Bayesian inference on stochastic gene transcription from flow cytometry data

Motivation Transcription in single cells is an inherently stochastic process as mRNA levels vary greatly between cells, even for genetically identical cells under the same experimental and environmental conditions. We present a stochastic two-state switch model for the population of mRNA molecules in single cells where genes stochastically alternate between a more active ON state and a less active OFF state. We derive the stationary solution of such a model and prove that it can be written as a mixture of a Poisson and a Poisson-beta probability distribution. This finding facilitates inference for single cell data, observed at a single time point, from flow cytometry experiments such as FACS or FISH as it allows one to sample directly from the equilibrium distribution of the mRNA population. We hence propose a Bayesian inferential methodology using a pseudo-marginal approach and a recent approximation to integrate over unobserved states associated with measurement error. Results We provide a general inferential framework which can be widely used to study transcription in single cells from the kind of data arising in flow cytometry experiments. The approach allows us to separate between the intrinsic stochasticity of the molecular dynamics and the measurement noise. The methodology is tested in simulation studies and results are obtained for experimental multiple single cell data from in situ hybridization (FISH) flow cytometry experiment

The early dynamical evolution of star clusters near the Galactic Centre

We examine the dynamical evolution of both Plummer sphere and substructured (fractal) star-forming regions in Galactic Centre (GC) strong tidal fields to see what initial conditions could give rise to an Arches-like massive star cluster by ∼2 Myr. We find that any initial distribution has to be contained within its initial tidal radius to survive, which sets a lower limit of the initial density of the Arches of ∼600 M⊙ pc−3 if the Arches is at 30 pc from the GC, or ∼200 M⊙ pc−3 if the Arches is at 100 pc from the GC. Plummer spheres that survive change little other than to dynamically mass segregate, but initially fractal distributions rapidly erase substructure, dynamically mass segregate and by 2 Myr look extremely similar to initial Plummer spheres, therefore it is almost impossible to determine the initial conditions of clusters in strong tidal fields

On-Chip Integration of Functional Hybrid Materials and Components in Nanophotonics and Optoelectronics

[No abstract available

Some results on compact convergence semigroups defined by filters

In this paper the concept of convergence defined by filters is used and applied in the study of semigroups. Special emphasis is placed on compact convergence semigroups and their properties

Management of Breast Abscesses in Jamaican Women Is There Need for a Paradigm Shift?

