Search

Abstract Background Indoor environmental factors, such as pet ownership, presence of cockroaches, mattress quality, fuel usage (gas or electricity), use of biomass for cooking and heating, exposure to tobacco smoke or household molds can significantly affect the sleep quality of children with chronic cough. However, data regarding the effects of indoor environmental conditions on sleep in this population are limited. This study aimed to assess the prevalence of abnormal sleep behaviors and to establish associations between indoor environmental factors and sleep behaviors among children with chronic cough in Wuxi, China. Methods A cross-sectional design was employed in this study, involving children aged 3–18 years. Data on sociodemographic factors, allergies, home environmental exposures, and sleep characteristics of the participants were collected using paper-based questionnaires. The association between indoor environmental factors and sleep behaviors in children with chronic cough was analyzed using logistic regression models. Results The findings demonstrated that the prevalence of chronic cough among children in Wuxi was 15.50%. The chronic cough group exhibited a significantly higher incidence of eczema, wheezing, rhinitis, food allergy, and nasosinusitis than the non-chronic cough group. In addition, children with chronic cough also tended to have a family history of sleep disorders and adenoid hypertrophy (P

Abstract Epigenetic mechanisms such as DNA methylation and hydroxymethylation play a significant role in depression. This research has shown that Ten‐eleven translocation 2 (Tet2) deficiency prompts depression‐like behaviors, but Tet2's transcriptional regulation remains unclear. In the study, bioinformatics is used to identify nuclear receptor subfamily 2 group E member 3 (Nr2e3) as a potential Tet2 regulator. Nr2e3 is found to enhance Tet2's transcriptional activity by binding to its promoter region. Nr2e3 knockdown in mouse hippocampus leads to reduced Tet2 expression, depression‐like behaviors, decreased hydroxymethylation of synaptic genes, and downregulation of synaptic proteins like postsynaptic density 95 KDa (PSD95) and N‐methy‐d‐aspartate receptor 1 (NMDAR1). Fewer dendritic spines are also observed. Nr2e3 thus appears to play an antidepressant role under stress. In search of potential treatments, small molecule compounds to increase Nr2e3 expression are screened. Azacyclonal (AZA) is found to enhance the Nr2e3/Tet2 pathway and exhibited antidepressant effects in stressed mice, increasing PSD95 and NMDAR1 expression and dendritic spine density. This study illuminates Tet2's upstream regulatory mechanism, providing a new target for identifying early depression biomarkers and developing treatments.

Abstract Vericiguat (Verquvo; US: Merck, other countries: Bayer) is a novel drug for the treatment of chronic heart failure. Preclinical studies have demonstrated that the primary route of metabolism for vericiguat is glucuronidation, mainly catalyzed by uridine diphosphate‐glucuronosyltransferase (UGT)1A9 and to a lesser extent UGT1A1. Whereas a drug–drug interaction (DDI) study of the UGT1A9 inhibitor mefenamic acid showed a 20% exposure increase, the effect of UGT1A1 inhibitors has not been assessed clinically. This modeling study describes a physiologically‐based pharmacokinetic (PBPK) approach to complement the clinical DDI liability assessment and support prescription labeling. A PBPK model of vericiguat was developed based on in vitro and clinical data, verified against data from the mefenamic acid DDI study, and applied to assess the UGT1A1 DDI liability by running an in silico DDI study with the UGT1A1 inhibitor atazanavir. A minor effect with an area under the plasma concentration‐time curve (AUC) ratio of 1.12 and a peak plasma concentration ratio of 1.04 was predicted, which indicates that there is no clinically relevant DDI interaction anticipated. Additionally, the effect of potential genetic polymorphisms of UGT1A1 and UGT1A9 was evaluated, which showed that an average modest increase of up to 1.7‐fold in AUC may be expected in the case of concomitantly reduced UGT1A1 and UGT1A9 activity for subpopulations expressing non‐wild‐type variants for both isoforms. This study is a first cornerstone to qualify the PK‐Sim platform for use of UGT‐mediated DDI predictions, including PBPK models of perpetrators, such as mefenamic acid and atazanavir, and sensitive UGT substrates, such as dapagliflozin and raltegravir.

