CHES1 modulated tumorigenesis and senescence of pancreas cancer cells through repressing AKR1B10.

Pancreatic ductal adenocarcinoma (PDAC), is characteristic by a heterogeneous tumor microenvironment and gene mutations, conveys a dismal prognosis and low response to chemotherapy and immunotherapy. Here, we found that checkpoint suppressor 1 (CHES1) served as a tumor repressor in PDAC and was associated with patient prognosis. Functional experiments indicated that CHES1 suppressed the proliferation and invasion of PDAC by modulating cellular senescence. To further identify the downstream factor of CHES1 in PDAC, label-free quantitative proteomics analysis was conducted, which showed that the oncogenic Aldo-keto reductase 1B10 (AKR1B10) was transcriptionally repressed by CHES1 in PDAC. And AKR1B10 facilitated the malignant activity and repressed senescent phenotype of PDAC cells. Moreover, pharmaceutical inhibition of AKR1B10 with Oleanolic acid (OA) significantly induced tumor regression and sensitized PDAC cells to gemcitabine, and this combined therapy did not cause obvious side effects. Rescued experiments revealed that CHES1 regulated the tumorigenesis and gemcitabine sensitivity through AKR1B10-mediated senescence in PDAC. In summary, this study revealed that the CHES1/AKR1B10 axis modulated the progression and cellular senescence in PDAC, which might provide revenues for drug-targeting and senescence-inducing therapies for PDAC.

TEAD1, MYO7A and NDUFC2 are novel functional genes associated with glucose metabolism in BXD recombinant inbred population.

AIM: The liver is an important metabolic organ that governs glucolipid metabolism, and its dysfunction may cause non-alcoholic fatty liver disease, type 2 diabetes mellitus, dyslipidaemia, etc. We aimed to systematic investigate the key factors related to hepatic glucose metabolism, which may be beneficial for understanding the underlying pathogenic mechanisms for obesity and diabetes mellitus. MATERIALS AND METHODS: Oral glucose tolerance test (OGTT) phenotypes and liver transcriptomes of BXD mice under chow and high-fat diet conditions were collected from GeneNetwork. QTL mapping was conducted to pinpoint genomic regions associated with glucose homeostasis. Candidate genes were further nominated using a multi-criteria approach and validated to confirm their functional relevance in vitro. RESULTS: Our results demonstrated that plasma glucose levels in OGTT were significantly affected by both diet and genetic background, with six genetic regulating loci were mapped on chromosomes 1, 4, and 7. Moreover, TEAD1, MYO7A and NDUFC2 were identified as the candidate genes. Functionally, siRNA-mediated TEAD1, MYO7A and NDUFC2 knockdown significantly decreased the glucose uptake and inhibited the transcription of genes related to insulin and glucose metabolism pathways. CONCLUSIONS: Our study contributes novel insights to the understanding of hepatic glucose metabolism, demonstrating the impact of TEAD1, MYO7A and NDUFC2 on mitochondrial function in the liver and their regulatory role in maintaining in glucose homeostasis.

Experimental study on the microwave radiation disinfection of E. coli on SiC composite filter.

Filter is an important component in the air-conditioning system. The airborne microorganisms can be intercepted and further multiply on the filter, which might cause a secondary pollution. The present work proposed a SiC composite filter (SCF), namely combining the filter with the absorbing material SiC. The disinfection efficiency (η) and mechanism of the microwave radiation method (MRM) on E. coli and S. aureus attached to the SCF were experimentally explored. The impacts of the microwave power (P) and disinfection time (t) on η were investigated. The results show that the SCF can be heated well by the microwave, but the normal filter (NF) cannot. The MRM can effectively and rapidly disinfect bacteria on the SCF at a sufficiently high P and an appropriate t. Generally, η increases with P and t. Under a specific P, η can be only increased with t at a certain range and a peak η might be reached. When this peak is achieved, η will not be further increased with t. The disinfection by the MRM is attributed to the thermal and non-thermal effects. Specially, at P = 600 W and t = 10 min, the non-thermal effect contributes about 89.6% to the disinfection of the E. coli and about 43.1% to the S. aureus. A universal relationship between η and temperature is given for E. coli and S. aureus to predict η at various P and t. Finally, the effective temperatures required by the MRM to satisfactorily disinfect bacteria on the SCF are identified, i.e., about 41 °C for E. coli and 71 °C for S. aureus.

