The Layer 0 Inner Silicon Detector of the D0 Experiment

This paper describes the design, fabrication, installation and performance of the new inner layer called Layer 0 (L0) that was inserted in the existing Run IIa Silicon Micro-Strip Tracker (SMT) of the D0 experiment at the Fermilab Tevatron collider. L0 provides tracking information from two layers of sensors, which are mounted with center lines at a radial distance of 16.1 mm and 17.6 mm respectively from the beam axis. The sensors and readout electronics are mounted on a specially designed and fabricated carbon fiber structure that includes cooling for sensor and readout electronics. The structure has a thin polyimide circuit bonded to it so that the circuit couples electrically to the carbon fiber allowing the support structure to be used both for detector grounding and a low impedance connection between the remotely mounted hybrids and the sensors.Comment: 28 pages, 9 figure

Research Progress Reports: Fruit and Vegetable Processing and Technology Division, Department of Horticulture [1969]

Blueberry cultivars for frozen pies / J. F. Gallander, W. A. Gould, and H. Stammer -- Grape cultivars for jelly making / J. F. Gallander, W. A. Gould and G. A. Cahoon -- Evaluation of various grape cultivars for processing. III. Table wines / J. F. Gallander -- Evaluation of snap bean cultivars for processing / William Hildebolt and W. A. Gould -- Kraut snacks / J. R. Geisman -- Mechanical harvesting and bulk handling evaluation of tomato cultivars for processing / W. A. Gould, Jonnie Budke, Carol Foglesong and Louise Howiler --The effects of lye peeling variables upon tomato cultivars / Loren Lucas and W. A. Gould -- Amino acids in canned tomato juice / Jenia D. Dormitorio and W. A. Gould -- Factors affecting the viscosity of tomato juice / David E. Crean and W. A. Goul

Acquisition of Relative Interstrand Crosslinker Resistance and PARP Inhibitor Sensitivity in Fanconi Anemia Head and Neck Cancers

PURPOSE: Fanconi anemia is an inherited disorder associated with a constitutional defect in the Fanconi anemia DNA repair machinery that is essential for resolution of DNA interstrand crosslinks. Individuals with Fanconi anemia are predisposed to formation of head and neck squamous cell carcinomas (HNSCC) at a young age. Prognosis is poor, partly due to patient intolerance of chemotherapy and radiation requiring dose reduction, which may lead to early recurrence of disease. EXPERIMENTAL DESIGN: Using HNSCC cell lines derived from the tumors of patients with Fanconi anemia, and murine HNSCC cell lines derived from the tumors of wild-type and Fancc(-/-) mice, we sought to define Fanconi anemia-dependent chemosensitivity and DNA repair characteristics. We utilized DNA repair reporter assays to explore the preference of Fanconi anemia HNSCC cells for non-homologous end joining (NHEJ). RESULTS: Surprisingly, interstrand crosslinker (ICL) sensitivity was not necessarily Fanconi anemia-dependent in human or murine cell systems. Our results suggest that the increased Ku-dependent NHEJ that is expected in Fanconi anemia cells did not mediate relative ICL resistance. ICL exposure resulted in increased DNA damage sensing and repair by PARP in Fanconi anemia-deficient cells. Moreover, human and murine Fanconi anemia HNSCC cells were sensitive to PARP inhibition, and sensitivity of human cells was attenuated by Fanconi anemia gene complementation. CONCLUSIONS: The observed reliance upon PARP-mediated mechanisms reveals a means by which Fanconi anemia HNSCCs can acquire relative resistance to the ICL-based chemotherapy that is a foundation of HNSCC treatment, as well as a potential target for overcoming chemoresistance in the chemosensitive individual

Defects in the Fanconi Anemia Pathway in Head and Neck Cancer Cells Stimulate Tumor Cell Invasion through DNA-PK and Rac1 Signaling

PURPOSE: Head and neck squamous cell carcinoma (HNSCC) remains a devastating disease, and Fanconi anemia (FA) gene mutations and transcriptional repression are common. Invasive tumor behavior is associated with poor outcome, but relevant pathways triggering invasion are poorly understood. There is a significant need to improve our understanding of genetic pathways and molecular mechanisms driving advanced tumor phenotypes, to develop tailored therapies. Here we sought to investigate the phenotypic and molecular consequences of FA pathway loss in HNSCC cells. EXPERIMENTAL DESIGN: Using sporadic HNSCC cell lines with and without FA gene knockdown, we sought to characterize the phenotypic and molecular consequences of FA deficiency. FA pathway inactivation was confirmed by the detection of classic hallmarks of FA following exposure to DNA cross-linkers. Cells were subjected to RNA sequencing with qRT-PCR validation, followed by cellular adhesion and invasion assays in the presence and absence of DNA-dependent protein kinase (DNA-PK) and Rac1 inhibitors. RESULTS: We demonstrate that FA loss in HNSCC cells leads to cytoskeletal reorganization and invasive tumor cell behavior in the absence of proliferative gains. We further demonstrate that cellular invasion following FA loss is mediated, at least in part, through NHEJ-associated DNA-PK and downstream Rac1 GTPase activity. CONCLUSIONS: These findings demonstrate that FA loss stimulates HNSCC cell motility and invasion, and implicate a targetable DNA-PK/Rac1 signaling axis in advanced tumor phenotypes

