An outbreak of coronavirus disease 2019 (COVID‐19) occurred in Wuhan and it has rapidly spread to almost all parts of the world. For coronaviruses, RNA‐dependent RNA polymerase (RdRp) is an important ...protease that catalyzes the replication of RNA from RNA template and is an attractive therapeutic target. In this study, we screened these chemical structures from traditional Chinese medicinal compounds proven to show antiviral activity in severe acute respiratory syndrome coronavirus (SARS‐CoV) and the similar chemical structures through a molecular docking study to target RdRp of SARS‐CoV‐2, SARS‐CoV, and Middle East respiratory syndrome coronavirus (MERS‐CoV). We found that theaflavin has a lower idock score in the catalytic pocket of RdRp in SARS‐CoV‐2 (−9.11 kcal/mol), SARS‐CoV (−8.03 kcal/mol), and MERS‐CoV (−8.26 kcal/mol) from idock. To confirm the result, we discovered that theaflavin has lower binding energy of −8.8 kcal/mol when it docks in the catalytic pocket of SARS‐CoV‐2 RdRp by using the Blind Docking server. Regarding contact modes, hydrophobic interactions contribute significantly in binding and additional hydrogen bonds were found between theaflavin and RdRp. Moreover, one π‐cation interaction was formed between theaflavin and Arg553 from the Blind Docking server. Our results suggest that theaflavin could be a potential SARS‐CoV‐2 RdRp inhibitor for further study.
Highlights
Theaflavin has a lower idock score in the catalytic pocket of RdRp in SARS‐CoV‐2, SARS‐CoV and MERS‐CoV from idock.
Theaflavin has a lowest binding energy when it docks in the catalytic pocket of SARS‐CoV‐2 RdRp.
Theaflavin could be potential SARS‐CoV‐2 RdRp inhibitor.
Abstract
Background
The pathogenesis of lupus nephritis (LN) remains not fully understood. In this study, we aimed to explore the pathogenic roles of autoantibodies against human renal glomerular ...endothelial cells (HRGEC) in LN patients.
Methods
The serum levels of anti-HRGEC antibodies in systemic lupus erythematosus (SLE) patients without LN and LN patients were determined by cell-based enzyme-linked immunosorbent assay (ELISA). Monoclonal IgG anti-HRGEC antibodies were subsequently generated from LN patients. The binding activities of these monoclonal antibodies to HRGEC, their cross-reactivity with double-stranded DNA (dsDNA), and the ability to activate HRGEC were further evaluated.
Results
LN patients had higher serum levels of IgG anti-HRGEC antibodies than SLE patients without LN and healthy controls. Four monoclonal IgG anti-HRGEC antibodies (LN1–4) were obtained; LN1 and LN2 were IgG3 while LN3 and LN4 were IgG1. Among these monoclonal antibodies, LN1–3 were cross-reactive with dsDNA. The functional assays showed that compared with IgG1/IgG3 isotype controls, LN3 had an effect on HRGEC to enhance interleukin (IL)-6 production, LN4 could enhance IL-8 and monocyte chemoattractant protein (MCP)-1 production, and LN1–3 possessed the ability to induce interferon (IFN)-α production by HRGEC. Moreover, the removal of DNA on the HRGEC surface by DNAse 1 did not interpose the binding of LN1–3 to HRGEC and the effects of LN1–3 on IFN-α induction by HRGEC.
Conclusions
Some IgG anti-HRGEC antibodies in LN patients had the ability to enhance endothelial proinflammatory cytokine (IL-6, IL-8, and MCP-1) production, and some could induce the DNA-independent production of IFN-α by HRGEC.
In addition to IgA, the deposition of complement (C)3 in dermal vessels is commonly found in Henoch-Schönlein purpura (HSP). The aim of this study is to elucidate the role of circulating complement ...proteins in the pathogenesis of childhood HSP.
