Joint Observation of the Galactic Center with MAGIC and CTA-LST-1

MAGIC is a system of two Imaging Atmospheric Cherenkov Telescopes (IACTs), designed to detect very-high-energy gamma rays, and is operating in stereoscopic mode since 2009 at the Observatorio del Roque de Los Muchachos in La Palma, Spain. In 2018, the prototype IACT of the Large-Sized Telescope (LST-1) for the Cherenkov Telescope Array, a next-generation ground-based gamma-ray observatory, was inaugurated at the same site, at a distance of approximately 100 meters from the MAGIC telescopes. Using joint observations between MAGIC and LST-1, we developed a dedicated analysis pipeline and established the threefold telescope system via software, achieving the highest sensitivity in the northern hemisphere. Based on this enhanced performance, MAGIC and LST-1 have been jointly and regularly observing the Galactic Center, a region of paramount importance and complexity for IACTs. In particular, the gamma-ray emission from the dynamical center of the Milky Way is under debate. Although previous measurements suggested that a supermassive black hole Sagittarius A* plays a primary role, its radiation mechanism remains unclear, mainly due to limited angular resolution and sensitivity. The enhanced sensitivity in our novel approach is thus expected to provide new insights into the question. We here present the current status of the data analysis for the Galactic Center joint MAGIC and LST-1 observations

Factor XIIIA in myocardial infarction: a dual role as specific prognostic biomarker and proposed reparative molecule in left ventricular remodeling

