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Biomedical subjects

Ming Yan

Publications and source records attributed to Ming Yan.

At least 19 recordsLinked to original sources

Genome-resolved multi-omics provide new insights into microbial nitrogen utilization by the rumen microbiota.

BACKGROUND: Optimizing nitrogen (N) utilization in ruminant production systems holds both economic and environmental significance. However, traditional paradigms of N metabolism, derived primarily from well-studied model rumen bacteria, do not fully reflect the diverse and complex N metabolism in the rumen ecosystem. RESULTS: To address this gap, we utilized comparative genomics and genome-resolved multi-omics analyses using a curated set of microbial genomes to investigate N assimilation and regulation in rumen microbes. We discovered that well-established mechanisms of ammonia assimilation and regulation, such as the glutamine synthetase (GS)/glutamate synthase (GOGAT) pathways and their regulatory proteins, are absent in many of the predominant rumen microbes, which likely utilize alternative pathways for ammonia assimilation. These findings challenge the applicability of E. coli-based N regulation models to rumen bacteria in response to ammonia availability. We further linked polysaccharide utilization and ammonia assimilation across hundreds of rumen microbial species. Furthermore, we identified specific microbial species involved in ureolysis and denitrification, as well as phages carrying auxiliary metabolic genes involved in N assimilation. Using an animal trial involving 11 pairs of lamb twins in a crossover design, we demonstrated that dietary crude protein (CP) at 10% and 13% had minimal impact on rumen microbiome composition and expression of N assimilation genes. Instead, changes in concentrate levels altered N assimilation, notably increasing expression of amino acid biosynthesis pathways. CONCLUSION: These findings indicate a nuanced, species-specific microbial response to dietary interventions, highlighting the limitations of traditional N metabolism models applied to rumen microbes and the need for more granular studies of rumen microbial ecosystems.

Multiomics↗

The relationship between gene polymorphism and CRP level in a Chinese Han population.

We investigated the relationships among the +1444C/T polymorphism in the C-reactive protein (CRP) gene and the concentration of CRP and the risk of coronary heart disease. Using polymerase chain reaction-restriction fragment length polymorphism, we analyzed the frequency distribution of genotypes and alleles of the +1444C/T polymorphism in samples from 128 patients with coronary heart disease (coronary stenosis more than 50%) and 119 unrelated normal individuals. The plasma levels of CRP and lipids in the subjects were also measured. The frequencies of the genotypes were CC 89.1%, CT 10.9%, and TT 0% in patients and CC 89.9%, CT 10.1%, and TT 0% in controls. The frequency of allele C was 94.5% in patients and 95.0% in controls, and allele T was 5.5% in patients and 5.1% in controls. The distribution of genotypes and alleles in the Chinese Han population was significantly different from that of the Caucasian population. There were no significant differences between frequencies of genotype and allele of controls and those of patients (P>0.05), but in controls the concentrations of CRP in the CC genotype subgroup were significantly higher than those in the CT genotype subgroup (P<0.05). This suggests that the +1444C/T variant in the CRP gene influences the basal CRP level in normal people. These findings imply that there may eventually be a need to establish genotype-specific risk thresholds of the CRP level.

Aged↗

Oridonin, a diterpenoid extracted from medicinal herbs, targets AML1-ETO fusion protein and shows potent antitumor activity with low adverse effects on t(8;21) leukemia in vitro and in vivo.

Studies have documented the potential antitumor activities of oridonin, a compound extracted from medicinal herbs. However, whether oridonin can be used in the selected setting of hematology/oncology remains obscure. Here, we reported that oridonin induced apoptosis of t(8;21) acute myeloid leukemic (AML) cells. Intriguingly, the t(8;21) product AML1-ETO (AE) fusion protein, which plays a critical role in leukemogenesis, was degraded with generation of a catabolic fragment, while the expression pattern of AE target genes investigated could be reprogrammed. The ectopic expression of AE enhanced the apoptotic effect of oridonin in U937 cells. Preincubation with caspase inhibitors blocked oridonin-triggered cleavage of AE, while substitution of Ala for Asp at residues 188 in ETO moiety of the fusion abrogated AE degradation. Furthermore, oridonin prolonged lifespan of C57 mice bearing truncated AE-expressing leukemic cells without suppression of bone marrow or reduction of body weight of animals, and exerted synergic effects while combined with cytosine arabinoside. Oridonin also inhibited tumor growth in nude mice inoculated with t(8;21)-harboring Kasumi-1 cells. These results suggest that oridonin may be a potential antileukemia agent that targets AE oncoprotein at residue D188 with low adverse effect, and may be helpful for the treatment of patients with t(8;21) AML.

