A graph-theoretic approach for classification and structure prediction of transmembrane β-barrel proteins

BACKGROUND: Non-synonymous coding SNPs (nsSNPs) that are associated to disease can also be related with alterations in protein stability. Computational methods are available to predict the effect of single amino acid substitutions (SASs) on protein stability based on a single folded structure. However, the native state of a protein is not unique and it is better represented by the ensemble of its conformers in dynamic equilibrium. The maintenance of the ensemble is essential for protein function. In this work we investigated how protein conformational diversity can affect the discrimination of neutral and disease related SASs based on protein stability estimations. For this purpose, we used 119 proteins with 803 associated SASs, 60% of which are disease related. Each protein was associated with its corresponding set of available conformers as found in the Protein Conformational Database (PCDB). Our dataset contains proteins with different extensions of conformational diversity summing up a total number of 1023 conformers. RESULTS: The existence of different conformers for a given protein introduces great variability in the estimation of the protein stability (\u394\u394G) after a single amino acid substitution (SAS) as computed with FoldX. Indeed, in 35% of our protein set at least one SAS can be described as stabilizing, destabilizing or neutral when a cutoff value of \ub12 kcal/mol is adopted for discriminating neutral from perturbing SASs. However, when the \u394\u394G variability among conformers is taken into account, the correlation among the perturbation of protein stability and the corresponding disease or neutral phenotype increases as compared with the same analysis on single protein structures. At the conformer level, we also found that the different conformers correlate in a different way to the corresponding phenotype. CONCLUSIONS: Our results suggest that the consideration of conformational diversity can improve the discrimination of neutral and disease related protein SASs based on the evaluation of the corresponding Gibbs free energy change

Changing the paradigm in postherpetic neuralgia treatment: lidocaine 700 mg medicated plaster

OBJECTIVE: Chronic pain is currently considered a disease state with biopsychosocial consequences and a negative impact on patients' quality of life (QoL). Pain from postherpetic neuralgia (PHN) can persist for months or years and is a prototypical example of chronic pain. We analyzed PHN as a model of chronic pain. including its effects on QoL and clinical aspects. We explored treatment options, focusing on the topical treatment with lidocaine 700 mg medicated plaster (LMP) and how this impacts PHN management.MATERIALS AND METHODS: This article is a narrative review of published studies. Preclinical and clinical studies were retrieved from literature through a search performed in PubMed/MEDLINE.RESULTS: To choose the appropriate treatment for chronic pains, such as PHN, not only efficacy but also tolerability, manageability, practicality, and compliance are important factors. especially in the long term. It is also important to set treatment expectations with the patients as total suppression of pain may be unrealistic. and a balance needs to be found between pain control and the minimization of adverse events. In this respect, LMP may be the best currently available treatment: it is easy to use, has low systemic absorption and thus a low risk for pharmacological interactions. Therefore, treatments can be personalized, and concomitant medications can be added, if needed. Recent data from a real-world study support this view by showing that LMP has superior effectiveness in reducing pain and improving the QoL compared to other commonly used systemic treatments and confirming its good tolerability profile that is mainly characterized by localized skin reactions.CONCLUSIONS: LMP is one of the best currently available treatment options for PHN patients balancing good efficacy with an excellent tolerability profile and can therefore be considered for use as a first-line treatment for PHN

Contar la historia a la nación. Dos adaptaciones transculturales de la serie española de televisión Cuéntame cómo pasó: Raccontami y Conta-me como foi

En septiembre de 2001, Televisión Española estrenó Cuéntame cómo pasó, una serie de ficción que narra la vida en España durante los últimos años del franquismo a través de la familia Alcántara. Concebida como un relato histórico de carácter popular y para todos los públicos, su inmediato éxito de audiencia significó la consolidación en prime time de una historia definida dramáticamente por el contexto dictatorial del franquismo y, pese a las especificidades históricas, la venta internacional de su formato. En diciembre de 2006, la RAI —Radio Televisione Italiana— estrenó Raccontami, la versión italiana que, con la familia Ferrucci como protagonista de la ficción, plantea el primer caso de adaptación de la serie española en un entorno sociocultural sin dictadura. En abril de 2007, la RTP — Radio Televisión Portuguesa — estrenó Conta-me como foi, la adaptación portuguesa con los Lopes como representantes de la familia de clase media y como testigos de la última etapa de la dictadura salazarista. Emitidas por televisiones públicas, ambas series, además de tener la nostalgia del pasado como punto de partida creativo común, utilizan una estructura narrativa similar a Cuéntame cómo pasó para ofrecer un relato propio y diferenciado de la realidad de sus países. Más allá de los paralelismos e intercambios argumentales establecidos con la serie original, el presente artículo ofrece un análisis de estas dos adaptaciones dispares con el fin de entender el tipo de representación histórica desde conceptos de transtextualidad e identidad

