Coronaviruses infect a variety of hosts in the animal kingdom, and while each virus is taxonomically different, they all infect their host
the same mechanism. The coronavirus main protease (M
, also ...called 3CL
), is an attractive target for drug development due to its essential role in mediating viral replication and transcription. An M
inhibitor, GC376, has been shown to treat feline infectious peritonitis (FIP), a fatal infection in cats caused by internal mutations in the feline enteric coronavirus (FECV). Recently, our lab demonstrated that the feline drug, GC373, and prodrug, GC376, are potent inhibitors of SARS-CoV-2 M
and solved the structures in complex with the drugs; however, no crystal structures of the FIP virus (FIPV) M
with the feline drugs have been published so far. Here, we present crystal structures of FIPV M
-GC373/GC376 complexes, revealing the inhibitors covalently bound to Cys144 in the active site, similar to SARS-CoV-2 M
. Additionally, GC376 has a higher affinity for FIPV M
with lower nanomolar K
values compared to SARS-CoV and SARS-CoV-2 M
. We also show that improved derivatives of GC376 have higher potency for FIPV M
. Since GC373 and GC376 represent strong starting points for structure-guided drug design, determining the crystal structures of FIPV M
with these inhibitors are important steps in drug optimization and structure-based broad-spectrum antiviral drug discovery.
The main protease of SARS-CoV-2 (Mpro) is the most promising drug target against coronaviruses due to its essential role in virus replication. With newly emerging variants there is a concern that ...mutations in Mpro may alter the structural and functional properties of protease and subsequently the potency of existing and potential antivirals. We explored the effect of 31 mutations belonging to 5 variants of concern (VOCs) on catalytic parameters and substrate specificity, which revealed changes in substrate binding and the rate of cleavage of a viral peptide. Crystal structures of 11 Mpro mutants provided structural insight into their altered functionality. Additionally, we show Mpro mutations influence proteolysis of an immunomodulatory host protein Galectin-8 (Gal-8) and a subsequent significant decrease in cytokine secretion, providing evidence for alterations in the escape of host-antiviral mechanisms. Accordingly, mutations associated with the Gamma VOC and highly virulent Delta VOC resulted in a significant increase in Gal-8 cleavage. Importantly, IC50s of nirmatrelvir (Pfizer) and our irreversible inhibitor AVI-8053 demonstrated no changes in potency for both drugs for all mutants, suggesting Mpro will remain a high-priority antiviral drug candidate as SARS-CoV-2 evolves.
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IJS, KILJ, NUK, PNG, UL, UM, UPUK
The main protease of SARS-CoV-2 (M
) is the most promising drug target against coronaviruses due to its essential role in virus replication. With newly emerging variants there is a concern that ...mutations in M
may alter the structural and functional properties of protease and subsequently the potency of existing and potential antivirals. We explored the effect of 31 mutations belonging to 5 variants of concern (VOCs) on catalytic parameters and substrate specificity, which revealed changes in substrate binding and the rate of cleavage of a viral peptide. Crystal structures of 11 M
mutants provided structural insight into their altered functionality. Additionally, we show M
mutations influence proteolysis of an immunomodulatory host protein Galectin-8 (Gal-8) and a subsequent significant decrease in cytokine secretion, providing evidence for alterations in the escape of host-antiviral mechanisms. Accordingly, mutations associated with the Gamma VOC and highly virulent Delta VOC resulted in a significant increase in Gal-8 cleavage. Importantly, IC50s of nirmatrelvir (Pfizer) and our irreversible inhibitor AVI-8053 demonstrated no changes in potency for both drugs for all mutants, suggesting M
will remain a high-priority antiviral drug candidate as SARS-CoV-2 evolves.
Full text
Available for:
IJS, KILJ, NUK, PNG, UL, UM, UPUK
The effect of marine omega-3 PUFAs on risk of stroke remains unclear.
We investigated the associations between circulating and tissue omega-3 PUFA levels and incident stroke (total, ischemic, and ...hemorrhagic) in 29 international prospective cohorts. Each site conducted a de novo individual-level analysis using a prespecified analytical protocol with defined exposures, covariates, analytical methods, and outcomes; the harmonized data from the studies were then centrally pooled. Multivariable-adjusted HRs and 95% CIs across omega-3 PUFA quintiles were computed for each stroke outcome.
