Economic and social ramifications of trends in the Israeli hi-tech industry

Израильская индустрия высоких технологий превратилась в один из самых важных секторов экономики страны настолько, что сейчас она известна, как «страна - Start-up». В статье представлены последние тенденции в индустрии высоких технологий Израиля. Обсуждаются некоторые последствия этих тенденций для экономики Израиля. Кроме того, статья показывает, что ускорение развития технологий приводит к некоторым социальным эффектам, которые не всегда носят позитивный характер.The Israeli Hi-Tech industry has evolved to become one of the most important sectors of the Israeli economy to the extent that the country is now labeled as the “start-up Nation”. The present paper presents recent trends in the Israeli Hi-Tech industry. The ramifications of these trends to the Israeli economy are discussed. In addition, the paper shows that the accelerated technological development has some social effects, not all positive

A genomic exploration of transmissibility in Mycobacterium tuberculosis

Tese de Doutoramento em Ciências da Saúde.The ability of Mycobacterium tuberculosis (Mtb) to be transmitted from host to host is not well understood. Previous molecular epidemiology studies have shown that while some clinical strains of Mtb are able to cause infection and disease in a large number of individuals exposed to them, others are confined in their transmission, despite the ample chance for the spread of the infection. Since preventing transmission of Mtb is the key to a continued decline in tuberculosis cases, understanding the host and bacterial factors that are associated with transmissibility could be useful in developing strategies to prevent transmission. Previous work has focused on cluster size as a measurable proxy for transmissibility, and several studies have found that host risk factors are associated with clustering and cluster size. This thesis set out to explore if and what bacterial factors, such as phylogenetic lineage and genomic markers, lie behind an increased transmissibility phenotype. We describe a novel approach, called the Propensity to Propagate (PPP), with which to adjust for host risk factors when quantifying transmissibility. Using this method, we found no significant differences to propagate between four different lineages within the Netherlands, as measured by molecular-typing defined cluster sizes. When looking more specifically at infectivity (as defined by mean number of positive contacts around each patient) and number of secondary cases within two years after diagnosis of an index case sharing the same fingerprint, we found evidence of phylogenetic lineage influencing these two indicators, namely, a decreased ability to infect and a lower secondary case rate in ancient phylogenetic lineages (Mycobacterium africanum and EAI) compared to their modern counterparts (Euro-American, Beijing, and CAS). One simple approach to discovering more specific genetic regions behind transmissibility involves checking the absence/presence of mutations in the genes of interest between transmissible and nontransmissible phenotypes. In one of our studies, a multivariate logistic regression-based analysis of patient-, microorganism- and disease-related factors failed to reveal any significant association between frameshift-causing indels in Mycobacterium cyclase/LuxR-like genes (mclxs) and transmissibility. Finally, using a large, well-characterized, complete data set of typed strains to identify strains found in large clusters as a proxy for a transmission phenotype as well as related strains that have not been transmitted, we selected 100 bacterial isolates after controlling for epidemiologic and host factors that may influence transmission. After whole genome sequencing, we subjected them to evolutionary convergence analysis. We identified six bacterial DNA regions - espE, PE-PGRS33, PE-PGRS56, Rv0197, Rv2813-14c and Rv2815-16c - to be associated with Mtb transmission and validated these regions by studying the response of human white blood cells to extracts from a subset of the tuberculosis bacteria that carried or did not carry mutations in these DNA regions. We show that there are differences in the immune response – as reflected by in vitro monocyte and T-cell cytokine production, reactive oxygen species release and neutrophil apoptosis - that associate with these genetic changes. These findings not only contribute to our understanding of the interplay of