Specific pupylation as IDEntity reporter (SPIDER) for the identification of protein-biomolecule interactions.

Protein-biomolecule interactions play pivotal roles in almost all biological processes. For a biomolecule of interest, the identification of the interacting protein(s) is essential. For this need, although many assays are available, highly robust and reliable methods are always desired. By combining a substrate-based proximity labeling activity from the pupylation pathway of Mycobacterium tuberculosis and the streptavidin (SA)-biotin system, we developed the Specific Pupylation as IDEntity Reporter (SPIDER) method for identifying protein-biomolecule interactions. Using SPIDER, we validated the interactions between the known binding proteins of protein, DNA, RNA, and small molecule. We successfully applied SPIDER to construct the global protein interactome for m6A and mRNA, identified a variety of uncharacterized m6A binding proteins, and validated SRSF7 as a potential m6A reader. We globally identified the binding proteins for lenalidomide and CobB. Moreover, we identified SARS-CoV-2-specific receptors on the cell membrane. Overall, SPIDER is powerful and highly accessible for the study of protein-biomolecule interactions.

Cell-liposome delivery system based on neuroinflammation to target the amygdala for ameliorating depressive-like behaviors.

Depression is a serious psychiatric disorder with unsatisfactory outcomes due to difficulties in delivering therapeutic molecules from the periphery to the brain. Neuroinflammation plays a key role in neurobiology and the treatment of depression. Neutrophils can cross the blood-brain barrier (BBB) and infiltrate key brain regions related to the pathophysiology of depression during neuroinflammation. N-Acetyl Pro-Gly-Pro (PGP) peptides efficiently bind to CXCR2 receptors on the surface of neutrophils. The neuropeptide oxytocin demonstrated antidepressant properties in preclinical and clinical studies, but its inability to penetrate the BBB hampers its therapeutic applications. In this study, we established a novel drug delivery system based on neutrophil infiltration in key brain regions during neuroinflammation. PGP was used to modify oxytocin-loaded liposomes (PGP-OTL) as the target ligand. Systematic administration of PGP-OTL exhibited enhanced antidepressant properties resulting from elevated oxytocin concentrations, especially in the amygdala, a crucial depression-implicated brain region. Enhanced antidepressant effects of PGP-OTL, similar to the ones caused by central oxytocin infusion, were observed in behavioral measurement including forced swim and tail suspension tests. Our study demonstrated that PGP-OTL can "hitchhike" neutrophils and enhance delivery of therapeutics into the brain, thus providing the means for developing novel cell-liposome-based drug delivery strategies for depression therapy.

Acetylation of Checkpoint suppressor 1 enhances its stability and promotes the progression of triple-negative breast cancer.

Checkpoint suppressor 1 (CHES1), a transcriptional regulator, had been dysregulated in many types of malignancies including breast cancer, and its expression level is strongly associated with progression and prognosis of patients. However, the underlying regulatory mechanisms of CHES1 expression in the breast cancer and the effects of post-translational modifications (PTMs) on its functional performance remain to be fully investigated. Herein, we found that CHES1 had a high abundance in triple-negative breast cancer (TNBC) and its expression was tightly associated with malignant phenotype and poor outcomes of patients. Furthermore, we confirmed that CHES1 was an acetylated protein and its dynamic modification was mediated by p300 and HDAC1, and CHES1 acetylation enhanced its stability via decreasing its ubiquitination and degradation, which resulted in the high abundance of CHES1 in TNBC. RNA-seq and functional study revealed that CHES1 facilitated the activation of oncogenic genes and pathways leading to proliferation and metastasis of TNBC. Taken together, this research established a novel regulatory role of acetylation on the stability and activity of CHES1. The results demonstrate the significance of CHES1 acetylation and underlying mechanisms in the progression of TNBC, offering new potential candidate for molecular-targeted therapy in breast cancer.

