Publications by authors named "Lin Lin"

1,861 Publications

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Higher pathologic threshold of increased tibial tuberosity-trochlear groove distance should be considered for taller patients.

Knee Surg Sports Traumatol Arthrosc 2022 May 17. Epub 2022 May 17.

Sports Medicine Department, Beijing Key Laboratory of Sports Injuries, Peking University Third Hospital, No. 49 North Garden Road, Haidian, Beijing, 100191, People's Republic of China.

Purpose: The aim of this study was to evaluate the correlation between tibial tuberosity-trochlear groove distance (TT-TG) and body height or knee size, and to find height-related pathologic thresholds of increased TT-TG.

Methods: One-hundred and fifty-three patients with recurrent patellar instability and 151 controls were included. The TT-TG was measured on axial computed tomography (CT) images. Femora width and tibial width were selected to represent knee size. The correlation of TT-TG and gender, body height, femora width, and tibial width was evaluated. The height-related pathologic threshold of increased TT-TG was produced according to Dejour's method. To combine TT-TG with body height and knee size, three new indexes were introduced, ratio of TT-TG to body height (RTH), ratio of TT-TG to femoral width (RTF), and ratio of TT-TG to tibial width (RTT). The ability to predict patellar instability was assessed by the receiver-operating characteristic (ROC) curve, odds ratios (ORs), sensitivity, and specificity.

Results: In patients with patellar instability, TT-TG showed significantly correlation with patient height, femoral width, and tibial width respectively (range r = 0.266-0.283). This correlation was not found in the control group. The pathologic threshold of TT-TG was 18 mm in patients < 169 cm (53%), and the mean TT-TG was 21 mm in patients ≥ 169 cm (54%). There was significant difference in RTH, RTF, and RTT between the two groups. RTH, RTF and RTT have similar large area under the curve (AUC) with TT-TG.

Conclusions: TT-TG showed significant correlation with body height and knee size, respectively. The pathologic threshold of increased TT-TG was suggested to be 21 mm for patients [Formula: see text] 169 cm and 18 mm for patients [Formula: see text] 169 cm. Body height-related pathologic threshold provided a supplement for indications of tibial tuberosity medialization.

Level Of Evidence: IV.
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http://dx.doi.org/10.1007/s00167-022-06992-7DOI Listing
May 2022

Talaromyces marneffei infection associated with bronchiolitis obliterans in an HIV-negative child: a case report.

BMC Infect Dis 2022 May 16;22(1):468. Epub 2022 May 16.

Department of Respiration, Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, No. 9, Jinsui Road, Zhujiang New City, Tianhe, Guangzhou, 510120, Guangdong, China.

Background: Talaromyces marneffei is an opportunistic pathogen that infects immunodeficient and immunocompromised patients. We presented a pediatric patient with a diagnosis of T. marneffei infection who was followed up in the Guangzhou Women and Children's Medical Centre.

Case Presentation: The child was a 5-year-old girl with persistent cough and gasping over 2 months who was confirmed with T. marneffei infection by bronchoalveolar lavage fluid culture and high-throughput sequencing technology. Human immunodeficiency virus (HIV) was negative according to a serum-specific antibody test. She was treated with amphotericin B and itraconazole as antifungal agents, with good clinical response. At follow-up, high-resolution computed tomography showed a mosaic sign in the whole lung field with a diagnosis of post-infectious bronchiolitis obliterans (PIBO) as the sequela. She has a mutated COPA gene with uncertain pathogenic potential on whole-exome sequencing.

Conclusions: Clinicians should consider PIBO as a possible sequela in an HIV-negative paediatric patient with T. marneffei infection.
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http://dx.doi.org/10.1186/s12879-022-07391-6DOI Listing
May 2022

Ovarian Response, Pregnancy Outcomes, and Complications Between Salpingectomy and Proximal Tubal Occlusion in Hydrosalpinx Patients Before Fertilization: A Meta-Analysis.

Front Surg 2022 29;9:830612. Epub 2022 Apr 29.

Medical Examination Center, China-Japan Friendship Hospital, Beijing, China.

Objectives: Contradictory findings exist in studies comparing salpingectomy and proximal tubal occlusion (PTO) in treating hydrosalpinx patients before fertilization (IVF). Therefore, this meta-analysis aimed to comprehensively compare ovarian response, pregnancy outcomes, and complications between salpingectomy and PTO in treating these patients.

Methods: Embase, PubMed, and Web of Science were searched to identify relevant articles published from 1980 to August 31, 2020. Eight studies that involve 716 hydrosalpinx patients before IVF were included, among whom 408 patients received salpingectomy and 308 patients received PTO. The data were pooled; the standardized mean difference (SMD) or odds ratio (OR) was calculated.

Results: Proximal tubal occlusion-treated patients had higher fertilization rate (SMD = 0.35, 95% CI: 0.11-0.59), while similar days of controlled ovarian hyperstimulation (COH) (SMD: 0.15, 95% CI: -0.36-0.67) and number of retrieved oocytes (SMD = -0.22, 95% CI: -0.54-0.10) compared with salpingectomy-treated patients. Furthermore, no difference of implantation rate (OR = 1.17, 95% CI: 0.62-2.20), clinical pregnancy rate (OR = 0.82, 95% CI: 0.59-1.15), ongoing pregnancy rate (OR = 0.64, 95% CI: 0.36-1.13), or live birth rate (OR = 0.67, 95% CI: 0.16-2.72) was shown between salpingectomy-treated patients and PTO-treated patients. Additionally, ectopic pregnancy rate (OR = 1.13, 95% CI: 0.21-5.92) and miscarriage rate (OR = 0.88, 95% CI: 0.31-2.48) were similar between salpingectomy-treated patients and PTO-treated patients.

Conclusion: Proximal tubal occlusion exhibits a higher fertilization rate but no obvious benefits on days of COH, number of retrieved oocytes, pregnancy outcomes, and complications over salpingectomy in hydrosalpinx patients before IVF.
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http://dx.doi.org/10.3389/fsurg.2022.830612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9099031PMC
April 2022

Application of composite coating of Nostoc commune Vauch polysaccharides and sodium carboxymethyl cellulose for preservation of salmon fillets.

Int J Biol Macromol 2022 May 10;210:394-402. Epub 2022 May 10.

