Perceived a community with shared future for doctor-patient and benefit finding: a moderated mediation model.

BACKGROUND: Under the background that the concept of a community with shared future for mankind has been advocated, the doctor-patient relationship has rapidly sublimated into a community with shared future for doctor-patient. The purpose of this study was to analyze the changes and relationships of anxiety, perceived a community with shared future for doctor-patient (PCSF), health self-consciousness (HSC) and benefit finding (BF) in the outbreak stage of COVID-19 and in the stable stage of COVID-19. METHODS: The questionnaire consisted of a self-designed health self-consciousness scale, perceived a community with shared future for doctor-patient scale, revised 7-item generalized anxiety disorder scale and benefit finding scale. Questionnaires were administered in the outbreak stage of COVID-19 and in the stable stage of COVID-19 to address public anxiety, BF, and trust between medical staff and patients. RESULTS: Risk perception will increase anxiety in public, and the public who trust medical staff and the ability of the government to prevent and control the epidemic will have a higher PCSF. Compared with those in the outbreak stage of COVID-19, PCSF, HSC and BF all decreased in the stable stage of COVID-19. HSC partly plays a mediating role in the process of the influence of PCSF and BF (95% CI = [0.3785, 0.5007], [0.2357, 0.3695], P < .001). The R-value of the model in the outbreak stage of COVID-19 and in the stable stage of COVID-19 were 0.555 and 0.429, and the value of R2 was 0.308 and 0.184 respectively (P < .001). In the stable stage of COVID-19, the coefficient of anxiety ✕ PCSF is negative. The B values of anxiety and PCSF are positive, and the moderating effect is negative (P = .038). Anxiety has a negative moderating effect between PCSF and HSC, indicating that anxiety will weaken the positive impact of PCSF on HSC. It means that there exists a substitution relationship between anxiety and PCSF. CONCLUSIONS: The common goal of medical staff and patients is health, and health is the premise of the meaning of life. Vigorously advocating for PCSF can not only promote a harmonious doctor-patient relationship, but also establish a good HSC and improve the understanding of the meaning of life in the public. Furthermore, if the common concept of a community with a shared future for doctor-patient is integrated into the values of life, it may be more stable and long-term to maintain a good doctor-patient relationship. In addition, we should guard against the influence of high-level anxiety on the path of meaning perception.

COVID-19 pandemic and neonatal birth weight: a systematic review and meta-analysis

Objectives Lockdown was implemented in many countries during the pandemic, which led to myriad changes in pregnant women's lives. However, the potential impacts of the COVID-19 pandemic on neonatal outcomes remain unclear. We aimed to evaluate the association between the pandemic and neonatal birth weight. Study Design A systematic review and meta-analysis of the previous literature. Methods We searched the Medline and Embase databases up to May 2022, and extracted 36 eligible studies that compared neonatal birth weight between the pandemic and the pre-pandemic period. The following outcomes were included: mean birth weight, low birth weight (LBW), very low birth weight (VLBW), macrosomia, small for gestational age (SGA), very small for gestational age (VSGA), and large for gestational age (LGA). Statistical heterogeneity among studies was assessed to determine whether a random-effects model or fixed-effects model was conducted. Results Of the 4514 studies identified, 36 articles were eligible for inclusion. A total of 1,883,936 neonates during the pandemic and 4,667,133 neonates during the pre-pandemic were reported. We identified a significant increase in mean birth weight [pooled mean difference (95% CI) = 15.06 (10.36, 19.76), I2 = 0.0%, 12 studies] and a reduction in VLBW [pooled OR (95%CI) = 0.86 (0.77, 0.97), I2 = 55.4%, 12 studies]. No overall effect was identified for other outcomes: LBW, macrosomia, SGA, VSGA, and LGA. There was publication bias for mean birth weight with a borderline significance (Egger's P = 0.050). Conclusion Pooled results showed the pandemic was significantly associated with an increase in mean birth weight and a reduction in VLBW, but not for other outcomes. This review provided clues about the indirect effects of the pandemic on neonatal birth weight, and more healthcare measures needed to improve neonatal long-term health.

