A nociceptive stress model of adolescent physical abuse induces contextual fear and cingulate nociceptive neuroplasticities.

Adolescent physical abuse impairs emotional development and evokes cingulate pathologies, but its neuronal and circuit substrates are unknown. Conditioning adolescent rabbits with noxious colorectal distension for only 2 h over 3 weeks simulated the human child abuse in amplitude, frequency, and duration. Thermal withdrawal thresholds were unchanged suggesting that sensitized spinal mechanisms may not be operable. Unchanged weight, stools, colorectal histology, and no evidence of abdominal pain argue against tissue injury or irritable bowel syndrome. Contextual fear was amplified as they avoided the site of their abuse. Conditioning impacted anterior cingulate and anterior midcingulate (ACC, aMCC) neuron excitability: (1) more neurons responded to cutaneous and visceral (VNox) noxious stimuli than controls engaging latent nociception (present but not manifest in controls). (2) Rear paw stimulation increased responses over forepaws with shorter onsets and longer durations, while forepaw responses were of higher amplitude. (3) There were more VNox responses with two excitatory phases and longer durations. (4) Some had unique three-phase excitatory responses. (5) Long-duration VNox stimuli did not inhibit neurons as in controls, suggesting the release of an inhibitory circuit. (6) aMCC changes in cutaneous but not visceral nociception confirmed its role in cutaneous nociception. For the first time, we report neuroplasticities that may be evoked by adolescent physical abuse and reflect psychogenic pain: i.e., no ongoing peripheral pain and altered ACC nociception. These limbic responses may be a cognitive trace of abuse and may shed light on impaired human emotional development and sexual function.

Bypassing the Kohn-Sham equations with machine learning.

Last year, at least 30,000 scientific papers used the Kohn-Sham scheme of density functional theory to solve electronic structure problems in a wide variety of scientific fields. Machine learning holds the promise of learning the energy functional via examples, bypassing the need to solve the Kohn-Sham equations. This should yield substantial savings in computer time, allowing larger systems and/or longer time-scales to be tackled, but attempts to machine-learn this functional have been limited by the need to find its derivative. The present work overcomes this difficulty by directly learning the density-potential and energy-density maps for test systems and various molecules. We perform the first molecular dynamics simulation with a machine-learned density functional on malonaldehyde and are able to capture the intramolecular proton transfer process. Learning density models now allows the construction of accurate density functionals for realistic molecular systems.Machine learning allows electronic structure calculations to access larger system sizes and, in dynamical simulations, longer time scales. Here, the authors perform such a simulation using a machine-learned density functional that avoids direct solution of the Kohn-Sham equations.

Powder diffraction and crystal structure prediction identify four new coumarin polymorphs.

Coumarin, a simple, commodity chemical isolated from beans in 1820, has, to date, only yielded one solid state structure. Here, we report a rich polymorphism of coumarin grown from the melt. Four new metastable forms were identified and their crystal structures were solved using a combination of computational crystal structure prediction algorithms and X-ray powder diffraction. With five crystal structures, coumarin has become one of the few rigid molecules showing extensive polymorphism at ambient conditions. We demonstrate the crucial role of advanced electronic structure calculations including many-body dispersion effects for accurate ranking of the stability of coumarin polymorphs and the need to account for anharmonic vibrational contributions to their free energy. As such, coumarin is a model system for studying weak intermolecular interactions, crystallization mechanisms, and kinetic effects.

Exploring polymorphism of benzene and naphthalene with free energy based enhanced molecular dynamics.

Prediction and exploration of possible polymorphism in organic crystal compounds are of great importance for industries ranging from organic electronics to pharmaceuticals to high-energy materials. Here we apply our crystal structure prediction procedure and the enhanced molecular dynamics based sampling approach called the Crystal-Adiabatic Free Energy Dynamics (Crystal-AFED) method to benzene and naphthalene. Crystal-AFED allows the free energy landscape of structures to be explored efficiently at any desired temperature and pressure. For each system, we successfully predict the most stable crystal structures at atmospheric pressure and explore the relative Gibbs free energies of predicted polymorphs at high pressures. Using Crystal-AFED sampling, we find that mixed structures, which typically cannot be discovered by standard crystal structure prediction methods, are prevalent in the solid forms of these compounds at high pressure.

