The emergence of SARS‐CoV‐2 variants is a significant concern in developing effective therapeutics and vaccines in the middle of the ongoing COVID‐19 pandemic. Here, we have identified a novel small ...molecule that inhibited the interactions between SARS‐CoV‐2 spike RBDs and ACE2 by modulating ACE2 without impairing its enzymatic activity necessary for normal physiological functions. Furthermore, the identified compounds suppressed viral infection in cultured cells by inhibiting the entry of ancestral and variant SARS‐CoV‐2. Our study suggests that targeting ACE2 could be a novel therapeutic strategy to inhibit SARS‐CoV‐2 entry into host cells and prevent the development of COVID‐19.
Targeting the receptor‐binding domain (RBD) of the SARS‐CoV‐2 spike protein could be limited in inhibiting viral entry via the RBD–ACE2 interaction due to the emerging spike mutations. Instead, targeting ACE2 with a small molecule could suppress the entry of ancestral and variant SARS‐CoV‐2 into the host cells, without impairing the enzymatic activity of ACE2, which is necessary for the physiological function of the host cells.
This paper uses a SEIR(D) model to analyse the time-varying transmission dynamics of the COVID-19 epidemic in Korea throughout its multiple stages of development. This multi-stage estimation of the ...model parameters offers a better model fit compared to the whole period analysis and shows how the COVID-19's infection patterns change over time, primarily depending on the effectiveness of the public health authority's non-pharmaceutical interventions (NPIs).
This paper uses the SEIR(D) compartment model to simulate and estimate the parameters for three distinctive stages of the COVID-19 epidemic in Korea, using a manually compiled COVID-19 epidemic dataset for the period between 18 February 2020 and 08 February 2021. The paper identifies three major stages of the COVID-19 epidemic, conducts multi-stage estimations of the SEIR(D) model parameters, and carefully infers context-dependent meaning of the estimation results to help better understand the unique patterns of the transmission of the novel coronavirus (SARS-CoV-2) in each stage.
The original SIR compartment model may produce a poor and even misleading estimation result if it is used to cover the entire period of the epidemic. However, if we use the model carefully in distinctive stages of the COVID-19 epidemic, we can find useful insights into the nature of the transmission of the novel coronavirus and the relative effectiveness of the government's non-pharmaceutical interventions over time.
Key messages
Identifies three distinctive waves of the COVID-19 epidemic in Korea.
Conducts multi-stage estimations of the COVID-19 transmission dynamics using SEIR(D) epidemic models.
The transmission dynamics of the COVID-19 vary over time, primarily depending on the relative effectiveness of the government's non-pharmaceutical interventions (NPIs).
The SEIR(D) epidemic model is useful and informative, but only when it is used carefully to account for the presence of multiple waves and context-dependent infection patterns in each wave.
Gut microbiota plays roles in host physiology including endocrine function. Although some data suggest a potential connection between biological sex differences and gut microbiota, the connection ...between sex steroid hormones and gut microbes remained unexplored. The current study investigates the relationship between gut microbes and serum levels of testosterone in men and estradiol in women. Fecal microbiota from a total of 57 men (n = 31) and women (n = 26) were assessed using 16s rRNA gene sequencing. Based on the levels of serum testosterone and estradiol in men and women, respectively, participants were stratified into three groups of Low, Medium, and High. Microbiome communities were analyzed as a function of the steroid hormone within sex. Men and women in the High group harbored more diverse gut microbial communities than others. In men, the abundance of Acinetobacter, Dorea, Ruminococcus, and Megamonas correlated significantly with testosterone levels. Women in the High group have more Bacteroidetes and less Firmicutes phyla than those in the Low group. Genera Slackia and Butyricimonas were significantly correlated with estradiol levels. These results demonstrate that sex steroid hormone levels are correlated with diversity and gut microbial composition, and provide fundamental information helpful for developing communication networks between human and microbial communities.
To investigate the impacts of depression screening, diagnosis and treatment on major adverse cardiac events (MACEs) in acute coronary syndrome (ACS).
Prospective cohort study including a nested ...24-week randomised clinical trial for treating depression was performed with 5-12 years after the index ACS. A total of 1152 patients recently hospitalised with ACS were recruited from 2006 to 2012, and were divided by depression screening and diagnosis at baseline and 24-week treatment allocation into five groups: 651 screening negative (N), 55 screening positive but no depressive disorder (S), 149 depressive disorder randomised to escitalopram (E), 151 depressive disorder randomised to placebo (P) and 146 depressive disorder receiving medical treatment only (M).
Cumulative MACE incidences over a median 8.4-year follow-up period were 29.6% in N, 43.6% in S, 40.9% in E, 53.6% in P and 59.6% in M. Compared to N, screening positive was associated with higher incidence of MACE adjusted hazards ratio 2.15 (95% confidence interval 1.63-2.83). No differences were found between screening positive with and without a formal depressive disorder diagnosis. Of those screening positive, E was associated with a lower incidence of MACE than P and M. M had the worst outcomes even compared to P, despite significantly milder depressive symptoms at baseline.
