Publications by authors named "Laszlo Kovacs"

300 Publications

Quality of Life and Satisfaction in Transgender Men After Phalloplasty in a Retrospective Study.

Ann Plast Surg 2021 Mar 4. Epub 2021 Mar 4.

From the Department of Plastic Surgery and Hand Surgery, University Hospital Rechts der Isar, Munich Technical University, Munich, Germany Department of Plastic Surgery and Burns, Alexandroupoli University Hospital, Democritus University of Thrace, Alexandroupoli, Greece Department of Plastic Surgery, University Teaching Hospital Rotkreuz-Klinikum München, Munich Technical University, Munich, Germany Department of Psychosomatic Medicine and Psychotherapy, University Hospital Rechts der Isar, Munich Technical University Roman-Herzog-Krebszentrum Comprehensive Cancer Center, Munich, Germany.

Background: Partly as a result of the increasing attention directed toward transgender individuals and despite much research work on the topic of quality of life (QOL) of transgender, there is still a lack of studies using standardized questionnaires in their evaluation.

Aims: We designed a survey to evaluate the influence of surgery after phalloplasty (osteofasciocutaneous fibula free flap or osteofasciocutaneous radial free forearm flap) on QOL, emotional stability, self-esteem, and psyche of postoperated transgender men.

Methods: The present study included 32 transgender men who had undergone gender-affirming surgery (GAS) exclusively in our department between 2000 and 2012. Apart from our self-developed, indication-specific questionnaire with questions on socioeconomic and demographic data as well as postoperative satisfaction, the testing instrument included 4 frequently used, standardized testing instruments, which we compared with normative data. These included (a) a self-assessment test Fragebogen zur Lebenszufriedenheit with questions on QOL consisting of 3 modules (general satisfaction, satisfaction with health, and satisfaction with body image/outer appearance), (b) the Freiburg Personality Inventory, (c) the Rosenberg Self-Esteem Questionnaire, and (d) the Patient Health Questionnaire 4.

Findings: Our self-developed, indication-specific questionnaire showed that 88% of our patients were very satisfied with the aesthetic result, 75% have had sex after surgery, and 72% were very satisfied with sexual function after GAS. Eighty-one percent had a strong improvement of QOL, and 91% would undergo the same treatment again. Eighty-four percent would recommend GAS to others. All patients lived as men fulltime.

Discussion: Our study reveals that GAS plays an important part in the interdisciplinary treatment of transgender individuals as it improves the QOL in transgender men in most aspects of everyday life and has a positive influence on the patients' psyche and self-esteem in a retrospective study.
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http://dx.doi.org/10.1097/SAP.0000000000002693DOI Listing
March 2021

Derivatization Design of Synthetically Accessible Space for Optimization: Synthesis vs Deep Generative Design.

ACS Med Chem Lett 2021 Feb 7;12(2):185-194. Epub 2021 Jan 7.

ChemPass Ltd., 7 Záhony St, Budapest 1031, Hungary.

Molecular design is of utmost importance in lead optimization programs ultimately determining the fate of the project and the speed to reach preclinical stage. Newly designed lead analogues or new chemotypes must successfully address the challenges in the multidimensional optimization process throughout several optimization cycles. The speed, quality, and creativity of the designs can have a major impact on the cycle time, the number of required cycles, and the number of compounds needed to be synthesized and evaluated that in combination affect the overall timeline and cost of the lead optimization phase. Recently, a new concept, generative design with deep learning, has become popular for de novo design of project relevant analogue sets. We have developed a de novo design technology called "derivatization design" that applies artificial-intelligence-assisted forward synthesis for the generation of near neighbor lead analogues as well as scaffold variations. The several attractive features of the methodology include synthetic feasibility, reagent availability and cost data associated with each new molecule; thus, detailed synthetic assessment is automatically generated during the design. As a result, these practically important data types can become an early part of the ranking and selection process for cycle time reduction. The power of derivatization design is demonstrated in a simple design study of DDR1 inhibitors and comparison of the produced molecules to a recently published data set obtained with deep generative design.
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http://dx.doi.org/10.1021/acsmedchemlett.0c00540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883369PMC
February 2021

Integrative Analysis Reveals a Molecular Stratification of Systemic Autoimmune Diseases.

Authors:
Guillermo Barturen Sepideh Babaei Francesc Català-Moll Manuel Martínez-Bueno Zuzanna Makowska Jordi Martorell-Marugán Pedro Carmona-Sáez Daniel Toro-Domínguez Elena Carnero-Montoro María Teruel Martin Kerick Marialbert Acosta-Herrera Lucas Le Lann Christophe Jamin Javier Rodríguez-Ubreva Antonio García-Gómez Jorge Kageyama Anne Buttgereit Sikander Hayat Joerg Mueller Ralf Lesche Maria Hernandez-Fuentes Maria Juarez Tania Rowley Ian White Concepción Marañón Tania Gomes Anjos Nieves Varela Rocío Aguilar-Quesada Francisco Javier Garrancho Antonio López-Berrio Manuel Rodriguez Maresca Héctor Navarro-Linares Isabel Almeida Nancy Azevedo Mariana Brandão Ana Campar Raquel Faria Fátima Farinha António Marinho Esmeralda Neves Ana Tavares Carlos Vasconcelos Elena Trombetta Gaia Montanelli Barbara Vigone Damiana Alvarez-Errico Tianlu Li Ricardo Blanco Alonso Alfonso Corrales Martínez Fernanda Genre Raquel López Mejías Miguel A Gonzalez-Gay Sara Remuzgo Begoña Ubilla Garcia Ricard Cervera Gerard Espinosa Ignasi Rodríguez-Pintó Ellen De Langhe Jonathan Cremer Rik Lories Doreen Belz Nicolas Hunzelmann Niklas Baerlecken Katja Kniesch Torsten Witte Michaela Lehner Georg Stummvoll Michael Zauner Maria Angeles Aguirre-Zamorano Nuria Barbarroja Maria Carmen Castro-Villegas Eduardo Collantes-Estevez Enrique de Ramon Isabel Díaz Quintero Alejandro Escudero-Contreras María Concepción Fernández Roldán Yolanda Jiménez Gómez Inmaculada Jiménez Moleón Rosario Lopez-Pedrera Rafaela Ortega-Castro Norberto Ortego Enrique Raya Carolina Artusi Maria Gerosa Pier Luigi Meroni Tommaso Schioppo Aurélie De Groof Julie Ducreux Bernard Lauwerys Anne-Lise Maudoux Divi Cornec Valérie Devauchelle-Pensec Sandrine Jousse-Joulin Pierre-Emmanuel Jouve Bénédicte Rouvière Alain Saraux Quentin Simon Montserrat Alvarez Carlo Chizzolini Aleksandra Dufour Donatienne Wynar Attila Balog Márta Bocskai Magdolna Deák Sonja Dulic Gabriella Kádár László Kovács Qingyu Cheng Velia Gerl Falk Hiepe Laleh Khodadadi Silvia Thiel Emanuele de Rinaldis Sambasiva Rao Robert J Benschop Chris Chamberlain Ernst R Dow Yiannis Ioannou Laurence Laigle Jacqueline Marovac Jerome Wojcik Yves Renaudineau Maria Orietta Borghi Johan Frostegård Javier Martín Lorenzo Beretta Esteban Ballestar Fiona McDonald Jacques-Olivier Pers Marta E Alarcón-Riquelme

Arthritis Rheumatol 2020 Dec 8. Epub 2020 Dec 8.

