Geochemical response of the mid-depth Northeast Atlantic Ocean to freshwater input during Heinrich events 1 to 4

PublishedArticleHeinrich events are intervals of rapid iceberg-sourced freshwater release to the high latitude North Atlantic Ocean that punctuate late Pleistocene glacials. Delivery of fresh water to the main North Atlantic sites of deep water formation during Heinrich events may result in major disruption to the Atlantic Meridional Overturning Circulation (AMOC), however, the simple concept of an AMOC shutdown in response to each freshwater input has recently been shown to be overly simplistic. Here we present a new multi-proxy dataset spanning the last 41,000 years that resolves four Heinrich events at a classic mid-depth North Atlantic drill site, employing four independent geochemical tracers of water mass properties: boron/calcium, carbon and oxygen isotopes in foraminiferal calcite and neodymium isotopes in multiple substrates. We also report rare earth element distributions to investigate the fidelity by which neodymium isotopes record changes in water mass distribution in the northeast North Atlantic. Our data reveal distinct geochemical signatures for each Heinrich event, suggesting that the sites of fresh water delivery and/or rates of input played at least as important a role as the stage of the glacial cycle in which the fresh water was released. At no time during the last 41 kyr was the mid-depth northeast North Atlantic dominantly ventilated by southern-sourced water. Instead, we document persistent ventilation by Glacial North Atlantic Intermediate Water (GNAIW), albeit with variable properties signifying changes in supply from multiple contributing northern sources.This research used samples provided by the Integrated Ocean Drilling (Discovery) Program IODP, which is sponsored by the US National Science Foundation and participating countries under management of Joint Oceanographic Institutions, Inc. We thank Walter Hale and Alex Wülbers for help with sampling, Kirsty Crocket for providing additional samples and Matt Cooper, Andy Milton, Mike Bolshaw and Dave Spanner for analytical support. Heiko Pälike, David Thornalley and Rachel Mills are thanked for productive discussions and comments on earlier versions of this work. We also thank three anonymous reviewers for their constructive feedback, which greatly improved the manuscript. Funding for this project was provided by NERC studentships to A.J.C. (grant NE/D005728/2) and T.B.C. (NE/I528626/1), with additional funding support from a Royal Society Wolfson Research Merit Award and NERC grants NE/F00141X/1 and NE/I006168/1 to P.A.W. and NE/D00876X/2 to G.L.F

Pleiotropic Associations of Risk Variants Identified for Other Cancers With Lung Cancer Risk: The PAGE and TRICL Consortia

BackgroundGenome-wide association studies have identified hundreds of genetic variants associated with specific cancers. A few of these risk regions have been associated with more than one cancer site; however, a systematic evaluation of the associations between risk variants for other cancers and lung cancer risk has yet to be performed.MethodsWe included 18023 patients with lung cancer and 60543 control subjects from two consortia, Population Architecture using Genomics and Epidemiology (PAGE) and Transdisciplinary Research in Cancer of the Lung (TRICL). We examined 165 single-nucleotide polymorphisms (SNPs) that were previously associated with at least one of 16 non–lung cancer sites. Study-specific logistic regression results underwent meta-analysis, and associations were also examined by race/ethnicity, histological cell type, sex, and smoking status. A Bonferroni-corrected P value of 2.5×10–5 was used to assign statistical significance.ResultsThe breast cancer SNP LSP1 rs3817198 was associated with an increased risk of lung cancer (odds ratio [OR] = 1.10; 95% confidence interval [CI] = 1.05 to 1.14; P = 2.8×10–6). This association was strongest for women with adenocarcinoma (P = 1.2×10–4) and not statistically significant in men (P = .14) with this cell type (P het by sex = .10). Two glioma risk variants, TERT rs2853676 and CDKN2BAS1 rs4977756, which are located in regions previously associated with lung cancer, were associated with increased risk of adenocarcinoma (OR = 1.16; 95% CI = 1.10 to 1.22; P = 1.1×10–8) and squamous cell carcinoma (OR = 1.13; CI = 1.07 to 1.19; P = 2.5×10–5), respectively.ConclusionsOur findings demonstrate a novel pleiotropic association between the breast cancer LSP1 risk region marked by variant rs3817198 and lung cancer risk

