Computing the structured pseudospectrum of a Toeplitz matrix and its extreme points

The computation of the structured pseudospectral abscissa and radius (with respect to the Frobenius norm) of a Toeplitz matrix is discussed and two algorithms based on a low rank property to construct extremal perturbations are presented. The algorithms are inspired by those considered in [SIAM J. Matrix Anal. Appl., 32 (2011), pp. 1166-1192] for the unstructured case, but their extension to structured pseudospectra and analysis presents several difficulties. Natural generalizations of the algorithms, allowing to draw significant sections of the structured pseudospectra in proximity of extremal points are also discussed. Since no algorithms are available in the literature to draw such structured pseudospectra, the approach we present seems promising to extend existing software tools (Eigtool, Seigtool) to structured pseudospectra representation for Toeplitz matrices. We discuss local convergence properties of the algorithms and show some applications to a few illustrative examples.Comment: 21 pages, 11 figure

Conflitto lavoro/famiglia, burnout e work engagement negli insegnanti: Il ruolo moderatore delle risorse lavorative e personali

The present study contributes to the literature on the Job Demands-resources model in the italian school context. the aim of this paper is to examine how the interaction between work-family conflict (i.e., a typical job demand) and opportunities to learn and to develop and self-efficacy (i.e., typical job and personal resources, respectively) affect the core dimensions of burnout (exhaustion and depersonalization) and work engagement (vigor and dedication). Hypotheses were tested with a cross-sectional design among 143 teachers of a junior high school in the north of Italy. Results of moderated multiple regression analysis partially supported the hypotheses as the opportunities to learn and to develop buffered against the aversive effects of work-family conflict on depersonalization, whereas self-efficacy moderated the relationship between work-family conflict and vigor. From a practical viewpoint, our findings suggest that opportunities to learn and to develop and self-efficacy are important re- sources that help teachers to reduce the negative effects related to work-family conflict.El presente estudio contribuye a la literatura sobre el modelo de demandas y recursos laborales en el contexto escolar italiano. El objetivo del artículo es examinar cómo la interacción entre el conflicto trabajo-familia (es decir, una típica demanda laboral), las oportunidades para aprender y desarrollarse, y la autoeficacia (es decir, recursos laborales y personales típicos, respectivamente) afectan a las dimensiones personales del burnout (agotamiento y despersonalización) y del involucramiento en el trabajo (vigor y dedicación). Las hipótesis fueron probadas con un diseño transversal con 143 maestros de escuela secundaria del norte de italia. los resultados del análisis de regresión múltiple moderada apoyaron hipótesis tales como que las oportunidades para aprender y desarrollarse son un amortiguador contra los efectos aversivos del conflicto trabajo-familia sobre la despersonalización, mientras que la autoeficacia modera la relación entre el conflicto trabajo-familia y el vigor. Desde un punto de vista práctico, nuestros hallazgos sugieren que las oportunidades para aprender y desarrollarse, y la autoeficacia son recursos importantes que ayudan a los maestros a reducir los efectos negativos relacionados con el conflicto trabajo-familia.O presente estudo contribui à literatura sobre o modelo de demandas e recursos laborais no contexto escolar italiano. O objetivo do artigo é examinar como a interação entre o conflito trabalho-família (é dizer, uma típica demanda laboral), as oportunidades para aprender y se desenvolver, e a auto-eficácia (é dizer, recursos laborais e pessoais típicos, respectivamente) afeitam as dimensões pessoais do esgotamento e despersonalização, e do envolvimento no trabalho (vigor e dedicação). As hipóteses foram experimentadas com uma programação transversal com 143 professores de colégio do norte da Itália. Os resultados da análise de regressão múltiple moderada apoiaram hipóteses tais como que as oportunidades para aprender e se desenvolver são um amortecedor contra os efeitos aversivos do conflito trabalho-família sobre a despersonalização, enquanto que a auto-eficácia modera a relação entre o conflito trabalho-família e o vigor. Desde um ponto de vista prático, nossos achados sugerem que as oportunidades para aprender e se desenvolver, e a auto-eficácia são recursos importantes que ajudam aos professores a reduzir os efeitos negativos relacionado com o conflito trabalho-famíli

