Tumor Necrosis Factor Alpha Mediates GABAA Receptor Trafficking to the Plasma Membrane of Spinal Cord Neurons In Vivo

The proinflammatory cytokine TNFα contributes to cell death in central nervous system (CNS) disorders by altering synaptic neurotransmission. TNFα contributes to excitotoxicity by increasing GluA2-lacking AMPA receptor (AMPAR) trafficking to the neuronal plasma membrane. In vitro, increased AMPAR on the neuronal surface after TNFα exposure is associated with a rapid internalization of GABAA receptors (GABAARs), suggesting complex timing and dose dependency of the CNS's response to TNFα. However, the effect of TNFα on GABAAR trafficking in vivo remains unclear. We assessed the effect of TNFα nanoinjection on rapid GABAAR changes in rats (N = 30) using subcellular fractionation, quantitative western blotting, and confocal microscopy. GABAAR protein levels in membrane fractions of TNFα and vehicle-treated subjects were not significantly different by Western Blot, yet high-resolution quantitative confocal imaging revealed that TNFα induces GABAAR trafficking to synapses in a dose-dependent manner by 60 min. TNFα-mediated GABAAR trafficking represents a novel target for CNS excitotoxicity

Correct quantum chemistry in a minimal basis from effective Hamiltonians

We describe how to create ab-initio effective Hamiltonians that qualitatively describe correct chemistry even when used with a minimal basis. The Hamiltonians are obtained by folding correlation down from a large parent basis into a small, or minimal, target basis, using the machinery of canonical transformations. We demonstrate the quality of these effective Hamiltonians to correctly capture a wide range of excited states in water, nitrogen, and ethylene, and to describe ground and excited state bond-breaking in nitrogen and the chromium dimer, all in small or minimal basis sets

Syndromics: A Bioinformatics Approach for Neurotrauma Research

Substantial scientific progress has been made in the past 50 years in delineating many of the biological mechanisms involved in the primary and secondary injuries following trauma to the spinal cord and brain. These advances have highlighted numerous potential therapeutic approaches that may help restore function after injury. Despite these advances, bench-to-bedside translation has remained elusive. Translational testing of novel therapies requires standardized measures of function for comparison across different laboratories, paradigms, and species. Although numerous functional assessments have been developed in animal models, it remains unclear how to best integrate this information to describe the complete translational “syndrome” produced by neurotrauma. The present paper describes a multivariate statistical framework for integrating diverse neurotrauma data and reviews the few papers to date that have taken an information-intensive approach for basic neurotrauma research. We argue that these papers can be described as the seminal works of a new field that we call “syndromics”, which aim to apply informatics tools to disease models to characterize the full set of mechanistic inter-relationships from multi-scale data. In the future, centralized databases of raw neurotrauma data will enable better syndromic approaches and aid future translational research, leading to more efficient testing regimens and more clinically relevant findings

Addressing first derivative discontinuities in orbital-optimised opposite-spin scaled second-order perturbation theory with regularisation

Orbital-optimised opposite-spin scaled second-order perturbation theory (O2) generates a single-reference wave function composed of approximate Brueckner orbitals with fourth-order computational scaling. While O2 provides significantly improved treatment of radicals by reducing spin contamination, it has been shown to suffer from first derivative discontinuities for bond stretching near the unrestriction point. That qualitative failure is resolved in this work by the implementation of regularised O2, which includes a regularisation parameter in the denominator of its second-order term. The value of the regularisation parameter is semi-empirically chosen to qualitatively describe bond stretching energetics of hydrogen, ethane and ethene, while also considering the effect of the regularisation parameter on thermochemical errors for the well-known Gaussian-2 (G2) test set. The generality of the empirical scaling and semi-empirical regularisation parameter is studied by application to the 3dMLBE20, DBH24, RSE43 and W4-11 test sets. We demonstrate that accuracy of O2 is roughly maintained and sometimes even improved by regularisation, with root mean squares of regularised O2 between factors of 1.6 and 0.8 from corresponding root mean squares of O2

Addressing first derivative discontinuities in orbital-optimised opposite-spin scaled second-order perturbation theory with regularisation

