The tyrosine kinase inhibitor dasatinib induces a marked adipogenic differentiation of human multipotent mesenchymal stromal cells

Background

The introduction of specific BCR-ABL inhibitors in chronic myelogenous leukemia therapy has entirely mutated the prognosis of this hematologic cancer from being a fatal disorder to becoming a chronic disease. Due to the probable long lasting treatment with tyrosine-kinase inhibitors (TKIs), the knowledge of their effects on normal cells is of pivotal importance.

Design and Methods

We investigated the effects of dasatinib treatment on human bone marrow-derived mesenchymal stromal cells (MSCs).

Results

Our findings demonstrate, for the first time, that dasatinib induces MSCs adipocytic differentiation. Particularly, when the TKI is added to the medium inducing osteogenic differentiation, a high MSCs percentage acquires adipocytic morphology and overexpresses adipocytic specific genes, including PPARγ, CEBPα, LPL and SREBP1c. Dasatinib also inhibits the activity of alkaline phosphatase, an osteogenic marker, and remarkably reduces matrix mineralization. The increase of PPARγ is also confirmed at protein level. The component of osteogenic medium required for dasatinib-induced adipogenesis is dexamethasone. Intriguingly, the increase of adipocytic markers is also observed in MSCs treated with dasatinib alone. The TKI effect is phenotype-specific, since fibroblasts do not undergo adipocytic differentiation or PPARγ increase.

Conclusions

Our data demonstrate that dasatinib treatment affects bone marrow MSCs commitment and suggest that TKIs therapy might modify normal phenotypes with potential significant negative consequences.     

Bayesian modeling of perceived surface slant from actively-generated and passively-observed optic flow

We measured perceived depth from the optic flow (a) when showing a stationary physical or virtual object to observers who moved their head at a normal or slower speed, and (b) when simulating the same optic flow on a computer and presenting it to stationary observers. Our results show that perceived surface slant is systematically distorted, for both the active and the passive viewing of physical or virtual surfaces. These distortions are modulated by head translation speed, with perceived slant increasing directly with the local velocity gradient of the optic flow. This empirical result allows us to determine the relative merits of two alternative approaches aimed at explaining perceived surface slant in active vision: an "inverse optics" model that takes head motion information into account, and a probabilistic model that ignores extra-retinal signals. We compare these two approaches within the framework of the bayesian theory. The "inverse optics" bayesian model produces veridical slant estimates if the optic flow and the head translation velocity are measured with no error; because of the influence of a "prior" for flatness, the slant estimates become systematically biased as the measurement errors increase. The bayesian model, which ignores the observer's motion, always produces distorted estimates of surface slant. Interestingly, the predictions of this second model, not those of the first one, are consistent with our empirical findings. The present results suggest that (a) in active vision perceived surface slant may be the product of probabilistic processes which do not guarantee the correct solution, and (b) extra-retinal signals may be mainly used for a better measurement of retinal information.     

Novel, meso-substituted cationic porphyrin molecule for photo-mediated larval control of the dengue vector Aedes aegypti

Background

Control of the mosquito vector population is the most effective strategy currently available for the prevention of dengue fever and the containment of outbreaks. Photo-activated oxidants may represent promising tools for developing effective, safe and ecofriendly novel larvicides. The purpose of this study was to evaluate the potential of the synthetic meso-substituted porphyrin meso-tri(N-methylpyridyl), meso-mono(N-tetradecylpyridyl)porphine (C14) as a photoactivatable larvicide against the dengue vector Aedes (Stegomyia) aegypti.

Methodology

The photophysical and photochemical properties of the C14 molecule were assessed spectrophotometrically. Photomediated larvicidal efficacy, route of intake and site of action were determined on Ae. aegypti larvae by laboratory bioassays and fluorescence microscopy. Using powdered food pellet for laboratory rodents (a common larval food used in the laboratory) as a carrier for C14, loading-release dynamics, larvicidal efficacy and residual activity of the C14-carrier complex were investigated.

