Publications by authors named "Hongyu Zhao"

688 Publications

Circadian Rhythm Analysis Using Wearable Device Data: Novel Penalized Machine Learning Approach.

J Med Internet Res 2021 Oct 14;23(10):e18403. Epub 2021 Oct 14.

Department of Biostatistics, Yale School of Public Health, New Haven, CT, United States.

Background: Wearable devices have been widely used in clinical studies to study daily activity patterns, but the analysis remains a major obstacle for researchers.

Objective: This study proposes a novel method to characterize sleep-activity rhythms using actigraphy and further use it to describe early childhood daily rhythm formation and examine its association with physical development.

Methods: We developed a machine learning-based Penalized Multiband Learning (PML) algorithm to sequentially infer dominant periodicities based on the Fast Fourier Transform (FFT) algorithm and further characterize daily rhythms. We implemented and applied the algorithm to Actiwatch data collected from a cohort of 262 healthy infants at ages 6, 12, 18, and 24 months, with 159, 101, 111, and 141 participants at each time point, respectively. Autocorrelation analysis and Fisher test in harmonic analysis with Bonferroni correction were applied for comparison with the PML. The association between activity rhythm features and early childhood motor development, assessed using the Peabody Developmental Motor Scales-Second Edition (PDMS-2), was studied through linear regression analysis.

Results: The PML results showed that 1-day periodicity was most dominant at 6 and 12 months, whereas one-day, one-third-day, and half-day periodicities were most dominant at 18 and 24 months. These periodicities were all significant in the Fisher test, with one-fourth-day periodicity also significant at 12 months. Autocorrelation effectively detected 1-day periodicity but not the other periodicities. At 6 months, PDMS-2 was associated with the assessment seasons. At 12 months, PDMS-2 was associated with the assessment seasons and FFT signals at one-third-day periodicity (P<.001) and half-day periodicity (P=.04), respectively. In particular, the subcategories of stationary, locomotion, and gross motor were associated with the FFT signals at one-third-day periodicity (P<.001).

Conclusions: The proposed PML algorithm can effectively conduct circadian rhythm analysis using time-series wearable device data. The application of the method effectively characterized sleep-wake rhythm development and identified the association between daily rhythm formation and motor development during early childhood.
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http://dx.doi.org/10.2196/18403DOI Listing
October 2021

A Phenome-Wide Association Study of genes associated with COVID-19 severity reveals shared genetics with complex diseases in the Million Veteran Program.

medRxiv 2021 Oct 6. Epub 2021 Oct 6.

The study aims to determine the shared genetic architecture between COVID-19 severity with existing medical conditions using electronic health record (EHR) data. We conducted a Phenome-Wide Association Study (PheWAS) of genetic variants associated with critical illness (n=35) or hospitalization (n=42) due to severe COVID-19 using genome-wide association summary from the Host Genetics Initiative. PheWAS analysis was performed using genotype-phenotype data from the Veterans Affairs Million Veteran Program (MVP). Phenotypes were defined by International Classification of Diseases (ICD) codes mapped to clinically relevant groups using published PheWAS methods. Among 658,582 Veterans, variants associated with severe COVID-19 were tested for association across 1,559 phenotypes. Variants at the locus (rs495828, rs505922) associated with the largest number of phenotypes (n = 53 and n =59); strongest association with venous embolism, odds ratio (OR 1.33 (p=1.32 × 10 ), and thrombosis OR 1.33, p=2.2 x10 . Among 67 respiratory conditions tested, 11 had significant associations including locus (rs35705950) with increased risk of idiopathic fibrosing alveolitis OR 2.83, p=4.12 × 10 ; rs61667602) associated with reduced risk of pulmonary fibrosis, OR 0.84, p=2.26× 10 . The locus (rs11085727) associated with reduced risk for autoimmune conditions, e.g., psoriasis OR 0.88, p=6.48 x10 , lupus OR 0.84, p=3.97 × 10 . PheWAS stratified by genetic ancestry demonstrated differences in genotype-phenotype associations across ancestry. (rs581342) associated with neutropenia OR 1.29 p=4.1 × 10 among Veterans of African ancestry but not European. Overall, we observed shared genetic architecture between COVID-19 severity and conditions related to underlying risk factors for severe and poor COVID-19 outcomes. Differing associations between genotype-phenotype across ancestries may inform heterogenous outcomes observed with COVID-19. Divergent associations between risk for severe COVID-19 with autoimmune inflammatory conditions both respiratory and non-respiratory highlights the shared pathways and fine balance of immune host response and autoimmunity and caution required when considering treatment targets.
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http://dx.doi.org/10.1101/2021.05.18.21257396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8509103PMC
October 2021

Prevalence of Dyslipidemia and Availability of Lipid-Lowering Medications Among Primary Health Care Settings in China.

JAMA Netw Open 2021 Sep 1;4(9):e2127573. Epub 2021 Sep 1.

National Clinical Research Center for Cardiovascular Diseases, National Health Commission Key Laboratory of Clinical Research for Cardiovascular Medications, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, National Center for Cardiovascular Diseases, Beijing, China.

Importance: Dyslipidemia, the prevalence of which historically has been low in China, is emerging as the second leading yet often unaddressed factor associated with the risk of cardiovascular diseases. However, recent national data on the prevalence, treatment, and control of dyslipidemia are lacking.

Objective: To assess the prevalence, treatment, and control of dyslipidemia in community residents and the availability of lipid-lowering medications in primary care institutions in China.

Design, Setting, And Participants: This cross-sectional study used data from the China-PEACE (Patient-Centered Evaluative Assessment of Cardiac Events) Million Persons Project, which enrolled 2 660 666 community residents aged 35 to 75 years from all 31 provinces in China between December 2014 and May 2019, and the China-PEACE primary health care survey of 3041 primary care institutions. Data analysis was performed from June 2019 to March 2021.

Exposures: Study period.

Main Outcomes And Measures: The main outcome was the prevalence of dyslipidemia, which was defined as total cholesterol greater than or equal to 240 mg/dL, low-density lipoprotein cholesterol (LDL-C) greater than or equal to 160 mg/dL, high-density lipoprotein cholesterol (HDL-C) less than 40 mg/dL, triglycerides greater than or equal to 200 mg/dL, or self-reported use of lipid-lowering medications, in accordance with the 2016 Chinese Adult Dyslipidemia Prevention Guideline.