Department of Medical Genomics, Center for Genomics and Oncological Research (GENYO), Granada, Spain.

Objective: Clinical heterogeneity, a hallmark of systemic autoimmune diseases (SADs) impedes early diagnosis and effective treatment, issues that may be addressed if patients could be grouped into a molecular defined stratification.

Methods: With the aim of reclassifying SADs independently of the clinical diagnoses, unsupervised clustering of integrated whole blood transcriptome and methylome cross-sectional data of 955 patients with 7 SADs and 267 healthy controls was undertaken. In addition, an inception cohort was prospectively followed for 6 and 14 months to validate the results and analyze if cluster assignment changed or not with time.

Results: Four clusters were identified and validated. Three were pathological representing 'inflammatory', 'lymphoid', and 'interferon' patterns each including all diagnoses and defined by genetic, clinical, serological, and cellular features. A fourth cluster with no specific molecular pattern associated with low activity, and accumulated also healthy controls. A longitudinal and independent inception cohort showed a relapse-remission pattern, where patients remained in their pathological cluster, moving only to the healthy one, thus showing that with time, the molecular clusters remain stable and that single pathogenic molecular signatures characterize each individual patient.

Conclusions: Patients with SADs can be jointly stratified into three stable disease clusters with specific molecular patterns differentiating different molecular disease mechanisms. These results have important implications for future clinical trials and the study of therapy non-responsiveness marking a paradigm shift in our view of SADs.
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http://dx.doi.org/10.1002/art.41610DOI Listing
December 2020

ESE audit on management of Adult Growth Hormone Deficiency in clinical practice.

Eur J Endocrinol 2020 Dec 1. Epub 2020 Dec 1.

R Verkauskiene, Institute of Endocrinology, Medical Academy, Lithuanian University of Health Sciencies, Kaunas, Lithuania.

Guidelines recommend adults with pituitary disease in whom GH therapy is contemplated, to be tested for GH deficiency (AGHD); however, clinical practice is not uniform.

Aims: 1) To record current practice of AGHD management throughout Europe and benchmark it against guidelines; 2) To evaluate educational status of healthcare professionals about AGHD.

Design: On-line survey in endocrine centres throughout Europe.

Patients And Methods: Endocrinologists voluntarily completed an electronic questionnaire regarding AGHD patients diagnosed or treated in 2017-2018.

Results: Twenty-eight centres from 17 European countries participated, including 2139 AGHD patients, 28% of childhood-onset GHD. Aetiology was most frequently non-functioning pituitary adenoma (26%), craniopharyngioma (13%) and genetic/congenital mid-line malformations (13%). Diagnosis of GHD was confirmed by a stimulation test in 52% (GHRH+arginine, 45%; insulin-tolerance, 42%, glucagon, 6%; GHRH alone and clonidine tests, 7%); in the remaining, ≥3 pituitary deficiencies and low serum IGF-I were diagnostic. Initial GH dose was lower in older patients, but only women <26 years were prescribed a higher dose than men; dose titration was based on normal serum IGF-I, tolerance and side-effects. In one country, AGHD treatment was not approved. Full public reimbursement was not available in four countries and only in childhood-onset GHD in another. AGHD awareness was low among non-endocrine professionals and healthcare administrators. Postgraduate AGHD curriculum training deserves being improved.

Conclusion: Despite guideline recommendations, GH replacement in AGHD is still not available or reimbursed in all European countries. Knowledge among professionals and health administrators needs improvement to optimize care of adults with GHD.
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http://dx.doi.org/10.1530/EJE-20-1180DOI Listing
December 2020

Ascorbate inactivates the oxygen-evolving complex in prolonged darkness.

Physiol Plant 2021 Feb 6;171(2):232-245. Epub 2020 Dec 6.

Institute of Plant Biology, Biological Research Centre, Szeged, Hungary.

Ascorbate (Asc, vitamin C) is an essential metabolite participating in multiple physiological processes of plants, including environmental stress management and development. In this study, we acquired knowledge on the role of Asc in dark-induced leaf senescence using Arabidopsis thaliana as a model organism. One of the earliest effects of prolonged darkness is the inactivation of oxygen-evolving complexes (OEC) as demonstrated here by fast chlorophyll a fluorescence and thermoluminescence measurements. We found that inactivation of OEC due to prolonged darkness was attenuated in the Asc-deficient vtc2-4 mutant. On the other hand, the severe photosynthetic phenotype of a psbo1 knockout mutant, lacking the major extrinsic OEC subunit PSBO1, was further aggravated upon a 24-h dark treatment. The psbr mutant, devoid of the PSBR subunit of OEC, performed only slightly disturbed photosynthetic activity under normal growth conditions, whereas it showed a strongly diminished B thermoluminescence band upon dark treatment. We have also generated a double psbo1 vtc2 mutant, and it showed a slightly milder photosynthetic phenotype than the single psbo1 mutant. Our results, therefore, suggest that Asc leads to the inactivation of OEC in prolonged darkness by over-reducing the Mn-complex that is probably enabled by a dark-induced dissociation of the extrinsic OEC subunits. Our study is an example that Asc may negatively affect certain cellular processes and thus its concentration and localization need to be highly controlled.
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http://dx.doi.org/10.1111/ppl.13278DOI Listing
February 2021

Decreased R:FR Ratio in Incident White Light Affects the Composition of Barley Leaf Lipidome and Freezing Tolerance in a Temperature-Dependent Manner.

Int J Mol Sci 2020 Oct 13;21(20). Epub 2020 Oct 13.

Centre for Agricultural Research, Agricultural Institute, 2462 Martonvásár, Hungary.

In cereals, C-repeat binding factor genes have been defined as key components of the light quality-dependent regulation of frost tolerance by integrating phytochrome-mediated light and temperature signals. This study elucidates the differences in the lipid composition of barley leaves illuminated with white light or white light supplemented with far-red light at 5 or 15 °C. According to LC-MS analysis, far-red light supplementation increased the amount of monogalactosyldiacylglycerol species 36:6, 36:5, and 36:4 after 1 day at 5 °C, and 10 days at 15 °C resulted in a perturbed content of 38:6 species. Changes were observed in the levels of phosphatidylethanolamine, and phosphatidylserine under white light supplemented with far-red light illumination at 15 °C, whereas robust changes were observed in the amount of several phosphatidylserine species at 5 °C. At 15 °C, the amount of some phosphatidylglycerol species increased as a result of white light supplemented with far-red light illumination after 1 day. The ceramide (42:2)-3 content increased regardless of the temperature. The double-bond index of phosphatidylglycerol, phosphatidylserine, phosphatidylcholine ceramide together with total double-bond index changed when the plant was grown at 15 °C as a function of white light supplemented with far-red light. white light supplemented with far-red light increased the monogalactosyldiacylglycerol/diacylglycerol ratio as well. The gene expression changes are well correlated with the alterations in the lipidome.
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http://dx.doi.org/10.3390/ijms21207557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593930PMC
October 2020

Site-selection criteria for the Einstein Telescope.

