Subduction controls of Hf and Nd isotopes in lavas of the Aleutian island arc

The Hf and Nd isotopic compositions of 71 Quaternary lavas collected from locations along the full length of the Aleutian island arc are used to constrain the sources of Aleutian magmas and to provide insight into the geochemical behavior of Nd and Hf and related elements in the Aleutian subduction-magmatic system. Isotopic compositions of Aleutian lavas fall approximately at the center of, and form a trend parallel to, the terrestrial Hf-Nd isotopic array with {var_epsilon}{sub Hf} of +12.0 to +15.5 and {var_epsilon}{sub Nd} of +6.5 to +10.5. Basalts, andesites, and dacites within volcanic centers or in nearby volcanoes generally all have similar isotopic compositions, indicating that there is little measurable effect of crustal or other lithospheric assimilation within the volcanic plumbing systems of Aleutian volcanoes. Hafnium isotopic compositions have a clear pattern of along-arc increase that is continuous from the eastern-most locations near Cold Bay to Piip Seamount in the western-most part of the arc. This pattern is interpreted to reflect a westward decrease in the subducted sediment component present in Aleutian lavas, reflecting progressively lower rates of subduction westward as well as decreasing availability of trench sediment. Binary bulk mixing models (sediment + peridotite) demonstrate that 1-2% of the Hf in Aleutian lavas is derived from subducted sediment, indicating that Hf is mobilized out of the subducted sediment with an efficiency that is similar to that of Sr, Pb and Nd. Low published solubility for Hf and Nd in aqueous subduction fluids lead us to conclude that these elements are mobilized out of the subducted component and transferred to the mantle wedge as bulk sediment or as a silicate melt. Neodymium isotopes also generally increase from east to west, but the pattern is absent in the eastern third of the arc, where the sediment flux is high and increases from east to west, due to the presence of abundant terrigenous sediment in the trench east of the Amlia Fracture Zone, which is being subducting beneath the arc at Seguam Island. Mixing trends between mantle wedge and sediment end members become flatter in Hf-Nd isotope space at locations further west along the arc, indicating that the sediment end member in the west has either higher Nd/Hf or is more radiogenic in Hf compared to Nd. This pattern is interpreted to reflect an increase in pelagic clay relative to the terrigenous subducted sedimentary component westward along the arc. Results of this study imply that Hf does not behave as a conservative element in the Aleutian subduction system, as has been proposed for some other arcs

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Comparison of forces developed by the leg of the rock lobster when walking free or on a treadmill

Clarac F, Cruse H. Comparison of forces developed by the leg of the rock lobster when walking free or on a treadmill. Biological cybernetics. 1982;43(2):109-114

Proposal for an index to classify irrigation water quality: a case study in northeastern Brazil

One way of classifying water quality is by means of indices, in which a series of parameters analyzed are joined a single value, facilitating the interpretation of extensive lists of variables or indicators, underlying the classification of water quality. The objective of this study was to develop a statistically based index to classify water according to the Irrigation Water Quality Index (IWQI), to evaluate the ionic composition of water for use in irrigation and classify it by its source. For this purpose, the database generated during the Technology Generation and Adaptation (GAT) program was used, in which, as of 1988, water samples were collected monthly from water sources in the states of Paraíba, Rio Grande do Norte and Ceará. To evaluate water quality, the electrical conductivity (EC) of irrigation water was taken as a reference, with values corresponding to 0.7 dS m-1. The chemical variables used in this study were: pH, EC, Ca, Mg, Na, K, Cl, HCO3, CO3, and SO4. The data of all characteristics evaluated were standardized and data normality was confirmed by Lilliefors test. Then the irrigation water quality index was determined by an equation that relates the standardized value of the variable with the number of characteristics evaluated. Thus, the IWQI was classified based on indices, considering normal distribution. Finally, these indices were subjected to regression analysis. The method proposed for the IWQI allowed a satisfactory classification of the irrigation water quality, being able to estimate it as a function of EC for the three water sources. Variation in the ionic composition was observed among the three sources and within a single source. Although the water quality differed, it was good in most cases, with the classification IWQI II

Estimativa de carbonato de cálcio aplicado via água de irrigação nas regiões da Chapada do Apodi e Baixo Açu, RN Estimate of the calcium carbonate applied through irrigation water in Chapada do Apodi and Baixo Açu regions of Rio Grande do Norte, Brazil