Routine depression screening in patients with recent ACS and subsequent appropriate treatment of depression could improve long-term cardiac outcomes.
Tau protein aggregates are a recognized neuropathological feature in Alzheimer's disease as well as many other neurodegenerative disorders, known as tauopathies. The development of tau‐targeting ...therapies is therefore extremely important but efficient strategies or protein targets are still unclear. Here, we performed a cell‐based phenotypic screening under endoplasmic reticulum (ER) stress conditions and identified a small molecule, SB1617, capable of suppressing abnormal tau protein aggregation. By applying label‐free target identification technology, we revealed that the transient enhancement of protein kinase‐like endoplasmic reticulum kinase (PERK) signaling pathway through the inhibition of stress‐responsive SB1617 targets, PDIA3 and DNAJC3, is an effective strategy for regulating proteostasis in tauopathies. The molecular mechanism and the promising efficacy of SB1617 were demonstrated in neuronal cells and a mouse model with traumatic brain injury, a tauopathy known to involve ER stress.
A novel neuroprotective compound, SB1617, was developed via phenotypic assay by image‐based monitoring of tau protein aggregation. Label‐free target identification study revealed that SB1617 inhibits PDIA3 and DNAJC3, thereby regulates tau proteostasis through the activation of PERK signaling pathway in a stress‐responsive manner. The administration of SB1617 showed neuroprotective effects in mice with tauopathy involving ER stress.
Glioblastoma (GBM), the most severe and common brain tumor in adults, is characterized by multiple somatic mutations and aberrant activation of inflammatory responses. Immune cell infiltration and ...subsequent inflammation cause tumor growth and resistance to therapy. Somatic loss-of-function mutations in the gene encoding tumor suppressor protein p53 (TP53) are frequently observed in various cancers. However, numerous studies suggest that TP53 regulates malignant phenotypes by gain-of-function (GOF) mutations. Here we demonstrate that a TP53 GOF mutation promotes inflammation in GBM. Ectopic expression of a TP53 GOF mutant induced transcriptomic changes, which resulted in enrichment of gene signatures related to inflammation and chemotaxis. Bioinformatics analyses revealed that a gene signature, upregulated by the TP53 GOF mutation, is associated with progression and shorter overall survival in GBM. We also observed significant correlations between the TP53 GOF mutation signature and inflammation in the clinical database of GBM and other cancers. The TP53 GOF mutant showed upregulated C-C motif chemokine ligand 2 (CCL2) and tumor necrosis factor alpha (TNFA) expression via nuclear factor kappa B (NFκB) signaling, consequently increasing microglia and monocyte-derived immune cell infiltration. Additionally, TP53 GOF mutation and CCL2 and TNFA expression correlated positively with tumor-associated immunity in patients with GBM. Taken together, our findings suggest that the TP53 GOF mutation plays a crucial role in inflammatory responses, thereby deteriorating prognostic outcomes in patients with GBM.
Systematic incorporation of ring-constrained β- and γ-amino acid residues into α-helix mimetics engenders stable helical secondary structures. In this paper, functional α/β/γ-helical peptidomimetics ...were explored for mimicry of BH3 helical domains, Bim as a pioneering study. The Bim-based α/β/γ-peptides in an αγααβα-hexad repeat with five helical turns inhibited the interaction between Bak and Bcl-x
with excellent resistance towards proteolytic digestion. Further optimization of the α/β/γ-backbone strategy will considerably expand the utility of functional α/β/γ-peptidomimetics, in particular due to its prominent stability against proteolysis.
and other related species of
are the major sources of the bis-benzylisoquinoline alkaloids tetrandrine (TET), fangchinoline (FAN), and cepharanthine (CEP). Although the pharmacological properties of ...these compounds include anticancer and anti-inflammatory activities, the antiviral effects of these compounds against human coronavirus (HCoV) remain unclear. Hence, the aims of the current study were to assess the antiviral activities of TET, FAN, and CEP and to elucidate the underlying mechanisms in HCoV-OC43-infected MRC-5 human lung cells. These compounds significantly inhibited virus-induced cell death at the early stage of virus infection. TET, FAN, and CEP treatment dramatically suppressed the replication of HCoV-OC43 as well as inhibited viral S and N protein expression. The virus-induced host response was reduced by compound treatment as compared with the vehicle control. Taken together, these findings demonstrate that TET, FAN, and CEP are potential natural antiviral agents for the prevention and treatment of HCoV-OC43 infection.
Seamless stitching of graphene domains on polished copper (111) is proved clearly not only at atomic scale by scanning tunnelling microscopy (STM) and transmission electron micoscopy (TEM), but also ...at the macroscale by optical microscopy after UV‐treatment. Using this concept of seamless stitching, synthesis of 6 cm × 3 cm monocrystalline graphene without grain boundaries on polished copper (111) foil is possible, which is only limited by the chamber size.
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