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Biomedical subjects

Z Lai

Publications and source records attributed to Z Lai.

At least 37 records · Page 2Linked to original sources
PubMed2000

I. The neurocognitive profile of Williams Syndrome: a complex pattern of strengths and weaknesses.

The rare, genetically based disorder, Williams syndrome (WMS), produces a constellation of distinctive cognitive, neuroanatomical, and electrophysiological features which we explore through the series of studies reported here. In this paper, we focus primarily on the cognitive characteristics of WMS and begin to forge links among these characteristics, the brain, and the genetic basis of the disorder. The distinctive cognitive profile of individuals with WMS includes relative strengths in language and facial processing and profound impairment in spatial cognition. The cognitive profile of abilities, including what is 'typical' for individuals with WMS is discussed, but we also highlight areas of variability across the group of individuals with WMS that we have studied. Although the overall cognitive abilities (IQs) of individuals with WMS are typically in the mild-to-moderate range of mental retardation, the peaks and valleys within different cognitive domains make this syndrome especially intriguing to study across levels. Understanding the brain basis (and ultimately the genetic basis) for higher cognitive functioning is the goal we have begun to undertake with this line of interdisciplinary research.

Child↗
PubMed2000

II. Hypersociability in Williams Syndrome.

Studies of abnormal populations provide a rare opportunity for examining relationships between cognition, genotype and brain neurobiology, permitting comparisons across these different levels of analysis. In our studies, we investigate individuals with a rare, genetically based disorder called Williams syndrome (WMS) to draw links among these levels. A critical component of such a cross-domain undertaking is the clear delineation of the phenotype of the disorder in question. Of special interest in this paper is a relatively unexplored unusual social phenotype in WMS that includes an overfriendly and engaging personality. Four studies measuring distinct aspects of hypersocial behavior in WMS are presented, each probing specific aspects in WMS infants, toddlers, school age children, and adults. The abnormal profile of excessively social behavior represents an important component of the phenotype that may distinguish WMS from other developmental disorders. Furthermore, the studies show that the profile is observed across a wide range of ages, and emerges consistently across multiple experimental paradigms. These studies of hypersocial behavior in WMS promise to provide the groundwork for crossdisciplinary analyses of gene-brain-behavior relationships.

Adolescent↗
PubMed2000

IV. Neuroanatomy of Williams syndrome: a high-resolution MRI study.

Williams syndrome (WMS), a genetic condition resulting from a contiguous deletion on the long arm of chromosome 7, is associated with a relatively consistent profile of neurocognitive and neurobehavioral features. The distinctiveness and regularity of the profile of learning and behavioral characteristics in this genetic condition suggests that underlying neurobiological correlates may be identifiable. In this initial study, we report findings derived from a high-resolution neuroimaging study of 14 young adult subjects with WMS and an individually matched normal control group. Compared to controls, subjects with WMS were noted to have decreased overall brain and cerebral volumes, relative preservation of cerebellar and superior temporal gyrus (STG) volumes, and disproportionate volume reduction of the brainstem. Analyses also suggested that the pattern of cerebral lobe proportions in WMS may be altered compared to normal controls with a greater ratio of frontal to posterior (parietal+occipital) tissue. Assessment of tissue composition indicated that, relative to controls, individuals with WMS have relative preservation of cerebral gray matter volume and disproportionate reduction in cerebral white matter volume. However, within the cerebral gray matter tissue compartment, the right occipital lobe was noted to have excess volume loss. Combined with our growing knowledge of the function of genes in the commonly deleted region for WMS, more detailed information regarding the structure and function of the WMS brain will provide a unique opportunity for elucidating meaningful correlations amongst genetic, neurobiological, and neurobehavioral factors in humans.

