New Therapeutic Targets for Mood Disorders

Existing pharmacological treatments for bipolar disorder (BPD) and major depressive disorder (MDD) are often insufficient for many patients. Here we describe a number of targets/compounds that clinical and preclinical studies suggest could result in putative novel treatments for mood disorders. These include: (1) glycogen synthase kinase-3 (GSK-3) and protein kinase C (PKC), (2) the purinergic system, (3) histone deacetylases (HDACs), (4) the melatonergic system, (5) the tachykinin neuropeptides system, (6) the glutamatergic system, and (7) oxidative stress and bioenergetics. The paper reviews data on new compounds that have shown antimanic or antidepressant effects in subjects with mood disorders, or similar effects in preclinical animal models. Overall, an improved understanding of the neurobiological underpinnings of mood disorders is critical in order to develop targeted treatments that are more effective, act more rapidly, and are better tolerated than currently available therapies

Unsteadiness characterisation of shock wave/turbulent boundary-layer interaction at moderate Reynolds number

A direct numerical simulation of an oblique shock wave impinging on a turbulent boundary layer at Mach number 2.28 is carried out at moderate Reynolds number, matching the full conditions of the reference experiment (Dupont et al., 2006). The low-frequency shock unsteadiness, whose characteristics have been the focus of considerable research efforts, is here investigated via the Morlet wavelet transform. Owing to its compact support in both physical and Fourier spaces, the wavelet transformation makes it possible to track the time evolution of the various scales of the wall-pressure fluctuations. This property also allows us to define a local intermittency measure, representing a frequency-dependent flatness factor, to pinpoint the bursts of energy that characterise the shock intermittency scale by scale. As a major result, we show that the broadband shock movement is actually the result of a collection of sparse events in time, each characterised by its own temporal scale. This feature is hidden by the classical Fourier analysis, which can only show the time-averaged behaviour. Then, we propose a procedure to process any relevant time series, such as the time history of the wall-pressure or that of the separation bubble extent,in which we use a condition based on the local intermittency measure to filter out the turbulent content in the proximity of the shock foot and to isolate only the intermittent component of the signal.In addition, wavelet analysis reveals the intermittent behaviour also of the breathing motion of the recirculation bubble behind the reflected shock, and allows us to detect a direct correspondence between the most significant intermittent events of the separation region and those of the wall-pressure at the foot of the shock

Direct numerical simulation of a microramp in a high-Reynolds number supersonic turbulent boundary layer

This paper is associated with a video winner of a 2022 American Physical Society's Division of Fluid Dynamics (DFD) Gallery of Fluid Motion (GFM) Award for work presented at the DFD Gallery of Fluid Motion. The original video is available online at the Gallery of Fluid Motion, https://doi.org/10.1103/APS.DFD.2022.GFM.V0037Aerodynamic

Measuring pathology using the PANSS across diagnoses: Inconsistency of the positive symptom domain across schizophrenia, schizoaffective, and bipolar disorder.

Although the Positive and Negative Syndrome Scale (PANSS) was developed for use in schizophrenia (SZ), antipsychotic drug trials use the PANSS to measure symptom change also for bipolar (BP) and schizoaffective (SA) disorder, extending beyond its original indications. If the dimensions measured by the PANSS are different across diagnoses, then the same score change for the same drug condition may have different meanings depending on which group is being studied. Here, we evaluated whether the factor structure in the PANSS was consistent across schizophrenia (n = 3647), bipolar disorder (n = 858), and schizoaffective disorder (n = 592). Along with congruency coefficients, Hancock's H, and Jaccard indices, we used target rotations and statistical tests of invariance based on confirmatory factor models. We found the five symptom dimensions measured by the 30-item PANSS did not generalize well to schizoaffective and bipolar disorders. A model based on an 18-item version of the PANSS generalized better across SZ and BP groups, but significant problems remained in generalizing some of the factors to the SA sample. Schizophrenia and bipolar disorder showed greater similarity in factor structure than did schizophrenia and schizoaffective disorder. The Anxiety/Depression factor was the most consistent across disorders, while the Positive factor was the least consistent