Animals↗

A leukemia fusion protein attenuates the spindle checkpoint and promotes aneuploidy.

The 8;21 chromosomal translocation occurs in 15% to 40% of patients with the FAB M2 subtype of acute myeloid leukemia (AML). This chromosomal abnormality fuses part of the AML1/RUNX1 gene to the ETO/MTG8 gene and generates the AML1-ETO protein. We previously identified a C-terminal truncated AML1-ETO protein (AEtr) in a mouse leukemia model. AEtr is almost identical to the AML1-ETO exon 9a isoform expressed in leukemia patients. Here, we describe a novel function of AEtr in the development of aneuploidy through spindle checkpoint attenuation. AEtr cells had a reduced mitotic index following nocodazole treatment, suggesting a failure in a subset of cells to arrest in mitosis with a functional spindle checkpoint. Additionally, primary leukemia cells and cell lines expressing AEtr were aneuploid. Moreover, AEtr cells had reduced levels of several spindle checkpoint proteins including BubR1 and securin following treatment with the spindle poison nocodazole. These results suggest that inactivation of the spindle checkpoint may contribute to the development of aneuploidy described in t(8;21) leukemia patients.

Aneuploidy↗

Encapsulation of single enzyme in nanogel with enhanced biocatalytic activity and stability.

Single protein encapsulated into nanogels with uniformed size and controllable shell thickness were prepared by surface acryloylation of a protein molecule followed by aqueous in situ polymerization. Compared to its free counterpart, the encapsulated protein exhibits similar biocatalytic behavior and significantly improved stability at high temperature and in the presence of organic solvent.

Catalysis↗

A previously unidentified alternatively spliced isoform of t(8;21) transcript promotes leukemogenesis.

The t(8;21)(q22;q22) translocation is one of the most common genetic abnormalities in acute myeloid leukemia (AML), identified in 15% of all cases of AML, including 40-50% of FAB M2 subtype and rare cases of M0, M1 and M4 subtypes. The most commonly known AML1-ETO fusion protein (full-length AML1-ETO) from this translocation has 752 amino acids and contains the N-terminal portion of RUNX1 (also known as AML1, CBFalpha2 or PEBP2alphaB), including its DNA binding domain, and almost the entire RUNX1T1 (also known as MTG8 or ETO) protein. Although alterations of gene expression and hematopoietic cell proliferation have been reported in the presence of AML1-ETO, its expression does not lead to the development of leukemia. Here, we report the identification of a previously unknown alternatively spliced isoform of the AML1-ETO transcript, AML1-ETO9a, that includes an extra exon, exon 9a, of the ETO gene. AML1-ETO9a encodes a C-terminally truncated AML1-ETO protein of 575 amino acids. Expression of AML1-ETO9a leads to rapid development of leukemia in a mouse retroviral transduction-transplantation model. More importantly, coexpression of AML1-ETO and AML1-ETO9a results in the substantially earlier onset of AML and blocks myeloid cell differentiation at a more immature stage. These results indicate that fusion proteins from alternatively spliced isoforms of a chromosomal translocation may work together to induce cancer development.

Alternative Splicing↗

SUMO-1 modification increases human SOD1 stability and aggregation.

The mutations in the gene encoding copper-zinc superoxide dismutase (SOD1) cause approximately 20% cases of familial amyotrophic lateral sclerosis (FALS), characterized by selective loss of motor neurons. Mutant SOD1 forms inclusions in tissues from FALS patients. However, the precise mechanism of the accumulation of mutant SOD1 remains unclear. Here we show that human SOD1 is a substrate modified by SUMO-1. A conversion of lysine 75 to an arginine within a SUMO consensus sequence in SOD1 completely abolishes SOD1 sumoylation. We further show that SUMO-1 modification, on both wild-type and mutant SOD1, increases SOD1 steady state level and aggregation. Moreover, SUMO-1 co-localizes onto the aggregates formed by SOD1. These findings imply that SUMO-1 modification on lysine 75 may participate in regulating SOD1 stability and its aggregation process. Thus, our results suggest that sumoylation of SOD1 may be involved in the pathogenesis of FALS associated with mutant SOD1.

Cell Line↗

Open reduction of irreducible atlantoaxial dislocation by transoral anterior atlantoaxial release and posterior internal fixation.