Rev Sci Instrum 2020 Sep;91(9):094504

Wigner Research Centre for Physics, Institute of Particle and Nuclear Physics, H-1121 Budapest, Hungary.

The Einstein Telescope (ET) is a proposed next-generation, underground gravitational-wave detector to be based in Europe. It will provide about an order of magnitude sensitivity increase with respect to the currently operating detectors and, also extend the observation band targeting frequencies as low as 3 Hz. One of the first decisions that needs to be made is about the future ET site following an in-depth site characterization. Site evaluation and selection is a complicated process, which takes into account science, financial, political, and socio-economic criteria. In this paper, we provide an overview of the site-selection criteria for ET, provide a formalism to evaluate the direct impact of environmental noise on ET sensitivity, and outline the necessary elements of a site-characterization campaign.
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http://dx.doi.org/10.1063/5.0018414DOI Listing
September 2020

Inhibition of Class IIa HDACs improves endothelial barrier function in endotoxin-induced acute lung injury.

J Cell Physiol 2021 Apr 22;236(4):2893-2905. Epub 2020 Sep 22.

Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, Georgia, USA.

Acute lung injury (ALI) is an acute inflammatory process arises from a wide range of lung insults. A major cause of ALI is dysfunction of the pulmonary vascular endothelial barrier but the mechanisms involved are incompletely understood. The therapeutic potential of histone deacetylase (HDAC) inhibitors for the treatment of cardiovascular and inflammatory diseases is increasingly apparent, but the mechanisms by which HDACs regulate pulmonary vascular barrier function remain to be resolved. We found that specific Class IIa HDACs inhibitor, TMP269, significantly attenuated the lipopolysaccharide (LPS)-induced human lung microvascular endothelial cells (HLMVEC) barrier compromise in vitro and improved vascular barrier integrity and lung function in murine model of ALI in vivo. TMP269 decreased LPS-induced myosin light chain phosphorylation suggesting the role for Class IIa HDACs in LPS-induced cytoskeleton reorganization. TMP269 did not affect microtubule structure and tubulin acetylation in contrast to the HDAC6-specific inhibitor, Tubastatin A suggesting that Class IIa HDACs and HDAC6 (Class IIb) regulate endothelial cytoskeleton and permeability via different mechanisms. Furthermore, LPS increased the expression of ArgBP2 which has recently been attributed to HDAC-mediated activation of Rho. Depletion of ArgBP2 abolished the ability of LPS to disrupt barrier function in HLMVEC and both TMP269 and Tubastatin A decreased the level of ArgBP2 expression after LPS stimulation suggesting that both Class IIa and IIb HDACs regulate endothelial permeability via ArgBP2-dependent mechanism. Collectively, our data strongly suggest that Class IIa HDACs are involved in LPS-induced ALI in vitro and in vivo via specific mechanism which involved contractile responses, but not microtubule reorganization.
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http://dx.doi.org/10.1002/jcp.30053DOI Listing
April 2021

Thylakoid membrane reorganizations revealed by small-angle neutron scattering of leaves associated with non-photochemical quenching.

Open Biol 2020 09 16;10(9):200144. Epub 2020 Sep 16.

Laboratory for Neutron Scattering and Imaging, Paul Scherrer Institute, CH-5232 Villigen PSI, Switzerland.

Non-photochemical quenching (NPQ) is an important photoprotective mechanism in plants and algae. Although the process is extensively studied, little is known about its relationship with ultrastructural changes of the thylakoid membranes. In order to better understand this relationship, we studied the effects of illumination on the organization of thylakoid membranes in leaves. This evergreen species is known to exhibit very large NPQ and to possess giant grana with dozens of stacked thylakoids. It is thus ideally suited for small-angle neutron scattering measurements (SANS)-a non-invasive technique, which is capable of providing spatially and statistically averaged information on the periodicity of the thylakoid membranes and their rapid reorganizations . We show that NPQ-inducing illumination causes a strong decrease in the periodic order of granum thylakoid membranes. Development of NPQ and light-induced ultrastructural changes, as well as the relaxation processes, follow similar kinetic patterns. Surprisingly, whereas NPQ is suppressed by diuron, it impedes only the relaxation of the structural changes and not its formation, suggesting that structural changes do not cause but enable NPQ. We also demonstrate that the diminishment of SANS peak does not originate from light-induced redistribution and reorientation of chloroplasts inside the cells.
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http://dx.doi.org/10.1098/rsob.200144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536078PMC
September 2020

Role of Protein-Water Interface in the Stacking Interactions of Granum Thylakoid Membranes-As Revealed by the Effects of Hofmeister Salts.

Front Plant Sci 2020 14;11:1257. Epub 2020 Aug 14.

Institute of Plant Biology, Biological Research Centre, Szeged, Hungary.

The thylakoid membranes of vascular plants are differentiated into stacked granum and unstacked stroma regions. The formation of grana is triggered by the macrodomain formation of photosystem II and light-harvesting complex II (PSII-LHCII) and thus their lateral segregation from the photosystem I-light-harvesting complex I (PSI-LHCI) super-complexes and the ATP-synthase; which is then stabilized by stacking interactions of the adjacent PSII-LHCII enriched regions of the thylakoid membranes. The self-assembly and dynamics of this highly organized membrane system and the nature of forces acting between the PSII-LHCII macrodomains are not well understood. By using circular dichroism (CD) spectroscopy, small-angle neutron scattering (SANS) and transmission electron microscopy (TEM), we investigated the effects of Hofmeister salts on the organization of pigment-protein complexes and on the ultrastructure of thylakoid membranes. We found that the kosmotropic agent (NH)SO and the Hofmeister-neutral NaCl, up to 2 M concentrations, hardly affected the macro-organization of the protein complexes and the membrane ultrastructure. In contrast, chaotropic salts, NaClO, and NaSCN destroyed the mesoscopic structures, the multilamellar organization of the thylakoid membranes and the chiral macrodomains of the protein complexes but without noticeably affecting the short-range, pigment-pigment excitonic interactions. Comparison of the concentration- and time-dependences of SANS, TEM and CD parameters revealed the main steps of the disassembly of grana in the presence of chaotropes. It begins with a rapid diminishment of the long-range periodic order of the grana membranes, apparently due to an increased stacking disorder of the thylakoid membranes, as reflected by SANS experiments. SANS measurements also allowed discrimination between the cationic and anionic effects-in stacking and disorder, respectively. This step is followed by a somewhat slower disorganization of the TEM ultrastructure, due to the gradual loss of stacked membrane pairs. Occurring last is the stepwise decrease and disappearance of the long-range chiral order of the protein complexes, the rate of which was faster in LHCII-deficient membranes. These data are interpreted in terms of a theory, from our laboratory, according to which Hofmeister salts primarily affect the hydrophylic-hydrophobic interactions of proteins, and the stroma-exposed regions of the intrinsic membrane proteins, in particular-pointing to the role of protein-water interface in the stacking interactions of granum thylakoid membranes.
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http://dx.doi.org/10.3389/fpls.2020.01257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456932PMC
August 2020

Similarities and Differences in the Effects of Toxic Concentrations of Cadmium and Chromium on the Structure and Functions of Thylakoid Membranes in .

