Anticooperativity in diffusion-controlled reactions with pairs of anisotropic domains: a model for the antigen-antibody encounter

The encounter between anisotropic agents in diffusion-controlled reactions is a topic of very general relevance in chemistry and biology. Here we introduce a simplified model of encounter of an isotropic molecule with a pair of partially reacting agents and apply it to the encounter reaction between an antibody and its antigen. We reduce the problem to the solution of dual series relations, which can be solved iteratively, yielding the exact solution for the encounter rate constant at any desired order of accuracy. We quantify the encounter effectiveness by means of a simple indicator and show that the two binding centers systematically behave in an anticooperative fashion. However, we demonstrate that a reduction of the binding active sites allows the composite molecule to recover binding effectiveness, in spite of the overall reduction of the rate constant. In addition, we provide a simple formula that enables one to calculate the anticooperativity as a function of the size of the binding site for any values of the separation between the two active lobes and of the antigen size. Finally, some biological implications of our results are discusse

La lipomatosi congenita infiltrante del volto. Caso Clinico

Congenital infiltrating lipomatosis of the face, first described by Beck in 1836, is a rare condition of unknown etiology, characterized by widespread infiltration of mature fat cells in the context of tissues softening of the face, with associated consequent bone deformities. It is presented as an isolated or associated condition hemimegalencephaly and neurocutaneous syndromes. We describe the case of a 10-year-old patient with known lipomatosis congenital of the face, arrived at our structure for follow up with Computed Tomography (CT) and Resonance Magnetic (RM) .

Stochastic dynamics of model proteins on a directed graph

A method for reconstructing the energy landscape of simple polypeptidic chains is described. We show that we can construct an equivalent representation of the energy landscape by a suitable directed graph. Its topological and dynamical features are shown to yield an effective estimate of the time scales associated with the folding and with the equilibration processes. This conclusion is drawn by comparing molecular dynamics simulations at constant temperature with the dynamics on the graph, defined by a temperature dependent Markov process. The main advantage of the graph representation is that its dynamics can be naturally renormalized by collecting nodes into "hubs", while redefining their connectivity. We show that both topological and dynamical properties are preserved by the renormalization procedure. Moreover, we obtain clear indications that the heteropolymers exhibit common topological properties, at variance with the homopolymer, whose peculiar graph structure stems from its spatial homogeneity. In order to obtain a clear distinction between a "fast folder" and a "slow folder" in the heteropolymers one has to look at kinetic features of the directed graph. We find that the average time needed to the fast folder for reaching its native configuration is two orders of magnitude smaller than its equilibration time, while for the bad folder these time scales are comparable. Accordingly, we can conclude that the strategy described in this paper can be successfully applied also to more realistic models, by studying their renormalized dynamics on the directed graph, rather than performing lengthy molecular dynamics simulations.Comment: 15 pages, 12 figure

Anti-cooperativity in diffusion-controlled reactions with pairs of anisotropic domains: a model for the antigen-antibody encounter

The encounter between anisotropic agents in diffusion-controlled reactions is a topic of very general relevance in chemistry and biology. Here we introduce a simplified model of encounter of an isotropic molecule with a pair of partially reacting agents and apply it to the encounter reaction between an antibody and its antigen. We reduce the problem to the solution of dual series relations, which can be solved iteratively, yielding the exact solution for the encounter rate constant at any desired order of accuracy. We quantify the encounter effectiveness by means of a simple indicator and show that the two binding centers systematically behave in an anti-cooperative fashion. However, we demonstrate that a reduction of the binding active sites allows the composite molecule to recover binding effectiveness, in spite of the overall reduction of the rate constant. In addition, we provide a simple formula that enables one to calculate the anti-cooperativity as a function of the size of the binding site for any values of the separation between the two active lobes and of the antigen size. Finally, some biological implications of our results are discussed

Development and Validation of a Comprehensive Model to Estimate Early Allograft Failure among Patients Requiring Early Liver Retransplant

