Biomedical subjects

X Lu

Publications and source records attributed to X Lu.

At least 37 records · Page 2Linked to original sources

PubMed2003

Shear modulus of porcine coronary artery: contributions of media and adventitia.

The epicardial coronary arteries experience significant torsion in the axial direction due to changes in the shape of the heart during the cardiac cycle. The objective of this study was to determine the torsional mechanical properties of the coronary arteries under various circumferential and longitudinal loadings. The coronary artery was treated as a two-layer composite vessel consisting of intima-medial and adventitial layers, and the shear modulus of each layer was determined. Eight porcine hearts were obtained at a local abattoir, and their right coronary and left anterior descending arteries were isolated and tested in vitro with a triaxial torsion machine (inflation, longitudinal stretch, and circumferential twist). After the intact vessel was tested, the adventitia was dissected away, leaving an intact media that was then tested under identical triaxial loading conditions. We proposed a biomechanical analysis to compute the shear modulus of the adventitia from the measured shear moduli of the intact vessel and the media. To validate our predictions, we used four additional hearts in which the shear modulus of the adventitia was measured after dissection of media. Our results show that the shear modulus does not depend on the shear stress or strain but varies linearly with circumferential and longitudinal stresses and in a nonlinear way with the corresponding strains. Furthermore, we found that the shear modulus of the adventitia is larger than that of the intact vessel, which is larger than the vessel media. These results may have important implications for baroreceptor sensitivity, circulation of the vasa vasorum, and coronary dissection.

Animals↗

PubMed2003

Thyrotropin-releasing hormone receptors -- similarities and differences.

Thyrotropin-releasing hormone (TRH) initiates its effects by interacting with cell-surface membrane receptors. Two G protein-coupled receptors for TRH, TRH receptor type 1 (TRH-R1) and TRH receptor type 2 (TRH-R2), have been cloned from mammals. In this review, we compare TRH-R1 and TRH-R2 with regard to their tIssue distribution, binding affinities for TRH and TRH analogs, basal and activated signaling activities and characteristics of internalization. TRH-R1 and TRH-R2 are distributed differently in the brain and peripheral tIssues, but exhibit indistinguishable binding affinities for TRH and TRH analogs. Although they both can be stimulated by TRH to similar maximal signaling levels, TRH-R2 exhibits higher basal signaling activity and is more rapidly internalized than TRH-R1. These differences in signaling and internalization properties are probably important in the distinct parts that TRH-R1 and TRH-R2 may play in mammalian physiology.

Animals↗

PubMed2003

Modulation of integrin-binding selectivity by mutation within the RGD-loop of snake venom proteins: a novel drug development approach.

Integrins are a family of heterodimeric class I transmembrane receptors, many of which bind to the RGD sequence in adhesive proteins and mediate the adhesive interactions of a variety of cells. The RGD motif has also been found in snake venom proteins that specifically inhibit integrin binding function and serve as potent integrin antagonists. The majority of these proteins interact with beta1 and beta3 associated integrins and their potency is at least 500-2000 times higher than short RGD peptides. Structural and functional studies suggest that the inhibitory potency of these proteins lies in subtle positional requirements of the tripeptide RGD that is harboured in a defined flexible loop. The integrin-binding specificity and selectivity of each of the proteins is controlled by amino acid residues in this loop in close vicinity to the RGD-motif. The review includes an overview of the structure and function of snake-venom integrin antagonists. The ability of these proteins to control platelet aggregation, cell adhesion and ligand binding is compared to that of short linear, cyclic RGD-peptides and RGD-containing proteins and the influence of modulation of amino acid residues flanking the RGD motif is also considered. The review is intended to provide insight into the development of novel inhibitors as drugs.

Amino Acid Sequence↗

PubMed2002

Long-term retention of motor skill in macaque monkeys and humans.

