Glomerular hyperfiltration, initiating development of obesity-related glomerulopathy, results in an enlargement of the glomeruli and unsealing of the filtration barrier. It can be followed by adaptive focal segmental glomerulosclerosis and chronic kidney disease (CKD). The aim of the study was to determine the expression pattern of lipid metabolism and selected kidney damage markers in obese adolescents and to identify potential factors which can predict CKD.z-score > 2. Sixty-two healthy and normal-weight individuals served as controls. The factors associated with the rate of glomerular filtration in obese adolescents were assessed by linear regression methods using univariate and multivariate analyses. The risk of developing CKD was estimated using the Fisher’s exact test.The study group consisted of 142 adolescents with a BMI The study group was divided into “elevated,” “normal,” and “decreased” glomerular filtration rate (GFR) patients. Increased urine galectin-3  concentration was diagnosed in all patients. “Decreased GFR” subjects expressed increased urine concentration of neutrophil gelatinase-associated lipocalin (NGAL) and daily megalin excretion. Thirty-nine study participants developed CKD. Increased uric acid (UA) concentration was associated with CKD development both in “normal” and “decreased GFR” patients. Additionally, in “normal” GFR patients, increased concentrations of cholesterol (Ch), triglycerides (TG), and NGAL were associated with CKD.Increased serum concentrations of Ch, TG, and UA and increased urine concentration of NGAL might predict CKD development in obese adolescents with normal and decreased GFR.A higher resolution version of the Graphical abstract is available as Supplementary informationThe online version contains supplementary material available at 10.1007/s00467-021-05403-2. Recent decades have revealed a significant change in the eating behavior and lifestyle of adolescents. These changes are mainly observed in the increasing consumption of high-calorie foods and sweet drinks, as well as in a more sedentary lifestyle and a significant lack of exercise . The lasAs a consequence, the steadily increasing global prevalence of overweight and obesity has reached epidemic proportions . It is fObesity is a well-established low-grade inflammatory state reflected by the presence of circulating endocrine bioactive proinflammatory compounds and accompanied by reduced levels of anti-inflammatory adipokines . The incIn animal models of ORG (Fisher rats ad libitum feeding), glomerulomegaly is followed by increasing cellular volume of podocytes, although at a lower rate than the increase in the volume of glomerular tuft . As the The process of kidney damage in obese people is, however, more complex. The visceral adipose tissue may release into the circulation nonesterified fatty acids which can be accumulated in the liver, heart and kidneys . In the The actual incidence of ORG is unknown. This is due to the fact that the undisputed diagnosis of ORG can only be made on the basis of a kidney biopsy (and these are performed less and less frequently) . MoreoveMany attempts have been made to indicate the marker(s) of ORG progression. These include microalbuminuria , researcGalectin-3 —a β-galactoside-binding lectin—has been shown to be involved in a number of biological processes including cell adhesion and activation , chemoatThere are very few reports of Gal-3 in urine. Primarily its presence and clinical significance are described in blood serum. It is regarded as a sensitive diagnostic or prognostic biomarker for various pathological conditions including heart failure and cardiovascular diseases, oxidative stress, inflammation, and autoimmunity , 25–27. Determine the expression pattern of lipid metabolism as well as kidney function markers  in obese adolescents with normal, increased, and decreased glomerular filtration rate (GFR).Identify markers that may indicate an increased risk of developing CKD in obese adolescents.In line with the above, the aim of the current report was to:The protocol of the present study was approved by the Poznan University of Medical Sciences Local Bioethics Committee (resolution No 679/17). All investigations have been carried out in accordance with the Helsinki Declaration. The study participants and/or their legal guardians have given their written consent to participate in the study. Finally, the study has followed the standards of Good Clinical Practice.The study was conducted between 1 January 2018 and 30 June 2021 and involved 458 patients (recruited between 1 January 2018 and 31 December 2020), admitted to the Department of Pediatric Nephrology and Hypertension, Poznan University of Medical Sciences because of suspicion of arterial hypertension (single rise in blood pressure recorded by the school nurse). All subjects were hospitalized to perform 24 h arterial blood pressure monitoring (ABPM), echocardiography (ECHO), electrocardiography, and to perform laboratory tests: peripheral blood morphology , serum creatinine, cystatin C, uric acid, urea, Na, K, Ca, Mg, total cholesterol, triglycerides, HDL, fasting glucose, TSH, fT3, fT4, liver enzymes , total protein, C-reactive protein (CRP), adiponectin as well as 24 h urine for albumin, Gal-3, megalin, NGAL, MMPs and TIMPs.As many as 224 subjects were not admitted to the study, as at least one of the following criteria was present: (1) age < 10 years or ≥ 16 years; (2) arterial hypertension; (3) genetic obesity or familial hyperlipidemia; (4) any aberrations in ECHO and electrocardiography; (5) hepatic dysfunction ; (6) autoimmune disease; (7) diabetes; (8) coexistence of neoplastic and/or any infectious disease; (9) morphological abnormalities in the urinary tract system; (10) renal hypotrophy (or a single kidney); (11) CKD; (12) kidney failure; (13) any complications of the perinatal period (including intrauterine growth restriction); (14) birth before the age of 36 weeks; (15) history of chronic disease; (16) history of oral contraceptive, antihypertensive, antidiabetic or lipid-lowering drugs as well as corticosteroids use; or (17) unsigned informed consent.Arterial hypertension, according to the guidelines of the European Society of Hypertension , for teez-score ≤ 2; (3) no arterial hypertension; (4) normal concentration of serum cortisol, glucose, thyroid hormones, and electrolytes; (5) no morphological abnormalities in the urinary tract system ; (6) GFR range between 90 and 130 ml/min/1.73m2; (7) absence of any chronic comorbidities; and (8) signed informed consent.One hundred and forty-two adolescents were allocated for the study group. Sixty-two served as control subjects who met the following inclusion criteria: (1) age 10–16 years; (2) BMI z-score > 2; (3) no arterial hypertension; and (4) signed informed consent.Patients enrolled in the study group had to meet the following inclusion criteria: (1) age 10–16 years; (2) BMI p < 0.05 level. The clinical and biochemical data in study subjects are summarized in Table With our available sample size, this study had 85% power for comparison of means in independent samples at the z-scores using WHO reference values for pediatric BMI [Weight and height were measured using a certified columnar scale  with BMI function. BMI values were transformed into BMI tric BMI .2/3 × H (m)1/2]  . It was pulation .A 5 ml whole blood was taken from all fasting adolescents in the morning between 7:00 and 8:00, after all-night rest on the first day of hospitalization. Half of the total blood was used for routine laboratory tests in all patients, and the rest of the blood sample was centrifuged. Serum with added BHT (10 ul 0.5 M BHT/1 ml sample) was frozen at – 80 °C and preserved for further analyses.Laboratory tests in all patients also included first morning urinalysis and 24-h urine collection . The 24-h urine amount was measured after thorough mixing. 10 ml of each urine sample was then centrifuged within 2 h after collection at 1,000 rpm for 10 min to remove cellular debris. The cleaned urine samples were stored at − 72 °C until next measurement.2. In contrast, a reduced GFR (hypofiltration) was defined as GFR < 90 ml/min/1.73 m2 [GFR was assessed by Filler formula involving serum cystatin C concentration, instead of plasma creatinine , 33. Hyp/1.73 m2 .2 for a period of at least 3 months [CKD was defined as kidney damage or GFR lower than 60 ml/min/1.73 m3 months .Daily megalin excretion was estimated using Human LRP2/Megalin ELISA assay . The concentrations of NGAL, Gal-3, MMP12, and TIMP2 were estimated using Human Lipocalin-2/NGAL Quantikine ELISA Kit , Human LGALS3/Galectin-3 ELISA Kit , Human MMP-12 ELISA Kit , and TIM2 Human ELISA Kit , respectively.Finally, serum adiponectin concentration was assessed with the use of Human Adiponectin ELISA kit .All samples from patients and controls were run in duplicate. The assays were performed according to the manufacturer’s instructions. The optical density (OD) value was determined twice, using a microplate reader, set to 450 nm and 540 nm as a wavelength correction. The readings at 540 nm were subtracted from the readings at 450 nm to correct for optical imperfections in the plate. The concentrations of NGAL, Gal-3, MMP12, TIMP2, and adiponectin were calculated based on the standard curve. These standards were also assayed in duplicate.2 test was employed to analyze nominal data.All continuous variables are expressed as the mean ± SD. Statistical analysis was performed through the following steps: (1) Shapiro–Wilk test was used to determine the normal distribution of data; (2) one-way analysis of variance was employed to compare “elevated GFR,” “normal GFR,” and “decreased GFR” study subjects and controls; (3) Bonferroni correction was used as a general alpha adjustment for all of the multiple comparisons performed in the study; (4) non-parametric continuous variables were compared using the Kruskal–Wallis test; and (5) Pearson χr greater than 0.7 was considered a strong correlation. Anything between 0.4 and 0.7 was a moderate correlation, and anything less than 0.4 was considered a weak or no correlation.The independent factors for CKD development were determined using Fisher’s exact test. Generally, in Pearson correlation, a value of The factors potentially affecting the rate of glomerular filtration in obese adolescents  were assessed using linear regression methods utilizing univariate and multivariate analyses. Regression coefficients (β) and 95% confidence interval (CI) for β were estimated for all linear models. The regression models were adjusted for age and sex.All of the statistical analyses were performed using the Statistica 13.3 PL software package . A value of p < 0.05 was considered statistically significant.z-score > 2), at the moment of entry into the analysis, were divided into “elevated GFR” (n = 42), “normal GFR” (n = 85), and “decreased GFR” (n = 15) according to GFR values estimated by Filler formula. As compared to controls, they presented albuminuria and had a significantly lower serum adiponectin concentration (p = 0.005) and higher urine Gal-3 concentration (p = 0.004). “Decreased GFR” obese adolescents (as compared to controls) have been additionally reported with significantly higher serum concentrations of uric acid (p = 0.004), triglycerides (p = 0.037), and cholesterol (p = 0.043) as well as significantly higher NGAL urine concentration and daily urine megalin excretion (p = 0.005).Obese study participants (BMI Obese and control adolescents did not differ in blood pressure (both office and during 24-h monitoring), peripheral blood morphology, and serum biochemical parameters .None of the examined adolescents had MMP12 in urine, and the concentrations of TIMP2 were comparable in all study participants. The clinical characteristics of all adolescents are summarized in Table As mentioned above, the group of obese adolescents was not homogeneous. It was composed of “elevated GFR,” “normal GFR,” and “decreased GFR” patients. Therefore, separate analyses were performed for each of the above-mentioned 3 subgroups.r = 0.528) and one moderate negative correlation between “urine galectin-3 concentration” and “serum adiponectin concentration.”In the “elevated GFR” obese study participants, we have noticed one moderate positive correlation between “urine galectin-3 concentration” and “albuminuria” (r = 0.706).The group of “normal GFR” obese patients had a strong correlation between “urine galectin-3 concentration” and “urine NGAL concentration” (r = 0.474), the next one between “urine NGAL concentration” and “urine megalin excretion” (r = 0.524), and the last one between “serum uric acid concentration and urine megalin excretion” (r = 0.511). These results are presented in Table In the “decreased GFR” obese adolescents, three positive moderate correlations were reported. The first one between “serum uric acid concentration” and “urine NGAL concentration” . Eleven of them were initially