Interventions for neurocognitive dysfunction

Purpose of review: To evaluate current barriers to HIV cure strategies and interventions for neurocognitive dysfunction with a particular focus on recent advancements over the last three years. Recent findings: Optimal anti-retroviral therapy (ART) poses challenges to minimise neurotoxicity, whilst ensuring blood brain barrier penetration and minimising the risk of cerebrovascular disease. CSF biomarkers, BCL11B and neurofilament light chain may be implicated with a neuroinflammatory cascade leading to cognitive impairment. Diagnostic imaging with diffusion tensor imaging as well as resting-state fMRI show promise in future diagnosis and monitoring of HAND. Summary: The introduction of ART has resulted in a dramatic decline in HIV-associated dementia. Despite this reduction, milder forms of HIV-associated neurocognitive disorder (HAND) are still prevalent and are clinically significant. The central nervous system (CNS) has been recognised as a probable reservoir and sanctuary for HIV, representing a significant barrier to management interventions

Limited Visual Range in the Social Force Model: Effects on Macroscopic and Microscopic Dynamics

The Social Force Model has been widely used to simulate pedestrian dynamics. Its simplicity and ability to reproduce some collective patterns of behavior make it an adequate tool in the field of pedestrian dynamics. However, its ability to reproduce common macroscopic empirical results, such as pedestrian flows through a bottleneck and the speed-density fundamental diagram, has scarcely been studied. In addition, the effect of each parameter of the model on the dynamics of the system has rarely been shown. In this contribution, a comprehensive parameter-sensitivity analysis in the social force model is provided, and an optimal set is introduced, capable of reproducing both macroscopic experimental flow data and collision avoidance between pedestrians in simple trajectories on the microscopic scale. We show that the incorporation of asymmetric visual range models in the inter-pedestrian interactions is required for quantitative agreement. The model is also capable of showing collision avoidance in simple pedestrian trajectories and lane formation in non-crowded bidirectional pedestrian flows

SPH simulations of thixo-viscoplastic fluid flow past a cylinder

Thixotropic materials are complex fluids that display time-dependent viscosity and/or yield-stress response upon the application of a fixed deformation, while recovering their original structured-state when the deformation is discontinued. Thixotropic effects are presents in many different systems and applications, ranging from food products, such as ketchup, to metals, such as molten aluminum. In this work we present a first attempt to simulate the rheological properties of thixo-viscoplastic flows using a Smoothed Particle Hydrodynamic (SPH) method. The study set up is a 2D flow around a circular cylinder as well as a simple shear flow between parallel plates to validate our numerical results. SPH solutions are compared with simulations performed using the open-source Finite Volume Method solver RheoTool, based on OpenFOAM. The viscoplastic model used in this work is the Papanastasiou model combined with a recently developed microstructural one, in order to include thixotropy. In this thixo-viscoplastic framework, we analyze the flow properties in terms of yield-fronts, streamlines and structure-parameter fields at different Bingham and Thixotropy numbers, through microstructural thixotropic and yield-stress parameters variation. Obtained results show an important novelty: an asymmetry in the thixo-viscoplastic flow around the cylinder

Tribological variable-friction coefficient models for the simulation of dense suspensions of rough polydisperse particles

The rheology of concentrated suspensions of particles is complex and typically exhibits a shear-thickening behavior in the case of repulsive interactions. Despite the recent interest arisen, the causes of the shear-thickening remain unclear. Frictional contacts have been able to explain the discontinuous shear thickening in simulations. However, the interparticle friction coefficient is considered to be constant in most simulations and theoretical works reported to date despite the fact that tribological experiments demonstrate that the friction coefficient can not only be constant (boundary regime) but also decrease (mixed regime) or even increase (full-film lubrication regime), depending on the normal force and the relative velocity between the particles and the interstitial liquid between them. Interestingly, the transition between the boundary regime and the full-lubrication regime is governed by the particle average roughness. Particle-level simulations of suspensions of hard spheres were carried out using short-range lubrication and roughness-dependent frictional forces describing the full Stribeck curve. Suspensions with different particle's roughness were simulated to show that the particle roughness is a key factor in the shear-thickening behavior; for sufficiently rough particles, the suspension exhibits a remarkable shear-thickening, while for sufficiently smooth particles, the discontinuous shear-thickening disappears

Study on NGF and VEGF during the Equine Perinatal Period—Part 2: Foals Affected by Neonatal Encephalopathy