A aplicação de água com elevados teores de carbonato e bicarbonato pela irrigação, pode contribuir para o aumento do pH dos solos após alguns anos de cultivo. Esse trabalho teve como objetivo avaliar a água de irrigação quanto a seu teor de carbonato e bicarbonato, baseado no conceito do equivalente carbonato de cálcio (E CACO3) da água de irrigação nas regiões da Chapada do Apodi e Baixo Açu no Estado do Rio Grande do Norte. Considerando uma lâmina de irrigação de 400 mm, os resultados mostraram que as águas da região da Chapada do Apodi apresentaram maiores valores de E CACO3 quando comparadas com as água da região do Baixo Açu. Na região da Chapada do Apodi os maiores valores de E CACO3 independente da origem foram para as águas da região de Mossoró, com média de 765 kg ha-1 e o menor valor foi para a região de Grossos e Upanema com 626 kg ha-1. Para a região do Baixo Açu, verifica-se que, independente da origem das águas, a região de Ipanguassu apresentou os maiores valores de E CACO3 com média de 654 kg ha-1, e o menor valor foi para a região de Carnaubais com 580 kg ha-1.<br>The application of irrigation water with high contents of carbonate and bicarbonate can contribute to pH elevation of the soils after some years of cultivation. This study had as its objective the evaluation of the irrigation water with respect to its carbonate and bicarbonate content, based on the concept of the Equivalent Calcium Carbonate (E CACO3) in the region of the Chapada do Apodi and Baixo Açu in the state of Rio Grande do Norte, Brazil. Considering an irrigation water depth of 400 mm, the results showed that the waters of the region of the Chapada do Apodi presented larger values of E CACO3 compared to those of the region of Baixo Açu. In the region of the Chapada do Apodi, independent of the origin, largest values of E CACO3 were found for the waters of the region of Mossoró, with an average of 765 kg ha-1 and the smallest value was observed for Grossos and Upanema with 626 kg ha-1. For the region of Baixo Açu, independent of the origin of the waters, the region of Ipanguassu presented the highest values of E CACO3 with an average of 654 kg ha-1 whereas the smallest values were found for the region of Carnaubais, with 580 kg ha-1

LBA79 - Association between tissue TMB (tTMB) and clinical outcomes with pembrolizumab monotherapy (pembro) in PD-L1-positive advanced NSCLC in the KEYNOTE-010 and -042 trials

