COVID-19 breakthrough infections in type 1 diabetes mellitus: a cross-sectional study by the COVID-19 Vaccination in Autoimmune Diseases (COVAD) Group

To investigate the frequency, profile, and severity of COVID-19 breakthrough infections (BI) in patients with type I diabetes mellitus (T1DM) compared to healthy controls (HC) after vaccination. The second COVID-19 Vaccination in Autoimmune Diseases (COVAD-2) survey is a multinational cross-sectional electronic survey which has collected data on patients suffering from various autoimmune diseases including T1DM. We performed a subgroup analysis on this cohort to investigate COVID-19 BI characteristics in patients with T1DM. Logistic regression with propensity score matching analysis was performed. A total of 9595 individuals were included in the analysis, with 100 patients having T1DM. Among the fully vaccinated cohort, 16 (16%) T1DM patients had one BI and 2 (2%) had two BIs. No morbidities or deaths were reported, except for one patient who required hospitalization with oxygen without admission to intensive care. The frequency, clinical features, and severity of BIs were not significantly different between T1DM patients and HCs after adjustment for confounding factors. Our study did not show any statistically significant differences in the frequency, symptoms, duration, or critical care requirements between T1DM and HCs after COVID-19 vaccination. Further research is needed to identify factors associated with inadequate vaccine response in patients with BIs, especially in patients with autoimmune diseases

COVID-19 breakthrough infections in type 1 diabetes mellitus: a cross-sectional study by the COVID-19 Vaccination in Autoimmune Diseases (COVAD) Group

To investigate the frequency, profile, and severity of COVID-19 breakthrough infections (BI) in patients with type I diabetes mellitus (T1DM) compared to healthy controls (HC) after vaccination. The second COVID-19 Vaccination in Autoimmune Diseases (COVAD-2) survey is a multinational cross-sectional electronic survey which has collected data on patients suffering from various autoimmune diseases including T1DM. We performed a subgroup analysis on this cohort to investigate COVID-19 BI characteristics in patients with T1DM. Logistic regression with propensity score matching analysis was performed. A total of 9595 individuals were included in the analysis, with 100 patients having T1DM. Among the fully vaccinated cohort, 16 (16%) T1DM patients had one BI and 2 (2%) had two BIs. No morbidities or deaths were reported, except for one patient who required hospitalization with oxygen without admission to intensive care. The frequency, clinical features, and severity of BIs were not significantly different between T1DM patients and HCs after adjustment for confounding factors. Our study did not show any statistically significant differences in the frequency, symptoms, duration, or critical care requirements between T1DM and HCs after COVID-19 vaccination. Further research is needed to identify factors associated with inadequate vaccine response in patients with BIs, especially in patients with autoimmune diseases

Induction of helical conformation in all beta-sheet proteins by trifluoroethanol

[[abstract]]The effect of 2,2,2-Trifluoroethanol (TFE) on the structure of five all P-sheet proteins, isolated from the venom of the Taiwan cobra (Naja naja atra), is studied. In all the toxins used, it is observed that significant amount of alpha-helix is induced at higher concentrations of TFE. In all these proteins, the induction of helical conformation and disruption of the tertiary structure Seem to occur simultaneously. The structural transitions induced by TFE in reduced and denatured protein appear to be different from those observed in the native protein(s). In our opinion, the findings reported herein could have significant implications on research in the area of protein folding.[[fileno]]2010329010095[[department]]化學

NMR study on the interaction between RPA and DNA decamer containing cis-syn cyclobutane pyrimidine dimer in the presence of XPA: implication for damage verification and strand-specific dual incision in nucleotide excision repair