Main Findings

The C14 molecule was found to exert a potent photosensitizing activity on Ae. aegypti larvae. At irradiation intervals of 12 h and 1 h, at a light intensity of 4.0 mW/cm², which is 50–100 times lower than that of natural sunlight, LC₅₀ values of 0.1 µM (0.15 mg/l) and 0.5 µM (0.77 mg/l) were obtained, respectively. The molecule was active after ingestion by the larvae and caused irreversible, lethal damage to the midgut and caecal epithelia. The amphiphilic nature of C14 allowed a formulate to be produced that not only was as active against the larvae as C14 in solution, but also possessed a residual activity of at least two weeks, in laboratory conditions.

Conclusions

The meso-substituted synthetic porphyrin C14, thanks to its photo-sensitizing properties represents an attractive candidate for the development of novel photolarvicides for dengue vector control.     

A multi‐perspective view of genetic variation in Cameroon

In this study, we report the genetic variation of autosomal and Y‐chromosomal microsatellites in a large Cameroon population dataset (a total of 11 populations) and jointly analyze novel and previous genetic data (mitochondrial DNA and protein coding loci) taking geographic and cultural factors into consideration. The complex pattern of genetic variation of Cameroon can in part be described by contrasting two geographic areas (corresponding to the northern and southern part of the country), which differ substantially in environmental, biological, and cultural aspects. Northern Cameroon populations show a greater within‐ and among‐group diversity, a finding that reflects the complex migratory patterns and the linguistic heterogeneity of this area. A striking reduction of Y‐chromosomal genetic diversity was observed in some populations of the northern part of the country (Podokwo and Uldeme), a result that seems to be related to their demographic history rather than to sampling issues. By exploring patterns of genetic, geographic, and linguistic variation, we detect a preferential correlation between genetics and geography for mtDNA. This finding could reflect a female matrimonial mobility that is less constrained by linguistic factors than in males. Finally, we apply the island model to mitochondrial and Y‐chromosomal data and obtain a female‐to‐male migration Nν ratio that was more than double in the northern part of the country. The combined effect of the propensity to inter‐populational admixture of females, favored by cultural contacts, and of genetic drift acting on Y‐chromosomal diversity could account for the peculiar genetic pattern observed in northern Cameroon. Am J Phys Anthropol, 2009. © 2009 Wiley‐Liss, Inc.     

Characterization of prion protein-enriched domains, isolated from rat cerebellar granule cells in culture

The biological functions of prion protein (PrP^C) and its possible interaction with other specific molecular membrane partners remain largely unknown. The aim of this study is to gain information on the molecular environment of PrP^C by analyzing the lipid and protein composition of a PrP^C-enriched membrane subfraction, called prion domain, PrD . This domain was obtained by immunoprecipitation of detergent-resistant microdomains (DRM) of rat cerebellar granule cells under conditions designed to preserve lipid-mediated membrane organization. The electrophoretic pattern of PrD , after staining with Coomassie blue, showed the enrichment of some protein bands in comparison with DRM. μLiquid cromatography-electrospray ionization-mass spectrometry (μLC-ESI-MS)/MS analysis showed that Thy-1 and different types of myosin were strongly enriched in PrD and, in a lesser extent, also OBCAM, LSAMP and tubulin, present altogether in a single band. Experiments using the chemical cross-linker BS³ suggested the existence of an interaction between PrP^C and neural cell adhesion molecule (NCAM). Concerning lipids, the comparison between PrD and DRM showed a similar phospholipid/sphingolipid ratio, a phospholipid/cholesterol ratio doubled, and a strong decrease of plasmenilethanolamine (19.7 ± 3.5% vs. 38.3 ± 1.2%). In conclusion, the peculiar lipid composition and in particular the presence of proteins involved in synaptic plasticity, cell adhesion, cytoskeleton regulation and signalling, suggest an important physiological role in neurons of Prion Domain.     