Plasma levels of C3a, C4a, C5a, and Bb in 30 HSP patients and 30 healthy controls were detected by enzyme-linked immunosorbent assay (ELISA). The expression of C3a receptor (C3aR), C5a receptor (CD88), E-selectin, intercellular adhesion molecule 1 (ICAM-1), C3, C5, interleukin (IL)-8, monocyte chemotactic protein (MCP)-1, and RANTES by human dermal microvascular endothelial cells (HMVEC-d) was evaluated either by flow cytometry or by ELISA.
At the acute stage, HSP patients had higher plasma levels of C3a (359.5 ± 115.3 vs. 183.3 ± 94.1 ng/ml, p < 0.0001), C5a (181.4 ± 86.1 vs. 33.7 ± 26.3 ng/ml, p < 0.0001), and Bb (3.7 ± 2.6 vs. 1.0 ± 0.6 μg/ml, p < 0.0001), but not C4a than healthy controls. Although HSP patient-derived acute phase plasma did not alter the presentation of C3aR and CD88 on HMVEC-d, it enhanced the production of endothelial C3 and C5. Moreover, C5a was shown in vitro to up-regulate the expression of IL-8, MCP-1, E-selectin, and ICAM-1 by HMVEC-d with a dose-dependent manner.
In HSP, the activation of the complement system in part through the alternative pathway may have resulted in increased plasma levels of C3a and C5a, which, especially C5a, may play a role in the disease pathogenesis by activating endothelium of cutaneous small vessels.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Chronic granulomatous disease (CGD) is a primary immunodeficiency of phagocyte function due to defective NADPH oxidase (phox). Compared with the common types of
CYBB/
gp91
phox
,
NCF1
/p47
phox
, and
...CYBA
/p22
phox
deficiency,
NCF4
/p40
phox
deficiency is a mild and atypical form of CGD without invasive bacterial or fungal infections. It can be diagnosed using serum-opsonized
E.coli
as a stimulus in dihydrorhodamine (DHR) assay. Patients with
CYBC1
/Eros deficiency, a new and rare form of CGD, present as loss of respiratory burst and gp91
phox
expression in phagocytes. Neutrophils from patients with CGD are deficient in neutrophil extracellular traps (NETosis), autophagy, and apoptosis. The hyper-activation of NF-ĸB and inflammasome in CGD phagocytes also lead to long-lasting production of pro-inflammatory cytokines and inflammatory manifestations, such as granuloma formation and inflammatory bowel disease-like colitis. Patients with CGD and X-linked female carriers also have a higher incidence of autoimmune diseases. The implementation of antimicrobial, anti-fungal, and interferon-γ prophylaxis has greatly improved overall survival. Residual NADPH oxidase activity is significantly associated with disease severity and the chance of survival of the patient. New therapeutic approaches using immunomodulators for CGD-related inflammatory manifestations are under investigation, including pioglitazone, tamoxifen, and rapamycin. Hematopoietic stem cell transplantation (HSCT) is the curative treatment. Outcomes of HSCT have improved substantially over the last decade with overall survival more than 84–90%, but there are debates about designing optimal conditioning protocols using myeloablative or reduced-intensity regimens. The gene therapy for X-linked CGD using hematopoietic stem and progenitor cells transduced ex vivo by lentiviral vector encoding the human gp91phox gene demonstrated persistence of adequate oxidase-positive neutrophils in a small number of patients. Gene therapy using genome-editing technology such as CRISPR/Cas9 nucleases is a promising approach for patients with CGD in the future.
Introduction
This study aimed to elucidate the bacterial profile of chronic rhinosinusitis (CRS) in patients with end‐stage renal disease (ESRD) and chronic kidney disease (CKD) compared with ...nonrenal patients, guiding antibiotic selection for clinicians.
Methods
We retrospectively analyzed 13,906 inpatients from the Chang Gung Research Database who underwent sinus surgery (2004–2018). Patients were categorized into ESRD‐CRS, CKD‐CRS, and non‐CKD‐CRS based on the estimated glomerular filtration rate. Bacterial cultures from surgical samples were classified as facultative anaerobes or aerobes (e.g., Klebsiella pneumoniae KP, Pseudomonas aeruginosa Ps.a), anaerobes, and fungi and ranked by prevalence.
