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M Chen

Publications and source records attributed to M Chen.

At least 397 records · Page 22Linked to original sources
PubMed1998

Epitope spreading: lessons from autoimmune skin diseases.

Autoimmune diseases are initiated when patients develop aberrant T and/or B cell responses against self proteins. These responses presumably are directed to single immunogenic epitopes on these proteins. Recent data in animal models of autoimmune diseases suggest that the targets of immune responses in autoimmunity do not remain fixed, but can be extended to include other epitopes on the same protein or other proteins in the same tissue, a phenomenon termed "epitope spreading." The "epitope spreading" phenomenon also applies to situations in which tissue damage from a primary inflammatory process causes the release and exposure of a previously "sequestered" antigen, leading to a secondary autoimmune response against the newly released antigen. In experimental autoimmune animal diseases, "epitope spreading" seems to have significant physiologic importance in determining the course and duration of disease. In this paper, we review the current concepts in animal models of autoimmune diseases in order to define the "epitope spreading" phenomenon, and we then propose how this phenomenon might play a significant role in the development and the course of autoimmune skin diseases. Hopefully, an understanding of "epitope spreading" will help the dermatology community to better understand the pathogenesis of autoimmune skin diseases and to rationally fashion disease-specific immune therapy in the future.

Animals↗
PubMed1998

Quality control of white cell-reduced red cells: white cell preservation and simplified counting.

BACKGROUND: White cell (WBC) degradation restricts the interval between the filtration process and the assay for residual WBCs. Maintaining WBC integrity would permit extended sample storage for batching and/or shipment to centralized laboratories. The usual quality control assay for WBC-reduced red cell units requires determining the number of WBCs in the entire counting area of a Nageotte hemocytometer, which consists of 40 rows. Reducing the counting area would simplify the quality control procedure. STUDY DESIGN AND METHODS: Adsol red cell units were prepared either on the day of collection (Day 0) or on Day 1 and WBC reduced by filtration on the same day. By using prefiltration and postfiltration red cells, samples containing WBC concentrations of 15, 10, and 3 WBCs per microL were prepared by serial dilution. Identical samples were treated with glutaraldehyde and stored at either 20 to 24 degrees C or 1 to 6 degrees C. All samples were assayed on the day of component preparation and on Days 7 and 14. The numbers of WBCs corresponding to 10- and 40-row areas of the Nageotte hemocytometer were determined. RESULTS: For the conditions and WBC concentration range studied, no significant changes in WBC concentrations were observed through Day 14 for glutaraldehyde-treated samples stored at either temperature, although there were substantial decreases in untreated samples. A 10-row measurement was determined to be sufficient for identifying WBC-reduced red cell units passing the present limit of 5 x 10(6) residual WBCs. CONCLUSION: Glutaraldehyde treatment can preserve WBCs in red cell samples at least up to Day 14, which provides increased efficiency in quality control for laboratories. Current red cell WBC-reduction filters produce components that, when assayed, contain fewer than 10 WBCs per full counting area. The simplified procedure would allow reduction of the counting area by 75 percent.

Blood Preservation↗
PubMed1998

72-kDa heat shock protein and mRNA expression after controlled cortical impact injury with hypoxemia in rats.

As part of the stress response, the 72 kDa heat shock protein (hsp72) is induced in neurons after ischemic and traumatic brain injury (TBI). To examine the stress response after TBI with secondary insult, we examined the regional and cellular expression of hsp72 mRNA and protein after controlled cortical impact (CCI) injury with secondary hypoxemia and mild hypotension in rats. Rats were killed at 6, 8, 24, 72, or 168 h after trauma. Naive and sham-operated rats were used as controls. Brains were removed, and in situ hybridization (n = 2/group), immunocytochemistry (n = 4/group), and Western blot analysis (n = 3 to 5/group) for hsp72 was performed. Hsp72 mRNA was expressed in neurons in the ipsilateral cortex, CA3 region of the hippocampus, hilus, and dentate gyrus at 6 h. Hsp72 mRNA was expressed primarily in the ipsilateral cortex, at 24 h, and by 72 h hsp72 mRNA expression returned to near basal levels. Hsp72 protein was seen in ipsilateral cortical neurons, hilar neurons, and neurons in the medial aspect of the CA3 region of the hippocampus (CA3-c) at 24 h. At 72 h, hsp72 immunoreactivity was reduced versus 24 h in these same regions, but it was increased versus baseline. Western blot analysis confirmed an increase in hsp72 protein in the ipsilateral cortex. The regional pattern of hsp72 mRNA induction in neurons was similar to the pattern of protein expression after CCI, with the exceptions that hsp72 mRNA, but not protein, was expressed in the dentate gyrus and the lateral aspect of the CA3 region of the hippocampus (CA3-a). The stress response, as detected by hsp72 expression, is induced in some neurons in some regions that are selectively vulnerable to delayed neuronal death in this model of TBI. The failure to translate some proteins including hsp72 may be associated with delayed neuronal death in certain hippocampal regions after TBI.

