Algorithms for the Sum of Discrete Random Variables. Actuarial Applications

In literature, the sum of discrete random variables becomes a problem of heavy (and often impracticable) computation no sooner does the number of convolutions exceed few units (at most in actuarial applications). In this paper, we show how this problem can be easily overcome when using random variables with integer (positive, negative, or null) or referable to integer numerical realizations but not necessarily identically distributed. Under the above-mentioned condition, we illustrate in particular two exact methods and an approximated one for calculating convolution: - the first exact method is based on the well-known Fast Fourier Transform (FFT); - the second exact method is derived from the classical approach using Discrete Fourier Transform (DFT) by means of algebraic manipulations; - the third method is derived from the definition of convolution and it is approximated by neglecting the probabilities less than a given bound ? =10-h (51?h?100)**. As for the error bounds of the approximated method, it is worth noting that the results obtained by this method differ in relative terms from the corresponding exact values of less than 10-9. This can be tested by comparing the convoluted probability distribution obtained by the approximated method with the one obtained by the other two methods and by also comparing the first four moments with those computed directly on the original random variables. The results (in particular the exact and the approximated probability distribution) are identical in practice. It does not exist therefore the problem of a difference along the tail. As a consequence, although the proposed method is an “approximated method” under a mathematical point of view, it can be considered an “exact method” in the actuarial applications. As for the efficiency of calculation, we have to distinguish between the simple sum of discrete random variables and the calculation of compound distributions with prefixed counting distributions (i.g. Poisson, Negative Binomial, Pareto): - in the first case, the approximated method and the second exact method are similar but the approximated method gives further information about the random variables (for instance, the information about the independence using some properties of the characteristic functions); - in the second case, only the approximated method is applicable in practice. Finally, in the conditions of interest, the exact method using FFT is less efficient than the other methods and it has a more limited application field

A new method for evaluating the distribution of aggregate claims

In the present paper, we propose a method of practical utility for calculating the aggregate claims distribution in a discrete framework. It is an approximated method but unlike the other approximated methods proposed in the literature: the approximation concerns both the counting distribution and the convolution of the severity distributions; the approximation does not consist in truncating the original distribution up to a given number of terms nor in replacing it with another distribution or a more general function (but simply in considering only the significant numerical realizations and in neglecting the others); the resulting approximation of the aggregate claims distribution is lower than a prefixed maximum error (10(-6) in our applications). In particular, the probability distribution and also the first three moments are exact with the prefixed maximum error. The proposed method does not require special assumptions on the counting distribution nor the identical distribution of the severity random variables and it does not incur in underflow and overflow computational problems. It proves to be more flexible, easier and cheaper than the (exact and approximated) methods using recursion and Fast Fourier Transform. We show some applications using both a Poisson distribution and a Generalized Pareto mixture of Poisson distributions as counting distribution. In addition to the specific application proposed in this paper, the method can be applied in many other (life and nonlife) actuarial fields where the sum of discrete random variables and the calculation of compound distributions are involved. Besides, it can be extended in multivariate cases. (c) 2005 Elsevier Inc. All rights reserved

Hyperexpression of CDRs and HWP1 genes negatively impacts on Candida albicans virulence

