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Nanomaterials ◽  
2022 ◽  
Vol 12 (2) ◽  
pp. 268
Author(s):  
Taesung Ha ◽  
Thi Tuyet Mai Pham ◽  
Mikyung Kim ◽  
Yeon-Hee Kim ◽  
Ji-Hyun Park ◽  
...  

The pandemic outbreak of COVID-19 in the year of 2020 that drastically changed everyone’s life has raised the urgent and intense need for the development of more efficacious antiviral material. This study was designed to develop copper nanoparticles (Cu NPs) as an antiviral agent and to validate the antiviral activities of developed copper NP. The Cu NPs were synthesized using a high energy electron beam, and the characteristic morphologies and antiviral activities of Cu NPs were evaluated. We found that Cu NPs are of spherical shape and uniformly distributed, with a diameter of around 100 nm, as opposed to the irregular shape of commercially available copper microparticles (Cu MPs). An X-ray diffraction analysis showed the presence of Cu and no copper oxide II and I in the Cu NPs. A virus inactivation assay revealed no visible viral DNA after 10- and 30-min treatment of H1N1 virus with the Cu NPs. The infectivity of the Cu NPs-treated H1N1 virus significantly decreased compared with that of the Cu MPs-treated H1N1 virus. The viability of A549 bronchial and Madin-Darby Canine Kidney (MDCK) cells infected with Cu NPs-treated H1N1 was significantly higher than those infected with Cu MPs-treated H1N1 virus. We also found cells infected with Cu NPs-treated H1N1 virus exhibited a markedly decreased presence of virus nucleoprotein (NuP), an influenza virus-specific structural protein, compared with cells infected with Cu MPs-treated H1N1 virus. Taken together, our study shows that Cu NPs are a more effective and efficacious antiviral agent compared with Cu MPs and offer promising opportunities for the prevention of devastatingly infectious diseases.


2022 ◽  
Vol 8 ◽  
Author(s):  
Felix Sebastian Nettersheim ◽  
Simon Braumann ◽  
Kouji Kobiyama ◽  
Marco Orecchioni ◽  
Melanie Vassallo ◽  
...  

Atherosclerosis is a chronic, lipid-driven disease of medium sized arteries which causes myocardial infarction and stroke. Recently, an adaptive immune response against the plaque-associated autoantigen Apolipoprotein B100 (ApoB), the structural protein component of low-density lipoprotein, has been implicated in atherogenesis. In healthy individuals, CD4+ T cells responding to ApoB mainly comprised regulatory T cells, which confer immune tolerance and atheroprotection. Mice and patients with atherosclerosis harbor increased numbers of proatherogenic ApoB-reactive T-helper cell subsets. Given the lack of therapies targeting proatherogenic immunity, clarification of the underlying mechanisms is of high clinical relevance. T cells develop in the thymus, where strong autoreactive T cells are eliminated in the process of negative selection. Herein, we investigated whether the transcription factor autoimmune regulator (AIRE), which controls expression of numerous tissue-restricted self-antigens in the thymus, is involved in mediating tolerance to ApoB and whether Aire deficiency might contribute to atherogenesis. Mice deficient for Aire were crossbred to apolipoprotein E-deficient mice to obtain atherosclerosis-prone Aire−/−Apoe−/− mice, which were fed a regular chow diet (CD) or western-type diet (WD). CD4+ T cells responding to the ApoB peptide p6 were analyzed by flow cytometry. We demonstrate that Aire deficiency influences neither generation nor activation of ApoB-reactive T cells and has only minor and overall inconsistent impacts on their phenotype. Furthermore, we show that atherosclerotic plaque size is not affected in Aire−/−Apoe−/− compared to Aire+/+Apoe−/−, irrespective of diet and gender. In conclusion, our data suggests that AIRE is not involved in regulating thymic expression of ApoB or atherosclerosis. Alternative mechanisms how ApoB-reactive CD4 T cells are selected in the thymus will have to be investigated.