NIR-II Fluorescence Imaging-Guided Oxygen Self-Sufficient Nano-Platform for Precise Enhanced Photodynamic Therapy.

Tumor hypoxia and systemic toxicity seriously affect the efficacy of photodynamic therapy (PDT) and are considered as the "Achilles' heel" of PDT. Herein, to combat such limitations, an intelligent orthogonal emissions LDNP@SiO2 -CaO2 and folic acid-polyethylene glycol-Ce6 nanodrug is rationally designed and fabricated not only for relieving the hypoxic tumor microenvironment (TME) to enhance PDT efficacy, but also for determining the optimal triggering time through second near-infrared (NIR-II) fluorescence imaging. The designed nanodrug continuously releases a large amount of O2 , H2 O2 , and Ca2+ ions when exposed to the acidic TME. Meanwhile, under downshifting NIR-II bioimaging guidance, chlorine e6 (Ce6) consumes oxygen to produce 1 O2 upon excitation of upconversion photon. Moreover, cytotoxic reactive oxygen species (ROS) and calcium overload can induce mitochondria injury and thus enhance the oxidative stress in tumor cells. As a result, the NIR-II bioimaging guided TME-responsive oxygen self-sufficient PDT nanosystem presents enhanced anti-tumor efficacy without obvious systemic toxicity. Thus, the fabricated nanodrug offers great potential for designing an accurate cancer theranostic system.

Age- and Severity-Associated Humoral Immunity Response in COVID-19 Patients: A Cohort Study from Wuhan, China.

Age has been found to be the single most significant factor in COVID-19 severity and outcome. However, the age-related severity factors of COVID-19 have not been definitively established. In this study, we detected SARS-CoV-2-specific antibody responses and infectious disease-related blood indicators in 2360 sera from 783 COVID-19 patients, with an age range of 1−92 years. In addition, we recorded the individual information and clinical symptoms of the patients. We found that the IgG responses for S1, N, and ORF3a and the IgM for NSP7 were associated with severe COVID-19 at different ages. The IgM responses for the S-protein peptides S1-113 (aa 673−684) and S2-97 (aa 1262−1273) were associated with severe COVID-19 in patients aged <60. Furthermore, we found that the IgM for S1-113 and NSP7 may play a protective role in patients aged <60 and >80, respectively. Regarding clinical parameters, we analyzed the diagnostic ability of five clinical parameters for severe COVID-19 in six age groups and identified three-target panel, glucose, IL-6, myoglobin, IL-6, and NT proBNP as the appropriate diagnostic markers for severe COVID-19 in patients aged <41, 41−50, 51−60, 61−70, 71−80, and >80, respectively. The age-associated severity factors revealed here will facilitate our understanding of COVID-19 immunity and diagnosis, and eventually provide meaningful information for combating the pandemic.

Estrogen-Related Receptor α: A Significant Regulator and Promising Target in Bone Homeostasis and Bone Metastasis.

Bone homeostasis is maintained with the balance between bone formation and bone resorption, which is involved in the functional performance of osteoblast and osteoclast. Disruption of this equilibrium usually causes bone disorders including osteoporosis, osteoarthritis, and osteosclerosis. In addition, aberrant activity of bone also contributes to the bone metastasis that frequently occurs in the late stage of aggressive cancers. Orphan nuclear receptor estrogen-related receptor (ERRα) has been demonstrated to control the bone cell fate and the progression of tumor cells in bone through crosstalk with various molecules and signaling pathways. However, the defined function of this receptor in bone is inconsistent and controversial. Therefore, we summarized the latest research and conducted an overview to reveal the regulatory effect of ERRα on bone homeostasis and bone metastasis, this review may broaden the present understanding of the cellular and molecular model of ERRα and highlight its potential implication in clinical therapy.

