The PI3K∂-Selective Inhibitor Idelalisib Induces T- and NK-Cell Dysfunction Independently of B-Cell Malignancy-Associated Immunosuppression

B-cell receptors, multiple receptor tyrosine kinases, and downstream effectors are constitutively active in chronic lymphocytic leukemia (CLL) B cells. Activation of these pathways results in resistance to apoptosis and enhanced survival of the leukemic cells. Idelalisib is a highly selective inhibitor of the PI3K p110∂ isoform and is approved for the treatment of CLL in patients with relapsed/refractory disease or in those harboring 17p deletions or tp53 mutations. Despite the initial excitement centered around high response rates in clinical trials of idelalisib, its therapeutic success has been hindered by the incidence of severe opportunistic infections. To examine the potential contribution of idelalisib to the increased risk of infection, we investigated the effects of idelalisib on the immune cell compartments of healthy donors (HDs) and CLL patients. PI3K∂ blockade by idelalisib reduced the expression levels of inhibitory checkpoint molecules in T cells isolated from both HDs and CLL patients. In addition, the presence of idelalisib in cultures significantly decreased T-cell-mediated cytotoxicity and granzyme B secretion, as well as cytokine secretion levels in both cohorts. Furthermore, idelalisib reduced the proliferation and cytotoxicity of HD NK cells. Collectively, our data demonstrate that both human T and NK cells are highly sensitive to PI3K∂ inhibition. Idelalisib interfered with the functions of T and NK cell cells from both HDs and CLL patients. Therefore, idelalisib might contribute to an increased risk of infections regardless of the underlying B-cell malignancy

Stable carbon isotopes of phytoplankton as a tool to monitor anthropogenic CO2 submarine leakages

This study aims to validate the stable carbon isotopic composition (d13C) of phytoplankton as a tool for detecting submarine leakages of anthropogenic CO2(g), since it is characterised by d13C values significantly lower than the natural CO2 dissolved in oceans. Three culture experiments were carried out to investigate the changes in d13C of the diatom Thalassiosira rotula during growth in an artificially modified medium (ASW). Three different dissolved inorganic carbon (DIC) concentrations were tested to verify if carbon availability affects phytoplankton d13C. Simultaneously, at each experiment, T. rotula was cultured under natural DIC isotopic composition (d13C DIC) and carbonate system conditions. The available DIC pool for diatoms grown in ASW was characterised by d13C DIC values (-44.2 ± 0.9‰) significantly lower than the typical marine range. Through photosynthetic DIC uptake, microalgae d13C rapidly changed, reaching significantly low values (until -43.4‰). Moreover, the different DIC concentrations did not affect the diatom d13C, exhibiting the same trend in d13C values in the three ASW experiments. The experiments prove that phytoplankton isotopic composition quickly responds to changes in the d13C of the medium, making this approach a promising and low-impact tool for detecting CO2(g) submarine leakages from CO2(g) deposits

Towards a Multi-Omics of Male Infertility

Infertility is a common problem affecting one in six couples and in 30% of infertile couples, the male factor is a major cause. A large number of genes are involved in spermatogenesis and a significant proportion of male infertility phenotypes are of genetic origin. Studies on infertility have so far primarily focused on chromosomal abnormalities and sequence variants in protein-coding genes and have identified a large number of disease-associated genes. However, it has been shown that a multitude of factors across various omics levels also contribute to infertility phenotypes. The complexity of male infertility has led to the understanding that an integrated, multi-omics analysis may be optimal for unravelling this disease. While there is a vast array of different factors across omics levels associated with infertility, the present review focuses on known factors from the genomics, epigenomics, transcriptomics, proteomics, metabolomics, glycomics, lipidomics, miRNomics, and integrated omics levels. These include: repeat expansions in AR, POLG, ATXN1, DMPK, and SHBG, multiple SNPs, copy number variants in the AZF region, disregulated miRNAs, altered H3K9 methylation, differential MTHFR, MEG3, PEG1, and LIT1 methylation, altered protamine ratios and protein hypo/hyperphosphorylation. This integrative review presents a step towards a multi-omics approach to understanding the complex etiology of male infertility. Currently only a few genetic factors, namely chromosomal abnormalities and Y chromosome microdeletions, are routinely tested in infertile men undergoing intracytoplasmic sperm injection. A multi-omics approach to understanding infertility phenotypes may yield a more holistic view of the disease and contribute to the development of improved screening methods and treatment options. Therefore, beside discovering as of yet unknown genetic causes of infertility, integrating multiple fields of study could yield valuable contributions to the understanding of disease development. Future multi-omics studies will enable to synthesise fragmented information and facilitate biomarker discovery and treatments in male infertility

Strain specific maturation of Dendritic cells and production of IL-1β controls CD40-driven colitis