A paradigm shift from operative to non-operative management of breast abscesses has occurred in surgical centres worldwide. The recent experience in managing these patients at the University Hospital of the West Indies (UHWI) was examined. Data were obtained retrospectively from dockets retrieved from the UHWI medical records department, and were analysed using the SPSS version 11.0 software package for Windows. Seventy-seven patients with breast abscesses presented during the 66-month study period, but complete data were unavailable for seventeen cases. The mean age of the remaining sixty patients was 32 years. There was one male patient. There were no cases of bilateral disease, and the majority was right-sided. Mean white blood cell count at presentation was mildly elevated at 11.9 x 109/L, and had no relationship to method of management or length of stay. There were two cases treated with aspiration and antibiotics only. All other cases were treated with incision and drainage. Culture results were available in forty-four cases, and in 80%, Staphylococcus aureus was identified, with one case of methicillin resistant Staphylococcus aureus. The mean delay to the operating theatre was one day after presentation and the mean length of stay was 4.5 days. Seventeen patients had a ‘non-cosmetic’ incision. The traditional management of breast abscess provides challenges in terms of delay to the operating theatre and prolonged hospital stays. There is increased expense, as well as loss of pro-ductive work hours, associated with this line of treatment. Non-operative management has not tra-ditionally been undertaken in our institution, but it is documented elsewhere to be safe, practical, and results in improved cosmetic outcomes. Prospective protocol-based trials are necessary to identify the patients most suitable for this line of management in a setting with limited resources. Keywords: Abscesses, aspiration, breast, incision, management "Tratamiento de Abscesos Mamarios en Mujeres Jamaicanas. ¿Es Necesario un Cambio de Paradigma?" RESUMEN Un cambio de paradigma de tratamiento operatorio a tratamiento no operatorio de los abscesos mamarios, se ha producido en los centros quirúrgicos a nivel mundial. Se examinó la experiencia reciente en el tratamiento de estos pacientes en el Hospital Universitario de West Indies (HUWI). Se obtuvieron datos tomados retrospectivamente de listas de casos archivados en el Departamento de Historias Clínicas de HUWI, los cuales fueron analizados usando la versión 11.0 del software SPSS para Windows. Durante el período de 66 meses de estudio, se presentaron setenta y siete pacientes con abscesos de mama, pero en diecisiete casos no pudo disponerse de todos los datos. La edad promedio de los otros sesenta pacientes fue 32 años. Hubo un paciente varón. No hubo ningún caso de enfer-medad bilateral, y la mayoría se trataba del lado derecho. El conteo promedio de leucocitos a la hora de la presentación fue ligeramente elevado en 11.9 x 109/L, y no guardaba ninguna relación con el método de tratamiento o duración de la estancia. Hubo dos casos tratados con aspiración y anti-bióticos solamente. Todos los otros casos se trataron con incisión y drenaje. Los resultados del cultivo se hallaban disponibles en cuarenta y cuatro casos, y en el 80% se identificó el estafilococo dorado, con un caso de Staphylococcus aureus resistente a la meticilina. La demora promedio para entrar al salón de operaciones fue de un día después de la presentación y la duración promedio de estancia eran 4.5 días. Diecisiete pacientes tenían una incisión ‘no cosmética’. El tratamiento tradicional del absceso mamario presenta retos en términos de demora para ingresar al salón de operaciones y estadía prolongada en el hospital. Esta línea de tratamiento conlleva un aumento de los gastos así como pérdida de horas de trabajo productivo. El tratamiento no operatorio no ha sido tradicionalmente practicado en nuestra institución, pero sí en otras partes donde se documenta que es seguro, práctico, y produce mejores resultados cosméticos. Se requieren ensayos protocolares prospectivos a fin de identificar a los pacientes más convenientes para esta línea de tratamiento en un contexto de recursos limitados. Palabras claves: Abscesos, aspiración, mama, incisión, tratamient

The Effect of Food or Omeprazole on the Pharmacokinetics of Osimertinib in Patients With Non-Small-Cell Lung Cancer and in Healthy Volunteers.

Two phase 1, open-label studies assessed the impact of food or gastric pH modification (omeprazole) on the exposure and safety/tolerability of osimertinib and its metabolites. The food effect study was an open-label, 2-period crossover study in patients with advanced non-small-cell lung cancer, randomized into 2 treatment sequences: single-dose osimertinib 80 mg in a fed then fasted state or fasted then fed. The gastric pH study was an open-label, 2-period fixed sequence study assessing the effect of omeprazole on osimertinib exposure in healthy male volunteers. In period 1, volunteers received omeprazole 40 mg (days 1-4), then omeprazole 40 mg plus osimertinib 80 mg (day 5). In period 2, volunteers received osimertinib 80 mg alone (single dose). Blood samples were collected at prespecified time points for pharmacokinetic analyses. Safety/tolerability was also assessed. In the food effect study 38 patients were randomized to fed/fasted (n = 18) or fasted/fed (n = 20) sequences with all patients completing treatment. Coadministration with food did not affect osimertinib exposure (geometric least-squares mean ratios [90% confidence intervals]: 106.05% [94.82%, 118.60%] [area under the plasma concentration time curve from zero to 72 hours] and 92.75% [81.40%, 105.68%] [maximum plasma concentration]). In the gastric pH study (n = 68 received treatment, n = 47 completed the study), coadministration with omeprazole did not affect osimertinib exposure (geometric least-squares mean ratios 106.66% [100.26%, 113.46%] [area under the concentration-time curve], 101.65% [94.65%, 109.16%] [peak concentration]). Osimertinib was well tolerated in both studies. Osimertinib may be administered without regard to food. Dose restriction is not required in patients whose gastric pH may be altered by concomitant agents or medical conditions. ClinicalTrials.gov: NCT02224053, NCT02163733