Results
Data from 47 ESRD‐CRS, 230 CKD‐CRS, and 13,123 non‐CKD‐CRS patients were analyzed. In ESRD‐CRS, the predominant species were KP (31.6%), Ps.a (21.1%), and Coagulase‐negative Staphylococcus (CoNS, 15.8%). CKD‐CRS showed Staphylococcus epidermidis (27.7%), CoNS (20.5%), and Ps.a (20.5%). Non‐CKD‐CRS had Staphylococcus epidermidis (29.8%), CoNS (25.0%), and Staphylococcus aureus (15.5%). For anaerobes, ESRD‐CRS was dominated by Fusobacterium nucleatum (10.5%) and Peptostreptococcus micros (10.5%), whereas CKD‐CRS and non‐CKD‐CRS showed Propionibacterium acnes as a primary strain (14.5% and 28.7%, respectively).
Conclusion
For CRS in ESRD, antibiotics targeting KP and Fusobacterium nucleatum are recommended. In CKD‐CRS, a focus on Staphylococcus epidermidis and Propionibacterium acnes is suggested.
Level of Evidence
4 Laryngoscope, 134:3499–3507, 2024
Solution‐processed perovskite solar cells have great potential for low‐cost roll‐to‐roll fabrication. However, the degradation of aged precursor solutions will become a critical obstacle to mass ...production. In this report, a small molecule (ITIC‐Th) is employed to stabilize the perovskite precursor solution containing mixed cations and halides. It is found that ITIC‐Th can effectively suppress the formation of yellow δ‐phase in the films made from aged precursor solutions. Consequently, the devices fabricated from the aged precursor solution with ITIC‐Th experience much less efficiency drop with the increase of the precursor aging time—from 19.20% (fresh) to 16.55% (39 d), compared with the devices made from conventional precursor solutions dropping from 18.07% (fresh) to 1.76% (39 d). The characterizations suggest that ITIC‐Th is beneficial for CH3NH3+ cations to be incorporated into the crystal structure, facilitating the formation of perovskite phase. Furthermore, the presence of ITIC‐Th in the perovskite thin film gives rise to additional photocurrent as well as improved fill factor due to the well‐matched energy levels, the passivation of defects, and the complementary absorption spectra, suggesting a new route toward future high‐efficiency solar cells—incorporating organic non‐fullerene acceptors and halide perovskite materials into the same active layer.
Herein, the authors report a novel route to greatly enhance the long‐term stability of perovskite precursor solutions by incorporating a non‐fullerene small molecule ITIC‐Th. The device fabricated from a 39‐day aged precursor solution with ITIC‐Th remains at a relatively high efficiency, exceeding 16%, while the device from a 39‐day precursor solution without ITIC‐Th only shows a PCE of 1.76%.
The Chang Gung Research Database (CGRD) is a de-identified database derived from original medical records of Chang Gung Memorial Hospital (CGMH), which comprises seven medical institutes located from ...the northeast to southern regions of Taiwan. The volume of medical services performed in CGMH is large, and clinical and scientific studies based on the CGRD are reported to be of high quality. However, the CGRD as a useful database for research has not been analyzed before. The objective of the study was to analyze the CGRD with regard to its characteristics and coverage of Taiwan's population.
We performed a nationwide cohort study using population-based data from the Taiwan National Health Insurance Research Database (NHIRD). All patients who had any medical record of outpatient visits or admission between January 1, 1997, and December 31, 2010, were included, and the sex ratio, age distribution, socioeconomic status, urbanicity, severity of illness, prevalence of specific disease, and coverage of the CGRD were analyzed.
