The role of bedrock fractures and rock mass strength is often considered a primary influence on the efficiency of surface processes and the morphology of landscapes. Quantifying bedrock ...characteristics at hillslope scales, however, has proven difficult. Here, we present a new field‐based method for quantifying the depth and apparent density of bedrock fractures within the shallow subsurface based on seismic refraction surveys. We examine variations in subsurface fracture patterns in both Fiordland and the Southern Alps of New Zealand to better constrain the influence of bedrock properties in governing rates and patterns of landslides, as well as the morphology of threshold landscapes. We argue that intense tectonic deformation produces uniform bedrock fracturing with depth, whereas geomorphic processes produce strong fracture gradients focused within the shallow subsurface. Additionally, we argue that hillslope strength and stability are functions of both the intact rock strength and the density of bedrock fractures, such that for a given intact rock strength, a threshold fracture‐density exists that delineates between stable and unstable rock masses. In the Southern Alps, tectonic forces have pervasively fractured intrinsically weak rock to the verge of instability, such that the entire rock mass is susceptible to failure and landslides can potentially extend to great depths. Conversely, in Fiordland, tectonic fracturing of the strong intact rock has produced fracture densities less than the regional stability threshold. Therefore, bedrock failure in Fiordland generally occurs only after geomorphic fracturing has further reduced the rock mass strength. This dependence on geomorphic fracturing limits the depths of bedrock landslides to within this geomorphically weakened zone.
Key Points
Seismic refraction surveys can be used to assess subsurface fracture patterns
Surface fractures influence surface strengths and threshold stability angles
Depth‐dependent fracture patterns strongly influence the depth of landslides
Skeletal muscle size depends upon a dynamic balance between anabolic (or hypertrophic) and catabolic (or atrophic) processes. Previously, no link between the molecular mediators of atrophy and ...hypertrophy had been reported. We demonstrate a hierarchy between the signals which mediate hypertrophy and those which mediate atrophy: the IGF-1/PI3K/Akt pathway, which has been shown to induce hypertrophy, prevents induction of requisite atrophy mediators, namely the muscle-specific ubiquitin ligases MAFbx and MuRF1. Moreover, the mechanism for this inhibition involves Akt-mediated inhibition of the FoxO family of transcription factors; a mutant form of FOXO1, which prevents Akt phosphorylation, thereby prevents Akt-mediated inhibition of
MuRF1 and
MAFbx upregulation. Our study thus defines a previously uncharacterized function for Akt, which has important therapeutic relevance: Akt is not only capable of activating prosynthetic pathways, as previously demonstrated, but is simultaneously and dominantly able to suppress catabolic pathways, allowing it to prevent glucocorticoid and denervation-induced muscle atrophy.
Bedrock fracturing and rock strength are widely believed to influence landscape morphology and erosional resistance. Yet, understanding of the quantitative relationship between rock-mass strength and ...landscape evolution remains limited. Here we present a new application of seismic refraction surveys that uses variations in seismic velocity to interpret differences in bedrock fracture density with depth. We use a comparative study of Fiordland and the western Southern Alps of New Zealand to examine how differences in rock type and bedrock fracturing influence landscape morphology and landslide response to rock uplift. In both regions, slopes appear invariant with differential rock-uplift rates and slope distributions reveal modal hillslope angles of ~
32°. The majority of landslides initiate on slopes steeper than the modal hillslope angle, however, landslide magnitude–frequency distributions reveal order-of-magnitude differences between the regions, with Fiordland experiencing considerably smaller and less frequent landsliding events. Landslide-driven denudation rates of ~
9
mm/yr in the western Southern Alps and between ~
0.1 and 0.3
mm/yr in Fiordland approximate estimates of long-term rock-uplift rates for each region. The invariance of hillslope angles, near-normal slope distributions, predominance of landslide initiation on slopes steeper than modal values, and the apparent balance between rates of uplift and landslide-driven erosion suggest that hillslopes in both regions are at threshold angles. Their similar modal slopes further suggest that both ranges are characterized by equivalent rock-mass strength, despite striking differences in lithology. Additionally, our seismic analysis reveals nearly identical surface p-wave velocities. The unexpected equivalence of both modal slopes and surface velocities between these lithologically distinct ranges is attributed to contrasting degrees of surface fracturing that have differentially affected the intact rock properties, such that they now yield equivalent surface velocities and hillslope-scale strengths. Given that surface fractures help regulate threshold angles by modulating hillslope strength; we propose that shallow seismic velocities may provide a quantitative proxy for rock-mass strength. We define two contrasting fracture and landsliding environments. In Fiordland, dense geomorphic fracturing that is focused within the shallow subsurface appears to limit the depth and magnitude of most bedrock landslides. Conversely, in the western Southern Alps, tectonic forces produce pervasive fracturing with depth that results in larger, and deeper landslides. Our data suggest that bedrock fracturing at the Earth's surface modulates threshold hillslope angles, whereas the depth of bedrock fracturing influences the magnitude and frequency of landslide response to tectonic rock uplift.
