Systematic Investigation of the Permeability of Androgen Receptor PROTACs

Bifunctional molecules known as PROTACs simultaneously bind an E3 ligase and a protein of interest to direct ubiquitination and clearance of that protein, and they have emerged in the past decade as an exciting new paradigm in drug discovery. In order to investigate the permeability and properties of these large molecules, we synthesized two panels of PROTAC molecules, constructed from a range of protein-target ligands, linkers, and E3 ligase ligands. The androgen receptor, which is a well-studied protein in the PROTAC field was used as a model system. The physicochemical properties and permeability of PROTACs are discussed

Fermi-Dirac statistics and the number theory

We relate the Fermi-Dirac statistics of an ideal Fermi gas in a harmonic trap to partitions of given integers into distinct parts, studied in number theory. Using methods of quantum statistical physics we derive analytic expressions for cumulants of the probability distribution of the number of different partitions.Comment: 7pages, 2 figures, epl.cls, revised versio

Saltmarsh blue carbon accumulation rates and their relationship with sea-level rise on a multi-decadal timescale in northern England

Feldwork and elemental and thermogravimetric analyses were conducted as a part of the NERC funded (NE/R010846/1) Carbon Storage in Intertidal Environments (C-SIDE) project (https://www.c-side.org/).Saltmarshes are widely thought to sequester carbon at rates significantly exceeding those found in terrestrial environments. This ability arises from the in-situ production of plant biomass and the effective trapping and storage of both autochthonous and allochthonous organic carbon. The role saltmarshes play in climate change mitigation, through accumulating ‘blue’ carbon, depends on both the rate at which carbon accumulates within sediments and the rapidity with which carbon is remineralised. It has been hypothesized that carbon accumulation rates, in turn, depend on the local rate of relative sea-level rise, with faster sea-level rise providing more accommodation space for carbon storage. This relationship has been investigated over long (millennial) and short (decadal) timescales but without accounting for the impact of higher quantities of labile carbon in more recently deposited sediment. This study addresses these three key aspects in a saltmarsh sediment study from Lindisfarne National Nature Reserve (NNR), northern England, where there is a comparatively pristine marsh. We quantify rates of carbon accumulation by combining a Bayesian age-depth model based on 210Pb and 137Cs activities with centimetre-resolution organic carbon density measurements. We also use thermogravimetric analyses to determine the relative proportions of labile and recalcitrant organic matter and calculate the net recalcitrant organic matter accumulation rate. Results indicate that during the 20th century more carbon accumulated at the Lindisfarne NNR saltmarsh during decades with relatively high rates of sea-level rise. The post-depositional loss of labile carbon down the core results in a weaker though still significant relationship between recalcitrant organic matter accumulation and sea-level change. Thus, increasing saltmarsh carbon accumulation driven by higher rates of sea-level rise is demonstrated over recent multi-decadal timescales.Peer reviewe

Construction of some missing eigenvectors of the XYZ spin chain at the discrete coupling constants and the exponentially large spectral degeneracy of the transfer matrix

We discuss an algebraic method for constructing eigenvectors of the transfer matrix of the eight vertex model at the discrete coupling parameters. We consider the algebraic Bethe ansatz of the elliptic quantum group $E_{\tau, \eta}(sl_2)$ for the case where the parameter $\eta$ satisfies $2 N \eta = m_1 + m_2 \tau$ for arbitrary integers $N$, $m_1$ and $m_2$. When $m_1$ or $m_2$ is odd, the eigenvectors thus obtained have not been discussed previously. Furthermore, we construct a family of degenerate eigenvectors of the XYZ spin chain, some of which are shown to be related to the $sl_2$ loop algebra symmetry of the XXZ spin chain. We show that the dimension of some degenerate eigenspace of the XYZ spin chain on $L$ sites is given by $N 2^{L/N}$, if $L/N$ is an even integer. The construction of eigenvectors of the transfer matrices of some related IRF models is also discussed.Comment: 19 pages, no figure (revisd version with three appendices

Inverse Estimation of an Annual Cycle of California's Nitrous Oxide Emissions

Nitrous oxide (N_2O) is a potent long‐lived greenhouse gas (GHG) and the strongest current emissions of global anthropogenic stratospheric ozone depletion weighted by its ozone depletion potential. In California, N_2O is the third largest contributor to the state's anthropogenic GHG emission inventory, though no study has quantified its statewide annual emissions through top‐down inverse modeling. Here we present the first annual (2013–2014) statewide top‐down estimates of anthropogenic N_2O emissions. Utilizing continuous N_2O observations from six sites across California in a hierarchical Bayesian inversion, we estimate that annual anthropogenic emissions are 1.5–2.5 times (at 95% confidence) the state inventory (41 Gg N_2O in 2014). Without mitigation, this estimate represents 4–7% of total GHG emissions assuming that other reported GHG emissions are reasonably correct. This suggests that control of N_2O could be an important component in meeting California's emission reduction goals of 40% and 80% below 1990 levels of the total GHG emissions (in CO_2 equivalent) by 2030 and 2050, respectively. Our seasonality analysis suggests that emissions are similar across seasons within posterior uncertainties. Future work is needed to provide source attribution for subregions and further characterization of seasonal variability