Computational insights on crystal structures of the oxygen-evolving complex of photosystem II with either Ca(2+) or Ca(2+) substituted by Sr(2+).

The oxygen-evolving complex of photosystem II can function with either Ca(2+) or Sr(2+) as the heterocation, but the reason for different turnover rates remains unresolved despite reported X-ray crystal structures for both forms. Using quantum mechanics/molecular mechanics (QM/MM) calculations, we optimize structures with each cation in both the resting state (S1) and in a series of reduced states (S0, S-1, and S-2). Through comparison with experimental data, we determine that the X-ray crystal structures with either Ca(2+) or Sr(2+) are most consistent with the S-2 state (i.e., Mn4[III,III,III,II] with O4 and O5 protonated). As expected, the QM/MM models show that Ca(2+)/Sr(2+) substitution results in the elongation of the heterocation bonds and the displacement of terminal waters W3 and W4. The optimized structures also show that hydrogen-bonded W5 is displaced in all S states with Sr(2+) as the heterocation, suggesting that this water may play a critical role during water oxidation.

Proton-Coupled Electron Transfer During the S-State Transitions of the Oxygen-Evolving Complex of Photosystem II.

The oxygen-evolving complex (OEC) of photosystem II (PSII) is a unique Mn4O5Ca cluster that catalyzes water oxidation via four photoactivated electron transfer steps. As the protein influence on the redox and protonation chemistry of the OEC remains an open question, we present a classical valence model of the OEC that allows the redox state of each Mn and the protonation state of bridging µ-oxos and terminal waters to remain in equilibrium with the PSII protein throughout the redox cycle. We find that the last bridging oxygen loses its proton during the transition from S0 to S1. Two possible S2 states are found depending on the OEC geometry: S2 has Mn4(IV) with a proton lost from a terminal water (W1) trapped by the nearby D1-D61 if O5 is closer to Mn4, or Mn1(IV), with partial deprotonation of D1-H337 and D1-E329 if O5 is closer to Mn1. In S3, the OEC is Mn4(IV) with W2 deprotonated. The estimated OEC Em's range from +0.7 to +1.3 V, enabling oxidation by P680(+), the primary electron donor in PSII. In chloride-depleted PSII, the proton release increases during the S1 to S2 transition, leaving the OEC unable to properly advance through the water-splitting cycle.

Oxygen-evolving complex of Photosystem II: an analysis of second-shell residues and hydrogen-bonding networks.

The oxygen-evolving complex (OEC) is a Mn4O5Ca cluster embedded in the Photosystem II (PSII) protein complex. As the site of water oxidation, the OEC is connected to the lumen by channels that conduct water, oxygen, and/or protons during the catalytic cycle. The hydrogen-bond networks found in these channels also serve to stabilize the oxidized intermediates, known as the S states. We review recent developments in characterizing these networks via protein mutations, molecular inhibitors, and computational modeling. On the basis of these results, we highlight regions of the PSII protein in which changes have indirect effects on the S1, S2, and S3 oxidation states of the OEC while still allowing photosynthetic activity.

Single Molecule Rectification Induced by the Asymmetry of a Single Frontier Orbital.

A mechanism for electronic rectification under low bias potentials is elucidated for the prototype molecule HS-phenyl-amide-phenyl-SH. We apply density functional theory (DFT) combined with the nonequilibrium Green's function formalism (NEGF), as implemented in the TranSIESTA computational code to calculate transport properties. We find that a single frontier orbital, the closest to the Fermi level, provides the dominant contribution to the overall transmission and determines the current. The asymmetric distribution of electron density in that orbital leads to rectification in charge transport due to its asymmetric response, shifting toward (or away from) the Fermi level under forward (or reverse) applied bias voltage. These findings provide a simple design principle to suppress recombination in molecular assemblies of dye-sensitized solar cells (DSSCs) where interfacial electron transfer is mediated by frontier orbitals with asymmetric character.

S0-State model of the oxygen-evolving complex of photosystem II.

