Search

Your search keyword '"LI Zhi"' showing total 485 results
Start Over Author "LI Zhi" Topic humans
485 results on '"LI Zhi"'

1. Multi-molecular hyperspectral PRM-SRS microscopy

Author

Zhang, Wenxu, Li, Yajuan, Fung, Anthony A, Li, Zhi, Jang, Hongje, Zha, Honghao, Chen, Xiaoping, Gao, Fangyuan, Wu, Jane Y, Sheng, Huaxin, Yao, Junjie, Skowronska-Krawczyk, Dorota, Jain, Sanjay, and Shi, Lingyan

Subjects
Analytical Chemistry, Chemical Sciences, Bioengineering, Brain Disorders, 1.1 Normal biological development and functioning, Underpinning research, Generic health relevance, Animals, Mice, Humans, Microscopy, Nonlinear Optical Microscopy, Spectrum Analysis, Raman, Lipids
Abstract

Lipids play crucial roles in many biological processes. Mapping spatial distributions and examining the metabolic dynamics of different lipid subtypes in cells and tissues are critical to better understanding their roles in aging and diseases. Commonly used imaging methods (such as mass spectrometry-based, fluorescence labeling, conventional optical imaging) can disrupt the native environment of cells/tissues, have limited spatial or spectral resolution, or cannot distinguish different lipid subtypes. Here we present a hyperspectral imaging platform that integrates a Penalized Reference Matching algorithm with Stimulated Raman Scattering (PRM-SRS) microscopy. Using this platform, we visualize and identify high density lipoprotein particles in human kidney, a high cholesterol to phosphatidylethanolamine ratio inside granule cells of mouse hippocampus, and subcellular distributions of sphingosine and cardiolipin in human brain. Our PRM-SRS displays unique advantages of enhanced chemical specificity, subcellular resolution, and fast data processing in distinguishing lipid subtypes in different organs and species.

Published
2024

2. Goldilocks Energy Minimum: Peptide-Based Reversible Aggregation and Biosensing

Author

Yim, Wonjun, Retout, Maurice, Chen, Amanda A, Ling, Chuxuan, Amer, Lubna, Jin, Zhicheng, Chang, Yu-Ci, Chavez, Saul, Barrios, Karen, Lam, Benjamin, Li, Zhi, Zhou, Jiajing, Shi, Lingyan, Pascal, Tod A, and Jokerst, Jesse V

Subjects
Analytical Chemistry, Engineering, Chemical Sciences, Nanotechnology, Bioengineering, Humans, Gold, COVID-19, Metal Nanoparticles, Peptides, Peptide Hydrolases, colorimetric biosensor, DLVO theory, reversibleaggregation, dissociation peptide, matrix-insensitive, SARS-CoV-19, reversible aggregation, Nanoscience & Nanotechnology, Chemical sciences, Physical sciences
Abstract

Colorimetric biosensors based on gold nanoparticle (AuNP) aggregation are often challenged by matrix interference in biofluids, poor specificity, and limited utility with clinical samples. Here, we propose a peptide-driven nanoscale disassembly approach, where AuNP aggregates induced by electrostatic attractions are dissociated in response to proteolytic cleavage. Initially, citrate-coated AuNPs were assembled via a short cationic peptide (RRK) and characterized by experiments and simulations. The dissociation peptides were then used to reversibly dissociate the AuNP aggregates as a function of target protease detection, i.e., main protease (Mpro), a biomarker for severe acute respiratory syndrome coronavirus 2. The dissociation propensity depends on peptide length, hydrophilicity, charge, and ligand architecture. Finally, our dissociation strategy provides a rapid and distinct optical signal through Mpro cleavage with a detection limit of 12.3 nM in saliva. Our dissociation peptide effectively dissociates plasmonic assemblies in diverse matrices including 100% human saliva, urine, plasma, and seawater, as well as other types of plasmonic nanoparticles such as silver. Our peptide-enabled dissociation platform provides a simple, matrix-insensitive, and versatile method for protease sensing.

Published
2023

3. Clinical significance and molecular annotation of cellular morphometric subtypes in lower-grade gliomas discovered by machine learning

Author

Liu, Xiao-Ping, Jin, Xiaoqing, Ahmadian, Saman Seyed, Yang, Xu, Tian, Su-Fang, Cai, Yu-Xiang, Chawla, Kuldeep, Snijders, Antoine M, Xia, Yankai, van Diest, Paul J, Weiss, William A, Mao, Jian-Hua, Li, Zhi-Qiang, Vogel, Hannes, and Chang, Hang

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Clinical Research, Human Genome, Brain Cancer, Cancer, Brain Disorders, Genetics, Rare Diseases, Orphan Drug, Detection, screening and diagnosis, 4.2 Evaluation of markers and technologies, Good Health and Well Being, Humans, Brain Neoplasms, Artificial Intelligence, Clinical Relevance, Glioma, Machine Learning, Tumor Microenvironment, cellular morphometric biomarkers, cellular morphometric subtypes, glioblastoma, immunohistochemistry, lower-grade glioma, nomogram, overall survival, stacked predictive sparse decomposition, Neurosciences, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

BackgroundLower-grade gliomas (LGG) are heterogeneous diseases by clinical, histological, and molecular criteria. We aimed to personalize the diagnosis and therapy of LGG patients by developing and validating robust cellular morphometric subtypes (CMS) and to uncover the molecular signatures underlying these subtypes.MethodsCellular morphometric biomarkers (CMBs) were identified with artificial intelligence technique from TCGA-LGG cohort. Consensus clustering was used to define CMS. Survival analysis was performed to assess the clinical impact of CMBs and CMS. A nomogram was constructed to predict 3- and 5-year overall survival (OS) of LGG patients. Tumor mutational burden (TMB) and immune cell infiltration between subtypes were analyzed using the Mann-Whitney U test. The double-blinded validation for important immunotherapy-related biomarkers was executed using immunohistochemistry (IHC).ResultsWe developed a machine learning (ML) pipeline to extract CMBs from whole-slide images of tissue histology; identifying and externally validating robust CMS of LGGs in multicenter cohorts. The subtypes had independent predicted OS across all three independent cohorts. In the TCGA-LGG cohort, patients within the poor-prognosis subtype responded poorly to primary and follow-up therapies. LGGs within the poor-prognosis subtype were characterized by high mutational burden, high frequencies of copy number alterations, and high levels of tumor-infiltrating lymphocytes and immune checkpoint genes. Higher levels of PD-1/PD-L1/CTLA-4 were confirmed by IHC staining. In addition, the subtypes learned from LGG demonstrate translational impact on glioblastoma (GBM).ConclusionsWe developed and validated a framework (CMS-ML) for CMS discovery in LGG associated with specific molecular alterations, immune microenvironment, prognosis, and treatment response.

Published
2023

4. NTRK fusion positive colorectal cancer is a unique subset of CRC with high TMB and microsatellite instability.

Author

Wang, Hui, Li, Zhi-Wei, Ou, Qiuxiang, Wu, Xue, Nagasaka, Misako, Shao, Yang, Ou, Sai-Hong, and Yang, Yu

Subjects
POLE/POLD1, NTRK, colorectal cancer, gene fusions, microsatellite instability, tumor mutation burden, Colorectal Neoplasms, Gene Fusion, Humans, Microsatellite Instability, Mutation
Abstract

TRK fusions are rare but targetable mutations which occur across a wide variety of cancer types. We report the prevalence of approximately 0.7% for NTRK-positive colorectal cancer (CRC) by genetically profiling 2519 colonic and rectal tumors. The aberrations of APC and TP53 frequently co-occurred with NTRK gene fusions, whereas RAS/BRAF oncogenic alterations and NTRK fusions were almost always mutually exclusive. NTRK-driven colorectal cancer patients demonstrated increased TMB (median = 53 mut/MB, 95% CI: 36.8-68.0 mut/MB), high microsatellite instability, and an enrichment for POLE/POLD1 mutations when compared to molecularly unstratified colorectal cancer population. These data shed light on possible future approach of multimodality treatment regimen including TRK-targeted therapy and immune checkpoint inhibitor therapy in NTRK-positive CRCs.

Published
2022

5. Engineering micro oxygen factories to slow tumour progression via hyperoxic microenvironments

Author

Wang, Weili, Zheng, Huizhen, Jiang, Jun, Li, Zhi, Jiang, Dongpeng, Shi, Xiangru, Wang, Hui, Jiang, Jie, Xie, Qianqian, Gao, Meng, Chu, Jianhong, Cai, Xiaoming, Xia, Tian, and Li, Ruibin

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Breast Neoplasms, Capsules, Cell Hypoxia, Disease Progression, Female, Humans, Hyperoxia, Hypoxia-Inducible Factor 1, alpha Subunit, Oxygen, Tumor Microenvironment
Abstract

While hypoxia promotes carcinogenesis, tumour aggressiveness, metastasis, and resistance to oncological treatments, the impacts of hyperoxia on tumours are rarely explored because providing a long-lasting oxygen supply in vivo is a major challenge. Herein, we construct micro oxygen factories, namely, photosynthesis microcapsules (PMCs), by encapsulation of acquired cyanobacteria and upconversion nanoparticles in alginate microcapsules. This system enables a long-lasting oxygen supply through the conversion of external radiation into red-wavelength emissions for photosynthesis in cyanobacteria. PMC treatment suppresses the NF-kB pathway, HIF-1α production and cancer cell proliferation. Hyperoxic microenvironment created by an in vivo PMC implant inhibits hepatocarcinoma growth and metastasis and has synergistic effects together with anti-PD-1 in breast cancer. The engineering oxygen factories offer potential for tumour biology studies in hyperoxic microenvironments and inspire the exploration of oncological treatments.

Published
2022

6. Psychological Well-Being of Left-Behind Children in China: Text Mining of the Social Media Website Zhihu

Author

Lyu, Yuwen, Chow, Julian Chun-Chung, Hwang, Ji-Jen, Li, Zhi, Ren, Cheng, and Xie, Jungui

Subjects
Clinical Research, Behavioral and Social Science, Depression, Mental Health, Prevention, Suicide, Mental health, Good Health and Well Being, Child, China, Data Mining, Humans, Social Media, Suicidal Ideation, left-behind children, personal narrative text, text mining, linguistic analysis, textual analysis, psychological well-being, Toxicology
Abstract

China's migrant population has significantly contributed to its economic growth; however, the impact on the well-being of left-behind children (LBC) has become a serious public health problem. Text mining is an effective tool for identifying people's mental state, and is therefore beneficial in exploring the psychological mindset of LBC. Traditional data collection methods, which use questionnaires and standardized scales, are limited by their sample sizes. In this study, we created a computational application to quantitively collect personal narrative texts posted by LBC on Zhihu, which is a Chinese question-and-answer online community website; 1475 personal narrative texts posted by LBC were gathered. We used four types of words, i.e., first-person singular pronouns, negative words, past tense verbs, and death-related words, all of which have been associated with depression and suicidal ideations in the Chinese Linguistic Inquiry Word Count (CLIWC) dictionary. We conducted vocabulary statistics on the personal narrative texts of LBC, and bilateral t-tests, with a control group, to analyze the psychological well-being of LBC. The results showed that the proportion of words related to depression and suicidal ideations in the texts of LBC was significantly higher than in the control group. The differences, with respect to the four word types (i.e., first-person singular pronouns, negative words, past tense verbs, and death-related words), were 5.37, 2.99, 2.65, and 2.00 times, respectively, suggesting that LBC are at a higher risk of depression and suicide than their counterparts. By sorting the texts of LBC, this research also found that child neglect is a main contributing factor to psychological difficulties of LBC. Furthermore, mental health problems and the risk of suicide in vulnerable groups, such as LBC, is a global public health issue, as well as an important research topic in the era of digital public health. Through a linguistic analysis, the results of this study confirmed that the experiences of left-behind children negatively impact their mental health. The present findings suggest that it is vital for the public and nonprofit sectors to establish online suicide prevention and intervention systems to improve the well-being of LBC through digital technology.

Published
2022

7. Conducting large, repeated, multi-game economic experiments using mobile platforms

Author

Li, Zhi, Lin, Po-Hsuan, Kong, Si-Yuan, Wang, Dongwu, and Duffy, John

Subjects
Clinical Research, Clinical Trials and Supportive Activities, Behavioral and Social Science, Prevention, Adult, Cell Phone, Female, Games, Experimental, Humans, Male, Sample Size, General Science & Technology
Abstract

We demonstrate the possibility of conducting synchronous, repeated, multi-game economic decision-making experiments with hundreds of subjects in-person or remotely with live streaming using entirely mobile platforms. Our experiment provides important proof-of-concept that such experiments are not only possible, but yield recognizable results as well as new insights, blurring the line between laboratory and field experiments. Specifically, our findings from 8 different experimental economics games and tasks replicate existing results from traditional laboratory experiments despite the fact that subjects play those games/task in a specific order and regardless of whether the experiment was conducted in person or remotely. We further leverage our large subject population to study the effect of large (N = 100) versus small (N = 10) group sizes on behavior in three of the scalable games that we study. While our results are largely consistent with existing findings for small groups, increases in group size are shown to matter for the robustness of those findings.

Published
2021

8. Integrating a multilevel approach to examine family conflict and parent-adolescent physiological synchrony.

Author

Li, Zhi, Sturge-Apple, Melissa L, Liu, Siwei, and Davies, Patrick T

Subjects
Pediatric, Good Health and Well Being, Adolescent, Adult, Child, Family Conflict, Female, Humans, Male, Multilevel Analysis, Parent-Child Relations, Respiratory Sinus Arrhythmia, physiological synchrony, coparenting conflict, respiratory sinus arrhythmia, parent-child relationship, adolescence, Psychology, Family Studies
Abstract

The present study investigated physiological synchrony across mothers, fathers, and adolescents during a conflict discussion. In particular, a multilevel, within-dyad approach was used to parameterize synchrony within the parasympathetic nervous system. Moreover, we examined how domains of conflict within the larger family system influenced the level of synchrony between family members. Participants were 191 families with adolescents (M age = 12.4 years), whose respiratory sinus arrhythmia (RSA) were measured during a triadic family conflict discussion. On the minute-to-minute basis, mothers and adolescents as well as mothers and fathers exhibited positive RSA concurrent synchrony, whereas no such concordance was observed between adolescents and fathers. In addition, the presence of conflict between parents with respect to coparenting moderated the level of mother-adolescent synchrony such that no concordant RSA synchrony emerged between mother and adolescents under high levels of coparenting conflict. In contrast, general interparental conflict did not moderate levels of physiological synchrony among any of the dyads. Findings suggest that mothers may be particularly physiologically in tune with family members in the context of conflict discussions and specific domains of family conflict may influence concordant physiological dynamics. Taken together, this is one of the first studies to examine physiological synchrony during the adolescent period and results suggest this may be an important developmental period for these dynamics. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Published
2020

9. Community Assessment of the Predictability of Cancer Protein and Phosphoprotein Levels from Genomics and Transcriptomics

Author

Yang, Mi, Petralia, Francesca, Li, Zhi, Li, Hongyang, Ma, Weiping, Song, Xiaoyu, Kim, Sunkyu, Lee, Heewon, Yu, Han, Lee, Bora, Bae, Seohui, Heo, Eunji, Kaczmarczyk, Jan, Stępniak, Piotr, Warchoł, Michał, Yu, Thomas, Calinawan, Anna P, Boutros, Paul C, Payne, Samuel H, Reva, Boris, Consortium, NCI-CPTAC-DREAM, Aderinwale, Tunde, Afyounian, Ebrahim, Agrawal, Piyush, Ali, Mehreen, Amadoz, Alicia, Azuaje, Francisco, Bachman, John, Bhalla, Sherry, Carbonell-Caballero, José, Chakraborty, Priyanka, Chaudhary, Kumardeep, Choi, Yonghwa, Choi, Yoonjung, Çubuk, Cankut, Dhanda, Sandeep Kumar, Dopazo, Joaquín, Elo, Laura L, Fóthi, Ábel, Gevaert, Olivier, Granberg, Kirsi, Greiner, Russell, Hidalgo, Marta R, Jayaswal, Vivek, Jeon, Hwisang, Jeon, Minji, Kalmady, Sunil V, Kambara, Yasuhiro, Kang, Jaewoo, Kang, Keunsoo, Kaoma, Tony, Kaur, Harpreet, Kazan, Hilal, Kesar, Devishi, Kesseli, Juha, Kim, Daehan, Kim, Keonwoo, Kim, Sang-Yoon, Kumar, Sajal, Liu, Yunpeng, Luethy, Roland, Mahajan, Swapnil, Mahmoudian, Mehrad, Muller, Arnaud, Nazarov, Petr V, Nguyen, Hien, Nykter, Matti, Okuda, Shujiro, Park, Sungsoo, Raghava, Gajendra Pal Singh, Rajapakse, Jagath C, Rantapero, Tommi, Ryu, Hobin, Salavert, Francisco, Saraei, Sohrab, Sharma, Ruby, Siitonen, Ari, Sokolov, Artem, Subramanian, Kartik, Suni, Veronika, Suomi, Tomi, Tranchevent, Léon-Charles, Usmani, Salman Sadullah, Välikangas, Tommi, Vega, Roberto, Zhong, Hua, Boja, Emily, Rodriguez, Henry, Stolovitzky, Gustavo, Guan, Yuanfang, Wang, Pei, Fenyö, David, and Saez-Rodriguez, Julio

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Biotechnology, Cancer, Genetics, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Crowdsourcing, Female, Genomics, Humans, Machine Learning, Male, Neoplasms, Phosphoproteins, Proteins, Proteomics, Transcriptome, NCI-CPTAC-DREAM Consortium, cancer, crowdsourcing, genomics, machine learning, protein regulation, proteogenomics, proteomics, Biochemistry and Cell Biology, Biochemistry and cell biology
Abstract

Cancer is driven by genomic alterations, but the processes causing this disease are largely performed by proteins. However, proteins are harder and more expensive to measure than genes and transcripts. To catalyze developments of methods to infer protein levels from other omics measurements, we leveraged crowdsourcing via the NCI-CPTAC DREAM proteogenomic challenge. We asked for methods to predict protein and phosphorylation levels from genomic and transcriptomic data in cancer patients. The best performance was achieved by an ensemble of models, including as predictors transcript level of the corresponding genes, interaction between genes, conservation across tumor types, and phosphosite proximity for phosphorylation prediction. Proteins from metabolic pathways and complexes were the best and worst predicted, respectively. The performance of even the best-performing model was modest, suggesting that many proteins are strongly regulated through translational control and degradation. Our results set a reference for the limitations of computational inference in proteogenomics. A record of this paper's transparent peer review process is included in the Supplemental Information.

Published
2020

10. Interactive effects of early-life income harshness and unpredictability on children's socioemotional and academic functioning in kindergarten and adolescence.

