Dynamics of relativistic solitons

Relativistic solitons are self-trapped, finite size, electromagnetic waves of relativistic intensity that propagate without diffraction spreading. They have been predicted theoretically within the relativistic fluid approximation, and have been observed in multi-dimensional particle in cell simulations of laser pulse interaction with the plasma. Solitons were observed in the laser irradiated plasmas with the proton imaging technique as well. This paper reviews many theoretical results on relativistic solitons in electron-ion plasmas.Comment: 12th International Congress on Plasma Physics, 25-29 October 2004, Nice (France

Decoherence of Quantum-Enhanced Timing Accuracy

Quantum enhancement of optical pulse timing accuracy is investigated in the Heisenberg picture. Effects of optical loss, group-velocity dispersion, and Kerr nonlinearity on the position and momentum of an optical pulse are studied via Heisenberg equations of motion. Using the developed formalism, the impact of decoherence by optical loss on the use of adiabatic soliton control for beating the timing standard quantum limit [Tsang, Phys. Rev. Lett. 97, 023902 (2006)] is analyzed theoretically and numerically. The analysis shows that an appreciable enhancement can be achieved using current technology, despite an increase in timing jitter mainly due to the Gordon-Haus effect. The decoherence effect of optical loss on the transmission of quantum-enhanced timing information is also studied, in order to identify situations in which the enhancement is able to survive.Comment: 12 pages, 4 figures, submitte

Worksite Health Promotion in Six Varied US Sites: Beta Testing as a Needed Translational Step

Background. Dissemination of health promotion interventions generally has followed an efficacy, effectiveness to full scale paradigm, and most programs have failed to traverse that sequence. Objective. Report national dissemination of a health promotion program and juxtapose sequential case study observations with the current technology transfer literature. Design. Multiple department-level case studies using contact logs, transcribed interactions, augmented with field notes and validated by respondent review; at least two investigators independently generated site summaries, which were compared to formulate a final report. Results. Adoption was facilitated with national partners and designing branded materials. Critical site influences included departmental features, local champions, and liaison relationships. Achieving distal reach and fidelity required sequential process and program revisions based on new findings at each site. Conclusions. Beta testing to redesign program elements and modify process steps appears to be a needed and often ignored translational step between efficacy and more widespread dissemination

A phenomenological approach to the simulation of metabolism and proliferation dynamics of large tumour cell populations

A major goal of modern computational biology is to simulate the collective behaviour of large cell populations starting from the intricate web of molecular interactions occurring at the microscopic level. In this paper we describe a simplified model of cell metabolism, growth and proliferation, suitable for inclusion in a multicell simulator, now under development (Chignola R and Milotti E 2004 Physica A 338 261-6). Nutrients regulate the proliferation dynamics of tumor cells which adapt their behaviour to respond to changes in the biochemical composition of the environment. This modeling of nutrient metabolism and cell cycle at a mesoscopic scale level leads to a continuous flow of information between the two disparate spatiotemporal scales of molecular and cellular dynamics that can be simulated with modern computers and tested experimentally.Comment: 58 pages, 7 figures, 3 tables, pdf onl

DEPTOR Is an mTOR Inhibitor Frequently Overexpressed in Multiple Myeloma Cells and Required for Their Survival

The mTORC1 and mTORC2 pathways regulate cell growth, proliferation, and survival. We identify DEPTOR as an mTOR-interacting protein whose expression is negatively regulated by mTORC1 and mTORC2. Loss of DEPTOR activates S6K1, Akt, and SGK1, promotes cell growth and survival, and activates mTORC1 and mTORC2 kinase activities. DEPTOR overexpression suppresses S6K1 but, by relieving feedback inhibition from mTORC1 to PI3K signaling, activates Akt. Consistent with many human cancers having activated mTORC1 and mTORC2 pathways, DEPTOR expression is low in most cancers. Surprisingly, DEPTOR is highly overexpressed in a subset of multiple myelomas harboring cyclin D1/D3 or c-MAF/MAFB translocations. In these cells, high DEPTOR expression is necessary to maintain PI3K and Akt activation and a reduction in DEPTOR levels leads to apoptosis. Thus, we identify a novel mTOR-interacting protein whose deregulated overexpression in multiple myeloma cells represents a mechanism for activating PI3K/Akt signaling and promoting cell survival.Howard Hughes Medical Institute (Investigator)Dana-Farber Cancer Institute (High-Tech Research Fund)National Cancer Institute (U.S.)National Institutes of Health (U.S.) (Intramural Research Program)American Cancer SocietyCanadian Institutes of Health Research (Fellowship)American Diabetes Association (Fellowship)W. M. Keck FoundationNational Institutes of Health (U.S.) (R01 CA103866)National Institutes of Health (U.S.) (NIH; R01 AI47389

Promiscuous translocations into immunoglobulin heavy chain switch regions in multiple myeloma

