Rapid Selection of HIV-2 Capsid Mutations in Salvage Therapy with Lenacapavir-Containing Regimen.

Lenacapavir is the first capsid inhibitor, its use is currently approved for multidrug resistant HIV-1 infection. We report that, despite an initial efficacy of a LEN-containing regimen in patients with multi-drug resistant HIV-2 viruses, virological suppression was not achieved after a year and most patients selected capsid drug-resistance associated mutations.

Microglia internalize tau monomers and fibrils using distinct receptors but similar mechanisms.

Introduction: Alzheimer's disease (AD) and other tauopathies are characterized by intracellular aggregates of microtubule-associated protein tau that are actively released and promote proteopathic spread. Microglia engulf pathological proteins, but how they endocytose tau is unknown.

Methods: We measured endocytosis of different tau species by microglia after pharmacological modulation of macropinocytosis or clathrin-mediated endocytosis (CME) or antagonism/genetic depletion of known tau receptors heparan-sulfate proteoglycans (HSPGs) and low-density lipoprotein receptor-related protein 1 (LRP1).

Loss of LRP1 in Adult Neural Stem Cells Impairs Migration to Ischemic Lesions.

After ischemia, cells in the brain parenchyma upregulate stromal derived factor 1 (SDF1), driving chemokine receptor CXCR4-mediated migration of adult neural stem cells to the ischemic injury. We discovered a novel regulator of CXCR4 in neural stem cells, low-density lipoprotein receptor related protein 1 (LRP1). We used Nestin-driven knockout of LRP1 and induction of td-tomato in neural stem cells of adult mice.

Inhibition of astrocyte hemichannel improves recovery from spinal cord injury.

Spinal cord injury (SCI) causes severe disability, and the current inability to restore function to the damaged spinal cord leads to lasting detrimental consequences to patients. One strategy to reduce SCI morbidity involves limiting the spread of secondary damage after injury. Previous studies have shown that connexin 43 (Cx43), a gap junction protein richly expressed in spinal cord astrocytes, is a potential mediator of secondary damage.

Acetazolamide Treatment Prevents Redistribution of Astrocyte Aquaporin 4 after Murine Traumatic Brain Injury.

After traumatic brain injury (TBI), multiple ongoing processes contribute to worsening and spreading of the primary injury to create a secondary injury. One major process involves disrupted fluid regulation to create vascular and cytotoxic edema in the affected area. Although understanding of factors that influence edema is incomplete, the astrocyte water channel Aquaporin 4 (AQP4) has been identified as an important mediator and therefore attractive drug target for edema prevention.

Respective roles of migration and social deprivation for virological non-suppression in HIV-infected adults on antiretroviral therapy in France.

Barriers to achieve sustained HIV virological suppression on antiretroviral therapy (ART) jeopardize the success of the 90:90:90 UNAIDS initiative which aims to end the HIV/AIDS epidemic. In France, where access to ART is free and universally available, we analyze the way in which social determinants of health (i.e.

Spinal cord injury and the human microbiome: beyond the brain-gut axis.

In addition to standard management for the treatment of the acute phase of spinal cord injury (SCI), implementation of novel neuroprotective interventions offers the potential for significant reductions in morbidity and long-term health costs. A better understanding of the systemic changes after SCI could provide insight into mechanisms that lead to secondary injury. An emerging area of research involves the complex interplay of the gut microbiome and the CNS, i.

Inhibition of mTOR protects the blood-brain barrier in models of Alzheimer's disease and vascular cognitive impairment.

An intact blood-brain barrier (BBB) limits entry of proinflammatory and neurotoxic blood-derived factors into the brain parenchyma. The BBB is damaged in Alzheimer's disease (AD), which contributes significantly to the progression of AD pathologies and cognitive decline. However, the mechanisms underlying BBB breakdown in AD remain elusive, and no interventions are available for treatment or prevention.

Stimulation of astrocyte fatty acid oxidation by thyroid hormone is protective against ischemic stroke-induced damage.

We previously demonstrated that stimulation of astrocyte mitochondrial ATP production via P2Y receptor agonists was neuroprotective after cerebral ischemic stroke. Another mechanism that increases ATP production is fatty acid oxidation (FAO). We show that in primary human astrocytes, FAO and ATP production are stimulated by 3,3,5 triiodo-l-thyronine (T3).

Purinergic receptor stimulation decreases ischemic brain damage by energizing astrocyte mitochondria.

As a leading cause of death in the world, cerebral ischemic stroke has limited treatment options. The lack of glucose and oxygen after stroke is particularly harmful in the brain because neuronal metabolism accounts for significantly more energy consumption per gram of body weight compared to other organs. Our laboratory has identified mitochondrial metabolism of astrocytes to be a key target for pharmacologic intervention, not only because astrocytes play a central role in regulating brain metabolism, but also because they are essential for neuronal health and support.

The trifunctional protein mediates thyroid hormone receptor-dependent stimulation of mitochondria metabolism.

We previously demonstrated that the thyroid hormone, T(3), acutely stimulates mitochondrial metabolism in a thyroid hormone receptor (TR)-dependent manner. T(3) has also recently been shown to stimulate mitochondrial fatty acid oxidation (FAO). Here we report that TR-dependent stimulation of metabolism is mediated by the mitochondrial trifunctional protein (MTP), the enzyme responsible for long-chain FAO.

Fatty acid metabolism and thyroid hormones.

The importance of thyroid hormone signaling in the acute regulation of metabolic activity has been recognized for decades. Slowly, the underlying mechanisms responsible for this activity are being elucidated. A prominent characteristic of thyroid signaling is rapid increases in oxygen consumption and ATP production.

Evaluation of an anti-tumor necrosis factor therapeutic in a mouse model of Niemann-Pick C liver disease.

Background: Niemann-Pick type C (NPC) disease is a lysosomal storage disease characterized by the accumulation of cholesterol and glycosphingolipids. The majority of NPC patients die in their teen years due to progressive neurodegeneration; however, half of NPC patients also suffer from cholestasis, prolonged jaundice, and hepatosplenomegaly. We previously showed that a key mediator of NPC liver disease is tumor necrosis factor (TNF) α, which is involved in both proinflammatory and apoptotic signaling cascades.

Recovery from liver disease in a Niemann-Pick type C mouse model.

Loss of function of Niemann-Pick C1 (NPC1) leads to lysosomal free cholesterol storage, resulting in the neurodegenerative disease Niemann-Pick disease type C (NPC). Significant numbers of patients with NPC also suffer from liver disease. Currently, no treatments exist that alter patient outcome, and it is unknown if recovery from tissue damage can occur even if a treatment were found.

Rapid molecular detection of the H275Y oseltamivir resistance gene mutation in circulating influenza A (H1N1) viruses.

In early 2008, drug susceptibility surveillance of influenza viruses in Europe revealed that some influenza A viruses (subtype H1N1) circulating during the winter season of 2007 and 2008 were resistant to the neuraminidase inhibitor, oseltamivir. This resistance arises due to a histidine to tyrosine substitution in the neuraminidase active site (H275Y in N1 nomenclature). Current methods to detect this mutation involve an end-point reverse transcription polymerase chain reaction followed by nucleotide sequencing.