Interaction of EF-Tu with EF-Ts: substitution of His-118 in EF-Tu destabilizes the EF-Tu·EF-Ts complex but does not prevent EF-Ts from stimulating the release of EF-Tu-bound GDP

AbstractElongation factor Tu from Escherichia coli with His-118 substituted by glycine (EF-TuH118G) was found to be defective in complex formation with EF-Ts. EF-Ts in excess failed to dissociate kirromycin from the EF-TuH118G·kirromycin complex and to form a stable complex with EF-TuH118G on column chromatography. However, the stimulatory effect of EF-Ts on GDP dissociation from EF-TuH118G·GDP and on poly(U)-directed poly(Phe) synthesis catalyzed by EF-TuH118G was only partially influenced. These results indicate that His-118, while very important for the formation of a stable EF-Tu·EF-Ts complex, is not essential for the transmission of the EF-Ts-dependent signal accelerating the release of the EF-Tu-bound GDP

Transport on a Lattice with Dynamical Defects

Many transport processes in nature take place on substrates, often considered as unidimensional lanes. These unidimensional substrates are typically non-static: affected by a fluctuating environment, they can undergo conformational changes. This is particularly true in biological cells, where the state of the substrate is often coupled to the active motion of macromolecular complexes, such as motor proteins on microtubules or ribosomes on mRNAs, causing new interesting phenomena. Inspired by biological processes such as protein synthesis by ribosomes and motor protein transport, we introduce the concept of localized dynamical sites coupled to a driven lattice gas dynamics. We investigate the phenomenology of transport in the presence of dynamical defects and find a novel regime characterized by an intermittent current and subject to severe finite-size effects. Our results demonstrate the impact of the regulatory role of the dynamical defects in transport, not only in biology but also in more general contexts

A Novel null homozygous mutation confirms <i>CACNA2D2</i> as a gene mutated in epileptic encephalopathy

Contribution to epileptic encephalopathy (EE) of mutations in CACNA2D2, encoding α2δ-2 subunit of Voltage Dependent Calcium Channels, is unclear. To date only one CACNA2D2 mutation altering channel functionality has been identified in a single family. In the same family, a rare CELSR3 polymorphism also segregated with disease. Involvement of CACNA2D2 in EE is therefore not confirmed, while that of CELSR3 is questionable. In a patient with epilepsy, dyskinesia, cerebellar atrophy, psychomotor delay and dysmorphic features, offspring to consanguineous parents, we performed whole exome sequencing (WES) for homozygosity mapping and mutation detection. WES identified extended autozygosity on chromosome 3, containing two novel homozygous candidate mutations: c.1295delA (p.Asn432fs) in CACNA2D2 and c.G6407A (p.Gly2136Asp) in CELSR3. Gene prioritization pointed to CACNA2D2 as the most prominent candidate gene. The WES finding in CACNA2D2 resulted to be statistically significant (p = 0.032), unlike that in CELSR3. CACNA2D2 homozygous c.1295delA essentially abolished α2δ-2 expression. In summary, we identified a novel null CACNA2D2 mutation associated to a clinical phenotype strikingly similar to the Cacna2d2 null mouse model. Molecular and statistical analyses together argued in favor of a causal contribution of CACNA2D2 mutations to EE, while suggested that finding in CELSR3, although potentially damaging, is likely incidental

Dynamic correlation functions and Boltzmann Langevin approach for driven one dimensional lattice gas

We study the dynamics of the totally asymmetric exclusion process with open boundaries by phenomenological theories complemented by extensive Monte-Carlo simulations. Upon combining domain wall theory with a kinetic approach known as Boltzmann-Langevin theory we are able to give a complete qualitative picture of the dynamics in the low and high density regime and at the corresponding phase boundary. At the coexistence line between high and low density phases we observe a time scale separation between local density fluctuations and collective domain wall motion, which are well accounted for by the Boltzmann-Langevin and domain wall theory, respectively. We present Monte-Carlo data for the correlation functions and power spectra in the full parameter range of the model.Comment: 10 pages, 9 figure

