Elucidation of the disulfide folding pathway of hirudin by a topology-based approach

A theoretical model for the folding of proteins containing disulfide bonds is introduced. The model exploits the knowledge of the native state to favour the progressive establishment of native interactions. At variance with traditional approaches based on native topology, not all native bonds are treated in the same way; in particular, a suitable energy term is introduced to account for the special strength of disulfide bonds (irrespective of whether they are native or not) as well as their ability to undergo intra-molecular reshuffling. The model thus possesses the minimal ingredients necessary to investigated the much debated issue of whether the re-folding process occurs through partially structured intermediates with native or non-native disulfide bonds. This strategy is applied to a context of particular interest, the re-folding process of Hirudin, a thrombin-specific protease inhibitor, for which conflicting folding pathways have been proposed. We show that the only two parameters in the model (temperature and disulfide strength) can be tuned to reproduce well a set of experimental transitions between species with different number of formed disulfide. This model is then used to provide a characterisation of the folding process and a detailed description of the species involved in the rate-limiting step of Hirudin refolding.Comment: 14 pages, 9 figure

Optimal shapes of compact strings

Optimal geometrical arrangements, such as the stacking of atoms, are of relevance in diverse disciplines. A classic problem is the determination of the optimal arrangement of spheres in three dimensions in order to achieve the highest packing fraction; only recently has it been proved that the answer for infinite systems is a face-centred-cubic lattice. This simply stated problem has had a profound impact in many areas, ranging from the crystallization and melting of atomic systems, to optimal packing of objects and subdivision of space. Here we study an analogous problem--that of determining the optimal shapes of closely packed compact strings. This problem is a mathematical idealization of situations commonly encountered in biology, chemistry and physics, involving the optimal structure of folded polymeric chains. We find that, in cases where boundary effects are not dominant, helices with a particular pitch-radius ratio are selected. Interestingly, the same geometry is observed in helices in naturally-occurring proteins.Comment: 8 pages, 3 composite ps figure

Production Technologies of Ancient Bricks from Padua, Italy: Changing Colors and Resistance over Time

Representative and very uneven texturally bricks having yellow/beige or pale or dark red colors from the Renaissance walls (16th century) of Padua, Northeast Italy, were studied by means of colorimetric, petrographic (MOP), chemical (XRF), mineralogical (PXRD) and microstructural analysis (FESEM-EDS). Starting from the color measurements of the ceramic bodies, the manufacturing technologies and their influence on the physical behavior and durability of the bricks were established. The porous system was characterized by means of hygric tests and mercury intrusion porosimetry; the compactness and structural anisotropy were defined through ultrasound velocity; the uniaxial compressive strength was determined; and durability to salt crystallization and frost action of the bricks was assessed. Mg- and Ca-rich illitic clays fired at temperatures ≥900 ◦C were used to manufacture the beige hue bodies, while the pale red bricks were made out with Ca- and Fe-rich illitic clays fired at 850–900 ◦C. A lower carbonate content on the base clays and a lower firing temperature were the main causes responsible for the changing colors from beige to red hue. The increase of the red color was associated to higher silicate inclusions content and lower development of reaction rims around grains. The low sintering degree achieved yielded highly porous bodies with diverse porous systems, leading to differential physical performance and durability of the bricks that may turn out beneficial for the conservation of the historic walls.Marie Sklodowska-Curie grant agreement No 836122CLAYONRISK ProjectResearch Group of the Junta de Andalucía RNM179MSC Actio

Conformations of Proteins in Equilibrium

We introduce a simple theoretical approach for an equilibrium study of proteins with known native state structures. We test our approach with results on well-studied globular proteins, Chymotrypsin Inhibitor (2ci2), Barnase and the alpha spectrin SH3 domain and present evidence for a hierarchical onset of order on lowering the temperature with significant organization at the local level even at high temperatures. A further application to the folding process of HIV-1 protease shows that the model can be reliably used to identify key folding sites that are responsible for the development of drug resistance .Comment: 6 pages, 3 eps figure

Fracture of cobalt-crome modular neck in total hip arthroplasty

Despite the advantages of modular total hip arthroplasty in terms of neck version, offset and length precise reproduction, titanium necks breakage became a concern. Consequently, titanium has been replaced by cobalt-chrome (Co-Cr). However, four cases of Co-Cr modular neck breakage have been reported in the literature. In the present paper, two cases of Co-Cr modular neck fractures are described together with a literature review. The aim of this work is to discuss the risk factors and characteristics of this rare complication. We described two cases of fracture of long varus Co-Cr modular femoral neck connected with cementless press-fit stem. Some risk factors, such as long varus type of modular neck, overweight and/or high demanding physical activity, might have contributed to implant failure. (www.actabiomedica.it)

