A nonparametric Bayesian approach to the rare type match problem

The "rare type match problem" is the situation in which the suspect's DNA profile, matching the DNA profile of the crime stain, is not in the database of reference. The evaluation of this match in the light of the two competing hypotheses (the crime stain has been left by the suspect or by another person) is based on the calculation of the likelihood ratio and depends on the population proportions of the DNA profiles, that are unknown. We propose a Bayesian nonparametric method that uses a two-parameter Poisson Dirichlet distribution as a prior over the ranked population proportions, and discards the information about the names of the different DNA profiles. This fits very well the data coming from European Y-STR DNA profiles, and the calculation of the likelihood ratio becomes quite simple thanks to a justified Empirical Bayes approach.Comment: arXiv admin note: text overlap with arXiv:1506.0844

ANALISI DELL¿ATTIVITÀ DI SCREENING DEL COLON RETTO NELL'ASL MILANO 1 (2006-12)

Objective Colorectal cancer is one of the main challenges in public health: it is cancer with higher incidence in Western society, and is available for its early diagnosis a screening test which can be followed a treatment effective. In particular, Europe countries in the last decade have developed screening programs. A program was developed in Asl Milano 1 (Lombardia \u2013 Italy) from 2006 to nowadays. The objective of the study is to analyze the overall performance of colon rectal screening in ASL Milano 1 in the period 2006-12 Methods Every two years, 50\u201369 year olds receive a letter from Asl Milano 1 that invite them to go in a pharmacy and take a FOBT-kit (fecal occult blood test). People complete the test in the privacy of their own home. Kit must be reported in a pharmacy that sent it to the laboratory for analysis. Negative people is informed about test result by mail. Positive people is usually informed by a telephone call by a nurse of his health territorial unit that recommend a colonoscopy and book one in an hospital. Participation in the program is voluntary and there is no cost involved in completing the test or colonoscopy. Quality-assurance requirements were established to ensure safe procedures and practice in every clinical aspect of a screening-program Results From 2006 to 2012 a total of 722.605 individuals were invited to screening , 274.167 returned with a correctly placed stool specimen on FOBT cards, 565 and 3344 High risk adenoma were identified . Some indicator were calculated(reported only last year- 2011): subjects invited 91%, crude compliance 45%; adjusted adherence 46%; delay between FOBT screening and negative result 99% within 21 days; Positivity rate 5,4%; participation to colonoscopy 90%; complete colonoscopy rate 93%; Delay between the call for colonoscopy and the colonoscopy procedure ; 61% within 60 calendar days ; positive predictive value of FOBT at colonoscopy 3,1% for cancer and 21,9 %for high risk adenoma; 1/3 of cancers screen-detected are T1; sensibility 86% (IC 95% 83-89) specificity 97%. Conclusion The screening program has provided the public with a service that meets the needs and sustainable over the years. Limit in the organizational process is the waiting time for the provision of colonoscopy: impact significantly on the ability to increase screening performaces. iFOBT-based screening programmes showed a high performance in terms of sensitivity as estimated through the interval cancers rates

Expected performance of the ASTRI-SST-2M telescope prototype

ASTRI (Astrofisica con Specchi a Tecnologia Replicante Italiana) is an Italian flagship project pursued by INAF (Istituto Nazionale di Astrofisica) strictly linked to the development of the Cherenkov Telescope Array, CTA. Primary goal of the ASTRI program is the design and production of an end-to-end prototype of a Small Size Telescope for the CTA sub-array devoted to the highest gamma-ray energy region. The prototype, named ASTRI SST-2M, will be tested on field in Italy during 2014. This telescope will be the first Cherenkov telescope adopting the double reflection layout in a Schwarzschild-Couder configuration with a tessellated primary mirror and a monolithic secondary mirror. The collected light will be focused on a compact and light-weight camera based on silicon photo-multipliers covering a 9.6 deg full field of view. Detailed Monte Carlo simulations have been performed to estimate the performance of the planned telescope. The results regarding its energy threshold, sensitivity and angular resolution are shown and discussed.Comment: In Proceedings of the 33rd International Cosmic Ray Conference (ICRC2013), Rio de Janeiro (Brazil). All CTA contributions at arXiv:1307.223

RNAseq Analyses Identify Tumor Necrosis Factor-Mediated Inflammation as a Major Abnormality in ALS Spinal Cord