Animals↗
PubMed1998

Dissection of de novo membrane insertion activities of internal transmembrane segments of ATP-binding-cassette transporters: toward understanding topological rules for membrane assembly of polytopic membrane proteins.

The membrane assembly of polytopic membrane proteins is a complicated process. Using Chinese hamster P-glycoprotein (Pgp) as a model protein, we investigated this process previously and found that Pgp expresses more than one topology. One of the variations occurs at the transmembrane (TM) domain including TM3 and TM4: TM4 inserts into membranes in an N(in)-C(out) rather than the predicted N(out)-C(in) orientation, and TM3 is in cytoplasm rather than the predicted N(in)-C(out) orientation in the membrane. It is possible that TM4 has a strong activity to initiate the N(in)-C(out) membrane insertion, leaving TM3 out of the membrane. Here, we tested this hypothesis by expressing TM3 and TM4 in isolated conditions. Our results show that TM3 of Pgp does not have de novo N(in)-C(out) membrane insertion activity whereas TM4 initiates the N(in)-C(out) membrane insertion regardless of the presence of TM3. In contrast, TM3 and TM4 of another polytopic membrane protein, cystic fibrosis transmembrane conductance regulator (CFTR), have a similar level of de novo Nin-Cout membrane insertion activity and TM4 of CFTR functions only as a stop-transfer sequence in the presence of TM3. Based on these findings, we propose that 1) the membrane insertion of TM3 and TM4 of Pgp does not follow the sequential model, which predicts that TM3 initiates N(in)-C(out) membrane insertion whereas TM4 stops the insertion event; and 2) "leaving one TM segment out of the membrane" may be an important folding mechanism for polytopic membrane proteins, and it is regulated by the N(in)-C(out) membrane insertion activities of the TM segments.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Sequence organization and conservation in sh2/a1-homologous regions of sorghum and rice.

Previously, we have demonstrated microcolinearity of gene composition and orientation in sh2/a1-homologous regions of the rice, sorghum, and maize genomes. However, the sh2 and a1 homologues are only about 20 kb apart in both rice and sorghum, while they are separated by about 140 kb in maize. In order to further define sequence organization and conservation in sh2/a1-homologous regions, we have completely sequenced a 42,446-bp segment of sorghum DNA. Four genes were identified: a homologue of sh2, two homologues of a1, and a putative transcriptional regulatory gene. A solo long terminal repeat of the retroelement Leriathan was detected between the two a1 homologues, and eight miniature inverted repeat transposable elements were found in this region. Comparison of the sorghum sequence with the sequence of the homologous segment from rice indicated that only the identified genes were evolutionarily conserved between these two species, which have evolved independently for over 50 million years. The introns of the a1 homologues have evolved faster than the introns of the sh2 homologue. The a1 tandem duplication appears to be an ancient event that may have preceded the ancestral divergence of maize, sorghum, and rice.

Amino Acid Sequence↗
PubMed1998

Detection of Borrelia burgdorferi from ticks (Acari) in Hebei Province, China.

From May 1992 to August 1993, 1,196 ticks were collected by flagging vegetation and from domestic animals in Chengde, Zhangjiakou, Shijiazhuang, and Handan districts of Hebei Province. Of those ticks collected, 954 were Haemaphysalis japonicum Warburton and H. longicornis Neumann, 205 were Ixodes persulcatus Schulze, and 37 were Dermacentor silvarum Olenev. Four strains of Borrelia burgdorferi were isolated from 135 I. persulcatus collected in Weichang and Zhuolu counties. Three of 574 Haemaphysalis spp. (collected in Laishui, Pingshan, and Xinglong counties) were positive for B. burgdorferi by direct immunofluorescent assay. One of 24 H. japonicum and 1 of 1 I. persulcatus (collected in Zhuolu) were positive for B. burgdorferi by polymerase chain reaction. This is the 1st report of a B. burgdorferi isolation from H. japonicum.