Nowadays, left ventricular remodelling (LVR) after acute myocardial infarction (MI) represents a remarkable clinical event, despite the increasing effectiveness of pharmacological and reperfusion therapies. LVR is the main determinant of survival after MI as it predisposes to the development of arrhythmias and heart failure associated with increased mortality and hospitalization. After MI, a first crucial step in the reparative process implies the formation of a 3D fibrin meshwork providing a provisional scaffold for neo-vessel formation, cell recruiting/spreading, and at physically limit lesion expansion. In this field, the transglutaminase FXIII, play a critical role in generating a stable haemostatic plug, in wound healing and in angiogenesis. Recently we have demonstrated that during the first days of MI (D0-D5) FXIII-A is characterized by an acute and transient fall in levels. Moreover, we found that patients undergoing excessive FXIII-consuming at the time of MI were more prone to die or to develop HF ascribing to FXIII a possible role as novel independent prognostic biomarker. In this study we focus on the LVR and the relation with FXIII-A levels in the early days after MI and also we take into account seven single nucleotide polymorphism (SNP) related to FXIII and Fibrinogen genes involved in MI onset. We monitored FXIII-A subunit level in 147 acute MI patients during the first day (D0), and the fourth and fifth (D4/D5) day after the MI event. By observing the entire cohort of patients analyzed during the three-month follow-up, LVR and subsequent development of the major adverse clinical event (MACE) during the extended follow-up of one year, we confirm different dynamics among subgroups and the mentioned trend of consumption. Within the subgroup of the LVR, the average levels in D0 were significantly lower in the remodeled subgroup (LVR+; FXIII-A 91.96%±24.37) than in the non-remodeled subgroup (LVR–; FXIII-A 96.19%±26.51). In the MACE subgroup, the differences between those who reached at least one endpoints after one year (MACE+) and those who did not (MACE–), it’s evident on both days considered. In D0, the MACE– subgroup showed an average of FXIII-A of 98.33%±29.58 while in MACE+ it reached 86.3%±24.12. However, we get the most interesting results, in D4/D5 where those in the MACE– subgroup reached an average of FXIII-A of 89.47%±28.76 and those in the MACE+ subgroup reached 76,93%±24.29. This value is similar to the cut-off value (<73.5 %) found in our previous work, below this cut-off patients were more prone to die or to develop heart failure. As far as the genetic analysis is concerned, we found a relation regarding the Val34Leu in a recessive model identifying a higher frequency of the Leu34-homozygotes in the LVR+ subgroup. By re-analyzing the cohort dividing men and women into further subgroups, significance emerged also in a dominant model only for the His95Arg SNP within the men subgroup identifying a higher frequency of the His95-homozygotes in the LVR- subgroup. We did not achieve appreciable significance for the other five selected SNPs. Overall, the results related to post-infarction FXIII-A levels are in line with previous works that ascribed to FXIII-A a role in tissue healing and in myocardial tissue regeneration after an acute infarct event. In fact, the monitoring of FXIII-A is confirmed as prognostic circulating biomarker for the development of MACE events after MI also including LVR. However, the completion of this study, by including the analysis of the remaining already enrolled patients not yet characterized for remodeling, could clarify some aspects. We are therefore of the idea that FXIII-A molecule might help and support endogenous physiological processes allowing the self-healing of a injured tissue during the very early phases of damage and that the complete understanding of the role of this multitasking factor could be also useful for potential therapeutic approachesOggigiorno, il rimodellamento ventricolare sinistro (LVR) a seguito d’infarto acuto del miocardico (MI) costituisce il principale determinante della sopravvivenza a lungo termine predisponendo allo sviluppo di aritmie e scompenso cardiaco. A seguito d’infarto, diversi processi flogistici e riparativi sono innescati. Un primo passo cruciale è la formazione di un’impalcatura transitoria di fibrina che assiste processi come la neoangiogenesi e il reclutamento/diffusione di cellule deputate alla riparazione. La transglutaminasi FXIII, introducendo legami crociati sulla fibrina polimerizzata, ha un comprovato ruolo nell’assistenza di tali processi riparativi. In una recente pubblicazione, abbiamo dimostrato che durante i primi giorni successivi all’infarto del miocardio, i livelli di FXIII-A subiscono una riduzione acuta e transitoria. Inoltre, i pazienti che presentavano un eccessivo consumo di FXIII al momento dell’infarto mostravano una maggiore probabilità di morte o di sviluppare uno scompenso cardiaco a un anno dall’evento, attribuendo al FXIII un ruolo come nuovo biomarcatore prognostico indipendente. Questi risultati ci hanno spinto a meglio caratterizzare questa poliedrica molecola nel contesto del “LVR”. In questo studio abbiamo focalizzato la nostra attenzione sull’esistenza di una relazione tra “LVR” e i livelli di FXIII-A nei primi giorni dopo l'infarto acuto e abbiamo preso in considerazione sette polimorfismi a singolo nucleotide concernenti i geni del FXIII e del Fibrinogeno coinvolti nell'insorgenza dell’infarto e nei relativi processi riparativi. Abbiamo monitorato il livello della subunità FXIII-A in 147 pazienti con “MI” acuto (STEMI) durante il primo giorno, quello dell’insorgenza, e in quarta e quinta giornata dopo l’evento “MI”. L’intera coorte di pazienti è stata monitorata per un anno dal “MI”. La popolazione analizzata è stata divisa in due sottogruppi, quello definito “LVR” relativo allo sviluppo di rimodellamento ventricolare a tre mesi dall’evento infatuante, e il sottogruppo dei “MACE” relativo allo sviluppo entro un anno dall’evento infatuante di uno dei principali eventi clinici avversi relativi all’infarto del miocardio (reinfarto, morte e scompenso cardiaco). Dallo studio sono emerse diverse dinamiche di consumo tra i sottogruppi. All'interno del sottogruppo “LVR”, i livelli medi di FXIII-A in prima giornata erano significativamente inferiori nel sottogruppo di chi aveva sviluppato rimodellamento ventricolare (91,96%) rispetto al sottogruppo che non lo aveva sviluppato (96, 19%). Nel sottogruppo “MACE”, le differenze tra i pazienti che hanno raggiunto almeno un endpoint dopo un anno (MACE +) e coloro che non l'hanno raggiunto (MACE-), sono evidenti in entrambi i giorni considerati. In D0, il sottogruppo MACE- presenta una media di FXIII-A del 98,33%mentre nel sottogruppo MACE + una media di 86,3%. Ancor più marcata, è la differenza tra le medie raggiunte nei sottogruppi in quarta/quinta giornata dove i pazienti nel sottogruppo MACE- hanno raggiunto una media di FXIII-A di 89,47%, e, quelli nel sottogruppo MACE + hanno raggiunto il 76,93%. Per quanto riguarda l'analisi genetica, abbiamo individuato una relazione riguardante il polimorfismo Val34Leu in un modello recessivo che identifica una frequenza più alta degli omozigoti Leu34 nel sottogruppo LVR +. Rianalizzando la coorte dividendo uomini e donne in ulteriori sottogruppi, una differenza significativa è emersa applicando un modello dominante nel polimorfismo His95Arg del FXIII. Nel sottogruppo degli uomini, l’omoziogote His95 è maggiormente rappresentato nei LVR- rispetto ai LVR+. Non apprezzabile la significatività per gli altri cinque SNP. I risultati raggiunti sono in linea con le nostre precedenti conclusioni. Infatti, il monitoraggio di FXIII-A è confermato come biomarcatore prognostico per lo sviluppo di MACE dopo infarto del miocardico compreso il “LVR”

Sudden sensorineural hearing loss and polymorphisms in iron homeostasis genes.