Objective To analyze differences in the indicator framework of the Global Health Security Index (GHSI) and the scores of GHSI indicators for 195 contracting countries of International Health Regulations 2005 (IHR2005) between 2019 and 2021. Methods Yearly GHSI evaluation reports and the data on 195 contracting countries of IHR2005 on GHSI indicator scores for years of 2019 and 2021 were downloaded from official GHSI website (https://www.ghsindex.org) and changes in GHSI indicator framework and contracting country-specific scores of GHSI indicators were analyzed. Paired T-test was used to compare between-year differences in and correlations of country-specific scores of GHSI indicators. General linear regression was adopted to assess the collinearities and correlations between total score and scores of primary/secondary indicators of GHSI for 195 contracting countries of IHR2005 in 2021. ResultsIn 2021, the average GHSI score was 38.9 (in a scale with 5 categories and the maximum score of 100) for the 195 contracting countries of IHR2005 nearly the same as that (40.2) of 2019; none of the 195 contracting countries was assessed as having the GHSI score of the optimum grade (the scores of > 80) and 66.7% of the countries were scored below 40, with a median score of 34.9. Compared to that of 2019, the GSHI 2021 index framework was supplemented with 3 secondary indicators, 11 tertiary indicators, and 31 questions. The results of paired T-test showed that the average score of GHSI for the 195 contracting countries in 2021 was increased by 0.1 point against that of 2019, but the difference was not statistically significant (P > 0.05). In comparison with those in 2019, following average scores decreased significantly for primary indicators of preventing the emergence or spread of pathogens (reduced by 0.6, t = – 2.413; P < 0.05) and rapidly responding to/reducing disease transmission (by 4.0, t = – 9.402; P < 0.05), secondary indicators of zoonosis prevention (by 4.8, t = – 6.590; P < 0.001) and trade and travel restrictions (by 58.3, t = – 33.158; P < 0.001). There were strong correlations between country-specific scores of secondary indicators of 2019 and those of 2021, except for the score of trade and travel restrictions (r = 0.117) and the score of implementing response plan (r = 0.237) . General linear regression analysis showed that there was no collinearity among the country-specific scores of 6 primary indicators in 2021, but the total scores of all indicators were significantly correlated with the scores of 6 primary indicators (P < 0.05 for all). Conclusion Based on the assessment using GHSI scores, none of the 195 IHR2005 contracting countries is well prepared for the next probable disease pandemic and the ability to prevent and respond to public health emergencies needs to be improved for the countries.

Abstract Background The two inactivated SARS-CoV-2 vaccines, CoronaVac and BBIBP-CorV, have been widely used to control the COVID-19 pandemic. The influence of multiple factors on inactivated vaccine effectiveness (VE) during long-term use and against variants is not well understood. Methods We selected published or preprinted articles from PubMed, Embase, Scopus, Web of Science, medRxiv, BioRxiv, and the WHO COVID-19 database by 31 August 2022. We included observational studies that assessed the VE of completed primary series or homologous booster against SARS-CoV-2 infection or severe COVID-19. We used DerSimonian and Laird random-effects models to calculate pooled estimates and conducted multiple meta-regression with an information theoretic approach based on Akaike’s Information Criterion to select the model and identify the factors associated with VE. Results Fifty-one eligible studies with 151 estimates were included. For prevention of infection, VE associated with study region, variants, and time since vaccination; VE was significantly decreased against Omicron compared to Alpha (P = 0.021), primary series VE was 52.8% (95% CI, 43.3 to 60.7%) against Delta and 16.4% (95% CI, 9.5 to 22.8%) against Omicron, and booster dose VE was 65.2% (95% CI, 48.3 to 76.6%) against Delta and 20.3% (95% CI, 10.5 to 28.0%) against Omicron; primary VE decreased significantly after 180 days (P = 0.022). For the prevention of severe COVID-19, VE associated with vaccine doses, age, study region, variants, study design, and study population type; booster VE increased significantly (P = 0.001) compared to primary; though VE decreased significantly against Gamma (P = 0.034), Delta (P = 0.001), and Omicron (P = 0.001) compared to Alpha, primary and booster VEs were all above 60% against each variant. Conclusions Inactivated vaccine protection against SARS-CoV-2 infection was moderate, decreased significantly after 6 months following primary vaccination, and was restored by booster vaccination. VE against severe COVID-19 was greatest after boosting and did not decrease over time, sustained for over 6 months after the primary series, and more evidence is needed to assess the duration of booster VE. VE varied by variants, most notably against Omicron. It is necessary to ensure booster vaccination of everyone eligible for SARS-CoV-2 vaccines and continue monitoring virus evolution and VE. Trial registration PROSPERO, CRD42022353272.