The Timing of Antidepressant Effects: A Comparison of Diverse Pharmacological and Somatic Treatments

Currently available antidepressants used to treat major depressive disorder (MDD) unfortunately often take weeks to months to achieve their full effects, commonly resulting in considerable morbidity and increased risk for suicidal behavior. Our lack of understanding of the precise cellular underpinnings of this illness and of the mechanism of action of existing effective pharmacological treatments is a large part of the reason that therapies with a more rapid onset of antidepressant action (ROAA) have not been developed. Other issues that need to be addressed include heterogeneous clinical concepts and statistical models to measure rapid antidepressant effects. This review describes the timing of onset of antidepressant effects for various therapies used to treat MDD. While several agents produce earlier improvement of depressive symptoms (defined as occurring within one week), the response rate associated with such agents can be quite variable. These agents include both currently available antidepressants as well as other pharmacological and non-pharmacological interventions. Considerably fewer treatments are associated with ROAA, defined as occurring within several hours or one day. Treatment strategies for MDD whose sustained antidepressant effects manifest within hours or even a few days would have an enormous impact on public health

STREAmS-2.0: Supersonic turbulent accelerated Navier-Stokes solver version 2.0

We present STREAmS-2.0, an updated version of the flow solver STREAmS, first introduced in Bernardini et al. (2021) [1]. STREAmS-2.0 has an object-oriented design which separates the physics equations from the specific back-end, making the code more suitable for future expansions, such as porting to novel computing architectures or implementation of additional flow physics. Similarly to the previous version, STREAmS-2.0 supports NVIDIA-GPU and CPU back-ends. Additionally, this version features improvements of the input/output data management, new energy and entropy preserving schemes for the discretization of the convective fluxes, recycling/rescaling inflow boundary condition, and a model for thermally perfect gases with variable specific heats. New version program summary: Program Title: STREAmS CPC Library link to program files: https://doi.org/10.17632/hdcgjpzr3y.2 Developer's repository link: https://github.com/STREAmS-CFD/STREAmS-2 Licensing provisions: GPLv3 Programming language: Fortran, CUDA Journal reference of previous version: M. Bernardini, D. Modesti, F. Salvadore, and S. Pirozzoli. STREAmS: a high-fidelity accelerated solver for direct numerical simulation of compressible turbulent flows. Comput. Phys. Commun. 263 (2021) 107906. Does the new version supersede the previous version?: Yes. Reasons for the new version: New code structure and release of new features. Summary of revisions: • The original solver [1] has been rewritten following an object-oriented design implemented through Fortran derived types that include variables and type bound procedures. The new software architecture has been designed to increase modularity and extensibility of the code, allowing users to add new back-ends and physics equations while maintaining the same code structure. This allows users to reuse portions of the code that are independent of the physics equations, the back-end, or both. The layer of computing procedures maintains a lean structure that can be highly optimized with respect to the implemented back-end. • Input handling is now based on the classic.ini format improving both user readability and input data management. • A family of new kinetic energy and entropy preserving schemes (KEEP) are now available and can be selected for stable, non-dissipative and accurate spatial discretization of the convective terms of the Navier–Stokes equations in smooth flow regions [2]. Concerning the shock-capturing flux, the improved low-dissipative WENO-Z scheme proposed by [3] is now available. • New inflow boundary conditions based on the recycling/rescale approach [4] have been implemented for the simulation of spatially evolving compressible turbulent boundary layers. Moreover, a new inflow condition based on the solution of the compressible Blasius equation is available to take into account the case of laminar boundary layers. • The constitutive relations have been generalized to take into account thermally perfect gases with variable specific heats, approximated with polynomial functions of the temperature that can be specified by the user [5]. • A new stretching function has been implemented to improve the distribution of grid nodes for the computation of wall-bounded turbulent flows. The formulation blends uniform near-wall spacing with uniform resolution in terms of Kolmogorov units in the outer wall layer, guaranteeing accuracy with higher computational efficiency [6]. Nature of problem: The code solves the compressible Navier–Stokes equations in Cartesian coordinates for a thermally perfect gas. The solver is designed for direct numerical simulation (DNS) of compressible supersonic turbulent boundary layers and various canonical configurations are supported, including turbulent channel flow, laminar and turbulent boundary layer and shock-wave/boundary layer interaction. Solution method: The equations are discretized using high-order finite difference approximations with hybrid low-dissipative/shock-capturing capabilities and the time advancement is performed using a Runge–Kutta scheme. References: [1] M. Bernardini, D. Modesti, F. Salvadore, S. Pirozzoli, STREAmS: A high-fidelity accelerated solver for direct numerical simulation of compressible turbulent flows, Comput. Phys. Commun. 263 (2021) 107906. [2] Y. Tamaki, Y. Kuya, S. Kawai, Comprehensive analysis of entropy conservation property of non-dissipative schemes for compressible flows: KEEP scheme redefined, J. Comput. Phys. 468 (2022) 111494. [3] R. Borges, M. Carmona, B. Costa, W. Don, An improved weighted essentially non-oscillatory scheme for hyperbolic conservation laws, J. Comput. Phys. 227 (6) (2008) 3191–3211, https://doi.org/10.1016/j.jcp.2007.11.038 [4] S. Pirozzoli, M. Bernardini, F. Grasso, Direct numerical simulation of transonic shock/boundary layer interaction under conditions of incipient separation, J. Fluid Mech. 657 (2010) 361–393. [5] B. J. McBride, M. J. Zehe, S. Gordon, NASA Glenn coefficients for calculating thermodynamic properties of individual species, NASA/TP 211556, NASA, 2002. [6] S. Pirozzoli, P. Orlandi, Natural grid stretching for DNS of wall-bounded flows, J. Comput. Phys. 439 (2021) 110408.Green Open Access added to TU Delft Institutional Repository ‘You share, we take care!’ – Taverne project https://www.openaccess.nl/en/you-share-we-take-care Otherwise as indicated in the copyright section: the publisher is the copyright holder of this work and the author uses the Dutch legislation to make this work public.Aerodynamic