ALS is a rapidly progressive, devastating neurodegenerative illness of adults that produces disabling weakness and spasticity arising from death of lower and upper motor neurons. No meaningful therapies exist to slow ALS progression, and molecular insights into pathogenesis and progression are sorely needed. In that context, we used high-depth, next generation RNA sequencing (RNAseq, Illumina) to define gene network abnormalities in RNA samples depleted of rRNA and isolated from cervical spinal cord sections of 7 ALS and 8 CTL samples. We aligned \u3e50 million 2X150 bp paired-end sequences/sample to the hg19 human genome and applied three different algorithms (Cuffdiff2, DEseq2, EdgeR) for identification of differentially expressed genes (DEG’s). Ingenuity Pathways Analysis (IPA) and Weighted Gene Co-expression Network Analysis (WGCNA) identified inflammatory processes as significantly elevated in our ALS samples, with tumor necrosis factor (TNF) found to be a major pathway regulator (IPA) and TNFα-induced protein 2 (TNFAIP2) as a major network “hub” gene (WGCNA). Using the oPOSSUM algorithm, we analyzed transcription factors (TF) controlling expression of the nine DEG/hub genes in the ALS samples and identified TF’s involved in inflammation (NFkB, REL, NFkB1) and macrophage function (NR1H2::RXRA heterodimer). Transient expression in human iPSC-derived motor neurons of TNFAIP2 (also a DEG identified by all three algorithms) reduced cell viability and induced caspase 3/7 activation. Using high-density RNAseq, multiple algorithms for DEG identification, and an unsupervised gene co-expression network approach, we identified significant elevation of inflammatory processes in ALS spinal cord with TNF as a major regulatory molecule. Overexpression of the DEG TNFAIP2 in human motor neurons, the population most vulnerable to die in ALS, increased cell death and caspase 3/7 activation. We propose that therapies targeted to reduce inflammatory TNFα signaling may be helpful in ALS patients

MEGA-V: detection of variant gene sets in patient cohorts

Detecting significant associations between genetic variants and disease may prove particularly challenging when the variants are rare in the population and/or act together with other variants to cause the disease. We have developed a statistical framework named Mutation Enrichment Gene set Analysis of Variants (MEGA-V) that specifically detects the enrichments of genetic alterations within a process in a cohort of interest. By focusing on the mutations of several genes contributing to the same function rather than on those affecting a single gene, MEGA-V increases the power to detect statistically significant associations. Supplementary data are available online.AVAILABILITY: MEGA-V is available at https://github.com/ciccalab/MEGA CONTACT: [email protected].</p

Synthetic lethal interaction between the tumour suppressor STAG2 and its paralog STAG1

Cohesin is a multi-protein complex that tethers sister chromatids during mitosis and mediates DNA repair, genome compartmentalisation and regulation of gene expression. Cohesin subunits frequently acquire cancer loss-of-function alterations and act as tumour suppressors in several tumour types. This has led to increased interest in cohesin as potential target in anti-cancer therapy. Here we show that the loss-of-function of STAG2, a core component of cohesin and an emerging tumour suppressor, leads to synthetic dependency of mutated cancer cells on its paralog STAG1. STAG1 and STAG2 share high sequence identity, encode mutually exclusive cohesin subunits and retain partially overlapping functions. We inhibited STAG1 and STAG2 in several cancer cell lines where the two genes have variable mutation and copy number status. In all cases, we observed that the simultaneous blocking of STAG1 and STAG2 significantly reduces cell proliferation. We further confirmed the synthetic lethal interaction developing a vector-free CRISPR system to induce STAG1/STAG2 double gene knockout. We provide strong evidence that STAG1 is a promising therapeutic target in cancers with inactivating alterations of STAG2

A Bioelectrochemical Approach to Characterize Extracellular Electron Transfer by Synechocystis sp. PCC6803

Biophotovoltaic devices employ photosynthetic organisms at the anode of a microbial fuel cell to generate electrical power. Although a range of cyanobacteria and algae have been shown to generate photocurrent in devices of a multitude of architectures, mechanistic understanding of extracellular electron transfer by phototrophs remains minimal. Here we describe a mediatorless bioelectrochemical device to measure the electrogenic output of a planktonically grown cyanobacterium, Synechocystis sp. PCC6803. Light dependent production of current is measured, and its magnitude is shown to scale with microbial cell concentration and light intensity. Bioelectrochemical characterization of a Synechocystis mutant lacking Photosystem II demonstrates conclusively that production of the majority of photocurrent requires a functional water splitting aparatus and electrons are likely ultimately derived from water. This shows the potential of the device to rapidly and quantitatively characterize photocurrent production by genetically modified strains, an approach that can be used in future studies to delineate the mechanisms of cyanobacterial extracellular electron transport

Advances with long non-coding rnas in alzheimer’s disease as peripheral biomarker

One of the most compelling needs in the study of Alzheimer’s disease (AD) is the characterization of cognitive decline peripheral biomarkers. In this context, the theme of altered RNA processing has emerged as a contributing factor to AD. In particular, the significant role of long non-coding RNAs (lncRNAs) associated to AD is opening new perspectives in AD research. This class of RNAs may offer numerous starting points for new investigations about pathogenic mechanisms and, in particular, about peripheral biomarkers. Indeed, altered lncRNA signatures are emerging as potential diagnostic biomarkers. In this review, we have collected and fully explored all the presented data about lncRNAs and AD in the peripheral system to offer an overview about this class of non-coding RNAs and their possible role in AD