Two complementary molecular energy decomposition schemes: the Mayer and Ziegler-Rauk methods in comparison

In the present paper we discuss and compare two different energy decomposition schemes: Mayer's Hartree-Fock energy decomposition into diatomic and monoatomic contributions [Chem. Phys. Lett. 382, 265 (2003)], and the Ziegler-Rauk dissociation energy decomposition [Inorg. Chem. 18, 1558 (1979)]. The Ziegler-Rauk scheme is based on a separation of a molecule into fragments, while Mayer's scheme can be used in the cases where a fragmentation of the system in clearly separable parts is not possible. In the Mayer scheme, the density of a free atom is deformed to give the one-atom Mulliken density that subsequently interacts to give rise to the diatomic interaction energy. We give a detailed analysis of the diatomic energy contributions in the Mayer scheme and a close look onto the one-atom Mulliken densities. The Mulliken density ρA has a single large maximum around the nuclear position of the atom A, but exhibits slightly negative values in the vicinity of neighboring atoms. The main connecting point between both analysis schemes is the electrostatic energy. Both decomposition schemes utilize the same electrostatic energy expression, but differ in how fragment densities are defined. In the Mayer scheme, the electrostatic component originates from the interaction of the Mulliken densities, while in the Ziegler-Rauk scheme, the undisturbed fragment densities interact. The values of the electrostatic energy resulting from the two schemes differ significantly but typically have the same order of magnitude. Both methods are useful and complementary since Mayer's decomposition focuses on the energy of the finally formed molecule, whereas the Ziegler-Rauk scheme describes the bond formation starting from undeformed fragment densities

Prox1 interacts with Atoh1 and Gfi1, and regulates cellular differentiation in the inner ear sensory epithelia.

Inner ear hair cells and supporting cells arise from common precursors and, in mammals, do not show phenotypic conversion. Here, we studied the role of the homeodomain transcription factor Prox1 in the inner ear sensory epithelia. Adenoviral-mediated Prox1 transduction into hair cells in explant cultures led to strong repression of Atoh1 and Gfi1, two transcription factors critical for hair cell differentiation and survival. Luciferase assays showed that Prox1 can repress transcriptional activity of Gfi1 independently of Atoh1. Prox1 transduction into cochlear outer hair cells resulted in degeneration of these cells, consistent with the known phenotype of Gfi1-deficient mice. These results together with the widespread expression of endogenous Prox1 within the population of inner ear supporting cells point to the role for Prox1 in antagonizing the hair cell phenotype in these non-sensory cells. Further, in vivo analyses of hair cells from Gfi1-deficient mice suggest that the cyclin-dependent kinase inhibitor p57(Kip2) mediates the differentiation- and survival-promoting functions of Gfi1. These data reveal novel gene interactions and show that these interactions regulate cellular differentiation within the inner ear sensory epithelia. The data point to the tight regulation of phenotypic characteristics of hair cells and supporting cells.

Density functional energy decomposition into one- and two-atom contributions

The present work provides a generalization of Mayer's energy decomposition for the density-functional theory (DFT) case. It is shown that one- and two-atom Hartree-Fock energy components in Mayer's approach can be represented as an action of a one-atom potential VA on a one-atom density ρ A or ρ B. To treat the exchange-correlation term in the DFT energy expression in a similar way, the exchange-correlation energy density per electron is expanded into a linear combination of basis functions. Calculations carried out for a number of density functionals demonstrate that the DFT and Hartree-Fock two-atom energies agree to a reasonable extent with each other. The two-atom energies for strong covalent bonds are within the range of typical bond dissociation energies and are therefore a convenient computational tool for assessment of individual bond strength in polyatomic molecules. For nonspecific nonbonding interactions, the two-atom energies are low. They can be either repulsive or slightly attractive, but the DFT results more frequently yield small attractive values compared to the Hartree-Fock case. The hydrogen bond in the water dimer is calculated to be between the strong covalent and nonbonding interactions on the energy scale

One- and two-center physical space partitioning of the energy in the density functional theory

A conceptually new approach is introduced for the decomposition of the molecular energy calculated at the density functional theory level of theory into sum of one- and two-atomic energy components, and is realized in the "fuzzy atoms" framework. (Fuzzy atoms mean that the three-dimensional physical space is divided into atomic regions having no sharp boundaries but exhibiting a continuous transition from one to another.) The new scheme uses the new concept of "bond order density" to calculate the diatomic exchange energy components and gives them unexpectedly close to the values calculated by the exact (Hartree-Fock) exchange for the same Kohn-Sham orbitals

Enteral versus parenteral nutrition: comparison of energy metabolism in lean and moderately obese women.

