Extracellular vesicle microRNAs contribute to the osteogenic inhibition of mesenchymal stem cells in multiple myeloma

Osteolytic bone disease is the major complication associated with the progression of multiple myeloma (MM). Recently, extracellular vesicles (EVs) have emerged as mediators of MM-associated bone disease by inhibiting the osteogenic differentiation of human mesenchymal stem cells (hMSCs). Here, we investigated a correlation between the EV-mediated osteogenic inhibition and MM vesicle content, focusing on miRNAs. By the use of a MicroRNA Card, we identified a pool of miRNAs, highly expressed in EVs, from MM cell line (MM1.S EVs), expression of which was confirmed in EVs from bone marrow (BM) plasma of patients affected by smoldering myeloma (SMM) and MM. Notably,we found that miR-129-5p, which targets different osteoblast (OBs) differentiation markers, is enriched in MM-EVs compared to SMM-EVs, thus suggesting a selective packaging correlated with pathological grade. We found that miR-129-5p can be transported to hMSCs by MM-EVs and, by the use of miRNA mimics, we investigated its role in recipient cells. Our data demonstrated that the increase of miR-129-5p levels in hMSCs under osteoblastic differentiation stimuli inhibited the expression of the transcription factor Sp1, previously described as a positive modulator of osteoblastic differentiation, and of its target the Alkaline phosphatase (ALPL), thus identifying miR-129-5p among the players of vesicle-mediated bone disease

Level set based eXtended finite element modelling of the response of fibrous networks under hygroscopic swelling

Materials like paper, consisting of a network of natural fibres, exposed to variations in moisture, undergo changes in geometrical and mechanical properties. This behaviour is particularly important for understanding the hygro-mechanical response of sheets of paper in applications like digital printing. A two-dimensional microstructural model of a fibrous network is therefore developed to upscale the hygro-expansion of individual fibres, through their interaction, to the resulting overall expansion of the network. The fibres are modelled with rectangular shapes and are assumed to be perfectly bonded where they overlap. For realistic networks the number of bonds is large and the network is geometrically so complex that discretizing it by conventional, geometry-conforming, finite elements is cumbersome. The combination of a level-set and XFEM formalism enables the use of regular, structured grids in order to model the complex microstructural geometry. In this approach, the fibres are described implicitly by a level-set function. In order to represent the fibre boundaries in the fibrous network, an XFEM discretization is used together with a Heaviside enrichment function. Numerical results demonstrate that the proposed approach successfully captures the hygro-expansive properties of the network with fewer degrees of freedom compared to classical FEM, preserving desired accuracy.Comment: 27 pages, 22 figures, 4 tables, J. Appl. Mech. June 19, 202

Cooperative role of thrombopoietin and vascular endothelial growth factor-a in the progression of liver cirrhosis to hepatocellular carcinoma

Primary thrombopoietic mediator thrombopoietin (THPO) is mainly produced by the liver; it may act as a growth factor for hepatic progenitors. Principal angiogenesis inducer vascular endothelial growth factor-A (VEGF-A) is critical for the complex vascular network within the liver architecture. As a cross-regulatory loop between THPO and VEGF-A has been demonstrated in the hematopoietic system, the two growth factors were hypothesized to cooperatively contribute to the progression from liver cirrhosis (LC) to hepatocellular carcinoma (HCC). The mRNA and protein expression levels of THPO, VEGF-A, and their receptors were examined, compared, and correlated in paired cancerous and LC tissues from 26 cirrhosis-related HCC patients, using qRT-PCR and immunohistochemistry. THPO and VEGF-A were alternatively silenced by small interfering RNA (siRNA) in human liver cancer cell lines Huh7 and HepG2. THPO and VEGF-A expressions significantly increased in tumor versus LC tissues. HCC and paired LC cells expressed similar levels of THPO receptor (R), whereas vascular endothelial growth factor receptor (VEGFR) -1 and VEGFR-2 levels were higher in HCC than in corresponding LC tissue samples. A significant linear correlation emerged between THPO and VEGF-A transcripts in HCC and, at the protein level, THPO and THPOR were significantly correlated with VEGF-A in tumor tissues. Both HCC and LC expressed similar levels of gene and protein hypoxia inducible factor (HIF)-1α. Positive cross-regulation occurred with the alternative administration of siRNAs targeting THPO and those targeting VEGF-A in hypoxic liver cancer cell lines. These results suggest THPO and VEGF-A might act as interdependently regulated autocrine and/or paracrine systems for cellular growth in HCC. This might be clinically interesting, since new classes of THPOR agonistic/antagonistic drugs may provide novel therapeutic options to correct the frequent hemostatic abnormality seen in HCC patients

