Human serum albumin: twenty-three genetic variants and their population distribution

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66001/1/j.1469-1809.1973.tb00602.x.pd

Pure O-sequences and matroid h-vectors

We study Stanley's long-standing conjecture that the h-vectors of matroid simplicial complexes are pure O-sequences. Our method consists of a new and more abstract approach, which shifts the focus from working on constructing suitable artinian level monomial ideals, as often done in the past, to the study of properties of pure O-sequences. We propose a conjecture on pure O-sequences and settle it in small socle degrees. This allows us to prove Stanley's conjecture for all matroids of rank 3. At the end of the paper, using our method, we discuss a first possible approach to Stanley's conjecture in full generality. Our technical work on pure O-sequences also uses very recent results of the third author and collaborators.Comment: Contains several changes/updates with respect to the previous version. In particular, a discussion of a possible approach to the general case is included at the end. 13 pages. To appear in the Annals of Combinatoric

Inhibition of the tyrosine phosphatase SHP-2 suppresses angiogenesis in vitro and in vivo

Endothelial cell survival is indispensable to maintain endothelial integrity and initiate new vessel formation. We investigated the role of SHP-2 in endothelial cell survival and angiogenesis in vitro as well as in vivo. SHP-2 function in cultured human umbilical vein and human dermal microvascular endothelial cells was inhibited by either silencing the protein expression with antisense-oligodesoxynucleotides or treatment with a pharmacological inhibitor (PtpI IV). SHP-2 inhibition impaired capillary-like structure formation (p < 0.01; n = 8) in vitro as well as new vessel growth ex vivo (p < 0.05; n = 10) and in vivo in the chicken chorioallantoic membrane (p < 0.01, n = 4). Additionally, SHP-2 knock-down abrogated fibroblast growth factor 2 (FGF-2)-dependent endothelial proliferation measured by MTT reduction ( p ! 0.01; n = 12). The inhibitory effect of SHP-2 knock-down on vessel growth was mediated by increased endothelial apoptosis ( annexin V staining, p ! 0.05, n = 9), which was associated with reduced FGF-2-induced phosphorylation of phosphatidylinositol 3-kinase (PI3-K), Akt and extracellular regulated kinase 1/2 (ERK1/2) and involved diminished ERK1/2 phosphorylation after PI3-K inhibition (n=3). These results suggest that SHP-2 regulates endothelial cell survival through PI3-K-Akt and mitogen-activated protein kinase pathways thereby strongly affecting new vessel formation. Thus, SHP-2 exhibits a pivotal role in angiogenesis and may represent an interesting target for therapeutic approaches controlling vessel growth. Copyright (C) 2007 S. Karger AG, Basel

Monitoring response to anti-angiogenic mTOR inhibitor therapy in vivo using 111In-bevacizumab

Abstract Background The ability to image vascular endothelial growth factor (VEGF) could enable prospective, non-invasive monitoring of patients receiving anti-angiogenic therapy. This study investigates the specificity and pharmacokinetics of 111In-bevacizumab binding to VEGF and its use for assessing response to anti-angiogenic therapy with rapamycin. Specificity of 111In-bevacizumab binding to VEGF was tested in vitro with unmodified radiolabelled bevacizumab in competitive inhibition assays. Uptake of 111In-bevacizumab in BALB/c nude mice bearing tumours with different amounts of VEGF expression was compared to that of isotype-matched control antibody (111In-IgG1κ) with an excess of unlabelled bevacizumab. Intratumoural VEGF was evaluated using ELISA and Western blot analysis. The effect of anti-angiogenesis therapy was tested by measuring tumour uptake of 111In-bevacizumab in comparison to 111In-IgG1κ following administration of rapamycin to mice bearing FaDu xenografts. Uptake was measured using gamma counting of ex vivo tumours and effect on vasculature by using anti-CD31 microscopy. Results Specific uptake of 111In-bevacizumab in VEGF-expressing tumours was observed. Rapamycin led to tumour growth delay associated with increased relative vessel size (8.5 to 10.3, P = 0.045) and decreased mean relative vessel density (0.27 to 0.22, P = 0.0015). Rapamycin treatment increased tumour uptake of 111In-bevacizumab (68%) but not 111In-IgGκ and corresponded with increased intratumoural VEGF165. Conclusions 111In-bevacizumab accumulates specifically in VEGF-expressing tumours, and changes after rapamycin therapy reflect changes in VEGF expression. Antagonism of mTOR may increase VEGF in vivo, and this new finding provides the basis to consider combination studies blocking both pathways and a way to monitor effects

