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MicroRNAs (miRNAs) control cell cycle progression by targeting the transcripts encoding for cyclins, CDKs and CDK inhibitors, such as p27 KIP1 (p27). p27 expression is controlled by multiple transcriptional and posttranscriptional mechanisms, including translational inhibition by miR-221/222 and posttranslational regulation by the SCF SKP2 complex. The oncosuppressor activity of miR-340 has been recently characterized in breast, colorectal and osteosarcoma tumor cells. However, the mechanisms underlying miR-340-induced cell growth arrest have not been elucidated. Here, we describe miR-340 as a novel tumor suppressor in non-small cell lung cancer (NSCLC). Starting from the observation that the growth-inhibitory and proapoptotic effects of miR-340 correlate with the accumulation of p27 in lung adenocarcinoma and glioblastoma cells, we have analyzed the functional relationship between miR-340 and p27 expression. miR-340 targets three key negative regulators of p27. The miR-340-mediated inhibition of both Pumilio family RNA-binding proteins (PUM1 and PUM2), required for the miR-221/222 interaction with the p27 3′-UTR, antagonizes the miRNA-dependent downregulation of p27. At the same time, miR-340 induces the stabilization of p27 by targeting SKP2, the key posttranslational regulator of p27. Therefore, miR-340 controls p27 at both translational and posttranslational levels. Accordingly, the inhibition of either PUM1 or SKP2 partially recapitulates the miR-340 effect on cell proliferation and apoptosis. In addition to the effect on tumor cell proliferation, miR-340 also inhibits intercellular adhesion and motility in lung cancer cells. These changes correlate with the miR-340-mediated inhibition of previously validated ( MET and ROCK1 ) and potentially novel ( RHOA and CDH1 ) miR-340 target transcripts. Finally, we show that in a small cohort of NSCLC patients ( n =23), representative of all four stages of lung cancer, miR-340 expression inversely correlates with clinical staging, thus suggesting that miR-340 downregulation contributes to the disease progression.

The role of heat pumps in a decarbonised (thermal) energy system is pivotal. This technology is often in competition with other technologies such as district heating or boilers. When comparing different heating technologies in respect to their CO 2 footprint and their costs, the calculation method of future greenhouse gas emission factors of the different energy carriers and energy prices is decisive. Emission factors need to be based on technical and physical fundamentals as (international) green certificates are not a satisfactory proxy for physical emissions, especially for the case of electricity. Currently the Swiss electricity generation system is mostly decarbonised with its high share of hydropower and nuclear energy. However, Switzerland, located in the heart of Europe, has the highest relative shares of cross border capacities, which are relevant for energy trading. In a still fossil dominated European power system, the high volatility of wholesale power prices is entailing a high (temporal) volatility of power related emissions. Thus, the overall carbon footprint of consumed electricity changes significantly over time. Heating demand also shows a dynamic behaviour. It is therefore likely, that a CO 2 footprint based on annual averages in heating demand and emission factors could lead to significant errors. The aim of the research was to draw a comparison of the resulting annual CO 2 emissions applying different time step aggregation levels (yearly, monthly, typical days) with the results calculated based on a complete year in hourly resolution. The aim was to determine the relative error made through aggregation.

Background Targeted resequencing has become the most used and cost-effective approach for identifying causative mutations of Mendelian diseases both for diagnostics and research purposes. Due to very rapid technological progress, NGS laboratories are expanding their capabilities to address the increasing number of analyses. Several open source tools are available to build a generic variant calling pipeline, but a tool able to simultaneously execute multiple analyses, organize, and categorize the samples is still missing. Results Here we describe VarGenius, a Linux based command line software able to execute customizable pipelines for the analysis of multiple targeted resequencing data using parallel computing. VarGenius provides a database to store the output of the analysis (calling quality statistics, variant annotations, internal allelic variant frequencies) and sample information (personal data, genotypes, phenotypes). VarGenius can also perform the “joint analysis” of hundreds of samples with a single command, drastically reducing the time for the configuration and execution of the analysis. VarGenius executes the standard pipeline of the Genome Analysis Tool-Kit (GATK) best practices (GBP) for germinal variant calling, annotates the variants using Annovar, and generates a user-friendly output displaying the results through a web page. VarGenius has been tested on a parallel computing cluster with 52 machines with 120GB of RAM each. Under this configuration, a 50 M whole exome sequencing (WES) analysis for a family was executed in about 7 h (trio or quartet); a joint analysis of 30 WES in about 24 h and the parallel analysis of 34 single samples from a 1 M panel in about 2 h. Conclusions We developed VarGenius, a “master” tool that faces the increasing demand of heterogeneous NGS analyses and allows maximum flexibility for downstream analyses. It paves the way to a different kind of analysis, centered on cohorts rather than on singleton. Patient and variant information are stored into the database and any output file can be accessed programmatically. VarGenius can be used for routine analyses by biomedical researchers with basic Linux skills providing additional flexibility for computational biologists to develop their own algorithms for the comparison and analysis of data. The software is freely available at: https://github.com/frankMusacchia/VarGenius

Retinitis pigmentosa is the most common form of retinal degeneration and is heterogeneous both clinically and genetically. The autosomal dominant forms (ADRP) can be caused by mutations in 12 different genes. This report describes the first simultaneous mutation analysis of all the known ADRP genes in the same population, represented by 43 Italian families. This analysis allowed the identification of causative mutations in 12 of the families (28% of the total). Seven different mutations were identified, two of which are novel (458delC and 6901C→T (P2301S), in the CRX and PRPF8 genes, respectively). Several novel polymorphisms leading to amino acid changes in the FSCN2, NRL, IMPDH1, and RP1 genes were also identified. Analysis of gene prevalences indicates that the relative involvement of the RHO and the RDS genes in the pathogenesis of ADRP is less in Italy than in US and UK populations. As causative mutations were not found in over 70% of the families analysed, this study suggests the presence of further novel genes or sequence elements involved in the pathogenesis of ADRP.

