Cis and Trans Effects of Human Genomic Variants on Gene Expression

This work was funded by the Louis-Jeantet Foundation (http://www.jeantet.ch/), the European Research Council (Grant ID: 260927 http://erc.europa.eu/), the Swiss National Foundation (Grant ID: 130342 http://www.snf.ch), NCCR Frontiers In Genetics (http://www.frontiers-in-genetics.org), the UK Medical Research Council (http://www.mrc.ac.uk) and the Wellcome Trust (Grant ID: 092731).

Climate-mediated diversification of turtles in the Cretaceous

The file attached is the published version of the article

Tyrosine Phosphorylation of the E3 Ubiquitin Ligase TRIM21 Positively Regulates Interaction with IRF3 and Hence TRIM21 Activity

Patients suffering from Systemic Lupus Erythematous (SLE) have elevated type I interferon (IFN) levels which correlate with disease activity and severity. TRIM21, an autoantigen associated with SLE, has been identified as an ubiquitin E3 ligase that targets the transcription factor IRF3 in order to turn off and limit type I IFN production following detection of viral and bacterial infection by Toll Like Receptors (TLRs). However, how the activity of TRIM21 is regulated downstream of TLRs is unknown. In this study we demonstrate that TRIM21 is tyrosine phosphorylated following TLR3 and TLR4 stimulation, suggesting that its activity is potentially regulated by tyrosine phosphorylation. Using Netphos, we have identified three key tyrosines that are strongly predicted to be phosphorylated, two of which are conserved between the human and murine forms of TRIM21, at residues 343, 388, and 393, all of which have been mutated from tyrosine to phenylalanine (Y343F, Y388F, and Y393F). We have observed that tyrosine phosphorylation of TRIM21 only occurs in the substrate binding PRY/SPRY domain, and that Y393, and to a lesser extent, Y388 are required for TRIM21 to function as a negative regulator of IFN-β promoter activity. Further studies revealed that mutating Y393 to phenylalanine inhibits the ability of TRIM21 to interact with its substrate, IRF3, thus providing a molecular explanation for the lack of activity of Y393 on the IFN-β promoter. Our data demonstrates a novel role for tyrosine phosphorylation in regulating the activity of TRIM21 downstream of TLR3 and TLR4. Given the pathogenic role of TRIM21 in systemic autoimmunity, these findings have important implications for the development of novel therapeutics

Expression of cyclooxygenase-2 (COX-2) in tumour and stroma compartments in cervical cancer: clinical implications

This study aims at investigating the relationship between cyclooxygenase-2 expression in tumour vs stroma inflammatory compartment and its possible clinical role. The study included 99 stage IB-IV cervical cancer patients: immunostaining of tumour tissue sections was performed with rabbit antiserum against cyclooxygenase-2. CD3, CD4, CD8, CD25, Mast Cell Tryptase monoclonal antibodies were used to characterise stroma inflammatory cells in nine cervical tumours. An inverse relation was found between cyclooxygenase-2 levels (cyclooxygenase-2 IDV) of tumour vs stroma compartment (r=−0.44, P<0.0001). The percentage of cases showing high tumour/stromal cyclooxygenase-2 IDV ratio was significantly higher in patients who did not respond to treatment (93.3%) with respect to patients with partial (60.5%), and complete (43.7%) response (P= 0.009). Cases with a high tumour/stroma cyclooxygenase-2 IDV ratio had a shorter overall survival rate than cases with a low tumour/stroma cyclooxygenase-2 IDV (P<0.0001). In the multivariate analysis advanced stage and the status of tumour/stroma cyclooxygenase-2 IDV ratio retained an independent negative prognostic role. The proportion of CD3+, CD4+, and CD25+ cells was significantly lower in tumours with high tumour/stroma cyclooxygenase-2 IDV ratio, while a higher percentage of mast cells was detected in tumours showing high tumour/stroma cyclooxygenase-2 IDV ratio. Our study showed the usefulness of assessing cyclooxygenase-2 status both in tumour and stroma compartment in order to identify cervical cancer patients endowed with a very poor chance of response to neoadjuvant therapy and unfavourable prognosis

A systematic review and critical assessment of incentive strategies for discovery and development of novel antibiotics

