Incidence of human brucellosis in a rural area in Western Greece after the implementation of a vaccination programme against animal brucellosis

<p>Abstract</p> <p>Background</p> <p>Brucellosis continues to be an important source of morbidity in several countries, particularly among agricultural and pastoral populations. The purpose of this study was to examine if there is an effect on the incidence of human brucellosis after the implementation of an animal brucellosis control programme.</p> <p>Methods</p> <p>The study was conducted in the Municipality of Tritaia in the Prefecture of Achaia in Western Greece during the periods 1997–1998 and 2000–2002. Health education efforts were made during 1997–1998 to make the public take preventive measures. In the time period from January 1999 to August 2002 a vaccination programme against animal brucellosis was realised in the specific region. The vaccine used was the <it>B. melitensis </it>Rev-1 administered by the conjuctival route. Comparisons were performed between the incidence rates of the two studied periods.</p> <p>Results</p> <p>There was a great fall in the incidence rate between 1997–1998 (10.3 per 1,000 population) and the period 2000–2002 after the vaccination (0.3 per 1,000 population). The considerable decrease of the human incidence rate is also observed in the period 2000–2002 among persons whose herds were not as yet vaccinated (1.4 vs. 10.3 per 1,000 population), indicating a possible role of health education in the decline of human brucellosis.</p> <p>Conclusion</p> <p>The study reveals a statistically significant decline in the incidence of human brucellosis after the vaccination programme and underlines the importance of an ongoing control of animal brucellosis in the prevention of human brucellosis. The reduction of human brucellosis can be best achieved by a combination of health education and mass animal vaccination.</p

CEP receptor signalling controls root system architecture in Arabidopsis and Medicago

© 2020 The Authors. New Phytologist © 2020 New Phytologist Trust Root system architecture (RSA) influences the effectiveness of resources acquisition from soils but the genetic networks that control RSA remain largely unclear. We used rhizoboxes, X-ray computed tomography, grafting, auxin transport measurements and hormone quantification to demonstrate that Arabidopsis and Medicago CEP (C-TERMINALLY ENCODED PEPTIDE)-CEP RECEPTOR signalling controls RSA, the gravitropic set-point angle (GSA) of lateral roots (LRs), auxin levels and auxin transport. We showed that soil-grown Arabidopsis and Medicago CEP receptor mutants have a narrower RSA, which results from a steeper LR GSA. Grafting showed that CEPR1 in the shoot controls GSA. CEP receptor mutants exhibited an increase in rootward auxin transport and elevated shoot auxin levels. Consistently, the application of auxin to wild-type shoots induced a steeper GSA and auxin transport inhibitors counteracted the CEP receptor mutant’s steep GSA phenotype. Concordantly, CEP peptides increased GSA and inhibited rootward auxin transport in wild-type but not in CEP receptor mutants. The results indicated that CEP–CEP receptor-dependent signalling outputs in Arabidopsis and Medicago control overall RSA, LR GSA, shoot auxin levels and rootward auxin transport. We propose that manipulating CEP signalling strength or CEP receptor downstream targets may provide means to alter RSA

Impact of clinical phenotypes on management and outcomes in European atrial fibrillation patients: a report from the ESC-EHRA EURObservational Research Programme in AF (EORP-AF) General Long-Term Registry

Background: Epidemiological studies in atrial fibrillation (AF) illustrate that clinical complexity increase the risk of major adverse outcomes. We aimed to describe European AF patients\u2019 clinical phenotypes and analyse the differential clinical course. Methods: We performed a hierarchical cluster analysis based on Ward\u2019s Method and Squared Euclidean Distance using 22 clinical binary variables, identifying the optimal number of clusters. We investigated differences in clinical management, use of healthcare resources and outcomes in a cohort of European AF patients from a Europe-wide observational registry. Results: A total of 9363 were available for this analysis. We identified three clusters: Cluster 1 (n = 3634; 38.8%) characterized by older patients and prevalent non-cardiac comorbidities; Cluster 2 (n = 2774; 29.6%) characterized by younger patients with low prevalence of comorbidities; Cluster 3 (n = 2955;31.6%) characterized by patients\u2019 prevalent cardiovascular risk factors/comorbidities. Over a mean follow-up of 22.5 months, Cluster 3 had the highest rate of cardiovascular events, all-cause death, and the composite outcome (combining the previous two) compared to Cluster 1 and Cluster 2 (all P &lt;.001). An adjusted Cox regression showed that compared to Cluster 2, Cluster 3 (hazard ratio (HR) 2.87, 95% confidence interval (CI) 2.27\u20133.62; HR 3.42, 95%CI 2.72\u20134.31; HR 2.79, 95%CI 2.32\u20133.35), and Cluster 1 (HR 1.88, 95%CI 1.48\u20132.38; HR 2.50, 95%CI 1.98\u20133.15; HR 2.09, 95%CI 1.74\u20132.51) reported a higher risk for the three outcomes respectively. Conclusions: In European AF patients, three main clusters were identified, differentiated by differential presence of comorbidities. Both non-cardiac and cardiac comorbidities clusters were found to be associated with an increased risk of major adverse outcomes

