Benchmark experiments for higher-order and full-Stokes ice sheet models (ISMIP-HOM)

We present the results of the first ice sheet model intercomparison project for higher-order and full-Stokes ice sheet models. These models are compared and verified in a series of six experiments of which one has an analytical solution obtained from a perturbation analysis. The experiments are applied to both 2-D and 3-D geometries; five experiments are steady-state diagnostic, and one has a time-dependent prognostic solution. All participating models give results that are in close agreement. A clear distinction can be made between higher-order models and those that solve the full system of equations. The full-Stokes models show a much smaller spread, hence are in better agreement with one another and with the analytical solution

Patient-specific cancer genes contribute to recurrently perturbed pathways and establish therapeutic vulnerabilities in esophageal adenocarcinoma

Abstract: The identification of cancer-promoting genetic alterations is challenging particularly in highly unstable and heterogeneous cancers, such as esophageal adenocarcinoma (EAC). Here we describe a machine learning algorithm to identify cancer genes in individual patients considering all types of damaging alterations simultaneously. Analysing 261 EACs from the OCCAMS Consortium, we discover helper genes that, alongside well-known drivers, promote cancer. We confirm the robustness of our approach in 107 additional EACs. Unlike recurrent alterations of known drivers, these cancer helper genes are rare or patient-specific. However, they converge towards perturbations of well-known cancer processes. Recurrence of the same process perturbations, rather than individual genes, divides EACs into six clusters differing in their molecular and clinical features. Experimentally mimicking the alterations of predicted helper genes in cancer and pre-cancer cells validates their contribution to disease progression, while reverting their alterations reveals EAC acquired dependencies that can be exploited in therapy

A comparative analysis of whole genome sequencing of esophageal adenocarcinoma pre- and post-chemotherapy

The scientific community has avoided using tissue samples from patients that have been exposed to systemic chemotherapy to infer the genomic landscape of a given cancer. Esophageal adenocarcinoma is a heterogeneous, chemoresistant tumor for which the availability and size of pretreatment endoscopic samples are limiting. This study compares whole-genome sequencing data obtained from chemo-naive and chemo-treated samples. The quality of whole-genomic sequencing data is comparable across all samples regardless of chemotherapy status. Inclusion of samples collected post-chemotherapy increased the proportion of late-stage tumors. When comparing matched pre- and post-chemotherapy samples from 10 cases, the mutational signatures, copy number, and SNV mutational profiles reflect the expected heterogeneity in this disease. Analysis of SNVs in relation to allele-specific copy-number changes pinpoints the common ancestor to a point prior to chemotherapy. For cases in which pre- and post-chemotherapy samples do show substantial differences, the timing of the divergence is near-synchronous with endoreduplication. Comparison across a large prospective cohort (62 treatment-naive, 58 chemotherapy-treated samples) reveals no significant differences in the overall mutation rate, mutation signatures, specific recurrent point mutations, or copy-number events in respect to chemotherapy status. In conclusion, whole-genome sequencing of samples obtained following neoadjuvant chemotherapy is representative of the genomic landscape of esophageal adenocarcinoma. Excluding these samples reduces the material available for cataloging and introduces a bias toward the earlier stages of cancer.This study was partly funded by a project grant from Cancer Research UK. R.C.F. is funded by an NIHR Professorship and receives core funding from the Medical Research Council and infrastructure support from the Biomedical Research Centre and the Experimental Cancer Medicine Centre. We acknowledge the support of The University of Cambridge, Cancer Research UK (C14303/A17197) and Hutchison Whampoa Limited

Subglacial Lake Ellsworth: a candidate for in situ exploration in West Antarctica

Radio-echo sounding reveals a 10 km-long lake beneath similar to3.4 km of ice near the Ellsworth Mountains in West Antarctica, 20 km from the ice divide. Subglacial Lake Ellsworth is located within a distinct topographic hollow, which is similar to1.5 km deeper than the surrounding bed. Judging by bed slopes flanking the lake, the water depth is at least 10s of metres. Calculations of basal temperature reveal the ice base to be warm both now and during full glacial periods. As the environments of subglacial lakes are broadly similar, life may be expected in Lake Ellsworth as in any other. Given this, its physical characteristics, and the fact that the West Antarctic Ice Sheet has been accessed on several occasions, Lake Ellsworth is an excellent candidate for in situ examination

Challenges of multimodality: Language and the body in social interaction

This article reflects on recent challenges emerging from the study of language and the body in social interaction. There is a general interest in language and the body across disciplines that has invited a reconceptualization of the broader issues relative to action, cognition, culture, knowledge, social relations and identities, spatiality and temporality. The study of social interaction focuses on how multimodal resources - including language and bodily movements - are holistically and situatedly used in building human action. This article discusses some consequences and challenges of putting the body at the center of attention: it repositions language as one among other modalities, and invites us to consider the involvement of entire bodies in social interaction, overcoming a logo-centric vision of communication, as well as a visuo-centric vision of embodiment. These issues are developed through a series of conversation analytic studies, firstly of classic topics in linguistics like deixis, then of more recent topics, such as mobility and sensoriality

Characteristics of volcanic tremor accompanying the September 24th, 1986 explosive eruption of Mt. Etna (Italy)

Features of the volcanic tremor recorded before, during and after the eruptive event which occurred at Mt. Etna on September 24th 1986, are described. The whole eruption was particularly short in time (about eight hours) and characterized by an extremely violent explosive activity with lava fountains a few hundred meters high. As the complete record of the seismic signals generated during the whole eruptive episode was available, a detailed spectral analysis of the volcanic tremor recorded at four stations, located at increasing distance from the summit of the volcano, was carried out. Fourier analysis, that was performed using temporal windows of about 11 min in duration, pointed to some large fluctuations of the overall spectral amplitude, as well as some frequency variations of the dominant spectral peaks. The ratio of the overall spectral amplitude recorded at the highest station and at the peripheral ones, was calculated in the two spectral bands 1.0-2.5 and 2.6-6.0 Hz, respectively. The significant contribution of energy at low frequency values supports the hypothesis of a subvertical planar source, which was active during the paroxysmal stage of the eruption. Such results are also supported by the analysis of the attenuation function of the spectral amplitude

Whole-genome sequencing provides new insights into the clonal architecture of Barrett's esophagus and esophageal adenocarcinoma

The molecular genetic relationship between esophageal adenocarcinoma (EAC) and its precursor lesion, Barrett's esophagus, is poorly understood. Using whole-genome sequencing on 23 paired Barrett's esophagus and EAC samples, together with one in-depth Barrett's esophagus case study sampled over time and space, we have provided the following new insights: (i) Barrett's esophagus is polyclonal and highly mutated even in the absence of dysplasia; (ii) when cancer develops, copy number increases and heterogeneity persists such that the spectrum of mutations often shows surprisingly little overlap between EAC and adjacent Barrett's esophagus; and (iii) despite differences in specific coding mutations, the mutational context suggests a common causative insult underlying these two conditions. From a clinical perspective, the histopathological assessment of dysplasia appears to be a poor reflection of the molecular disarray within the Barrett's epithelium, and a molecular Cytosponge technique overcomes sampling bias and has the capacity to reflect the entire clonal architecture.</p