Microglia become progressively activated and seemingly dysfunctional with age, and genetic studies have linked these cells to the pathogenesis of a growing number of neurodegenerative diseases. Here ...we report a striking buildup of lipid droplets in microglia with aging in mouse and human brains. These cells, which we call 'lipid-droplet-accumulating microglia' (LDAM), are defective in phagocytosis, produce high levels of reactive oxygen species and secrete proinflammatory cytokines. RNA-sequencing analysis of LDAM revealed a transcriptional profile driven by innate inflammation that is distinct from previously reported microglial states. An unbiased CRISPR-Cas9 screen identified genetic modifiers of lipid droplet formation; surprisingly, variants of several of these genes, including progranulin (GRN), are causes of autosomal-dominant forms of human neurodegenerative diseases. We therefore propose that LDAM contribute to age-related and genetic forms of neurodegeneration.
An aged circulatory environment can activate microglia, reduce neural precursor cell activity and impair cognition in mice. We hypothesized that brain endothelial cells (BECs) mediate at least some ...of these effects. We observe that BECs in the aged mouse hippocampus express an inflammatory transcriptional profile with focal upregulation of vascular cell adhesion molecule 1 (VCAM1), a protein that facilitates vascular-immune cell interactions. Concomitantly, levels of the shed, soluble form of VCAM1 are prominently increased in the plasma of aged humans and mice, and their plasma is sufficient to increase VCAM1 expression in cultured BECs and the hippocampi of young mice. Systemic administration of anti-VCAM1 antibody or genetic ablation of Vcam1 in BECs counteracts the detrimental effects of plasma from aged individuals on young brains and reverses aging aspects, including microglial reactivity and cognitive deficits, in the brains of aged mice. Together, these findings establish brain endothelial VCAM1 at the blood-brain barrier as a possible target to treat age-related neurodegeneration.
Brain aging and neurodegeneration are associated with prominent microglial reactivity and activation of innate immune response pathways, commonly referred to as neuroinflammation. One such pathway, ...the type I interferon response, recognizes viral or mitochondrial DNA in the cytoplasm via activation of the recently discovered cyclic dinucleotide synthetase cGAS and the cyclic dinucleotide receptor STING. Here we show that the FDA-approved antiviral drug ganciclovir (GCV) induces a type I interferon response independent of its canonical thymidine kinase target. Inhibition of components of the STING pathway, including STING, IRF3, Tbk1, extracellular IFNβ, and the Jak-Stat pathway resulted in reduced activity of GCV and its derivatives. Importantly, functional STING was necessary for GCV to inhibit inflammation in cultured myeloid cells and in a mouse model of multiple sclerosis. Collectively, our findings uncover an unexpected new activity of GCV and identify the STING pathway as a regulator of microglial reactivity and neuroinflammation.
•Ganciclovir induces type I interferon signaling and modulates microglial reactivity•Microglial reactivity is associated with upregulation of innate immune adaptor STING•Ganciclovir inhibits microglial inflammation in EAE mouse model through STING
Mathur et al. describe a non-canonical function of the antiviral drug ganciclovir in microglia. Ganciclovir induces a type I interferon response and reduces neuroinflammation in a mouse model of multiple sclerosis. The innate immune adaptor STING is required for this activity of ganciclovir.
Cross-lingual transfer learning using multilingual models has shown promise for improving performance on natural language processing tasks with limited training data. However, translation can ...introduce superficial patterns that negatively impact model generalization. This paper evaluates two state-of-the-art multilingual models, Cross-Lingual Model-Robustly Optimized BERT Pretraining Approach (XLM-Roberta) and Multilingual Bi-directional Auto-Regressive Transformer (mBART), on the cross-lingual natural language inference (XNLI) natural language inference task using both original and machine-translated evaluation sets. Our analysis demonstrates that translation can facilitate cross-lingual transfer learning, but maintaining linguistic patterns is critical. The results provide insights into the strengths and limitations of state-of-the-art multilingual natural language processing architectures for cross-lingual understanding.