Photobiomodulation (PBM), as a form of light therapy, has been applied broadly in the medical practice. The biological photoreceptors use small-molecule cofactors called chromophores to detect light and convert a physical signal into a biochemical signal transmission cascade. Visible light (380–780 nm) can activate specialized photoreceptors to stimulate vision and regulate circadian rhythm. Compared with visible light, near-infrared (NIR) light (780–1,100 nm) has better tissue penetration depths, enabling us to carry out non-invasive low-level laser therapy (LLLT) for different tissues. Mitochondrial cytochrome c oxidase is the main NIR photoreceptor. The basic effect is to promote the generation of ATP through the respiratory chain. LLLT can enhance blood circulation, alleviate inflammation, promote muscle damage repair, stem cell proliferation and so on. The neuroprotective effect of LLLT on central nervous system (CNS) diseases has been preliminarily verified in animal models, which is expected to improve the cognitive function of Alzheimer’s patients, motor symptoms of Parkinson’s patients and mental disorders of patients with depression, thus improving the quality of life of patients. Understanding its protective effect and mechanisms will contribute to better therapeutic application in the future. In this review, we will discuss the antidepressant effect of LLLT, its possible mechanisms, and existing problems with its applications.

Electronic cigarette (e-cigarette) use is becoming more widespread, and studies show that they are not absolutely harmless. To investigate the association between the dual use of e-cigarettes and marijuana with sleep duration among adults in the United States, this cross-sectional study used data from 6,573 participants aged 18–64 years from 2015 to 2018 from the National Health and Nutrition Examination Survey database. Chi-square tests and analysis of variance were used for bivariate analyses of binary and continuous variables, respectively. Multinomial logistic regression models were used for univariate and multivariate analyses of e-cigarette use, marijuana use, and sleep duration. Sensitivity analyses were conducted in populations with dual e-cigarette and traditional cigarette use and dual marijuana and traditional cigarette use. People who concurrently use e-cigarettes and marijuana had higher odds of not having the recommended sleep duration than neither users (short sleep duration: odds ratio [OR], 2.34; 95% confidence interval [CI], 1.19–4.61; P = 0.014; long sleep duration: OR, 2.09; 95% CI, 1.53–2.87; P

Cancer and microbial infections are significant worldwide health challenges. Numerous studies have demonstrated that bacteria may contribute to the emergence of cancer. In this review, we assemble bacterial species discovered in various cancers to describe their variety and specificity. The relationship between bacteria and macrophages in cancer is also highlighted, and we look for ample proof to establish a biological basis for bacterial-induced macrophage polarization. Finally, we quickly go over the potential roles of metabolites, cytokines, and microRNAs in the regulation of the tumor microenvironment by bacterially activated macrophages. The complexity of bacteria and macrophages in cancer will be revealed as we gain a better understanding of their pathogenic mechanisms, which will lead to new therapeutic approaches for both inflammatory illnesses and cancer.

Abstract Background The MYC oncoprotein, also known as the master regulator of genes, is a transcription factor that regulates numerous physiological processes, including cell cycle control, apoptosis, protein synthesis and cell adhesion, among others. MYC is overexpressed in approximately 70% of human cancers. Given its pervasive role in cancer biology, MYC down‐regulation has become an attractive cancer treatment strategy. Methods The CRISPR/Cas9 method was used to produce KO cell models. Western blot was used to analyzed the expressions of MYC and TATA‐binding proteinassociated factors 10 (TAF10) in cancer cells (MCF7, A549, HepG2 cells) Cell culture studies were performed to determine the mechanisms by which small molecules (Z363119456, Z363) affects MYC and TAF10 expressions and functions. Mouse studies were carried out to investigate the impact of Z363 regulation on tumor growth. Results Z363 activate Thyroid hormone Receptor‐interacting Protein 12 (TRIP12), which phosphorylates MYC at Thr58, resulting in MYC ubiquitination and degradation and thereby regulating MYC target genes. Importantly, TRIP12 also induces TAF10 degradation, which reduces MYC protein levels. TRIP12, an E3 ligase, controls MYC levels both directly and indirectly by inhibiting MYC or TAF10 activity. Conclusions In summary,these results demonstrate the anti‐cancer properties of Z363, a small molecule that is co‐regulated by TAF10 and MYC.