Effects on human transcriptome of mutated BRCA1 BRCT domain: A microarray study

BACKGROUND: BRCA1 (breast cancer 1, early onset) missense mutations have been detected in familial breast and ovarian cancers, but the role of these variants in cancer predisposition is often difficult to ascertain. In this work, the molecular mechanisms affected in human cells by two BRCA1 missense variants, M1775R and A1789T, both located in the second BRCT (BRCA1 C Terminus) domain, have been investigated. Both these variants were isolated from familial breast cancer patients and the study of their effect on yeast cell transcriptome has previously provided interesting clues to their possible role in the pathogenesis of breast cancer. METHODS: We compared by Human Whole Genome Microarrays the expression profiles of HeLa cells transfected with one or the other variant and HeLa cells transfected with BRCA1 wild-type. Microarray data analysis was performed by three comparisons: M1775R versus wild-type (M1775RvsWT-contrast), A1789T versus wild-type (A1789TvsWT-contrast) and the mutated BRCT domain versus wild-type (MutvsWT-contrast), considering the two variants as a single mutation of BRCT domain. RESULTS: 201 differentially expressed genes were found in M1775RvsWT-contrast, 313 in A1789TvsWT-contrast and 173 in MutvsWT-contrast. Most of these genes mapped in pathways deregulated in cancer, such as cell cycle progression and DNA damage response and repair. CONCLUSIONS: Our results represent the first molecular evidence of the pathogenetic role of M1775R, already proposed by functional studies, and give support to a similar role for A1789T that we first hypothesized based on the yeast cell experiments. This is in line with the very recently suggested role of BRCT domain as the main effector of BRCA1 tumor suppressor activity

Reconciling the discrepancies on the involvement of large-conductance Ca2+-activated K channels in glioblastoma cell migration

Glioblastoma (GBM) is the most common and aggressive primary brain tumor, and is notable for spreading so effectively through the brain parenchyma to make complete surgical resection virtually impossible, and prospect of life dismal. Several ion channels have been involved in GBM migration and invasion, due to their critical role in supporting volume changes and Ca2+ influx occuring during the process. The large-conductance, Ca2+-activated K (BK) channels, markedly overexpressed in biopsies of patients with GBMs and in GBM cell lines, have attracted much interest and have been suggested to play a central role in cell migration and invasion as candidate channels for providing the ion efflux and consequent water extrusion that allow cell shrinkage during migration. Available experimental data on the role of BK channel in migration and invasion are not consistent though. While BK channels block typically resulted in inhibition of cell migration or in no effect, their activation would either enhance or inhibit the process. This short review reexamines the relevant available data on the topic, and presents a unifying paradigm capable of reconciling present discrepancies. According to this paradigm, BK channels would not contribute to migration under conditions where the [Ca2+]i is too low for their activation. They will instead positively contribute to migration for intermediate [Ca2+]i, insufficient as such to activate BK channels, but capable of predisposing them to cyclic activation following oscillatory [Ca2+]i increases. Finally, steadily active BK channels because of prolonged high [Ca2+]i would inhibit migration as their steady activity would be unsuitable to match the cyclic cell volume changes needed for proper cell migration.peer-reviewe

Myo-inositol in autoimmune thyroiditis, and hypothyroidism

Myo-inositol (Myo-Ins) plays an important role in thyroid function and autoimmunity. Myo-Ins is the precursor for the synthesis of phosphoinositides, which takes part in the phosphatidylinositol (PtdIns) signal transduction pathway, and plays a decisive role in several cellular processes. In the thyroid cells, PtdIns is involved in the intracellular thyroid-stimulating hormone (TSH) signaling, via Phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3) (PIP-3). Moreover, the phosphatidyl inositol 3 kinases (PI3K) family of lipid kinases regulates diverse aspects of T, B, and Tregs lymphocyte behaviour. Different mouse models deficient for the molecules involved in the PIP3 pathway suggest that impairment of PIP3 signaling leads to dysregulation of immune responses and, sometimes, autoimmunity. Studies have shown that cytokines modulate Myo-Ins in thyroid cells. Moreover, clinical studies have shown that after treatment with Myo-inositol plus seleniomethionine (Myo-Ins + Se), TSH levels significantly declined in patients with subclinical hypothyroidism due to autoimmune thyroiditis. The treatment was accompanied by a decline of antithyroid autoantibodies. After treatment serum CXCL10 levels declined, confirming the immune-modulatory effect of Myo-Ins. Additional research is necessary in larger population to evaluate the effect on the quality of life, and to study the mechanism of the effect on chemokines

Beyond Weight Loss: Added Benefits Could Guide the Choice of Anti-Obesity Medications