STUDY DESIGN: A retrospective study of surgical outcome of 33 patients with irreducible atlantoaxial dislocation (IAAD). OBJECTIVE: To evaluate the safety efficacy of one stage anterior release and posterior fixation and fusion to reduce and stabilize IAAD. SUMMARY OF BACKGROUND DATA: The traditional treatment of symptomatic IAAD is ventral decompression by transoral approach. This procedure is accompanied with high morbidity and mortality. It does not correct the swan neck deformity, which could precipitate the degenerative changes in the lower cervical spine. Our hypotheses were that it is the contraction of the muscles, ligaments, and capsules of atlantoaxial joint that prevent reduction, and that most of IAADs might be reduced by anterior atlantoaxial joint release without the odontoid resection, and that further reduction and stabilization might be achieved by special posterior fixation. METHODS: A consecutive series of 33 patients with IAAD were surgically treated. Dislocation or reduction was assessed before surgery, immediately after surgery, and at the final fol5786-up. Etiology, instrumentation, levels fused, and complications were documented. All patients were assessed clinically for neurologic recovery by Odom's method. RESULTS: The mean age was 32 years (range, 7-63 years). The pathology included os odontoideum in 8 patients, occipitalization of C1 in 19 patients, malunion of odontoid fracture in 5, and relaxation of transverse ligament of atlas in 1. Twenty five patients presented neurologic signs and symptoms. Anterior release was performed without odontoid resection in all cases. Four patients underwent transarticular C1-C2 screw fixation, 3 had C1-C2 pedicle screw and plate fixation, and 26 required occipitocervical fixation. Twenty-five cases resulted in an anatomic reduction, 8 had partial reduction. Complication included one dysphagia and two nasal phonations. The mean follow-up period was 33.7 months (range, 24-55 months). There was no pseudarthrosis, and all but 1 of the patients with neurologic deficit showed improvement. CONCLUSION: This series has demonstrated the safety and efficacy of the transoral anterior atlantoaxial release in the reduction of IAAD. Most of the so-called irreducible/fixed AAD could become reducible after anterior release without odontoid resection. The posterior short-segment atlantoaxial or occipitocervical fixation, especially the plate screw instrumentation, could achieve further reduction and provide immediate stabilization. One-stage anterior release and posterior instrumentation and fusion are a safe and reliable operation in experienced hands.

Adolescent↗

Nephrotoxicity study of total rhubarb anthraquinones on Sprague Dawley rats using DNA microarrays.

Total rhubarb anthraquinones (TRAs) are the active therapeutic components from the rhizomes of Rheum palmatum L. (Polygonaceae), which are widely used in traditional Chinese medicines (TCMs) and have been reported to have cell toxicity recently. This study focuses on the toxicity of TRAs on Sprague Dawley (S.D.) rats. TRAs administrated per os for 13 weeks induced nephrotoxicity on S.D. rats as renal tubule epithelial cells swelled and denatured in tissue slice examination. After high-density oligonucleotide microarrays scanning, we have identified mitogen-activated protein kinase (MAPK) kinase 6 to be the target gene which causes cell cycle arrest and proliferation inhibition and contributes to nephrotoxicity on S.D. rats.

Animals↗

No mutation was detected in the LMNA gene among sporadic Charcot-Marie-Tooth patients.

OBJECTIVE: To intensively investigate sporadic CMT patients, we have analyzed the LMNA gene in this study in a series of 32 unrelated CMT patients. METHODS: Twelve exons of the LMNA gene were amplified from genetic DNA. PCR products of each exon were analyzed by single strand conformational polymorphism (SSCP). RESULTS: No abnormal SSCP pattern, suggesting no mutation in our CMT patients, was detected. CONCLUSION: The CMT diseases resulted from the mutations of LMNA gene were rare.

Charcot-Marie-Tooth Disease↗

[Reliability of direct probing isthmus of axial vertebrae to defining the screw path in atlas during Magerl technique].

OBJECTIVE: To evaluate the accuracy and reliability of atlantoaxial transarticular screw insertion (Magerl's technique) in atlas under lateral fluoroscopic monitoring without anteroposterior view. METHOD: Seventy-five consecutive patients with atlantoaxial instability, 48 males and 27 females, aged 35.1, were treated by Magerl's technique. The screw path in atlas was achieved by direct probing the isthmus of axial vertebrae then identifying its position through the atlantoaxial joint correlation. Postoperative transoral X ray and CT film were used for analysis of the position of the 150 screws in the mass of atlas. Three areas were delimitated in and around the lateral mass of atlas: area A (inside the joint face), area: B (outside the joint face but still in lateral mass), and area C area (outside the lateral mass) so as to analyze the location of screws. RESULTS: Among the 150 screws 139 (92.7%) were located in area A, 8 in area B(1) and 3 in area B(2) (7.3%), and none in area C. All cases got atlantoaxial union 3 months after operation. CONCLUSION: The method of "direct probing" is reliable for identifying the path of screw in atlas.

