In 2017, surveillance for tickborne diseases in China led to the identification of a patient who presented to a hospital in Inner Mongolia with a febrile illness that had an unknown cause. The ...clinical manifestation of the illness was similar to that of tickborne encephalitis virus (TBEV) infection, but neither TBEV RNA nor antibodies against the virus were detected.
We obtained a blood specimen from the index patient and attempted to isolate and identify a causative pathogen, using genome sequence analysis and electron microscopy. We also initiated a heightened surveillance program in the same hospital to screen for other patients who presented with fever, headache, and a history of tick bites. We used reverse-transcriptase-polymerase-chain-reaction (RT-PCR) and cell-culture assays to detect the pathogen and immunofluorescence and neutralization assays to determine the levels of virus-specific antibodies in serum specimens from the patients.
We found that the index patient was infected with a previously unknown segmented RNA virus, which we designated Alongshan virus (ALSV) and which belongs to the jingmenvirus group of the family Flaviviridae. ALSV infection was confirmed by RT-PCR assay in 86 patients from Inner Mongolia and Heilongjiang who presented with fever, headache, and a history of tick bites. Serologic assays showed that seroconversion had occurred in all 19 patients for whom specimens were available from the acute phase and the convalescent phase of the illness.
A newly discovered segmented virus was found to be associated with a febrile illness in northeastern China. (Funded by the National Key Research and Development Program of China and the National Natural Science Foundation of China.).
Background and Purpose
Short‐chain fatty acids are fermentation end products produced by gut bacteria, which have been shown to ameliorate inflammatory bowel diseases and allergic asthma. However, ...the mechanism involved remains largely unknown. Here, we investigate the protective effects and mechanisms of sodium butyrate (SB) on LPS‐induced mastitis model.
Experimental Approach
Effects of increasing doses of SB on blood‐milk barrier function and inflammation are studied in BALB/c mice with LPS‐induced mastitis. The underlying mechanisms of anti‐inflammatory effects of SB were further investigated in LPS‐stimulated mouse mammary epithelial cells (mMECs).
Key Results
The results show that SB decreased LPS‐induced disruption in mammary tissues, infiltration of inflammatory cells and the levels of TNF‐α, IL‐6 and IL‐1β. SB up‐regulated the tight junction proteins occludin and claudin‐3 and reduced blood‐milk barrier permeability in LPS‐induced mastitis. Studies in vitro revealed that SB inhibited LPS‐induced inflammatory response by inhibition of the NF‐κB signalling pathway and histone deacetylases in LPS‐stimulated mMECs.
Conclusions and Implications
In our model, SB protected against LPS‐induced mastitis by preserving blood‐milk barrier function and depressing pro‐inflammatory responses, suggesting the potential use of SB as a prophylactic agent to protect blood‐milk barrier function in mastitis.
Purpose
To expand the mutation spectrum of patients with familial exudative vitreoretinopathy (FEVR) disease.
Participants
74 probands (53 families and 21 sporadic probands) with familial exudative ...vitreoretinopathy (FEVR) disease and their available family members (n = 188) were recruited for sequencing.
Methods
Panel‐based targeted screening was performed on all subjects. Before sanger sequencing, variants of LRP5, NDP, FZD4, TSPAN12, ZNF408, KIF11, RCBTB1, JAG1, and CTNNA1 genes were verified by a series of bioinformatics tools and genotype–phenotype co‐segregation analysis.
Results
40.54% (30/74) of the probands were sighted to possess at least one etiological mutation of the nine FEVR‐causative genes. The etiological mutation detection rate was 37.74% (20/53) in family‐attainable probands while 47.62% (10/21) in sporadic cases. The diagnosis rate of patients in the early‐onset subgroup (≤5 years old, 45.4%) is higher than that of the children or adolescence‐onset subgroup (6–16 years old, 42.1%) and the late‐onset subgroup (≥17 years old, 39.4%). A total of 36 etiological mutations were identified in this study, comprising 26 novel mutations and 10 reported mutations. LRP5 was the most prevalent mutant gene among the 36 mutation types with a percentage of 41.67% (15/36). Followed by FZD4 (10/36, 27.78%), TSPAN12 (5/36, 13.89%), NDP (4/36, 11.11%), KIF11 (1/36, 2.78%), and RCBTB1 (1/36, 2.78%). Among these mutations, 63.89% (23/36) were missense mutations, 25.00% (9/36) were frameshift mutations, 5.56% (2/36) were splicing mutations, 5.56% (2/36) were nonsense mutations. Moreover, the clinical pathogenicity of these variants was defined according to American College of Medical Genetics (ACMG) and genomics guidelines: 41.67% (15/36) were likely pathogenic variants, 27.78% (10/36) pathogenic variants, 30.55% (11/36) variants of uncertain significance. No etiological mutations discovered in the ZNF408, JAG1, and CTNNA1 genes in this FEVR cohort.