Amorphous ferric oxide-coating selenium core-shell nanoparticles: a self-preservation Pt(IV) platform for multi-modal cancer therapies through hydrogen peroxide depletion-mediated anti-angiogenesis, apoptosis and ferroptosis.

A self-preservation Pt(IV) nanoplatform, amorphous ferric oxide-coating selenium core-shell nanoparticles (iAIO@NSe-Pt), was developed for H2O2 depletion-mediated tumor anti-angiogenesis, apoptosis, and ferroptosis. Upon entry into the blood, the ferric oxide shell effectively blocked the contact Pt(IV) prodrug with reduced molecules, then avoided the inactivation of the Pt(IV) prodrug and increased its accumulation in the tumor. After entering cancer cells, iAIO@NSe-Pt caused a series of cascade reactions: (1) AIO on the surface of iAIO@NSe-Pt quickly dissolved, released an abundance of Fe(II) because of the weakly acidic tumor microenvironment, and then catalyzed cellular H2O2 into highly toxic ˙OH, resulting in cellular H2O2 deficiency and cell ferroptosis. (2) The platinum(IV) prodrugs were exposed and quickly reduced to highly toxic Pt(II) by depleting GSH. This process inactivated GPX4, promoted ROS accumulation, and further accelerated ferroptosis. In addition, the generated Pt(II) quickly inhibited DNA replication, achieving effective apoptotic cell death. Meanwhile, Pt(II) inactivated SOD1, which blocked the synthesis of cellular H2O2 and accelerated ROS (superoxide anion radical) accumulation. (3) The deficiency of cellular H2O2 significantly inhibited the expression of vascular endothelial growth factor-A (VEGF-A), blocking tumor angiogenesis and then improving the anticancer effect. (4) After such a cascade reaction, the exposed NSe successively disrupted mitochondrial respiration and inhibited cancer angiogenesis, further inducing cancer cell death. Collectively, our functional and mechanical investigation suggested that iAIO@NSe-Pt exhibits excellent tumor targeting, biocompatibility and anti-tumor efficiency in vitro and in vivo, and provides a novel example of a self-preservation Pt(IV) nanoplatform for H2O2 depletion-mediated tumor anti-angiogenesis, apoptosis, and ferroptosis, showing great promise for future clinical use.

15-Month Health Outcomes and the Related Risk Factors of Hospitalized COVID-19 Patients From Onset: A Cohort Study.

Objective: The long-term impact of COVID-19 on patient health has been a recent focus. This study aims to determine the persistent symptoms and psychological conditions of patients hospitalized with COVID-19 15 months after onset, that patients first developed symptoms. The potential risk factors were also explored. Methods: A cohort of COVID-19 patients discharged from February 20, 2020 to March 31, 2020 was recruited. Follow-ups were conducted using validated questionnaires and psychological screening scales at 15 months after onset to evaluate the patients' health status. The risk factors for long-term health impacts and their associations with disease severity was analyzed. Findings: 534 COVID-19 patients were enrolled. The median age of the patients was 62.0 years old (IQR 52.0-70.0) and 295 were female (55.2%). The median time from onset to follow-up was 460.0 (451.0-467.0) days. Sleep disturbance (18.5%, 99/534) and fatigue (17.2%, 92/534) were the most common persistent symptoms. 6.4% (34/534) of the patients had depression, 9.2% (49/534) were anxious, 13.0% (70/534) had insomnia and 4.7% (25/534) suffered from post-traumatic stress disorder (PTSD). Multivariate adjusted logistic regression analysis showed that glucocorticoid use during hospitalization (OR 3.58, 95% CI 1.12-11.44) was significantly associated with an increased risk of fatigue. The OR values for anxiety and sleep disorders were 2.36 (95% CI 1.07-5.20) and 2.16 (95% CI 1.13-4.14) in females to males. The OR value of PTSD was 25.6 (95% CI 3.3-198.4) in patients with persistent symptoms to those without persistent symptoms. No significant associations were observed between fatigue syndrome or adverse mental outcomes and disease severity. Conclusions: 15-month follow-up in this study demonstrated the need of extended rehabilitation intervention for complete recovery in COVID-19 patients.