2022 ◽  
Author(s):  
Susanne Krasemann ◽  
Carsten Dittmayer ◽  
Saskia v. Stillfried ◽  
Jenny Meinhardt ◽  
Fabian Heinrich ◽  
...  

Background Autopsy studies have provided valuable insights into the pathophysiology of COVID-19. Controversies remain whether the clinical presentation is due to direct organ damage by SARS-CoV-2 or secondary effects, e.g. by an overshooting immune response. SARS-CoV-2 detection in tissues by RT-qPCR and immunohistochemistry (IHC) or electron microscopy (EM) can help answer these questions, but a comprehensive evaluation of these applications is missing. Methods We assessed publications using IHC and EM for SARS-CoV-2 detection in autopsy tissues. We systematically evaluated commercially available antibodies against the SARS-CoV-2 spike protein and nucleocapsid, dsRNA, and non-structural protein Nsp3 in cultured cell lines and COVID-19 autopsy tissues. In a multicenter study, we evaluated specificity, reproducibility, and inter-observer variability of SARS-CoV-2 nucleocapsid staining. We correlated RT-qPCR viral tissue loads with semiquantitative IHC scoring. We used qualitative and quantitative EM analyses to refine criteria for ultrastructural identification of SARS-CoV-2. Findings Publications show high variability in the detection and interpretation of SARS-CoV-2 abundance in autopsy tissues by IHC or EM. In our study, we show that IHC using antibodies against SARS-CoV-2 nucleocapsid yields the highest sensitivity and specificity. We found a positive correlation between presence of viral proteins by IHC and RT-qPCR-determined SARS-CoV-2 viral RNA load (r=-0.83, p-value <0.0001). For EM, we refined criteria for virus identification and also provide recommendations for optimized sampling and analysis. 116 of 122 publications misinterpret cellular structures as virus using EM or show only insufficient data. We provide publicly accessible digitized EM and IHC sections as a reference and for training purposes. Interpretation Since detection of SARS-CoV-2 in human autopsy tissues by IHC and EM is difficult and frequently incorrect, we propose criteria for a re-evaluation of available data and guidance for further investigations of direct organ effects by SARS-CoV-2.


2022 ◽  
Vol 221 (2) ◽  
Author(s):  
Gregory C. Addicks ◽  
Hongbo Zhang ◽  
Dongryeol Ryu ◽  
Goutham Vasam ◽  
Alexander E. Green ◽  
...  

Protein lysine acetylation is a post-translational modification that regulates protein structure and function. It is targeted to proteins by lysine acetyltransferases (KATs) or removed by lysine deacetylases. This work identifies a role for the KAT enzyme general control of amino acid synthesis protein 5 (GCN5; KAT2A) in regulating muscle integrity by inhibiting DNA binding of the transcription factor/repressor Yin Yang 1 (YY1). Here we report that a muscle-specific mouse knockout of GCN5 (Gcn5skm−/−) reduces the expression of key structural muscle proteins, including dystrophin, resulting in myopathy. GCN5 was found to acetylate YY1 at two residues (K392 and K393), disrupting the interaction between the YY1 zinc finger region and DNA. These findings were supported by human data, including an observed negative correlation between YY1 gene expression and muscle fiber diameter. Collectively, GCN5 positively regulates muscle integrity through maintenance of structural protein expression via acetylation-dependent inhibition of YY1. This work implicates the role of protein acetylation in the regulation of muscle health and for consideration in the design of novel therapeutic strategies to support healthy muscle during myopathy or aging.