Animals↗
PubMed1998

Genomic structure of PIR-B, the inhibitory member of the paired immunoglobulin-like receptor genes in mice.

The genes encoding the murine paired immunoglobulin-like receptors PIR-A and PIR-B are members of a novel gene family which encode cell-surface receptors bearing immunoreceptor tyrosine-based inhibitory motifs (ITIMs) and their non-inhibitory/activatory counterparts. PIR-A and PIR-B have highly homologous extracellular domains but distinct transmembrane and cytoplasmic regions. A charged arginine in the transmembrane region of PIR-A suggests its potential association with other transmembrane proteins to form a signal transducing unit. PIR-B, in contrast, has an uncharged transmembrane region and several ITIMs in its cytoplasmic tail. These characteristics suggest that PIR-A and PIR-B which are coordinately expressed by B cells and myeloid cells, serve counter-regulatory roles in humoral and inflammatory responses. In the present study we have determined the genomic structure of the single copy PIR-B gene. The gene consists of 15 exons and spans approximately 8 kilobases. The first exon contains the 5' untranslated region, the ATG translation start site, and approximately half of the leader peptide sequence. The remainder of the leader peptide sequence is encoded by exon 2. Exons 3-8 encode the six extracellular immunoglobulin-like domains and exons 9 and 10 code for the extracellular membrane proximal and transmembrane regions. The final five exons (exons 11-15) encode for the ITIM-bearing cytoplasmic tail and the 3' untranslated region. The intron/exon boundaries of PIR-B obey the GT-AG rule and are in phase I, with the notable exception of the three boundaries determined for ITIM-containing exons. A microsatellite composed of the trinucleotide repeat AAG in the intron between exons 9 and 10 provides a useful marker for studying population genetics.

Amino Acid Sequence↗
PubMed1998

Characterization of anti-histone antibodies in patients with type 1 autoimmune hepatitis.

We have recently found that antibodies to total histones are common in a group of American patients with type 1 autoimmune hepatitis (AIH). In an attempt to determine the profile and clinical association of anti-histone antibody (AHA), 45 Japanese AIH patients were studied for serum isotypic reactivity with individual histones (H1, H2A, H2B, H3, H4) by enzyme-linked immunosorbent assay and western blotting. The results revealed that 40% of sera had reactivities with at least one of individual histones and that the antibodies were detected in all three classes of immunoglobulins (IgG, IgM, IgA). Immunoglobulin G type anti-H3 showed the dominant reactivity and it characterized 72% of sera with AHA. The titre of anti-H3 decreased significantly (P < 0.0075) after steroid therapy and the index of decrease for anti-H3 was correlated in individuals with that for serum aminotransferase. In general, patients with AHA showed higher serum level of alanine aminotransferase (P < 0.05), immunoglobulin G (P < 0.025), and higher frequency of A2-DR4 haplotype (53 vs 17%) than their seronegative counterparts. However, the titre of AHA was low in this disease condition and histone class-specific antibodies did not distinguish patients with distinctive clinical features, although patients with anti-H3 tended to be younger than those without AHA.

Adolescent↗
PubMed1998

Antibiotic susceptibility patterns of Streptococcus pneumoniae in china and comparison of MICs by agar dilution and E-test methods.

