ABSTRACT
In eukaryotic cells, phosphorus is assimilated and utilized primarily as phosphate (Pi). Pi homeostasis is mediated by transporters that have not yet been adequately characterized in green algae. This study reports on PHOSPHATE TRANSPORTER 4-7 (CrPHT4-7) from Chlamydomonas reinhardtii, a member of the PHT4 transporter family, which exhibits remarkable similarity to AtPHT4;4 from Arabidopsis (Arabidopsis thaliana), a chloroplastic ascorbate transporter. Using fluorescent protein tagging, we show that CrPHT4-7 resides in the chloroplast envelope membrane. Crpht4-7 mutants, generated by the CRISPR/Cas12a-mediated single-strand templated repair, show retarded growth, especially in high light, reduced ATP level, strong ascorbate accumulation, and diminished non-photochemical quenching in high light. On the other hand, total cellular phosphorous content was unaffected, and the phenotype of the Crpht4-7 mutants could not be alleviated by ample Pi supply. CrPHT4-7-overexpressing lines exhibit enhanced biomass accumulation under high light conditions in comparison with the wild-type strain. Expressing CrPHT4-7 in a yeast (Saccharomyces cerevisiae) strain lacking Pi transporters substantially recovered its slow growth phenotype, demonstrating that CrPHT4-7 transports Pi. Even though CrPHT4-7 shows a high degree of similarity to AtPHT4;4, it does not display any substantial ascorbate transport activity in yeast or intact algal cells. Thus, the results demonstrate that CrPHT4-7 functions as a chloroplastic Pi transporter essential for maintaining Pi homeostasis and photosynthesis in C. reinhardtii.
Subject(s)
Arabidopsis , Chlamydomonas , Chlamydomonas/genetics , Saccharomyces cerevisiae , Photosynthesis/genetics , Chloroplasts , Homeostasis , Ascorbic Acid , Membrane Transport ProteinsABSTRACT
Ascorbate is a major plant metabolite that plays crucial roles in various processes, from reactive oxygen scavenging to epigenetic regulation. However, to what extent and how ascorbate modulates metabolism is largely unknown. We investigated the consequences of chloroplastic and total cellular ascorbate-deficiencies by studying chloroplastic ascorbate-transporter mutant lines lacking PHOSPHATE TRANSPORTER 4; 4 (PHT4; 4) , and the ascorbate-deficient vtc2-4 mutant of Arabidopsis (Arabidopsis thaliana). Under regular growth conditions, both ascorbate deficiencies caused minor alterations in photosynthesis, with no apparent signs of oxidative damage. In contrast, metabolomics analysis revealed global and largely overlapping alterations in the metabolome profiles of both ascorbate-deficiency mutants, suggesting that chloroplastic ascorbate modulates plant metabolism. We observed significant alterations in amino acid metabolism, particularly in arginine metabolism, activation of nucleotide salvage pathways, and changes in secondary metabolism. In addition, proteome-wide analysis of thermostability revealed that ascorbate may interact with enzymes involved in arginine metabolism, the Calvin-Benson cycle, and several photosynthetic electron transport components. Overall, our results suggest that, independently of oxidative stress, chloroplastic ascorbate modulates the activity of diverse metabolic pathways in vascular plants and may act as an internal metabolic signal.
ABSTRACT
Cyanobacteria play a key role in primary production in both oceans and fresh waters and hold great potential for sustainable production of a large number of commodities. During their life, cyanobacteria cells need to acclimate to a multitude of challenges, including shifts in intensity and quality of incident light. Despite our increasing understanding of metabolic regulation under various light regimes, detailed insight into fitness advantages and limitations under shifting light quality remains underexplored. Here, we study photo-physiological acclimation in the cyanobacterium Synechocystis sp. PCC 6803 throughout the photosynthetically active radiation (PAR) range. Using light emitting diodes (LEDs) with qualitatively different narrow spectra, we describe wavelength dependence of light capture, electron transport and energy transduction to main cellular pools. In addition, we describe processes that fine-tune light capture, such as state transitions, or the efficiency of energy transfer from phycobilisomes to photosystems (PS). We show that growth was the most limited under blue light due to inefficient light harvesting, and that many cellular processes are tightly linked to the redox state of the plastoquinone (PQ) pool, which was the most reduced under red light. The PSI-to-PSII ratio was low under blue photons, however, it was not the main growth-limiting factor, since it was even more reduced under violet and near far-red lights, where Synechocystis grew faster compared to blue light. Our results provide insight into the spectral dependence of phototrophic growth and can provide the foundation for future studies of molecular mechanisms underlying light acclimation in cyanobacteria, leading to light optimization in controlled cultivations.
