Hes1 expression and CYLD repression are essential events downstream of Notch1 in T-cell leukemia

Notch activation is a current event in T Acute Lymphoblastic Leukemia (T-ALL) but the downstream elements that are able to support Notch-dependent leukemias are not well characterized. We have recently shown that the Notch-Hes1-CYLD-NFκB axis is crucial in the maintenance of T-ALL, but detailed evaluation of the contribution of each one of these elements is still missing. Here we use a Notch1-induced leukemia in vivo model to study the effect of silencing the Notch-target gene, Hes1 or overexpressing the Hes1-target, CYLD. We here show that both strategies completely abolish the ability of constitutive active Notch1 to generate T-ALL.     

Dietary fat intake and the risk of depression: the SUN Project

Emerging evidence relates some nutritional factors to depression risk. However, there is a scarcity of longitudinal assessments on this relationship.

Objective

To evaluate the association between fatty acid intake or the use of culinary fats and depression incidence in a Mediterranean population.

Material and Methods

Prospective cohort study (1999–2010) of 12,059 Spanish university graduates (mean age: 37.5 years) initially free of depression with permanently open enrolment. At baseline, a 136-item validated food frequency questionnaire was used to estimate the intake of fatty acids (saturated fatty acids (SFA), polyunsaturated fatty acids (PUFA), trans unsaturated fatty acids (TFA) and monounsaturated fatty acids (MUFA) and culinary fats (olive oil, seed oils, butter and margarine) During follow-up participants were classified as incident cases of depression if they reported a new clinical diagnosis of depression by a physician and/or initiated the use of antidepressant drugs. Cox regression models were used to calculate Hazard Ratios (HR) of incident depression and their 95% confidence intervals (CI) for successive quintiles of fats.

Results

During follow-up (median: 6.1 years), 657 new cases of depression were identified. Multivariable-adjusted HR (95% CI) for depression incidence across successive quintiles of TFA intake were: 1 (ref), 1.08 (0.82–1.43), 1.17 (0.88–1.53), 1.28 (0.97–1.68), 1.42 (1.09–1.84) with a significant dose-response relationship (p for trend = 0.003). Results did not substantially change after adjusting for potential lifestyle or dietary confounders, including adherence to a Mediterranean Dietary Pattern. On the other hand, an inverse and significant dose-response relationship was obtained for MUFA (p for trend = 0.05) and PUFA (p for trend = 0.03) intake.

Conclusions

A detrimental relationship was found between TFA intake and depression risk, whereas weak inverse associations were found for MUFA, PUFA and olive oil. These findings suggest that cardiovascular disease and depression may share some common nutritional determinants related to subtypes of fat intake.     

Polycomb in stem cells: PRC1 branches out

Polycomb group proteins (PcGs) generate chromatin-modifying complexes that regulate gene expression. PcGs are categorized into two major groups, polycomb repressive complex 1 (PRC1) and 2 (PRC2), which have classically been thought to function together. Here we discuss recent data challenging this model indicating that the distinct subunit composition of PRC1 confers specific and nonoverlapping functions in embryonic and adult stem cells.     

Cannabinoid receptors CB1 and CB2 form functional heteromers in brain

Exploring the role of cannabinoid CB(2) receptors in the brain, we present evidence of CB(2) receptor molecular and functional interaction with cannabinoid CB(1) receptors. Using biophysical and biochemical approaches, we discovered that CB(2) receptors can form heteromers with CB(1) receptors in transfected neuronal cells and in rat brain pineal gland, nucleus accumbens, and globus pallidus. Within CB(1)-CB(2) receptor heteromers expressed in a neuronal cell model, agonist co-activation of CB(1) and CB(2) receptors resulted in a negative cross-talk in Akt phosphorylation and neurite outgrowth. Moreover, one specific characteristic of CB(1)-CB(2) receptor heteromers consists of both the ability of CB(1) receptor antagonists to block the effect of CB(2) receptor agonists and, conversely, the ability of CB(2) receptor antagonists to block the effect of CB(1) receptor agonists, showing a bidirectional cross-antagonism phenomenon. Taken together, these data illuminate the mechanism by which CB(2) receptors can negatively modulate CB(1) receptor function.     