Sensitivity of historical climate simulations to uncertain aerosol forcing

The relative importance of anthropogenic aerosol in decadal variations of historical climate is uncertain, largely due to uncertainty in aerosol radiative forcing. We analyse a novel large ensemble of simulations with HadGEM3-GC3.1 for 1850-2014, where anthropogenic aerosol and precursor emissions are scaled to sample a wide range of historical aerosol radiative forcing with present-day values ranging from -0.38 to -1.50 Wm-2. Five ensemble members are run for each of five aerosol scaling factors. Decadal variations in surface temperatures are strongly sensitive to aerosol forcing, particularly between 1950 and 1980. Post-1980, trends are dominated by greenhouse-gas forcing, with much lower sensitivity to aerosol emission differences. Most realisations with aerosol forcing more negative than about -1 Wm-2 simulate stronger cooling trends in the mid-twentieth century compared to observations, while the simulated warming post-1980 always exceeds observed warming, likely due to a warm bias in the Transient Climate Response in HadGEM3-GC3.1

Evaluation and Treatment in Urology for Nocturia Caused by Nonurological Mechanisms:Guidance from the PLANET Study

Patients with nocturia are commonly referred to urology clinics, including many for whom a nonurological medical condition is responsible for their symptoms. The PLanning Appropriate Nocturia Evaluation and Treatment (PLANET) study was established to develop practical approaches to equip healthcare practitioners to deal with the diverse causes of nocturia, based on systematic reviews and expert consensus. Initial assessment and therapy need to consider the possibility of one or more medical conditions falling into the “SCREeN” areas of Sleep medicine (insomnia, periodic limb movements of sleep, parasomnias, and obstructive sleep apnoea), Cardiovascular (hypertension and congestive heart failure), Renal (chronic kidney disease), Endocrine (diabetes mellitus, thyroid disease, pregnancy/menopause, and diabetes insipidus), and Neurology. Medical and medication causes of xerostomia should also be considered. Some key indicators for these conditions can be identified in urology clinics, working in partnership with the primary care provider. Therapy of the medical condition in some circumstances lessens the severity of nocturia. However, in many cases there is a conflict between the two, in which case the medical condition generally takes priority on safety grounds. It is important to provide patients with a realistic expectation of therapy and awareness of limitations of current therapeutic options for nocturia.Patient summaryNocturia is the symptom of waking at night to pass urine. Commonly, this problem is referred to urology clinics. However, in some cases, the patient does not have a urological condition but actually a condition from a different speciality of medicine. This article describes how best the urologist and the primary care doctor can work together to assess the situation and make sensible and safe treatment suggestions. Unfortunately, there is sometimes no safe or effective treatment choice for nocturia, and treatment needs to focus instead on supportive management of symptoms

Lifetime economic impact of the burden of childhood stunting attributable to maternal psychosocial risk factors in 137 low/middle-income countries

Introduction: The first 1000 days of life is a period of great potential and vulnerability. In particular, physical growth of children can be affected by the lack of access to basic needs as well as psychosocial factors, such as maternal depression. The objectives of the present study are to: (1) quantify the burden of childhood stunting in low/middle-income countries attributable to psychosocial risk factors; and (2) estimate the related lifetime economic costs. Methods: A comparative risk assessment analysis was performed with data from 137 low/middle-income countries throughout Asia, Latin America and the Caribbean, North Africa and the Middle East, and sub-Saharan Africa. The proportion of stunting prevalence, defined as <-2 SDs from the median height for age according to the WHO Child Growth Standards, and the number of cases attributable to low maternal education, intimate partner violence (IPV), maternal depression and orphanhood were calculated. The joint effect of psychosocial risk factors on stunting was estimated. The economic impact, as reflected in the total future income losses per birth cohort, was examined. Results: Approximately 7.2 million cases of stunting in low/middle-income countries were attributable to psychosocial factors. The leading risk factor was maternal depression with 3.2 million cases attributable. Maternal depression also demonstrated the greatest economic cost at $14.5 billion, followed by low maternal education ($10.0 billion) and IPV ($8.5 billion). The joint cost of these risk factors was$29.3 billion per birth cohort. Conclusion: The cost of neglecting these psychosocial risk factors is significant. Improving access to formal secondary school education for girls may offset the risk of maternal depression, IPV and orphanhood. Focusing on maternal depression may play a key role in reducing the burden of stunting. Overall, addressing psychosocial factors among perinatal women can have a significant impact on child growth and well-being in the developing world

Global meteorological influences on the record UK rainfall of winter 2013-14

The UK experienced record average rainfall in winter 2013–14, leading to widespread and prolonged flooding. The immediate cause of this exceptional rainfall was a very strong and persistent cyclonic atmospheric circulation over the North East Atlantic Ocean. This was related to a very strong North Atlantic jet stream which resulted in numerous damaging wind storms. These exceptional meteorological conditions have led to renewed questions about whether anthropogenic climate change is noticeably influencing extreme weather. The regional weather pattern responsible for the extreme UK winter coincided with highly anomalous conditions across the globe. We assess the contributions from various possible remote forcing regions using sets of ocean–atmosphere model relaxation experiments, where winds and temperatures are constrained to be similar to those observed in winter 2013–14 within specified atmospheric domains. We find that influences from the tropics were likely to have played a significant role in the development of the unusual extra-tropical circulation, including a role for the tropical Atlantic sector. Additionally, a stronger and more stable stratospheric polar vortex, likely associated with a strong westerly phase of the stratospheric Quasi-Biennial Oscillation (QBO), appears to have contributed to the extreme conditions. While intrinsic climatic variability clearly has the largest effect on the generation of extremes, results from an analysis which segregates circulation-related and residual rainfall variability suggest that emerging climate change signals made a secondary contribution to extreme rainfall in winter 2013–14