Descriptive and functional anatomy of the Heschl Gyrus: historical review, manual labelling and current perspectives.

PURPOSE: The Heschl Gyrus (HG), which includes the Primary Auditory Cortex (PAC), lies on the upper surface of the superior temporal gyrus (T1). It has been the subject of growing interest in the fields of neuroscience over the past decade. Given the considerable interhemispheric and interindividual variability of its morphology, manual labelling remains the gold standard for its radio-anatomical study. The aim of this study was to revisit the original work of Richard L. Heschl, to provide a broad overview of the available anatomical knowledge and to propose a manually labelled 3D digital model. METHODS: We reviewed existing works on the HG, from Heschl's original publication of 1878, Dejerine neuroanatomical atlas of 1895 to the most recent digital atlases (Julich-Brain Cytoarchitectonic Atlas, the Human Connectome Project). Our segmentation work was based on data from the BigBrain Project and used the MRIcron 2019 software. RESULTS: The original publication by Heschl has been translated into French and English. We propose a correspondence of previous nomenclatures with the most recent ones, including the Terminologia Neuroanatomica. Finally, despite the notable anatomical variability of the HG, clear and coherent segmentation criteria allowed us to generate a 3D digital model of the HG. DISCUSSION AND CONCLUSION: Heschl's work is still relevant and could impulse further anatomical and functional studies. The segmentation criteria could serve as a reference for manual labelling of the HG. Furthermore, a thorough, and historically based understanding of the morphological, microstructural and functional characteristics of the HG could be useful for manual segmentation.

Uncovering potential interspecies signaling factors in plant-derived mixed microbial culture.

Microbes use signaling factors for intraspecies and interspecies communications. While many intraspecies signaling factors have been found and characterized, discovery of factors for interspecies communication is lagging behind. To facilitate the discovery of such factors, we explored the potential of a mixed microbial culture (MMC) derived from wheatgrass, in which heterogeneity of this microbial community might elicit signaling factors for interspecies communication. The stability of Wheatgrass MMC in terms of community structure and metabolic output was first characterized by 16S ribosomal RNA amplicon sequencing and liquid chromatography/mass spectrometry (LC/MS), respectively. In addition, detailed MS analyses led to the identification of 12-hydroxystearic acid (12-HSA) as one of the major metabolites produced by Wheatgrass MMC. Stereochemical analysis revealed that Wheatgrass MMC produces mostly the (R)-isomer, although a small amount of the (S)-isomer was also observed. Furthermore, 12-HSA was found to modulate planktonic growth and biofilm formation of various marine bacterial strains. The current study suggests that naturally derived MMCs could serve as a simple and reproducible platform to discover potential signaling factors for interspecies communication. In addition, the study indicates that hydroxylated long-chain fatty acids, such as 12-HSA, may constitute a new class of interspecies signaling factors.

Temperature dependence of differential capacitance in the electric double layer.Symmetric valency 1:1 electrolytes.

The differential capacitance of an electric double layer formed by an aqueous solution of KNO3 on a glassy carbon electrode is measured by impedance analysis at constant frequency. Results are obtained at electrolyte concentrations of 0.1 mol/dm3, 0.5 mol/dm3, and 1.0 mol/dm3, and at a series of temperatures, viz., 288 K, 298 K, 308 K, 318 K, and 328 K. The differential capacitance envelopes reveal a rich, complex pattern of maxima, minima, and local minima, whose magnitude and position change with a change in solution concentration. At the two lower concentrations, the temperature dependence of the capacitance, for example, at zero electrode potential, shows an alternating positive-negative behavior, while at the highest concentration of 1.0 mol/dm3, the slope of the differential capacitance-electrode potential curve is always positive. The experimental results are supplemented by a numerical grand canonical Monte Carlo simulation study of a restricted primitive model double layer but with an off-center cationic charge achieved by displacing the charge center from the ion sphere center toward its surface. The simulations, performed at the electrolyte concentration of 1.0 mol/dm3 and constant cation charge center displacement, and at varying electrode potentials and temperatures, show, in general, a negative temperature dependence of the differential capacitance. However, this temperature dependence can also be positive for a negative electrode charge and for a sufficiently large gradient of the cation charge center displacement with temperature. This feature is seen to be associated with an increase in the entropy of formation of the double layer.