designated as “increased GFR” individuals (26.2%), 16 as “normal GFR” study participants (18.9%), and 12 initially recognized with decreased GFR (80%)."Elevated GFR" obese study participants, who developed CKD during the follow-up period, did not differ in peripheral blood morphology, serum creatinine, cystatin C, uric acid, urea, Na, K, Ca, Mg, total cholesterol, triglycerides, HDL, fasting glucose, TSH, fT3, fT4, liver enzymes, total protein, CRP, adiponectin as well as 24 h urine for albumin, Gal-3, megalin, NGAL, or TIMP2 values from their peers who did not develop CKD.n = 14; 87.5%), cholesterol , and triglycerides  as well as urine NGAL concentration , as compared to “normal GFR” obese adolescents who did not develop CKD.The majority of “normal GFR” obese study participants who developed CKD, were initially found with increased concentrations of serum uric acid  were found initially to have normal serum uric acid concentration (4.1 ± 0.3 mg/dL) as compared to their peers who developed CKD.Finally, “decreased GFR” obese adolescents who did not develop CKD within the observation period (p < 0.0001), serum triglycerides concentration (p = 0.0006), serum cholesterol concentration (p < 0.0001), and urine NGAL concentration (p = 0.0003), developed CKD over a follow-up period of 6 to 30 months. “Decreased GFR” obese study participants who continue to have normal values of serum uric acid concentration are at lower risk of CKD development (p = 0.0088).Using Fisher’s exact test, it was determined that “normal GFR” obese adolescents, who initially had elevated serum uric acid concentration , and, according to GFR value estimated by Filler formula, they were divided into “elevated GFR,” “normal GFR,” and “decreased GFR” subjects. As expected, all of the study participants had albuminuria and decreased serum concentrations of adiponectin. However, the indicators of dyslipidemia , as well as increased serum uric acid concentration, increased urine NGAL concentration, and increased megalin daily excretion, appeared only in “decreased GFR” adolescents. On the other hand, all of the study group participants  had increased urine Gal-3 concentrations.Our study group did not include adolescents diagnosed with hypertension. All of them were obese  correlations have also been shown between urine Gal-3 concentration and serum adiponectin and albuminuria (“elevated GFR” participants), as well as daily megalin excretion and NGAL urine concentration and serum uric acid concentration (“decreased GFR” subjects). These results suggest not only the key role of adiponectin in obesity-related kidney damage but also indicate megalin and NGAL as markers illustrating the progress of kidney injury in obese adolescents who have no arterial hypertension.z-score > 2 in children and adolescents corresponds to 97.7 percentile and indicates the risk of multiple organ damage, including kidney injury [z-score between 1 and 2); therefore, the weight loss and appropriate treatment should be initiated promptly. In numerous studies, introduction of angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers in obese patients with proteinuria or biopsy-proven ORG resulted in significant decrease of proteinuria [BMI y injury . These steinuria –16. Whatteinuria . For thiIn line with the above, the implementation of dietary treatment and the introduction of ACE inhibitors in obese adolescents should be adapted to appropriate stage of disease defined not only by GFR and albuminuria, but also by the increased concentrations of urine Gal-3 and NGAL, daily megalin excretion, as well as increased serum uric acid concentration.Several limitations must be mentioned when discussing the results of the present study. First, it is a single-center study, so our cohort of 142 obese adolescents is not representative of the overall national population. Moreover, the participants were not randomly selected. Simply, all study subjects who met inclusion criteria were involved in the study protocol. Third, our study uses data that were collected two years ago and thus might not precisely reflect the current epidemiological situation.None of the study participants had a kidney biopsy. For this reason, we were unable to recognize ORG despite the presence of subnephrotic albuminuria in any of them. This means that potential kidney remodeling in obese adolescents (which we described as obesity-related kidney damage) could only be identified indirectly.We also present a relatively short observation period. Thus, we do not know how many patients would eventually develop CKD and kidney failure. The size of the “decreased GFR” obese adolescents group is relatively small, so it is difficult to draw an unambiguous conclusion that the normal concentration of uric acid may have a protective effect on the development of CKD.Supplementary file1 (DOCX 31 KB)Supplementary file2 (DOCX 31 KB)Supplementary file3(PPTX 76.3 KB)Below is the link to the electronic supplementary material.


Many studies have reported a relationship between the vascular endothelial growth factor receptor 2 single nucleotide polymorphism (SNP) rs2305948 and glioma, but their conclusions have been controversial. A meta-analysis was performed to assess the association between rs2305948 and glioma susceptibility.Inclusion criteria and a strategy for screening of original literature were created. Eligible articles on the correlation between the SNP rs2305948 and glioma were identified in the PubMed, Embase, Web of Science, Cochrane Library, CNKI and Wanfang databases. After extracting the data, Stata 12. 0 software was used to perform statistical analysis under 5 genetic models and to calculate the combined odds ratio (OR) value and its 95% confidence interval (CI).P = .162; dominant: OR = 1.17, 95% CI = 0.93–1.46, P = .174; recessive: OR = 1.72, 95% CI = 0.94–3.15, P = .076; heterozygous: OR = 1.11, 95% CI = 0.94–1.30, P = .226; homozygous: OR = 1.74, 95% CI = 0.92–3.29, P = .088). The subgroup analysis suggested that the SNP rs2305948 was related to glioma susceptibility under allele, dominant, recessive and homozygote models in the Asian population .Four case-control studies including 1595 cases and 1657 controls were entered into the study. The overall analysis showed that no obvious association existed between rs2305948 and glioma risk (allele: OR = 1.20, 95% CI = 0.93–1.54, The vascular endothelial growth factor receptor 2 rs2305948 gene polymorphism may be related to glioma susceptibility in the Asian population. However, the association is not clear in non-Asian populations, for which there has been less research. According to the latest statistics, even if the tumors are removed to the greatest extent possible and the patients receive temozolomide chemoradiotherapy in accordance with the treatment guidelines,,9 the median survival is <2 years. The main reason for this poor survival is a lack of understanding of the nature of gliomas. Etiological research is the key to addressing the problems associated with these tumors. Most tumors result from the combined effects of environmental and genetic factors, and research has shown that genetic factors play important roles in carcinogenesis. Gliomas are vessel-rich tumors of the central nervous system. Vascular endothelial cell growth factor (VEGF) and VEGF receptor 2 (VEGFR2) are closely related to angiogenesis in glioma.,13 Main functions of VEGFR2 include increasing the expression of VEGF and inducing tumor angiogenesis. In addition, VEGF plays a role in promoting vascular endothelial cell division and angiogenesis through VEGFR2 and is also involved in promoting the aggressive growth of tumors. Previous research has revealed that genetic mutations and polymorphisms are closely related to disease susceptibility and can lead to different responses to environmental factors and drugs.–17 Thus far, many studies have reported an association between the VEGFR2 gene polymorphism rs2305948 and glioma risk, but the results of individual studies have been inconsistent. Therefore, we conducted this meta-analysis to evaluate the association of rs2305948 with glioma and to obtain a stronger conclusion.Glioma, a type of cancer that originates from glial cells, is the most common malignancy of the central nervous system.22.1A comprehensive search of studies on the association between the VEGFR2 gene polymorphism rs2305948 and glioma published before March 2020 was performed with the PubMed, Embase, Web of Science, Cochrane Library, CNKI, and Wanfang databases. The following search terms were used: (((((“Glioma”[Mesh]) OR ((((((((((((Gliomas[Title/Abstract]) OR ) OR ) OR ) OR ) OR (Mixed Glioma[Title/Abstract])) OR ) OR ) OR ) OR ) OR (Mixed Gliomas[Title/Abstract])) OR ))) AND  OR (((((((((Polymorphism∗[Title/Abstract])) OR (Variants[Title/Abstract])) OR (Variant[Title/Abstract])) OR (Mutation[Title/Abstract])) OR (Mutations[Title/Abstract])) OR (SNP[Title/Abstract])) OR (Single Nucleotide Polymorphism[Title/Abstract])))) AND  OR (VEGF∗[Title/Abstract]))) OR (rs2305948[Title/Abstract])). All analyses were based on previous published studies, thus no ethical approval and patient consent are required.2.2P < .01), and the study was a case-control study. No restrictions on ethnicity or geographic region were established.The inclusion criteria were as follows: the study assessed the association between VEGFR2 rs2305948 and glioma, the study provided genotype frequency distribution information, the genotype frequency of the control group in the study was in accordance with Hardy–Weinberg equilibrium  was used to conduct data analyses. The odds ratios (ORs) and their 95% confidence intervals (CIs) were determined to assess the relationship between the genetic polymorphism rs2305948 and glioma susceptibility. In the analysis, the capital letter “T” was defined as the mutant allele of rs2305948, while the capital letter “C” was defined as the wild-type allele. TT is a homozygote of a mutant allele, CT is a heterozygote, and CC is a homozygote of a wild-type allele. The genetic models used in this study were as follows: an allele model (T vs C), a dominant model (TT + CT vs CC), a recessive model (TT vs CT + CC), a heterozygote model (CT vs CC), and a homozygote model (TT vs CC). Heterogeneity among the included studies was assessed by Q test, and a 33.1A total of 73 relevant articles were included in the study after searching of the PubMed, Embase, Web of Science, Cochrane Library, CNKI, and Wanfang databases. Twenty duplicate articles were excluded, 44 articles were excluded after reading the title and abstract, and 5 articles were excluded after reading the full text. Ultimately, 4 articles were included in the meta-analysis. The characteristics of the included studies are shown in Table 3.2P = .162; dominant: OR = 1.17, 95% CI = 0.93–1.46, P = .174; recessive: OR = 1.72, 95% CI = 0.94–3.15, P = .076; heterozygous: OR = 1.11, 95% CI = 0.94–1.30, P = .226; homozygous: OR = 1.74, 95% CI = 0.92–3.29, P = .088)  but was not significantly correlated with glioma risk in non-Asian populations  and tumor susceptibility has been a popular research topic in the field of cancer research. Importantly, genome-wide association study (GWAS) has become an effective method for detecting cancer susceptibility genes. Some genetic factors, such as pleckstrin homology-like domain family B member 1, telomerase reverse transcriptase, glutathione S-transferase P1, coiled-coil domain-containing 26, regulator of telomerase elongation helicase 1 and epidermal growth factor receptor genes, were confirmed to be related to glioma in genetic studies, including GWAS.This study had a few limitations. Few studies were included, especially studies on non-Asian populations, of which only 1 study selected local Brazilian residents was included. Most of the included studies were from Asian regions and were conducted on the Chinese Han population. In addition, due to a lack of data, subgroup analyses for age, sex, glioma grade, and other variables were not performed in the meta-analysis.5The results of the meta-analysis suggest that no significant correlation between the rs2305948 gene polymorphism and glioma susceptibility. However, subgroup analysis based on ethnicity demonstrated that rs2305948 may be associated with susceptibility to glioma specifically in Asian populations; the relationship among non-Asian populations was not clear due to a lack of research. Therefore, more case-control studies of reasonable design and with larger sample sizes, particularly GWAS of glioma, are needed to reveal the association between the VEGFR2 rs2305948 gene polymorphism and susceptibility to glioma.Conceptualization: Shushu Sun, Junjie Miao.Data curation: Shushu Sun, Bingkun Qu.Formal analysis: Shushu Sun.Investigation: Xiaotian Li, Bingkun Qu.Methodology: Xiaotian Li, Jinlei Li.Project administration: Junjie Miao.Software: Kunming Xie.Writing – original draft: Shushu Sun.Writing – review & editing: Junjie Miao.