Simple Summary Based on human medicine, Neonatal Encephalopathy is the term used by equine clinicians for newborn foals which develop a variety of non-infectious neurological signs in the immediate postpartum period. It has become the preferred term because it does not imply a specific underlying etiology or pathophysiology, as hypoxia and ischemia may not be recognized in all cases. Understanding the underlying pathophysiology is important in formulating a rational approach to diagnosis. Our aim is to clinically characterize a population of foals spontaneously affected by Neonatal Encephalopathy and to evaluate the levels of trophic factors, such as nerve growth factor and vascular epithelial growth factor, and thyroid hormones obtained at birth/admission from a population of affected foals and in the first 72 h of life/hospitalization, as well as the expression of trophic factors in the placenta of mares that delivered foals affected by Neonatal Encephalopathy. The less pronounced decrease of the two trophic factors compared to healthy foals, their close relationship with thyroid hormones over time, and the dysregulation of trophic factor expression in placental tissues, could be key regulators in the mechanisms of equine Neonatal Encephalopathy. Neonatal Encephalopathy (NE) may be caused by hypoxic ischemic insults or inflammatory insults and modified by innate protective or excitatory mechanisms. Understanding the underlying pathophysiology is important in formulating a rational approach to diagnosis. The preliminary aim was to clinically characterize a population of foals spontaneously affected by NE. The study aimed to: (i) evaluate nerve growth factor (NGF) and vascular endothelial growth factor (VEGF) levels in plasma samples obtained in the affected population at parturition from the mare's jugular vein, umbilical cord vein and foal's jugular vein, as well as in amniotic fluid; (ii) evaluate the NGF and VEGF content in the plasma of foals affected by NE during the first 72 h of life/hospitalization; (iii) evaluate NGF and VEGF levels at birth/admission in relation to selected mare's and foal's clinical parameters; (iv) evaluate the relationship between the two trophic factors and thyroid hormone levels (TT3 and TT4) in the first 72 h of life/hospitalization; and (v) assess the mRNA expression of NGF, VEGF and brain-derived neurotrophic factor (BDNF), and their cell surface receptors, in the placenta of mares that delivered foals affected by NE. Thirteen affected foals born from mares hospitalized for peripartum monitoring (group NE) and twenty affected foals hospitalized after birth (group exNE) were included in the study. Dosage of NGF and VEGF levels was performed using commercial ELISA kits, whereas NGF, VEGF, and BDNF placental gene expression was performed using a semi-quantitative real-time PCR. In group NE, NGF levels decreased significantly from T0 to T24 (p = 0.0447) and VEGF levels decreased significantly from T0 to T72 (p = 0.0234), whereas in group exNE, only NGF levels decreased significantly from T0 to T24 (p = 0.0304). Compared to healthy foals, a significant reduction of TT3 levels was observed in both NE (T24, p = 0.0066; T72 p = 0.0003) and exNE (T0, p = 0.0082; T24, p < 0.0001; T72, p < 0.0001) groups, whereas a significant reduction of TT4 levels was observed only in exNE group (T0, p = 0.0003; T24, p = 0.0010; T72, p = 0.0110). In group NE, NGF levels were positively correlated with both TT3 (p = 0.0475; r = 0.3424) and TT4 levels (p = 0.0063; r = 0.4589).In the placenta, a reduced expression of NGF in the allantois (p = 0.0033) and a reduced expression of BDNF in the amnion (p = 0.0498) were observed. The less pronounced decrease of the two trophic factors compared to healthy foals, their relationship with thyroid hormones over time, and the reduced expression of NGF and BDNF in placental tissues of mares that delivered affected foals, could be key regulators in the mechanisms of equine NE

Hair Cortisol and DHEA-S in Foals and Mares as a Retrospective Picture of Feto-Maternal Relationship under Physiological and Pathological Conditions

Equine fetal hair starts to grow at around 270 days of pregnancy, and hair collected at birth reflects hormones of the last third of pregnancy. The study aimed to evaluate cortisol (CORT) and dehydroepiandrosterone-sulfate (DHEA-S) concentrations and their ratio in the trichological matrix of foals and mares in relation to their clinical parameters; the clinical condition of the neonate (study 1); the housing place at parturition (study 2). In study 1, 107 mare-foal pairs were divided into healthy (group H; n = 56) and sick (group S; n = 51) foals, whereas in study 2, group H was divided into hospital (n = 30) and breeding farm (n = 26) parturition. Steroids from hair were measured using a solid-phase microtiter radioimmunoassay. In study 1, hair CORT concentrations measured in foals did not differ between groups and did not appear to be influenced by clinical parameters. A correlation between foal and mare hair CORT concentrations (p = 0.019; r = 0.312, group H; p = 0.006; r = 0.349, group S) and between CORT and DHEA-S concentrations in foals (p = 0.018; r = 0.282, group H; p < 0.001; r = 0.44, group S) and mares (p = 0.006; r = 0.361, group H; p = 0.027; r = 0.271, group S) exists in both groups. Increased hair DHEA-S concentrations (p = 0.033) and decreased CORT/DHEA-S ratio (p < 0.001) appear to be potential biomarkers of chronic stress in the final third of pregnancy, as well as a potential sign of resilience and allostatic load in sick foals, and deserve further attention in the evaluation of prenatal hypothalamus-pituitary-adrenal (HPA) axis activity in the equine species. In study 2, hormone concentrations in the hair of mares hospitalized for attended parturition did not differ from those that were foaled at the breeding farm. This result could be related to a too brief period of hospitalization to cause significant changes in steroid deposition in the mare’s hair

Numerical simulations of thixotropic semi-solid aluminium alloys in open-rotor and rotor-stator mixers