Implications of the diagnostic criteria of idiopathic pulmonary fibrosis in clinical practice: Analysis from the Australian Idiopathic Pulmonary Fibrosis Registry.

BACKGROUND AND OBJECTIVE: Current guidelines for the diagnosis of idiopathic pulmonary fibrosis (IPF) provide specific criteria for diagnosis in the setting of multidisciplinary discussion (MDD). We evaluate the utility and reproducibility of these diagnostic guidelines, using clinical data from the Australian IPF Registry. METHODS: All patients enrolled in the registry undergo a diagnostic review whereby international IPF guidelines are applied via a registry MDD. We investigated the clinical applicability of these guidelines with regard to: (i) adherence to guidelines, (ii) Natural history of IPF diagnostic categories and (iii) Concordance for diagnostic features. RESULTS: A total of 417 participants (69% male, 70.6 ± 8.0 years) with a clinical diagnosis of IPF underwent MDD. The 23% of participants who did not meet IPF diagnostic criteria displayed identical disease behaviour to those with confirmed IPF. Honeycombing on radiology was associated with a worse prognosis and this translated into poorer prognosis in the 'definite' IPF group. While there was moderate agreement for IPF diagnostic categories, agreement for specific radiological features, other than honeycombing, was poor. CONCLUSION: In clinical practice, physicians do not always follow IPF diagnostic guidelines. We demonstrate a cohort of IPF patients who do not meet IPF diagnostic guideline criteria, based largely on their radiology and lack of lung biopsy, but who have outcomes identical to those with IPF.

Off-center charge model revisited: Electrical double layer with multivalent cations.

The off-center charge model of ions is a relatively simple model for introducing asymmetry in Coulomb interaction while retaining the simplicity and convenience of the spherical hard core geometry. A Monte Carlo simulation analysis of the planar electric double layer formed by this ionic model for 1+:1- valence systems [S. Lamperski et al., Langmuir 33, 11554-11560 (2017)] is extended to include solutions of multivalent (2+, 3+) hard spherical cations and single valence (1-) hard spherical anions near a uniformly charged, planar electrode. The solvent is modelled as a uniform dielectric continuum with a dielectric constant equal to that of the pure solvent, viz., the primitive model. Results are reported for the ion density, the cation charge profile, and the electrostatic potential profile at 1 mol/dm3 salt concentration. Additionally, the double layer potential drop, that is, the electrode potential, and the integral and the differential capacitances are computed as functions of the electrode surface charge density. The latter two quantities show an expected asymmetry as long as the cation valence is not too great and the charge of the off-center ion cannot approach too close to the electrode surface. It is unusual that the integral and differential capacitances are negative for high valence cations and a negatively charged electrode when the off-center charge is large and can be very near the surface of the electrode. The corresponding electrode potential versus surface charge density curve becomes non-monotonic and shows a change of slope, and thus the resultant integral and differential capacitances can become negative. This nonphysical result is the result of an incipient singularity when a large positive charge is too near a negatively charged electrode. Overall, the off-center charge model suggests a useful recipe to model electrical asymmetry within the broader context of the primitive model provided that the off-center charge is not too near the surface of the electrode.

Monte Carlo Study of a Planar Electric Double Layer Formed by Ions with Off-Center Charge.