Beta-lactam resistance by Streptococcus pneumoniae is becoming a significant threat to public health worldwide. However, data concerning antibiotic susceptibility patterns in China have not been published. In this study, a total of 79 clinical isolates and 244 nasopharyngeal isolates of S. pneumoniae were recovered between June and November 1997 in Beijing. The agreement between the MICs (+/-1 log2 dilution) of penicillin and ceftriaxone obtained by the agar dilution and E-test methods for the 79 clinical strains was very good (97.5 and 93.7%, respectively). Of these 79 strains, 9 (11.4%) were intermediate and 2 (2.5%) were resistant to penicillin. Of the 244 nasopharyngeal strains, 32 (13.1%) were intermediate and 3 (1. 2%) were resistant to penicillin. The total of 277 penicillin-susceptible clinical and nasopharyngeal isolates of Streptococcus pneumoniae were 100% susceptible to amoxicillin-clavulanic acid, cefuroxime, ceftriaxone, and cefotaxime. In the 35 penicillin-intermediate and -resistant nasopharyngeal strains, elevated MICs of amoxicillin-clavulanic acid, cefuroxime, ceftriaxone, and cefotaxime were seen for </=4 isolates. Of 244 nasopharyngeal isolates, the overall percentages of tetracycline, erythromycin, chloramphenicol, ofloxacin, and trimethoprim-sulfamethoxazole resistance were 87.6, 74.0, 47.8, 3.7 and 63.3, respectively. Vancomycin and rifampin resistance were not detected. These findings demonstrate that the rate of penicillin-resistant pneumococci is relatively low in China compared to those of other Asian countries. Resistance to non-beta-lactams was much higher than to beta-lactams. The E-test and agar dilution methods appeared to be comparable in identifying resistant strains.

Agar↗
PubMed1998

Efficient class II major histocompatibility complex presentation of endogenously synthesized hepatitis C virus core protein by Epstein-Barr virus-transformed B-lymphoblastoid cell lines to CD4(+) T cells.

The induction of an efficient CD4(+) T-cell response against hepatitis C virus (HCV) is critical for control of the chronicity of HCV infection. The ability of HCV structural protein endogenously expressed in an antigen-presenting cell (APC) to be presented by class II major histocompatibility complex molecules to CD4(+) T cells was investigated by in vitro culture analyses using HCV core-specific T-cell lines and autologous Epstein-Barr virus-transformed B-lymphoblastoid cell lines (B-LCLs) expressing structural HCV antigens. The T- and B-cell lines were generated from peripheral blood mononuclear cells derived from HCV-infected patients. Expression and intracellular localization of core protein in transfected cells were determined by immunoblotting and immunofluorescence. By stimulation with autologous B-LCLs expressing viral antigens, strong T-cell proliferative responses were induced in two of three patients, while no substantial stimulatory effects were produced by B-LCLs expressing a control protein (chloramphenicol acetyltransferase) or by B-LCLs alone. The results showed that transfected B cells presented mainly endogenously synthesized core peptides. Presentation of secreted antigens from adjacent antigen-expressing cells was not enough to stimulate a core-specific T-cell response. Only weak T-cell proliferative responses were generated by stimulation with B-LCLs that had been pulsed beforehand with at least a 10-fold-higher amount of transfected COS cells in the form of cell lysate, suggesting that presentation of antigens released from dead cells in the B-LCL cultures had a minimal role. Titrating numbers of APCs, we showed that as few as 10(4) transfected B-LCL APCs were sufficient to stimulate T cells. This presentation pathway was found to be leupeptin sensitive, and it can be blocked by antibody to HLA class II (DR). In addition, expression of a costimulatory signal by B7/BB1 on B cells was essential for T-cell activation.

Animals↗
PubMed1998

Esophageal varices: evaluation with transabdominal US.

PURPOSE: To prospectively evaluate the clinical usefulness of transabdominal ultrasound (US) in the detection of esophageal varices. MATERIALS AND METHODS: Transabdominal US was performed in 47 patients (30 men, 17 women; age range, 18-75 years) with liver cirrhosis or idiopathic portal hypertension. The intraabdominal esophagus was demonstrated satisfactorily, and the findings were correlated with the presence of esophageal varices at endoscopy and angiography. The thickness of the anterior wall of the intraabdominal esophagus was measured and the irregularity of the wall surface documented. Blood flow signal in the esophageal wall also was evaluated with color Doppler and pulsed Doppler examinations. RESULTS: The mean thickness of the esophageal wall was 5.7 mm +/- 1.7 (standard deviation) in patients with esophageal varices and 3.6 mm +/- 0.96 in patients without varices. This difference was statistically significant (P < .001). Varices also caused irregular wall surfaces. Another specific finding was hepatofugal venous flow within the esophageal wall at Doppler examination. When an esophageal wall thickness of at least 5 mm or an irregular wall surface was used as a diagnostic criterion for esophageal varices, the sensitivity, specificity, and accuracy were 93%, 82%, and 89%, respectively. CONCLUSION: Transabdominal US can play a role in screening for esophageal varices. The intraabdominal esophagus should be observed during standard abdominal US in patients with chronic liver disease.