School of Food and Biological Engineering, Jiangsu University, Zhenjiang 212013, China; State Key Laboratory of Utilization of Woody Oil Resource, Hunan Academy of Forestry, Changsha 410007, China. Electronic address:

The spoilage of fish products and the growth of pathogenic bacteria cause great economic loss and serious harm to human health, so fish preservation is very important issue. In this study, Nostoc commune Vauch polysaccharides (NVP) was added into sodium carboxymethyl cellulose (CMC) to form a mixed coating to prepare an active packaging material. The antibacterial and antioxidant activities of NVP, physicochemical properties of the mixed coating, and preservative effects of the coating on salmon fillets were evaluated. The results showed that NVP had good antibacterial and antioxidant activities. Physical characterization of the coating solution showed that when the ratio of NVP to CMC was 1:3, the coating had the best dispersion, denser structure and strongest hydrogen bond. On this basis, NVP/CMC coating can significantly prolong the shelf life of salmon fillets during cold storage by reducing pH, improving the color and texture, delaying the oxidation of fat and protein, inhibiting the growth of microorganisms. At the same time, the coated salmon fillets had good sensory acceptance. The results showed that the edible coating has a broad application prospect in the preservation of fish products.
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http://dx.doi.org/10.1016/j.ijbiomac.2022.05.051DOI Listing
May 2022

Prucalopride might improve intestinal motility by promoting the regeneration of the enteric nervous system in diabetic rats.

Int J Mol Med 2022 Jul 11;50(1). Epub 2022 May 11.

Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China.

The present study aimed to investigate whether prucalopride, as a 5‑hydroxytryptamine 4 (5‑HT4) receptor agonist, improved intestinal motility by promoting the regeneration of the enteric nervous system (ENS) in rats with diabetes mellitus (DM). A rat model of DM was established using an intraperitoneal injection of streptozotocin. The rats were randomly divided into four groups of 6 rats/group: Control, DM (DM model), DM + A (5 µg/kg prucalopride) and DM + B (10 µg/kg prucalopride). The rats in the Control group were given an equal volume of citric acid solvent. After successful model establishment, high blood glucose levels were maintained for 2 weeks before administration of prucalopride. The colonic transit time was measured using the glass bead discharge method. It was revealed that the colonic transit time of diabetic rats was the longest, and this was significantly shortened in the DM + B group. Subsequently, the colons were collected. The expression levels of Nestin, glial fibrillary acidic protein (GFAP), SOX10, RNA‑binding protein human antigen D (HuD) and ubiquitin thiolesterase (PGP9.5) were determined via immunohistochemical analysis. Immunofluorescence double staining of 5‑HT4 + Nestin and Ki67 + Nestin was performed. The 5‑HT level was measured using ELISA. Compared with that in the control group, Nestin expression was significantly increased in the DM and DM + A groups, and it was concentrated in columnar epithelial cells and the mesenchyme. Furthermore, the expression levels of Nestin in the DM + A group were higher than those in the DM group. No difference was observed in the expression levels of Nestin between the DM + B group and the Control group. The expression levels of 5‑HT protein were highest in the Control group; however, the expression levels of 5‑HT protein in the DM group, DM + A group and DM + B group exhibited an increasing trend. Similar trends in the expression of 5‑HT4 and Nestin were not observed; however, similar trends in the expression of Nestin and Ki67 were observed. The expression levels of GFAP, SOX10, PGP9.5 and Ki67 in the DM + A and DM + B groups were higher compared with those in the DM group. In the DM + A group, HuD expression was decreased compared with that in the Control group but it was markedly higher compared with that in the DM group. In conclusion, prucalopride may improve intestinal motility by promoting ENS regeneration in rats with DM.
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http://dx.doi.org/10.3892/ijmm.2022.5143DOI Listing
July 2022

Trends and associated factors in place of death among individuals with cardiovascular disease in China, 2008-2020: A population-based study.

Lancet Reg Health West Pac 2022 Apr 2;21:100383. Epub 2022 Feb 2.

National Center for Chronic and Noncommunicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.

Background: Cardiovascular disease (CVD) is the leading cause of death (COD) in China. Understanding the characteristics of place of death (POD) among CVD deaths would be of great importance to evaluate the healthcare service utilization at the end stage of life. Limited studies have reported the POD distribution among CVD deaths, and little was known about the associated factors of hospital CVD deaths.

Methods: By using data from National Mortality Surveillance System (NMSS) in China, this study presented the characteristics of POD distribution during 2008 and 2020. Afterwards, multilevel logistic regression was used to explore associated factors of hospital CVD deaths and quantify the magnitude to which the spatial variations of hospital CVD deaths could be explained by those associated factors.

Findings: During 2008-2020, there was 7101871 CVD deaths collected by NMSS in China, with 77·13% home deaths and 18·49% hospital deaths. Shanghai (59·40%) had the highest percentage of hospital CVD deaths. Age, sex, ethnicity, marital status, education, occupation, underlying COD were significant influential factors of hospital CVD deaths. Spatial variations were shown at provincial level, with 33·88% of them being explained by factors at individual level.

Interpretation: Home was the leading POD among CVD deaths in China, those CVD decedents characterized as the female, the youngest, Han population, the married, the retiree, lived in urban areas, with higher socioeconomic status and died of chronic CVDs had a higher probability of hospital deaths. Providing accessible and available healthcare services were priorities to improve quality of end-of-life care, significant variations among provinces and sub-population also reminded us of the requirements for equal healthcare resources allocation and multiple options for minorities of POD preference at the end stage of life.

Funding: National Key Research & Development Program of China (grant number 2018YFC1315301).
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http://dx.doi.org/10.1016/j.lanwpc.2022.100383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9079349PMC
April 2022

Computational identification of preneoplastic cells displaying high stemness and risk of cancer progression.

Cancer Res 2022 May 10. Epub 2022 May 10.

National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Evidence points towards the differentiation state of cells as a marker of cancer risk and progression. Measuring the differentiation state of single cells in a preneoplastic population could thus enable novel strategies for early detection and risk prediction. Recent maps of somatic mutagenesis in normal tissues from young healthy individuals have revealed cancer driver mutations, indicating that these do not correlate well with differentiation state and that other molecular events also contribute to cancer development. We hypothesized that the differentiation state of single cells can be measured by estimating the regulatory activity of the transcription factors (TFs) that control differentiation within that cell lineage. To this end, we present a novel computational method called CancerStemID that estimates a stemness index of cells from single-cell RNA-Seq data. CancerStemID is validated in two human esophageal squamous cell carcinoma (ESCC) cohorts, demonstrating how it can identify undifferentiated preneoplastic cells whose transcriptomic state is overrepresented in invasive cancer. Spatial transcriptomics and whole-genome bisulfite sequencing demonstrated that differentiation activity of tissue-specific TFs was decreased in cancer cells compared to the basal cell-of-origin layer and established that differentiation state correlated with differential DNA methylation at the promoters of these TFs, independently of underlying NOTCH1 and TP53 mutations. The findings were replicated in a mouse model of ESCC development, and the broad applicability of CancerStemID to other cancer-types was demonstrated. In summary, these data support an epigenetic stem-cell model of oncogenesis and highlight a novel computational strategy to identify stem-like preneoplastic cells that undergo positive selection.
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http://dx.doi.org/10.1158/0008-5472.CAN-22-0668DOI Listing
May 2022

The promotion of menopausal hormone therapy might be determined by the attitude of health-care professionals.