Grand canonical Monte Carlo simulation results are reported for an electric double layer (EDL) modeled by a planar charged hard wall, hard sphere cations with an off-center charge, and spherical anions with a charge at the center of the sphere. The ion charge numbers are Z+ = +1 and Z- = -1, and the diameter, d, of a hard sphere is the same for anions and cations. The ions are immersed in a solvent mimicked by a continuum dielectric medium at standard temperature. The results are obtained for three values of charge displacement, s+0 = d/16, d/4, 7d/16 from the center of the sphere and the following electrolyte concentrations: 0.5, 1.0, 2.0, and 3.0 M. The profiles of electrode-ion singlet distributions, cation reduced charge density, angular function, and mean electrostatic potential are reported for an electrode surface charge density σ = -0.30 C m-2, whereas the electrode potential and the differential capacitance of EDL are shown as functions of the electrode charge density varying from -1.00 to +1.00 C m-2. At negative electrode charges and with increasing values of the charge separation, the differential capacitance curve rises. As the electrolyte concentration increases, the shape of the differential capacitance curve changes from that of a minimum surrounded by two maxima into that of a distorted single maximum.

On the capacitance of narrow nanotubes.

The storage of ions in narrow nanotubes is investigated by grand-canonical Monte Carlo simulations. The interaction between the ions is screened by the image charge on the wall of the tube, but at close distances it is still much larger than the thermal energy. Depending on the electrochemical potential imposed by the contact with an electrolyte solution, two different regimes can be distinguished at the potential of zero charge: for low values corresponding to an ionophobic pore the tube is almost empty; for high values - ionophilic pore - a one dimensional salt is formed. The two regions are separated by a narrow transition zone marked by strong fluctuations. Depending on the regime and on the value assumed for the dielectric constant, the interfacial capacity shows four, two, or in rare cases three maxima. The results are compared to a reference system of non-interacting ions, and discussed with respect to recent calculations within classical density functional theory.

Ion distribution and selectivity of ionic liquids in microporous electrodes.

The energy density of an electric double layer capacitor, also known as supercapacitor, depends on ion distributions in the micropores of its electrodes. Herein we study ion selectivity and partitioning of symmetric, asymmetric, and mixed ionic liquids among different pores using the classical density functional theory. We find that a charged micropore in contact with mixed ions of the same valence is always selective to the smaller ions, and the ion selectivity, which is strongest when the pore size is comparable to the ion diameters, drastically falls as the pore size increases. The partitioning behavior in ionic liquids is fundamentally different from those corresponding to ion distributions in aqueous systems whereby the ion selectivity is dominated by the surface energy and entropic effects insensitive to the degree of confinement.

Usefulness of Aquaporin 1 as a Prognostic Marker in a Prospective Cohort of Malignant Mesotheliomas.

(1) BACKGROUND: Malignant mesothelioma (MM) is an aggressive tumour of the serosal membranes, associated with exposure to asbestos. Survival is generally poor, but prognostication for individual patients is difficult. We recently described Aquaporin 1 (AQP1) as independent prognostic factor in two separate retrospective cohorts of MM patients. Here we assess the usefulness of AQP1 prospectively, and determine the inter-observer agreement in assessing AQP1 scores; (2) METHODS: A total of 104 consecutive cases of MM were included. Sufficient tissue for immunohistochemistry was available for 100 cases, and these cases were labelled for AQP1. Labelling was assessed by two pathologists. Complete clinical information and follow up was available for 91 cases; (3) RESULTS: Labelling of ≥50% of tumour cells for AQP indicated improved prognosis in a univariate model (median survival 13 versus 8 months, p = 0.008), but the significance was decreased in a multivariate analysis. Scoring for AQP1 was robust, with an inter-observer kappa value of 0.722, indicating substantial agreement between observers; (4) CONCLUSION: AQP1 is a useful prognostic marker that can be easily incorporated in existing diagnostic immunohistochemical panels and which can be reliably interpreted by different pathologists.

A contact-corrected density functional theory for electrolytes at an interface.

We present a contact-corrected density functional theory for ionic distributions at an interface that not only accounts for the steric effects and electrostatic correlations often ignored by conventional electrochemical methods but also conforms to the exact statistical-mechanical sum rule for the contact ionic densities. The theoretical predictions are in excellent agreement with the simulation results for both the interfacial structure and electrochemical properties over a wide variety of electric double layer systems including those containing asymmetric electrolytes with multivalent ions.