bacterial factors in creating more successful strains at transmitting, but also have implications in the future of disease surveillance and curbing of transmission, by providing for instance tools with which to flag patients carrying particularly transmissible strains.A forma com que a bacteria Mycobacterium tuberculosis (Mtb) é transmitida de um hospedeiro para outro não está ainda bem estudada. Estudos de epidemiologia molecular têm demonstrado que, enquanto que algumas estirpes de Mtb tendem a causar infecção e doença num grande número de indivíduos, sugerindo uma grande capacidade de transmissão entre estes, outras apresentam uma propagação restrita, independentemente de terem elevadas oportunidades de disseminação. Uma vez que a prevenção da transmissão da Mtb é fundamental para o declínio continuado da tuberculose, o estudo dos fatores bacterianos que estão associados à transmissibilidade poderá ser útil para o desenvolvimento de novas estratégias de controlo da tuberculose. Trabalhos anteriores focaram-se no tamanho dos clusters como medida de transmissibilidade, e vários estudos demonstraram uma associação entre os fatores de risco do hospedeiro e o agrupamento e tamanho dos clusters. Nesta foi explorada a existência de fatores bacterianos, tais como linhagem filogenética ou marcadores genéticos, responsáveis por um fenótipo de maior ou menor transmissibilidade. Descrevemos assim uma nova abordagem, chamada propensão para propagar (PPP), com a qual é possível corrigir o viés dos factores de risco do hospedeiro na quantificação da transmissibilidade de uma estirpe. Ao aplicar este método não foi possível detectar diferenças significativas de propagação - considerando o tamanho de clusters definidos por tipagem molecular - entre quatro linhagens diferentes presentes na Holanda. Mas uma análise específica da capacidade de infetar (definida pelo número médio de contatos positivos de cada doente) e do número de casos secundários, no espaço de dois anos após o diagnóstico de um caso índice com o mesmo perfil genético, determinou que a linhagem filogenética influencia estes dois indicadores. Concretamente, as linhagens filogenéticas mais antigas (Mycobacterium africanum e EAI) apresentam uma menor capacidade de infectar e um menor número de casos secundários quando comparadas com as suas equivalentes modernas (Euro-Americano, Beijing, e CAS). Uma abordagem simples para identificar regiões genéticas específicas responsáveis pelas diferenças na transmissibilidade das estirpes envolve a análise da distribuição de mutações nos genes de interesse entre o fenótipo transmissível e o não-transmissível. Neste sentido uma análise baseada em regressão logística multivariada de fatores relacionados com o doente, o microorganismo ou a doença, não revelou qualquer associação significativa entre frameshift-causing indels (a presença de inserções ou deleções nucleotídicas causando a interrupção precoce da grelha de leitura dos genes) em genes Mycobacterium ciclase / LuxR-like (mclxs) e a transmissibilidade. Finalmente, uma grande coleção de isolados bem caracterizados e sujeitos a tipagem molecular foi usada para identificar estirpes pertencentes a clusters grandes - representativas de um fenótipo de transmissão elevada - bem como estirpes com propagação limitada. Selecionamos 100 estirpes tendo em consideração os factores epidemiológicos do hospedeiro com influência na transmissibilidade da estirpe. Após sequenciação do genoma, estas estirpes foram submetidas a uma análise de convergência evolutiva. Identificamos seis genes/regiões intergénicas - Espe, PE PGRS33, PE PGRS56, Rv0197, e Rv2815-16c Rv2813-14c - como estando associados com a transmissão de Mtb, e validamos estes resultados através da análise da resposta de leucócitos a extractos de bactérias com ou sem as mutações nos seis genes/regiões intergénicas mencionados. Demostramos que existem diferenças na resposta imunitária – em termos da produção in vitro de citoquinas pelos monócitos e células T, espécies reativas de oxigénio e apoptose de neutrófilos - associadas às alterações genéticas estudadas. As conclusões desta tese não só contribuem para a melhor compreensão da interação de fatores bacterianos no estabelecimento de linhagens com uma maior transmissibilidade, como têm implicações para o futuro da vigilância e contenção da transmissão, providenciando, por exemplo, as ferramentas necessárias para a identificação de doentes portadores de estirpes particularmente transmissíveis

