The Mechanisms of Codon Reassignments in Mitochondrial Genetic Codes

Many cases of non-standard genetic codes are known in mitochondrial genomes. We carry out analysis of phylogeny and codon usage of organisms for which the complete mitochondrial genome is available, and we determine the most likely mechanism for codon reassignment in each case. Reassignment events can be classified according to the gain-loss framework. The gain represents the appearance of a new tRNA for the reassigned codon or the change of an existing tRNA such that it gains the ability to pair with the codon. The loss represents the deletion of a tRNA or the change in a tRNA so that it no longer translates the codon. One possible mechanism is Codon Disappearance, where the codon disappears from the genome prior to the gain and loss events. In the alternative mechanisms the codon does not disappear. In the Unassigned Codon mechanism, the loss occurs first, whereas in the Ambiguous Intermediate mechanism, the gain occurs first. Codon usage analysis gives clear evidence of cases where the codon disappeared at the point of the reassignment and also cases where it did not disappear. Codon disappearance is the probable explanation for stop to sense reassignments and a small number of reassignments of sense codons. However, the majority of sense to sense reassignments cannot be explained by codon disappearance. In the latter cases, by analysis of the presence or absence of tRNAs in the genome and of the changes in tRNA sequences, it is sometimes possible to distinguish between the Unassigned Codon and Ambiguous Intermediate mechanisms. We emphasize that not all reassignments follow the same scenario and that it is necessary to consider the details of each case carefully.Comment: 53 pages (45 pages, including 4 figures + 8 pages of supplementary information). To appear in J.Mol.Evo

Roles of the creatine kinase system and myoglobin in maintaining energetic state in the working heart

<p>Abstract</p> <p>Background</p> <p>The heart is capable of maintaining contractile function despite a transient decrease in blood flow and increase in cardiac ATP demand during systole. This study analyzes a previously developed model of cardiac energetics and oxygen transport to understand the roles of the creatine kinase system and myoglobin in maintaining the ATP hydrolysis potential during beat-to-beat transient changes in blood flow and ATP hydrolysis rate.</p> <p>Results</p> <p>The theoretical investigation demonstrates that elimination of myoglobin only slightly increases the predicted range of oscillation of cardiac oxygenation level during beat-to-beat transients in blood flow and ATP utilization. In silico elimination of myoglobin has almost no impact on the cytoplasmic ATP hydrolysis potential (Δ<it>G</it>_ATPase). In contrast, disabling the creatine kinase system results in considerable oscillations of cytoplasmic ADP and ATP levels and seriously deteriorates the stability of Δ<it>G</it>_ATPasein the beating heart.</p> <p>Conclusion</p> <p>The CK system stabilizes Δ<it>G</it>_ATPaseby both buffering ATP and ADP concentrations and enhancing the feedback signal of inorganic phosphate in regulating mitochondrial oxidative phosphorylation.</p

Conditions for Set Agreement with an Application to Synchronous Systems

The $k$-set agreement problem is a generalization of the consensus problem: considering a system made up of $n$ processes where each process proposes a value, each non-faulty process has to decide a value such that a decided value is a proposed value, and no more than $k$ different values are decided. While this problem cannot be solved in an asynchronous system prone to $t$ process crashes when $t \geq k$, it can always be solved in a synchronous system; $\lfloor \frac{t}{k} \rfloor +1$ is then a lower bound on the number of rounds (consecutive communication steps) for the non-faulty processes to decide. The {\it condition-based} approach has been introduced in the consensus context. Its aim was to both circumvent the consensus impossibility in asynchronous systems, and allow for more efficient consensus algorithms in synchronous systems. This paper addresses the condition-based approach in the context of the $k$-set agreement problem. It has two main contributions. The first is the definition of a framework that allows defining conditions suited to the $\ell$-set agreement problem. More precisely, a condition is defined as a set of input vectors such that each of its input vectors can be seen as ``encoding'' $\ell$ values, namely, the values that can be decided from that vector. A condition is characterized by the parameters $t$, $\ell$, and a parameter denoted $d$ such that the greater $d+\ell$, the least constraining the condition (i.e., it includes more and more input vectors when $d+\ell$ increases, and there is a condition that includes all the input vectors when $d+\ell>t$). The conditions characterized by the triple of parameters $t$, $d$ and $\ell$ define the class of conditions denoted ${\cal S}_t^{d,\ell}$, $0\leq d\leq t$, $1\leq \ell \leq n-1$. The properties of the sets ${\cal S}_t^{d,\ell}$are investigated, and it is shown that they have a lattice structure. The second contribution is a generic synchronous $k$-set agreement algorithm based on a condition $C\in {\cal S}_t^{d,\ell}$, i.e., a condition suitedto the $\ell$-set agreement problem, for $\ell \leq k$. This algorithm requires at most $\left\lfloor \frac{d-1+\ell}{k} \right\rfloor +1$ rounds when the input vector belongs to $C$, and $\left\lfloor \frac{t}{k} \right\rfloor +1$ rounds otherwise. (Interestingly, this algorithm includes as particular cases the classical synchronous $k$-set agreement algorithm that requires $\left\lfloor \frac{t}{k} \right\rfloor+1$ rounds (case $d=t$ and $\ell=1$), and the synchronous consensus condition-based algorithm that terminates in $d+1$ rounds when the input vector belongs to the condition, and in $t+1$ rounds otherwise (case $k=\ell=1$).