The S0 → S1 transition of the oxygen-evolving complex (OEC) of photosystem II is one of the least understood steps in the Kok cycle of water splitting. We introduce a quantum mechanics/molecular mechanics (QM/MM) model of the S0 state that is consistent with extended X-ray absorption fine structure spectroscopy and X-ray diffraction data. In conjunction with the QM/MM model of the S1 state, we address the proton-coupled electron-transfer (PCET) process that occurs during the S0 → S1 transition, where oxidation of a Mn center and deprotonation of a µ-oxo bridge lead to a significant rearrangement in the OEC. A hydrogen bonding network, linking the D1-D61 residue to a Mn-bound water molecule, is proposed to facilitate the PCET mechanism.

Cingulate area 32 homologies in mouse, rat, macaque and human: cytoarchitecture and receptor architecture.

Homologizing between human and nonhuman area 32 has been impaired since Brodmann said he could not homologize with certainty human area 32 to a specific cortical domain in other species. Human area 32 has four divisions, however, and two can be structurally homologized to nonhuman species with cytoarchitecture and receptor architecture: pregenual (p32) and subgenual (s32) in human and macaque monkey and areas d32 and v32 in rat and mouse. Cytoarchitecture showed that areas d32/p32 have a dysgranular layer IV in all species and that areas v32/s32 have large and dense neurons in layer V, whereas a layer IV is not present in area v32. Areas v32/s32 have the largest neurons in layer Va. Features unique to humans include large layer IIIc pyramids in both divisions, sparse layer Vb in area p32, and elongated neurons in layer VI, with area s32 having the largest layer Va neurons. Receptor fingerprints of both subdivisions of area 32 differed between species in size and shape, although AMPA/GABAA and NMDA/GABAA ratios were comparable among humans, monkeys, and rats and were significantly lower than in mice. Layers I-III of primate and rodent area 32 subdivisions share more similarities in their receptor densities than layers IV-VI. Monkey and human subdivisions of area 32 are more similar to each other than to rat and mouse subdivisions. In combination with intracingulate connections, the location, cytoarchitecture, and ligand binding studies demonstrate critical homologies among the four species.

Electrostatic effects on proton coupled electron transfer in oxomanganese complexes inspired by the oxygen-evolving complex of photosystem II.

The influence of electrostatic interactions on the free energy of proton coupled electron transfer in biomimetic oxomanganese complexes inspired by the oxygen-evolving complex (OEC) of photosystem II (PSII) are investigated. The reported study introduces an enhanced multiconformer continuum electrostatics (MCCE) model, parametrized at the density functional theory (DFT) level with a classical valence model for the oxomanganese core. The calculated pKa's and oxidation midpoint potentials (E(m)'s) match experimental values for eight complexes, indicating that purely electrostatic contributions account for most of the observed couplings between deprotonation and oxidation state transitions. We focus on pKa's of terminal water ligands in [Mn(II/III)(H2O)6](2+/3+) (1), [Mn(III)(P)(H2O)2](3-) (2, P = 5,10,15,20-tetrakis(2,6-dichloro-3-sulfonatophenyl)porphyrinato), [Mn2(IV,IV)(µ-O)2(terpy)2(H2O)2](4+) (3, terpy = 2,2':6',2″-terpyridine), and [Mn3(IV,IV,IV)(µ-O)4(phen)4(H2O)2](4+) (4, phen = 1,10-phenanthroline) and the pKa's of µ-oxo bridges and Mn E(m)'s in [Mn2(µ-O)2(bpy)4] (5, bpy = 2,2'-bipyridyl), [Mn2(µ-O)2(salpn)2] (6, salpn = N,N'-bis(salicylidene)-1,3-propanediamine), [Mn2(µ-O)2(3,5-di(Cl)-salpn)2] (7), and [Mn2(µ-O)2(3,5-di(NO2)-salpn)2] (8). The analysis of complexes 6-8 highlights the strong coupling between electron and proton transfers, with any Mn oxidation lowering the pKa of an oxo bridge by 10.5 ± 0.9 pH units. The model also accounts for changes in the E(m)'s by ligand substituents, such as found in complexes 6-8, due to the electron withdrawing Cl (7) and NO2 (8). The reported study provides the foundation for analysis of electrostatic effects in other oxomanganese complexes and metalloenzymes, where proton coupled electron transfer plays a fundamental role in redox-leveling mechanisms.