In randomized open-label trials, pembro monotherapy demonstrated an OS benefit vs chemo in pts with previously treated (KEYNOTE-010, NCT01905657) or treatment naïve (KEYNOTE-042, NCT02220894), PD-L1+(TPS ≥1%), advanced NSCLC. Associations between tTMB and efficacy were retrospectively explored in a subset of pts with evaluable tTMB in these trials.tTMB was determined by whole exome sequencing of tumor and matched normal DNA. tTMB was evaluable for 253 (24%) pts in KEYNOTE-010 and 793 (62%) pts in KEYNOTE-042. For each study, association of tTMB (continuous log10 scale) with outcomes in each arm was evaluated using Cox proportional hazards models (OS, PFS) and logistic regression (ORR). Statistical significance was determined at the 0.05 level, unadjusted for multiplicity. Clinical utility of tTMB was assessed using a prespecified cutpoint of 175 mut/exome*.Baseline characteristics of the tTMB evaluable subset and total study population were similar. tTMB was not correlated with TPS (continuous score) in both pembro and chemotherapy (chemo) arms (r<0.18). tTMB was associated with OS, PFS and ORR for pembro (pembro arms pooled) in KEYNOTE-010 (1-sided p=0.006, 0.001, 0.009, respectively) and in KEYNOTE-042 (all 1-sided p<0.001); whereas tTMB was in general not associated with outcomes for chemo. In both trials, improvements in OS, PFS and ORR were generally observed for pembro treated pts with high tTMB ≥175 (Table).In this exploratory analysis, associations between higher tTMB levels and improved clinical outcome with pembro monotherapy were observed in pts with PD-L1+ NSCLC. While the results suggest that tTMB may provide additional information regarding the clinical benefit of pembro monotherapy among pts with PD-L1+ NSCLC tumors, the analyses and effect estimates were limited to observational subsets of the randomized cohorts.TableLBA79TableTMB ≥175 Mut/exome*TMB <175 Mut/exome*KEYNOTE-010Pembroa N=81Chemob N=51Pembroa N=83Chemob N=38Median OS (95% CI)14.1 (10.0-19.2)7.6 (5.0-10.7)9.3 (8.3-12.5)7.2 (4.5-14.3)OS HR (95% CI)0.56 (0.38-0.83)0.85 (0.56-1.30)Median PFS (95% CI)4.2 (2.2-10.0)2.4 (2.1-6.0)3.7 (2.1-4.5)3.4 (2.1-7.5)PFS HR (95% CI)0.59 (0.40-0.87)1.09 (0.72-1.63)ORR % (95% CI)23.5 (14.8-34.2)9.8 (3.3-21.4)16.9 (9.5-26.7)21.1 (9.6-37.3)KEYNOTE-042Pembroc N=189Chemod N=165Pembroc N=234Chemod N=214Median OS (95% CI)21.9 (17.0-26.7)11.6 (9.9-14.2)12.0 (9.2-14.8)12.3 (11.3-16.2)OS HR (95% CI)0.62 (0.48-0.80)1.09 (0.88-1.36)Median PFS (95% CI)6.3 (5.5-8.5)6.5 (6.2-8.1)4.1 (3.1-4.3)6.3 (6.1-8.1)PFS HR (95% CI)0.75 (0.59-0.95)1.27 (1.04-1.55)ORR % (95% CI)34.4 (27.5-41.9)30.9 (24.0-38.6)18.8 (14.0-24.4)22.4 (17.0-28.6)*Cutpoint derived by meta-analysis of TMB and gene expression data from pembro clinical trials across multiple tumor types;apembro 10mg/kg (Q3W)+pembro 2mg/kg Q3W;bdocetaxel 75mg/m2 Q3W;cpembro 200mg Q3W;dplatinum-based chemo.KEYNOTE-10 (NCT01905657), originally posted July 23, 2013; KEYNOTE-042 (NCT02220894), originally posted August 20, 2014.Joanne Tomassini of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ USA.Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ USA.Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ USAR.S. Herbst: Advisory / Consultancy: AbbVie Pharmaceuticals; Advisory / Consultancy: ARMO Biosciences; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Biodesix; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly and Company; Advisory / Consultancy: EMD Serrano; Advisory / Consultancy: Genentech/Roche; Advisory / Consultancy: Genmab; Advisory / Consultancy: Heat Biologics; Advisory / Consultancy: Halozyme; Advisory / Consultancy: Loxo Oncology; Advisory / Consultancy, Research grant / Funding (institution): Merck Sharp & Dohme Corp.; Advisory / Consultancy: Nektar; Advisory / Consultancy: NextCure; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Shire PLC; Officer / Board of Directors: Junshi Pharmaceuticals; Advisory / Consultancy: Spectrum Pharmaceuticals; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy: Symphogen; Advisory / Consultancy: Tocagen; Advisory / Consultancy: Tesaro; Advisory / Consultancy: Neon Therapeutics; Advisory / Consultancy: Infinity Pharmaceuticals. G. Lopes: Research grant / Funding (institution): MSD; Research grant / Funding (institution): EMD Serono; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Blueprint Medicines; Research grant / Funding (institution): Tesaro; Research grant / Funding (institution): Bavarian Nordic; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): GI Therapeutics; Honoraria (self), Research grant / Funding (self): Bristol-Myers Squibb; Honoraria (self), Travel / Accommodation / Expenses: Boehringer Ingelheim; Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: ER Squibb Sons, LLC; Travel / Accommodation / Expenses: Janssen; Honoraria (self), Research grant / Funding (self): Merck. D.M. Kowalski: Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Roche; Advisory / Consultancy: Pfizer; Advisory / Consultancy: MSD; Advisory / Consultancy: Bristol-Myers Squibb. M. Nishio: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Ono Pharmaceutical; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Chugai Pharmaceutical; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Taiho Pharmaceutical; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): MSD; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Daiichi Sankyo Healthcare; Advisory / Consultancy: Merck Serono; Research grant / Funding (institution): Astellas. Y. Wu: Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self): Eli Lilly; Honoraria (self): Pierre Fabre; Honoraria (self): Pfizer; Honoraria (self): Sanofi; Advisory / Consultancy: Merck & Co., Inc.. G. de Castro Junior: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Boehringer Ingelheim; Advisory / Consultancy: TEVA; Advisory / Consultancy: Yuhan; Advisory / Consultancy: Merck Serono. P. Baas: Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): MSD; Honoraria (institution), Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Aldeyra Therapeutics; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Theradex. D. Kim: Research grant / Funding (institution): Alpha Biopharma; Research grant / Funding (institution): AstraZeneca/MedImmune; Research grant / Funding (institution): Hanmi; Research grant / Funding (institution): Janssen; Research grant / Funding (institution): Merus; Research grant / Funding (institution): Mirati Therapeutics; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): ONO Pharmaceuticals; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche/Genentech; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): TP Therapeutics; Research grant / Funding (institution): Xcovery; Research grant / Funding (institution): Yuhan. M.A. Gubens: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Beyond Spring; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Genentech/Roche; Advisory / Consultancy: Heron; Advisory / Consultancy: Takeda; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Merck & Co., Inc.; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): OncoMed; Research grant / Funding (institution): Roche. R. Cristescu: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc. D. Aurora-Garg: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc.. A. Al