The structural architecture of seismogenic faults, Sierra Nevada, California; implications for earthquake rupture processes

Earthquake ruptures along tectonically active faults nucleate predominantly at depths of 5 to 12km in the crust, so the portions of faults that slip in these events cannot be directly observed. The geometry and composition of seismogenic faults controls the nucleation, propagation and termination of the earthquake rupture process. This study aims to place constraints on the geometry and composition of seismogenic faults by examining ancient faults exhumed from the depths at which earthquakes are observed to nucleate. Faults exposed in the Sierra Nevada, California, show that the internal architecture of earthquake faults is heterogeneous at a variety of scales. Field and microstructural observations are used to describe in detail the architecture of two pseudotachylyte-bearing fault systems in the Granite Pass region of Sequoia and Kings Canyon National Park; the Granite Pass fault (GPF) and associated faults, and the Glacier Lakes fault (GLF) and faults that splay from the GLF. The GPF and sub-parallel faults are 1 to 6.7km long with left-lateral strike-slip displacements up to 80m. The GPF and GPF-parallel faults have architectures that are heterogeneous along strike. They are composed of one to four fault core strands containing cataclasites and ultracataclasites that cross-cut early localized crystal-plastic deformation. Slip surfaces developed at the edges of, within and between fault cores are defined by pseudotachylytes and cataclasites with thicknesses of ~0.01 to 20mm. Fault-related subsidiary structures are developed on either side of fault cores, and comprise damage zones with widths orthogonal to the fault of up to 30m. The GLF and splay faults have architectures that are more homogeneous along strike. These faults are composed of a tabular volume of heavily fractured and altered host rock between approximately planar fault core strands. The fault cores are centimetres wide and contain cataclasites and foliated cataclasites that are cross-cut by pseudotachylytes. Fault-related damage is limited in extent to several metres beyond the bounding fault cores. The GLF contains additional cataclasites, ultracataclasites and pseudotachylytes in a fault core strand within the tabular zone of fractured rock. Thermochronologic analyses of the host rock granodiorite, combined with previously published palaeogeobarometry and apatite fission track data, define the temperature and pressure changes associated with cooling and exhumation of the pluton. The P-T conditions prevalent during the deformation history of the GPF fault system are evaluated by relating recrystallisation mechanisms in quartz to temperature, showing that the early stages of deformation occurred at temperatures of 450 to 600ºC. Dating of pseudotachylytes by the K-Ar isotopic method suggests subsequent brittle deformation took place at temperatures <350ºC and pressures ≤150MPa. A model for the architecture of the GPF architecture therefore has well constrained environmental controls, and should be transferrable to faults with comparable deformation histories. Small faults (cumulative displacements <1m) in the Mount Abbot Quadrangle, 55km north of Granite Pass, have been examined to illustrate the processes associated with the earliest stages of slip in the Sierra Nevada faults. The faults have branched or straight fault traces. Pseudotachylytes in branching faults show that these faults accumulated displacement in high velocity slip events, rather than by quasi-static fault growth. Branching faults without pseudotachylytes contain chlorite breccias interpreted to have formed in response to slip along faults with elevated pore fluid pressure. Straight faults also likely underwent slip events, but contain cataclased chlorite and epidote, suggesting low fluid pressures during slip. The small faults show that fluid-rock interactions are critical to fault geometry, and that lateral structural heterogeneity is established after small finite displacements. Field and thin section observations of exhumed seismogenic faults show that fault architecture and fault rock assemblage are critical to the earthquake rupture process. The heterogeneous composition of slip surfaces in the GPF faults imply that melt lubrication cannot account for all of the dynamic slip weakening as there are no continuous pseudotachylyte generation surfaces through the fault zones. Multiple slip weakening mechanisms must have been active during single rupture events. Slip weakening mechanisms also change at a given point on the fault in response to continued deformation. Splay faults at the GLF termination suggest that structural complexity observed at the terminations of fault surface traces can also be expected at depth. The off-fault damage at the termination of the GLF will change the bulk elastic properties of the host rock and must be accounted for in models of rupture propagation beyond fault terminations, or across geometrical discontinuities. Additionally, aftershock distributions and focal mechanisms may be controlled by the geometry of structures present at fault terminations.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Self-organized Emergence of Navigability on Small-World Networks