ABSTRACT
OBJECTIVES: To unveil biological milieus underlying low disease activity (LDA) and remission versus active systemic lupus erythematosus (SLE). METHODS: We determined differentially expressed pathways (DEPs) in SLE patients from the PRECISESADS project (NTC02890121) stratified into patients fulfilling and not fulfilling the criteria of (1) Lupus LDA State (LLDAS), (2) Definitions of Remission in SLE remission, and (3) LLDAS exclusive of remission. RESULTS: We analysed data from 321 patients; 40.8% were in LLDAS, and 17.4% in DORIS remission. After exclusion of patients in remission, 28.3% were in LLDAS. Overall, 604 pathways differed significantly in LLDAS versus non-LLDAS patients with an false-discovery rate-corrected p (q)<0.05 and a robust effect size (dr)≥0.36. Accordingly, 288 pathways differed significantly between DORIS remitters and non-remitters (q<0.05 and dr≥0.36). DEPs yielded distinct molecular clusters characterised by differential serological, musculoskeletal, and renal activity. Analysis of partially overlapping samples showed no DEPs between LLDAS and DORIS remission. Drug repurposing potentiality for treating SLE was unveiled, as were important pathways underlying active SLE whose modulation could aid attainment of LLDAS/remission, including toll-like receptor (TLR) cascades, Bruton tyrosine kinase (BTK) activity, the cytotoxic T lymphocyte antigen 4 (CTLA-4)-related inhibitory signalling, and the nucleotide-binding oligomerization domain leucine-rich repeat-containing protein 3 (NLRP3) inflammasome pathway. CONCLUSIONS: We demonstrated for the first time molecular signalling pathways distinguishing LLDAS/remission from active SLE. LLDAS/remission was associated with reversal of biological processes related to SLE pathogenesis and specific clinical manifestations. DEP clustering by remission better grouped patients compared with LLDAS, substantiating remission as the ultimate treatment goal in SLE; however, the lack of substantial pathway differentiation between the two states justifies LLDAS as an acceptable goal from a biological perspective.
Subject(s)
Lupus Erythematosus, Systemic , Remission Induction , Transcriptome , Humans , Lupus Erythematosus, Systemic/drug therapy , Lupus Erythematosus, Systemic/blood , Lupus Erythematosus, Systemic/genetics , Female , Adult , Male , Middle Aged , Severity of Illness Index , Cohort StudiesABSTRACT
OBJECTIVES: To update the EULAR recommendations for the management of systemic lupus erythematosus (SLE) based on emerging new evidence. METHODS: An international Task Force formed the questions for the systematic literature reviews (January 2018-December 2022), followed by formulation and finalisation of the statements after a series of meetings. A predefined voting process was applied to each overarching principle and recommendation. Levels of evidence and strengths of recommendation were assigned, and participants finally provided their level of agreement with each item. RESULTS: The Task Force agreed on 5 overarching principles and 13 recommendations, concerning the use of hydroxychloroquine (HCQ), glucocorticoids (GC), immunosuppressive drugs (ISDs) (including methotrexate, mycophenolate, azathioprine, cyclophosphamide (CYC)), calcineurin inhibitors (CNIs, cyclosporine, tacrolimus, voclosporin) and biologics (belimumab, anifrolumab, rituximab). Advice is also provided on treatment strategies and targets of therapy, assessment of response, combination and sequential therapies, and tapering of therapy. HCQ is recommended for all patients with lupus at a target dose 5 mg/kg real body weight/day, considering the individual's risk for flares and retinal toxicity. GC are used as 'bridging therapy' during periods of disease activity; for maintenance treatment, they should be minimised to equal or less than 5 mg/day (prednisone equivalent) and, when possible, withdrawn. Prompt initiation of ISDs (methotrexate, azathioprine, mycophenolate) and/or biological agents (anifrolumab, belimumab) should be considered to control the disease and facilitate GC tapering/discontinuation. CYC and rituximab should be considered in organ-threatening and refractory disease, respectively. For active lupus nephritis, GC, mycophenolate or low-dose intravenous CYC are recommended as anchor drugs, and add-on therapy with belimumab or CNIs (voclosporin or tacrolimus) should be considered. Updated specific recommendations are also provided for cutaneous, neuropsychiatric and haematological disease, SLE-associated antiphospholipid syndrome, kidney protection, as well as preventative measures for infections, osteoporosis, cardiovascular disease. CONCLUSION: The updated recommendations provide consensus guidance on the management of SLE, combining evidence and expert opinion.