Author

Li, Zhi, Liu, Siwei, Hartman, Sarah, and Belsky, Jay

Subjects
Humans, Adolescent Behavior, Child Behavior, Impulsive Behavior, Risk-Taking, Sexual Behavior, Interpersonal Relations, Poverty, Socioeconomic Factors, Schools, Adolescent, Child, Preschool, Infant, Income, Female, Male, Social Skills, Problem Behavior, School Teachers, Academic Success, environmental unpredictability, environmental harshness, life history, income, Pediatric Research Initiative, Behavioral and Social Science, Pediatric, Specialist Studies in Education, Psychology, Cognitive Sciences, Developmental & Child Psychology
Abstract

This research investigates whether and how two fundamental environmental factors-harshness and unpredictability-interact in regulating child and adolescent development, informed by life-history theory and drawing on data from the National Institute of Child Health & Human Development Study of Early Child Care and Youth Development (N = 1,364). Early life harshness was operationalized as the typical level of family income-to-needs based on six repeated measurements across the first 4.5 years of life and early life unpredictability as random variation using the same family income measurements. Results revealed that children functioned most competently in the social and academic domain as kindergarteners when exposed to low environmental harshness and low unpredictability and least competently when they experienced high harshness and low unpredictability. The same interaction pattern emerged in adolescence in forecasting cognitive-academic competence and sexual behavior. Findings are discussed in terms of how reliable and unreliable environmental cues shape developmental trajectories. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Published
2018

11. Systematic Analysis of Splice-Site-Creating Mutations in Cancer

Author

Jayasinghe, Reyka G, Cao, Song, Gao, Qingsong, Wendl, Michael C, Vo, Nam Sy, Reynolds, Sheila M, Zhao, Yanyan, Climente-González, Héctor, Chai, Shengjie, Wang, Fang, Varghese, Rajees, Huang, Mo, Liang, Wen-Wei, Wyczalkowski, Matthew A, Sengupta, Sohini, Li, Zhi, Payne, Samuel H, Fenyö, David, Miner, Jeffrey H, Walter, Matthew J, Network, The Cancer Genome Atlas Research, Caesar-Johnson, Samantha J, Demchok, John A, Felau, Ina, Kasapi, Melpomeni, Ferguson, Martin L, Hutter, Carolyn M, Sofia, Heidi J, Tarnuzzer, Roy, Wang, Zhining, Yang, Liming, Zenklusen, Jean C, Zhang, Jiashan, Chudamani, Sudha, Liu, Jia, Lolla, Laxmi, Naresh, Rashi, Pihl, Todd, Sun, Qiang, Wan, Yunhu, Wu, Ye, Cho, Juok, DeFreitas, Timothy, Frazer, Scott, Gehlenborg, Nils, Getz, Gad, Heiman, David I, Kim, Jaegil, Lawrence, Michael S, Lin, Pei, Meier, Sam, Noble, Michael S, Saksena, Gordon, Voet, Doug, Zhang, Hailei, Bernard, Brady, Chambwe, Nyasha, Dhankani, Varsha, Knijnenburg, Theo, Kramer, Roger, Leinonen, Kalle, Liu, Yuexin, Miller, Michael, Reynolds, Sheila, Shmulevich, Ilya, Thorsson, Vesteinn, Zhang, Wei, Akbani, Rehan, Broom, Bradley M, Hegde, Apurva M, Ju, Zhenlin, Kanchi, Rupa S, Korkut, Anil, Li, Jun, Liang, Han, Ling, Shiyun, Liu, Wenbin, Lu, Yiling, Mills, Gordon B, Ng, Kwok-Shing, Rao, Arvind, Ryan, Michael, Wang, Jing, Weinstein, John N, Zhang, Jiexin, Abeshouse, Adam, Armenia, Joshua, Chakravarty, Debyani, Chatila, Walid K, de Bruijn, Ino, Gao, Jianjiong, Gross, Benjamin E, Heins, Zachary J, Kundra, Ritika, La, Konnor, Ladanyi, Marc, Luna, Augustin, Nissan, Moriah G, Ochoa, Angelica, and Phillips, Sarah M

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Cancer Genomics, Human Genome, Rare Diseases, Cancer, Immunotherapy, Genetics, 5.1 Pharmaceuticals, 2.1 Biological and endogenous factors, BRCA1 Protein, GATA3 Transcription Factor, HEK293 Cells, Humans, Mutation, Neoplasms, Poly (ADP-Ribose) Polymerase-1, Programmed Cell Death 1 Receptor, RNA Splice Sites, Tumor Suppressor Protein p53, X-linked Nuclear Protein, Cancer Genome Atlas Research Network, RNA, mutations of clinical relevance, splicing, Biochemistry and Cell Biology, Medical Physiology, Biological sciences
Abstract

For the past decade, cancer genomic studies have focused on mutations leading to splice-site disruption, overlooking those having splice-creating potential. Here, we applied a bioinformatic tool, MiSplice, for the large-scale discovery of splice-site-creating mutations (SCMs) across 8,656 TCGA tumors. We report 1,964 originally mis-annotated mutations having clear evidence of creating alternative splice junctions. TP53 and GATA3 have 26 and 18 SCMs, respectively, and ATRX has 5 from lower-grade gliomas. Mutations in 11 genes, including PARP1, BRCA1, and BAP1, were experimentally validated for splice-site-creating function. Notably, we found that neoantigens induced by SCMs are likely several folds more immunogenic compared to missense mutations, exemplified by the recurrent GATA3 SCM. Further, high expression of PD-1 and PD-L1 was observed in tumors with SCMs, suggesting candidates for immune blockade therapy. Our work highlights the importance of integrating DNA and RNA data for understanding the functional and the clinical implications of mutations in human diseases.

Published
2018

12. Peer Problems and Hyperactivity-Impulsivity Among Norwegian and American Children: The Role of 5-HTTLPR.

Author

Stenseng, Frode, Li, Zhi, Belsky, Jay, Hygen, Beate W, Skalicka, Vera, Guzey, Ismail C, and Wichstrøm, Lars

Subjects
Humans, Psychomotor Agitation, Cohort Studies, Child Behavior, Impulsive Behavior, Peer Group, Interpersonal Relations, Child, Child, Preschool, United States, Norway, Female, Male, Serotonin Plasma Membrane Transport Proteins, Developmental & Child Psychology, Psychology, Cognitive Sciences
Abstract

Peer problems are linked to attention deficit hyperactivity disorder (ADHD) symptoms and the serotonin system is thought to be involved in ADHD-related behavior. Hence, from a Gene × Environment perspective, the serotonin transporter 5-HTTLPR may play a moderating role. In two large community samples, the moderating role of 5-HTTLPR was examined related to more hyperactivity-impulsivity symptoms (HI symptoms) predicted by more peer problems. In Study 1, involving 642 Norwegian children, results indicated that for s-allele carriers only, caregiver-reported peer problems at age 4 predicted more parent-reported HI symptoms at age 6. In Study 2, similar results emerged involving 482 American children. Discussion focuses on differential sensitivity to the adverse effects of poor peer relations.

Published
2018

13. Photoactivated in Vitro Anticancer Activity of Rhenium(I) Tricarbonyl Complexes Bearing Water-Soluble Phosphines

Author

Marker, Sierra C, MacMillan, Samantha N, Zipfel, Warren R, Li, Zhi, Ford, Peter C, and Wilson, Justin J

Subjects
Rare Diseases, Antineoplastic Agents, Carboxylic Acids, Cell Line, Tumor, Cell Proliferation, Cell Survival, Coordination Complexes, Crystallography, X-Ray, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Humans, Models, Molecular, Molecular Structure, Phosphines, Photochemical Processes, Rhenium, Solubility, Structure-Activity Relationship, Water, Inorganic Chemistry, Physical Chemistry (incl. Structural), Other Chemical Sciences, Inorganic & Nuclear Chemistry
Abstract

Fifteen water-soluble rhenium compounds of the general formula [Re(CO)3(NN)(PR3)]+, where NN is a diimine ligand and PR3 is 1,3,5-triaza-7-phosphaadamantane (PTA), tris(hydroxymethyl)phosphine (THP), or 1,4-diacetyl-1,3,7-triaza-5-phosphabicylco[3.3.1]nonane (DAPTA), were synthesized and characterized by multinuclear NMR spectroscopy, IR spectroscopy, and X-ray crystallography. The complexes bearing the THP and DAPTA ligands exhibit triplet-based luminescence in air-equilibrated aqueous solutions with quantum yields ranging from 3.4 to 11.5%. Furthermore, the THP and DAPTA complexes undergo photosubstitution of a CO ligand upon irradiation with 365 nm light with quantum yields ranging from 1.1 to 5.5% and sensitize the formation of 1O2 with quantum yields as high as 70%. In contrast, all of the complexes bearing the PTA ligand are nonemissive and do not undergo photosubstitution upon irradiation with 365 nm light. These compounds were evaluated as photoactivated anticancer agents in human cervical (HeLa), ovarian (A2780), and cisplatin-resistant ovarian (A2780CP70) cancer cell lines. All of the complexes bearing THP and DAPTA exhibited a cytotoxic response upon irradiation with minimal toxicity in the absence of light. Notably, the complex with DAPTA and 1,10-phenanthroline gave rise to an IC50 value of 6 μM in HeLa cells upon irradiation, rendering it the most phototoxic compound in this library. The nature of the photoinduced cytotoxicity of this compound was explored in further detail. These data indicate that the phototoxic response may result from the release of both CO and the rhenium-containing photoproduct, as well as the production of 1O2.

Published
2018

14. External-environmental and internal-health early life predictors of adolescent development

Author

Hartman, Sarah, Li, Zhi, Nettle, Daniel, and Belsky, Jay

Subjects
Biological Psychology, Clinical and Health Psychology, Psychology, Applied and Developmental Psychology, Youth Violence, Behavioral and Social Science, Prevention, Basic Behavioral and Social Science, Pediatric, Violence Research, Generic health relevance, Good Health and Well Being, Adolescent, Adolescent Behavior, Adolescent Development, Age Factors, Body Mass Index, Child, Child Development, Child, Preschool, Depression, Female, Health Status, Humans, Income, Loneliness, Male, Maternal Behavior, Menarche, Parenting, Problem Behavior, Risk-Taking, Sexual Behavior, Social Environment, Social Skills, Cognitive Sciences, Developmental & Child Psychology, Applied and developmental psychology, Biological psychology, Clinical and health psychology
Abstract

A wealth of evidence documents associations between various aspects of the rearing environment and later development. Two evolutionary-inspired models advance explanations for why and how such early experiences shape later functioning: (a) the external-prediction model, which highlights the role of the early environment (e.g., parenting) in regulating children's development, and (b) the internal-prediction model, which emphasizes internal state (i.e., health) as the critical regulator. Thus, by using data from the NICHD Study of Early Child Care and Youth Development, the current project draws from both models by investigating whether the effect of the early environment on later adolescent functioning is subject to an indirect effect by internal-health variables. Results showed a significant indirect effect of internal health on the relation between the early environment and adolescent behavior. Specifically, early environmental adversity during the first 5 years of life predicted lower quality health during childhood, which then led to problematic adolescent functioning and earlier age of menarche for girls. In addition, for girls, early adversity predicted lower quality health that forecasted earlier age of menarche leading to increased adolescent risk taking. The discussion highlights the importance of integrating both internal and external models to further understand the developmental processes that effect adolescent behavior.

Published
2017

15. Change in Parenting, Change in Student–Teacher Relationships, and Oxytocin Receptor Gene (OXTR): Testing a Gene-×-Environment (G×E) Hypothesis in Two Samples

Author

Hygen, Beate Wold, Belsky, Jay, Li, Zhi, Stenseng, Frode, Güzey, Ismail Cuneyt, and Wichstrøm, Lars

Subjects
Social and Personality Psychology, Psychology, Behavioral and Social Science, Clinical Research, Genetics, Pediatric, Adult, Child, Child, Preschool, Female, Gene-Environment Interaction, Humans, Interpersonal Relations, Male, Middle Aged, Norway, Parenting, Receptors, Oxytocin, School Teachers, Young Adult, diathesis stress, differential susceptibility, OXTR rs53576, parenting, student-teacher relationship, Specialist Studies in Education, Cognitive Sciences, Developmental & Child Psychology, Specialist studies in education, Applied and developmental psychology, Cognitive and computational psychology
Abstract

Prior research suggests that parenting affects children's relationships, including those with teachers, although there is variation across individuals in such effects. Given evidence suggesting that oxytocin may be particularly important for the quality of social relationships, we tested the hypotheses (a) that change in parenting from 4 to 6 years of age influences and predicts change in the student-teacher relationship from 6 to 8 years of age and (b) that this effect is moderated by a polymorphism related to the child's oxytocin receptor gene (OXTR), rs53576. In 2 studies, participants included, respectively, 652 socioeconomically diverse Norwegian children from a community sample (50.8% male; mean age of 54.9 months at first assessment) and 559 such children from 8 different U.S. locales (49.0% male; approximately 54 months at the first assessment). Norwegian results showed that change in parenting predicted change in student-teacher relationships, but only in the case of children homozygous for the A allele of rs53576 and in a manner consistent with differential-susceptibility theory: for AA carriers, when parenting changed for the worse, so did children's relationship with teachers, whereas when parenting changed for the better, the teacher-child relationships improved accordingly. Such G×E findings could not be replicated in the American sample. Results are discussed in terms of 2 contrasting models of Person-×-Environment interaction (differential susceptibility and diathesis stress) and potential reasons for failure to replicate. (PsycINFO Database Record

Published
2017

16. STAT2 is an essential adaptor in USP18-mediated suppression of type I interferon signaling

Author

Arimoto, Kei-ichiro, Löchte, Sara, Stoner, Samuel A, Burkart, Christoph, Zhang, Yue, Miyauchi, Sayuri, Wilmes, Stephan, Fan, Jun-Bao, Heinisch, Jürgen J, Li, Zhi, Yan, Ming, Pellegrini, Sandra, Colland, Frédéric, Piehler, Jacob, and Zhang, Dong-Er

Subjects
Animals, Cell Line, Tumor, Endopeptidases, Feedback, Physiological, Humans, Immunoblotting, Interferon Type I, Mice, Mutant Proteins, Protein Binding, Protein Domains, Receptor, Interferon alpha-beta, STAT2 Transcription Factor, Signal Transduction, Two-Hybrid System Techniques, Ubiquitin Thiolesterase, Chemical Sciences, Biological Sciences, Medical and Health Sciences, Biophysics, Developmental Biology
Abstract

Type I interferons (IFNs) are multifunctional cytokines that regulate immune responses and cellular functions but also can have detrimental effects on human health. A tight regulatory network therefore controls IFN signaling, which in turn may interfere with medical interventions. The JAK-STAT signaling pathway transmits the IFN extracellular signal to the nucleus, thus resulting in alterations in gene expression. STAT2 is a well-known essential and specific positive effector of type I IFN signaling. Here, we report that STAT2 is also a previously unrecognized, crucial component of the USP18-mediated negative-feedback control in both human and mouse cells. We found that STAT2 recruits USP18 to the type I IFN receptor subunit IFNAR2 via its constitutive membrane-distal STAT2-binding site. This mechanistic coupling of effector and negative-feedback functions of STAT2 may provide novel strategies for treatment of IFN-signaling-related human diseases.

Published
2017

17. Development and Validation of a Risk Score for Prediction of Acute Kidney Injury in Patients With Acute Decompensated Heart Failure: A Prospective Cohort Study in China.

Author

Zhou, Li Zhi, Yang, Xiao Bing, Guan, Ying, Xu, Xing, Tan, Ming T, Hou, Fan Fan, and Chen, Ping Yan

Subjects
Humans, Acute Disease, Angiotensinogen, Logistic Models, Risk Assessment, Risk Factors, Cohort Studies, Prospective Studies, Reproducibility of Results, Aged, Aged, 80 and over, Middle Aged, China, Female, Male, Renal Insufficiency, Chronic, Heart Failure, Acute Kidney Injury, Cardio-Renal Syndrome, Lipocalin-2, acute decompensated heart failure, acute kidney injury, risk prediction, risk stratification, Kidney Disease, Patient Safety, Cardiovascular, Heart Disease, Prevention, Clinical Research, 4.2 Evaluation of markers and technologies, Detection, screening and diagnosis, Cardiorespiratory Medicine and Haematology
Abstract

Although several risk factors for acute kidney injury (AKI) have been identified, early detection of AKI in acute decompensated heart failure patients remains a challenge. The aim of this study was to develop and validate a risk score for early prediction of AKI in acute decompensated heart failure patients. A total of 676 consecutive acute decompensated heart failure participants were prospectively enrolled from 6 regional central hospitals. Data from 507 participants were analyzed. Participants from 4 of the 6 hospitals (n=321) were used to develop a risk score and conduct internal validation. External validation of the developed risk score was conducted in participants from the other 2 hospitals (n=186). Sequential logistic regression was used to develop and validate the risk score. The c statistic and calibration plot were used to assess the discrimination and calibration of the proposed risk score. The overall occurrence of AKI was 33.1% (168/507). The risk score, ranging from 0 to 55, demonstrated good discriminative power with an optimism-corrected c statistic of 0.859. Similar results were obtained from external validation with c statistic of 0.847 (95% CI 0.819-0.927). The risk score had good calibration with no apparent over- or under-prediction observed from calibration plots. The novel risk score is a simple and accurate tool that can help clinicians assess the risk of AKI in acute decompensated heart failure patients, which in turn helps them plan and initiate the most appropriate disease management for patients in time.

Published
2016

18. Divergent biosynthesis yields a cytotoxic aminomalonate-containing precolibactin

Author

Li, Zhong-Rui, Li, Jie, Gu, Jin-Ping, Lai, Jennifer YH, Duggan, Brendan M, Zhang, Wei-Peng, Li, Zhi-Long, Li, Yong-Xin, Tong, Rong-Biao, Xu, Ying, Lin, Dong-Hai, Moore, Bradley S, and Qian, Pei-Yuan

Subjects
Escherichia coli, Humans, Malonates, Molecular Conformation, Peptides, Polyketides, Medicinal and Biomolecular Chemistry, Biochemistry and Cell Biology, Biochemistry & Molecular Biology
Abstract

Colibactin is an as-yet-uncharacterized genotoxic secondary metabolite produced by human gut bacteria. Here we report the biosynthetic discovery of two new precolibactin molecules from Escherichia coli, including precolibactin-886, which uniquely incorporates the highly sought genotoxicity-associated aminomalonate building block into its unprecedented macrocyclic structure. This work provides new insights into the biosynthetic logic and mode of action of this colorectal-cancer-linked microbial chemical.

Published
2016

19. The BDNF Val66Met Polymorphism Interacts with Maternal Parenting Influencing Adolescent Depressive Symptoms: Evidence of Differential Susceptibility Model.

Author

Zhang, Leilei, Li, Zhi, Chen, Jie, Li, Xinying, Zhang, Jianxin, and Belsky, Jay

Subjects
Humans, Genetic Predisposition to Disease, Brain-Derived Neurotrophic Factor, Depression, Mother-Child Relations, Parenting, Mothers, Genotype, Polymorphism, Genetic, Adolescent, Child, Ethnic Groups, China, Female, Male, Gene-Environment Interaction, Adolescent depressive symptoms, BDNF Val66Met polymorphism, Differential susceptibility, Gene–environment interaction, Maternal parenting, Gene-environment interaction, Developmental & Child Psychology, Specialist Studies in Education, Psychology
Abstract

Although depressive symptoms are common during adolescence, little research has examined gene-environment interaction on youth depression. This study chose the brain-derived neurotrophic factor (BDNF) gene, tested the interaction between a functional polymorphism resulting amino acid substitution of valine (Val) to methionine (Met) in the proBDNF protein at codon 66 (Val66Met), and maternal parenting on youth depressive symptoms in a sample of 780 community adolescents of Chinese Han ethnicity (aged 11-17, M = 13.6, 51.3 % females). Participants reported their depressive symptoms and perceived maternal parenting. Results indicated the BDNF Val66Met polymorphism significantly moderated the influence of maternal warmth-reasoning, but not harshness-hostility, on youth depressive symptoms. Confirmatory model evaluation indicated that the interaction effect involving warmth-reasoning conformed to the differential-susceptibility rather than diathesis-stress model of person-X-environment interaction. Thus, Val carriers experienced less depressive symptoms than Met homozygotes when mothering was more positive but more symptoms when mothering was less positive. The findings provided evidence in support of the differential susceptibility hypothesis of youth depressive symptoms and shed light on the importance of examining the gene-environment interaction from a developmental perspective.

