Hydrothermal oxide and nontronite deposits at Seamount 3, Wolf-Darwin lineament, Galapagos Archipelago, Ecuador

An unusual deposit of Fe-rich hydrothermal nontronite was recovered by remotely operated vehicle (ROV) from Seamount 3 of the Wolf-Darwin lineament, Galapagos Marine Reserve. X-ray diffraction, ICP-MS/ICP-AES, and SEM-EDS analyses show that this deposit is chemically and mineralogically similar to other deep-sea hydrothermal nontronites, indicating a formation temperature of about 30o to 50o Celsius. These Fe-Si-oxides and Fe-rich Al-poor nontronite deposits contain about 38-51 weight % SiO2 and 40-50 weight % Fe2O3. Although hydrothermal nontronite has been sampled at a number of sites by coring and dredging, this is the first in situ documentation of its sinuous, tubular structure on the sea floor. Image-analysis of ROV imagery suggests that this unusual pattern might be controlled by fluid pathways in the underlying pillow lavas

Comparison of threshold hydrologic response across northern catchments

Funded by Leverhulme Trust. Grant Number: F/00 152/AGPeer reviewedPostprin

Characterization of Vascular Disease Risk in Postmenopausal Women and Its Association with Cognitive Performance

Objectives: While global measures of cardiovascular (CV) risk are used to guide prevention and treatment decisions, these estimates fail to account for the considerable interindividual variability in pre-clinical risk status. This study investigated heterogeneity in CV risk factor profiles and its association with demographic, genetic, and cognitive variables. Methods: A latent profile analysis was applied to data from 727 recently postmenopausal women enrolled in the Kronos Early Estrogen Prevention Study (KEEPS). Women were cognitively healthy, within three years of their last menstrual period, and free of current or past CV disease. Education level, apolipoprotein E ε4 allele (APOE4), ethnicity, and age were modeled as predictors of latent class membership. The association between class membership, characterizing CV risk profiles, and performance on five cognitive factors was examined. A supervised random forest algorithm with a 10-fold cross-validation estimator was used to test accuracy of CV risk classification. Results: The best-fitting model generated two distinct phenotypic classes of CV risk 62% of women were “low-risk” and 38% “high-risk”. Women classified as low-risk outperformed high-risk women on language and mental flexibility tasks (p = 0.008) and a global measure of cognition (p = 0.029). Women with a college degree or above were more likely to be in the low-risk class (OR = 1.595, p = 0.044). Older age and a Hispanic ethnicity increased the probability of being at high-risk (OR = 1.140, p = 0.002; OR = 2.622, p = 0.012; respectively). The prevalence rate of APOE-ε4 was higher in the high-risk class compared with rates in the low-risk class. Conclusion: Among recently menopausal women, significant heterogeneity in CV risk is associated with education level, age, ethnicity, and genetic indicators. The model-based latent classes were also associated with cognitive function. These differences may point to phenotypes for CV disease risk. Evaluating the evolution of phenotypes could in turn clarify preclinical disease, and screening and preventive strategies

Human observations of late Quaternary coastal change: examples from Australia, Europe and the Pacific Islands

In the aftermath of the last ice age, when sea level rose along most of the world's coastline, the activities of coastal peoples were impacted by coastal submergence, land loss and sometimes isolation as offshore islands formed. In some parts of the world, there is clear evidence that people encoded their observations of postglacial sea-level rise into oral traditions that were communicated across hundreds of generations to reach us today in an intelligible form. In other contexts, people's observations of rising sea level are likely to have formed the foundations of ‘legends’ about undersea places and the peoples inhabiting them. For a selection of coastal sites in Australia and northwest Europe, this study discusses a range of contrasting situations in which culturally-grounded stories about coastal submergence, land loss and isolation plausibly recollect the nature and effects of postglacial sea-level rise. Using science-based histories of postglacial sea-level change, minimum ages are determined for each group of site-specific stories; in the case of Australia, these range from 7000–11,500 BP, for northwest Europe from 5500 to 9500 BP. For selected sites in the Pacific Islands, where human settlement about 3000 years BP post-dated the end of postglacial sea-level rise, localized submergence is recalled in traditional stories of local people. It is argued that studies of late Quaternary coastal evolution can often be filled out by adding details from stories preserved in local cultures, something which leads to a clearer picture of the human-societal impacts of coastal submergence and land loss than can be obtained from palaeoenvironmental reconstructions and geological evidence alone

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

A first update on mapping the human genetic architecture of COVID-19

peer reviewe

Novel Nucleotide Human Immunodeficiency Virus Reverse Transcriptase Inhibitor GS-9148 with a Low Nephrotoxic Potential: Characterization of Renal Transport and Accumulation▿