Subject(s)
Azathioprine , Lupus Erythematosus, Systemic , Humans , Azathioprine/therapeutic use , Tacrolimus/therapeutic use , Rituximab/therapeutic use , Methotrexate/therapeutic use , Lupus Erythematosus, Systemic/complications , Immunosuppressive Agents/therapeutic use , Cyclophosphamide/therapeutic use , Hydroxychloroquine/therapeutic use , Glucocorticoids/therapeutic use , Enzyme Inhibitors/therapeutic useABSTRACT
Our society, in general, and health care, in particular, faces notable challenges due to the emergence of innovative digital technologies. The use of socially assistive robots in aged care is a particular digital application that provokes ethical reflection. The answers we give to the ethical questions associated with socially assistive robots are framed by ontological and anthropological considerations of what constitutes human beings and how the meaning of being human relates to how these robots are conceived. Religious beliefs and secular worldviews, each of which may participate fully in pluralist societies, have an important responsibility in this foundational debate, as anthropological theories can be inspired by religious and secular viewpoints. This article identifies seven anthropological considerations grounded in the synthesis of biblical scriptures, Roman Catholic documents, and recent research literature. We highlight the inspirational quality of these anthropological considerations when dealing with ethical issues regarding the development and use of socially assistive robots in aged care. With this contribution, we aim to foster a global and inclusive dialogue on digitalization in aged care that deeply challenges our basic understanding of what constitutes a human being and how this notion relates to machine artefacts.
ABSTRACT
The darkling beetle, Alphitobius diaperinus, and the poultry red mite, Dermanysuss gallinae are among the most common pests of poultry farms. Both pests can be carriers and reservoirs of various pathogens including zoonotic ones like Salmonella. Salmonellosis is one of the most common foodborne diseases reported in the EU. We developed a semi-nested PCR method for the direct detection of Salmonella enterica. When testing the specificity of the novel PCR, we successfully detected various S. enterica strains, whereas Escherichia coli and Citrobacter strains gave negative results. The authenticity of the PCR products was confirmed by DNA sequencing. The sensitivity of the semi-nested PCR was tested on serial dilution of bacterial cultures and extracted DNA. We found our new method more sensitive than the previous PCRs. We also screened ectoparasite samples, collected from a poultry farm in Hungary, and three out of the eight samples were positive for S. Enteritidis. This novel PCR seems suitable for the detection of S. enterica strains in poultry ectoparasites without the need of sample pre-enrichment.
Subject(s)
Poultry Diseases , Salmonella enterica , Animals , Salmonella enterica/genetics , Poultry , Chickens , Polymerase Chain Reaction/veterinary , Hungary/epidemiology , Poultry Diseases/diagnosis , Poultry Diseases/microbiologyABSTRACT
The authors aimed to investigate eight strains of Escherichia coli (E. coli) strains from Hungarian layer flocks for antimicrobial resistance genes (ARG), using metagenomic methods. The strains were isolated from cloacal swabs of healthy adult layers. This study employed shotgun sequencing-based genetic and bioinformatic analysis along with determining phenotypic minimum inhibitory concentrations. A total of 59 ARGs were identified in the eight E. coli isolates, carrying ARGs against 15 groups of antibiotics. Among these, 28 ARGs were identified as transferable. Specifically, four ARGs were plasmid-derived, 18 ARGs were phage-derived and an additional six ARGs were predicted to be mobile, contributing to their mobility and potential spread between bacteria.
