Intracellular CO₂ Tension: Practice and Theory

I have been asked to discuss methods of measuring intracellular Pco₂ and to discuss the physiology and biochemistry of intracellular CO₂ tensions. Actually, I am in a relatively fortunate position in that my difficulties in discussing the methodology of intracellular Pco₂ measurements are considerably less than those which face my two colleagues. The reason for this becomes apparent if one analyzes the following quantitative relationships. [Includes discussion.

Shared air: a renewed focus on ventilation for the prevention of tuberculosis transmission

BACKGROUND: Despite an improvement in the overall TB cure rate from 40-74% between 1995 and 2011, TB incidence in South Africa continues to increase. The epidemic is notably disquieting in schools because the vulnerable population is compelled to be present. Older learners (age 15-19) are at particular risk given a smear-positive rate of 427 per 100,000 per year and the significant amount of time they spend indoors. High schools are therefore important locations for potential TB infection and thus prevention efforts. Methods and FINDINGS: Using portable carbon dioxide monitors, we measured CO 2 in classrooms under non-steady state conditions. The threshold for tuberculosis transmission was estimated using a carbon dioxide-based risk equation. We determined a critical rebreathed fraction of carbon dioxide ( ) of 1·6%, which correlates with an indoor CO 2 concentration of 1000 ppm. These values correspond with a ventilation rate of 8·6 l/s per person or 12 air exchanges per hour (ACH) for standard classrooms of 180 m 3 . CONCLUSIONS: Given the high smear positive rate of high-school adolescents in South Africa, the proposal to achieve CO 2 levels of 1000ppm through natural ventilation (in the amount 12 ACH) will not only help achieve WHO guidelines for providing children with healthy indoor environments, it will also provide a low-cost intervention for helping control the TB epidemic in areas of high prevalence

Energy gain of wetted-foam implosions with auxiliary heating for inertial fusion studies

Low convergence ratio implosions (where wetted-foam layers are used to limit capsule convergence, achieving improved robustness to instability growth) and auxiliary heating (where electron beams are used to provide collisionless heating of a hotspot) are two promising techniques that are being explored for inertial fusion energy applications. In this paper, a new analytic study is presented to understand and predict the performance of these implosions. Firstly, conventional gain models are adapted to produce gain curves for fixed convergence ratios, which are shown to well-describe previously simulated results. Secondly, auxiliary heating is demonstrated to be well understood and interpreted through the burn-up fraction of the deuterium-tritium fuel, with the gradient of burn-up with respect to burn-averaged temperature shown to provide good qualitative predictions of the effectiveness of this technique for a given implosion. Simulations of auxiliary heating for a range of implosions are presented in support of this and demonstrate that this heating can have significant benefit for high gain implosions, being most effective when the burn-averaged temperature is between 5 and 20 keV

Radial decoupling of small and large dust grains in the transitional disk RX J1615.3-3255

We present H-band (1.6 {\mu}m) scattered light observations of the transitional disk RX J1615.3-3255, located in the ~1 Myr old Lupus association. From a polarized intensity image, taken with the HiCIAO instrument of the Subaru Telescope, we deduce the position angle and the inclination angle of the disk. The disk is found to extend out to 68 $\pm$ 12 AU in scattered light and no clear structure is observed. Our inner working angle of 24 AU does not allow us to detect a central decrease in intensity similar to that seen at 30 AU in the 880 {\mu}m continuum observations. We compare the observations with multiple disk models based on the Spectral Energy Distribution (SED) and submm interferometry and find that an inner rim of the outer disk at 30 AU containing small silicate grains produces a polarized intensity signal which is an order of magnitude larger than observed. We show that a model in which the small dust grains extend smoothly into the cavity found for large grains is closer to the actual H-band observations. A comparison of models with different dust size distributions suggests that the dust in the disk might have undergone significant processing compared to the interstellar medium.Comment: 8 pages, 7 figures, 4 tables. Accepted for publication in A&

Mechanisms of amphetamine action illuminated through optical monitoring of dopamine synaptic vesicles in Drosophila brain

Amphetamines elevate extracellular dopamine, but the underlying mechanisms remain uncertain. Here we show in rodents that acute pharmacological inhibition of the vesicular monoamine transporter (VMAT) blocks amphetamine-induced locomotion and self-administration without impacting cocaine-induced behaviours. To study VMAT’s role in mediating amphetamine action in dopamine neurons, we have used novel genetic, pharmacological and optical approaches in Drosophila melanogaster. In an ex vivo whole-brain preparation, fluorescent reporters of vesicular cargo and of vesicular pH reveal that amphetamine redistributes vesicle contents and diminishes the vesicle pH-gradient responsible for dopamine uptake and retention. This amphetamine-induced deacidification requires VMAT function and results from net H+ antiport by VMAT out of the vesicle lumen coupled to inward amphetamine transport. Amphetamine-induced vesicle deacidification also requires functional dopamine transporter (DAT) at the plasma membrane. Thus, we find that at pharmacologically relevant concentrations, amphetamines must be actively transported by DAT and VMAT in tandem to produce psychostimulant effects

Ancient and recent differences in the intrinsic susceptibility of Mycobacterium tuberculosis complex to pretomanid

OBJECTIVES: To develop a robust phenotypic antimicrobial susceptibility testing (AST) method with a correctly set breakpoint for pretomanid (Pa), the most recently approved anti-tuberculosis drug. METHODS: The Becton Dickinson Mycobacterial Growth Indicator Tube™ (MGIT) system was used at six laboratories to determine the MICs of a phylogenetically diverse collection of 356 Mycobacterium tuberculosis complex (MTBC) strains to establish the epidemiological cut-off value for pretomanid. MICs were correlated with WGS data to study the genetic basis of differences in the susceptibility to pretomanid. RESULTS: We observed ancient differences in the susceptibility to pretomanid among various members of MTBC. Most notably, lineage 1 of M. tuberculosis, which is estimated to account for 28% of tuberculosis cases globally, was less susceptible than lineages 2, 3, 4 and 7 of M. tuberculosis, resulting in a 99th percentile of 2 mg/L for lineage 1 compared with 0.5 mg/L for the remaining M. tuberculosis lineages. Moreover, we observed that higher MICs (≥8 mg/L), which probably confer resistance, had recently evolved independently in six different M. tuberculosis strains. Unlike the aforementioned ancient differences in susceptibility, these recent differences were likely caused by mutations in the known pretomanid resistance genes. CONCLUSIONS: In light of these findings, the provisional critical concentration of 1 mg/L for MGIT set by EMA must be re-evaluated. More broadly, these findings underline the importance of considering the global diversity of MTBC during clinical development of drugs and when defining breakpoints for AST