Revisiting density functionals for the primitive model of electric double layers.

Density functional theory (DFT) calculations are typically based on approximate functionals that link the free energy of a multi-body system of interest with the underlying one-body density distributions. Whereas good performance is often proclaimed for new developments, it is difficult to vindicate the theoretical merits relative to alternative versions without extensive comparison with the numerical results from molecular simulations. Besides, approximate functionals may defy statistical-mechanical sum rules and result in thermodynamic inconsistency. Here we compare systematically several versions of density functionals for ionic distributions near a charged surface using the primitive model of electric double layers. We find that the theoretical performance is sensitive not only to the specific forms of the density functional but also to the range of parameter space and the precise properties under consideration. In general, incorporation of the thermodynamic sum rule into the DFT calculations shows significant improvements for both electrochemical properties and ionic distributions.

Size asymmetric hard spheres as a convenient model for the capacitance of the electrical double layer of an ionic liquid.

Even though ionic liquids are composed of nonspherical ions, it is shown here that the general features of the capacitance of an electrical double layer can be obtained using a charged hard sphere model. We have shown in our earlier studies that at high electrolyte concentrations or large magnitudes of the electrode charge density the fact that the ions have a finite size, and are not point ions, cause the capacitance near the potential of zero charge to increase and change from a minimum to a maximum as the ionic concentration is increased and to decrease as the magnitude of the electrode charge density increases. Here, we show that the asymmetry of the capacitance of an ionic liquid can be explained qualitatively by using spherical ions of different size without attempting to introduce the ionic shape in a detailed manner. This means that the general features of the capacitance of the double layer of an ionic liquid can be studied without using a complex model, although the study of the density or charge profiles of an ionic fluid would require one. However, this is often unnecessary in the analysis of many experiments.

The role of solvation in the binding selectivity of the L-type calcium channel.

We present grand canonical Monte Carlo simulation results for a reduced model of the L-type calcium channel. While charged residues of the protein amino acids in the selectivity filter are treated explicitly, most of the degrees of freedom (including the rest of the protein and the solvent) are represented by their dielectric response, i.e., dielectric continua. The new aspect of this paper is that the dielectric coefficient in the channel is different from that in the baths. The ions entering the channel, thus, cross a dielectric boundary at the entrance of the channel. Simulating this case has been made possible by our recent methodological development [D. Boda, D. Henderson, B. Eisenberg, and D. Gillespie, J. Chem. Phys. 135, 064105 (2011)]. Our main focus is on the effect of solvation energy (represented by the Born energy) on monovalent vs. divalent ion selectivity in the channel. We find no significant change in selectivity by changing the dielectric coefficient in the channel because the larger solvation penalty is counterbalanced by the enhanced Coulomb attraction inside the channel as soon as we use the Born radii (fitted to experimental hydration energies) to compute the solvation penalty from the Born equation.

The tail effect on the shape of an electrical double layer differential capacitance curve.

The differential capacitance curve for the double layer formed by an electrolyte dissolved in a solvent is commonly believed to be parabolic-like with a minimum at low electrolyte charge concentration and low electrode surface charge density, and independent of electrolyte concentration at high electrolyte concentrations and high electrode charge and would be, in the absence of solvent effects, featureless at these latter conditions. This is the prediction of the popular Gouy-Chapman-Stern theory. In contrast, for an ionic liquid this curve can have a single or a double hump (or a bell or camel shape). Fedorov et al. [Electrochem. Commun. 12, 296 (2010)]10.1016/j.elecom.2009.12.019 have related these humps, particularly the double hump, to the neutral tails of ions in many ionic liquids. Evidence presented here shows, however, that such humps are general features of the differential capacitance of a double layer, whether it be formed by ions with or without a neutral tail. The presence of a double or single hump results from the magnitude of the electrolyte charge concentration. For both spherical ions or non-spherical ions consisting of charged heads and neutral tails, the shape of the differential capacitance transforms continuously from a double hump to a single hump as the electrolyte concentration is increased.

