Relaxation of finite perturbations: Beyond the Fluctuation-Response relation

We study the response of dynamical systems to finite amplitude perturbation. A generalized Fluctuation-Response relation is derived, which links the average relaxation toward equilibrium to the invariant measure of the system and points out the relevance of the amplitude of the initial perturbation. Numerical computations on systems with many characteristic times show the relevance of the above relation in realistic cases.Comment: 7 pages, 5 figure

Power-Law Distributions in a Two-sided Market and Net Neutrality

"Net neutrality" often refers to the policy dictating that an Internet service provider (ISP) cannot charge content providers (CPs) for delivering their content to consumers. Many past quantitative models designed to determine whether net neutrality is a good idea have been rather equivocal in their conclusions. Here we propose a very simple two-sided market model, in which the types of the consumers and the CPs are {\em power-law distributed} --- a kind of distribution known to often arise precisely in connection with Internet-related phenomena. We derive mostly analytical, closed-form results for several regimes: (a) Net neutrality, (b) social optimum, (c) maximum revenue by the ISP, or (d) maximum ISP revenue under quality differentiation. One unexpected conclusion is that (a) and (b) will differ significantly, unless average CP productivity is very high

Lagrangian Statistics and Temporal Intermittency in a Shell Model of Turbulence

We study the statistics of single particle Lagrangian velocity in a shell model of turbulence. We show that the small scale velocity fluctuations are intermittent, with scaling exponents connected to the Eulerian structure function scaling exponents. The observed reduced scaling range is interpreted as a manifestation of the intermediate dissipative range, as it disappears in a Gaussian model of turbulence.Comment: 4 pages, 5 figure

Workplace noise exposure and audiometric thresholds in dental technicians

Noise is a well-known risk factor in occupational medicine. Several studies have been performed in workplaces with noise sources, especially in the industrial field; on the contrary, only a few studies have been carried to evaluate the noise exposure effects in non-industrial workplaces such as small factories, handicraft laboratories, and dental laboratories. The aims of this study were to evaluate workplace noise exposure and hearing thresholds in dental technicians. Four laboratories and 51 dental technicians were included in the study. Noise exposure levels during a nominal eight-hour working day (LEX, 8 h) were assessed in the included laboratories. Audiometric thresholds with pure tone audiometry were performed in 51 dental technicians, and results were compared with those expected in subjects not exposed to noise. The environmental noise measures showed moderate differences of the LEX, 8 h among the four laboratories (range 71.4 to 76.2); average LEX, 8 h was 73.9 ± 2.2 dB(A). The audiometric results showed a progressive increase of hearing threshold values at the frequencies mostly involved in noise-induced hearing loss (3, 4 and 6 kHz) and a correlation with age and working seniority especially in males (p<0.005). Nevertheless, in the 92.1% of subjects the threshold increases were in line with those expected in subjects of the same age and sex not exposed to noise and in the remaining 7.8% were not statistically significant (p>0.05). In 3.9% of the cases the increases were bilateral, typical of noise-induced hearing loss, and only 1.9% showed involvement of several frequencies with worsening of expected thresholds >25 dB. In conclusion, our study showed that exposure to noise in dental laboratories was not sufficient to represent a hazard to hearing, as demonstrated by the LEX, 8 h, which were below 80 dB(A) and therefore below the European exposure limit values and exposure action values for workers

Protein folding mediated by solvation: water expelling and formation of the hydrophobic core occurs after the structure collapse

The interplay between structure-search of the native structure and desolvation in protein folding has been explored using a minimalist model. These results support a folding mechanism where most of the structural formation of the protein is achieved before water is expelled from the hydrophobic core. This view integrates water expulsion effects into the funnel energy landscape theory of protein folding. Comparisons to experimental results are shown for the SH3 protein. After the folding transition, a near-native intermediate with partially solvated hydrophobic core is found. This transition is followed by a final step that cooperatively squeezes out water molecules from the partially hydrated protein core.Comment: Proceedings of the National Academy of Science, 2002, Vol.99. 685-69

Multidimensional frailty predicts mortality better than physical frailty in community-dwelling older people: A five-year longitudinal cohort study

Frailty is a common syndrome in older people that carries an increased risk of mortality. Two main models describe frailty, either as a loss of physical functions or as an accumulation of multiple deficits. The aim of our study was to compare the physical frailty index developed in the Cardiovascular Health Study (CHS) with a multidimensional frailty tool, the Multidimensional Prognostic Index (MPI), in predicting death in community-dwelling older subjects. Four hundred and seven community-dwelling older subjects were enrolled. Each subject underwent a comprehensive geriatric assessment (CGA) with calculation of the MPI and CHS index. Mortality was recorded over the following 5 years. In the overall sample (mean age of 77.9 ± 4.5 years; 51.6% female), 53 subjects (13%) died during the 5-year follow-up period. Both the MPI and CHS index were able to predict mortality; however, the MPI was significantly more accurate than the CHS index in predicting mortality (C-index = 0.69 and 0.59, respectively; p < 0.001), with a statistically significant difference of 10%. In conclusion, multidimensional frailty, assessed by the MPI, predicts five-year mortality in community-dwelling older people better than physical frailty, as assessed by the CHS index. These findings suggest the usefulness of assessing frailty by means of CGA-based tools to predict relevant health-negative outcomes in older people

