Thallium(I) induces a prolonged inhibition of (6-4)photoproduct binding and UV damage excision repair activities in zebrafish (Danio rerio) embryos via protein inactivation.

Cyclobutane pyrimidine dimer (CPD) and (6-4)photoproduct (6-4 PP) are two major types of UV-induced DNA lesion and 6-4 PP is more mutagenic than CPD. Activated by lesion detection, nucleotide excision repair (NER) eliminates CPDs and 6-4 PPs. Thallium (Tl) is a toxic metal existing primarily as Tl+ in the aquatic environment. Ingestion of Tl+-contaminated foods and water is a major route of human poisoning. As Tl+ may inhibit enzyme activities via binding to sulfhydryl groups, this study explored if Tl+ could intensify UV mutagenicity by inactivating NER-linked damage recognition factors using zebrafish (Danio rerio) embryo as a model system. Incubation of Tl+ (as thallium nitrate) at 0.1-0.4 µg/mL with zebrafish extracts for 20 min caused a concentration-dependent inhibition of 6-4 PP binding activities as shown by a photolesion-specific band shift assay, while CPD binding activities were insensitive to Tl+. The ability of Tl+ to suppress 6-4 PP detection was stronger than that of Hg2+. Exposure of zebrafish embryos at 1 h post fertilization (hpf) to Tl+ at 0.4-1 µg/mL for 9 or 71 h also specifically inhibited 6-4 PP detection, indicating that Tl+ induced a prolonged inhibition of 6-4 PP sensing ability primarily via its direct interaction with damage recognition molecules. Tl+-mediated inhibition of 6-4 PP binding in embryos at distinct stages resulted in a suppression of NER capacity monitored by a transcription-based DNA repair assay. Our results revealed the potential of Tl+ to enhance UV mutagenicity by disturbing the removal of 6-4 PP through repressing the lesion detection step of NER.

Improving Dental Implant Outcomes: CNN-Based System Accurately Measures Degree of Peri-Implantitis Damage on Periapical Film.

As the popularity of dental implants continues to grow at a rate of about 14% per year, so do the risks associated with the procedure. Complications such as sinusitis and nerve damage are not uncommon, and inadequate cleaning can lead to peri-implantitis around the implant, jeopardizing its stability and potentially necessitating retreatment. To address this issue, this research proposes a new system for evaluating the degree of periodontal damage around implants using Periapical film (PA). The system utilizes two Convolutional Neural Networks (CNN) models to accurately detect the location of the implant and assess the extent of damage caused by peri-implantitis. One of the CNN models is designed to determine the location of the implant in the PA with an accuracy of up to 89.31%, while the other model is responsible for assessing the degree of Peri-implantitis damage around the implant, achieving an accuracy of 90.45%. The system combines image cropping based on position information obtained from the first CNN with image enhancement techniques such as Histogram Equalization and Adaptive Histogram Equalization (AHE) to improve the visibility of the implant and gums. The result is a more accurate assessment of whether peri-implantitis has eroded to the first thread, a critical indicator of implant stability. To ensure the ethical and regulatory standards of our research, this proposal has been certified by the Institutional Review Board (IRB) under number 202102023B0C503. With no existing technology to evaluate Peri-implantitis damage around dental implants, this CNN-based system has the potential to revolutionize implant dentistry and improve patient outcomes.

Aluminum (Al) causes a delayed suppression of nucleotide excision repair (NER) capacity in zebrafish (Danio rerio) embryos via disturbance of DNA lesion detection.

