Chronic Intermittent Ethanol Regulates Hippocampal GABA(A) Receptor Delta Subunit Gene Expression.

Chronic ethanol consumption causes structural and functional reorganization in the hippocampus and induces alterations in the gene expression of gamma-aminobutyric acid type A receptors (GABAARs). Distinct forced intermittent exposure models have been used previously to investigate changes in GABAAR expression, with contrasting results. Here, we used repeated cycles of a Chronic Intermittent Ethanol paradigm to examine the relationship between voluntary, dependence-associated ethanol consumption, and GABAAR gene expression in mouse hippocampus. Adult male C57BL/6J mice were exposed to four 16-h ethanol vapor (or air) cycles in inhalation chambers alternated with limited-access two-bottle choice between ethanol (15%) and water consumption. The mice exposed to ethanol vapor showed significant increases in ethanol consumption compared to their air-matched controls. GABAAR alpha4 and delta subunit gene expression were measured by qRT-PCR at different stages. There were significant changes in GABAAR delta subunit transcript levels at different time points in ethanol-vapor exposed mice, while the alpha4 subunit levels remained unchanged. Correlated concurrent blood ethanol concentrations suggested that GABAAR delta subunit mRNA levels fluctuate depending on ethanol intoxication, dependence, and withdrawal state. Using a vapor-based Chronic Intermittent Ethanol procedure with combined two-bottle choice consumption, we corroborated previous evidences showing that discontinuous ethanol exposure affects GABAAR delta subunit expression but we did not observe changes in alpha4 subunit. These findings indicate that hippocampal GABAAR delta subunit expression changes transiently over the course of a Chronic Intermittent Ethanol paradigm associated with voluntary intake, in response to ethanol-mediated disturbance of GABAergic neurotransmission

A possible cause of misdiagnosis in tumors of the axilla: schwannoma of the brachial plexus

The Authors report a rare case of a 57 years old man affected by a left radial nerve schwannoma that occurred as an asymptomatic lesion of the axilla. At clinical examination the lump was undistinguishable from the most common axillary lymphadenopathy. A lymphoadenopathy was erroneously diagnosed with ultrasonography (US). This mistake was due to the low specificity of the instrumental methodology and to the rarity of an asymptomatic schwannoma of the infraclavicular brachial plexus. The neoplasia was excised without using the microscope. In the early post-operative follow up, a “falling” attitude of the wirst, the hand and the fingers appeared, peculiar for a lesion of the radial nerve. Furthermore a hypoaesthesia of the skin of first finger and of the first interosseus space was associated. The sensitive and motor electromyography showed a radial nerve suffering. The “stupor” of the nerve trunk was treated with steroid therapy for 7 days and the patient underwent to some series of neuro-rehabilitative physical therapy for 12 weeks. The postoperative total body CT, showed that the lesion was unique: therefore it was possible to exclude the diagnosis of neurofibromatosis. After 28 months electromyography and axillary US were performed showing the complete resolution of the motor and sensitive deficit and the absence of local recurrence

Picturing Cities : The Photobook as Urban Narrative

What is a photobook? And how can we assess its historical and cultural re-levance for the representation of cities? The terms ‘photographic book’ and ‘picture book’ refer to various illustrated publications, with or without text, in which photographic images play a key role. Often resulting from the col-laboration between photographers, editors and graphic designers, they are intended to build visual narratives on specific places or subjects. Throughout its history, this versatile form of publication has allowed photographers to depict urban environments in widely different ways. Although the photobo-ok has been integral to the construction of urban narratives since the early-twentieth century, its significance for the experience and perception of cities has so far been rarely investigated. Picturing Cities addresses this gap by mapping the shifting nature and function of photobooks onto the history of urban representation. This collection of essays from Europe and the Ameri-cas illustrates a broad range of aesthetic attitudes as well as analytical ap-proaches to Western cities expressed through photobooks. The anthology, stemming from a conference session chaired by the editors, focuses on the photobook as a form of urban narrative: a tool that has been deployed to read, analyse and interpret cities through curated sequences of images, of-ten in conjunction with literary or critical texts. It opens up a multidisciplinary field of research with the potential to expand into further geographical and cultural areas

Alteration of lipid bilayer mechanics by volatile anesthetics: insights from μs-long molecular dynamics simulations