Prevalence of human immunodeficiency virus, hepatitis C virus, hepatitis B virus and syphilis among individuals attending anonymous testing for HIV in Luanda, Angola

Background. Human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV) and syphilis remain major infections around the world. In Angola, about 166 000 individuals are living with HIV, representing a prevalence of 1.98% in adults between 15 and 49 years of age. In a 2003 study in Luanda, 4.5% of pregnant women had antibodies to HIV and 8.1% to HBV, and 5.4% were infected with Treponema pallidum. Objectives. The aim of this study was to determine the prevalence of HIV-1 and 2, HBV, HCV and T. pallidum serological markers, and hence the prevalence of these infections, in individuals attending a sexually transmitted disease clinic in Luanda, Angola, and the burden of these infections in the Angolan population. Methods. Individuals attending a centre for anonymous testing for HIV were randomly included in the study. All samples were tested for HBV surface antigen (HBsAg), anti-HCV and anti-HIV-1 and 2 antibodies and antibodies to T. pallidum. Results. A total of 431 individuals (262 women and 169 men) were studied, of whom 10.0% (43/431) were seropositive for T. pallidum and 4.6% had active syphilis; 8.8% (38/431) were seropositive for HIV-1 and/or HIV-2 (of these, 78.9% were HIV-1-positive, 2.6% HIV- 2-positive and 18.4% co-infected); 9.3% (40/431) were HBsAg-positive, while 8.1% (35/431) had antibodies to HCV. Of 102 patients with positive results, 26 (25.5%, or 6.0% of the total of 431 patients) were positive for more than one of the organisms studied. Rates of co-infection were as follows: 2.3% (10/431) for HIV/HBV, 0.9% (4/431) for HIV/HCV, and 0.9% (4/431) for HCV/HBV. Three individuals with active syphilis had viral co-infection, hepatitis B in 1 case and HIV in 2. Five individuals (1.2% of the total) were seropositive for 3 infections: HIV, hepatitis B and hepatitis C in 3 cases and HIV, hepatitis C and syphilis in 2. Conclusions. A high prevalence of co-infection with the infections studied was found in this population, including HIV infection (8.8%). These results demonstrate the need to improve screening for and treatment of HIV and other sexually transmitted infections in Angola, and for educational campaigns to prevent not only the morbidity and mortality associated with these diseases, but also their further transmission.publishersversionpublishe

Finite and Infinite Models for Generalized Group-Testing with Unequal Probabilities of Success for Each Item

1 online resource (PDF, 50 pages

Transmission and progression to disease of Mycobacterium tuberculosis phylogenetic lineages in The Netherlands

The aim of this study was to determine if mycobacterial lineages affect infection risk, clustering, and disease progression among Mycobacterium tuberculosis cases in The Netherlands. Multivariate negative binomial regression models adjusted for patient-related factors and stratified by patient ethnicity were used to determine the association between phylogenetic lineages and infectivity (mean number of positive contacts around each patient) and clustering (as defined by number of secondary cases within 2 years after diagnosis of an index case sharing the same fingerprint) indices. An estimate of progression to disease by each risk factor was calculated as a bootstrapped risk ratio of the clustering index by the infectivity index. Compared to the Euro-American reference, Mycobacterium africanum showed significantly lower infectivity and clustering indices in the foreign-born population, while Mycobacterium bovis showed significantly lower infectivity and clustering indices in the native population. Significantly lower infectivity was also observed for the East African Indian lineage in the foreign-born population. Smear positivity was a significant risk factor for increased infectivity and increased clustering. Estimates of progression to disease were significantly associated with age, sputum-smear status, and behavioral risk factors, such as alcohol and intravenous drug abuse, but not with phylogenetic lineages. In conclusion, we found evidence of a bacteriological factor influencing indicators of a strain's transmissibility, namely, a decreased ability to infect and a lower clustering index in ancient phylogenetic lineages compared to their modern counterparts. Confirmation of these findings via follow-up studies using tuberculin skin test conversion data should have important implications on M. tuberculosis control efforts.This study was supported by the Portuguese Foundation for Science and Technology (FCT) (reference SFRH/BD/33902/2009 to H.N.-G

Brand origin identification by consumers: A classification perspective

The authors apply a classification perspective to (1) examine the extent to which consumers can identify the correct country of origin (COO) of different brands of consumer durables, (2) investigate the factors facilitating/hindering correct COO identification, and (3) trace the implications of correct/incorrect COO identification on brand evaluation. The results from a U.K. sample indicate that consumers' ability to classify brands correctly according to their origin is limited and also reveal substantial differences in the classification of different brands to their COO. Moreover, the key antecedent of correct COO identification is consumer ethnocentrism, with sociodemographics (e.g., age, gender) also playing a role. Finally, the authors find that though there are differences in brand evaluations depending on whether the correct COO was identified, such differences are not observed for all brands investigated

Difference in Resistance to Streptococcus pneumoniae Infection in Mice

Streptococcus pneumoniae is a major pathogen that causes various diseases, including pneumonia and sepsis, as millions of people suffer from S. pneumoniae infection worldwide. To better understand the immune and inflammatory responses to S. pneumoniae, we produced murine models. To investigate the differences between intranasal and intratracheal infection, BALB/c mice were infected with S. pneumoniae D39 intranasally or intratracheally. Mice showed no significant differences in survival rates, body weight changes, and bacterial loads. To investigate resistance and susceptibility among mouse strains, BALB/c, C57BL/6J, tumor necrosis factor-α (TNF-α) knockout, and interleukin-10 (IL-10) knockout mice were infected with S. pneumoniae D39 via intranasal or intravenous routes. In this study, BALB/c and C57BL/6J mice were resistant, IL-10 knockout mice were intermediate, and TNF-α knokout mice were susceptible to S. pneumoniae infection. These data show that intranasal and intratracheal infection induced similar results after S. pneumoniae infection, and the genetic background of mice must be considered when studying S. pneumoniae infection in vivo