The influence of intergranular interaction on the magnetization of the ensemble of oriented Stoner-Wohlfarth nanoparticles

We consider the influence of interparticle interaction on the magnetization reversal in the oriented Stoner-Wohlfarth nanoparticles ensemble. To do so, we solve a kinetic equation for the relaxation of the overall ensemble magnetization to its equilibrium value in some effective mean field. Latter field consists of external magnetic field and interaction mean field proportional to the instantaneous value of above magnetization. We show that the interparticle interaction influences the temperature dependence of a coercive field. This influence manifests itself in the noticeable coercivity at $T>T_{b}$ ($T_{b}$ is so-called blocking temperature). The above interaction can also lead to a formation of the "superferromagnetic" state with correlated directions of particle magnetic moments at $T>T_{b}$. This state possesses coercivity if the overall magnetization has a component directed along the easy axis of each particle. We have shown that the coercive field in the "superferromagnetic" state does not depend on measuring time. This time influences both $T_{b}$ and the temperature dependence of coercive field at $T<T_{b}$. We corroborate our theoretical results by measurements on nanogranular films (CoFeB)$_{x}$-(SiO$_{2}$)$_{1-x}$ with concentration of ferromagnetic particles close, but below percolation threshold

Towards the theory of ferrimagnetism

Two-sublattice ferrimagnet, with spin-$s_1$ operators $\bf{S_{1i}}$ at the sublattice $A$ site and spin-$s_2$ operators $\bf{S_{2i}}$ at the sublattice $B$ site, is considered. The magnon of the system, the transversal fluctuation of the total magnetization, is a complicate mixture of the transversal fluctuations of the sublattice $A$ and $B$ spins. As a result, the magnons' fluctuations suppress in a different way the magnetic orders of the $A$ and $B$ sublattices and one obtains two phases. At low temperature $(0,T^*)$ the magnetic orders of the $A$ and $B$ spins contribute to the magnetization of the system, while at the high temperature $(T^*,T_N)$, the magnetic order of the spins with a weaker intra-sublattice exchange is suppressed by magnon fluctuations, and only the spins with stronger intra-sublattice exchange has non-zero spontaneous magnetization. The $T^*$ transition is a transition between two spin-ordered phases in contrast to the transition from spin-ordered state to disordered state ($T_N$-transition). There is no additional symmetry breaking, and the Goldstone boson has a ferromagnetic dispersion in both phases. A modified spin-wave theory is developed to describe the two phases. All known Neel's anomalous $M(T)$ curves are reproduced, in particular that with "compensation point". The theoretical curves are compared with experimental ones for sulpho-spinel $MnCr2S_{4-x}Se_{x}$ and rare earth iron garnets.Comment: 9 pages, 8 figure

Metaphors in search of a target: the curious case of epigenetics

Carrying out research in genetics and genomics and communicating about them would not be possible without metaphors such as "information," "code," "letter" or "book." Genetic and genomic metaphors have remained relatively stable for a long time but are now beginning to shift in the context of synthetic biology and epigenetics. This article charts the emergence of metaphors in the context of epigenetics, first through collecting some examples of metaphors in scientific and popular writing and second through a systematic analysis of metaphors used in two UK broadsheets. Findings show that while source domains for metaphors can be identified, such as our knowledge of electrical switches or of bookmarks, it is difficult to pinpoint target domains for such metaphors. This may be indicative both of struggles over what epigenetics means for scientists (natural and social) and of difficulties associated with talking about this, as yet, young field in the popular press

Cytokine Signature in Schnitzler Syndrome: Proinflammatory Cytokine Production Associated to Th Suppression