NLRP3 Inflammasome: A key contributor to the inflammation formation.

Inflammation is an important part of the development of various organ diseases. The inflammasome, as an innate immune receptor, plays an important role in the formation of inflammation. Among various inflammasomes, the NLRP3 inflammasome is the most well studied. The NLRP3 inflammasome is composed of skeletal protein NLRP3, apoptosis-associated speck-like protein (ASC) and pro-caspase-1. There are three types of activation pathways: (1) "classical" activation pathway; (2) "non-canonical" activation pathway; (3) "alternative" activation pathway. The activation of NLRP3 inflammasome is involved in many inflammatory diseases. A variety of factors (such as genetic factors, environmental factors, chemical factors, viral infection, etc.) have been proved to activate NLRP3 inflammasome and promote the inflammatory response of the lung, heart, liver, kidney and other organs in the body. Especially, the mechanism of NLRP3 inflammation and its related molecules in its associated diseases remains not to be summarized, namely they may promote or delay inflammatory diseases in different cells and tissues. This article reviews the structure and function of the NLRP3 inflammasome and its role in various inflammations, including inflammations caused by chemically toxic substances.

ZBP1-Mediated Necroptosis: Mechanisms and Therapeutic Implications.

Cell death is a fundamental pathophysiological process in human disease. The discovery of necroptosis, a form of regulated necrosis that is induced by the activation of death receptors and formation of necrosome, represents a major breakthrough in the field of cell death in the past decade. Z-DNA-binding protein (ZBP1) is an interferon (IFN)-inducing protein, initially reported as a double-stranded DNA (dsDNA) sensor, which induces an innate inflammatory response. Recently, ZBP1 was identified as an important sensor of necroptosis during virus infection. It connects viral nucleic acid and receptor-interacting protein kinase 3 (RIPK3) via two domains and induces the formation of a necrosome. Recent studies have also reported that ZBP1 induces necroptosis in non-viral infections and mediates necrotic signal transduction by a unique mechanism. This review highlights the discovery of ZBP1 and its novel findings in necroptosis and provides an insight into its critical role in the crosstalk between different types of cell death, which may represent a new therapeutic option.

miR-615 facilitates porcine epidemic diarrhea virus replication by targeting IRAK1 to inhibit type III interferon expression.

Porcine epidemic diarrhea virus (PEDV) in the Coronavirus family is a highly contagious enteric pathogen in the swine industry, which has evolved mechanisms to evade host innate immune responses. The PEDV-mediated inhibition of interferons (IFNs) has been linked to the nuclear factor-kappa B (NF-κB) pathway. MicroRNAs (miRNAs) are involved in virus-host interactions and IFN-I regulation. However, the mechanism by which the PEDV regulates IFN during PEDV infection has not yet been investigated in its natural target cells. We here report a novel mechanism of viral immune escape involving miR-615, which was screened from a high-throughput sequencing library of porcine intestinal epithelial cells (IECs) infected with PEDV. PEDV infection altered the profiles of miRNAs and the activities of several pathways involved in innate immunity. Overexpression of miR-615 increased PEDV replication, inhibited IFN expression, downregulated the NF-κB pathway, and blocked p65 nuclear translocation. In contrast, knockdown of miR-615 enhanced IFN expression, suppressed PEDV replication, and activated the NF-κB pathway. We further determined that IRAK1 is the target gene of miR-615 in IECs. Our findings show that miR-615 suppresses activation of the NF-κB pathway by suppressing the IRAK1 protein and reducing the generation of IFN-IIIs, which in turn facilitates PEDV infection in IECs. Moreover, miR-615 inhibited PEDV replication and NF-κB pathway activation in both IECs and MARC-145 cells. These findings support an important role for miR-615 in the innate immune regulation of PEDV infections and provide a novel perspective for developing new treatments.