Aluminum (Al) is extensively used for making cooking utensils and its presence in the aquatic environment may occur through acid mine drainage and wastewater discharge. Al is known to induce genotoxicity in human cells, rodents, and fish. Nucleotide excision repair (NER) eliminates helix-twisting DNA lesions such as UV-induced dipyrimidine photoproducts. Because our earlier investigation revealed the operation of NER in zebrafish (Danio rerio) embryos, this study explored if inhibition of NER could be a mechanism of Al-induced genotoxicity using zebrafish embryo as a model system. An acute fish embryo toxicity test indicated that Al (as aluminum sulfate) at 2-15 mg/L were nonlethal to zebrafish embryos, yet exposure of embryos at 1 h post fertilization (hpf) to Al at 10-15 mg/L for 71 h significantly repressed their NER capacity monitored by a transcription-based DNA repair assay. Band shift analysis indicated a higher sensitivity of (6-4) photoproduct (6-4PP) than cyclobutane pyrimidine dimer (CPD) detecting activities to Al, reflecting the preferential influence of Al on the detection of strongly distorted DNA lesions. Time-course experiments showed a delayed response of NER to Al as repair machinery was unaffected by Al at 15 mg/L following a 35-h exposure, while Al treatment for the same period obviously inhibited 6-4PP binding activities although the gene expression of damage recognition factors remained active. Inhibition of 6-4PP detection blocked downstream lesion incision/excision detected by a terminal deoxy transferase-mediated end labeling assay. As the disturbance of damage sensing preceded that of the overall repair process, Al exposure was believed to downregulate NER capacity by inhibiting the activities of lesion detection proteins. Our results revealed the ability of Al to enhance its genotoxicity by suppressing NER capacity.

Correlations between Clinical and Histopathologic Characteristics in Idiopathic Epiretinal Membrane.

PURPOSE: To investigate correlations between clinical and histopathologic characteristics of idiopathic epiretinal membrane (ERM). DESIGN: Retrospective interventional case series. PARTICIPANTS: In total, 87 eyes from 87 patients with idiopathic ERM who underwent pars plana vitrectomy with peeling of the ERM from 2019 to 2020 were included. METHODS: The outcomes of clinical ophthalmic examination, including measurement of best-corrected visual acuity (BCVA) and spectral-domain OCT (SD-OCT), before and after surgery were reviewed. Surgical specimens were fixed in formalin and embedded in paraffin for histologic and immunohistochemical analysis. MAIN OUTCOMES MEASURES: The association between morphological characteristics revealed on SD-OCT images and the cellular composition of the surgically excised ERM demonstrated with immunohistochemical staining were the main outcome measures. Changes in the BCVA and central macular thickness (CMT) were assessed through a comparison of preoperative and postoperative measurements. RESULTS: Based on SD-OCT morphological characteristics in the foveal area, 15 cases were classified into group 1A (mainly outer retinal thickening), 39 into group 1B (more tenting of the outer retina and distorted inner retina), and 33 into group 1C (prominent inner retina thickening). Overall, postoperative final BCVA and CMT at 1 year improved in all groups. Patients who presented with a better initial BCVA exhibited a more favorable final BCVA. Epiretinal membranes in group 1C demonstrated the greatest decrease in CMT compared with those in groups 1B and 1A, but the final CMT did not differ among the groups. A negative correlation between the density of hyalocytes (P = 0.003) and myofibroblasts (P = 0.047) was noted between the 3 groups. Total cell density and glial cell density of the ERMs were strongly associated with poor final BCVA and BCVA improvement. CONCLUSIONS: The present study provides new histopathologic information regarding the formation and progression of idiopathic ERM. Glial cell proliferation plays a predominant role in these processes. Epiretinal membranes with high cellularity and glial cell density may cause damage to the retina structure, resulting in poor postoperative visual outcomes. These findings provide additional evidence supporting early surgical intervention in patients with idiopathic ERM reported with visual disturbance.

Three-Year Outcomes of Intravitreal Aflibercept Injections for Retinal Angiomatous Proliferation According to Disease Stage.

