Effects of non-universal large scales on conditional structure functions in turbulence

We report measurements of conditional Eulerian and Lagrangian structure functions in order to assess the effects of non-universal properties of the large scales on the small scales in turbulence. We study a 1m $\times$ 1m $\times$ 1.5m flow between oscillating grids which produces $R_\lambda=285$ while containing regions of nearly homogeneous and highly inhomogeneous turbulence. Large data sets of three-dimensional tracer particle velocities have been collected using stereoscopic high speed cameras with real-time image compression technology. Eulerian and Lagrangian structure functions are measured in both homogeneous and inhomogeneous regions of the flow. We condition the structure functions on the instantaneous large scale velocity or on the grid phase. At all scales, the structure functions depend strongly on the large scale velocity, but are independent of the grid phase. We see clear signatures of inhomogeneity near the oscillating grids, but even in the homogeneous region in the center we see a surprisingly strong dependence on the large scale velocity that remains at all scales. Previous work has shown that similar correlations extend to very high Reynolds numbers. Comprehensive measurements of these effects in a laboratory flow provide a powerful tool for assessing the effects of shear, inhomogeneity and intermittency of the large scales on the small scales in turbulence

Slip-velocity of large neutrally-buoyant particles in turbulent flows

We discuss possible definitions for a stochastic slip velocity that describes the relative motion between large particles and a turbulent flow. This definition is necessary because the slip velocity used in the standard drag model fails when particle size falls within the inertial subrange of ambient turbulence. We propose two definitions, selected in part due to their simplicity: they do not require filtration of the fluid phase velocity field, nor do they require the construction of conditional averages on particle locations. A key benefit of this simplicity is that the stochastic slip velocity proposed here can be calculated equally well for laboratory, field, and numerical experiments. The stochastic slip velocity allows the definition of a Reynolds number that should indicate whether large particles in turbulent flow behave (a) as passive tracers; (b) as a linear filter of the velocity field; or (c) as a nonlinear filter to the velocity field. We calculate the value of stochastic slip for ellipsoidal and spherical particles (the size of the Taylor microscale) measured in laboratory homogeneous isotropic turbulence. The resulting Reynolds number is significantly higher than 1 for both particle shapes, and velocity statistics show that particle motion is a complex non-linear function of the fluid velocity. We further investigate the nonlinear relationship by comparing the probability distribution of fluctuating velocities for particle and fluid phases

Evolution of Bow-Tie Architectures in Biology

Bow-tie or hourglass structure is a common architectural feature found in many biological systems. A bow-tie in a multi-layered structure occurs when intermediate layers have much fewer components than the input and output layers. Examples include metabolism where a handful of building blocks mediate between multiple input nutrients and multiple output biomass components, and signaling networks where information from numerous receptor types passes through a small set of signaling pathways to regulate multiple output genes. Little is known, however, about how bow-tie architectures evolve. Here, we address the evolution of bow-tie architectures using simulations of multi-layered systems evolving to fulfill a given input-output goal. We find that bow-ties spontaneously evolve when the information in the evolutionary goal can be compressed. Mathematically speaking, bow-ties evolve when the rank of the input-output matrix describing the evolutionary goal is deficient. The maximal compression possible (the rank of the goal) determines the size of the narrowest part of the network—that is the bow-tie. A further requirement is that a process is active to reduce the number of links in the network, such as product-rule mutations, otherwise a non-bow-tie solution is found in the evolutionary simulations. This offers a mechanism to understand a common architectural principle of biological systems, and a way to quantitate the effective rank of the goals under which they evolved.clos

Effects of concurrent vaginal miconazole treatment on the absorption and exposure of Nestorone® (segesterone acetate) and ethinyl estradiol delivered from a contraceptive vaginal ring: A randomized, crossover drug–drug interaction study