Abstract Neutrophils release neutrophil extracellular traps (NETs), via NETosis, as a defense mechanism against pathogens. Neutrophils can release NETs spontaneously; however, the mechanisms underlying spontaneous NETosis remain unclear. Neutrophils isolated from healthy donors were tested for NET formation and autophagy at 1, 6, 12, and 24 h after incubation. Autophagy response was evaluated in response to various autophagy inducers and inhibitors. The relationship between autophagy and NETosis was detected in vivo using an ovalbumin-induced mouse model of asthma. We found that the increase in the proportion of spontaneous NETosis was time-dependent. The number of autophagy-positive cells also increased over time and LC3B protein played an integral role in NET formation. Trehalose (an inducer of mTOR-independent autophagy) treatment significantly increased NET formation, whereas rapamycin (an mTOR-dependent autophagy inducer) did not increase NET release by neutrophils. Compared with the control group, 3-methyladenine (an autophagy sequestration inhibitor) and hydroxychloroquine sulfate (autophagosome-lysosome fusion inhibitor) treatments significantly reduced the percentage of NET-positive cells. In vivo studies on ovalbumin-induced asthma lung sections revealed NETs and LC3B and citH3 proteins were found to co-localize with DNA. Our findings suggest that autophagy plays a crucial role in aging-related spontaneous NETosis.

SNAREs (soluble N-ethylmaleimide-sensitive-factor attachment protein receptors) are engines for almost all of the membrane fusion and exocytosis events in organism cells. In this study, we identified 84 SNARE genes from banana (Musa acuminata). Gene expression analysis revealed that the expression of MaSNAREs varied a lot in different banana organs. By analyzing their expression patterns under low temperature (4 °C), high temperature (45 °C), mutualistic fungus (Serendipita indica, Si) and fungal pathogen (Fusarium oxysporum f. sp. Cubense Tropical Race 4, FocTR4) treatments, many MaSNAREs were found to be stress responsive. For example, MaBET1d was up-regulate by both low and high temperature stresses; MaNPSN11a was up-regulated by low temperature but down-regulated by high temperature; and FocTR4 treatment up-regulated the expression of MaSYP121 but down-regulated MaVAMP72a and MaSNAP33a. Notably, the upregulation or downregulation effects of FocTR4 on the expression of some MaSNAREs could be alleviated by priorly colonized Si, suggesting that they play roles in the Si-enhanced banana wilt resistance. Foc resistance assays were performed in tobacco leaves transiently overexpressing MaSYP121, MaVAMP72a and MaSNAP33a. Results showed that transient overexpression of MaSYP121 and MaSNPA33a suppressed the penetration and spread of both Foc1 (Foc Race 1) and FocTR4 in tobacco leaves, suggesting that they play positive roles in resisting Foc infection. However, the transient overexpression of MaVAMP72a facilitated Foc infection. Our study can provide a basis for understanding the roles of MaSNAREs in the banana responses to temperature stress and mutualistic and pathogenic fungal colonization.

Abstract Background Sleep-disordered breathing (SDB) is a common syndrome in children, related to their immune responses, cardiovascular function, and neurocognitive function. This study aimed to determine the prevalence of SDB among children in Wuxi, China, and to evaluate the protective and risk factors of SDB in children. Methods A cross-sectional study was conducted on children attending different schools across Wuxi, China, aged 3–14 years old. Of a total of 5630 questionnaires distributed to the parents of the children, 3997 (71.0%) were deemed to be valid. The data on the general sociodemographic factors, children’s allergy and sleep characteristics, and the parents’ sleep characteristics were also collected. The Paediatric Sleep Questionnaire (PSQ) score was used to identify children at high risk of SDB. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression. Results The prevalence of SDB in this cohort was 13.4% (N = 534). SDB prevalence significantly differed in children with asthma (28.2% vs. 12.8%, P

