Rural Malta : first results of the joint Belgo-Maltese survey project

The paper presents the first interdisciplinary results of a joint survey project in the north-west of Malta, with finds ranging from the Prehistoric till the Early Modern period. Three permanently inhabited sites were encountered dating to at least the late 6th or early 5th century BCE, with a clearer attestation in the Hellenistic/Roman and Late Antique periods. The resulting reconstructed settlement pattern of the Phoenician/Punic period suggests a managed landscape that seems to be a good reflexion of what is happening in North Africa and elsewhere in the central and western Mediterranean. At least from the Roman period on, these sites seem to have specialised on the production of olive oil.peer-reviewe

The VMC ESO Public Survey

The VISTA near-infrared YJKs survey of the Magellanic Clouds system (VMC) has entered its core phase: about 50% of the observations across the Large and Small Magellanic Clouds (LMC, SMC), the Magellanic Bridge and Stream have already been secured and the data are processed and analysed regularly. The initial analyses, concentrated on the first two completed tiles in the LMC (including 30 Doradus and the South Ecliptic Pole), show the superior quality of the data. The photometric depth of the VMC survey allows the derivation of the star formation history (SFH) with unprecedented quality compared to previous wide-area surveys, while reddening maps of high angular resolution are constructed using red clump stars. The multi-epoch Ks-band data reveal tight period-luminosity relations for variable stars and permit the measurement of accurate proper motions of the stellar populations. The VMC survey continues to acquire data that will address many issues in the field of star and galaxy evolution

Active-site structure, binding and redox activity of the heme–thiolate enzyme CYP2D6 immobilized on coated Ag electrodes: a surface-enhanced resonance Raman scattering study

Surface-enhance resonance Raman scattering spectra of the heme–thiolate enzyme cytochrome P450 2D6 (CYP2D6) adsorbed on Ag electrodes coated with 11-mercaptoundecanoic acid (MUA) were obtained in various experimental conditions. An analysis of these spectra, and a comparison between them and the RR spectra of CYP2D6 in solution, indicated that the enzyme’s active site retained its nature of six-coordinated low-spin heme upon immobilization. Moreover, the spectral changes detected in the presence of dextromethorphan (a CYP2D6 substrate) and imidazole (an exogenous heme axial ligand) indicated that the immobilized enzyme also preserved its ability to reversibly bind a substrate and form a heme–imidazole complex. The reversibility of these processes could be easily verified by flowing alternately solutions of the various compounds and the buffer through a home-built spectroelectrochemical flow cell which contained a sample of immobilized protein, without the need to disassemble the cell between consecutive spectral data acquisitions. Despite immobilized CYP2D6 being effectively reduced by a sodium dithionite solution, electrochemical reduction via the Ag electrode was not able to completely reduce the enzyme, and led to its extensive inactivation. This behavior indicated that although the enzyme’s ability to exchange electrons is not altered by immobilization per se, MUA-coated electrodes are not suited to perform direct electrochemistry of CYP2D6

Lack of Chemokine Signaling through CXCR5 Causes Increased Mortality, Ventricular Dilatation and Deranged Matrix during Cardiac Pressure Overload

RATIONALE: Inflammatory mechanisms have been suggested to play a role in the development of heart failure (HF), but a role for chemokines is largely unknown. Based on their role in inflammation and matrix remodeling in other tissues, we hypothesized that CXCL13 and CXCR5 could be involved in cardiac remodeling during HF. OBJECTIVE: We sought to analyze the role of the chemokine CXCL13 and its receptor CXCR5 in cardiac pathophysiology leading to HF. METHODS AND RESULTS: Mice harboring a systemic knockout of the CXCR5 (CXCR5(-/-)) displayed increased mortality during a follow-up of 80 days after aortic banding (AB). Following three weeks of AB, CXCR5(-/-) developed significant left ventricular (LV) dilatation compared to wild type (WT) mice. Microarray analysis revealed altered expression of several small leucine-rich proteoglycans (SLRPs) that bind to collagen and modulate fibril assembly. Protein levels of fibromodulin, decorin and lumican (all SLRPs) were significantly reduced in AB CXCR5(-/-) compared to AB WT mice. Electron microscopy revealed loosely packed extracellular matrix with individual collagen fibers and small networks of proteoglycans in AB CXCR5(-/-) mice. Addition of CXCL13 to cultured cardiac fibroblasts enhanced the expression of SLRPs. In patients with HF, we observed increased myocardial levels of CXCR5 and SLRPs, which was reversed following LV assist device treatment. CONCLUSIONS: Lack of CXCR5 leads to LV dilatation and increased mortality during pressure overload, possibly via lack of an increase in SLRPs. This study demonstrates a critical role of the chemokine CXCL13 and CXCR5 in survival and maintaining of cardiac structure upon pressure overload, by regulating proteoglycans essential for correct collagen assembly