Subject(s)
Escherichia coli , Genes, Bacterial , Animals , Escherichia coli/genetics , Hungary/epidemiology , Anti-Bacterial Agents/pharmacology , BacteriaABSTRACT
Acute lung injury (ALI) is characterized by lung vascular endothelial cell (EC) barrier compromise resulting in increased endothelial permeability and pulmonary edema. The infection of gram-negative bacteria that produce toxins like LPS is one of the major causes of ALI. LPS activates Toll-like receptor 4, leading to cytoskeleton reorganization, resulting in lung endothelial barrier disruption and pulmonary edema in ALI. However, the signaling pathways that lead to the cytoskeleton reorganization and lung microvascular EC barrier disruption remain largely unexplored. Here we show that LPS induces calpain activation and talin cleavage into head and rod domains and that inhibition of calpain attenuates talin cleavage, RhoA activation, and pulmonary EC barrier disruption in LPS-treated human lung microvascular ECs in vitro and lung EC barrier disruption and pulmonary edema induced by LPS in ALI in vivo. Moreover, overexpression of calpain causes talin cleavage and RhoA activation, myosin light chain (MLC) phosphorylation, and increases in actin stress fiber formation. Furthermore, knockdown of talin attenuates LPS-induced RhoA activation and MLC phosphorylation and increased stress fiber formation and mitigates LPS-induced lung microvascular endothelial barrier disruption. Additionally, overexpression of talin head and rod domains increases RhoA activation, MLC phosphorylation, and stress fiber formation and enhances lung endothelial barrier disruption. Finally, overexpression of cleavage-resistant talin mutant reduces LPS-induced increases in MLC phosphorylation in human lung microvascular ECs and attenuates LPS-induced lung microvascular endothelial barrier disruption. These results provide the first evidence that calpain mediates LPS-induced lung microvascular endothelial barrier disruption in ALI via cleavage of talin.
Subject(s)
Acute Lung Injury , Pulmonary Edema , Humans , Lipopolysaccharides/pharmacology , Calpain/metabolism , Talin/metabolism , Lung/metabolism , Acute Lung Injury/chemically induced , Acute Lung Injury/metabolism , Myosin Light Chains/metabolism , Capillary PermeabilityABSTRACT
Carotenoids contribute to a variety of physiological processes in plants, functioning also as biosynthesis precursors of ABA and strigolactones (SLs). SL biosynthesis starts with the enzymatic conversion of all-trans-ß-carotene to 9-cis-ß-carotene by the DWARF27 (D27) isomerase. In Arabidopsis, D27 has two closely related paralogs, D27-LIKE1 and D27-LIKE2, which were predicted to be ß-carotene-isomerases. In the present study, we characterised D27-LIKE1 and identified some key aspects of its physiological and enzymatic functions in Arabidopsis. d27-like1-1 mutant does not display any strigolactone-deficient traits and exhibits a substantially higher 9-cis-violaxanthin content, which is accompanied by a slightly higher ABA level. In vitro feeding assays with recombinant D27-LIKE1 revealed that the protein exhibits affinity to all ß-carotene isoforms but with an exclusive preference towards trans/cis conversions and the interconversion between 9-cis, 13-cis and 15-cis-ß-carotene forms, and accepts zeaxanthin and violaxanthin as substrates. Finally, we present evidence showing that D27-LIKE1 mRNA is phloem mobile and D27-LIKE1 is an ancient isomerase with a long evolutionary history. In summary, we demonstrate that D27-LIKE1 is a carotenoid isomerase with multi-substrate specificity and has a characteristic preference towards the catalysation of cis/cis interconversion of carotenoids. Therefore, D27-LIKE1 is a potential regulator of carotenoid cis pools and, eventually, SL and ABA biosynthesis pathways.