Remarkable human performance, such as playing the violin, is often based on motor skills that, once acquired, are retained for a long time. To examine how motor skills are retained, we trained monkeys and humans extensively to perform many visuomotor sequences and examined their performance after a long retention period of up to 18 months. For both monkeys and humans, we found strong evidence for long-term retention of motor skills. Each of the monkey subjects initially learned 6-18 sequences of button presses extensively by trial-and-error for up to 18 months. After a long retention period, they were asked to perform the previously learned (OLD) sequences together with completely new (NEW) sequences. The performance for OLD sequences was much better than for NEW sequences in terms of accuracy (assessed by the number of errors to criterion) and speed (assessed by the performance time). However, the retention was interfered with in two conditions, but in selective manners: (1) Learning of other sequences during the retention period interfered with accuracy, but not speed, of performance; (2) Inter-manual transfer was absent for speed, but not accuracy, of performance. The human subjects performed basically the same task as the monkeys. Each subject initially learned one sequence of 20 button presses by trial-and-error during an 8-10 day learning session. After 16 months, they were asked to perform the previously learned sequence (OLD sequence) and additional sequences including RECENT sequences (learned one day before) and NEW sequences. Their performance was considerably better on OLD and RECENT sequences than NEW sequences. Whereas the number of errors (reflecting 'accuracy') was lower for RECENT than for OLD sequences, the performance time (reflecting 'speed') was shorter for OLD than for RECENT sequences. Interestingly, the subjects were unaware that they had experienced OLD sequences. The results suggest that a motor skill is acquired and retained in two different forms, accuracy and speed. This occurs separately but concurrently. This conclusion is consistent with the hypothesis that at least two neural mechanisms operate independently to represent a motor skill.

Adult↗

PubMed2002

Effects of delay time on transient Ni-like x-ray lasers.

In transient collisional excitation scheme, a long (nanosecond) prepulse is used to perform and ionize plasmas. After a delay time, a short (sub- or picosecond) intense laser pulse is used to rapidly heat the plasma. This results in transient x-ray lasers with high gain. Effects of delay time on transient collisional excitation nickel-like x-ray lasers are investigated analytically using a simple model. The calculations show that the longer delay time can greatly relax the density gradient. This is very critical for the propagation of x-ray lasers. However, a too long delay will reduce the electron temperature of the plasma before the arrival of the short pulse. Increasing the intensity of the long pulse or extending the pulse duration can keep the temperature required to maintain a high percentage of Ni-like ions while the delay time is longer. Similarly, increasing the intensity of the short pulse or extending the duration can also raise the electron temperature, resulting in higher gain coefficient. Our results indicate that extending the pulse duration is more efficient than that of increasing the intensity.

Journal Article↗

PubMed2002

Progastrin1-80 stimulates growth of intestinal epithelial cells in vitro via high-affinity binding sites.

Proliferation and carcinogenesis of the large intestinal epithelial cells (IEC) cells is significantly increased in transgenic mice that overexpress the precursor progastrin (PG) peptide. It is not known if the in vivo growth effects of PG on IEC cells are mediated directly or indirectly. Full-length recombinant human PG (rhPG(1-80)) was generated to examine possible direct effects of PG on IEC cells. Surprisingly, rhPG (0.1-1.0 nM) was more effective than the completely processed gastrin 17 (G17) peptide as a growth factor. Even though IEC cells did not express CCK(1) and CCK(2) receptors (-R), fluorescently labeled G17 and Gly-extended G17 (G-Gly) were specifically bound to the cells, suggesting the presence of binding proteins other than CCK(1)-R and CCK(2)-R on IEC cells. High-affinity (K(d) = 0.5-1.0 nM) binding sites for (125)I-rhPG were discovered on IEC cells that demonstrated relative binding affinity for gastrin-like peptides in the order PG >or= COOH-terminally extended G17 >or= G-Gly > G17 > *CCK-8 (* significant difference; P < 0.05). In conclusion, our studies demonstrate for the first time direct growth effects of the full-length precursor peptide on IEC cells in vitro that are apparently mediated by the high-affinity PG binding sites that were discovered on these cells.

Amino Acids↗

PubMed2002

Investigations on a clinically and functionally unusual and novel germline p53 mutation.

This report describes an individual with a rare choroid plexus papilloma in adulthood (age 29) after earlier having an osteosarcoma (age 22). The results from this study, and others, suggest that it may be advisable to consider the possibility of a germline p53 mutation in adults presenting with choroid plexus tumours. In the current study automated DNA sequencing of genomic DNA detected a novel germline 7 base pair insertion in exon 5 of the p53 gene in this patient. The alteration in frame would produce amino acid substitutions beginning with alanine to glycine at position 161 and a stop codon at position 182 in the mutated protein. Surprisingly two assays of p53 function gave apparently wild-type results on peripheral blood lymphocytes from this individual. These results led us to carry out more detailed functional tests on the mutant protein. The mutant allele was expressed either at very low levels or not at all in phytohaemagglutinin stimulated lymphocytes. Further, the mutant protein was completely non-functional in terms of its ability to transactivate a series of p53-responsive genes (p21(WAF1), bax, PIG3), to transrepress a target gene and to inhibit colony growth in transfected Saos-2 cells. However, surprisingly, data from irradiated peripheral blood lymphocytes and transfected Saos-2 cells, suggested that this truncated, mutant protein retains significant ability to induce apoptosis.