Design and Expression of a Dimeric Form of the Human Immunodeficiency Virus Type 1 Antibody 2G12 with Increased Neutralization Potency

The antigen-binding fragment of the broadly neutralizing Human Immunodeficiency Virus Type 1 (HIV-1) antibody 2G12 has an unusual 3D domain-swapped structure with two aligned combining sites that facilitates recognition of its carbohydrate epitope on gp120. When expressed as an intact IgG, 2G12 formed typical IgG monomers containing two combining sites and a small fraction of a higher molecular weight species, which showed a significant increase in neutralization potency (50- to 80-fold compared to 2G12 monomer) across a range of clade A and B strains of HIV-1. Here we show that the higher molecular weight species corresponds to a 2G12 dimer containing four combining sites, and present a model for how intermolecular 3D domain swapping could create a 2G12 dimer. Based on the structural model for a 3D domain-swapped 2G12 dimer, we designed and tested a series of 2G12 mutants predicted to increase the ratio of 2G12 dimer to monomer. We report a mutation that effectively increases the 2G12 dimer/monomer ratio without decreasing the expression yield. Increasing the proportion of 2G12 dimer compared with monomer could lead to a more potent reagent for gene therapy or passive immunization

Design and Implementation of the New D0 Level-1 Calorimeter Trigger

Increasing luminosity at the Fermilab Tevatron collider has led the D0 collaboration to make improvements to its detector beyond those already in place for Run IIa, which began in March 2001. One of the cornerstones of this Run IIb upgrade is a completely redesigned level-1 calorimeter trigger system. The new system employs novel architecture and algorithms to retain high efficiency for interesting events while substantially increasing rejection of background. We describe the design and implementation of the new level-1 calorimeter trigger hardware and discuss its performance during Run IIb data taking. In addition to strengthening the physics capabilities of D0, this trigger system will provide valuable insight into the operation of analogous devices to be used at LHC experiments.Comment: 43 pages, 20 figures, version published in Nucl. Instrum. and Methods

Cancer cell adaptation to chemotherapy

BACKGROUND: Tumor resistance to chemotherapy may be present at the beginning of treatment, develop during treatment, or become apparent on re-treatment of the patient. The mechanisms involved are usually inferred from experiments with cell lines, as studies in tumor-derived cells are difficult. Studies of human tumors show that cells adapt to chemotherapy, but it has been largely assumed that clonal selection leads to the resistance of recurrent tumors. METHODS: Cells derived from 47 tumors of breast, ovarian, esophageal, and colorectal origin and 16 paired esophageal biopsies were exposed to anticancer agents (cisplatin; 5-fluorouracil; epirubicin; doxorubicin; paclitaxel; irinotecan and topotecan) in short-term cell culture (6 days). Real-time quantitative PCR was used to measure up- or down-regulation of 16 different resistance/target genes, and when tissue was available, immunohistochemistry was used to assess the protein levels. RESULTS: In 8/16 paired esophageal biopsies, there was an increase in the expression of multi-drug resistance gene 1 (MDR1) following epirubicin + cisplatin + 5-fluorouracil (ECF) chemotherapy and this was accompanied by increased expression of the MDR-1 encoded protein, P-gp. Following exposure to doxorubicin in vitro, 13/14 breast carcinomas and 9/12 ovarian carcinomas showed >2-fold down-regulation of topoisomerase IIα (TOPOIIα). Exposure to topotecan in vitro, resulted in >4-fold down-regulation of TOPOIIα in 6/7 colorectal tumors and 8/10 ovarian tumors. CONCLUSION: This study suggests that up-regulation of resistance genes or down-regulation in target genes may occur rapidly in human solid tumors, within days of the start of treatment, and that similar changes are present in pre- and post-chemotherapy biopsy material. The molecular processes used by each tumor appear to be linked to the drug used, but there is also heterogeneity between individual tumors, even those with the same histological type, in the pattern and magnitude of response to the same drugs. Adaptation to chemotherapy may explain why prediction of resistance mechanisms is difficult on the basis of tumor type alone or individual markers, and suggests that more complex predictive methods are required to improve the response rates to chemotherapy

How to End a Cold War

Histories of the end of the Cold War that have focused on the roles of the top leaders of the United States and the Soviet Union have neglected an important dimension of the ending of the antagonism between the West and the East. Before Ronald Reagan and M.S. Gorbachev met at Geneva in November 1985, citizens of the USA, the USSR, and European nations who were alarmed by the danger of nuclear war formed new organizations dedicated to overcoming the hostility between their nations. British members of European Nuclear Disarmament and American activists in groups such as Beyond War and Peace Links established connections to independent groups in Eastern Europe and the Soviet Union as well as the Committee of Soviet Women and the Committee for the Defense of Peace in the USSR. These relationships made it possible to organize very ambitious citizen diplomacy projects. Hundreds of Soviet citizens made extensive speaking tours in the United States while numerous British and American activists visited the Soviet Union. These exchanges dispelled negative stereotypes and helped to end the mutual demonization that had been central to the Cold War since the late 1940s. Analysis of the experiences of the citizen diplomats in the 1980s yields lessons for contemporary international relations about the importance of avoiding one-sided blame for conflicts and the need to move beyond recriminations about the past in order to develop cooperation in the present and future