A hydrogen bond for a local-minimum-energy structure can be identified according to the definition of the International Union of Pure and Applied Chemistry (IUPAC recommendation 2011) or by finding a ...special bond critical point on the density map of the structure in the framework of the atoms-in-molecules theory. Nonetheless, a given structural conformation may be simply favored by electrostatic interactions. The present review surveys the in-solution competition of the conformations with intramolecular vs. intermolecular hydrogen bonds for different types of small organic molecules. In their most stable gas-phase structure, an intramolecular hydrogen bond is possible. In a protic solution, the intramolecular hydrogen bond may disrupt in favor of two solute-solvent intermolecular hydrogen bonds. The balance of the increased internal energy and the stabilizing effect of the solute-solvent interactions regulates the new conformer composition in the liquid phase. The review additionally considers the solvent effects on the stability of simple dimeric systems as revealed from molecular dynamics simulations or on the basis of the calculated potential of mean force curves. Finally, studies of the solvent effects on the type of the intermolecular hydrogen bond (neutral or ionic) in acid-base complexes have been surveyed.
The voltage-dependent anion channel (VDAC) of the outer mitochondrial membrane mediates metabolic flow, Ca2+, and cell death signaling between the endoplasmic reticulum (ER) and mitochondrial ...networks. We demonstrate that VDAC1 is physically linked to the endoplasmic reticulum$Ca^{2+}-release$channel inositol 1,4,5-trisphosphate receptor (IP3R) through the molecular chaperone glucose-regulated protein 75 (grp75). Functional interaction between the channels was shown by the recombinant expression of the ligand-binding domain of the IP3R on the ER or mitochondrial surface, which directly enhanced Ca2+accumulation in mitochondria. Knockdown of grp75 abolished the stimulatory effect, highlighting chaperone-mediated conformational coupling between the IP3R and the mitochondrial Ca2+uptake machinery. Because organelle Ca2+homeostasis influences fundamentally cellular functions and death signaling, the central location of grp75 may represent an important control point of cell fate and pathogenesis.
Gap junctions provide the basis for electrical synapses between neurons. Early studies in well-defined circuits in lower vertebrates laid the foundation for understanding various properties conferred ...by electrical synaptic transmission. Knowledge surrounding electrical synapses in mammalian systems unfolded first with evidence indicating the presence of gap junctions between neurons in various brain regions, but with little appreciation of their functional roles. Beginning at about the turn of this century, new approaches were applied to scrutinize electrical synapses, revealing the prevalence of neuronal gap junctions, the connexin protein composition of many of those junctions, and the myriad diverse neural systems in which they occur in the mammalian CNS. Subsequent progress indicated that electrical synapses constitute key elements in synaptic circuitry, govern the collective activity of ensembles of electrically coupled neurons, and in part orchestrate the synchronized neuronal network activity and rhythmic oscillations that underlie fundamental integrative processes. This article is part of a Special Issue entitled: Gap Junction Proteins edited by Jean Claude Herve.
•Analyses of electrical synapses in lower vertebrates led to their study in mammals.•Key factors revealed functional roles of electrical synapses in mammalian CNS.•Neuronal gap junctions are structurally diverse and occur between various neuron types.•Morphologically mixed synapses are identified at many sites in the mammalian CNS.•Recent advances point to exciting new research directions.
We investigate the probabilistic forecasting of solar and wind power generation in connection with the Global Energy Forecasting Competition 2014. We use a voted ensemble of a quantile regression ...forest model and a stacked random forest–gradient boosting decision tree model to predict the probability distribution. The raw probabilities thus obtained need to be post-processed using isotonic regression in order to conform to the monotonic-increase attribute of probability distributions. The results show a great performance in terms of the weighted pinball loss, with the model achieving second place on the final competition leaderboard.
The
N
-harmonium boson system, i.e., a completely integrable model of
N
particles where both the external confinement and the two-particle interaction are harmonic, is investigated under the action ...of sudden time-dependent perturbation. This quench-like external perturbation of confinement has a quadrupolar space-character. The time-independent transition probabilities, which characterize the impact of quench as average occupation numbers, form a complete distribution in the sense of probability theory. The quench-generated energy shift
Δ
E
in the correlated many-body system, and a purity-type Rényi entropy
S
α
=
2
are calculated. Challenging reinterpretations of such an energy change in terms of variables of a classical thermodynamical system of
N
(
N
-
1
)
/
2
pairs are given as well. As in the case of the ground-state correlated system, an entropy could characterize a global link to energetically optimized independent-particle models.
The last decade has witnessed an explosion in novel findings relating to the molecules involved in mediating the sensation of pain in humans. Transient receptor potential (TRP) ion channels emerged ...as the greatest group of molecules involved in the transduction of various physical stimuli into neuronal signals in primary sensory neurons, as well as, in the development of pain. Here, we review the role of TRP ion channels in primary sensory neurons in the development of pain associated with peripheral pathologies and possible strategies to translate preclinical data into the development of effective new analgesics. Based on available evidence, we argue that nociception‐related TRP channels on primary sensory neurons provide highly valuable targets for the development of novel analgesics and that, in order to reduce possible undesirable side effects, novel analgesics should prevent the translocation from the cytoplasm to the cell membrane and the sensitization of the channels rather than blocking the channel pore or binding sites for exogenous or endogenous activators.