Results: This study included 2 314 538 participants with lipid measurements (1 389 322 women [60.0%]; mean [SD] age, 55.8 [9.8] years). Among them, 781 865 participants (33.8%) had dyslipidemia. Of 71 785 participants (3.2%) who had established atherosclerotic cardiovascular disease (ASCVD) and were recommended by guidelines for lipid-lowering medications regardless of LDL-C levels, 10 120 (14.1%) were treated. The overall control rate of LDL-C (≤70 mg/dL) among adults with established ASCVD was 26.6% (19 087 participants), with the control rate being 44.8% (4535 participants) among those who were treated and 23.6% (14 552 participants) among those not treated. Of 236 579 participants (10.2%) with high risk of ASCVD, 101 474 (42.9%) achieved LDL-C less than or equal to 100 mg/dL. Among participants with established ASCVD, advanced age (age 65-75 years, odds ratio [OR], 0.63; 95% CI, 0.56-0.70), female sex (OR, 0.56; 95% CI, 0.53-0.58), lower income (reference category), smoking (OR, 0.89; 95% CI, 0.85-0.94), alcohol consumption (OR, 0.87; 95% CI, 0.83-0.92), and not having diabetes (reference category) were associated with lower control of LDL-C. Among participants with high risk of ASCVD, younger age (reference category) and female sex (OR, 0.58; 95% CI, 0.56-0.59) were associated with lower control of LDL-C. Of 3041 primary care institutions surveyed, 1512 (49.7%) stocked statin and 584 (19.2%) stocked nonstatin lipid-lowering drugs. Village clinics in rural areas had the lowest statin availability.

Conclusions And Relevance: These findings suggest that dyslipidemia has become a major public health problem in China and is often inadequately treated and uncontrolled. Statins were available in less than one-half of the primary care institutions. Strategies aimed at detection, prevention, and treatment are needed.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.27573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8482054PMC
September 2021

Single-Cell RNA-Sequencing Portraying Functional Diversity and Clinical Implications of IFI6 in Ovarian Cancer.

Front Cell Dev Biol 2021 25;9:677697. Epub 2021 Aug 25.

Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China.

Ovarian cancer (OC) is one of the most lethal gynecologic malignancies. Most patients die of metastasis due to a lack of other treatments aimed at improving the prognosis of OC patients. In the present study, we use multiple methods to identify prognostic S1 as the dominant subtype in OC, possessing the most ligand-receptor pairs with other cell types. Based on markers of S1, the consensus clustering algorithm is used to explore the clinical treatment subtype in OC. As a result, we identify two clusters associated with distinct survival and drug response. Notably, IFI6 contributes to the cluster classification and seems to be a vital gene in OC carcinogenesis. Functional enrichment analysis demonstrates that its functions involve G2M and cisplatin resistance, and downregulation of IFI6 suppresses proliferation capabilities and significantly potentiates cisplatin-induced apoptosis of OC cells . To explore possible mechanisms of IFI6 influencing OC proliferation and cisplatin resistance, GSEA is conducted and shows that IFI6 is positively correlated with the NF-κB pathway, which is validated by RT-qPCR. Significantly, we develop a prognostic model including IFI6, RiskScore, which is an independent prognostic factor and presents encouraging prognostic values. Our findings provide novel insights into elucidating the biology of OC based on single-cell RNA-sequencing. Moreover, this approach is potentially helpful for personalized anti-cancer strategies and predicting outcomes in the setting of OC.
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http://dx.doi.org/10.3389/fcell.2021.677697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8425592PMC
August 2021

Dopamine promotes the progression of AML via activating NLRP3 inflammasome and IL-1β.

Hum Immunol 2021 Sep 8. Epub 2021 Sep 8.

Department of Hematology, Qilu Hospital of Shandong University, Jinan 250012, China. Electronic address:

Mental stress has been shown to activate sympathetic adrenergic system to produce dopamine and finally promote the progression of cancer. Dopamine can also regulate the immune system through secreting kinds of cytokines. However, what role does dopamine play in acute myeloid leukemia (AML) remains unclear. Here, we investigated the effects and mechanisms of dopamine in NLRP3 inflammasome activation and cellular viability of acute myeloid leukemia U937 cells. Our results showed that dopamine enhanced the viability of U937 cells and activated the NLRP3 inflammasome in U937 cells. To further explore the mechanism of dopamine on U937 cells, we examined the expression level of dopamine receptors (DRs). We found that the mRNA expression level of DR5 in U937 cells was significantly higher than other dopamine receptors. Furthermore, we treated U937 cells with DR1/2/3/5 antagonist before dopamine, and it manifestly reversed the NLRP3 inflammasome activation and the viability-enhancing effect in U937 cells induced by dopamine. Anti-IL-1β antibody also could partly reversed the viability-enhancing effect by dopamine. We concluded that dopamine could enhance the viability of U937 cells through DR1/5 receptor pathway and activate NLRP3 inflammasome.
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http://dx.doi.org/10.1016/j.humimm.2021.07.005DOI Listing
September 2021

SUPERGNOVA: local genetic correlation analysis reveals heterogeneous etiologic sharing of complex traits.

Genome Biol 2021 09 7;22(1):262. Epub 2021 Sep 7.

Department of Biostatistics, Yale School of Public Health, 60 College Street, New Haven, CT, 06520, USA.

Local genetic correlation quantifies the genetic similarity of complex traits in specific genomic regions. However, accurate estimation of local genetic correlation remains challenging, due to linkage disequilibrium in local genomic regions and sample overlap across studies. We introduce SUPERGNOVA, a statistical framework to estimate local genetic correlations using summary statistics from genome-wide association studies. We demonstrate that SUPERGNOVA outperforms existing methods through simulations and analyses of 30 complex traits. In particular, we show that the positive yet paradoxical genetic correlation between autism spectrum disorder and cognitive performance could be explained by two etiologically distinct genetic signatures with bidirectional local genetic correlations.
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http://dx.doi.org/10.1186/s13059-021-02478-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8422619PMC
September 2021

Calculating Orthologous Protein-Coding Sequence Set Probability Using the Poisson Process.

J Comput Biol 2021 Oct 1;28(10):961-974. Epub 2021 Sep 1.

Department of Biostatistics, Yale School of Public Health, New Haven, Connecticut, USA.

We extend the popular Jukes-Cantor evolution model and calculate the probability of an orthologous nucleotide sequence set [a reference sequence () stays with the other sequences ()], where the sequence evolution [from a last common ancestral sequence ()] follows the (prospective) Poisson process with the overall event rate prorated among mutation types (nucleotide/codon substitution, insertion, and deletion) and sites along each sequence. The corresponding retrospective process (reversing the prospective process) facilitates developing algorithms to calculate the marginal probability [Pr()] (Monte Carlo integration) and sample (given ). We calculate probability Pr() based on the identified events (during "") from pairwise sequence alignment to implement Pr(|) calculation (Monte Carlo integration). Event queue sampling and probability magnifiers are used to improve the computational efficiency when the number of events is large. We finally test our procedure on both simulated and recently studied hexapod transcriptome data (Brandt et al.), where each asexual lineage pairs with its closest related sexual lineage. Rate estimates (for and ) and model comparison indicate that the asexual lineages likely mutate several times faster than their sexual relatives.
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http://dx.doi.org/10.1089/cmb.2020.0507DOI Listing
October 2021

Clinical Benefit of Therapeutic Drug Monitoring in Colorectal Cancer Patients Who Received Fluorouracil-Based Chemotherapy.

Med Sci Monit 2021 Jul 31;27:e929474. Epub 2021 Jul 31.

Department of General Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China (mainland).

