Parametric analysis of the transmission dynamics during indigenous aggregated outbreaks caused by five SARS-CoV-2 strains in Nanjing, China.

Background: SARS-CoV-2 strains have been of great concern due to their high infectivity and antibody evasion. Methods: In this study, data were collected on indigenous aggregated outbreaks in Nanjing from January 2020 to December 2022, caused by five strains including the original strain, the Delta variant, and the Omicron variant (BA.2, BA.5.2, and BF.7). The basic epidemiological characteristics of infected individuals were described and then parametric analysis of transmission dynamics was performed, including the calculation of incubation period, serial interval (SI), the basic reproductive number (R0), and the household secondary attack rate (HSAR). Finally, we compared the trends of transmission dynamic parameters of different strains. Results: The incubation period for the original strain, the Delta variant, Omicron BA.2, Omicron BA.5.2, and Omicron BF.7 were 6 d (95% CI: 3.5-7.5 d), 5 d (95% CI: 4.0-6.0 d), 3 d (95% CI: 3.0-4.0 d), 3 d (95% CI: 3.0-3.0 d), and 2 d (95% CI: 2.0-3.0 d), respectively; Also, the SI of the five strains were 5.69 d, 4.79 d, 2.7 d, 2.12 d, and 2.43 d, respectively. Notably, the incubation period and SI of the five had both a progressive shortening trend (p < 0.001); Moreover, R0 of the five were 2.39 (95% CI: 1.30-4.29), 3.73 (95% CI: 2.66-5.15), 5.28 (95% CI: 3.52-8.10), 5.54 (95% CI: 2.69-11.17), 7.39 (95% CI: 2.97-18.76), with an increasing trend gradually (p < 0.01); HSAR of the five were 25.5% (95% CI: 20.1-31.7%), 27.4% (95% CI: 22.0-33.4%), 42.9% (95% CI: 34.3-51.8%), 53.1% (95% CI: 45.0-60.9%), 41.4% (95% CI, 25.5-59.3%), also with an increasing trend (p < 0.001). Conclusion: Compared to the original strain, the incubation period and SI decreased while R0 and HSAR increased, suggesting that transmission in the population was faster and the scope of the population was wider. Overall, it's crucial to keep implementing comprehensive measures like monitoring and alert systems, herd immunization plans, and outbreak control.

Repeated COVID-19 Relapse of an Imported Patient Infected with SARS-CoV-2 Delta Variant of Concern.

BACKGROUND: Repeated re-positive of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) B.1.617.2 (Delta) variants of concern (VOC) in recovered coronavirus disease 2019 (COVID-19) patients have not been reported yet. METHODS: We reported a rare case of repeated COVID-19 relapse during the post-discharge surveillance. RESULTS: This case had long-term viral shedding for 79 days. CONCLUSIONS: This case highlights that longer observation and isolation periods need be considered for patients with SARS-CoV-2 delta VOC infection.

Dynamic characteristics of a COVID-19 outbreak in Nanjing, Jiangsu province, China.

Objectives: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lineage B.1.617.2 (also named the Delta variant) was declared as a variant of concern by the World Health Organization (WHO). This study aimed to describe the outbreak that occurred in Nanjing city triggered by the Delta variant through the epidemiological parameters and to understand the evolving epidemiology of the Delta variant. Methods: We collected the data of all COVID-19 cases during the outbreak from 20 July 2021 to 24 August 2021 and estimated the distribution of serial interval, basic and time-dependent reproduction numbers (R0 and Rt), and household secondary attack rate (SAR). We also analyzed the cycle threshold (Ct) values of infections. Results: A total of 235 cases have been confirmed. The mean value of serial interval was estimated to be 4.79 days with the Weibull distribution. The R0 was 3.73 [95% confidence interval (CI), 2.66-5.15] as estimated by the exponential growth (EG) method. The Rt decreased from 4.36 on 20 July 2021 to below 1 on 1 August 2021 as estimated by the Bayesian approach. We estimated the household SAR as 27.35% (95% CI, 22.04-33.39%), and the median Ct value of open reading frame 1ab (ORF1ab) genes and nucleocapsid protein (N) genes as 25.25 [interquartile range (IQR), 20.53-29.50] and 23.85 (IQR, 18.70-28.70), respectively. Conclusions: The Delta variant is more aggressive and transmissible than the original virus types, so continuous non-pharmaceutical interventions are still needed.

The latent period of coronavirus disease 2019 with SARS-CoV-2 B.1.617.2 Delta variant of concern in the postvaccination era.