Adult↗

PubMed2002

Tyrosine phosphatase inhibition enhances neurotrophin potency and rescues nigrostriatal neurons in adult rats.

Neurotrophic factors regulate a variety of cellular processes, including neuronal survival during development and after injury. For instance, brain-derived neurotrophic factor (BDNF) can prevent the death of dopaminergic substantia nigra neurons in rats. Most neurotrophic factor receptors, such as TrkB for BDNF, are tyrosine kinases whose signaling is terminated by protein tyrosine phosphatases (PTPs). We tested the idea that inhibition of PTPs, and thus potentially enhancement of the efficiency of endogenous trophic factors and their receptors, would lead to increased neuronal survival. After a 2-week infusion of the small PTP inhibitor molecule peroxovanadium (pVa, pervanadate) close to the substantia nigra of adult rats, up to 66% of axotomized substantia nigra neurons had survived, compared to only 33% in control rats infused with PBS. PVa most likely affected TrkB and/or downstream signaling molecules, as ineffective doses of BDNF and pVa had a synergistic effect when given simultaneously, rescuing 82% of the neurons. PVa stimulated tyrosine hydroxylase (TH) expression in the noninjured substantia nigra but did not prevent axotomy-induced loss of TH. These results raise the possibility that PTP inhibition can prevent neuronal death by enhancing neurotrophic factor signaling pathways in the adult mammalian nervous system, identifies an important role for PTPs in neuronal functioning, and points to a novel small molecule treatment approach for neurologic disorders

Animals↗

PubMed2002

Growth pH does not affect the initial physiological state parameter (pO) of Listeria monocytogenes.

It has proven difficult to develop adequate mathematical models for the lag phase (lambda) which characterizes the adaptation period prior to the initiation of exponential growth by microorganisms. This is due, in part, to our incomplete understanding of the nature of the initial physiological state of cells (defined as h0 or p0 depending on the model), and changes taking place during adaptation. The objectives of the present study were to characterize p0 using data from growth of Listeria monocytogenes in an automated turbidimetric instrument (Bioscreen), and to determine the influence of limiting growth pH. A model was developed for individual cells which combined a continuous adaptation phase (defined by p0) with a discrete step marking the transition to a continuous exponential growth phase (the CDC model). Parameters of the new model were: p0; the specific growth rate (mu); the initial cell number (N0); and the maximum cell density (Nmax). Progressive reduction of the growth pH in the Bioscreen to 4.7 decreased the p. It was noted that the regression lines for all trials at all pH values appeared to have a common x-intercept (20.086+/-1.092), and it was deduced that, when the Bioscreen detection limit (15.07 In cfu well(-1)) was subtracted, the resulting value represented the "true" value for the initial physiological state of the cells.

Adaptation, Physiological↗

PubMed2002

Proposal of a novel parameter to describe the influence of pH on the lag phase of Listeria monocytogenes.

Predictive models for lag phase duration (lambda) have been less reliable than specific growth rate (mu) models due, in part, to the influence of the pre-growth environment on lambda. A discrete modelling approach was taken to more completely define the response of individual cells to new environments. Time to detection (td) data was obtained from serial twofold dilutions of Listeria monocytogenes growing in a Bioscreen at 30 degrees C. Comparison of the inoculum densities required to achieve maximum td at growth pH values from 7.2 to 4.7 revealed that, as the growth pH decreased, fewer cells were capable of making the transition to the exponential phase. The proportion of these cells (termed "adaptable cells") in the original inoculum was used to define a new parameter (r0) which, when combined with the constant mean individual cell physiological state parameter (p0), the variation in p0 (SDp0), the inital inoculum (N0) and the maximum population density (Nmax) was able to simulate a complete growth curve. Power transformations with rescaled explanatory variables provided suitable models for the influence of pH on mu, r0, and SDp0, (r2>0.70).

Colony Count, Microbial↗

PubMed2002

Morphometric and biomechanical remodelling in the intestine after small bowel resection in the rat.