BACKGROUND The impact of therapeutic drug management (TDM) on reducing toxicity and improving efficacy in colorectal cancer (CRC) patients receiving fluorouracil-based chemotherapy is still unclear. MATERIAL AND METHODS A total of 207 patients (Study Group n=54, Historical Group n=153) with metastatic colorectal cancer were enrolled. All of them received 6 administrations of the 5-FU based regimens. Initial 5-FU dosing of all patients was calculated using body surface area (BSA). In the Study Group, individual exposure during each cycle was measured using a nanoparticle immunoassay, and the 5-FU blood concentration was calculated using the area under the curve (AUC). We adjusted the 5-FU infusion dose of the next cycle based on the AUC data of the previous cycle to achieve the target of 20-30 mg×h/L. RESULTS In the fourth cycle, patients in the target concentration range (AUC mean, 26.3 mg×h/L; Median, 28 mg×h/L; Range, 14-38 mg×h/L; CV, 22.4%) accounted for 46.8% of all patients, which were more than the ones in the first cycle (P<0.001). 5-FU TDM significantly reduced the toxicity of chemotherapy and improved its efficacy. The Study Group (30/289) showed a lower percentage of severe adverse events than that in the Historical Group (185/447) (P<0.001). The incidences of complete response and partial response in the Study Group were higher than those in the Historical Group (P=0.032). CONCLUSIONS TDM in colorectal cancer can reduce toxicity, improve efficacy and clinical outcome, and can be routinely used in 5-FU-based chemotherapy.
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http://dx.doi.org/10.12659/MSM.929474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8336255PMC
July 2021

A fast and robust Bayesian nonparametric method for prediction of complex traits using summary statistics.

PLoS Genet 2021 07 26;17(7):e1009697. Epub 2021 Jul 26.

Program of Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut, United States of America.

Genetic prediction of complex traits has great promise for disease prevention, monitoring, and treatment. The development of accurate risk prediction models is hindered by the wide diversity of genetic architecture across different traits, limited access to individual level data for training and parameter tuning, and the demand for computational resources. To overcome the limitations of the most existing methods that make explicit assumptions on the underlying genetic architecture and need a separate validation data set for parameter tuning, we develop a summary statistics-based nonparametric method that does not rely on validation datasets to tune parameters. In our implementation, we refine the commonly used likelihood assumption to deal with the discrepancy between summary statistics and external reference panel. We also leverage the block structure of the reference linkage disequilibrium matrix for implementation of a parallel algorithm. Through simulations and applications to twelve traits, we show that our method is adaptive to different genetic architectures, statistically robust, and computationally efficient. Our method is available at https://github.com/eldronzhou/SDPR.
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http://dx.doi.org/10.1371/journal.pgen.1009697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8341714PMC
July 2021

Transformation and differential abundance analysis of microbiome data incorporating phylogeny.

Bioinformatics 2021 Jul 24. Epub 2021 Jul 24.

Department of Bioinformatics and Biostatistics, Shanghai Jiao Tong University, Shanghai, China.

Motivation: Microbiome data have proven extremely useful for understanding microbial communities and their impacts in health and disease. Although microbiome analysis methods and standards are evolving rapidly, obtaining meaningful and interpretable results from microbiome studies still requires careful statistical treatment. In particular, many existing and emerging methods for differential abundance analysis fail to account for the fact that microbiome data are high-dimensional and sparse, compositional, negatively and positively correlated, and phylogenetically structured. To better describe microbiome data and improve the power of differential abundance testing, there is still a great need for the continued development of appropriate statistical methodology.

Results: In this paper, we propose a model-based approach for microbiome data transformation, and a phylogenetically informed procedure for differential abundance (DA) testing based on the transformed data. First, we extend the Dirichlet-tree multinomial (DTM) to zero-inflated DTM (ZIDTM) for multivariate modeling of microbial counts, addressing data sparsity, and correlation and phylogeny among bacterial taxa. Then, within this framework and using a Bayesian formulation, we introduce posterior mean transformation to convert raw counts into nonzero relative abundances that sum to one, accounting for the compositionality nature of microbiome data. Second, using the transformed data, we propose adaptive analysis of composition of microbiomes (adaANCOM) for DA testing by constructing log-ratios adaptively on the tree for each taxon, greatly reducing the computational complexity of ANCOM in high dimensions. Finally, we present extensive simulation studies, an analysis of HMP data across 18 body sites and 2 visits, and an application to a gut microbiome and malnutrition study, to investigate the performance of posterior mean transformation and adaANCOM. Comparisons with ANCOM and other DA testing procedures show that adaANCOM controls the false discovery rate well, allows for easy interpretation of the results, and is computationally efficient for high-dimensional problems.

Availability: The developed R package is available at https://github.com/ZRChao/adaANCOM. For replicability purposes, scripts for our simulations and data analysis are available at https://github.com/ZRChao/Papers_supplementary.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btab543DOI Listing
July 2021

TRIM66 Overexpression Promotes Glioma Progression and Regulates Glucose Uptake Through cMyc/GLUT3 Signaling.

Cancer Manag Res 2021 30;13:5187-5201. Epub 2021 Jun 30.

Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, People's Republic of China.

Objective: Tripartite motif 66 (TRIM66) is reported to be closely associated with human cancers. However, the roles of TRIM66 in glioma remain unclear. The present study aimed to investigate the clinical significance and biological roles of TRIM66 in human glioma.

Methods: TRIM66 expression in glioma tissues was examined by immunohistochemistry. TRIM66 overexpression and siRNA knockdown were performed in glioblastoma cell lines. CCK8, colony formation assay, transwell assay, Annexin V and JC1 staining, glucose uptake assay, and Western blotting were used to explore the biological roles and potential underlying mechanisms of TRIM66 in glioma progression.

Results: Our results showed that TRIM66 was overexpressed in 52/95 glioma cases. The rates of TRIM66 overexpression in Grade I, Grade II, Grade III, and Grade IV gliomas were 16.6%, 41.3%, 58.6%, and 70.9%, respectively. Oncomine data showed that TRIM66 was upregulated in glioblastoma and oligodendroglioma compared with normal brain tissues. TRIM66 expression was higher in glioblastoma cell lines compared with normal SVG p12 glial cell line. TRIM66 promoted in vitro and in vivo proliferation, invasion, and inhibited temozolomide (TMZ)-induced apoptosis. Notably, TRIM66 increased glucose metabolism by upregulating glucose uptake, glucose consumption, and ATP production. Western blotting showed that TRIM66 positively regulated cMyc and GLUT3. Depletion of cMyc by siRNA abolished the effect of TRIM66 on GLUT3. Chromatin immunoprecipitation (ChIP) assay showed that cMyc could bind to the promoter regions of GLUT3 in glioblastoma cells.

Conclusion: TRIM66 was upregulated in human gliomas, where it promoted cell growth and chemoresistance. Our data also identified novel roles of TRIM66 in glioma progression. TRIM66 upregulates glucose uptake and mitochondrial function through the cMyc/GLUT3 signaling, which makes it a potential therapeutic target.
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http://dx.doi.org/10.2147/CMAR.S293728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256720PMC
June 2021

Instrumentation-Compact Digital Microfluidic Reaction Interface-Extended Loop-Mediated Isothermal Amplification for Sample-to-Answer Testing of .