Published
2016

20. Take your mind off it: Coping style, serotonin transporter linked polymorphic region genotype (5-HTTLPR), and children's internalizing and externalizing problems

Author

Cline, Jessie I, Belsky, Jay, Li, Zhi, Melhuish, Edward, Lysenko, Laura, McFarquhar, Tara, Stevens, Suzanne, and Jaffee, Sara R

Subjects
Biological Psychology, Clinical and Health Psychology, Psychology, Applied and Developmental Psychology, Basic Behavioral and Social Science, Behavioral and Social Science, Genetics, Mental Health, Pediatric, Human Genome, Neurosciences, 2.3 Psychological, social and economic factors, Aetiology, Adaptation, Psychological, Alleles, Child, Child Behavior Disorders, Defense Mechanisms, Female, Genetic Carrier Screening, Genetic Linkage, Genetic Predisposition to Disease, Genotype, Humans, Internal-External Control, Life Change Events, Male, Parenting, Polymorphism, Genetic, Serotonin Plasma Membrane Transport Proteins, Cognitive Sciences, Developmental & Child Psychology, Applied and developmental psychology, Biological psychology, Clinical and health psychology
Abstract

Individuals with the short variant of the serotonin transporter linked polymorphic region gene are more susceptible than individuals homozygous for the long allele to the effects of stressful life events on risk for internalizing and externalizing problems. We tested whether individual differences in coping style explained this increased risk for problem behavior among youth who were at both genetic and environmental risk. Participants included 279 children, ages 8-11, from the Children's Experiences and Development Study. Caregivers and teachers reported on children's internalizing and externalizing symptoms, and caregivers and children on children's exposure to harsh parenting and parental warmth in middle childhood, and traumatic events. Children reported how frequently they used various coping strategies. Results revealed that short/short homozygotes had higher levels of internalizing problems compared with long allele carriers and that short allele carriers had higher levels of externalizing problems compared with long/long homozygotes under conditions of high cumulative risk. Moreover, among children who were homozygous for the short allele, those who had more cumulative risk indicators less frequently used distraction coping strategies, which partly explained why they had higher levels of internalizing problems. Coping strategies did not significantly mediate Gene × Environment effects on externalizing symptoms.

Published
2015

21. miR-517b-3p promotes the progression of portal vein tumor thrombus via activating Wnt/β-catenin signaling pathway in hepatocellular carcinoma

Author

Rui-Sheng Ke, Kun-Zhai Huang, De-sheng Bao, Jing-Rui Yang, Hua-xiang Wang, Li-Zhi Lv, Yi Jiang, Zhao-Hui Liu, and Fu-Xing Zhang

Subjects
Carcinoma, Hepatocellular, Portal Vein, Liver Neoplasms, Thrombosis, General Medicine, Gene Expression Regulation, Neoplastic, MicroRNAs, Cell Movement, Cell Line, Tumor, Genetics, Humans, Neoplasm Invasiveness, Wnt Signaling Pathway, Molecular Biology, Biomarkers, beta Catenin, Cell Proliferation
Abstract

Aims: The aim of this study was to investigate the expression patterns and prognostic value of microRNA-517b-3p (miR-517b-3p) in hepatocellular carcinoma (HCC) patients with portal vein tumor thrombus (PVTT).Methods: Expression of miR-517b-3p in PVTT tissues and cells was estimated using qRT-PCR. The significance of miR-517b-3p were explored by Kaplan-Meier survival analysis, Cox regression assay and ROC analysis. Cell experiments were performed to examine the functional role of miR-517b-3p during progression of PVTT. The Biological process and Biological pathway analysis analyses were conducted through GSEA and FunRich. The protein-protein interaction (PPI) network of the DEGs was established through cBioPortal website. Results: miR-517b-3p upregulated in both PVTT tissues and cells compared with the controls. The upregulated miR-517b-3p served as a potential diagnostic biomarker to distinguish PVTT from PT and controls, associated with poor overall survival and acted as an independent prognostic factor. The cell proliferation, migration and invasion were proved to be enhanced by overexpression of miR-517b-3p. Wnt/β-catenin signaling was suppressed by miR-517b-3p knockdown and might be involved in progression of PVTT. Conclusion: miR-517b-3p may promote PVTT cell proliferation, migration and invasion via activating Wnt/β-catenin signaling pathway. miR-517b-3p overexpression in PVTT samples, and serves as a candidate diagnostic and prognostic biomarker in HCC patients with PVTT.

Published
2022

22. Correlation between Surface Area Ratio of Medial to Lateral Tibial Plateau and Knee Alignment in Adults

Author

Song, Gong, Li-Zhi, Han, Tian-Lun, Gong, Yi-Hu, Yi, Ruo-Yu, Wang, and Wei-Hua, Xu

Subjects
Adult, Male, Knee Joint, Lower Extremity, Tibia, Genetics, Humans, Female, Knee, Femur, Biochemistry
Abstract

This study aimed to investigate the correlation between the surface area ratio of medial tibial plateau (MTP) to lateral tibial plateau (LTP) and the mechanical tibiofemoral angle (mTFA).Lower limb computed tomography (CT) images were collected at our hospital. Then, the original CT data were analyzed and reconstructed using medical image processing software. The proximal and distal centres of the femur and tibia were marked. The surface areas of MTP and LTP were identified using image processing software. GraphPad Prism 8.0.2 was used to perform the statistical analysis.The surface area ratio of MTP to LTP was significantly correlated with the mTFA in all patients (P0.0001), male group (P0.0001), female group (P0.0001), varus group (P0.0001), and valgus group (P=0.002). Furthermore, the surface area of MTP and LTP was significantly greater in the male group than in the female group (P0.0001). There was significant difference in the surface area of the MTP between the varus and valgus groups (P0.0001). Significant difference was also observed in the surface area ratio of MTP to LTP between the varus and valgus groups (P0.0001).The surface area ratio of MTP to LTP was correlated with the mTFA. Within a certain range, the smaller the mTFA, the greater the surface area ratio of MTP to LTP. For patients undergoing total knee arthroplasty, of whom the surface area of the MTP was basically equal to that of the LTP, it is recommended that the osteotomy should be performed in accordance with mechanical alignment standards, and that a symmetrical tibial plateau prosthesis should be used. For patients whose surface area of MTP is significantly greater than that of the LTP, it is recommended that the osteotomy should be performed in accordance with kinematic alignment standards, and that an anatomical tibial plateau prosthesis should be used.

Published
2022

23. Overexpression of chaperonin containing TCP1 subunit 7 has diagnostic and prognostic value for hepatocellular carcinoma

Author

Tingting Liu, Yi Jiang, Bin Jiang, Fengfeng Feng Xu, Huaxiang Wang, Xinghua Huang, Huan-Zhang Hu, Ruling Wang, and Li-Zhi Lv

Subjects
Aging, Carcinoma, Hepatocellular, Chaperonins, Chemistry, Protein subunit, Liver Neoplasms, Cell Biology, Prognosis, medicine.disease, Chaperonin, Gene Expression Regulation, Neoplastic, Hepatocellular carcinoma, Biomarkers, Tumor, Cancer research, medicine, Humans, RNA, Messenger, alpha-Fetoproteins, Value (mathematics), Chaperonin Containing TCP-1
Abstract

Background Chaperonin containing TCP1 subunit 7 (CCT7), a member of the chaperonin containing TCP1 complex (CCT), has been reported regulating the expression of many tumor-related proteins. In this study, we investigated the diagnostic and prognostic value of CCT7 expression for hepatocellular carcinoma (HCC). Methods We investigated the CCT7 expression in HCC in The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) and our cohort. The diagnostic and prognostic value were verified by receiver operating characteristic curve (ROC) analysis and Kaplan-Meier analysis, respectively. The association between CCT7 expression with DNA methylation status was investigated in the TCGA database. Gene ontology (GO), The Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) analysis were employed to identify the potential pathway in which CCT7 is involved in tumorigenesis and progression. Results CCT7 expression in HCC was significantly higher than adjacent normal tissues, and elevated CCT7 expression correlated with tumor stages and tumor grade. Furthermore, the ROC curve showed CCT mRNA expression has a better diagnostic value for HCC with early-stage and low alpha-fetoprotein expression. Positive predictive value (PPV) of CCT7 was higher than alpha-fetoprotein both in the GEO and TCGA database. The Multivariate Cox Regression analysis of clinicopathologic characteristics revealed that both high mRNA and protein expression of CCT7 were independent risk factors for overall survival (OS) and recurrence-free survival (RFS). High DNA methylation of CpG site(cg19515186) was associated with low CCT7 expression and better OS in HCC. The GO, KEGG and GSEA analysis demonstrated that CCT7 mRNA expression was associated with Spliceosome signaling pathway. Conclusions The findings of this study demonstrated that CCT7 has diagnostic and prognostic value for HCC.

Published
2022

24. Development of gut microbiota along with its metabolites of preschool children

Author

Hongwei Hu, Jingjing Xiong, Yongkun Huang, Jianwen Yin, Yong Duan, Li-Zhi Zhang, Mei Liu, and Chuan-Zhi Xu

Subjects
Genetics, Adult, biology, Infant, Newborn, Infant, Short chain fatty acids, Gut microbiota, Gut flora, biology.organism_classification, Fatty Acids, Volatile, Microbial metabolism, Pediatrics, Bile acids, RJ1-570, Gastrointestinal Microbiome, Bile Acids and Salts, Feces, Child, Preschool, RNA, Ribosomal, 16S, Pediatrics, Perinatology and Child Health, Humans, Children development, Research Article
Abstract

Background To reveal the changes of intestinal microbial abundance and composition, as well as the microbiota metabolic levels of bile acids and short chain fatty acids of healthy preschool children during their growth. Methods Feces of 120 healthy newborns and 150 healthy children aged 6 months to 6 years were collected. Then the composition of intestinal flora was analyzed by 16S rRNA, and the contents of bile acids and short chain fatty acids in feces were detected by LC-MS and GS methods, respectively. Results The composition and function of intestinal microflora were not stable in neonatal period but significantly improved at 6 months after birth, and gradually stabilized and tended to adult-like formation after 2–3 years old. The levels of short chain fatty acids and secondary bile acids were consistent with the development of gut microbiota. Conclusion The age of 6 months may be a critical period for the development of intestinal microflora in children.

Published
2022

25. PPDPF Promotes the Progression and acts as an Antiapoptotic Protein in Non-Small Cell Lung Cancer

Author

Deng Yuezhen, Zeng Zimei, Nie Yingjie, Li Yingzi, Li Zhi, Liu Guanxin, Cao Zhen, Mu Yun, Zhou Chengzhi, Chen Tao, Gao Jie, and Sun Lunquan

Subjects
Lung Neoplasms, Carcinogenesis, Down-Regulation, Mice, Nude, NSCLC, Applied Microbiology and Biotechnology, Mice, MDM2, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, medicine, Animals, Humans, Lung cancer, Molecular Biology, Ecology, Evolution, Behavior and Systematics, Chemistry, BABAM2, Intracellular Signaling Peptides and Proteins, Cell Biology, PPDPF, Prognosis, medicine.disease, Xenograft Model Antitumor Assays, respiratory tract diseases, Up-Regulation, radioresistance, Antiapoptotic protein, Disease Progression, Cancer research, Non small cell, Apoptosis Regulatory Proteins, Research Paper, Developmental Biology
Abstract

Resistance to radiotherapy is frequently observed in the clinic and leads to poor prognosis of non-small cell lung cancer (NSCLC). How to overcome resistance to radiotherapy is a challenge in the treatment of NSCLC. In this study, PPDPF was found to be upregulated in NSCLC tissues and cell lines, and its expression negatively correlated with the overall survival of patients with NSCLC. PPDPF promoted the growth, colony formation and invasion of lung cancer cells. Moreover, knockout of PPDPF inhibited tumorigenesis in the KL (KrasG12D; LKB1f/f) mouse model of lung cancer. Additionally, overexpression of PPDPF led to radioresistance in lung cancer cells, and knockdown of PPDPF sensitized lung cancer cells to radiotherapy. Mechanistically, PPDPF interacted with BABAM2 (an antiapoptotic protein) and blocked its ubiquitination by MDM2, thus stabilizing BABAM2 and promoting the radioresistance of lung cancer cells. Our present study suggested PPDPF as a therapeutic target in NSCLC.

Published
2022

26. In vivo labeling reveals continuous trafficking of TCF-1+ T cells between tumor and lymphoid tissue

Author

Li, Zhi, Tuong, Zewen K, Dean, Isaac, Willis, Claire, Gaspal, Fabrina, Fiancette, Rémi, Idris, Suaad, Kennedy, Bethany, Ferdinand, John R, Peñalver, Ana, Cabantous, Mia, Murtuza Baker, Syed, Fry, Jeremy W, Carlesso, Gianluca, Hammond, Scott A, Dovedi, Simon J, Hepworth, Matthew R, Clatworthy, Menna R, Withers, David R, Li, Zhi [0000-0002-0583-1116], Tuong, Zewen K [0000-0002-6735-6808], Dean, Isaac [0000-0002-4750-5335], Willis, Claire [0000-0001-5504-6741], Gaspal, Fabrina [0000-0001-8828-4594], Fiancette, Rémi [0000-0003-1531-9770], Idris, Suaad [0000-0002-6070-4670], Kennedy, Bethany [0000-0001-9529-7545], Ferdinand, John R [0000-0003-0936-0128], Peñalver, Ana [0000-0002-5799-6780], Cabantous, Mia [0000-0002-3530-494X], Murtuza Baker, Syed [0000-0002-6633-333X], Fry, Jeremy W [0000-0003-3689-6606], Carlesso, Gianluca [0000-0002-9592-3267], Hammond, Scott A [0000-0001-5800-4328], Dovedi, Simon J [0000-0003-0486-1206], Hepworth, Matthew R [0000-0002-9613-7858], Clatworthy, Menna R [0000-0002-3340-9828], Withers, David R [0000-0003-3757-7594], and Apollo - University of Cambridge Repository

Subjects
Lymphoid Tissue, T-Lymphocyte Subsets, Neoplasms, Immunology, Humans, Immunology and Allergy, Immunotherapy, CD8-Positive T-Lymphocytes
Abstract

Funder: Lister Institute of Preventative Medicine, Funder: NIHR Cambridge Biomedical Research Centre, Funder: AstraZeneca, Improving the efficacy of immune checkpoint therapies will require a better understanding of how immune cells are recruited and sustained in tumors. Here, we used the photoconversion of the tumor immune cell compartment to identify newly entering lymphocytes, determine how they change over time, and investigate their egress from the tumor. Combining single-cell transcriptomics and flow cytometry, we found that while a diverse mix of CD8 T cell subsets enter the tumor, all CD8 T cells retained within this environment for more than 72 h developed an exhausted phenotype, revealing the rapid establishment of this program. Rather than forming tumor-resident populations, non-effector subsets, which express TCF-1 and include memory and stem-like cells, were continuously recruited into the tumor, but this recruitment was balanced by concurrent egress to the tumor-draining lymph node. Thus, the TCF-1+ CD8 T cell niche in tumors is highly dynamic, with the circulation of cells between the tumor and peripheral lymphoid tissue to bridge systemic and intratumoral responses.

Published
2022

27. Apigenin Inhibits Proliferation, Migration, and Invasion of Human Tongue Carcinoma Tca8113 Cells Through Regulating the MAPK Signaling Pathways

Author

Yun-Ze Xuan, Kang-Juan Yang, Li-Zhi Xu, and Cheng-Ri Jin

Subjects
MAPK/ERK pathway, MAP Kinase Signaling System, Cell, Biochemistry, chemistry.chemical_compound, Western blot, Cell Movement, Cell Line, Tumor, medicine, Humans, Neoplasm Invasiveness, MTT assay, Apigenin, Protein kinase A, Molecular Biology, Cell Proliferation, medicine.diagnostic_test, Cell growth, General Medicine, Molecular biology, Neoplasm Proteins, Tongue Neoplasms, medicine.anatomical_structure, chemistry, Cytoplasm, Molecular Medicine
Abstract

Objective: This study aimed to examine the effects of apigenin (API) on the proliferation, migration, and invasion of human tongue squamous cell carcinoma Tca8113 cells and explore its probable mechanisms. Methods: After treating Tca8113 cells with API, the cell proliferation, migration, and invasive capacities were identified by tetrazolium salt colorimetry (MTT) assay, cell scratch test, and Transwell chamber test. Cellular immunofluorescence staining was used to localize mitogen-activated protein kinase 1 (MAPK1) and extracellular regulated protein kinase (ERK) 1/2 proteins. Western blot was used to detect the variations of the related protein expression levels. Results: ① Through the MTT assay, API significantly inhibited cell proliferation (P Conclusion: Apigenin (API) significantly inhibits the proliferation, migration, and invasion of Tca8113 cells and its mechanism may be associated with the MAPK signaling pathway.

Published
2021

28. Targeting hexokinase 2 increases the sensitivity of oxaliplatin by Twist1 in colorectal cancer

Author

Zhao-Xia Dong, Li-Zhi Deng, Shu-Na Chen, Zhi-Ying Mai, Xue-Qi Liu, Di-Sheng Zhou, Xingding Zhang, Yuan-Yuan Shi, Xin-Rong Shao, Sze-Hoi Chan, Bo Zhang, Li-Yuan Zheng, Tian-Liang Fang, and Miao Li

Subjects
Colorectal cancer, Regulator, Vimentin, colorectal cancer, Metastasis, Mice, In vivo, Cell Line, Tumor, Hexokinase, medicine, Animals, Humans, neoplasms, Gene knockdown, Mice, Inbred BALB C, biology, business.industry, Twist-Related Protein 1, chemoresistance, Nuclear Proteins, Cell Biology, Original Articles, medicine.disease, hexokinase 2, digestive system diseases, Oxaliplatin, Gene Expression Regulation, Neoplastic, Apoptosis, Drug Resistance, Neoplasm, Cancer research, biology.protein, Molecular Medicine, Original Article, business, Colorectal Neoplasms, medicine.drug, Twist1
Abstract

Colorectal cancer (CRC) is the third most malignant tumour worldwide, with high mortality and recurrence. Chemoresistance is one of the main factors leading to metastasis and poor prognosis in advanced CRC patients. By analysing the Gene Expression Omnibus data set, we found higher hexokinase 2 (HK2) expression levels in patients with metastatic CRC than in those with primary CRC. Moreover, we observed higher enrichment in oxaliplatin resistance‐related gene sets in metastatic CRC than in primary CRC. However, the underlying relationship has not yet been elucidated. In our study, HK2 expression was significantly elevated in CRC patients. Gene set enrichment analysis (GSEA) revealed multi‐drug resistance and epithelial‐mesenchymal transition (EMT) pathways related to high HK2 expression. Our results showed that knockdown of HK2 significantly inhibited vimentin and Twist1 expression and promoted TJP1 and E‐cadherin expression in CRC cells. Additionally, transcriptional and enzymatic inhibition of HK2 by 3‐bromopyruvate (3‐bp) impaired oxaliplatin resistance in vitro and in vivo. Mechanistically, HK2 interacts with and stabilized Twist1 by preventing its ubiquitin‐mediated degradation, which is related to oxaliplatin resistance, in CRC cells. Overexpression of Twist1 reduced the apoptosis rate by HK2 knockdown in CRC cells. Collectively, we discovered that HK2 is a crucial regulator that mediates oxaliplatin resistance through Twist1. These findings identify HK2 and Twist1 as promising drug targets for CRC chemoresistance.

