Heavy-traffic asymptotics for networks of parallel queues with Markov-modulated service speeds

We study a network of parallel single-server queues, where the speeds of the servers are varying over time and governed by a single continuous-time Markov chain. We obtain heavy-traf¿c limits for the distributions of the joint workload, waiting time and queue length processes. We do so by using a functional central limit theorem approach, which requires the interchange of steady-state and heavy-traf¿c limits. The marginals of these limiting distributions are shown to be exponential with rates that can be computed by matrix-analytic methods. Moreover, we show how to numerically compute the joint distributions, by viewing the limit processes as multi-dimensional semi-martingale re¿ected Brownian motions in the non-negative orthant

Prospects of gravitational-wave follow-up through a wide-field ultraviolet satellite: A Dorado case study

The detection of gravitational waves from the binary neuron star merger GW170817 and electromagnetic counterparts GRB170817A and AT2017gfo kick-started the field of gravitational-wave multimessenger astronomy. The optically red to near-infrared emission ("red" component) of AT2017gfo was readily explained as produced by the decay of newly created nuclei produced by rapid neutron capture (a kilonova). However, the ultraviolet to optically blue emission ("blue" component) that was dominant at early times (up to 1.5 days) received no consensus regarding its driving physics. Among many explanations, two leading contenders are kilonova radiation from a lanthanide-poor ejecta component and shock interaction (cocoon emission). In this work, we simulate AT2017gfo-like light curves and perform a Bayesian analysis to study whether an ultraviolet satellite capable of rapid gravitational-wave follow-up, could distinguish between physical processes driving the early "blue" component. We find that ultraviolet data starting at 1.2 hr distinguishes the two early radiation models up to 160 Mpc, implying that an ultraviolet mission like Dorado would significantly contribute to insights into the driving emission physics of the postmerger system. While the same ultraviolet data and optical data starting at 12 hr have limited ability to constrain model parameters separately, the combination of the two unlocks tight constraints for all but one parameter of the kilonova model up to 160 Mpc. We further find that a Dorado-like ultraviolet satellite can distinguish the early radiation models up to at least 130 (60) Mpc if data collection starts within 3.2 (5.2) hr for AT2017gfo-like light curves

Mutant huntingtin activates Nrf2-responsive genes and impairs dopamine synthesis in a PC12 model of Huntington's disease

<p>Abstract</p> <p>Background</p> <p>Huntington's disease is a progressive autosomal dominant neurodegenerative disorder that is caused by a CAG repeat expansion in the HD or Huntington's disease gene. Although micro array studies on patient and animal tissue provide valuable information, the primary effect of mutant huntingtin will inevitably be masked by secondary processes in advanced stages of the disease. Thus, cell models are instrumental to study early, direct effects of mutant huntingtin. mRNA changes were studied in an inducible PC12 model of Huntington's disease, before and after aggregates became visible, to identify groups of genes that could play a role in the early pathology of Huntington's disease.</p> <p>Results</p> <p>Before aggregation, up-regulation of gene expression predominated, while after aggregates became visible, down-regulation and up-regulation occurred to the same extent. After aggregates became visible there was a down-regulation of dopamine biosynthesis genes accompanied by down-regulation of dopamine levels in culture, indicating the utility of this model to identify functionally relevant pathways. Furthermore, genes of the anti-oxidant Nrf2-ARE pathway were up-regulated, possibly as a protective mechanism. In parallel, we discovered alterations in genes which may result in increased oxidative stress and damage.</p> <p>Conclusion</p> <p>Up-regulation of gene expression may be more important in HD pathology than previously appreciated. In addition, given the pathogenic impact of oxidative stress and neuroinflammation, the Nrf2-ARE signaling pathway constitutes a new attractive therapeutic target for HD.</p

Proper genomic profiling of (BRCA1-mutated) basal-like breast carcinomas requires prior removal of tumor infiltrating lymphocytes