INTRODUCTION: To evaluate the outcomes of intravitreal aflibercept injections for retinal angiomatous proliferation (RAP) according to disease stage. METHODS: This retrospective chart review included 68 eyes of 53 individuals diagnosed as having RAP and 109 neovascular age-related macular degeneration (nAMD) eyes of 109 patients as controls. All patients received intravitreal injections of aflibercept in a real-world setting. The main outcome measures were the changes in the mean of best-corrected visual acuity (BCVA) and central retinal thickness (CRT) as well as the total number of injections received during the 3-year follow-up period. RESULTS: The average BCVA and CRT changes in eyes affected by RAP and the controls at 3 years were non-significant. Both populations received a similar number of injections. After 3 years of treatment, patients with RAP had visual decline despite stable anatomical outcomes. Approximately 50% of the eyes with stage II RAP exhibited significant BCVA decline at the end of the third year. Among those eyes that had deteriorated BCVA, persistently worsening BCVA and thinning CRT were observed from year 2 to year 3. CONCLUSION: Similar to treating nAMD, intensive injections or aggressive treatment strategies are required to treat RAP to achieve optimal visual outcomes in a real-world setting. The response to aflibercept treatment at the second year is associated with the final visual outcome of eyes with stage II RAP lesions.

Psoriasis and Dry Eye Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: Psoriasis is a chronic inflammatory skin disease with potential systemic involvement. Some evidence suggests an increased risk of dry eye in patients with psoriasis. However, the relationship between these two conditions remains unclear. The aim of our study is to investigate the association between psoriasis and dry eye disease. METHODS: This meta-analysis was registered in PROSPERO (CRD42020199445) and adhered to MOOSE checklist and PRISMA guidance for all processes. PubMed, Embase, Web of Science, and Cochrane databases were searched for studies examining the association between psoriasis and dry eye disease from inception to December 13, 2020. The primary outcome was the prevalence of dry eye disease in patients with psoriasis relative to controls. The secondary outcomes were the Schirmer I test score, tear film breakup time (TBUT), and ocular surface disease index (OSDI). The risk of bias of the selected studies was assessed using the Newcastle-Ottawa Scale. RESULTS: The meta-analysis showed a significant association between dry eye disease and psoriasis (OR, 8.49; 95% CI, 3.34-21.58). Moreover, patients with psoriasis had a significantly lower Schirmer I test score (MD, -2.80; 95% CI, -4.07 to -1.52), shorter TBUT (MD, -4.12; 95% CI, -5.22 to -3.02), and higher OSDI (MD, 20.15; 95% CI, 6.24-34.05; p < 0.01), compared to controls. CONCLUSIONS: The current evidence supports an association between dry eye disease and psoriasis. These results suggest ophthalmologic assessment for the early recognition and management of dry eye in patients with psoriasis.

Heat stress modulates nucleotide excision repair capacity in zebrafish (Danio rerio) early and mid-early embryos via distinct mechanisms.

Discharge of heated effluent at 8-12 °C above ambient into water areas is known to retard the growth of aquatic organisms due to heat stress. Nucleotide excision repair (NER) maintains genome integrity by removing helix-distorting adducts such as UV-induced DNA lesions. This study explored how NER in zebrafish (Danio rerio) embryos at different hours post fertilization (hpf) responded to + 8.5 °C heat shock for 30 min. Our transcription-based repair assay monitoring the ability of zebrafish extracts to upregulate a UV-suppressed gene expression detected a 2-fold increase of NER capacity in 10 hpf early embryos after heat stress. In contrast, heat stress caused a mild inhibition of NER capacity in 24 hpf mid-early embryos. Heat-treated and untreated 10 hpf zebrafish extracts displayed similar levels of UV-damaged-DNA binding activities, while an apparently weaker (6-4) photoproduct (6-4 PP) binding activity was present in heat-stressed 24 hpf zebrafish extracts. Heat stress enhanced UV-induced NER in 10 hpf embryos by increasing the efficiency of damage incision/excision based on both genomic DNA electrophoresis and terminal deoxytransferase (TdT)-mediated end labeling assay. UV-irradiated embryos preexposed to heat stress produced a significantly larger amount of NER-associated DNA fragments about 20-30 nucleotides in length than embryos only heat-treated or irradiated. Correlated with its inhibitory effect on 6-4 PP damage recognition, heat stress downregulated damage incision/excision activities in 24 hpf embryos. Hence, thermal stress may positively or negatively modulate NER capacity in zebrafish embryos at different stages by targeting at the step of DNA incision/excision or damage recognition.