Published
2021

29. FTO downregulation mediated by hypoxia facilitates colorectal cancer metastasis

Author

Kai Yu, Qi Zhao, Qi Meng, Rui-Hua Xu, Yang Li, Long Bai, Zexian Liu, Ting Li, Huai-Qiang Ju, Junzhong Lin, Min Wang, Dan-Yun Ruan, De Shen Wang, Xiang-Yuan Wu, Li-Zhi Luo, Ying-Nan Wang, and Jin-Fei Lin

Subjects
0301 basic medicine, Cancer Research, Adenosine, medicine.medical_treatment, Down-Regulation, Protein degradation, Biology, Article, Metastasis, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, Genetics, medicine, Humans, Molecular Biology, Annexin A2, Messenger RNA, Kinase, Growth factor, nutritional and metabolic diseases, RNA-Binding Proteins, medicine.disease, Colorectal cancer, Ubiquitin ligase, 030104 developmental biology, Tumor progression, 030220 oncology & carcinogenesis, biology.protein, Cancer research, Epigenetics, Colorectal Neoplasms
Abstract

Fat mass and obesity-associated protein (FTO), an N6-methyladenosine (m6A) demethylase, participates in tumor progression and metastasis in many malignancies, but its role in colorectal cancer (CRC) is still unclear. Here, we found that FTO protein levels, but not RNA levels, were downregulated in CRC tissues. Reduced FTO protein expression was correlated with a high recurrence rate and poor prognosis in resectable CRC patients. Moreover, we demonstrated that hypoxia restrained FTO protein expression, mainly due to an increase in ubiquitin-mediated protein degradation. The serine/threonine kinase receptor associated protein (STRAP) might served as the E3 ligase and K216 was the major ubiquitination site responsible for hypoxia-induced FTO degradation. FTO inhibited CRC metastasis both in vitro and in vivo. Mechanistically, FTO exerted a tumor suppressive role by inhibiting metastasis-associated protein 1 (MTA1) expression in an m6A-dependent manner. Methylated MTA1 transcripts were recognized by an m6A “reader”, insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2), which then stabilized its mRNA. Together, our findings highlight the critical role of FTO in CRC metastasis and reveal a novel epigenetic mechanism by which the hypoxic tumor microenvironment promotes CRC metastasis.

Published
2021

30. Long-term tumor-free survival after cyst excision plus pancreaticoduodenectomy for the treatment of congenital choledochal cyst with malignant change

Author

Xinghua Huang, Li-Zhi Lv, Huan-Zhang Hu, and Yi Jiang

Subjects
medicine.medical_specialty, RD1-811, business.industry, Choledochal cyst, Carcinogenesis, medicine.medical_treatment, Anastomosis, Surgical, Surgical procedures, medicine.disease, Pancreaticoduodenectomy, Surgery, P rognosis, Pancreatectomy, Bile Duct Neoplasms, Congenital Choledochal Cyst, Medicine, Humans, Cyst, Choledochal cysts, business, Tumor free survival
Published
2021

31. COVID-19 and inflammatory bowel disease crosstalk: From emerging association to clinical proposal

Author

Sha‐Sha Tao, Xin‐Yi Wang, Xiao‐Ke Yang, Yu‐Chen Liu, Zi‐Yue Fu, Li‐Zhi Zhang, Zhi‐Xin Wang, Jing Ni, Zong‐Wen Shuai, and Hai‐Feng Pan

Subjects
Infectious Diseases, SARS-CoV-2, Virology, COVID-19, Humans, Angiotensin-Converting Enzyme 2, Peptidyl-Dipeptidase A, Cytokine Release Syndrome, Inflammatory Bowel Diseases
Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can cause coronavirus disease 2019 (COVID-19), an acute respiratory inflammation that has emerged worldwide since December 2019, and it quickly became a global epidemic. Inflammatory bowel disease (IBD) is a group of chronic nonspecific intestinal inflammatory diseases whose etiology has not been elucidated. The two have many overlapping symptoms in clinical presentation, such as abdominal pain, diarrhea, pneumonia, etc. Imbalance of the autoimmune system in IBD patients and long-term use of immunosuppressive drugs may increase the risk of infection; and systemic symptoms caused by COVID-19 may also induce or exacerbate intestinal inflammation. It has been found that the SARS-CoV-2 receptor angiotensin converting enzyme 2, which is highly expressed in the lung and intestine, is an inflammatory protective factor, and is downregulated and upregulated in COVID-19 and IBD, respectively, suggesting that there may be a coregulatory pathway. In addition, the immune activation pattern of COVID-19 and the cytokine storm in the inflammatory response have similar roles in IBD, indicating that the two diseases may influence each other. Therefore, this review aimed to address the following research questions: whether SARS-CoV-2 infection leads to the progression of IBD; whether IBD increases the risk of COVID-19 infection and poor prognosis; possible common mechanisms and genetic cross-linking between the two diseases; new treatment and care strategies for IBD patients, and the feasibility and risk of vaccination in the context of the COVID-19 epidemic.

Published
2022

32. Anatomical Morphology and Related Angles of Foramen Ovale: A Three-dimensional Computed Tomography Reconstruction

Author

Zhe, Cheng, Yuan Liang, Hu, Yu Xi, Sun, Li Zhi, Liang, di di, Pan, and da Wei, Wang

Subjects
Adult, Skull, Humans, Tomography, X-Ray Computed, Neurosurgical Procedures, Foramen Ovale, Retrospective Studies
Abstract

This study aimed to report the three-dimensional reconstruction of the foramen ovale (FO) based on computed tomography angiography and describe its shape and related angles. A retrospective analysis of 199 adult patients who were hospitalised at the Department of Neurosurgery, The Second Affiliated Hospital of Bengbu Medical College, Bengbu, China, from January to December 2020 was conducted. The original DICOM files of patients' computed tomography scans were processed by 3D Slicer software to reconstruct the three-dimensional skull. The morphological characteristics of the FO on both sides were analysed. Their size, related angles and volumes, and the differences between the two sides and gender were compared. A total of 398 FO from 199 patients were studied. The most frequent shape of the FO was oval, accounting for 54.27%. The mean lengths of the right and the left sides were 5.40±1.51 and 5.10±1.18mm, respectively. The mean width on the right and left sides was 3.23±1.16 and 3.33±1.19 mm, respectively. The FO is most commonly oval in shape. Clinicians may use the anatomical characteristics regarding the size and shape of the FO for diagnosis and treatment. Key Words: Foramen ovale, Computed tomographic angiography, 3-Dimensional anatomy.

Published
2022

33. Prognostic value of PaO

Author

Tao, Li, Wan-Qin, Hu, Xian, Li, Jia-Peng, Zhang, Li-Zhi, Tan, Li-Xia, Yu, Hai-Rong, Gu, and Ze-Ya, Shi

Subjects
Fibrin Fibrinogen Degradation Products, Oxygen, Intensive Care Units, ROC Curve, Sepsis, Humans, Prognosis, Palladium, Aged, Retrospective Studies
Abstract

To investigate the prognostic value for predicting mortality of partial pressure of oxygen/fraction of inspired oxygen (PaOThis retrospective cohort study enrolled elderly patients with sepsis admitted to the intensive care unit (ICU) between January 2019 and October 2020. Patients were divided into a survival group and a non-survival group. Biomarkers, SOFA, Acute Physiology and Chronic Health Evaluation II and Glasgow Coma Scale scores were recorded within 24 h after admission to the ICU.A total of 135 elderly patients with sepsis were enrolled in the study: 89 were in the survival group and 46 were in the non-survival group at 28 days. Univariate and multivariate regression analyses demonstrated that PaOThe combination of PaO

Published
2022

34. Mineralization of tribromophenol under anoxic/oxic conditions in the presence of copper(II) doped green rust: Importance of sequential reduction-oxidation process

Author

Xuejie Zhang, Jia Deng, Qianqian Jia, Bingbing Ji, Yitao Dai, and Li-Zhi Huang

Subjects
Environmental Engineering, Ecological Modeling, Iron, Humans, Oxides, Adsorption, Pollution, Waste Management and Disposal, Oxidation-Reduction, Copper, Water Science and Technology, Civil and Structural Engineering
Abstract

The groundwater environment often undergoes the transition from anoxic to oxic due to natural processes or human activities, but the influence of this transition on the fate of groundwater contaminates are not entirely understood. In this work, the degradation of tribromophenol (TBP) in the presence of environmentally relevant iron (oxyhydr)oxides (green rust, GR) and trace metal ions Cu(II) under anoxic/oxic-alternating conditions was investigated. Under anoxic conditions, GR-Cu(II) reduced TBP to 4-BP completely within 7 h while GR only had an adsorption effect on TBP. Under oxic conditions, GR-Cu(II) could generate •OH via dioxygen activation, which resulted in the oxidative transformation of TBP. Sixty-five percentage of TBP mineralization was achieved via a sequential reduction-oxidation process, which was not achieved through single reduction or oxidation process. The produced Cu(I) in GR-Cu(II) enhanced not only the reductive dehalogenation under anoxic conditions, but also the O

Published
2022

35. Chinese clinical practice guidelines for ultrasound-guided irreversible electroporation of liver cancer (version 2022)

Author

Min Xu, Li-Ting Xie, Yue-Yong Xiao, Ping Liang, Qi-Yu Zhao, Zhong-Min Wang, Wei-Lu Chai, Ying-Tian Wei, Lin-Feng Xu, Xiao-Kun Hu, Ming Kuang, Li-Zhi Niu, Chen-Guo Yao, Hai-Ying Kong, Guo Tian, Xiao-Yan Xie, Xin-Wu Cui, Dong Xu, Jun Zhao, and Tian-An Jiang

Subjects
Ablation Techniques, China, Electroporation, Hepatology, Liver Neoplasms, Gastroenterology, Humans, Ultrasonography, Interventional, Ultrasonography
Published
2022

36. Nanobodies: from structure to applications in non-injectable and bispecific biotherapeutic development

Author

Bingxuan Li, Xiaohong Qin, and Li-Zhi Mi

Subjects
Diagnostic Imaging, Humans, General Materials Science, Antigens, Single-Domain Antibodies, Antibodies, COVID-19 Drug Treatment
Abstract

The increasing demand for convenient, miniaturized and multifunctional antibodies necessitates the development of novel antigen-recognition molecules for biological and medical studies. Nanobodies, the functional variable regions of camelid heavy-chain-only antibodies, as a new tool, complement the conventional antibodies and are in the stage of rapid development. The outstanding advantages of nanobodies include a stable structure, easy production, excellent water solubility, high affinity toward antigens and low immunogenicity. With promising application potential, nanobodies are now increasingly applied to various studies, including protein structure analysis, microscopic imaging, medical diagnosis, and drug development. The approval of the first nanobody drug Caplacizumab by the FDA disclosed the therapeutic potential of nanobodies. The outbreak of COVID-19 accelerated the development of nanobody drugs in non-injectable and bispecific biotherapeutic applications. Herein, we reviewed recent studies on the nanobody structure, screening and their applications in protein structure analysis and nanobody drugs, especially on non-injectable nanobody and bispecific nanobody development.

Published
2022

37. PDGF-D Prodomain Differentially Inhibits the Biological Activities of PDGF-D and PDGF-B

Author

Linli Li, Dan Wu, Xiaohong Qin, and Li-Zhi Mi

Subjects
Platelet-Derived Growth Factor, Lymphokines, Vascular Endothelial Growth Factor D, Receptor, Platelet-Derived Growth Factor beta, Mice, Protein Domains, Structural Biology, NIH 3T3 Cells, Animals, Humans, Protein Multimerization, Molecular Biology, Cell Proliferation, Signal Transduction
Abstract

As a member of PDGF/VEGF (Platelet-derived growth factor/ Vascular endothelial growth factor) growth factors, PDGF-D regulates blood vessel development, wound healing, innate immunity, and organogenesis. Unlike PDGF-A and PDGF-B, PDGF-D has an additional CUB (Complement C1r/C1s, Uegf, Bmp1) domain at the N-terminus of its growth factor domain, and thus it is secreted in a latent, inactive complex, which needs to be proteolytically activated for its biological activities. However, how the CUB domain contributes to the latency and activation of the growth factor remains elusive. In this study, we modeled the dimeric structure of PDGF-D pro-complex and studied the inhibitory functions of PDGF-D prodomain on PDGF-B and PDGF-D signaling. In our model, the growth factor domain of PDGF-D forms a VEGF-D-like dimer through their β1 and β3 interactions. The hinge and CUB domains of PDGF-D bind at the opposite sides of the growth factor domain and exclude the PDGFR-β (PDGF Receptor β) D2 and D3 domains from recognizing the growth factor. In addition, we verified that PDGF-D prodomain could inhibit both PDGF-B and PDGF-D mediated PDGFR-β transphosphorylation in a dose-dependent manner. However, PDGF-D prodomain could only inhibit the proliferation of NIH 3T3 cells stimulated by PDGF-D but not by PDGF-B, indicating its differential inhibitory activities toward PDGF-B and PDGF-D signaling.

Published
2022

38. Overexpression of Notch2 enhances radiosensitivity via inhibition of the AKT/mTOR signaling pathway in nasopharyngeal carcinoma

Author

Rui Yang, Li-Jun Shen, Mao-Ling Huang, Cheng-Lin Qi, You Zou, Jian-Fei Sheng, Li-Zhi Wu, and Shi-Ming Chen

Subjects
endocrine system, Bioengineering, Applied Microbiology and Biotechnology, Radiation Tolerance, akt/mtor signaling pathway, Cell Line, Tumor, medicine, Humans, Radiosensitivity, Receptor, Notch2, Protein kinase B, notch2, PI3K/AKT/mTOR pathway, Chemistry, Cell growth, TOR Serine-Threonine Kinases, nasopharyngeal carcinoma, Nasopharyngeal Neoplasms, General Medicine, Transfection, Cell cycle, medicine.disease, Nasopharyngeal carcinoma, Apoptosis, radiosensitivity, Cancer research, Proto-Oncogene Proteins c-akt, TP248.13-248.65, Signal Transduction, Research Article, Research Paper, Biotechnology
Abstract

Our previous study found that in nasopharyngeal carcinoma (NPC) cells, overexpression of Notch2 can inhibit epithelial-mesenchymal transition (EMT), which plays a vital role in mediating radiosensitivity. The purpose of this study was to explore the radiosensitizing efficacy of the Notch2 gene in NPC cells and its potential mechanism. We used the recombinant plasmid transfection technique to establish Notch2-overexpressing 5-8 F and CNE-2 NPC cells. Cell proliferation, radiosensitivity, apoptosis and cell cycle distribution were assessed by cell counting kit-8 (CCK-8) experiments, colony formation experiments and flow cytometry. The levels of proteins related to cell cycle, apoptosis, and the AKT/mTOR signaling pathway were evaluated by using Western blotting. The results suggested that Notch2 overexpression increased the radiosensitivity of NPC cells, with sensitizing enhancement ratios (SERs) of 1.24 (5-8 F cells) and 1.34 (CNE-2 cells). Flow cytometry indicated that the level of apoptosis and percentage of cells in G2/M-phase were highest in NPC cells overexpressing Notch2 and treated with radiotherapy compared to cells overexpressing Notch2 alone or administered radiotherapy alone. Western blotting showed that compared to that of cells treated with Notch2 overexpression or radiotherapy alone, the levels of γH2AX, Bax, Bcl-2, Cyclin D1 and AKT/mTOR signaling pathway-related proteins were modified in NPC cells overexpressing Notch2 and treated with radiotherapy. These findings showed that overexpression of Notch2 can increase the radiosensitivity of NPC cells by inhibiting the AKT/mTOR pathway.AbbreviationsNPC: Nasopharyngeal carcinoma; EMT: Epithelial-mesenchymal transition; CCK8: Cell counting kit-8; EBV: Epstein-Barr virus; FBS: Fetal bovine serum; PE: Plating efficiency; SF: Survival fraction; SER: Sensitizing enhancement ratio; DSBs: DNA double-strand breaks[Figure: see text].

Published
2021

39. Magnetic Resonance Imaging Assessment of Abdominal Ectopic Fat Deposition in Correlation With Cardiometabolic Risk Factors

Author

Qin-He, Zhang, Lu-Han, Xie, Hao-Nan, Zhang, Jing-Hong, Liu, Ying, Zhao, Li-Hua, Chen, Ye, Ju, An-Liang, Chen, Nan, Wang, Qing-Wei, Song, Li-Zhi, Xie, and Ai-Lian, Liu

Subjects
Male, Endocrinology, Diabetes and Metabolism, Abdominal Fat, Subcutaneous Fat, Cardiometabolic Risk Factors, Humans, Female, Intra-Abdominal Fat, Middle Aged, Magnetic Resonance Imaging
Abstract

PurposeEctopic fat accumulation and abdominal fat distribution may have different cardiometabolic risk profiles. This study aimed to assess the associations between various magnetic resonance imaging (MRI)-acquired fat depots and cardiometabolic risk factors.MethodsA total of 320 subjects with median age of 59 years, 148 men and 172 women, were enrolled in the study. Visceral adipose tissue (VAT) area and fat fraction (FF), subcutaneous adipose tissue (SAT) area and FF at the L1–L2 levels, preperitoneal adipose tissue (pPAT) area and FF, hepatic FF, pancreatic FF, and intramuscular FF were assessed by MRI FF maps. The associations of various MRI-acquired fat depots with blood pressure, glucose, and lipid were examined using sex-stratified linear regression. Logistic regression stratified by sex was used to analyze the association of various MRI-acquired fat depots with the risk of hypertension, T2DM, and dyslipidemia.ResultsThe intraclass correlation coefficient (ICC) values were >0.9, which suggested good interobserver and intraobserver agreement. VAT area, V/S, hepatic fat, pancreatic fat, and pPAT rather than SAT area were significantly associated with multiple cardiometabolic risk factors (all p < 0.05). However, the patterns of these correlations varied by sex and specific risk factors. Also, VAT and SAT FF were only significantly associated with multiple cardiometabolic risk factors in women (all p < 0.05).ConclusionsVAT, hepatic fat, pancreatic fat, and pPAT were associated with cardiovascular metabolic risk factors independent of BMI. The patterns of these correlations were related to gender. These findings further the understanding of the association between ectopic fat deposition and cardiometabolic risk factors and help to better understand the obesity heterogeneity.

Published
2022

40. Association of rare PPARGC1A variants with Parkinson's disease risk

Author

Li-Zhi, Li, Yu-Wen, Zhao, Hong-Xu, Pan, Ya-Qin, Xiang, Yi-Ge, Wang, Qian, Xu, Xin-Xiang, Yan, Jie-Qiong, Tan, Jin-Chen, Li, Bei-Sha, Tang, and Ji-Feng, Guo

Subjects
Cohort Studies, China, Exome Sequencing, Humans, Parkinson Disease, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
Abstract

Recent researches on Parkinson's disease (PD) pathogenesis discovered the correlation between PD and peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) dysfunction and reduction of PPARGC1A gene expression. Hence, we detected PPARGC1A rare variants to clarify their effect on PD risk in a large population of PD patients in mainland China.We applied whole-exome sequencing (WES) to 1917 patients with early-onset or familial PD and 1652 controls (WES cohort), and whole-genome sequencing (WGS) to 1962 patients with sporadic late-onset PD and 1279 controls (WGS cohort). To identify PPARGC1A rare variants, we used burden analysis to assess the relationship between PPARGC1A rare variants and PD susceptibility.30 rare missense variants in the cohort WES and 21 missense variants in the cohort WGS have been detected in the study and PPARGC1A missense variants are significantly associated with early-onset and familial PD susceptibility in our study (P = 0.012), which supports evidence that PPARGC1A rare variants are involved in the onset of early-onset and familial PD.The study suggested that PPARGC1A rare variants may contribute to the risk of early-onset and familial PD.

Published
2022

41. Effects of lifestyle interventions on glucose regulation and diabetes risk in adults with impaired glucose tolerance or prediabetes: a meta-analysis

Author

Qiang Jiang, Jian-Ting Li, Pei Sun, Lu-Lu Wang, Li-Zhi Sun, and Shu-Guang Pang

Subjects
Adult, Blood Glucose, lifestyle interventions, glucose tolerance, Endocrinology, Diabetes and Metabolism, Diabetes, Prediabetic State, Glucose, Diabetes Mellitus, Type 2, Glucose Intolerance, adults, Humans, Life Style, risk
Abstract

The prevalence of diabetes mellitus is increasing and is related to sedentary lifestyles and obesity. Many studies were published on the effect of lifestyle interventions on glucose regulation and delay the onset of diabetes in adults with impaired glucose tolerance (IGT) or prediabetes. This study aimed to investigate the role of lifestyle interventions in individuals with IGT or prediabetes using a meta-analytic approach. PubMed, Embase, and the Cochrane Central Register of Controlled Trials databases were searched from their inception up to January 2020 to select eligible randomized controlled trials (RCTs). The weighted mean difference (WMD; for fasting plasma glucose (FPG) and 2-hour plasma glucose (2hPPG)) or relative risk (RR; for the risk of diabetes) with 95% confidence interval (CI) were calculated for pooled effect estimates using the random-effects model. Thirteen RCTs involving 3376 individuals with IGT or prediabetes were selected for this meta-analysis. The results showed that lifestyle interventions were associated with lower FPG (WMD: -0.14; 95% CI: -0.24 to -0.05 mmol/L; p=0.004) and 2hPPG (WMD: -0.66; 95% CI: -1.12 to -0.20 mmol/L; p=0.005) in adults with IGT or prediabetes. Moreover, the risk of diabetes was significantly reduced in individuals who received lifestyle interventions (RR: 0.75; 95% CI: 0.60-0.95; p=0.015). Lifestyle interventions could help improve glucose dysregulation and prevent the progression of diabetes in adults with IGT or prediabetes. Further large-scale RCTs should be conducted to assess the effects of long-term lifestyle interventions on diabetic complications in adults with IGT or prediabetes.