Continuous respiratory-exchange measurements were performed on ten moderately obese and ten lean young women for 1 h before, 3 h during, and 3 h after either parenteral (IV) or intragastric (IG) administration of a nutrient mixture infused at twice the postabsorptive, resting energy expenditure (REE). REE rose significantly from 0.98 +/- 0.02 to 1.13 +/- 0.03 kcal/min (IV) and from 0.99 +/- 0.02 to 1.13 +/- 0.02 kcal/min (IG) in the lean group; from 1.10 +/- 0.02 to 1.27 +/- 0.03 kcal/min (IV) and from 1.11 +/- 0.02 to 1.29 +/- 0.03 (IG) in the obese group. These increases resulted in similar nutrient-induced thermogenesis of 10.0 +/- 0.7% (IV) and 9.3 +/- 0.9% (IG) in the lean group; of 9.2 +/- 0.7% (IV) and 10.1 +/- 0.8% (IG) in the obese. Nutrient utilization was comparable in both groups and in both routes of administration, although the response time to IG feeding was delayed. These results showed no significant difference in both the thermogenic response and nutrient utilization between moderately obese and control groups using acute IV or IG feeding.

Molecular chaperones and associated cellular clearance mechanisms against toxic protein conformers in Parkinson's disease.

Parkinson's disease (PD) is a slowly progressive neurodegenerative disorder marked by the loss of dopaminergic neurons (in particular in the substantia nigra) causing severe impairment of movement coordination and locomotion, associated with the accumulation of aggregated α-synuclein (α-Syn) into proteinaceous inclusions named Lewy bodies. Various early forms of misfolded α-Syn oligomers are cytotoxic. Their formation is favored by mutations and external factors, such as heavy metals, pesticides, trauma-related oxidative stress and heat shock. Here, we discuss the role of several complementing cellular defense mechanisms that may counteract PD pathogenesis, especially in youth, and whose effectiveness decreases with age. Particular emphasis is given to the 'holdase' and 'unfoldase' molecular chaperones that provide cells with potent means to neutralize and scavenge toxic protein conformers. Because chaperones can specifically recognize misfolded proteins, they are key specificity factors for other cellular defenses, such as proteolysis by the proteasome and autophagy. The efficiency of the cellular defenses decreases in stressed or aging neurons, leading to neuroinflammation, apoptosis and tissue loss. Thus, drugs that can upregulate the molecular chaperones, the ubiquitin-proteasome system and autophagy in brain tissues are promising avenues for therapies against PD and other mutation-, stress- or age-dependent protein-misfolding diseases.

Humoral and cellular immune responses against Type I cysteine proteinase of Leishmania infantum are higher in asymptomatic than symptomatic dogs selected from a naturally infected population.

Canids are natural reservoirs of Leishmania infantum and have been promoted as experimental hosts to decipher the pathogenesis of human visceral leishmaniasis (VL). In this study, the presence of IgG antibodies as well as the presence of mononuclear leukocytes reactive to different cysteine proteinases (CPs) were examined in 13 L. infantum-infected dogs (six with symptoms, seven asymptomatic). Cysteine proteinases which belong to papain-like enzymes known as clan CA are the most studied CPs of parasite protozoa. These molecules are expressed by the intracellular stages of the parasite and could be immunogenic. We studied Type II CP (CPA) and Type I CP (CPB) with its long C-terminal extension (CTE) which could be highly immunogenic. We showed that the level of antibodies reactive to rCPA is low in both symptomatic and asymptomatic dogs. In contrast, when CPB and CTE were used as antigens, the level of total IgG (with IgG2 superior to IgG1) reached higher values in asymptomatic dogs than in dogs with VL. While the peripheral blood mononuclear cell (PBMC) reactivity was significant when cultured in the presence of freezed/thawed (F/T) lysate, it remained low in presence of CP although always higher for PBMC recovered from asymptomatic dogs. We showed the importance of CPB and CTE in particular as a target of immune response and their potential use for serodiagnosis in asymptomatic dogs.