Background: Schnitzler&nbsp;syndrome (SchS) is a rare autoinflammatory disease characterized by urticarial exanthema, bone and joint alterations, fever and monoclonal IgM gammopathy. Overactivation of the&nbsp;interleukin(IL)-1 system is reported, even though the exact pathophysiological pathways remain unknown. Objective: To determine ex vivo cytokine profiles of Peripheral Blood Mononuclear Cells (PBMCs) from SchS patients prior to treatment and after initiation of anti-IL-1 therapy (anakinra). The sera cytokine profile was studied in parallel. Methods: We collected blood samples from thirty-six untreated or treated SchS. PBMCs were cultured with and without LPS or anti-CD3/CD28. Cytokine levels were evaluated in serum and cell culture supernatants using Luminex technology. Results: Spontaneous TNFα, IL-6, IL-1β, IL-1α, and IL-1RA release by PBMCs of SchS patients were higher than in controls. LPS-stimulation further induced the secretion of these cytokines. In contrast, after T-cell stimulation, TNFα, IL-10, IFNγ, IL-17A, and IL-4 production decreased in SchS patients compared to healthy controls, but less in treated patients. Whereas IL-1β serum level was not detected in most sera, IL-6, IL-10, and TNFα serum levels were higher in patients with SchS and IFNγ and IL-4 levels were lower. Of note, IL-6 decreased after treatment in SchS (p = 0.04). Conclusion: Our data strengthen the hypothesis of myeloid inflammation in SchS, mediated in particular by IL-1β, TNFα, and IL-6, associated with overproduction of the inhibitors IL-1RA and IL-10. In contrast, we observed a loss of Th1, Th2, and Th17 cell functionalities that tends to be reversed by anakinra

Novel sol–gel preparation of (P2O5)0.4–(CaO)0.25–(Na2O)X–(TiO2)(0.35−X) bioresorbable glasses (X = 0.05, 0.1, and 0.15)

Quaternary phosphate-based glasses in the P2O5–CaO–Na2O–TiO2 system with a fixed P2O5 and CaO content of 40 and 25 mol% respectively have been successfully synthesised via sol–gel method and bulk, transparent samples were obtained. The structure, elemental proportion, and thermal properties of stabilised sol–gel glasses have been characterised using X-ray diffraction (XRD), energy dispersive X-ray spectroscopy (EDX), 31P nuclear magnetic resonance (31P NMR), titanium K-edge X-ray absorption near-edge structure (XANES), fourier transform infrared (FTIR) spectroscopy, and differential thermal analysis (DTA). The XRD results confirmed the amorphous nature for all stabilized sol–gel derived glasses. The EDX result shows the relatively low loss of phosphorus during the sol–gel process and Ti K-edge XANES confirmed titanium in the glass structure is in mainly six-fold coordination environment. The 31P NMR and FTIR results revealed that the glass structure consist of mainly Q1 and Q2 phosphate units and the Ti4+ cation was acting as a cross-linking between phosphate units. In addition DTA results confirmed a decrease in the glass transition and crystallisation temperature with increasing Na2O content. Ion release studies also demonstrated a decrease in degradation rates with increasing TiO2 content therefore supporting the use of these glasses for biomedical applications that require a degree of control over glass degradation. These sol–gel glasses also offer the potential to incorporate proactive molecules for drug delivery application due to the low synthesis temperature employed

A Comparative Evaluation of Ultrasound Molecular Imaging, Perfusion Imaging, and Volume Measurements in Evaluating Response to Therapy in Patient-Derived Xenografts

Most pre-clinical therapy studies use the change in tumor volume as a measure for disease response. However, tumor size measurements alone may not reflect early changes in tumor physiology that occur as a response to treatment. Ultrasonic molecular imaging (USMI) and Dynamic Contrast Enhanced - Perfusion Imaging (DCE-PI) with ultrasound are two attractive alternatives to tumor volume measurements. Since these techniques can provide information prior to the appearance of gross phenotypic changes, it has been proposed that USMI and DCE-PI could be used to characterize response to treatment earlier than traditional methods. This study evaluated the ability of tumor volume measurements, DCE-PI, and USMI to characterize response to therapy in two different types of patient-derived xenografts (known responders and known non-responders). For both responders and non-responders, 7 animals received a dose of 30 mg/kg of MLN8237, an investigational aurora-A kinase inhibitor, for 14 days or a vehicle control. Volumetric USMI (target integrin: αvβ3) and DCE-PI were performed on day 0, day 2, day 7, and day 14 in the same animals. For USMI, day 2 was the earliest point at which there was a statistical difference between the untreated and treated populations in the responder cohort (Untreated: 1.20±0.53 vs. Treated: 0.49±0.40; p < 0.05). In contrast, statistically significant differences between the untreated and treated populations as detected using DCE-PI were not observed until day 14 (Untreated: 0.94±0.23 vs. Treated: 1.31±0.22; p < 0.05). Volume measurements alone suggested no statistical differences between treated and untreated populations at any readpoint. Monitoring volumetric changes is the “gold standard” for evaluating treatment in pre-clinical studies, however, our data suggests that volumetric USMI and DCE-PI may be used to earlier classify and robustly characterize tumor response