Adult↗
PubMed2000

VI. Genome structure and cognitive map of Williams syndrome.

Williams syndrome (WMS) is a most compelling model of human cognition, of human genome organization, and of evolution. Due to a deletion in chromosome band 7q11.23, subjects have cardiovascular, connective tissue, and neurodevelopmental deficits. Given the striking peaks and valleys in neurocognition including deficits in visual-spatial and global processing, preserved language and face processing, hypersociability, and heightened affect, the goal of this work has been to identify the genes that are responsible, the cause of the deletion, and its origin in primate evolution. To do this, we have generated an integrated physical, genetic, and transcriptional map of the WMS and flanking regions using multicolor metaphase and interphase fluorescence in situ hybridization (FISH) of bacterial artificial chromosomes (BACs) and P1 artificial chromosomes (PACs), BAC end sequencing, PCR gene marker and microsatellite, large-scale sequencing, cDNA library, and database analyses. The results indicate the genomic organization of the WMS region as two nested duplicated regions flanking a largely single-copy region. There are at least two common deletion breakpoints, one in the centromeric and at least two in the telomeric repeated regions. Clones anchoring the unique to the repeated regions are defined along with three new pseudogene families. Primate studies indicate an evolutionary hot spot for chromosomal inversion in the WMS region. A cognitive phenotypic map of WMS is presented, which combines previous data with five further WMS subjects and three atypical WMS subjects with deletions; two larger (deleted for D7S489L) and one smaller, deleted for genes telomeric to FZD9, through LIMK1, but not WSCR1 or telomeric. The results establish regions and consequent gene candidates for WMS features including mental retardation, hypersociability, and facial features. The approach provides the basis for defining pathways linking genetic underpinnings with the neuroanatomical, functional, and behavioral consequences that result in human cognition.

Adolescent↗
PubMed2000

[The evaluation of cagA and other vaccine candidate proteins of Helicobacter pylori on T cell apoptosis mediated by Fas/Fas ligand interaction].

OBJECTIVE: To evaluate the effect of several surface proteins of Helicobacter pylori (H. pylori) on inducing apoptosis of T cells through the modulation of Fas/Fas ligand (FasL) interaction and to provide information on the screen of safe and effective immunogen for H. pylori vaccine. METHODS: T cell apoptosis induced by cagA+ and isogenic cagA knockout strain, recombinant urease, HpaA and outer membrane proteins, Hop25, Hop35 and Hop38 was detected by JAM assay. Flow cytometry was used to evaluate the increase in FasL expression on T cells under the stimulation of these bacterial proteins. Metalloprotease inhibitor, 1, 10-Phenanthroline (PHE) and protein synthesis inhibitor, emetine, were used to change the activity of FasL to confirm the association of FasL with H. pylori mediated killing toward T cells. RESULTS: The effect of cagA+ H. pylori was stronger in both the induction of apoptosis and FasL expression of T cells than that of cagA knockout strain. H. pylori urease could not kill T cell, while Hop38 had the strongest effect among the tested H. pylori proteins on the induction of T cell apoptosis through increasing FasL expression. Metaloprotease inhibitor could increase the killing of T cells induced by H. pylori because of its ability to prevent the cleavage of membrane-bound FasL protein. On the other hand, emetine could decrease H. pylori mediated killing by inhibiting of FasL synthesis on T cells. CONCLUSION: cagA and Hop38 protein might be involved in the negative regulation of T cell growth through upregulating FasL expression urease and other Hop proteins tested might be safe and effective to be used as the antigens for H. pylori vaccine.

Antigens, Bacterial↗
PubMed2000

[Poly-static quantitative perimetry for detection of open angle glaucoma].

OBJECTIVE: To evaluate the sensitivity of poly-static quantitative perimetry for the detection of visual field defect in open angle glaucoma. METHODS: 48 patients (95 eyes) of open angle glaucoma were examined with poly-static quantitative perimetry [Friedmann visual field analyzer (FVFA)] and dynamic perimetry (tangent screen) respectively. RESULTS: 26 eyes showed small defect of visual field on tangent screen with 2/1,000 visual size, and 23 eyes (88%) showed the same defects checked with FVFA; visual field defects of early stage glaucoma were found in 26 eyes checked with FVFA, but only 16 eyes showed the same defects on tangent screen with 1/1,000 visual size; the visual field defects of glaucoma on tangent screen in 43 eyes were found larger when they were checked with FVFA. CONCLUSION: Comparing with dynamic perimetry, poly-static quantitative perimetry is more sensitive to detect visual field defect of early stage glaucoma.

Adult↗
PubMed1999

Elevated O-linked N-acetylglucosamine metabolism in pancreatic beta-cells.

High intracellular glucose concentrations increase flux though the hexosamine biosynthetic pathway, resulting in elevated UDP-N-acetylglucosamine (GlcNAc) concentrations. The nucleocytoplasmic enzyme O-linked N-acetylglucosaminyltransferase (OGT) uses UDP-GlcNAc as a donor to modify numerous critical substrates, including nuclear pore proteins and transcription factors. Here, we document (a) the overwhelming enrichment of pancreatic OGT transcripts in the beta-cells of the islets of Langerhans, (b) the physiologically significant increase in the level of O-GlcNAc residues present in beta-cells, and (c) the action of streptozotocin, a close analogue of GlcNAc, to selectively inhibit O-GlcNAcase, an enzyme involved in the removal of O-GlcNAc residues. Taken together, these findings suggest that pancreatic beta cells maintain a highly elevated O-GlcNAc metabolism and that the diabetes inducing drug streptozotocin inhibits O-GlcNAcase.