Influence of anisotropic ion shape on structure and capacitance of an electric double layer: a Monte Carlo and density functional study.

The effect of anisotropic ion shapes on the structure and the differential capacitance of an electric double layer in the electrolyte solution regime is studied using the density functional theory and Monte Carlo simulations. The double layer is modelled by a uniformly charged, non-polarizable planar electrode next to an electrolyte where the cation is a dimer consisting of two tangentially touching rigid spheres one of which is positively charged while the other is neutral, the anion is a negatively charged rigid sphere, and the solvent is a dielectric continuum. Numerical results are reported for monovalent electrolytes at room temperature for a series of electrolyte concentrations and varying electrode surface charge densities. Asymmetry in ionic shape leads to more structure near the electrode when its charge is opposite to that of the non-spherical ions. Overall, the theoretically predicted density and mean electrostatic profiles reproduce the corresponding simulation results to a very good degree. The asymmetry of the ion shape also yields asymmetry in the differential capacitance curve plotted as a function of the electrode charge density. The differential capacity evolves from being distorted bactrian camel-shaped (a minimum flanked by a maximum on either side) at low electrolyte concentrations to being bell-like (a single broad maximum) at higher concentrations. The theoretical capacitance results again agree well with the simulations.

Aquaporin 1 is an independent prognostic factor in pleural malignant mesothelioma.

BACKGROUND: Malignant mesothelioma (MM) is an aggressive cancer of serosal membranes, mostly pleura. It is related to asbestos exposure and its incidence in most industrialized countries is projected to remain stable or to increase until 2020. Prognosis remains poor. Clinical prognostic scoring systems lack precision. No prognostic tissue markers are available. Aquaporin 1 (AQP1) is a cell membrane channel involved in water transport, cell motility, and proliferation. A blocker and an agonist are available. METHODS: Two independent cohorts of MM were studied. Cohort 1 consisted of 80 consecutive patients who underwent radical surgery (extrapleural pneumonectomy [EPP]). Cohort 2 included 56 conservatively managed patients from another institution. Clinical information was obtained from files. Diagnoses were histologically verified. Immunohistochemical labeling for AQP1 was performed on tumor tissue and the percentage of positive cells was scored. RESULTS: We demonstrated expression of AQP1 in normal and neoplastic mesothelium at the apical aspect of the cell, in keeping with a role in water transport. For both cohorts, expression of AQP1 by ≥50% of tumor cells was associated with significantly enhanced survival (9.4 months vs 30.4 months in EPP patients and 5 months vs 15 months in conservatively treated patients). This was independent of established prognostic factors, including histologic subtype, pathologic stage, sex, and age at time of diagnosis. CONCLUSION: Expression of AQP1 correlated significantly with prognosis in MM, irrespective of treatment or established prognostic factors. Immunohistochemical labeling for AQP1 should be included in the routine histopathologic workup. An agonist or blocker may become useful for treatment.

Validation of GPU based TomoTherapy dose calculation engine.

PURPOSE: The graphic processing unit (GPU) based TomoTherapy convolution/superposition(C/S) dose engine (GPU dose engine) achieves a dramatic performance improvement over the traditional CPU-cluster based TomoTherapy dose engine (CPU dose engine). Besides the architecture difference between the GPU and CPU, there are several algorithm changes from the CPU dose engine to the GPU dose engine. These changes made the GPU dose slightly different from the CPU-cluster dose. In order for the commercial release of the GPU dose engine, its accuracy has to be validated. METHODS: Thirty eight TomoTherapy phantom plans and 19 patient plans were calculated with both dose engines to evaluate the equivalency between the two dose engines. Gamma indices (Γ) were used for the equivalency evaluation. The GPU dose was further verified with the absolute point dose measurement with ion chamber and film measurements for phantom plans. Monte Carlo calculation was used as a reference for both dose engines in the accuracy evaluation in heterogeneous phantom and actual patients. RESULTS: The GPU dose engine showed excellent agreement with the current CPU dose engine. The majority of cases had over 99.99% of voxels with Γ(1%, 1 mm) < 1. The worst case observed in the phantom had 0.22% voxels violating the criterion. In patient cases, the worst percentage of voxels violating the criterion was 0.57%. For absolute point dose verification, all cases agreed with measurement to within ±3% with average error magnitude within 1%. All cases passed the acceptance criterion that more than 95% of the pixels have Γ(3%, 3 mm) < 1 in film measurement, and the average passing pixel percentage is 98.5%-99%. The GPU dose engine also showed similar degree of accuracy in heterogeneous media as the current TomoTherapy dose engine. CONCLUSIONS: It is verified and validated that the ultrafast TomoTherapy GPU dose engine can safely replace the existing TomoTherapy cluster based dose engine without degradation in dose accuracy.