INTRODUCTION: Emerging variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have resulted in new challenges for epidemic prevention and control worldwide. However, little is known about the latent period of coronavirus disease by the SARS-CoV-2 Delta variant of concern (VOC) in the postvaccination era. METHODS: The epidemiology and clinical data of cases with confirmed SARS-CoV-2 Delta VOC infection were retrospective collected. Dates of the first positive PCR test were collected to estimate the distribution of latent period. RESULTS: Of the 40 patients, 16 were male (40%). The median age of patients was 47.5 years. The median latent period of patients was 6.0 days (interquartile range [IQR], 4.0-9.0 days) and the longest latent period was 13.0 days after exposure. The latent periods were longer in male patients compared to female patients (median, 8.5 days vs. 5.0 days, p = .041). The median latent period was comparable among fully vaccinated cases (6.5 days), no vaccinated cases (7.5 days), and partially vaccinated cases (5.5 days). CONCLUSIONS: The median latent period of SARS-CoV-2 Delta VOC infection was 6.0 days. The latent period between vaccinated and non-vaccinated patients was not significantly different. The 14-day quarantine program is sufficient to prevent the transmission of COVID-19 by Delta VOC in the postvaccination era.

Cypermethrin induces Sertoli cell apoptosis through mitochondrial pathway associated with calcium.

Cypermethrin, one kind of pyrethroid pesticides, has been shown to act as endocrine-disrupting chemicals (EDCs). The purpose of this study was to explore the roles of Sertoli cell apoptosis through mitochondrial pathway associated with calcium (Ca2+) in cypermethrin-induced male reproductive toxicology. The mouse Sertoli cells TM4 were cultured with 0 µM, 10 µM, 20 µM, 40 µM and 80 µM of cypermethrin. We used flow cytometry, Fluo-4 AM, western blot and JC-1 Assay Kit to examine apoptosis, intracellular Ca2+, expressions of mitochondrial apoptotic pathway-related proteins and mitochondrial membrane potential. We found cypermethrin increased apoptosis rate of TM4 cells significantly and with a significant increase in intracellular Ca2+ concentration. Cypermethrin significantly decreased the protein expressions of cytosolic B-cell lymphoma-2 (Bcl-2) and mitochondrial cytochrome c (Cyt-c). The protein expressions of cytosolic Bcl-2-associated x (Bax), Cyt-c, cleaved caspase-3, calmodulin (CaM), Ca2+/CaM-dependent protein kinases II (CaMKII) and phosphorylated CaMKII were increased significantly in cypermethrin-exposed TM4 cells. Cypermethrin decreased mitochondrial membrane potential significantly. Then, Bcl-2 family and Ca2+/CaM/CaMKII pathway participate in cypermethrin-induced homeostasis. Ca2+ overload activates mitochondrial pathway by increasing permeability of mitochondrial membrane and decreasing mitochondrial membrane potential. We suggest cypermethrin induces Sertoli cell apoptosis involving mitochondrial pathway associated with Ca2+ regulated by Bcl-2 family and Ca2+/CaM/CaMKII pathway. The study provides a new insight into mechanisms involved in cypermethrin-induced male reproductive toxicology.

Effects and mechanisms of pyrethroids on male reproductive system.

Synthetic pyrethroids are used as insecticides in agriculture and a variety of household applications worldwide. Pyrethroids are widely distributed in all environmental compartments and the general populations are exposed to pyrethroids through various routes. Pyrethroids have been identified as endocrine-disrupting chemicals (EDCs) which are responsible for the male reproductive impairments. The data confirm pyrethroids cause male reproductive damages. The insecticides exert the toxic effects on male reproductive system through various complex mechanisms including antagonizing androgen receptor (AR), inhibiting steroid synthesis, affecting the hypothalamic-pituitary-gonadal (HPG) axis, acting as estrogen receptor (ER) modulators and inducing oxidative stress. The mechanisms of male reproductive toxicity of pyrethroids involve multiple targets and pathways. The review will provide further insight into pyrethroid-induced male reproductive toxicity and mechanisms, which is crucial to preserve male reproductive health.

The anti-androgenic effects of cypermethrin mediated by non-classical testosterone pathway activation of mitogen-activated protein kinase cascade in mouse Sertoli cells.