Objectives: To evaluate the effects of concurrent administration of three vaginal miconazole nitrate formulations on the absorption and exposure of Nestorone® (segesterone acetate) and ethinyl estradiol from a novel contraceptive vaginal ring (NES/EE CVR). Study design: This was an open-label, randomized, crossover, drug-drug interaction study conducted over three menstrual cycles in healthy women with regular menses. We compared systemic exposure to NES and EE by determining area under the curve (AUC_8–21d) with CVR-only and CVR with each miconazole treatment. Three different miconazole formulations (single dose suppository, multiple dose suppository or multiple dose cream) were administered in a single dose on day 8 or multiple doses on days 8–10 after CVR insertion. We evaluated safety and tolerability of the CVR in the presence of antimycotic co-medication. Results: 45 participants were randomized and 29 completed participation. Systemic exposure to NES and EE released from the CVR increased with single or multiple doses of miconazole suppositories but not with multiple dose cream. The maximum EE geometric mean ratio (GMR) for AUC_8–21d was 1.67 (1.51–1.86) for single dose and 1.42 (1.21–1.66) for multiple dose suppositories. By contrast, systemic exposure to NES and EE was comparable with and without miconazole cream (all GMRs and confidence intervals within 0.80 to 1.25). Adverse events (AEs) were similar with CVR only and with all miconazole treatment groups. There were no serious treatment related AEs. Conclusions: Miconazole vaginal suppositories were associated with increased systemic levels of NES and EE, while systemic exposure with miconazole vaginal cream was comparable to no-miconazole exposure. Implications: Co-administration of miconazole suppositories with the investigational NES/EE CVR led to higher systemic exposure of both hormones, while co-administration with miconazole cream did not affect hormone levels. Women utilizing the NES/EE CVR may be advised to use an oral formulation or miconazole cream rather than suppository to treat vaginal candidiasis

Safety and Availability of Dapivirine (TMC120) Delivered from an Intravaginal Ring

Vaginal delivery of 200 mg or 25 mg dapivirine from intravaginal rings (IVRs) was evaluated over a 7-day period in two phase 1 safety trials (IPM001 and IPM008, respectively) in a total of 25 healthy women 19 to 46 years of age. The IVR was generally safe and well tolerated with similar adverse events observed in the placebo and dapivirine groups. Across both studies, dapivirine concentrations in vaginal fluids measured at the introitus, cervix, and ring area were within the mean range of 0.7-7.1 mg/ml. Mean dapivirine concentrations in vaginal and cervical tissues on day 7 were 0.3-0.7 mg/g in IPM001 and 1.5-3.5 mg/g in IPM008. Mean plasma concentrations of dapivirine were 1000x the EC50 against wild-type HIV-1 (LAI) in MT4 cells suggesting that IVR delivery of microbicides is a viable option meriting further study

Endometrial effect of progesterone delivered by vaginal rings in estrogen-treated postmenopausal women

Aim: The type of estrogen and progestin as well as their doses, route and regimens of administration may each affect the benefit–risk profile of postmenopausal hormone therapy. The aim of this study was to evaluate the endometrial effect of progesterone released continuously from a vaginal ring, combined with transdermal estradiol in postmenopausal women. Method: Forty-four postmenopausal women participated in a randomized, double-blind, dose-finding study evaluating two hormonal treatments, combining 50μg/day of estradiol delivered by transdermal patches and either 0.5-g or 1-g progesterone vaginal rings (PVR) given for 12 weeks. The effect on the endometrium was assessed by histology and the detection of the proliferative marker Ki-67. We also measured the serum concentration of estradiol and progesterone, the tissue concentration of progesterone and the immunolocalization of estradiol and progesterone receptors in the endometrium. Results: Endometrial thickness was increased after both treatments, although endometrial histology appeared atrophic in most biopsies. A circulating dose-response of serum progesterone levels was observed from the first to the 12th week of PVR use. In the high-progesterone-dose group, the scarce presence of Ki-67 and hormone receptors reflected the predominant action of progesterone in endometrial glands and stroma, in parallel with a lower tissue concentration of progesterone in this group. Conclusion: The PVR appears to be a promising method of administering natural progesterone to postmenopausal women treated with estrogen. Estradiol levels corrected the menopausal symptoms, as expected, and the presence of atrophic endometrium in the majority of women indicated that both doses of progesterone oppose the stimulatory estradiol effects, although the percentage of proliferative tissue was not negligible in both groups