PDGFB targeting biodegradable FePt alloy assembly for MRI guided starvation-enhancing chemodynamic therapy of cancer.

The application of chemodynamic therapy (CDT) for cancer is a serious challenge owing to the low efficiency of the Fenton catalyst and insufficient H2O2 expression in cells. Herein, we fabricated a PDGFB targeting, biodegradable FePt alloy assembly for magnetic resonance imaging (MRI)-guided chemotherapy and starving-enhanced chemodynamic therapy for cancer using PDGFB targeting, pH-sensitive liposome-coated FePt alloys, and GOx (pLFePt-GOx). We found that the Fenton-catalytic activity of FePt alloys was far stronger than that of traditional ultrasmall iron oxide nanoparticle (UION). Upon entry into cancer cells, pLFePt-GOx nanoliposomes degraded into many tiny FePt alloys and released GOx owing to the weakly acidic nature of the tumor microenvironment (TME). The released GOx-mediated glucose consumption not only caused a starvation status but also increased the level of cellular H2O2 and acidity, promoting Fenton reaction by FePt alloys and resulting in an increase in reactive oxygen species (ROS) accumulation in cells, which ultimately realized starving-enhanced chemodynamic process for killing tumor cells. The anticancer mechanism of pLFePt-GOx involved ROS-mediated apoptosis and ferroptosis, and glucose depletion-mediated starvation death. In the in vivo assay, the systemic delivery of pLFePt-GOx showed excellent antitumor activity with low biological toxicity and significantly enhanced T2-weighted magnetic resonance imaging (MRI) signal of the tumor, indicating that pLFePt-GOx can serve as a highly efficient theranostic tool for cancer. This work thus describes an effective, novel multi-modal cancer theranostic system.

SARS-CoV-2-specific antibody response characteristics in COVID-19 patients of different ages.

Age has been found to be one of the main risk factors for the severity and outcome of COVID-19. However, differences in SARS-CoV-2 specific antibody responses among COVID-19 patients of different age groups remain largely unknown. In this study, we analyzed the IgG/IgM responses to 21 SARS-CoV-2 proteins and 197 peptides that fully cover the spike protein against 731 sera collected from 731 COVID-19 patients aged from 1 to We show that there is no overall difference in SARS-CoV-2 antibody responses in COVID-19 patients in the 4 age groups. By antibody response landscape maps, we find that the IgG response profiles of SARS-CoV-2 proteins are positively correlated with age. The S protein linear epitope map shows that the immunogenicity of the S-protein peptides is related to peptide sequence, disease severity and age of the COVID-19 patients. Furthermore, the enrichment analysis indicates that low S1 IgG responses are enriched in patients aged <50 and high S1 IgG responses are enriched in mild COVID-19 patients aged >60. In addition, high responses of non-structural/accessory proteins are enriched in severe COVID-19 patients aged >70. These results suggest the distinct immune response of IgG/IgM to each SARS-CoV-2 protein in patients of different age, which may facilitate a deeper understanding of the immune responses in COVID-19 patients.

Anti-SARS-CoV-2 IgG responses are powerful predicting signatures for the outcome of COVID-19 patients.