Nodular ground-glass lesions have become increasingly common with the increased use of computed tomography (CT), while the genomic features of ground-glass opacities (GGOs) remain unclear. This study aims to comprehensively investigate the molecular alterations of GGOs and their correlation with radiological progression.Studies from PubMed, Embase, Cochrane Library, and Web of Science, using PCR, targeted panel sequencing, whole exosome sequencing, and immunohistochemistry, and reporting genomic alterations or PD-L1 expressions in lung nodules presenting as GGOs until January 21, 2021 were included in this study. Chi-square test, random-effects model, and Z-test analysis were adopted to analyze the data.A total of 22 studies describing mutations in lung adenocarcinoma (LUAD) with GGOs were analyzed. EGFR was the most frequently mutative gene , followed by TP53 , HER2 , ROS1 , and KRAS . The correlation between the frequency of EGFR mutation and radiological was observed and the differences were found to be not statistically significant in the subgroups, which are listed as below: radiological: gGGO 47.40%, 95%CI ; sGGO 51.94%, 95%CI . The differences of the frequency of KRAS mutation in the different subgroups were also consistent with this conclusion, which are listed as: radiological gGGO 3.42, 95%CI ; sGGO 12.27%, 95%CI . The pooled estimated rate of PD-L1 was 8.82%, 95%CI [5.20%–13.23%]. A total of 11.54% (3/26) of the SMGGNs were confirmed to be intrapulmonary spread by WES.Somatic genetic alterations are considered in early-stage GGO patients without distinct changes of the frequency following the progress of the tumor. This review sheds insight on molecular alterations in LUAD with GGOs. Ground-glass opacities (GGOs), defined as hazy increased density of the lungs with bronchial and vascular margins on computed tomography (CT) , 2, ofteTherefore, we meta-analyzed the extracted data under certain criteria to demonstrate the dynamic genomic alterations in the diversity of GGO patients. This review can provide a novel insight into the molecular alterations in LUAD patients with GGOs and new views for the biology behavior of GGOs.Three distinctive keywords were identified as follows: “ground-glass opacity”, “gene alterations”, and “PD-L1”. MeSH term database from the National Center for Biotechnology Information (NCBI) was searched to find all the possible expressions for these keywords which were defined as free words. The final search strategy was combined with both the MeSH terms and free words, which is listed as follows: #1: “GGO” OR “GGN” OR “ground glass opacity” OR “ground glass nodule” OR “ground glass nodules” OR “ground-glass opacity” OR “ground-glass nodule” OR “ground-glass nodules” OR “subsolid nodule” OR “subsolid nodules” OR “subsolid pulmonary nodules”, #2: “Gene” OR “Cistron” OR “Cistrons” OR “Genetic Materials” OR “Genetic Material” OR “genetic feature” OR “genetic characteristics” OR “genetic characteristic” OR “genetic features” OR “Genomic alteration” OR “Genomic alterations” OR “EGFR” OR “epidermal growth factor receptor” OR “TTF-1” OR “thyroid transcription factor 1” OR “ALK” OR “anaplastic lymphoma kinase” OR “KRAS” OR “Kirsten rat sarcoma” OR “HER2” OR “human epidermal growth factor receptor type 2” OR “oncogenic driver”, and #3: “PD-L1” OR “programmed cell death 1 ligand 1 protein” OR “PDL1” OR “CD274” OR “B7-H1” OR “B7H1”. “#1 AND #2” and “#1 AND #3” were searched in the four databases up to January 21, 2021, without language limitations, respectively.Firstly, all the papers retrieved from the search were screened by reviewing the titles and abstracts, during which period, reviews, case studies, editorials, meeting abstracts, and papers not meeting any of our search criteria were excluded. Then, the full contents of the rest papers were evaluated carefully to distinguish the ones that perfectly fit our inclusion criteria, analyzing the molecular alterations in a consecutive cohort of patients with GGOs, during which period, some papers were excluded for the following reasons (1): the cohort was developed to analyze the characters of the nodules with specific molecular alterations (2); insufficient data for analyses; and (3) papers not written in English. Two authors (ZWe and ZWa) conducted the procedure independently to evaluate the study eligibility for our review. This analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement .The following basic data were extracted from the selected papers: author(s), year of publication, size and region of the cohort, characteristics of the patients in the study, radiological and pathological details of the nodules, the methodological details, and relevant statistical findings for the entire cohort and/or by population subgroups. Two authors (ZWe and ZWa) collected these data independently, and any discrepancies between the two authors were resolved by discussions with a third author (KC).2 statistics were calculated to assess the heterogeneity between study-specific estimates  who were not involved in any of the reviewed studies. As recommended by the Agency for Healthcare Research and Quality, the assessment of the methodological quality of the included studies was made from 11 perspectives with the Cross-Sectional/Prevalence Study Quality, a scoring system specific for a cross-sectional study ], followed by TP53 , HER2 , ROS1 , KRAS  ] in the EGFR(+) group and 47.17% [95%CI ] in the EGFR (–) group, with a p-value at 0.5122 .The rate of ALK rearrangement in GGOs, reported in 4 of the 22 studies, was 18/504 (3.57%) after enumeration  were found with the PD-L1 expression  that pro% were foA total of 6/22 articles included synchronous multiple ground-glass nodules (SMGGNs) in their cohorts, while only the data from 4 articles could be extracted for analysis. In the 123 cases with SMGGNs included, 8 cases (6.50%) possessed identical mutations in their resected nodules which were doubted to be an intrapulmonary spread. Only one article used whole-exosome sequencing (WES) and confirmed 3/26 (11.54%) cases to have an intrapulmonary spread. The genetic alterations of the cases are listed below  than solid nodules , Zhao et al  reportedDespite PCR, WES, and WGS which are used in the studies included in our study, with the development of molecular diagnostic technology, the field of liquid biopsy has gradually developed a lot. Analyzing circulating tumor DNA (ctDNA) at the genomic level, a newly-emerged non-invasive approach, is proposed to have the ability to distinguish between malignant and benign disease , 54 and Two studies reported independently that different pathological lesions could share identical mutations even in pre-invasive LUADs, such as AAH and AIS lesions , 57. ThiWith the development of an immune checkpoint inhibitor treatment, especially the inspiring results of neoadjuvant immune therapy, a series of studies have focused on the immune-environment of early-stage lung cancer patients. The TRACEx cohort reported that sparsely infiltrated tumors exhibited a waning of neoantigen editing during tumor evolution, compared with immune-infiltrated tumor regions exhibiting an ongoing immunoediting, with either loss of heterozygosity in human leukocyte antigens or depletion of expressed neoantigens .RecentlyOur research revealed that EGFR mutation is not associated with the radiological progression of GGOs, which means EGFR mutation was a driver mutation for lung cancer in a fairly early stage, and maintains consistency in the progression of tumors. On the contrary, the frequency of KRAS mutation was higher in progressed lung nodules, indicating a position for KRAS mutation in tumor progression. Immunotherapy, as one of the recently discovered effective therapies for advanced lung cancer, is less effective against GGOs, which may be due to the low expression level of PD-L1 in early-stage lung cancer, found by our research. Though GGOs are usually considered early-stage lesions, there does have a possibility for SMGGNs to have an intrapulmonary spread, the mechanism behind which is still unclear. The limitation of our meta-analysis lies in its retrospective design; postsurgical follow-up or treatment plans at recurrence would differ among attending surgeons. Also, the high heterogeneity between the methodologies and results of researches is another limitation of our research. Overall, this review summarizes the published estimates of the rates of molecular alterations in lung nodules presenting as GGOs, which may help clinical treatment decisions for GGOs and provide a novel insight in revealing the molecular alterations behind GGOs.The original contributions presented in the study are included in the article/ZWe and ZWa conceived and planned the experiments. ZWe and ZWa carried out the experiments. ZWe, ZWa, HS, XW, and MW contributed to the data preparation. ZWe, ZWa, YN, and KZ verified the analytical methods. ZWe, ZWa, YN, KZ, HS, XW, and MW contributed to the interpretation of the results. ZWe and ZWa took the lead in writing the manuscript. All authors contributed to the article and approved the submitted version.This study was supported by the National Natural Science Funds (grant No. 82072566) and Peking University People’s Hospital Research and Development Funds (grant No. RS2019-01).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Both rock groups show positive Δ199Hg values up to 0.34‰ and 0.22‰, respectively, which deviate from recent estimates of the primitive mantle 1. The positive Δ199Hg values indicate recycling of marine Hg into the asthenospheric mantle. Such a crustal Hg isotope signature was not observed in our samples of ocean island basalts and continental flood basalts, but has recently been identified in canonical end-member samples of the deep mantle1, therefore demonstrating that recycling of mercury can affect both the upper and lower mantle. Our study reveals large-scale translithospheric Hg recycling via plate tectonics.The geochemical cycle of mercury in Earth’s surface environment  has been extensively studied; however, the deep geological cycling of this element is less well known. Here we document distinct mass-independent mercury isotope fractionation (expressed as Δ This work demonstrates distinct mass-independent mercury isotope fractionation in global basalts, which suggests mantle Hg isotope heterogeneity and reveals large-scale translithospheric Hg recycling via plate tectonics. Both natural and anthropogenic activities emit large amounts of Hg to the atmosphere, mainly in the form of elemental Hg (Hg0)3. Gaseous Hg0 has a lifetime of ~1 year in the atmosphere, allowing its global transport before deposition into terrestrial and oceanic ecosystems via both wet and dry deposition pathways4. Due to its toxicity to humans and wildlife, the geochemical cycle of Hg in Earth’s surface environment  has been extensively studied2. However, the cycling of Hg in Earth’s interior reservoirs  remains less studied5.Mercury (Hg) is a unique heavy metal that has an active redox chemistry, high volatility, strong bioaccumulation, and extreme toxicity4, implying a causal link between Hg metallogenesis and plate subduction. Mercury in oceanic reservoirs  may be carried by subducting ocean slabs into the asthenospheric mantle, and can then be emitted during arc magmatism to form Hg-enriched hydrothermal ore deposits in active continental margin settings6. A recent study, based on Hg isotopes in ocean island basalts, suggests that crustal Hg is also recycled into the lower mantle1.Mercury ore deposits are predominantly located in active continental margin settings, with two well-known mercuriferous belts—the Pacific rim metallogenic belt and the Alpine-Himalayan belt202Hg) and mass-independent fractionation 8. Hg-MDF is produced during essentially all biological, chemical, and physical processes