Abstract Background Pseudorabies virus (PRV, or suid herpesvirus, SuHV-1), a member of the herpesvirus family, has an extremely broad host range and threatens the pig industry in China. PRV can evade host innate immunity and infect the kidney, lung, brain and other tissues. At the same time, many studies have reported that microRNA (miRNA) can affect the replication of viruses by regulating gene expression levels. Results Here, to identify changes in miRNA expression and post-transcriptional regulation associated with PRV infection in the lung, spleen, and olfactory bulb, we sequenced small RNAs in tissues of rats infected or uninfected with PRV strain XJ (PRV-XJ). Sixty-one, 199 and 29 differentially-expressed miRNAs were identified in the lung, spleen, and olfactory bulb, respectively, of infected compared with uninfected rats. Among the miRNAs differentially-expressed in PRV-infected rats, 36, 171, and 15 miRNAs showed tissue-selective expression in the olfactory bulb, lung and spleen, respectively. All differentially-expressed miRNAs were analyzed for their GO functional annotations and KEGG pathway associations . Conclusions In PRV-XJ-infected rats, miRNAs were differentially expressed in the lung, spleen and olfactory bulb. These miRNAs were involved in regulating various pathways of the nervous, respiratory and immune systems, and may affect the tissue tropism of the virus and play pivotal roles in viral infection and proliferation.

Inflammation underlies a variety of physiological and pathological processes and plays an essential role in shaping the ensuing adaptive immune responses and in the control of pathogens. However, its physiological functions are not completely clear. Using a LPS-treated RAW264.7 macrophage inflammation model, we found that the production of inflammatory cytokines in ISOC1-deficient cells was significantly higher than that in the control group. It was further proved that ISOC1 deficiency could activate AKT1, and the overactivation of AKT1 could reduce the stability of PEX11B through protein modification, thereby reducing the peroxisome biogenesis and thus affecting inflammation. In this study, we reported for the first time the role of ISOC1 in innate immunity and elucidated the mechanism by which ISOC1 regulates inflammation through AKT1/PEX11B/peroxisome. Our results defined a new role of ISOC1 in the regulatory mechanism underlying the LPS-induced inflammatory response.

Breast cancer is one of the leading causes of death worldwide, and synthetic chemicals targeting specific proteins or various molecular pathways for tumor suppression, such as ERK inhibitors and degraders, have been intensively investigated. The targets of ERK participate in the regulation of critical cellular mechanisms and underpin the progression of anticancer therapy. In this study, we identified a novel small molecule, which we named Z734, as a new mitogen–activated protein kinase 1 (ERK2) degrader and demonstrated that Z734 inhibits cell growth by inducing p53–mediated apoptotic pathways in human breast cancer cells. Treatment with Z734 resulted in the inhibition of cancer cell proliferation, colony formation and migration invasion, as well as cancer cell death via apoptosis. In addition, the Co–IP and GST pulldown assays indicated that the HECT and RLD domains containing E3 ubiquitin protein ligase 3 (HERC3) could directly interact with ERK2 through the HECT domain, promoting ERK2 ubiquitination. We also observed a strong link between HERC3 and p53 for the modulation of apoptosis. HERC3 can increase the protein and phosphorylation levels of p53, which further promotes apoptotic activity. In a xenograft mouse model, the effect was obtained in a treatment group that combined Z734 with lapatinib compared with that of the single–treatment groups. In summary, our results indicated that Z734 actively controls the development of breast cancer through apoptosis, and HERC3 may mediate ERK2 and p53 signaling, which offers new potential targets for clinical therapy.

Summary: Recently, COVID-19 caused by the novel coronavirus SARS-CoV-2 has brought great challenges to the world. More and more studies have shown that patients with severe COVID-19 may suffer from cytokine storm syndrome; however, there are few studies on its pathogenesis. Here we demonstrated that SARS-CoV-2 coding protein open reading frame 8 (ORF8) acted as a contributing factor to cytokine storm during COVID-19 infection. ORF8 could activate IL-17 signaling pathway and promote the expression of pro-inflammatory factors. Moreover, we demonstrated that treatment of IL17RA antibody protected mice from ORF8-induced inflammation. Our findings are helpful to understand the pathogenesis of cytokine storm caused by SARS-CoV-2 and provide a potential target for the development of COVID-19 therapeutic drugs.