Impact of COVID-19 pandemic on birth outcomes: A retrospective cohort study in Nanjing, China.

Introduction: The coronavirus disease 2019 (COVID-19) pandemic have significantly affected health care systems and daily wellbeing. However, the indirect impacts of the pandemic on birth outcomes are not fully understood. We aimed to examine whether the pandemic altered risk of adverse birth outcomes. Methods: This retrospective cohort study included all singleton births during 2016-2020 identified in Women's Hospital of Nanjing Medical University. We compared birth outcomes during COVID-19 pandemic (January-December 2020) with before the pandemic (January-December 2016-2019) using Logstic regression adjusted for confounders. Results: A total of 19,792 and 92,750 births occurred during and before the pandemic, respectively. Maternal characteristics were similar between groups, except maternal age was higher in pandemic cohort. We observed a reduction in preterm birth (PTB, <37 weeks) during the pandemic [5.9 vs. 5.1%, OR (95%CI) = 0.86 (0.80, 0.92)], but the difference disappeared after multivariable adjustment [adjusted OR (95%CI) = 1.02 (0.94, 1.11)]. Moreover, full term infants born during the pandemic had lower birth weights than those born before the pandemic [adjusted ß (95% CI) = -17.4 (-23.9, -10.8)]. Consistently, the risks of low birthweight (LBW, <2,500 g) and small for gestational age (SGA, < P10) were increased [LBW: adjusted OR (95%CI) = 1.13 (1.02, 1.24); SGA: adjusted OR (95%CI) = 1.11 (1.02, 1.21)], and the risks of macrosomia (≥4,000 g) and large for gestational age (LGA, ≥P90) were decreased in the pandemic cohort [macrosomia: adjusted OR (95%CI) = 0.82 (0.77, 0.88); LGA: adjusted OR (95%CI) = 0.73 (0.69, 0.77)]. Conclusion: In this study, we observed no change in preterm birth and a decrease in birth weight of full term infants during the pandemic in Nanjing, China.

Amyloid Protein Cross-Seeding Provides a New Perspective on Multiple Diseases In Vivo.

Amyloid protein cross-seeding is a peculiar phenomenon of cross-spreading among different diseases. Unlike traditional infectious ones, diseases caused by amyloid protein cross-seeding are spread by misfolded proteins instead of pathogens. As a consequence of the interactions among misfolded heterologous proteins or polypeptides, amyloid protein cross-seeding is considered to be the crucial cause of overlapping pathological transmission between various protein misfolding disorders (PMDs) in multiple tissues and cells. Here, we briefly review the phenomenon of cross-seeding among amyloid proteins. As an interesting example worth mentioning, the potential links between the novel coronavirus pneumonia (COVID-19) and some neurodegenerative diseases might be related to the amyloid protein cross-seeding, thus may cause an undesirable trend in the incidence of PMDs around the world. We then summarize the theoretical models as well as the experimental techniques for studying amyloid protein cross-seeding. Finally, we conclude with an outlook on the challenges and opportunities for basic research in this field. Cross-seeding of amyloid opens up a new perspective in our understanding of the process of amyloidogenesis, which is crucial for the development of new treatments for diseases. It is therefore valuable but still challenging to explore the cross-seeding system of amyloid protein as well as to reveal the structural basis and the intricate processes.

Impacts of COVID-19 pandemic on preterm birth: a systematic review and meta-analysis

