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How the lung achieves immune homeostasis after a pulmonary infection is not fully understood. Here, we analyzed the spatiotemporal changes in the lungs over a 2-week natural recovery from severe pneumonia in a Syrian hamster model of SARS-CoV-2 infection. We find that SARS-CoV-2 infects multiple cell types and causes massive cell death at the early stage, including alveolar macrophages. We identify a group of monocyte-derived Slamf9+ macrophages, which are induced after SARS-CoV-2 infection and resistant to impairment caused by SARS-CoV-2. Slamf9+ macrophages contain SARS-CoV-2, recruit and interact with Isg12+Cst7+ neutrophils to clear the viruses. After viral clearance, Slamf9+ macrophages differentiate into Trem2+ and Fbp1+ macrophages, contributing to inflammation resolution at the late stage, and finally replenish alveolar macrophages. These findings are validated in a SARS-CoV-2-infected hACE2 mouse model and confirmed with publicly available human autopsy single-cell RNA-seq data, demonstrating the potential role of Slamf9+ macrophages and their coordination with neutrophils in post-injury tissue repair and inflammation resolution. [ABSTRACT FROM AUTHOR]

How immune cells are spatiotemporally coordinated in the lung to effectively monitor, respond to, and resolve infection and inflammation in primed form needs to be fully illustrated. Here we apply immunocartography, a high-resolution technique that integrates spatial and single-cell RNA sequencing (scRNA-seq) through deconvolution and co-localization analyses, to the SARS-CoV-2-infected Syrian hamster model. We generate a comprehensive transcriptome map of the whole process of pulmonary infection from physiological condition, infection initiation, severe pneumonia to natural recovery at organ scale and single-cell resolution, with 142,965 cells and 45 lung lobes from 25 hamsters at 5 time points. Integrative analysis identifies that alveolar dendritic cell–T cell immunity hubs, where Ccr7+Ido1+ dendritic cells, Cd160+Cd8+ T cells, and Tnfrsf4+Cd4+ T cells physiologically co-localize, rapidly expand during SARS-CoV-2 infection, eliminate SARS-CoV-2 with the aid of Slamf9+ macrophages, and then restore to physiological levels after viral clearance. We verify the presence of these cell subpopulations in the immunity hubs in normal and SARS-CoV-2-infected hACE2 mouse models, as well as in publicly available human scRNA-seq datasets, demonstrating the potential broad relevance of our findings in lung immunity. [ABSTRACT FROM AUTHOR]

This study explores the effects of varied pulsed magnetic field strengths (0 mT, 16 mT, and 80 mT) on the microstructure and mechanical properties of A356 aluminum alloy. Advanced characterization techniques including an electron universal stretching machine, metallographic microscope (OM), scanning electron microscopy (SEM), electron backscatter diffraction (EBSD), and transmission electron microscopy (TEM), were employed. Key findings demonstrate a progressive enhancement in the alloy's mechanical strength correlating with increased magnetic field intensities, achieving peak properties at 80 mT. This intensity level resulted in significant increases in tensile strength (27.35%), yield strength (19.05%), and elongation (9.23%) compared to the baseline (0 mT). SEM analyses reveal a marked improvement in both the quantity and size of eutectic Si under magnetic influence. EBSD outcomes show a notable shift in grain orientation disorder, with a clear preference emerging at the (111) crystal plane post 80 mT treatment. TEM examinations further confirm an uptick in Si particle numbers and Mg2Si phase precipitation at this intensity, indicating profound microstructural transformations induced by the magnetic field. [ABSTRACT FROM AUTHOR]

The pathophysiology of psoriasis is complex and has not been completely elucidated. Better understanding of the pathogenesis may contribute to further improvement of our therapeutic strategies controlling psoriasis. Emerging evidence points to a causative relationship between altered activity of peroxisome proliferator-activated receptor γ (PPARγ) and psoriasis. The present review focuses on deeper understanding of the possible role of PPARγ in the pathogenesis of psoriasis and the potential of PPARγ agonist to improve the treatment of psoriasis. PPARγ is decreased in psoriasis. PPARγ possibly has effects on the multiple aspects of the pathogenesis of psoriasis, including abnormal lipid metabolism, insulin resistance, immune cells, pro-inflammatory cytokines, keratinocytes, angiogenesis, oxidative stress, microRNAs and nuclear factor kappa B. As defective activation of PPARγ is involved in psoriasis development, PPARγ agonists may be promising agents for treatment of psoriasis. Pioglitazone appears an effective and safe option in the treatment of patients with psoriasis, but there are still concerns about its potential side effects. Research effort has recently been undertaken to explore the PPARγ-activating potential of natural products. Among them some have been studied clinically or preclinically for treatment of psoriasis with promising results. [ABSTRACT FROM AUTHOR]