Previous studies have demonstrated that the anti-androgenic effects of cypermethrin (CYP) are associated with testosterone (T) - related signaling pathway. This study was to investigate the effects of CYP on mouse Sertoli cells (TM4) and clarify whether the mechanisms were mediated by non-classical T signaling pathway activating mitogen-activated protein kinase (MAPK) cascade. The Cell Counting Kit 8 (CCK8) and Real-Time Cell Analysis iCELLigence (RTCA-iCELLigence) system were performed to detect the effects of 10 µM, 20 µM, 40 µM and 80 µM CYP on the viability and proliferation of TM4. The mammalian two hybrid assay, quantitative Real-Time PCR (qRT-PCR) and western blot were conducted to analyze the key genes and proteins involved in T-mediated MAPK signaling pathway. CYP was found to inhibit the viability and proliferation of TM4. Additionally, CYP disturbed the functions of Sertoli cells by inhibiting inhibin B (INH B) expression and facilitating androgen binding protein (ABP) and transferrin (TF) expression. Moreover, CYP suppressed the interaction of AR and Src kinase and inhibited androgen-mediated phosphorylation of Src, epidermal growth factor receptor (EGFR), extracellular-regulated kinase1/2 (ERK1/2) and transcription factor cAMP response element binding protein (CREB). Furthermore, the androgen-induced mRNA and protein expression of CREB-regulated gene early growth response factor (Egr1) decreased after treated with CYP. It is indicated that CYP inhibits the viability and proliferation of Sertoli cells and non-classical T signaling pathway activation of MAPK cascade is involved in anti-androgenic effect of CYP. This study provides a novel insight into the CYP-induced reproductive toxicity.

Targeting YOD1 by RNA Interference Inhibits Proliferation and Migration of Human Oral Keratinocytes through Transforming Growth Factor-ß3 Signaling Pathway.

OBJECTIVE: We have identified a gene YOD1 encoding deubiquitinating enzyme (DUB) responsible for nonsyndromic cleft lip with or without cleft palate (NSCL/P). We aimed to determine the effects of YOD1 RNA interference (RNAi) on cell proliferation and migration, playing an important role in lip and palate formation, and to clarify whether the mechanisms involved TGF-ß3 signaling associated with NSCL/P. METHODS: RNAi was applied to construct vectors expressing YOD1 small interference RNAs (siRNAs). The vectors were transfected into the human oral keratinocytes (HOK) cells. The cell proliferation and migration were evaluated by the cell counting kit-8 (CCK-8) assay and wound healing assay, respectively. The mRNA levels were detected by quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR). The protein levels were investigated by western blotting. RESULTS: The proliferation of YOD1 siRNA-transfected HOK cells was remarkably inhibited. The migration rate was significantly decreased in the YOD1 siRNA-transfected HOK cells. The TGF-ß3 mRNA and protein levels were decreased significantly by siRNA-mediated knockdown of YOD1. YOD1 RNAi reduced the phosphor-Smad2/3 levels significantly. CONCLUSIONS: YOD1 RNAi may inhibit cell proliferation and migration associated with the pathogenesis of NSCL/P through TGF-ß3 signaling. The study indicates a novel role of YOD1 in regulating TGF-ß3 signaling to affect cell proliferation and migration resulting in NSCL/P.

Identification of key genes in cleft lip with or without cleft palate regulated by miR-199a-5p.

BACKGROUND: Cleft lip with or without cleft palate (CL/P) is one of the most common congenital defects, which etiology involves both genetic and environmental factors. Previous studies have shown that miR-199a-5p may mediate the occurrence of CL/P. However, the key target genes regulated by miR-199a-5p are not clear. In this study, we employed a systematic bioinformatics analysis of target genes regulated by miR-199a-5p which may be involved in CL/P. METHODS: The miRBase, Human miRNA tissue atlas, miRecords, miRpathDB, miRWalk, miRTarBase, DIANA-TarBase (v7.0), Literature search, DAVID software, Cytoscape plugin ClueGO + Cluepedia app, MalaCards, TargetScanhuman7.1, Venny 2.1, STRING and GEO databases were comprehensive employed to identify the key genes regulated by miR-199a-5p associated with CL/P. RESULTS: Total 429 experimentally validated target genes were obtained from five miRNAs related databases. Expressions of miR-199a-5p and its experimentally validated target genes were elevated in bone, brain and skin. KEGG pathway analysis revealed that the target genes were enriched in focal adhesion, microRNAs in cancer and hippo signaling pathway. Biological process categorization revealed that significant portions of the target genes were grouped as transcription, DNA-templated. Total eight intersection genes were identified by using MalaCards and TargetScanhuman7.1. The target gene transforming growth factor alpha (TGFA) of miR-199a-5p involved in CL/P is screened and verified. CONCLUSION: MiR-199a-5p may mediate CL/P by regulating key target gene TGFA. The study may contribute to a better understanding of the etiology of CL/P.

Association Between CRISPLD2 Polymorphisms and the Risk of Nonsyndromic Clefts of the Lip and/or Palate: A Meta-analysis.