Symptom-based stratification of patients with primary Sjögren's syndrome: multi-dimensional characterisation of international observational cohorts and reanalyses of randomised clinical trials

Background Heterogeneity is a major obstacle to developing effective treatments for patients with primary Sjögren's syndrome. We aimed to develop a robust method for stratification, exploiting heterogeneity in patient-reported symptoms, and to relate these differences to pathobiology and therapeutic response. Methods We did hierarchical cluster analysis using five common symptoms associated with primary Sjögren's syndrome (pain, fatigue, dryness, anxiety, and depression), followed by multinomial logistic regression to identify subgroups in the UK Primary Sjögren's Syndrome Registry (UKPSSR). We assessed clinical and biological differences between these subgroups, including transcriptional differences in peripheral blood. Patients from two independent validation cohorts in Norway and France were used to confirm patient stratification. Data from two phase 3 clinical trials were similarly stratified to assess the differences between subgroups in treatment response to hydroxychloroquine and rituximab. Findings In the UKPSSR cohort (n=608), we identified four subgroups: Low symptom burden (LSB), high symptom burden (HSB), dryness dominant with fatigue (DDF), and pain dominant with fatigue (PDF). Significant differences in peripheral blood lymphocyte counts, anti-SSA and anti-SSB antibody positivity, as well as serum IgG, κ-free light chain, β2-microglobulin, and CXCL13 concentrations were observed between these subgroups, along with differentially expressed transcriptomic modules in peripheral blood. Similar findings were observed in the independent validation cohorts (n=396). Reanalysis of trial data stratifying patients into these subgroups suggested a treatment effect with hydroxychloroquine in the HSB subgroup and with rituximab in the DDF subgroup compared with placebo. Interpretation Stratification on the basis of patient-reported symptoms of patients with primary Sjögren's syndrome revealed distinct pathobiological endotypes with distinct responses to immunomodulatory treatments. Our data have important implications for clinical management, trial design, and therapeutic development. Similar stratification approaches might be useful for patients with other chronic immune-mediated diseases. Funding UK Medical Research Council, British Sjogren's Syndrome Association, French Ministry of Health, Arthritis Research UK, Foundation for Research in Rheumatology

Multimode Representation of the Magnetic Field for the Analysis of the Nonlinear Behavior of Solar Activity as a Driver of Space Weather

ISSP UL as the Center of Excellence is supported through the Framework Program for European universities Union Horizon 2020, H2020-WIDESPREAD-01-2016-2017-TeamingPhase2 under Grant Agreement No. 739508, CAMART2 project; Internal Foundation of University of Maryland.Estimating and predicting space weather is important to the space industry and space missions. The driver of space weather, especially near the Earth, is solar activity, the study of which is an important task. In particular, there is a direction of problems based on models of solar magnetic field generation that require research. In our work, we build a nonlinear dynamic system of equations that describes the behavior of the solar magnetic field harmonics based on the alpha-omega dynamo model. We found that, at the beginning of the magnetic field generation process, when the dynamo number significantly exceeds the threshold, the most rapidly growing waves are in the lead. Then, over time, these waves stop growing quite quickly. In this case, the initially slowly increasing harmonics of the magnetic field become the leaders, which then make the main contribution to the process of magnetic field generation. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.ISSP UL as the Center of Excellence is supported through the Framework Program for European universities Union Horizon 2020, H2020-WIDESPREAD-01-2016-2017-TeamingPhase2 under Grant Agreement No. 739508, CAMART2 project; Internal Foundation of University of Maryland