Human leukocyte formin: a novel protein expressed in lymphoid malignancies and associated with Akt

The very large family of Formin proteins is involved in processes such as morphogenesis, embryonic differentiation, cell polarity, and cytokinesis. A novel human gene from the Formin family, denominated human leukocyte formin gene, was cloned. The cDNA of the gene was determined to be 3959bp long with an open reading frame of 3302bp and computational analysis located this gene on chromosome 17, suggesting that it is composed of 27 exons. Northern blot analysis revealed a restricted expression of mRNA in the thymus, spleen, and peripheral blood leukocytes in normal human tissues. Western blot analysis demonstrated that the protein encoded by this gene is overexpressed in lymphoid malignancies; cancer cell lines and peripheral blood leukocyte from chronic lymphocytic leukemia (CLL) patients. Furthermore, the human leukocyte formin protein was observed to associate with Akt, a critical survival regulator in many different cell types.     

Genomic GC level, optimal growth temperature, and genome size in prokaryotes

Two years ago, we showed that positive correlations between optimal growth temperature (T(opt)) and genome GC are observed in 15 out of the 20 families of prokaryotes we analyzed, thus indicating that "T(opt) is one of the factors that influence genomic GC in prokaryotes". Our results were disputed, but these criticisms were demonstrated to be mistaken and based on misconceptions. In a recent report, Wang et al. [H.C. Wang, E. Susko, A.J. Roger, On the correlation between genomic G+C content and optimal growth temperature in prokaryotes: data quality and confounding factors, Biochem. Biophys. Res. Commun. 342 (2006) 681-684] criticize our results by stating that "all previous simple correlation analyses of GC versus temperature have ignored the fact that genomic GC content is influenced by multiple factors including both intrinsic mutational bias and extrinsic environmental factors". This statement, besides being erroneous, is surprising because it applies in fact not to ours but to the authors' article. Here, we rebut the points raised by Wang et al. and review some issues that have been a matter of debate, regarding the influence of environmental factors upon GC content in prokaryotes. Furthermore, we demonstrate that the relationship that exists between genome size and GC level is valid for aerobic, facultative, and microaerophilic species, but not for anaerobic prokaryotes.     

A new approach to antiglaucoma drugs: carbonic anhydrase inhibitors with or without NO donating moieties. Mechanism of action and preliminary pharmacology

The clinically used sulfonamide carbonic anhydrase (CA, EC 4.2.1.1) inhibitor dorzolamide (DRZ), a new sulfonamide CA inhibitor also incorporating NO-donating moieties, NCX250, and isosorbide mononitrate (ISMN) (an NO-donating compound with no CA inhibitory properties) were investigated for their intraocular pressure (IOP) lowering effects in rabbits with carbomer-induced glaucoma. NCX250 was more effective than DRZ or ISMN on lowering IOP, increasing ocular hemodynamics, decreasing the inflammatory processes and ocular apoptosis in this animal model of glaucoma. NO participate to the regulation of IOP in glaucoma, having also antiapoptotic and anti-inflammatory effects. The ophthalmic artery, both systolic and diastolic velocities, were significantly reduced in NCX250-treated eyes in comparison to DRZ treated ones, suggesting thus a beneficial effect of NCX250 on the blood supply to the optic nerve. Combining CA inhibition with NO-donating moieties in the same compound offers an excellent approach for the management of glaucoma.     

Microhabitat amelioration and reduced competition among understorey plants as drivers of facilitation across environmental gradients: Towards a unifying framework

Studies of facilitative interactions as drivers of plant richness along environmental gradients often assume the existence of an overarching stress gradient that equally affects the performance of all the species in a given community. However, co-existing species differ in their ecophysiological adaptations, and do not experience the same stress level under particular environmental conditions. Moreover, these studies assume a unimodal relationship between richness and biomass, which is not as general as previously thought. We ignored these assumptions to assess changes in plant–plant interactions and their effect on local species richness across environmental gradients in semi-arid areas of Spain and Australia. We aimed to understand the relative importance of direct (microhabitat amelioration) and indirect (changes in the competitive relationships among the understorey species: niche segregation, competitive exclusion or intransitivity) mechanisms that might underlie the effects of nurse plants on local species richness. By jointly studying these direct and indirect mechanisms using a unifying framework, we found that nurse plants (trees, shrubs and tussock grasses) increased local richness not only by expanding the niche of neighbouring species but also by increasing niche segregation among them, though the latter was not important in all cases. The outcome of the competition-facilitation continuum varied depending on the study area, likely because the different types of stress gradient considered. When driven by both rainfall and temperature, or rainfall alone, the community-wide importance of nurse plants remained constant (Spanish sites), or showed a unimodal relationship along the gradient (Australian sites). This study expands our understanding of the relative roles of plant–plant interactions and environmental conditions as drivers of local species richness in semi-arid environments. The results can also be used to refine predictions about the response of plant communities to environmental change, and to clarify the relative importance of biotic interactions as drivers of such responses.     