OBJECTIVE: Nonsyndromic clefts of the lip and/or palate (NSCL/P) are one of the most common polygenic diseases. Recently, many studies focused on the association between CRISPLD2 polymorphisms and NSCL/P risk. However, some studies have shown opposite results. In this study, meta-analysis was used to confirm whether CRISPLD2 polymorphism was associated with NSCL/P, and the possible mechanism between CRISPLD2 and NSCL/P was explored. METHODS: Relevant studies were conducted on PubMed, Ovid, EBSCO, CINAHL, FMRS, Web of Science, CNKI, and Wanfang databases from their inception up to June 31, 2016. Review Manager 5.0.24 was used to analyze whether CRISPLD2 polymorphism was involved in NSCL/P by pooling odds ratios (ORs) and 95% confidence intervals (CIs). Potential publication bias was evaluated by visual inspection of the funnel plot. RESULTS: CRISPLD2 rs4783099 was associated with cleft lip and/or palate (CL/P) statistically (OR = 3.18, P < .01). Compared to genotype TT, genotypes CC and CT were correlated significantly (OR = 2.04, P = .04) with CL/P. No evidence showed an association between genetic variation at the CRISPLD2 locus and cleft palate only (CP). CONCLUSION: The polymorphism of CRISPLD2 rs4783099 is correlated with an increased risk of CL/P.

Association of androgen receptor gene CAG and GGN repeat polymorphism with cryptorchidism: A meta-analysis.

Researches on association between variations in the androgen receptor (AR) gene repeat polymorphisms and cryptorchidism (CO) had conflicting results. The aim of this meta-analysis was to analyse the potential effects of AR CAG and/or GGN repeat polymorphism on CO. Studies were independently appraised by two investigators on PubMed, Web of Science, EBSCO databases and Foreign Medical Retrieval System. Case-control studies with measurement of CAG and/or GGN repeat length were included. Weighted mean difference (WMD) and 95% confidence intervals (CIs) for the CAG or GGN repeat polymorphism and CO were calculated. Five reports were included in this analysis. Overall, no difference was identified between patients and fertile men in CAG repeat length. However, when the CO was divided into unilateral and bilateral, longer CAG repeat region was significantly associated with CO in bilateral group (WMD = 0.74; 95% CI, 0.01-1.47; p < .05). In addition, GGN lengths were significantly higher in patients compared with those in controls (WMD = 1.17; 95% CI, 0.28-2.06; p < .05). No obvious effect was found in the GGN length when compared unilateral or bilateral group with control respectively. The results in this meta-analysis indicated that AR CAG and GGN repeat polymorphisms may be an important pathogenesis of CO.

Cypermethrin inhibits interleukin-6-induced androgen receptor transactivation through signal transducer and activator of transcription 3.

The insecticide cypermethrin has been considered as an endocrine-disrupting chemicals (EDCs) with anti-androgenic activity by interfering with interleukin-6 (IL-6) - induced ligand-independent AR signaling. The purpose of this study was to clarify whether the signal transducer and activator of transcription 3 (STAT3) was involved in the antagonism effect of cypermethrin. In this study, the Western blot was to test the level of STAT3 phosphorylation and the mammalian two-hybrid assay was developed to assess the AR-STAT3 interaction. The date showed that IL-6 increased the phosphorylation level of STAT3 and enhanced the AR-STAT3 interaction. Cypermethrin did not affect the phosphorylation level of STAT3 induced by IL-6, while suppressed the AR-STAT3 interaction induced by IL-6 significantly at the concentration of 10-5 M (p < 0.05). The study indicates cypermethrin inhibits IL-6-induced AR signaling by suppressing the interaction between the AR and STAT3. We provide a novel mechanism of cypermethrin-mediated antagonism on IL-6-induced AR activation associated with STAT3.

Anti-androgenic mechanisms of Bisphenol A involve androgen receptor signaling pathway.

We have shown Bisphenol A (BPA) acts as an androgen receptor (AR) antagonist in the previous study. However, the mechanisms underlying anti-androgenic effects of BPA remain unclear. The objective of this study was to explore whether the AR signaling was involved in AR antagonism of BPA. The Cell Counting Kit-8 (CCK-8) assay and Real-Time Cell Analysis (RTCA) iCELLigence system were applied to analyze the mouse Sertoli cell TM4 proliferation. The mammalian two-hybrid assays were performed to investigate the effects of BPA on the AR amino- and carboxyl-terminal regions (N/C) interaction and the interactions of the AR with steroid receptor coactivator-1 (SRC-1), co-repressors including silencing mediator for thyroid hormone receptors (SMRT) and nuclear receptor co-repressor (NCoR). BPA exposure resulted in decreased TM4 cell proliferation. BPA inhibited the AR N/C interaction significantly. Furthermore, BPA enhanced the interactions of AR-SMRT and AR-NCoR significantly. In conclusion, these data suggest BPA inhibits Sertoli cell proliferation due to its anti-androgenic actions. The mechanisms responsible for AR antagonism of BPA involve inhibiting the AR N/C interaction and enhancing the interactions of AR-SMRT and AR-NCoR. The data uncover novel anti-androgenic mechanisms by which BPA antagonizes AR signaling, contributing to Sertoli cell proliferation suppression and male reproductive toxicology.