Acetylglucosamine↗
PubMed1999

The yan gene is highly conserved in Drosophila and its expression suggests a complex role throughout development.

Competence for cell fate determination and cellular differentiation is under tight control of regulatory genes. Yan, a nuclear target of receptor tyrosine kinase (RTK) signaling, is an E twenty six (ETS) DNA-binding protein that functions as a negative regulator of cell differentiation and proliferation in Drosophila. Most members of RTK signaling pathways are highly conserved through evolution, yet no yan orthologues have been identified to date in vertebrates. To investigate the degree of yan conservation during evolution, we have characterized a yan homologue from a sibling species of D. melanogaster, D. virilis. Our results show that the organization, primary structure and expression pattern of yan are highly conserved. Both genes span over 20 kb and contain four exons with introns at identical positions. The areas with highest amino acid similarity include the Pointed and ETS domain but there are other discrete regions with a high degree of similarity. Phylogenetic analysis reveals that yan's closest relative is the human tel gene, a negative regulator of differentiation in hematopoetic precursors. In both species, Yan is dynamically expressed beginning as early as stage 4/5 and persisting throughout embryogenesis. In third instar larvae, Yan is expressed in and behind the morphogenetic furrow of the eye imaginal disc as well as in the laminar precursor cells of the brain. Ovarian follicle cells also contain Yan protein. Conservation of the structure and expression patterns of yan genes strongly suggests that regulatory mechanisms for their expression are also conserved in these two species.

Amino Acid Sequence↗
PubMed1999

A shotgun optical map of the entire Plasmodium falciparum genome.

The unicellular parasite Plasmodium falciparum is the cause of human malaria, resulting in 1.7-2.5 million deaths each year. To develop new means to treat or prevent malaria, the Malaria Genome Consortium was formed to sequence and annotate the entire 24.6-Mb genome. The plan, already underway, is to sequence libraries created from chromosomal DNA separated by pulsed-field gel electrophoresis (PFGE). The AT-rich genome of P. falciparum presents problems in terms of reliable library construction and the relative paucity of dense physical markers or extensive genetic resources. To deal with these problems, we reasoned that a high-resolution, ordered restriction map covering the entire genome could serve as a scaffold for the alignment and verification of sequence contigs developed by members of the consortium. Thus optical mapping was advanced to use simply extracted, unfractionated genomic DNA as its principal substrate. Ordered restriction maps (BamHI and NheI) derived from single molecules were assembled into 14 deep contigs corresponding to the molecular karyotype determined by PFGE (ref. 3).

Animals↗
PubMed1999

Optical mapping of Plasmodium falciparum chromosome 2.

Detailed restriction maps of microbial genomes are a valuable resource in genome sequencing studies but are toilsome to construct by contig construction of maps derived from cloned DNA. Analysis of genomic DNA enables large stretches of the genome to be mapped and circumvents library construction and associated cloning artifacts. We used pulsed-field gel electrophoresis purified Plasmodium falciparum chromosome 2 DNA as the starting material for optical mapping, a system for making ordered restriction maps from ensembles of individual DNA molecules. DNA molecules were bound to derivatized glass surfaces, cleaved with NheI or BamHI, and imaged by digital fluorescence microscopy. Large pieces of the chromosome containing ordered DNA restriction fragments were mapped. Maps were assembled from 50 molecules producing an average contig depth of 15 molecules and high-resolution restriction maps covering the entire chromosome. Chromosome 2 was found to be 976 kb by optical mapping with NheI, and 946 kb with BamHI, which compares closely to the published size of 947 kb from large-scale sequencing. The maps were used to further verify assemblies from the plasmid library used for sequencing. Maps generated in silico from the sequence data were compared to the optical mapping data, and good correspondence was found. Such high-resolution restriction maps may become an indispensable resource for large-scale genome sequencing projects.

Animals↗
PubMed1999

[Effect of integrated Traditional Chinese and Western medicine on immune function in patient of acute cerebral infarction].

