Biomedical subjects

Ping Yuan

Publications and source records attributed to Ping Yuan.

At least 19 recordsLinked to original sources

PubMed2026

Maternal genetic variants associated with aneuploid conception: a narrative review.

BACKGROUND: Human aneuploid conception, a leading cause of infertility, pregnancy loss, and congenital disorders (e.g. Down's syndrome), arises from errors in chromosome segregation during oocyte meiosis or embryonic mitosis. While advanced maternal age is a well-established risk factor, significant inter-individual variation exists among younger women, suggesting a substantial role for maternal genetic determinants. OBJECTIVE AND RATIONALE: This review summarizes the identified maternal genetic variants associated with aneuploid conceptions and highlights directions for future research. SEARCH METHODS: We systematically searched PubMed, Embase, and the Cochrane Library (up to 12 January 2026), using key terms related to maternal genetics, genetic variants, aneuploidy, and pregnancy. Inclusion criteria were human studies, genetic confirmation of aneuploidy (in oocytes/embryos/products of conception/fetal cells), maternal variants (rare single-nucleotide variations, single-nucleotide polymorphisms, and small indels [≤50 bp]), and English-language publications. Exclusion criteria were non-human studies, structural/non-aneuploid numerical abnormalities, paternal factors, and conference abstracts. Extracted data items included study identifiers, population characteristics, variant details, detection methods, clinical phenotypes, type and origin of aneuploidy, pathogenicity or effect assessment, and gene inclusion in currently commercially available infertility next-generation sequencing (NGS) panels. Rare variants were classified per American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines, whereas common variants were evaluated based on effect estimates and functional validation. Study quality was appraised using a modified Newcastle-Ottawa Scale. Supplementary searches explored associations between the identified genes and a broader range of reproductive phenotypes. OUTCOMES: From 28 studies covering the broad clinical spectrum of aneuploid pregnancies (including embryo arrest, implantation failure, pregnancy loss, hydatidiform mole, and fetal aneuploidy), we identified maternal variants associated with aneuploid conceptions. These were functionally categorized into meiotic recombination, spindle dynamics, checkpoint enforcement, and the maternal-to-zygotic transition. Among them, variants in several genes are supported by higher-quality evidence, including likely pathogenic rare variants in KIF18A, ELL3, and CEP120, as well as common variants in PLK4 and CCDC66. Although some identified genes (HFM1, MCM9, MEI1, BUB1B, NLRP2, NLRP7, and TLE6) are included in commercial infertility NGS panels, their direct association with aneuploidy requires further validation. WIDER IMPLICATIONS: This review proposes that 'aneuploidy predisposition' constitutes a critical, mechanism-driven dimension for the genetic diagnosis of infertility, complementing phenotype-based frameworks. This approach would best serve women with unexplained infertility and a normal karyotype who have either a history of recurrent aneuploidy or heterogeneous reproductive phenotypes across different cycles. Adopting this perspective refines clinical genetic testing paradigms and underscores the need to prioritize artificial intelligence-enhanced clinico-genomic association studies and develop polygenic risk models integrated with clinical factors. PROSPERO REGISTRATION NUMBER: CRD42025636217.

Humans↗

PubMed2006

Analytical analysis of the Pennes bioheat transfer equation with sinusoidal heat flux condition on skin surface.

This study focuses on the effect of the temperature response of a semi-infinite biological tissue due to a sinusoidal heat flux at the skin. The Pennes bioheat transfer equation such as rho(t)c(t)( partial differentialT/ partial differentialt)+W(b)c(b)(T-T(a))=k partial differential(2)T/ partial differentialx(2) with the oscillatory heat flux boundary condition such as q(0,t)=q(0)e(iomegat) was investigated. By using the Laplace transform, the analytical solution of the Pennes bioheat transfer equation with surface sinusoidal heating condition is found. This analytical expression is suitable for describing the transient temperature response of tissue for the whole time domain from the starting periodic oscillation to the final steady periodic oscillation. The results show that the temperature oscillation due to the sinusoidal heating on the skin surface is unstable in the initial period. Further, it is unavailable to predict the blood perfusion rate via the phase shifting between the surface heat flux and the surface temperature. Moreover, the lower frequency of sinusoidal heat flux on the skin surface induces a more sensitive phase shift response to the blood perfusion rate change, but extends the beginning time of sampling because of the avoidance of the unavailable first cyclic oscillation.