Simulations of calcium channel block by trivalent cations: Gd(3+) competes with permeant ions for the selectivity filter.

Current through L-type calcium channels (Ca(V)1.2 or dihydropyridine receptor) can be blocked by micromolar concentrations of trivalent cations like the lanthanide gadolinium (Gd(3+)). It has been proposed that trivalent block is due to ions competing for a binding site in both the open and closed configuration, but possibly with different trivalent affinities. Here, we corroborate this general view of trivalent block by computing conductance of a model L-type calcium channel. The model qualitatively reproduces the Gd(3+) concentration dependence and the effect that substantially more Gd(3+) is required to produce similar block in the presence of Sr(2+) (compared to Ba(2+)) and even more in the presence of Ca(2+). Trivalent block is explained in this model by cations binding in the selectivity filter with the charge/space competition mechanism. This is the same mechanism that in the model channel governs other selectivity properties. Specifically, selectivity is determined by the combination of ions that most effectively screen the negative glutamates of the protein while finding space in the midst of the closely packed carboxylate groups of the glutamate residues.

Self-organized models of selectivity in calcium channels.

The role of flexibility in the selectivity of calcium channels is studied using a simple model with two parameters that accounts for the selectivity of calcium (and sodium) channels in many ionic solutions of different compositions and concentrations using two parameters with unchanging values. We compare the distribution of side chains (oxygens) and cations (Na(+) and Ca(2+)) and integrated quantities. We compare the occupancies of cations Ca(2+)/Na(+) and linearized conductance of Na(+). The distributions show a strong dependence on the locations of fixed side chains and the flexibility of the side chains. Holding the side chains fixed at certain predetermined locations in the selectivity filter distorts the distribution of Ca(2+) and Na(+) in the selectivity filter. However, integrated quantities-occupancy and normalized conductance-are much less sensitive. Our results show that some flexibility of side chains is necessary to avoid obstruction of the ionic pathway by oxygen ions in 'unfortunate' fixed positions. When oxygen ions are mobile, they adjust 'automatically' and move 'out of the way', so they can accommodate the permeable cations in the selectivity filter. Structure is the computed consequence of the forces in this model. The structures are self-organized, at their free energy minimum. The relationship of ions and side chains varies with an ionic solution. Monte Carlo simulations are particularly well suited to compute induced-fit, self-organized structures because the simulations yield an ensemble of structures near their free energy minimum. The exact location and mobility of oxygen ions has little effect on the selectivity behavior of calcium channels. Seemingly, nature has chosen a robust mechanism to control selectivity in calcium channels: the first-order determinant of selectivity is the density of charge in the selectivity filter. The density is determined by filter volume along with the charge and excluded volume of structural ions confined within it. Flexibility seems a second-order determinant. These results justify our original assumption that the important factor in Ca(2+) versus Na(+) selectivity is the density of oxygen ions in the selectivity filter along with (charge) polarization (i.e. dielectric properties). The assumption of maximum mobility of oxygens seems to be an excellent approximate working hypothesis in the absence of exact structural information. These conclusions, of course, apply to what we study here. Flexibility and fine structural details may have an important role in other properties of calcium channels that are not studied in this paper. They surely have important roles in other channels, enzymes, and proteins.