Authors:
Qi Yu Lin Lin

Climacteric 2022 06;25(3):213-214

Department of Obstetrics and Gynecology, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China.

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http://dx.doi.org/10.1080/13697137.2022.2057038DOI Listing
June 2022

Contribution of secondary bonds to the storage stability of ready-to-eat sea cucumber.

Food Chem 2022 Apr 25;389:133061. Epub 2022 Apr 25.

College of Food Science and Engineering, Ocean University of China, No. 5, Yu Shan Road, Qingdao, Shandong Province 266003, PR China; Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao, Shandong Province 266237, PR China. Electronic address:

To explore the contribution of secondary bonds on storage stability of RSC, urea, n-propanol and sodium nitrite (NaNO) were used for the breakdown of hydrogen bonds, hydrophobic bonds, side-chain groups, respectively. The impact of the breakdown of secondary bonds before and after storage on texture properties and microstructure were investigated. The breakdown of hydrogen bonds, especially before storage, significantly reduced the hardness (from 3.12 to 2.21 N), chewiness (from 1.82 to 1.05 mJ), and springiness (from 2.57 to 1.57 mJ) of RSC, while the breakdown of hydrophobic bonds and side-chain groups had a slight effect. Similarly, degradation of collagen fibers by breaking hydrogen bonds before storage was more serious than other groups. Furthermore, moisture content and water activity decreased and the degradation degree of collagen in RSC body wall increased with hydrogen bonds breaking. The results showed that hydrogen bonds were essential for the storage stability of RSC.
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http://dx.doi.org/10.1016/j.foodchem.2022.133061DOI Listing
April 2022

Towards more efficient ophthalmic disease classification and lesion location via convolution transformer.

Comput Methods Programs Biomed 2022 Apr 27;220:106832. Epub 2022 Apr 27.

College of Big Data and Internet, Shenzhen Technology University, Shenzhen 518118, China. Electronic address:

Objective: A retina optical coherence tomography (OCT) image differs from a traditional image due to its significant speckle noise, irregularity, and inconspicuous features. A conventional deep learning architecture cannot effectively improve the classification accuracy, sensitivity, and specificity of OCT images, and noisy images are not conducive to further diagnosis.  This paper proposes a novel lesion-localization convolution transformer (LLCT) method, which combines both convolution and self-attention to classify ophthalmic diseases more accurately and localize the lesions in retina OCT images.

Methods: A novel architecture design is accomplished through applying customized feature maps generated by convolutional neutral network (CNN) as the input sequence of self-attention network. This design takes advantages of CNN's extracting image features and transformer's consideration of global context and dynamic attention. Part of the model is backward propagated to calculate the gradient as a weight parameter, which is multiplied and summed with the global features generated by the forward propagation process to locate the lesion.

Results: Extensive experiments show that our proposed design achieves improvement of about 7.6% in overall accuracy, 10.9% in overall sensitivity, and 9.2% in overall specificity compared with previous methods. And the lesions can be localized without the labeling data of lesion location in OCT images.

Conclusion: The results prove that our method significantly improves the performance and reduces the computation complexity in artificial intelligence assisted analysis of ophthalmic disease through OCT images.

Significance: Our method has a significance boost in ophthalmic disease classification and location via convolution transformer. This is applicable to assist ophthalmologists greatly..
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http://dx.doi.org/10.1016/j.cmpb.2022.106832DOI Listing
April 2022

Mortality and Years of Life Lost in Diabetes Mellitus and Its Subcategories in China and Its Provinces, 2005-2020.

J Diabetes Res 2022 22;2022:1609267. Epub 2022 Apr 22.

National Center for Chronic and Noncommunicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.

Objectives: To analyze diabetes mellitus (DM) mortality and years of life lost (YLL) in different years and different subgroups at the national and regional levels in China from 2005 to 2020.

Methods: We estimated mortality and YLL of DM and its subcategories for 31 provinces in China during 2005-2020 using multisource data from the National Mortality Surveillance System (NMSS).

Results: The age standardized mortality rate (ASMR) of DM increased from 12.18 per 100,000 in 2005 to 13.62 per 100,000 in 2020, which was an increase of 11.86%. The ASMR of type 2 diabetes mellitus (T2DM) was much higher than that of type 1 diabetes mellitus (T1DM). The ASMR of T1DM remained stable, but the rate of T2DM increased, and the increase in male patients was higher than that in their female counterparts. At the same time, the burden of premature death was highest in the group ≥ 80 years old, and ASMR increased from 236.02 per 100,000 in 2005 to 358.86 per 100,000 in 2020. In 2005, the eastern region had the highest ASMR of DM, but the western region's ASMR grew faster and eventually became the highest in 2020. In addition, the YLL rate in the eastern region showed a downward trend; however, in the middle and western regions the YLL rate continued to rise, with that of the western region rapidly increasing.

Conclusion: A dramatically upward trend in DM deaths can be seen in China from 2005 to 2020. DM remains a chronic disease in urgent need of prevention and control, especially in the elderly and people in less-affluent provinces. We must put forward more targeted policies to effectively allocate medical resources and focus on high-risk groups to reduce the premature-mortality burden of DM and its subcategories.
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http://dx.doi.org/10.1155/2022/1609267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9054436PMC
May 2022

Hydrogen-oxidizing bacteria and their applications in resource recovery and pollutant removal.

Sci Total Environ 2022 Apr 26;835:155559. Epub 2022 Apr 26.