BRCA1-mutated breast carcinomas may have distinct biological features, suggesting the involvement of specific oncogenic pathways in tumor development. The identification of genomic aberrations characteristic for BRCA1-mutated breast carcinomas could lead to a better understanding of BRCA1-associated oncogenic events and could prove valuable in clinical testing for BRCA1-involvement in patients. Methods: For this purpose, genomic and gene expression profiles of basal-like BRCA1-mutated breast tumors (n=27) were compared with basal-like familial BRCAX (non-. BRCA1/. 2/. CHEK2*1100delC) tumors (n=14) in a familial cohort of 120 breast carcinomas. Results: Genome wide copy number profiles of the BRCA1-mutated breast carcinomas in our data appeared heterogeneous. Gene expression analyses identifi

Cigarette smoke induces genetic instability in airway epithelial cells by suppressing FANCD2 expression

Chromosomal abnormalities are commonly found in bronchogenic carcinoma cells, but the molecular causes of chromosomal instability (CIN) and their relationship to cigarette smoke has not been defined. Because the Fanconi anaemia (FA)/BRCA pathway is essential for maintenance of chromosomal stability, we tested the hypothesis that cigarette smoke suppresses that activity of this pathway. Here, we show that cigarette smoke condensate (CSC) inhibited translation of FANCD2 mRNA (but not FANCC or FANCG) in normal airway epithelial cells and that this suppression of FANCD2 expression was sufficient to induce both genetic instability and programmed cell death in the exposed cell population. Cigarette smoke condensate also suppressed FANCD2 function and induced CIN in bronchogenic carcinoma cells, but these cells were resistant to CSC-induced apoptosis relative to normal airway epithelial cells. We, therefore, suggest that CSC exerts pressure on airway epithelial cells that results in selection and emergence of genetically unstable somatic mutant clones that may have lost the capacity to effectively execute an apoptotic programme. Carcinogen-mediated suppression of FANCD2 gene expression provides a plausible molecular mechanism for CIN in bronchogenic carcinogenesis

Conscious uncoupling between FANCI and FANCD2 in DNA repair

The Fanconi anemia (FA)-BRCA pathway mediates repair of DNA interstrand crosslinks. The FA core complex, a multi-subunit ubiquitin ligase, participates in the detection of DNA lesions and monoubiquitinates two downstream FA proteins, FANCD2 and FANCI (or the ID complex). However, the regulation of the FA core complex itself is poorly understood. Here we show that the FA core complex proteins are recruited to sites of DNA damage and form nuclear foci in S and G2 phases of the cell cycle. ATR kinase activity, an intact FA core complex and FANCM-FAAP24 were crucial for this recruitment. Surprisingly, FANCI, but not its partner FANCD2, was needed for efficient FA core complex foci formation. Monoubiquitination or ATR-dependent phosphorylation of FANCI were not required for the FA core complex recruitment, but FANCI deubiquitination by USP1 was. Additionally, BRCA1 was required for efficient FA core complex foci formation. These findings indicate that FANCI functions upstream of FA core complex recruitment independently of FANCD2, and alter the current view of the FA-BRCA pathway

Detection and localization of early- and late-stage cancers using platelet RNA

Cancer patients benefit from early tumor detection since treatment outcomes are more favorable for less advanced cancers. Platelets are involved in cancer progression and are considered a promising biosource for cancer detection, as they alter their RNA content upon local and systemic cues. We show that tumor-educated platelet (TEP) RNA-based blood tests enable the detection of 18 cancer types. With 99% specificity in asymptomatic controls, thromboSeq correctly detected the presence of cancer in two-thirds of 1,096 blood samples from stage I–IV cancer patients and in half of 352 stage I–III tumors. Symptomatic controls, including inflammatory and cardiovascular diseases, and benign tumors had increased false-positive test results with an average specificity of 78%. Moreover, thromboSeq determined the tumor site of origin in five different tumor types correctly in over 80% of the cancer patients. These results highlight the potential properties of TEP-derived RNA panels to supplement current approaches for blood-based cancer screening