This paper mainly investigates why small-world networks are navigable and how to navigate small-world networks. We find that the navigability can naturally emerge from self-organization in the absence of prior knowledge about underlying reference frames of networks. Through a process of information exchange and accumulation on networks, a hidden metric space for navigation on networks is constructed. Navigation based on distances between vertices in the hidden metric space can efficiently deliver messages on small-world networks, in which long range connections play an important role. Numerical simulations further suggest that high cluster coefficient and low diameter are both necessary for navigability. These interesting results provide profound insights into scalable routing on the Internet due to its distributed and localized requirements.Comment: 3 figure

Copper chelation suppresses epithelial-mesenchymal transition by inhibition of canonical and non-canonical TGF-β signaling pathways in cancer

Background: Metastatic cancer cells exploit Epithelial-mesenchymal-transition (EMT) to enhance their migration, invasion, and resistance to treatments. Recent studies highlight that elevated levels of copper are implicated in cancer progression and metastasis. Clinical trials using copper chelators are associated with improved patient survival; however, the molecular mechanisms by which copper depletion inhibits tumor progression and metastasis are poorly understood. This remains a major hurdle to the clinical translation of copper chelators. Here, we propose that copper chelation inhibits metastasis by reducing TGF-β levels and EMT signaling. Given that many drugs targeting TGF-β have failed in clinical trials, partly because of severe side effects arising in patients, we hypothesized that copper chelation therapy might be a less toxic alternative to target the TGF-β/EMT axis. Results: Our cytokine array and RNA-seq data suggested a link between copper homeostasis, TGF-β and EMT process. To validate this hypothesis, we performed single-cell imaging, protein assays, and in vivo studies. Here, we used the copper chelating agent TEPA to block copper trafficking. Our in vivo study showed a reduction of TGF-β levels and metastasis to the lung in the TNBC mouse model. Mechanistically, TEPA significantly downregulated canonical (TGF-β/SMAD2&amp;3) and non-canonical (TGF-β/PI3K/AKT, TGF-β/RAS/RAF/MEK/ERK, and TGF-β/WNT/β-catenin) TGF-β signaling pathways. Additionally, EMT markers of MMP-9, MMP-14, Vimentin, β-catenin, ZEB1, and p-SMAD2 were downregulated, and EMT transcription factors of SNAI1, ZEB1, and p-SMAD2 accumulated in the cytoplasm after treatment. Conclusions: Our study suggests that copper chelation therapy represents a potentially effective therapeutic approach for targeting TGF-β and inhibiting EMT in a diverse range of cancers

Novel therapies in breast cancer: what is new from ASCO 2008

<p>Abstract</p> <p>Introduction</p> <p>Breast cancer is the most common female cancer and the second most common cause of female cancer-related deaths in the United States. World-wide, more than one million women will be diagnosed with breast cancer annually. In 2007, more than 175,000 women were diagnosed with breast cancer in the United States. However, deaths due to breast cancer have decreased in the recent years in part because of improved screening techniques, surgical interventions, understanding of the pathogenesis of the disease, and utilization of traditional chemotherapies in a more efficacious manner. One of the more exciting areas of improvement in the treatment of breast cancer is the entrance of novel therapies now available to oncologists. In the field of cancer therapeutics, the area of targeted and biologic therapies has been progressing at a rapid rate, particularly in the treatment of breast cancer.</p> <p>Since the advent of imatinib for the successful treatment of chronic myelogenous leukemia in the 2001, clinicians have been searching for comparable therapies that could be as efficacious and as tolerable. In order for targeted therapies to be effective, the agent must be able to inhibit critical regulatory pathways which promote tumor cell growth and proliferation. The targets must be identifiable, quantifiable and capable of being interrupted.</p> <p>In the field of breast cancer, two advances in targeted therapy have led to great strides in the understanding and treatment of breast cancer, namely hormonal therapy for estrogen positive receptor breast cancer and antibodies directed towards the inhibition of human epidermal growth factor receptor (HER)2. These advances have revolutionized the understanding and the treatment strategies for breast cancer. Building upon these successes, a host of novel agents are currently being investigated and used in clinical trials that will hopefully prove to be as fruitful. This review will focus on novel therapies in the field of breast cancer with a focus on metastatic breast cancer (MBC) and updates from the recent annual ASCO meeting and contains a summary of the results.</p