Importance: Expansion of donor acceptance criteria for liver transplant increased the risk for early allograft failure (EAF), and although EAF prediction is pivotal to optimize transplant outcomes, there is no consensus on specific EAF indicators or timing to evaluate EAF. Recently, the Liver Graft Assessment Following Transplantation (L-GrAFT) algorithm, based on aspartate transaminase, bilirubin, platelet, and international normalized ratio kinetics, was developed from a single-center database gathered from 2002 to 2015. Objective: To develop and validate a simplified comprehensive model estimating at day 10 after liver transplant the EAF risk at day 90 (the Early Allograft Failure Simplified Estimation [EASE] score) and, secondarily, to identify early those patients with unsustainable EAF risk who are suitable for retransplant. Design, Setting, and Participants: This multicenter cohort study was designed to develop a score capturing a continuum from normal graft function to nonfunction after transplant. Both parenchymal and vascular factors, which provide an indication to list for retransplant, were included among the EAF determinants. The L-GrAFT kinetic approach was adopted and modified with fewer data entries and novel variables. The population included 1609 patients in Italy for the derivation set and 538 patients in the UK for the validation set; all were patients who underwent transplant in 2016 and 2017. Main Outcomes and Measures: Early allograft failure was defined as graft failure (codified by retransplant or death) for any reason within 90 days after transplant. Results: At day 90 after transplant, the incidence of EAF was 110 of 1609 patients (6.8%) in the derivation set and 41 of 538 patients (7.6%) in the external validation set. Median (interquartile range) ages were 57 (51-62) years in the derivation data set and 56 (49-62) years in the validation data set. The EASE score was developed through 17 entries derived from 8 variables, including the Model for End-stage Liver Disease score, blood transfusion, early thrombosis of hepatic vessels, and kinetic parameters of transaminases, platelet count, and bilirubin. Donor parameters (age, donation after cardiac death, and machine perfusion) were not associated with EAF risk. Results were adjusted for transplant center volume. In receiver operating characteristic curve analyses, the EASE score outperformed L-GrAFT, Model for Early Allograft Function, Early Allograft Dysfunction, Eurotransplant Donor Risk Index, donor age × Model for End-stage Liver Disease, and Donor Risk Index scores, estimating day 90 EAF in 87% (95% CI, 83%-91%) of cases in both the derivation data set and the internal validation data set. Patients could be stratified in 5 classes, with those in the highest class exhibiting unsustainable EAF risk. Conclusions and Relevance: This study found that the developed EASE score reliably estimated EAF risk. Knowledge of contributing factors may help clinicians to mitigate risk factors and guide them through the challenging clinical decision to allocate patients to early liver retransplant. The EASE score may be used in translational research across transplant centers

Neuer Kopf, alte Ideen? : "Normalisierung" des Front National unter Marine Le Pen

In this article, it is investigated whether vibrational entropy (VE) is an important contribution to the free energy of globular proteins at ambient conditions. VE represents the major configurational-entropy contribution of these proteins. By definition, it is an average of the configurational entropies of the protein within single minima of the energy landscape, weighted by their occupation probabilities. Its large part originates from thermal motion of flexible torsion angles giving rise to the finite peak widths observed in torsion angle distributions. While VE may affect the equilibrium properties of proteins, it is usually neglected in numerical calculations as its consideration is difficult. Moreover, it is sometimes believed that all well-packed conformations of a globular protein have similar VE anyway. Here, we measure explicitly the VE for six different conformations from simulation data of a test protein. Estimates are obtained using the quasi-harmonic approximation for three coordinate sets, Cartesian, bond-angle-torsion (BAT), and a new set termed rotamer-degeneracy lifted BAT coordinates by us. The new set gives improved estimates as it overcomes a known shortcoming of the quasi-harmonic approximation caused by multiply populated rotamer states, and it may serve for VE estimation of macromolecules in a very general context. The obtained VE values depend considerably on the type of coordinates used. However, for all coordinate sets we find large entropy differences between the conformations, of the order of the overall stability of the protein. This result may have important implications on the choice of free energy expressions used in software for protein structure prediction, protein design, and NMR refinement

CONFORMATIONAL PROPERTIES OF 3,3'-, 3,4'- AND 4,4'-DIMETHYL- AND -BIS(METHYLSULFANYL)-2,2'-BITHIOPHENES

The conformational properties of the title compounds, which are the basic head-to-head, head-to-tail and tail-to-tail repeat units of regioregular poly(3-methylthiophenes) and poly[3-(methylsulfanyl)thiophenes], are discussed. The paper reports the X-ray structures of the two 4,4'-derivatives, H-1 NMR NOE data on the 3,4'- and 4,4'-derivatives and force field MM2 calculations of the conformation of the three bis(methylsulfanyl) derivatives

Chest fast MRI: an imaging alternative on pre-operative evaluation of pectus excavatum.

Abstract BACKGROUND: Standard imaging methods in evaluating chest wall deformities, such as Pectus Excavatum (PE) in paediatric and adolescent patients, include baseline 2-view chest radiography and chest CT scan. Only few studies to date investigated the value of fast MRIin the pre operative assessment of patient affected by PE. OBJECTIVE: To evaluate the efficacy of chest fast MRI in pre-operative management of patient affected by PE. To obtain the Haller Index (HI) and Asymmetry Index (AI) from chest fast MRI protecting patients from radiation exposure. MATERIALS AND METHODS: We analyzed the data of 42 consecutive patients with severe PE who underwent minimally invasive repair between March 2007 and March 2010. All 42 patients received chest fast MRI, but only the first 5 in view of the results, were studied also with chest ultrafast CT scan. In both examinations, data at the deepest point of the depression were collected. RESULTS: Severity indices of the deformity using HI and AI, collected from CT scan and fast MRI in the first 5 patients, were comparable. In the remaining 37 fast chest MRI offered good images of the chest wall deformities with no radiation exposure, detailing anatomical information such as displacement and rotation of the heart or great vessels anomalies. CONCLUSION: This study suggests the use of chest MRI in pre operative workup for patients with PE to obtain severity indices (Haller Index and Asymmetry Index avoiding radiation exposure to paediatric patients. Copyright © 2012 Elsevier Inc. All rights reserved