The short-bowel syndrome is a clinical condition caused by intestinal resection. As intestinal adaptation occurs after resection, it can be used as a model for studying morphometric and biomechanical remodelling in the small intestine and to get a better understanding of the pathophysiology of the short-bowel syndrome. The resected rats had a 67% resection of jejunum and ileum. Control animals underwent no operation (nonoperated controls) or an ileal transection with subsequent end-to-end anastomosis (sham-resected controls). The animals were followed for up to 4 weeks after the operation. Changes in biomechanical properties were studied in terms of residual strain (the internal strain remaining when all external loads are removed), opening angle and stress--strain relations referenced to the zero-stress state (the cut-open state where external and internal stresses are released). The resected animals gained less weight than the controls. The intestinal length and diameter increased more in the resected groups than the control groups (P < 0.05), resulting in a larger absorptive surface. Resection induced profound gross morphometric changes and histological alterations characterized by proliferative increases in the tissue layers. The opening angle, along with residual strain at the mucosal and serosal surface, increased in the remnant small intestine (P < 0.05). All changes increased as function of postoperative time and were most prominent in the remnant ileum. However, the stress-strain relationship remained unchanged. In conclusion, this study demonstrated that resection of the majority of the small bowel results in significant remodelling in structural and residual strain properties in the remnant small intestine. The remodelling seems to be guided by the need for a greater absorptive surface area rather than for a change in the stress-strain properties.

Adaptation, Physiological↗

PubMed2002

Transporter gene expression in lactating and nonlactating human mammary epithelial cells using real-time reverse transcription-polymerase chain reaction.

Transporter-mediated processes in the lactating mammary gland may explain the significant accumulation of certain drugs in breast milk. The purpose of this study was to identify potential candidate drug transport proteins involved in drug accumulation in milk. Quantitative reverse transcription-polymerase chain reaction methods were developed to determine the relative RNA levels of 30 different drug transporter genes. Transporter gene RNA levels in lactating mammary epithelial cells (MEC) purified from pooled fresh breast milk samples were compared with levels in nonlactating MEC, liver, and kidney tissue. Transcripts were detected in lactating MEC for OCT1, OCT3, OCTN1, OCTN2, OATP-A, OATP-B, OATP-D, OATP-E, MRP1, MRP2, MRP5, MDR1, CNT1, CNT3, ENT1, ENT3, NCBT1, PEPT1, and PEPT2. No transcripts were detected for OCT2, OAT1, OAT2, OAT3, OAT4, OATP-C, MRP3, MRP4, CNT2, ENT2, and NCBT2. Lactating MEC demonstrated more than 4-fold higher RNA levels of OCT1, OCTN1, PEPT2, CNT1, CNT3, and ENT3, and more than 4-fold lower RNA levels of MDR1 and OCTN2 relative to nonlactating MEC. Lactating MEC showed significantly higher RNA levels of CNT3 relative to liver and kidney, increased PEPT2 RNA levels relative to liver, and increased OATP-A RNA levels relative to kidney. These data imply CNT3 may play a specialized role in nucleoside accumulation in milk and may identify an important role for PEPT2 and OATP-A transporters at the lactating mammary epithelium. Furthermore, transporters expressed in lactating MEC identify a potential role for these transporters in drug disposition at the mammary gland.

Breast↗

PubMed2001

Arsenic-induced congenital malformations in genetically susceptible folate binding protein-2 knockout mice.

Arsenic is a well-known carcinogen, which has been suspected of being a human teratogen, although there is currently insufficient and inadequate supportive data to make any definitive judgments. In addition, the significance of individual genetic differences on pregnancy outcomes following in utero exposure to arsenic is currently unknown. In order to better understand the role of folate transport mechanisms in arsenic-induced neural tube defects, we examined the effect of in utero exposure to sodium arsenate in a genetically altered murine model in which the folate binding protein 2 (Folbp2) gene has been inactivated by homologous recombination. In utero sodium arsenate exposure induced exencephaly in 40.6% of Folbp2(-/-) embryos compared with 24.0% in control Folbp2(+/+) embryos. The differences in response frequencies were further exacerbated when the dams were fed a folate-deficient diet. Under these conditions, exencephaly was observed in 64.0% of Folbp2(-/-) embryos compared with 25.7% in control Folbp2(+/+) embryos. Analysis of arsenic metabolites excreted in the urine following sodium arsenate injection to Folbp2(-/-) and Folbp2(+/+) mice indicated that there were no significant differences in arsenic metabolism between the two groups. Thus, the increased susceptibility of Folbp2(-/-) mice to arsenate-induced teratogenicity may not be due to differences in biomethylation and exposure. In conclusion, the data suggest that impaired folate transport in the developing mouse embryo increases the risk for developmental defects following in utero exposure to sodium arsenate and that these differences are not due to differences in metabolism of arsenic.

Animals↗

PubMed2001

Palladium(II)-catalyzed tandem reaction of intramolecular aminopalladation of allenyl N-tosylcarbamates and conjugate addition.

