Low-dosage inhibition of Dll4 signaling promotes wound healing by inducing functional neo-angiogenesis

Recent findings regarding Dll4 function in physiological and pathological conditions indicate that this Notch ligand may constitute an important therapeutic target. Dll4 appears to be a major anti-angiogenic agent, occupying a central role in various angiogenic pathways. The first trials of anti-Dll4 therapy in mice demonstrated a paradoxical effect, as it reduced tumor perfusion and growth despite leading to an increase in vascular density. This is seen as the result of insufficient maturation of the newly formed vasculature causing a circulatory defect and increased tumor hypoxia. As Dll4 function is known to be closely dependent on expression levels, we envisioned that the therapeutic anti-Dll4 dosage could be modulated to result in the increase of adequately functional blood vessels. This would be useful in conditions where vascular function is a limiting factor for recovery, like wound healing and tissue hypoxia, especially in diabetic patients. Our experimental results in mice confirmed this possibility, revealing that low dosage inhibition of Dll4/Notch signaling causes improved vascular function and accelerated wound healing.     

Identification of olive (Olea europaea) seed and pulp proteins by nLC-MS/MS via combinatorial peptide ligand libraries

Different types of extraction protocols are described for identifying proteins in seed and pulp of olive (Olea europea), by employing both conventional extraction methods and capture with ProteoMiner as well as with in house-made combinatorial peptide ligand libraries (HM-CPLLs) at pH 7.4 and at pH 2.2. Thanks to the use of CPLLs, able to dramatically amplify the signal of low-abundance species, a quite large number of compounds has been indeed identified: 61 in the seed (vs. only four reported in current literature) and 231 in the pulp (vs. 56 described so far), the deepest investigation up to the present of the olive proteome. In the seed, it highlights the presence of seed storage proteins, oleosins and histones. In the pulp, the allergenic thaumatin-like protein (Ole e 13) was confirmed, among the other 231, as the most abundant protein in the olive pulp. The present research has also been undertaken with the aim of identifying proteins in olive oil and ascertaining the relative contribution of seed and pulp proteins in their presence, if any, in oils.     

Relation between augmentation index and adiponectin during one-year metformin treatment for nonalcoholic steatohepatosis: effects beyond glucose lowering?

ABSTRACT: BACKGROUND: Insulin resistance (IR) is the major driving force behind development and progression of atherosclerosis in patients with nonalcoholic fatty liver disease (NAFLD). Therefore, correction of IR is a relevant therapeutic target. We performed the current trial to evaluate whether 12- month metformin therapy improves vascular stiffness in patients with NAFLD and to assess if this improvement is associated with change in glucose control, insulin resistance or circulating adiponectin. METHODS: In randomized, placebo controlled study, 63 patients with NAFLD were assigned to one of two groups: Group 1 received daily metformin; Group 2 received placebo. Central aortic augmentation index (AI) was performed using SphygmoCor (version 7.1, AtCor Medical, Sydney, Australia) at baseline, at 4-and 12-month treatment period. Metabolic parameters, insulin resistance markers and serum adiponectin levels were determined. RESULTS: In placebo group: AI did not improve during the treatment period. Liver function and adiponectin levels did not change during the study. In multiple linear regression analysis, the independent predictors of arterial stiffness improvement were metformin treatment and increase in circulating adiponectin levels. Among metformin treated patients: AI decreased significantly during the study. ALP and ALT decreased during initial 4-month treatment period, however raised to the pretreatment levels after 12 months. Serum adiponectin level tended to increase during treatment period with metformin. CONCLUSIONS: Metformin treatment was associated with significant decrease in AI during one year treatment in NAFLD patients. These beneficial vascular effects was associated with exposure to metformin per se as well as change in adiponectin levels suggesting that metformin may mediate its vascular effects via glicemic control-independent mechanisms.     

Direct maximization of protein identifications from tandem mass spectra

The goal of many shotgun proteomics experiments is to determine the protein complement of a complex biological mixture. For many mixtures, most methodological approaches fall significantly short of this goal. Existing solutions to this problem typically subdivide the task into two stages: first identifying a collection of peptides with a low false discovery rate and then inferring from the peptides a corresponding set of proteins. In contrast, we formulate the protein identification problem as a single optimization problem, which we solve using machine learning methods. This approach is motivated by the observation that the peptide and protein level tasks are cooperative, and the solution to each can be improved by using information about the solution to the other. The resulting algorithm directly controls the relevant error rate, can incorporate a wide variety of evidence and, for complex samples, provides 18-34% more protein identifications than the current state of the art approaches.     

Different cranial ontogeny in Europeans and Southern Africans

Modern human populations differ in developmental processes and in several phenotypic traits. However, the link between ontogenetic variation and human diversification has not been frequently addressed. Here, we analysed craniofacial ontogenies by means of geometric-morphometrics of Europeans and Southern Africans, according to dental and chronological ages. Results suggest that different adult cranial morphologies between Southern Africans and Europeans arise by a combination of processes that involve traits modified during the prenatal life and others that diverge during early postnatal ontogeny. Main craniofacial changes indicate that Europeans differ from Southern Africans by increasing facial developmental rates and extending the attainment of adult size and shape. Since other studies have suggested that native subsaharan populations attain adulthood earlier than Europeans, it is probable that facial ontogeny is linked with other developmental mechanisms that control the timing of maturation in other variables. Southern Africans appear as retaining young features in adulthood. Facial ontogeny in Europeans produces taller and narrower noses, which seems as an adaptation to colder environments. The lack of these morphological traits in Neanderthals, who lived in cold environments, seems a paradox, but it is probably the consequence of a warm-adapted faces together with precocious maturation. When modern Homo sapiens migrated into Asia and Europe, colder environments might establish pressures that constrained facial growth and development in order to depart from the warm-adapted morphology. Our results provide some answers about how cranial growth and development occur in two human populations and when developmental shifts take place providing a better adaptation to environmental constraints.     

Learning to use illumination gradients as an unambiguous cue to three dimensional shape

The luminance and colour gradients across an image are the result of complex interactions between object shape, material and illumination. Using such variations to infer object shape or surface colour is therefore a difficult problem for the visual system. We know that changes to the shape of an object can affect its perceived colour, and that shading gradients confer a sense of shape. Here we investigate if the visual system is able to effectively utilise these gradients as a cue to shape perception, even when additional cues are not available. We tested shape perception of a folded card object that contained illumination gradients in the form of shading and more subtle effects such as inter-reflections. Our results suggest that observers are able to use the gradients to make consistent shape judgements. In order to do this, observers must be given the opportunity to learn suitable assumptions about the lighting and scene. Using a variety of different training conditions, we demonstrate that learning can occur quickly and requires only coarse information. We also establish that learning does not deliver a trivial mapping between gradient and shape; rather learning leads to the acquisition of assumptions about lighting and scene parameters that subsequently allow for gradients to be used as a shape cue. The perceived shape is shown to be consistent for convex and concave versions of the object that exhibit very different shading, and also similar to that delivered by outline, a largely unrelated cue to shape. Overall our results indicate that, although gradients are less reliable than some other cues, the relationship between gradients and shape can be quickly assessed and the gradients therefore used effectively as a visual shape cue.