Abstract. Retinitis pigmentosa (RP), a major cause of inherited blindness worldwide, is highly heterogeneous. This study aimed to identify mutations in a Chinese cohort of sporadic probands with presumptive RP. Whole exome sequencing represents a considerable advancement in the identification of mutations associated with Mendelian diseases, such as RP. In this study, whole exome sequencing analysis was performed in a Chinese cohort of 95 sporadic probands who were initially diagnosed with RP, in order to identify disease mutations. All detected variations were confirmed by direct Sanger sequencing, and potential pathogenicity was assessed by predictions of the mutations’ functions. The overall mutation rate of presumptive RP genes for this cohort was 30.5% (n = 29 of 95 probands). Forty-four mutations were identified in 19 RP genes, among which 40 mutations were novel. Eleven probands carried mutations in autosomal dominant genes (38.0%), 16 probands carried mutations in autosomal recessive genes (55.2%), and 2 probands carried mutations in X-linked genes (6.9%). Twenty-eight mutations in 18 genes linked to other retinal diseases in 23 probands were also identified. Overall, mutations were detected in 52 probands (54.7%). The recurrent and novel mutations reported here will expand potential understanding of the pathogenesis of RP and other retinal diseases.

Background: Hydroxy-carboxylic acid receptor 2 (HCA2, also called GPR109A) belongs to the G protein-coupled receptor (GPCR) family and is found in humans, rats, mice, hamsters and guinea pigs, but there are almost no reports of this protein in other species. In this investigation, we speculated that AMP010014A09 (AMP+) is a homologue of GPR109A in swine. Methods: To test this hypothesis, the following experiments were designed: monocytes isolated from the peripheral blood of swine were treated with LPS after pretreating with or without β-hydroxybutyric acid (BHBA), and the levels of pro-inflammatory cytokines and inflammatory proteins were assessed. cAMP levels induced by Forskolin in swine testicular (ST) and IPEC-J2 cells were detected with or without BHBA treatment and following silencing or stable transfection of the AMP+ gene. Results: AMP+ in swine exhibited a high level of homology with HM74A in humans and PUMA-G in mice. BHBA inhibited the LPS-induced secretion of the pro-inflammatory cytokines TNF-α, IL-6 and IL-1β and the inflammatory protein COX-2 in monocytes of swine. BHBA suppressed the Forskolin-induced cAMP level increase in ST cells, but failed to inhibit the accumulation of cAMP after the AMP+ gene was silenced with shRNA by transfecting cells with the pGPU6-GFP-Neo-AMP+-sus-392 plasmid. BHBA had no effect on cAMP levels in IPEC-J2 cells, but significantly inhibited the increase in cAMP induced by Forskolin treatment following transfection of the AMP+ gene into IPEC-J2 cells by a lentivirus vector. Conclusion: Our results indicated that AMP+ encodes a G protein-coupled receptor in Sus scrofa that inhibits cAMP levels and mediates anti-inflammatory effects in swine monocytes.

Physical activity promotes metabolic and cardiovascular health benefits that derive in part from the transcriptional responses to exercise that occur within skeletal muscle and other organs. There is interest in discovering a pharmacologic exercise mimetic that could imbue wellness and alleviate disease burden. However, the molecular physiology by which exercise signals the transcriptional response is highly complex, making it challenging to identify a single target for pharmacological mimicry. The current studies evaluated the transcriptome responses in skeletal muscle, heart, liver, and white and brown adipose to novel small molecule activators of AMPK (pan-activators for all AMPK isoforms) compared to that of exercise. A striking level of congruence between exercise and pharmacological AMPK activation was observed across the induced transcriptome of these five tissues. However, differences in acute metabolic response between exercise and pharmacologic AMPK activation were observed, notably for acute glycogen balances and related to the energy expenditure induced by exercise but not pharmacologic AMPK activation. Nevertheless, intervention with repeated daily administration of short-acting activation of AMPK was found to mitigate hyperglycemia and hyperinsulinemia in four rodent models of metabolic disease and without the cardiac glycogen accretion noted with sustained pharmacologic AMPK activation. These findings affirm that activation of AMPK is a key node governing exercise mediated transcription and is an attractive target as an exercise mimetic.