Most neutralizing human monoclonal antibodies target novel epitopes requiring both Lassa virus glycoprotein subunits

Lassa fever is a severe multisystem disease that often has haemorrhagic manifestations. The epitopes of the Lassa virus (LASV) surface glycoproteins recognized by naturally infected human hosts have not been identified or characterized. Here we have cloned 113 human monoclonal antibodies (mAbs) specific for LASV glycoproteins from memory B cells of Lassa fever survivors from West Africa. One-half bind the GP2 fusion subunit, one-fourth recognize the GP1 receptor-binding subunit and the remaining fourth are specific for the assembled glycoprotein complex, requiring both GP1 and GP2 subunits for recognition. Notably, of the 16 mAbs that neutralize LASV, 13 require the assembled glycoprotein complex for binding, while the remaining 3 require GP1 only. Compared with non-neutralizing mAbs, neutralizing mAbs have higher binding affinities and greater divergence from germline progenitors. Some mAbs potently neutralize all four LASV lineages. These insights from LASV human mAb characterization will guide strategies for immunotherapeutic development and vaccine design

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Reducing the Affective Filter: Using Canine Assisted Therapy to Support International University Students’ English Language Development

This exploratory mixed-methods study examined the influence of an on-campus canine therapy program on linguistically diverse international students’ perceptions of their English language development and stress. Participants were recruited from English language support classes at a mid-size western Canadian university and were randomly selected from a larger pool of participants indicating interest in the study. Seven participants attended five canine therapy sessions in which they interacted with certified therapy dogs working as part of a campus initiative to reduce stress and homesickness on campus. Both formative and summative data collection was done with students completing weekly stress assessments, responding to summative questions asked in an interview, and elaborating on their views in a focus group discussion. The following key themes emerged with students describing: 1) decreased overall stress; 2) improvements in their sense of belonging in the campus community with dogs as social catalysts; and 3) increased opportunities to practice oral language skills through interactions with dog handlers and fellow students in the lab. Implications are discussed within the context of reducing the affective filter for language learners and increasing accessibility to programs for international students

Monoclonal antibody therapy demonstrates increased virulence of a lineage VII strain of Lassa virus in nonhuman primates

ABSTRACTLassa virus (LASV) is a World Health Organization (WHO) priority pathogen that causes high morbidity and mortality. Recently, we showed that a combination of three broadly neutralizing human monoclonal antibodies known as Arevirumab-3 (8.9F, 12.1F, 37.2D) based on the lineage IV Josiah strain protected 100% of cynomolgus macaques against heterologous challenge with lineage II and III strains of LASV when therapy was initiated beginning at day 8 after challenge. LASV strains from Benin and Togo represent a new lineage VII that are more genetically diverse from lineage IV than strains from lineages II and III. Here, we tested the ability of Arevirumab-3 to protect macaques against a LASV lineage VII Togo isolate when treatment was administered beginning 8 days after exposure. Unexpectedly, only 40% of treated animals survived challenge. In a subsequent study we showed that Arevirumab-3 protected 100% of macaques from lethal challenge when treatment was initiated 7 days after LASV Togo exposure. Based on our transcriptomics data, successful Arevirumab-3 treatment correlated with diminished neutrophil signatures and the predicted development of T cell responses. As the in vitro antiviral activity of Arevirumab-3 against LASV Togo was equivalent to lineage II and III strains, the reduced protection in macaques against Togo likely reflects the faster disease course of LASV Togo in macaques than other strains. This data causes concern regarding the ability of heterologous vaccines and treatments to provide cross protection against lineage VII LASV isolates