Virus Replication as a Phenotypic Version of Polynucleotide Evolution

In this paper we revisit and adapt to viral evolution an approach based on the theory of branching process advanced by Demetrius, Schuster and Sigmund ("Polynucleotide evolution and branching processes", Bull. Math. Biol. 46 (1985) 239-262), in their study of polynucleotide evolution. By taking into account beneficial effects we obtain a non-trivial multivariate generalization of their single-type branching process model. Perturbative techniques allows us to obtain analytical asymptotic expressions for the main global parameters of the model which lead to the following rigorous results: (i) a new criterion for "no sure extinction", (ii) a generalization and proof, for this particular class of models, of the lethal mutagenesis criterion proposed by Bull, Sanju\'an and Wilke ("Theory of lethal mutagenesis for viruses", J. Virology 18 (2007) 2930-2939), (iii) a new proposal for the notion of relaxation time with a quantitative prescription for its evaluation, (iv) the quantitative description of the evolution of the expected values in in four distinct "stages": extinction threshold, lethal mutagenesis, stationary "equilibrium" and transient. Finally, based on these quantitative results we are able to draw some qualitative conclusions.Comment: 23 pages, 1 figure, 2 tables. arXiv admin note: substantial text overlap with arXiv:1110.336

High field hybrid photoinjector electron source for advanced light source applications

The production of high spectral brilliance radiation from electron beam sources depends critically on the electron beam qualities. One must obtain very high electron beam brightness, implying simultaneous high peak current and low emittance. These attributes are enabled through the use of very high field acceleration in a radio-frequency (rf) photoinjector source. Despite the high fields currently utilized, there is a limit on the achievable peak current in high brightness operation, in the range of tens of Ampere. This limitation can be overcome by the use of a hybrid standing wave/traveling wave structure; the standing wave portion provides acceleration at a high field from the photocathode, while the traveling wave part yields strong velocity bunching. This approach is explored here in a C-band scenario, at field strengths (>100 MV/m) at the current state-of-the-art. It is found that one may arrive at an electron beam with many hundreds of Amperes with well-sub-micron normalized emittance. This extremely compact injector system also possesses attractive simplification of the rf distribution system by eliminating the need for an rf circulator. We explore the use of this device in a compact 400 MeV-class source, driving both inverse Compton scattering and free-electron laser radiation sources with unique, attractive properties

Muon `Depth -- Intensity' Relation Measured by LVD Underground Experiment and Cosmic-Ray Muon Spectrum at Sea Level

We present the analysis of the muon events with all muon multiplicities collected during 21804 hours of operation of the first LVD tower. The measured angular distribution of muon intensity has been converted to the `depth -- vertical intensity' relation in the depth range from 3 to 12 km w.e.. The analysis of this relation allowed to derive the power index, $\gamma$, of the primary all-nucleon spectrum: $\gamma=2.78 \pm 0.05$. The `depth -- vertical intensity' relation has been converted to standard rock and the comparison with the data of other experiments has been done. We present also the derived vertical muon spectrum at sea level.Comment: 7 pages, 3 figures, to be published on Phys. Rev.