OBJECTIVE: To investigate the change of serum soluble vascular cell adhesion molecule-1 (sVCAM-1) in acute cerebral infarction patients treated with integrated traditional Chinese and western medicine (TCM-WM). METHODS: Serum sVCAM-1 level of patients treated with TCM-WM or western medicine alone was measured by ELISA, and compared with that of healthy person. RESULTS: TCM-WM could reduce the sVCAM-1 level in patients with cerebral infarction (P < 0.05). The therapeutic effect of TCM-WM was better than that of western treatment alone, P < 0.05. CONCLUSION: The therapeutic mechanism of TCM-WM may be related with the modulation on immune status of patients.

Aged↗
PubMed1998

Characterization of the transthyretin acid denaturation pathways by analytical ultracentrifugation: implications for wild-type, V30M, and L55P amyloid fibril formation.

Analytical ultracentrifugation methods were utilized to further characterize the acid denaturation pathways of wild-type, V30M, and L55P transthyretin (TTR) that generate intermediates leading to amyloid fibril formation and possibly the diseases senile systemic amyloidosis and familial amyloid polyneuropathy. Equilibrium and velocity methods were employed herein to characterize the TTR quaternary structural requirements for amyloid fibril formation. From neutral to slightly acidic conditions (pH 7.5-5.1), wild-type transthyretin (0.2-0.3 mg/mL, 100 mM KCl, 37 degrees C) exists as a tetramer and is incapable of fibril formation. Under more acidic conditions (pH 5 to 3.9), tetrameric wild-type TTR slowly dissociates to a monomer having an alternatively folded tertiary structure(s) that self-assembles at physiological concentration (0.2 mg/mL) into a ladder of quaternary structural intermediates of increasing molecular weight. These intermediates appear to be on the pathway of amyloid fibril formation, since they ultimately disappear when amyloid fibrils are observed. The V30M and L55P TTR variants exhibit similar acid denaturation pathways, with the exception that dissociation of the tetramer to the monomeric amyloidogenic intermediate occurs at a higher pH and to a much greater extent, allowing the quaternary structural intermediates to be readily observed by velocity methods. Partial denaturation and assembly of the monomeric amyloidogenic intermediate(s) occur at pH 5.4 for V30M and L55P TTR over a 72 h period, during which wild-type TTR maintains its normal tetrameric three-dimensional structure. Interestingly, the L55P and V30M familial amyloid polyneuropathy (FAP) associated variants form amyloid protofilaments at pH 7.5 (37 degrees C) after several weeks of incubation, suggesting that the activation barriers for TTR tetramer dissociation to the monomeric amyloidogenic intermediate are much lower for the FAP variants relative to wild-type TTR, which does not form amyloid or amyloid protofilaments under these conditions. This study establishes the key role of the monomeric amyloidogenic intermediate and its self-assembly into a ladder of quaternary structural intermediates for the formation of wild-type, V30M, and L55P transthyretin amyloid fibrils.

Amyloid↗
PubMed1998

Metal and RNA binding properties of the hdm2 RING finger domain.

The hdm2 oncoprotein contains a C-terminal domain that binds RNA and has been suggested to bind zinc(II) in an unusual RING finger domain in which Thr 455 was postulated as a ligand. We have reported experiments to test whether this C-terminal cysteine-rich motif is indeed a RING finger domain. We also tested the affinity of the hdm2 C-terminal peptide for metal binding, metal linkage to the folding of the C-terminal peptide, and the peptide's affinity for RNA. Truncation mutants demonstrate that amino acids 425-491 are necessary and sufficient for RNA binding. However, divalent metal ions do not seem to affect the specific RNA recognition. Metal binding studies suggest that hdm2 indeed binds to two molecules of zinc in an intertwined motif similar to the BRCA1 RING finger peptide. However, there is no similarity in overall tertiary structure, nor is there direct sequence homology with other RING fingers. Fluorescence energy transfer studies give a dissociation constant of (0.22 +/- 0.03) microM for cobalt(II) binding to site 1, while K2 for cobalt(II) binding was estimated to be 15 +/- 5 microM from ultraviolet absorbance. Studies of two mutant peptides confirm the assignment of binding residues in hdm2 and suggest that the coordination of Thr 455 previously proposed by sequence alignments is incorrect. Structural studies of hdm2 in the presence and absence of metal indicate only a small amount of secondary structure by circular dichroic spectroscopy. Metal binding did not seem to nucleate folding as in the case of two other RING finger proteins. However, distance measurement from fluorescence energy transfer indicated that the Tyr 489 residue was only approximately 14 A away from the first metal center, suggesting that the hdm2 protein exists in a compact form, at least in the presence of metal ion. In summary, hdm2 binds metal and RNA, but the RNA binding does not seem to occur in a zinc-dependent manner.