Blood Flow Velocity↗

PubMed2006

Overexpression of podoplanin in oral cancer and its association with poor clinical outcome.

BACKGROUND: Podoplanin is a mucin-like glycoprotein that is important in lymphangiogenesis but not blood vessel formation. Recent studies suggested a potential role of podoplanin in certain tumor cells. The purpose of the current study was to determine the role of podoplanin in head and neck squamous cell carcinoma (HNSCC). METHODS: Podoplanin expression was analyzed in 35 patients with HNSCC including 16 oral tumors and 19 hypopharyngeal tumors by immunohistochemical analysis and the association between the podoplanin expression status and patients' clinical and pathologic characteristics was evaluated. An independent set of 60 patients with oral tongue cancer was then analyzed for associations between the podoplanin expression status and patients' clinical and pathologic characteristics, including survivals. RESULTS: Podoplanin was not expressed in normal oral epithelial cells but was detected in some hyperplastic and dysplastic lesions. High podoplanin expression was found in 20 (57%) of the 35 tumors and was more frequent in tumors with lymph node metastasis, particularly for tumors in the oral cavity. In the second set of 60 oral tongue cancers, 36 (60%) expressed high levels of podoplanin. Patients whose tumors expressed high levels of podoplanin had a statistically significantly higher rate of lymph node metastasis (P < .0001). Patients with lymph node metastasis and high-level podoplanin showed the shortest disease-specific survival (P = .0004) than other patients. CONCLUSIONS: Podoplanin is involved in oral tumorigenesis and may serve as a predictor for lymph node metastasis and poor clinical outcome.

Biomarkers, Tumor↗

PubMed2006

Down-regulation of hepatoma-derived growth factor inhibits anchorage-independent growth and invasion of non-small cell lung cancer cells.

We recently reported that a high level of hepatoma-derived growth factor (HDGF) expression in tumors correlates with a high incidence of tumor relapse or distant metastasis and shortened survival time in patients with non-small cell lung cancer (NSCLC). However, the mechanisms of the HDGF-associated aggressive biological behavior are unknown. In this study, we knocked down HDGF expression in NSCLC cells to determine the biological consequences. Transfection with HDGF-specific small interfering RNA (siRNA) resulted in down-regulation of HDGF expression in four NSCLC cell lines. Down-regulation of HDGF resulted in no detectable effect on anchorage-dependent cell growth as determined with a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, a microelectronic cell sensor system, and flow cytometry. In contrast, cells transfected with HDGF-siRNA grew more slowly and formed significantly fewer colonies in soft agar than did cells treated with LipofectAMINE alone or transfected with negative control siRNA. In an in vitro invasion assay, significantly fewer cells transfected with HDGF-siRNA than cells treated with LipofectAMINE alone were able to invade across a Matrigel membrane barrier. In an in vivo mouse model, A549 cells treated with HDGF-siRNA grown significantly slower than the cells treated with LipofectAMINE alone or negative control siRNA. Morphologically, HDGF-siRNA-treated tumors exhibited markedly reduced blood vessel formation and increased necrosis, whereas the Ki67 labeling indices were similar in tumors treated with controls. Our results suggest that HDGF is involved in anchorage-independent growth, cell invasion, and formation of neovasculature of NSCLC. These qualities may contribute to the HDGF-associated aggressive biological behavior of NSCLC.

Animals↗

PubMed2006

Targeting signal transducer and activator of transcription 3 with G-quartet oligonucleotides: a potential novel therapy for head and neck cancer.