2022 ◽  
Author(s):  
Klaudia Maruszczak ◽  
Martin Jung ◽  
Shafqat Rasool ◽  
Jean-Francois Trempe ◽  
Doron Rapaport

Mitochondria dysfunction is involved in the pathomechanism of many illnesses including Parkinson's disease. PINK1, which is mutated in some cases of familiar Parkinsonism, is a key component in the degradation of damaged mitochondria by mitophagy. The accumulation of PINK1 on the mitochondrial outer membrane (MOM) of compromised organelles is crucial for the induction of mitophagy, but the molecular mechanism of this process is still unresolved. Here, we investigate the association of PINK1 with the TOM complex. We demonstrate that PINK1 heavily relies on the import receptor TOM70 for its association with mitochondria and directly interacts with this receptor. The structural protein TOM7 appears to play only a moderate role in PINK1 association with the TOM complex, probably due to its role in stabilizing this complex. PINK1 requires the TOM40 pore lumen for its stable interaction with the TOM complex and apparently remains there during its further association with the MOM. Overall, this study provides new insights on the role of the individual TOM subunits in the association of PINK1 with the MOM of depolarized mitochondria.


2022 ◽  
Vol 14 ◽  
Author(s):  
Elizabeth Gage ◽  
Devansh Agarwal ◽  
Calvin Chenault ◽  
Kameron Washington-Brown ◽  
Sarah Szvetecz ◽  
...  

Complex transcriptional gene regulation allows for multifaceted isoform production during retinogenesis, and novel isoforms transcribed from a single locus can have unlimited potential to code for diverse proteins with different functions. In this study, we explored the CTBP2/RIBEYE gene locus and its unique repertoire of transcripts that are conserved among vertebrates. We studied the transcriptional coregulator (CTBP2) and ribbon synapse-specific structural protein (RIBEYE) in the chicken retina by performing comprehensive histochemical and sequencing analyses to pinpoint cell and developmental stage-specific expression of CTBP2/RIBEYE in the developing chicken retina. We demonstrated that CTBP2 is widely expressed in retinal progenitors beginning in early retinogenesis but becomes limited to GABAergic amacrine cells in the mature retina. Inversely, RIBEYE is initially epigenetically silenced in progenitors and later expressed in photoreceptor and bipolar cells where they localize to ribbon synapses. Finally, we compared CTBP2/RIBEYE regulation in the developing human retina using a pluripotent stem cell derived retinal organoid culture system. These analyses demonstrate that similar regulation of the CTBP2/RIBEYE locus during chick and human retinal development is regulated by different members of the K50 homeodomain transcription factor family.


Author(s):  
Yang Wang ◽  
Shuai Cui ◽  
Ting Xin ◽  
Xixi Wang ◽  
Hainan Yu ◽  
...  

African swine fever (ASF) is a devastating infectious disease caused by African swine fever virus (ASFV). The ASFV genome encodes multiple structural and non-structural proteins that contribute to evasion of host immunity. In this study, we determined that the viral non-structural protein MGF360-14L inhibits interferon-β (IFN-β) promoter activity induced by cGAS-STING signaling. MGF360-14L was also found to downregulate expression of the IRF3 protein and promote its degradation through ubiquitin-meditated proteolysis. Moreover, MGF360-14L was shown to interact with and destabilize IRF3 by facilitating E3 ligase TRIM21-mediated K63-linked ubiquitination of IRF3. Overall, our study revealed that MGF360-14L promotes degradation of IRF3 through TRIM21, thereby inhibiting type I interferon production. These findings provide new insights into the mechanisms underlying ASFV immune evasion.


Author(s):  
Dwaipayan Sarathi Chakraborty ◽  
Shouvik Choudhury ◽  
Sandeep Lahiry

Despite dynamic drug and vaccine development processes to reduce the disease burden of COVID-19, the treatment options are still very limited. Vasoactive intestinal peptide (VIP) has a diversified physiological action with specific features of lung protection-related activities. VIP inhibits severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) gene replication in human monocytes and the viral replication in Calu-3 cells, thus further reducing the generation of proinflammatory mediators. Aviptadil, a synthetic form of VIP, is the only pulmonary therapeutic agent to have been granted ‘fast track’ status by the U.S. Food and Drug Administration (FDA) and to be allowed into both Phase II and III clinical trials. Initial binding of Aviptadil with non-structural protein (nsp) 10 and nsp16, which may inhibit the 2’-O-methyltransferase activity of the SARS-CoV-2 nsp10 and nsp16 complex. Aviptadil has already proved to be an effective option in the treatment of severe respiratory failures due to sepsis and other related lung injuries. Interim analysis results of this drug used in respiratory failure caused by SARS-CoV-2 has evolved a new hope in regard to safety and efficacy. The final results from a recently completed trial, as well as all currently ongoing trials, will clarify the class effect of this drug in the treatment of COVID-19 in future days.