Test of the Kolmogorov-Johnson-Mehl-Avrami picture of metastable decay in a model with microscopic dynamics

The Kolmogorov-Johnson-Mehl-Avrami (KJMA) theory for the time evolution of the order parameter in systems undergoing first-order phase transformations has been extended by Sekimoto to the level of two-point correlation functions. Here, this extended KJMA theory is applied to a kinetic Ising lattice-gas model, in which the elementary kinetic processes act on microscopic length and time scales. The theoretical framework is used to analyze data from extensive Monte Carlo simulations. The theory is inherently a mesoscopic continuum picture, and in principle it requires a large separation between the microscopic scales and the mesoscopic scales characteristic of the evolving two-phase structure. Nevertheless, we find excellent quantitative agreement with the simulations in a large parameter regime, extending remarkably far towards strong fields (large supersaturations) and correspondingly small nucleation barriers. The original KJMA theory permits direct measurement of the order parameter in the metastable phase, and using the extension to correlation functions one can also perform separate measurements of the nucleation rate and the average velocity of the convoluted interface between the metastable and stable phase regions. The values obtained for all three quantities are verified by other theoretical and computational methods. As these quantities are often difficult to measure directly during a process of phase transformation, data analysis using the extended KJMA theory may provide a useful experimental alternative.Comment: RevTex, 21 pages including 14 ps figures. Submitted to Phys. Rev. B. One misprint corrected in Eq.(C1

Upper Limit on the Prompt Muon Flux Derived from the LVD Underground Experiment

We present the analysis of the muon events with all muon multiplicities collected during 21804 hours of operation of the first LVD tower. The measured depth-angular distribution of muon intensities has been used to obtain the normalization factor, A, the power index, gamma, of the primary all-nucleon spectrum and the ratio, R_c, of prompt muon flux to that of pi-mesons - the main parameters which determine the spectrum of cosmic ray muons at the sea level. The value of gamma = 2.77 +/- 0.05 (68% C.L.) and R_c < 2.0 x 10^-3 (95% C.L.) have been obtained. The upper limit to the prompt muon flux favours the models of charm production based on QGSM and the dual parton model.Comment: 10 pages, 4 figures, RevTex. To appear in Phys. Rev.

The -786T>C promoter polymorphism of the NOS3 gene is associated with prostate cancer progression

<p>Abstract</p> <p>Background</p> <p>There is no biological or epidemiological data on the association between <it>NOS3 </it>promoter polymorphisms and prostate cancer. The polymorphisms in the promoter region of <it>NOS3 </it>gene may be responsible for variations in the plasma NO, which may promote cancer progression by providing a selective growth advantage to tumor cells by angiogenic stimulus and by direct DNA damage.</p> <p>Methods</p> <p>This study aimed evaluating the <it>NOS3 </it>promoter polymorphisms by PCR-SSCP and sequencing, associating genotypes and haplotypes with <it>NOS3 </it>expression levels through semi-quantitative RT-PCR, and with <it>PCA</it>3 mRNA detection, a specific tumor biomarker, in the peripheral blood of pre-surgical samples from 177 patients; 83 PCa and 94 BPH.</p> <p>Results</p> <p>Three novel SNPs were identified -764A>G, -714G>T and -649G>A in the <it>NOS3 </it>gene promoter region, which together with the -786T>C generated four haplotypes (N, T, C, A). <it>NOS3 </it>gene expression levels were affected by the -786T>C polymorphism, and there was a 2-fold increase in <it>NOS3 </it>levels favored by the incorporation of each C allele. <it>NOS3 </it>levels higher than 80% of the constitutive gene expression level (<it>B2M</it>) presented a 4-fold increase in PCa occurrence.</p> <p>Conclusion</p> <p>The -786T>C polymorphism was the most important promoter alteration of the <it>NOS3 </it>gene that may affect the PCa progression, but not its occurrence, and the incorporation of the C allele is associated with increased levels of <it>NOS3 </it>transcripts. The <it>NOS3 </it>transcript levels presented a bimodal behavior in tumor development and may be used as a biomarker together with the <it>PCA3 </it>marker for molecular staging of the prostate cancer.</p

Zippin’ up my boots, goin’ back to my roots: Radical left parties in Southern Europe

Radical left parties actively encourage the participation of their members in internal decision-making and insist on promoting organised links to trade unions and social movements. As a party family, they deviate from what is considered to be the trend in which Western political parties have turned their backs on their social roots. Drawing on the experience of South European radical left parties from the fall of the Berlin Wall until the recent financial crisis, we argue that ideology, electoral incentives, party competition and external events explain the radical left's pronounced emphasis on linkage, while organisational trajectory explains variation within the party family in terms of the linkage strategies pursued