Study of Human RIG-I Polymorphisms Identifies Two Variants with an Opposite Impact on the Antiviral Immune Response

Background

RIG-I is a pivotal receptor that detects numerous RNA and DNA viruses. Thus, its defectiveness may strongly impair the host antiviral immunity. Remarkably, very little information is available on RIG-I single-nucleotide polymorphisms (SNPs) presenting a functional impact on the host response.

Methodology/Principal Findings

Here, we studied all non-synonymous SNPs of RIG-I using biochemical and structural modeling approaches. We identified two important variants: (i) a frameshift mutation (P₂₂₉fs) that generates a truncated, constitutively active receptor and (ii) a serine to isoleucine mutation (S₁₈₃I), which drastically inhibits antiviral signaling and exerts a down-regulatory effect, due to unintended stable complexes of RIG-I with itself and with MAVS, a key downstream adapter protein.

Conclusions/Significance

Hence, this study characterized P₂₂₉fs and S₁₈₃I SNPs as major functional RIG-I variants and potential genetic determinants of viral susceptibility. This work also demonstrated that serine 183 is a residue that critically regulates RIG-I-induced antiviral signaling.     

Serum manganese concentrations in a representative sample of the Canarian population

Serum manganese (Mn) concentrations of 368 individuals 6–75 yr of age (179 males and 189 females) living in the Canary Islands were determined by graphite furnace atomic absorption spectrometry. The mean manganese concentration was 1.06 ± 0.62 μg/L, ranging between 0.19 and 3.33 μg/L. Most of the analyzed samples (63.3% of the samples) fall within the reference interval (0.54–1.76 μg/L) for apparently healthy people. Individuals from Fuerteventura presented with mean Mn concentrations significantly higher than individuals from the rest of the islands. This could be attributed to differences in the Mn content of soil and/or differences in dietary habits of the population. Serum Mn concentration did not vary with gender, and individuals younger than 18 yr old had the highest mean Mn concentration, compared to the rest of the age groups considered. No relation to socioeconomic status, educational level, and tobacco or alcohol consumption was found. However, the serum Mn concentration tended to decrease when increasing the consumption of wine or beer. Sportsmen presented significantly higher serum Mn concentrations than the rest.     

Dipropylcyclopentylxanthine triggers apoptosis in cells from patients with myeloid leukaemia

1,3-Dipropyl-8-cyclopentylxanthine (DPCPX), a xanthine analogue used as a selective antagonist of adenosine receptors, caused apoptosis in a variety of leukaemia-derived cell lines as well as in cells from patients with myeloid leukaemia. Apoptosis was assessed by flow cytometry, by DNA fragmentation and by accumulation of histones, H2A, H2B, R3 and H4, in the nucleoplasm of cells. Cell cycle analysis indicated that apoptosis occurred irrespective of the cell cycle phase. DPCPX did not trigger apoptosis in resting human peripheral blood lymphocytes; neither did it potentiate the apoptotic effect of phytohemagglutinin (PHA), when these cells were activated by PHA. These results indicate that DPCPX may be useful in the therapy of proliferative disorders of the hematopoietic system. This revised version was published online in June 2006 with corrections to the Cover Date.     

TCAV-1, a monoclonal antibody specific to epithelial pharyngeal cells in the planarian Dugesia (Girardia) tigrina. Application to pattern formation of the pharynx during regeneration

During regeneration in planarians, anterior (head and prepharyngeal) and posterior (postpharyngeal and tail) fragments rebuild one of the most peculiar structures of planarians: the pharynx and the pharynx cavity. Previous studies (see Brønsted, 1969, for a general review, and Asai, 1990, 1991, for anterior regeneration) have shown that within postpharyngeal pieces both structures appear in the old stump from clusters of undifferentiated cells. However, the lineage and differentiation of their elements (inner and outer epithelial cells, muscle layers, gland cells, nerve rings) and the overall pattern of growth and differentiation is not clear.