Adult↗
PubMed1998

Phospholipase A2 is not responsible for lysophosphatidylcholine-induced damage in cardiomyocytes.

Lysophosphatidylcholine (LPC) is known to increase the intracellular concentration of Ca2+ ([Ca2+]i), leading to cell damage. In the present study we examined whether LPC activates phospholipase A2 (PLA2) and whether the activation of PLA2 is responsible for the LPC-induced cell damage in isolated rat cardiomyocytes. LPC (15 microM) produced an increase in [Ca2+]i, a change in cell shape from rod to round, and the release of creatine kinase (CK) accompanied by a significant elevation of the cellular level of nonesterified fatty acids (NEFA), especially arachidonic acid. Three PLA2 inhibitors, 7, 7-dimethyl-(5Z,8Z)-eicosadienoic acid (DEDA), 3-(4-octadecylbenzoyl)acrylic acid (OBAA), and manoalide, attenuated the LPC-induced accumulation of unsaturated NEFA to a similar degree. Nevertheless, whereas both DEDA and OBAA attenuated the LPC-induced increase in [Ca2+]i, change in cell shape, and release of CK, manoalide attenuated none of them. In the Ca2+-free solution, LPC did not increase [Ca2+]i with significantly less accumulation of NEFA, but it changed the cell shape from rod to round and increased the release of CK. These results suggest that exogenous LPC increases the PLA2 activity, which, however, may not be responsible for the LPC-induced damage in cardiomyocytes.

Animals↗
PubMed1998

Fission yeast expression vectors adapted for positive identification of gene insertion and green fluorescent protein fusion.

A pYZ series of fission yeast expression vectors, derivatives of the pREP series, was designed to allow positive identification of cloned gene insertion and fusion to the green fluorescent protein (GFP) gene for in vivo analysis of gene expression. To validate this new vector system, the human immunodeficiency virus type 1 (HIV-1) vpr gene of viral isolate pNL4-3 was expressed in the pYZ1N vector. Vpr-induced phenotypic changes were the same as those observed with vpr expressed from pREP1N. Consistent with observations in mammalian cells, a Vpr-GFP fusion protein localizes on the nuclear membrane of fission yeast cells. Additionally, we were able to detect a naturally occurring mixture of vpr genes from a plasma sample of an HIV-infected pediatric long-term surviving patient. These pYZ vectors expedite gene cloning for general purposes and are particularly suited for largescale random gene screening.

Cloning, Molecular↗
PubMed1998

Examination of full fat and reduced fat Cheddar cheese during ripening by Fourier transform infrared spectroscopy.

The Fourier transform infrared spectra of reduced fat Cheddar cheese and full fat Cheddar cheese during ripening were examined. A suitable sampling procedure was used to obtain the spectra of cheese samples. The spectra were affected by the moisture contents of the samples, but this effect could be eliminated by equilibration of the sample for at least 10 min before data collection. Strong and well-separated bands at 1744, 1450, 1240, 1170, and 1115 cm-1 arising from fat were observed in the frozen samples. The bands observed at 1650 and 1540 cm-1 were attributed to the protein contents of the cheese samples. The absorption intensities of protein and fat bands corresponded to the amounts of protein and fat that were present in the samples. Distinct changes in the bands of fat and protein of reduced fat and full fat cheese samples occurred during ripening. This technique could provide a basis for a rapid characterization and determination of the age of cheese undergoing ripening.

Caseins↗
PubMed1998

Regulation of 10P2 murine mast cell proliferation and secretory function by stem cell factor or IL-9.