Proceedings of the Sixth International Workshop on Web Caching and Content Distribution

OVERVIEW The International Web Content Caching and Distribution Workshop (WCW) is a premiere technical meeting for researchers and practitioners interested in all aspects of content caching, distribution and delivery on the Internet. The 2001 WCW meeting was held on the Boston University Campus. Building on the successes of the five previous WCW meetings, WCW01 featured a strong technical program and record participation from leading researchers and practitioners in the field. This report includes all the technical papers presented at WCW'01. Note: Proceedings of WCW'01 are published by Elsevier. Hardcopies of these proceedings can be purchased through the workshop organizers. As a service to the community, electronic copies of all WCW'01 papers are accessible through Technical Report BUCS‐TR‐2001‐017, available from the Boston University Computer Science Technical Report Archives at http://www.cs.bu.edu/techreps. [Ed.note: URL outdated. Use http://www.bu.edu/cs/research/technical-reports/ or http://hdl.handle.net/2144/1455 in this repository to access the reports.]Cisco Systems; InfoLibria; Measurement Factory Inc; Voler

Multilineage hematopoietic recovery with concomitant antitumor effects using low dose Interleukin-12 in myelosuppressed tumor-bearing mice

<p>Abstract</p> <p>Background</p> <p>Interleukin-12 (IL-12) is a cytokine well known for its role in immunity. A lesser known function of IL-12 is its role in hematopoiesis. The promising data obtained in the preclinical models of antitumor immunotherapy raised hope that IL-12 could be a powerful therapeutic agent against cancer. However, excessive clinical toxicity, largely due to repeat dose regimens, and modest clinical response observed in the clinical trials have pointed to the necessity to design protocols that minimize toxicity without affecting the anti-tumor effect of IL-12. We have focused on the lesser known role of IL-12 in hematopoiesis and hypothesized that an important clinical role for IL-12 in cancer may be as an adjuvant hematological cancer therapy. In this putative clinical function, IL-12 is utilized for the prevention of cancer therapy-related cytopenias, while providing concomitant anti-tumor responses over and above responses observed with the primary therapy alone. This putative clinical function of IL-12 focuses on the dual role of IL-12 in hematopoiesis and immunity.</p> <p>Methods</p> <p>We assessed the ability of IL-12 to facilitate hematopoietic recovery from radiation (625 rad) and chemotherapy (cyclophosphamide) in two tumor-bearing murine models, namely the EL4 lymphoma and the Lewis lung cancer models. Antitumor effects and changes in bone marrow cellularity were also assessed.</p> <p>Results</p> <p>We show herein that carefully designed protocols, in mice, utilizing IL-12 as an adjuvant to radiation or chemotherapy yield facile and consistent, multilineage hematopoietic recovery from cancer therapy-induced cytopenias, as compared to vehicle and the clinically-utilized cytokine granulocyte colony-stimulating factor (G-CSF) (positive control), while still providing concomitant antitumor responses over and above the effects of the primary therapy alone. Moreover, our protocol design utilizes single, low doses of IL-12 that did not yield any apparent toxicity.</p> <p>Conclusion</p> <p>Our results portend that despite its past failure, IL-12 appears to have significant clinical potential as a hematological adjuvant cancer therapy.</p

Biomarker analyses in the phase III ASCENT study of sacituzumab govitecan versus chemotherapy in patients with metastatic triple-negative breast cancer