Aberrant microglial responses contribute to neuroinflammation in many neurodegenerative diseases, but no current therapies target pathogenic microglia. We discovered unexpectedly that the antiviral ...drug ganciclovir (GCV) inhibits the proliferation of microglia in experimental autoimmune encephalomyelitis (EAE), a mouse model for multiple sclerosis (MS), as well as in kainic acid-induced excitotoxicity. In EAE, GCV largely prevented infiltration of T lymphocytes into the central nervous system (CNS) and drastically reduced disease incidence and severity when delivered before the onset of disease. In contrast, GCV treatment had minimal effects on peripheral leukocyte distribution in EAE and did not inhibit generation of antibodies after immunization with ovalbumin. Additionally, a radiolabeled analogue of penciclovir, (18)FFHBG, which is similar in structure to GCV, was retained in areas of CNS inflammation in EAE, but not in naive control mice, consistent with the observed therapeutic effects. Our experiments suggest GCV may have beneficial effects in the CNS beyond its antiviral properties.
Complement C1q, the initiating molecule of the classical complement cascade, is involved in synapse elimination and neuronal loss in neurodegenerative diseases including glaucoma. Here we report an ...evaluation of the safety, tolerability, and ocular pharmacokinetics (PK) and pharmacodynamics of intravitreal (IVT) injections of ANX007, an anti-C1q monoclonal antibody fragment that blocks activation of the classical complement cascade.
An open-label, single-dose-escalation phase Ia study followed by a double-masked, randomized, sham-controlled, repeat-injection phase Ib study.
A total of 26 patients with primary open-angle glaucoma.
Nine patients with primary open-angle glaucoma (mean Humphrey visual field deviation between −3 and −18 decibels dB) were enrolled in phase Ia and received single doses of ANX007 (1.0 mg, n = 3; 2.5 mg, n = 3; or 5.0 mg, n = 3). Seventeen patients (mean Humphrey visual field deviation between −3 and −24 dB) were enrolled in phase Ib and randomized to 2 monthly doses of ANX007 (sham, n = 6; 2.5 mg ANX007, n = 6; or 5 mg ANX007, n = 5).
Safety and tolerability (including laboratory evaluation of urinalysis, complete blood count, and serum chemistries), ANX007 PK, target engagement, and immunogenicity.
The mean age overall was 70 years in phase Ia and 68 years in phase Ib. In both studies, no serious adverse events were observed, no non-ocular treatment-emergent adverse events (TEAEs) attributable to study drug were reported, and ocular TEAEs were mild. Intraocular pressure returned to normal levels for all patients within 45 minutes of IVT injection. No clinically significant deviations in laboratory results were observed. In the phase Ib study, C1q in the aqueous humor was reduced to undetectable levels in both the 2.5 mg and 5 mg cohorts 4 weeks after the first ANX007 dose.
In these studies, single and repeat IVT ANX007 injections were well tolerated and demonstrated full target engagement 4 weeks after dosing with both low and high doses, supporting monthly or less-frequent dosing. Further investigation in neurodegenerative ocular diseases is warranted.
Proprietary or commercial disclosure may be found after the references.
Technology has played a role to revolutionise the food delivery service from phone based to online ordering to satiate consumers’ ever-shifting demands, making its way to the top. Today, the business ...of food delivery services is one of the fastest segments of e-commerce. This study is conducted to know how consumer expectations from online food service providers. Customer value creation is the utmost requirement for the sustainability of these services. To create value the bottlenecks need to be removed from the service process to enhance highest quality of customer experience through the application of blockchain technology. This paper studies the relationship between information quality and availability at various levels with customer satisfaction through a technology adoption model and value creation through blockchain.
COVID-19 had an impact on the market, causing consumers’ perceptions and attitudes regarding the dine-in business to shift, and their buying intent to migrate to online food and service delivery. ...This phase highlights people’s business chances to demonstrate their culinary expertise and offer the local market via online meal delivery services. Cloud kitchen is the name given to this idea. The research looked at the aspects and how they influenced people’s perceptions, and attitudes, and ultimately built the purchase behavior for the cloud kitchen. The data were collected from the youth. The sampling technique was stratified sampling. Smart partial least square was used to confirm the factors influencing the perception, attitude, and purchase behavior. The data were analyzed using partial least square modeling. The factors studied and their impact assessed which is forming the consumer perception. Perception builds attitude and purchase behavior. It was discovered that there is a strong impact and modifying the consumer purchase intention toward cloud kitchen in India. The analysis also revealed that factors affecting perception and attitude toward the cloud kitchen are strong and there is a positive purchase behavior in India. The research would be useful for the cloud kitchen companies already functioning in India. The factor assessment and confirmation help the existing and upcoming cloud kitchens to work efficiently and effectively in the context of satisfaction among the future of India, that is, among youth.
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