Anal Chem 2021 07 6;93(28):9728-9736. Epub 2021 Jul 6.

Medical school, Dalian University, Dalian 116622, China.

is usually spread via consumption of contaminated seafood and causes vibriosis. By combination of digital microfluidic (DMF) and loop-mediated isothermal amplification (LAMP), we provided an automated instrumentation-compact DMF-LAMP device for sample-to-answer detection of . For the first time, how much the proper mixing might facilitate the DMF-LAMP process is explored. The results illustrated that increasing the number of flow configurations and decreasing the fluid-reversibility will extend the interfacial surface available for diffusion-based mass transfer within a droplet microreactor, thus contributing to the overall amplification reaction rate. Noticeably, the DMF-LAMP amplification plateau time is shortened by proper mixing, from 60 min in static mixing and traditional bulk LAMP to 30 min in 2-electrode mixing and 15 min in 3-electrode mixing. The device achieved much higher detection sensitivity (two copies per reaction) than previously reported devices. from spiked shrimps is detected by Q-tip sampling associated with 3-electrode mixing DMF-LAMPs. The detectable signal occurs within only 3 min at a higher concentration and, at most, is delayed to 18 min, with a detection limit of <0.23 × 10 CFU/g. Thus, the developed DMF-LAMP device demonstrates potential for being used as a sample-to-answer system with a quick analysis time, high sensitivity, and sample-to-answer format.
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http://dx.doi.org/10.1021/acs.analchem.1c00917DOI Listing
July 2021

Cytoplasmic Localization Isoform of Cyclin Y Enhanced the Metastatic Ability of Lung Cancer Regulating Tropomyosin 4.

Front Cell Dev Biol 2021 18;9:684819. Epub 2021 Jun 18.

Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China.

Cyclin Y (CCNY) is a novel cyclin and highly conserved in metazoan species. Previous studies from our and other laboratory indicate that CCNY play a crucial role in tumor progression. There are two CCNY isoform which has different subcellular distributions, with cytoplasmic isoform (CCNYc) and membrane distribution isoform (CCNYm). However, the expression and function of CCNY isoforms is still unclear. We firstly found CCNYc was expressed in natural lung cancer tissue and cells through the subcellular distribution. Co-IP and immunofluorescence showed that both CCNYm and CCNYc could interact with PFTK1. Further studies illustrated that CCNYc but not CCNYm enhanced cell migration and invasion activity both and vitro. The function of CCNYc could be inhibited by suppression of PFTK1 expression. In addition, our data indicated that tropomyosin 4 (TPM4), a kind of actin-binding proteins, was down-regulated by suppression of CCNY. F-actin assembly could be controlled by CCNYc as well as PFTK1 and TPM4. As a result, CCNY was mainly expressed in lung cancer. CCNYc could promote cell motility and invasion. It indicated that CCNYc/PFTK1 complex could promote cell metastasis by regulating the formation of F-actin via TPM4.
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http://dx.doi.org/10.3389/fcell.2021.684819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8250429PMC
June 2021

relieve the visceral hypersensitivity in mice induced by infection with chronic stress.

PeerJ 2021 21;9:e11585. Epub 2021 Jun 21.

Department of Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.

Background: Visceral hypersensitivity is a common symptom in patients with post-infectious irritable bowel syndrome (PI-IBS), and change of the microbiota is a vital etiological factor of it. () is one of the probiotics which is reported as the active components in the treatment of IBS, especially IBS with diarrhea. () is an enteropathogenic bacteria which can produce self-limiting colitis in mice, which have been used to produce a PI-IBS-like mice model. Whether could influence the visceral hypersensitivity and gut microbiota of PI-IBS is still unknown. Our study aimed to examine whether the intervention of or antibiotics could affect the etiology of visceral hypersensitivity.

Methods: C57BL/6 male mice were gavaged with the to induce a infective colitis. The and antibiotic compound were used to intervene the infected mice 3 days later. A 9-day chronic water avoidance stress (WAS) process was implemented to help induce the visceral hypersensitivity. The abdominal withdrawal reflex (AWR) score was assayed to indicate the visceral hypersensitivity of different groups. On the 7th, 14th, and 30th days after infection, mice feces were collected and high-throughput sequencing was carried out to analyze their gut microbiota.

Results: Combined, the infection plus chronic stress (WAS) could induce the visceral hypersensitivity in mice. Treatment of the after infection could relieve visceral hypersensitivity of mice, while no difference was observed in the antibiotic treatment group. The gut microbiota diversity of infected mice was similar to the uninfected mice, while there were different microbial communities structure between them. The Shannon and Chao indexes significantly decreased in the antibiotic treatment group compared to other groups at 7th, 14th, and 30th days post-infection, while treatment of could maintain the indexes within normal range. At day 14 after infection, the structure of microbiota headed towards normality after the treatment. After the WAS, the Shannon and Chao indexes of the control group decreased and the structure of microbiota changed. The treatment could prevent these changes of the gut microbiota induced by WAS.

Conclusion: could relieve the visceral hypersensitivity in mice induced by infection plus chronic stress. It could also remodel the microbiota change caused by the infection and chronic stress. It may be a more effective treatment strategy for PI-IBS than antibiotics.
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http://dx.doi.org/10.7717/peerj.11585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223894PMC
June 2021

Genomics of Gulf War Illness in U.S. Veterans Who Served during the 1990-1991 Persian Gulf War: Methods and Rationale for Veterans Affairs Cooperative Study #2006.

Brain Sci 2021 Jun 25;11(7). Epub 2021 Jun 25.

Cooperative Studies Program Clinical Epidemiology Research Center (CSP-CERC), VA Connecticut Healthcare System, West Haven, CT 06516, USA.

Background: Approximately 697,000 members of the U.S. Armed Forces were deployed to the Persian Gulf in support of the 1990-1991 Persian Gulf War (GW). Subsequently, many deployed and some non-deployed veterans developed a chronic multi-symptom illness, now named Gulf War Illness (GWI). This manuscript outlines the methods and rationale for studying the genomics of GWI within the Million Veteran Program (MVP), a VA-based national research program that has linked medical records, surveys, and genomic data, enabling genome-wide association studies (GWASs).

Methods: MVP participants who served in the military during the GW era were contacted by mail and invited to participate in the GWI study. A structured health questionnaire, based on a previously tested instrument, was also included in the mailing. Data on deployment locations and exposures, symptoms associated with GWI, clinical diagnoses, personal habits, and health care utilization were collected. Self-reported data will be augmented with chart reviews and structured international classification of disease codes, to classify participants by GWI case status. We will develop a phenotyping algorithm, based on two commonly used case definitions, to determine GWI status, and then conduct a nested case-control GWAS. Genetic variants associated with GWI will be investigated, and gene-gene and gene-environment interactions studied. The genetic overlap of GWI with, and causative mechanisms linking this illness to, other health conditions and the effects of genomic regulatory mechanisms on GWI risk will also be explored.