Energy requirements during reproduction and reproductive effort in shrews (Soricidae)

The energy requirements of reproducing and non-reproducing females of three species of Crocidura (C. russula, C. viaria, C. olivieri), and two species of Sorex (S. coronatus, S. minutus) were measured. Members of these two genera show different rates of metabolism and reproductive strategies (extreme altriciality and larger litter size in Sorex). During pregnancy, the daily energy intake (on either an absolute or a mass-specific basis) remained close to the non-reproductive value in all species. The absolute energy intake increased strongly after parturition and was influenced by the litter size. Peak energy intake of lactating females was extremely high, typically between 100% and 200% above the non-reproductive requirements in the Crocidura and about 300% above the non-reproductive intake in the Sorex. The mass-specific daily energy intake was reduced during lactation in the three smaller species but not in C. viaria and C. olivieri. This decrease probably involves the different thermoregulatory abilities and/or basal rate of metabolism of the pups. Average reproductive effort was about 50%, in the Crocidura species and above 150% in the Sorex species. The higher effort in the latter is partly due to a larger litter size. But in addition, extreme altriciality in the Sorex leads to an earlier increase in the energy requirements and thus is an energetically more expensive reproductive mode. The present results support the hypothesis that a higher basal rate of metabolism is associated with a higher reproductive effort in shrews.

Cellular and molecular mechanisms underlying the effects of sleep loss on hippocampal synaptic plasticity