Intestinal integrity is maintained by balanced numbers of CD103 + Dendritic cells (DCs), which generate peripherally induced regulatory T cells (iTregs). We have developed a mouse model where DC-specific constitutive CD40 signals caused a strong reduction of CD103 + DCs in the lamina propria (LP) and intestinal lymph nodes (LN). As a consequence, also iTregs were strongly reduced and transgenic mice on the C57Bl/6-background (B6) developed fatal colitis. Here we describe that transgenic mice on a pure Balb/c-background (B/c) do not show any pathologies, while transgenic C57Bl/6 x Balb/c (F1) mice develop weak colon inflammation, without fatal colitis. This graded pathology correlated with the effects of CD40-signalling on DCs in each background, with striking loss of CD103 + DCs in B6, but reduced in F1 and diminished in B/c background. We further show direct correlation of CD103 + DC-numbers with numbers of iTregs, the frequencies of which behave correspondingly. Striking effects on B6-DCs reflected robust loss of surface MHCII, known to be crucial for iTreg induction. Furthermore, elevated levels of IL-23 together with IL-1, found only in B6 mice, support generation of intestinal IFN-γ + IL-17 + Th17 cells and IFN-γ + Th1 cells, responsible for onset of disease. Together, this demonstrates a novel aspect of colitis-control, depending on genetic background. Moreover, strain-specific environmental sensing might alter the CD103 + DC/iTreg-axis to tip intestinal homeostatic balance to pathology

Initiative for standardization of reporting genetics of male infertility

<p>The number of publications on research of male infertility is increasing. Technologies used in research of male infertility generate complex results and various types of data that need to be appropriately managed, arranged, and made available to other researchers for further use. In our previous study, we collected over 800 candidate loci for male fertility in seven mammalian species. However, the continuation of the work towards a comprehensive database of candidate genes associated with different types of idiopathic human male infertility is challenging due to fragmented information, obtained from a variety of technologies and various omics approaches. Results are published in different forms and usually need to be excavated from the text, which hinders the gathering of information. Standardized reporting of genetic anomalies as well as causative and risk factors of male infertility therefore presents an important issue. The aim of the study was to collect examples of diverse genomic loci published in association with human male infertility and to propose a standardized format for reporting genetic causes of male infertility. From the currently available data we have selected 75 studies reporting 186 representative genomic loci which have been proposed as genetic risk factors for male infertility. Based on collected and formatted data, we suggested a first step towards unification of reporting the genetics of male infertility in original and review studies. The proposed initiative consists of five relevant data types: 1) genetic locus, 2) race/ethnicity, number of participants (infertile/controls), 3) methodology, 4) phenotype (clinical data, disease ontology, and disease comorbidity), and 5) reference. The proposed form for standardized reporting presents a baseline for further optimization with additional genetic and clinical information. This data standardization initiative will enable faster multi-omics data integration, database development and sharing, establishing more targeted hypotheses, and facilitating biomarker discovery.</p

Distribution of stable isotopes in surface water along the Danube River in Serbia

Stable hydrogen and oxygen isotopes were analysed in water samples from the River Danube and its tributaries during a longitudinal survey performed in August 2005 on Serbian territory. Danube river water data ranged from -80 parts per thousand to -66 parts per thousand for delta(2)H, and from -11.2 parts per thousand to -9.3 parts per thousand for delta(18)O with delta values increasing downstream. The isotopic signatures of the adjacent tributaries (the Tisza, the Sava and the Velika Morava) sampled at the locations close to their confluence with the Danube (Titel, Ostruznica and Ljubicevski most, respectively) just about the time of the campaign were enriched (-67 parts per thousand and -63 parts per thousand for delta(2)H, and -9.3 parts per thousand and -8.9 parts per thousand for delta(18)O) with respect to the Danube water because of their catchment effects. Hydrogen and oxygen stable isotope values were used in combination with measured physico-chemical and biological parameters to trace hydrological and transport processes in these river systems. The mixing relationships between the Danube main stream and its tributaries were estimated using the mass balance for isotopic composition and electrical conductivity as conservative parameters. Evidence of an incomplete mixing process at the Centa location, 8 km below the confluence of the Tisza river, with its participation of 88% was shown by its oxygen-18 content. The correlations between river water isotope composition and physico-chemical and biological parameters are discussed.9th Symposium of the European-Society-for-Isotope-Research, Jun 23-28, 2007, Cluj Napoca, Romani

Obesity gene atlas in mammals

Obesity in humans has increased at an alarming rate over the past two decades and has become one of the leading public health problems worldwide. Studies have revealed a large number of genes/markers that are associated with obesity and/or obesity-related phenotypes, indicating an urgent need to develop a central database for helping the community understand the genetic complexity of obesity. In the present study, we collected a total of 1.736 obesity associated loci and created a freely available obesity database, including 1,515 protein-coding genes and 221 microRNAs (miRNA) collected from four mammalian species: human, cattle, rat and mouse. These loci were integrated as orthologs on comparative genomic views in human, cattle, and mouse. The database and genomic views are freely available online at: http://www.integratomics-time.com/fat_deposition. Bioinformatics analyses of the collected data revealed some potential novel obesity related molecular markers which represent focal points for testing more targeted hypotheses and designing experiments for further studies. We belive that this centralized database on obesity and adipogenesis will facilitate development of comparative systems biology approaches to address this important health issue in human and their potential applications in animals