Adjusting Phenotypes by Noise Control

Genetically identical cells can show phenotypic variability. This is often caused by stochastic events that originate from randomness in biochemical processes involving in gene expression and other extrinsic cellular processes. From an engineering perspective, there have been efforts focused on theory and experiments to control noise levels by perturbing and replacing gene network components. However, systematic methods for noise control are lacking mainly due to the intractable mathematical structure of noise propagation through reaction networks. Here, we provide a numerical analysis method by quantifying the parametric sensitivity of noise characteristics at the level of the linear noise approximation. Our analysis is readily applicable to various types of noise control and to different types of system; for example, we can orthogonally control the mean and noise levels and can control system dynamics such as noisy oscillations. As an illustration we applied our method to HIV and yeast gene expression systems and metabolic networks. The oscillatory signal control was applied to p53 oscillations from DNA damage. Furthermore, we showed that the efficiency of orthogonal control can be enhanced by applying extrinsic noise and feedback. Our noise control analysis can be applied to any stochastic model belonging to continuous time Markovian systems such as biological and chemical reaction systems, and even computer and social networks. We anticipate the proposed analysis to be a useful tool for designing and controlling synthetic gene networks

Measurement of the total cross section and ρ -parameter from elastic scattering in pp collisions at √s=13 TeV with the ATLAS detector

In a special run of the LHC with β⋆=2.5 km, proton–proton elastic-scattering events were recorded at s√=13 TeV with an integrated luminosity of 340 μb−1 using the ALFA subdetector of ATLAS in 2016. The elastic cross section was measured differentially in the Mandelstam t variable in the range from −t=2.5⋅10−4 GeV2 to −t=0.46 GeV2 using 6.9 million elastic-scattering candidates. This paper presents measurements of the total cross section σtot, parameters of the nuclear slope, and the ρ-parameter defined as the ratio of the real part to the imaginary part of the elastic-scattering amplitude in the limit t→0. These parameters are determined from a fit to the differential elastic cross section using the optical theorem and different parameterizations of the t-dependence. The results for σtot and ρ are σtot(pp→X)=104.7±1.1 mb ,ρ=0.098±0.011. The uncertainty in σtot is dominated by the luminosity measurement, and in ρ by imperfect knowledge of the detector alignment and by modelling of the nuclear amplitude.publishedVersio

Efficacy and safety of posteromedial translation for correction of thoracic curves in adolescent idiopathic scoliosis using a new connection to the spine: the Universal Clamp

Correction of adolescent idiopathic scoliosis (AIS) has been reported with various systems. All-screw constructs are currently the most popular, but they have been associated with a significant decrease in thoracic kyphosis, with a potential risk of junctional kyphosis, not observed with hybrid constructs in the literature. In addition, it is important to weigh potential advantages of pedicle screw fixation against risks specific to its use. Because hybrid constructs are associated with a lower risk of complications and better sagittal correction than all-screw constructs, at present we use lumbar pedicle screws combined with a new sublaminar connection to the spine (Universal Clamps) at thoracic levels. The purpose of this study was to determine the efficacy and safety of the Universal Clamp (UC) posteromedial translation technique for correction of AIS. Seventy-five consecutive patients underwent posterior spinal fusion and hybrid instrumentation for progressive AIS. Correction was performed at the thoracic level using posteromedial translation. At the lumbar level, correction was performed using in situ contouring and compression/distractions maneuvers. A minimum 2-year follow-up was required. Medical data and radiographs were prospectively analyzed and compared using a paired t test. The average age at surgery was 15 years and 4 months (±19 months). The average number of levels fused was 12 ± 1.6. The mean follow-up was 30 ± 5 months. The average preoperative Cobb angle of the major curve was 60° ± 20°. The immediate postoperative major curve correction averaged 66 ± 13%. The average loss of correction of the major curve between the early postoperative assessment and latest follow-up was 3.5° ± 1.4°. The mean Cincinnati correction index was 1.7 ± 0.8 postoperatively, and 1.57 ± 1 at last follow up. The mean rotation of the apical vertebra was corrected from 23.3° ± 9° preoperatively to 7.3° ± 5° at last follow up (69% improvement, P < 0.0001). In the sagittal plane, the mean thoracic kyphosis improved from 23.8° ± 14.2° preoperatively to 32.3° ± 7.3° at last follow up. For the 68 patients who had a normokyphotic or a hypokyphotic sagittal modifier, thoracic kyphosis increased from 20.5° ± 9.9° to 31.8° ± 7.4°, corresponding to a mean kyphosis correction of 55% at last follow up. No intraoperative complication occurred and none of the patients developed proximal junctional kyphosis during the follow up. The principal limitation of the UC technique was the rate of proximal posterior prominence (14.6%), leading us to recommend the use of conventional claws at the upper extremity of the construct. The technique was safe, and reduced operative time, radiation exposure, and blood loss. While achieving correction of deformity in the coronal and axial planes equivalent to the best reported results of all-screw or previous hybrid constructs, the UC hybrid technique appears to provide superior correction in the sagittal plane. The excellent outcome in all three planes was maintained at 2 year follow up

Kinetic Modeling of ABCG2 Transporter Heterogeneity: A Quantitative, Single-Cell Analysis of the Side Population Assay

The side population (SP) assay, a technique used in cancer and stem cell research, assesses the activity of ABC transporters on Hoechst staining in the presence and absence of transporter inhibition, identifying SP and non-SP cell (NSP) subpopulations by differential staining intensity. The interpretation of the assay is complicated because the transporter-mediated mechanisms fail to account for cell-to-cell variability within a population or adequately control the direct role of transporter activity on staining intensity. We hypothesized that differences in dye kinetics at the single-cell level, such as ABCG2 transporter-mediated efflux and DNA binding, are responsible for the differential cell staining that demarcates SP/NSP identity. We report changes in A549 phenotype during time in culture and with TGFβ treatment that correlate with SP size. Clonal expansion of individually sorted cells re-established both SP and NSPs, indicating that SP membership is dynamic. To assess the validity of a purely kinetics-based interpretation of SP/NSP identity, we developed a computational approach that simulated cell staining within a heterogeneous cell population; this exercise allowed for the direct inference of the role of transporter activity and inhibition on cell staining. Our simulated SP assay yielded appropriate SP responses for kinetic scenarios in which high transporter activity existed in a portion of the cells and little differential staining occurred in the majority of the population. With our approach for single-cell analysis, we observed SP and NSP cells at both ends of a transporter activity continuum, demonstrating that features of transporter activity as well as DNA content are determinants of SP/NSP identity