State Key Laboratory of Pollution Control and Resource Reuse, School of Environmental Science and Engineering, Tongji University, 1239 Siping Road, Shanghai 200092, China. Electronic address:

Hydrogen oxidizing bacteria (HOB), a type of chemoautotroph, are a group of bacteria from different genera that share the ability to oxidize H and fix CO to provide energy and synthesize cellular material. Recently, HOB have received growing attention due to their potential for CO capture and waste recovery. This review provides a comprehensive overview of the biological characteristics of HOB and their application in resource recovery and pollutant removal. Firstly, the enzymes, genes and corresponding regulation systems responsible for the key metabolic processes of HOB are discussed in detail. Then, the enrichment and cultivation methods including the coupled water splitting-biosynthetic system cultivation, mixed cultivation and two-stage cultivation strategies for HOB are summarized, which is the critical prerequisite for their application. On the basis, recent advances of HOB application in the recovery of high-value products and the removal of pollutants are presented. Finally, the key points for future investigation are proposed that more attention should be paid to the main limitations in the large-scale industrial application of HOB, including the mass transfer rate of the gases, the safety of the production processes and products, and the commercial value of the products.
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http://dx.doi.org/10.1016/j.scitotenv.2022.155559DOI Listing
April 2022

Synthesis of 2-methoxybenzamide derivatives and evaluation of their hedgehog signaling pathway inhibition.

RSC Adv 2021 Jun 28;11(37):22820-22825. Epub 2021 Jun 28.

School of Pharmacy, Shenyang Medical College Shenyang 110034 China

Aberrant hedgehog (Hh) signaling is implicated in the development of a variety of cancers. Smoothened (Smo) protein is a bottleneck in the Hh signal transduction. The regulation of the Hh signaling pathway to target the Smo receptor is a practical approach for development of anticancer agents. We report herein the design and synthesis of a series of 2-methoxybenzamide derivatives as Hh signaling pathway inhibitors. The pharmacological data demonstrated that compound 21 possessed potent Hh pathway inhibition with a nanomolar IC value, and it prevented Shh-induced Smo from entering the primary cilium. Furthermore, mutant Smo was effectively suppressed compound 21. The antiproliferative activity of compound 21 against a drug-resistant cell line gave encouraging results.
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http://dx.doi.org/10.1039/d1ra00732gDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9034380PMC
June 2021

Circle-Seq reveals genomic and disease-specific hallmarks in urinary cell-free extrachromosomal circular DNAs.

Clin Transl Med 2022 04;12(4):e817

IBMC-BGI Center, the Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China.

Background: Extrachromosomal circular deoxyribonucleic acid (eccDNA) is evolving as a valuable biomarker, while little is known about its presence in urine.

Methods: Here, we report the discovery and analysis of urinary cell-free eccDNAs (ucf-eccDNAs) in healthy controls and patients with advanced chronic kidney disease (CKD) by Circle-Seq.

Results: Millions of unique ucf-eccDNAs were identified and comprehensively characterised. The ucf-eccDNAs are GC-rich. Most ucf-eccDNAs are less than 1000 bp and are enriched in four pronounced peaks at 207, 358, 553 and 732 bp. Analysis of the genomic distribution of ucf-eccDNAs shows that eccDNAs are found on all chromosomes but enriched on chromosomes 17, 19 and 20 with a high density of protein-coding genes, CpG islands, short interspersed transposable elements (SINEs) and simple repeat elements. Analysis of eccDNA junction sequences further suggests that microhomology and palindromic repeats might be involved in eccDNA formation. The ucf-eccDNAs in CKD patients are significantly higher than those in healthy controls. Moreover, eccDNA with miRNA genes is highly enriched in CKD ucf-eccDNA.

Conclusions: This work discovers and provides the first deep characterisation of ucf-eccDNAs and suggests ucf-eccDNA as a valuable noninnvasive biomarker for urogenital disorder diagnosis and monitoring.
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http://dx.doi.org/10.1002/ctm2.817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9042798PMC
April 2022

Effect of Local Corticosteroid Administration on CD8+CD25+Foxp3+ Tregs in Neutrophilic CRSwNP.

ORL J Otorhinolaryngol Relat Spec 2022 Apr 25:1-10. Epub 2022 Apr 25.

Department of Otorhinolaryngology-Head and Neck Surgery, Huashan Hospital of Fudan University, Shanghai, China.

Introduction: CD8+CD25+Foxp3+ regulatory T cells (Tregs) play an important role in human's immune tolerance. The study was aimed to assess the influence of budesonide nasal spray on CD8+CD25+Foxp3+ Tregs and to evaluate their cellular functions in neutrophilic chronic rhinosinusitis with nasal polyps (CRSwNPs).

Methods: Fifteen patients with neutrophilic CRSwNPs were enrolled and received physiological saline or budesonide nasal spray treatment (Saline or Budesonide group) for 3 months. Nasal tissue samples were obtained from normal subjects or those patients and cultured in vitro. CD8+CD25+Foxp3+ Tregs were separated from normal or NP tissues and also cultured in vitro. Then interleukin (IL)-10 and its mRNA were evaluated in the above cell cultures. The cells were applied into NP cultures. Finally, myeloperoxidase (MPO), interferon (IFN)-γ, IL-1β, and tumor necrosis factor (TNF)-α were assessed in the tissue cultures.

Results: CD8+CD25+Foxp3+ Tregs decreased in NP tissues. Budesonide administration did not enhance the percentage of these cells in polypoid tissues. IL-10 and its mRNA were increased in the above cell cultures from NPs. However, there were no statistical differences between the two treatments in the IL-10 expression. Additionally, levels of MPO, IFN-γ, IL-1β, and TNF-α were totally elevated in NP tissue cultures and reduced after the administration of CD8+CD25+Foxp3+ Tregs. However, there were no significant differences in concentrations of these mediators between these two groups of the CD8+CD25+Foxp3+ Tregs treatment in vitro.

Conclusion: The findings indicate that CD8+CD25+Foxp3+ Tregs might regulate the neutrophilic inflammation, and budesonide nasal spray therapy could not ameliorate the inflammation in neutrophilic CRSwNPs.
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http://dx.doi.org/10.1159/000524385DOI Listing
April 2022

Spatial variations and social determinants of life expectancy in China, 2005-2020: A population-based spatial panel modelling study.

Lancet Reg Health West Pac 2022 Jun 11;23:100451. Epub 2022 Apr 11.

National Center for Chronic and Noncommunicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.

Background: Social determinants of health (SDOH) produce a broad range of life expectancy (LE) disparities. In China, limited literatures were found to report association between SDOH and LE at ecological level during a consecutive period of time from the spatial perspectives. This study aimed to determine the existence, quantify the magnitude, and interpret the association between SDOH and LE in China.

Methods: Provincial-level LE were estimated from mortality records during 2005-2020 from National Mortality Surveillance System in China. A spatial panel Durbin model was used to investigate LE associated SDOH proxies. Spatial spillover effects were introduced to interpret direct and indirect effects caused by SDOH during long-term and short-term period on LE disparities.