Conclusions: The proposed initial GWAS described in this report will investigate the genomic underpinnings of GWI with a large sample size and state-of-the-art genomic analyses and phenotyping. The data generated will provide a rich and expansive foundation on which to build additional analyses.
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http://dx.doi.org/10.3390/brainsci11070845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301942PMC
June 2021

Prevalence of GII.4 Sydney Norovirus Strains and Associated Factors of Acute Gastroenteritis in Children: 2019/2020 Season in Guangzhou, China.

Food Environ Virol 2021 Sep 21;13(3):357-367. Epub 2021 Jun 21.

Medical Genetic Centre, Guangdong Women and Children's Hospital, Guangzhou Medical University, Guangzhou, 511442, People's Republic of China.

Norovirus, the leading cause of non-bacterial acute gastroenteritis (AGE) worldwide, is constantly mutating. Continuous monitoring of the evolution of epidemic genotypes and emergence of novel genotypes is, therefore, necessary. This study determined the prevalence and clinical characteristics of norovirus strains in AGE in Guangzhou, China in 2019/2020 season. This study included children aged 2-60 months diagnosed with AGE in Guangzhou Women and Children Hospital, from August 2019 to January 2020. Norovirus was detected by real-time polymerase chain reaction and clinical data were obtained. Genotyping and phylogenetic analyses were performed with partial gene sequence fragments located within the open reading frames 1 and 2. During the study period, 168 children (61.3% males) were confirmed as norovirus infectious AGE. The main symptoms were diarrhoea and vomiting and 38 patients (22.6%) had seizures. Norovirus was mainly prevalent in October and November, and GII.4 Sydney[P31] was the major genotype circulating in Guangzhou. The phylogenetic tree showed that the Guangzhou strains had high homology with the strains circulating in 2017-2019 worldwide. GII.4 Sydney was the main prevalent norovirus genotype in Guangzhou from August 2019 to January 2020, which had more severe diarrhoea than those of other genotypes. These findings provide a valuable reference for the prevention, control, and treatment of norovirus in the future.
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http://dx.doi.org/10.1007/s12560-021-09482-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215640PMC
September 2021

Proteome characterization of two contrasting soybean genotypes in response to different phosphorus treatments.

AoB Plants 2021 Jun 14;13(3):plab019. Epub 2021 Apr 14.

College of Agronomy, Shenyang Agricultural University, Shenyang 110866, China.

Phosphorus (P) is an essential element for the growth and development of plants. Soybean () is an important food crop that is grown worldwide. Soybean yield is significantly affected by P deficiency in the soil. To investigate the molecular factors that determine the response and tolerance at low-P in soybean, we conducted a comparative proteomics study of a genotype with low-P tolerance (Liaodou 13, L13) and a genotype with low-P sensitivity (Tiefeng 3, T3) in a paper culture experiment with three P treatments, i.e. P-free (0 mmol·L), low-P (0.05 mmol·L) and normal-P (0.5 mmol·L). A total of 4126 proteins were identified in roots of the two genotypes. Increased numbers of differentially expressed proteins (DEPs) were obtained from low-P to P-free conditions compared to the normal-P treatment. All DEPs obtained in L13 (660) were upregulated in response to P deficiency, while most DEPs detected in T3 (133) were downregulated under P deficiency. Important metabolic pathways such as oxidative phosphorylation, glutathione metabolism and carbon metabolism were suppressed in T3, which could have affected the survival of the plants in P-limited soil. In contrast, L13 increased the metabolic activity in the 2-oxocarboxylic acid metabolism, carbon metabolism, glycolysis, biosynthesis of amino acids, pentose phosphatase, oxidative phosphorylation, other types of -glycan biosynthesis and riboflavin metabolic pathways in order to maintain normal plant growth under P deficiency. Three key proteins I1KW20 (prohibitins), I1K3U8 (alpha-amylase inhibitors) and C6SZ93 (alpha-amylase inhibitors) were suggested as potential biomarkers for screening soybean genotypes with low-P tolerance. Overall, this study provides new insights into the response and tolerance to P deficiency in soybean.
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http://dx.doi.org/10.1093/aobpla/plab019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209930PMC
June 2021

DIAPH1 Variants in Non-East Asian Patients With Sporadic Moyamoya Disease.

JAMA Neurol 2021 Aug;78(8):993-1003

Yale Center for Genome Analysis, West Haven, Connecticut.

Importance: Moyamoya disease (MMD), a progressive vasculopathy leading to narrowing and ultimate occlusion of the intracranial internal carotid arteries, is a cause of childhood stroke. The cause of MMD is poorly understood, but genetic factors play a role. Several familial forms of MMD have been identified, but the cause of most cases remains elusive, especially among non-East Asian individuals.

Objective: To assess whether ultrarare de novo and rare, damaging transmitted variants with large effect sizes are associated with MMD risk.

Design, Setting, And Participants: A genetic association study was conducted using whole-exome sequencing case-parent MMD trios in a small discovery cohort collected over 3.5 years (2016-2019); data were analyzed in 2020. Medical records from US hospitals spanning a range of 1 month to 1.5 years were reviewed for phenotyping. Exomes from a larger validation cohort were analyzed to identify additional rare, large-effect variants in the top candidate gene. Participants included patients with MMD and, when available, their parents. All participants who met criteria and were presented with the option to join the study agreed to do so; none were excluded. Twenty-four probands (22 trios and 2 singletons) composed the discovery cohort, and 84 probands (29 trios and 55 singletons) composed the validation cohort.

Main Outcomes And Measures: Gene variants were identified and filtered using stringent criteria. Enrichment and case-control tests assessed gene-level variant burden. In silico modeling estimated the probability of variant association with protein structure. Integrative genomics assessed expression patterns of MMD risk genes derived from single-cell RNA sequencing data of human and mouse brain tissue.

Results: Of the 24 patients in the discovery cohort, 14 (58.3%) were men and 18 (75.0%) were of European ancestry. Three of 24 discovery cohort probands contained 2 do novo (1-tailed Poisson P = 1.1 × 10-6) and 1 rare, transmitted damaging variant (12.5% of cases) in DIAPH1 (mammalian diaphanous-1), a key regulator of actin remodeling in vascular cells and platelets. Four additional ultrarare damaging heterozygous DIAPH1 variants (3 unphased) were identified in 3 other patients in an 84-proband validation cohort (73.8% female, 77.4% European). All 6 patients were non-East Asian. Compound heterozygous variants were identified in ena/vasodilator-stimulated phosphoproteinlike protein EVL, a mammalian diaphanous-1 interactor that regulates actin polymerization. DIAPH1 and EVL mutant probands had severe, bilateral MMD associated with transfusion-dependent thrombocytopenia. DIAPH1 and other MMD risk genes are enriched in mural cells of midgestational human brain. The DIAPH1 coexpression network converges in vascular cell actin cytoskeleton regulatory pathways.