Tests of candidate genes in breed cross populations for QTL mapping in livestock

In recent years, several F₂ crosses between outbred lines of livestock have been developed to identify quantitative trait loci (QTL). These populations are valuable for further genetic analysis, including positional candidate gene loci (CGL). Analysis of CGL in F₂ populations is, however, hindered by extensive between-breed linkage disequilibrium (LD). The objectives here were to develop and evaluate three tests for CGL in simulated F₂ breed-cross populations. 1) A standard association test, based on the fixed effect of CGL genotype. This test was significant for CGL at considerable distances from the QTL. 2) A marker-assisted association test, based on a test at the CGL of the fixed effect of CGL genotype in a breed-cross QTL interval mapping model. This removed the impact of between-breed LD, but was not powerful in detecting CGL closely linked to the QTL, unless the CGL was the QTL. 3) An F-drop test, comparing F ratios for a QTL at the CGL with and without the CGL included as fixed effect. It had low power to distinguish close from distant CGL. Power to distinguish two CGL within 10 cM from the QTL was limited and little improved by including QTL effects associated with markers to remove between-breed LD, although the power was greater when one of the CGL was the causative mutation. Therefore, while we conclude that candidate gene tests in QTL mapping populations must be interpreted with caution, we now have a clearer picture of the value of candidate gene tests in these populations.     

MicroRNAs: new players in heart failure

MicroRNAs (miRNAs) are a class of non-coding small RNAs representing one of the most exciting areas of modern medical science. miRNAs modulate a large and complex regulatory network of gene expression of the majority of the protein-coding genes. Currently, evidences suggest that miRNAs play a crucial role in the pathogenesis of heart failure. Some miRNAs as miR-1, miR-133 and miR-208a are highly expressed in the heart and strongly associated with the development of cardiac hypertrophy. Recent data indicate that these miRNAs as well as miR-206 change their expression quickly in response to physical activity. The differential regulation of miRNAs in response to exercise suggests a potential value of circulating miRNAs (c-miRNAs) as biomarkers of physiological mediators of the cardiovascular adaptation induced by exercise. Likewise, serum levels of c-miRNAs such as miR-423-5p have been evaluated as potential biomarkers in the diagnosis and prognosis of heart failure. On the other hand, the manipulation of miRNAs levels using techniques such as ‘miR mimics’ and ‘antagomiRs’ is becoming evident the enormous potential of miRNAs as promising therapeutic strategies in heart failure.     

Targeting of a T cell agonist peptide to lysosomes by DNA vaccination induces tolerance in the nonobese diabetic mouse

CD4 T cells are crucial effectors in the pathology of type 1 diabetes (T1D). Successful therapeutic interventions for prevention and cure of T1D in humans are still elusive. Recent research efforts have focused on the manipulation of T cells by treatment with DNA. In this paper, we studied the effects of a DNA treatment strategy designed to target antigenic peptides to the lysosomal compartment on a monospecific T cell population termed 2.5mi(+) T cells that shares reactivity with the diabetogenic T cell clone BDC-2.5 in the NOD mouse. MHC class II tetramer analysis showed that repeated administrations were necessary to expand 2.5mi(+) T cells in vivo. This expansion was independent of Ag presentation by B cells. A single peptide epitope was sufficient to induce protection against T1D, which was not due to Ag-specific T cell anergy. Typical Th2 cytokines such as IL-10 or IL-4 were undetectable in 2.5mi(+) T cells, arguing against a mechanism of immune deviation. Instead, the expanded 2.5mi(+) T cell population produced IFN-γ similar to 2.5mi(+) T cells from naive mice. Protection against T1D by DNA treatment was completely lost in NOD.CD28(-/-) mice which are largely deficient of natural regulatory T cells (Treg). Although Ag-specific Foxp3(+) Treg did not expand in response to DNA treatment, diabetes onset was delayed in Treg-reconstituted and DNA-treated NOD.SCID mice. These observations provide evidence for a Treg-mediated protective mechanism that is independent of the expansion or de novo generation of Ag-specific Treg.