In mammalian cells, nucleotide excision repair (NER) is the major pathway for the removal of bulky DNA adducts. Many of the key NER proteins are members of the XP family (XPA, XPB, etc.), which was named on the basis of its association with the disorder xerodoma pigmentosum. Human replication protein A (RPA), the ubiquitous single-stranded DNA-binding protein, is another of the essential proteins for NER. RPA stimulates the interaction of XPA with damaged DNA by forming an RPA-XPA complex on damaged DNA sites. Binding of RPA to the undamaged DNA strand is most important during NER, because XPA, which directs the excision nucleases XPG and XPF, must bind to the damaged strand. In this study, nuclear magnetic resonance (NMR) spectroscopy was used to assess the binding of the tandem high affinity DNA-binding domains, RPA-AB, and of the isolated domain RPA-A, to normal DNA and damaged DNA containing the cyclobutane pyrimidine dimer (CPD) lesion. Both RPA-A and RPA-AB were found to bind non- specifically to both strands of normal and CPD- containing DNA duplexes. There were no differences observed when binding to normal DNA duplex was examined in the presence of the minimal DNA-binding domain of XPA (XPA-MBD). However, there is a drastic difference for CPD-damaged DNA duplex as both RPA-A and RPA-AB bind specifically to the undamaged strand. The strand-specific binding of RPA and XPA to the damaged duplex DNA shows that RPA and XPA play crucial roles in damage verification and guiding cleavage of damaged DNA during NER

Conformational study of a custom antibacterial peptide cecropin B1: implications of the lytic activity

Cecropin B1 (CB1) with two amphipathic alpha-helical segments is a derivative of the natural antibacterial peptide, cecropin B. The assays of cell lysis show that, compared with cecropin A (CA), CB1 has a similar ability to lyse bacteria with a higher potency (two- to six-fold higher) in killing cancer cells. The difference may be due to the fact that the peptides possess different structures and sequences. In this study, the solution structure of CB1 in 20\% hexafluoroisopropanol was determined by two-dimensional nuclear magnetic resonance (NMR) spectroscopy. The H-1 NMR resonances were assigned. A total of 350 inter-proton distances were used to calculate the solution structure of CB1. The final ensemble structures were well converged, showing the minimum root mean square deviation. The results indicate that CB1 has two stretches of helices spanning from residues 3 to 22 and from residues 26 to 33, which are connected by a hinge section formed by Gly-23 and Pro-24. Lys-25 is partially incorporated in the hinge region. The bent angle between two helical segments located in two planes was between 100 and 110 degrees. With comparisons of the known NMR structure of CA and its activities on bacteria and cancer cells, the structure-function relationship of the peptides is discussed. (C) 2000 Elsevier Science B.V. All rights reserved

Structural mechanism of RPA loading on DNA during activation of a simple pre-replication complex

We report that during activation of the simian virus 40 (SV40) pre-replication complex, SV40 T antigen (Tag) helicase actively loads replication protein A (RPA) on emerging single-stranded DNA (ssDNA). This novel loading process requires physical interaction of Tag origin DNA-binding domain (OBD) with the RPA high-affinity ssDNA-binding domains (RPA70AB). Heteronuclear NMR chemical shift mapping revealed that Tag-OBD binds to RPA70AB at a site distal from the ssDNA-binding sites and that RPA70AB, Tag-OBD, and an 8-nucleotide ssDNA form a stable ternary complex. Intact RPA and Tag also interact stably in the presence of an 8-mer, but Tag dissociates from the complex when RPA binds to longer oligonucleotides. Together, our results imply that an allosteric change in RPA quaternary structure completes the loading reaction. A mechanistic model is proposed in which the ternary complex is a key intermediate that directly couples origin DNA unwinding to RPA loading on emerging ssDNA

The protein shuffle. Sequential interactions among components of the human nucleotide excision repair pathway

Xeroderma pigmentosum (XP) is an inherited disease in which cells from patients exhibit defects in nucleotide excision repair (NER). XP proteins A-G are crucial in the processes of DNA damage recognition and incision, and patients with XP can carry mutations in any of the genes that specify these proteins. In mammalian cells, NER is a dynamic process in which a variety of proteins interact with one another, via modular domains, to carry out their functions. XP proteins are key players in several steps of the NER process, including DNA strand discrimination (XPA, in complex with replication protein A), repair complex formation (XPC, in complex with hHR23B; XPF, in complex with ERCC1) and repair factor recruitment (transcription factor IIH, in complex with XPG). Through these protein-protein interactions, various types of bulky DNA adducts can be recognized and repaired. Communication between the NER system and other cellular pathways is also achieved by selected binding of the various structural domains. Here, we summarize recent studies on the domain structures of human NER components and the regulatory networks that utilize these proteins. Data provided by these studies have helped to illuminate the complex molecular interactions among NER factors in the context of DNA repair