Subject(s)
Arabidopsis , Carotenoids , Carotenoids/metabolism , Arabidopsis/genetics , Arabidopsis/metabolism , beta Carotene/metabolism , Isomerases/chemistry , Isomerases/genetics , Isomerases/metabolismABSTRACT
BACKGROUND: Grafting is a horticultural practice used widely across woody perennial crop species to fuse together the root and shoot system of two distinct genotypes, the rootstock and the scion, combining beneficial traits from both. In grapevine, grafting is used in nearly 80% of all commercial vines to optimize fruit quality, regulate vine vigor, and enhance biotic and abiotic stress-tolerance. Rootstocks have been shown to modulate elemental composition, metabolomic profiles, and the shape of leaves in the scion, among other traits. However, it is currently unclear how rootstock genotypes influence shoot system gene expression as previous work has reported complex and often contradictory findings. RESULTS: In the present study, we examine the influence of grafting on scion gene expression in leaves and reproductive tissues of grapevines growing under field conditions for three years. We show that the influence from the rootstock genotype is highly tissue and time dependent, manifesting only in leaves, primarily during a single year of our three-year study. Further, the degree of rootstock influence on scion gene expression is driven by interactions with the local environment. CONCLUSIONS: Our results demonstrate that the role of rootstock genotype in modulating scion gene expression is not a consistent, unchanging effect, but rather an effect that varies over time in relation to local environmental conditions.
Subject(s)
Gene-Environment Interaction , Plant Roots , Plant Roots/metabolism , Plant Leaves/genetics , Genotype , Gene ExpressionABSTRACT
In cyanobacteria, phycobilisomes (PBS) serve as peripheral light-harvesting complexes of the two photosystems, extending their antenna size and the wavelength range of photons available for photosynthesis. The abundance of PBS, the number of phycobiliproteins they contain, and their light-harvesting function are dynamically adjusted in response to the physiological conditions. PBS are also thought to be involved in state transitions that maintain the excitation balance between the two photosystems. Unlike its eukaryotic counterpart, PSI is trimeric in many cyanobacterial species and the physiological significance of this is not well understood. Here, we compared the composition and light-harvesting function of PBS in cells of Synechocystis sp. PCC 6803, which has primarily trimeric PSI, and the ΔpsaL mutant, which lacks the PsaL subunit of PSI and is unable to form trimers. We also investigated a mutant additionally lacking the PsaJ and PsaF subunits of PSI. Both strains with monomeric PSI accumulated significantly more allophycocyanin per chlorophyll, indicating higher abundance of PBS. On the other hand, a higher phycocyanin:allophycocyanin ratio in the wild type suggests larger PBS or the presence of APC-less PBS (CpcL-type) that are not assembled in cells with monomeric PSI. Steady-state and time-resolved fluorescence spectroscopy at room temperature and 77 K revealed that PSII receives more energy from the PBS at the expense of PSI in cells with monomeric PSI, regardless of the presence of PsaF. Taken together, these results show that the oligomeric state of PSI impacts the excitation energy flow in Synechocystis.