Signal transducer and activator of transcription 3 (Stat3) is a critical mediator of oncogenic signaling activated frequently in many types of human cancer where it contributes to tumor cell growth and resistance to apoptosis. Stat3 has been proposed as a promising target for anticancer drug discovery. Recently, we developed a series of G-quartet oligodeoxynucleotides (GQ-ODN) as novel and potent Stat3 inhibitors, which significantly suppressed the growth of prostate and breast tumors in nude mice. In the present study, we showed that GQ-ODN specifically inhibited DNA-binding activity of Stat3 as opposed to Stat1. Computer-based docking analysis revealed that GQ-ODN predominantly interacts with the SH2 domains of Stat3 homodimers to destabilize dimer formation and disrupt DNA-binding activity. We employed five regimens in the treatment of nude mice with tumors of head and neck squamous cell carcinoma (HNSCC): placebo, paclitaxel, GQ-ODN T40214, GQ-ODN T40231, and T40214 plus paclitaxel. The mean size of HNSCC tumors over 21 days only increased by 1.7-fold in T40214-treated mice and actually decreased by 35% in T40214 plus paclitaxel-treated mice whereas the mean size of HNSCC tumors increased 9.4-fold in placebo-treated mice in the same period. These findings show that GQ-ODN has potent activity against HNSCC tumor xenografts alone and in combination with paclitaxel.

Animals↗

PubMed2006

[A potential use of collagen-hyaluronan-chondroitin sulfate tri-copolymer scaffold for cartilage tissue engineering].

OBJECTIVE: To evaluate collagen(Col)-hyaluronan (HA)-chondroitin sulfate (CS) tri-copolymer as a new biomimetic biodegradable polymer scaffold for application of the articular cartilage tissue engineering. METHODS: The Col-HA-CS tri-copolymer was prepared by freezing and lyophilization and was cross-linked by 1-ethyl-3-(3-dimethy inaminoproyl) carbodiimide (EDC). The morphological characteristics of the matrices were evaluated by the SME and HE stainings. The rabbit chondrocytes were isolated and seeded in the tri-copolymer scaffold. Morphology, proliferation and differentiation of glycosaminoglycan (GAG), and phenotypic expression of the rabbit articular chondrocytes cultured within the tri-copolymer scaffold were indicated by the histological examination, SEM, biochemical analysis, and reverse transcriptase PCR for collagen type II (Col II). RESULTS: The chondrocytes proliferated and differentiated well, and they preserved the phenotypic expression of Col II in the Col-HA-CS scaffold. After the 21-day cell culture within the Col-HA-CS scaffolds, the cartilage-specific morphology and the structural characteristics such as lacunae appeared, and DNA and GAG contents increased with the time. In addition, DNA and GAG contents were significantly higher in the Col-HA-CS matrix than in the collagen matrix alone (P < 0.05). CONCLUSION: These results show that the Col-HA-CS tri-copolymer matrices can provide an appropriate environment for the generation of cartilage-like tissues and have a potential application in the cartilage tissue engineering scaffold field.

Animals↗

PubMed2006

[The spectral properties of an intense lightning return stroke].

The spectrum in the range of 400-600 nm from the first return stroke of an intense cloud-to-ground lightning flash was obtained by a slit-free spectrograph. Applying the atomic structure theory to the research work on lightning spectra, the wavelengths, oscillator strengths and excitation energies of upper levels were calculated for the transitions of related lightning spectrum. Multi-configuration Dirac-Fock method was employed in the calculation. From the results, re-identifications were carried out for the lines of 419.0 and 425.3 nm. It was found by spectral analysis combined with corresponding electrical information finds that the spectrum characteristic is closely related to the intensity of lightning discharge, as during an intense lightning return stroke the lines of O II with high excitation energies are enhanced.

English Abstract↗

PubMed2005

Expression of cyclooxygenase-2 mRNA and identification of its splice variant in human myometrium obtained from women in labor.

In order to investigate the expression of cyclooxygenase-2 (COX-2) in human lower segments of myometrium obtained from women in labor and those not in labor and identify the splicing variant of COX-2, reverse transcriptase-polymerase chain reaction (RT-PCR) was used to detect the expression of COX-2. The primers were designed and synthesized according to the sequence of rat COX-2 splice variant which was discovered firstly by us. Then the splicing variant of COX-2 in human myometrium from woman in labor was identified, cloned into vector and sequenced. The results showed that the expression of COX-2 mRNA was lower in human myometrium obtained from women who were not in labor than that in labor women and a new band of COX-2 was obtained in myometrium from labor woman. The fragment included an unspliced intron, which pitched between exons 7 and 8. It was suggested that COX-2 gene was not only expressed highly in human myometrium from woman in labor, but also produced splicing variant by alternative splicing.

Adult↗

PubMed2005

A study on methods of estimating the population size of men who have sex with men in Southwest China.