Conclusions And Relevance: These findings provide the largest collection to date of non-East Asian individuals with sporadic MMD harboring pathogenic variants in the same gene. The results suggest that DIAPH1 is a novel MMD risk gene and impaired vascular cell actin remodeling in MMD pathogenesis, with diagnostic and therapeutic ramifications.
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http://dx.doi.org/10.1001/jamaneurol.2021.1681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204259PMC
August 2021

Correlating genomic copy number alterations with clinicopathologic findings in 75 cases of hepatocellular carcinoma.

BMC Med Genomics 2021 06 8;14(1):150. Epub 2021 Jun 8.

Department of Cell Biology and Genetics, School of Pre-Clinical Medicine, Guangxi Medical University, Nanning, Guangxi, People's Republic of China.

Background: Oligonucleotide array comparative genomic hybridization (aCGH) analysis has been used for detecting somatic copy number alterations (CNAs) in various types of tumors. This study aimed to assess the clinical utility of aCGH for cases of hepatocellular carcinoma (HCC) and to evaluate the correlation between CNAs and clinicopathologic findings.

Methods: aCGH was performed on 75 HCC cases with paired DNA samples from tumor and adjacent nontumor tissues. Survival outcomes from these cases were analyzed based on Barcelona-Clinic Liver Cancer Stage (BCLC), Edmondson-Steiner grade (E-S), and recurrence status. Correlation of CNAs with clinicopathologic findings was analyzed by Wilcoxon rank test and clustering vs. K means.

Results: The survival outcomes indicated that BCLC stages and recurrence status could be predictors and E-S grades could be a modifier for HCC. The most common CNAs involved gains of 1q and 8q and a loss of 16q (50%), losses of 4q and 17p and a gain of 5p (40%), and losses of 8p and 13q (30%). Analyses of genomic profiles and clusters identified that losses of 4q13.2q35.2 and 10q22.3q26.13 seen in cases of stage A, grade III and nonrecurrence were likely correlated with good survival, while loss of 1p36.31p22.1 and gains of 2q11.2q21.2 and 20p13p11.1 seen in cases of stage C, grade III and recurrence were possibly correlated with worst prognosis.

Conclusions: These results indicated that aCGH analysis could be used to detect recurrent CNAs and involved key genes and pathways in patients with HCC. Further analysis on a large case series to validate the correlation of CNAs with clinicopathologic findings of HCC could provide information to interpret CNAs and predict prognosis.
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http://dx.doi.org/10.1186/s12920-021-00998-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185937PMC
June 2021

Hematopoietic mosaic chromosomal alterations increase the risk for diverse types of infection.

Nat Med 2021 06 7;27(6):1012-1024. Epub 2021 Jun 7.

Institute for Molecular Medicine Finland, Helsinki, Finland.

Age is the dominant risk factor for infectious diseases, but the mechanisms linking age to infectious disease risk are incompletely understood. Age-related mosaic chromosomal alterations (mCAs) detected from genotyping of blood-derived DNA, are structural somatic variants indicative of clonal hematopoiesis, and are associated with aberrant leukocyte cell counts, hematological malignancy, and mortality. Here, we show that mCAs predispose to diverse types of infections. We analyzed mCAs from 768,762 individuals without hematological cancer at the time of DNA acquisition across five biobanks. Expanded autosomal mCAs were associated with diverse incident infections (hazard ratio (HR) 1.25; 95% confidence interval (CI) = 1.15-1.36; P = 1.8 × 10), including sepsis (HR 2.68; 95% CI = 2.25-3.19; P = 3.1 × 10), pneumonia (HR 1.76; 95% CI = 1.53-2.03; P = 2.3 × 10), digestive system infections (HR 1.51; 95% CI = 1.32-1.73; P = 2.2 × 10) and genitourinary infections (HR 1.25; 95% CI = 1.11-1.41; P = 3.7 × 10). A genome-wide association study of expanded mCAs identified 63 loci, which were enriched at transcriptional regulatory sites for immune cells. These results suggest that mCAs are a marker of impaired immunity and confer increased predisposition to infections.
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http://dx.doi.org/10.1038/s41591-021-01371-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245201PMC
June 2021

Epigenetic age acceleration, fatigue, and inflammation in patients undergoing radiation therapy for head and neck cancer: A longitudinal study.

Cancer 2021 Sep 24;127(18):3361-3371. Epub 2021 May 24.

Emory University School of Medicine, Atlanta, Georgia.

Background: The authors measured epigenetic age acceleration (EAA) during and after cancer treatment and its association with inflammation and fatigue, which is a debilitating symptom in patients with cancer.

Methods: Patients who had head and neck cancer without distant metastases were assessed before, immediately after, and at 6 months and 12 months postradiotherapy. Blood DNA methylation was assessed using a proprietary bead chip (the Illumina MethylationEPIC BeadChip). EAA was calculated using the Levine epigenetic clock (DNAmPhenoAge), adjusted for chronological age. Fatigue was assessed using the Multidimensional Fatigue Inventory-20. Inflammatory markers were measured using standard techniques.

Results: Most patients (N = 133) were men, White, had advanced disease, and received concurrent chemoradiation. EAA changes over time were significant, with the largest increase (4.9 years) observed immediately after radiotherapy (P < .001). Increased EAA was associated with elevated fatigue (P = .003) over time, and patients who had severe fatigue experienced 3.1 years higher EAA than those who had low fatigue (P < .001), which was more prominent (5.6 years; P = .018) for patients who had human papillomavirus-unrelated disease at 12 months posttreatment. EAA was also positively associated with inflammatory markers, including C-reactive protein (CRP) and interleukin-6 (IL-6), over time (P < .001), and patients who had high CRP and IL-6 levels exhibited increases of 4.6 and 5.9 years, respectively, in EAA compared with those who had low CRP and IL-6 levels (P < .001). CRP and IL-6 mediated the association between EAA and fatigue (CRP: 95% CI, 0.060-0.279; IL-6: 95% CI, 0.024-0.220).

Conclusions: Patients with head and neck cancer experienced increased EAA, especially immediately after treatment completion. EAA was associated with greater fatigue and inflammation, including 1 year after treatment. Inflammation may be a target to reduce the impact of age acceleration on poor functional outcomes.
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http://dx.doi.org/10.1002/cncr.33641DOI Listing
September 2021

Effects of dexmedetomide, propofol and remifentanil on perioperative inflammatory response and lung function during lung cancer surgery.

Am J Transl Res 2021 15;13(4):2537-2545. Epub 2021 Apr 15.

Department of Anesthesiology, Jinan Central Hospital Affiliated to Shandong University Jinan 250014, Shandong Province, China.

Objective: To investigate the effects of combined anesthesia with dexmedetomide, propofol and remifentanil on perioperative inflammatory response and pulmonary function in patients with lung cancer.

Methods: 90 patients with lung cancer admitted to our hospital from April 2017 to April 2019 were selected. According to different anesthesia schemes, patients undergoing combined anesthesia with propofol and remifentanil were included in group A (GA), and patients receiving combined anesthesia with dexmedetomidine, propofol and remifentanil were included in group B (GB). The blood gas, pulmonary function index, inflammatory factor level in serum, anesthetic effect and complications were compared between the two groups.