Subject(s)
Phycobilisomes , Synechocystis , Energy Transfer , Photosynthesis , Photosystem I Protein Complex/metabolism , Photosystem II Protein Complex/metabolism , Phycobilisomes/metabolism , Spectrometry, Fluorescence , Synechocystis/genetics , Synechocystis/metabolismABSTRACT
BACKGROUND: Our previous retrospective study indicates that esthetic surgery in general results in a significant improvement in Quality of life (QoL). This is the first indication-specific prospective evaluation of QoL after blepharoplasty using standardized and validated questionnaires. OBJECTIVES: To report changes in QoL after blepharoplasty prospectively with a 6-month follow-up. METHODS: The same surgical team performed an esthetic blepharoplasty on 50 patients. Participants answered 1 set of questionnaires preoperatively and 6 months postoperatively. The instrument consisted of a self-developed indication-specific part specially designed for blepharoplasty and 4 validated and standardized testing instruments (FLZ, FPI-R, RSES, and PHQ-4) with norm data for German-speaking countries available. RESULTS: This study reveals a high rate of satisfaction after blepharoplasty. 96% felt better about themselves and 94% would undergo the procedure again. Statistically significant increased values were found postoperatively in the items "income" ( P =0.016), "family life" ( P =0.028), "partner relationship" ( P =0.039), "ability to relax" ( P <0.001), "energy" ( P <0.001), "hobbies" ( P <0.001), and with their outer appearance in general ( P =0.018). Blepharoplasty showed a statistically significant improvement in emotional stability ( P =0.017) and a reduction in depressive symptoms ( P <0.001). Our patients had statistically significantly higher self-esteem before ( P <0.001) and after ( P <0.001) the intervention. CONCLUSION: Our prospective study shows that blepharoplasty increases most aspects of QoL significantly, has a positive effect on emotional and physical well-being, and reduces the incidence of depressive symptoms and anxiety.
Subject(s)
Blepharoplasty , Humans , Blepharoplasty/methods , Prospective Studies , Quality of Life/psychology , Patient Satisfaction , Esthetics, Dental , Surveys and QuestionnairesABSTRACT
As the field of routine pathology transitions into the digital realm, there is a surging demand for the full automation of microscope scanners, aiming to expedite the process of digitizing tissue samples, and consequently, enhancing the efficiency of case diagnoses. The key to achieving seamless automatic imaging lies in the precise detection and segmentation of tissue sample regions on the glass slides. State-of-the-art approaches for this task lean heavily on deep learning techniques, particularly U-Net convolutional neural networks. However, since samples can be highly diverse and prepared in various ways, it is almost impossible to be fully prepared for and cover every scenario with training data. We propose a data augmentation step that allows artificially modifying the training data by extending some artifact features of the available data to the rest of the dataset. This procedure can be used to generate images that can be considered synthetic. These artifacts could include felt pen markings, speckles of dirt, residual bubbles in covering glue, or stains. The proposed approach achieved a 1-6% improvement for these samples according to the F1 Score metric.
Subject(s)
Artifacts , Image Processing, Computer-Assisted , Image Processing, Computer-Assisted/methods , Neural Networks, Computer , AutomationABSTRACT
Numerous in vitro and in vivo models of Parkinson's disease (PD) demonstrate that pituitary adenylate cyclase-activating polypeptide (PACAP) conveys its strong neuroprotective actions mainly via its specific PAC1 receptor (PAC1R) in models of PD. We recently described the decrease in PAC1R protein content in the basal ganglia of macaques in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD that was partially reversed by levodopa therapy. In this work, we tested whether these observations occur also in the rotenone model of PD in the rat. The rotarod test revealed motor skill deterioration upon rotenone administration, which was reversed by benserazide/levodopa (B/L) treatment. The sucrose preference test suggested increased depression level while the open field test showed increased anxiety in rats rendered parkinsonian, regardless of the received B/L therapy. Reduced dopaminergic cell count in the substantia nigra pars compacta (SNpc) diminished the dopaminergic fiber density in the caudate-putamen (CPu) and decreased the peptidergic cell count in the centrally projecting Edinger-Westphal nucleus (EWcp), supporting the efficacy of rotenone treatment. RNAscope in situ hybridization revealed decreased PACAP mRNA (Adcyap1) and PAC1R mRNA (Adcyap1r1) expression in the CPu, globus pallidus, dopaminergic SNpc and peptidergic EWcp of rotenone-treated rats, but no remarkable downregulation occurred in the insular cortex. In the entopeduncular nucleus, only the Adcyap1r1 mRNA was downregulated in parkinsonian animals. B/L therapy attenuated the downregulation of Adcyap1 in the CPu only. Our current results further support the evolutionarily conserved role of the PACAP/PAC1R system in neuroprotection and its recruitment in the development/progression of neurodegenerative states such as PD.
