An N Server Cutoff Multi-Priority Queue

Consider a multi-priority, nonpreemptive, N-server Poisson arrival queueing system. Service times are negative exponential. In order to save available servers for higher priority customers, arriving customers of each lower priority are deliberately queued whenever the number of servers busy equals or exceeds a given priority-dependent cutoff number. A queued priority i customer enters service the instant there are fewer than the respective cutoff number of servers busy and all higher priority queues are empty. The principal result is the priority i waiting time mean, second moment, and distribution (in transforms). The analysis is extended to systems in which any subset of priority levels may overflow to some other system, rather than join infinite capacity queues. The paper concludes with illustrative computational results

An N Server Cutoff Priority Queue Where Customers Request a Random Number of Servers

Consider a multi-priority, nonpreemptive, N-server Poisson arrival queueing system. The number of servers requested by an arrival has a known probability distribution. Service times are negative exponential. In order to save available servers for higher priority customers, arriving customers of each lower priority are deliberately queued whenever the number of servers busy equals or exceeds a given priority-dependent cutoff number. A queued priority i customer enters service the instant the number of servers busy is at most the respective cutoff number of servers minus the number of servers requested (by the customer) and all higher priority queues are empty. In other words the queueing discipline is in a sense HOL by priorities, FCFS within a priority. All servers requested by a customer start service simultaneously; service completion instants are independent. We derive the priority i waiting time distribution (in transform domain) and other system statistics

Toxicity Assays in Nanodrops Combining Bioassay and Morphometric Endpoints

BACKGROUND: Improved chemical hazard management such as REACH policy objective as well as drug ADMETOX prediction, while limiting the extent of animal testing, requires the development of increasingly high throughput as well as highly pertinent in vitro toxicity assays. METHODOLOGY: This report describes a new in vitro method for toxicity testing, combining cell-based assays in nanodrop Cell-on-Chip format with the use of a genetically engineered stress sensitive hepatic cell line. We tested the behavior of a stress inducible fluorescent HepG2 model in which Heat Shock Protein promoters controlled Enhanced-Green Fluorescent Protein expression upon exposure to Cadmium Chloride (CdCl(2)), Sodium Arsenate (NaAsO(2)) and Paraquat. In agreement with previous studies based on a micro-well format, we could observe a chemical-specific response, identified through differences in dynamics and amplitude. We especially determined IC50 values for CdCl(2) and NaAsO(2), in agreement with published data. Individual cell identification via image-based screening allowed us to perform multiparametric analyses. CONCLUSIONS: Using pre/sub lethal cell stress instead of cell mortality, we highlighted the high significance and the superior sensitivity of both stress promoter activation reporting and cell morphology parameters in measuring the cell response to a toxicant. These results demonstrate the first generation of high-throughput and high-content assays, capable of assessing chemical hazards in vitro within the REACH policy framework

Host insulin stimulates Echinococcus multilocularis insulin signalling pathways and larval development.

BACKGROUND The metacestode of the tapeworm Echinococcus multilocularis is the causative agent of alveolar echinococcosis, a lethal zoonosis. Infections are initiated through establishment of parasite larvae within the intermediate host's liver, where high concentrations of insulin are present, followed by tumour-like growth of the metacestode in host organs. The molecular mechanisms determining the organ tropism of E. multilocularis or the influences of host hormones on parasite proliferation are poorly understood. RESULTS Using in vitro cultivation systems for parasite larvae we show that physiological concentrations (10 nM) of human insulin significantly stimulate the formation of metacestode larvae from parasite stem cells and promote asexual growth of the metacestode. Addition of human insulin to parasite larvae led to increased glucose uptake and enhanced phosphorylation of Echinococcus insulin signalling components, including an insulin receptor-like kinase, EmIR1, for which we demonstrate predominant expression in the parasite's glycogen storage cells. We also characterized a second insulin receptor family member, EmIR2, and demonstrated interaction of its ligand binding domain with human insulin in the yeast two-hybrid system. Addition of an insulin receptor inhibitor resulted in metacestode killing, prevented metacestode development from parasite stem cells, and impaired the activation of insulin signalling pathways through host insulin. CONCLUSIONS Our data indicate that host insulin acts as a stimulant for parasite development within the host liver and that E. multilocularis senses the host hormone through an evolutionarily conserved insulin signalling pathway. Hormonal host-parasite cross-communication, facilitated by the relatively close phylogenetic relationship between E. multilocularis and its mammalian hosts, thus appears to be important in the pathology of alveolar echinococcosis. This contributes to a closer understanding of organ tropism and parasite persistence in larval cestode infections. Furthermore, our data show that Echinococcus insulin signalling pathways are promising targets for the development of novel drugs

Computational archaeology of the Pristionchus pacificus genome reveals evidence of horizontal gene transfers from insects