Mast cells are effectors of inflammatory responses. When triggered by immunological or nonimmunological mechanisms, mast cells release potent biological mediators from preformed stores and synthesize others de novo. In previous investigations from this laboratory, the signal transduction pathways of cloned 10P2 cytokine-independent mast cells were explored. Results suggested that 10P2 cells undergo activation-secretion coupling assessed as release of stored [14C]serotonin (5-HT) when challenged with IgE-specific antigen, influx of extracellular calcium, release of intracellular calcium stores, or by direct activation of protein kinase C isozymes. In the present investigations, cytokine proliferative effects and modulatory roles on release of stored [14C]5-HT have been explored. Following passive sensitization with anti-dinitrophenol (anti-DNP) IgE and challenge with DNP, mast cells released up to 32% of the stored [14C]5-HT. Pretreatment of cells with 10, 30, or 50 ng/ml stem cell factor (SCF) did not alter the response. SCF did not directly induce [14C]5-HT release. Pretreatment with 25 ng/ml interleukin-9 (IL-9) significantly potentiated the IgE-antigen release by 51.1%, 35.7%, or 31.6% when challenged with 3, 10 or 30 ng/ml DNP-HSA. Treatment of cells with 1-100 ng/ml SCF for 72 hr resulted in significantly enhanced proliferation whereas this did not occur when cells were treated with 1-100 ng/ml IL-9. Collectively, these results suggest that SCF alone has a proliferative effect, does not alter the IgE-specific antigen signal transduction pathway, and does not directly stimulate mast cell degranulation. In contrast, IL-9 potentiates the IgE-antigen signal transduction response but exerts no proliferative response. Reports of effects of orally administered cytokines are now beginning to emerge. This raises the possibility that cytokines may be a future therapeutic approach to treatment of allergic and nonallergic inflammatory diseases. The 10P2 cytokine-independent mast cell line may be a valuable adjunct to existing mast cell models as this avenue of drug discovery is explored.

Animals↗
PubMed1998

Preventive effect of artemether on schistosome infection.

OBJECTIVE: To study the preventive effect of artemether (Art) in protecting the people from schistosome infection during flood fighting in schistosomiasis endemic area of Poyang Lake, Jiangxi Province. METHODS: From mid July to mid August in 1996, the water level in Poyang Lake rose due to torrential rains and 2 embankments, Zhedi and Jiangtongdi, which appeared in dangerous situation and were selected as the pilot spots. After those who went to fight against flood arrived at the pilots their sera were collected within 48 hours and were examined with indirect hemagglutination test (IHA), enzyme-linked immunosorbent assay (ELISA) and McAb-ELISA. Individuals with negative outcome in the 3 tests were then selected as the study subjects and were allocated randomly to the Art or the control group. The first dose of Art given to the individuals contacted with the infested water within 11-15 days was 6 mg/kg. If the individual continually contacted the infested water, the same dose of Art was given once every 15 days. After the individuals withdrew from the pilot, one more dose of Art was administered 7-15 days later. Placebo (starch) was given to individuals in the control group at the same period as in artemether group. Stool examinations were made in both groups 40-50 days after the last medication for evaluation of the preventive effect of artemether. Double blind method was used in the administration of both artemether and placebo. RESULTS: In Zhedi pilot, the individuals fought against flood for about 1 month. In Art group, 99 individuals receiving 3 doses of the drug completed the stool examination with egg-positive rate of 4% and no acute schistosomiasis was seen. In the control group, among 110 people who completed the observation, 44 were egg-positive with an infection rate of 40%, and 29 were identified as having acute schistosomiasis. In Jiangtondi, the studied individuals contacted the infested water for only about 4 hours. But in the control group 4 out of 102 individuals were egg-positive, while none of the 103 individuals in Art group receiving 2 doses of the drug showed schistosome infection. No apparent side effect was seen in the people treated with artemether. CONCLUSION: After oral Art was given to the people fighting against flood in schistosomiasis endemic area of Poyang Lake, it was shown that the oral Art has a promising effect on controlling acute schistosomiasis and reducing the infection rate.

Adolescent↗
PubMed1998

[Multiple-layer composite rhytidectomy].

OBJECTIVE: The multiple-layer composite rhytidectomy is presented in this paper for correction of the facial aging. METHODS: The operative procedures include multiple-layer dissection, suspension reconstruction of the zygomatic ligament, and thinning of the zygoma. RESULTS: The method has produced a good result in 28 patients since 1993. CONCLUSION: Study of clinical cases and cadaver dissections had led to better understanding of the aging face. With advancing age, all tissues of the face lose their balanced relationship. These changes occur in their volume shape, position, and consistency. With the multiple-layer dissection and suspension, the soft tissues of the check, forehead, nasolabial fold, lateral canthus and eyebrow can be lifted to reestablish their previously youthful relationship with the underlying skeleton.

Aged↗