Analysis of Three Compounds in Flos Farfarae by Capillary Electrophoresis with Large-Volume Sample Stacking.

The aim of this study was to develop a method combining an online concentration and high-efficiency capillary electrophoresis separation to analyze and detect three compounds (rutin, hyperoside, and chlorogenic acid) in Flos Farfarae. In order to get good resolution and enrichment, several parameters such as the choice of running buffer, pH and concentration of the running buffer, organic modifier, temperature, and separation voltage were all investigated. The optimized conditions were obtained as follows: the buffer of 40 mM NaH2P04-40 mM Borax-30% v/v methanol (pH 9.0); the sample hydrodynamic injection of up to 4 s at 0.5 psi; 20 kV applied voltage. The diode-array detector was used, and the detection wavelength was 364 nm. Based on peak area, higher levels of selective and sensitive improvements in analysis were observed and about 14-, 26-, and 5-fold enrichment of rutin, hyperoside, and chlorogenic acid were achieved, respectively. This method was successfully applied to determine the three compounds in Flos Farfarae. The linear curve of peak response versus concentration was from 20 to 400 µg/ml, 16.5 to 330 µg/mL, and 25 to 500 µg/mL, respectively. The regression coefficients were 0.9998, 0.9999, and 0.9991, respectively.

[New Strategy for anti-HBV therapy: blocking P-8 interaction].

Clinically being applied treatment against chronic hepatitis has three limitations: low response rates, severe adverse effects and a high rate of drug resistance. Hence, novel targets for antiviral therapy need to be developed so as to provide an armory of different strategies. During the replication of hepatitis B virus, the interaction of viral polymerase (P protein, also called P) and epsilonRNA is indispensable for the initiation of reverse transcription via protein priming and the pregenome RNA (pgRNA) packaging. Three strategies are currently developed for blocking P-epsilon interaction: heat shock protein inhibitors, epsilonaptamers and chemical compounds for blocking formation of P-epsilon complex. Previously, our group has for the first time worldwide in vitro screened several aptamers, which are able to interfere with the P-epsilon interaction. A strong inhibition against HBV was observed in vitro and in vivo experiments, respectively. In conclusion, the so far developed chemicals suppressing the P-epsilon interaction may bypass or overcome the viral resistance problems during clinic treatment and represent a highly attractive option for therapeutic intervention.

Adjunctive oral methylprednisolone in pediatric acute pyelonephritis alleviates renal scarring.

OBJECTIVE: To determine if glucocorticoids can prevent renal scar formation after acute pyelonephritis in pediatric patients. METHODS: Patients younger than 16 years diagnosed with their first episode of acute pyelonephritis with a high risk of renal scar formation (ie, inflammatory volume ≥ 4.6 mL on technetium-99m-labeled dimercaptosuccinic acid scan [DMSA] or abnormal renal ultrasonography results) were randomly assigned to receive either antibiotics plus methylprednisolone sodium phosphate (1.6 mg/kg per day for 3 days [MPD group]) or antibiotics plus placebo (placebo group) every 6 hours for 3 days. Patients were reassessed by using DMSA 6 months after treatment. The primary outcome was the development of renal scars. RESULTS: A total of 84 patients were enrolled: 19 in the MPD group and 65 in the placebo group. Patient characteristics were similar between the 2 groups, including the acute inflammatory parameters and the initial DMSA result. Renal scarring was found in 33.3% of children treated with MPD and in 60.0% of those who received placebo (P < .05). The median cortical defect volumes on follow-up DMSA were 0.0 mL (range: 0-4.5 mL) and 1.5 mL (range: 0-14.8 mL) for the MPD and placebo groups, respectively (P < .01). Patients in the MPD group experienced faster defervescence after treatment than the placebo group. CONCLUSIONS: Adjunctive oral MPD therapy reduced the occurrence and/or severity of renal scarring after acute pyelonephritis in these hospitalized children who had a high risk of renal scar formation.