The sex ratio, age distribution, socioeconomic status, and urbanicity of the population of the CGRD are different from those of Taiwan NHIRD and medical centers in Taiwan (all the pairwise p < 0.05). The severity of comorbidities, and prevalence of specific diseases of the population of the CGRD are significantly higher than those of Taiwan NHIRD and medical centers in Taiwan for both outpatient and inpatient samples (all the pairwise p < 0.05). The overall coverage of the CGRD was 21.2% for outpatients and 12.4% for inpatients. The disease-specific coverage of the CGRD was 27-34% for outpatients and 14-21% for inpatients.
The CGRD is a multi-institutional, original medical record-based research database with high overall and disease-specific coverage of Taiwan. The population of the CGRD has significantly higher severity of comorbidities, and prevalence of specific diseases than those of Taiwan NHIRD and medical centers in Taiwan.
Summary
Background
There remains an unmet need for convenient biomarkers to assess the risks of discontinuing nucleos(t)ide analogues (NAs) in chronic hepatitis B (CHB).
Aim
To investigate if ...hepatitis B core‐related antigen (HBcrAg) is an independent of surface antigen (HBsAg) for risk prediction of NA cessation.
Methods
This prospective multicentre study enrolled 135 CHB patients who stopped entecavir or tenofovir after achieving viral remission for a median of 25.2 months. All patients stopped NA with negative HBeAg and undetectable viral DNA, and were then observed for clinical relapse and HBsAg loss. Predictors including HBsAg and HBcrAg levels were explored using Cox proportional hazard model and weighted to develop a risk score.
Results
During a median follow‐up of 25.9 months, clinical relapse and HBsAg loss occurred in 66 and eight patients, respectively, with a 5‐year cumulative incidence of 56.1% (95% CI 46.7‐66.0%) and 8.8% (95% CI 4.3‐17.4%), respectively. HBcrAg was an independent relapse predictor, as well as HBsAg, age, ALT and tenofovir use. A score (SCALE‐B) was calculated by the equation of 35*HBsAg (log IU/mL) + 20*HBcrAg (log U/mL) + 2*age (year) + ALT (U/L) + 40 for tenofovir use. The concordance rates for clinical relapse were 0.87, 0.88, 0.87, 0.85 and 0.90 at 1, 2, 3, 4 and 5 years, respectively. Moreover, HBsAg loss occurred exclusively in low‐risk patients predicted by the score.
Conclusions
Serum HBcrAg and HBsAg levels were independent predictors of off‐NA relapse and can be factored into a risk score to guide treatment cessation in patients with CHB.
In first-line treatment of Helicobacter pylori, we have previously shown that the eradication frequency was 83·7% (95% CI 80·4–86·6) for triple therapy for 14 days (T14; lansoprazole 30 mg, ...amoxicillin 1 g, and clarithromycin 500 mg, all given twice daily), 85·9% (82·7–88·6) for concomitant therapy for 10 days (C10; lansoprazole 30 mg, amoxicillin 1 g, clarithromycin 500 mg, and metronidazole 500 mg, all given twice daily), and 90·4% (87·6–92·6) for bismuth quadruple therapy for 10 days (BQ10; bismuth tripotassium dicitrate 300 mg four times a day, lansoprazole 30 mg twice daily, tetracycline 500 mg four times a day, and metronidazole 500 mg three times a day). In this follow-up study, we assess short-term and long-term effects of these therapies on the gut microbiota, antibiotic resistance, and metabolic parameters.
This was a multicentre, open-label, randomised trial done at nine medical centres in Taiwan. Adult patients (>20 years) with documented H pylori infection were randomly assigned (1:1:1, with block sizes of six) to receive T14, C10, or BQ10. We assessed long-term outcomes (reinfection frequency, changes in the gut microbiota, antibiotic resistance, and metabolic parameters) in patients with available data, excluding all protocol violators and those with unknown post-treatment H pylori status. Faecal samples were collected before treatment and 2 weeks, 2 months, and at least 1 year after eradication therapy. Amplification of the V3 and V4 hypervariable regions of the 16S rRNA was done followed by high-throughput sequencing. Susceptibility testing for faecal Escherichia coli and Klebsiella pneumoniae was done. This trial is complete and registered with ClinicalTrials.gov, NCT01906879.