Orbital-optimised opposite-spin scaled second-order perturbation theory (O2) generates a single-reference wave function composed of approximate Brueckner orbitals with fourth-order computational scaling. While O2 provides significantly improved treatment of radicals by reducing spin contamination, it has been shown to suffer from first derivative discontinuities for bond stretching near the unrestriction point. That qualitative failure is resolved in this work by the implementation of regularised O2, which includes a regularisation parameter in the denominator of its second-order term. The value of the regularisation parameter is semi-empirically chosen to qualitatively describe bond stretching energetics of hydrogen, ethane and ethene, while also considering the effect of the regularisation parameter on thermochemical errors for the well-known Gaussian-2 (G2) test set. The generality of the empirical scaling and semi-empirical regularisation parameter is studied by application to the 3dMLBE20, DBH24, RSE43 and W4-11 test sets. We demonstrate that accuracy of O2 is roughly maintained and sometimes even improved by regularisation, with root mean squares of regularised O2 between factors of 1.6 and 0.8 from corresponding root mean squares of O2

Syndromics: a bioinformatics approach for neurotrauma research.

Substantial scientific progress has been made in the past 50 years in delineating many of the biological mechanisms involved in the primary and secondary injuries following trauma to the spinal cord and brain. These advances have highlighted numerous potential therapeutic approaches that may help restore function after injury. Despite these advances, bench-to-bedside translation has remained elusive. Translational testing of novel therapies requires standardized measures of function for comparison across different laboratories, paradigms, and species. Although numerous functional assessments have been developed in animal models, it remains unclear how to best integrate this information to describe the complete translational "syndrome" produced by neurotrauma. The present paper describes a multivariate statistical framework for integrating diverse neurotrauma data and reviews the few papers to date that have taken an information-intensive approach for basic neurotrauma research. We argue that these papers can be described as the seminal works of a new field that we call "syndromics", which aim to apply informatics tools to disease models to characterize the full set of mechanistic inter-relationships from multi-scale data. In the future, centralized databases of raw neurotrauma data will enable better syndromic approaches and aid future translational research, leading to more efficient testing regimens and more clinically relevant findings

Wavefunction stability analysis without analytical electronic Hessians: Application to orbital-optimised second-order Møller-Plesset theory and VV10-containing density functionals

Wavefunction stability analysis is commonly applied to converged self-consistent field (SCF) solutions to verify whether the electronic energy is a local minimum with respect to second-order variations in the orbitals. By iterative diagonalisation, the procedure calculates the lowest eigenvalue of the stability matrix or electronic Hessian. However, analytical expressions for the electronic Hessian are unavailable for most advanced post-Hartree-Fock (HF) wave function methods and even some Kohn-Sham (KS) density functionals. To address such cases, we formulate the Hessian-vector product within the iterative diagonalisation procedure as a finite difference of the electronic gradient with respect to orbital perturbations in the direction of the vector. As a model application, following the lowest eigenvalue of the orbital-optimised second-order Møller-Plesset perturbation theory (OOMP2) Hessian during H2 dissociation reveals the surprising stability of the spin-restricted solution at all separations, with a second independent unrestricted solution. We show that a single stable solution can be recovered by using the regularised OOMP2 method (δ-OOMP2), which contains a level shift. Internal and external stability analyses are also performed for SCF solutions of a recently developed range-separated hybrid density functional, ωB97X-V, for which the analytical Hessian is not yet available due to the complexity of its long-range non-local VV10 correlation functional

Wavefunction stability analysis without analytical electronic Hessians: Application to orbital-optimised second-order Møller-Plesset theory and VV10-containing density functionals

Wavefunction stability analysis is commonly applied to converged self-consistent field (SCF) solutions to verify whether the electronic energy is a local minimum with respect to second-order variations in the orbitals. By iterative diagonalisation, the procedure calculates the lowest eigenvalue of the stability matrix or electronic Hessian. However, analytical expressions for the electronic Hessian are unavailable for most advanced post-Hartree-Fock (HF) wave function methods and even some Kohn-Sham (KS) density functionals. To address such cases, we formulate the Hessian-vector product within the iterative diagonalisation procedure as a finite difference of the electronic gradient with respect to orbital perturbations in the direction of the vector. As a model application, following the lowest eigenvalue of the orbital-optimised second-order Møller-Plesset perturbation theory (OOMP2) Hessian during H2 dissociation reveals the surprising stability of the spin-restricted solution at all separations, with a second independent unrestricted solution. We show that a single stable solution can be recovered by using the regularised OOMP2 method (δ-OOMP2), which contains a level shift. Internal and external stability analyses are also performed for SCF solutions of a recently developed range-separated hybrid density functional, ωB97X-V, for which the analytical Hessian is not yet available due to the complexity of its long-range non-local VV10 correlation functional