Subject(s)
Edinger-Westphal Nucleus , Parkinson Disease , Animals , Rats , Basal Ganglia/metabolism , Dopamine/metabolism , Down-Regulation , Edinger-Westphal Nucleus/metabolism , Levodopa/metabolism , Parkinson Disease/drug therapy , Parkinson Disease/genetics , Parkinson Disease/metabolism , Pituitary Adenylate Cyclase-Activating Polypeptide/genetics , Pituitary Adenylate Cyclase-Activating Polypeptide/metabolism , Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide/genetics , Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide/metabolism , Rotenone/metabolism , Substantia Nigra/metabolismABSTRACT
IgG4-related (IgG4-RD) disease is a relatively newly identified, chronic autoimmune disorder that can affect any organ system. The disease is relatively rare. It has mostly systemic presentation, however it can also appear in isolated form in one single organ. In our report, we demonstrate an elderly male patient's case with IgG4-RD presented in the form of diffuse meningeal inflammation and hypertrophic pachymeningitis with one-sided cranial nerve and intraventricular involvement.
Subject(s)
Immunoglobulin G4-Related Disease , Meningitis , Humans , Male , Aged , Immunoglobulin G4-Related Disease/complications , Immunoglobulin G4-Related Disease/diagnosis , Immunoglobulin G , Hypertrophy , Inflammation , Cranial Nerves , Magnetic Resonance ImagingABSTRACT
BACKGROUND: The neuropathological background of major depression and anxiety as non-motor symptoms of Parkinson's disease is much less understood than classical motor symptoms. Although, neurodegeneration of the Edinger-Westphal nucleus in human Parkinson's disease is a known phenomenon, its possible significance in mood status has never been elucidated. In this work we aimed at investigating whether neuron loss and alpha-synuclein accumulation in the urocortin 1 containing (UCN1) cells of the centrally-projecting Edinger-Westphal (EWcp) nucleus is associated with anxiety and depression-like state in the rat. METHODS: Systemic chronic rotenone administration as well as targeted leptin-saporin-induced lesions of EWcp/UCN1 neurons were conducted. Rotarod, open field and sucrose preference tests were performed to assess motor performance and mood status. Multiple immunofluorescence combined with RNAscope were used to reveal the functional-morphological changes. Two-sample Student's t test, Spearman's rank correlation analysis and Mann-Whitney U tests were used for statistics. RESULTS: In the rotenone model, besides motor deficit, an anxious and depression-like phenotype was detected. Well-comparable neuron loss, cytoplasmic alpha-synuclein accumulation as well as astro- and microglial activation were observed both in the substantia nigra pars compacta and EWcp. Occasionally, UCN1-immunoreactive neuronal debris was observed in phagocytotic microglia. UCN1 peptide content of viable EWcp cells correlated with dopaminergic substantia nigra cell count. Importantly, other mood status-related dopaminergic (ventral tegmental area), serotonergic (dorsal and median raphe) and noradrenergic (locus ceruleus and A5 area) brainstem centers did not show remarkable morphological changes. Targeted partial selective EWcp/UCN1 neuron ablation induced similar mood status without motor symptoms. CONCLUSIONS: Our findings collectively suggest that neurodegeneration of urocortinergic EWcp contributes to the mood-related non-motor symptoms in toxic models of Parkinson's disease in the rat.
Subject(s)
Edinger-Westphal Nucleus , Parkinson Disease , Animals , Anxiety , Humans , Neurons/physiology , Rats , Urocortins/geneticsABSTRACT
Coronavirus disease 2019 (COVID-19) is associated with autoimmunity and systemic inflammation. Patients with autoimmune rheumatic and musculoskeletal disease (RMD) may be at high risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In this review, based on evidence from the literature, as well as international scientific recommendations, we review the relationships between COVID-19, autoimmunity and patients with autoimmune RMDs, as well as the basics of a multisystemic inflammatory syndrome associated with COVID-19. We discuss the repurposing of pharmaceutics used to treat RMDs, the principles for the treatment of patients with autoimmune RMDs during the pandemic and the main aspects of vaccination against SARS-CoV-2 in autoimmune RMD patients.