Front Plant Sci 2020 7;11:1006. Epub 2020 Jul 7.

Department of Biology Nyíregyháza, Institute of Environmental Sciences, University of Nyíregyháza, Nyíregyháza, Hungary.

Trace metal contaminations in natural waters, wetlands, and wastewaters pose serious threats to aquatic ecosystems-mainly targeting microalgae. In this work, we investigated the effects of toxic amounts of chromium and cadmium ions on the structure and function of the photosynthetic machinery of cells. To halt the propagation of cells, we used high concentrations of Cd and Cr, 50-50 mg L, in the forms of CdCl x 2.5 HO and KCrO, respectively. Both treatments led to similar, about 50% gradual diminishment of the chlorophyll contents of the cells in 48 h, which was, however, accompanied by a small (~10%) but statistically significant enrichment (Cd) and loss (Cr) of ß-carotene. Both Cd and Cr inhibited the activity of photosystem II (PSII)-but with more severe inhibitions with Cr. On the contrary, the PsbA (D1) protein of PSII and the PsbO protein of the oxygen-evolving complex were retained more in Cr-treated cells than in the presence of Cd. These data and the higher susceptibility of P700 redox transients in Cr-treated cells suggest that, unlike with Cd, PSII is not the main target in the photochemical apparatus. These differences at the level of photochemistry also brought about dissimilarities at higher levels of the structural complexity of the photosynthetic apparatus. Circular dichroism (CD) spectroscopy measurements revealed moderate perturbations in the macro-organization of the protein complexes-with more pronounced decline in Cd-treated cells than in the cells with Cr. Also, as reflected by transmission electron microscopy and small-angle neutron scattering, the thylakoid membranes suffered shrinking and were largely fragmented in Cd-treated cells, whereas no changes could be discerned with Cr. The preservation of integrity of membranes in Cr-treated cells was most probably aided by high proportion of the de-epoxidized xanthophylls, which were absent with Cd. It can thus be concluded that beside strong similarities of the toxic effects of Cr and Cd, the response of the photosynthetic machinery of to these two trace metal ions substantially differ from each other-strongly suggesting different inhibitory and protective mechanisms following the primary toxic events.
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http://dx.doi.org/10.3389/fpls.2020.01006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7358611PMC
July 2020

Phycobilisome integrity and functionality in lipid unsaturation and xanthophyll mutants in Synechocystis.

Photosynth Res 2020 Aug 27;145(2):179-188. Epub 2020 Jul 27.

Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, Sofia, Bulgaria.

The major light-harvesting system in cyanobacteria, the phycobilisome, is an essential component of the photosynthetic apparatus that regulates the utilization of the natural light source-the Sun. Earlier works revealed that the thylakoid membrane composition and its physical properties might have an important role in antennas docking. Polyunsaturated lipids and xanthophylls are among the most significant modulators of the physical properties of thylakoid membranes. In the nature, the action of these molecules is orchestrated in response to environmental stimuli among which the growth temperature is the most influential. In order to further clarify the significance of thylakoid membrane physical properties for the phycobilisomes assembly (i.e. structural integrity) and their ability to efficiently direct the excitation energy towards the photosynthetic complexes, in this work, we utilize cyanobacterial Synechocystis sp. PCC 6803 mutants deficient in polyunsaturated lipids (AD mutant) and xanthophylls (RO mutant), as well as a strain depleted of both xanthophylls and polyunsaturated lipids (ROAD multiple mutant). For the first time, we discuss the effect of those mutations on the phycobilisomes assembly, integrity and functionality at optimal (30 °C) and moderate low (25 °C) and high (35 °C) temperatures. Our results show that xanthophyll depletion exerts a much stronger effect on both phycobilisome's integrity and the response of cells to growth at suboptimal temperatures than lipid unsaturation level. The strongest effects were observed for the combined ROAD mutant, which exhibited thermally destabilized phycobilisomes and a population of energetically uncoupled phycocyanin units.
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http://dx.doi.org/10.1007/s11120-020-00776-1DOI Listing
August 2020

Genome-wide whole blood transcriptome profiling in a large European cohort of systemic sclerosis patients.

Ann Rheum Dis 2020 09 19;79(9):1218-1226. Epub 2020 Jun 19.

Instituto de Parasitologia y Biomedicina Lopez-Neyra, Granada, Spain.

Objectives: The analysis of annotated transcripts from genome-wide expression studies may help to understand the pathogenesis of complex diseases, such as systemic sclerosis (SSc). We performed a whole blood (WB) transcriptome analysis on RNA collected in the context of the European PRECISESADS project, aiming at characterising the pathways that differentiate SSc from controls and that are reproducible in geographically diverse populations.

Methods: Samples from 162 patients and 252 controls were collected in RNA stabilisers. Cases and controls were divided into a discovery (n=79+163; Southern Europe) and validation cohort (n=83+89; Central-Western Europe). RNA sequencing was performed by an Illumina assay. Functional annotations of Reactome pathways were performed with the Functional Analysis of Individual Microarray Expression (FAIME) algorithm. In parallel, immunophenotyping of 28 circulating cell populations was performed. We tested the presence of differentially expressed genes/pathways and the correlation between absolute cell counts and RNA transcripts/FAIME scores in regression models. Results significant in both populations were considered as replicated.

Results: Overall, 15 224 genes and 1277 functional pathways were available; of these, 99 and 225 were significant in both sets. Among replicated pathways, we found a deregulation in type-I interferon, Toll-like receptor cascade, tumour suppressor p53 protein function, platelet degranulation and activation. RNA transcripts or FAIME scores were jointly correlated with cell subtypes with strong geographical differences; neutrophils were the major determinant of gene expression in SSc-WB samples.

Conclusions: We discovered a set of differentially expressed genes/pathways validated in two independent sets of patients with SSc, highlighting a number of deregulated processes that have relevance for the pathogenesis of autoimmunity and SSc.
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http://dx.doi.org/10.1136/annrheumdis-2020-217116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456554PMC
September 2020

Profiles of criteria and non-criteria anti-phospholipid autoantibodies are associated with clinical phenotypes of the antiphospholipid syndrome.

Auto Immun Highlights 2020 Dec 15;11(1). Epub 2020 May 15.

1Clinical Immunology, Angioedema and Allergy Unit, Zabludowicz Center for Autoimmune Diseases, The Chaim Sheba Medical Center, Tel-Hashomer, 52621 Israel.