Author(s):  
Xiao Sun ◽  
Yingzhi Liu ◽  
Ziheng Huang ◽  
Wenye Xu ◽  
Wei Hu ◽  
...  

AbstractA recent mutation analysis suggested that Non-Structural Protein 6 (NSP6) of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a key determinant of the viral pathogenicity. Here, by transcriptome analysis, we demonstrated that the inflammasome-related NOD-like receptor signaling was activated in SARS-CoV-2-infected lung epithelial cells and Coronavirus Disease 2019 (COVID-19) patients’ lung tissues. The induction of inflammasomes/pyroptosis in patients with severe COVID-19 was confirmed by serological markers. Overexpression of NSP6 triggered NLRP3/ASC-dependent caspase-1 activation, interleukin-1β/18 maturation, and pyroptosis of lung epithelial cells. Upstream, NSP6 impaired lysosome acidification to inhibit autophagic flux, whose restoration by 1α,25-dihydroxyvitamin D3, metformin or polydatin abrogated NSP6-induced pyroptosis. NSP6 directly interacted with ATP6AP1, a vacuolar ATPase proton pump component, and inhibited its cleavage-mediated activation. L37F NSP6 variant, which was associated with asymptomatic COVID-19, exhibited reduced binding to ATP6AP1 and weakened ability to impair lysosome acidification to induce pyroptosis. Consistently, infection of cultured lung epithelial cells with live SARS-CoV-2 resulted in autophagic flux stagnation, inflammasome activation, and pyroptosis. Overall, this work supports that NSP6 of SARS-CoV-2 could induce inflammatory cell death in lung epithelial cells, through which pharmacological rectification of autophagic flux might be therapeutically exploited.


Author(s):  
Pengfei Wang ◽  
Chunguo Liu ◽  
Shida Wang ◽  
Lili Wen ◽  
Zhibin Shi ◽  
...  

AbstractAfrican swine fever (ASF) is an acute hemorrhagic disease of domestic pigs. The causative agent of ASF, ASF virus (ASFV), is a double-stranded DNA virus, the sole member in the family Asfarviridae. The non-structural protein pB602L of ASFV is a molecular chaperone of the major capsid protein p72 and plays a key role in icosahedral capsid assembly. This protein is antigenic and is a target for developing diagnostic tools for ASF. To generate monoclonal antibodies (mAbs) against pB602L, a prokaryotically expressed recombinant pB602L protein was produced, purified, and used as an antigen to immunize mice. A total of eight mouse mAbs were obtained, and their binding epitopes were screened by Western blot using an overlapping set of polypeptides from pB602L. Three linear epitopes were identified and designated epitope 1 (366ANRERYNY373), epitope 2 (415GPDAPGLSI423), and epitope 3 (498EMLNVPDD505). Based on the epitope recognized, the eight mAbs were placed into three groups: group 1 (B2A1, B2F1, and B2D10), group 2 (B2H10, B2B2, B2D8, and B2A3), and group 3 (B2E12). The mAbs B2A1, B2H10, and B2E12, each representing one of the groups, were used to detect pB602L in ASFV-infected porcine alveolar macrophages (PAMs) and pig tissues, using an indirect fluorescence assay (IFA) and immunohistochemical staining, respectively. The results showed that pB602L was detectable with all three mAbs in immunohistochemical staining, but only B2H10 was suitable for detecting the proteins in ASFV-infected PAMs by IFA. In summary, we developed eight anti-pB602L mouse mAbs recognizing three linear epitopes in the protein, which can be used as reagents for basic and applied research on ASFV.


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