SUMMARY : The function of sleep for the organism is one of the most persistent and perplexing questions in biology. Current findings lead to the conclusion that sleep is primarily for the brain. In particular, a role for sleep in cognitive aspects of brain function is supported by behavioral evidence both in humans and animals. However, in spite of remarkable advancement in the understanding of the mechanisms underlying sleep generation and regulation, it has been proven difficult to determine the neurobiological mechanisms underlying the beneficial effect of sleep, and the detrimental impact of sleep loss, on learning and memory processes. In my thesis, I present results that lead to several critical steps forward in the link between sleep and cognitive function. My major result is the molecular identification and physiological analysis of a protein, the NR2A subunit of NMDA receptor (NMDAR), that confers sensitivity to sleep loss to the hippocampus, a brain structure classically involved in mnemonic processes. Specifically, I used a novel behavioral approach to achieve sleep deprivation in adult C57BL6/J mice, yet minimizing the impact of secondary factors associated with the procedure,.such as stress. By using in vitro electrophysiological analysis, I show, for the first time, that sleep loss dramatically affects bidirectional plasticity at CA3 to CA1 synapses in the hippocampus, a well established cellular model of learning and memory. 4-6 hours of sleep loss elevate the modification threshold for bidirectional synaptic plasticity (MT), thereby promoting long-term depression of CA3 to CA 1 synaptic strength after stimulation in the theta frequency range (5 Hz), and rendering long-term potentiation induction.more difficult. Remarkably, 3 hours of recovery sleep, after the deprivation, reset the MT at control values, thus re-establishing the normal proneness of synapses to undergo long-term plastic changes. At the molecular level, these functional changes are paralleled by a change in the NMDAR subunit composition. In particular, the expression of the NR2A subunit protein of NMDAR at CA3 to CA1 synapses is selectively and rapidly increased by sleep deprivation, whereas recovery sleep reset NR2A synaptic content to control levels. By using an array of genetic, pharmacological and computational approaches, I demonstrate here an obligatory role for NR2A-containing NMDARs in conveying the effect of sleep loss on CA3 to CAl MT. Moreover, I show that a genetic deletion of the NR2A subunit fully preserves hippocampal plasticity from the impact of sleep loss, whereas it does not alter sleepwake behavior and homeostatic response to sleep deprivation. As to the mechanism underlying the effects of the NR2A subunit on hippocampal synaptic plasticity, I show that the increased NR2A expression after sleep loss distinctly affects the contribution of synaptic and more slowly recruited NMDAR pools activated during plasticity-induction protocols. This study represents a major step forward in understanding the mechanistic basis underlying sleep's role for the brain. By showing that sleep and sleep loss affect neuronal plasticity by regulating the expression and function of a synaptic neurotransmitter receptor, I propose that an important aspect of sleep function could consist in maintaining and regulating protein redistribution and ion channel trafficking at central synapses. These findings provide a novel starting point for investigations into the connections between sleep and learning, and they may open novel ways for pharmacological control over hippocampal .function during periods of sleep restriction. RÉSUMÉ DU PROJET La fonction du sommeil pour l'organisme est une des questions les plus persistantes et difficiles dans la biologie. Les découvertes actuelles mènent à la conclusion que le sommeil est essentiel pour le cerveau. En particulier, le rôle du sommeil dans les aspects cognitifs est soutenu par des études comportementales tant chez les humains que chez les animaux. Cependant, malgré l'avancement remarquable dans la compréhension des mécanismes sous-tendant la génération et la régulation du sommeil, les mécanismes neurobiologiques qui pourraient expliquer l'effet favorable du sommeil sur l'apprentissage et la mémoire ne sont pas encore clairs. Dans ma thèse, je présente des résultats qui aident à clarifier le lien entre le sommeil et la fonction cognitive. Mon résultat le plus significatif est l'identification moléculaire et l'analyse physiologique d'une protéine, la sous-unité NR2A du récepteur NMDA, qui rend l'hippocampe sensible à la perte de sommeil. Dans cette étude, nous avons utilisé une nouvelle approche expérimentale qui nous a permis d'induire une privation de sommeil chez les souris C57BL6/J adultes, en minimisant l'impact de facteurs confondants comme, par exemple, le stress. En utilisant les techniques de l'électrophysiologie in vitro, j'ai démontré, pour la première fois, que la perte de sommeil est responsable d'affecter radicalement la plasticité bidirectionnelle au niveau des synapses CA3-CA1 de l'hippocampe. Cela correspond à un mécanisme cellulaire de l'apprentissage et de la mémoire bien établi. En particulier, 4-6 heures de privation de sommeil élèvent le seuil de modification pour la plasticité synaptique bidirectionnelle (SM). Comme conséquence, la dépression à long terme de la transmission synaptique est induite par la stimulation des fibres afférentes dans la bande de fréquences thêta (5 Hz), alors que la potentialisation à long terme devient plus difficile. D'autre part, 3 heures de sommeil de récupération sont suffisant pour rétablir le SM aux valeurs contrôles. Au niveau moléculaire, les changements de la plasticité synaptiques sont associés à une altération de la composition du récepteur NMDA. En particulier, l'expression synaptique de la protéine NR2A du récepteur NMDA est rapidement augmentée de manière sélective par la privation de sommeil, alors que le sommeil de récupération rétablit l'expression de la protéine au niveau contrôle. En utilisant des approches génétiques, pharmacologiques et computationnelles, j'ai démontré que les récepteurs NMDA qui expriment la sous-unité NR2A sont responsables de l'effet de la privation de sommeil sur le SM. De plus, nous avons prouvé qu'une délétion génétique de la sous-unité NR2A préserve complètement la plasticité synaptique hippocampale de l'impact de la perte de sommeil, alors que cette manipulation ne change pas les mécanismes de régulation homéostatique du sommeil. En ce qui concerne les mécanismes, j'ai .découvert que l'augmentation de l'expression de la sous-unité NR2A au niveau synaptique modifie les propriétés de la réponse du récepteur NMDA aux protocoles de stimulations utilisés pour induire la plasticité. Cette étude représente un pas en avant important dans la compréhension de la base mécaniste sous-tendant le rôle du sommeil pour le cerveau. En montrant que le sommeil et la perte de sommeil affectent la plasticité neuronale en régulant l'expression et la fonction d'un récepteur de la neurotransmission, je propose qu'un aspect important de la fonction du sommeil puisse être finalisé au règlement de la redistribution des protéines et du tracking des récepteurs aux synapses centraux. Ces découvertes fournissent un point de départ pour mieux comprendre les liens entre le sommeil et l'apprentissage, et d'ailleurs, ils peuvent ouvrir des voies pour des traitements pharmacologiques dans le .but de préserver la fonction hippocampale pendant les périodes de restriction de sommeil.

