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K Lee

Publications and source records attributed to K Lee.

At least 19 recordsLinked to original sources
PubMed2026

Development of RS1-specific ACMG/AMP variant classification criteria with pilot variant curation.

Gene-based therapies are being developed for retinal diseases, including RS1-related X-linked retinoschisis. Therefore it is essential to determine which variants are pathogenic and which are benign when enrolling patients. The Clinical Genome Resource (ClinGen) X-Linked Inherited Retinal Diseases (XLRD) Variant Curation Expert Panel (VCEP) brings together clinician scientists, molecular biologists, and geneticists to apply their expertise and review the clinical, genetic, population, and functional evidence for variants. American College of Medical Genetics (ACMG) guidelines have been modified for RS1 to develop a highly systematic and conservative framework for evaluating variants. The curation process involves applying 28 different codes, each with 4 strength levels (very strong, strong, moderate, supporting) across different domains of phenotype, population data, computational assessment, functional impact, and segregation. With RS1-specific rules, a total of 54 pilot variants were tested. These included 47 variants in ClinVar. Of these 21 variants were re-classified: 2 likely pathogenic variants and one likely benign were changed to variants of uncertain significance and 4 previously unclassified variants were changed to pathogenic, likely pathogenic and likely benign. Other changes resolved conflicts or multiple classifications.

Humans↗
PubMed2007

Toluene-induced accumulation of trehalose by Pseudomonas sp. BCNU 106 through the expression of otsA and otsB homologues.

AIM: The objective of this study was to investigate toluene-induced accumulation mechanism of trehalose in a toluene-tolerant bacterium Pseudomonas sp. BCNU 106. METHODS AND RESULTS: The accumulation of trehalose by a toluene-tolerant bacterium Pseudomonas sp. BCNU 106 was examined at various cultivation time by measuring the total intracellular trehalose content, trehalase activity and mRNA levels of the trehalose-biosynthetic genes. The pattern of trehalose accumulation corresponded to the mRNA expression pattern of the trehalose-biosynthetic genes with the maximum level at 12 h or 4 h of cultivation with 10% (v/v) toluene, respectively. The trehalose-biosynthetic genes were also cloned and sequenced. Furthermore, the effects of toluene addition on the intracellular osmotic pressure and pH were investigated. It was shown that homeostasis was maintained in the bacterial cells. CONCLUSIONS: In a toluene-tolerant bacterium Pseudomonas sp. BCNU 106, a significant amount of trehalose was accumulated through the toluene-induced expression of the trehalose-biosynthetic genes after the exposure to toluene. SIGNIFICANCE AND IMPACT OF THE STUDY: The accumulation of the high level of intracellular trehalose was preceded by the expression of otsA/B genes in toluene-tolerant bacteria, contributing to the elucidation of the tolerance mechanism.

Gene Expression Regulation, Bacterial↗
PubMed2006

Use of modified U1 snRNAs to inhibit HIV-1 replication.

Control of RNA processing plays a central role in regulating the replication of HIV-1, in particular the 3' polyadenylation of viral RNA. Based on the demonstration that polyadenylation of mRNAs can be disrupted by the targeted binding of modified U1 snRNA, we examined whether binding of U1 snRNAs to conserved 10 nt regions within the terminal exon of HIV-1 was able to inhibit viral structural protein expression. In this report, we demonstrate that U1 snRNAs complementary to 5 of the 15 regions targeted result in significant suppression of HIV-1 protein expression and viral replication coincident with loss of viral RNA. Suppression of viral gene expression is dependent upon appropriate assembly of a U1 snRNP particle as mutations of U1 snRNA that affect binding of U1 70K or Sm proteins significantly reduced efficacy. However, constructs lacking U1A binding sites retained significant anti-viral activity. This finding suggests a role for these mutants in situations where the wild-type constructs cause toxic effects. The conserved nature of the sequences targeted and the high efficacy of the constructs suggests that this strategy has significant potential as an HIV therapeutic.

Anti-HIV Agents↗
PubMed2006

Pharmacological and molecular characterization of ATP-sensitive K(+) conductances in CART and NPY/AgRP expressing neurons of the hypothalamic arcuate nucleus.