Findings: Nationwide, LE increased from 73.1 (95% confidence interval (CI): 71.3, 74.4) years to 77.7 (95%CI: 76.5, 78.7) years from 2005 to 2020. Unequally spatial distribution of LE with High-High clustering in coastal areas and Low-Low clustering in western regions were observed. Locally, it was estimated that SDOH proxies statistically significant related to an increase of LE, including GDP (coefficient: 0.02, 95%CI: 0.00, 0.03), Gini index (coefficient: 2.35, 95%CI: 1.82, 2.88), number of beds in health care institutions (coefficient: 0.02, 95%CI: 0.00, 0.05) and natural growth rate of resident population (coefficient: 0.02, 95%CI: 0.01, 0.02). Direct and indirect effects decomposition during long-term and short-term of LE associated SDOH proxies demonstrated that GDP, urbanization rate, unemployment rate, education attainment, Gini index, number of beds in health care institutions, sex ratio, gross dependence ratio and natural growth rate of resident population not only affected local LE, but also exerted spatial spillover effects towards geographical neighbors.

Interpretation: Spatial variations of LE existed at provincial-level in China. SDOH regarding socioeconomic development and equity, healthcare resources, as well as population characteristics not only affected LE disparities at local scale but also among nearby provinces. Externalities of policy of those SDOH proxies should be took into consideration to promote health equity nationally. Comprehensive approaches on the basis of population strategy should be consolidated to optimize supportive socioeconomic environment and narrow the regional gap to reduce health disparities and increase LE.

Funding: National Key Research & Development Program of China (Grant No.2018YFC1315301); Ministry of Education of China Humanities and Social Science General Program (Grant No.18YJC790138).
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http://dx.doi.org/10.1016/j.lanwpc.2022.100451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9019400PMC
June 2022

Executive Function Improvement for Children with Autism Spectrum Disorder: A Comparative Study between Virtual Training and Physical Exercise Methods.

Children (Basel) 2022 Apr 3;9(4). Epub 2022 Apr 3.

Department of PE, Northeastern University, Shenyang 110819, China.

This study evaluated and compared the effects of virtual training and physical exercise on the executive function of children with autism spectrum disorder (ASD). After screening, the final analysis of this study was conducted on three groups: a virtual training group ( = 34), a physical exercise group ( = 33), and a control group ( = 33). The experiment was conducted for nine weeks, of which the virtual training group and physical exercise group were conducted three times a week for one hour each time during the first six weeks, while the control group did not conduct virtual training nor physical exercise. During the last three weeks (week 6 to week 9), virtual training and physical exercise were not performed on all three groups. The three main components of executive function (working memory, inhibition, flexibility) of children with ASD were measured before the intervention, after the intervention (week 1 to week 6) and in the last three weeks (week 6 to week 9). The final results are that firstly, the executive function of the virtual training and physical exercise groups were simultaneously improved after the intervention. Secondly, after the intervention stopped, the executive function of the virtual training and physical exercise groups showed a downward trend. Therefore, the study concludes that the application of virtual training and physical exercise can effectively enhance the executive function of children with ASD.
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http://dx.doi.org/10.3390/children9040507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9029765PMC
April 2022

Interrelating Grain Hardness Index of Wheat with Physicochemical and Structural Properties of Starch Extracted Therefrom.

Foods 2022 Apr 9;11(8). Epub 2022 Apr 9.

College of Agriculture and Biotechnology, Zhejiang University, Hangzhou 310058, China.

To investigate the physicochemical, structural, and rheological characteristics of starch from wheat cultivars varying in grain hardness index employed in making and to interrelate grain hardness index with physicochemical and structural properties of starch. Starch extracted therefrom was investigated for structural and physicochemical properties. Starch granules showed relatively wide granule size distribution; large size granules showed lenticular shapes while medium and small size granules exhibited spherical or irregular shapes. Starch from wheat with a lower grain hardness index exhibited a relatively higher degree of crystallinity. Chain-length profiles of amylopectin showed distinct differences; among the fractions of fa, fb, fb and fb representing the weight-based chain-length proportions in amylopectin, the fa fractions ranged from 19.7% to 21.6%, the fb fractions ranged from 44.4% to 45.6%, the fb fractions ranged from 16.2% to 17.0%, and the fb fractions ranged from 16.1% to 18.8%, respectively. T, T, T, and ∆H of starch ranged from 57.8 to 59.7 °C, 61.9 to 64.2 °C, 67.4 to 69.8 °C, and 11.9 to 12.7 J/g, respectively. Peak viscosity, hot pasting viscosity, cool pasting viscosity, breakdown, and setback of starch ranged from 127 to 221 RVU, 77 to 106 RVU, 217 to 324 RVU, 44 to 116 RVU, and 137 to 218 RVU, respectively. Both G' and G" increased in the frequency range of 0.628 to 125.6 rad/s; the wheat starch gels were more solid-like during the whole range of frequency sweep.
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http://dx.doi.org/10.3390/foods11081087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9025240PMC
April 2022

LncRNA SBF2-AS1 Facilitates Nonsmall Cell Lung Cancer Progression by Targeting miR-520a-3p.

J Healthc Eng 2022 11;2022:2223149. Epub 2022 Apr 11.

No. 1 Department of Respiratory and Critical Care Medicine, Shengjing Hospital of China Medical University, Shenyang 110004, China.

Background: Long noncoding RNA (lncRNA) SET-binding factor 2 (SBF2) antisense RNA1 (SBF2-AS1), which acts as an oncogene in various cancers, can promote tumors progression. The study aimed to explore the role and molecular mechanism of SBF2-AS1 in nonsmall cell lung cancer (NSCLC).

Methods: qRT-PCR was introduced to detect SBF2-AS1 and miR-520a-3p expression in NSCLC. The effects of SBF2-AS1 and miR-520a-3p on the proliferation, migration, and invasion of NSCLC cells were assessed through cell counting kit-8 (CCK-8) and transwell assay. Furthermore, the relationship of SBF2-AS1 and miR-520a-3p was verified by the RNA immunoprecipitation (RIP) assay, dual-luciferase assay, and Spearman correlation analysis.

Results: In NSCLC tissues, SBF2-AS1 was highly expressed, while miR-520a-3p expression has decreased. The overall survival of NSCLC patients with high SBF2-AS1 expression was lower. SBF2-AS1 silencing repressed the proliferation, migration, and invasion of NSCLC cells. SBF2-AS1 directly interacted with miR-520a-3p, and a negative relationship was observed between their expression levels in NSCLC tissues. More importantly, the suppression of SBF2-AS1 silencing on the proliferation, migration, and invasion in NSCLC cells was counteracted by miR-520a-3p inhibition.

