White matter abnormalities in fetal alcohol spectrum disorders: Focus on axon growth and guidance

Fetal Alcohol Spectrum Disorders (FASDs) describe a range of deficits, affecting physical, mental, cognitive, and behavioral function, arising from prenatal alcohol exposure. FASD causes widespread white matter abnormalities, with significant alterations of tracts in the cerebral cortex, cerebellum, and hippocampus. These brain regions present with white-matter volume reductions, particularly at the midline. Neural pathways herein are guided primarily by three guidance cue families: Semaphorin/Neuropilin, Netrin/DCC, and Slit/Robo. These guidance cue/receptor pairs attract and repulse axons and ensure that they reach the proper target to make functional connections. In several cases, these signals cooperate with each other and/or additional molecular partners. Effects of alcohol on guidance cue mechanisms and their associated effectors include inhibition of growth cone response to repellant cues as well as changes in gene expression. Relevant to the corpus callosum, specifically, developmental alcohol exposure alters GABAergic and glutamatergic cell populations and glial cells that serve as guidepost cells for callosal axons. In many cases, deficits seen in FASD mirror aberrancies in guidance cue/receptor signaling. We present evidence for the need for further study on how prenatal alcohol exposure affects the formation of neural connections which may underlie disrupted functional connectivity in FASD.     

Diphenyl diselenide reverses cadmium-induced oxidative damage on mice tissues

The concept that selenium-containing molecules may be better antioxidants than classical antioxidants, has led to the design of synthetic organoselenium compounds. In the present investigation subchronic deleterious effects of cadmium-intoxication in mice and a possible protective effect of diphenyl diselenide (PhSe)2 (5 micromol/kg) were studied. Male adult Swiss albino mice (25-35 g) received CdCl2 (10 micromol/kg, subcutaneously), five times/week, for 4 weeks. A number of toxicological parameters in blood, liver, kidney, spleen and brain of mice were examined including delta-aminolevulinic acid dehydratase (delta-ALA-D) activity, lipid peroxidation and ascorbic acid content, the parameters that indicate tissue damage such as plasma alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea, creatinine and lactate dehydrogenase (LDH) were also determined. The results demonstrated that cadmium caused inhibition of delta-ALA-D activity in liver (24%), kidney (33%) and spleen (73%) and (PhSe)2 therapy was effective in restoring enzyme activity in all tissues. A reduction in ascorbic acid content was observed in kidney (11%) and spleen (10.7%) of cadmium-treated mice and (PhSe)2 was only effective in improving this reduction in kidney. An increase of lipid peroxidation induced by cadmium was noted in liver (29%) and brain (28%) tissues and (PhSe)2 therapy was effective in restoring TBARS levels in both tissues. We also observed an increase on plasma LDH (1.99-times), AST (1.93-times) and ALT (4.24-times) activities. (PhSe)2 therapy was effective in restoring AST activity at control level. (PhSe)2 did not present toxic effects when plasma parameters were evaluated. The results suggest that the administration of an antioxidant (PhSe)2, during cadmium intoxication may provide beneficial effects by reducing oxidative stress in tissues.     

Tumor necrosis factor-alpha production is differently regulated in gamma delta and alpha beta human T lymphocytes

Tumor necrosis factor-alpha (TNF-alpha) plays a crucial role in the early defense against pathogens. This cytokine is produced by several cell types including T lymphocytes expressing the alphabeta as well as the gammadelta T cell receptor (TcR). In human, the circulating gammadelta T cells, which mostly express Vgamma9Vdelta2 TcR, have been strongly suggested to play an important protective role against infectious agents. These activated cells early produce high amounts of TNF-alpha, which induce a determinant beneficial effect against development of intracellular pathogens; however, sustained production of this cytokine can result in immunopathological diseases. The signals that regulate TNF-alpha production in Vgamma9Vdelta2 T cells are totally unknown. In primary alphabeta T cells, TNF-alpha production was shown to necessitate engagement of the TcR and CD28, and to be independent of the p38 mitogen activated protein kinase pathway. We demonstrate herein that, in contrast to alphabeta T cells, TNF-alpha production in Vgamma9Vdelta2 T lymphocytes is independent of CD28 costimulation and highly dependent on TcR-induced p38 kinase and extracellular signal-regulated kinase 2 pathway activation for optimal cytokine release. Moreover, we bring elements supporting the idea that the "activation threshold" of gammadelta T cells leading to cytokine production is lower than that of alphabeta T cells.     