Results: HR indexes at T1 and T2 in GB were significantly lower than those in GA (P<0.001). There was no significant fluctuation in PaCO2 and PaO2 indexes in the two groups at different time points (P>0.05). At T0, T1 and T2, RV/TLC levels in serum increased significantly in the two groups. (MVV-VE)/FEV1 and MVV/FEV levels were significantly decreased (all P<0.05). The fluctuation levels of RV/TLC, (MVV-VE)/FEV1 and MVV/FEV levels in serum of GB were significantly lower than those of GA at T1 and T2 (P<0.05). At T0, T1 and T2, the levels of inflammatory factors in serum were significantly decreased in the two groups (P<0.05), but the levels of inflammatory factors in serum of GB were significantly lower than those of GA at T1 and T2 (P<0.05). The VAS scores of GB were significantly lower than those of GA at 1 hour and 4 hours after operation (P<0.05). Ramsay scores of GB were significantly higher than those of GA at 1 hour and 4 hours after operation (P<0.05). The restlessness score and choking cough score in GB were lower than those in GA (P<0.05). Perioperative complications in GB were better than those in GA (P<0.05).

Conclusion: On the basis of propofol and remifentanil anesthesia, the combination of dexmedetomidine for anesthesia induction can achieve satisfactory anesthesia effect. On the basis of propofol and remifentanil anesthesia combined with dexmedetomidine for anesthesia induction, it can significantly inhibit the inflammatory response of lung cancer patients during perioperative period and it can more effectively stabilize the blood gas microcirculation and lung function of patients.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129352PMC
April 2021

Transcriptome-wide association analysis of brain structures yields insights into pleiotropy with complex neuropsychiatric traits.

Nat Commun 2021 05 17;12(1):2878. Epub 2021 May 17.

Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Structural variations of the human brain are heritable and highly polygenic traits, with hundreds of associated genes identified in recent genome-wide association studies (GWAS). Transcriptome-wide association studies (TWAS) can both prioritize these GWAS findings and also identify additional gene-trait associations. Here we perform cross-tissue TWAS analysis of 211 structural neuroimaging and discover 278 associated genes exceeding Bonferroni significance threshold of 1.04 × 10. The TWAS-significant genes for brain structures have been linked to a wide range of complex traits in different domains. Through TWAS gene-based polygenic risk scores (PRS) prediction, we find that TWAS PRS gains substantial power in association analysis compared to conventional variant-based GWAS PRS, and up to 6.97% of phenotypic variance (p-value = 7.56 × 10) can be explained in independent testing data sets. In conclusion, our study illustrates that TWAS can be a powerful supplement to traditional GWAS in imaging genetics studies for gene discovery-validation, genetic co-architecture analysis, and polygenic risk prediction.
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http://dx.doi.org/10.1038/s41467-021-23130-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128893PMC
May 2021

Atlastin 2/3 regulate ER targeting of the ULK1 complex to initiate autophagy.

J Cell Biol 2021 07 14;220(7). Epub 2021 May 14.

National Laboratory of Biomacromolecules, Chinese Academy of Sciences Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, People's Republic of China.

Dynamic targeting of the ULK1 complex to the ER is crucial for initiating autophagosome formation and for subsequent formation of ER-isolation membrane (IM; autophagosomal precursor) contact during IM expansion. Little is known about how the ULK1 complex, which comprises FIP200, ULK1, ATG13, and ATG101 and does not exist as a constitutively coassembled complex, is recruited and stabilized on the ER. Here, we demonstrate that the ER-localized transmembrane proteins Atlastin 2 and 3 (ATL2/3) contribute to recruitment and stabilization of ULK1 and ATG101 at the FIP200-ATG13-specified autophagosome formation sites on the ER. In ATL2/3 KO cells, formation of FIP200 and ATG13 puncta is unaffected, while targeting of ULK1 and ATG101 is severely impaired. Consequently, IM initiation is compromised and slowed. ATL2/3 directly interact with ULK1 and ATG13 and facilitate the ATG13-mediated recruitment/stabilization of ULK1 and ATG101. ATL2/3 also participate in forming ER-IM tethering complexes. Our study provides insights into the dynamic assembly of the ULK1 complex on the ER for autophagosome formation.
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http://dx.doi.org/10.1083/jcb.202012091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129792PMC
July 2021

Association of Epigenetic Age Acceleration With Risk Factors, Survival, and Quality of Life in Patients With Head and Neck Cancer.

Int J Radiat Oncol Biol Phys 2021 09 18;111(1):157-167. Epub 2021 Apr 18.

Nell Hodgson Woodruff School of Nursing, Emory University, Atlanta, Georgia.

Purpose: Epigenetic age acceleration (EAA) is robustly linked with mortality and morbidity. This study examined risk factors of EAA and its association with overall survival (OS), progression-free survival (PFS), and quality of life (QOL) in patients with head and neck cancer (HNC) receiving radiation therapy.

Methods And Materials: Patients without distant metastasis were enrolled and followed before and at the end of radiation therapy and at 6 and 12 months after radiation therapy. EAA was calculated with DNAmPhenoAge at all 4 time points. Risk factors included demographic characteristics, lifestyle, clinical characteristics, treatment-related symptoms, and blood biomarkers. Survival data were collected until August 2020, and QOL was measured using Functional Assessment of Cancer Therapy-HNC.

Results: Increased comorbidity, symptoms unrelated to human papilloma virus, and more severe treatment-related symptoms were associated with higher EAA (P = .03 to P < .001). A nonlinear association (quadratic) between body mass index (BMI) and EAA was observed: decreased BMI (<35 kg/m; P = .04) and increased BMI (≥35 kg/m; P = .01) were linked to higher EAA. Increased EAA (per year) was associated with worse OS (hazard ratio [HR], 1.11 [95% confidence interval {CI}, 1.03-1.18; P = .004]; HR, 1.10 [95% CI, 1.01-1.19; P = .02] for EAA at 6 and 12 months after treatment, respectively) and PFS (HR, 1.10 [95% CI, 1.02-1.19; P = .02]; HR, 1.14 [95% CI, 1.06-1.23; P < .001]; and HR, 1.08 [95% CI, 1.02-1.14; P = .01]) for EAA before, immediately after, and 6 months after radiation therapy, respectively) and QOL over time (β = -0.61; P = .001). An average of 3.25 to 3.33 years of age acceleration across time, which was responsible for 33% to 44% higher HRs of OS and PFS, was observed in those who died or developed recurrence compared with those who did not (all P < .001).

Conclusions: Compared with demographic and lifestyle factors, clinical characteristics were more likely to contribute to faster biological aging in patients with HNC. Acceleration in epigenetic age resulted in more aggressive adverse events, including OS and PFS. EAA could be considered as a marker for cancer outcomes, and decelerating aging could improve survival and QOL.
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http://dx.doi.org/10.1016/j.ijrobp.2021.04.002DOI Listing
September 2021

The impact of removing former drinkers from genome-wide association studies of AUDIT-C.

Addiction 2021 11 6;116(11):3044-3054. Epub 2021 May 6.