Published
2022

42. Pathological Changes and Expression of JAK-STAT Signaling Pathway Hallmark Proteins in Rat Retinas at Different Time Points After Retinal Ischemia Reperfusion Injury

Author

Wang, Shun, Yu, Aihua, Han, Mengyao, Chen, Xiaomin, Li, Zhi, Ke, Min, Cai, Xiaojun, Ai, Ming, and Xing, Yiqiao

Subjects
Male, STAT3 Transcription Factor, Cancer Research, Apoptosis, General Medicine, Retina, Pathology and Forensic Medicine, Rats, Rats, Sprague-Dawley, Oncology, Reperfusion Injury, Animals, Eosine Yellowish-(YS), Humans, Hematoxylin, Proto-Oncogene Proteins c-akt, Signal Transduction, bcl-2-Associated X Protein
Abstract

Retinal ischemia reperfusion injury (RIRI) is a conventional pathological process in various retinal vascular diseases. Many studies select only one specific time point to apply drugs and then assess the therapeutic effect of drugs; however, the baselines are not the same at different time points, which may cause variation in the judgement. Therefore, further investigation is needed. Accordingly, this study aimed to investigate the pathological changes of retinal structure, expression of JAK-STAT signaling pathway hallmark proteins, and apoptosis at different time points after retinal ischemia reperfusion injury in rats. Sixty-six male SPF Sprague-Dawley rats were randomly divided into six groups: control group, RIRI 0, 6-, 24-, 72-, and 144-h groups. RIRI models were induced by perfusing equilibrium solution into the right eye anterior chamber to increase intraocular pressure to 110 mmHg for 60 min. Rats were sacrificed at different time points after reperfusion. Then hematoxylin-eosin staining, transmission electron microscope, immunohistochemistry, western blot, and TUNEL were used. Hematoxylin-eosin showed the pathological changes while transmission electron microscope revealed the ultra-structure changes of retina after RIRI. Immunohistochemistry showed that JAK2, STAT3, p-JAK2, p-STAT3, Bax, and Bcl-2 proteins mainly located in ganglion cell layer and inner nuclear layer, the relative expression of former five proteins had significant differences vs. control group (p < 0.05), while Bcl-2 had no significant difference. In western blot, the protein expressing of JAK2, STAT3, p-JAK2, p-STAT3, p-Akt, and Bax had significant differences vs. control group (p < 0.05), while Akt and Bcl-2 had no significant differences. TUNEL staining showed the number of apoptosis positive cells rose initially but declined later, with a peak value at RIRI 24 h group. The dynamic changes of hallmark proteins at different time points after RIRI indicate that JAK-STAT signaling pathway activates rapidly but weakens later and plays a vital role in RIRI, and apoptosis is involved in RIRI with a peak value at 24 h in the process, suggesting a potential therapeutic direction and time window for treating RIRI.

Published
2022

43. Public Awareness and Mask Usage during the COVID-19 Epidemic: A Survey by China CDC New Media

Author

SUN, Cheng Xi, HE, Bin, MU, Di, LI, Pei Long, ZHAO, Hong Ting, LI, Zhi Li, ZHANG, Mu Li, FENG, Lu Zhao, ZHENG, Jian Dong, CHENG, Ying, CUI, Ying, and LI, Zhong Jie

Subjects
Adult, China, Mask, Adolescent, SARS-CoV-2, Health Behavior, Pneumonia, Viral, Masks, COVID-19, Middle Aged, Disease Outbreaks, Social media platform, Betacoronavirus, Young Adult, Age Distribution, Surveys and Questionnaires, Public behaviors, Humans, Public awareness, Coronavirus Infections, Letter to the Editor, Pandemics, Social Media
Abstract

An online survey conducted March 18–19, 2020 on the official China CDC WeChat account platform was used to evaluate the effect of public education about masks usage during the new coronavirus disease 2019 (COVID-19) epidemic. Chinese nationals older than 18 were eligible for the survey. The survey collected 5,761 questionnaires from the 31 provinces, municipalities, and autonomous regions of mainland China. 99.7% and 97.2% of the respondents answered correctly that respiratory droplets and direct contact were the main transmission routes. 73.3% of the respondents considered COVID-19 to be ‘serious’ or ‘very serious’. When going to the hospital, 96.9% (2,885/2,976 had gone to a hospital) used a mask during the COVID-19 epidemic, while 41.1% (2,367/5,761) did not use a mask before the epidemic. Among the respondents that used public transportation and went shopping, 99.6% and 99.4%, respectively, wore masks. Among respondents who returned to work, 75.5% wore a mask at the workplace, while 86.3% of those who have not returned to work will choose to use masks when they return to the workplace. The Chinese public is highly likely to use a mask during COVID-19 epidemic, and the mask usage changed greatly since the COVID-19 outbreak. Therefore, public education has played an important role during the COVID-19 epidemic.

Published
2020

44. Association Between Plasma Homocysteine Levels and Subclinical Hypothyroidism in Adult Subjects: A Meta-Analysis

Author

Fang-Fang Liu, Ya-Qing Zhang, Li-Zhi Li, Jin-Rong Guo, Kai Ma, Shao-Hua Chen, Shou-Fa Zhang, and Wei Zhang

Subjects
Adult, Hyperhomocysteinemia, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, 030204 cardiovascular system & hematology, Cochrane Library, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Hypothyroidism, Risk Factors, Internal medicine, Humans, Medicine, Euthyroid, 030212 general & internal medicine, Homocysteine, Subclinical infection, business.industry, Biochemistry (medical), General Medicine, Publication bias, medicine.disease, Meta-analysis, Plasma homocysteine, Observational study, business
Abstract

Increased plasma homocysteine (Hcy) levels have been widely documented in patients with overt hypothyroidism; however, the significance of Hcy level changes in patients with subclinical hypothyroidism (SCH) remains controversial. The aim of this meta-analysis was to determine the Hcy status in patients with SCH compared with euthyroid subjects. We searched PubMed, Embase, and Cochrane Library databases prior to December 2019 to identify eligible studies and assessed the quality of selected studies using the Newcastle-Ottawa Quality Assessment Scale. Publication bias was evaluated by Begg’s test and Egger’s test. Meta-regression analysis was conducted to investigate the source of heterogeneity. A likely source of heterogeneity was the year of the study. All statistical analyses were performed with RevMan 5.3 and Stata 12.0 software. Our meta-analysis of twelve observational studies with 684 patients showed that those with SCH aged between 18 and 65 years old were associated with a slightly increased plasma Hcy level compared with euthyroid controls. The pooled result of the weighted mean difference (WMD) of increased tHcy levels was 1.16 μmol/l (95% CI: 0.51, 1.82; p=0.0005). The Hcy level in patients with SCH aged between 18 and 65 years old is significantly increased compared to euthyroid controls.

Published
2020

45. Influences of different drying methods on the structural characteristics and prebiotic activity of polysaccharides from bamboo shoot (Chimonobambusa quadrangularis) residues

Author

Li-zhi Ma, Qing-yue Hong, Wu Wenneng, Guangjing Chen, and Ning Ji

Subjects
Vacuum, medicine.medical_treatment, 02 engineering and technology, Uronic acid, Poaceae, Polysaccharide, Biochemistry, 03 medical and health sciences, chemistry.chemical_compound, Polysaccharides, Structural Biology, medicine, Humans, Food science, Desiccation, Solubility, Molecular Biology, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, Gastric Juice, Chemistry, Prebiotic, General Medicine, 021001 nanoscience & nanotechnology, Chimonobambusa quadrangularis, Bamboo shoot, Freeze Drying, Prebiotics, Shoot, Particle size, alpha-Amylases, 0210 nano-technology
Abstract

In the present study, in order to assess the influences of drying methods on the chemical structures, in vitro digestibility and prebiotic potential of polysaccharides extracted from Chimonobambusa quadrangularis shoot (CPSs), four drying methods, including hot air-, vacuum-, freeze-, and spray-drying, were utilized to dry CPSs. Results revealed that the physicochemical characteristics and prebiotic activity of CPSs varied by different drying methods. In comparison with the other drying methods, freeze-dried CPSs had higher uronic acid content (9.58%), lower medium-high molecular weight (117.63 kDa), smaller particle size (115.97 nm) and better solubility. All four CPSs fractions exhibited low degree of digestibility to pretended human gastric juice (2%) and α-amylase (5%). The freeze-dried CPSs showed the greatest prebiotic activity as this polysaccharide induced the strongest proliferation effect of probiotic bacteria and the highest production of total short chain fatty acids. Our results collectively provided substantial evidence that the freeze-drying method proposed in this study could be an effective technique in improving the prebiotic potentiality of CPSs.

Published
2020

46. The independent risks and specific biomarker of breast cancer-related ischemic stroke

Author

Xue-Min Cheng, Zhijian Liang, Yunfei Wei, Chunyong Chen, Daobin Cheng, Dacheng Wang, Hong-Bin Liang, Shengyu Li, Li-Zhi Lu, Qixiong Qin, Guohui Li, and Haihua Li

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, Breast Neoplasms, Sensitivity and Specificity, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Risk Factors, Internal medicine, Biomarkers, Tumor, medicine, Humans, Aged, Ischemic Stroke, Retrospective Studies, business.industry, General Neuroscience, Retrospective cohort study, General Medicine, Middle Aged, medicine.disease, humanities, 030104 developmental biology, Ischemic stroke, Biomarker (medicine), Female, business, 030217 neurology & neurosurgery
Abstract

This retrospective study was designed to investigate the independent risks and specific biomarker for breast cancer-related ischemic stroke (BCRS).Clinical features and laboratory findings were compared between BCRS group and breast cancer group without stroke, and further multivariate analyses were performed to predict independent risks factors for BCRS patients. A receiver operator characteristic (ROC) curve analysis was configured to estimate the diagnostic efficacy of each independent risk and the product of these risks and to obtain the optimal cut-off value of diagnosis, which was termed the BCRS Index.BCRS patients had elevated plasma D-dimer and CA153 levels and platelet-to-lymphocyte ratio (PLR), as well as more patients received endocrine therapy (allEndocrine therapy, as well as elevated plasma D-dimer and CA153 levels and PLR values may be independent risks for BCRS. Furthermore, BCRS Index should be served as a novel specific biomarker for BCRS, which is useful to distinguish BCRS for clinicians.

Published
2020

47. Different Numbers of Long-Pulse 1064-nm Nd-YAG Laser Treatments for Onychomycosis: A Pilot Study

Author

Linfeng Li, Dong-kun Wang, Rui-na Zhang, Jun-ying Zhao, Li-zhi Ma, and Feng-lin Zhuo

Subjects
Adult, Male, China, Long pulse, Article Subject, Adolescent, Dentistry, Pilot Projects, Lasers, Solid-State, General Biochemistry, Genetics and Molecular Biology, Group B, Young Adult, 030207 dermatology & venereal diseases, 03 medical and health sciences, Laser treatments, 0302 clinical medicine, Onychomycosis, Humans, Medicine, In patient, 030212 general & internal medicine, Pulse, Aged, General Immunology and Microbiology, business.industry, Laser treatment, Significant difference, General Medicine, Middle Aged, Treatment Outcome, Nails, Nd:YAG laser, Female, business, Research Article
Abstract

Purpose. To examine the benefits of different numbers of 1064-nm Nd-YAG laser treatments in patients with onychomycosis. Methods. This was a pilot study of patients with onychomycosis who were divided into three groups: four treatment sessions (group A), eight sessions (group B), and 12 sessions (group C). Only infected nails of degrees II–III (Scoring Clinical Index for Onychomycosis) were included. Treatment was given once a week using a long-pulse Nd-YAG 1064-nm laser. Patients were followed at 8, 16, and 24 weeks after the first treatment. Side effects were recorded. Results. Treatments were completed for 442 nails in 102 patients. The efficacy rates at 8, 16, and 24 weeks were 35.5%, 38.7%, and 37.4% for group A; 31.4%, 41.7%, and 44.0% for group B; and 27.7%, 50.0%, and 55.4% for group C, respectively. There was a significant difference in the efficacy rate at 24 weeks (P=0.016) between groups A and C, but not for groups A vs. B, or for groups B vs. C. No difference in the efficacy rate at 8 or 16 weeks was observed among the three groups. In all three groups, the efficacy was better for degree II nails than for degree III nails (all P<0.05). No side effects occurred. Conclusions. The 1064-nm Nd-YAG laser had clinical benefits against onychomycosis. Higher numbers of treatments provided better long-term (24-week) benefits, but had no impact on the short-term outcomes. The efficacy of laser treatment on degree II onychomycosis was better than for degree III.

Published
2020

48. Multi-directional cellular alignment in 3D guided by electrohydrodynamically-printed microlattices

Author

Kang Han, Mao Mao, Jiankang He, Dichen Li, and Li Zhi

Subjects
Materials science, 0206 medical engineering, Biomedical Engineering, 02 engineering and technology, Biochemistry, Cell Line, Biomaterials, Human Umbilical Vein Endothelial Cells, Humans, Myocytes, Cardiac, Molecular Biology, Process (anatomy), Tissue Scaffolds, Hydrogels, Electrochemical Techniques, General Medicine, 021001 nanoscience & nanotechnology, 020601 biomedical engineering, Longitudinal direction, Printing, Three-Dimensional, Multi directional, Collagen, Cellular frequencies, 0210 nano-technology, Artificial tissue, Biotechnology, Biomedical engineering
Abstract

Recapitulating aligned cellular architectures of native tissues in vitro is important to engineer artificial tissue analogs with desired biological functions. Here a novel strategy is presented to direct three-dimensional (3D) cellular alignment by embedding cell/collagen hydrogel into the predefined electrohydrodynamically-printed microlattices. The cell/collagen hydrogel, originally filled within the printed microlattices uniformly, was found to gradually develop into densely-populated and highly-aligned bands along the longitudinal direction of the printed microlattices. The cellular alignment was highly dependent on the height, spacing and orientation of the microlattices. The presented method was applicable to multiple cell types including primary cardiomyocytes and the gaps formed between the aligned bands and the lateral walls of the microlattice facilitated the subsequent seeding and rapid alignment of other cell types which enables to engineer anisotropic multicellular tissue constructs. The engineered cardiac patches expressed mature cardiomyocyte-specific phenotypes and exhibited synchronous contractive activities. Multilayer cellular alignment with varied orientation in 3D collagen hydrogel was successfully achieved by using electrohydrodynamically-printed microlattices with layer-specific orientations. This exploration offers a promising way to engineer complex 3D tissue constructs with predefined cellular alignments. Statement of significance Fabrication of biomimetic highly-aligned complex cellular architectures has a great significance to recapitulate the unique mechanical and physiological functions of the engineered tissues (e.g., heart tissue, neuron, muscle). Here, we introduced a novel strategy to direct 3D cellular alignment by embedding cell/collagen hydrogel into the predefined electrohydrodynamically-printed microlattices without any external stimuli. The microscopical study of the dynamic alignment process of cells and collagen fibers contributed to exploring the mechanism of autonomous formation of highly-aligned cellular bands. Multilayer cellular alignment with varied orientation in 3D collagen hydrogel was successfully achieved by using the microlattices with layer-specific orientations, which showed a promising way to engineer complex 3D tissue constructs with predefined cellular alignments.

Published
2020

49. Structural Optimization and Improving Antitumor Potential of Moreollic Acid from Gamboge

Author

Li-Zhi Cheng, Dan-Ling Huang, Min Liao, Ke-Ming Li, Zhao-Qiu Wu, and Yong-Xian Cheng

Subjects
synthesis, Cell Survival, Xanthones, Cell Cycle, Organic Chemistry, Pharmaceutical Science, Antineoplastic Agents, Analytical Chemistry, Structure-Activity Relationship, QD241-441, Piperidines, Chemistry (miscellaneous), Gamboge, Cell Line, Tumor, Colonic Neoplasms, Drug Discovery, Humans, Molecular Medicine, structural optimization, antitumor, Physical and Theoretical Chemistry, Garcinia, Cell Proliferation
Abstract

Moreollic acid, a caged-tetraprenylated xanthone from Gamboge, has been indicated as a potent antitumor molecule. In the present study, a series of moreollic acid derivatives with novel structures were designed and synthesized, and their antitumor activities were determined in multifarious cell lines. The preliminary screening results showed that all synthesized compounds selectively inhibited human colon cancer cell proliferation. TH12-10, with an IC50 of 0.83, 1.10, and 0.79 μM against HCT116, DLD1, and SW620, respectively, was selected for further antitumor mechanism studies. Results revealed that TH12-10 effectively inhibited cell proliferation by blocking cell-cycle progression from G1 to S. Besides, the apparent structure–activity relationships of target compounds were discussed. To summarize, a series of moreollic acid derivatives were discovered to possess satisfactory antitumor potentials. Among them, TH12-10 displays the highest antitumor activities against human colon cancer cells, in which the IC50 values in DLD1 and SW620 are lower than that of 5-fluorouracil.

