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The use of dual-mobility cups has gained popularity in recent years. Thus, surgeons can expect an increase in known and new causes of failure. We report a previously undescribed form of a late intraprosthetic dislocation consisting of a complete breakage of a polyethylene mobile bearing that suffered a dislocation 3 months after its implantation. Two years later, he began feeling anterior groin pain and suffered gait changes. Computed tomography scan revealed an eccentric alignment of the mobile polyethylene bearing suggestive of poly wear. During the revision surgery, the polyethylene was found to be split in 2. Possible causes of this complication are proposed. Our case shows a previously unreported implant-specific complication, so surgeons can identify it.

Recurrent posterior glenohumeral instability is an entity that demands a high clinical suspicion and a detailed study for a correct approach and treatment. Its classification must consider its biomechanics, whether it is due to functional muscular imbalance or to structural changes, volition, and intentionality. Due to its varied clinical presentations and different structural alterations, ranging from capsule-labral lesions and bone defects to glenoid dysplasia and retroversion, the different treatment alternatives available have historically had a high incidence of failure. A detailed radiographic assessment, with both CT and MRI, with a precise assessment of glenoid and humeral bone defects and of glenoid morphology, is mandatory. Physiotherapy focused on periscapular muscle reeducation and external rotator strengthening is always the first line of treatment. When conservative treatment fails, surgical treatment must be guided by the structural lesions present, ranging from soft tissue repair to posterior bone block techniques to restore or increase the articular surface. Bone block procedures are indicated in cases of recurrent posterior instability after the failure of conservative treatment or soft tissue techniques, as well as symptomatic demonstrable nonintentional instability, presence of a posterior glenoid defect >10%, increased glenoid retroversion between 10 and 25°, and posterior rim dysplasia. Bone block fixation techniques that avoid screws and metal allow for satisfactory initial clinical results in a safe and reproducible way. An algorithm for the approach and treatment of recurrent posterior glenohumeral instability is presented, as well as the author’s preferred surgical technique for arthroscopic posterior bone block.

Molecular dynamics (MD) simulations have become a standard tool to correlate the structure and function of biomolecules and significant advances have been made in the study of proteins and their complexes. A major drawback of conventional MD simulations is the difficulty and cost of obtaining converged results, especially when exploring potential energy surfaces containing considerable energy barriers. This limits the wide use of MD calculations to determine the thermodynamic properties of biomolecular processes. Indeed, this is true when considering the conformational entropy of such processes, which is ultimately critical in assessing the simulations' convergence. Alternatively, a wide range of structure-based models (SBMs) has been used in the literature to unravel the basic mechanisms of biomolecular dynamics. These models introduce simplifications that focus on the relevant aspects of the physical process under study. Because of this, SBMs incorporate the need to modify the force field definition and parameters to target specific biophysical simulations. Here we introduce SBMOpenMM, a Python library to build force fields for SBMs, that uses the OpenMM framework to create and run SBM simulations. The code is flexible and user-friendly and profits from the high customizability and performance provided by the OpenMM platform.

Soluble guanylate cyclase (sGC), the main target of nitric oxide (NO), has been proven to have a significant role in coronary artery disease, pulmonary hypertension, erectile dysfunction, and myocardial infarction. One of its agonists, BAY 41-2272 (Riociguat), has been recently approved for treatment of pulmonary arterial hypertension (PHA), while some others are in clinical phases of development. However, the location of the binding sites for the two known types of agonists, heme-dependent stimulators and heme-independent activators, is a matter of debate, particularly for the first group where both a location on the regulatory (H-NOX) and on the catalytic domain have been suggested by different authors. Here, we address its potential location on the catalytic domain, the unique well characterized at the structural level, by an "in silico" approach. Homology models of the catalytic domain of sGC in "inactive" or "active" conformations were constructed using the structure of previously described crystals of the catalytic domains of "inactive" sGCs (2WZ1, 3ET6) and of "active" adenylate cyclase (1CJU). Each model was submitted to six independent molecular dynamics simulations of about 1 μs. Docking of YC-1, a classic heme-dependent stimulator, to all frames of representative trajectories of "inactive" and "active" conformations, followed by calculation of absolute binding free energies with the linear interaction energy (LIE) method, revealed a potential high-affinity binding site on the "active" structure. The site, located between the pseudo-symmetric and the catalytic site just over the loop β2 -β3 , does not overlap with the forskolin binding site on adenylate cyclases. Proteins 2016; 84:1534-1548. © 2016 Wiley Periodicals, Inc.