Conclusions
We systematically screened nine FEVR disease‐associated genes in a cohort of 74 Chinese probands with FEVR disease. With a detection rate of 40.54%, 36 etiological mutations of six genes were authenticated in 30 probands, including 26 novel mutations and 10 reported mutations. The most prevalent mutated gene is LRP5, followed by FZD4, TSPAN12, NDP, KIF11, and RCBTB1. In total, a de novo mutation was confirmed. Our study significantly clarified the mutation spectrum of variants bounded up to FEVR disease.
Our genetic finding can serve as an efficient reference and comprehensive research strategy for the design of panel‐based genetic diagnostic testing, genetic counseling, and future diagnosis for suspected patients with family exudative vitreoretinopathy disease.
Purpose. To study the influence of parents’ educational backgrounds and understanding on the progress of myopia in their offspring. Methods. Spherical equivalent refraction (SE) of the children (aged ...6–14) in China was assessed with cycloplegic autorefraction in a two-year longitudinal study. The parents’ background information and myopia-related cognition were collected by questionnaires. Results. The offspring of parents with lower education and more myopic SE had higher myopic progression (mean = –1.42 ± 1.06) than the children of other groups (P<0.05). The parents’ understanding of the proper outdoor activity time, sleep duration, reading distance, and indoor illumination for children was not significantly correlated with the progression of myopia in their offspring. The parent’s preference for eye care visit frequency had a significant correlation with the myopia development of their children (r = 0.076, P=0.001∗). The mean SE progression was −0.84 ± 1.37 and −0.58 ± 1.29 in the children whose parents considered that extracurricular classes would negatively affect myopia development progression and the children whose parents believed it would not, respectively (P=0.026∗). Conclusions. Most parents misunderstand the influence of insufficient outdoor sports time and extracurricular classes, which require extra near-vision work. Besides, for parents with low educational background and more myopic SE, their offspring had higher myopia progression and may be the key group for myopia control. Finally, parents may obtain life advice and knowledge related to preventing myopia after their children become myopic. It may be of positive significance if this process could take place before myopia onset.
Purposes:
We aimed to characterize the USH2A genotypic spectrum in a Chinese cohort and provide a detailed genetic profile for Chinese patients with USH2A-IRD.
Methods:
We designed a retrospective ...study wherein a total of 1,334 patients diagnosed with IRD were included as a study cohort, namely 1,278 RP and 56 USH patients, as well as other types of IEDs patients and healthy family members as a control cohort. The genotype-phenotype correlation of all participants with USH2A variant was evaluated.
Results:
Etiological mutations in USH2A, the most common cause of RP and USH, were found in 16.34% (n = 218) genetically solved IRD patients, with prevalences of 14.87% (190/1,278) and 50% (28/56). After bioinformatics and QC processing, 768 distinct USH2A variants were detected in all participants, including 136 disease-causing mutations present in 665 alleles, distributed in 5.81% of all participants. Of these 136 mutations, 43 were novel, nine were founder mutations, and two hot spot mutations with allele count ≥10. Furthermore, 38.5% (84/218) of genetically solved USH2A-IRD patients were caused by at least one of both c.2802T>G and c.8559–2 A>G mutations, and 36.9% and 69.6% of the alleles in the RP and USH groups were truncating, respectively.
Conclusion:
USH2A-related East Asian-specific founder and hot spot mutations were the major causes for Chinese RP and USH patients. Our study systematically delineated the genotype spectrum of USH2A-IRD, enabled accurate genetic diagnosis, and provided East Asian and other ethnicities with baseline data of a Chinese origin, which would better serve genetic counseling and therapeutic targets selection.
Zearalenone (ZEA) is a non-steroidal estrogenic mycotoxin synthesized in Fusarium species, mainly Fusarium graminearum and Fusarium culmorum, and it has strong estrogenic activity and causes ...genotoxic effects, reproductive disorders, and immunosuppressive effects. Neutrophil extracellular trap (NET) has been studied for many years. Initially, NET was considered a form of the innate response that combats invading microorganisms. However, NET is involved in a series of pathophysiological mechanisms, including thrombosis, tissue necrosis, autoinflammation, and even autoimmunity. We recently found that polymorphonuclear neutrophils response to ZEA exposure by undergoing NET formation. However, the molecular mechanisms involved in this process remain poorly characterized. Here, we analyze whether estrogen receptors (ERs) can affect NET formation after ZEA stimulation. The involvement of ERs is investigated with the selective ER antagonists. Moreover, we investigate the mechanisms of NET formation using immunofluorescence staining, fluorescence microplate, and western blot analysis. Our results show that ERs (ERα and ERβ) are not involved in ZEA-induced NET formation, but reactive oxygen species (ROS), extracellular signal-regulated kinase (ERK), and p38 are postulated to be involved. Specifically, we provide data demonstrating that ZEA-induced ROS may promote activation of ERK and p38 as well as subsequent NET release. We are the first to demonstrate this new mechanism of ZEA-induced NET formation, which may help in understanding the role of ZEA in overexposure diseases and provide a relevant basis for therapeutic applications.