Conclusion: SBF2-AS1 accelerated the proliferation, migration, and invasion of NSCLC cells via mediating miR-520a-3p, thus promoting NSCLC progression.
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http://dx.doi.org/10.1155/2022/2223149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9015877PMC
April 2022

Quantitative systems pharmacology modeling provides insight into inter-mouse variability of Anti-CTLA4 response.

CPT Pharmacometrics Syst Pharmacol 2022 Apr 19. Epub 2022 Apr 19.

Applied BioMath, Inc., Concord, Massachusetts, USA.

Clinical responses of immuno-oncology therapies are highly variable among patients. Similar response variability has been observed in syngeneic mouse models. Understanding of the variability in the mouse models may shed light on patient variability. Using a murine anti-CTLA4 antibody as a case study, we developed a quantitative systems pharmacology model to capture the molecular interactions of the antibody and relevant cellular interactions that lead to tumor cell killing. Nonlinear mixed effect modeling was incorporated to capture the inter-animal variability of tumor growth profiles in response to anti-CTLA4 treatment. The results suggested that intratumoral CD8+ T cell kinetics and tumor proliferation rate were the main drivers of the variability. In addition, simulations indicated that nonresponsive mice to anti-CTLA4 treatment could be converted to responders by increasing the number of intratumoral CD8+ T cells. The model provides a mechanistic starting point for translation of CTLA4 inhibitors from syngeneic mice to the clinic.
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http://dx.doi.org/10.1002/psp4.12800DOI Listing
April 2022

Modeling and Evaluation of Vesicle Release Mechanisms in Neuro-Spike Communication.

Authors:
Wenlong Yu Lin Lin

IEEE Trans Nanobioscience 2022 Apr 18;PP. Epub 2022 Apr 18.

Neuro-spike communication (NSC) is a communication method that includes electrical communication process and molecular communication process, which has been investigated extensively in recent years. The vesicle release process has a great influence on the accuracy of NSC systems. So the modeling of the vesicle release process has become a hot spot. There exist different vesicle release mechanisms, including univesicular release (UVR) case, multivesicular release (MVR) case and hybrid vesicle release (HVR) case. When a spike arrives, the UVR case refers to that at most one vesicle can be released. The MVR case refers to that more than one vesicle can be released. The HVR case is a mixed case of the UVR and MVR cases. This paper proposes the modeling of these three vesicle release cases. The theoretical analysis is conducted to compare them in terms of efficiency. Simulations are performed to evaluate the impacts of main vesicle releasing parameters on signal transmission accuracy. The simulation results show that the HVR model can effectively improve the transmission accuracy compared with UVR and MVR models under some conditions.
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http://dx.doi.org/10.1109/TNB.2022.3168027DOI Listing
April 2022

The Interference Mechanism of Basil Essential Oil on the Cell Membrane Barrier and Respiratory Metabolism of .

Front Microbiol 2022 1;13:855905. Epub 2022 Apr 1.

State Key Laboratory of Utilization of Woody Oil Resource, Hunan Academy of Forestry, Changsha, China.

In order to prevent food-borne diseases caused by () safely and effectively, plant essential oils that have no toxic side effects and are not prone to drug resistance have become the focus of research. This article takes basil ( L.) essential oil (BEO) as the research object and explores its antibacterial mechanism against . The site of action was preliminarily determined to provide a theoretical basis for the development of natural antibacterial agents. The results show that BEO has good antibacterial activity against . After 8 h of treatment with BEO (1 mg/ml), the number of remaining bacteria reached an undetectable level. Combining spectroscopic analysis techniques (Raman, UV, and fluorescence spectroscopy) and fluorescence microscopy imaging techniques, it was found that BEO increased the disorder of the hydrocarbyl chain of phospholipid tail, which in turn led to increased cell membrane permeability, thereby causing the leakage of intracellular proteins and DNA. Meanwhile, respiratory metabolism experiments showed that BEO inhibited the EMP pathway by inhibiting the activity of key enzymes. From the molecular docking results, this inhibition may be attributed to the hydrophobic interaction between α-bergamotene and the amino acid residues of phosphofructokinase (PFK) and pyruvate kinase (PK). In addition, BEO can also cause oxidative stress, and reactive oxygen species (ROS) may also be related to the damage of cell membranes and enzymes related to respiratory metabolism.
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http://dx.doi.org/10.3389/fmicb.2022.855905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9010862PMC
April 2022

Evaluating the contributions of leaf organ to wheat grain cadmium at the filling stage.

Sci Total Environ 2022 Apr 14;833:155217. Epub 2022 Apr 14.

Henan Collaborative Innovation Center of Environmental Pollution Control and Ecological Restoration, Zhengzhou University of Light Industry, Zhengzhou 45000, China.

Cadmium (Cd) is an element of global concern in agricultural fields owing to its high bioavailability and its risk to human health via the consumption of wheat products. However, whether wheat leaves can directly absorb atmospheric Cd and transport them to the grains along with the contribution of leaves to Cd accumulation in the grains is not clear. We evaluated this mechanism through three comparative treatments: 1) exposure to atmospheric deposition (CK), 2) no exposure to atmospheric deposition (T1), and 3) exposure to atmospheric deposition with leaf cutting (T2). The Cd accumulation rate of grains in the CK, T1, and T2 groups all showed an increasing trend, followed by a decreasing trend, which was consistent with the trend of filling rate. Moreover, the critical period for leaf Cd accumulation in the grains was the early filling period, and its contribution decreased gradually as filling progressed. The contribution of the leaves to grain Cd reached 31.73% at maturity, with the reactivation of stored Cd in leaves pre-flowering and the newly absorbed atmospheric Cd by leaves post-flowering contributing 19.76% and 11.97% to Cd accumulation in grains, respectively, at maturity. Sub-microstructure analysis of the leaves further confirmed that the direct Cd absorption by leaves from atmospheric deposition through stomata contributed to Cd accumulation in wheat grains. Therefore, controlling the sources of atmospheric Cd pollution and reducing Cd absorption by leaves during grain filling can effectively control Cd pollution of wheat grains. This study provides significant insights on how to more effectively control the Cd content of edible part of wheat and ensure food security.
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http://dx.doi.org/10.1016/j.scitotenv.2022.155217DOI Listing
April 2022

RNF8 up-regulates AR/ARV7 action to contribute to advanced prostate cancer progression.

Cell Death Dis 2022 Apr 15;13(4):352. Epub 2022 Apr 15.

Department of Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, School of Life Sciences, China Medical University, Shenyang, Liaoning Province, 110122, P. R. China.