Introduction: The COVID-19 global pandemic is far from ending. There is an urgent need to identify applicable biomarkers for early predicting the outcome of COVID-19. Growing evidences have revealed that SARS-CoV-2 specific antibodies evolved with disease progression and severity in COIVD-19 patients. Objectives: We assumed that antibodies may serve as biomarkers for predicting the clinical outcome of hospitalized COVID-19 patients on admission. Methods: By taking advantage of a newly developed SARS-CoV-2 proteome microarray, we surveyed IgG responses against 20 proteins of SARS-CoV-2 in 1034 hospitalized COVID-19 patients on admission and followed till 66 days. The microarray results were further correlated with clinical information, laboratory test results and patient outcomes. Cox proportional hazards model was used to explore the association between SARS-CoV-2 specific antibodies and COVID-19 mortality. Results: Nonsurvivors (n = 955) induced higher levels of IgG responses against most of non-structural proteins than survivors (n = 79) on admission. In particular, the magnitude of IgG antibodies against 8 non-structural proteins (NSP1, NSP4, NSP7, NSP8, NSP9, NSP10, RdRp, and NSP14) and 2 accessory proteins (ORF3b and ORF9b) possessed significant predictive power for patient death, even after further adjustments for demographics, comorbidities, and common laboratory biomarkers for disease severity (all with p trend < 0.05). Additionally, IgG responses to all of these 10 non-structural/accessory proteins were also associated with the severity of disease, and differential kinetics and serum positive rate of these IgG responses were confirmed in COVID-19 patients of varying severities within 20 days after symptoms onset. The area under curves (AUCs) for these IgG responses, determined by computational cross-validations, were between 0.62 and 0.71. Conclusions: Our findings might have important implications for improving clinical management of COVID-19 patients.

COVID-ONE-hi: The One-stop Database for COVID-19-specific Humoral Immunity and Clinical Parameters.

Coronavirus disease 2019 (COVID-19), which is caused by SARS-CoV-2, varies with regard to symptoms and mortality rates among populations. Humoral immunity plays critical roles in SARS-CoV-2 infection and recovery from COVID-19. However, differences in immune responses and clinical features among COVID-19 patients remain largely unknown. Here, we report a database for COVID-19-specific IgG/IgM immune responses and clinical parameters (named COVID-ONE-hi). COVID-ONE-hi is based on the data that contain the IgG/IgM responses to 24 full-length/truncated proteins corresponding to 20 of 28 known SARS-CoV-2 proteins and 199 spike protein peptides against 2360 serum samples collected from 783 COVID-19 patients. In addition, 96 clinical parameters for the 2360 serum samples and basic information for the 783 patients are integrated into the database. Furthermore, COVID-ONE-hi provides a dashboard for defining samples and a one-click analysis pipeline for a single group or paired groups. A set of samples of interest is easily defined by adjusting the scale bars of a variety of parameters. After the "START" button is clicked, one can readily obtain a comprehensive analysis report for further interpretation. COVID-ONE-hi is freely available at www.COVID-ONE.cn.

CuO dot-decorated Cu@Gd2O3 core-shell hierarchical structure for Cu(i) self-supplying chemodynamic therapy in combination with MRI-guided photothermal synergistic therapy.

Theoretically, the Fenton catalytic efficiency of the Cu-based nanoplatform is approximately 160 times that of traditional Fe-based agents. However, the coordination interaction between Cu(ii) and intracellular GSH significantly inhibits the high catalytic activity of Cu(i) generation, dramatically decreasing the Fenton-like catalytic efficiency. Herein, we designed a completely new and highly efficient hierarchical structural nanoplatform to enhance the mimic-peroxidase activity through utilizing comproportionation between CuO and elemental Cu core to self-supply Cu(i). The catalytic rate of this nanoplatform was approximately 55-fold that of traditional Fe-based agents. In a cell assay, this nanoplatform could function as an antagonist of GPX4 and agonist of SOD-1, resulting in intracellular ROS and H2O2 accumulation. Next, the accumulated H2O2 could be quickly catalyzed to highly toxic ˙OH by self-supplying Cu(i), causing strong oxidative stress damage to mitochondria and cell membranes. Under 808 nm laser irradiation, this nanoplatform exhibited a stronger inhibition of tumor growth, and effectively overcame the tumor resistance and recurrence. In addition, this hierarchical structure significantly promoted the interaction between water molecules and gadolinium centers, making TRF-mCuGd possess an ultrahigh T1 MRI contrast performance, and hence, more pathological information of the tumor could be achieved. Overall, this work provides a promising pattern for the design and development of cancer theranostics.