Ensembles from Ordered and Disordered Proteins Reveal Similar Structural Constraints during Evolution

The conformations accessible to proteins are determined by the inter-residue interactions between amino acid residues. During evolution, structural constraints that are required for protein function providing biologically relevant information can exist. Here, we studied the proportion of sites evolving under structural constraints in two very different types of ensembles, those coming from ordered and disordered proteins. Using a structurally constrained model of protein evolution, we found that both types of ensembles show comparable, near 40%, number of positions evolving under structural constraints. Among these sites, ~ 68% are in disordered regions and ~ 57% of them show long-range inter-residue contacts. Also, we found that disordered ensembles are redundant in reference to their structurally constrained evolutionary information and could be described on average with ~ 11 conformers. Despite the different complexity of the studied ensembles and proteins, the similar constraints reveal a comparable level of selective pressure to maintain their biological functions. These results highlight the importance of the evolutionary information to recover meaningful biological information to further characterize conformational ensembles.Fil: Marchetti, Julia. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Monzón, Alexander. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Università di Padova; Italia. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Tosatto, Silvio C.E.. Università di Padova; ItaliaFil: Parisi, Gustavo Daniel. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Fornasari, Maria Silvina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Desogestrel down-regulates PHOX2B and its target genes in progesterone responsive neuroblastoma cells

The paired-like homeobox 2B gene (PHOX2B) encodes a key transcription factor that plays a role in the development of the autonomic nervous system and the neural structures involved in controlling breathing. In humans, PHOX2B over-expression plays a role in the pathogenesis of tumours arising from the sympathetic nervous system such as neuroblastomas, and heterozygous PHOX2B mutations cause Congenital Central Hypoventilation Syndrome (CCHS), a life-threatening neurocristopathy characterised by the defective autonomic control of breathing and involving altered CO2/H+ chemosensitivity. The recovery of CO2/H+ chemosensitivity and increased ventilation have been observed in two CCHS patients using the potent contraceptive progestin desogestrel. Given the central role of PHOX2B in the pathogenesis of CCHS, and the progesterone-mediated effects observed in the disease, we generated progesterone-responsive neuroblastoma cells, and evaluated the effects of 3-Ketodesogestrel (3-KDG), the biologically active metabolite of desogestrel, on the expression of PHOX2B and its target genes. Our findings demonstrate that, through progesterone nuclear receptor PR-B, 3-KDG down-regulates PHOX2B gene expression, by a post-transcriptional mechanism, and its target genes and open up the possibility that this mechanism may contribute to the positive effects observed in some CCHS patients

Evaluation of macular pigment optical density following femtosecond laser-assisted cataract surgery

Background: To evaluate macular pigment optical density (MPOD) after bimanual femtosecond laser-assisted cataract surgery (FLACS) compared to standard bimanual phacoemulsification (B-MICS). Methods: Aprospective, casematched, comparative cohort study conducted at theInstitute of Ophthalmology, University of Modena and Reggio Emilia (Italy); 30 eyes under wentbimanual FLACS with low-energy Ziemer LDV Z8 (FLACS) and 30 underwent B-MICS standard technique (B-MICS). All interventions were conducted by the same expert surgeon. MPOD using the Macular Pigment Screener II (MPS II) was evaluated at baseline, 7 and 30 days after surgery. As secondary outcomes, we considered best corrected visual acuity (BCVA) and central macular thickness (CMT) obtained using optical coherence tomography. Results: In all cases, a BunnyLens AF IOL was safely implanted in the capsular bag through a1.4 mm incision. We found asignificant reductionin MPOD in both groups at 7 and 30 days; 0.16 ±0.14 and 0.10±0.12 (FLACS) and 0.18±0.13 and 0.15±0.14 (B-MICS), respectively (P<0.05). However, there was no significant difference between the two groups at either 7 (P=0.52) or 30 days (P=0.18). BCVA improved significantly in both groups and CMT increased in both groups (P<0.001, P<0.001, respectively). BCVA and CMT were similar between the groups with a significant difference in CMT in favor of the FLACS group at 30 days (P=0.017). Conclusions: MPOD was reduced in both groups without any significant difference between the FLACS and B-MICS cataract interventions. FLACS is associated with a significantly higher increase of macular thickness at 30 days compared to B-MICS

