn are critical for experimental models of gout, as well as for genetically determined systemic inflammation in the Ptpn6me-v/me-v (motheaten viable) mouse model. The Hck-/-Fgr-/-Lyn-/- mutation abrogated various monosodium urate (MSU) crystal-induced pro-inflammatory responses of neutrophils, and protected mice from the development of gouty arthritis. The Src-family inhibitor dasatinib abrogated MSU crystal-induced responses of human neutrophils and reduced experimental gouty arthritis in mice. The Hck-/-Fgr-/-Lyn-/- mutation also abrogated spontaneous inflammation and prolonged the survival of the Ptpn6me-v/me-v mice. Spontaneous adhesion and superoxide release of Ptpn6me-v/me-v neutrophils were also abolished by the Hck-/-Fgr-/-Lyn-/- mutation. Excessive activation of tyrosine phosphorylation pathways in myeloid cells may characterize a subset of autoinflammatory diseases.

Percutaneous Superficial Temporal Artery Access Facilitating Carotid Artery Stenting Performed From Distal Radial Artery.

PURPOSE: The purpose of the study is to describe carotid artery stenting (CAS) via distal transradial access (dTRA) facilitated by additional superficial temporal artery (STA) access, in a patient with complex aortic arch vessel anatomy. TECHNIQUE: A 72-year-old woman with a prior history of complex cervical surgery and radiotherapy due to laryngeal malignancy, presented with a symptomatic 90% stenosis of the left internal carotid artery (ICA). Due to high cervical lesion, the patient was rejected from carotid endarterectomy. Angiography demonstrated 90% stenosis of the left ICA and a type III aortic arch. After failure of left common carotid artery (CCA) cannulation with appropriate catheter support via dTRA and transfemoral approaches, CAS was attempted a second time. After percutaneous ultrasound guided access to right dTRA and left STA, a 0.035 inch guidewire introduced to the left CCA from the contralateral dTRA was snared and externalized via left STA to improve wire support for guiding advancement. Thereafter, the left ICA lesion was successfully stented with a 7×30 mm self-expanding stent via right dTRA. All vessels involved were patent at 6-month follow-up. CONCLUSION: The STA may be a promising adjunctive access site to increase transradial catheter support for CAS or neurointerventional procedures in the anterior circulation. CLINICAL IMPACT: Transradial cerebrovascular interventions have been gaining popularity, however, unstable catheter access to distal cerebrovascular structures limits its widespread use. Guidewire externalization technique via additional STA access may improve transradial catheter stabilty and increase procedural success with possibly low access stie complication rate.

Neutrophil-Specific Syk Expression Is Crucial for Skin Disease in Experimental Epidermolysis Bullosa Acquisita.

Autoantibodies against the dermal-epidermal junction component type VII collagen (C7) trigger skin disease in the inflammatory form of epidermolysis bullosa acquisita. We have previously identified the Syk tyrosine kinase as a crucial participant in anti-C7 antibody-induced experimental epidermolysis bullosa acquisita. However, it is still unclear which cellular lineage needs to express Syk during the disease process. In this study, we show that the loss of Syk, specifically from neutrophils, results in complete protection from the anti-C7 antibody-initiated skin disease both macroscopically and microscopically. Mice with a neutrophil-specific Syk deletion had decreased neutrophil accumulation and abrogated CXCL2 and IL-1ß levels in the skin upon anti-C7 treatment, whereas isolated Syk-deficient neutrophils had decreased superoxide release, cell spreading, and cytokine release on C7-anti-C7 immune complex surfaces. Entospletinib and lanraplenib, two second-generation Syk-specific inhibitors, effectively abrogated immune complex-induced responses of human neutrophils and decreased the anti-C7 antibody-initiated, neutrophil-mediated ex vivo dermal-epidermal separation in human skin samples. Taken together, these results point to a crucial role for Syk in neutrophils in the development and progression of epidermolysis bullosa acquisita and suggest Syk inhibition as a potential therapeutic strategy.

On the Radical-Induced Degradation of Quaternary Ammonium Cations for Anion-Exchange Membrane Fuel Cells and Electrolyzers.