In multiple myeloma, karyotypic 14q32 translocations have been identified at a variable frequency (10–60% in different studies). In the majority of cases, the partner chromosome has not been identified (14q+), and in the remaining cases, a diverse array of chromosomal partners has been implicated, with 11q13 being the most common. We developed a comprehensive Southern blot assay to identify and distinguish different kinds of immunoglobulin heavy chain (IgH) switch recombination events. Illegitimate switch recombination fragments (defined as containing sequences from only one switch region) are potential markers of translocation events into IgH switch regions and were identified in 15 of 21 myeloma cell lines, including seven of eight karyotyped lines that have no detectable 14q32 translocation. From all nine lines or tumor samples analyzed further, cloned illegitimate switch recombination fragments were confirmed to be IgH switch translocation breakpoints. In three of these cases, the translocation breakpoint was shown to be present in the primary tumor. These translocation breakpoints involve six chromosomal loci: 4p16.3 (two lines and the one tumor); 6; 8q24.13; 11q13.3 (in three lines); 16q23.1; and 21q22.1. We suggest that translocations into the IgH locus (i) are frequent (karyotypic 14q32 translocations and/or illegitimate switch recombination fragments are present in primary tumor samples and in 19 of 21 lines that we have analyzed); (ii) occur mainly in switch regions; and (iii) involve a diverse but nonrandom array (i.e., frequently 11q13 or 4p16) of chromosomal partners. This appears to be the most frequent genetic abnormality in multiple myeloma

Liver Enzyme Abnormalities and Associated Risk Factors in HIV Patients on Efavirenz-Based HAART with or without Tuberculosis Co-Infection in Tanzania.

To investigate the timing, incidence, clinical presentation, pharmacokinetics and pharmacogenetic predictors for antiretroviral and anti-tuberculosis drug induced liver injury (DILI) in HIV patients with or without TB co-infection. A total of 473 treatment naïve HIV patients (253 HIV only and 220 with HIV-TB co-infection) were enrolled prospectively. Plasma efavirenz concentration and CYP2B6*6, CYP3A5*3, *6 and *7, ABCB1 3435C/T and SLCO1B1 genotypes were determined. Demographic, clinical and laboratory data were collected at baseline and up to 48 weeks of antiretroviral therapy. DILI case definition was according to Council for International Organizations of Medical Sciences (CIOMS). Incidence of DILI and identification of predictors was evaluated using Cox Proportional Hazards Model. The overall incidence of DILI was 7.8% (8.3 per 1000 person-week), being non-significantly higher among patients receiving concomitant anti-TB and HAART (10.0%, 10.7 per 1000 person-week) than those receiving HAART alone (5.9%, 6.3 per 1000 person-week). Frequency of CYP2B6*6 allele (p = 0.03) and CYP2B6*6/*6 genotype (p = 0.06) was significantly higher in patients with DILI than those without. Multivariate cox regression model indicated that CYP2B6*6/*6 genotype and anti-HCV IgG antibody positive as significant predictors of DILI. Median time to DILI was 2 weeks after HAART initiation and no DILI onset was observed after 12 weeks. No severe DILI was seen and the gain in CD4 was similar in patients with or without DILI. Antiretroviral and anti-tuberculosis DILI does occur in our setting, presenting early following HAART initiation. DILI seen is mild, transient and may not require treatment interruption. There is good tolerance to HAART and anti-TB with similar immunological outcomes. Genetic make-up mainly CYP2B6 genotype influences the development of efavirenz based HAART liver injury in Tanzanians

A gene expression signature distinguishes innate response and resistance to proteasome inhibitors in multiple myeloma

Extensive interindividual variation in response to chemotherapy is a major stumbling block in achieving desirable efficacy in the treatment of cancers, including multiple myeloma (MM). In this study, our goal was to develop a gene expression signature that predicts response specific to proteasome inhibitor (PI) treatment in MM. Using a well-characterized panel of human myeloma cell lines (HMCLs) representing the biological and genetic heterogeneity of MM, we created an in vitro chemosensitivity profile in response to treatment with the four PIs bortezomib, carfilzomib, ixazomib and oprozomib as single agents. Gene expression profiling was performed using next-generation high-throughput RNA-sequencing. Applying machine learning-based computational approaches including the supervised ensemble learning methods Random forest and Random survival forest, we identified a 42-gene expression signature that could not only distinguish good and poor PI response in the HMCL panel, but could also be successfully applied to four different clinical data sets on MM patients undergoing PI-based chemotherapy to distinguish between extraordinary (good and poor) outcomes. Our results demonstrate the use of in vitro modeling and machine learning-based approaches to establish predictive biomarkers of response and resistance to drugs that may serve to better direct myeloma patient treatment options

Dual role of USP 30 in controlling basal pexophagy and mitophagy

USP 30 is an integral protein of the outer mitochondrial membrane that counteracts PINK 1 and Parkin‐dependent mitophagy following acute mitochondrial depolarisation. Here, we use two distinct mitophagy reporter systems to reveal tonic suppression by USP 30, of a PINK 1‐dependent component of basal mitophagy in cells lacking detectable Parkin. We propose that USP 30 acts upstream of PINK 1 through modulation of PINK 1‐substrate availability and thereby determines the potential for mitophagy initiation. We further show that a fraction of endogenous USP 30 is independently targeted to peroxisomes where it regulates basal pexophagy in a PINK 1‐ and Parkin‐independent manner. Thus, we reveal a critical role of USP 30 in the clearance of the two major sources of ROS in mammalian cells and in the regulation of both a PINK 1‐dependent and a PINK 1‐independent selective autophagy pathway