Interstitial 2q24.3 deletion including SCN2A and SCN3A genes in a patient with autistic features,psychomotor delay,microcephaly and no history of seizures

Mutations in neuronal voltage-gated sodium channel genes SCN1A, SCN2A, and SCN3A may play an important role in the etiology of neurological diseases and psychiatric disorders, besides various types of epilepsy. Here we describe a 3-year-old boy with autistic features, language delay, microcephaly and no history of seizures. Array-CGH analysis revealed an interstitial deletion of ~ 291.9 kB at band 2q24.3 disrupting the entire SCN2A gene and part of SCN3A. We discuss the effects of haploinsufficiency of SCN2A and SCN3A on the genetic basis of neurodevelopmental and neurobehavioral disorders and we propose that this haploinsufficiency may be associated not only with epilepsy, but also with autistic features.     

Role of particle coating in controlling skin damage photoinduced by titania nanoparticles

TiO₂ nanoparticles hazard is associated to their photocatalytic activity causing release of DNA damaging ROS (Reactive Oxygen Species), lipid peroxidation and skin damage. Various coatings have been proposed to minimize photocatalysis, while keeping the potential to block UV radiations. Uncoated and variously coated commercial nano-titania have been classified on the basis of UVB-induced lipoperoxidation of linoleic acid. A selection of the most and the least protective specimens was then examined by ESR (Electron Spin Resonance) to evidence the presence of surface paramagnetic centres and the release of ROS in aqueous suspensions (spin trapping). Paramagnetic centres and ROS were correlated with the extent of lipid peroxidation. When tested on porcine skin (mimicking the human one), titania acted as on linoleic acid. The combined use of lipid peroxidation of simple fatty acids with ESR analysis is here proposed as a possible screening tool for the evaluation of the potential toxicity of nano-titania in sunscreen preparations.     

Thermal, dynamic and structural properties of drug AT1 antagonist olmesartan in lipid bilayers

It is proposed that AT1 antagonists (ARBs) exert their biological action by inserting into the lipid membrane and then diffuse to the active site of AT1 receptor. Thus, lipid bilayers are expected to be actively involved and play a critical role in drug action. For this reason, the thermal, dynamic and structural effects of olmesartan alone and together with cholesterol were studied using differential scanning calorimetry (DSC), 13C magic-angle spinning (MAS) nuclear magnetic resonance (NMR), cross-polarization (CP) MAS NMR, and Raman spectroscopy as well as small- and wide angle X-ray scattering (SAXS and WAXS) on dipalmitoyl-phosphatidylcholine (DPPC) multilamellar vesicles. 13C CP/MAS spectra provided direct evidence for the incorporation of olmesartan and cholesterol in lipid bilayers. Raman and X-ray data revealed how both molecules modify the bilayer's properties. Olmesartan locates itself at the head-group region and upper segment of the lipid bilayers as 13C CP/MAS spectra show that its presence causes significant chemical shift changes mainly in the A ring of the steroidal part of cholesterol. The influence of olmesartan on DPPC/cholesterol bilayers is less pronounced. Although, olmesartan and cholesterol are residing at the same region of the lipid bilayers, due to their different sizes, display distinct impacts on the bilayer's properties. Cholesterol broadens significantly the main transition, abolishes the pre-transition, and decreases the membrane fluidity above the main transition. Olmesartan is the only so far studied ARB that increases the gauche:trans ratio in the liquid crystalline phase. These significant differences of olmesartan may in part explain its distinct pharmacological profile.     

Synthesis and in vitro activity of 2-thiazolylhydrazone derivatives compared with the activity of clotrimazole against clinical isolates of Candida spp

In this paper, we report on the synthesis of a novel series of 2-thiazolylhydrazone derivatives and the influence of the substituents on the thiazole ring on antifungal activity. All synthesized compounds were screened for their in vitro activities against 22 clinical isolates of Candida spp., representing six different species, compared to clotrimazole as a reference compound. Some of the tested compounds were found to possess significant antifungal activity when compared to clotrimazole, in particular compound 14 which exhibited higher potency against most of the Candida spp. considered. The compounds that were most active as anti-Candida agents were also submitted to cytotoxic screening by the Trypan Blue dye exclusion assay and in general they were shown to induce low cytotoxic effects.     