RAP: a new computer program for de novo identification of repeated sequences in whole genomes

MOTIVATION: DNA repeats are a common feature of most genomic sequences. Their de novo identification is still difficult despite being a crucial step in genomic analysis and oligonucleotides design. Several efficient algorithms based on word counting are available, but too short words decrease specificity while long words decrease sensitivity, particularly in degenerated repeats. RESULTS: The Repeat Analysis Program (RAP) is based on a new word-counting algorithm optimized for high resolution repeat identification using gapped words. Many different overlapping gapped words can be counted at the same genomic position, thus producing a better signal than the single ungapped word. This results in better specificity both in terms of low-frequency detection, being able to identify sequences repeated only once, and highly divergent detection, producing a generally high score in most intron sequences. AVAILABILITY: The program is freely available for non-profit organizations, upon request to the authors. CONTACT: giorgio.valle@unipd.it SUPPLEMENTARY INFORMATION: The program has been tested on the Caenorhabditis elegans genome using word lengths of 12, 14 and 16 bases. The full analysis has been implemented in the UCSC Genome Browser and is accessible at http://genome.cribi.unipd.it.     

Effects of High-Intensity Swimming on Lung Inflammation and Oxidative Stress in a Murine Model of DEP-Induced Injury

Studies have reported that exposure to diesel exhaust particles (DEPs) induces lung inflammation and increases oxidative stress, and both effects are susceptible to changes via regular aerobic exercise in rehabilitation programs. However, the effects of exercise on lungs exposed to DEP after the cessation of exercise are not clear. Therefore, the aim of this study was to evaluate the effects of high-intensity swimming on lung inflammation and oxidative stress in mice exposed to DEP concomitantly and after exercise cessation. Male Swiss mice were divided into 4 groups: Control (n = 12), Swimming (30 min/day) (n = 8), DEP (3 mg/mL—10 μL/mouse) (n = 9) and DEP+Swimming (n = 8). The high-intensity swimming was characterized by an increase in blood lactate levels greater than 1 mmoL/L between 10th and 30th minutes of exercise. Twenty-four hours after the final exposure to DEP, the anesthetized mice were euthanized, and we counted the number of total and differential inflammatory cells in the bronchoalveolar fluid (BALF), measured the lung homogenate levels of IL-1β, TNF-α, IL-6, INF-ϫ, IL-10, and IL-1ra using ELISA, and measured the levels of glutathione, non-protein thiols (GSH-t and NPSH) and the antioxidant enzymes catalase and glutathione peroxidase (GPx) in the lung. Swimming sessions decreased the number of total cells (p<0.001), neutrophils and lymphocytes (p<0.001; p<0.05) in the BALF, as well as lung levels of IL-1β (p = 0.002), TNF-α (p = 0.003), IL-6 (p = 0.0001) and IFN-ϫ (p = 0.0001). However, the levels of IL-10 (p = 0.01) and IL-1ra (p = 0.0002) increased in the swimming groups compared with the control groups, as did the CAT lung levels (p = 0.0001). Simultaneously, swimming resulted in an increase in the GSH-t and NPSH lung levels in the DEP group (p = 0.0001 and p<0.002). We concluded that in this experimental model, the high-intensity swimming sessions decreased the lung inflammation and oxidative stress status during DEP-induced lung inflammation in mice.     

The Oral Tolerance as a Complex Network Phenomenon

The phenomenon of oral tolerance refers to a local and systemic state of tolerance induced in the gut after its exposure to innocuous antigens. Recent findings have shown the interrelationship between cellular and molecular components of oral tolerance, but its representation through a network of interactions has not been investigated. Our work aims at identifying the causal relationship of each element in an oral tolerance network, and also to propose a phenomenological model that’s capable of predicting the stochastic behavior of this network when under manipulation. We compared the changes of a “healthy” network caused by “knock-outs” (KOs) in two approaches: an analytical approach by the Perron Frobenius theory; and a computational approach, which we describe within this work in order to find numerical results for the model. Both approaches have shown the most relevant immunological components for this phenomena, that happens to corroborate the empirical results from animal models. Besides explain in a intelligible fashion how the components interacts in a complex manner, we also managed to describe and quantify the importance of KOs that hasn’t been empirically tested.     

A dual process for the coupled Wright–Fisher diffusion

Journal of Mathematical Biology - Discrete-state stochastic models are a popular approach to describe the inherent stochasticity of gene expression in single cells. The analysis of such models is...     