C. albicans is a commensal organism present in the human microbiome of more than 60% of the healthy population. Transition from commensalism to invasive candidiasis may occur after a local or a general failure of host's immune system. This transition to a more virulent phenotype may reside either on the capacity to form hyphae or on an acquired resistance to antifungal drugs. Indeed, overexpression of genes coding drug efflux pumps or adhesins, cell wall proteins facilitating the contact between the fungus and the host, usually marks the virulence profile of invasive Candida spp. In this paper, we compare virulence of two clinical isolates of C. albicans with that of laboratory-induced resistant strains by challenging G. mellonella larvae with these pathogens along with monitoring transcriptional profiles of drug efflux pumps genes CDR1, CDR2, MDR1 and the adhesin genes ALS1 and HWP1. Although both clinical isolates were found resistant to both fluconazole and micafungin they were found less virulent than laboratory-induced resistant strains. An unexpected behavior emerged for the former clinical isolate in which three genes, CDR1, CDR2 and HWP1, usually correlated with virulence, although hyperexpressed, conferred a less aggressive phenotype. On the contrary, in the other isolate, we observed a decreased expression of CDR1, CDR2 and HWP1as well as of MDR1 and ALS1 that may be consistent with the less aggressive performance observed in this strain. These altered gene expressions might directly influence Candida virulence or they might be an epiphenomenon of a vaster rearrangement occurred in these strains during the challenge with the host's environment. An in-deepth comprehension of this scenario could be crucial for developing interventions able to counteract C. albicans invasiveness and lethality.C. albicans is a commensal organism present in the human microbiome of more than 60% of the healthy population. Transition from commensalism to invasive candidiasis may occur after a local or a general failure of host's immune system. This transition to a more virulent phenotype may reside either on the capacity to form hyphae or on an acquired resistance to antifungal drugs. Indeed, overexpression of genes coding drug efflux pumps or adhesins, cell wall proteins facilitating the contact between the fungus and the host, usually marks the virulence profile of invasive Candida spp. In this paper, we compare virulence of two clinical isolates of C. albicans with that of laboratory-induced resistant strains by challenging G. mellonella larvae with these pathogens along with monitoring transcriptional profiles of drug efflux pumps genes CDR1, CDR2, MDR1 and the adhesin genes ALS1 and HWP1. Although both clinical isolates were found resistant to both fluconazole and micafungin they were found less virulent than laboratory-induced resistant strains. An unexpected behavior emerged for the former clinical isolate in which three genes, CDR1, CDR2 and HWP1, usually correlated with virulence, although hyperexpressed, conferred a less aggressive phenotype. On the contrary, in the other isolate, we observed a decreased expression of CDR1, CDR2 and HWP1as well as of MDR1 and ALS1 that may be consistent with the less aggressive performance observed in this strain. These altered gene expressions might directly influence Candida virulence or they might be an epiphenomenon of a vaster rearrangement occurred in these strains during the challenge with the host's environment. An in-deepth comprehension of this scenario could be crucial for developing interventions able to counteract C. albicans invasiveness and lethality

Membrane protein remodeling in microglia exposed to amyloid peptides

Infection, neurodegeneration, and other conditions associated with loss of brain homeostasis, induce changes in microglial morphology, gene expression and function, generally referred to as “activation”. Alzheimer’s disease (AD) is the most common dementia and is characterized by neuroinfammatory changes, including alterations in the morphology and distribution of microglia and astrocytes, and deposition of complement and other infammatory mediators. Our previous observations show that microglial cells challenged in vitro with amyloid peptides clustered and rounded up, dramatically changing their morphology. Besides, in these cells we observed the early acetylation and then the phosphorylation of STAT3 which is required for the expression of the epsilon isoform of 14-3-3, a marker of Abeta-activated microglia (1, 2). We applied afnity partitioning approach combined with high throughput mass spectrometric analysis in order to identify variation of proteins on plasma membrane of BV2 immortalized microglia upon treatment with amyloid peptides. By this method several proteins up- or down-regulated by amyloid treatment were identifed in microglial plasma membrane. Among them annexins (5 and 7), IFITM3 and MARK3. These data have been confrmed in primary microglial cultures. In microglia, plasma membrane plays a relevant role in the cross-talking with the external neuronal environment and in the resulting trophic or infammatory response of these sentinel cells. As such, knowledge of the microglia responsiveness to beta amyloids in term of changes in its plasma membrane proteome is imperative for unveiling the molecular landscape in which AD occurs

Enzyme Replacement Therapy for FABRY Disease: Possible Strategies to Improve Its Efficacy

Enzyme replacement therapy is the only therapeutic option for Fabry patients with completely absent AGAL activity. However, the treatment has side effects, is costly, and requires conspicuous amounts of recombinant human protein (rh-AGAL). Thus, its optimization would benefit patients and welfare/health services (i.e., society at large). In this brief report, we describe preliminary results paving the way for two possible approaches: i. the combination of enzyme replacement therapy with pharmacological chaperones; and ii. the identification of AGAL interactors as possible therapeutic targets on which to act. We first showed that galactose, a low-affinity pharmacological chaperone, can prolong AGAL half-life in patient-derived cells treated with rh-AGAL. Then, we analyzed the interactomes of intracellular AGAL on patient-derived AGAL-defective fibroblasts treated with the two rh-AGALs approved for therapeutic purposes and compared the obtained interactomes to the one associated with endogenously produced AGAL (data available as PXD039168 on ProteomeXchange). Common interactors were aggregated and screened for sensitivity to known drugs. Such an interactor-drug list represents a starting point to deeply screen approved drugs and identify those that can affect (positively or negatively) enzyme replacement therapy

Progressive multifocal leukoencephalopathy presenting with bilateral myoclonus: a case report