Published
2022
Full Text
View/download PDF

50. The risk of COVID-19 death is much greater and age-dependent with type I IFN autoantibodies

Author

Manry, Jérémy, Bastard, Paul, Gervais, Adrian, Le Voyer, Tom, Rosain, Jérémie, Philippot, Quentin, Michailidis, Eleftherios, Hoffmann, Hans-Heinrich, Eto, Shohei, Garcia-Prat, Marina, Bizien, Lucy, Parra-Martínez, Alba, Yang, Rui, Haljasmägi, Liis, Migaud, Mélanie, Särekannu, Karita, Maslovskaja, Julia, de Prost, Nicolas, Tandjaoui-Lambiotte, Yacine, Luyt, Charles-Edouard, Amador-Borrero, Blanca, Gaudet, Alexandre, Poissy, Julien, Morel, Pascal, Richard, Pascale, Cognasse, Fabrice, Troya, Jesús, Trouillet-Assant, Sophie, Belot, Alexandre, Saker, Kahina, Garçon, Pierre, Rivière, Jacques, Lagier, Jean-Christophe, Gentile, Stéphanie, Rosen, Lindsey, Shaw, Elana, Morio, Tomohiro, Tanaka, Junko, Dalmau, David, Tharaux, Pierre-Louis, Sene, Damien, Stepanian, Alain, Mégarbane, Bruno, Triantafyllia, Vasiliki, Fekkar, Arnaud, Heath, James, Franco, José Luis, Anaya, Juan-Manuel, Solé-Violán, Jordi, Imberti, Luisa, Biondi, Andrea, Bonfanti, Paolo, Castagnoli, Riccardo, Delmonte, Ottavia, Zhang, Yu, Snow, Andrew, Holland, Steven, Biggs, Catherine, Moncada-Vélez, Marcela, Arias, Andrés Augusto, Lorenzo, Lazaro, Boucherit, Soraya, Anglicheau, Dany, Planas, Anna, Haerynck, Filomeen, Duvlis, Sotirija, Ozcelik, Tayfun, Keles, Sevgi, Bousfiha, Ahmed, El Bakkouri, Jalila, Ramirez-Santana, Carolina, Paul, Stéphane, Pan-Hammarström, Qiang, Hammarström, Lennart, Dupont, Annabelle, Kurolap, Alina, Metz, Christine, Aiuti, Alessandro, Casari, Giorgio, Lampasona, Vito, Ciceri, Fabio, Barreiros, Lucila, Dominguez-Garrido, Elena, Vidigal, Mateus, Zatz, Mayana, van de Beek, Diederik, Sahanic, Sabina, Tancevski, Ivan, Stepanovskyy, Yurii, Boyarchuk, Oksana, Nukui, Yoko, Tsumura, Miyuki, Vidaur, Loreto, Tangye, Stuart, Burrel, Sonia, Duffy, Darragh, Quintana-Murci, Lluis, Klocperk, Adam, Kann, Nelli, Shcherbina, Anna, Lau, Yu-Lung, Leung, Daniel, Coulongeat, Matthieu, Marlet, Julien, Koning, Rutger, Reyes, Luis Felipe, Chauvineau-Grenier, Angélique, Venet, Fabienne, Monneret, Guillaume, Nussenzweig, Michel, Arrestier, Romain, Boudhabhay, Idris, Baris-Feldman, Hagit, Hagin, David, Wauters, Joost, Meyts, Isabelle, Dyer, Adam, Kennelly, Sean, Bourke, Nollaig, Halwani, Rabih, Sharif-Askari, Fatemeh Saheb, Dorgham, Karim, Sallette, Jérôme, Sedkaoui, Souad Mehlal, Alkhater, Suzan, Rigo-Bonnin, Raúl, Morandeira, Francisco, Roussel, Lucie, Vinh, Donald, Erikstrup, Christian, Condino-Neto, Antonio, Prando, Carolina, Bondarenko, Anastasiia, Spaan, András, Gilardin, Laurent, Fellay, Jacques, Lyonnet, Stanislas, Bilguvar, Kaya, Lifton, Richard, Mane, Shrikant, Anderson, Mark, Boisson, Bertrand, Béziat, Vivien, Zhang, Shen-Ying, Andreakos, Evangelos, Hermine, Olivier, Pujol, Aurora, Peterson, Pärt, Mogensen, Trine, Rowen, Lee, Mond, James, Debette, Stéphanie, de Lamballerie, Xavier, Burdet, Charles, Bouadma, Lila, Zins, Marie, Soler-Palacin, Pere, Colobran, Roger, Gorochov, Guy, Solanich, Xavier, Susen, Sophie, Martinez-Picado, Javier, Raoult, Didier, Vasse, Marc, Gregersen, Peter, Piemonti, Lorenzo, Rodríguez-Gallego, Carlos, Notarangelo, Luigi, Su, Helen, Kisand, Kai, Okada, Satoshi, Puel, Anne, Jouanguy, Emmanuelle, Rice, Charles, Tiberghien, Pierre, Zhang, Qian, Casanova, Jean-Laurent, Abel, Laurent, Cobat, Aurélie, Zhang, Peng, Seeleuthner, Yoann, Talouarn, Estelle, Marchal, Astrid, Matuozzo, Daniela, de la Chapelle, Aliénor, Chen, Jie, Chrabieh, Maya, Liu, Dana, Nemirowskaya, Yelena, Cruz, Inés Marín, Materna, Marie, Pelet, Sophie, Thibault, Chloé, Liu, Zhiyong, Abad, Jorge, Accordino, Giulia, Achille, Cristian, Aguilera-Albesa, Sergio, Aguiló-Cucurull, Aina, Özkan, Esra Akyüz, Darazam, Ilad Alavi, Albisures, Jonathan Antonio Roblero, Aldave, Juan, Ramos, Miquel Alfonso, Khan, Taj Ali, Aliberti, Anna, Nadji, Seyed Alireza, Alkan, Gulsum, Allardet-Servent, Jerome, Allende, Luis, Alonso-Arias, Rebeca, Alshahrani, Mohammed, Alsina, Laia, Alyanakian, Marie-Alexandra, Borrero, Blanca Amador, Amoura, Zahir, Antolí, Arnau, Aubart, Mélodie, Auguet, Teresa, Avramenko, Iryna, Aytekin, Gökhan, Azot, Axelle, Bahram, Seiamak, Bajolle, Fanny, Baldanti, Fausto, Baldolli, Aurélie, Ballester, Maite, Feldman, Hagit Baris, Barrou, Benoit, Barzaghi, Federica, Basso, Sabrina, Bayhan, Gulsum Iclal, Bezrodnik, Liliana, Bilbao, Agurtzane, Blanchard-Rohner, Geraldine, Blanco, Ignacio, Blandinières, Adeline, Blázquez-Gamero, Daniel, Bleibtreu, Alexandre, Bloomfield, Marketa, Bolivar-Prados, Mireia, Borghesi, Alessandro, Borie, Raphael, Botdhlo-Nevers, Elisabeth, Bousquet, Aurore, Boutolleau, David, Bouvattier, Claire, Bravais, Juliette, Briones, M. Luisa, Brunner, Marie-Eve, Bruno, Raffaele, Bueno, Maria Rita P., Bukhari, Huda, Bustamante, Jacinta, Agra, Juan José Cáceres, Capra, Ruggero, Carapito, Raphael, Carrabba, Maria, Casasnovas, Carlos, Caseris, Marion, Cassaniti, Irene, Castelle, Martin, Castelli, Francesco, de Vera, Martín Castillo, Castro, Mateus, Catherinot, Emilie, Celik, Jale Bengi, Ceschi, Alessandro, Chalumeau, Martin, Charbit, Bruno, Cheng, Matthew, Clavé, Pere, Clotet, Bonaventura, Codina, Anna, Cohen, Yves, Comarmond, Cloé, Combes, Alain, Comoli, Patrizia, Corsico, Angelo, Coşkuner, Taner, Cvetkovski, Aleksandar, Cyrus, Cyril, Danion, François, Darley, David Ross, Das, Vincent, Dauby, Nicolas, Dauger, Stéphane, de Munter, Paul, de Pontual, Loic, Dehban, Amin, Delplancq, Geoffroy, Demoule, Alexandre, Desguerre, Isabelle, Di Sabatino, Antonio, Diehl, Jean-Luc, Dobbelaere, Stephanie, Domínguez-Garrido, Elena, Dubost, Clément, Ekwall, Olov, Bozdemir, Şefika Elmas, Elnagdy, Marwa, Emiroglu, Melike, Endo, Akifumi, Erdeniz, Emine Hafize, Aytekin, Selma Erol, Lasa, Maria Pilar Etxart, Euvrard, Romain, Fabio, Giovanna, Faivre, Laurence, Falck, Antonin, Fartoukh, Muriel, Faure, Morgane, Arquero, Miguel Fernandez, Ferrer, Ricard, Ferreres, Jose, Flores, Carlos, Francois, Bruno, Fumadó, Victoria, Fung, Kitty, Fusco, Francesca, Gagro, Alenka, Solis, Blanca Garcia, Gaussem, Pascale, Gayretli, Zeynep, Gil-Herrera, Juana, Gatineau, Audrey Giraud, Girona-Alarcón, Mònica, Godínez, Karen Alejandra Cifuentes, Goffard, Jean-Christophe, Gonzales, Nacho, Gonzalez-Granado, Luis, González-Montelongo, Rafaela, Guerder, Antoine, Gülhan, Belgin, Gumucio, Victor Daniel, Hanitsch, Leif Gunnar, Gunst, Jan, Gut, Marta, Hadjadj, Jérôme, Hancerli, Selda, Hariyan, Tetyana, Hatipoglu, Nevin, Heppekcan, Deniz, Hernandez-Brito, Elisa, Ho, Po-Ki, Holanda-Peña, María Soledad, Horcajada, Juan, Hraiech, Sami, Humbert, Linda, Hung, Ivan, Iglesias, Alejandro, Íñigo-Campos, Antonio, Jamme, Matthieu, Arranz, María Jesús, Jimeno, Marie-Thérèse, Jordan, Iolanda, Kanık-Yüksek, Saliha, Kara, Yalcin Burak, Karahan, Aydın, Karbuz, Adem, Yasar, Kadriye Kart, Kasapcopur, Ozgur, Kashimada, Kenichi, Demirkol, Yasemin Kendir, Kido, Yasutoshi, Kizil, Can, Kılıç, Ahmet Osman, Daganou, Maria, Koukaki, Evangelia, Koutsoukou, Antonia, Rapti, Vasiliki, Syrigos, Konstantinos, Król, Zbigniew, Ksouri, Hatem, Kuentz, Paul, Kwan, Arthur, Kwan, Yat Wah M., Kwok, Janette, Lam, David, Conti, Francesca, Pession, Andrea, Lampropoulou, Vicky, Lanternier, Fanny, Bourgeois, Fleur Le, Leo, Yee-Sin, Lopez, Rafael Leon, Levin, Michael, Levy, Michael, Lévy, Romain, Li, Zhi, Lilleri, Daniele, Lima, Edson Jose Adrian Bolanos, Linglart, Agnes, López-Collazo, Eduardo, Lorenzo-Salazar, José, Louapre, Céline, Lubetzki, Catherine, Lung, Kwok-Cheung, Lye, David, Magnone, Cinthia, Mansouri, Davood, Marchioni, Enrico, Marioli, Carola, Marjani, Majid, Marques, Laura, Pereira, Jesus Marquez, Martín-Nalda, Andrea, Pueyo, David Martínez, Marzana, Iciar, Mata-Martínez, Carmen, Mathian, Alexis, Matos, Larissa Rb, Matthews, Gail, Mayaux, Julien, Mclaughlin-Garcia, Raquel, Meersseman, Philippe, Mège, Jean-Louis, Mekontso-Dessap, Armand, Melki, Isabelle, Meloni, Federica, Meritet, Jean-François, Merlani, Paolo, Akcan, Özge Metin, Mezidi, Mehdi, Migeotte, Isabelle, Millereux, Maude, Million, Matthieu, Mirault, Tristan, Mircher, Clotilde, Mirsaeidi, Mehdi, Mizoguchi, Yoko, Modi, Bhavi, Mojoli, Francesco, Moncomble, Elsa, Melián, Abián Montesdeoca, Martinez, Antonio Morales, Morange, Pierre-Emmanuel, Mordacq, Clémence, Morelle, Guillaume, Mouly, Stéphane, Muñoz-Barrera, Adrián, Nafati, Cyril, Nagashima, Shintaro, Nakagama, Yu, Neven, Bénédicte, Neves, João Farela, Ng, Lisa, Ng, Yuk-Yung, Nielly, Hubert, Medina, Yeray Novoa, Cuadros, Esmeralda Nuñez, Ocejo-Vinyals, J. Gonzalo, Okamoto, Keisuke, Oualha, Mehdi, Ouedrani, Amani, Özçelik, Tayfun, Ozkaya-Parlakay, Aslinur, Pagani, Michele, Papadaki, Maria, Parizot, Christophe, Parola, Philippe, Pascreau, Tiffany, Paz-Artal, Estela, Pedraza-Sánchez, Sigifredo, Gálvez-Romero, José Luis, Pellecer, Nancy Carolina González, Pellegrini, Silvia, Diego, Rebeca Pérez De, Pérez-Fernández, Xosé Luis, Philippe, Aurélien, Picod, Adrien, de Chambrun, Marc Pineton, Piralla, Antonio, Planas-Serra, Laura, Ploin, Dominique, Poncelet, Géraldine, Poulakou, Garyphallia, Pouletty, Marie, Pourshahnazari, Persia, Qiu-Chen, Jia Li, Quentric, Paul, Rambaud, Thomas, Raoult, Violette, Rebillat, Anne-Sophie, Redin, Claire, Resmini, Léa, Ricart, Pilar, Richard, Jean-Christophe, Rivet, Nadia, Rocamora-Blanch, Gemma, Rodero, Mathieu, Rodrigo, Carlos, Rodriguez, Luis Antonio, Rodriguez-Gallego, Carlos, Rodriguez-Palmero, Agustí, Romero, Carolina Soledad, Rothenbuhler, Anya, Roux, Damien, Rovina, Nikoletta, Rozenberg, Flore, Ruch, Yvon, Ruiz, Montse, Prado, Maria Yolanda Ruiz Del, Ruiz-Rodriguez, Juan Carlos, Sabater-Riera, Joan, Saks, Kai, Salagianni, Maria, Sanchez, Oliver, Sánchez-Montalvá, Adrián, Sánchez-Ramón, Silvia, Schidlowski, Laire, Schluter, Agatha, Schmidt, Julien, Schmidt, Matthieu, Schuetz, Catharina, Schweitzer, Cyril, Scolari, Francesco, Sediva, Anna, Seijo, Luis, Seminario, Analia Gisela, Seng, Piseth, Senoglu, Sevtap, Seppänen, Mikko, Llovich, Alex Serra, Shahrooei, Mohammad, Siguret, Virginie, Siouti, Eleni, Smadja, David, Smith, Nikaia, Sobh, Ali, Soler, Catherine, Soler-Palacín, Pere, Sözeri, Betül, Stella, Giulia Maria, Stepanovskiy, Yuriy, Stoclin, Annabelle, Taccone, Fabio, Taupin, Jean-Luc, Tavernier, Simon, Terrier, Benjamin, Thiery, Guillaume, Thorball, Christian, Thorn, Karolina, Thumerelle, Caroline, Tipu, Imran, Tolstrup, Martin, Tomasoni, Gabriele, Toubiana, Julie, Alvarez, Josep Trenado, Tsang, Owen, Tserel, Liina, Tso, Eugene, Tucci, Alessandra, Öz, Şadiye Kübra Tüter, Ursini, Matilde Valeria, Utsumi, Takanori, Uzunhan, Yurdagul, Vabres, Pierre, Valencia-Ramos, Juan, van den Rym, Ana Maria, Vandernoot, Isabelle, Velez-Santamaria, Valentina, Veliz, Silvia Patricia Zuniga, Viel, Sébastien, Villain, Cédric, Vilaire-Meunier, Marie, Villar-García, Judit, Vincent, Audrey, Vogt, Guillaume, Voiriot, Guillaume, Volokha, Alla, Vuotto, Fanny, Wauters, Els, Wu, Alan, Wu, Tak-Chiu, Yahşi, Aysun, Yesilbas, Osman, Yildiz, Mehmet, Young, Barnaby, Yükselmiş, Ufuk, Ghirardello, Stefano, Zuccaro, Valentina, Andrés, Ana De, van Praet, Jens, Lambrecht, Bart, van Braeckel, Eva, Bosteels, Cédric, Hoste, Levi, Hoste, Eric, Bauters, Fré, Clercq, Jozefien De, Heijmans, Cathérine, Slabbynck, Hans, Naesens, Leslie, Florkin, Benoit, Boulanger, Cécile, Vanderlinden, Dimitri, Foti, Giuseppe, Bellani, Giacomo, Citerio, Giuseppe, Contro, Ernesto, Pesci, Alberto, Valsecchi, Maria Grazia, Cazzaniga, Marina, Danielson, Jeffrey, Dobbs, Kerry, Kashyap, Anuj, Ding, Li, Dalgard, Clifton, Sottini, Alessandra, Quaresima, Virginia, Quiros-Roldan, Eugenia, Rossi, Camillo, Bettini, Laura Rachele, D’angio, Mariella, Beretta, Ilaria, Montagna, Daniela, Licari, Amelia, Marseglia, Gian Luigi, Batten, Isabella, Reddy, Conor, Mcelheron, Matt, Noonan, Claire, Connolly, Emma, Fallon, Aoife, Storgaard, Merete, Jørgensen, Sofie, Pedersen, Ole Birger, Sørensen, Erik, Mikkelsen, Susan, Dinh, Khoa Manh, Larsen, Margit Anita Hørup, Paulsen, Isabella Worlewenut, von Stemann, Jakob Hjorth, Hansen, Morten Bagge, Ostrowski, Sisse Rye, Townsend, Liam, Ni Cheallaigh, Cliona, Bergin, Colm, Martin-Loeches, Ignacio, Dunne, Jean, Conlon, Niall, O’farrelly, Cliona, Allavena, Clotilde, Andrejak, Claire, Angoulvant, François, Azoulay, Cecile, Bachelet, Delphine, Bartoli, Marie, Basmaci, Romain, Behillill, Sylvie, Beluze, Marine, Benech, Nicolas, Benkerrou, Dehbia, Bhavsar, Krishna, Bitker, Laurent, Bouscambert-Duchamp, Maude, Paz, Pauline Caraux, Cervantes-Gonzalez, Minerva, Chair, Anissa, Chirouze, Catherine, Coelho, Alexandra, Cordel, Hugues, Couffignal, Camille, Couffin-Cadiergues, Sandrine, D’ortenzio, Eric, de Montmollin, Etienne, Debard, Alexa, Debray, Marie-Pierre, Deplanque, Dominique, Descamps, Diane, Desvallée, Mathilde, Diallo, Alpha, Diouf, Alphonsine, Dorival, Céline, Dubos, François, Duval, Xavier, Eloy, Philippine, Enouf, Vincent, Epaulard, Olivier, Esperou, Hélène, Esposito-Farase, Marina, Etienne, Manuel, Garot, Denis, Gault, Nathalie, Gaymard, Alexandre, Ghosn, Jade, Gigante, Tristan, Gilg, Morgane, Goehringer, François, Guedj, Jérémie, Hoctin, Alexandre, Hoffmann, Isabelle, Houas, Ikram, Hulot, Jean-Sébastien, Jaafoura, Salma, Kafif, Ouifiya, Kaguelidou, Florentia, Kali, Sabrina, Kerroumi, Younes, Khalil, Antoine, Khan, Coralie, Kimmoun, Antoine, Laine, Fabrice, Laouénan, Cédric, Laribi, Samira, Le, Minh, Le Bris, Cyril, Le Gac, Sylvie, Le Hingrat, Quentin, Le Mestre, Soizic, Le Nagard, Hervé, Lemaignen, Adrien, Lemee, Véronique, Lescure, François-Xavier, Letrou, Sophie, Levy, Yves, Lina, Bruno, Lingas, Guillaume, Lucet, Jean Christophe, Machado, Moïse, Malvy, Denis, Mambert, Marina, Manuel, Aldric, Mentré, France, Meziane, Amina, Mouquet, Hugo, Mullaert, Jimmy, Neant, Nadège, Nguyen, Duc, Noret, Marion, Papadopoulos, Aurélie, Paul, Christelle, Peiffer-Smadja, Nathan, Peigne, Vincent, Petrov-Sanchez, Ventzislava, Peytavin, Gilles, Pham, Huong, Picone, Olivier, Piquard, Valentine, Puéchal, Oriane, Rosa-Calatrava, Manuel, Rossignol, Bénédicte, Rossignol, Patrick, Roy, Carine, Schneider, Marion, Su, Richa, Tardivon, Coralie, Tellier, Marie-Capucine, Téoulé, François, Terrier, Olivier, Timsit, Jean-François, Tual, Christelle, Tubiana, Sarah, van der Werf, Sylvie, Vanel, Noémie, Veislinger, Aurélie, Visseaux, Benoit, Wiedemann, Aurélie, Yazdanpanah, Yazdan, Annereau, Jean-Philippe, Briseño-Roa, Luis, Gribouval, Olivier, Jaïs, Jean-Philippe, Pelet, Anna, Alcover, Andres, Aschard, Hugues, Bousso, Philippe, Brodin, Petter, Bruhns, Pierre, Cerf-Bensussan, Nadine, Cumano, Ana, D’enfert, Christophe, Deriano, Ludovic, Dillies, Marie-Agnès, Di Santo, James, Dromer, Françoise, Eberl, Gérard, Enninga, Jost, Gomperts-Boneca, Ivo, Hasan, Milena, Hedestam, Gunilla Karlsson, Hercberg, Serge, Ingersoll, Molly, Lantz, Olivier, Kenny, Rose Anne, Ménager, Mickaël, Michel, Frédérique, Patin, Etienne, Pellegrini, Sandra, Rausell, Antonio, Rieux-Laucat, Frédéric, Rogge, Lars, Fontes, Magnus, Sakuntabhai, Anavaj, Schwartz, Olivier, Schwikowski, Benno, Shorte, Spencer, Tangy, Frédéric, Toubert, Antoine, Touvier, Mathilde, Ungeheuer, Marie-Noëlle, Zimmer, Christophe, Albert, Matthew, Alavoine, Loubna, Behillil, Sylvie, Charpentier, Charlotte, Dechanet, Aline, Ecobichon, Jean-Luc, Frezouls, Wahiba, Houhou, Nadhira, Lehacaut, Jonathan, Lucet, Jean-Christophe, Manchon, Pauline, Nouroudine, Mariama, Quintin, Caroline, Thy, Michael, Vignali, Valérie, Chahine, Abir, Waucquier, Nawal, Migaud, Maria-Claire, Djossou, Félix, Mergeay-Fabre, Mayka, Lucarelli, Aude, Demar, Magalie, Bruneau, Léa, Gérardin, Patrick, Maillot, Adrien, Payet, Christine, Laviolle, Bruno, Paris, Christophe, Desille-Dugast, Mireille, Fouchard, Julie, Pistone, Thierry, Perreau, Pauline, Gissot, Valérie, Le Goas, Carole, Montagne, Samatha, Richard, Lucie, Bouiller, Kévin, Desmarets, Maxime, Meunier, Alexandre, Bourgeon, Marilou, Lefèvre, Benjamin, Jeulin, Hélène, Legrand, Karine, Lomazzi, Sandra, Tardy, Bernard, Gagneux-Brunon, Amandine, Bertholon, Frédérique, Botelho-Nevers, Elisabeth, Kouakam, Christelle, Leturque, Nicolas, Roufai, Layidé, Amat, Karine, Espérou, Hélène, Hendou, Samia, van Agtmael, Michiel, Algera, Anne Geke, Appelman, Brent, van Baarle, Frank, Bax, Diane, Beudel, Martijn, Bogaard, Harm Jan, Bomers, Marije, Bonta, Peter, Bos, Lieuwe, Botta, Michela, de Brabander, Justin, de Bree, Godelieve, de Bruin, Sanne, Buis, David, Bugiani, Marianna, Bulle, Esther, Chouchane, Osoul, Cloherty, Alex, Dijkstra, Mirjam, Dongelmans, Dave, Dujardin, Romein, Elbers, Paul, Fleuren, Lucas, Geerlings, Suzanne, Geijtenbeek, Theo, Girbes, Armand, Goorhuis, Bram, Grobusch, Martin, Hafkamp, Florianne, Hagens, Laura, Hamann, Jorg, Harris, Vanessa, Hemke, Robert, Hermans, Sabine, Heunks, Leo, Hollmann, Markus, Horn, Janneke, Hovius, Joppe, de Jong, Menno, Lim, Endry, van Mourik, Niels, Nellen, Jeaninne, Nossent, Esther, Paulus, Frederique, Peters, Edgar, Pina-Fuentes, Dan, van der Poll, Tom, Preckel, Bennedikt, Prins, Jan, Raasveld, Jorinde, Reijnders, Tom, de Rotte, Maurits, Schinkel, Michiel, Schultz, Marcus, Schrauwen, Femke, Schuurman, Alex, Schuurmans, Jaap, Sigaloff, Kim, Slim, Marleen, Smeele, Patrick, Smit, Marry, Stijnis, Cornelis, Stilma, Willemke, Teunissen, Charlotte, Thoral, Patrick, Tsonas, Anissa, Tuinman, Pieter, van der Valk, Marc, Veelo, Denise, Volleman, Carolien, de Vries, Heder, Vught, Lonneke, van Vugt, Michèle, Wouters, Dorien, Zwinderman, A., Brouwer, Matthijs, Wiersinga, W. Joost, Vlaar, Alexander, Al-Muhsen, Saleh, Al-Mulla, Fahd, Arias, Andrés, Bogunovic, Dusan, Bolze, Alexandre, Bryceson, Yenan, Bustamante, Carlos, Butte, Manish, Chakravorty, Samya, Christodoulou, John, Constantinescu, Stefan, Cooper, Megan, Desai, Murkesh, Drolet, Beth, El Baghdadi, Jamila, Espinosa-Padilla, Sara, Froidure, Antoine, Henrickson, Sarah, Hsieh, Elena, Husebye, Eystein, Imai, Kohsuke, Itan, Yuval, Jarvis, Erich, Karamitros, Timokratis, Ku, Cheng-Lung, Ling, Yun, Lucas, Carrie, Maniatis, Tom, Maródi, László, Milner, Joshua, Mironska, Kristina, Novelli, Antonio, Novelli, Giuseppe, de Diego, Rebeca Perez, Perez-Tur, Jordi, Arkin, Lisa, Asano, Takaki, Oriol, Roger Colobran, Renia, Laurent, Resnick, Igor, Sancho-Shimizu, Vanessa, Seppänen, Mikko R.J., Shahrooei, Mohammed, Slaby, Ondrej, Tayoun, Ahmad Abou, Ramaswamy, Sathishkumar, Turvey, Stuart, Uddin, K., Uddin, Mohammed, von Bernuth, Horst, Zawadzki, Pawel, Grimbacher, Bodo, Pape, Jean, Perlin, David, Pesole, Graziano, García, Paula Andrea Gaviria, López, Gustavo Andrés Salguero, Rojas-Villaraga, Adriana, Vélez, Verónica Posada, Landinez, Lina Marcela Acevedo, Correales, Luisa Paola Duarte, Gómez, Oscar, Guaqueta, Jeser Santiago Grass, Pérez, Cristian Alejandro Ricaurte, Carrillo, Jorge, Vergara, José Alejandro Daza, Landinez, Sandra, Mantilla, Rubén, Yepes, Jairo David Torres, Ricaurte, Oscar Andrés Briceño, Pérez-Díaz, Carlos, Mateus, Yady Nataly, Navarro, Laura Mancera, Rodríguez, Yhojan, Acosta-Ampudia, Yeny, Monsalve, Diana, Rojas, Manuel, Nadif, Rachel, Goldberg, Marcel, Ozguler, Anna, Henny, Joseph, Lemonnier, Sylvie, Coeuret-Pellicer, Mireille, Got, Stéphane Le, Tzourio, Christophe, Dufouil, Carole, Soumaré, Aïcha, Lachaize, Morgane, Fievet, Nathalie, Flaig, Amandine, Martin, Fernando, Bonneaudeau, Brigitte, Cannet, Dorothée, Gallian, Pierre, Jeanne, Michel, Perroquin, Magali, Hamzeh-Cognasse, Hind, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Rockefeller University [New York], Hiroshima University, Vall d’Hebron Research Institute (VHIR), University of Tartu, CHU Henri Mondor, Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de cardiologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Lariboisière-Fernand-Widal [APHP], Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Etablissement Français du Sang [La Plaine Saint-Denis] (EFS), Etablissement français du sang - Auvergne-Rhône-Alpes (EFS), Hospital Universitario Infanta Leonor [Madrid], Hospices Civils de Lyon (HCL), Grand Hôpital de l'Est Francilien (GHEF), Vall d'Hebron University Hospital [Barcelona], Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), Assistance Publique - Hôpitaux de Marseille (APHM), National Institutes of Health [Bethesda] (NIH), Tokyo Medical and Dental University [Japan] (TMDU), Universitat de Barcelona (UB), Institut National de la Santé et de la Recherche Médicale (INSERM), Biomedical Research Foundation of the Academy of Athens (BRFAA), Institute for Systems Biology [Seattle] (ISB), Universidad de Antioquia = University of Antioquia [Medellín, Colombia], Universidad del Rosario [Bogota], Hospital Universitario de Gran Canaria Dr Negrin, Azienda Socio Sanitaria Territoriale Spedali Civili di Brescia [Brescia], Università degli Studi