Evidence for excess pore pressures in southwest Indian Ocean sediments

Brown clay cores from the Madagascar and Crozet basins show the following evidence of excess pore pressures: large amounts of flow-in, increasing average sedimentation rate with age, and nonlinear temperature gradients. Additionally, many hilltops in these basins have no visible sediment cover. The bare hilltops may result from periodic slumping caused by excess pore pressures. Calculated excess pore pressures which equal or exceed the overburden pressure were inferred from water fluxes predicted by nonlinear temperature gradients and laboratory permeability measurements by using Darcy's law. Since pore pressures which exceed the overburden pressure are unreasonable, we attribute this discrepancy to laboratory measurements which underestimate the in situ permeability. The widespread presence of overpressured sediments in areas of irregular topography provides a process for resuspension of clay-sized particles. This mechanism does not require high current velocities for the erosion of clay and therefore can be applied to many areas where no strong currents are evident. Carbonate-rich sediments from the Madagascar Ridge, the Mozambique Ridge, and the Agulhas Plateau had almost no flow-in and occurred in areas where all topography was thickly draped with sediment. Since the age and tectonic location of the ridges and plateaus preclude water circulation in the basement, we attribute these differences between the brown clay and the carbonate-rich material to an absence of significant excess pore pressures in the plateau and ridge sediments

Correlated sediment thickness, temperature gradient and excess pore pressure in a marine fault block basin

Measurements of temperature gradient and excess pore pressure in the surficial sediment of a fault block basin in the Guatemala Basin correlate with sediment thickness. The temperature gradient is smaller and the excess pore pressure gradient is more negative in areas of thinner sediment. This correlation is explained by postulating downward pore water advection within the sediments, with flow velocities on the order of 10−9 to 10−8 m/s in the thinnest sediments and much less flow in the thickest sediments. Sediment physical properties and pore water chemistry also support this interpretation. Since the conductive heat flow of the basin as a whole is less than one third that predicted by sea floor spreading models, the oceanic basement may be the site of a vigorous hydrothermal circulation system. The pore water advection in the sediments may be driven by this larger scale circulation

Discovery of common and rare genetic risk variants for colorectal cancer.

To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 × 10-8, bringing the number of known independent signals for CRC to ~100. New signals implicate lower-frequency variants, Krüppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.Goncalo R Abecasis has received compensation from 23andMe and Helix. He is currently an employee of Regeneron Pharmaceuticals. Heather Hampel performs collaborative research with Ambry Genetics, InVitae Genetics, and Myriad Genetic Laboratories, Inc., is on the scientific advisory board for InVitae Genetics and Genome Medical, and has stock in Genome Medical. Rachel Pearlman has participated in collaborative funded research with Myriad Genetics Laboratories and Invitae Genetics but has no financial competitive interest

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals &lt;1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data

Genetic architectures of proximal and distal colorectal cancer are partly distinct.

OBJECTIVE: An understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for CRC differs by anatomical subsite of the primary tumor has not been examined. DESIGN: To identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48 214 CRC cases and 64 159 controls of European ancestry. We characterised effect heterogeneity at CRC risk loci using multinomial modelling. RESULTS: We identified 13 loci that reached genome-wide significance (p<5×10-8) and that were not reported by previous GWASs for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer. CONCLUSION: Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumour

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure &lt; 100 mmHg (n = 1127), estimated glomerular filtration rate &lt; 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Malcolm on Moore’s Defense of Common Sense

The aim of this thesis is purposely limited.It is not to give an account of G. E. Moore’s philosophic practice but instead, my aim is to show that Professor Norman Malcolm’s conception of what he calls Moore’s ‘defense of Common Sense,’ can not be successful in illuminating this particular feature of Moore’s philosophic practice. I shall not argue that Malcolm’s conception of this feature is unsuccessful on the grounds that it conflicts with Moore’s own explanation of his ‘Common Sense’ doctrine.Malcolm has explicitly stated: “It must not be assumed that Professor Moore would agree with my interpretation…” In fact, Moore rejected the very premises upon which Malcolm’s conception (or interpretation) is based. Malcolm’s claim, however, is that if Moore’s ‘defense of Common Sense’ is to have relevance to philosophy , it can not be conceived as Moore himself conceived it.It must rather be conceived in terms of Malcolm’s account of it.Put differently, then, my aim in this thesis is to show that on the contrary, if Moore’s so-called ‘defense of Common Sense’ is relevant to philosophy, its relevance can not be accounted for on Malcolm’s interpretation. It is not at all clear to me what precisely Moore was doing when he was defending the so-called ‘views of Common Sense.’Nor is it at all clear to me what exactly Moore’s philosophical opponents are doing either.This much can, I think, be said. Philosophers who have wished to deny, e.g, the existence or reality of material things or, that we ever do perceive material things, do not appear to be urging views which entail a direct confliction with either common sense or the facts of ordinary language.This is not to say, of course, that such philosophers are, on the other hand, expressing views consistent with, e.g., the ordinary use of language.Since, as I have maintained, the philosopher’s words seem to resist both Moore’s and Malcolm’s translations, the impression I am left with is that such philosophers have somewhere early in their reasoning, performed (to use Professor Lazerowitz’s expression) a ‘linguistic alteration’ with certain ordinary concepts.Hence, it is questionable as to whether it makes sense to speak of refuting their philosophical views. At any rate, all that I have attempted to show in this thesis is that if Moore’s ‘defense of Common Sense’ is to be an interesting and tenable philosophical position, it can not be, at least on Professor Malcolm’s premises, a defense of ordinary language. Advisor: Robert E. Dewe