Objectives The coronavirus disease 2019 (COVID-19) pandemic has significantly affected healthcare systems and daily wellbeing. However, the reports of the indirect impacts of the pandemic on preterm birth remain conflicting. We performed a meta-analysis to examine whether the pandemic altered the risk of preterm birth. Study Design A systematic review and meta-analysis of the previous literature. Methods We searched MEDLINE and Embase databases until March 2022 using appropriate keywords and extracted 63 eligible studies that compared preterm between the COVID-19 pandemic period and the pre-pandemic period. A random-effects model was used to obtain the pooled odds of each outcome. The study protocol was registered with PROSPERO (No. CRD42022326717). Results The search identified 3827 studies, of which 63 reports were included. A total of 3,220,370 pregnancies during the COVID-19 pandemic period and 6,122,615 pregnancies during the pre-pandemic period were studied. Compared with the pre-pandemic period, we identified a significant decreased odds of preterm birth (PTB, < 37 weeks’ gestation) [pooled OR (95%CI) = 0.96 (0.94, 0.98);I2 = 78.7%;62 studies] and extremely preterm birth (EPTB, < 28 weeks’ gestation) [pooled OR (95%CI) = 0.92 (0.87, 0.97);I2 = 26.4%;25 studies] during the pandemic, while there was only a borderline significant reduction in the odds of very preterm birth (VPTB, < 32 weeks’ gestation) [pooled OR (95%CI) = 0.93 (0.86, 1.01);I2 = 90.1%;33 studies] between the two periods. There was significant publication bias for PTB. Conclusion Pooled results suggested the COVID-19 pandemic was associated with preterm birth, even though there was only a borderline significant reduction for VPTB during the pandemic compared with the pre-pandemic period. Large studies showed conflicting results, and further research on whether the change is related to pandemic mitigation measures was warranted.

Research on commodity business value and customer value of e-commerce platforms: Based on consumer psychology and cognition

Under the background of economic globalization and COVID-19, online shopping has gradually replaced offline shopping as the main shopping mode. In this paper, consumers’ perceptions are introduced into the traditional BCG matrix to form a new BCG matrix, and according to it, the small gifts of a gift e-commerce platform are classified. We then performed a robustness test comparing the BCG matrix with K-means clustering. We found that new BCG matrix can objectively reflect the value of small gifts and provide suggestions for the e-commerce platform to make subsequent product decisions. Then we judge the customer value of the platform based on the improved RFM model and K-means++ clustering, and provide a reasonable customer value classification method for the e-commerce platform. Finally, we comprehensively consider the relationship between the commodity value and customer value, and analyze the preferences of different types of customer groups for different types of small gifts. Our research result shows that small gifts can be divided into 4 categories according to commodity value, namely “stars,” “cash cows,” “questions marks,” and “dogs.” These four categories of small gifts can be converted into each other through marketing ploys. Customers can be divided into important retention customers, key loyal customers and general development customers according to their values. Faced with different types of customers, managers can adopt different strategies to extract customer value. However, consumer psychology will affect consumer cognition, and different types of consumers prefer different types of small gifts, so the precise implementation of marketing strategies will effectively improve the profitability of the gift e-commerce platform. Compared with the traditional classification method, the commodity business value classification method proposed in this paper uses management analysis and planning methods, and introduces consumer psychological factors into the commodity and customer classification, so that the classification results are more credible. In addition, we jointly analyze the results of commodity value classification and customer value classification, and analyze in detail the preferences of different valued customer groups for different types of commodities, so as to provide directions for subsequent research on customer preference.

Influencing factors, prediction and prevention of depression in college students: A literature review.

The high prevalence of depression among college students has a strong negative impact on individual physical and mental health, academic development, and interpersonal communication. This paper reviewed the extant literature by identifying nonpathological factors related to college students' depression, investigating the methods of predicting depression, and exploring nonpharmaceutical interventions for college students' depression. The influencing factors of college students' depression mainly fell into four categories: biological factors, personality and psychological state, college experience, and lifestyle. The outbreak of coronavirus disease 2019 has exacerbated the severity of depression among college students worldwide and poses grave challenges to the prevention and treatment of depression, given that the coronavirus has spread quickly with high infection rates, and the pandemic has changed the daily routines of college life. To predict and measure mental health, more advanced methods, such as machine algorithms and artificial intelligence, have emerged in recent years apart from the traditional commonly used psychological scales. Regarding nonpharmaceutical prevention measures, both general measures and professional measures for the prevention and treatment of college students' depression were examined in this study. Students who experience depressive disorders need family support and personalized interventions at college, which should also be supplemented by professional interventions such as cognitive behavioral therapy and online therapy. Through this literature review, we insist that the technology of identification, prediction, and prevention of depression among college students based on big data platforms will be extensively used in the future. Higher education institutions should understand the potential risk factors related to college students' depression and make more accurate screening and prevention available with the help of advanced technologies.