Clayey materials for traditional bricks production in North-Eastern Italy through a combined compositional study: From firing dynamics to provenance

The compositional study of two main types of clayey materials outcropping nearby Padua (Veneto region, north-eastern Italy) and bricks used in historical constructions of the city is here addressed. Mineralogically, the clayey materials are illitic-chloritc clays, both non-carbonatic and carbonatic/highly-carbonatic clays, that chemically correspond to clays with important contents of silica and/or iron and of calcium and/or magnesium, respectively. Two main type of historic bricks were produced: i) one using mixtures of illitic/illitic-chloritic clays with abundant quartz and of carbonatic clays and firing temperatures between 950 and 1000 °C, and ii) a second one made out of illitic-chloritic clays non-carbonatic and fired around 850–900 °C. The comparative analysis between the mineralogical changes occurred in the clayey materials with increasing temperatures and the mineral assemblages detected in the studied bricks have provided evidences about the mixture of raw clays, that could be in turn compositionally similar to those analysed. The development of aluminium and magnesium-calcium silicates and/or magnesium silicates during the firing was fostered by mixing such base clays, giving rise to very durable and highly calcareous bricks. Whereas titanium and the trace elements zircon, vanadium, chromium and zinc may entail markers of provenance of illitic-chloritic clays quarried in the area, the strontium may represent a geochemical fingerprint for constraining supply areas of carbonatic clays. The compositional analysis carried out through the combined use of X-Ray Powder Diffraction (XRPD) and X-Ray Fluorescence Spectrometry (XRF) has provided data regarding to the composition and provenance of the starting clays as well as procedures and firing dynamics adopted for the manufacturing of the traditional bricks in the city of Padua from Roman Times to Renaissance.European Union’s Horizon 2020 Research and Innovation Programme under the Marie Sklodowska-Curie Individual Fellowship (grant agreement No 836122)Research Group of the Junta de Andalucía, Spain (RNM179

The ideal trefoil knot

The most tight conformation of the trefoil knot found by the SONO algorithm is presented. Structure of the set of its self-contact points is analyzed.Comment: 11 pages, 8 figure

Early onset retinal dystrophies: Clinical clues to diagnosis for pediatricians

Introduction: Inherited retinal dystrophies are major cause of severe progressive vision loss in children. Early recognition and diagnosis are essential for timely visual rehabilitation during the appropriate stages of the visual development, as well as for genetic diagnosis and possible gene therapy. The aim of this study is to characterize a pattern of the initial visual symptoms, which could help the pediatricians and the primary care providers to suspect an inherited retinal disorder in its early stage. Methods: We analyzed the initial clinical symptoms, based on parental report during the first visit to specialist, in 50 children diagnosed with retinal dystrophy confirmed by full-field electroretinography. The analysis included the age of symptoms onset and the type of visual symptoms, both in the total population and in the following diagnostic subgroups: rod-cone dystrophy (n.17), cone-rod dystrophy (n.12), achromatopsia (n.13), congenital stationary night blindness (n.6) and Leber's congenital amaurosis (n.2). Results: The majority of children (80%) had the onset of clinical symptoms before one year of age. The most frequent visual complaints reported by parents were nystagmus (76%), visual loss (28%) and photophobia (8%). Nystagmus was the first symptom reported by parents if the disease onset was before the age of six months, while the onset after the six months of age was more likely associated with the complain of vision loss. Conclusions: Low vision and nystagmus observed by parents, particularly in the first year of life, may represent a red flag, prompting an appropriate ophthalmological workup for inherited retinal dystrophy

On the relationship between directed percolation and the synchronization transition in spatially extended systems

We study the nature of the synchronization transition in spatially extended systems by discussing a simple stochastic model. An analytic argument is put forward showing that, in the limit of discontinuous processes, the transition belongs to the directed percolation (DP) universality class. The analysis is complemented by a detailed investigation of the dependence of the first passage time for the amplitude of the difference field on the adopted threshold. We find the existence of a critical threshold separating the regime controlled by linear mechanisms from that controlled by collective phenomena. As a result of this analysis we conclude that the synchronization transition belongs to the DP class also in continuous models. The conclusions are supported by numerical checks on coupled map lattices too

Scaling of the Random-Field Ising Model at Zero Temperature

The exact determination of ground states of small systems is used in a scaling study of the random-field Ising model. While three variants of the model are found to be in the same universality class in 3 dimensions, the Gaussian and bimodal models behave distinctly in 4 dimensions with the latter apparently having a discontinuous jump in the magnetization. A finite-size scaling analysis is presented for this transition.Comment: 14 pages Latex, 4 figure