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Jets and accretion in heavy black holes across cosmic time.
Get PDFBlazars are Active Galactic Nuclei (AGN) characterized by relativistic jets launched in the vicinity of the central engine (i.e. a supermassive black hole; SMBH), that are oriented close to our line of sight.
How jets in AGN form, collimate and accelerate is still an open issue, but a connection with the accretion process is sometimes suggested. We first investigated this issue, finding that in jetted AGN the SMBH can accrete both through a radiatively efficient, optically thick, geometrically thin accretion disc, and through a radiatively inefficient, geometrically thick hot accretion flow. The occurrence of these two accretion regimes depends on the accretion rate: if it is larger than ˙M ~ 0.1˙MEdd, the accretion is radiatively efficient, while if it is less than ~ 0.1˙MEdd the accretion is inefficient.
After this first insight on accretion and jets, we used these components as tools to study the extremely massive black hole population at high redshift (i.e. MBH > 109M, z > 4). A deep knowledge of these objects can provide fundamental clues to the models of formation and growth of the first supermassive black holes (106M_ < MBH < 109M). The peculiar orientation of blazars makes them the most effective tracers of their parent population, namely all the jetted AGN with similar intrinsic properties, but oriented in random directions. For this reason, we set up a systematic search of blazar candidates from a large quasar sample, in order to collect a complete sample of high–redshift blazars. We selected a sample of 19 extremely radio–loud, high–redshift quasars. We characterized their nuclear features (i.e. SMBH mass and accretion rate) by fitting their accretion disc spectra: we find that our criteria are efficient in selecting very massive and fast accreting black holes. We started our classification campaign, through X–ray observations. We successfully classified three quasars from our sample as blazars, along with a serendipitously selected (but analogous) candidate from the same area of sky. This means that our criteria are efficient in selecting good blazar candidates.
Comparing our findings with the known distribution of non–jetted AGN, we find that there are different formation epochs for extremely massive black holes hosted in jetted (z ~ 4) and non–jetted systems (z ~ 2.5). This is not easy to explain, according to the current black hole formation models in the early Universe. The search of very high–redshift jetted sources must be pursued, to learn more about the early stages of heavy black hole formation
Optimizing non-natural protein functions with protein engineering. Evolution of a cephalosporin C acylase.
No full textSemi-synthetic cephalosporins are synthesized starting from the 7-amino cephalosporanic acid (7-ACA) nucleus obtained from the natural antibiotic cephalosporin C (CephC). In recent years, a single-step enzymatic process in which CephC is directly converted into 7-ACA by a cephalosporin C acylase (CA) has attracted industrial interest because of the prospects of simplifying the process and reducing costs. CAs are members of the glutaryl acylase family that should use CephC as preferred substrate; however, known natural glutaryl acylases show very low activity on this antibiotic. At the host laboratory ("The Protein Factory" Research Center) in the past years the catalytic efficiency on CephC of a glutaryl acylase from Pseudomonas N176 (named VAC) was enhanced by a protein engineering approach, and the VAC crystal structure was recently solved, thus providing insight into the substrate binding and catalytic activity of CAs. However, the properties of the evolved enzymes are not sufficient to encourage 7-ACA manufacturers to shift to single-step CephC enzymatic conversion.
By a combination of structural knowledge, semi-rational design, computational approaches and evolution analysis we isolated VAC variants with an altered substrate specificity (i.e. with a > 11,000-fold increase in specificity constant for CephC versus glutaryl-7-amino cephalosporanic acid, compared to wild-type) and with the highest kinetic efficiency so far obtained for a CA. This approach allowed the isolation of VAC variants suitable for the industrial application of the mono-step CephC conversion process.
Indeed, taking advantage of the availability of a number of VAC variants with different kinetic properties, we setup a one-pot system in which DAAO and VAC work together to directly convert cephalosporin C into 7-ACA. The process has been optimized by identifying the most favorable operational conditions, substrate and enzymes concentrations. Under optimized conditions and the addition of further aliquots of the biocatalysts, > 98% of CephC was converted yielding 7-ACA as the main reaction product. At the 20 mL bioconversion scale, approx 81 mg of 7-ACA are produced in 41 hours from 15 mM CephC.
Moreover, a study on the substrate specificity of cephalosporin derivative compounds of main industrial interest was undertaken. Molecular docking analysis allowed to deep inside the mode of binding of CephC derivatives at the active site of wild-type and different VAC variants. The ongoing molecular dynamics studies will shed light on the structure-function relationships of this class of hydrolytic enzymes as well as to identify the most suitable enzyme variant for each cephalosporin derivative
Coordination between intrinsic and extrinsic mechanism in thoracic lymphatics.