The state of social science research on COVID-19.

Research on COVID-19 has proliferated rapidly since the outbreak of the pandemic at the end of 2019. Many articles have aimed to provide insight into this fast-growing theme. The social sciences have also put effort into research on problems related to COVID-19, with numerous documents having been published. Some studies have evaluated the growth of scientific literature on COVID-19 based on scientometric analysis, but most of these analyses focused on medical research while ignoring social science research on COVID-19. This is the first scientometric study of the performance of social science research on COVID-19. It provides insight into the landscape, the research fields, and international collaboration in this domain. Data obtained from SSCI on the Web of Science platform was analyzed using VOSviewer. The overall performance of the documents was described, and then keyword co-occurrence and co-authorship networks were visualized. The six main research fields with highly active topics were confirmed by analysis and visualization. Mental health and psychology were clearly shown to be the focus of most social science research related to COVID-19. The USA made the most contributions, with the most extensive collaborations globally, with Harvard University as the leading institution. Collaborations throughout the world were strongly related to geographical location. Considering the social impact of the COVID-19 pandemic, this scientometric study is significant for identifying the growth of literature in the social sciences and can help researchers within this field gain quantitative insights into the development of research on COVID-19. The results are useful for finding potential collaborators and for identifying the frontier and gaps in social science research on COVID-19 to shape future studies.

Tubular epithelial cell-to-macrophage communication forms a negative feedback loop via extracellular vesicle transfer to promote renal inflammation and apoptosis in diabetic nephropathy.

Background: Macrophage infiltration around lipotoxic tubular epithelial cells (TECs) is a hallmark of diabetic nephropathy (DN). However, how these two types of cells communicate remains obscure. We previously demonstrated that LRG1 was elevated in the process of kidney injury. Here, we demonstrated that macrophage-derived, LRG1-enriched extracellular vesicles (EVs) exacerbated DN. Methods: We induced an experimental T2DM mouse model with a HFD diet for four months. Renal primary epithelial cells and macrophage-derived EVs were isolated from T2D mice by differential ultracentrifugation. To investigate whether lipotoxic TEC-derived EV (EVe) activate macrophages, mouse bone marrow-derived macrophages (BMDMs) were incubated with EVe. To investigate whether activated macrophage-derived EVs (EVm) induce lipotoxic TEC apoptosis, EVm were cocultured with primary renal tubular epithelial cells. Subsequently, we evaluated the effect of LRG1 in EVe by investigating the apoptosis mechanism. Results: We demonstrated that incubation of primary TECs of DN or HK-2 mTECs with lysophosphatidyl choline (LPC) increased the release of EVe. Interestingly, TEC-derived EVe activated an inflammatory phenotype in macrophages and induced the release of macrophage-derived EVm. Furthermore, EVm could induce apoptosis in TECs injured by LPC. Importantly, we found that leucine-rich α-2-glycoprotein 1 (LRG1)-enriched EVe activated macrophages via a TGFßR1-dependent process and that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-enriched EVm induced apoptosis in injured TECs via a death receptor 5 (DR5)-dependent process. Conclusion: Our findings indicated a novel cell communication mechanism between tubular epithelial cells and macrophages in DN, which could be a potential therapeutic target.

Exploration of severe Covid-19 associated risk factor in China: Meta-analysis of current evidence.

