51 research outputs found
Metabolic Futile Cycles and Their Functions: A Systems Analysis of Energy and Control
It has long been hypothesized that futile cycles in cellular metabolism are
involved in the regulation of biochemical pathways. Following the work of
Newsholme and Crabtree, we develop a quantitative theory for this idea based on
open-system thermodynamics and metabolic control analysis. It is shown that the
{\it stoichiometric sensitivity} of an intermediary metabolite concentration
with respect to changes in steady-state flux is governed by the effective
equilibrium constant of the intermediate formation, and the equilibrium can be
regulated by a futile cycle. The direction of the shift in the effective
equilibrium constant depends on the direction of operation of the futile cycle.
High stoichiometric sensitivity corresponds to ultrasensitivity of an
intermediate concentration to net flow through a pathway; low stoichiometric
sensitivity corresponds to super-robustness of concentration with respect to
changes in flux. Both cases potentially play important roles in metabolic
regulation. Futile cycles actively shift the effective equilibrium by expending
energy; the magnitude of changes in effective equilibria and sensitivities is a
function of the amount of energy used by a futile cycle. This proposed
mechanism for control by futile cycles works remarkably similarly to kinetic
proofreading in biosynthesis. The sensitivity of the system is also intimately
related to the rate of concentration fluctuations of intermediate metabolites.
The possibly different roles of the two major mechanisms for cellular
biochemical regulation, namely reversible chemical modifications via futile
cycles and shifting equilibrium by macromolecular binding, are discussed.Comment: 11 pages, 5 figure
Magnetohydrodynamic Oscillations in the Solar Corona and Earthâs Magnetosphere: Towards Consolidated Understanding
Using the physical properties of artefacts to manage throughâlife knowledge flows in the built environment: an initial exploration
Effective throughâlife management of built facilities requires effective throughâlife knowledge management to support it. The KIM (Immortal Information and ThroughâLife Knowledge Management) project attempted to develop such an approach, based on a dichotomy of knowledge and information. Knowledge is conceived in terms of communities of practice. An initial philosophical analysis demonstrates deficiencies in this conception. Drawing inspiration from production theory, a tripartite analysis is offered, suggesting that knowledge flows consist of: social practices, information and physical properties. Literature on physical properties from design studies, production management and ethnomethodology is briefly reviewed to demonstrate the information bearing functions of physical properties. Fieldwork conforming to the unique adequacy requirement of methods was carried out on construction sites, in hotel and hospital facilities during the use stage of their life cycles. Safety barriers on construction sites were found to have informational properties beyond their function as a physical barrier. The quality of information delivered by wayfinding signs was found to depend upon both the physical placement of the signs in relation to the surrounding environment and the physical layout of the sign itself. It was found that social practices are institutionalized to repair the knowledge flow when the physically instantiated wayfinding system breaks down. Finally, through the investigation of practices surrounding emergency resuscitation equipment, it was found that if the physical properties of information are not designed to mesh with the work practices of the setting, this will lead to a breakdown in the knowledge flow. It is suggested that elements of knowledge management, ethnomethodology, production management and design studies might be integrated to form the basis of a hybrid discipline
Influence of ambient and thoracic temperatures upon sexual behaviour of the gypsy moth, Lymantria dispar
To Stay or Not to Stay: Issues in Rural Primary Care Physician Retention in Eastern Kentucky
Efficacy and safety of efavirenz 400 mg daily versus 600 mg daily: 96-week data from the randomised, double-blind, placebo-controlled, non-inferiority ENCORE1 study
Background
The week 48 primary analysis of the ENCORE1 trial established the virological non-inferiority and safety of efavirenz 400 mg compared with the standard 600 mg dose, combined with tenofovir and emtricitabine, as first-line HIV therapy. This 96-week follow-up of the trial assesses the durability of efficacy and safety of this treatment over 96 weeks.
Methods
ENCORE1 was a double-blind, placebo-controlled, non-inferiority trial done at 38 clinical sites in 13 countries. HIV-infected adult patients (âĽ16 years of age) with no previous antiretroviral therapy, a CD4 cell count of 50â500 cells per ÎźL, and plasma HIV-1 viral load of at least 1000 copies per mL were randomly assigned (1:1) by an electronic case report form to receive fixed-dose daily tenofovir 300 mg and emtricitabine 200 mg plus efavirenz either 400 mg daily or 600 mg daily. Participants, physicians, and all other trial staff were masked to treatment assignment. Randomisation was stratified by HIV-1 viral load at baseline (⤠or >100â000 copies per mL). The primary endpoint was the difference in the proportions of patients in the two treatment groups with a plasma HIV-1 viral load below 200 copies per mL at week 96. Treatment groups were deemed to be non-inferior if the lower limit of the 95% CI for the difference in viral load was above â10% by modified intention-to-treat analysis. Non-inferiority was assessed in the modified intention-to-treat, per-protocol, and non-completer=failure (NC=F) populations. Adverse events and serious adverse events were summarised by treatment group. This study is registered with ClinicalTrials.gov, number NCT01011413.
Findings
Between Aug 24, 2011, and March 19, 2012, 636 eligible participants were enrolled and randomly assigned to the two treatment groups (324 to efavirenz 400 mg and 312 to efavirenz 600 mg). The intention-to-treat population who received at least one dose of study drug comprised 630 patients: 321 in the efavirenz 400 mg group and 309 in the efavirenz 600 mg group. 585 patients (93%; 299 in the efavirenz 400 mg group and 286 in the 600 mg group) completed 96 weeks of follow-up. At 96 weeks, 289 (90¡0%) of 321 patients in the efavirenz 400 mg group and 280 (90¡6%) of 309 in the efavirenz 600 mg group had a plasma HIV-1 viral load less than 200 copies per mL (difference â0¡6, 95% CI â5¡2 to 4¡0; p=0¡72), which suggests continued non-inferiority of the lower efavirenz dose. Non-inferiority was recorded for thresholds of less than 50 and less than 400 copies per mL, irrespective of baseline plasma viral load. Adverse events were reported by 291 (91%) of 321 patients in the efavirenz 400 mg group and by 285 (92%) of 309 in the 600 mg group (p=0¡48). The proportions of patients reporting an adverse event that was definitely or probably related to efavirenz were 126 (39%) for efavirenz 400 mg and 148 (48%) for efavirenz 600 mg (p=0¡03). The number of patients who reported serious adverse events did not differ between the groups (p=0¡20).
Interpretation
Our findings confirm that efavirenz 400 mg is non-inferior to the standard dose of 600 mg in combination with tenofovir and emtricitabine as initial HIV therapy over 96 weeks. Fewer efavirenz-related adverse events were reported with the 400 mg efavirenz dose than with the 600 mg dose. These findings support the routine use of efavirenz 400 mg. The coadministration of rifampicin and efavirenz 400 mg needs further investigation.
Funding
Bill & Melinda Gates Foundation, and UNSW Australi
Role of helicobacter pylori infection in the incidence and clinical course of monoclonal gammopathy of undetermined significance
Schistosoma mansoni: histological analysis of the synergistic interaction between vaccine immunity and praziquantel therapy in the lungs of mice
- âŚ