Introduction: Adalimumab has been used successfully in the treatment of psoriasis. The objective of the study is to compare the efficacy, safety, and immunogenicity between HLX03, an adalimumab biosimilar, and adalimumab in Chinese patients with moderate-to-severe plaque psoriasis. Methods: In this double-blind, active-controlled, parallel-group study, 262 patients with moderate-to-severe plaque psoriasis were randomized (1:1) to receive HLX03 or adalimumab (80 mg at week 1, 40 mg at week 2, and then 40 mg every 2 weeks) for 48 weeks. The primary endpoint was improvement in Psoriasis Area and Severity Index (PASI) score at week 16 comparing to baseline. Equivalence was demonstrated if 95% confidence interval (CI) of the between group difference fell within the equivalence margins of ± 15%. Other efficacy endpoints, safety and immunogenicity were also evaluated. Results: In the full analysis set, PASI improvements at week 16 was 83.5% (n = 131) in the HLX03 group and 82.0% (n = 130) in the adalimumab group, with a least-square-mean difference of 1.5% (95% CI − 3.9% to 6.8%). There were no significant between-group differences in all secondary efficacy analyses including proportion of patients achieving ≥ 75% improvement from baseline PASI (PASI 75), physician global assessment (PGA) 0/1 (clear or almost clear) and change in dermatology life quality index (DLQI) score. The incidences of adverse events and the proportion of patients with antidrug antibodies were also comparable between the two treatment groups. Conclusion: HLX03 demonstrated equivalent efficacy, similar safety and immunogenicity to reference adalimumab, supporting its development as an alternative treatment for patients with plaque psoriasis in China. Clinical trial registration: Chinadrugtrials.org.cn, CTR20171123 (November 27, 2017); ClinicalTrials.gov, NCT03316781 (October 20, 2017). Plain Language Summary: Plaque psoriasis is a chronic, autoimmune, inflammatory skin disease associated with significant morbidity and reduced quality of life. In China, the prevalence of plaque psoriasis increased four-fold between 1987 and 2012. Adalimumab is a biologic antibody used to treat plaque psoriasis globally. However, high treatment costs remain as a significant barrier to adalimumab therapy. Therefore, HLX03 has been developed as an adalimumab (Humira®) biosimilar, which is almost identical to the licensed reference adalimumab, but less expensive and more accessible to patients. In this randomized clinical trial, the efficacy (ability of a drug to produce the desired treatment effects), safety, and immunogenicity (ability of a drug to induce immune response which would affect its efficacy and safety) of HLX03 were compared with the reference adalimumab in Chinese patients with moderate-to-severe plaque psoriasis. Efficacy was evaluated by comparing the changes in severity and extent of disease using Psoriasis Area and Severity Index score between treatment initiation and week 16. Safety was monitored by adverse events, laboratory tests and vital signs. Immunogenicity was assessed by the incidence of antidrug antibodies. Among the 262 randomized patients, 131 received HLX03 and 130 received adalimumab. Both groups reported similar improvements in Psoriasis Area and Severity Index scores (between-group difference fell within the prespecified equivalence margins), and also in other efficacy evaluations. Additionally, the two treatment groups showed similar safety and immunogenicity profiles. In summary, HLX03 demonstrated equivalent efficacy to adalimumab, validating it as an alternative treatment for patients with plaque psoriasis in China. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of coronavirus disease 2019 (COVID-19), which has become a public health emergency of international concern1. Angiotensin-converting enzyme 2 (ACE2) is the cell-entry receptor for severe acute respiratory syndrome coronavirus (SARS-CoV)2. Here we infected transgenic mice that express human ACE2 (hereafter, hACE2 mice) with SARS-CoV-2 and studied the pathogenicity of the virus. We observed weight loss as well as virus replication in the lungs of hACE2 mice infected with SARS-CoV-2. The typical histopathology was interstitial pneumonia with infiltration of considerable numbers of macrophages and lymphocytes into the alveolar interstitium, and the accumulation of macrophages in alveolar cavities. We observed viral antigens in bronchial epithelial cells, macrophages and alveolar epithelia. These phenomena were not found in wild-type mice infected with SARS-CoV-2. Notably, we have confirmed the pathogenicity of SARS-CoV-2 in hACE2 mice. This mouse model of SARS-CoV-2 infection will be valuable for evaluating antiviral therapeutic agents and vaccines, as well as understanding the pathogenesis of COVID-19. Infection with SARS-CoV-2 causes interstitial pneumonia and viral replication in the lungs of transgenic mice that express a human version of ACE2, confirming the pathogenicity of the virus in this model. [ABSTRACT FROM AUTHOR]