involving Hg7. MIF of 200Hg and Δ204Hg is detected mainly in atmospherically derived samples, and values in rocks are generally too small to enable source tracing8. MIF of 199Hg and 201Hg mainly occurs during photochemical processes with little contribution from other reactions, and therefore provides clear source constraints7. On Earth’s surface, photochemical processes result in negative Δ199Hg (−0.6 to 0‰) in terrestrial reservoirs  and positive Δ199Hg (0 to 0.4‰) in oceanic reservoirs 8. It has been estimated that the primitive mantle has near-zero Δ199Hg  and negative δ202Hg , based on Hg isotope analyses of 3He-rich lavas1. A recent study also found significantly positive Δ199Hg (0 to 0.4‰) in hydrothermal ore deposits associated with arc magmatism, implying the recycling of Hg from marine sediments into arc lavas6.Mercury is the only metal that exhibits both significant isotopic mass-dependent fractionation . OIBs and CFBs are genetically related to mantle plumes, which originate from the lower mantle or the core-mantle boundary11. A landmark study recently observed deviations in Δ199Hg in three well-characterized mantle endmembers , compared to the estimate of the primitive mantle  based on Hg isotope analyses of 3He-rich lavas, highlighting the great potential of using Hg isotopes to trace crustal Hg recycling into the mantle1.Distinct Sr-Nd-Pb isotopic compositions of mid-ocean ridge basalts (MORBs), island arc basalts (IABs), ocean island basalts (OIBs), and continental flood basalts (CFBs) demonstrate a pronounced mantle isotope heterogeneity, which is generally accepted to result from recycling of crustal materials into the mantle via plate subductionn = 5), Southwest Indian Ridge , and East Pacific Rise ; IABs (n = 9) from the southern part of the Mariana Island Arc; HIMU-like OIBs (n = 2) and EM1-like OIBs (n = 5) from the Pako guyot of the Magellan Seamount Chain in the West Pacific Seamount Province; and CFBs (n = 17) from the Siberian Trap, the world’s largest flood basalt province. The geological background of these samples and analytical methods are given in the Materials and Methods section in detail. The sample information and analytical results are summarized in Supplementary Tables To aid in understanding the deep Hg cycle and to probe possible mantle Hg isotope heterogeneity, we measured the Hg isotopic compositions of a variety of types of basalts at a global scale Fig. . SamplesOIBs n =  and EM1-13.In this study, total Hg (THg) concentrations vary from 0.65 to 2.35 ng/g for MORBs, from 0.54 to 1.28 ng/g for IABs, from 0.48 to 2.08 ng/g for OIBs, and from 0.91 to 4.29 ng/g for CFBs, with mean values of 1.48 ng/g, 2.25 ng/g, 1.63 ng/g, and 0.80 ng/g, respectively Fig. . These c202Hg was observed for all basalts studied . Specifically, MORBs and IABs have δ202Hg ranging from −1.58 to −0.50‰ and −1.72 to 0.13‰, with similar mean values of −0.93 ± 0.62‰ (2 SD) and −0.80 ± 1.22‰ (2 SD), respectively. OIBs and CFBs have relatively lower δ202Hg values of -2.13 to −1.60‰ and −2.13 to −1.48‰, with mean values of −1.85 ± 0.30‰ (2 SD) and −1.66 ± 0.54‰ (2 SD), respectively.A large variation of δ202Hg in the studied basalts could be caused by MDF during magmatic processes. Lighter Hg isotopes may be preferentially volatilized during Hg degassing14, and thus generate enrichment of heavy Hg isotopes in the residue phases. The lower δ202Hg of fumarolic gas  compared to condensed particles  in an active volcano  strongly supports this view14. In our study, the more negative values of δ202Hg in OIBs and CFBs  relative to those of MORBs and IABs (that originate from the upper mantle), as shown in Fig. The large variation of δ202Hg in the basalts studied is the mixing of Hg sources with distinct δ202Hg values. The continental crust, in particular sedimentary rocks and sediments, displays large variations of δ202Hg (−3 to 1‰), with a mean value of −0.7 ± 1.6‰ (2 SD) . The large variations of δ202Hg in MORBs and IABs in our study, coupled with their higher mean δ202Hg values compared to OIBs and CFBs, may be explained by the recycling of crustal rocks into the upper mantle. However, many different processes could trigger Hg-MDF7, which hinders the full understanding of Hg-MDF during magmatic processes. Thus, δ202Hg is not considered to be highly diagnostic of Hg sources. Instead, we focus on the Hg-MIF signal as a more reliable source tracer, as discussed below.An alternative explanation for the variation of δ200Hg, with Δ200Hg ranging from −0.08 to 0.08‰, which is nearly within the analytical uncertainty for Δ200Hg (±0.06‰). However, large variations of Δ199Hg (−0.08 to 0.34‰) and Δ201Hg (−0.09 to 0.23‰) are observed in the samples studied, compared to the analytical uncertainties for Δ199Hg (±0.07‰) and Δ201Hg (±0.06‰). MIF of 199Hg and 201Hg is mainly produced during aqueous Hg(II) photoreduction on Earth’s surface with little contribution from other processes15. Magmatic degassing could produce limited Hg-MIF of <0.1‰ in Δ199Hg and Δ201Hg5. Hg(II) photoreduction imparts negative Δ199Hg in the product gaseous Hg(0) and positive Δ199Hg in the residual Hg(II) phase15, with Δ199Hg/Δ201Hg of ~1. For this reason, terrestrial vegetation mostly shows negative Δ199Hg  and marine sediments24  and near-zero Δ199Hg values , which are within the range of the estimate of the primitive mantle  based on Hg isotope analyses of 3He-rich lavas1. The recently observed significant Δ199Hg signals in two EM-1 OIBs (−0.45 and −0.11‰), an EM-2 OIB (0.23‰), and a HIMU OIB (−0.14‰)1, imply that Hg in oceanic and continental crustal materials can be recycled into the lower mantle. However, the amount of recycled Hg is likely small with respect to the total Hg pool in the lower mantle, given the fact that OIBs and CFBs in this study as well as 16 previously studied OIBs (including 11 3He-rich lavas)1 show near-zero Δ199Hg values  ranging from −0.9 to 0.4 wt% and 6.2 to 8.0 wt%, respectively 25, seawater-rock reactions can be further precluded as a reason for the positive Δ199Hg values in MORBs and IABs.MORBs and IABs have mostly positive Δ4‰ Figs. , with Δ1 ~1 Fig. . These v199Hg signals in the studied IABs to recycled marine sediments. At convergent margins, subduction of the oceanic slab carries a substantial amount of Hg from marine sediments into subduction zones. The downgoing slab undergoes dehydration and metamorphism and releases fluids and melts that in turn metasomatize the mantle wedge. Partial melting of such metasomatized mantle could generate IABs with positive Δ199Hg. Notably, given the low volatilization temperature of Hg, subducted Hg may be mostly released from the downgoing slab and returned to the Earth’s surface through arc volcanism. This is supported by the positive Δ199Hg signal observed in volcanic arc-related epithermal Hg-Au deposits in NE China and the Pacific rim . The most recent estimate of present-day global volcanic Hg flux (76 ± 30 t/year)26 is slightly lower than the total mass of Hg in global subducted sediments (~87.4 t/year), calculated from the mass of global subducted sediment (1.4 × 1015 g/year)27 multiplied by the Hg concentration of average marine sediments (62.4 ng/g)28.We attribute the positive Δ199Hg of MORBs could also be the result of the recycling of oceanic crust. In subduction zones, the subducted marine Hg may not be completely released via arc volcanism. The remaining Hg in the subducted slab could continue to descend into the asthenospheric mantle. This fraction of Hg is recycled into the asthenosphere and could be brought back to Earth’s surface via basaltic magmatism at mid-ocean ridges. The upper mantle is heterogeneous in Hg isotopes, apparently due to the variable involvement of recycled crustal Hg. Such isotopic heterogeneities are consistent with large variations in Sr-Nd-Pb isotope compositions for MORBs from different mid-ocean ridges , which supports the model of recycling of crustal materials into the upper mantle31. The recycling of oceanic Hg into the upper mantle is also favored by the positive Δ199Hg values (0.07 to 0.27‰) observed in hotspring and sinter samples from the Yellowstone Plateau volcanic field32, which might be explained by upwelling asthenospheric mantle flow induced by the subducting Pacific plate33.The positive Δ199Hg values in terrestrial reservoirs  and significant positive Δ199Hg values in marine reservoirs . Mercury from terrestrial and marine reservoirs is subducted at convergent margins. Due to the low volatilization temperature of Hg, much of the subducted Hg is likely released back to the surface environment through arc volcanism, forming IABs and arc-related epithermal Hg deposits with significantly positive Δ199Hg values. The remaining Hg in the subducted slab is recycled into the asthenosphere and released at mid-ocean ridges by MORBs, which are characterized by significantly positive Δ199Hg values.Based on our current knowledge of Hg isotopic variation in mantle-derived rocks, the deep cycling of Hg is illustrated in Fig. 199Hg signals in some OIB samples1; however, given that most OIBs and CFBs show near-zero Δ199Hg values, this recycled Hg likely represents only a small proportion of Hg in the lower mantle, and may be mostly located in the source of the mantle end-members. In the future, analysis of OIBs and CFBs from additional sites will be needed to better quantified the amount of recycled Hg in the lower mantle.Some of the subducted Hg may also be recycled into the lower mantle, consistent with the recently observed significant Δ28). Given the significantly large Δ199Hg values and high Hg concentrations in crustal materials, we infer that the crustal signature cannot easily be erased by the primitive mantle signature (Δ199Hg ~ 0). We conclude that Hg-MIF (Δ199Hg) can be a useful tool for studying crust-mantle interactions.Overall, our study demonstrates mantle Hg isotopic heterogeneity and reveals large-scale translithospheric Hg recycling via plate tectonics. Hg tends to be depleted in volcanic rocks derived from the mantle  and enriched in crustal sedimentary rocks , MAR (n = 5), and SWIR (n = 3), during the DY115-21, DY115-22, DY125-30, and DY135-40 cruises, by the Chinese R/V DayangYihao using TV grab (grab system controlled via a TV camera). The three regions have different spreading rates , representing a broad spectrum of crustal accretion modes35.The sample locations are shown in Fig. n = 9) were collected from the southern part of the Mariana Island Arc, using the submersible Jiaolong, during the R/V Xiangyanghong 09 Dayang 37th cruise. The Mariana Island Arc is a classic young island arc in the western Pacific Ocean. Most of the islands and underwater volcanoes in the southern part of the Mariana Island Arc were formed during the Eocene to Miocene36.IABs  show HIMU-like Sr-Nd-Pb-Hf isotopic compositions indicating recycled ancient oceanic crust in their mantle source, while the others display EM1-like isotopic compositions consistent with recycled sub-continental lithospheric components in their mantle source.The Pako guyot was formed by the large-scale eruption of a hotspot at 120–90 Man = 17) were sampled from the Norilsk region at the northwestern margin of the Siberian platform, which is a part of the world’s largest flood basalt province, the Siberian Traps . Major elements were analyzed at the ALS Minerals-ALS Chemex, Guangzhou, China, using a PANalytical PW2424 X-ray fluorescence spectrometer. LOI values were measured by combustion loss of weight, with analytical uncertainties (RSD) of <5%. Total Hg (THg) concentration was determined by an RA-915+ Hg analyzer , with a detection limit of 0.01 ng/g. Standard reference materials  were measured, yielding Hg recoveries of 94–106% and RSD of <9%.3/HCl = 2/1, v/v) trapping solutions41. Standard reference materials (GSR-2 and BCR-2) and method blanks were processed in the same way as the samples. The former yielded Hg recoveries of 90–105% and the latter showed Hg concentrations lower than the detection limit, precluding lab contamination. The preconcentrated solutions were diluted to 0.5 ng/mL with an acid concentration of 10–20% prior to Hg isotope analysis using a Neptune Plus multi-collector inductively coupled plasma mass spectrometry42. Hg isotope ratios were reported following the convention proposed by Blum and Bergquist43. MDF is expressed in δ202Hg notation in units of ‰ referenced to the NIST-3133 :xxxHg and the theoretically predicted δxxxHg value, in units of ‰:199Hg, 0.5024 for 200Hg, and 0.752 for 201Hg. Hg concentration and acid matrices in the bracketing NIST-3133 solutions were matched with neighboring samples. NIST-3177 secondary standard solutions, diluted to 0.5 ng/mL Hg with 10% HCl, were measured every 10 samples. The overall average and uncertainty of NIST-3177  and GSR-2  and BCR-2  agree well with previous results45. The larger of the values of standard deviation (2 SD) for either NIST-3177, GSR-2, or BCR-2 are used to reflect maximum analytical uncertainties.The samples were prepared for Hg isotope analysis using a double-stage tube furnace coupled with 40% anti aqua regia (HNOSupplementary Information