Get PDFThe lymphatic system runs in parallel with the blood vasculature, it plays a key role in maintaining tissue fluid homeostasis, as a tissue-drainage system, and it contributes to the immunosurveillance by providing a route for migrating cells. The lymphatic system is a highly branched network of thin-walled blind-ended vessels, which drain fluid, macromolecules and cells from the extracellular spaces within most organs, carrying them into larger thicker-walled collectors running deeper in the body. Fluid and solutes extravasated from vascular capillaries into the interstitial space enter blind-ended initial lymphatics, which are anchored to the interstitial matrix via anchoring filaments and possess overlapping endothelial cell-cell junctions behaving like valve structures, only permitting unidirectional lymph entry into the lymphatic vessel lumen. Valves in collecting lymphatics consist of two modified adjacent endothelial cell leaflets which meet in the vessel lumen forming a funnel inside the vessel and separating adjacent lymphangions, the functional units of the lymphatic system. Lymph is formed along a hydraulic pressure gradient developing between the interstitial tissue and the lumen of initial lymphatics. This pressure gradient depends upon both extrinsic and intrinsic pump systems. Tissue movements provide the extrinsic factor affecting lymphatic function, causing cycles of external compression/expansion of the lymphatic vessels lumen.. Lymphangions, segments of lymphatic vessel delimited by unidirectional valves and surrounded by smooth muscle cells, represent the functional units of the intrinsic pump mechanism. Their rhythmic active contraction is essential to guarantee the correct lymph flow either as the only source of pressure gradient formation or along with the extrinsic pump, where the mechanical features of the surrounding tissue are able to generate such an external pump action. During active contraction, lymphatic smooth muscle cells create an increase in intraluminal pressure and generate a local positive pressure gradient which drives lymph propulsion. The subsequent relaxation of the smooth muscle layer generates a decrease in intraluminal pressure which drives lymph from the interstitial space into the vessel itself.
The aim of the present thesis was to study the interaction between the intrinsic and extrinsic mechanisms in a highly moving tissue such as the diaphragm. By in vivo fluorescence staining of diaphragmatic lymphatics we were able to identify vessels organized in loop structures and located both in the tendineous and in the peripheral muscle region. Lymphatic loops were classified into four groups (active, hybrid, passive and invariant) according to their functional behavior, forming functionally distinct regions. By whole mount immunostaining against smooth muscle actin we identified a dense smooth muscle mesh surrounding actively pumping sites, whereas in not contracting tracts smooth muscle fibers were more sparsely organized, showing a lot of large gaps around the vessel wall. Actively pumping lymphatic sites did not differ in diameter from all other classes of vessels. We found that their amplitude of contraction was independent on vessel size but strongly correlated to contraction frequency. By temporal analysis we were also able to identify trigger sites which controlled the diameter change of both other active and passive sites belonging to the same network.
We then made an extensive study on the temporal correlation of activity among active, hybrid and passive sites belonging to the same network, and were able to identify trigger regions and follower regions whose behavior was dependent upon their respective trigger sites
Lastly, we started an ongoing project in order to understand the extrinsic pump effect due to respiratory and cardiogenic movements on diaphragmatic lymphatic function. By locally injecting KCl into the interstitium next to invariant longitudinal and/or transverse lymphatics we tested diameter and/or length changes and then intraluminal pressure gradients due to extrinsic forces. Further analysis are required in order to define the actual contribution of intrinsic and extrinsic mechanisms in diaphragmatic lymphatics
Valutazione del funzionamento psicosociale di pazienti in terapia con paliperidone. Confronto con aloperidolo nel "real world".
Get PDFAims: endpoints of psychotic patients treatments changed a lot in the last years, just as the way of evaluate their efficacy. This happened especially because of the introduction of new psychotropic drugs, able to improve many aspects concerning with psychotic disease. From the ’90s was clear that an improvement only in symptoms could not be identified with a clinical success; actually, interpersonal abilities, quality of life and psychosocial functioning were indicated as the real endpoints of a psychiatric treatment. Paliperidone is an antipsychotic recently introduced in the market. It is a second generation antipsychotic. Many first generation antipsychotics are still widely used in clinical practice, especially haloperidol. A comparison between these two drugs, in terms of social functioning, has been short investigated. First aim of the study is the comparison between patients treated with paliperidone and patients treated with haloperidol, evaluating their social functioning with PSP (Personal and Social Performace Scale). The second aim concerns with symptomatic improvement, evaluated with PANSS (Positive and Negative Syndrome Scale).
Methods: This is a study related to patients from Operative Unity of Psychiatry I and II of Varese. Inclusion methods are a diagnosis of Schizophrenia or other Psychotic Disorders according to DSM IV-TR, and the beginning of a treatment with paliperidone (3-12 mg/day) or haloperidol (2-10 mg/day). Personal data and rating scales scores are marked. Symptomatic recrudescence leading to a new psychiatric hospital admission must not be present in the last three months. Patients are followed up for 6 months.
Risults: 34 patients have been investigated for 6 months (17 treated with paliperidone, 17 treated with haloperidol). The general trend is concerning with a psychosocial and a clinical improvement, both with paliperidone and haloperidol, but no statistically significant difference was found.
Conclusions: Treatment with paliperidone didn’t show a better outcome than haloperidol about psychosocial functioning and symptomatic improvement in psychotic patients