This research uses the Bautista-Manero-Puig (BMP) model to examine flow patterns of semi-solid aluminium alloys (Al) in open-rotor and stator-rotor mixers via numerical solutions. The model captures the distinct thixo-viscoelastic behavior of the Al-alloys at low temperatures, near melting point. The analysis involves using 2D structured-meshes for open-rotor and rotor-stator geometries. Solutions for Newtonian and thixo-viscoelastic model fluids are reported through fields of velocity, strain-rate, stress, fluidity, and streamlines, revealing distinct features. Findings reveal nonlinear thixo-viscoelastic vortex patterns that vary with rotational speed, resulting in different fluidity and stress profiles compared to the invariant response of Newtonian fluids. At lower rotational speeds, rotor-pallets are dominated by structured material that gradually becomes unstructured to cover the outer vessel walls. When including a stator, the inner stator region resembles the Newtonian solution, but the outflow through stator gaps is reduced due to flow-structure levels outside. This information is of interest for industrial design and optimization of molten Al-alloy processing.Programa de Transferencia de Tecnología de la DFB FEDER Consejo Nacional de Ciencias, Humanidades y Tecnologı́as (CONAHCYT, Mexico) Universidad Nacional Autónoma de México UNA

Study on NGF and VEGF during the Equine Perinatal Period—Part 1: Healthy Foals Born from Normal Pregnancy and Parturition

The importance of trophic factors, such as nerve growth factor (NGF), vascular endothelial growth factor (VEGF), and brain-derived neurotrophic factor (BDNF) during the perinatal period, is now emerging. Through their functional activities of neurogenesis and angiogenesis, they play a key role in the final maturation of the nervous and vascular systems. The present study aims to: (i) evaluate the NGF and VEGF levels obtained at parturition from the mare, foal and umbilical cord vein plasma, as well as in amniotic fluid; (ii) evaluate NGF and VEGF content in the plasma of healthy foals during the first 72 h of life (T0, T24 and T72); (iii) evaluate NGF and VEGF levels at parturition in relation to the selected mares’ and foals’ clinical parameters; (iv) evaluate the relationship between the two trophic factors and the thyroid hormone levels (TT3 and TT4) in the first 72 h of life; (v) assess mRNA expression of NGF, VEGF and BDNF and their cell surface receptors in the placenta. Fourteen Standardbred healthy foals born from mares with normal pregnancies and parturitions were included in the study. The dosage of NGF and VEGF levels was performed using commercial ELISA kits, whereas NGF, VEGF and BDNF placental gene expression was performed using semi-quantitative real-time PCR. In foal plasma, both NGF and VEGF levels decreased significantly over time, from T0 to T24 (p = 0.0066 for NGF; p < 0.0001 for VEGF) and from T0 to T72 (p = 0.0179 for NGF; p = 0.0016 for VEGF). In foal serum, TT3 levels increased significantly over time from T0 to T24 (p = 0.0058) and from T0 to T72 (p = 0.0013), whereas TT4 levels decreased significantly over time from T0 to T24 (p = 0.0201) and from T0 to T72 (p < 0.0001). A positive correlation was found in the levels of NGF and VEGF in foal plasma at each time point (p = 0.0115; r = 0.2862). A positive correlation was found between NGF levels in the foal plasma at T0 and lactate (p = 0.0359; r = 0.5634) as well as between VEGF levels in the foal plasma at T0 and creatine kinase (p = 0.0459; r = 0.5407). VEGF was expressed in all fetal membranes, whereas NGF and its receptors were not expressed in the amnion. The close relationship between the two trophic factors in foal plasma over time and their fine expression in placental tissues appear to be key regulators of fetal development and adaptation to extra-uterine life

Combined transcriptomic-(1)H NMR metabonomic study reveals yhat monoethylhexyl phthalate stimulates adipogenesis and glyceroneogenesis in human adipocytes

Adipose tissue is a major storage site for lipophilic environmental contaminants. The environmental metabolic disruptor hypothesis postulates that some pollutants can promote obesity or metabolic disorders by activating nuclear receptors involved in the control of energetic homeostasis. In this context, monoethylhexyl phthalate (MEHP) is of particular concern since it was shown to activate the peroxisome proliferator-activated receptor γ (PPARγ) in 3T3-L1 murine preadipocytes. In the present work, we used an untargeted, combined transcriptomic-(1)H NMR-based metabonomic approach to describe the overall effect of MEHP on primary cultures of human subcutaneous adipocytes differentiated in vitro. MEHP stimulated rapidly and selectively the expression of genes involved in glyceroneogenesis, enhanced the expression of the cytosolic phosphoenolpyruvate carboxykinase, and reduced fatty acid release. These results demonstrate that MEHP increased glyceroneogenesis and fatty acid reesterification in human adipocytes. A longer treatment with MEHP induced the expression of genes involved in triglycerides uptake, synthesis, and storage; decreased intracellular lactate, glutamine, and other amino acids; increased aspartate and NAD, and resulted in a global increase in triglycerides. Altogether, these results indicate that MEHP promoted the differentiation of human preadipocytes to adipocytes. These mechanisms might contribute to the suspected obesogenic effect of MEHP