Yale University School of Public Health, New Haven, CT, USA.

Background And Aims: The Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) questionnaire screens for harmful drinking using a 12-month timeframe. A score of 0 is assigned to individuals who report abstaining from alcohol in the past year. However, many middle-age individuals reporting current abstinence are former drinkers (FDs). Because FDs may be more genetically prone to harmful alcohol use than lifelong abstainers (LAs) and are often combined with LAs, we evaluated the impact of differentiating them on the identification of genetic association.

Design And Setting: The United Kingdom Biobank (UKBB) includes AUDIT-C and alcohol drinker status.

Participants: 131 510 Europeans, including 5135 FDs.

Measurements: We compared three genome-wide association (GWAS) analyses to explore the effects of removing FDs: the full AUDIT-C data, AUDIT-C data without FDs, and data from a random sample numerically matched to the data without FDs. Because prior studies show a consistent association of the ADH1B polymorphism rs1229984 with both alcohol consumption and alcohol use disorder, we compared allele frequencies for rs1229984 stratified by AUDIT-C value and FD versus LA status. Additionally, we calculated polygenic risk scores (PRS) of related diseases.

Findings: The rs1229984 allele frequencies among FDs were numerically comparable to those with high AUDIT-C scores and very different from those of LAs. Removing FDs from GWAS yielded a stronger association with rs1229984 (P value after removal: 1.9 × 10 vs 1.7 × 10 and 2.5 × 10 ), more statistically significant single nucleotide polymorphisms (SNPs) (after removal: 11 vs 9 and 8), and genomic loci (after removal: 11 vs 9 and 7). Additional independent SNPs were identified after removal of FDs: rs2817866 (PTGER3), rs7105867 (ANO3), and rs17601612 (DRD2). For PRS of alcohol use disorder and major depressive disorder, there are statistically significant differences between FDs and LAs.

Conclusions: Differentiating between former drinkers and lifelong abstainers can improve Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) genome-wide association results.
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http://dx.doi.org/10.1111/add.15511DOI Listing
November 2021

Posttraumatic Stress Disorder Brain Transcriptomics: Convergent Genomic Signatures Across Biological Sex.

Biol Psychiatry 2021 Feb 22. Epub 2021 Feb 22.

Department of Psychiatry, Yale School of Medicine, New Haven, Connecticut; Psychiatry Service, Veterans Administration Connecticut Healthcare System, West Haven, Connecticut; Veterans Administration National Center for PTSD, West Haven, Connecticut. Electronic address:

While a definitive understanding of the molecular pathology of posttraumatic stress disorder (PTSD) is far from a current reality, it has become increasingly clear that many of the molecular effects of PTSD are sex specific. Women are twice as likely as men to develop PTSD after a traumatic event, and neurobiological evidence suggests that there are structural differences between the brains of males versus females with PTSD. Recent advances in genomic technologies have begun to shed light on the sex-specific molecular determinants of PTSD, which seem to be governed predominantly by dysfunction of GABAergic (gamma-aminobutyric acidergic) signaling and immune function. We review the current state of the field of PTSD genomics focusing on the effect of sex. We provide an overview of difference in heritability of PTSD based on sex, how difference in gene regulation based on sex impacts the PTSD brain, and what is known about genomic regulation that is dysregulated in specific cell types in PTSD.
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http://dx.doi.org/10.1016/j.biopsych.2021.02.012DOI Listing
February 2021

Isorhynchophylline ameliorates paraquat-induced acute kidney injury by attenuating oxidative stress and mitochondrial damage via regulating toll-interacting expression.

Toxicol Appl Pharmacol 2021 06 8;420:115521. Epub 2021 Apr 8.

Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China. Electronic address:

Isorhynchophylline (IRN) is an alkaloid with anti-inflammatory and anti-oxidative activities in cardiovascular and brain diseases, but its role in paraquat (PQ)-induced acute kidney injury (AKI) is yet unknown. The model of PQ-induced AKI in rats was established by intraperitoneal injection of PQ (25 mg/kg). We found that the tail vein injection of IRN (4 mg/kg) significantly increased the survival rate of PQ-intoxicated rats. IRN administration alleviated PQ-induced renal injury and renal dysfunction in rats, as evidenced by decreased apoptosis in renal cortex and reduced serum creatinine, serum BUN, and urine NGAL levels. Furthermore, IRN treatment improved the PQ-triggered oxidative stress in renal cortex by increasing the levels of anti-oxidant indicators (SOD activity, GSH/GSSG ratio, levels of Nrf-2, NQO-1, and HO-1 in renal cortex) and decreasing the levels of oxidative stress indexes (ROS and MDA levels in renal cortex). Interestingly, toll-interacting protein (Tollip), a negative regulator of interleukin 1 receptor associated kinase 1 (IRAK1) phosphorylation, was demonstrated to be increased by IRN injection in the renal cortex of PQ-intoxicated rats. In vitro experiments revealed that IRN protected renal tubular epithelial cells against PQ toxicity through suppressing oxidative stress and mitochondrial damage, and these protective effects were reversed by Tollip shRNA. Collectively, the present study demonstrated that IRN ameliorated PQ-induced AKI by attenuating oxidative stress and mitochondrial damage through upregulating Tollip, which provides new insights into the pathogenesis and treatment of PQ poisoning.
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http://dx.doi.org/10.1016/j.taap.2021.115521DOI Listing
June 2021

Polygenic risk score, healthy lifestyles, and risk of incident depression.

Transl Psychiatry 2021 03 29;11(1):189. Epub 2021 Mar 29.

School of Public Health, Tianjin Medical University, Tianjin, China.

Genetic factors increase the risk of depression, but the extent to which this can be offset by modifiable lifestyle factors is unknown. We investigated whether a combination of healthy lifestyles is associated with lower risk of depression regardless of genetic risk. Data were obtained from the UK Biobank and consisted of 339,767 participants (37-73 years old) without depression between 2006 and 2010. Genetic risk was categorized as low, intermediate, or high according to polygenic risk score for depression. A combination of healthy lifestyles factors-including no current smoking, regular physical activity, a healthy diet, moderate alcohol intake and a body mass index <30 kg/m-was categorized into favorable, intermediate, and unfavorable lifestyles. The risk of depression was 22% higher among those at high genetic risk compared with those at low genetic risk (HR = 1.22, 95% CI: 1.14-1.30). Participants with high genetic risk and unfavorable lifestyle had a more than two-fold risk of incident depression compared with low genetic risk and favorable lifestyle (HR = 2.18, 95% CI: 1.84-2.58). There was no significant interaction between genetic risk and lifestyle factors (P for interaction = 0.69). Among participants at high genetic risk, a favorable lifestyle was associated with nearly 50% lower relative risk of depression than an unfavorable lifestyle (HR = 0.51, 95% CI: 0.43-0.60). We concluded that genetic and lifestyle factors were independently associated with risk of incident depression. Adherence to healthy lifestyles may lower the risk of depression regardless of genetic risk.
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http://dx.doi.org/10.1038/s41398-021-01306-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007584PMC
March 2021
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