A divalent palladium-catalyzed tandem cyclization-coupling reaction of allenyl N-tosylcarbamates and acrolein was developed. The reaction gave aldehyde-functionalized 2-oxazolidinones in one step with high regioselectivity. A mechanism involving intramolecular aminopalladation of allene, followed by insertion of alkene and C-Pd bond protonolysis, is proposed. [reaction: see text]

Journal Article↗

PubMed2001

Palladium(II)-catalyzed asymmetric cyclization of (Z)-4'-acetoxy-2'-butenyl 2-alkynoates. Role of nitrogen-containing ligands in palladium(II)-mediated reactions.

Pd(OAc)(2) combined with nitrogen-containing ligands (e.g., 2,2'-bipyridine) catalyzed the cyclization of (Z)-4'-acetoxy-2'-butenyl 2-alkynoates (1) in acetic acid to afford the alpha-(Z)-acetoxyalkylidene-beta-vinyl-gamma-butyrolactones (2) with high efficiency and high stereoselectivity. The nitrogen-containing ligands, like halides, served to favor beta-heteroatom elimination over beta-hydride elimination in Pd(II)-mediated reactions. The generality of this ligand effect was probed in both stoichiometric and catalytic reactions. With these results in hand, the catalytic asymmetric protocol was achieved with high enantioselectivity (up to 92% ee) when pymox (pyridyl monooxazoline) or bisoxazoline was used. The absolute configuration of the products and the synthetic utility of this asymmetric transformation were established through the convenient synthesis of (3S)-(+)-A-factor.

Journal Article↗

PubMed2001

Palladium(II)-catalyzed synthesis of alpha-alkylidene-gamma-butyrolactams from N-allylic 2-alkynamides. Total synthesis of (+/-)-isocynodine and (+/-)-isocynometrine.

An efficient method for preparing alpha-alkylidene-gamma-butyrolactams via the Pd(II)-catalyzed cyclization of acyclic N-allylic 2-alkynamides via halopalladation, intramolecular olefin insertion, and beta-heteroatom elimination was developed. The reaction is less influenced by the leaving group and the concentration of the halide ions in comparison with the cyclization of acyclic alkynoates. The total syntheses of (+/-)-isocynodine and (+/-)-isocynometrine were realized using this method.

Alkaloids↗

PubMed2001

[An application value of detecting K-ras and p53 gene mutation in the stool and pure pancreatic juice for diagnosis of early pancreatic cancer].

OBJECTIVE: To explore new methods for the early diagnosis of pancreatic cancer through detecting of K-ras, p53 mutations in pancreatic juice and stool. METHODS: 201 patients in PUMC Hospital from 1994-2000. 5 and 60-control individuals were enrolled. K-ras point mutations were detected by PCR-RFLP, however p53 mutation was detected by PCR-SSCP. RESULTS: K-ras mutations in pancreatic juice were found in 87.8% (36/41) of pancreatic cancer, 23.5% (4/17) of benign pancreatic disease. Of 261 stools specimens, amplification was successful in 235 (90.0%). K-ras mutation in stool were found in 88.0% (66/75) of pancreatic cancer 51.1% (24/47) of benign pancreatic disease, 19.6% (9/46) of normal individuals. p53 mutation in pancreatic juice were found in 47.4% (18/38), 12.5% (2/16) of benign pancreatic disease, p53 mutation in stool were found in 37.1% (23/62), 19.1% (4/12) of chronic pancreatitis. CONCLUSION: K-ras mutation in pancreatic juice has high sensitivity and specificity, so it can be used as a adjunct in the diagnosis of pancreatic cancer. Detection of K-ras mutation combined with p53 mutation in stool can be helpful to screen for pancreatic carcinoma. Combined with serum CA19-9 detection, it might increase the early diagnostic rate of pancreatic carcinoma.

Adult↗

PubMed2001

A novel phosphotyrosine mimetic 4'-carboxymethyloxy-3'-phosphonophenylalanine (Cpp): exploitation in the design of nonpeptide inhibitors of pp60(Src) SH2 domain.

The novel phosphotyrosine (pTyr) mimetic 4'-carboxymethyloxy-3'-phosphonophenylalanine (Cpp) has been designed and incorporated into a series of nonpeptide inhibitors of the SH2 domain of pp60(c-Src) (Src) tyrosine kinase. A 2.2 A X-ray crystal structure of 1a bound to a mutant form of Lck SH2 domain provides insight regarding the structure-activity relationships and supports the design concept of this new pTyr mimetic.

Animals↗