Gangliosides and the multiscale modulation of membrane structure

Cellular membranes are highly organized structures with multiple and multi-dimensional levels of order where lipid components are active players. The lipid role is especially evident in rafts, where lipid-driven collective interaction dictates the local structure of a membrane. However, lipids play as well other roles in many aspects of membrane mechanics and function.In this review, we would like to re-focus the attention of the readers on the importance of gangliosides in organizing the fine structure of cellular membranes, in lateral and transverse directions. Important biological events are likely to be affected such as the dynamic control of the shape of specialized plasma membrane areas and of the intracellular organelles, the in- and outward budding and fusion of membrane vesicles, the physical and functional coupling of the outer and the inner plasma membrane leaflet, involved in the transduction of signals across the membrane.     

Subdose of human chorionic gonadotropin applied at the Hou Hai acupoint on follicular dynamics and luteal development in donkeys

The objective of this study was to evaluate the effects of an hCG subdose applied at the Hou Hai acupoint as an ovulation inducer in donkeys. Eleven donkeys were distributed in randomized blocks in T1 = application of 1,500 IU of hCG intravenous (IV); T2 = 450 IU of hCG applied at the false acupoint (IV), and T3 = 450 IU of hCG applied at the Hou Hai acupoint. There was no difference (P > 0.05) between the treatments regarding the mean diameter of the pre-ovulatory follicle (34.5 ± 1.3 mm), the ovulation rate (96.97%), the interval between induction and ovulation (58.07 ± 16.82 h), the mean diameter of the CL (D0 = 23.0 ± 0.6; D2 = 27.7 ± 1.9 and D8 = 28.2 ± 0.8mm), and serum P₄ concentrations (10.50 ± 2.99 ng.mL^-1). The application of 450 IU of hCG at the Hou Hai acupoint increased ovulation rate (72.73%) more than 48 h after induction (P = 0.03) and a larger diameter of the CL on D4 (30.7 ± 5.1 mm) (P = 0.04). The vascularization area of the CL on D8, obtained by minimum number of colored pixel (NCP), was greater (P < 0.05) in the donkeys that received 1,500 IU of IV hCG (T1, 41.91 ± 1.17), and we found a positive correlation (P < 0.05) between mean NCP and P₄ concentration in the donkeys that received 450 IU of hCG IV at the false acupoint (T2) or at the Hou Hai acupoint (T3). The application of 450 IU of hCG by IV route at the false acupoint or the Hou Hai acupoint was sufficient to induce ovulation in donkeys, demonstrating that the average dosage commonly used for this species is too high.     

Tomato-oleoresin supplement prevents doxorubicin-induced cardiac myocyte oxidative DNA damage in rats

Doxorubicin (DOX) is an efficient chemotherapeutic agent used against several types of tumors; however, its use is limited due to severe cardiotoxicity. Since it is accepted that reactive oxygen species are involved in DOX-induced cardiotoxicity, antioxidant agents have been used to attenuate its side effects. To determine tomato-oleoresin protection against cardiac oxidative DNA damage induced by DOX, we distributed Wistar male rats in control (C), lycopene (L), DOX (D) and DOX+lycopene (DL) groups. They received corn oil (C, D) or tomato-oleoresin (5mg/kg body wt. day) (L, DL) by gavage for a 7-week period. They also received saline (C, L) or DOX (4mg/kg body wt.) (D, DL) intraperitoneally at the 3rd, 4th, 5th, and at 6th week. Lycopene absorption was checked by HPLC. Cardiac oxidative DNA damage was evaluated by the alkaline Comet assay using formamidopyrimidine-DNA glycosylase (FPG) and endonuclease III (endo III). Cardiomyocyte levels of SBs, SBs FPG and SBs Endo III were higher in rats from D when compared to other groups. DNA damage levels in cardiomyocytes from DL were not different when compared to C and L groups. The viability of cardiomyocytes from D or DL was lower than C or L groups (p<0.01). Lycopene levels (mean+/-S.D.nmol/kg) in saponified hearts were similar between L (47.43+/-11.78) and DL (49.85+/-16.24) groups. Our results showed: (1) lycopene absorption was confirmed by its cardiac levels; (2) DOX-induced oxidative DNA damage in cardiomyocyte; (3) tomato-oleoresin supplementation protected against cardiomyocyte oxidative DNA damage.