OBJECTIVE: To ascertain practical methods of estimating the population size of men who have sex with men (MSM) by field application. METHODS: Nine public places were selected, where men who have sex with men (MSM) frequented. Capture-recapture method and multiplier method were used to count the number of men who have sex with men (MSM) in the assigned places in 10 days. RESULTS: The population size estimated using multiplier method counted 877. Three estimates produced by capture-recapture method were 1408 (95% CI: 1116-1908), 1207 (95% CI: 932-1712) and 949 (95% CI: 757-1272), respectively. CONCLUSIONS: Multiplier method was easy and smooth in practice and produced highly reliable results, which yet was expensive. The application of capture-recapture method cost less in both time and funds, and the three results produced could verify each other, which was fit for the estimation.

China↗

PubMed2005

Functional expression of the gene encoding cytidine triphosphate synthetase from Plasmodium falciparum which contains two novel sequences that are potential antimalarial targets.

CTP synthetase (E C 6.3.4.2 UTP: ammonia ligase (ADP-forming)) catalyses the formation of CTP from UTP and, in the human parasite Plasmodium falciparum, is the sole source of cytidine nucleotides. It is thus a potential chemotherapeutic target, especially as the gene sequence indicated that the encoded GAT-domain of the enzyme contains two extended peptide segments (42aa and 223aa as compared to the host enzyme). Here, we circumvent the codon usage problems associated with the high A/T content of the P. falciparum sequence, especially evident in sequences encoding the extra peptides, to successfully express active recombinant P. falciparum CTP synthetase using preferred E. coli codons. This partially synthetic gene produced recombinant enzyme, containing the additional segments, which was functionally assayed for activity in vitro. We also show the native enzyme contains the additional peptides using immunoblots with antibodies derived from the recombinant protein. Confocal microscopy, using antibodies to the recombinant protein, provided evidence that the enzyme is expressed in vivo. This establishes for the first time that P. falciparum contain active CTP synthetase and that this enzyme contains two novel insert sequences in the functional enzyme.

Animals↗

PubMed2005

Structural studies of the parainfluenza virus 5 hemagglutinin-neuraminidase tetramer in complex with its receptor, sialyllactose.

The paramyxovirus hemagglutinin-neuraminidase (HN) functions in virus attachment to cells, cleavage of sialic acid from oligosaccharides, and stimulating membrane fusion during virus entry into cells. The structural basis for these diverse functions remains to be fully understood. We report the crystal structures of the parainfluenza virus 5 (SV5) HN and its complexes with sialic acid, the inhibitor DANA, and the receptor sialyllactose. SV5 HN shares common structural features with HN of Newcastle disease virus (NDV) and human parainfluenza 3 (HPIV3), but unlike the previously determined HN structures, the SV5 HN forms a tetramer in solution, which is thought to be the physiological oligomer. The sialyllactose complex reveals intact receptor within the active site, but no major conformational changes in the protein. The SV5 HN structures do not support previously proposed models for HN action in membrane fusion and suggest alternative mechanisms by which HN may promote virus entry into cells.

Amino Acid Sequence↗

PubMed2005

[Vascular reconstruction of infected pseudoaneurysm in 17 drug addicts].

OBJECTIVE: To evaluate surgical treatment of infected pseudoaneurysm (PA) caused by injection of addictive drugs. METHODS: The clinical data of 17 cases of infected PA caused by drug injection were reviewed retrospectively. Of them, 1 case was female, and the other 16 cases were male, aging 24-38 years. The locations were brachial artery in 1 case and femoral artery in 16 cases. Fourteen cases were treated by artificial blood vessel transplantation after resection of the aneurysm and radical debridement, 1 case by amputation for serious infection, and 2 cases by non-operation for different reasons. RESULTS: Among 14 cases treated by prosthetic grafts, 13 cases achieved satisfactory results, no blood drawback of lower extremity occurred after operation; 1 case had to be amputated for serious infection. After 3 months of operation, the color Doppler examination showed that the 9 artificial vessel grafts were patent and the pulse of arteria dorsal pedis was good. CONCLUSION: Though artificial vessel grafting has high risk in the vicinity of infected PA, it is still an effective procedure for revascularization in condition that there is no suitable autogenous conduit available for auto transplantation. Sufficient drainage, anti-infection and anti-coagulation therapy should be the key factors after the operation.