Deafness is one of the most widespread, costly and poorly understood disabilities in the world. Hearing impairment is a condition that involves medical, psychological and social aspects. According to the World Health Organization (WHO) about 250 million people have disabling hearing loss and two-thirds of them live in the developing world. Millions of people progressively lose their most important means of communication and became socially isolated, especially in the later years of their life. This handbook provides recent research on several different hearing disorders

Inherited genetic predispositions in F13A1 and F13B genes predict abdominal adhesion formation: identification of gender prognostic indicators

Abdominal adhesions (AA) account for the most common complication of peritoneal surgery with bowel obstruction being the severest problem in the absence of effective predicting biomarkers. Anti-AA-barriers or adhesiolysis did not completely prevent bowel obstruction, although there is evidence they might reduce related complications requiring reoperation. In addition, gender-related predispositions have not been adequately investigated. We explored the role of coagulation Factor XIII (F13A1 and F13B subunit-genes) in patients following laparotomy, mostly median/lower median incision line. Globally, 426 patients (54%,♀), were PCR-SNP-genotyped for FXIIIA V34L (rs5985), FXIIIA P564L (rs5982), FXIIIA Y204F (rs3024477) and FXIIIB H95R (rs6003). Patients' clinical phenotypes were: Group-A (n = 212), those who developed AA, and 55.2% of them developed bowel obstruction (subgroup-A1), the remaining were subgroup-A2; Group B (n = 214) were those who did not develop AA (subgroup-B1; 53.3%) or symptoms/complications (subgroup-B2). Among different laparotomy, colon surgery associated with AA at a major extent (OR = 5.1; 3.24-7.8; P < 0.0001) with different gender scores (♀OR = 5.33; 2.32-12.23; P < 0.0001 and ♂OR = 3.44; 1.58-7.49; P < 0.0001). Among SNPs, P564L (OR = 4.42; 1.45-13.4; P = 0.008) and Y204F (OR = 7.78; 1.62-37.3; P = 0.01) significantly predicted bowel obstruction and survival-analyses yielded interesting gender distinctions (♀HR = 5.28; 2.36-11.8; P = 0.00005; ♂HR = 2.22; 1.31-3.85; P = 0.0034). Active compounds preventing AA belong to the anticoagulant/fibrinolysis areas, suggesting them candidate investigation targets. We identified novel prognostic markers to predict AA/bowel obstruction giving insights to design novel therapeutic and gender prevention programs

Sudden Sensorineural Hearing Loss and Polymorphisms in Iron Homeostasis Genes: New Insights from a Case-Control Study

Background. Even if various pathophysiological events have been proposed as explanations, the putative cause of sudden hearing loss remains unclear. Objectives. To investigate and to reveal associations (if any) between the main iron-related gene variants and idiopathic sudden sensorineural hearing loss. Study Design. Case-control study. Materials and Methods. A total of 200 sudden sensorineural hearing loss patients (median age 63.65 years; range 10-92) were compared with 400 healthy control subjects. The following genetic variants were investigated: the polymorphism c.-8CG in the promoter of the ferroportin gene (FPN1; SLC40A1), the two isoforms C1 and C2 (p.P570S) of the transferrin protein (TF), the amino acidic substitutions p.H63D and p.C282Y in the hereditary hemochromatosis protein (HFE), and the polymorphism c.-582AG in the promoter of the HEPC gene, which encodes the protein hepcidin (HAMP). Results. The homozygous genotype c.-8GG of the SLC40A1 gene revealed an OR for ISSNHL risk of 4.27 (CI 95%, 2.65-6.89; P = 0.001), being overrepresented among cases. Conclusions. Our study indicates that the homozygous genotype FPN1 -8GG was significantly associated with increased risk of developing sudden hearing loss. These findings suggest new research should be conducted in the field of iron homeostasis in the inner ear

The active metabolite of warfarin (3′-hydroxywarfarin) and correlation with INR, warfarin and drug weekly dosage in patients under oral anticoagulant therapy: A pharmacogenetics study