<p>Abstract</p> <p>Background</p> <p>The recent sequencing of nematode genomes has laid the basis for comparative genomics approaches to study the impact of horizontal gene transfer (HGT) on the adaptation to new environments and the evolution of parasitism. In the beetle associated nematode <it>Pristionchus pacificus </it>HGT events were found to involve cellulase genes of microbial origin and Diapausin genes that are known from beetles, but not from other nematodes. The insect-to-nematode horizontal transfer is of special interest given that <it>P. pacificus </it>shows a tight association with insects.</p> <p>Results</p> <p>In this study we utilized the observation that horizontally transferred genes often exhibit codon usage patterns more similar to that of the donor than that of the acceptor genome. We introduced GC-normalized relative codon frequencies as a measure to detect characteristic features of <it>P. pacificus </it>orphan genes that show no homology to other nematode genes. We found that atypical codon usage is particularly prevalent in <it>P. pacificus </it>orphans. By comparing codon usage profiles of 71 species, we detected the most significant enrichment in insect-like codon usage profiles. In cross-species comparisons, we identified 509 HGT candidates that show a significantly higher similarity to insect-like profiles than genes with nematode homologs. The most abundant gene family among these genes are non-LTR retrotransposons. Speculating that retrotransposons might have served as carriers of foreign genetic material, we found a significant local clustering tendency of orphan genes in the vicinity of retrotransposons.</p> <p>Conclusions</p> <p>Our study combined codon usage bias, phylogenetic analysis, and genomic colocalization into a general picture of the computational archaeology of the <it>P. pacificus </it>genome and suggests that a substantial fraction of the gene repertoire is of insect origin. We propose that the <it>Pristionchus</it>-beetle association has facilitated HGT and discuss potential vectors of these events.</p

Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome associated with COVID-19: An Emulated Target Trial Analysis.

RATIONALE: Whether COVID patients may benefit from extracorporeal membrane oxygenation (ECMO) compared with conventional invasive mechanical ventilation (IMV) remains unknown. OBJECTIVES: To estimate the effect of ECMO on 90-Day mortality vs IMV only Methods: Among 4,244 critically ill adult patients with COVID-19 included in a multicenter cohort study, we emulated a target trial comparing the treatment strategies of initiating ECMO vs. no ECMO within 7 days of IMV in patients with severe acute respiratory distress syndrome (PaO2/FiO2 <80 or PaCO2 ≥60 mmHg). We controlled for confounding using a multivariable Cox model based on predefined variables. MAIN RESULTS: 1,235 patients met the full eligibility criteria for the emulated trial, among whom 164 patients initiated ECMO. The ECMO strategy had a higher survival probability at Day-7 from the onset of eligibility criteria (87% vs 83%, risk difference: 4%, 95% CI 0;9%) which decreased during follow-up (survival at Day-90: 63% vs 65%, risk difference: -2%, 95% CI -10;5%). However, ECMO was associated with higher survival when performed in high-volume ECMO centers or in regions where a specific ECMO network organization was set up to handle high demand, and when initiated within the first 4 days of MV and in profoundly hypoxemic patients. CONCLUSIONS: In an emulated trial based on a nationwide COVID-19 cohort, we found differential survival over time of an ECMO compared with a no-ECMO strategy. However, ECMO was consistently associated with better outcomes when performed in high-volume centers and in regions with ECMO capacities specifically organized to handle high demand. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Electronic Raman scattering in p-doped GaAs/Ga1-xAlxAs quantum-well structures: Scattering mechanisms and many-particle interactions

By means of resonance Raman spectroscopy we have investigated intersubband transitions of quasi-two-dimensional (2D) hole gases in p-type modulation-doped GaAs/Ga1-xAlxAs quantum-well structures. The observed excitations have an essentially single-particle character due to Landau damping of collective excitations and due to single-particle scattering by energy-density fluctuations under conditions of extreme resonance. In samples with well widths of typically 100–200 Å and 2D hole densities ρ∼1011 cm-2, we observe a characteristic variation of intersubband-transition energies with laser frequency in depolarized and in polarized scattering configurations. This variation is caused by the nonparabolic subband dispersion of the 2D single-particle hole subbands. Experiments under variation of p, by illuminating the sample with photons that have energies above the band gap of the Ga1-xAlxAs barriers, allow an estimate of the relative strengths of direct and exchange Coulomb interactions. From these experiments a greater relative strength of the exchange interaction, in comparison to that found for 2D electron gases, can be deduced

Collective intersubband excitations in p-doped GaAs-AlGaAs multiple quantum wells

We report on Raman spectroscopic investigations of collective spin-density (SDW) and charge-density waves (CDW) in the two-dimensional hole gas of a p-modulation doped GaAs/AlxGa1-xAs multiple quantum-well (MQW) structure and on the consequence of Landau damping of these excitations. From the existence of collective SDW with energies lower than the border of the single-particle continuum we derive that exchange and correlation effects are of considerable strength in such hole gases

Consequences of subband nonparabolicity on intersubband excitations in p-doped GaAs/AlxGa1-xAs quantum wells

By means of resonance Raman spectroscopy we have observed a characteristic shift of hole-intersubband transitions with excitation energy in p-doped GaAs/AlxGa1-xAs quantum-well structures. As possible reasons for the shift, the nonparabolicity of the valence subbands as well as fluctuations of the well width are discussed. Both contributions can be separated experimentally by application of an external magnetic field, which quantizes the in-plane motion of the carriers. For our samples, we can show that the shifts observed for B=0 T are mainly caused by subband nonparabolicity. This interpretation is confirmed by a comparison with results of a simulation of single-particle Raman spectra based on a subband calculation with Luttinger’s 4×4 Hamiltonian. Corresponding shifts are observed both in depolarized and polarized spectra