Suppression of peroxiredoxin 4 in glioblastoma cells increases apoptosis and reduces tumor growth

Glioblastoma multiforme (GBM), the most common and aggressive primary brain malignancy, is incurable despite the best combination of current cancer therapies. For the development of more effective therapies, discovery of novel candidate tumor drivers is urgently needed. Here, we report that peroxiredoxin 4 (PRDX4) is a putative tumor driver. PRDX4 levels were highly increased in a majority of human GBMs as well as in a mouse model of GBM. Reducing PRDX4 expression significantly decreased GBM cell growth and radiation resistance in vitro with increased levels of ROS, DNA damage, and apoptosis. In a syngenic orthotopic transplantation model, Prdx4 knockdown limited GBM infiltration and significantly prolonged mouse survival. These data suggest that PRDX4 can be a novel target for GBM therapies in the future.     

Rhizobium promotes non-legumes growth and quality in several production steps: towards a biofertilization of edible raw vegetables healthy for humans

The biofertilization of crops with plant-growth-promoting microorganisms is currently considered as a healthy alternative to chemical fertilization. However, only microorganisms safe for humans can be used as biofertilizers, particularly in vegetables that are raw consumed, in order to avoid sanitary problems derived from the presence of pathogenic bacteria in the final products. In the present work we showed that Rhizobium strains colonize the roots of tomato and pepper plants promoting their growth in different production stages increasing yield and quality of seedlings and fruits. Our results confirmed those obtained in cereals and alimentary oil producing plants extending the number of non-legumes susceptible to be biofertilized with rhizobia to those whose fruits are raw consumed. This is a relevant conclusion since safety of rhizobia for human health has been demonstrated after several decades of legume inoculation ensuring that they are optimal bacteria for biofertilization.     

Respiration rate and oxy-regulatory capacity in cold stenothermal chironomids

The effects of temperature and oxygen saturation on the respiration rate of two cold stenothermal chironomids, Diamesa insignipes and Pseudodiamesa branickii were investigated. Fourth instar larvae were collected in winter in a glacio-rhithral stream (1300 m a.s.l., Alps, NE-Italy) and their respiration rate was measured with a Clark's electrode in the range 0-14 °C. The respiration rate was significantly higher in D. insignipes than in P. branickii at low temperatures (≤4 °C), higher in P. branickii between 8 and 12 °C and comparable at 14 °C. Higher values of R (regulation value), R_25% (respiration rate at 25% oxygen saturation) and b₁/b₂ (slope ratio in piecewise linear regression), and lower values of P_c (critical pressure) and I (initial decrease) were recorded in P. branickii than in D. insignipes. These values are compatible with oxy-regulatory behaviour in P. branickii, whereas D. insignipes appeared to be almost an oxy-conformer. On the basis of this autoecological information, new implications regarding survival of species from cold, high altitude habitats under changing climatic conditions are made.     

Lis1 and Ndel1 influence the timing of nuclear envelope breakdown in neural stem cells

Lis1 and Ndel1 are essential for animal development. They interact directly with one another and with cytoplasmic dynein. The developing brain is especially sensitive to reduced Lis1 or Ndel1 levels, as both proteins influence spindle orientation, neural cell fate decisions, and neuronal migration. We report here that Lis1 and Ndel1 reduction in a mitotic cell line impairs prophase nuclear envelope (NE) invagination (PNEI). This dynein-dependent process facilitates NE breakdown (NEBD) and occurs before the establishment of the bipolar spindle. Ndel1 phosphorylation is important for this function, regulating binding to both Lis1 and dynein. Prophase cells in the ventricular zone (VZ) of embryonic day 13.5 Lis1^+/− mouse brains show reduced PNEI, and the ratio of prophase to prometaphase cells is increased, suggesting an NEBD delay. Moreover, prophase cells in the VZ contain elevated levels of Ndel1 phosphorylated at a key cdk5 site. Our data suggest that a delay in NEBD in the VZ could contribute to developmental defects associated with Lis1–Ndel1 disruption.     

The role of the acrosomal matrix in fertilization

Mammalian sperm must have properly formed acrosomes to be fully functional in the process of binding and penetrating the zona pellucida (ZP), the extracellular matrix surrounding the egg. There is much evidence to raise doubts about the old "bag of enzymes" paradigm of acrosomal function, although this is the model that seems to prevail. We concur with other scientists that acrosomal exocytosis is not an all or none event where the acrosome is either "intact" or "reacted". As determined by transmission electron microscopy of human sperm undergoing acrosomal exocytosis, six stages can be identified, with the intermediate ones involving loss of acrosomal matrix material. In the mouse, there is a temporal relationship among four stages of acrosomal exocytosis. Numerous evidences suggest a more complex role for the acrosome in fertilization in which the acrosomal matrix is a scaffold for sperm-ZP interactions that self-regulates by a controlled disassembly mechanism.     