In the original article, we neglected to include the funder. The correct Funding statement appears below. “This work was developed at i3S/IPATIMUP, an Associate Laboratory of the Portuguese Ministry of Science, Technology and Higher Education, and partially supported by Fundação para a Ciência e a Tecnologia (FCT). This research was supported by European Regional Development Funds (ERDF) funds through the COMPETE 2020–Operational Program for Competitiveness and Internationalization (POCI), Portugal 2020, Fundação para a Ciência e a Tecnologia (FCT)/Ministério da Ciência, Tecnologia e Inovação (MCTES), under the project POCI 01-0145-FEDER-029503 (PTDC/MEC-ONC/29503/2017) and CESPU (Cooperativa de Ensino Superior Politécnico e Universitário) under the project ComeTarget_CESPU_2017 (to HB). MN acknowledges FCT/MCTES and UE for financial support through a PhD fellowship (2020.04720.BD) co-sponsored by Fundo Social Europeu (FSE) through Programa Operacional Regional Norte (Norte 2020).”In the published article, there was an error in affiliation 4. Instead of “TOXRUN, Toxicology Research Unit, University Institute of Health Sciences, Advanced Polytechnic and University Cooperative (CESPU), Gandra, Portugal” it should be “TOXRUN, Toxicology Research Unit, University Institute of Health Sciences, Polytechnic and University Cooperative (CESPU), Gandra, Portugal”.The authors apologize for these errors and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Recently, it wasfound that adsorbed O2 molecules provide the dominant contributionto flux noise in superconducting quantum interference devices. Toclarify the basic principles of such adsorbate noise, we have investigatedlow-frequency noise, while the mobility of surface adsorbates is variedby temperature. We measured low-frequency current noise in suspendedmonolayer graphene Corbino samples under the influence of adsorbedNe atoms. Owing to the extremely small intrinsic noise of suspendedgraphene, we could resolve a combination of 1/f γ and Lorentzian noise induced by the presence of Ne.We find that the 1/f γ noiseis caused by surface diffusion of Ne atoms and by temporary formationof few-Ne-atom clusters. Our results support the idea that clusteringdynamics of defects is relevant for understanding of 1/f noise in metallic systems.Low-frequency 1/ Thesame issue, however, does pertain to various areas of 1/f noise.17 In this work, our goal is to test fundamental aspects of theoriesbased on mobile impurities.23 We generate 1/f γ noiseby adsorbing neon atoms onto a graphene membrane. We are employingsuspended graphene as a platform for studying impurity-induced low-frequencynoise, because the inherent 1/f γ noise level is exceedingly small in mechanically exfoliated, suspendedgraphene. Since the background impurity scattering is almost nonexistentfor graphene electrons, even weak scatterers such as neon atoms maymake a difference in the impurity scattering and thereby alter thenoise substantially.In general,the f γ noise spectrumwith γ ≃ 1. The answer to this question bears significancealso to quantum technology, as the interfacial states and adsorbateatoms present important noise sources for qubits.26All solid materials contain structuraldefects that may diffusearound at room temperature. When temperature is lowered, the diffusionslows down, but it remains still visible all the way down to the quantumtunneling regime. We are interested in diffusion of defects or impuritiesand their possible role in scattering fluctuations due to clusteringof defects/impurities. Diffusion influences the relative locationsof impurities, which then affect the total scattering cross section(length in two dimensions) experienced by the charge carriers traversingthe sample. Variation of the scattering will, in turn, lead to modificationof resistance, and the fundamental question is whether this will leadto a 1/27 It has experimentally been demonstrated thatadsorbed gas molecules at room temperature will lead to Lorentziannoise spectra, with characteristics specific to the adsorbent species.28 Noble gases on graphite interact quite weaklywith the substrate and the adsorbed atoms remain mobile at cryogenictemperatures. The most interesting regime is attained around 10 Kwhere surface diffusion leads to fluctuations in the number and inthe distribution of the atoms on the graphene membrane, while thedesorption rate of Ne can be neglected. In this regime, we may testuniversal 1/f theories based on mobile impurities.Our results can also be employed to determine the adsorption energyof a Ne atom onto a graphene monolayer.Owingto its large surface-to-volume ratio, graphene is alwaysvery susceptible to surface adsorbates, and even individual Hall resistancesteps have been demonstrated due to single-atom adsorption events.SI for details of the measurement setup). Withoutadsorbed Ne, the low-frequency noise increases approximately linearlywith T, whereas the background level of SI/I2 withNe is nearly constant up to T ≃ 20 K. At temperaturesof 20–30 K, there is a strong peak in the noise, which canbe attributed to the dynamics of neon atoms on the graphene surface,governed basically by adsorption/desorption processes; the SI/I2 reading at 10 Hz with Ne in f γ and a Lorentzian spectrum to the data over 1–100 Hz. Thesmaller peak at T = 12–16 K may be due toresidual hydrogen present in the system, but more likely, it is relatedto diffusion phenomena of neon atoms across the graphene sample. Thequality of the sample is exemplified by the product f × SI/I2 ≃ 2 × 10–10, which ison par with the best noise levels reported so far.23He atoms on a carbon nanotube.32fm(Vg) curve33 under the influence of neon. The re-entrantW-shape indicates a crossover from the built-in-tension-dominatedbehavior to gate-induced-tension dependence, the minimum frequencyposition of which moves to larger Vg with enhanced initial tension.The increase in strain is also corroboratedin the shift of theminimum of the re-entrant-looking 35 and enhance the generation of 1/f γ noise.Strain variation on theatomic scale due to adsorbed atoms willlead to local pseudomagnetic fields as well as changes in the scalarpotential, which can strongly modify the mobilityf × SI/I2 so thatpure SI/I2 ∝ 1/f form becomes a constantin this plot. A Lorentzian fluctuator spectrum ∝1/(f2 + fc2), on the other hand,would display a peak at the corner frequency f = fc. The data in f over the measured range, which covers frequenciesfrom 1 to 100 Hz while temperature is varied across T = 4–23 K.f× SI/I2 displaya maximum characteristic to a Lorentzian spectrum, in which the cornerfrequency fc moves exponentiallywith inverse temperature. Exponential behavior exp[−Ea/kBT] is expected for a thermally activatedprocess following the Arrhenius law; here, kB is the Boltzmann constant. Inspection of Ea1/kB = 410 K and Ea2/kB = 200 K. We identify Ea1 = Ea as theadsorption energy of neon onto graphene, while the latter Ea2 = Eb is identified as describing trap statesat the boundary (see Sect III of SI). Thesetrap states can act as expediters of trapping/detrapping behavior,potentially providing a similar resistance (current) noise mechanismas adsorption/desorption phenomena. Furthermore, the atomic graphenelattice potential has corrugations with saddle-point-like barriersseparating nearby graphene hexagons. The ensuing diffusion barrierheight for neon atoms amounts to approximately Ed = 32 K based on the values for graphite.37 Consequently, the observed current noise due to adsorbate dynamicson graphene is governed partly by surface diffusion with intermediatetrapping and partly by adsorption/desorption, the relative weightof them depending on the temperature.39The low-frequency noise is substantially strongerwith adsorbedneon as seen in T. As discussedin the SI, we think that adsorption fromthe gas phase to the graphene membrane is limited due to lack of stickingsites except at the electrodes. The trap states at the boundary feedatoms back to the graphene surface at a rate governed by the relevantArrhenius law, namely ∝exp[−Eb/kBT], where Eb describes the depth of the trapping potential with respect to thepotential surface in graphene .Initiallyat low temperatures, we have thermally activated diffusionalong the substrate, which becomes gradually influenced by desorptionfrom the surface with increasing Ṅ in thenumber of the adsorbed Ne atoms on the graphene membrane, we employa model with N mobile adsorbed atoms and a supplyof Nb atoms capturedby the additional trapping potential at the electrodes. Thus, ourmodel has two coupled rate equations, one for N andone for Nb as outlinedin the SI. The rates of exchange of atomsbetween the gas phase, the graphene membrane, and the surface trappingyield N and its fluctuation rate that governs thelow-frequency scattering noise in the electronic transport. At hightemperatures T > 25 K, desorption of atoms isfasterthan their diffusion, and direct adsorption/desorption processes governthe current noise. At low temperatures, on the other hand, exchangeof atoms with the gas phase becomes irrelevant, and the dynamics ofatoms is governed by release from the electrodes and ensuing diffusionon the Corbino disk.To describe the rate of change g reflects the strengthof individual scatterers, N describes the numberof particles involved in the process, and fc is the frequency of desorption and adsorption processeswhich are equal at equilibrium. For thermal activation, we may write fc = f0 exp(−Ea/kBT) where f0 is the attempt frequency and Ea is the binding energy ofNe atoms on the graphene substrate. By fitting Ea/kB =410 K with f0 in the range of 108 s–1, which is rather low for an attempt frequency.However, low values for f0 have been obtainedfor surface diffusion of noble gases on metallic surfaces.40 Compared with neon adsorption energy on graphite Ea/kB = 350 K,41 our valueis reasonable, taking into account the possible increase in interactionenergy due to local deformation in a single-layer substrate. We emphasizethat we always see a single Lorentzian line in the adsorption/desorptionregime, never a collection of two level systems as seen for examplein high-Ohmic graphene tunneling devices.42Adsorption/desorption processes lead toLorentzian noise spectrumgiven byT = 15 K (with f0 = 108 s–1). The diffusiontime of Ne atoms across the Corbinoring varies between τd = 250···2ms at temperatures T = 4···10 K (seeSect. III of the SI). Consequently, theprobability of desorption from the surface during diffusion T < 10 K. Therefore, diffusion of Ne atoms will