Capsaicin 8% dermal patch in clinical practice: an expert opinion

Introduction: Neuropathic pain (NP) is caused by a lesion or disease of the somatosensory system, which can severely impact patients’ quality of life. The current-approved treatments for NP comprise of both centrally acting agents and topical drugs, including capsaicin 8% dermal patches, which is approved for the treatment of peripheral NP. / Areas covered: The authors summarize literature data regarding capsaicin use in patients who suffer from NP and discuss the clinical applications of this topical approach. / Expert opinion: Overall, the capsaicin 8% dermal patch is as effective in reducing pain intensity as other centrally active agents (i.e. pregabalin). Some studies have also reported fewer systemic side effects, a faster onset of action and superior treatment satisfaction compared with systemic agents. In our opinion, capsaicin 8% dermal patches also present additional advantages, such as a good systemic tolerability, the scarcity of adverse events, the possibility to combine it with other agents, and a good cost-effective profile. It is important to note that, as the mechanism of action of capsaicin 8% is the ‘defunctionalization’ of small afferent fibers through interaction with TRPV1 receptors, the peripheral expression of this receptor on nociceptor fibers, is crucial to predict patient’s response to treatment

Structural and functional differences in PHOX2B frameshift mutations underlie isolated or syndromic congenital central hypoventilation syndrome

Heterozygous mutations in the PHOX2B gene are causative of congenital central hypoventilation syndrome (CCHS), a neurocristopathy characterized by defective autonomic control of breathing due to the impaired differentiation of neural crest cells. Among PHOX2B mutations, polyalanine (polyAla) expansions are almost exclusively associated with isolated CCHS, whereas frameshift variants, although less frequent, are often more severe than polyAla expansions and identified in syndromic CCHS. This article provides a complete review of all the frameshift mutations identified in cases of isolated and syndromic CCHS reported in the literature as well as those identified by us and not yet published. These were considered in terms of both their structure, whether the underlying indels induced frameshifts of either 1 or 2 steps (\u201cframe 2\u201d and \u201cframe 3\u201d mutations respectively), and clinical associations. Furthermore, we evaluated the structural and functional effects of one \u201cframe 3\u201d mutation identified in a patient with isolated CCHS, and one \u201cframe 2\u201d mutation identified in a patient with syndromic CCHS, also affected with Hirschsprung's disease and neuroblastoma. The data thus obtained confirm that the type of translational frame affects the severity of the transcriptional dysfunction and the predisposition to isolated or syndromic CCH

MCM-41 supported co-based bimetallic catalysts for aqueous phase transformation of glucose to biochemicals

The transformation of glucose into valuable biochemicals was carried out on different MCM-41-supported metallic and bimetallic (Co, Co-Fe, Co-Mn, Co-Mo) catalysts and under different reaction conditions (150 °C, 3 h; 200 °C, 0.5 h; 250 °C, 0.5 h). All catalysts were characterized using N2 physisorption, Temperature Programmed Reduction (TPR), Raman, X-ray Diffraction (XRD) and Temperature Programmed Desorption (TPD) techniques. According to the N2-physisorption results, a high surface area and mesoporous structure of the support were appropriate for metal dispersion, reactant diffusion and the formation of bioproducts. Reaction conditions, bimetals synergetic effects and the amount and strength of catalyst acid sites were the key factors affecting the catalytic activity and biochemical selectivity. Sever reaction conditions including high temperature and high catalyst acidity led to the formation mainly of solid humins. The NH3-TPD results demonstrated the alteration of acidity in different bimetallic catalysts. The 10Fe10CoSiO2 catalyst (MCM-41 supported 10 wt. þ, 10 wt. %Co) possessing weak acid sites displayed the best catalytic activity with the highest carbon balance and desired product selectivity in mild reaction condition. Valuable biochemicals such as fructose, levulinic acid, ethanol and hydroxyacetone were formed over this catalyst