Four benzylic-type quaternary ammonium (QA) compounds with different electron density at the phenyl group were evaluated for their susceptibility against degradation by radicals. Time-resolved absorption spectroscopy indicated that radicals with oxidizing and reducing character were formed upon oxidation by HO⋅ and O⋅- (conjugate base of HO⋅). It was estimated that, dependent on the QA, 18-41 % of the formed radicals were oxidizing with standard electrode potentials (E0 ) above 0.276 V and 13-23 % exceeded 0.68 V, while 13-48 % were reducing with E0 <-0.448 V. The stability of these model compounds against oxidation and reductive dealkylation was evaluated at both neutral and strongly alkaline conditions, pH 14. Under both conditions, electron-donating groups promoted radical degradation, while electron-withdrawing ones increased stability. Therefore, durability against radical-induced degradation shows an opposite trend to alkaline stability and needs to be considered during the rational design of novel anion-exchange membranes for fuel cells and electrolyzers.

EPR Study on the Oxidative Degradation of Phenyl Sulfonates, Constituents of Aromatic Hydrocarbon-Based Proton-Exchange Fuel Cell Membranes.

Sulfonated aromatic hydrocarbon-based ionomers are potential constituents of next-generation polymer electrolyte fuel cells (PEFCs). Widespread application is currently limited due to their susceptibility to radical-initiated oxidative degradation that, among other intermediates, involves the formation of highly reactive aromatic cation radicals. The intermediates undergo chain cleavage (dealkylation/dearylation) and the loss of protogenic sulfonate groups, all leading to performance loss and eventual membrane failure. Laser flash photolysis experiments indicated that cation radicals can also be formed via direct electron ejection. We aim to establish the major degradation pathway of proton-exchange membranes (PEMs). To this end, we irradiated aqueous solutions of phenyl sulfonate-type model compounds with a Xe arc lamp, thus generating radicals. The radicals were trapped by 5,5-dimethyl-1-pyrroline N-oxide (DMPO), and the formed adducts were observed by electron paramagnetic resonance (EPR). The formed DMPO spin adducts were assigned and relative adduct concentrations were quantified by simulation of the experimental EPR spectra. Through the formation of the DMPO/•SO3 - adduct, we established that desulfonation dominates for monoaromatic phenyl sulfonates. We observed that diaryl ether sulfonates readily undergo homolytic C-O scission that produces DMPO/•aryl adducts. Our results support the notion that polyphenylene sulfonates are the most stable against oxidative attack and effectively transfer electrons from DMPO, forming DMPO/•OH. Our findings help to identify durable moieties that can be used as building blocks in the development of next-generation PEMs.

Synovial fibroblasts as potential drug targets in rheumatoid arthritis, where do we stand and where shall we go?

Fibroblast-like synoviocytes or synovial fibroblasts (FLS) are important cellular components of the inner layer of the joint capsule, referred to as the synovial membrane. They can be found in both layers of this synovial membrane and contribute to normal joint function by producing extracellular matrix components and lubricants. However, under inflammatory conditions like in rheumatoid arthritis (RA), they may start to proliferate, undergo phenotypical changes and become central elements in the perpetuation of inflammation through their direct and indirect destructive functions. Their importance in autoimmune joint disorders makes them attractive cellular targets, and as mesenchymal-derived cells, their inhibition may be carried out without immunosuppressive consequences. Here, we aim to give an overview of our current understanding of the target potential of these cells in RA.

The first mainland European Mesozoic click-beetle (Coleoptera: Elateridae) revealed by X-ray micro-computed tomography scanning of an Upper Cretaceous amber from Hungary.

Fossil bioinclusions in amber are invaluable source of information on the past evolution and diversity of various organisms, as well as on the paleoecosystems in general. The click-beetles, Elateridae, which originated and greatly diversified during the Mesozoic, are mostly known from the adpression-like fossils, and their diversity in the Cretaceous ambers is only poorly documented. In this study, we describe a new click-beetle based on an incomplete inclusion in ajkaite, an Upper Cretaceous (Santonian) amber from the Ajka Coal Formation from Hungary. We used X-ray micro-computed tomography scanning to reconstruct its morphology because it is deposited in an opaque piece of amber. Our results suggest that the newly described Ajkaelater merkli gen. et sp. nov. belongs to subfamily Elaterinae. It represents the first Mesozoic beetle reported from Hungary, and the first Mesozoic Elateridae formally described from mainland Europe. Our discovery supports an Eurasian distribution and diversification of Elaterinae already in the Cretaceous. The paleoenvironment of the Ajka Coal Formation agrees well with the presumed habitat preference of the new fossil taxon. The discovery of a presumably saproxylic click-beetle shed further light on the yet poorly known paleoecosystem of the Santonian present-day western Hungary.