Background: Specific anti-phospholipids antibodies (aPLs) are used as classification criteria of the antiphospholipid syndrome (APS). These aPLs, although essential for diagnosis, do not predict disease phenotypes, which may require specific therapies. Non-criteria aPLs are rarely evaluated and their role is yet to be defined. In the current study, we aimed to examine the association between criteria and non-criteria aPLs and APS phenotypes.

Methods: Serum samples from 188 subjects, 130 APS patients and 58 controls were analyzed for the presence of 20 aPLs (IgG and IgM isotypes to cardiolipin (CL), beta2-glycoprotein1 (β2GP1), phosphatidic acid (P-acid), phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylglycerol (PG), phosphatidylinositol (PI), phosphatidylserine (PS), annexin-5 (AN) and prothrombin (PT) using a line immunoassay (GA Generic Assays, Germany). Sero-positivity to the different aPLs/aPLs profiles was correlated to APS phenotypes (i.e. arterial thrombosis, CNS manifestations, venous thrombosis, relapsing disease, obstetric morbidity).

Results: In this cohort, arterial thrombosis was associated with accumulative number of ≥ 7/20 aPLs evaluated (OR 4.1; CI 95% 1.9-96, p = 0.001) as well as the sole presence of aPT (IgG) (OR 2.3;CI 95% 1.1-5.1, p = 0.03). CNS manifestations were linked with a profile of 4 aPLs (IgG): aPT, aPG, aPI and aAN (OR 2.6;CI 95% 1.1-6.3, p = 0.03). Symptom-free period of ≥ 3 years was linked with lower number of aPLs and the presence of aPI (IgG) (OR 3.0;CI 95% 1.08-8.1, p < 0.05) or aAN (IgG) (OR 3.4;CI 95% 1.08-10.9, p < 0.05). APS related pregnancy morbidity correlated with a profile of 2 aPLs (IgG): aCL and aPS (OR 2.9; CI 95% 1.3-6.5, p < 0.05) or the sole presence of aAN (IgG) (OR 2.8; CI 95% 1.02-8, p = 0.05).

Conclusion: In this study, we observed an association between specific criteria/non-criteria aPLs or aPLs profiles and clinical phenotypes of APS. Our data suggest that examination of a wider variety of aPLs may allow better characterization of APS.
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http://dx.doi.org/10.1186/s13317-020-00131-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229627PMC
December 2020

18F-FDG-PET/CT in the evaluation and differential diagnosis of active large-vessel vasculitis. A prospective study.

Orv Hetil 2020 05 1;161(20):829-838. Epub 2020 May 1.

Szegedi Tudományegyetem, Szeged, Korányi fasor 6., 6720.

Introduction: Large-vessel vasculitis has non-specific clinical symptoms, which can delay the diagnosis. Early recognition and treatment of the disease can help to avoid late complications. F-FDG-PET can detect the inflammation of the vessel wall in the early stage of the disease with high sensitivity. CT is used to localize vasculitis. Aim: To examine the performance of F-FDG-PET/CT in patients with suspected large-vessel vasculitis, during relapse and remission, focusing on disease activity and extent. Method: 43 patients were evaluated. They were classified according to the clinical questions: steroid-naive suspected vasculitis, suspected vasculitis on steroid treatment, patients with relapse and in remission. We examined 10 cancer patients in control. We carried out visual and quantitative analysis of the F-FDG uptake of vessel walls. During quantitative evaluation, we determined standardised uptake values (SUVmax) of vessel wall segments compared to liver. Results: We found active disease in 5 patients examined for primary diagnosis, moreover, in 5 patients with relapse. The disease involved 3 or more vessel segments in fifty percent of the active cases. In the visually active group, the SUVmax was significantly lower in patients on steroid treatment than in steroid-naive cases (1.17 ± 0.11 vs. 1.43 ± 0.29; p = 0.005). We confirmed remission in 2 cases after therapy. In the inactive group, we found other types of inflammatory disorders in 8 cases. Conclusion: F-FDG-PET/CT is an effective diagnostic tool for large-vessel vasculitis, and can be used to determine the activity and extent of the disease. Steroid treatment influences the F-FDG-uptake of vessel wall. Orv Hetil. 2020; 161(20): 829-838.
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http://dx.doi.org/10.1556/650.2020.31710DOI Listing
May 2020

Specific T-Cell Subsets Can Predict the Efficacy of Anti-TNF Treatment in Inflammatory Bowel Diseases.

Arch Immunol Ther Exp (Warsz) 2020 Apr 4;68(2):12. Epub 2020 Apr 4.

Department of Rheumatology and Immunology, Faculty of Medicine, Albert Szent-Györgyi Health Center, University of Szeged, Kálvária sgt. 57, Szeged, 6725, Hungary.

The effect of TNF-blockers on T-lymphocyte subsets is largely unknown in inflammatory bowel diseases (IBDs). The aim of the present study was to analyze the prevalence of T-cell subtypes and their correlation to therapeutic response. Sixty-eight patients with Crohn's disease (CD), 46 with ulcerative colitis (UC) were enrolled. (1) The clinical course was followed after the initiation of TNF-blockers (prospective study). (2) The immunophenotype was also compared between long-term anti-TNF treated-responders and non-responders (cross-sectional study). The results were compared with those of therapy-naïve patients with active disease and those in remission with non-biological immunosuppressive therapy, and with healthy controls. Fourteen subtypes of peripheral blood T cells were measured with flow cytometry. The prevalence of Th2 and Th17 cells, of HLA-DR- and CD69-positive CD4 and CD8 cells, was higher, whereas the percentage of CD45RA-positive CD4 and CD8 cells was lower in both IBDs than in controls. CD8CD69 cell frequency was lower in remission, and decreased during anti-TNF therapy in CD responders. CD8CD45RO memory cells had higher prevalence in UC non-responders than in those starting anti-TNF. CD4CD45RO percentage < 49.05 at the initiation of TNF-blockers was predictive of a subsequent therapeutic response in CD, and Th2 and Th17 prevalence correlated with the duration of remission on TNF-blockers in UC. This study provided a detailed description of the T-cell composition in IBDs. CD8CD69 prevalence may be an activity marker in CD, and CD4CD45RO, Th2 and Th17 levels could be predictive for a therapeutic response to anti-TNF.
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http://dx.doi.org/10.1007/s00005-020-00575-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7128008PMC
April 2020

Giant cell arteritis presenting with pericardial effusion, hoarseness, and amaurosis.

Anatol J Cardiol 2020 Mar;23(4):235-237

Department of Family Medicine, Faculty of Medicine, University of Szeged; Szeged-Hungary.

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http://dx.doi.org/10.14744/AnatolJCardiol.2019.00502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7163215PMC
March 2020

The Usage of Pedicled or Free Muscle Flaps Represents a Beneficial Approach for Periprosthetic Infection After Knee Arthroplasty.

Ann Plast Surg 2020 11;85(5):539-545

From the Department for Plastic Surgery and Hand Surgery, Klinikum rechts der Isar, Technische Universität Munich, Munich.