AIM: This meta-analysis aimed to explore potential risk factors for severe Covid-19. METHODS: We systemically and comprehensively retrieved the eligible study evaluating clinical differences between severe vs non-severe Covid-19. Main effect sizes were demographic characteristics, comorbidities, signs and symptoms, laboratory findings as well as radiological features of chest CT. RESULTS: A total of 2566 Covid-19 people (771 in the severe group and 1795 in the non-severe group) from 14 studies were eligible for this meta-analysis. It was demonstrated that older age and males were more likely to have severe Covid-19. Patients with underlying comorbidities, such as hypertension, diabetes, heart disease and COPD were significantly more susceptible to severe Covid-19. Patients with dyspnoea were more likely to be severely ill. Depressed total lymphocytes were observed in this article. Meanwhile, although reticulation (30.8%), intrathoracic lymph node enlargement (20.5%) and pleural effusions (30.8%) were relatively infrequent, meta-analysis revealed that patients with these presentations in chest CT were associated with increased risk of severe Covid-19. CONCLUSIONS: There are significant differences in clinical characteristics between the severe and non-severe Covid-19 patients. Many factors are related to the severity of the disease, which can help clinicians to differentiate severe patients from non-severe patients.

Changes in weight and height among Chinese preschool children during COVID-19 school closures.

BACKGROUND AND OBJECTIVES: COVID-19-related school closures may increase the prevalence of childhood obesity, which has aroused public concerns. We aimed to analyze the weight and height changes in Chinese preschool children during the COVID-19-related school closures period. METHODS: A total of 124,603 children from multi-city kindergartens in China were included in this study. We evaluated the prevalence of overweight and obese in preschool children experienced school closures, and compared the changes in BMI, weight, and height of preschool children among COVID-19 school closures period, the same period last year and the same period the year before last. RESULTS: After the school closures, childhood obesity prevalence increased, whereas overweight prevalence decreased. During school closures, the average increase in height was about 1 cm less as compared with the same period last year and the year before last, but no noteworthy difference in the weight change was observed among the three periods. CONCLUSIONS: During COVID-19 school closures, children's height increase seemed to be more affected than weight change. Innovative, robust, and highly adaptable strategies should be taken to increase physical activity, reduce sedentary time and promote healthy diets, to minimize the adverse impact of school closures.

A cohort autopsy study defines COVID-19 systemic pathogenesis.

Severe COVID-19 disease caused by SARS-CoV-2 is frequently accompanied by dysfunction of the lungs and extrapulmonary organs. However, the organotropism of SARS-CoV-2 and the port of virus entry for systemic dissemination remain largely unknown. We profiled 26 COVID-19 autopsy cases from four cohorts in Wuhan, China, and determined the systemic distribution of SARS-CoV-2. SARS-CoV-2 was detected in the lungs and multiple extrapulmonary organs of critically ill COVID-19 patients up to 67 days after symptom onset. Based on organotropism and pathological features of the patients, COVID-19 was divided into viral intrapulmonary and systemic subtypes. In patients with systemic viral distribution, SARS-CoV-2 was detected in monocytes, macrophages, and vascular endothelia at blood-air barrier, blood-testis barrier, and filtration barrier. Critically ill patients with long disease duration showed decreased pulmonary cell proliferation, reduced viral RNA, and marked fibrosis in the lungs. Permanent SARS-CoV-2 presence and tissue injuries in the lungs and extrapulmonary organs suggest direct viral invasion as a mechanism of pathogenicity in critically ill patients. SARS-CoV-2 may hijack monocytes, macrophages, and vascular endothelia at physiological barriers as the ports of entry for systemic dissemination. Our study thus delineates systemic pathological features of SARS-CoV-2 infection, which sheds light on the development of novel COVID-19 treatment.

The effects of narrative exposure therapy on COVID-19 patients with post-traumatic stress symptoms: A randomized controlled trial.