Impact of substitution on reactions and stability of one-electron oxidised phenyl sulfonates in aqueous solution.

Highly reactive aromatic cation radicals have been invoked lately in synthetic routes and in the degradation pathways of hydrocarbon-based polymers. Changes in the electron density of aromatic compounds are expected to alter the reaction pathway following one electron oxidation through altering the pKa of the formed intermediate cation radical. Electron-donating groups increase its stability, however, little experimental data are known. While, in theory, the cation radical can be repaired by simple electron transfer, electron transfer to or from its deprotonated form, the hydroxycyclohexadienyl radical, will cause permanent modification or degradation. Time-resolved absorption spectroscopy indicates a pKa ≈ 2-3 for the 4-(tert-butyl)-2-methoxyphenylsulfonate (BMPS) radical cation, while its parent compound 4-(tert-butyl) phenylsulfonate (BPS) is much more acidic. The stability of both compounds towards oxidation by HO˙ was evaluated under air at pH 5 and pH 0. At pH 5, both BMPS and BPS are unstable, and superstoichiometric degradation was observed. Degradation was slightly reduced for BPS at pH 0. In contrast, the more electron rich BMPS showed 80% lower degradation. We unambigously showed that in the presence of Ce(III) and H2O2 at pH 0 both BMPS and BPS could be catalytically repaired via one electron reduction, resulting in further damage moderation.

Signaling through Syk or CARD9 Mediates Species-Specific Anti-Candida Protection in Bone Marrow Chimeric Mice.

The spleen tyrosine kinase (Syk) and the downstream adaptor protein CARD9 are crucial signaling molecules in antimicrobial immunity. Candida parapsilosis is an emerging fungal pathogen with a high incidence in neonates, while Candida albicans is the most common agent of candidiasis. While signaling through Syk/CARD9 promotes protective host mechanisms in response to C. albicans, its function in immunity against C. parapsilosis remains unclear. Here, we generated Syk-/- and CARD9-/- bone marrow chimeric mice to study the role of Syk/CARD9 signaling in immune responses to C. parapsilosis compared to C. albicans. We demonstrate various functions of this pathway (e.g., phagocytosis, phagosome acidification, and killing) in Candida-challenged, bone marrow-derived macrophages with differential involvement of Syk and CARD9 along with species-specific differences in cytokine production. We report that Syk-/- or CARD9-/- chimeras rapidly display high susceptibility to C. albicans, while C. parapsilosis infection exacerbates over a prolonged period in these animals. Thus, our results establish that Syk and CARD9 contribute to systemic resistance to C. parapsilosis and C. albicans differently. Additionally, we confirm prior studies but also detail new insights into the fundamental roles of both proteins in immunity against C. albicans. Our data further suggest that Syk has a more prominent influence on anti-Candida immunity than CARD9. Therefore, this study reinforces the Syk/CARD9 pathway as a potential target for anti-Candida immune therapy. IMPORTANCE While C. albicans remains the most clinically significant Candida species, C. parapsilosis is an emerging pathogen with increased affinity to neonates. Syk/CARD9 signaling is crucial in immunity to C. albicans, but its role in in vivo responses to other pathogenic Candida species is largely unexplored. We used mice with hematopoietic systems deficient in Syk or CARD9 to comparatively study the function of these proteins in anti-Candida immunity. We demonstrate that Syk/CARD9 signaling has a protective role against C. parapsilosis differently than against C. albicans. Thus, this study is the first to reveal that Syk can exert immune responses during systemic Candida infections species specifically. Additionally, Syk-dependent immunity to a nonalbicans Candida species in an in vivo murine model has not been reported previously. We highlight that the contribution of Syk and CARD9 to fungal infections are not identical and underline this pathway as a promising immune-therapeutic target to fight Candida infections.

Scanning Electron Microscopy Reveals the Antennal Micromorphology of Lamprodila (Palmar) festiva (Coleoptera: Buprestidae), an Invasive Pest of Ornamental Cupressaceae in Western Palaearctic.