Despite the growing threat of antimicrobial resistance, pharmaceutical and biotechnology firms are reluctant to develop novel antibiotics because of a host of market failures. This problem is complicated by public health goals that demand antibiotic conservation and equitable patient access. Thus, an innovative incentive strategy is needed to encourage sustainable investment in antibiotics. This systematic review consolidates, classifies and critically assesses a total of 47 proposed incentives. Given the large number of possible strategies, a decision framework is presented to assist with the selection of incentives. This framework focuses on addressing market failures that result in limited investment, public health priorities regarding antibiotic stewardship and patient access, and implementation constraints and operational realities. The flexible nature of this framework allows policy makers to tailor an antibiotic incentive package that suits a country’s health system structure and needs

Shape coexistence in neutron-deficient Hg-188 investigated via lifetime measurements

Shape coexistence in the $Z \approx 82$ region has been established in mercury, lead and polonium isotopes. Even-even mercury isotopes with $100 \leq N \leq 106$ present multiple fingerprints of this phenomenon, which seems to be no longer present for $N \geq 110$. According to a number of theoretical calculations, shape coexistence is predicted in the $^{188}$Hg isotope. The $^{188}$Hg nucleus was populated using two different fusion-evaporation reactions with two targets, $^{158}$Gd and $^{160}$Gd, and a beam of $^{34}$S, provided by the Tandem-ALPI accelerators complex at the Laboratori Nazionali di Legnaro. The channels of interest were selected using the information from the Neutron Wall array, while the $\gamma$ rays were detected using the GALILEO $\gamma$-ray array. The lifetimes of the excited states were determined using the Recoil Distance Doppler-Shift method, employing the dedicated GALILEO plunger device. Using the two-bands mixing and rotational models, the deformation of the pure configurations was obtained from the experimental results. The extracted transition strengths were compared with those calculated with the state-of-the-art symmetry-conserving configuration-mixing (SCCM) and five-dimentional collective Hamiltonian (5DCH) approaches in order to shed light on the nature of the observed structures in the $^{188}$Hg nucleus. An oblate, a normal- and a super-deformed prolate bands were predicted and their underlying shell structure was also discussed.Comment: v1: 13 pages, 10 figures, comparison between IBM-CM and SCCM calculations; v2: 16 pages, 13 figures, discussion on the mixing amplitudes from the experimental B(E2) values, comparison between SCCM and 5DCH calculation

Identification of 55,000 Replicated DNA Methylation QTL

DNA methylation plays an important role in the regulation of transcription. Genetic control of DNA methylation is a potential candidate for explaining the many identified SNP associations with disease that are not found in coding regions. We replicated 52,916 cis and 2,025 trans DNA methylation quantitative trait loci (mQTL) using methylation from whole blood measured on Illumina HumanMethylation450 arrays in the Brisbane Systems Genetics Study (n = 614 from 177 families) and the Lothian Birth Cohorts of 1921 and 1936 (combined n = 1366). The trans mQTL SNPs were found to be over-represented in 1 Mbp subtelomeric regions, and on chromosomes 16 and 19. There was a significant increase in trans mQTL DNA methylation sites in upstream and 5' UTR regions. The genetic heritability of a number of complex traits and diseases was partitioned into components due to mQTL and the remainder of the genome. Significant enrichment was observed for height (p = 2.1 × 10), ulcerative colitis (p = 2 × 10), Crohn's disease (p = 6 × 10) and coronary artery disease (p = 5.5 × 10) when compared to a random sample of SNPs with matched minor allele frequency, although this enrichment is explained by the genomic location of the mQTL SNPs

Integrated method for quantitative morphometry and oxygen transport modeling in striated muscle

Identifying structural limitations in O2 transport is primarily restricted by current methods employed to characterize the nature of physiological remodeling. Inadequate resolution or breadth of available data has impaired development of routine diagnostic protocols and effective therapeutic strategies. Understanding O2 transport within striated muscle faces major challenges, most notably in quantifying how well individual fibers are supplied by the microcirculation, which has necessitated exploring tissue O2 supply using theoretical modeling of diffusive exchange. With capillary domains identified as a suitable model for the description of local O2 supply and requiring less computation than numerically calculating the trapping regions that are supplied by each capillary via biophysical transport models, we sought to design a high-throughput method for histological analysis. We present an integrated package that identifies optimal protocols for identification of important input elements, processing of digitized images with semiautomated routines, and incorporation of these data into a mathematical modeling framework with computed output visualized as the tissue partial pressure of O2 (Po2) distribution across a biopsy sample. Worked examples are provided using muscle samples from experiments involving rats and humans