We reviewed 37 patients treated for bacteremia due to carbapenem-resistant (CR) Pseudomonas aeruginosa Although 65% of isolates were multiple-drug resistant, therapeutic options were available, as ...all were susceptible to ≥1 antibiotic. A total of 92% of patients received active antimicrobial therapy, but only 57% received early active therapy (within 48 h). Fourteen-day mortality was 19%. Microbiologic failure occurred in 29%. The Pitt bacteremia score (P = 0.046) and delayed active therapy (P = 0.027) were predictive of death and microbiologic failure, respectively.
Affinity-optimized T cell receptors can enhance the potency of adoptive T cell therapy. Afamitresgene autoleucel (afami-cel) is a human leukocyte antigen-restricted autologous T cell therapy ...targeting melanoma-associated antigen A4 (MAGE-A4), a cancer/testis antigen expressed at varying levels in multiple solid tumors. We conducted a multicenter, dose-escalation, phase 1 trial in patients with relapsed/refractory metastatic solid tumors expressing MAGE-A4, including synovial sarcoma (SS), ovarian cancer and head and neck cancer ( NCT03132922 ). The primary endpoint was safety, and the secondary efficacy endpoints included overall response rate (ORR) and duration of response. All patients (N = 38, nine tumor types) experienced Grade ≥3 hematologic toxicities; 55% of patients (90% Grade ≤2) experienced cytokine release syndrome. ORR (all partial response) was 24% (9/38), 7/16 (44%) for SS and 2/22 (9%) for all other cancers. Median duration of response was 25.6 weeks (95% confidence interval (CI): 12.286, not reached) and 28.1 weeks (95% CI: 12.286, not reached) overall and for SS, respectively. Exploratory analyses showed that afami-cel infiltrates tumors, has an interferon-γ-driven mechanism of action and triggers adaptive immune responses. In addition, afami-cel has an acceptable benefit-risk profile, with early and durable responses, especially in patients with metastatic SS. Although the small trial size limits conclusions that can be drawn, the results warrant further testing in larger studies.
Everyday Ethics Michael Lamb, Brian A. Williams
10/2019
eBook
What might we learn if the study of ethics focused less on hard cases and more on the practices of everyday life? InEveryday Ethics, Michael Lamb and Brian Williams gather some of the world's leading ...scholars and practitioners of moral theology (including some GUP authors) to explore that question in dialogue with anthropology and the social sciences. Inspired by the work of Michael Banner, these scholars cross disciplinary boundaries to analyze the ethics of ordinary practices-from eating, learning, and loving thy neighbor to borrowing and spending, using technology, and working in a flexible economy. Along the way, they consider the moral and methodological questions that emerge from this interdisciplinary dialogue and assess the implications for the future of moral theology.
Skeletal muscle atrophy occurs as a side effect of treatment with synthetic glucocorticoids such as dexamethasone (DEX) and is a hallmark of cachectic syndromes associated with increased cortisol ...levels. The E3 ubiquitin ligase MuRF1 (muscle RING finger protein 1) is transcriptionally upregulated by DEX treatment. Differentiated myotubes treated with DEX undergo depletion of myosin heavy chain protein (MYH), which physically associates with MuRF1. This loss of MYH can be blocked by inhibition of MuRF1 expression. When wild-type and MuRF1−/− mice are treated with DEX, the MuRF1−/− animals exhibit a relative sparing of MYH. In vitro, MuRF1 is shown to function as an E3 ubiquitin ligase for MYH. These data identify the mechanism by which MYH is depleted under atrophy conditions and demonstrate that inhibition of a single E3 ligase, MuRF1, is sufficient to maintain this important sarcomeric protein.
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