Prefrontal cortical abnormalities in currently depressed versus currently remitted patients with major depressive disorder

Previous neuromorphometric investigations of major depressive disorder (MDD) have reported abnormalities in gray matter in several regions, although the results have been inconsistent across studies. Some discrepancies in the results across studies may reflect design limitations such as small sample sizes, whereas others may reflect biological variability that potentially manifests as differences in clinical course. For example, it remains unclear whether the abnormalities found in persistently depressed MDD subjects extend to or persist in patients who experience prolonged remission. The aim of the present study was to investigate gray matter (GM) differences in unmedicated, currently-depressed participants (dMDD) and unmedicated, currently-remitted (rMDD) participants with MDD compared to healthy controls (HC). The GM density and volume were compared across groups using voxel-based morphometry, a quantitative neuroanatomical technique, and high-resolution MRI images from 107 HC, 58 dMDD and 27 rMDD subjects. Relative to the HC group the dMDD group had reduced GM in the dorsal anterolateral (DALPFC), the dorsomedial (DMPFC) and the ventrolateral prefrontal cortex (VLPFC). Relative to the rMDD group the dMDD group showed reduced GM in the DALPFC, the VLPFC, the anterior cingulate cortex (ACC), the precuneus and the inferior parietal lobule. No regions were identified in which the rMDD group showed significantly lower GM compared to the HC group after p-values were corrected for the number of comparisons performed. In unmedicated patients in the depressed phase of MOD, we found evidence of morphometric abnormalities in DALPFC and in medial prefrontal cortical regions belonging to the visceromotor network. These findings, along with the absence of GM abnormalities in the remitted sample imply a possible link between greater GM tissue and better clinical outcome. Consistent with other neuroimaging and post-mortem neuropathological studies of MDD, we also found evidence of decreased white matter in patients with dMDD and rMDD. Published by Elsevier Inc