Folding mechanisms steer the amyloid fibril formation propensity of highly homologous proteins

Significant advances in the understanding of the molecular determinants of fibrillogenesis can be expected from comparative studies of the aggregation propensities of proteins with highly homologous structures but different folding pathways. Here, we fully characterize, by means of stopped-flow, T-jump, CD and DSC experiments, the unfolding mechanisms of three highly homologous proteins, zinc binding Ros87 and Ml153-149 and zinc-lacking Ml452-151. The results indicate that the three proteins significantly differ in terms of stability and (un)folding mechanisms. Particularly, Ros87 and Ml153-149 appear to be much more stable to guanidine denaturation and are characterized by folding mechanisms including the presence of an intermediate. On the other hand, metal lacking Ml452-151 folds according to a classic two-state model. Successively, we have monitored the capabilities of Ros87, Ml452-151 and Ml153-149 to form amyloid fibrils under native conditions. Particularly, we show, by CD, fluorescence, DLS, TEM and SEM experiments, that after 168 hours, amyloid formation of Ros87 has started, while Ml153-149 has formed only amorphous aggregates and Ml452-151 is still monomeric in solution. This study shows how metal binding can influence protein folding pathways and thereby control conformational accessibility to aggregation-prone states, which in turn changes aggregation kinetics, shedding light on the role of metal ions in the development of protein deposition diseases

12.1 Enhanced Proatherogenic Inflammation After Recombinant Human TSH Administration in Patients Monitored for Thyroid Cancer Remnant

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A 3d and 4d anatomical study of the human heart: analysis by direct volume rendering technique

In this report we demonstrated an innovative use of 3D and 4D volume rendering, processing the data set images obtained by CT on heart of subjects not affected by any cardiologic disorders. This method is a direct technique for visualizing primitive volumes without any intermediate conversion of the volume data to surface presentation. Here, we are able to highlight all anatomical structures of the heart examining them contemporarily in the same image or selecting a tissue type. The present report demonstrates how the manipulation of appropriate algorithms permits to meliorate the interactive anatomical morphology visualization, observing the heart within thorax, contemporarily, and creating a good perception of depth. Besides, it was possible to study the integrity of papillary muscles, or the fibrous tissue of cardiac valve and cordae tendineae, or finally to designate the exact morphology and location of coronary arteries studying and describing their wall morphology. Furthermore, by 4D analysis it was possible to obtain three-dimensional images in movement, highlighting both the movement of the vessels during cardiac phases and the modification of internal cardiac structures during these phases. Our results demonstrated that one of the greatest advantage of algorithmic modifications of volume rendering is that this method provides all the necessary informations in a single radiologic study, meliorating anatomical description of all cardiac structures. Moreover, avoiding the invasive diagnostic methods as well as coronarography this methods allows to meliorate clinical study of the region also facilitating the therapeutic plans of the cardiac disease

The connection between basal ganglia and cerebellum in human brain

Our recent anatomical studies on direct connections between the cerebral cortex and medial pallidum nucleus, we observed the presence of interesting connections between this nucleus and the cerebellum, highlighting as these subcortical structures are part of a densely interconnected network. Through DTI method with Constrained Deconvolution System (CDS) techniques we evaluated these connections in ten healthy subjects and in three patients with Parkinson’s syndrome. Our results demonstrate that the pathways linking the cerebellum to basal ganglia are topographically organized. Furthermore, the cerebellum not only provides output exclusively to the primary motor cortex via the thalamus for the motor control and coordination of movements but it is involved in the process of lock and un-lock of the motor gesture through the planning role of the basal ganglia. These pathways provide evidence for substantial communication between the cerebellum and the basal ganglia that is independent of the cerebral cortex. Communication between these major subcortical nuclei is likely to have important clinical implications. We discuss how the pathways linking the cerebellum with the basal ganglia may provide a useful framework for understanding cerebellar contributions to the manifestation of two prototypical basal ganglia disorders, Parkinson’s disease and dystonia

Proposal for taking data with the KLOE-2 detector at the DAΦ\PhiNE collider upgraded in energy

This document reviews the physics program of the KLOE-2 detector at DA$\Phi$NE upgraded in energy and provides a simple solution to run the collider above the $\phi$-peak (up to 2, possibly 2.5 GeV). It is shown how a precise measurement of the multihadronic cross section in the energy region up to 2 (possibly 2.5) GeV would have a major impact on the tests of the Standard Model through a precise determination of the anomalous magnetic moment of the muon and the effective fine-structure constant at the $M_Z$ scale. With a luminosity of about $10^{32}$cm$^{-2}$s$^{-1}$, DA$\Phi$NE upgraded in energy can perform a scan in the region from 1 to 2.5 GeV in one year by collecting an integrated luminosity of 20 pb$^{-1}$ (corresponding to a few days of data taking) for single point, assuming an energy step of 25 MeV. A few years of data taking in this region would provide important tests of QCD and effective theories by $\gamma\gamma$ physics with open thresholds for pseudo-scalar (like the $\eta'$), scalar ($f_0,f'_0$, etc...) and axial-vector ($a_1$, etc...) mesons; vector-mesons spectroscopy and baryon form factors; tests of CVC and searches for exotics. In the final part of the document a technical solution for the energy upgrade of DA$\Phi$NE is proposed.Comment: 19 pages, 8 figure

DaΦ{\Phi}ne developments for the KLOE-2 experimental run

Recently the peak luminosity achieved on the DA{\Phi}NE collider has been improved by almost a factor three by implementing a novel collision scheme based on large Piwinski angle and Crab-Waist. This encouraging result opened new perspectives for physics research and a new run with the KLOE-2 detector has been scheduled to start by spring 2010. The KLOE-2 installation is a complex operation requiring a careful design effort and a several months long shutdown. The high luminosity interaction region has been deeply revised in order to take into account the effect on the beam caused by the solenoidal field of the experimental detector and to ensure background rejection. The shutdown has been also used to implement several other modifications aimed at improving beam dynamics: the wiggler poles have been displaced from the magnet axis in order to cancel high order terms in the field, the feedback systems have been equipped with stronger power supplies and more efficient kickers and electrodes have been inserted inside the wiggler and the dipole vacuum chambers, in the positron ring, to avoid the e-cloud formation. A low level RF feedback has been added to the cavity control in both rings.Comment: 3 pages, 3 figures, presented to the IPAC10 conferenc

Experience with DAΦNE Upgrade Including Crab Waist

International audienceIn 2007 DAΦNE was upgraded to operate in a regime of large Piwinski angle, with a novel IR optics, reduced vertical beta at the interaction point, and additional sextupoles providing for crab waist collisions. The specific luminosity was boosted by more than a factor of four, and the peak luminosity was more than doubled with respect to the maximum value obtained with the original collider configuration. The DAΦNE commissioning as well as the first experience with large Piwinski angle and crab waist collisions scheme will be reported