Temporal progression of tau pathology and neuroinflammation in a rhesus monkey model of Alzheimer's disease.

Introduction: The understanding of the pathological events in Alzheimer's disease (AD) has advanced dramatically, but the successful translation from rodent models into efficient human therapies is still problematic.

Methods: To examine how tau pathology can develop in the primate brain, we injected 12 macaques with a dual tau mutation (P301L/S320F) into the entorhinal cortex (ERC). An investigation was performed using high-resolution microscopy, magnetic resonance imaging (MRI), positron emission tomography (PET), and fluid biomarkers to determine the temporal progression of the pathology 3 and 6 months after the injection.

Deep analysis of CD4 T cells in the rhesus CNS during SIV infection.

Virologic suppression with antiretroviral therapy (ART) has significantly improved health outcomes for people living with HIV, yet challenges related to chronic inflammation in the central nervous system (CNS)-known as Neuro-HIV- persist. As primary targets for HIV-1 with the ability to survey and populate the CNS and interact with myeloid cells to co-ordinate neuroinflammation, CD4 T cells are pivotal in Neuro-HIV. Despite their importance, our understanding of CD4 T cell distribution in virus-targeted CNS tissues, their response to infection, and potential recovery following initiation of ART remain limited.

CCR7+ CD4 T Cell Immunosurveillance Disrupted in Chronic SIV-Induced Neuroinflammation in Rhesus Brain.

Unlabelled: CD4 T cells survey and maintain immune homeostasis in the brain, yet their differentiation states and functional capabilities remain unclear. Our approach, combining single-cell transcriptomic analysis, ATAC-seq, spatial transcriptomics, and flow cytometry, revealed a distinct subset of CCR7+ CD4 T cells resembling lymph node central memory (T ) cells. We observed chromatin accessibility at the CCR7, CD28, and BCL-6 loci, defining molecular features of T .

CD4 T cell Responses in the CNS during SIV infection.

Virologic suppression with antiretroviral therapy (ART) has significantly improved health outcomes for people living with HIV, yet challenges related to chronic inflammation in the central nervous system (CNS) - known as Neuro-HIV- persist. As primary targets for HIV-1 with the ability to survey and populate the CNS and interact with myeloid cells to co-ordinate neuroinflammation, CD4 T cells are pivotal in Neuro-HIV. Despite their importance, our understanding of CD4 T cell distribution in virus-targeted CNS tissues, their response to infection, and potential recovery following initiation of ART remain limited.

SARS-CoV-2 infects neurons and induces neuroinflammation in a non-human primate model of COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of coronavirus disease 2019 (COVID-19), can induce a plethora of neurological complications in some patients. However, it is still under debate whether SARS-CoV-2 directly infects the brain or whether CNS sequelae result from systemic inflammatory responses triggered in the periphery. By using high-resolution microscopy, we investigated whether SARS-CoV-2 reaches the brain and how viral neurotropism can be modulated by aging in a non-human primate model of COVID-19.

A novel tau-based rhesus monkey model of Alzheimer's pathogenesis.

Introduction: Alzheimer's disease (AD) is a devastating condition with no effective treatments, with promising findings in rodents failing to translate into successful therapies for patients.

Methods: Targeting the vulnerable entorhinal cortex (ERC), rhesus monkeys received two injections of an adeno-associated virus expressing a double tau mutation (AAV-P301L/S320F) in the left hemisphere, and control AAV-green fluorescent protein in the right ERC. Noninjected aged-matched monkeys served as additional controls.

Oligomeric Aβ in the monkey brain impacts synaptic integrity and induces accelerated cortical aging.

As the average age of the population continues to rise, the number of individuals affected with age-related cognitive decline and Alzheimer's disease (AD) has increased and is projected to cost more than $290 billion in the United States in 2019. Despite significant investment in research over the last decades, there is no effective treatment to prevent or delay AD progression. There is a translational gap in AD research, with promising drugs based on work in rodent models failing in clinical trials.

Quantitative assessment of cyanide in cystic fibrosis sputum and its oxidative catabolism by hypochlorous acid.

Rationale: Cystic fibrosis (CF) patients are known to produce cyanide (CN) although challenges exist in determinations of total levels, the precise bioactive levels, and specificity of its production by CF microflora, especially P. aeruginosa. Our objective was to measure total CN levels in CF sputa by a simple and novel technique in P.

Farnesyltransferase Inhibition Exacerbates Eosinophilic Inflammation and Airway Hyperreactivity in Mice with Experimental Asthma: The Complex Roles of Ras GTPase and Farnesylpyrophosphate in Type 2 Allergic Inflammation.

Ras, a small GTPase protein, is thought to mediate Th2-dependent eosinophilic inflammation in asthma. Ras requires cell membrane association for its biological activity, and this requires the posttranslational modification of Ras with an isoprenyl group by farnesyltransferase (FTase) or geranylgeranyltransferase (GGTase). We hypothesized that inhibition of FTase using FTase inhibitor (FTI)-277 would attenuate allergic asthma by depleting membrane-associated Ras.

Autophagy and the unfolded protein response promote profibrotic effects of TGF-β in human lung fibroblasts.

Idiopathic pulmonary fibrosis (IPF) is a lethal fibrotic lung disease in adults with limited treatment options. Autophagy and the unfolded protein response (UPR), fundamental processes induced by cell stress, are dysregulated in lung fibroblasts and epithelial cells from humans with IPF. Human primary cultured lung parenchymal and airway fibroblasts from non-IPF and IPF donors were stimulated with transforming growth factor-β (TGF-β) with or without inhibitors of autophagy or UPR (IRE1 inhibitor).

Intratracheal instillation of pravastatin for the treatment of murine allergic asthma: a lung-targeted approach to deliver statins.

Systemic treatment with statins mitigates allergic airway inflammation, TH2 cytokine production, epithelial mucus production, and airway hyperreactivity (AHR) in murine models of asthma. We hypothesized that pravastatin delivered intratracheally would be quantifiable in lung tissues using mass spectrometry, achieve high drug concentrations in the lung with minimal systemic absorption, and mitigate airway inflammation and structural changes induced by ovalbumin. Male BALB/c mice were sensitized to ovalbumin (OVA) over 4 weeks, then exposed to 1% OVA aerosol or filtered air (FA) over 2 weeks.

Inhibition of myeloperoxidase: evaluation of 2H-indazoles and 1H-indazolones.

Myeloperoxidase (MPO) produces hypohalous acids as a key component of the innate immune response; however, release of these acids extracellularly results in inflammatory cell and tissue damage. The two-step, one-pot Davis-Beirut reaction was used to synthesize a library of 2H-indazoles and 1H-indazolones as putative inhibitors of MPO. A structure-activity relationship study was undertaken wherein compounds were evaluated utilizing taurine-chloramine and MPO-mediated H2O2 consumption assays.

Sarcolipin and ubiquitin carboxy-terminal hydrolase 1 mRNAs are over-expressed in skeletal muscles of alpha-tocopherol deficient mice.

The transcriptome of ataxic muscles from alpha-tocopherol transfer protein deficient (ATTP-KO), 23-month old, mice was compared with that of their normal littermates. Genes encoding sarcolipin (sln) and ubiquitin carboxyl-terminal hydrolase (uchl1) were over-expressed (> or =10-fold) in ataxic muscles. SLN is a 3.