Aims: To describe the clinical phenotype of X linked juvenile retinoschisis in eight Italian families with six different mutations in the XLRS1 gene. Methods: Complete ophthalmic examinations, electroretinography and A and B-scan standardised echography were performed in 18 affected males. The coding sequences of the XLRS1 gene were amplified by polymerase chain reaction and directly sequenced on an automated sequencer. Results: Six different XLRS1 mutations were identified; two of these mutations Ile81Asn and the Trp122Cys, have not been previously described. The affected males showed an electronegative response to the standard white scotopic stimulus and a prolonged implicit time of the 30 Hz flicker. In the families with Trp112Cys and Trp122Cys mutations we observed a more severe retinoschisis (RS) clinical picture compared with the other genotypes. Conclusion: The severe RS phenotypes associated with Trp112Cys and to Trp122Cys mutations suggest that these mutations determine a notable alteration in the function of the retinoschisin protein.

ABCA4 is the most frequently mutated gene leading to inherited retinal disease (IRD) with over 2200 pathogenic variants reported to date. Of these, ~1% are copy number variants (CNVs) involving the deletion or duplication of genomic regions, typically >50 nucleotides in length. An in-depth assessment of the current literature based on the public database LOVD, regarding the presence of known CNVs and structural variants in ABCA4, and additional sequencing analysis of ABCA4 using single-molecule Molecular Inversion Probes (smMIPs) for 148 probands highlighted recurrent and novel CNVs associated with ABCA4-associated retinopathies. An analysis of the coverage depth in the sequencing data led to the identification of eleven deletions (six novel and five recurrent), three duplications (one novel and two recurrent) and one complex CNV. Of particular interest was the identification of a complex defect, i.e., a 15.3 kb duplicated segment encompassing exon 31 through intron 41 that was inserted at the junction of a downstream 2.7 kb deletion encompassing intron 44 through intron 47. In addition, we identified a 7.0 kb tandem duplication of intron 1 in three cases. The identification of CNVs in ABCA4 can provide patients and their families with a genetic diagnosis whilst expanding our understanding of the complexity of diseases caused by ABCA4 variants.

Targeted resequencing has become the most used and cost-effective approach for identifying causative mutations of Mendelian diseases both for diagnostics and research purposes. Due to very rapid technological progress, NGS laboratories are expanding their capabilities to address the increasing number of analyses. Several open source tools are available to build a generic variant calling pipeline, but a tool able to simultaneously execute multiple analyses, organize, and categorize the samples is still missing. Here we describe VarGenius, a Linux based command line software able to execute customizable pipelines for the analysis of multiple targeted resequencing data using parallel computing. VarGenius provides a database to store the output of the analysis (calling quality statistics, variant annotations, internal allelic variant frequencies) and sample information (personal data, genotypes, phenotypes). VarGenius can also perform the \"joint analysis\" of hundreds of samples with a single command, drastically reducing the time for the configuration and execution of the analysis. We developed VarGenius, a \"master\" tool that faces the increasing demand of heterogeneous NGS analyses and allows maximum flexibility for downstream analyses. It paves the way to a different kind of analysis, centered on cohorts rather than on singleton. Patient and variant information are stored into the database and any output file can be accessed programmatically. VarGenius can be used for routine analyses by biomedical researchers with basic Linux skills providing additional flexibility for computational biologists to develop their own algorithms for the comparison and analysis of data.

The Q & U Bolometric Interferometer for Cosmology (QUBIC) is a cosmology experiment that aims to measure the B-mode polarization of the cosmic microwave background (CMB). Measurements of the primordial B-mode pattern of the CMB polarization are in fact among the most exciting goals in cosmology as it would allow testing of the inflationary paradigm. Many experiments are attempting to measure the B-modes, from the ground and the stratosphere, using imaging Stokes polarimeters. The QUBIC collaboration developed an innovative concept to measure CMB polarization using bolometric interferometry. This approach mixes the high sensitivity of bolometric detectors with the accurate control of systematics due to the interferometric layout of the instrument. We present the calibration results for the Technological Demonstrator, before its commissioning in the Argentinian observing site and preparation for first light.

Genome-wide expression analyses have a crucial role in functional genomics. High resolution methods, such as RNA in situ hybridization provide an accurate description of the spatiotemporal distribution of transcripts as well as a three-dimensional ‘ in vivo ’ gene expression overview 1 , 2 , 3 , 4 , 5 . We set out to analyse systematically the expression patterns of genes from an entire chromosome. We chose human chromosome 21 because of the medical relevance of trisomy 21 (Down's syndrome) 6 . Here we show the expression analysis of all identifiable murine orthologues of human chromosome 21 genes (161 out of 178 confirmed human genes) by RNA in situ hybridization on whole mounts and tissue sections, and by polymerase chain reaction with reverse transcription on adult tissues. We observed patterned expression in several tissues including those affected in trisomy 21 phenotypes (that is, central nervous system, heart, gastrointestinal tract, and limbs). Furthermore, statistical analysis suggests the presence of some regions of the chromosome with genes showing either lack of expression or, to a lesser extent, co-expression in specific tissues. This high resolution expression ‘atlas’ of an entire human chromosome is an important step towards the understanding of gene function and of the pathogenetic mechanisms in Down's syndrome.