Structural characterisation of Fe₂O₃ nanoparticles

The structure of nano-crystalline Fe₂O₃ particles, synthesized using the microwave plasma technique, has been analysed using synchrotron based X-ray absorption spectroscopy and X-ray powder diffraction, as well as transmission electron microscopy. Furthermore, magnetic properties, the crystal structure, and the microstructures are compared and the potential model character of the samples for structure simulations is discussed

A slowly rotating coil system for AC field measurements of Fermilab booster correctors

A method for measurement of rapidly changing magnetic fields has been developed and applied to the testing of new room temperature corrector packages designed for the Fermilab Booster Synchrotron. The method is based on fast digitization of a slowly rotating tangential coil probe, with analysis combining the measured coil voltages across a set of successive magnet current cycles. This paper presents results on the field quality measured for the normal and skew dipole, quadrupole, and sextupole elements in several of these corrector packages

Local Structure and Magnetism of Fe2O3 Maghemite Nanocrystals: The Role of Crystal Dimension

Here we report on the impact of reducing the crystalline size on the structural and magnetic properties of γ-Fe2O3 maghemite nanoparticles. A set of polycrystalline specimens with crystallite size ranging from ~2 to ~50 nm was obtained combining microwave plasma synthesis and commercial samples. Crystallite size was derived by electron microscopy and synchrotron powder diffraction, which was used also to investigate the crystallographic structure. The local atomic structure was inquired combining pair distribution function (PDF) and X-ray absorption spectroscopy (XAS). PDF revealed that reducing the crystal dimension induces the depletion of the amount of Fe tetrahedral sites. XAS confirmed significant bond distance expansion and a loose Fe-Fe connectivity between octahedral and tetrahedral sites. Molecular dynamics revealed important surface effects, whose implementation in PDF reproduces the first shells of experimental curves. The structural disorder affects the magnetic properties more and more with decreasing the nanoparticle size. In particular, the saturation magnetization reduces, revealing a spin canting effect. Moreover, a large effective magnetic anisotropy is measured at low temperature together with an exchange bias effect, a behavior that we related to the existence of a highly disordered glassy magnetic phase

Genome-wide shRNA screen revealed integrated mitogenic signaling between dopamine receptor D2 (DRD2) and epidermal growth factor receptor (EGFR) in glioblastoma

Glioblastoma remains one of the deadliest of human cancers, with most patients succumbing to the disease within two years of diagnosis. The available data suggest that simultaneous inactivation of critical nodes within the glioblastoma molecular circuitry will be required for meaningful clinical efficacy. We conducted parallel genome-wide shRNA screens to identify such nodes and uncovered a number of G-Protein Coupled Receptor (GPCR) neurotransmitter pathways, including the Dopamine Receptor D2 (DRD2) signaling pathway. Supporting the importance of DRD2 in glioblastoma, DRD2 mRNA and protein expression were elevated in clinical glioblastoma specimens relative to matched non-neoplastic cerebrum. Treatment with independent si-/shRNAs against DRD2 or with DRD2 antagonists suppressed the growth of patient-derived glioblastoma lines both in vitro and in vivo. Importantly, glioblastoma lines derived from independent genetically engineered mouse models (GEMMs) were more sensitive to haloperidol, an FDA approved DRD2 antagonist, than the premalignant astrocyte lines by approximately an order of magnitude. The pro-proliferative effect of DRD2 was, in part, mediated through a GNAI2/Rap1/Ras/ERK signaling axis. Combined inhibition of DRD2 and Epidermal Growth Factor Receptor (EGFR) led to synergistic tumoricidal activity as well as ERK suppression in independent in vivo and in vitro glioblastoma models. Our results suggest combined EGFR and DRD2 inhibition as a promising strategy for glioblastoma treatment

Test Results of the AC Field Measurements of Fermilab Booster Corrector Magnets

Multi-element corrector magnets are being produced at Fermilab that enable correction of orbits and tunes through the entire cycle of the Booster, not just at injection. The corrector package includes six different corrector elements--normal and skew orientations of dipole, quadrupole, and sextupole--each independently powered. The magnets have been tested during typical AC ramping cycles at 15Hz using a fixed coil system to measure the dynamic field strength and field quality. The fixed coil is comprised of an array of inductive pick-up coils around the perimeter of a cylinder which are sampled simultaneously at 100 kHz with 24-bit ADC's. The performance of the measurement system and a summary of the field results are presented and discussed

A Genetic Screen Identifies FAN1, a Fanconi Anemia-Associated Nuclease Necessary for DNA Interstrand Crosslink Repair