Introduction: Periprosthetic joint infection (PJI) is a severe complication after a total knee replacement that is primarily associated with soft tissue defects. Finding an appropriate therapy for PJI is a major challenge because of the lack of guidelines and research comparing treatment options.

Methods: In this study, we retrospectively compared 78 patients who had a knee prosthetic infection within a mean follow-up period of 24 months. Group A received a soft tissue coverage in addition to orthopedic surgical therapy with or without a component replacement (CR) of the prosthesis. Group B received the same orthopedic treatment without plastic surgery for soft tissue coverage.

Results: Only 21% of the patients in group A received a CR compared with 70% in group B (P = 0.0001). In group A, 83% did not have a recurrent infection, and in group B, 57% of the patients had no further infection and regained joint function (P = 0.0376). In group A, only 15% of the patients who received a CR had a significant complication within the follow-up period of 2 years, whereas in group B, 75% of patients exhibiting a major complication (P = 0.0048*).

Conclusions: Soft tissue coverage improves the outcome after PJI of the knee with soft tissue defects. Patients who simultaneously needed plastic surgery for defect coverage and orthopedic surgery for CR had the lowest number of complications overall. Based on the results of this study, a therapy algorithm could be identified considering the soft tissue defect grade leading to the lowest major complication rates and maximizing the outcome of knee prosthesis infection therapies.
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http://dx.doi.org/10.1097/SAP.0000000000002293DOI Listing
November 2020

Trimeric organization of photosystem I is required to maintain the balanced photosynthetic electron flow in cyanobacterium Synechocystis sp. PCC 6803.

Photosynth Res 2020 Mar 17;143(3):251-262. Epub 2019 Dec 17.

Department of Plant Physiology and Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-387, Kraków, Poland.

In Synechocystis sp. PCC 6803 and some other cyanobacteria photosystem I reaction centres exist predominantly as trimers, with minor contribution of monomeric form, when cultivated at standard optimized conditions. In contrast, in plant chloroplasts photosystem I complex is exclusively monomeric. The functional significance of trimeric organization of cyanobacterial photosystem I remains not fully understood. In this study, we compared the photosynthetic characteristics of PSI in wild type and psaL knockout mutant. The results show that relative to photosystem I trimer in wild-type cells, photosystem I monomer in psaL mutant has a smaller P700 pool size under low and moderate light, slower P700 oxidation upon dark-to-light transition, and slower P700 reduction upon light-to-dark transition. The mutant also shows strongly diminished photosystem I donor side limitations [quantum yield Y(ND)] at low, moderate and high light, but enhanced photosystem I acceptor side limitations [quantum yield Y(NA)], especially at low light (22 µmol photons m s). In line with these functional characteristics are the determined differences in the relative expression genes encoding of selected electron transporters. The psaL mutant showed significant (ca fivefold) upregulation of the photosystem I donor cytochrome c, and downregulation of photosystem I acceptors (ferredoxin, flavodoxin) and proteins of alternative electron flows originating in photosystem I acceptor side. Taken together, our results suggest that photosystem I trimerization in wild-type Synechocystis cells plays a role in the protection of photosystem I from photoinhibition via maintaining enhanced donor side electron transport limitations and minimal acceptor side electron transport limitations at various light intensities.
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http://dx.doi.org/10.1007/s11120-019-00696-9DOI Listing
March 2020

Lack of Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Disturbs Callus Formation.

J Mol Neurosci 2019 Dec 5. Epub 2019 Dec 5.

Department of Anatomy, Histology and Embryology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a naturally secreted signaling peptide and has important regulatory roles in the differentiation of the central nervous system and its absence results in disorders in femur development. PACAP has an important function in prevention of oxidative stress or mechanical stress in chondrogenesis but little is known about its function in bone regeneration. A new callus formation model was set to investigate its role in bone remodeling. Fracturing was 5 mm distal from the proximal articular surface of the tibia and the depth was 0.5 mm. Reproducibility of callus formation was investigated with CT 3, 7, and 21 days after the operation. Absence of PACAP did not alter the alkaline phosphatase (ALP) activation in PACAP KO healing process. In developing callus, the expression of collagen type I increased in wild-type (WT) and PACAP KO mice decreased to the end of healing process. Expression of the elements of BMP signaling was disturbed in the callus formation of PACAP KO mice, as bone morphogenic protein 4 (BMP4) and 6 showed an early reduction in bone regeneration. However, elevated Smad1 expression was demonstrated in PACAP KO mice. Our results indicate that PACAP KO mice show various signs of disturbed bone healing and suggest PACAP compensatory and fine tuning effects in proper bone regeneration.
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http://dx.doi.org/10.1007/s12031-019-01448-zDOI Listing
December 2019

Y-chromosome haplogroups from Hun, Avar and conquering Hungarian period nomadic people of the Carpathian Basin.

Sci Rep 2019 11 12;9(1):16569. Epub 2019 Nov 12.

Department of Genetics, University of Szeged, Szeged, H-6726, Hungary.

Hun, Avar and conquering Hungarian nomadic groups arrived to the Carpathian Basin from the Eurasian Steppes and significantly influenced its political and ethnical landscape, however their origin remains largely unknown. In order to shed light on the genetic affinity of above groups we have determined Y chromosomal haplogroups and autosomal loci, suitable to predict biogeographic ancestry, from 49 individuals, supposed to represent the power/military elit. Haplogroups from the Hun-age are consistent with Xiongnu ancestry of European Huns. Most of the Avar-age individuals carry east Eurasian Y haplogroups typical for modern north-eastern Siberian and Buryat populations and their autosomal loci indicate mostly un-admixed Asian characteristics. In contrast the conquering Hungarians seem to be a recently assembled population incorporating un-admixed European, Asian as well as admixed components. Their heterogeneous paternal and maternal lineages indicate similar supposed phylogeographic origin of males and females, derived from Central-Inner Asian and European Pontic Steppe sources.
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http://dx.doi.org/10.1038/s41598-019-53105-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6851379PMC
November 2019

Psychological Pathologies and Sexual Orientation in Transgender Women Undergoing Gender Confirming Treatment.

Ann Plast Surg 2020 03;84(3):312-316

Department of Plastic Surgery, University Teaching Hospital Rotkreuzklinikum München, Munich Technical University, Munich, Germany.

Background: There are few studies evaluating depression, self-esteem, and mental health after gender confirming treatment of transgender women. Most of these studies include different surgical techniques and nonvalidated questionnaires. With our survey, we are aiming to assess psychopathologies and mental health as well as sexuality among a group of patients treated by the same surgeon performing our self-developed combined surgical technique. This vaginoplasty approach is characterized by constructing the vaginal cavity with parts of the penile and scrotal skin as well as the longitudinally incised urethra.

Materials And Methods: Forty-seven transgender women who underwent gender confirming treatment between 2007 and 2013 were included in a retrospective study. The assessment of our study group was performed by means of self-developed indication-specific questionnaires and 3 standardized questionnaires that can be compared with norm data.