govern fluctuationsin the absorbent number and configuration patterns, which in turn,govern the low-frequency resistance noise in our system. The samediffusion processes on graphene govern also fluctuations in the numberof atoms at the edge. This will lead to noise in the contact noiseresistance Rc, the separationof which is discussed in Sect. IV in the SI.With lowering temperature well below 25 K, the desorptionrateof atoms becomes very small. Using the exponential activation fitto 44 i.e., the inverse of diffusiontime across the sample fc = (2πτd)−1 ,and N in T = 4–10 K, surface diffusion provides low-frequencynoise in the range of investigated frequencies of 1–100 Hz.However, the diffusion of individual, noninteracting particles willlead to a noise spectrum of 1/f1.5 form.47 Only if there are additional correlations, for example, generatedby clustering/declustering of neon atoms via thermally driven surfacediffusion, the noise power spectral density may approach the 1/f spectrum. Basically, multipartite clustering dynamicsleads to long-term memory effects, which modify the random walk natureof regular low-frequency diffusion noise.The diffusion process leads to a random walk type of noisewherethe characteristic frequency is given by the inverse of a typicalrandom walk time,f × SI/I2 is measuredat different temperatures between 4–37 K. With increasing temperature,the peak in f × SI/I2 due to the cutofffrequency fc shifts towardhigher frequencies. The overlaid traces at temperatures T = 22.1 K, T = 25.0 K, and T =29.8 K are fits calculated using fc = 1.5, 12, and 120 Hz, respectively. These values hold remarkablywell together with fc = f0 exp(−Ea/kBT) where f0 =1.4 ± 0.25 × 108 s–1. The absenceof temperature dependence in the maximum amplitude of these three f × SI/I2 traces arises from the specific behaviorof the sticking sites at the boundaries, i.e., due to the fact thatthe feed from the Na trappedatoms is able to compensate the desorption rate of ∼N so that N = const. (see SI).In order to detailthe noise in the desorption regime, SI ∝ 1/f γ. Resultsof these unconditional fits to the data are illustrated in fc across the studied frequencyrange as a function of T is visible here as a nonmonotonicchange in γ. A change in the exponent from 2 to 0 is expectedon the basis of f noise, we may conclude that the presence of Ne is able to destroythe character of the noise when the sloped noise part ∝1/f2 is dominating. At T = 4–10K, the noise spectrum is described by a single exponent γ =1.2–1.4. One spectrum with γ = 1.24 measured at T = 4.7 K is displayed for reference in Besides the Lorentzian-based fits of 48 In our hopping transport, the complexity of neon diffusion dependson Ne–Ne interactions and the boundary conditions. If one calculatesnumerically the lifetime distribution of diffusing particles in aCorbino disk geometry with fully absorbing boundary conditions (seeSect. IV of SI), one obtains a noise spectrumof the form 1/f1.5, similar to the one-dimensionalcase.44 On the other hand, if we assumea probability of reflection of particles from the boundary (the relevantsticking site occupied), then we obtain γ > 1.5. Thus, withoutadditional assumptions on time-dependent correlations among neon atoms,for example changes in scattering via clustering/declustering, thediffusion model is not sufficient for explaining the observed exponentγ = 1.2–1.4.Noise induced by thermaldiffusion has been demonstrated to leadto complex frequency dependence of noise.SI, it is known thatNe atoms have an attractive interaction on the order of ϵ/kB ≃ 40 K which tendsto stabilize 71/2× 71/2 commensurate structureson graphite. Thus, clusters of Ne atoms on graphene may form and theymodify random diffusion by their interaction energy and by hoppingrestrictions imposed on the atoms sitting within the cluster. We haveperformed kinetic Monte Carlo (kMC) simulations (see Sect. V in SI) to investigate these effects and have foundthat the significance of clusters depends on temperature. At highertemperatures more atoms are diffusing and the interactions and clustersbecome more important. According to these kMC simulations, the resistancenoise is first close to 1/f 1.6 at low T, at which mostly single atoms are diffusing,but there are also prominent fluctuations due to hopping in the boundarylayer causing noise in the contact resistance Rc . The noise becomes closer to 1/f 1.2 when temperature is increased by a factorof approximately two. These simulation results agree quite well withour data in T = 4–10 K.This agreement strongly supports the importance of clustering of theadsorbates for generation of 1/f resistance noise,in similarity with adsorbate-induced flux noise in Al-based SQUIDs.The central question of low-frequencynoise due to diffusing adsorbatesis the nature and strength of their mutual interactions. As discussedin Sect. I of the 50 Interactions have also been found to lead to clustering of spins,which gives rise to interesting spin dynamics producing flux noise.52 Contrary to our resistance noise, the flux noise is argued to arisefrom spin flips (either single spin or a cluster) and spin diffusiondue to interactions, not from lattice hopping of adsorbates as inour case. There is recent experimental evidence that surface spinsdue to adsorbed O225 provide major contributionsfor flux noise in AlOx tunnel junctions.Indeed, our results suggest that spatial clustering of such surfacespins may play an important role also in flux noise.SQUID-based experiments indicate that fluctuations of unpairedmicroscopic surface spins with interactions are responsible for fluxnoise in superconducting quantum circuits.f noise amounting to f ·SI/I2 = (2 ± 0.5) × 10–10 for clean graphene at intermediate charge densities n = ± 7 ·1011 cm–2 at 4 K;the noise was enhanced by a factor of 3 when adding neon on the sampleat these carrier densities.In summary,we have investigated low-frequency noise in suspendedgraphene with and without adsorbed neon, in particular, in Corbinogeometry, in which there are no free edges to interact with adsorbedgas atoms. We find ultralow 1/T ≫ 10K, desorption of Ne atoms ledto fluctuations in the number of mobile Ne atoms on the graphene surface,which caused a temperature-dependent characteristic fluctuation frequency fc = f0 exp(−Ea/kBT) that corresponds to adsorption energy Ea/kB =410 K. At T < 20 K, the noise is governed by surfacediffusion of Ne atoms, and models based on dynamical clustering ofmobile impurities were tested at T = 4–10K. Our work clearly demonstrates that a substantial amount of low-frequencynoise is created by diffusing impurities on a 2D sample. The observednoise spectra around 4–10 K display a power law behavior 1/f γ with γ = 1.2–1.4.Fundamental agreement with our Monte Carlo simulations supports theconclusion that weakening of the frequency exponent from the single-particlediffusion noise with γ = 1.5 toward γ = 1 is due to thevariation in the scattering cross section caused by clustering/declusteringof the mobile neon impurities. Our results carry direct relevancefor ultraclean graphene technologies,53 and they provide strong evidence that diffusing defects and theirrelative grouping/regrouping play a role in various systems displaying1/f type of noise.At


The incidence of differentiated thyroid cancer (DTC) has steadily increased since the 1980´s . This hiHowever, not all cancer registries worldwide recorded a significant increase of only small, early-stage tumours but a rise of larger, later-stage tumours too , 2, 7, wFifteen papers in this Research Topic address important questions, which have to be answered if the approach of “personalized” or “precision” medicine, which today is generally accepted, shall be applied to DTC too.Very relevant issues to be solved relate to risk-benefit considerations covering a broad spectrum from small, non-aggressive papillary thyroid cancers (PTC) in young patients, to aggressive, metastasizing cancers in elderly people.Krajewska et al., Gliwice Poland contribute a comprehensive review on: “Early diagnosis of low-risk papillary thyroid cancer results rather in overtreatment than a better survival” with more than 100 references. The main message of this paper is that there is overdiagnosis in (very) early stages of PTC cases stage pT1 worldwide, which need not be treated aggressively - if at all. But – on the contrary – the increasing detection of more advanced cases of PTC demands adequate treatment. Benefits and side effects of surgical therapy, I-131 treatment and thyroid hormone supplementation should be carefully considered. Finally, the authors state that “numerous clinical trials are needed to change the clinical management of low and intermediate risk PTC”.Qiu et al. from Shanghai, China, present a paper on “Long-term Outcomes and Prognoses of Elderly Patients (≥65-years-old) with Distant Metastases from Well-differentiated Thyroid Cancer during Radioiodine Therapy and Follow-up”. In a study of 193 DTC patients ≥ 65 years of age, distant metastases are prevalent in 31% of the cases, which were followed-up for up to 24 years. The 5 and 10 year disease specific survival is reported to be 77% and 49% respectively. Gross thyroidal extension and I-131 responsiveness could be identified to be significant, independent prognostic indicators, thus confirming the effectiveness of radioiodine therapy (RIT) in patients with advanced thyroid cancer.Concerning the other side of the spectrum of DTC’s aggressiveness, Zhao et al., Hangzhou China present “Identification of A Prognostic 3-Gene Risk Prediction Model for Thyroid Cancer” using 506 DTC samples and 56 controls from the TCGA cancer genome database. Using receiver operator characteristics (ROC) to test predictability of 3-year survival, the area under the curve (AUC) corresponds remarkably to 0.85 for the 3 gene model with GHR, GPR125 and AtP2c2 versus AUC´s of 0.79-0.84 for single genes. GHR is a gene coding for transmembrane receptors of growth hormone, GPR125 promotes cell adhesion and AtP2c2 is a calcium transport coding gene.To decide properly which treatment should be recommended to a given patient, it is necessary to stage the tumour properly and to assign this clinical stage to defined risk categories. This today should be done including appropriate instruments of genetic profiling. Xie et al. from Shenyang, China, used the same TCGA database for “Analysis of the prognostic value and potential molecular mechanisms of TREM-1 overexpression in papillary thyroid cancer via bioinformatics methods”. They focus on the triggering receptor expressed on myeloid cells-1 (TREM-1) described as biomarker in many cancers, but not up to now in thyroid cancer. Genes co-expressed with TREM-1 participate in immune related pathways. Xie et al. identified TREM-1 expression to be correlated with immune infiltration, tumour progression, and poor overall survival, with an AUC of 0.84. These interesting results obtained with bioinformatics methods have to be confirmed with much larger samples and experimental research.Similarly, PTCs are frequently diagnosed by chance if a non-suspicious nodule is surgically resected or lobectomy is performed for non-oncological reasons. In this case it is of utmost importance to know if the cancer disease is restricted to the lobe surgically resected or if possibly the contralateral lobe is affected too.Feng et al., Changzhou, China, present a study on “Management of Clinically Solitary Papillary Thyroid Carcinoma Patients According to Risk-scoring Model for Contralateral Occult Carcinoma” in which 573 clinically solitary PTC patients undergo lobectomy, identifying 3.7% ipsilateral and 15,5% contralateral occult cancers with their approach. The 10-point risk scoring model for contralateral cancer includes the points “benign nodule (point-load 2)”, “tumour size > 1cm (load 