Adolescent↗

A complete protein pattern of cellulase and hemicellulase genes in the filamentous fungus Trichoderma reesei.

The complete protein pattern of cellulase and hemicellulase genes was studied through the Genome-wide analysis in Trichoderma reesei. The genome database revealed the presence of 39 ORFs encoding related proteins, including 32 enzymes with a catalysis domain related to cellulases and hemicellulases and 7 related proteins with a cellulose-binding module (CBM). Ten of these encoded yet undescribed enzymes, including six novel beta-glucosidases or xylosidases, two putative xylanases and two undescribed mannases. To better illustrate the relation of these 39 related proteins, four groups were created and analyzed by phylogenetic analysis: group A corresponding to xylanases, group B belonging to mannases and acting to degrade mannan; group C containing all known and putative cellulose-degrading proteins that have highly conserved CBMs; and group D containing beta-glucosidase and beta-xylosidase. Group D was the largest group, in which 8 beta-glucosidases appeared to be non-secreted proteins.

Cellulase↗

Practical application of fluorescent quantitative PCR on Trisomy 21 in Chinese Han population.

OBJECTIVE: To apply the fluorescent quantitative PCR method on the detection of Trisomy 21 by D21S11 locus and make a foundation for rapid prenatal diagnosis of Trisomy 21. METHODS: About 409 controls (39 amniotic fluid samples and 370 peripheral blood samples) and 35 patients (4 amniotic fluid samples and 31 peripheral blood samples) with Trisomy 21 were tested using fluorescent quantitative PCR by amplification of DNA fragment on D21S11 STR locus. The results were compared with conventional cytogenetic analysis to confirm the utility of this method. And the allele frequency distributions of D21S11 STR locus were analyzed. RESULTS: The 95% reference interval of fluorescent intensity ratios of peak heights of PCR products amplified from two alleles on D21S11 locus ranged from 0.84 to 1.42 (1.13 +/- 0.29) in heterozygous controls. About 19 out of 35 patients showed a "diallelic" pattern and their height ratio of fluorescent peaks of PCR products amplified from two alleles in patients with "diallelic" patterns were all outside of the 95% reference range of controls. The PCR products of DNA from 12 patients presented the third allele. No sample with the "monoallelic" pattern was found. Four chimeras diagnosed by cytogenetic method could not be diagnosed by this method. There were 17 and 11 alleles found in controls and patients, respectively. About 343 out of 409 controls were heterozygous and the heterozygosity was 83.86%. We did not find any significant differences in the frequency distributions of alleles on D21S11 locus between controls and patients. But there were significant differences in the frequency distributions of alleles on D21S11 locus between controls and patients. But there were significant differences in the frequency distributions of alleles on D21S11 locus among different populations. CONCLUSIONS: The fluorescent quantitative polymerase chain reaction method was rapid, accurate, and only small amount of starting material was needed, it could be applied in rapid prenatal diagnosis of Trisomy 21. D21S11 was a good marker with high heterozygosity for the screening of Trisomy 21. And the frequency distributions of alleles on D21S11 locus were significantly related to ethnic background.

Amniotic Fluid↗

Mutation frequency for Charcot-Marie-Tooth disease type 1 in the Chinese population is similar to that in the global ethnic patients.

PURPOSE: To investigate the genetic loci/mutations among the Chinese Charcot-Marie-Tooth disease type 1 (CMT1), which accounts for approximately 70% of Charcot-Marie-Tooth; and to study the genetic heterogeneity and mutation frequency. METHODS: CMT1A duplication and mutations at loci of MPZ, Cx32/GJB1, EGR2, and LITAF/SIMPLE were analyzed among 32 clinically diagnosed CMT1 patients of Chinese ancestry. RESULTS: The CMT1A duplication was detected in 62.5% (20/32) CMT1 patients. This duplication accounts for the major mutation for Chinese CMT1. Among 12 cases that have no CMT1A duplication detected, three point mutations including one (3.1%) in MPZ and two (6.3%) in Cx32 were identified. No mutation was detected in genes PMP22, EGR2 and LITAF among the remaining nine (28.1%) CMT1 patients. CONCLUSION: The mutation frequency for the Chinese CMT1 is similar to that seen in the global ethnic population. Molecular testing of the CMT1A duplication, along with the loci of MPZ and Cx32, may detect the majority of Chinese CMT1 patients.