Results: Preoperative psychotherapy was mostly considered as helpful by the patients, yet postoperatively, only a third of our study participants were still under therapeutic treatment. Furthermore, we could show a change in sexual preference toward a more bisexual orientation. Gender confirming treatment satisfied the expectations for most of the patients and, in their opinion, should have been performed earlier. Results of the standardized Patient Health Questionnaire 4, a short depression screening questionnaire, did not significantly differ from healthy norm data. The Freiburg Personality Inventory, Revised, revealed normal emotionality and sane self-assessment within our study group. High self-esteem and significantly higher scores than norm data were found for the Rosenberg Self-esteem Scale.

Conclusions: Gender confirming treatment with the combined technique is an important part of a multi-structured treatment of transgenders and does have effects on psychological well-being. It seems to decrease psychopathologies and implicates several ameliorations for transgender women. Findings need to be verified in prospective studies including preoperative evaluations.
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http://dx.doi.org/10.1097/SAP.0000000000002035DOI Listing
March 2020

Ascorbate Deficiency Does Not Limit Nonphotochemical Quenching in .

Plant Physiol 2020 01 29;182(1):597-611. Epub 2019 Oct 29.

Institute of Plant Biology, Biological Research Centre, Szeged, Hungary

Ascorbate (Asc; vitamin C) plays essential roles in development, signaling, hormone biosynthesis, regulation of gene expression, stress resistance, and photoprotection. In vascular plants, violaxanthin de-epoxidase requires Asc as a reductant; thereby, Asc is required for the energy-dependent component of nonphotochemical quenching (NPQ). To assess the role of Asc in NPQ in green algae, which are known to contain low amounts of Asc, we searched for an insertional mutant affected in the gene encoding GDP-l-Gal phosphorylase, which catalyzes the first committed step in the biosynthesis of Asc. The knockout mutant was viable and, depending on the growth conditions, contained 10% to 20% Asc relative to its wild type. When was grown photomixotrophically at moderate light, the zeaxanthin-dependent component of NPQ emerged upon strong red illumination both in the mutant and in its wild type. Deepoxidation was unaffected by Asc deficiency, demonstrating that the Chlorophycean violaxanthin de-epoxidase found in does not require Asc as a reductant. The rapidly induced, energy-dependent NPQ component characteristic of photoautotrophic cultures grown at high light was not limited by Asc deficiency either. On the other hand, a reactive oxygen species-induced photoinhibitory NPQ component was greatly enhanced upon Asc deficiency, both under photomixotrophic and photoautotrophic conditions. These results demonstrate that Asc has distinct roles in NPQ formation in as compared to vascular plants.
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http://dx.doi.org/10.1104/pp.19.00916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6945847PMC
January 2020

Corticotropin-Releasing Factor-Producing Cells in the Paraventricular Nucleus of the Hypothalamus and Extended Amygdala Show Age-Dependent FOS and FOSB/DeltaFOSB Immunoreactivity in Acute and Chronic Stress Models in the Rat.

Front Aging Neurosci 2019 9;11:274. Epub 2019 Oct 9.

Department of Anatomy, University of Pécs Medical School, Pécs, Hungary.

Corticotropin-releasing factor (CRF) immunoreactive (ir) neurons of the paraventricular nucleus of the hypothalamus (PVN) play pivotal role in the coordination of stress response. CRF-producing cells in the central nucleus of amygdala (CeA) and oval division of the bed nucleus of stria terminalis (BNSTov) are also involved in stress adaptation and mood control. Immediate early gene products, subunits of the transcription factor activator protein 1 (AP1) are commonly used as acute (FOS) and/or chronic (FOSB/deltaFOSB) markers for the neuronal activity in stress research. It is well known that the course of aging affects stress adaptation, but little is known about the aging-related stress sensitivity of CRF neurons. To the best of our knowledge, the stress-induced neuronal activity of CRF neurons in the course of aging in acute and chronic stress models was not studied systematically yet. Therefore, the aim of the present study was to quantify the acute restraint stress (ARS) and chronic variable mild stress (CVMS) evoked neuronal activity in CRF cells of the PVN, CeA, and BNSTov using triple-label immunofluorescence throughout the whole lifespan in the rat. We hypothesized that the FOS and FOSB content of CRF cells upon ARS or CVMS decreases with age. Our results showed that the FOS and FOSB response to ARS declined with age in the PVN-CRF cells. BNSTov and CeA CRF cells did not show remarkable stress-induced elevation of these markers neither in ARS, nor in CVMS. Exposure to CVMS resulted in an age-independent significant increase of FOSB/delta FOSB immunosignal in PVN-CRF neurons. Unexpectedly, we detected a remarkable stress-independent FOSB/deltaFOSB signal in CeA- and BNSTov-CRF cells that declined with the course of aging. In summary, PVN-CRF cells show decreasing acute stress sensitivity (i.e., FOS and FOSB immunoreactivity) with the course of aging, while their (FOSB/deltaFOSB) responsivity to chronic challenge is maintained till senescence. Stress exposure does not affect the occurrence of the examined gene products in CeA- and BNSTov-CRF cells remarkably suggesting that their contribution to stress adaptation response does not require AP1-controlled transcriptional changes.
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http://dx.doi.org/10.3389/fnagi.2019.00274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6794369PMC
October 2019

Altered Cell Surface N-Glycosylation of Resting and Activated T Cells in Systemic Lupus Erythematosus.

Int J Mol Sci 2019 Sep 10;20(18). Epub 2019 Sep 10.

Department of Rheumatology and Immunology, Faculty of Medicine, University of Szeged, 6725 Szeged, Hungary.

Altered cell surface glycosylation in congenital and acquired diseases has been shown to affect cell differentiation and cellular responses to external signals. Hence, it may have an important role in immune regulation; however, T cell surface glycosylation has not been studied in systemic lupus erythematosus (SLE), a prototype of autoimmune diseases. Analysis of the glycosylation of T cells from patients suffering from SLE was performed by lectin-binding assay, flow cytometry, and quantitative real-time PCR. The results showed that resting SLE T cells presented an activated-like phenotype in terms of their glycosylation pattern. Additionally, activated SLE T cells bound significantly less galectin-1 (Gal-1), an important immunoregulatory lectin, while other lectins bound similarly to the controls. Differential lectin binding, specifically Gal-1, to SLE T cells was explained by the increased gene expression ratio of sialyltransferases and neuraminidase 1 (), particularly by elevated ST6 beta-galactosamide alpha-2,6-sialyltranferase 1 ()/ and ST3 beta-galactoside alpha-2,3-sialyltransferase 6 (S/ ratios. These findings indicated an increased terminal sialylation. Indeed, neuraminidase treatment of cells resulted in the increase of Gal-1 binding. Altered T cell surface glycosylation may predispose the cells to resistance to the immunoregulatory effects of Gal-1, and may thus contribute to the pathomechanism of SLE.
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http://dx.doi.org/10.3390/ijms20184455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770513PMC
September 2019

Insight Into the Microbial Co-occurrence and Diversity of 73 Grapevine () Crown Galls Collected Across the Northern Hemisphere.