The Nanostructure of Myoendothelial Junctions Contributes to Signal Rectification between Endothelial and Vascular Smooth Muscle Cells

Micro-anatomical structures in tissues have potential physiological effects. In arteries and arterioles smooth muscle cells and endothelial cells are separated by the internal elastic lamina, but the two cell layers often make contact through micro protrusions called myoendothelial junctions. Cross talk between the two cell layers is important in regulating blood pressure and flow. We have used a spatiotemporal mathematical model to investigate how the myoendothelial junctions affect the information flow between the two cell layers. The geometry of the model mimics the structure of the two cell types and the myoendothelial junction. The model is implemented as a 2D axi-symmetrical model and solved using the finite element method. We have simulated diffusion of Ca2+ and IP3 between the two cell types and we show that the micro-anatomical structure of the myoendothelial junction in itself may rectify a signal between the two cell layers. The rectification is caused by the asymmetrical structure of the myoendothelial junction. Because the head of the myoendothelial junction is separated from the cell it is attached to by a narrow neck region, a signal generated in the neighboring cell can easily drive a concentration change in the head of the myoendothelial protrusion. Subsequently the signal can be amplified in the head, and activate the entire cell. In contrast, a signal in the cell from which the myoendothelial junction originates will be attenuated and delayed in the neck region as it travels into the head of the myoendothelial junction and the neighboring cell

Investigation of Mitochondrial Dysfunction by Sequential Microplate-Based Respiration Measurements from Intact and Permeabilized Neurons

Mitochondrial dysfunction is a component of many neurodegenerative conditions. Measurement of oxygen consumption from intact neurons enables evaluation of mitochondrial bioenergetics under conditions that are more physiologically realistic compared to isolated mitochondria. However, mechanistic analysis of mitochondrial function in cells is complicated by changing energy demands and lack of substrate control. Here we describe a technique for sequentially measuring respiration from intact and saponin-permeabilized cortical neurons on single microplates. This technique allows control of substrates to individual electron transport chain complexes following permeabilization, as well as side-by-side comparisons to intact cells. To illustrate the utility of the technique, we demonstrate that inhibition of respiration by the drug KB-R7943 in intact neurons is relieved by delivery of the complex II substrate succinate, but not by complex I substrates, via acute saponin permeabilization. In contrast, methyl succinate, a putative cell permeable complex II substrate, failed to rescue respiration in intact neurons and was a poor complex II substrate in permeabilized cells. Sequential measurements of intact and permeabilized cell respiration should be particularly useful for evaluating indirect mitochondrial toxicity due to drugs or cellular signaling events which cannot be readily studied using isolated mitochondria

Biocatalytic Synthesis of Polymers of Precisely Defined Structures

The fabrication of functional nanoscale devices requires the construction of complex architectures at length scales characteristic of atoms and molecules. Currently microlithography and micro-machining of macroscopic objects are the preferred methods for construction of small devices, but these methods are limited to the micron scale. An intriguing approach to nanoscale fabrication involves the association of individual molecular components into the desired architectures by supramolecular assembly. This process requires the precise specification of intermolecular interactions, which in turn requires precise control of molecular structure

Daily consumption of a fruit and vegetable smoothie alters facial skin color

Consumption of dietary carotenoids or carotenoid supplements can alter the color (yellowness) of human skin through increased carotenoid deposition in the skin. As fruit and vegetables are the main dietary sources of carotenoids, skin yellowness may be a function of regular fruit and vegetable consumption. However, most previous studies have used tablets or capsules to supplement carotenoid intake, and less is known of the impact of increased fruit and vegetable consumption on skin color. Here, we examined skin color changes in an Asian population (Malaysian Chinese ethnicity) over a six week dietary intervention with a carotenoid-rich fruit smoothie. Eighty one university students (34 males, 47 females; mean age 20.48) were assigned randomly to consuming either a fruit smoothie (intervention group) or mineral water (control group) daily for six weeks. Participants’ skin yellowness (CIELab b*), redness (a*) and luminance (L*) were measured at baseline, twice during the intervention period and at a two-week follow-up, using a handheld reflectance spectrophotometer. Results showed a large increment in skin yellowness (p<0.001) and slight increment in skin redness (p<0.001) after 4 weeks of intervention for participants in the intervention group. Skin yellowness and skin redness remained elevated at the two week follow up measurement. In conclusion, intervention with a carotenoid-rich fruit smoothie is associated with increased skin redness and yellowness in an Asian population. Changes in the reflectance spectrum of the skin suggest that this color change was caused by carotenoid deposition in the skin