Telomere Length Variation in Juvenile Acute Myocardial Infarction

Leukocyte telomere length (LTL) provides a potential marker of biological age, closely related to the endothelial dysfunction and consequently to the atherosclerotic process. To investigate the relationship between the LTL and the risk of premature acute myocardial infarction and to evaluate the predictive value of LTL on the onset of major cardiovascular events, 199 patients from 18 to 48 years old with first diagnosis of acute myocardial infarction were enrolled and were matched with 190 controls for sex and age (±1 year). Clinical data and coronary artery disease were evaluated at enrollment and at follow up. LTL was measured at enrollment using a quantitative PCR-based method. No significant differences were observed in LTL between cases and controls (p = 0.20) and with the presence of coronary artery disease in patients (p = 0.47). Hypercholesterolemic cases presented LTL significantly longer than cases without hypercholesterolemia (t/s: 0.82±0.16 p = 0.79 and t/s norm: 0.79±0.19 p = 0.01), as confirmed in multivariate regression analysis (p = 0.005, β = 0.09). Furthermore, multivariate regression analysis showed LTL significantly shorter in hypertensive cases than in normotensive cases (p = 0.04, β = −0.07). One hundred seventy-one cases (86%) ended the average follow up of 9±5 years, 92 (54%) presented a major cardiovascular event. At multivariate regression analysis the LTL detected at enrollment did not represent a predictive factor of major cardiovascular events nor it significantly impacted with cumulative events. Based on present cohort of young Italian patients, the LTL did not represent a marker of acute myocardial infarction nor had a predictive role at medium term follow up.     

Is there evidence of involvement of DNA repair polymorphisms in human cancer?

DNA suffers from a wide range of damage, both from extracellular agents and via endogenous mechanisms. Damage of DNA can lead to cancer and other diseases. Therefore, it is plausible that sequence variants in DNA repair genes are involved in cancer development. A recent systematic review and meta-analysis, based on the "Venice criteria", showed that out of 241 associations investigated, only three resulted to have a strong grade of cumulative evidence. These associations were: two SNPs rs1799793 and rs13181 in the ERCC2 gene and lung cancer (recessive model) and rs1805794 in the NBN gene and bladder cancer (dominant model). An update of this meta-analysis has been performed in the present paper, and we found partially inconsistent results. Inconsistencies in the literature are thus far not easy to explain. In addition, none of the cancer genome-wide association studies (GWAs) published so far showed highly statistically significant associations for any of the common DNA repair gene variants, in such a way as to place DNA repair genes among the top 10-20 hits identified in GWAs. Though this suggests that it is unlikely that DNA repair gene polymorphisms per se play a major role, a clarification of the discrepancies in the literature is needed. Also, gene/environment and gene/lifestyle interactions for the carcinogenic mechanisms involving DNA repair should be investigated more systematically and with less classification error. Finally, the combined effect of multiple SNPs in several genes in one or more relevant DNA repair pathways could have a greater impact on pathological phenotypes than SNPs in single genes, but this has been investigated only occasionally.     

Perceived surface slant is systematically biased in the actively-generated optic flow

Humans make systematic errors in the 3D interpretation of the optic flow in both passive and active vision. These systematic distortions can be predicted by a biologically-inspired model which disregards self-motion information resulting from head movements (Caudek, Fantoni, & Domini 2011). Here, we tested two predictions of this model: (1) A plane that is stationary in an earth-fixed reference frame will be perceived as changing its slant if the movement of the observer's head causes a variation of the optic flow; (2) a surface that rotates in an earth-fixed reference frame will be perceived to be stationary, if the surface rotation is appropriately yoked to the head movement so as to generate a variation of the surface slant but not of the optic flow. Both predictions were corroborated by two experiments in which observers judged the perceived slant of a random-dot planar surface during egomotion. We found qualitatively similar biases for monocular and binocular viewing of the simulated surfaces, although, in principle, the simultaneous presence of disparity and motion cues allows for a veridical recovery of surface slant.     

Moonlighting by different stressors: crystal structure of the chaperone species of a 2-Cys peroxiredoxin

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Highlights? The Schistosoma mansoni peroxiredoxin I (SmPrxI) is a moonlighting protein ? SmPrxI switches from LMW peroxidase to HMW chaperone due to chemical stressors ? The three-dimensional structures of both LMW and HMW SmPrxI have been solved ? SmPrxI HMW is the structure of a Prx chaperone