Adult↗

PubMed2005

[Analysis of hepatitis virus infection in hepatocellular carcinoma patients receiving surgical operation in China and Japan].

OBJECTIVE: To describe and compare the hepatitis virus infection in hepatocellular carcinoma (HCC) patients receiving surgical operation in China and Japan. METHODS: Information of surgical HCC patients was retrieved from the medical records. The concerned characteristics of the HCC cases from two countries were described and compared. RESULTS: A total of 425 diagnosed cases that underwent surgical resection for HCC in China were investigated, and the corresponding cases in Japan were 247. The proportion of the hepatitis virus infection was 75.53% in patients with HCC from China. Within the infection cases, 91.28% were positive for HBsAg but negative for anti-HCV. The proportion was 82.59% in patients with HCC from Japan. Within the infection cases, 77.94% were positive for anti-HCV but negative for HBsAg. The proportion of hepatocirrhosis in the hepatitis virus infection patients with HCC were 89.10% and 68.14% in China and Japan, respectively. CONCLUSION: The hepatitis B virus infection showed be a main cause of HCC in China, however, the HCC in Japan be mostly related to hepatitis C virus infection.

Adolescent↗

PubMed2005

[Time-series analysis on road traffic injury in China].

OBJECTIVE: To establish the predictive models of road traffic injury(RTI) in China, to know the trend of RTI, and to provide the reference data for controlling RTI in China. METHODS: The China RTI data from 1951 to 2003 were collected, and in view of the problem of missing values, the method of intrapolation was adopted. The Box-Jenkins technique was used to analyze and predict the trend of RTI in China. Following the process for stationary time-series analysis, model identification, parameter estimation and model diagnosis, the predictive equation for RTI would be established. RESULTS: A series of predictive equations on RTI were finally established based on ARIMA models. The curve fitting is effective and the predictive data of RTI in 2003 are close to the true statistical data. CONCLUSION: The time-series model thus established proves to be of significant usefulness in RTI prediction.

Accidents, Traffic↗

PubMed2005

[A case-crossover study on road traffic injury].

OBJECTIVE: To explore the risk factors of road traffic injury (RTI), and to provide evidence for stretagy development on the prevention and control of RTI. METHODS: Case-crossover study was used. 402 drivers were face to face interviewed by specially designed questionnaire including the items as drinking alcohol before driving, onset anger scale (OAS), anxiety/irritation, Stanford sleepiness scale (SSS), vehicle breakdown, carelessness, violating the rules on right of way and traffic signs when driving. Tables related to case-control study on 1:1 matching was used for single factor analysis, and conditional logistic regression was used for multifactor analysis. RESULTS: The risk factors that were associated with RTI including high OAS (OAS = 5-7, OR = 114.88, 95% CI:4.29-3074.86), violating the rules on right of way (OR = 46.96, 95% CI:12.74-173.11), violating traffic signs when driving(OR = 24.57, 95% CI: 8.69-69.45), carelessness (OR = 14. 54,95% CI: 6.85-30.86), unsafe distance between vehicles( OR = 14.30,95% CI: 3.68-55.60), wrong judgement (OR = 14.67,95% CI:4.88-44.10), vehicle breakdown (OR = 8.57, 95% CI: 1.38- 53.27) and improper measure ( OR = 8.46, 95% CI: 2.46-29.14) etc. CONCLUSION: Improper driving behaviors, abnormal psychological status and driving skills of drivers were related to RTI, suggesting that it was necessary to carry out continous traffic security education to the drivers.

Accidents, Traffic↗

PubMed2005

[Significance of galectin-3 and CD44v6 expression in differential diagnosis of thyroid nodules].