The creatine kinase system and pleiotropic effects of creatine

The pleiotropic effects of creatine (Cr) are based mostly on the functions of the enzyme creatine kinase (CK) and its high-energy product phosphocreatine (PCr). Multidisciplinary studies have established molecular, cellular, organ and somatic functions of the CK/PCr system, in particular for cells and tissues with high and intermittent energy fluctuations. These studies include tissue-specific expression and subcellular localization of CK isoforms, high-resolution molecular structures and structure–function relationships, transgenic CK abrogation and reverse genetic approaches. Three energy-related physiological principles emerge, namely that the CK/PCr systems functions as (a) an immediately available temporal energy buffer, (b) a spatial energy buffer or intracellular energy transport system (the CK/PCr energy shuttle or circuit) and (c) a metabolic regulator. The CK/PCr energy shuttle connects sites of ATP production (glycolysis and mitochondrial oxidative phosphorylation) with subcellular sites of ATP utilization (ATPases). Thus, diffusion limitations of ADP and ATP are overcome by PCr/Cr shuttling, as most clearly seen in polar cells such as spermatozoa, retina photoreceptor cells and sensory hair bundles of the inner ear. The CK/PCr system relies on the close exchange of substrates and products between CK isoforms and ATP-generating or -consuming processes. Mitochondrial CK in the mitochondrial outer compartment, for example, is tightly coupled to ATP export via adenine nucleotide transporter or carrier (ANT) and thus ATP-synthesis and respiratory chain activity, releasing PCr into the cytosol. This coupling also reduces formation of reactive oxygen species (ROS) and inhibits mitochondrial permeability transition, an early event in apoptosis. Cr itself may also act as a direct and/or indirect anti-oxidant, while PCr can interact with and protect cellular membranes. Collectively, these factors may well explain the beneficial effects of Cr supplementation. The stimulating effects of Cr for muscle and bone growth and maintenance, and especially in neuroprotection, are now recognized and the first clinical studies are underway. Novel socio-economically relevant applications of Cr supplementation are emerging, e.g. for senior people, intensive care units and dialysis patients, who are notoriously Cr-depleted. Also, Cr will likely be beneficial for the healthy development of premature infants, who after separation from the placenta depend on external Cr. Cr supplementation of pregnant and lactating women, as well as of babies and infants are likely to be of benefit for child development. Last but not least, Cr harbours a global ecological potential as an additive for animal feed, replacing meat- and fish meal for animal (poultry and swine) and fish aqua farming. This may help to alleviate human starvation and at the same time prevent over-fishing of oceans

A European study investigating patterns of transition from home care towards institutional dementia care: the protocol of a RightTimePlaceCare study

<p>Abstract</p> <p>Background</p> <p>Health care policies in many countries aim to enable people with dementia to live in their own homes as long as possible. However, at some point during the disease the needs of a significant number of people with dementia cannot be appropriately met at home and institutional care is required. Evidence as to best practice strategies enabling people with dementia to live at home as long as possible and also identifying the right time to trigger admission to a long-term nursing care facility is therefore urgently required. The current paper presents the rationale and methods of a study generating primary data for best-practice development in the transition from home towards institutional nursing care for people with dementia and their informal caregivers. The study has two main objectives: 1) investigate country-specific factors influencing institutionalization and 2) investigate the circumstances of people with dementia and their informal caregivers in eight European countries. Additionally, data for economic evaluation purposes are being collected.</p> <p>Methods/design</p> <p>This paper describes a prospective study, conducted in eight European countries (Estonia, Finland, France, Germany, Netherlands, Sweden, Spain, United Kingdom). A baseline assessment and follow-up measurement after 3 months will be performed. Two groups of people with dementia and their informal caregivers will be included: 1) newly admitted to institutional long-term nursing care facilities; and 2) receiving professional long-term home care, and being at risk for institutionalization. Data will be collected on outcomes for people with dementia (e.g. quality of life, quality of care), informal caregivers (e.g. caregiver burden, quality of life) and costs (e.g. resource utilization). Statistical analyses consist of descriptive and multivariate regression techniques and cross-country comparisons.</p> <p>Discussion</p> <p>The current study, which is part of a large European project 'RightTimePlaceCare', generates primary data on outcomes and costs of long-term nursing care for people with dementia and their informal caregivers, specifically focusing on the transition from home towards institutional care. Together with data collected in three other work packages, knowledge gathered in this study will be used to inform and empower patients, professionals, policy and related decision makers to manage and improve health and social dementia care services.</p