Nociceptive processing by anterior cingulate pyramidal neurons.

Although the cingulate cortex is frequently activated in acute human pain studies, postsynaptic responses are not known nor are links between nociceptive afferents, neuronal responses, and outputs to other structures. Intracellular potentials were recorded from neurobiotin-injected, pyramidal neurons in anterior cingulate area 24b following noxious stimulation of the sciatic nerve in anesthetized rabbits. Layer IIIc pyramids had extensive and horizontally oriented basal dendrites in layer IIIc where nociceptive afferents terminate. They had the longest excitatory postsynaptic potentials (EPSPs; 545 ms) that were modulated with hyperpolarizing currents. Pyramids in layer V had an intermediate tuft of oblique apical dendrites in layer IIIc that were 150-350 microm from somata in layer Va and 351-550 microm in layer Vb. Although average EPSP durations were short in layers II-IIIab (222 +/- 31), Va (267 +/- 65), and Vb (159 +/- 31), there were five neurons in layers IIIab-Va that had EPSP durations lasting >300 ms (548 +/- 63 ms). Neurons in layers IIIc, Va, and Vb had the highest amplitude EPSPs (6.25, 6.84 +/- 0.58, and 6.4 +/- 0.47 mV, respectively), whereas those in layers II-IIIab were 5 +/- 0.56 mV. Nociceptive responses in layer Vb were complex and some had initial inhibitory postsynaptic potentials with shorter-duration EPSPs. Layers II-IIIab had dye-coupled pyramids and EPSPs in these layers had short durations (167 +/- 33 ms) compared with those in layers IIIc-Va (487 +/- 28 ms). In conclusion there are two populations of anterior cingulate cortex pyramids with EPSPs of significantly different durations, although their dendritic morphologies do not predict EPSP duration. Short-duration EPSPs are thalamic-mediated, nociceptive responses lasting < or =200 ms. Longer, "integrative" EPSPs are >350 ms and are likely modulated by intracortical axon collateral discharges. These findings suggest that links between nociception and projections to cortical and motor systems are instantaneous because nociceptive responses are generated directly by pyramidal projection neurons in all layers.

Accelerating Correlated Quantum Chemistry Calculations Using Graphical Processing Units and a Mixed Precision Matrix Multiplication Library.

Two new tools for the acceleration of computational chemistry codes using graphical processing units (GPUs) are presented. First, we propose a general black-box approach for the efficient GPU acceleration of matrix-matrix multiplications where the matrix size is too large for the whole computation to be held in the GPU's onboard memory. Second, we show how to improve the accuracy of matrix multiplications when using only single-precision GPU devices by proposing a heterogeneous computing model, whereby single- and double-precision operations are evaluated in a mixed fashion on the GPU and central processing unit, respectively. The utility of the library is illustrated for quantum chemistry with application to the acceleration of resolution-of-the-identity second-order Møller-Plesset perturbation theory calculations for molecules, which we were previously unable to treat. In particular, for the 168-atom valinomycin molecule in a cc-pVDZ basis set, we observed speedups of 13.8, 7.8, and 10.1 times for single-, double- and mixed-precision general matrix multiply (SGEMM, DGEMM, and MGEMM), respectively. The corresponding errors in the correlation energy were reduced from -10.0 to -1.2 kcal mol(-1) for SGEMM and MGEMM, respectively, while higher accuracy can be easily achieved with a different choice of cutoff parameter.

Norepinephrinergic afferents and cytology of the macaque monkey midline, mediodorsal, and intralaminar thalamic nuclei.

