Computational approaches to shed light on molecular mechanisms in biological processes

Computational approaches based on Molecular Dynamics simulations, Quantum Mechanical methods and 3D Quantitative Structure-Activity Relationships were employed by computational chemistry groups at the University of Milano-Bicocca to study biological processes at the molecular level. The paper reports the methodologies adopted and the results obtained on Aryl hydrocarbon Receptor and homologous PAS proteins mechanisms, the properties of prion protein peptides, the reaction pathway of hydrogenase and peroxidase enzymes and the defibrillogenic activity of tetracyclines. © Springer-Verlag 2007

Super-hydrodynamic limit in interacting particle systems

This paper is a follow-up of the work initiated in [3], where it has been investigated the hydrodynamic limit of symmetric independent random walkers with birth at the origin and death at the rightmost occupied site. Here we obtain two further results: first we characterize the stationary states on the hydrodynamic time scale and show that they are given by a family of linear macroscopic profiles whose parameters are determined by the current reservoirs and the system mass. Then we prove the existence of a super-hyrdrodynamic time scale, beyond the hydrodynamic one. On this larger time scale the system mass fluctuates and correspondingly the macroscopic profile of the system randomly moves within the family of linear profiles, with the randomness of a Brownian motion.Comment: 22 page

The Infrared Luminosity of Galaxy Clusters

The aim of this study is to quantify the infrared luminosity of clusters as a function of redshift and compare this with the X-ray luminosity. This can potentially constrain the origin of the infrared emission to be intracluster dust and/or dust heated by star formation in the cluster galaxies. We perform a statistical analysis of a large sample of galaxy clusters selected from existing databases and catalogues.We coadd the infrared IRAS and X-ray RASS images in the direction of the selected clusters within successive redshift intervals up to z = 1. We find that the total infrared luminosity is very high and on average 20 times higher than the X-ray luminosity. If all the infrared luminosity is to be attributed to emission from diffuse intracluster dust, then the IR to X-ray ratio implies a dust-to-gas mass abundance of 5e-4. However, the infrared luminosity shows a strong enhancement for 0.1 < z < 1, which cannot be attributed to cluster selection effects. We show that this enhancement is compatible with a star formation rate in the member galaxies that is typical of the central Mpc of the Coma cluster at z = 0 and evolves with the redshift as (1+z)^5. It is likely that most of the infrared luminosity that we measure is generated by the ongoing star formation in the member galaxies. From theoretical predictions calibrated on extinction measurements (dust mass abundance equal to 1e-5), we expect only a minor contribution, of a few percent, from intracluster dust.Comment: 9 pages, 7 figures, accepted july 31st 2008 for publication in Astronomy and Astrophysics, language improved for this versio

Neural stem cell transplantation for neurodegenerative diseases

Neurodegenerative diseases are disabling and fatal neurological disorders that currently lack effective treatment. Neural stem cell (NSC) transplantation has been studied as a potential therapeutic approach and appears to exert a beneficial effect against neurodegeneration via different mechanisms, such as the production of neurotrophic factors, decreased neuroinflammation, enhanced neuronal plasticity and cell replacement. Thus, NSC transplantation may represent an effective therapeutic strategy. To exploit NSCs\u2019 potential, some of their essential biological characteristics must be thoroughly investigated, including the specific markers for NSC subpopulations, to allow profiling and selection. Another key feature is their secretome, which is responsible for the regulation of intercellular communication, neuroprotection, and immunomodulation. In addition, NSCs must properly migrate into the central nervous system (CNS) and integrate into host neuronal circuits, enhancing neuroplasticity. Understanding and modulating these aspects can allow us to further exploit the therapeutic potential of NSCs. Recent progress in gene editing and cellular engineering techniques has opened up the possibility of modifying NSCs to express select candidate molecules to further enhance their therapeutic effects. This review summarizes current knowledge regarding these aspects, promoting the development of stem cell therapies that could be applied safely and effectively in clinical settings

DNA-binding protects p53 from interactions with cofactors involved in transcription-independent functions

Binding-induced conformational changes of a protein at regions distant from the binding site may play crucial roles in protein function and regulation. The p53 tumour suppressor is an example of such an allosterically regulated protein. Little is known, however, about how DNA binding can affect distal sites for transcription factors. Furthermore, the molecular details of how a local perturbation is transmitted through a protein structure are generally elusive and occur on timescales hard to explore by simulations. Thus, we employed state-of-the-art enhanced sampling atomistic simulations to unveil DNA-induced effects on p53 structure and dynamics that modulate the recruitment of cofactors and the impact of phosphorylation at Ser215. We show that DNA interaction promotes a conformational change in a region 3 nm away from the DNA binding site. Specifically, binding to DNA increases the population of an occluded minor state at this distal site by more than 4-fold, whereas phosphorylation traps the protein in its major state. In the minor conformation, the interface of p53 that binds biological partners related to p53 transcription-independent functions is not accessible. Significantly, our study reveals a mechanism of DNA-mediated protection of p53 from interactions with partners involved in the p53 transcription-independent signalling. This also suggests that conformational dynamics is tightly related to p53 signalling

Discovery of a cluster of galaxies behind the Milky Way: X-ray and optical observations

