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).

A toothed turtle from the Late Jurassic of China and the global biogeographic history of turtles

Turtles (Testudinata) are a successful lineage of vertebrates with about 350 extant species that inhabit all major oceans and landmasses with tropical to temperate climates. The rich fossil record of turtles documents the adaptation of various sub- lineages to a broad range of habitat preferences, but a synthetic biogeographic model is still lacking for the group.Results: We herein describe a new species of fossil turtle from the Late Jurassic of Xinjiang, China, Sichuanchelys palatodentata sp. nov., that is highly unusual by plesiomorphically exhibiting palatal teeth. Phylogenetic analysis places the Late Jurassic Sichuanchelys palatodentata in a clade with the Late Cretaceous Mongolochelys efremovi outside crown group Testudines thereby establishing the prolonged presence of a previously unrecognized clade of turtles in Asia, herein named Sichuanchelyidae. In contrast to previous hypotheses, M. efremovi and Kallokibotion bajazidi are not found within Meiolaniformes, a clade that is here reinterpreted as being restricted to Gondwana.Conclusions: A revision of the global distribution of fossil and recent turtle reveals that the three primary lineages of derived, aquatic turtles, including the crown, Paracryptodira, Pan-Pleurodira, and Pan- Cryptodira can be traced back to the Middle Jurassic of Euramerica, Gondwana, and Asia, respectively, which resulted from the primary break up of Pangaea at that time. The two primary lineages of Pleurodira, Pan-Pelomedusoides and Pan-Chelidae, can similarly be traced back to the Cretaceous of northern and southern Gondwana, respectively, which were separated from one another by a large desert zone during that time. The primary divergence of crown turtles was therefore driven by vicariance to the primary freshwater aquatic habitat of these lineages. The temporally persistent lineages of basal turtles, Helochelydridae, Meiolaniformes, Sichuanchelyidae, can similarly be traced back to the Late Mesozoic of Euramerica, southern Gondwana, and Asia. Given the ambiguous phylogenetic relationships of these three lineages, it is unclear if their diversification was driven by vicariance as well, or if they display a vicariance-like pattern. The clean, primary signal apparent among early turtles is secondarily obliterated throughout the Late Cretaceous to Recent by extensive dispersal of continental turtles and by multiple invasions of marine habitats

Climate-mediated diversification of turtles in the Cretaceous

The file attached is the published version of the article

Influence of arthritis and non-arthritis related factors on areal bone mineral density (BMDa) in women with longstanding inflammatory polyarthritis: a primary care based inception cohort

<p>Abstract</p> <p>Background</p> <p>The aim of this analysis was to determine the relative influence of disease and non-disease factors on areal bone mineral density (BMD_a) in a primary care based cohort of women with inflammatory polyarthritis.</p> <p>Methods</p> <p>Women aged 16 years and over with recent onset inflammatory polyarthritis were recruited to the Norfolk Arthritis Register (NOAR) between 1990 and 1993. Subjects were examined at both baseline and follow up for the presence of tender, swollen and deformed joints. At the 10^thanniversary visit, a sub-sample of women were invited to complete a bone health questionnaire and attend for BMD_a(Hologic, QDR 4000). Linear regression was used to examine the association between BMD_awith both (i) arthritis-related factors assessed at baseline and the 10^thanniversary visit and (ii) standard risk factors for osteoporosis. Adjustments were made for age.</p> <p>Results</p> <p>108 women, mean age 58.0 years were studied. Older age, decreasing weight and BMI at follow up were all associated with lower BMD_aat both the spine and femoral neck. None of the lifestyle factors were linked. Indices of joint damage including 10^thanniversary deformed joint count and erosive joint count were the arthritis-related variables linked with a reduction in BMD_aat the femoral neck. By contrast, disease activity as determined by the number of tender and or swollen joints assessed both at baseline and follow up was not linked with BMD_aat either site.</p> <p>Conclusion</p> <p>Cumulative disease damage was the strongest predictor of reduced femoral bone density. Other disease and lifestyle factors have only a modest influence.</p

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

Late Replicating Domains Are Highly Recombining in Females but Have Low Male Recombination Rates: Implications for Isochore Evolution

In mammals sequences that are either late replicating or highly recombining have high rates of evolution at putatively neutral sites. As early replicating domains and highly recombining domains both tend to be GC rich we a priori expect these two variables to covary. If so, the relative contribution of either of these variables to the local neutral substitution rate might have been wrongly estimated owing to covariance with the other. Against our expectations, we find that sex-averaged recombination rates show little or no correlation with replication timing, suggesting that they are independent determinants of substitution rates. However, this result masks significant sex-specific complexity: late replicating domains tend to have high recombination rates in females but low recombination rates in males. That these trends are antagonistic explains why sex-averaged recombination is not correlated with replication timing. This unexpected result has several important implications. First, although both male and female recombination rates covary significantly with intronic substitution rates, the magnitude of this correlation is moderately underestimated for male recombination and slightly overestimated for female recombination, owing to covariance with replicating timing. Second, the result could explain why male recombination is strongly correlated with GC content but female recombination is not. If to explain the correlation between GC content and replication timing we suppose that late replication forces reduced GC content, then GC promotion by biased gene conversion during female recombination is partly countered by the antagonistic effect of later replicating sequence tending increase AT content. Indeed, the strength of the correlation between female recombination rate and local GC content is more than doubled by control for replication timing. Our results underpin the need to consider sex-specific recombination rates and potential covariates in analysis of GC content and rates of evolution

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

Lawson criterion for ignition exceeded in an inertial fusion experiment

For more than half a century, researchers around the world have been engaged in attempts to achieve fusion ignition as a proof of principle of various fusion concepts. Following the Lawson criterion, an ignited plasma is one where the fusion heating power is high enough to overcome all the physical processes that cool the fusion plasma, creating a positive thermodynamic feedback loop with rapidly increasing temperature. In inertially confined fusion, ignition is a state where the fusion plasma can begin "burn propagation" into surrounding cold fuel, enabling the possibility of high energy gain. While "scientific breakeven" (i.e., unity target gain) has not yet been achieved (here target gain is 0.72, 1.37 MJ of fusion for 1.92 MJ of laser energy), this Letter reports the first controlled fusion experiment, using laser indirect drive, on the National Ignition Facility to produce capsule gain (here 5.8) and reach ignition by nine different formulations of the Lawson criterion