di Milano-Bicocca = University of Milano-Bicocca (UNIMIB), National Institute of Allergy and Infectious Diseases [Bethesda] (NIAID-NIH), Uniformed Services University of the Health Sciences (USUHS), University of British Columbia (UBC), CHU Necker - Enfants Malades [AP-HP], Spanish National Research Council (CSIC), Ghent University Hospital, Goce Delchev University (UGD), Invitae Corporation, Bilkent University [Ankara], Necmettin Erbakan University [Konya, Turquie], Centre Hospitalier Universitaire Hassan II (CHU HII), CHU Ibn Rochd [Casablanca], Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Karolinska Institute, Réseau International des Instituts Pasteur (RIIP), Tel Aviv Sourasky Medical Center [Te Aviv], The Feinstein Institute for Medical Research, IRCCS San Raffaele Scientific Institute [Milan, Italie], IRCCS Ospedale San Raffaele [Milan, Italy], Universidade de São Paulo = University of São Paulo (USP), Fundacion Rioja Salud, Amsterdam Neuroscience [Pays-Bas], Vrije Universiteit Amsterdam [Amsterdam] (VU)-University of Amsterdam [Amsterdam] (UvA)-VU University Medical Center [Amsterdam], Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Shupyk National Medical Academy of Postgraduate Education [Kiev] (SNMAPE), I.Horbachevsky Ternopil State Medical University, Ternopil, Ukraine, Hospital Donostia, Garvan Institute of medical research, Sorbonne Université (SU), Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Institut Pasteur [Paris] (IP), Charles University [Prague] (CU), University Hospital Motol [Prague], Dmitriy Rogachev National Center for Pediatric Hematology, Oncology and Immunology [Moscow, Russia], The University of Hong Kong (HKU), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Morphogénèse et antigénicité du VIH et du virus des Hépatites (MAVIVH - U1259 Inserm - CHRU Tours ), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of La Sabana = Universitad de la Sabana, Hôpital Robert Ballanger [Aulnay-sous-Bois], Sackler Faculty of Medicine, Tel Aviv University (TAU), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), University Hospitals Leuven [Leuven], Tallaght Hospital, Trinity College Dublin, University of Sharjah (UoS), Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire CERBA [Saint Ouen l'Aumône], King Fahad University, Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), McGill University = Université McGill [Montréal, Canada], Aarhus University [Aarhus], Instituto de Pesquisa Pelé Pequeno Principe, Hôpital Jean Verdier [AP-HP], Ecole Polytechnique Fédérale de Lausanne (EPFL), Yale University [New Haven], University of California [San Francisco] (UC San Francisco), University of California (UC), Academy of Athens, Institució Catalana de Recerca i Estudis Avançats (ICREA), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Aix Marseille Université (AMU), Centre d'investigation Clinique [CHU Bichat] - Épidémiologie clinique (CIC 1425), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM), CIC Hôpital Bichat, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-UFR de Médecine, Université Paris-Saclay, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), European Genomic Institute for Diabetes - FR 3508 (EGID), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), IrsiCaixa (Institut de Recerca de la Sida), Hôpital Foch [Suresnes], Etablissement Français du Sang, EFS, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Howard Hughes Medical Institute, Rockefeller University, St. Giles Foundation, National Institutes of Health (US), George Mason University, Yale University, National Human Genome Research Institute (US), Fisher Center for Alzheimer's Research Foundation, Meyer Foundation, JPB Foundation, Agence Nationale de la Recherche (France), Fondation pour la Recherche Médicale, Agence Nationale de Recherches sur le SIDA et les Hépatites Virales (France), Scientific Committee on Oceanic Research, Ministre de l'Enseignement Supérieur, de la Recherche et de l'Innovation (France), Institut National de la Santé et de la Recherche Médicale (France), Université de Paris, Fondation Bettencourt Schueller, Centro de Investigación Biomédica en Red Enfermedades Raras (España), European Commission, G. Harold & Leila Y. Mathers Foundation, Hospital Universitario Infanta Leonor, National Institute of Allergy and Infectious Diseases (US), National Institute of Dental and Craniofacial Research (US), Estonian Research Council, Al Jalila Foundation, American University of Sharjah, National Health and Medical Research Council (Australia), University of New South Wales (Australia), Regione Lombardia, Instituto de Salud Carlos III, Japan Agency for Medical Research and Development, Sorbonne Université, Université de Bordeaux, National Cancer Institute (US), Research Foundation - Flanders, Hellenic Foundation for Research and Innovation, Sao Paulo Research Foundation, The Meath Foundation, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), INSERM UMRS-1144, Université Paris Cité, Réanimation Médicale et Toxicologique, Hôpital Lariboisière, Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), The Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute, The Rockefeller University, the St. Giles Foundation, the NIH (Grants R01AI088364 and R01AI163029), the National Center for Advancing Translational Sciences, NIH Clinical and Translational Science Awards program (Grant UL1 TR001866), a Fast Grant from Emergent Ventures, Mercatus Center at George Mason University, the Yale Center for Mendelian Genomics and the Genome Sequencing Program Coordinating Center funded by the National Human Genome Research Institute (Grants UM1HG006504 and U24HG008956), the Yale High Performance Computing Center (Grant S10OD018521), the Fisher Center for Alzheimer’s Research Foundation, the Meyer Foundation, the JPB Foundation, the French National Research Agency (ANR) under the 'Investments for the Future' program (Grant ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (Grant ANR-10-LABX-62-IBEID), the French Foundation for Medical Research (FRM) (Grant EQU201903007798), the French Agency for Research on AIDS and Viral hepatitis (ANRS) Nord-Sud (Grant ANRS-COV05), the ANR GENVIR (Grant ANR-20-CE93-003), AABIFNCOV (Grant ANR-20-CO11-0001), CNSVIRGEN (Grant ANR-19-CE15-0009-01), and GenMIS-C (Grant ANR-21-COVR-0039) projects, the Square Foundation, Grandir–Fonds de solidarité pour l’Enfance, the Fondation du Souffle, the SCOR Corporate Foundation for Science, The French Ministry of Higher Education, Research, and Innovation (Grant MESRI-COVID-19), Institut National de la Santé et de la Recherche Médicale (INSERM), REACTing-INSERM, and the University Paris Cité. P. Bastard was supported by the FRM (Award EA20170638020). P. Bastard., J.R., and T.L.V. were supported by the MD-PhD program of the Imagine Institute (with the support of Fondation Bettencourt Schueller). Work at the Neurometabolic Disease lab received funding from Centre for Biomedical Research on Rare Diseases (CIBERER) (Grant ACCI20-767) and the European Union's Horizon 2020 research and innovation program under grant agreement 824110 (EASI Genomics). Work in the Laboratory of Virology and Infectious Disease was supported by the NIH (Grants P01AI138398-S1, 2U19AI111825, and R01AI091707-10S1), a George Mason University Fast Grant, and the G. Harold and Leila Y. Mathers Charitable Foundation. The Infanta Leonor University Hospital supported the research of the Department of Internal Medicine and Allergology. The French COVID Cohort study group was sponsored by INSERM and supported by the REACTing consortium and by a grant from the French Ministry of Health (Grant PHRC 20-0424). The Cov-Contact Cohort was supported by the REACTing consortium, the French Ministry of Health, and the European Commission (Grant RECOVER WP 6). This work was also partly supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases and the National Institute of Dental and Craniofacial Research, NIH (Grants ZIA AI001270 to L.D.N. and 1ZIAAI001265 to H.C.S.). This program is supported by the Agence Nationale de la Recherche (Grant ANR-10-LABX-69-01). K.K.’s group was supported by the Estonian Research Council, through Grants PRG117 and PRG377. R.H. was supported by an Al Jalila Foundation Seed Grant (Grant AJF202019), Dubai, United Arab Emirates, and a COVID-19 research grant (Grant CoV19-0307) from the University of Sharjah, United Arab Emirates. S.G.T. is supported by Investigator and Program Grants awarded by the National Health and Medical Research Council of Australia and a University of New South Wales COVID Rapid Response Initiative Grant. L.I. reports funding from Regione Lombardia, Italy (project 'Risposta immune in pazienti con COVID-19 e co-morbidità'). This research was partially supported by the Instituto de Salud Carlos III (Grant COV20/0968). J.R.H. reports funding from Biomedical Advanced Research and Development Authority (Grant HHSO10201600031C). S.O. reports funding from Research Program on Emerging and Re-emerging Infectious Diseases from Japan Agency for Medical Research and Development (Grant JP20fk0108531). G.G. was supported by the ANR Flash COVID-19 program and SARS-CoV-2 Program of the Faculty of Medicine from Sorbonne University iCOVID programs. The 3C Study was conducted under a partnership agreement between INSERM, Victor Segalen Bordeaux 2 University, and Sanofi-Aventis. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The 3C Study was also supported by the Caisse Nationale d’Assurance Maladie des Travailleurs Salariés, Direction générale de la Santé, Mutuelle Générale de l’Education Nationale, Institut de la Longévité, Conseils Régionaux of Aquitaine and Bourgogne, Fondation de France, and Ministry of Research–INSERM Program 'Cohortes et collections de données biologiques.' S. Debette was supported by the University of Bordeaux Initiative of Excellence. P.K.G. reports funding from the National Cancer Institute, NIH, under Contract 75N91019D00024, Task Order 75N91021F00001. J.W. is supported by a Research Foundation - Flanders (FWO) Fundamental Clinical Mandate (Grant 1833317N). Sample processing at IrsiCaixa was possible thanks to the crowdfunding initiative YoMeCorono. Work at Vall d’Hebron was also partly supported by research funding from Instituto de Salud Carlos III Grant PI17/00660 cofinanced by the European Regional Development Fund (ERDF/FEDER). C.R.-G. and colleagues from the Canarian Health System Sequencing Hub were supported by the Instituto de Salud Carlos III (Grants COV20_01333 and COV20_01334), the Spanish Ministry for Science and Innovation (RTC-2017-6471-1, AEI/FEDER, European Union), Fundación DISA (Grants OA18/017 and OA20/024), and Cabildo Insular de Tenerife (Grants CGIEU0000219140 and 'Apuestas científicas del ITER para colaborar en la lucha contra la COVID-19'). T.H.M. was supported by grants from the Novo Nordisk Foundation (Grants NNF20OC0064890 and NNF21OC0067157). C.M.B. is supported by a Michael Smith Foundation for Health Research Health Professional-Investigator Award. P.Q.H. and L. Hammarström were funded by the European Union’s Horizon 2020 research and innovation program (Antibody Therapy Against Coronavirus consortium, Grant 101003650). Work at Y.-L.L.’s laboratory in the University of Hong Kong (HKU) was supported by the Society for the Relief of Disabled Children. MBBS/PhD study of D.L. in HKU was supported by the Croucher Foundation. J.L.F. was supported in part by the Evaluation-Orientation de la Coopération Scientifique (ECOS) Nord - Coopération Scientifique France-Colombie (ECOS-Nord/Columbian Administrative department of Science, Technology and Innovation [COLCIENCIAS]/Colombian Ministry of National Education [MEN]/Colombian Institute of Educational Credit and Technical Studies Abroad [ICETEX, Grant 806-2018] and Colciencias Contract 713-2016 [Code 111574455633]). A. Klocperk was, in part, supported by Grants NU20-05-00282 and NV18-05-00162 issued by the Czech Health Research Council and Ministry of Health, Czech Republic. L.P. was funded by Program Project COVID-19 OSR-UniSR and Ministero della Salute (Grant COVID-2020-12371617). I.M. is a Senior Clinical Investigator at the Research Foundation–Flanders and is supported by the CSL Behring Chair of Primary Immunodeficiencies (PID), by the Katholieke Universiteit Leuven C1 Grant C16/18/007, by a Flanders Institute for Biotechnology-Grand Challenges - PID grant, by the FWO Grants G0C8517N, G0B5120N, and G0E8420N, and by the Jeffrey Modell Foundation. I.M. has received funding under the European Union’s Horizon 2020 research and innovation program (Grant Agreement 948959). E.A. received funding from the Hellenic Foundation for Research and Innovation (Grant INTERFLU 1574). M. Vidigal received funding from the São Paulo Research Foundation (Grant 2020/09702-1) and JBS SA (Grant 69004). The NH-COVAIR study group consortium was supported by a grant from the Meath Foundation., HGID Lab, COVID Clinicians, COVID-STORM Clinicians, NIAID Immune Response to COVID Group, NH-COVAIR Study Group, Danish CHGE, Danish Blood Donor Study, St. James's Hospital, SARS CoV2 Interest Group, French COVID Cohort Study Group, Imagine COVID-Group, Milieu Intérieur Consortium, CoV-Contact Cohort, Amsterdam UMC Covid-19 Biobank Investigators, COVID Human Genetic Effort, CP-COVID-19 Group, CONSTANCES cohort, 3C-Dijon Study, Cerba Health-Care, Etablissement Français du Sang Study group, ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-20-COVI-0003,GENCOVID,Identification des défauts monogéniques de l'immunité responsables des formes sévères de COVID-19 chez les patients précédemment en bonne santé(2020), ANR-20-CE93-0003,GENVIR,Analyse multi-omique de l'immunité anti-virale: de l'identification des circuits biologiques pertinents à la découverte de défauts monogéniques héréditaires de l'immunité chez les patients avec infections virales sévères(2020), ANR-19-CE15-0009,CNSVIRGEN,Déficits immunitaires innés dans les infections sévères du tronc cérébral(2019), ANR-20-CO11-0001,AABIFNCOV,Bases génétiques et immunologiques des auto-anticorps contre les interférons de type I prédisposant aux formes sévères de COVID-19.(2020), ANR-21-COVR-0039,GenMIS-C,Recherche des Déficits immunitaires innées monogéniques prédisposant au syndrome inflammatoire multisystémique chez l'enfant.(2021), European Project: 948959,ERC-2020-STG,MORE2ADA2(2021), Manry, J, Bastard, P, Gervais, A, Le Voyer, T, Rosain, J, Philippot, Q, Michailidis, E, Hoffmann, H, Eto, S, Garcia-Prat, M, Bizien, L, Parra-Martínez, A, Yang, R, Haljasmägi, L, Migaud, M, Särekannu, K, Maslovskaja, J, de Prost, N, Tandjaoui-Lambiotte, Y, Luyt, C, Amador-Borrero, B, Gaudet, A, Poissy, J, Morel, P, Richard, P, Cognasse, F, Troya, J, Trouillet-Assant, S, Belot, A, Saker, K, Garçon, P, Rivière, J, Lagier, J, Gentile, S, Rosen, L, Shaw, E, Morio, T, Tanaka, J, Dalmau, D, Tharaux, P, Sene, D, Stepanian, A, Mégarbane, B, Triantafyllia, V, Fekkar, A, Heath, J, Franco, J, Anaya, J, Solé-Violán, J, Imberti, L, Biondi, A, Bonfanti, P, Castagnoli, R, Delmonte, O, Zhang, Y, Snow, A, Holland, S, Biggs, C, Moncada-Vélez, M, Arias, A, Lorenzo, L, Boucherit, S, Anglicheau, D, Planas, A, Haerynck, F, Duvlis, S, Ozcelik, T, Keles, S, Bousfiha, A, El Bakkouri, J, Ramirez-Santana, C, Paul, S, Pan-Hammarström, Q, Hammarström, L, Dupont, A, Kurolap, A, Metz, C, Aiuti, A, Casari, G, Lampasona, V, Ciceri, F, Barreiros, L, Dominguez-Garrido, E, Vidigal, M, Zatz, M, van de Beek, D, Sahanic, S, Tancevski, I, Stepanovskyy, Y, Boyarchuk, O, Nukui, Y, Tsumura, M, Vidaur, L, Tangye, S, Burrel, S, Duffy, D, Quintana-Murci, L, Klocperk, A, Kann, N, Shcherbina, A, Lau, Y, Leung, D, Coulongeat, M, Marlet, J, Koning, R, Reyes, L, Chauvineau-Grenier, A, Venet, F, Monneret, G, Nussenzweig, M, Arrestier, R, Boudhabhay, I, Baris-Feldman, H, Hagin, D, Wauters, J, Meyts, I, Dyer, A, Kennelly, S, Bourke, N, Halwani, R, Sharif-Askari, F, Dorgham, K, Sallette, J, Sedkaoui, S, Alkhater, S, Rigo-Bonnin, R, Morandeira, F, Roussel, L, Vinh, D, Erikstrup, C, Condino-Neto, A, Prando, C, Bondarenko, A, Spaan, A, Gilardin, L, Fellay, J, Lyonnet, S, Bilguvar, K, Lifton, R, Mane, S, Anderson, M, Boisson, B, Béziat, V, Zhang, S, Andreakos, E, Hermine, O, Pujol, A, Peterson, P, Mogensen, T, Rowen, L, Mond, J, Debette, S, de Lamballerie, X, Burdet, C, Bouadma, L, Zins, M, Soler-Palacin, P, Colobran, R, Gorochov, G, Solanich, X, Susen, S, Martinez-Picado, J, Raoult, D, Vasse, M, Gregersen, P, Piemonti, L, Rodríguez-Gallego, C, Notarangelo, L, Su, H, Kisand, K, Okada, S, Puel, A, Jouanguy, E, Rice, C, Tiberghien, P, Zhang, Q, Casanova, J, Abel, L, Cobat, A, Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Imagine Institute, Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Unité des Virus Emergents (UVE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cohortes épidémiologiques en population (CONSTANCES), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université Paris Cité (UPCité), UFR Médecine [Santé] - Université Paris Cité (UFR Médecine UPCité), Université Paris Cité (UPCité), Neurology, AII - Infectious diseases, ANS - Neuroinfection & -inflammation, Graduate School, Université Paris Cité - UFR Médecine [Santé] (UPCité UFR Médecine), Gunst, Jan, Acibadem University Dspace, Manry, Jérémy, Bastard, Paul, Gervais, Adrian, Le Voyer, Tom, Rosain, Jérémie, Philippot, Quentin, Michailidis, Eleftherio, Hoffmann, Hans-Heinrich, Eto, Shohei, Garcia-Prat, Marina, Bizien, Lucy, Parra-Martínez, Alba, Yang, Rui, Haljasmägi, Lii, Migaud, Mélanie, Särekannu, Karita, Maslovskaja, Julia, de Prost, Nicola, Tandjaoui-Lambiotte, Yacine, Luyt, Charles-Edouard, Amador-Borrero, Blanca, Gaudet, Alexandre, Poissy, Julien, Morel, Pascal, Richard, Pascale, Cognasse, Fabrice, Troya, Jesú, Trouillet-Assant, Sophie, Belot, Alexandre, Saker, Kahina, Garçon, Pierre, Rivière, Jacques G, Lagier, Jean-Christophe, Gentile, Stéphanie, Rosen, Lindsey B, Shaw, Elana, Morio, Tomohiro, Tanaka, Junko, Dalmau, David, Tharaux, Pierre-Loui, Sene, Damien, Stepanian, Alain, Mégarbane, Bruno, Triantafyllia, Vasiliki, Fekkar, Arnaud, Heath, James R, Franco, José Lui, Anaya, Juan-Manuel, Solé-Violán, Jordi, Imberti, Luisa, Biondi, Andrea, Bonfanti, Paolo, Castagnoli, Riccardo, Delmonte, Ottavia M, Zhang, Yu, Snow, Andrew L, Holland, Steven M, Biggs, Catherine M, Moncada-Vélez, Marcela, Arias, Andrés Augusto, Lorenzo, Lazaro, Boucherit, Soraya, Anglicheau, Dany, Planas, Anna M, Haerynck, Filomeen, Duvlis, Sotirija, Ozcelik, Tayfun, Keles, Sevgi, Bousfiha, Ahmed A, El Bakkouri, Jalila, Ramirez-Santana, Carolina, Paul, Stéphane, Pan-Hammarström, Qiang, Hammarström, Lennart, Dupont, Annabelle, Kurolap, Alina, Metz, Christine N, Aiuti, Alessandro, Casari, Giorgio, Lampasona, Vito, Ciceri, Fabio, Barreiros, Lucila A, Dominguez-Garrido, Elena, Vidigal, Mateu, Zatz, Mayana, van de Beek, Diederik, Sahanic, Sabina, Tancevski, Ivan, Stepanovskyy, Yurii, Boyarchuk, Oksana, Nukui, Yoko, Tsumura, Miyuki, Vidaur, Loreto, Tangye, Stuart G, Burrel, Sonia, Duffy, Darragh, Quintana-Murci, Llui, Klocperk, Adam, Kann, Nelli Y, Shcherbina, Anna, Lau, Yu-Lung, Leung, Daniel, Coulongeat, Matthieu, Marlet, Julien, Koning, Rutger, Reyes, Luis Felipe, Chauvineau-Grenier, Angélique, Venet, Fabienne, Monneret, Guillaume, Nussenzweig, Michel C, Arrestier, Romain, Boudhabhay, Idri, Baris-Feldman, Hagit, Hagin, David, Wauters, Joost, Meyts, Isabelle, Dyer, Adam H, Kennelly, Sean P, Bourke, Nollaig M, Halwani, Rabih, Sharif-Askari, Fatemeh Saheb, Dorgham, Karim, Sallette, Jérôme, Sedkaoui, Souad Mehlal, Alkhater, Suzan, Rigo-Bonnin, Raúl, Morandeira, Francisco, Roussel, Lucie, Vinh, Donald C, Erikstrup, Christian, Condino-Neto, Antonio, Prando, Carolina, Bondarenko, Anastasiia, Spaan, András N, Gilardin, Laurent, Fellay, Jacque, Lyonnet, Stanisla, Bilguvar, Kaya, Lifton, Richard P, Mane, Shrikant, Anderson, Mark S, Boisson, Bertrand, Béziat, Vivien, Zhang, Shen-Ying, Andreakos, Evangelo, Hermine, Olivier, Pujol, Aurora, Peterson, Pärt, Mogensen, Trine H, Rowen, Lee, Mond, Jame, Debette, Stéphanie, de Lamballerie, Xavier, Burdet, Charle, Bouadma, Lila, Zins, Marie, Soler-Palacin, Pere, Colobran, Roger, Gorochov, Guy, Solanich, Xavier, Susen, Sophie, Martinez-Picado, Javier, Raoult, Didier, Vasse, Marc, Gregersen, Peter K, Piemonti, Lorenzo, Rodríguez-Gallego, Carlo, Notarangelo, Luigi D, Su, Helen C, Kisand, Kai, Okada, Satoshi, Puel, Anne, Jouanguy, Emmanuelle, Rice, Charles M, Tiberghien, Pierre, Zhang, Qian, Casanova, Jean-Laurent, Abel, Laurent, Cobat, Aurélie, Vougny, Marie-Christine, and Amsterdam Neuroscience - Neuroinfection & -inflammation