Modelling the effect of ribosome mobility on the rate of protein synthesis

Translation is one of the main steps in the synthesis of proteins. It consists of ribosomes that translate sequences of nucleotides encoded on mRNA into polypeptide sequences of amino acids. Ribosomes bound to mRNA move unidirectionally, while unbound ribosomes diffuse in the cytoplasm. It has been hypothesized that finite diffusion of ribosomes plays an important role in ribosome recycling and that mRNA circularization enhances the efficiency of translation. In order to estimate the effect of cytoplasmic diffusion on the rate of translation, we consider a Totally Asymmetric Simple Exclusion Process (TASEP) coupled to a finite diffusive reservoir, which we call the Ribosome Transport model with Diffusion (RTD). In this model, we derive an analytical expression for the rate of protein synthesis as a function of the diffusion constant of ribosomes, which is corroborated with results from continuous-time Monte Carlo simulations. Using a wide range of biological relevant parameters, we conclude that diffusion in biological cells is fast enough so that it does not play a role in controlling the rate of translation initiation.Comment: article, 16 pages, 5 figure

Clinical and Rehabilitative Management of Retinitis Pigmentosa: Up-to-Date

The term retinitis pigmentosa (RP) indicates a heterogeneous group of genetic rare ocular diseases in which either rods or cones are prevalently damaged. RP represents the most common hereditary cause of blindness in people from 20 to 60 years old. In general, the different RP forms consist of progressive photo-receptorial neuro-degenerations, which are characterized by variable visual disabilities and considerable socio-sanitary burden. Sometimes, RP patients do not become visually impaired or legally blind until their 40-50 years of age and/or maintain a quite acceptable sight for all their life. Other individuals with RP become completely blind very early or in middle childhood. Although there is no treatment that can effectively cure RP, in some case-series the disease’s progression seems to be reducible by specific preventive approaches. In the most part of RP patients, the quality of vision can be considerably increased by means of nanometer-controlled filters. In the present review, the main aspects of the routine clinical and rehabilitative managements for RP patients are described, particularly focusing on the importance of specific referral Centers to practice a real multidisciplinary governance of these dramatic diseases

Clinical and Rehabilitative Management of Retinitis Pigmentosa: Up-to-Date

The term retinitis pigmentosa (RP) indicates a heterogeneous group of genetic rare ocular diseases in which either rods or cones are prevalently damaged. RP represents the most common hereditary cause of blindness in people from 20 to 60 years old. In general, the different RP forms consist of progressive photo-receptorial neuro-degenerations, which are characterized by variable visual disabilities and considerable socio-sanitary burden. Sometimes, RP patients do not become visually impaired or legally blind until their 40-50 years of age and/or maintain a quite acceptable sight for all their life. Other individuals with RP become completely blind very early or in middle childhood. Although there is no treatment that can effectively cure RP, in some case-series the disease’s progression seems to be reducible by specific preventive approaches. In the most part of RP patients, the quality of vision can be considerably increased by means of nanometer-controlled filters. In the present review, the main aspects of the routine clinical and rehabilitative managements for RP patients are described, particularly focusing on the importance of specific referral Centers to practice a real multidisciplinary governance of these dramatic diseases

Brain correlates of spike and wave discharges in GLUT1 deficiency syndrome

Purpose To provide imaging biomarkers of generalized spike-and-wave discharges (GSWD) in patients with GLUT1 deficiency syndrome (GLUT1DS). Methods Eighteen GLUT1DS patients with pathogenetic mutation in SLC2A1 gene were studied by means of Video-EEG simultaneously recorded with functional MRI (VideoEEG-fMRI). A control group of sex and age-matched patients affected by Genetic Generalized Epilepsy (GGE) with GSWD were investigated with the same protocol. Within and between groups comparison was performed as appropriated. For GLUT1DS, correlations analyses between the contrast of interest and the main clinical measurements were provided. Results EEG during fMRI revealed interictal GSWD in 10 GLUT1DS patients. Group-level analysis showed BOLD signal increases at the premotor cortex and putamen. With respect to GGE, GLUT1DS patients demonstrated increased neuronal activity in the putamen, precuneus, cingulate cortex, SMA and paracentral lobule. Whole-brain correlation analyses disclosed a linear relationship between the GSWD-related BOLD changes and the levels of glycorrhachia at diagnosis over the sensory-motor cortex and superior parietal lobuli. Conclusion The BOLD dynamics related to GSWD in GLUT1DS are substantially different from typical GGE showing the former an increased activity in the premotor-striatal network and a decrease in the thalamus. The revealed hemodynamic maps might represent imaging biomarkers of GLUT1DS, being potentially useful for a precocious diagnosis of this genetic disorder