Amino Acid Substitution↗

Ube1L and protein ISGylation are not essential for alpha/beta interferon signaling.

The expression of ubiquitin-like modifier ISG15 and its conjugation to target proteins are highly induced by interferon (IFN) stimulation and during viral and bacterial infections. However, the biological significance of this modification has not been clearly understood. To investigate the function of protein modification by ISG15, we generated a mouse model deficient in UBE1L, an ISG15-activating enzyme. Ube1L-/- mice did not produce ISG15 conjugates but expressed free ISG15 normally. ISGylation has been implicated in the reproduction and innate immunity. However, Ube1L-/- mice were fertile and exhibited normal antiviral responses against vesicular stomatitis virus and lymphocytic choriomeningitis virus infection. Our results indicate that UBE1L and protein ISGylation are not critical for IFN-alpha/beta signaling via JAK/STAT activation. Moreover, using Ube1L/Ubp43 double-deficient mice, we showed that lack of UBP43, but not the increase of protein ISGylation, is related to the increased IFN signaling in Ubp43-deficient mice.

Animals↗

Establishment and application of a high throughput model for Rho kinase inhibitors screening based on fluorescence polarization.

Rho kinase (ROCK) inhibitors are effective candidates for neural or cardiovascular disorders. High throughput model for screening ROCK inhibitors is a basic foundation to pick up ROCK inhibitors from thousands of compounds for drug developing. The high throughput model was established based on purified recombinant rat ROCK catalytic domain (rROCK-CD) from Escherichia coli (E. coli). There are two steps of reaction in the model: incubation of 5.0 microl recombinant rROCK-CD (2.0 microg/ml), 5.0 microl different compounds, 5.0 microl fluorescent S6-peptide (200 nM), and 5.0 microl ATP (10 microM) at 37 degrees C for 60 min was made the first reaction, and the second reaction was made by incubating them with additional 60 microl binding reagent at ambient temperature for 30 min. The phosphorylated S6 peptide can bind to a binding reagent, and the fluorescence varies from low polarization to high according to the amount of the phosphorylated peptide. IC50 was calculated based on polarization variation. Compound, which IC50 was less than 10 microM, was recognized as a lead compound which taken bioactivity evaluation in PC12 by observing neurite outgrowth. The Z'-factor of the model is 0.81 (above 0.5). The model screened five lead compounds from 3294, which promoted neurite outgrowth to different extent. The results suggested that the model is suitable for high throughput screening (HTS), and the five lead compounds are worth of further investigation.

Animals↗

Harvest active recombinant Rho kinase from Escherichia coli.

Rho kinase (ROCK) inhibitors are effective candidates for treating nerve or myocardial injury, erectile dysfunction, and other cardiovascular diseases. Purified ROCK is a foundation for ROCK inhibitors screening and for its function research in vitro. This article established an easy way to harvest active recombinant ROCK catalytic domain (ROCK-CD) of rat in Escherichia coli (E. coli). The cDNA of ROCK-CD was amplified by RT-PCR, and subcloned to pET28a(+) vector to express the protein in E. coli BL(21) as inclusion bodies. The protein was purified by HiTrap chelating column, and its refolding was achieved by gradient dilution from guanidine hydrochloride solution, and desalinated by ultrafiltration. The result of DNA sequencing and protein sequence analysis indicate there were three amino acid residua of mutation, but the activity was not significantly affected. The activity of the recombinant protein was confirmed by ROCK II activity fluorescence polarization kit. Therefore, this is an easy and rapid procedure to harvest a large quantity of activity recombinant ROCK-CD at low cost.

Amino Acid Sequence↗

Determination of the concentration of diallyl trisulfide in rat whole blood using gas chromatography with electron-capture detection and identification of its major metabolite with gas chromatography mass spectrometry.

A simple, rapid, and sensitive procedure has been developed using gas chromatography with electron-capture detection to measure diallyl trisulfide levels in rat blood. Blood samples were acidified, and the analyte was extracted with hexane, and then degradation was stopped with acetonitrile before gas chromatographic separation. Two calibration curves were linear over the range of 10-500 ng/ml and 0.2-20 microg/ml, with typical r values of 0.9986 and 0.9993, respectively. The structure of its major metabolite was confirmed using combined gas chromatography-mass spectrometry. The limit of detection was less than 10 ng/ml, and the assay was highly reproducible, giving peaks with excellent chromatographic properties. The method is suitable for pharmacokinetic and therapeutic purposes.

Allyl Compounds↗