Between July 17, 2013, and April 20, 2016, 1620 participants were randomly assigned to the three treatment groups (540 33% per group). 1214 (75%) attended 1-year follow-up and are included in this analysis. Compared with baseline, alpha diversity was significantly reduced 2 weeks after T14 (p=0·0002), C10 (p<0·0001), and BQ10 (p<0·0001) treatment. Beta diversity was also significantly altered 2 weeks after T14 (p=0·0010), C10 (p=0·0001), and BQ10 (p=0·0001). Alpha diversity and beta diversity were restored at week 8 (p=0·14 and p=0·918, respectively) and 1 year (p=0·14 and p=0·918) after T14, but were not fully recovered at week 8 and after 1 year in patients treated with C10 (p=0·0001 and p=0·013 at week 8; p=0·019 and p=0·064 at 1 year) and BQ10 (p<0·0001 and p=0·0002; p=0·001 and p=0·029). A transient increase at week 2 after T14 and C10 of the resistance rates of E coli to ampicillin-sulbactam (12% 15/127 to 66% 38/58 for T14, 7% 10/135 to 64% 28/44 for C10), cefazolin (13% 16/127 to 43% 25/58 for T14, 10% 13/135 to 41% 18/44 for C10), cefmetazole (8% 10/127 to 26% 15/58 for T14, 4% 5/135 to 18% 8/44 for C10), levofloxacin (8% 10/127 to 35% 20/58 for T14, 7% 10/135 to 32% 14/44 for C10), gentamicin (13% 19/146 to 47% 27/58 for T14, 15% 22/149 to 45% 20/44 for C10), and trimethoprim–sulfamethoxazole (33% 48/146 to 86% 50/58 for T14, 28% 42/148 to 86% 38/44 for C10; p<0·05 in paired samples in the above analyses) returned to basal state at week 8 and after 1 year. Although bodyweight and body-mass index slightly increased, there were significant improvements in metabolic parameters, with a decrease in insulin resistance, triglycerides, and LDL and an increase in HDL. Overall, there was no significant change in the prevalence of metabolic syndrome at week 8 and 1 year after T14, C10, and BQ10.
Eradication of H pylori infection has minimal disruption of the microbiota, no effect on antibiotic resistance of E coli, and some positive effects on metabolic parameters. Collectively, these results lend support to the long-term safety of H pylori eradication therapy.
National Taiwan University Hospital and Ministry of Science and Technology of Taiwan.
Objective/Hypothesis
To investigate the risk of nasal septal abscess (NSA) in patients with type 2 diabetes mellitus (T2DM) after septoplasty.
Study Design
Retrospective cohort study through Taiwan ...National Health Insurance database.
Methods
The Taiwan National Health Insurance Research Database was used to conduct this retrospective cohort study. A total of 382 patients with T2DM (DM group) diagnosed between 2000 and 2010 and 382 matched patients without a DM diagnosis (non‐DM group) were enrolled. Patients were followed up until death or December 31, 2013. NSA incidence was the main outcome.
Results
After septoplasty, the cumulative incidence of NSA in the DM group was significantly higher than that in the non‐DM group (P < .001). Cox proportional hazards regression indicated a significant association between T2DM and higher NSA incidence (adjusted hazard ratio, 2.62; 95% CI, 1.44–3.61; P < .001). However, subgroup analysis and sensitivity testing demonstrated that the effect of T2DM on NSA risk was stable. In addition, the subgroup with a Diabetes Complications Severity Index (DCSI) of ≥1 had higher NSA risk than that with DCSI = 0 (adjusted hazard ratio, 3.58; 95% CI, 2.10–6.09; P < .001). The treatment type for NSA did not differ between the groups.
Conclusions
T2DM is an independent risk factor for NSA in patients undergoing nasal septoplasty, and the NSA risk is greater among patients with high DM severity.
Level of Evidence
IV Laryngoscope, 131:E2420–E2425, 2021
PDF