Androgen receptor (AR) signaling drives prostate cancer (PC) progression. Androgen deprivation therapy (ADT) is temporally effective, whereas drug resistance inevitably develops. Abnormal expression of AR/ARV7 (the most common AR splicing variant) is critical for endocrine resistance, while the detailed mechanism is still elusive. In this study, bioinformatics and immunohistochemical analyses demonstrate that RNF8 is high expressed in PC and castration-resistant PC (CRPC) samples and the expression of RNF8 is positively correlated with the Gleason score. The high expression of RNF8 in PCs predicts a poor prognosis. These results provide a potential function of RNF8 in PC progression. Furthermore, the mRNA expression of RNF8 is positively correlated with that of AR in PC. Mechanistically, we find that RNF8 upregulates c-Myc-induced AR transcription via altering histone modifications at the c-Myc binding site within the AR gene. RNF8 also acts as a co-activator of AR, promoting the recruitment of AR/ARV7 to the KLK3 (PSA) promoter, where RNF8 modulates histone modifications. These functions of RNF8 are dependent on its E3 ligase activity. RNF8 knockdown further reduces AR transactivation and PSA expression in CRPC cells with enzalutamide treatment. RNF8 depletion restrains cell proliferation and alleviates enzalutamide resistance in CRPC cells. Our findings indicate that RNF8 may be a potential therapeutic target for endocrine resistance in PC.
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http://dx.doi.org/10.1038/s41419-022-04787-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9012884PMC
April 2022

The role and mechanism of TLR4-siRNA in the impairment of learning and memory in young mice induced by isoflurane.

Adv Clin Exp Med 2022 Apr 8. Epub 2022 Apr 8.

Department of Anesthesiology, Jiangxi Provincial People's Hospital, Nanchang, China.

Background: Isoflurane can significantly induce inflammation in children without surgical stress. The toll-like receptor 4 (TLR4) is closely related to noninfectious inflammation in the brain.

Objectives: To investigate the role of TLR4-small interfering RNA (siRNA) in learning and memory impairment in young mice induced by isoflurane.

Material And Methods: The C57 newborn mice were randomly allocated into normal control (control), isoflurane anesthesia (isoflurane), TLR4 interference empty vector+isoflurane anesthesia (siRNA-NC), and TLR4 interference+isoflurane anesthesia (TLR-siRNA) groups. Their behavior and pathological condition were detected using Morris water maze and hematoxylin and eosin (H&E) staining, respectively. The TLR4, brain-derived neurotrophic factor (BDNF) and cyclic adenosine monophosphate response element-binding protein 1 (CREB1) mRNA expressions were detected using quantitative real-time polymerase chain reaction (qRT-PCR). Serum tumor necrosis factor alpha (TNF-α) and interleukin (IL)-6 were detected by means of the enzyme-linked immunosorbent assay (ELISA). Apoptosis rate was detected with terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). The TLR4, TNF-α, IL-6, BDNF, CREB1, extracellular signal-regulated kinase 1/2 (ERK1/2), and c-Jun N-terminal kinase (JNK) protein expressions were detected using western blot (WB).

Results: Compared with the control group, the number of times the mice crossed the platform, and the time spent at the circumjacent area I and II of the platform were significantly decreased in the isoflurane group; the TLR4, TNF-α and IL-6 expressions were significantly increased in the isoflurane group, as compared to control; the results were reversed after the TLR4 interference. The hippocampal neurons in the isoflurane and siRNA-NC groups showed arrangement disorder and a high number of inflammatory infiltrates, while in the TLR-siRNA group they were closely and orderly arranged. Compared with the control group, the apoptosis rate and JNK protein expression in the isoflurane group were significantly increased, CREB1 protein expression was significantly decreased, and BDNF and ERK1/2 protein expressions showed no significant changes. Compared with the isoflurane group, the apoptosis rate of the TLR-siRNA group was significantly decreased, BDNF and CREB1 protein expressions were significantly increased, and ERK1/2 and JNK did not change significantly.

Conclusions: Isoflurane stimulates the overexpression of inflammatory response factors, playing an important role in the cognitive impairment process. As a mediator of the innate immune inflammatory response, TLR4 plays an important role in the process of cell injury, which may be delayed by blocking the TLR4 signal.
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http://dx.doi.org/10.17219/acem/147047DOI Listing
April 2022

Effects of individualized nursing combined with graded psychological nursing intervention on postoperative recovery of patients in the perioperative period of hepatobiliary surgery.

Minerva Surg 2022 Apr 7. Epub 2022 Apr 7.

Department of Hepatobiliary Surgery, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China -

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http://dx.doi.org/10.23736/S2724-5691.22.09553-3DOI Listing
April 2022

Systematic review and meta-analysis of candidate gene association studies of benign prostate hyperplasia.

Syst Rev 2022 Apr 5;11(1):60. Epub 2022 Apr 5.

TAGC, Aix Marseille University, Marseille, France.

Background: Benign prostate hyperplasia (BPH) is the most common urological problem in elderly males. Recent studies have reported polymorphism in various metabolic genes in BPH. However, their association with the susceptibility of BPH is still inconsistent. Here, we systematically reviewed and performed a meta-analysis of CYP17, VDR, and ACE genes to determine their precise association with the risk of BPH.

Methods: A comprehensive literature search for published studies on candidate gene associations involving vitamin D receptor (VDR), angiotensin-converting enzyme (ACE), and CYP17 genes with the risk of BPH was done up to April 2020 in PubMed, Scopus, Cochrane Central Register of Controlled Trials (CENTRAL), and Google Scholar databases. Fixed/random effects models were used to estimate the odd's ratio (OR) and 95% confidence intervals (CIs). Begg's funnel plot was used to assess the potential for publication bias.

Results: We found a total of 23 studies containing 3461 cases and 3833 controls for these gene polymorphisms. A significant association of ACE gene polymorphism was observed under the recessive (II vs. ID + DD) model for BPH susceptibility compared to control subjects (overall OR = 1.67, 95% CI = 1.03-2.73). Similar trends were observed for ACE gene polymorphism in Caucasian (OR = 6.18, 95% CI = 1.38-27.68) and Asian (OR = 1.42, 95% CI = 0.99-2.03) populations under study. No significant association was observed in VDR and CYP17 gene polymorphisms in any dominant or recessive models.

Conclusion: Significant OR demonstrated the implication of ACE gene polymorphism in the proliferation of prostate tissue, which in turn is associated with BPH susceptibility. However, prospective studies at large scale and sample size are needed to confirm the current findings.
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http://dx.doi.org/10.1186/s13643-022-01914-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8985373PMC
April 2022

Identification of Germline Mutations in Upper Tract Urothelial Carcinoma With Suspected Lynch Syndrome.