The midline and intralaminar thalamic nuclei (MITN), locus coeruleus (LC) and cingulate cortex contain nociceptive neurons. The MITN that project to cingulate cortex have a prominent innervation by norepinephrinergic axons primarily originating from the LC. The hypothesis explored in this study is that MITN neurons that project to cingulate cortex receive a disproportionately high LC input that may modulate nociceptive afferent flow into the forebrain. Ten cynomolgus monkeys were evaluated for dopamine-beta hydroxylase (DBH) immunohistochemistry, and nuclei with moderate or high DBH activity were analyzed for intermediate neurofilament proteins, calbindin (CB), and calretinin (CR). Sections of all but DBH were thionin counterstained to assure precise localization in the mediodorsal and MITN, and cytoarchitecture was analyzed with neuron-specific nuclear binding protein. Moderate-high levels of DBH-immunoreactive (ir) axons were generally associated with high densities of CB-ir and CR-ir neurons and low levels of neurofilament proteins. The paraventricular, superior centrolateral, limitans and central nuclei had relatively high and evenly distributed DBH, the magnocellular mediodorsal and paracentral nuclei had moderate DBH-ir, and other nuclei had an even and low level of activity. Some nuclei also have heterogeneities in DBH-ir that raised questions of functional segregation. The anterior multiformis part of the mediodorsal nucleus but not middle and caudal levels had high DBH activity. The posterior parafascicular nucleus (Pf) was heterogeneous with the lateral part having little DBH activity, while its medial division had most DBH-ir axons and its multiformis part had only a small number. These findings suggest that the LC may regulate nociceptive processing in the thalamus. The well established role of cingulate cortex in premotor functions and the projections of Pf and other MITN to the limbic striatum suggests a specific role in mediating motor outflow for the LC-innervated nuclei of the MITN.

Using computer modeling to predict and optimize separations for comprehensive two-dimensional gas chromatography.

In order to fully realize the separation power of comprehensive two-dimensional gas chromatography (GC x GC), a means of predicting and optimizing separations based on operating variables was developed. This approach initially calculates the enthalpy (DeltaH) and entropy (DeltaS) for the target compounds from experimental input data, and then uses this information to simultaneously optimize all column and runtime variables, including stationary phase composition, by comparing the performance of large numbers of simulated separations. This use of computer simulation has been shown to be a useful aid in conventional separations. It becomes almost essential for GC x GC optimization because of the large number of variables involved and their very complex interaction. Agreement between experimental and predicted values of standard test samples (Grob mix) using GC x GC separation shows that this approach is accurate. We believe that this success can be extended to more challenging mixtures resulting in optimizations that are simpler and transferable between GC x GC instruments.

Accelerating resolution-of-the-identity second-order Møller-Plesset quantum chemistry calculations with graphical processing units.

The modification of a general purpose code for quantum mechanical calculations of molecular properties (Q-Chem) to use a graphical processing unit (GPU) is reported. A 4.3x speedup of the resolution-of-the-identity second-order Møller-Plesset perturbation theory (RI-MP2) execution time is observed in single point energy calculations of linear alkanes. The code modification is accomplished using the compute unified basic linear algebra subprograms (CUBLAS) library for an NVIDIA Quadro FX 5600 graphics card. Furthermore, speedups of other matrix algebra based electronic structure calculations are anticipated as a result of using a similar approach.

Distribution and properties of visceral nociceptive neurons in rabbit cingulate cortex.

Human imaging localizes most visceral nociceptive responses to anterior cingulate cortex (ACC), however, imaging in conscious subjects cannot completely control anticipatory and reflexive activity or resolve neuron activity. This study overcame these shortcomings by recording individual neuron responses in 12 anesthetized and paralyzed rabbits to define the visceronociceptive response pattern by region and layer. Balloon distension was applied to the colon at innocuous (15 mmHg) or noxious (60 mmHg) intensities, and innocuous and noxious mechanical, thermal and electrical stimuli were applied to the skin. Simultaneous recording from multiple regions assured differences were not due to anesthesia and neuron responses were resolved by spike sorting using principal components analysis. Of the total 346 neurons, 48% were nociceptive; responding to noxious levels of visceral or cutaneous stimulation, or both. Visceronociceptive neurons were most frequent in ACC (39%) and midcingulate cortex (MCC, 36%) and infrequent in retrosplenial cortex (RSC, 12%). In contrast, cutaneous nociceptive units were higher in MCC (MCC, 43%; ACC, 32%; RSC, 23%). Visceral-specific neurons were proportionately more frequent in ACC (37%), while cutaneous-specific units predominated in RSC (62.5%). Visceral nociceptive response durations were longer than those for cutaneous responses. Postmortem analysis of electrode tracks confirmed regional designations, and laminar analysis found inhibitory responses mainly in superficial layers and excitatory in deep layers. Thus, cingulate visceral nociception extends beyond ACC, this is the first report of nociceptive activity in RSC including nociceptive cutaneous responses, and these regional differences require a new model of cingulate nociceptive processing.