To be or not to be a pseudogene: a molecular epidemiological approach to the mclx genes and its impact in tuberculosis

Tuberculosis presents a myriad of symptoms, progression routes and propagation patterns not yet fully understood. Whereas for a long time research has focused solely on the patient immunity and overall susceptibility, it is nowadays widely accepted that the genetic diversity of its causative agent, Mycobacterium tuberculosis, plays a key role in this dynamic. This study focuses on a particular family of genes, the mclxs (Mycobacterium cyclase/LuxR-like genes), which codify for a particular and nearly mycobacterial-exclusive combination of protein domains. mclxs genes were found to be pseudogenized by frameshift-causing insertion(s)/deletion(s) in a considerable number of M. tuberculosis complex strains and clinical isolates. To discern the functional implications of the pseudogenization, we have analysed the pattern of frameshift-causing mutations in a group of M. tuberculosis isolates while taking into account their microbial-, patient- and disease-related traits. Our logistic regression-based analyses have revealed disparate effects associated with the transcriptional inactivation of two mclx genes. In fact, mclx2 (Rv1358) pseudogenization appears to be primarily driven by the microbial phylogenetic background, being mainly related to the Euro-American (EAm) lineage; on the other hand, mclx3 (Rv2488c) presents a higher tendency for pseudogenization among isolates from patients born on the Western Pacific area, and from isolates causing extra-pulmonary infections. These results contribute to the overall knowledge on the biology of M. tuberculosis infection, whereas at the same time launch the necessary basis for the functional assessment of these so far overlooked genes.This work was supported by Fundacao para a Ciencia e Tecnologia (FCT), Portugal, and cofunded by Programa Operacional Regional do Norte (ON.2-O Novo Norte), Quadro de Referencia Estrategico Nacional (QREN), through the Fundo Europeu de Desenvolvimento Regional (FEDER), and from Projeto Estrategico - LA 26 - 2013-2014 (PEst-C/SAU/LA0026/2013). H.N.-G. received a personal FCT Grant (SFRH/BD/33902/2209). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Systematic review of allelic exchange experiments aimed at identifying mutations that confer drug resistance in Mycobacterium tuberculosis

First published online: September 20, 2013BACKGROUND: Improving our understanding of the relationship between the genotype and the drug resistance phenotype of Mycobacterium tuberculosis will aid the development of more accurate molecular diagnostics for drug-resistant tuberculosis. Studies that use direct genetic manipulation to identify the mutations that cause M. tuberculosis drug resistance are superior to associational studies in elucidating an individual mutation's contribution to the drug resistance phenotype. METHODS: We systematically reviewed the literature for publications reporting allelic exchange experiments in any of the resistance-associated M. tuberculosis genes. We included studies that introduced single point mutations using specialized linkage transduction or site-directed/in vitro mutagenesis and documented a change in the resistance phenotype. RESULTS: We summarize evidence supporting the causal relationship of 54 different mutations in eight genes (katG, inhA, kasA, embB, embC, rpoB, gyrA and gyrB) and one intergenic region (furA-katG) with resistance to isoniazid, the rifamycins, ethambutol and fluoroquinolones. We observed a significant role for the strain genomic background in modulating the resistance phenotype of 21 of these mutations and found examples of where the same drug resistance mutations caused varying levels of resistance to different members of the same drug class. CONCLUSIONS: This systematic review highlights those mutations that have been shown to causally change phenotypic resistance in M. tuberculosis and brings attention to a notable lack of allelic exchange data for several of the genes known to be associated with drug resistance.This work was supported by the Portuguese Foundation for Science and Technology (FCT) (SFRH/BD/33902/2009 to H. N.-G.), the National Institutes of Health/Fogarty International Center (1K01 TW009213 to K.R.J.), departmental funds of the pulmonary division of Massachusetts General Hospital to M. R. F. and the National Institutes of Health/NIAID (U19 A1076217 to M.B.M.)