OBJECTIVE: To investigate the difference of galectin-3 and CD44v6 expression between benign and malignant thyroid nodules, and to evaluate their clinical value in distinguishing thyroid cancer from benign thyroid nodules. METHODS: The expression of galectin-3 and CD44v6 was immunohistochemically detected by the ABC method in 143 benign and malignant thyroid nodule samples. RESULTS: Expression of these two markers in benign thyroid nodules: galectin-3 was negative in 10 cases of para-cancer normal tissue and 14 cases of benign nodules found in the other benign thyroid disease. It was weakly positive in 4 of 52 nodular goiter (7.7%). Also it was weakly positive in 2 of 22 follicular adenomas (9.1%). But all three eosinophilic follicular adenomas were diffusely or focally positive for galectin-3. CD44v6 was negative in 10 cases of para-cancer normal tissue, but positive in 4 of 14 nodular lesions found in benign thyroid diseases (28.6%). It was also positive in 16 of 52 nodular goiters (30.8%), and weakly positive in 7 of 22 follicular adenomas (31.8%). The two markers in malignant lesions: galectin-3 was positive in 50 of 52 thyroid adenocarcinoma (96.2%), CD44v6 was positive in 42 of 52 thyroid adenocarcinoma (80.8%). The positive rate of galectin-3 and CD44v6 expression in thyroid cancer was significantly higher than that in benign thyroid nodule and normal tissue (P < 0.001). The sensitivity, specificity and accuracy of galectin-3 combined with CD44v6 in differentiating benign from malignant thyroid nodule were 80.8%, 93.4%, 88.8%; they were 96.2%, 90.1%, 92.3% for Galectin-3 alone. CONCLUSION: The immunohistochemical expression of galectin-3 and CD44v6 by the ABC method is significantly higher in thyroid cancers than in benign thyroid nodules, especially galectin-3 in thyrocyte being helpful in differentiating benign thyroid nodule from thyroid cancer.

Adenocarcinoma, Papillary↗

PubMed2004

A dimerized coiled-coil domain and an adjoining part of geminin interact with two sites on Cdt1 for replication inhibition.

Geminin is a cellular protein that associates with Cdt1 and inhibits Mcm2-7 loading during S phase. It prevents multiple cycles of replication per cell cycle and prevents episome replication. It also directly inhibits the HoxA11 transcription factor. Here we report that geminin forms a parallel coiled-coil homodimer with atypical residues in the dimer interface. Point mutations that disrupt the dimerization abolish interaction with Cdt1 and inhibition of replication. An array of glutamic acid residues on the coiled-coil domain surface interacts with positive charges in the middle of Cdt1. An adjoining region interacts independently with the N-terminal 100 residues of Cdt1. Both interactions are essential for replication inhibition. The negative residues on the coiled-coil domain and a different part of geminin are also required for interaction with HoxA11. Therefore a rigid cylinder with negative surface charges is a critical component of a bipartite interaction interface between geminin and its cellular targets.

Amino Acid Sequence↗

PubMed2004

[A follow-up study on dietary factors of kidney stones in Bao'an district, Shenzhen City].

OBJECTIVE: To evaluate the major dietary factors of kidney stones in Bao'an District of Shenzhen City and provide a scientific base for further effective prevention of kidney stones. METHODS: Following the process of stratified cluster random sampling in Bao'an district, a cross-sectional study (July-Aug, 2000) was conducted for collecting the base-line data on kidney stones from a population of permanent residents who were over 15 years old, exclusive of those who had had kidney stones or could not correctly respond to the questionnaire review. Then, a follow-up survey (July-Sept, 2002) for incident kidney stone cases was carried out among those residents. The methods for measurement included questionnaire and face-to-face interview, clinical examination and abdominal ultrasonography. All the investigators and interviewers were trained for the field work. And the data processing, dataset and analyses were performed using Visual-Fox 6.0 and SAS 6.12. The risk factors of kidney stoned were comprehensively analyzed for dietary, life style, and family history of stones. The statistical analyses included case-control comparison, factor analysis, correlation analysis, cluster analysis and logistic regression. RESULTS: There were 305 kidney stones patients among 4552 follow-up members, the cumulative incidence of 2 years was 6.92%. The kidney stones were associated with the factors: menopause, RR=2.433; family history of stones, RR=1.544; sea foods, the RR (5-7 times/week vs < or = 1-2 times/month) was 9.032; fruits, the RR (< or = 1-2 times/month vs > or = 1-2 times/week) was 2. 249; sweet foods, the RR (5-7 times/week vs 1-2 times/week) was 2. 568; bean and bean products, the RR (5-7 times/week and < or = 1-2 times/month vs 1-2 times/week) was 2.184 and 1.689. CONCLUSION: Changing the inappropriate habitual eating patterns and generalizing the use of proportioning dietary should be the main measures to prevent kidney stones.

Adolescent↗