1)”, “extrathyroidal extension (load 3)”, “central LN-metastases (load 2)”, “lateral LN-metastases (load 2)”, the ROC area under the curve amounting to 0.91 for a cut-off of 3.5 summarized points.Zhang et al., Shenyang, China, contribute to the same Research Topic with a paper on “Risk Factors for Contralateral Occult Carcinoma in Patients with Unilateral Papillary Thyroid Carcinoma: A Retrospective Study and Meta-Analysis”. The meta-analysis in 4,347 patients includes 26% occult contralateral cancers. Significant risk factors are “tumour size > 1cm” with an odds ratio (OR) of 2.16, “central neck lymph node metastases” OR 2.80 and “multifocality ipsilateral” OR 5.62. Sex, age, ETE, capsular invasion, Hashimoto´s disease and lateral lymph node metastases are not described as risk factors for contralateral occult carcinoma.Today’s guidelines for treatment of early-stage DTC , 10 stro“Predictive factors of lymph node metastasis in patients with papillary microcarcinoma of the thyroid: a retrospective analysis on 293 cases” is the title of a paper by Medas et al. from Cagliari, Italy. An incidence of 13.7% of LNM (in any location) is described in their single hospital study in 293 PTC patients. Independent risk factors are: “age < 45”, “tumour size > 6 mm”, “tall cell variant”, “extrathyroidal extension (ETE)” and “angioinvasion”. The authors conclude that “size of the tumour being the most significant predictive factor” and that “smaller size of the tumour should be considered for active surveillance strategies”.Chen et al. from Changsha, China, describe “Sonographic characteristics of papillary thyroid carcinoma with coexistent Hashimoto’s thyroiditis in the preoperative prediction of central lymph node metastasis”. They report a single hospital study of 177 patients with histologically verified PTC and Hashimoto Thyroiditis using colour-doppler (CDUS) and contrast enhanced ultrasound (CEUS). Risk factors for central lymph node metastases (CLNM) by univariate statistics are “age < 45” (P=0.03), “tumour size >10mm” (P<0.0001), “shape wider than tall” (P=0.0019), “CEUS hypoenhancement” (P=0.012), “CDUS peak intensity < 1” (P=0.11). Using multivariate logistic regression, the most significant risk factors for CLNM are “tumour size > 10mm”  and “CEUS hypoenhancement” .Two papers focus on preoperative prediction of central lymph node metastases. Xue et al. from Changchun, China, include strap muscle infiltration (SMI) as risk factor, studying “Predictive Factors of Central-Compartment Lymph Node Metastasis for Clinical N0 Papillary Thyroid Carcinoma with Strap Muscle Invasion”. Their single hospital study comprises the considerable number of 9,866 PTC patients recruited between 2009 and 2017, among them 281 with SMI and 50.7% with CLNM. Risk factors for CLNM in patients with SMI turn out to be “male gender” with an OR of 6.22  and “age < 40” OR=9.94 .Du et al. from Zhengzhou, China, investigate risk factors for such LNM in patients who presented clinically without central LNM. Their single hospital study comprises 357 patients who underwent bilateral central lymph node dissection. LNM posterior to the right RLN are described in 23 cases (6.7%) and only, when other LNM were prevalent . Other significant independent factors were “tumour size > 5mm” (OR=2.8), “multifocality” (OR=2.2), and extrathyroidal extension (ETE) (OR=5.8). Zheng et al., Yantai, China focus on the “Clinical relevance and management of recurrent laryngeal nerve inlet zone lymph nodes metastasis in papillary thyroid cancer”, defining the zone of 10 mm around the inlet of the RLN as “inlet zone”. In their single hospital study of 947 patients with PTC, 150 received lymph node dissection, among them 47 (31%) present with such RLN inlet zone LNM. Additional ipsilateral LNM turn out to be highly predictive for RLN inlet zone LNM (OR 7.1). The authors conclude that “Once central or lateral LNM are confirmed preoperatively, RLN inlet zone dissection should be carefully performed to reduce the rate of structural recurrence in the central compartment”.LNM of PTC anatomically close to the right recurrent laryngeal nerve (RLN) represent a special challenge for the surgeon. In their paper “Metastasis of cN0 Papillary Thyroid Carcinoma of the Isthmus to the Lymph Node Posterior to the Right Recurrent laryngeal Nerve”, A more advanced approach for lymph node staging is to combine clinical and sonographic parameters in a model with a whole set of findings. This can be done using relatively simple nomograms or better applying recent advances of artificial intelligence and machine learning. The first two among three papers on nomograms for PTC consider all stages of primaries but focus on central LNM, whereas the last one focuses on microPTC considering all possible locations of LNM.Li et al. from Tianjin, China, describe a “Diagnostic model incorporating clinicopathological characteristics of Delphian lymph node metastasis risk profiles in papillary thyroid cancer” The Delphian lymph node is located pretracheally and considered an effective indicator of aggressive disease and recurrence. In their single hospital study with 936 PTC patients, 177 presented with LNM to the prelaryngeal nodes (18.9%). Risk factors by multivariate statistics are “male gender” , “younger age , “larger tumour size” , “ETE” , “lymphovascular invasion” , “central LNM” . The proposed nomogram to predict LNM to the Delphian node is considered to be a clinically sensitive predictor of further LN in the central compartment” .Feng et al., Changzhou, China, present “A Nomogram Based on Clinical and Ultrasound Characteristics to Predict Central Lymph Node Metastasis of Papillary Thyroid Carcinoma”. This has been developed in single hospital study with 886 PTC patients with LNM in 50% of the cases. It has to be emphasized that two different subsets of the cohort were used for training (n=617) and validation (n=269). Clinical and US variables are tested as potential predictors for central LNMs: “male sex” , chronic lymphocytic thyroiditis ,”tumour size > 1cm” , “tumour size > 2cm” , “irregular margin” , “tumour location middle/lower quadrant” . ROC analysis results in AUCs for training of 0.81 and for validation of 0.80 respectively.Sun et al., Wuxi, China, “Nomogram for preoperative estimation of cervical lymph node metastasis risk in papillary thyroid microcarcinoma” focuses on micro-PTC, but not on central LNM only, as the previous papers. The single hospital study comprises 552 patients, among them 61% with LNM. Seven variables of clinical and US features are identified as potential predictors including “male sex” , “age < 45 years” , “US-reported central LN status” , “multifocality of the tumour “ , “tumour size ≥ 0.6cm” , “ETE”  and “microcalcification by US” . In this study ROC analysis results in an AUC of 0.84.The third paper on nomograms by Wu et al. from Beijing, China, on “Machine learning algorithms for the prediction of central lymph node metastasis in patients with papillary thyroid cancer” takes another approach. The single hospital study in 1,103 PTC patients aims at predicting central LNM comparing seven different machine learning approaches and a set of 22 variables . For prediction of central LNM, a seven parameter machine learning gradient boosting decision tree, works best by including male sex, young age, low TPO-AB, US suspected LNM, microcalcifications, tumour size > 1.1 cm and TSH. The AUC is 0.73 in the training dataset, but no validation in a separate dataset has been performed up to now. Such approaches will gain rapidly increasing clinical relevance, provided that the data sets used are well defined, much larger and separate as well as independent sets are used for training and validation. Only cooperative networks of clinicians and computer scientists can meet these challenges.According to a recent review, artificial intelligence and machine learning are very promising methods to improve the diagnostic sensitivity and specificity of ultrasound thyroid imaging . Up to nBoth authors contributed equally. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Catechins are crucial in determining the flavour and health benefits of tea, but it remains unclear that how the light intensity regulates catechins biosynthesis. Therefore, we cultivated tea plants in a phytotron to elucidate the response mechanism of catechins biosynthesis to light intensity changes.− 2·s− 1 treatment, the contents of epigallocatechin, epigallocatechin gallate and total catechins were increased by 98.94, 14.5 and 13.0% respectively, compared with those in the 550 μmol·m− 2·s− 1 treatment. Meanwhile, the photosynthetic capacity was enhanced in the 250 μmol·m− 2·s− 1 treatment, including the electron transport rate, net photosynthetic rate, transpiration rate and expression of related genes . In contrast, the extremely low or high light intensity decreased the catechins accumulation and photosynthetic capacity of the tea plants.In the 250 μmol·mCsaroB, CsaroDE1, CsaroDE2 and CsaroDE3) co-regulated the response of GA accumulation to light intensity. Eventually, the epigallocatechin gallate content was enhanced by the increased contents of its precursors (EGC and GA) and the upregulation of the CsSCPL gene.The comprehensive analysis revealed that the response of catechins biosynthesis to the light intensity was mediated by the photosynthetic capacity of the tea plants. Appropriately high light upregulated the expression of genes related to photosynthetic capacity to improve the net photosynthetic rate (Pn), transpiration rate (Tr), and electron transfer rate (ETR), which enhanced the contents of substrates for non-esterified catechins biosynthesis (such as EGC). Meanwhile, these photosynthetic capacity-related genes and gallic acid (GA) biosynthesis-related genes (− 2·s− 1 and 350 μmol·m− 2·s− 1) but decreased under extremely low or high light intensities (150 μmol·m− 2·s− 1 or 550 μmol·m− 2·s− 1). We found that the control of catechin accumulation by light intensity in tea plants is mediated by the plant photosynthetic capacity. The research provided useful information for improving catechins content and its light-intensity regulation mechanism in tea plant.In this study, the catechin content and photosynthetic capacity of tea plants increased under appropriately high light intensities (250 μmol·mThe online version contains supplementary material available at 10.1186/s12870-021-03260-7. Catechins, which are the major secondary metabolites in tea, promote the sensory qualities and health benefits of tea, including cancer prevention and antioxidant activity –3, neuroLight is the core environmental factor affecting the growth and quality of tea , 15, As F3H, F3’H and DFR in tea plants [CHS, DFR1, DER2, ANS and ANR1 [ANR, ANS, LAR, C4H, PAL, CHI, CHS and DFR) were related to high light intensity in summer [ANS plays a critical role in catechin biosynthesis in tea plants [ANS1 expression in safflower flowers, whereas high light upregulated ANS expression in red leaf lettuce [CsANS expression to light is also inconsisitent [The genes involved in catechins biosynthesis are related to the phenylalanine pathway, flavonoid pathway and shikimic acid pathway , 42. Liga plants , while land ANR1 . Meanwhin summer . Howevera plants : low lig lettuce , 47. Thesisitent , 43. We − 2·s− 1) to explore: 1) the effect of light intensity to catechins content; 2) the response of catechins biosynthesis to light intensity; and 3) the relationship between catechins content and photosynthesis.Catechins content is also affected by other environmental factors in the field, and there remains relatively few studies regarding the response mechanisms of catechins biosynthesis in tea plants to light intensity. Our research used the same of environmental conditions between for five light treatments  O. Kuntze), which were one-year-old