An integrated care pathway for cancer patients with diabetes: A proposal from the Italian experience

Diabetes and cancer frequently coexist in the same subject, often with relevant clinical effects on the management and prognosis of the comorbid patient. The existing guidelines, however, do not appropriately address many clinical issues in this setting. Although collaboration between diabetologists and oncologists should play an important role in achieving appropriate levels of care, close coordination or agreement between these specialists is seldom offered. There is an urgent need for greater interdisciplinary integration between all specialists involved in this setting, for a shared approach ensuring that organisational silos are overcome. To this end, the Italian Associations of Medical Diabetologists (AMD) and the Italian Association of Medical Oncology (AIOM) recently established a dedicated Working Group on 'Diabetes and Cancer'. The working group outlined a diagnostic and therapeutic clinical pathway dedicated to hospitalised patients with diabetes and cancer. In this article, we describe the Italian proposal including some suggested measures to assess, monitor and improve blood glucose control in the hospital setting, to integrate different specialists from both areas, as well as to ensure discharge planning and continuity of care from the hospital to the territory

Targeting the Mitotic Checkpoint to Kill Tumor Cells

One of the most common hallmarks of cancer cells is aneuploidy or an abnormal number of chromosomes. This abnormal chromosome content is a consequence of chromosome missegregation during mitosis, a defect that is seen more frequently in tumor cell divisions as in normal cell divisions. In fact, a large fraction of human tumors display a chromosome instable phenotype, meaning that they very frequently missegregate chromosomes. This can cause variegated aneuploidy within the tumor tissue. It has been argued that this hallmark of cancer could be exploited in anti-cancer therapies. Here we test this hypothesis by inactivation of the mitotic checkpoint through RNAi-mediated depletion of an essential checkpoint component, Mps1. The mitotic checkpoint delays segregation of chromosomes during mitosis until all chromosomes are properly attached to the mitotic spindle. Its inactivation will therefore lead to increased segregation errors. Indeed, we show that this can lead to increased cell death in tumor cells. We demonstrate that increased cell death is associated with a dramatic increase in segregation errors. This suggests that inhibition of the mitotic checkpoint might represent a useful anti-cancer strategy

Genome Wide Transcriptome Analysis of Dendritic Cells Identifies Genes with Altered Expression in Psoriasis

Activation of dendritic cells by different pathogens induces the secretion of proinflammatory mediators resulting in local inflammation. Importantly, innate immunity must be properly controlled, as its continuous activation leads to the development of chronic inflammatory diseases such as psoriasis. Lipopolysaccharide (LPS) or peptidoglycan (PGN) induced tolerance, a phenomenon of transient unresponsiveness of cells to repeated or prolonged stimulation, proved valuable model for the study of chronic inflammation. Thus, the aim of this study was the identification of the transcriptional diversity of primary human immature dendritic cells (iDCs) upon PGN induced tolerance. Using SAGESeq approach, a tag-based transcriptome sequencing method, we investigated gene expression changes of primary human iDCs upon stimulation or restimulation with Staphylococcus aureus derived PGN, a widely used TLR2 ligand. Based on the expression pattern of the altered genes, we identified non-tolerizeable and tolerizeable genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (Kegg) analysis showed marked enrichment of immune-, cell cycle- and apoptosis related genes. In parallel to the marked induction of proinflammatory mediators, negative feedback regulators of innate immunity, such as TNFAIP3, TNFAIP8, Tyro3 and Mer are markedly downregulated in tolerant cells. We also demonstrate, that the expression pattern of TNFAIP3 and TNFAIP8 is altered in both lesional, and non-lesional skin of psoriatic patients. Finally, we show that pretreatment of immature dendritic cells with anti-TNF-α inhibits the expression of IL-6 and CCL1 in tolerant iDCs and partially releases the suppression of TNFAIP8. Our findings suggest that after PGN stimulation/restimulation the host cell utilizes different mechanisms in order to maintain critical balance between inflammation and tolerance. Importantly, the transcriptome sequencing of stimulated/restimulated iDCs identified numerous genes with altered expression to date not associated with role in chronic inflammation, underlying the relevance of our in vitro model for further characterization of IFNprimed iDCs

Aurora B potentiates Mps1 activation to ensure rapid checkpoint establishment at the onset of mitosis

The mitotic checkpoint prevents mitotic exit until all chromosomes are attached to spindle microtubules. Aurora B kinase indirectly invokes this checkpoint by destabilizing incorrect attachments; however, a more direct role remains controversial. In contrast, activity of the kinase Mps1 is indispensible for the mitotic checkpoint. Here we show that Aurora B and Hec1 are needed for efficient Mps1 recruitment to unattached kinetochores, allowing rapid Mps1 activation at the onset of mitosis. Live monitoring of cyclin B degradation reveals that this is essential to establish the mitotic checkpoint quickly at the start of mitosis. Delayed Mps1 activation and checkpoint establishment upon Aurora B inhibition or Hec1 depletion are rescued by tethering Mps1 to kinetochores, demonstrating that Mps1 recruitment is the primary role of Aurora B and Hec1 in mitotic checkpoint signalling. These data demonstrate a direct role for Aurora B in initiating the mitotic checkpoint rapidly at the onset of mitosis