Accumulation of antiviral nucleotides in renal proximal tubules is controlled by their basolateral uptake via the human renal organic anion transporters type 1 (hOAT1) and 3 (hOAT3) and apical efflux via the multidrug resistance protein 4 (MRP4). GS-9148 is a novel ribose-modified nucleotide human immunodeficiency virus (HIV) reverse transcriptase inhibitor, and its oral prodrug GS-9131 is currently being evaluated in the clinic as an anti-HIV agent. To assess the potential of GS-9148 for nephrotoxicity, its mechanism of renal transport, cytotoxicity, and renal accumulation were explored in vitro and in vivo. In comparison with the acyclic nucleotides cidofovir, adefovir, and tenofovir, GS-9148 showed 60- to 100-fold lower efficiency of transport (Vmax/Km) by hOAT1 and was 20- to 300-fold less cytotoxic in cells overexpressing hOAT1, indicating its lower hOAT1-mediated intracellular accumulation and reduced intrinsic cytotoxicity. GS-9148 was also relatively inefficiently transported by hOAT3. Similar to acyclic nucleotides, GS-9148 was a substrate for MRP4 as evidenced by its reduced intracellular retention in cells overexpressing the efflux pump. Consistent with these molecular observations, GS-9148 was inefficiently taken up by fresh human renal cortex tissue in vitro and showed a limited accumulation in kidneys in vivo following oral administration of [14C]GS-9131 to dogs. Compared to acyclic nucleotide analogs, GS-9148 was also found to have lower net active tubular secretion in dogs. Collectively, these results suggest that GS-9148 exhibits a low potential for renal accumulation and nephrotoxicity

CCL2 Promotes Colorectal Carcinogenesis by Enhancing Polymorphonuclear Myeloid-Derived Suppressor Cell Population and Function

Our study reveals a non-canonical role for CCL2 in modulating non-macrophage, myeloid-derived suppressor cells (MDSCs) and shaping a tumor-permissive microenvironment during colon cancer development. We found that intratumoral CCL2 levels increased in patients with colitis-associated colorectal cancer (CRC), adenocarcinomas, and adenomas. Deletion of CCL2 blocked progression from dysplasia to adenocarcinoma and reduced the number of colonic MDSCs in a spontaneous mouse model of colitis-associated CRC. In a transplantable mouse model of adenocarcinoma and an APC-driven adenoma model, CCL2 fostered MDSC accumulation in evolving colonic tumors and enhanced polymorphonuclear (PMN)-MDSC immunosuppressive features. Mechanistically, CCL2 regulated T cell suppression of PMN-MDSCs in a STAT3-mediated manner. Furthermore, CCL2 neutralization decreased tumor numbers and MDSC accumulation and function. Collectively, our experiments support that perturbing CCL2 and targeting MDSCs may afford therapeutic opportunities for colon cancer interception and prevention

Comparison of threshold hydrologic response across northern catchments

Nine mid-latitude to high-latitude headwater catchments – part of the Northern Watershed Ecosystem Response to Climate Change (North-Watch) programme – were used to analyze threshold response to rainfall and snowmelt-driven events and link the different responses to the catchment characteristics of the nine sites. The North-Watch data include daily time-series of various lengths of multiple variables such as air temperature, precipitation and discharge. Rainfall and meltwater inputs were differentiated using a degree-day snowmelt approach. Distinct hydrological events were identified, and precipitation-runoff response curves were visually assessed. Results showed that eight of nine catchments showed runoff initiation thresholds and effective precipitation input thresholds. For rainfall-triggered events, catchment hydroclimatic and physical characteristics (e.g. mean annual air temperature, median flow path distance to the stream, median sub-catchment area) were strong predictors of threshold strength. For snowmelt-driven events, however, thresholds and the factors controlling precipitation-runoff response were difficult to identify. The variability in catchments responses to snowmelt was not fully explained by runoff initiation thresholds and input magnitude thresholds. The quantification of input intensity thresholds (e.g. snow melting and permafrost thawing rates) is likely required for an adequate characterization of nonlinear spring runoff generation in such northern environments

Analysis of hydrological seasonality across northern catchments using monthly precipitation–runoff polygon metrics

Seasonality is an important hydrological signature for catchment comparison. Here, the relevance of monthly precipitation–runoff polygons (defined as scatter points of 12 monthly average precipitation–runoff value pairs connected in the chronological monthly sequence) for characterizing seasonality patterns was investigated to describe the hydrological behaviour of 10 catchments spanning a climatic gradient across the northern temperate region. Specifically, the research objectives were to: (a) discuss the extent to which monthly precipitation–runoff polygons can be used to infer active hydrological processes in contrasting catchments; (b) test the ability of quantitative metrics describing the shape, orientation and surface area of monthly precipitation–runoff polygons to discriminate between different seasonality patterns; and (c) examine the value of precipitation–runoff polygons as a basis for catchment grouping and comparison. This study showed that some polygon metrics were as effective as monthly average runoff coefficients for illustrating differences between the 10 catchments. The use of precipitation–runoff polygons was especially helpful to look at the dynamics prevailing in specific months and better assess the coupling between precipitation and runoff and their relative degree of seasonality. This polygon methodology, linked with a range of quantitative metrics, could therefore provide a new simple tool for understanding and comparing seasonality among catchments