Automated compound classification for ambient aerosol sample separations using comprehensive two-dimensional gas chromatography-time-of-flight mass spectrometry.

Comprehensive two-dimensional gas chromatography-time-of-flight mass spectrometry (GCxGC-TOF-MS) is useful in analyzing complex samples, such as the semi-volatile organic compounds (SVOC) in daily aerosol samples collected in Augsburg, Germany. For efficient routine analysis, a partial classification system based on mass spectra has been proposed to group compounds into substance classes. Classifiers based on fragmentation patterns, retention time, and spectral transformations are incorporated into software scripts for automated classification. Fragmentation pattern rules are also applied to an aerosol sample analyzed using direct thermal desorption (DTD)-GCxGC-TOF-MS and a non-traditional column combination.

Cytology and functionally correlated circuits of human posterior cingulate areas.

Human posterior cingulate cortex (PCC) and retrosplenial cortex (RSC) form the posterior cingulate gyrus, however, monkey connection and human imaging studies suggest that PCC area 23 is not uniform and atlases mislocate RSC. We histologically assessed these regions in 6 postmortem cases, plotted a flat map, and characterized differences in dorsal (d) and ventral (v) area 23. Subsequently, functional connectivity of histologically guided regions of interest (ROI) were assessed in 163 [(18)F]fluorodeoxyglucose human cases with PET. Compared to area d23, area v23 had a higher density and larger pyramids in layers II, IIIc, and Vb and more intermediate neurofilament-expressing neurons in layer Va. Coregisrtration of each case to standard coordinates showed that the ventral branch of the splenial sulci coincided with the border between d/v PCC at -5.4 +/- 0.17 cm from the vertical plane and +1.97 +/- 0.08 cm from the bi-commissural line. Correlation analysis of glucose metabolism using histologically guided ROIs suggested important circuit differences including dorsal and ventral visual stream inputs, interactions between the vPCC and subgenual cingulate cortex, and preferential relations between dPCC and the cingulate motor region. The RSC, in contrast, had restricted correlated activity with pericallosal cortex and thalamus. Visual information may be processed with an orbitofrontal link for synthesis of signals to drive premotor activity through dPCC. Review of the literature in terms of a PCC duality suggests that interactions of dPCC, including area 23d, orient the body in space via the cingulate motor areas, while vPCC interacts with subgenual cortex to process self-relevant emotional and non-emotional information and objects and self-reflection.

Architecture and neurocytology of monkey cingulate gyrus.

Human functional imaging and neurocytology have produced important revisions to the organization of the cingulate gyrus and demonstrate four structure/function regions: anterior, midcingulate (MCC), posterior (PCC), and retrosplenial. This study evaluates the brain of a rhesus and 11 cynomolgus monkeys with Nissl staining and immunohistochemistry for neuron-specific nuclear binding protein, intermediate neurofilament proteins, and parvalbumin. The MCC region was identified along with its two subdivisions (a24' and p24'). The transition between areas 24 and 23 does not involve a simple increase in the number of neurons in layer IV but includes an increase in neuron density in layer Va of p24', a dysgranular layer IV in area 23d, granular area 23, with a neuron-dense layer Va and area 31. Each area on the dorsal bank of the cingulate gyrus has an extension around the fundus of the cingulate sulcus (f 24c, f 24c', f 24d, f 23c), whereas most cortex on the dorsal bank is composed of frontal motor areas. The PCC is composed of a dysgranular area 23d, area 23c in the caudal cingulate sulcus, a dorsal cingulate gyral area 23a/b, and a ventral area 23a/b. Finally, a dysgranular transition zone includes both area 23d and retrosplenial area 30. The distribution of areas was plotted onto flat maps to show the extent of each and their relationships to the vertical plane at the anterior commissure, corpus callosum, and cingulate sulcus. This major revision of the architectural organization of monkey cingulate cortex provides a new context for connection studies and for devising models of neuron diseases.