The Fanconi anemia (FA) pathway is responsible for interstrand crosslink repair. At the heart of this pathway is the FANCI-FAND2 (ID) complex, which, upon ubiquitination by the FA core complex, travels to sites of damage to coordinate repair that includes nucleolytic modification of the DNA urrounding the lesion and translesion synthesis. How the ID complex regulates these events is unknown. Here we describe a shRNA screen that led to the identification of two nucleases necessary for crosslink repair, FAN1 (KIAA1018) and EXDL2. FAN1 colocalizes at sites of DNA damage with the ID complex in a manner dependent on FAN1’s ubiquitin-binding domain (UBZ), the ID complex, and monoubiquitination of FANCD2. FAN1 possesses intrinsic 50 -30 exonuclease activity and endonuclease activity that cleaves nicked and branched structures. We propose that FAN1 is a repair nuclease that is recruited to sites of crosslink damage in part through binding the ubiquitinated ID complex through its UBZ domain

In Vivo RNAi Screening Identifies Regulators of Actin Dynamics as Key Determinants of Lymphoma Progression

April 1, 2010Mouse models have markedly improved our understanding of cancer development and tumor biology. However, these models have shown limited efficacy as tractable systems for unbiased genetic experimentation. Here, we report the adaptation of loss-of-function screening to mouse models of cancer. Specifically, we have been able to introduce a library of shRNAs into individual mice using transplantable Eμ-myc lymphoma cells. This approach has allowed us to screen nearly 1,000 genetic alterations in the context of a single tumor-bearing mouse. These experiments have identified a central role for regulators of actin dynamics and cell motility in lymphoma cell homeostasis in vivo. Validation experiments confirmed that these proteins represent bona fide lymphoma drug targets. Additionally, suppression of two of these targets, Rac2 and twinfilin, potentiated the action of the front-line chemotherapeutic vincristine, suggesting a critical relationship between cell motility and tumor relapse in hematopoietic malignancies.National Institutes of Health (U.S.) (RO1 CA128803-01)Massachusetts Institute of Technology. Dept. of Biology (Training Grant)Massachusetts Institute of Technology. Undergraduate Research Opportunities ProgramNational Cancer Institute (U.S.). Integrative Cancer Biology Program (Grant 1-U54-CA112967

Identification and Replication of Loci Involved in Camptothecin-Induced Cytotoxicity Using CEPH Pedigrees

To date, the Centre d'Etude Polymorphism Humain (CEPH) cell line model has only been used as a pharmacogenomic tool to evaluate which genes are responsible for the disparity in response to a single drug. The purpose of this study was demonstrate the model's ability to establish a specific pattern of quantitative trait loci (QTL) related to a shared mechanism for multiple structurally related drugs, the camptothecins, which are Topoisomerase 1 inhibitors. A simultaneous screen of six camptothecin analogues for in vitro sensitivity in the CEPH cell lines resulted in cytotoxicity profiles and orders of potency which were in agreement with the literature. For all camptothecins studied, heritability estimates for cytotoxic response averaged 23.1±2.6%. Nonparametric linkage analysis was used to identify a relationship between genetic markers and response to the camptothecins. Ten QTLs on chromosomes 1, 3, 5, 6, 11, 12, 16 and 20 were identified as shared by all six camptothecin analogues. In a separate validation experiment, nine of the ten QTLs were replicated at the significant and suggestive levels using three additional camptothecin analogues. To further refine this list of QTLs, another validation study was undertaken and seven of the nine QTLs were independently replicated for all nine camptothecin analogues. This is the first study using the CEPH cell lines that demonstrates that a specific pattern of QTLs could be established for a class of drugs which share a mechanism of action. Moreover, it is the first study to report replication of linkage results for drug-induced cytotoxicity using this model. The QTLs, which have been identified as shared by all camptothecins and replicated across multiple datasets, are of considerable interest; they harbor genes related to the shared mechanism of action for the camptothecins, which are responsible for variation in response

First measurement of electron neutrino appearance in NOvA

We report results from the first search for νμ→νe transitions by the NOvA experiment. In an exposure equivalent to 2.74×1020 protons on target in the upgraded NuMI beam at Fermilab, we observe 6 events in the Far Detector, compared to a background expectation of 0.99±0.11(syst) events based on the Near Detector measurement. A secondary analysis observes 11 events with a background of 1.07±0.14(syst). The 3.3σ excess of events observed in the primary analysis disfavors 0.1π<δCP<0.5π in the inverted mass hierarchy at the 90% C.L