Association with coregulators is the major determinant governing peroxisome proliferator-activated receptor mobility in living cells.

The nucleus is an extremely dynamic compartment, and protein mobility represents a key factor in transcriptional regulation. We showed in a previous study that the diffusion of peroxisome proliferator-activated receptors (PPARs), a family of nuclear receptors regulating major cellular and metabolic functions, is modulated by ligand binding. In this study, we combine fluorescence correlation spectroscopy, dual color fluorescence cross-correlation microscopy, and fluorescence resonance energy transfer to dissect the molecular mechanisms controlling PPAR mobility and transcriptional activity in living cells. First, we bring new evidence that in vivo a high percentage of PPARs and retinoid X receptors is associated even in the absence of ligand. Second, we demonstrate that coregulator recruitment (and not DNA binding) plays a crucial role in receptor mobility, suggesting that transcriptional complexes are formed prior to promoter binding. In addition, association with coactivators in the absence of a ligand in living cells, both through the N-terminal AB domain and the AF-2 function of the ligand binding domain, provides a molecular basis to explain PPAR constitutive activity.

Adipose tissue integrity as a prerequisite for systemic energy balance: a critical role for peroxisome proliferator-activated receptor gamma.

Peroxisome proliferator-activated receptor gamma (PPARgamma) is an essential regulator of adipocyte differentiation, maintenance, and survival. Deregulations of its functions are associated with metabolic diseases. We show here that deletion of one PPARgamma allele not only affected lipid storage but, more surprisingly, also the expression of genes involved in glucose uptake and utilization, the pentose phosphate pathway, fatty acid synthesis, lipolysis, and glycerol export as well as in IR/IGF-1 signaling. These deregulations led to reduced circulating adiponectin levels and an energy crisis in the WAT, reflected in a decrease to nearly half of its intracellular ATP content. In addition, there was a decrease in the metabolic rate and physical activity of the PPARgamma(+/-) mice, which was abolished by thiazolidinedione treatment, thereby linking regulation of the metabolic rate and physical activity to PPARgamma. It is likely that the PPARgamma(+/-) phenotype was due to the observed WAT dysfunction, since the gene expression profiles associated with metabolic pathways were not affected either in the liver or the skeletal muscle. These findings highlight novel roles of PPARgamma in the adipose tissue and underscore the multifaceted action of this receptor in the functional fine tuning of a tissue that is crucial for maintaining the organism in good health.

De-hyping transmit diversity in modern MIMO cellular systems

A contemporary perspective on the tradeoff between transmit antenna diversity and spatial multi-plexing is provided. It is argued that, in the context of modern cellular systems and for the operating points of interest, transmission techniques that utilize all available spatial degrees of freedom for multiplexingoutperform techniques that explicitly sacrifice spatialmultiplexing for diversity. Reaching this conclusion, however, requires that the channel and some key system features be adequately modeled; failure to do so may bring about starkly different conclusions. As a specific example, this contrast is illustrated using the 3GPP Long-Term Evolution system design.

Society, politcs and nuclear energy in Switzerland

After the Fukushima accident, the Swiss Federal Council opted for withdrawal from nuclear energy in the horizon 2035. Considering that this decision cannot be studied in historical isolation, this article describes the evolution of the relationship between nuclear energy and the Swiss society by highlighting four distinctive periods: the social mobilisation of the seventies and eighties, the turning point of the nineties, the nuclear revival in the late 2000s and the Fukushima accident. To describe this relationship, we will analyse social mobilisation and the results of initiatives and empirical studies related to nuclear energy in Switzerland.

The endoplasmic reticulum: a sensor of cellular stress that modulates immune responses.

Many inflammatory and infectious diseases are characterized by the activation of signaling pathways steaming from the endoplasmic reticulum (ER). These pathways, primarily associated with loss of ER homeostasis, are emerging as key regulators of inflammation and infection. Recent advances shed light on the mechanisms linking ER-stress and immune responses.