Objectives: Warfarin oral anticoagulant therapy (OAT) requires regular and frequent drug adjustment monitored by INR. Interindividual variability, drug and diet interferences, and genetics (VKORC1 and CYP2C9) make the maintenance/reaching of stable INR a not so easy task. HPLC assessment of warfarin/enantiomers was suggested as a valid monitoring-tool along with INR, but definite results are still lacking. We evaluated possible correlations between INR, warfarin/3′-hydroxywarfarin, and drug weekly dosage aimed at searching novel alternatives to OAT monitoring. VKORC1/CYP2C9 pharmacogenetics investigation was performed to account for the known influence on warfarin homeostasis. Methods: 133 OAT patients were recruited and assessed for warfarin/3′-hydroxywarfarin serum levels (HPLC), INR, and VKORC1 and CYP2C9 genotypes. A subgroup of 52 patients were monitored in detail (5 consecutive controls; c0-c4) till the target INR was reached. Correlation analyses were performed in both groups Results: In the whole OAT group both warfarin and 3′-hydroxywarfarin correlate with INR at comparable degree (r2 = 0.0388 and 0.0362 respectively). Conversely, warfarin weekly dosage better correlates with warfarin than with 3′-hydroxywarfarin (r2 = 0.0975 and r2 = 0.0381 respectively), but considering together warfarin plus 3′-hydroxywarfarin the correlation strongly increased (r2 = 0.1114; p<0.0001). Interestingly, 3′-hydroxywarfarin reached a strong correlation at c4 respect to warfarin (r2 = 0.2157 and r2 = 0.0549; p = 0.0005 and p = 0.0944 respectively) seeming less affected by drug adjustments in the subgroup of 52 patients who started OAT. The multivariate analyses aimed at estimating the true contribution of 3′-hydroxywarfarin on INR value ascribed it the unique significant value (p = 0.0021) in spite of warfarin who lost association. The pharmacogenetics studies confirmed that patients carrying the VKORC1 variant-allele required lower warfarin maintenance dosage and that the combination of VKORC1 and CYP2C9 yielded a warfarin responsive index (WRI) inversely related to the number variant alleles Conclusion: Our results overall suggest that 3′-hydroxywarfarin monitoring could be of great advantage in INR monitoring respect to classical warfarin assessment showing significant contribution also in multivariate analysis. Therefore, additional active metabolites should be recognized and investigated as novel useful indicators

Coagulation Factor XIIIA (F13A1): novel perspectives in treatment and pharmacogenetics.

Factor XIII (FXIII) is a key molecule in the field of blood coagulation and in the last decades it has weakened attention within the field of angiogenesis and tissue repair. FXIII positively influences wound healing in several tissues by exerting multiple plasma and cellular functions. In the field of haemostasis, FXIII cross-links the neo formed fibrin fibers and supports platelet adhesion to the damaged sub-endothelium warranting a solid architecture. In addition, the pro-angiogenic functions of FXIII are directed by the interaction of vascular endothelial growth factor receptor 2 (VEGFR2) and the integrin αVβ3, on the cell membrane, favouring an important step in the formation of granulation tissue at the wound site for optimal tissue healing. Conversely, the same mechanisms could lead to undesired increased neovascularisation, for example in inflammatory bowel disease or in the retinal degenerative pathologies. The classical symptoms of FXIII deficiency span from intracranial haemorrhage to delay bleeding or the staying of chronic wounds in the skin including impaired mucosal healing. In this view, FXIII bridges primary haemostasis, coagulation and definite tissue healing. Another important recently discovered function ascribed to FXIII is its ability to limit bacterial spreading from the lesion by incorporating specific macromolecules addressed to cellular infiltration, favouring in turn cell migration and survival, as observed also in fibrin-heart cultures for stem cell recruitment. In the field of the novel prognostic biomarkers, the monitoring of the residual circulating FXIII level during acute myocardial infarction has been considered predictive of the post-myocardial infarction healing. Accordingly, adequate FXIII levels can drive and predict the prognosis of complex diseases and the outcome of the associated therapies or interventions. In addition, peculiar pharmacogenetics aspects of the FXIII gene are of extraordinary interest. The present review accounts for the recognized role of FXIII in the healing process and gives some examples on how to use it as prognostic biological/molecular marker or as potential tailored therapeutic molecule in complex diseases

ASPIS prototype for causal chains of space weather phenomena

The Italian Space Agency (ASI) and the Italian National Institute for Astrophysics (INAF) funded a project to design and develop an archive prototype for the ASI SPace weather InfraStructure (ASPIS). The project, CAESAR (Comprehensive Space Weather Studies for the ASPIS Prototype Realization) created a prototype aiming at unifying multiple Space Weather (SWE) resources through a flexible and adaptable architecture, allowing scientists to adopt an integrated approach, encompassing the whole chain of phenomena from the Sun to the Earth up to planetary environments. In this contribution we present various aspects and stages of the CAESAR project from its design phase to the final prototype. The definition of a template (metadata schema) to collect metadata or the resources (products) contributed to the prototype and management. The management of those same metadata documents through the development of a dedicated tool (ProSpecT, Product Specification Template, using JSON and JSONForms). The challenges in keeping it updated while helping the research community in providing both data and data description. The definition of a set of constraints to handle datasets and their metadata in a homogenized way (as much as possible), identifying potential common data formats and reference frames to follow a chain of phenomena from the Sun to the interplanetary medium up to Earth or planetary surfaces. The actual design and implementation of the prototype archive, its ingestion system and API considerations. The design and development of a web base graphical user interface to enable science research on top of the prototype archive, as well as the development of a dedicated python module (ASPISpy) for advanced data investigation and easier integration with other community drive software. The automation of documentation of the contributed resources (data collections, software tools, modules) from the machine-readable templated documents. All of the above aspects will be presented, highlighting challenges and specific solutions, as well as potential future evolution of the prototype into the actual archive infrastructure for ASPIS