Front Oncol 2022 16;12:774202. Epub 2022 Mar 16.

Department of Urology, Peking University First Hospital, Beijing, China.

Objective: Whole-exon sequencing (WES) is a commercially available tool for hereditary disease testing. However, little is known about hereditary upper-tract urothelial carcinoma (UTUC) in the Chinese population. This study aims to investigate the prevalence of Lynch syndrome (LS) in UTUC patients with high-risk features and identify the germline mutations of genetic predisposition gene mutations in those patients.

Methods: In total, 354 consecutive UTUC patients undergoing surgery were universally recruited, of whom 108 patients under 60 years old or with a personal/family history of cancer underwent universal immunohistochemistry staining to detect the expression of mismatch repair (MMR) proteins (MLH1, MSH2, MSH6 and PMS2). Patients with deficient or weak MMR protein staining or meeting the Amsterdam II criterion were defined as suspected LS patients, who further experienced microsatellite instability (MSI) (BAT25, BAT26, BAT40, D2S123, D5S346, D17S250) detection and performed WES analysis to explore germline pathogenic/likely pathogenic (P/LP) alterations.

Results: Of 108 patients, 90 (83.3%) cases were included due to younger than 60 years, and 18 cases due to personal/family history. IHC staining identified 21 patients with deficient MMR protein staining and 15 cases with weak MMR protein staining. Three cases met the Amsterdam II criterion but with proficient MMR protein staining. Finally, WES analysis was performed in 38 suspected LS patients and P/LP germline mutations were identified in 22 individuals. Genetic testing confirmed 5 LS cases, including 3 cases with novel mutations. MSI-harboring tumor was discovered in 4 LS cases, one of whom had weak MMR protein staining. Germline P/LP variants in DNA damage repair genes were found in 11 cases. In addition, we found that 11 patients had high- or moderate- penetrance P/LP mutations other than MMR genes. The common P/LP variants in high- or moderate-penetrance genes were 4 in ATM, 3 in MSH6 and KIT, and 2 in APC, NF1 and DICER.

Conclusions: We identified approximately 11% of UTUC cases as suspected LS and at least 1.4% patients with confirmed LS-associated UTUC. In addition, broader germline genetic testing could be considered to screen for cancer severity in hereditary UTUC patients.
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http://dx.doi.org/10.3389/fonc.2022.774202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8966221PMC
March 2022

A novel heterozygous missense variant of the ARID4A gene identified in Han Chinese families with schizophrenia-diagnosed siblings that interferes with DNA-binding activity.

Mol Psychiatry 2022 Apr 1. Epub 2022 Apr 1.

Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Shanghai, China.

ARID4A plays an important role in regulating gene expression and cell proliferation. ARID4A belongs to the AT-rich interaction domain (ARID)-containing family, and a PWWP domain immediately precedes its ARID region. The molecular mechanism and structural basis of ARID4A are largely unknown. Whole-exome sequencing (WES) revealed that a novel heterozygous missense variant, ARID4A c.1231 C > G (p.His411Asp), was associated with schizophrenia (SCZ) in this study. We determined the crystal structure of the PWWP-ARID tandem at 2.05 Å, revealing an unexpected mode in which ARID4A assembles with its PWWP and ARID from a structural and functional supramodule. Our results further showed that compared with the wild type, the p.His411Asp ARID mutant protein adopts a less compact conformation and exhibits a weaker dsDNA-binding ability. The p.His411Asp mutation decreased the number of cells that were arrested in the G0-G1 phase and caused more cells to progress to the G2-M phase. In addition, the missense mutation promoted the proliferation of HEK293T cells. In conclusion, our data provide evidence that ARID4A p.His411Asp could cause a conformational change in the ARID4A ARID domain, influence the DNA binding function, and subsequently disturb the cell cycle arrest in the G1 phase. ARID4A is likely a susceptibility gene for SCZ; thus, these findings provide new insight into the role of ARID4A in psychiatric disorders.
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http://dx.doi.org/10.1038/s41380-022-01530-wDOI Listing
April 2022

Comparative Pharmacokinetics of Δ-Tetrahydrocannabinol in Adolescent and Adult Male and Female Rats.

Cannabis Cannabinoid Res 2022 Mar 28. Epub 2022 Mar 28.

Department of Anatomy and Neurobiology, University of California, Irvine, California, USA.

Studies in rodent models have shown that adolescent exposure to Δ-THC, the psychotropic constituent of cannabis, produces long-lasting alterations in brain function and behavior. However, our understanding of how age and sex might influence the distribution and metabolism of THC in laboratory rodents is still incomplete. In the present report, we provide a comparative analysis of the pharmacokinetic (PK) properties of THC in adolescent and adult rats of both sexes, and outline several dissimilarities across these groups. A single (acute) or 2-week daily (subchronic) administration of THC (0.5 or 5 mg/kg, acute; 5 mg/kg, subchronic; intraperitoneal) was given to adolescent (33-day-old, acute; 30-44-day-old, subchronic) and young adult (70-day-old, acute only) male and female rats. THC and its first-pass metabolites-11-hydroxy-Δ-THC (11-OH-THC) and 11-nor-9-carboxy-Δ-THC (11-COOH-THC)-were quantified in plasma and brain tissue using a selective isotope-dilution liquid chromatography/tandem mass spectrometry assay. Changes in body temperature were measured using abdominally implanted microchips. Biotransformation of THC to its metabolites using freshly prepared liver microsomes was assessed. At the acute 5 mg/kg dose, maximal plasma concentrations of THC were twice as high in adult than in adolescent rats. Conversely, in adults, brain concentrations and brain-to-plasma ratios for THC were substantially lower (25-50%) than those measured in adolescents. Similarly, plasma and brain concentrations of THC metabolites were higher in adolescent male rats compared with adult males. Interestingly, plasma and brain concentrations of the psychoactive THC metabolite 11-OH-THC were twofold to sevenfold higher in female animals of both ages compared with males. Moreover, liver microsomes from adolescent males and adolescent and adult females converted THC to 11-OH-THC twice as fast as adult male microsomes. A dose-dependent hypothermic response to THC was observed in females with 0.5 and 5 mg/kg THC, whereas only the highest dose elicited a response in males. Finally, subchronic administration of THC during adolescence did not significantly affect the drug's PK profile. The results reveal the existence of multiple age and sex differences in the distribution and metabolism of THC in rats, which might influence the pharmacological response to the drug.
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http://dx.doi.org/10.1089/can.2021.0205DOI Listing
March 2022
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