The effect of obesity management on body image in patients seeking treatment at medical centers

Objective: Body image dissatisfaction is common in treatment‐seeking patients with obesity. We aimed to investigate the effects of obesity management on body image in patients with obesity attending Italian medical centers for weight loss programs. Research Methods and Procedures: A total of 473 obese patients seeking treatment in 13 Italian medical centers (80% females; age, 45.9 ± standard deviation 11.0 years; BMI, 36.8 ± 5.7 kg/m²) were evaluated at baseline and after a 6‐month weight loss treatment. Body uneasiness, psychiatric distress, and binge eating were tested by Body Uneasiness Test (BUT, Part A), Symptom CheckList‐90 (SCL‐90), and Binge Eating Scale (BES), respectively. Results: At 6‐month follow‐up, the percentage weight loss was significantly higher in men (9.0 ± 6.3%) than in women (6.8 ± 7.3%; p = 0.010). Both men and women had a significant improvement in BUT Global Severity Index and in all of the BUT subscales with the exception of the Compulsive Self‐Monitoring subscale. Linear regression analysis selected baseline psychological and behavioral measures (global score of BUT and SCL‐90) and improved psychiatric distress and binge eating as independent predictors of changes in basal body dissatisfaction in females, whereas in males, changes were associated only with baseline BUT‐Global Severity Index score, binge eating, and its treatment‐associated improvement. Pre‐treatment BMI and BMI changes did not enter the regression. Discussion: Obesity treatment, even with a modest degree of weight loss, is associated with a significant improvement of body image, in both females and males. This effect depends mainly on psychological factors, not on the amount of weight loss.     

Identification of tissue transglutaminase-reactive lysine residues in glyceraldehyde-3-phosphate dehydrogenase

Polyglutamine domains are excellent substrates for tissue transglutaminase resulting in the formation of cross-links with polypeptides containing lysyl residues. This finding suggests that tissue transglutaminase may play a role in the pathology of neurodegenerative diseases associated with polyglutamine expansion. The glycolytic enzyme GAPDH previously was shown to tightly bind several proteins involved in such diseases. The present study confirms that GAPDH is an in vitro lysyl donor substrate of tissue transglutaminase. A dansylated glutamine-containing peptide was used as probe for labeling the amino-donor sites. SDS gel electrophoresis of a time-course reaction mixture revealed the presence of both fluorescent GAPDH monomers and high molecular weight polymers. Western blot analysis performed using antitransglutaminase antibodies reveals that tissue transglutaminase takes part in the formation of heteropolymers. The reactive amino-donor sites were identified using mass spectrometry. Here, we report that of the 26 lysines present in GAPDH, K191, K268, and K331 were the only amino-donor residues modified by tissue transglutaminase.     

Identification of DSB-1, a Protein Required for Initiation of Meiotic Recombination in Caenorhabditis elegans,Illuminates a Crossover Assurance Checkpoint

Meiotic recombination, an essential aspect of sexual reproduction, is initiated by programmed DNA double-strand breaks (DSBs). DSBs are catalyzed by the widely-conserved Spo11 enzyme; however, the activity of Spo11 is regulated by additional factors that are poorly conserved through evolution. To expand our understanding of meiotic regulation, we have characterized a novel gene, dsb-1, that is specifically required for meiotic DSB formation in the nematode Caenorhabditis elegans. DSB-1 localizes to chromosomes during early meiotic prophase, coincident with the timing of DSB formation. DSB-1 also promotes normal protein levels and chromosome localization of DSB-2, a paralogous protein that plays a related role in initiating recombination. Mutations that disrupt crossover formation result in prolonged DSB-1 association with chromosomes, suggesting that nuclei may remain in a DSB-permissive state. Extended DSB-1 localization is seen even in mutants with defects in early recombination steps, including spo-11, suggesting that the absence of crossover precursors triggers the extension. Strikingly, failure to form a crossover precursor on a single chromosome pair is sufficient to extend the localization of DSB-1 on all chromosomes in the same nucleus. Based on these observations we propose a model for crossover assurance that acts through DSB-1 to maintain a DSB-permissive state until all chromosome pairs acquire crossover precursors. This work identifies a novel component of the DSB machinery in C. elegans, and sheds light on an important pathway that regulates DSB formation for crossover assurance.     

Chiral arylpyrrolidinols: preparation and biological profile

The preparation and biological evaluation of a new class of arylpyrrolidinols is reported. The antinociceptive activity was evaluated in vivo with the hot plate test (HPT) and formalin test (FT), excluding any involvement on motor coordination with the rota-rod test (RRT). The nociceptive behavior in the late phase of FT (representative of chronic pain) suggests an involvement of the antiinflammatory process and it is clearly influenced by the stereochemical features, being the eutomer of phenylpyrrolidinols, the (2R,3S) enantiomer. Despite this, a specific mechanism of action is not yet clarified.