BACKGROUND: With the global attack of Coronavirus Disease 2019 (COVID-19), cases with Post-traumatic Stress Disorder (PTSD) have been increasing steadily, which seriously affects the quality of life of patients and as such, seeking effective treatments is an urgent matter. Narrative Exposure Therapy (NET) is a typical cognitive behavioral therapy targeting trauma-related psychological disorders and may be an effective intervention. METHODS: A total of 111 COVID-19 patients near the discharge stage with positive screening results for posttraumatic stress symptoms (PTSS) were randomly assigned (1:1) to either the study group or the control group. The study group received NET and personalized psychological intervention, while the control group only received personalized psychological intervention. PTSS, depression, anxiety and sleep quality were measured pre- and post-intervention to evaluate the effect of NET. This trial was registered with the International Standard Randomized Clinical Trial Registry (No. ChiCTR2000039369). RESULTS: NET participants showed a significantly greater PTSS reduction in comparison with the control group after the intervention. Improvement in sleep quality, anxiety and depression after the intervention were pronounced but not significantly different between the two treatment groups. LIMITATIONS: The assessors weren't blinded for the convenience of measurement and protection of participants' psychological security. CONCLUSIONS: NET likely had a positive impact on PTSS of COVID-19 patients. Clinical staff should consider applying NET to improve the psychological well-being of patients who have experienced an epidemic such as COVID-19.

Targeting novel LSD1-dependent ACE2 demethylation domains inhibits SARS-CoV-2 replication.

Treatment options for COVID-19 remain limited, especially during the early or asymptomatic phase. Here, we report a novel SARS-CoV-2 viral replication mechanism mediated by interactions between ACE2 and the epigenetic eraser enzyme LSD1, and its interplay with the nuclear shuttling importin pathway. Recent studies have shown a critical role for the importin pathway in SARS-CoV-2 infection, and many RNA viruses hijack this axis to re-direct host cell transcription. LSD1 colocalized with ACE2 at the cell surface to maintain demethylated SARS-CoV-2 spike receptor-binding domain lysine 31 to promote virus-ACE2 interactions. Two newly developed peptide inhibitors competitively inhibited virus-ACE2 interactions, and demethylase access to significantly inhibit viral replication. Similar to some other predominantly plasma membrane proteins, ACE2 had a novel nuclear function: its cytoplasmic domain harbors a nuclear shuttling domain, which when demethylated by LSD1 promoted importin-α-dependent nuclear ACE2 entry following infection to regulate active transcription. A novel, cell permeable ACE2 peptide inhibitor prevented ACE2 nuclear entry, significantly inhibiting viral replication in SARS-CoV-2-infected cell lines, outperforming other LSD1 inhibitors. These data raise the prospect of post-exposure prophylaxis for SARS-CoV-2, either through repurposed LSD1 inhibitors or new, nuclear-specific ACE2 inhibitors.

Pharmacokinetics and tissue distribution of remdesivir and its metabolites nucleotide monophosphate, nucleotide triphosphate, and nucleoside in mice.

Remdesivir (RDV) exerts anti-severe acute respiratory coronavirus 2 activity following metabolic activation in the target tissues. However, the pharmacokinetics and tissue distributions of the parent drug and its active metabolites have been poorly characterized to date. Blood and tissue levels were evaluated in the current study. After intravenous administration of 20 mg/kg RDV in mice, the concentrations of the parent drug, nucleotide monophosphate (RMP) and triphosphate (RTP), as well as nucleoside (RN), in the blood, heart, liver, lung, kidney, testis, and small intestine were quantified. In blood, RDV was rapidly and completely metabolized and was barely detected at 0.5 h, similar to RTP, while its metabolites RMP and RN exhibited higher blood levels with increased residence times. The area under the concentration versus time curve up to the last measured point in time (AUC0-t) values of RMP and RN were 4558 and 136,572 h∙nM, respectively. The maximum plasma concentration (Cmax) values of RMP and RN were 2896 nM and 35,819 nM, respectively. Moreover, RDV presented an extensive distribution, and the lung, liver and kidney showed high levels of the parent drug and metabolites. The metabolic stabilities of RDV and RMP were also evaluated using lung, liver, and kidney microsomes. RDV showed higher clearances in the liver and kidney than in the lung, with intrinsic clearance (CLint) values of 1740, 1253, and 127 mL/(min∙g microsomal protein), respectively.