COVID-2019 lockdown in Beijing: A rare opportunity to analyze the contribution rate of road traffic to air pollutants.

In Beijing, the lockdown imposed to curb the spread of COVID-2019 has led to a sharp drop in road traffic. This provides an opportunity to quantify the contribution rate of road traffic to PM2.5 and NO2 concentrations. This paper creatively puts forward the concept of the Maximum Possible Contribution Rate (MPCR) and estimates the MPCR of road traffic to PM2.5 and NO2 by analyzing the daily air pollution data and road traffic data in Beijing from January 24 to March 31, 2020 and the same period in 2019. The findings of this paper include: The decrease in SO2 concentration during the lockdown indicates a reduction in pollutant emissions from industry and households. During the lockdown, road traffic in Beijing reduced by 46.9 %, while the concentrations of PM2.5 and NO2 in the atmosphere reduced by 5.6 % and 29.2 % respectively. The MPCR of road traffic to PM2.5 and NO2 concentrations are 11.9 % and 62.3 %, respectively. The concentration of O3 did not increase significantly with the decrease of PM2.5 and NO2 concentrations. The findings of this paper provide a reference for city managers to evaluate the contribution rate of Beijing's road traffic to air pollutants and to formulate reasonable emission reduction policies.

Antibody landscape against SARS-CoV-2 reveals significant differences between non-structural/accessory and structural proteins.

The immunogenicity of the SARS-CoV-2 proteome is largely unknown, especially for non-structural proteins and accessory proteins. In this study, we collect 2,360 COVID-19 sera and 601 control sera. We analyze these sera on a protein microarray with 20 proteins of SARS-CoV-2, building an antibody response landscape for immunoglobulin (Ig)G and IgM. Non-structural proteins and accessory proteins NSP1, NSP7, NSP8, RdRp, ORF3b, and ORF9b elicit prevalent IgG responses. The IgG patterns and dynamics of non-structural/accessory proteins are different from those of the S and N proteins. The IgG responses against these six proteins are associated with disease severity and clinical outcome, and they decline sharply about 20 days after symptom onset. In non-survivors, a sharp decrease of IgG antibodies against S1 and N proteins before death is observed. The global antibody responses to non-structural/accessory proteins revealed here may facilitate a deeper understanding of SARS-CoV-2 immunology.

A nanoselenium-coating biomimetic cytomembrane nanoplatform for mitochondrial targeted chemotherapy- and chemodynamic therapy through manganese and doxorubicin codelivery.

The cell membrane is widely considered as a promising delivery nanocarrier due to its excellent properties. In this study, self-assembled Pseudomonas geniculate cell membranes were prepared with high yield as drug nanocarriers, and named BMMPs. BMMPs showed excellent biosafety, and could be more efficiently internalized by cancer cells than traditional red cell membrane nanocarriers, indicating that BMMPs could deliver more drug into cancer cells. Subsequently, the BMMPs were coated with nanoselenium (Se), and subsequently loaded with Mn2+ ions and doxorubicin (DOX) to fabricate a functional nanoplatform (BMMP-Mn2+/Se/DOX). Notably, in this nanoplatform, Se nanoparticles activated superoxide dismutase-1 (SOD-1) expression and subsequently up-regulated downstream H2O2 levels. Next, the released Mn2+ ions catalyzed H2O2 to highly toxic hydroxyl radicals (·OH), inducing mitochondrial damage. In addition, the BMMP-Mn2+/Se nanoplatform inhibited glutathione peroxidase 4 (GPX4) expression and further accelerated intracellular reactive oxygen species (ROS) generation. Notably, the BMMP-Mn2+/Se/DOX nanoplatform exhibited increased effectiveness in inducing cancer cell death through mitochondrial and nuclear targeting dual-mode therapeutic pathways and showed negligible toxicity to normal organs. Therefore, this nanoplatform may represent a promising drug delivery system for achieving a safe, effective, and accurate cancer therapeutic plan.