Purpose of ReviewTo highlight the added benefits of approved and upcoming, centrally-acting, anti-obesity drugs, focusing not only on the most common metabolic and cardiovascular effects but also on their less explored clinical benefits and drawbacks, in order to provide clinicians with a tool for more comprehensive, pharmacological management of obesity.Recent FindingsObesity is increasingly prevalent worldwide and has become a challenge for healthcare systems and societies. Reduced life expectancy and cardiometabolic complications are some of the consequences of this complex disease. Recent insights into the pathophysiology of obesity have led to the development of several promising pharmacologic targets, so that even more effective drugs are on the horizon. The perspective of having a wider range of treatments increases the chance to personalize therapy. This primarily has the potential to take advantage of the long-term use of anti-obesity medication for safe, effective and sustainable weight loss, and to concomitantly address obesity complications/comorbidities when already established.SummaryThe evolving scenario of the availability of anti-obesity drugs and the increasing knowledge of their added effects on obesity complications will allow clinicians to move into a new era of precision medicine

TLR5-dependent immunogenicity of a recombinant fusion protein containing an immunodominant epitope of malarial circumsporozoite protein and the FliC flagellin of Salmonella Typhimurium

Recently, we described the improved immunogenicity of new malaria vaccine candidates based on the expression of fusion proteins containing immunodominant epitopes of merozoites and Salmonella enterica serovar Typhimurium flagellin (FliC) protein as an innate immune agonist. Here, we tested whether a similar strategy, based on an immunodominant B-cell epitope from malaria sporozoites, could also generate immunogenic fusion polypeptides. A recombinant His6-tagged FliC protein containing the C-terminal repeat regions of the VK210 variant of Plasmodium vivax circumsporozoite (CS) protein was constructed. This recombinant protein was successfully expressed in Escherichia coli as soluble protein and was purified by affinity to Ni-agarose beads followed by ion exchange chromatography. A monoclonal antibody specific for the CS protein of P. vivax sporozoites (VK210) was able to recognise the purified protein. C57BL/6 mice subcutaneously immunised with the recombinant fusion protein in the absence of any conventional adjuvant developed protein-specific systemic antibody responses. However, in mice genetically deficient in expression of TLR5, this immune response was extremely low. These results extend our previous observations concerning the immunogenicity of these recombinant fusion proteins and provide evidence that the main mechanism responsible for this immune activation involves interactions with TLR5, which has not previously been demonstrated for any recombinant FliC fusion protein.FAPESPCNPq - INCTVCoordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES

One-carbon genetic variants and the role of MTHFD1 1958G>A in liver and colon cancer risk according to global DNA methylation

Several polymorphic gene variants within one-carbon metabolism, an essential pathway for nucleotide synthesis and methylation reactions, are related to cancer risk. An aberrant DNA methylation is a common feature in cancer but whether the link between one-carbon metabolism variants and cancer occurs through an altered DNA methylation is yet unclear. Aims of the study were to evaluate the frequency of one-carbon metabolism gene variants in hepatocellular-carcinoma, cholangiocarcinoma and colon cancer, and their relationship to cancer risk together with global DNA methylation status. Genotyping for BHMT 716A>G, DHFR 19bp ins/del, MTHFD1 1958G>A, MTHFR 677C>T, MTR 2756A>G, MTRR 66A>G, RFC1 80G>A, SHMT1 1420C>T, TCII 776C>G and TS 2rpt-3rpt was performed in 102 cancer patients and 363 cancer-free subjects. Methylcytosine (mCyt) content was measured by LC/MS/MS in peripheral blood mononuclear cells (PBMCs) DNA. The MTHFD1 1958AA genotype was significantly less frequent among cancer patients as compared to controls (p = 0.007) and related to 63% reduction of overall cancer risk (p = 0.003) and 75% of colon cancer risk (p = 0.006). When considering PBMCs mCyt content, carriers of the MTHFD1 1958GG genotype showed a lower DNA methylation as compared to carriers of the A allele (p = 0.048). No differences were highlighted by evaluating a possible relationship between the other polymorphisms analyzed with cancer risk and DNA methylation. The MTHFD1 1958AA genotype is linked to a significantly reduced cancer risk. The 1958GG genotype is associated to PBMCs DNA hypomethylation as compared to the A allele carriership that may exert a protective effect for cancer risk by preserving from DNA hypomethylation