Amino Acid Sequence↗
PubMed1998

Chromosome 2 sequence of the human malaria parasite Plasmodium falciparum.

Chromosome 2 of Plasmodium falciparum was sequenced; this sequence contains 947,103 base pairs and encodes 210 predicted genes. In comparison with the Saccharomyces cerevisiae genome, chromosome 2 has a lower gene density, introns are more frequent, and proteins are markedly enriched in nonglobular domains. A family of surface proteins, rifins, that may play a role in antigenic variation was identified. The complete sequencing of chromosome 2 has shown that sequencing of the A+T-rich P. falciparum genome is technically feasible.

Amino Acid Sequence↗
PubMed1998

Protein subunit interactions and structural integrity of amyloidogenic transthyretins: evidence from electrospray mass spectrometry.

Wild-type and variant transthyretins form amyloid fibrils in two different diseases. The biologically active form of transthyretin is a tetramer but there is evidence that a monomeric species is the amyloidogenic intermediate. Using mass spectrometry we have developed an approach to monitor the proportions of monomer and tetramer in wild-type and variant transthyretins, and found a strong correlation between the instability of the tetramer in the gas phase and the amyloidogenicity of the protein variant. The presence of water molecules in the central channel has been found to be critical for maintaining intact the complex in the gas phase, with additional stability observed in the presence of excess thyroxine. The solution structure of monomeric transthyretin under fibril-forming conditions was studied using hydrogen exchange monitored by mass spectrometry. The results show that Val30Met transthyretin, the commonest amyloidogenic variant, exhibits loss of hydrogen exchange protection substantially more rapidly than the wild-type protein, suggesting partial unfolding of the beta-sheet structure. These results provide new insights into the correlation between tetramer stability and amyloidogenicity as well as supporting a possible route to fibril formation via transient unfolding of the transthyretin monomer.

Amyloid↗
PubMed1998

Effects of acupuncture at fengchi point (GB 20) on cerebral blood flow.

Blood velocity in the vertebral artery and the basilar artery was observed before and after acupuncture at Fengchi point (GB 20) in 97 patients by transcranial Doppler ultrasonic detecting. The results showed that the blood velocity in patients with either high or low blood flow had significant changes after acupuncture (P < 0.001).

Acupuncture Points↗
PubMed1997

Guanidine hydrochloride-induced denaturation and refolding of transthyretin exhibits a marked hysteresis: equilibria with high kinetic barriers.

Fluorescence and circular dichroism spectroscopy as well as analytical ultracentrifugation and glutaraldehyde cross-linking were utilized to evaluate the tertiary and quaternary structural changes occurring on the denaturation and reconstitution pathways of transthyretin (TTR) as a function of guanidine hydrochloride (GdnHCl) concentration. These results demonstrate that the GdnHCl-mediated denaturation and reconstitution of TTR is reversible. However, the lowest GdnHCl concentration that dissociates and unfolds transthyretin does not allow the unfolded monomer to refold to tetramer at a rate that is measurable. As a result, there is a striking hysteresis observed upon comparison of the GdnHCl-mediated denaturation and reconstitution transitions. The TTR tetramer does not dissociate into unfolded monomer until the denaturant concentration exceeds 4 M GdnHCl, whereas unfolded monomeric TTR (denatured in 7 M GdnHCl) does not refold and assemble into a native tetrameric structure until the GdnHCl concentration is reduced to less than 2 M. These results imply that a significant kinetic barrier intervenes between the folded tetramer and unfolded monomer in both the denaturation and reconstitution directions at pH 7. A kinetics study of the denaturation of TTR as a function of GdnHCl concentration yields a first-order rate constant for unfolding of (9.0 +/- 7.5) x 10(-11) s-1, estimated by extrapolation of the rate constants for the tetramer to unfolded monomer transition as a function of GdnHCl to 0 M GdnHCl. This rate is very slow; as a result, wild-type TTR is predicted to be kinetically stable as a tetrameric quaternary structure once formed. These results imply that the rate of TTR dissociation and partial unfolding to the monomeric amyloidogenic intermediate under denaturing conditions may play a role in transthyretin-based amyloid diseases.

Circular Dichroism↗