Acetylation of BMAL1 by TIP60 controls BRD4-P-TEFb recruitment to circadian promoters.

Many physiological processes exhibit circadian rhythms driven by cellular clocks composed of interlinked activating and repressing elements. To investigate temporal regulation in this molecular oscillator, we combined mouse genetic approaches and analyses of interactions of key circadian proteins with each other and with clock gene promoters. We show that transcriptional activators control BRD4-PTEFb recruitment to E-box-containing circadian promoters. During the activating phase of the circadian cycle, the lysine acetyltransferase TIP60 acetylates the transcriptional activator BMAL1 leading to recruitment of BRD4 and the pause release factor P-TEFb, followed by productive elongation of circadian transcripts. We propose that the control of BRD4-P-TEFb recruitment is a novel temporal checkpoint in the circadian clock cycle

Rodent models for the analysis of tissue clock function in metabolic rhythms research

The circadian timing system consists on a distributed network of cellular clocks that together coordinate 24-h rhythms of physiology and behavior. Clock function and metabolism are tightly coupled, from the cellular to the organismal level. Genetic and non-genetic approaches in rodents have been employed to study circadian clock function in the living organism. Due to the ubiquitous expression of clock genes and the intricate interaction between the circadian system and energy metabolism, genetic approaches targeting specific tissue clocks have been used to assess their contribution in systemic metabolic processes. However, special requirements regarding specificity and efficiency have to be met to allow for valid conclusions from such studies. In this review, we provide a brief summary of different approaches developed for dissecting tissue clock function in the metabolic context in rodents, compare their strengths and weaknesses, and suggest new strategies in assessing tissue clock output and the consequences of circadian clock disruption in vivo.Fil: Tsang, Anthony H.. University of Lübeck; Alemania. University of Cambridge; Reino UnidoFil: Astiz, Mariana. University of Lübeck; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Leinweber, Brinja. University of Lübeck; AlemaniaFil: Oster, Henrik. University of Lübeck; Alemani

Loose mechanochemical coupling of molecular motors

In living cells, molecular motors convert chemical energy into mechanical work. Its thermodynamic energy efficiency, i.e. the ratio of output mechanical work to input chemical energy, is usually high. However, using two-state models, we found the motion of molecular motors is loosely coupled to the chemical cycle. Only part of the input energy can be converted into mechanical work. Others is dissipated into environment during substeps without contributions to the macro scale unidirectional movement

The mean velocity of two-state models of molecular motor

The motion of molecular motor is essential to the biophysical functioning of living cells. In principle, this motion can be regraded as a multiple chemical states process. In which, the molecular motor can jump between different chemical states, and in each chemical state, the motor moves forward or backward in a corresponding potential. So, mathematically, the motion of molecular motor can be described by several coupled one-dimensional hopping models or by several coupled Fokker-Planck equations. To know the basic properties of molecular motor, in this paper, we will give detailed analysis about the simplest cases: in which there are only two chemical states. Actually, many of the existing models, such as the flashing ratchet model, can be regarded as a two-state model. From the explicit expression of the mean velocity, we find that the mean velocity of molecular motor might be nonzero even if the potential in each state is periodic, which means that there is no energy input to the molecular motor in each of the two states. At the same time, the mean velocity might be zero even if there is energy input to the molecular motor. Generally, the velocity of molecular motor depends not only on the potentials (or corresponding forward and backward transition rates) in the two states, but also on the transition rates between the two chemical states

Circadian regulation of lipid mobilization in white adipose tissues.

In mammals, a network of circadian clocks regulates 24-h rhythms of behavior and physiology. Circadian disruption promotes obesity and the development of obesity-associated disorders, but it remains unclear to which extent peripheral tissue clocks contribute to this effect. To reveal the impact of the circadian timing system on lipid metabolism, blood and adipose tissue samples from wild-type, Clock Delta 19, and Bmall(-/-) circadian mutant mice were subjected to biochemical assays and gene expression profiling. We show diurnal variations in lipolysis rates and release of free fatty acids (FFAs) and glycerol into the blood correlating with rhythmic regulation of two genes encoding the lipolysis pacemaker enzymes, adipose triglyceride (TG) lipase and hormone-sensitive lipase, by self-sustained adipocyte clocks. Circadian clock mutant mice show low and nonrhythmic FFA and glycerol blood content together with decreased lipolysis rates and increased sensitivity to fasting. Instead circadian clock disruption promotes the accumulation of TGs in white adipose tissue (WAT), leading to increased adiposity and adipocyte hypertrophy. In summary, circadian modulation of lipolysis rates regulates the availability of lipid-derived energy during the day, suggesting a role for WAT clocks in the regulation of energy homeostasis

Analisis Implementasi Standar Pelayanan Minimal Bidang Kesehatan Kabupaten/kota

Ministry of Health has set a Health Minimum Service Standards (HMSS) for District/City by Minister of Health Decree No. 741/Menkes/Per/VII/2008, which consist of 18 indicators. After three years of implementation, an analysis of the HMSS implementation has conducted. Using a cross-sectional study design, site selection is done purposively to represent Eastern, Central, and Western part of Indonesia. There were nine districts/cities of 9 provinces selected. The analysis showed that problems in the implementation of HMSS are: some indicators do not meet the SMART criteria, inconsistency between the title of indicators, operational definitions and formulas, wide gap in the coverage both within the district at different times and among districts/cities. Differences also occur at the operational level, including dissemination of HMSS, advocacy, monitoring and evaluation. It is recommended that the Ministry of Health should provide sufficient training, proper socialization of HMSS, set up a special unit to monitor and facilitate the implementation of HMSS. The existing MSS should be revised, no longer focusing on the achievement of the program but rather based on a form of health care provided. In addition, revision is necessary to gain consistency between definitions, operational definitions and formulas of HMSS indicators