2'-O-(2-methoxyethyl) nucleosides are not phosphorylated or incorporated into the genome of Human Lymphoblastoid TK6 Cells

Nucleoside analogues with 2'-modified sugar moieties are often used to improve the RNA target affinity and nuclease resistance of therapeutic oligonucleotides in preclinical and clinical development. Despite their enhanced nuclease resistance, oligonucleotides could slowly degrade releasing nucleoside analogues that have the potential to become phosphorylated and incorporated into cellular DNA and RNA. For the first time, the phosphorylation and DNA and RNA incorporation of 2'-O-(2-methoxyethyl) (2'-O-MOE) nucleoside analogues have been investigated. Using LC/MS/MS, we showed that enzymes in the nucleotide salvage pathway including deoxycytidine kinase (dCK) and thymidine kinase (TK1) displayed poor reactivity toward 2'-O-MOE nucleoside analogues. On the other hand, 2'-fluoro (F) nucleosides, regardless of the nucleobase, were efficiently phosphorylated to their monophosphate forms by dCK and TK1. Consistent with their efficient phosphorylation by dCK and TK1, 2'-F nucleosides analogues were incorporated into cellular DNA and RNA while no incorporation was detected with 2'-O-MOE nucleoside analogues. In conclusion, these data suggest that the inability of dCK and TK1 to create the monophosphates of 2'-O-MOE nucleoside analogues reduces the risk of their incorporation into cellular DNA and RNA

Stime di emissioni di inquinanti provenienti da sorgenti di traffico nell’area veneziana.

Purpose: Wnt signalling has been implicated in breast cancer, and in particular aberrant β-catenin-independent Wnt signalling has been associated with breast cancer metastasis and Tamoxifen resistance. Despite Wnt pathway involvement in many human cancers, attempts to target the pathway therapeutically have been disappointing. The recent discovery that the receptor tyrosine kinase-like orphan receptor 2 (ROR2) is a novel Wnt receptor provides a potential new therapeutic and diagnostic target

Decomposing the drivers of polar amplification with a single-column model

This is the final version. Available from the American Meteorological Society via the DOI in this record. The code and data needed to reproduce all figures, tables, and supplemental figures are available at https:// github.com/matthewjhenry/HMLR19_SCM. Documentation for the Python ClimLab package can be found at https://climlab. readthedocs.io/. The top-of-atmosphere albedo data from the Cloud and the Earth’s Radiant Energy System (CERES) can be found at https://ceres.larc.nasa.gov/. The CMIP6 data are available on the Earth System Grid Federation database. TThe precise mechanisms driving Arctic amplification are still under debate. Previous attribution methods compute the vertically uniform temperature change required to balance the top-of-atmosphere energy imbalance caused by each forcing and feedback, with any departures from vertically uniform warming collected into the lapse-rate feedback. We propose an alternative attribution method using a single-column model that accounts for the forcing dependence of high-latitude lapse-rate changes. We examine this method in an idealized general circulation model (GCM), finding that, even though the column-integrated carbon dioxide (CO2) forcing and water vapor feedback are stronger in the tropics, they contribute to polar-amplified surface warming as they produce bottom-heavy warming in high latitudes. A separation of atmospheric temperature changes into local and remote contributors shows that, in the absence of polar surface forcing (e.g., sea ice retreat), changes in energy transport are primarily responsible for the polar-amplified pattern of warming. The addition of surface forcing substantially increases polar surface warming and reduces the contribution of atmospheric dry static energy transport to the warming. This physically based attribution method can be applied to comprehensive GCMs to provide a clearer view of the mechanisms behind Arctic amplification.Natural Sciences and Engineering Research Council of CanadaNational Science Foundation (USA

Variation in excess all-cause mortality by age, sex, and province during the first wave of the COVID-19 pandemic in Italy.

Although previous evidence suggests that the infection fatality rate from COVID-19 varies by age and sex, and that transmission intensity varies geographically within countries, no study has yet explored the age-sex-space distribution of excess mortality associated with the COVID pandemic. By applying the principles of small-area estimation to existing model formulations for excess mortality, this study develops a novel method for assessing excess mortality across small populations and assesses the pattern of COVID excess mortality by province, year, week, age group, and sex in Italy from March through May 2020. We estimate that 53,200 excess deaths occurred across Italy during this time period, compared to just 35,500 deaths where COVID-19 was registered as the underlying cause of death. Out of the total excess mortality burden, 97% of excess deaths occurred among adults over age 60, and 68% of excess deaths were concentrated among adults over age 80. The burden of excess mortality was unevenly distributed across the country, with just three of Italy's 107 provinces accounting for 32% of all excess mortality. This method for estimating excess mortality can be adapted to other countries where COVID-19 diagnostic capacity is still insufficient, and could be incorporated into public health rapid response systems

State‐Dependence of the Equilibrium Climate Sensitivity in a Clear‐Sky GCM

This is the final version. Available on open access from Wiley via the DOI in this recordData Availability Statement: The code to reproduce the figures is available at Henry (2023b) and the data is available at Henry (2023a).The climate sensitivity peaks around 310 K in a wide variety of climate models, ranging from idealized single column models to fully comprehensive climate models. Here, we increase CO2 using a clear-sky three-dimensional atmospheric model with a radiation scheme which maintains accuracy for high CO2 and temperature levels. In contrast, the Equilibrium Climate Sensitivity (ECS) of our model plateaus around 310 K. We show that this is due to the moistening of the subtropical regions caused by a slowdown in atmospheric circulation, which increases the ECS at very high CO2 values. When relative humidity is fixed, the ECS peak is consistent with single column model results. This work does not rule out that clouds or other complex processes impact the ECS in comprehensive climate models. Though the changes in CO2 here are extreme, this study underlines the importance of changes in atmospheric circulation and relative humidity in quantitative assessments of climate sensitivity.Natural Environment Research Council (NERC)NOAA Climate Program Offic

The influence of rs53576 polymorphism in the oxytocin receptor (OXTR) gene on empathy in healthy adults by subtype and ethnicity: a systematic review and meta-analysis

Empathy is essential for navigating complex social environments. Prior work has shown associations between rs53576, a single nucleotide polymorphism (SNP) located in the oxytocin receptor gene (OXTR), and generalized empathy. We undertook a systematic review and meta-analysis to assess the effects of rs53576 on subdomains of empathy, specifically cognitive empathy (CE) and affective empathy (AE), in healthy adults. Twenty cohorts of 8933 participants aged 18-98 were identified, including data from the Sydney Memory and Ageing Study, a cohort of older community adults. Meta-analyses found G homozygotes had greater generalized empathic abilities only in young to middle-aged adults. While meta-analyses of empathy subdomains yielded no significant overall effects, there were differential effects based on ethnicity. G homozygotes were associated with greater CE abilities in Asian cohorts (standardized mean difference; SMD: 0.09 [2.8·10-3-0.18]), and greater AE performance in European cohorts [SMD: 0.12 (0.04-0.21)]. The current literature highlights a need for further work that distinguishes between genetic and ethnocultural effects and explores effects of advanced age on this relationship