The Cypress jewel beetle, Lamprodila (Palmar) festiva festiva (Linnaeus, 1767), is a serious invasive pest of ornamental Cupressaceae, which has recently expanded its range from the Mediterranean region northwards to central and eastern Europe, and to the Russian Black Sea coast. In this study, we conducted a scanning electron microscopy study of the micromorphology of the male and female antennae of L. festiva to examine the morphology, numbers, distribution, and possible functions of antennal sensilla. Most sensilla are located in the sensory fields within the apical depressions on antennomeres IV-XI. We identified four main types of antennal sensilla in L. festiva: sensilla chaetica (seven subtypes, of which two occur only in females), sensilla basiconica (five subtypes), multiporous grooved pegs (two subtypes), and Böhm sensilla. Females have relatively more sensilla chaetica and multiporous grooved pegs, whereas males have more sensilla basiconica. We discuss possible functions of all examined sensilla and compare them with those in other Buprestidae or other insects. Our study should serve as background information for advanced electrophysiological and behavioral experiments to better understand the functions of different sensilla and mechanisms related to semiochemically based pest control strategies.

Dima spicata Schimmel, 1999 (Elateridae: Dimini), a morphologically remarkable species endemic to China.

Dima spicata Schimmel, 1999 has a unique pronotal morphology within Dimini, with the posterior angles extremely elongate and surpassing humeral part of elytra. It was described based on a female specimen from Southwest China (Sichuan, Ya'an). Here, we report the discovery of additional specimens including males from several localitites in Liangshan, Sichuan. We redescribe the species in detail and discuss its intraspecific variability and distribution.

Discovery of a new species of Lacon Laporte (Coleoptera: Elateridae: Agrypninae) endemic to Cyprus, with a modified tarsal morphology.

In this study, we describe a new species of the click-beetle genus Lacon Laporte, 1838 from Cyprus, and provide brief data on its ecology. Lacon cyprius sp. nov. is morphologically similar to L. punctatus (Herbst, 1779) but differs from the latter in the body surface and shapes of median antennomeres, pronotum, male tarsi, and genitalia. This is the first known Lacon species with an elongate projection ventrally on the pro- and mesotarsomere III. Additionally, we provide an identification key to Lacon species in Cyprus.

Comparative Antennal Morphology of Agriotes (Coleoptera: Elateridae), with Special Reference to the Typology and Possible Functions of Sensilla.

Species of the click-beetle genus Agriotes Eschscholtz are economically important crop pests distributed mainly in the Northern Hemisphere. They can inflict considerable damage on various field crops. Therefore, the detection, monitoring, and control of Agriotes include the adult trapping using species-specific sex pheromones, which is a critical component of pest research. To obtain a better understanding of the detailed antennal morphology as background information for subsequent chemical ecology research, we conducted a scanning electron microscopy study of the antennal sensilla of both sexes in 10 European Agriotes species. We identified 16 different sensilla in Agriotes, belonging to six main types: sensilla chaetica (subtypes C1 and C2), sensilla trichodea, sensilla basiconica (subtypes B1-B9), dome-shaped sensilla (subtypes D1 and D2), sensilla campaniformia, and Böhm sensilla. We discuss their possible functions and compare the sensilla of Agriotes with those of other Elateridae in order to consolidate the sensillum nomenclature in this family. Additionally, our study reveals the remarkable interspecific variability in sensillar equipment of Agriotes and identifies several characters of potential importance for future use in systematic studies. The present study provides a strong preliminary framework for subsequent research on the antennal morphology of this crop pest on a wider scale.

Neutrophils as emerging therapeutic targets.

Neutrophils are the most abundant circulating leukocytes, being the first line of defence against bacterial and fungal infections. However, neutrophils also contribute to tissue damage during various autoimmune and inflammatory diseases, and play important roles in cancer progression. The intimate but complex involvement of neutrophils in various diseases makes them exciting targets for therapeutic intervention but also necessitates differentiation of beneficial responses from potentially detrimental side effects. A variety of approaches to therapeutically target neutrophils have emerged, including strategies to enhance, inhibit or restore neutrophil function, with several agents entering clinical trials. However, challenges and controversies in the field remain.