Severe neurologic impairment in mice with targeted disruption of the electrogenic sodium bicarbonate cotransporter NBCe2 (Slc4a5 gene)

The choroid plexus lining the four ventricles in the brain is where the majority of cerebrospinal fluid (CSF) is produced. The secretory function of the choroid plexus is mediated by specific transport systems that allow the directional flux of nutrients and ions into the CSF and the removal of toxins. Normal CSF dynamics and chemistry ensure that the environment for neural function is optimal. Here, we report that targeted disruption of the Slc4a5 gene encoding the electrogenic sodium bicarbonate cotransporter NBCe2 results in significant remodeling of choroid plexus epithelial cells, including abnormal mitochondrial distribution, cytoskeletal protein expression, and ion transporter polarity. These changes are accompanied by very significant abnormalities in intracerebral ventricle volume, intracranial pressure, and CSF electrolyte levels. The Slc4a5(-/-) mice are significantly more resistant to induction of seizure behavior than wild-type controls. In the retina of Slc4a5(-/-) mice, loss of photoreceptors, ganglion cells, and retinal detachment results in visual impairment assessed by abnormal electroretinogram waveforms. Our findings are the first demonstration of the fundamental importance of NBCe2 in the biology of the nervous system.     

First description of nodular onchocercosis (Onchocerca jakutensis) in free-ranging Italian red deer (Cervus elaphus)

Onchocercosis is a vector-transmitted parasitic disease involving wild and domestic ungulates, humans, and dogs. Red deer (Cervus elaphus) host numerous Onchocerca spp. which have precise anatomic sites in the host and two species, Onchocerca flexuosa Wedl, 1856 and Onchocerca jakutensis Guba-now, 1964, are found inside subcutaneous nodules. Between September and November 2007, subcutaneous nodules were observed on both thighs in shot red deer of a Tuscany population. We observed cystic structures, surrounded by a fibrous capsule, containing nematodes. Filamentous worms were male and female; microfilariae were also described. Although morphologically we could not distinguish between O. flexuosa and O. jakutensis, genetic studies implicated O. jakutensis. This is the first report of this parasite in Italy.     

Combining peptide recognition specificity and context information for the prediction of the 14-3-3-mediated interactome in S. cerevisiae and H. sapiens

Large‐scale interaction studies contribute the largest fraction of protein interactions information in databases. However, co‐purification of non‐specific or indirect ligands, often results in data sets that are affected by a considerable number of false positives. For the fraction of interactions mediated by short linear peptides, we present here a combined experimental and computational strategy for ranking the reliability of the inferred partners. We apply this strategy to the family of 14‐3‐3 domains. We have first characterized the recognition specificity of this domain family, largely confirming the results of previous analyses, while revealing new features of the preferred sequence context of 14‐3‐3 phospho‐peptide partners. Notably, a proline next to the carboxy side of the phospho‐amino acid functions as a potent inhibitor of 14‐3‐3 binding. The position‐specific information about residue preference was encoded in a scoring matrix and two regular expressions. The integration of these three features in a single predictive model outperforms publicly available prediction tools. Next we have combined, by a naïve Bayesian approach, these “peptide features” with “protein features”, such as protein co‐expression and co‐localization. Our approach provides an orthogonal reliability assessment and maps with high confidence the 14‐3‐3 peptide target on the partner proteins.     

Situational and dispositional determinants of intentional deceiving

Does opportunity make the thief or are people dispositionally prone to deceive? The interaction between personality and the circumstances surrounding deception is crucial to understand what promotes dishonesty in our society. Due to its inherent spontaneity and sociality, deceptive behaviour may be hardly reproducible in experimental settings. We developed a novel paradigm in the form of an interactive game where participants can choose whether to lie to another person in situations of loss vs. gain, and of no-reputation-risk vs. reputation-risk linked to the disclosure of their deceptive behaviour to others. Thus, our ecological paradigm allowed subjects to spontaneously decide when to lie and face the challenge of deceiving others. In the case of loss, participants lied to reverse the outcome in their favour. Deception was lower in the reputation-risk condition where personality traits concerning social interactions also played an important role.The results suggest that deception is definitely promoted by unfavourable events, and that maintaining one''s own reputation encourages honesty, particularly in socially inclined individuals.     

Built-in mechanical stress in viral shells

Mechanical properties of biological molecular aggregates are essential to their function. A remarkable example are double-stranded DNA viruses such as the φ29 bacteriophage, that not only has to withstand pressures of tens of atmospheres exerted by the confined DNA, but also uses this stored elastic energy during DNA translocation into the host. Here we show that empty prolated φ29 bacteriophage proheads exhibit an intriguing anisotropic stiffness which behaves counterintuitively different from standard continuum elasticity predictions. By using atomic force microscopy, we find that the φ29 shells are approximately two-times stiffer along the short than along the long axis. This result can be attributed to the existence of a residual stress, a hypothesis that we confirm by coarse-grained simulations. This built-in stress of the virus prohead could be a strategy to provide extra mechanical strength to withstand the DNA compaction during and after packing and a variety of extracellular conditions, such as osmotic shocks or dehydration.     

Pyridobenzothiazole derivatives as new chemotype targeting the HCV NS5B polymerase

Hepatitis C virus (HCV) infection has been recognized as the major cause of liver failure that can lead to hepatocellular carcinoma. Among all the HCV proteins, NS5B polymerase represents a leading target for drug discovery strategies. Herein, we describe our initial research efforts towards the identification of new chemotypes as allosteric NS5B inhibitors. In particular, the design, synthesis, in vitro anti-NS5B and in cellulo anti-HCV evaluation of a series of 1-oxo-1H-pyrido[2,1-b][1,3]benzothiazole-4-carboxylate derivatives are reported. Some of the newly synthesized compounds showed an IC(50) ranging from 11 to 23 μM, and molecular modeling and biochemical studies suggested that the thumb domain could be the target site for this new class of NS5B inhibitors.