Linked Articles
This article is part of a themed section on the pharmacology of TRP channels. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue‐10
Astrocytes express neurotransmitter receptors that serve as sensors of synaptic activity and initiate signals leading to activity-dependent local vasodilation and increases in blood flow. We ...previously showed that arteriolar vasodilation produced by activation of cortical astrocytes is dependent on endothelial nitric oxide synthase (eNOS) and endogenous agonists of N-methyl-D-aspartate (NMDA) receptors. Here, we tested the hypothesis that these effects are mediated by NMDA receptors expressed by brain endothelial cells. Primary endothelial cultures expressed NMDA receptor subunits and produced nitric oxide in response to co-agonists, glutamate and D-serine. In cerebral cortex in situ, immunoelectron microscopy revealed that endothelial cells express the GluN1 NMDA receptor subunit at basolateral membrane surfaces in an orientation suitable for receiving intercellular messengers from brain cells. In cortical slices, activation of astrocytes by two-photon flash photolysis of a caged Ca2+ compound or application of a metabotropic glutamate receptor agonist caused endothelial NO generation and local vasodilation. These effects were mitigated by NMDA receptor antagonists and conditional gene silencing of endothelial GluN1, indicating at least partial dependence on endothelial NMDA receptors. Our observations identify a novel astrocyte-endothelial vasodilatory signaling axis that could contribute to endothelium-dependent vasodilation in brain functional hyperemia.
Several studies using genome-wide molecular techniques have reported various degrees of genetic heterogeneity between primary tumours and their distant metastases. However, it has been difficult to ...discern patterns of dissemination owing to the limited number of patients and available metastases. Here, we use phylogenetic techniques on data generated using whole-exome sequencing and copy number profiling of primary and multiple-matched metastatic tumours from ten autopsied patients to infer the evolutionary history of breast cancer progression. We observed two modes of disease progression. In some patients, all distant metastases cluster on a branch separate from their primary lesion. Clonal frequency analyses of somatic mutations show that the metastases have a monoclonal origin and descend from a common 'metastatic precursor'. Alternatively, multiple metastatic lesions are seeded from different clones present within the primary tumour. We further show that a metastasis can be horizontally cross-seeded. These findings provide insights into breast cancer dissemination.
The ultrastructure and cellular composition of thrombi has a profound effect on the outcome of acute ischemic stroke (AIS), coronary (CAD) and peripheral artery disease (PAD). Activated neutrophils ...release a web-like structure composed mainly of DNA and citrullinated histones, called neutrophil extracellular traps (NET) that modify the stability and lysability of fibrin. Here, we investigated the NET-related structural features of thrombi retrieved from different arterial localizations and their interrelations with routinely available clinical data.
Thrombi extracted from AIS (n = 78), CAD (n = 66) or PAD (n = 64) patients were processed for scanning electron microscopy, (immune)stained for fibrin, citrullinated histone H3 (cH3) and extracellular DNA. Fibrin fiber diameter, cellular components, DNA and cH3 were measured and analyzed in relation to clinical parameters.
DNA was least present in AIS thrombi showing a 2.5-fold lower DNA/fibrin ratio than PAD, whereas cH3 antigen was unvaryingly present at all locations. The NET content of thrombi correlated parabolically with systemic inflammatory markers and positively with patients' age. The median platelet content was lower in PAD (2.2%) than in either AIS (3.9%) or CAD (3.1%) and thrombi from smokers contained less platelets than non-smokers. Fibrin fibers were significantly thicker in male patients with CAD (median fiber diameter 76.3 nm) compared to AIS (64.1 nm) or PAD (62.1 nm) and their diameter correlated parabolically with systemic inflammatory markers.
The observed NET-related variations in thrombus structure shed light on novel determinants of thrombus stability that eventually affect both the spontaneous progress and therapeutic outcome of ischemic arterial diseases.
•Neutrophil extracellular traps (NETs) modify the structure and stability of fibrin.•NET content of thrombi varies at different locations (brain, heart, peripheral arteries).•DNA and histones in thrombi correlate with age and systemic inflammatory markers.•The amount of fibrin is similar at all examined arterial locations.•Thicker fibrin fibers are formed in coronaries than in brain and peripheral arteries.
Electrical synapses are known to form networks of extensively coupled neurons in various regions of the mammalian brain. The mesencephalic trigeminal (MesV) nucleus, formed by the somata of primary ...afferents originating in jaw-closing muscles, constitutes one of the first examples supporting the presence of electrical synapses in the mammalian CNS; however, the properties, functional organization, and developmental emergence of electrical coupling within this structure remain unknown. By combining electrophysiological, tracer coupling, and immunochemical analysis in brain slices of rat and mouse, we found that coupling is mostly restricted to pairs or small clusters of MesV neurons. Electrical transmission is supported by connexin36 (Cx36)-containing gap junctions at somato-somatic contacts where only a small proportion of channels appear to be open (∼0.1%). In marked contrast with most brain structures, coupling among MesV neurons increases with age, such that it is absent during early development and appears at postnatal day 8. Interestingly, the development of coupling parallels the development of intrinsic membrane properties responsible for repetitive firing in these neurons. We found that, acting together, sodium and potassium conductances enhance the transfer of signals with high-frequency content via electrical synapses, leading to strong spiking synchronization of the coupled neurons. Together, our data indicate that coupling in the MesV nucleus is restricted to mostly pairs of somata between which electrical transmission is supported by a surprisingly small fraction of the channels estimated to be present, and that coupling synergically interacts with specific membrane conductances to promote synchronization of these neurons.
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