We report the discovery of Cl 2334+48, a rich cluster of galaxies in the Zone of Avoidance, identified in public images from the XMM-Newton archive. We present the main properties of this cluster using the XMM-Newton X-ray data, along with new optical spectroscopic and photometric observations. Cl 2334+48 is located at z = 0.271 +/- 0.001, as derived from the optical spectrum of the brightest member galaxy. Such redshift agrees with a determination from the X-ray spectrum (z = 0.263 (+0.012/-0.010)), in which an intense emission line is matched to the rest wavelength of the Fe Kalpha complex. Its intracluster medium has a plasma temperature of 4.92 (+0.50/-0.48) keV, sub-solar abundance (0.38 +/- 0.12 Zsun), and a bolometric luminosity of 3.2 x 10^44 erg/s. A density contrast delta = 2500 is obtained in a radius of 0.5 Mpc/h70, and the corresponding enclosed mass is 1.5 x 10^14 Msun. Optical images show an enhancement of g'-i' > 2.5 galaxies around the central galaxy, as expected if these were cluster members. The central object is a luminous E-type galaxy, which is displaced ~ 40 kpc/h70 from the cluster X-ray center. In addition, it has a neighbouring arc-like feature (~ 22" or 90 kpc/h70 from it), probably due to strong gravitational lensing. The discovery of Cl 2334+48 emphasises the remarkable capability of the XMM-Newton to reveal new clusters of galaxies in the Zone of Avoidance.Comment: 9 pages, 11 figures, Accepted for publication in A&A (on July 12, 2006

Effects of chronic exercise on severity, quality of life and functionality in an elderly Parkinson’s disease patient: case report

Exercise produces potential influences on physical and mental capacity in patients with neuropsychiatric disor- ders, and can be made a viable form of therapy to treat Parkinson’s disease (PD). We report the chronic effects of a regu- lar physical exercise protocol on cognitive and motor functions, functional capacity, and symptoms in an elderly PD pa- tient without dementia. The patient participated of a program composed of proprioceptive, aerobic and flexibility exer- cises, during 1 hour, three days a week, for nine months. Patient used 600 mg of L-DOPA daily, and 1 hour prior to each exercise session. Assessment was conducted in three stages, 0-3, 3-6 and 6 to 9 months, using percentual variation to the scales Hoehn and Yahr, Mini-Mental State Examination (MMSE), Parkinson Activity Scale (PAS), Beck Depression In- ventory (BDI), and Unified Parkinson's Disease Rating Scale (UPDRS-III). Reassessment showed clear changes in clini- cal parameters for Hoehn and Yahr (4 to 2.5), MMSE (14 to 22), PAS (13 to 29), BDI (9 to 7) and UPDRS-III (39 to 27) at the end of 9 months. According to our data, exercise seems to be effective in promoting the functional capacity and the maintenance of cognitive and motor functions of PD patients. Regular exercise protocols can be implemented as an ad- junctive treatment for reducing the severity of PD

Does the site of origin of the microcarcinoma with respect to the thyroid surface matter? A multicenter pathologic and clinical study for risk stratification

It is unclear whether the site of origin of papillary thyroid microcarcinoma (mPTC) with respect to the thyroid surface has an influence on clinicopathologic parameters. The objectives of the study were to: (i) Accurately measure the mPTC distance from the thyroid surface; (ii) analyze whether this distance correlates with relevant clinicopathologic parameters; and (iii) investigate the impact of the site of origin of the mPTC on risk stratification. Clinicopathologic features and BRAF mutational status were analyzed and correlated with the site of origin of the mPTC in a multicenter cohort of 298 mPTCs from six Italian medical institutions. Tumors arise at a median distance of 3.5 mm below the surface of the thyroid gland. Statistical analysis identified four distinct clusters. Group A, mPTC: size 65 5 mm and distance of the edge of the tumor from the thyroid capsule = 0 mm; group B, mPTC: size 65 5 mm and distance of the edge of the tumor from the thyroid capsule &gt; 0 mm; group C, mPTC: size &lt; 5 mm and distance of the edge of the tumor from the thyroid capsule = 0 mm; and group D, mPTC: size &lt; 5 mm and distance of the edge of the tumor from the thyroid capsule &gt; 0 mm. Univariate analysis demonstrates significant differences between the groups: Group A shows the most aggressive features, and group D the most indolent ones. By multivariate analysis, group A tumors are characterized by tall cell histotype, BRAF V600E mutation, tumor fibrosis, aggressive growth with invasive features, vascular invasion, lymph node metastases, and intermediate ATA risk. The mPTC clinicopathologic features vary according to the tumor size and distance from the thyroid surface. A four-group model may be useful for risk stratification and to refine the selection of nodules to be targeted for fine needle aspiration

Probing the location of the substrate binding site of ascorbate oxidase near type 1 copper: an investigation through spectroscopic, inhibition and docking studies

The present investigation addresses the problem of the binding mode of phenolic inhibitors and the substrate ascorbate to the active site of ascorbate oxidase. The results from both types of compounds indicate that the binding site is located in a pocket near the type 1 copper center. This information is of general interst for blue multicopper oxidases. Docking calculations performed on the ascorbate oxidase\u2013ascorbate complex show that binding of the substrate occurs in a pocket near type 1 Cu, and is stabilized by at least five hydrogen bonding interactions with protein residues, one of which involves the His512 Cu ligand. Similar docking studies show that the isomeric fluorophenols, which act as competitive inhibitors toward ascorbate, bind to the enzyme in a manner similar to ascorbate. The docking calculations are supported by 19F NMR relaxation measurements performed on fluorophenols in the presence of the enzyme, which show that the bound inhibitors undergo enhanced relaxation by the paramagnetic effect of a nearby Cu center. Unambiguous support to the location of the inhibitor close to type 1 Cu was obtained by comparative relaxation measurements of the fluorophenols in the presence of the ascorbate oxidase derivative where a Zn atom selectively replaces the paramagnetic type 2 Cu. The latter experiments show that contribution to relaxation of the bound inhibitors by the type 2 Cu site is negligible