Very few drugs in clinical practice feature the chemical diversity, narrow therapeutic window, unique route of administration, and reversible cognitive effects of volatile anesthetics. The correlation between their hydrophobicity and their potency and the increasing amount of evidence suggesting that anesthetics exert their action on transmembrane proteins, justifies the investigation of their effects on phospholipid bilayers at the molecular level, given the strong functional and structural link between transmembrane proteins and the surrounding lipid matrix. Molecular dynamics simulations of a model lipid bilayer in the presence of ethylene, desflurane, methoxyflurane, and the nonimmobilizer 1,2-dichlorohexafluorocyclobutane (also called F6 or 2N) at different concentrations highlight the structural consequences of VA partitioning in the lipid phase, with a decrease of lipid order and bilayer thickness, an increase in overall lipid lateral mobility and area-per-lipid, and a marked reduction in the mechanical stiffness of the membrane, that strongly correlates with the compounds' hydrophobicity

In silico investigation of molecular interactions of Volatile Anesthetics: Effects on phospholipid membranes and subcellular targets

The ability of anesthetics to reversibly suppress consciousness must reside in the effects exerted onto specific molecular tar- gets. Interactions between Volatile Anesthetics and the phospholipid mem- brane as well as intracellular tubulin, were investigated using Computational Molecular Modelling, which showed rapid ligand partitioning inside the membrane and significant effects on the mechanical char- acteristics thereof, while transient binding locations have been found on the tubulin dimer

Deformation pattern in vibrating microtubule: Structural mechanics study based on an atomistic approach

The mechanical properties of microtubules are of great importance for understanding their biological function and for applications in artificial devices. Although microtubule mechanics has been extensively studied both theoretically and experimentally, the relation to its molecular structure is understood only partially. Here, we report on the structural analysis of microtubule vibration modes calculated by an atomistic approach. Molecular dynamics was applied to refine the atomic structure of a microtubule and a C α elastic network model was analyzed for its normal modes. We mapped fluctuations and local deformations up to the level of individual aminoacid residues. The deformation is mode-shape dependent and principally different in α-tubulins and β-tubulins. Parts of the tubulin dimer sequence responding specifically to longitudinal and radial stress are identified. We show that substantial strain within a microtubule is located both in the regions of contact between adjacent dimers and in the body of tubulins. Our results provide supportive evidence for the generally accepted assumption that the mechanics of microtubules, including its anisotropy, is determined by the bonds between tubulins

Prediction of Protein–Protein Interactions Between Alsin DH/PH and Rac1 and Resulting Protein Dynamics

Alsin is a protein of 1,657 amino acids known for its crucial role in vesicular trafficking in neurons thanks to its ability to interact with two guanosine triphosphatases, Rac1 and Rab5. Evidence suggests that Rac1 can bind Alsin central region, composed by a Dbl Homology (DH) domain followed by a Pleckstrin Homology (PH) domain, leading to Alsin relocalization. However, Alsin three-dimensional structure and its relationship with known biological functions of this protein are still unknown. In this work, a homology model of the Alsin DH/PH domain was developed and studied through molecular dynamics both in the presence and in the absence of its binding partner, Rac1. Due to different conformations of DH domain, the presence of Rac1 seems to stabilize an open state of the protein, while the absence of its binding partner results in closed conformations. Furthermore, Rac1 interaction was able to reduce the fluctuations in the second conserved region of DH motif, which may be involved in the formation of a homodimer. Moreover, the dynamics of DH/PH was described through a Markov State Model to study the pathways linking the open and closed states. In conclusion, this work provided an all-atom model for the DH/PH domain of Alsin protein; moreover, molecular dynamics investigations suggested underlying molecular mechanisms in the signal transduction between Rac1 and Alsin, providing the basis for a deeper understanding of the whole structure–function relationship for Alsin protein

Structure–property relation and relevance of beam theories for microtubules: a coupled molecular and continuum mechanics study

Quasi-one-dimensional microtubules (MTs) in cells enjoy high axial rigidity but large transverse flexibility due to the inter-protofilament (PF) sliding. This study aims to explore the structure–property relation for MTs and examine the relevance of the beam theories to their unique features. A molecular structural mechanics (MSM) model was used to identify the origin of the inter-PF sliding and its role in bending and vibration of MTs. The beam models were then fitted to the MSM to reveal how they cope with the distinct mechanical responses induced by the inter-PF sliding. Clear evidence showed that the inter-PF sliding is due to the soft inter-PF bonds and leads to the length-dependent bending stiffness. The Euler beam theory is found to adequately describe MT deformation when the inter-PF sliding is largely prohibited. Nevertheless, neither shear deformation nor the nonlocal effect considered in the ‘more accurate’ beam theories can fully capture the effect of the inter-PF sliding. This reflects the distinct deformation mechanisms between an MT and its equivalent continuous body