Transmissible spongiform encephalopathies (TSEs) are caused by the accumulation of the abnormal prion protein scrapie (PrP). Prion protein aggregation, misfolding, and cytotoxicity in the brain are the major causes of neuronal dysfunction and ultimate neurodegeneration in all TSEs. Parkin, an E3 ubiquitin ligase, has been studied extensively in all major protein misfolding aggregating diseases, especially Parkinson's disease and Alzheimer's disease, but the role of parkin in TSEs remains unknown. Here we investigated the role of parkin in a prion disease cell model in which neuroblastoma2a (N2a) cells were treated with prion peptide PrP106-126. We observed a gradual decrease in the soluble parkin level upon treatment with PrP106-126 in a time-dependent manner. Furthermore, endogenous parkin colocalized with FITC-tagged prion fragment106-126. Overexpression of parkin in N2a cells via transfection repressed apoptosis by enhancing autophagy. Parkin-overexpressing cells also showed reductions in apoptotic BAX translocation to the mitochondria and cytochrome c release to the cytosol, which ultimately inhibited activation of proapoptotic caspases. Taken together, our findings reveal a parkin-mediated cytoprotective mechanism against PrP106-126 toxicity, which is a novel potential therapeutic target for treating prion diseases. [ABSTRACT FROM AUTHOR]

Axonal degeneration is a hallmark of many neurodegenerative disorders including transmissible spongiform encephalopathies (TSE). However, the full complement of axonal degeneration triggers is not fully understood. In an in vitro prion model, we observed that treatment of rat spinal neurons with the prion peptide, PrP106-126, activated death receptor 6 (DR6, also known as TNFRSF21), caspase-6, caspase-3, and induced axonal degeneration. Knockdown of DR6 by siRNA blocked caspase-6 and caspase-3 activation and axonal degeneration. We also found that cleaved caspase-3 is only enriched in cell bodies, but cleaved caspase-6 is expressed in both cell bodies and axons. Axonal degeneration was prevented by preincubation of neurons with a caspase-6 inhibitor or siRNA of caspase-6. Our findings suggest that both DR6 and caspase-6 play important roles in axonal degeneration and caspase-6 acts downstream of DR6. We also observed that nicotinamide nucleotide adenylyltransferase 1 protein (Nmnat1), which had been reported to protect neurons from degeneration, alleviated axonal degeneration without blocking caspase-6 activation, suggesting that Nmnat acts downstream or parallel to caspase-6 activation. Our results indicate that PrP106-126 triggered axonal degeneration of the spinal cord neurons, DR6 is a key regulator of axonal degeneration, and the signaling pathway of DR6/caspase-6 mediates axonal degeneration induced by the prion fragment. Our findings raise the hope of targeting the DR6 as a potential therapeutic strategy in prion-related neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

The neuron-restrictive silencer factor (NRSF) a transcriptional regulator that function as a hub that coordinately regulates multiple aspects of neurogenesis, orchestrates neural differentiation, and preserves the unique neural phenotype. NRSF also acts as an oncogene in neural tumorigenesis, although its effect differs depending on the cell type and tissues. Intriguingly, far more than above functions, potential roles for NRSF and its target genes have also been implicated in the pathogenesis and therapeutic mechanism of neurodegenerative diseases. NRSF acts as a flexible and complicated regulator in nervous system, from transcriptional repressor to activator or modulator, and plays a part in neuronal survival or neuronal death. Here, we present the mechanisms proposed to account for the multiple roles of NRSF in neurogenesis and neurological diseases and discuss the therapeutic perspective of recent advances. The mechanisms underlying this duality of NRSF are helpful to understanding the physiological and pathological conditions of neurons and provide new therapeutic approaches to neurological disorders and diseases. [ABSTRACT FROM AUTHOR]

Under the 'protein-only' hypothesis, prion-based diseases are proposed to result from an infectious agent that is an abnormal isoform of the prion protein in the scrapie form, PrP. However, since PrP is highly insoluble and easily aggregates in vivo, this view appears to be overly simplistic, implying that the presence of PrP may indirectly cause neurodegeneration through its intermediate soluble form. We generated a neurotoxic PrP dimer with partial pathogenic characteristics of PrP by protein misfolding cyclic amplification in the presence of 1-palmitoyl-2-oleoylphosphatidylglycerol consisting of recombinant hamster PrP (23-231). After intracerebral injection of the PrP dimer, wild-type hamsters developed signs of neurodegeneration. Clinical symptoms, necropsy findings, and histopathological changes were very similar to those of transmissible spongiform encephalopathies. Additional investigation showed that the toxicity is primarily related to cellular apoptosis. All results suggested that we generated a new neurotoxic form of PrP, PrP dimer, which can cause neurodegeneration. Thus, our study introduces a useful model for investigating PrP-linked neurodegenerative mechanisms. [ABSTRACT FROM AUTHOR]