Altres ajuts: Programa HIVACAT, programa CERCA (Generalitat de Catalunya), Red Temática Cooperativa de Investigación en SIDA (RD12/0017/0002)), Govern Basc (IT838-13), Spanish Supercomputing Network (grant numbers BCV-2015-2-0009 and BCV-2016-2-0005) The HIV-1 gp41 Membrane Proximal External Region (MPER) is recognized by broadly neutralizing antibodies and represents a promising vaccine target. However, MPER immunogenicity and antibody activity are influenced by membrane lipids. To evaluate lipid modulation of MPER immunogenicity, we generated a 1-Palmitoyl-2-oleoylphosphatidylcholine (POPC)-based proteoliposome collection containing combinations of phosphatidylserine (PS), GM3 ganglioside, holesterol (CHOL), sphingomyelin (SM) and the TLR4 agonist monophosphoryl lipid A (MPLA). A recombinant gp41-derived miniprotein (gp41-MinTT) exposing the MPER and a tetanus toxoid (TT) peptide that favors MHC-II presentation, was successfully incorporated into lipid mixtures (>85%). Immunization of mice with soluble gp41-MinTT exclusively induced responses against the TT peptide, while POPC proteoliposomes generated potent anti-gp41 IgG responses using lower protein doses. The combined addition of PS and GM3 or CHOL/SM to POPC liposomes greatly increased gp41 immunogenicity, which was further enhanced by the addition of MPLA. Responses generated by all proteoliposomes targeted the N-terminal moiety of MPER overlapping the 2F5 neutralizing epitope. Our data show that lipids impact both, the epitope targeted and the magnitude of the response to membrane-dependent antigens, helping to improve MPER-based lipid carriers. Moreover, the identification of immunodominant epitopes allows for the redesign of immunogens targeting MPER neutralizing determinants.

Soluble guanylate cyclase (sGC), the main target of nitric oxide (NO), has been proven to have a significant role in coronary artery disease, pulmonary hypertension, erectile dysfunction, and myocardial infarction. One of its agonists, BAY 41-2272 (Riociguat), has been recently approved for treatment of pulmonary arterial hypertension (PHA), while some others are in clinical phases of development. However, the location of the binding sites for the two known types of agonists, heme-dependent stimulators and heme-independent activators, is a matter of debate, particularly for the first group where both a location on the regulatory (H-NOX) and on the catalytic domain have been suggested by different authors. Here, we address its potential location on the catalytic domain, the unique well characterized at the structural level, by an "in silico" approach. Homology models of the catalytic domain of sGC in "inactive" or "active" conformations were constructed using the structure of previously described crystals of the catalytic domains of "inactive" sGCs (2WZ1, 3ET6) and of "active" adenylate cyclase (1CJU). Each model was submitted to six independent molecular dynamics simulations of about 1 μs. Docking of YC-1, a classic heme-dependent stimulator, to all frames of representative trajectories of "inactive" and "active" conformations, followed by calculation of absolute binding free energies with the linear interaction energy (LIE) method, revealed a potential high-affinity binding site on the "active" structure. The site, located between the pseudo-symmetric and the catalytic site just over the loop β2 -β3 , does not overlap with the forskolin binding site on adenylate cyclases. Proteins 2016; 84:1534-1548. © 2016 Wiley Periodicals, Inc.

The tumor necrosis factor receptor superfamily, member 1A (TNFRSF1A) gene encodes the TNF-R1, one of the main TNF receptors that mediates its inflammatory actions. In a recent study, serum levels of the soluble TNF-R1 and mRNA levels of the full-length receptor were found to be significantly increased in multiple sclerosis (MS) patients carrying the R92Q mutation. Interestingly, R92Q-mutated patients were younger at disease onset and progressed slower as compared to non-carriers. Building on these previous findings, here we aimed to investigate by means of both in silico and in vitro approaches the mechanisms relating the R92Q substitution with functional changes of the receptor and their potential effects modulating MS disease course. Models of the extracellular domains of the human TNF-R1 and human TNF-R1 carrying the R92Q mutation, alone or bound to TNF, were constructed and submitted to molecular dynamics. TRAF2 and CASP3 mRNA expression levels were determined by real-time PCR in peripheral blood mononuclear cells (PBMC) from 61 MS patients, 9 R92Q carriers and 52 non-carriers (CT and CC genotypes for SNP rs4149584, respectively). Molecular dynamic studies revealed that the R92Q mutation increased the contact area between receptor and TNF (1070 and 1388A(2) for native and mutated receptor) and decreased the distance between them (28.7 to 27.9A), while Van der Waals and electrostatic interaction energies were increased. In PBMC from MS patients carrying the R92Q mutation, CASP3 mRNA expression levels were significantly increased compared to non-carriers, whereas a trend was observed for TRAF2. These data suggest that the R92Q mutation gives rise to a stronger interaction between the receptor and its ligand, which results in the potentiation of TNF-mediated pathways. Although further studies are needed, these functional changes may be related with the modulation in disease course reported in MS patients carrying the R92Q mutation.

Soluble guanylate cyclase (sGC), the main target of nitric oxide (NO), has been proven to have a significant role in coronary artery disease, pulmonary hypertension, erectile dysfunction and myocardial infarction. Several drugs that increase the activity of this enzyme are now in clinical phase of development: some of them are heme-dependent and might interact with the catalytic domain and others are heme-independent and supposedly bind to the sensory domain. The absence of reliable structural information is one of the factors that have precluded knowledge of the precise site of interaction of these molecules and of the mechanism of activation of the enzyme.