Subjects
Adult, Male, Risk, infection fatality rate, [SDV.IMM] Life Sciences [q-bio]/Immunology, autoantibodies, chronic mucocutaneous candidiasis, CHRONIC MUCOCUTANEOUS CANDIDIASIS, Autoimmunity, IMMUNITY, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Article, DISEASE, Basic medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, INFECTION, Medicine and Health Sciences, Humans, IMUNOLOGIA, Aged, Autoantibodies, Aged, 80 and over, disease, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, Multidisciplinary, SARS-CoV-2, type I IFNs, Age Factors, COVID-19, Type I IFNs, Middle Aged, autoantibodie, immunity, Antibodies, Neutralizing, infection, Infection fatality rate, Relative risk, relative risk, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Interferon Type I, [SDV.IMM]Life Sciences [q-bio]/Immunology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Female, type I IFN
Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection fatality rate (IFR) doubles with every 5 y of age from childhood onward. Circulating autoantibodies neutralizing IFN-α, IFN-ω, and/or IFN-β are found in ∼20% of deceased patients across age groups, and in ∼1% of individuals aged 4% of those >70 y old in the general population. With a sample of 1,261 unvaccinated deceased patients and 34,159 individuals of the general population sampled before the pandemic, we estimated both IFR and relative risk of death (RRD) across age groups for individuals carrying autoantibodies neutralizing type I IFNs, relative to noncarriers. The RRD associated with any combination of autoantibodies was higher in subjects under 70 y old. For autoantibodies neutralizing IFN-α2 or IFN-ω, the RRDs were 17.0 (95% CI: 11.7 to 24.7) and 5.8 (4.5 to 7.4) for individuals, The Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute; The Rockefeller University; the St. Giles Foundation; the NIH (Grants R01AI088364 and R01AI163029); the National Center for Advancing Translational Sciences; NIH Clinical and Translational Science Awards program (Grant UL1 TR001866); a Fast Grant from Emergent Ventures; Mercatus Center at George Mason University; the Yale Center for Mendelian Genomics and the Genome Sequencing Program Coordinating Center funded by the National Human Genome Research Institute (Grants UM1HG006504 and U24HG008956); the Yale High Performance Computing Center (Grant S10OD018521); the Fisher Center for Alzheimer’s Research Foundation; the Meyer Foundation; the JPB Foundation; the French National Research Agency (ANR) under the “Investments for the Future” program (Grant ANR-10-IAHU-01); the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (Grant ANR-10-LABX-62-IBEID); the French Foundation for Medical Research (FRM) (Grant EQU201903007798); the French Agency for Research on AIDS and Viral hepatitis (ANRS) Nord-Sud (Grant ANRS-COV05); the ANR GENVIR (Grant ANR-20-CE93-003), AABIFNCOV (Grant ANR-20-CO11-0001), CNSVIRGEN (Grant ANR-19-CE15-0009-01), and GenMIS-C (Grant ANR-21-COVR-0039) projects; the Square Foundation; Grandir–Fonds de solidarité pour l’Enfance; the Fondation du Souffle; the SCOR Corporate Foundation for Science; The French Ministry of Higher Education, Research, and Innovation (Grant MESRI-COVID-19); Institut National de la Santé et de la Recherche Médicale (INSERM), REACTing-INSERM; and the University Paris Cité. P. Bastard was supported by the FRM (Award EA20170638020). P. Bastard., J.R., and T.L.V. were supported by the MD-PhD program of the Imagine Institute (with the support of Fondation Bettencourt Schueller). Work at the Neurometabolic Disease lab received funding from Centre for Biomedical Research on Rare Diseases (CIBERER) (Grant ACCI20-767) and the European Union's Horizon 2020 research and innovation program under grant agreement 824110 (EASI Genomics). Work in the Laboratory of Virology and Infectious Disease was supported by the NIH (Grants P01AI138398-S1, 2U19AI111825, and R01AI091707-10S1), a George Mason University Fast Grant, and the G. Harold and Leila Y. Mathers Charitable Foundation. The Infanta Leonor University Hospital supported the research of the Department of Internal Medicine and Allergology. The French COVID Cohort study group was sponsored by INSERM and supported by the REACTing consortium and by a grant from the French Ministry of Health (Grant PHRC 20-0424). The Cov-Contact Cohort was supported by the REACTing consortium, the French Ministry of Health, and the European Commission (Grant RECOVER WP 6). This work was also partly supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases and the National Institute of Dental and Craniofacial Research, NIH (Grants ZIA AI001270 to L.D.N. and 1ZIAAI001265 to H.C.S.). This program is supported by the Agence Nationale de la Recherche (Grant ANR-10-LABX-69-01). K.K.’s group was supported by the Estonian Research Council, through Grants PRG117 and PRG377. R.H. was supported by an Al Jalila Foundation Seed Grant (Grant AJF202019), Dubai, United Arab Emirates, and a COVID-19 research grant (Grant CoV19-0307) from the University of Sharjah, United Arab Emirates. S.G.T. is supported by Investigator and Program Grants awarded by the National Health and Medical Research Council of Australia and a University of New South Wales COVID Rapid Response Initiative Grant. L.I. reports funding from Regione Lombardia, Italy (project “Risposta immune in pazienti con COVID-19 e co-morbidità”). This research was partially supported by the Instituto de Salud Carlos III (Grant COV20/0968). J.R.H. reports funding from Biomedical Advanced Research and Development Authority (Grant HHSO10201600031C). S.O. reports funding from Research Program on Emerging and Re-emerging Infectious Diseases from Japan Agency for Medical Research and Development (Grant JP20fk0108531). G.G. was supported by the ANR Flash COVID-19 program and SARS-CoV-2 Program of the Faculty of Medicine from Sorbonne University iCOVID programs. The 3C Study was conducted under a partnership agreement between INSERM, Victor Segalen Bordeaux 2 University, and Sanofi-Aventis. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The 3C Study was also supported by the Caisse Nationale d’Assurance Maladie des Travailleurs Salariés, Direction générale de la Santé, Mutuelle Générale de l’Education Nationale, Institut de la Longévité, Conseils Régionaux of Aquitaine and Bourgogne, Fondation de France, and Ministry of Research–INSERM Program “Cohortes et collections de données biologiques.” S. Debette was supported by the University of Bordeaux Initiative of Excellence. P.K.G. reports funding from the National Cancer Institute, NIH, under Contract 75N91019D00024, Task Order 75N91021F00001. J.W. is supported by a Research Foundation - Flanders (FWO) Fundamental Clinical Mandate (Grant 1833317N). Sample processing at IrsiCaixa was possible thanks to the crowdfunding initiative YoMeCorono. Work at Vall d’Hebron was also partly supported by research funding from Instituto de Salud Carlos III Grant PI17/00660 cofinanced by the European Regional Development Fund (ERDF/FEDER). C.R.-G. and colleagues from the Canarian Health System Sequencing Hub were supported by the Instituto de Salud Carlos III (Grants COV20_01333 and COV20_01334), the Spanish Ministry for Science and Innovation (RTC-2017-6471-1; AEI/FEDER, European Union), Fundación DISA (Grants OA18/017 and OA20/024), and Cabildo Insular de Tenerife (Grants CGIEU0000219140 and “Apuestas científicas del ITER para colaborar en la lucha contra la COVID-19”). T.H.M. was supported by grants from the Novo Nordisk Foundation (Grants NNF20OC0064890 and NNF21OC0067157). C.M.B. is supported by a Michael Smith Foundation for Health Research Health Professional-Investigator Award. P.Q.H. and L. Hammarström were funded by the European Union’s Horizon 2020 research and innovation program (Antibody Therapy Against Coronavirus consortium, Grant 101003650). Work at Y.-L.L.’s laboratory in the University of Hong Kong (HKU) was supported by the Society for the Relief of Disabled Children. MBBS/PhD study of D.L. in HKU was supported by the Croucher Foundation. J.L.F. was supported in part by the Evaluation-Orientation de la Coopération Scientifique (ECOS) Nord - Coopération Scientifique France-Colombie (ECOS-Nord/Columbian Administrative department of Science, Technology and Innovation [COLCIENCIAS]/Colombian Ministry of National Education [MEN]/Colombian Institute of Educational Credit and Technical Studies Abroad [ICETEX, Grant 806-2018] and Colciencias Contract 713-2016 [Code 111574455633]). A. Klocperk was, in part, supported by Grants NU20-05-00282 and NV18-05-00162 issued by the Czech Health Research Council and Ministry of Health, Czech Republic. L.P. was funded by Program Project COVID-19 OSR-UniSR and Ministero della Salute (Grant COVID-2020-12371617). I.M. is a Senior Clinical Investigator at the Research Foundation–Flanders and is supported by the CSL Behring Chair of Primary Immunodeficiencies (PID); by the Katholieke Universiteit Leuven C1 Grant C16/18/007; by a Flanders Institute for Biotechnology-Grand Challenges - PID grant; by the FWO Grants G0C8517N, G0B5120N, and G0E8420N; and by the Jeffrey Modell Foundation. I.M. has received funding under the European Union’s Horizon 2020 research and innovation program (Grant Agreement 948959). E.A. received funding from the Hellenic Foundation for Research and Innovation (Grant INTERFLU 1574). M. Vidigal received funding from the São Paulo Research Foundation (Grant 2020/09702-1) and JBS SA (Grant 69004). The NH-COVAIR study group consortium was supported by a grant from the Meath Foundation.

Published
2022

Catalog

Books, media, physical & digital resources
See catalog results