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system (CNS) caused by John Cunningham virus lytic infection of the oligodendrocytes, the myelin-producing cells in the CNS. Symptoms largely vary depending on location and size of the lesions, and the most frequent clinical presentation is characterized by motor deficits, altered consciousness, gait ataxia, and visual symptoms. Despite limb weakness or hemiparesis as the most frequent presenting symptom, involuntary movement is far less common, and very few cases are described in the literature with focal movement disorders without additional neurologic abnormalities. Here we described a case of PML in a patient treated for non-Hodgkin lymphoma with immunomodulatory chemotherapies who presented with bilateral myoclonus of the upper limbs. This report highlights the importance of considering PML in the differential diagnosis of focal movement disorders and discusses the potential causative mechanism of this atypical presentation

Wearable Sensor for Real-time Monitoring of Hydrogen Peroxide in Simulated Exhaled Air

In this work, an innovative and cheap electrochemical sensor for hydrogen peroxide quantification in exhaled breath was developed. H2O2 is the most used biomarker among the Reactive Oxygen Species (ROS) for monitoring the level of oxidative stress in the respiratory system. This is due to its stability and ability to cross biological membranes and also because it is detectable in extracellular space. The electrochemical sensor was obtained using the silver layer of wasted compact discs (CDs). All three electrodes, working (WE), counter (CE), and pseudo-reference electrode (RE), were fabricated using a laser cutter. The working electrode was used directly, while an Ag/AgCl paste and a graphite paste were applied respectively on the RE and the CE. In addition, a chitosan layer was deposited by Electro-Phoretic Deposition (EPD) on the surface of the sensor. This biopolymer improves the wettability of the sensor in presence of a humid atmosphere such as that given by exhaled air. The sensor was tested in both liquid and nebulized solutions containing different concentrations of hydrogen peroxide. The detection of H2O2 was evaluated using Linear Sweep Voltammetry (LSV) as electrochemical technique. The results show that the peak current increases linearly with hydrogen peroxide concentration from 100 to 500 μM with a sensitivity of 0.068 µA µM−1 cm−2 and 0.108 µA µM−1 cm−2, a Limit Of Detection (LOD) of 60 μM and 30 μM respectively for liquid and nebulized solutions. Therefore, the use of the electrochemical sensor can allow the monitoring of hydrogen peroxide in real time with good results

The Palace of Knossos Case Study and Material Characterization

The funding from the European Union Horizon 2020 research and innovation programme H2020-DRS-2015 GA nr. 700395 (HERACLES project).The study and characterization of mortars is generally related to the knowledge of the properties of the material, which guarantee or improve its performance and durability. When we consider the study of historical mortars, the main objective is to understand the characteristics of the material and how it has reached the present day, considering that, often, the time of its preparation and application is separated from the present by a long period of time, perhaps centuries, and is thus difficult to specify. This type of study may give indications on historical issues relevant to the understanding of a particular site or monument and, in addition, can assist in actions related to its preservation. Mortars can be used with different functions, ranging from structural function, protection, or finish, which requires distinct properties that are suitable for this functionality. It is necessary to consider that the desired characteristics, after drying the mortar, will depend on a set of factors, including the selection and quality of the raw material, the proportion between the main components, the way they are prepared and applied, and the environmental conditions they will be subjected to over time. Furthermore, the larger the monument is, the greater the chances of changes, reconstructions or interventions, including materials prepared in different periods with different raw materials and techniques. This is precisely the case of the Palace of Knossos, located near the Heraklion in Crete. It is estimated that the first palace was built in 2000 B.C.; however, it was destroyed and rebuilt more majestically in 1700 B.C. The definitive abandonment of the palace would have occurred around 1450 B.C., but the site where it was built maintained its importance for many centuries. Excavated at the beginning of the 20th century, the Palace of Knossos is one of the most important archaeological sites in Europe, both for its size and the complexity of its plant, with architectural solutions worthy of a well-developed civilization, as well as for the many reclaimed materials and frescos found. In addition to all of the material wealth found in its excavation, the palace has undergone peculiar historical conservation including the reconstruction of many of its structures, even as late as the early 20th century, all considered of great importance for the history of the monument. For this study, samples of mortars were collected at different points of the Palace of Knossos, both from areas of archaeological remains as well as from reconstructed areas. For the characterization, we opted for a multi-analyses approach which involved optical microscopy observation, X-ray fluorescence, X-ray diffraction, FTIR, -Raman, simultaneous thermogravimetry and differential thermal analysis. The results obtained indicated that the samples were mostly lime mortars with different hydraulicity indexes produced from local raw materials. The results also indicated that the samples presented considerable differences depending on the area in which they were collected, showing the variety and complexity of the materials produced in different periods, even when used for the same function.publishersversionpublishe