Background: The pivotal phase III ASCENT trial demonstrated improved survival outcomes associated with sacituzumab govitecan (SG), an anti-trophoblast cell-surface antigen 2 (anti-Trop-2) antibody-drug conjugate linked with the topoisomerase-inhibitor SN-38, over single-agent chemotherapy treatment of physician's choice (TPC) in previously treated metastatic triple-negative breast cancer (mTNBC). This prespecified, exploratory biomarker analysis from the ASCENT trial evaluates the association between tumor Trop-2 expression and germline BRCA1/2 mutation status with clinical outcomes. Patients and methods: Patients with mTNBC refractory to or progressing after two or more prior chemotherapies, with one or more in the metastatic setting, were randomized to receive SG (10 mg/kg intravenously days 1 and 8, every 21 days) or TPC (capecitabine, eribulin, vinorelbine, or gemcitabine) until disease progression/unacceptable toxicity. Biopsy or surgical specimens were collected at study entry to determine Trop-2 expression level using a validated immunohistochemistry assay and histochemical scoring. Germline BRCA1/2 mutation status was collected at baseline. Results: Of 468 assessable patients, 290 had Trop-2 expression data [64% (n = 151 SG) versus 60% (n = 139 TPC)] and 292 had known BRCA1/2 mutation status [63% (n = 149 SG) versus 61% (n = 143 TPC)]. Median progression-free survival in SG- versus TPC-treated patients was 6.9, 5.6, and 2.7 months versus 2.5, 2.2, and 1.6 months for high, medium, and low Trop-2 expression, respectively. Median overall survival (14.2, 14.9, and 9.3 months versus 6.9, 6.9, and 7.6 months) and objective response rates (44%, 38%, and 22% versus 1%, 11%, and 6%) were numerically higher with SG versus TPC in patients with high, medium, and low Trop-2 expression, respectively. Efficacy outcomes were numerically higher with SG versus TPC in patients with and without germline BRCA1/2 mutations. Conclusions: SG benefits patients with previously treated mTNBC expressing high/medium Trop-2 compared with standard-of-care chemotherapy and regardless of germline BRCA1/2 mutation status. The small number of patients with low Trop-2 expression precludes definitive conclusions on the benefit of SG in this subgroup

Performance Assessment of Fragmentation Mechanisms for Vehicular Delay-Tolerant Networks

[EN] Vehicular Delay-Tolerant Networks (VDTNs) are a new approach for vehicular communications where vehicles cooperate with each other, acting as the communication infrastructure, to provide low-cost asynchronous opportunistic communications. These communication technologies assume variable delays and bandwidth constraints characterized by a non-transmission control protocol/internet protocol architecture but interacting with it at the edge of the network. VDTNs are based on the principle of asynchronous communications, bundle-oriented communication from the DTN architecture, employing a store-carry-and-forward routing paradigm. In this sense, VDTNs should use the tight network resources optimizing each opportunistic contact among nodes. Given the limited contact times among nodes, fragmentation appears as a possible solution to improve the overall network performance, increasing the bundle delivery probability. This article proposes the use of several fragmentation approaches (proactive, source, reactive, and toilet paper) for VDTNs. They are discussed and evaluated through a laboratory testbed. Reactive and toilet paper approaches present the best results. It was also shown that only the source fragmentation approach presents worst results when compared with non-fragmentation approaches.This study was partially supported by the Instituto de Telecomunicacoes, Next Generation Networks and Applications Group (NetGNA), Portugal, by the Euro-NF Network of Excellence of the Seventh Framework Programme of EU, in the framework of the Specific Joint Research Project VDTN, and by the INESC-ID multiannual funding through the PIDDAC program funds and National Funding from the FCT - Fundacao para a Ciencia e a Tecnologia through the PEst-OE/EEI/LA0008/2011 and PTDC/EEA-TEL/099074/2008 (MPSat) Projects.Dias, JAFF.; Rodrigues, JJPC.; Isento, JN.; Pereira, PRBA.; Lloret, J. (2011). 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