Model selection for factorial Gaussian graphical models with an application to dynamic regulatory networks

Factorial Gaussian graphical Models (fGGMs) have recently been proposed for inferring dynamic gene regulatory networks from genomic high-throughput data. In the search for true regulatory relationships amongst the vast space of possible networks, these models allow the imposition of certain restrictions on the dynamic nature of these relationships, such as Markov dependencies of low order-some entries of the precision matrix are a priori zeros-or equal dependency strengths across time lags-some entries of the precision matrix are assumed to be equal. The precision matrix is then estimated by l1-penalized maximum likelihood, imposing a further constraint on the absolute value of its entries, which results in sparse networks. Selecting the optimal sparsity level is a major challenge for this type of approaches. In this paper, we evaluate the performance of a number of model selection criteria for fGGMs by means of two simulated regulatory networks from realistic biological processes. The analysis reveals a good performance of fGGMs in comparison with other methods for inferring dynamic networks and of the KLCV criterion in particular for model selection. Finally, we present an application on a high-resolution time-course microarray data from the Neisseria meningitidis bacterium, a causative agent of life-threatening infections such as meningitis. The methodology described in this paper is implemented in the R package sglasso, freely available at CRAN, http://CRAN.R-project.org/package=sglasso

The role of bioenergy and biochemicals in CO2 mitigation through the energy system - a scenario analysis for the Netherlands

Bioenergy as well as bioenergy with carbon capture and storage are key options to embark on cost-efficient trajectories that realize climate targets. Most studies have not yet assessed the influence on these trajectories of emerging bioeconomy sectors such as biochemicals and renewable jet fuels (RJFs). To support a systems transition, there is also need to demonstrate the impact on the energy system of technology development, biomass and fossil fuel prices. We aim to close this gap by assessing least-cost pathways to 2030 for a number of scenarios applied to the energy system of the Netherlands, using a cost-minimization model. The type and magnitude of biomass deployment are highly influenced by technology development, fossil fuel prices and ambitions to mitigate climate change. Across all scenarios, biomass consumption ranges between 180 and 760 PJ and national emissions between 82 and 178 Mt CO2. High technology development leads to additional 100-270 PJ of biomass consumption and 8-20 Mt CO2 emission reduction compared to low technology development counterparts. In high technology development scenarios, additional emission reduction is primarily achieved by bioenergy and carbon capture and storage. Traditional sectors, namely industrial biomass heat and biofuels, supply 61-87% of bioenergy, while wind turbines are the main supplier of renewable electricity. Low technology pathways show lower biochemical output by 50-75%, do not supply RJFs and do not utilize additional biomass compared to high technology development. In most scenarios the emission reduction targets for the Netherlands are not met, as additional reduction of 10-45 Mt CO2 is needed. Stronger climate policy is required, especially in view of fluctuating fossil fuel prices, which are shown to be a key determinant of bioeconomy development. Nonetheless, high technology development is a no-regrets option to realize deep emission reduction as it also ensures stable growth for the bioeconomy even under unfavourable conditions.</p

Weekly cisplatin and daily oral etoposide is highly effective in platinum pretreated ovarian cancer

We investigated the potential of weekly cisplatin and daily oral etoposide followed by oral etoposide maintenance therapy in patients with platinum-refractory ovarium cancer. One hundred and seven patients were entered on the study, 98 patients completed the induction therapy consisting of cisplatin at either 50 or 70 mg m−2 weekly for six administrations plus oral etoposide at a dose of 50 mg daily. Of these 98 patients, 38 had a platinum treatment-free interval of more than 12 months, 32 had an interval between 4 and 12 months, and 28 had progressed during or within 4 months after last platinum therapy. We assessed response rates and time to progression, and also response duration and survival. Analyses were done on the 98 evaluable patients. All 107 patients were considered evaluable for toxicity. Of the 38 patients with a treatment-free interval of more than 12 months, 92% responded, with 63% complete responses. The median progression-free survival in these patients was 14 months, and the median survival was 26 months. Of the 32 patients with an interval of 4–12 months, 91% responded, with 31% complete responses, a median progression-free interval of 8 and a median overall survival of 16 months. Of the 28 patients with platinum-refractory disease, 46% as yet responded, with 29% complete responses, median progression-free interval of 5 and an overall survival of 13 months. Haematologic and non-haematologic, particularly renal toxicity and neurotoxicity, were notably mild. We conclude that this intensive regimen of weekly cisplatin plus daily etoposide is highly effective and well tolerated in patients with ovarian cancer relapsing after conventional platinum-based combination chemotherapy, including patients who have progressed during or within 4 months after platinum treatment