The T-786C and C774T endothelial nitric oxide synthase gene polymorphisms independently affect the onset pattern of severe diabetic retinopathy.

Genetic factors could be implicated in the pathogenesis of severe diabetic retinopathy (DR). Recently, we reported a strong association between the eNOS4b/a endothelial nitric oxide synthase (eNOS) polymorphism and severe DR. To examine whether T-786C and C774T eNOS polymorphisms are involved in severe DR, 254 Caucasians with longstanding C-peptide-negative type 1 diabetes, 128 patients with absent/mild DR (control group), and 126 patients with preproliferative/proliferative DR (study group) were genotyped. The distribution of T-786C and C774T eNOS polymorphisms was in Hardy-Weinberg equilibrium and did not differ between the study and control groups. However, in case patients (n=126), T-786C and C774T polymorphisms influenced the onset pattern of severe DR (P=0.0169 and P=0.0257, respectively). The C-786C genotype was associated with early-onset severe DR (duration of diabetes: 15.2+/-5.9 vs. 19.4+/-6.3 years, P=0.0105), and the homozygous T774T genotype was associated with late-onset severe DR (24.3+/-7.0 vs. 18.4+/-6.2 years, P=0.0067). In the case of patients with high glycosylated hemoglobin levels (HbA1c >8%, n=88), the association between the T-786C polymorphism and early-onset severe DR was stronger (P=0.0068). Case patients carrying the C-786C genotype had higher HbA1c values (9.61+/-1.89%) than those carrying the T-786T genotype (8.93+/-1.47%, P=0.0173). Multivariate analysis showed that T-786C polymorphism was the best independent factor for onset pattern of severe DR (P<0.001). These findings, supported by previous associations between eNOS4b/a polymorphism and DR, suggest that T-786C and C774T eNOS polymorphisms affect the onset pattern of severe DR.     

Effect of Radiation Spectral Composition on Nicotiana spp. Seedlings Grown in vitro

The aim of this work was to assess the responses of seedlings of five species of Nicotiana genus to red and far red radiation. N. acuminata exhibits positive photoblastic behaviour and germination was completely inhibited under far red and darkness. In N. glauca germination was reduced under far red and darkness, but the other species showed neutral behaviour. The hypocotyl elongation was inhibited in N. glauca and N. tabacum under white and far red radiation. In N. langsdorffii and N. debneyi hypocotyl was elongated under far red radiation. Only in N. acuminata red radiation promote greater hypocotyl elongation than dark condition. On the phylogenetic tree obtained from restriction analysis N. glauca and N. acuminata are grouped in one branch, while the other species, N. langsdorffii, N. debneyi and N. tabacum, are grouped in the other branch cluster. Moreover, the N. debneyi behaviours under different radiation treatments were similar to those of N. tabacum. These two species are allopolyploid members of the genus Nicotiana, as also was confirmed by this study. This revised version was published online in July 2006 with corrections to the Cover Date.     

Phosphodiesterase 8B gene variants are associated with serum TSH levels and thyroid function

Thyroid-stimulating hormone (TSH) controls thyroid growth and hormone secretion through binding to its G protein-coupled receptor (TSHR) and production of cyclic AMP (cAMP). Serum TSH is a sensitive indicator of thyroid function, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over a life span. By genotyping 362,129 SNPs in 4,300 Sardinians, we identified a strong association (p = 1.3 x 10(-11)) between alleles of rs4704397 and circulating TSH levels; each additional copy of the minor A allele was associated with an increase of 0.13 muIU/ml in TSH. The single-nucleotide polymorphism (SNP) is located in intron 1 of PDE8B, encoding a high-affinity cAMP-specific phosphodiesterase. The association was replicated in 4,158 individuals, including additional Sardinians and two genetically distant cohorts from Tuscany and the Old Order Amish (overall p value = 1.9 x 10(-20)). In addition to association of TSH levels with SNPs in PDE8B, our genome scan provided evidence for association with PDE10A and several biologically interesting candidates in a focused analysis of 24 genes. In particular, we found evidence for association of TSH levels with SNPs in the THRB (rs1505287, p = 7.3 x 10(-5)), GNAQ (rs10512065, p = 2.0 x 10(-4)), TG (rs2252696, p = 2.2 x 10(-3)), POU1F1 (rs1976324, p = 3.9 x 10(-3)), PDE4D (rs27178, p = 8.3 x 10(-3)), and TSHR (rs4903957, p = 8.6 x 10(-3)) loci. Overall, the results suggest a primary effect of PDE8B variants on cAMP levels in the thyroid. This would affect production of T4 and T3 and feedback to alter TSH release by the pituitary. PDE8B may thus provide a candidate target for the treatment of thyroid dysfunction.