Front Microbiol 2019 13;10:1896. Epub 2019 Aug 13.

Thomas H. Gosnell School of Life Sciences, Rochester Institute of Technology, Rochester, NY, United States.

Crown gall (CG) is a globally distributed and economically important disease of grapevine and other important crop plants. The causal agent of CG is or strains that harbor a tumor-inducing plasmid (pTi). The microbial community within the CG tumor has not been widely elucidated and it is not known if certain members of this microbial community promote or inhibit CG. This study investigated the microbiotas of grapevine CG tumor tissues from seven infected vineyards located in Hungary, Japan, Tunisia, and the United States. Heavy co-amplification of grapevine chloroplast and mitochondrial ribosomal RNA genes was observed with the widely used Illumina V3-V4 16S rRNA gene primers, requiring the design of a new reverse primer to enrich for bacterial 16S rRNA from CG tumors. The operational taxonomic unit (OTU) clustering approach is not suitable for CG microbiota analysis as it collapsed several ecologically distinct species into a single OTU due to low interspecies genetic divergence. The CG microbial community assemblages were significantly different across sampling sites (ANOSIM global = 0.63, value = 0.001) with evidence of site-specific differentially abundant ASVs. The presence of in the CG microbiota is almost always accompanied by and , the latter may promote the spread of pTi plasmid by way of acyl-homoserine lactone signal production, whereas the former may take advantage of the presence of substrates associated with plant cell wall growth and repair. The technical and biological insights gained from this study will contribute to the understanding of complex interaction between the grapevine and its microbial community and may facilitate better management of CG disease in the future.
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http://dx.doi.org/10.3389/fmicb.2019.01896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700373PMC
August 2019

TMEM203 is a binding partner and regulator of STING-mediated inflammatory signaling in macrophages.

Proc Natl Acad Sci U S A 2019 08 25;116(33):16479-16488. Epub 2019 Jul 25.

Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, S10 2RX Sheffield, United Kingdom;

Regulation of IFN signaling is critical in host recognition and response to pathogens while its dysregulation underlies the pathogenesis of several chronic diseases. STimulator of IFN Genes (STING) has been identified as a critical mediator of IFN inducing innate immune pathways, but little is known about direct coregulators of this protein. We report here that TMEM203, a conserved putative transmembrane protein, is an intracellular regulator of STING-mediated signaling. We show that TMEM203 interacts, functionally cooperates, and comigrates with STING following cell stimulation, which in turn leads to the activation of the kinase TBK1, and the IRF3 transcription factor. This induces target genes in macrophages, including IFN-β. Using knockout bone marrow-derived macrophages and transient knockdown of TMEM203 in human monocyte-derived macrophages, we show that TMEM203 protein is required for cGAMP-induced STING activation. Unlike , mRNA levels are elevated in T cells from patients with systemic lupus erythematosus, a disease characterized by the overexpression of type I interferons. Moreover, mRNA levels are associated with disease activity, as assessed by serum levels of the complement protein C3. Identification of TMEM203 sheds light into the control of STING-mediated innate immune responses, providing a potential novel mechanism for therapeutic interventions in STING-associated inflammatory diseases.
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http://dx.doi.org/10.1073/pnas.1901090116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697806PMC
August 2019

PFKFB3-mediated endothelial glycolysis promotes pulmonary hypertension.

Proc Natl Acad Sci U S A 2019 07 18;116(27):13394-13403. Epub 2019 Jun 18.

Vascular Biology Center, Augusta University, Augusta, GA 30912;

Increased glycolysis in the lung vasculature has been connected to the development of pulmonary hypertension (PH). We therefore investigated whether glycolytic regulator 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase (PFKFB3)-mediated endothelial glycolysis plays a critical role in the development of PH. Heterozygous global deficiency of protected mice from developing hypoxia-induced PH, and administration of the PFKFB3 inhibitor 3PO almost completely prevented PH in rats treated with Sugen 5416/hypoxia, indicating a causative role of PFKFB3 in the development of PH. Immunostaining of lung sections and Western blot with isolated lung endothelial cells showed a dramatic increase in PFKFB3 expression and activity in pulmonary endothelial cells of rodents and humans with PH. We generated mice that were constitutively or inducibly deficient in endothelial and found that these mice were incapable of developing PH or showed slowed PH progression. Compared with control mice, endothelial -knockout mice exhibited less severity of vascular smooth muscle cell proliferation, endothelial inflammation, and leukocyte recruitment in the lungs. In the absence of , lung endothelial cells from rodents and humans with PH produced lower levels of growth factors (such as PDGFB and FGF2) and proinflammatory factors (such as CXCL12 and IL1β). This is mechanistically linked to decreased levels of HIF2A in lung ECs following knockdown. Taken together, these results suggest that targeting PFKFB3 is a promising strategy for the treatment of PH.
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http://dx.doi.org/10.1073/pnas.1821401116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6613097PMC
July 2019

Reactive Oxygen Species-Dependent Calpain Activation Contributes to Airway and Pulmonary Vascular Remodeling in Chronic Obstructive Pulmonary Disease.

Antioxid Redox Signal 2019 10 24;31(12):804-818. Epub 2019 Jun 24.

Department of Pharmacology & Toxicology, Medical College of Georgia, Augusta University, Augusta, Georgia.

Airway and pulmonary vascular remodeling is an important pathological feature in the pathogenesis of chronic obstructive pulmonary disease (COPD). Tobacco smoke (TS) induces the production of large amounts of reactive oxygen species (ROS) in COPD lungs. We investigated how ROS lead to airway and pulmonary vascular remodeling in COPD. We used bronchial and pulmonary artery smooth muscle cells (BSMCs and PASMCs), TS-induced COPD rodent models, and lung tissues of COPD patients. We found that HO and TS extract (TSE) induced calpain activation in BSMCs and PASMCs. Calpain activation was elevated in smooth muscle of bronchi and pulmonary arterioles in COPD patients and TS-induced COPD rodent models. Calpain inhibition attenuated HO- and TSE-induced collagen synthesis and proliferation of BSMCs and PASMCs. Exposure to TS causes increases in airway resistance, right ventricular systolic pressure (RVSP), and thickening of bronchi and pulmonary arteries. Calpain inhibition by smooth muscle-specific knockout of calpain and the calpain inhibitor MDL28170 attenuated increases in airway resistance, RVSP, and thickening of bronchi and pulmonary arteries. Moreover, smooth muscle-specific knockout of calpain did not reduce TS-induced emphysema in the mouse model, but MDL28170 did reduce TS-induced emphysema in the rat model. This study provides the first evidence that ROS-induced calpain activation contributes to airway and pulmonary vascular remodeling in TS-induced COPD. Calpain might be a novel therapeutic target for the treatment of COPD. These results indicate that ROS-induced calpain activation contributes to airway and pulmonary vascular remodeling and pulmonary hypertension in COPD.
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http://dx.doi.org/10.1089/ars.2018.7648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7061305PMC
October 2019