Subject(s)
COVID-19 Drug Treatment , COVID-19 , Musculoskeletal Diseases , Autoimmunity , COVID-19/complications , Humans , Inflammation , Musculoskeletal Diseases/therapy , SARS-CoV-2ABSTRACT
OBJECTIVE: The pathogenesis of calcinosis cutis, a disabling complication of SSc, is poorly understood and effective treatments are lacking. Inorganic pyrophosphate (PPi) is a key regulator of ectopic mineralization, and its deficiency has been implicated in ectopic mineralization disorders. We therefore sought to test the hypothesis that SSc may be associated with reduced circulating PPi, which might play a pathogenic role in calcinosis cutis. METHODS: Subjects with SSc and age-matched controls without SSc were recruited from the outpatient rheumatology clinics at Rutgers and Northwestern Universities (US cohort), and from the Universities of Szeged and Debrecen (Hungarian cohort). Calcinosis cutis was confirmed by direct palpation, by imaging or both. Plasma PPi levels were determined in platelet-free plasma using ATP sulfurylase to convert PPi into ATP in the presence of excess adenosine 5' phosphosulfate. RESULTS: Eighty-one patients with SSc (40 diffuse cutaneous, and 41 limited cutaneous SSc) in the US cohort and 45 patients with SSc (19 diffuse cutaneous and 26 limited cutaneous SSc) in the Hungarian cohort were enrolled. Calcinosis was frequently detected (40% of US and 46% of the Hungarian cohort). Plasma PPi levels were significantly reduced in both SSc cohorts with and without calcinosis (US: P = 0.003; Hungarian: P < 0.001). CONCLUSIONS: Circulating PPi are significantly reduced in SSc patients with or without calcinosis. Reduced PPi may be important in the pathophysiology of calcinosis and contribute to tissue damage with chronic SSc. Administering PPi may be a therapeutic strategy and larger clinical studies are planned to confirm our findings.
Subject(s)
Calcinosis/blood , Calcinosis/etiology , Diphosphates/blood , Scleroderma, Systemic/blood , Scleroderma, Systemic/complications , Adult , Aged , Female , Humans , Male , Middle AgedABSTRACT
ABSTRACTMycoplasma iowae, a potential re-emerging avian pathogen mainly affecting turkeys, has been reported from many parts of the world. Poor hatchability, embryonic death, joint and skeletal abnormalities, poor ossification, runting-stunting, poor feathering and airsacculitis may be observed in infected flocks. The reduction of the severity of clinical signs and short-term control of M. iowae are performed by antibiotic treatment. However, M. iowae develops resistance more rapidly and is considered to be more resistant to antimicrobials than other avian pathogenic mycoplasmas. The aim of the present study was to determine the in vitro susceptibility of 101 M. iowae isolates and strains to ten clinically important antimicrobial agents, and to analyse and compare the susceptibility patterns of isolates of various origins and from a wide time-period. The examined reference strains showed high susceptibility to all antimicrobials except for spectinomycin. Low concentrations of tiamulin, florfenicol and oxytetracycline inhibited the growth of the clinical isolates. Nevertheless, slow tendency of increasing minimum inhibitory concentration (MIC) values was observed over time in the case of the above mentioned agents, while MIC values of enrofloxacin showed relatively rapid changes. Spiramycin, erythromycin, tilmicosin, tylosin, lincomycin and spectinomycin did not inhibit the bacterial growth in most of the cases. Isolates originating from captive game birds showed similar susceptibility profiles to isolates from industrial turkey hosts. The widely detected low susceptibility of M. iowae isolates to macrolides, lincomycin and spectinomycin, and the increase of MIC values of frequently used antimicrobials against this pathogen, emphasize the importance of targeted antibiotic therapy.RESEARCH HIGHLIGHTSAntimicrobial susceptibilities of 101 Mycoplasma iowae isolates were determined.Minimum inhibitory concentrations were determined by broth micro-dilution method.Tiamulin, oxytetracycline and florfenicol showed low MIC values.Isolates rapidly adapted to antimicrobial pressure.