Abstract
Introduction: This study analyzed the effectiveness of 650-nm red-light feeding instruments in the control of myopia. Methods: In this study, 164 school-aged participants diagnosed with ...myopia in the city of Shenzhen were enrolled in a red-light feeding instrument study. Of these, 41 were enrolled in the mild-to-moderate myopia group that received red-light feeding (RLMM group), 65 were enrolled in the mild-to-moderate myopia group that received single-vision spectacle treatment (SVSMM group), and 58 were included in the severe myopia group that received red-light feeding (RLS group). Results: After the baseline values of the three groups were matched, the right eye data were used for statistical analysis. The average return visit time of each group was 60.42 days, and changes in the observation indexes before treatment and after follow-up treatment were compared. As the primary outcome, the axial length changes in the right eye of the SVSMM group (0.08 ± 0.40 mm), the RLMM group (−0.03 ± 0.11 mm), and the RLS group (−0.07 ± 0.11 mm) were compared and showed a statistical result of p < 0.001. Conclusion: The study results verified that red light had a noticeable effect on the control of myopia and that low-level red-light therapy played a vital role in the treatment of severe myopia.
The purpose of this study was to describe genotype-phenotype associations and novel insights into genetic characteristics in a trio-based cohort of inherited eye diseases (IEDs).
To determine the ...etiological role of de novo mutations (DNMs) and genetic profile in IEDs, we retrospectively reviewed a large cohort of proband-parent trios of Chinese origin. The patients underwent a detailed examination and was clinically diagnosed by an ophthalmologist. Panel-based targeted exome sequencing was performed on DNA extracted from blood samples, containing coding regions of 792 IED-causative genes and their flanking exons. All participants underwent genetic testing.
All proband-parent trios were divided into 22 subgroups, the overall diagnostic yield was 48.67% (605/1243), ranging from 4% to 94.44% for each of the subgroups. A total of 108 IED-causative genes were identified, with the top 24 genes explaining 67% of the 605 genetically solved trios. The genetic etiology of 6.76% (84/1243) of the trio was attributed to disease-causative DNMs, and the top 3 subgroups with the highest incidence of DNM were aniridia (n = 40%), Marfan syndrome/ectopia lentis (n = 38.78%), and retinoblastoma (n = 37.04%). The top 10 genes have a diagnostic yield of DNM greater than 3.5% in their subgroups, including PAX6 (40.00%), FBN1 (38.78%), RB1 (37.04%), CRX (10.34%), CHM (9.09%), WFS1 (8.00%), RP1L1 (5.88%), RS1 (5.26%), PCDH15 (4.00%), and ABCA4 (3.51%). Additionally, the incidence of DNM in offspring showed a trend of correlation with paternal age at reproduction, but not statistically significant with paternal (P = 0.154) and maternal (P = 0.959) age at reproduction.
Trios-based genetic analysis has high accuracy and validity. Our study helps to quantify the burden of the full spectrum IED caused by each gene, offers novel potential for elucidating etiology, and plays a crucial role in genetic counseling and patient management.
In recent years, numerous studies paid more attention to the molecular mechanisms associated with fluoride toxicity. However, the detailed mechanisms of fluoride immunotoxicity in bovine neutrophils ...remain unclear. Neutrophil extracellular traps (NETs) is a novel immune mechanism of neutrophils. We hypothesized that sodium fluoride (NaF) can trigger NETs activation and release, and investigate the related molecular mechanisms during the process. We exposed peripheral blood neutrophils to 1 mM NaF for 120 min in bovine neutrophils. The results showed that NaF exposure triggered NET-like structures decorated with histones and granule proteins. Quantitative measurement of NETs content correlated positively with the concentration of NaF. Mechanistically, NaF exposure increased reactive oxygen species (ROS) levels and phosphorylation levels of ERK, p38, whereas inhibiting the activities of superoxide dismutase (SOD) and catalase (CAT) compared with control neutrophils. NETs formation is induced by NaF and this effect was inhibited by the inhibitors diphenyleneiodonium chloride (DPI), U0126 and SB202190. Our findings described the potential importance of NaF-triggered NETs related molecules, which might help to extend the current understanding of NaF immunotoxicity.
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•NaF induced NETs formation.•NaF caused imbalance between ROS and antioxidant system.•NaF induced NETs formation via ROS, ERK, and p38 signaling pathways.
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