cuttings of the Huangdan cultivar, were purchased from the Qianhe Tea Cooperative, Anxi County, China. The seedlings were transplanted into breeding bags (diameter = 16 cm and height = 18 cm), and cultivated in the nursery of Sino-Science Photobiotech Co. from March to August 2019. The composition of the culture medium was coconut bran, peat soil, vermiculite and perlite, and the volume ratio was 2:2:1:1. The composition of the culture medium was optimised by the Sino-Science Photobiotech Co. to provide a good growth environment for the roots of tea plants. In September, we transported the seedlings indoors to adapt to the environment of the plant growth facility, and the culture conditions are described in the Supplementary Table Tea seedlings  were ground in a centrifuge tube, and then 25 ml 95% ethanol was added. The mixtures were placed in the dark for 24 h and shaken every 5-6 h. The supernatant was extracted and analysed with a spectrophotometer , and the absorbance at the following wavelengths was recorded: 665 nm, 649 nm and 470 nm.Chlorophyll fluorescence was measured with an Imaging-PAM . Tea plants were dark-adapted for 30 min before the measurement, and the third mature leaf from the top was used for the measurements. The minimum fluorescence (Fo) and maximum fluorescence (Fm) were obtained by applying measuring light pulses at a low frequency. The yield of variable fluorescence (Fv) was calculated as Fm − Fo, from which the maximum PSII quantum yield (Fv/Fm) was automatically calculated by the ImagingWin software . Other parameters  were also automatically calculated by the ImagingWin software .The photosynthesis characteristics including net photosynthetic rate (Pn), transpiration rate (Tr), stomatal conductance (Gs), and intercellular CO2 concentration (Ci), were measured using a Li-6800 portable photosynthesis system . All measurements were conducted from 10:00 to 12:00 am. The irradiance and temperature of the leaf chamber were set according to the conditions in each treatment, and the results were recorded when Pn reached a steady state.The catechins content determination was performed according to the method described by Lin et al. (2017) . CatechiMobile phase A:100% pure water + 0.02% EDTA-2Na + 2% glacial acetic acid; Mobile phase B: 100% acetonitrile + 2% glacial acetic acid. PDA detection conditions: scanning range of 200 nm-400 nm, characteristic detection wavelength of 278 nm, scanning time of 10 min, injection volume of 2 ul. Standard stock solution is listed as follows: caffeine stock solution 2.00 mg/ml, gallic acid (GA) stock solution 0.100 mg/ml, catechin stock solution: C 1.00 mg/ml, EC 1.00 mg/ml, EGC 2.00 mg/ml, EGCG 2.00 mg/ml, ECG 2.00 mg/ml. All samples were analysed with three biological replicates, and the average values were used for data analysis.β-Actin was used as an endogenous control in this assay. The expression levels of related genes were calculated using the 2−ΔΔCt method.Total RNA was isolated using the RNAprep Pure Plant Kit  according to the operating instructions. First-strand cDNAs were synthesized using FastKing gDNA Dispelling RT SuperMix . The qRT-PCR analyses were carried out on an ABI 7500 HT Real-time PCR system . The PCR reaction conditions were as follows: incubation at 95 °C for 15 min, 40 cycles at 95 °C for 10s, and annealing at 61 °C for 32 s, in triplicate for each reaction. All primers used for qRT-PCR are listed in Supplementary Table One-way analysis of variance was used to determine significance, and Duncan’s multiple range test was used to evaluate differences between groups with SPSS 21.0 statistical software. This software was also be used for the correlation analysis and regression analysis between the content of catechins and other variables. The data are presented as the means ± standard deviations from three biological replicates, and the different letters represent significant differences between groups .Principal component analysis (PCA) of nine morphological traits was performed using the SIMCA 13.0 software with the nine variables as the primary ID and the treatments as the second ID. The figure legend indicates the representation of the three biological replicates.Partial least square (PLS) analysis was performed using the Minitab 16 software, and the confidence level was set to 95%. The r-squared value represents the degree of fitting between the measured ranking and predicted ranking in PLS.− 2·s− 1) were significantly higher than those under extremely high and low light intensities (550 μmol·m− 2·s− 1 and 150 μmol·m− 2·s− 1), which suggested that an appropriately high light intensity promoted catechins accumulation.When tea plants were grown in the same environment at different light intensities, the contents of EGCG, gallic acid (GA) and total catechins (TC) under an appropriately high light intensity , total non-esterified catechins (TNEC), EGC and C were 16.16, 74.73, 98.94 and 19.50% higher than those in 550 μmol·m− 2·s− 1 treatment, respectively , were the highest in the 250 μmol·mCsPAL, CsC4H, Cs4CL1, Cs4CL2, CsF3’H, CsLAR1, CsLAR2, CsDFR1, CsANR2, CsSCPL, CsaroB, CsaroDE1, CsaroDE2 and CsaroDE3) was the highest in the 250 μmol·m− 2·s− 1 treatment but was suppressed in the extremely high and low light intensity (550 μmol·m− 2·s− 1 and 150 μmol·m− 2·s− 1). Notably, the response patterns of 8 catechins-related genes to the light intensity changes were similar to those of the content of EGCG, TEC and TC  resulted in the highest photosynthetic rate (Pn), transpiration rate (Tr) and electron transport rate (ETR), which were 130.49, 53.88 and 8.10% higher than those at 550 μmol·m− 2·s− 1, respectively . The scattered tea samples grown under the different light intensities in the PCA score plot and the score of comprehensive evaluation (F) in the model demonstrated the diverse photosynthesis capacities of the different treatments  upregulated the expression of 9 photosynthesis-related genes  were significantly and positively related to the photosynthetic pigment content , but the contents of EGCG, TEC and TC were significantly and positively related to chlorophyll fluorescence  and photosynthetic capacity Fig. A. MeanwhCspsbE, CspsbC, CspsbD, CsCHLG, bchG) were similar to those of 3 catechins-related genes .The response of catechins-related genes to light intensity was regulated by gene expression related to photosynthetic capacity. The expression of 34 photosynthesis- and catechin-related genes was the highest under the 250 or 350 treatment, and the expression patterns under different treatments of 4 photosynthesis-related genes  were positively related to PSII-related genes  and ETR-related genes (CsPETD), clustering in one group  and in the shikimic acid pathway  were positively correlated with those of chlorophyll-related genes . In contrast, the expression levels of CsRCA and Csrbcl were negatively related to CsF35H and CsANR1, respectively.The expression levels of catechins-related genes involved in the phenylalanine pathway , the downstream of flavonoid pathway  and the shikimic acid pathway .Gene expression was related to catechins biosynthesis, which was regulated by photosynthesis-related genes and thereby controls catechins accumulation Fig. C. For exPhotosynthate is the substrate for catechins synthesis. On the one hand, the expression of photosynthesis-related genes affected the photosynthesis capacity of tea plants, including Pn, Tr, and ETR, and thereby regulated the content of substrate for catechins biosynthesis. On the other hand, genes related to photosynthetic capacity regulated the expression of catechins-related genes by the promoter of structural genes and transcription factors and thereby affected the catechins content of tea plants Fig. .Fig. 7ThCspsbA, CspsbB, CspsbC, CspsbD, CsPsbR), photosynthetic pigments , electron transfer rate (CsPETD), and Rubisco activity (CsRCA), which enhanced the photosynthetic capacity of tea plants, including the net photosynthetic rate (Pn), transpiration rate (Tr), and electron transfer rate (ETR). On the other hand, the genes related to PSII and photosynthetic pigments regulated the the expression of genes related to non-esterified catechins biosynthesis . These results suggested that the substrate content (such as PEP) and the expression of genes related non-esterified catechins biosynthesis, which were regulated by the genes related to photosynthesis capacity, co-affected the content of non-esterified catechins (such as EGC). Meanwhile, these photosynthesis-related genes also regulated the expression of gallic acid (GA) biosynthesis genes in the shikimic acid pathway  to affect the GA content. Eventually, the increased contents of the precursor of esterified catechins (EGC and GA) and the upregulation of CsSCPL were mediated by the photosynthetic capacity and the related genes in the tea plant, which promoted the accumulation of esterified catechins (such as EGCG).The appropriately high light intensity upregulated the expression of genes related to PSII  is essential for catechins biosynthesis. In the previous research, the flavonoids pathway was closely related to photosynthesis and chlorophyll content , 54, andWe also found that the catechins content was related to Fm, ETR, FM’ and v’/FM’, and gene expression was related to photosynthetic capacity. A previous study has indicated that the differentially expressed genes between the normal plant and pale green mutant were mainly involved in photosynthesis and flavonoids pathway. Other environmental factors regulating the secondary metabolism of tea plants were dynamic under field conditions, and we confirmed the precise responses of catechins to light intensity and its underlying mechanism using phytotron. In summary, our results indicated that photosynthetic capacity controls catechins biosynthesis by regulating the substrate content and the expression of catechins-related genes when tea plants are grown under different light intensities.Interestingly, consistent with the responses of catechins and photosynthetic capacity to light intensity changes, the young shoots grew slowly under excessively low or high light but grew more quickly under appropriately high light. We speculated that the regulation of catechins by light intensity was affected by shoot growth. We previously observed that catechins biosynthesis responded to temperature changes through shoot growth . The higThe catechins content and photosynthetic capacity of tea plants increased under appropriately high light intensity but decreased under the the extremely low or high light intensity. Photosynthesis- and catechins-related genes exhibited the same response pattern under the different light intensities. Based on PCA, correlation analysis and regression analysis, we found that catechins accumulation was affected by photosynthesis, and catechins-related genes were regulated by photosynthesis-related genes. In summary, the control of catechin accumulation by light in tea plants is mediated by the plant photosynthetic capacity. The research provided useful information for improving catechins content and its light-intensity regulation mechanism in tea plant.Additional file 1: Supplemental Table 1. Culture conditions of tea plants.Additional file 2: Supplemental Table 2. Primer sequences used for reverse transcription-quantitative PCR.Additional file 3: Supplementary Table 3. The cubic function equations in curve-fitting analysis.Additional file 4: Supplemental Figure 1. The PLS analysis between catechins content and the indexes of photosynthesis capacity of tea plants under different light intensity.Additional file 5: Supplemental Figure 2. The expression of related genes under the different light intensity and their clustering.Additional file 6: Supplemental data 1. The corresponding indexes of the numbers in the correlation analysis.