Identification of a Catalytic Exosite for Complement Component C4 on the Serine Protease Domain of C1s

The classical pathway of complement is crucial to the immune system, but it also contributes to inflammatory diseases when dys-regulated. Binding of the C1 complex to ligands activates the pathway by inducing autoactivation of associated C1r, after which C1r activates C1s. C1s cleaves complement component C4 and then C2 to cause full activation of the system. The interaction between C1s and C4 involves active site and exosite-mediated events, but the molecular details are unknown. In this study, we identified four positively charged amino acids on the serine protease domain that appear to form a catalytic exosite that is required for efficient cleavage of C4. These residues are coincidentally involved in coordinating a sulfate ion in the crystal structure of the protease. Together with other evidence, this pointed to the involvement of sulfate ions in the interaction with the C4 substrate, and we showed that the protease interacts with a peptide from C4 containing three sulfotyrosine residues. We present a molecular model for the interaction between C1s and C4 that provides support for the above data and poses questions for future research into this aspect of complement activation. The Journal of Immunology, 2012, 189: 2365-2373

CCR7 Sulfotyrosine Enhances CCL21 Binding

Chemokines are secreted proteins that direct the migration of immune cells and are involved in numerous disease states. For example, CCL21 (CC chemokine ligand 21) and CCL19 (CC chemokine ligand 19) recruit antigen-presenting dendritic cells and naïve T-cells to the lymph nodes and are thought to play a role in lymph node metastasis of CCR7 (CC chemokine receptor 7)-expressing cancer cells. For many chemokine receptors, N-terminal posttranslational modifications, particularly the sulfation of tyrosine residues, increases the affinity for chemokine ligands and may contribute to receptor ligand bias. Chemokine sulfotyrosine (sY) binding sites are also potential targets for drug development. In light of the structural similarity between sulfotyrosine and phosphotyrosine (pY), the interactions of CCL21 with peptide fragments of CCR7 containing tyrosine, pY, or sY were compared using protein NMR (nuclear magnetic resonance) spectroscopy in this study. Various N-terminal CCR7 peptides maintain binding site specificity with Y8-, pY8-, or sY8-containing peptides binding near the α-helix, while Y17-, pY17-, and sY17-containing peptides bind near the N-loop and β3-stand of CCL21. All modified CCR7 peptides showed enhanced binding affinity to CCL21, with sY having the largest effect

Sulfopeptide probes of the CXCR4/CXCL12 interface reveal oligomer-specific contacts and chemokine allostery

Tyrosine sulfation is a post-translational modification that enhances protein–protein interactions and may identify druggable sites in the extracellular space. The G protein-coupled receptor CXCR4 is a prototypical example with three potential sulfation sites at positions 7, 12, and 21. Each receptor sulfotyrosine participates in specific contacts with its chemokine ligand in the structure of a soluble, dimeric CXCL12:CXCR4(1–38) complex, but their relative importance for CXCR4 binding and activation by the monomeric chemokine remains undefined. NMR titrations with short sulfopeptides showed that the tyrosine motifs of CXCR4 varied widely in their contributions to CXCL12 binding affinity and site specificity. Whereas the Tyr21 sulfopeptide bound the same site as in previously solved structures, the Tyr7 and Tyr12 sulfopeptides interacted nonspecifically. Surprisingly, the unsulfated Tyr7 peptide occupied a hydrophobic site on the CXCL12 monomer that is inaccessible in the CXCL12 dimer. Functional analysis of CXCR4 mutants validated the relative importance of individual CXCR4 sulfotyrosine modifications (Tyr21 > Tyr12 > Tyr7) for CXCL12 binding and receptor activation. Biophysical measurements also revealed a cooperative relationship between sulfopeptide binding at the Tyr21 site and CXCL12 dimerization, the first example of allosteric behavior in a chemokine. Future ligands that occupy the sTyr21 recognition site may act as both competitive inhibitors of receptor binding and allosteric modulators of chemokine function. Together, our data suggests that sulfation does not ubiquitously enhance complex affinity and that distinct patterns of tyrosine sulfation could encode oligomer selectivity, implying another layer of regulation for chemokine signaling