Among 183 291 study participants, there were 10 561 total strokes, 8220 ischemic strokes, and 1142 hemorrhagic strokes recorded over a median of 14.3 years follow-up. For eicosapentaenoic acid, comparing quintile 5 (Q5, highest) with quintile 1 (Q1, lowest), total stroke incidence was 17% lower (HR, 0.83 CI, 0.76-0.91;
<0.0001), and ischemic stroke was 18% lower (HR, 0.82 CI, 0.74-0.91;
<0.0001). For docosahexaenoic acid, comparing Q5 with Q1, there was a 12% lower incidence of total stroke (HR, 0.88 CI, 0.81-0.96;
=0.0001) and a 14% lower incidence of ischemic stroke (HR, 0.86 CI, 0.78-0.95;
=0.0001). Neither eicosapentaenoic acid nor docosahexaenoic acid was associated with a risk for hemorrhagic stroke. These associations were not modified by either baseline history of AF or prevalent CVD.
Higher omega-3 PUFA levels are associated with lower risks of total and ischemic stroke but have no association with hemorrhagic stroke.
The predictive value of non-invasive electrocardiographic examination findings for the risk of sudden cardiac death (SCD) in populations with structurally normal hearts remains unclear. This study ...aimed to investigate the characteristics of the QRS vectorcardiography of surface electrocardiography in patients with structurally normal hearts who experienced SCD. We consecutively enrolled patients who underwent vectorcardiography between March 2017 and December 2018 in a tertiary referral medical center. These patients didn’t have structural heart diseases, histories of congestive heart failure, or reduced ejection fraction, and they were classified into SCD (with aborted SCD history and cerebral performance category score of 1) and control groups (with an intervention for atrioventricular node reentrant tachycardia and without SCD history). A total of 162 patients (mean age, 54.3±18.1 years; men, 75.9%), including 59 in the SCD group and 103 in the control group, underwent propensity analysis. The baseline demographic variables, underlying diseases, QRS loop descriptors (the percentage of the loop area, loop dispersion, and inter-lead QRS dispersion), and other electrocardiographic parameters were compared between the two groups. In the univariate and multivariate analyses, a smaller percentage of the loop area (odds ratio, 0.0003; 95% confidence interval, 0.00–0.02; p<0.001), more significant V4-5 dispersion (odds ratio, 1.04; 95% confidence interval, 1.02–1.07; p = 0.002), and longer QRS duration (odds ratio, 1.05; 95% confidence interval, 1.00–1.10; p = 0.04) were associated with SCD. In conclusion, the QRS loop descriptors of surface electrocardiography could be used as non-invasive markers to identify patients experiencing aborted SCD from a healthy population. A decreased percentage of loop area and elevated V4-5 QRS dispersion values assessed using vectorcardiography were associated with an increased risk of SCD in patients with structurally normal hearts.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
28.
Pseudoxanthoma elasticum Fellner, M J; Chen, A S; McCabe, J B
Archives of dermatology (1960)
114, Issue:
2
Journal Article
碩士
國立臺灣大學
外國語文學研究所
107
In this thesis, I read the works of the Irish novelist Eimear McBride, A Girl is a Half-formed Thing (2013) and The Lesser Bohemians (2016), as failed stories of development ...and trauma narratives. Marked by truncated words and broken syntax, McBride''s elliptical style enacts the impacts of sexual abuse on language and human psyche, and penetrates to the core of bodily experience and trauma, breaking out of the radical interiority of pain. Read together, Girl and Bohemians are two sides of the same coin, as they explore alternative models of subject formation in a hostile environment that hinders maturation. In Girl, the nameless girl''s interior monologue shows that she is incapable of externalizing trauma, and her profound isolation culminates in her half-formed identity and life. By contrast, in Bohemians, the conversation between the two protagonists indicates that survival is possible through the witnessing of trauma based on the responsibility towards the other''s alterity. A relational model of subjectivity, then, is needed in the face of trauma. On the other hand, the silenced mothers in the two novels suggest that the breakdown of the balance between self-assertion and mutual recognition, which leads to the polarities of effacement or unconditional elevation of the other, is the potential origin of trauma.
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