Global Chromatin Domain Organization of the Drosophila Genome

In eukaryotes, neighboring genes can be packaged together in specific chromatin structures that ensure their coordinated expression. Examples of such multi-gene chromatin domains are well-documented, but a global view of the chromatin organization of eukaryotic genomes is lacking. To systematically identify multi-gene chromatin domains, we constructed a compendium of genome-scale binding maps for a broad panel of chromatin-associated proteins in Drosophila melanogaster. Next, we computationally analyzed this compendium for evidence of multi-gene chromatin domains using a novel statistical segmentation algorithm. We find that at least 50% of all fly genes are organized into chromatin domains, which often consist of dozens of genes. The domains are characterized by various known and novel combinations of chromatin proteins. The genes in many of the domains are coregulated during development and tend to have similar biological functions. Furthermore, during evolution fewer chromosomal rearrangements occur inside chromatin domains than outside domains. Our results indicate that a substantial portion of the Drosophila genome is packaged into functionally coherent, multi-gene chromatin domains. This has broad mechanistic implications for gene regulation and genome evolution

Evolution of infectious bronchitis virus in the field after homologous vaccination introduction

International audienceAbstractDespite the fact that vaccine resistance has been typically considered a rare phenomenon, some episodes of vaccine failure have been reported with increasing frequency in intensively-raised livestock. Infectious bronchitis virus (IBV) is a widespread avian coronavirus, whose control relies mainly on extensive vaccine administration. Unfortunately, the continuous emergence of new vaccine-immunity escaping variants prompts the development of new vaccines. In the present work, a molecular epidemiology study was performed to evaluate the potential role of homologous vaccination in driving IBV evolution. This was undertaken by assessing IBV viral RNA sequences from the ORF encoding the S1 portion of viral surface glycoprotein (S) before and after the introduction of a new live vaccine on broiler farms in northern-Italy. The results of several biostatistics analyses consistently demonstrate the presence of a higher pressure in the post-vaccination period. Natural selection was detected essentially on sites located on the protein surface, within or nearby domains involved in viral attachment or related functions. This evidence strongly supports the action of vaccine-induced immunity in conditioning viral evolution, potentially leading to the emergence of new vaccine-escape variants. The great plasticity of rapidly-evolving RNA-viruses in response to human intervention, which extends beyond the poultry industry, is demonstrated, claiming further attention due to their relevance for animal and especially human health

Height and timing of growth spurt during puberty in young people living with vertically acquired HIV in Europe and Thailand.

OBJECTIVE: The aim of this study was to describe growth during puberty in young people with vertically acquired HIV. DESIGN: Pooled data from 12 paediatric HIV cohorts in Europe and Thailand. METHODS: One thousand and ninety-four children initiating a nonnucleoside reverse transcriptase inhibitor or boosted protease inhibitor based regimen aged 1-10 years were included. Super Imposition by Translation And Rotation (SITAR) models described growth from age 8 years using three parameters (average height, timing and shape of the growth spurt), dependent on age and height-for-age z-score (HAZ) (WHO references) at antiretroviral therapy (ART) initiation. Multivariate regression explored characteristics associated with these three parameters. RESULTS: At ART initiation, median age and HAZ was 6.4 [interquartile range (IQR): 2.8, 9.0] years and -1.2 (IQR: -2.3 to -0.2), respectively. Median follow-up was 9.1 (IQR: 6.9, 11.4) years. In girls, older age and lower HAZ at ART initiation were independently associated with a growth spurt which occurred 0.41 (95% confidence interval 0.20-0.62) years later in children starting ART age 6 to 10 years compared with 1 to 2 years and 1.50 (1.21-1.78) years later in those starting with HAZ less than -3 compared with HAZ at least -1. Later growth spurts in girls resulted in continued height growth into later adolescence. In boys starting ART with HAZ less than -1, growth spurts were later in children starting ART in the oldest age group, but for HAZ at least -1, there was no association with age. Girls and boys who initiated ART with HAZ at least -1 maintained a similar height to the WHO reference mean. CONCLUSION: Stunting at ART initiation was associated with later growth spurts in girls. Children with HAZ at least -1 at ART initiation grew in height at the level expected in HIV negative children of a comparable age

Selection of a phylogenetically informative region of the norovirus genome for outbreak linkage

The recognition of a common source norovirus outbreak is supported by finding identical norovirus sequences in patients. Norovirus sequencing has been established in many (national) public health laboratories and academic centers, but often partial and different genome sequences are used. Therefore, agreement on a target sequence of sufficient diversity to resolve links between outbreaks is crucial. Although harmonization of laboratory methods is one of the keystone activities of networks that have the aim to identify common source norovirus outbreaks, this has proven difficult to accomplish, particularly in the international context. Here, we aimed at providing a method enabling identification of the genomic region informative of a common source norovirus outbreak by bio-informatic tools. The data set of 502 unique full length capsid gene sequences available from the public domain, combined with epidemiological data including linkage information was used to build over 3,000 maximum likelihood (ML) trees for different sequence lengths and regions. All ML trees were evaluated for robustness and specificity of clustering of known linked norovirus outbreaks against the background diversity of strains. Great differences were seen in the robustness of commonly used PCR targets for cluster detection. The capsid gene region spanning nucleotides 900–1,400 was identified as the region optimally substituting for the full length capsid region. Reliability of this approach depends on the quality of the background data set, and we recommend periodic reassessment of this growing data set. The approach may be applicable to multiple sequence-based data sets of other pathogens