The role of hypothalamic ATP-sensitive potassium channels in the maintenance of energy homeostasis has been extensively explored. However, how these channels are incorporated into the neuronal networks of the arcuate nucleus remains unclear. Whole-cell patch-clamp recordings from rat arcuate nucleus neurons in hypothalamic slice preparations revealed widespread expression of functional ATP-sensitive potassium channels within the nucleus. ATP-sensitive potassium channels were expressed in orexigenic neuropeptide Y/agouti-related protein (NPY/AgRP) and ghrelin-sensitive neurons and in anorexigenic cocaine-and-amphetamine regulated transcript (CART) neurons. In 70% of the arcuate nucleus neurons recorded, exposure to glucose-free bathing medium induced inhibition of electrical excitability, the response being characterized by membrane hyperpolarization, a reduction in neuronal input resistance and a reversal potential consistent with opening of potassium channels. These effects were reversible upon re-introduction of glucose to the bathing medium or upon exposure to the ATP-sensitive potassium channel blockers tolbutamide or glibenclamide. The potassium channel opener diazoxide, but not pinacidil, also induced a tolbutamide and glibenclamide-sensitive inhibition of electrical excitability. Single-cell reverse transcription-polymerase chain reaction revealed expression of mRNA for sulfonylurea receptor 1 but not sulfonylurea receptor 2 subunits of ATP-sensitive potassium channels. Thus, rat arcuate nucleus neurons, including those involved in functionally antagonistic orexigenic and anorexigenic pathways express functional ATP-sensitive potassium channels which include sulfonylurea receptor 1 subunits. These data indicate a crucial role for these ion channels in central sensing of metabolic and energy status. However, further studies are needed to clarify the differential roles of these channels, the organization of signaling pathways that regulate them and how they operate in functionally opposing cell types.

ATP-Binding Cassette Transporters↗
PubMed2006

Little or no ability of obestatin to interact with ghrelin or modify motility in the rat gastrointestinal tract.

BACKGROUND AND PURPOSE: Obestatin, encoded by the ghrelin gene may inhibit gastrointestinal (GI) motility. This activity was re-investigated. EXPERIMENTAL APPROACH: Rat GI motility was studied in vitro (jejunum contractility and cholinergically-mediated contractions of forestomach evoked by electrical field stimulation; EFS) and in vivo (gastric emptying and intestinal myoelectrical activity). Ghrelin receptor function was studied using a GTPgammaS assay and transfected cells. KEY RESULTS: Contractions of the jejunum or forestomach were unaffected by obestatin 100 nM or 0.01-1000 nM, respectively (P>0.05 each; n=4-18). Obestatin (0.1-1 nM) reduced the ability of ghrelin 1 microM to facilitate EFS-evoked contractions of the stomach (increases were 42.7+/-7.8% and 21.2+/-5.0 % in the absence and presence of obestatin 1 nM; P<0.05; n=12); higher concentrations (10-1000 nM) tended to reduce the response to ghrelin but changes were not statistically significant. Similar concentrations of obestatin did not significantly reduce a facilitation of contractions caused by the 5-HT(4) receptor agonist prucalopride, although an inhibitory trend occurred at the higher concentrations (increases were 69.3+/-14.0% and 42.6+/-8.7% in the absence and presence of 1000 nM obestatin; n=10). Obestatin (up to 10 microM) did not modulate recombinant ghrelin receptor function. Ghrelin increased gastric emptying and reduced MMC cycle time; obestatin (1000 and 30,000 pmol kg(-1) min(-1)) had no effects. Obestatin (2500 pmol kg(-1) min(-1), starting 10 min before ghrelin) did not prevent the ability of ghrelin (500 pmol kg(-1) min(-1)) to shorten MMC cycle time. CONCLUSIONS AND IMPLICATIONS: Obestatin has little ability to modulate rat GI motility.

Animals↗
PubMed2006

Molecular mechanisms involved in progesterone receptor regulation of uterine function.

The ovarian steroid hormone progesterone is a major regulator of uterine function. The actions of this hormone is mediated through its cognate receptor, the progesterone receptor, Pgr. Ablation of the Pgr has shown that this receptor is critical for all female reproductive functions including the ability of the uterus to support and maintain the development of the implanting mouse embryo. High density DNA microarray analysis has identified direct and indirect targets of Pgr action. One of the targets of Pgr action is a member of the Hedgehog morphogen Indian Hedgehog, Ihh. Ihh and members of the Hh signaling cascade show a coordinate expression pattern in the mouse uterus during the preimplantation period of pregnancy. The expression of Ihh and its receptor Patched-1, Ptc1, as well as, down stream targets of Ihh-Ptch1 signaling, such as the orphan nuclear receptor COUP-TF II show that this morphogen pathway mediates communication between the uterine epithelial and stromal compartments. The members of the Ihh signaling axis may function to coordinate the proliferation, vascularization and differentiation of the uterine stroma during pregnancy. This analysis demonstrates that progesterone regulates uterine function in the mouse by coordinating the signals from the uterine epithelium to stroma in the preimplantation mouse uterus.

Animals↗
PubMed2006

alpha2delta and the mechanism of action of gabapentin in the treatment of pain.

Gabapentin is a drug that has been widely used in the treatment of chronic pain states. Despite its widespread usage, it is only recently that light has been shed on the mechanism of action of this agent. In the current review, the authors document the pharmacological, biochemical and molecular information that has led to the identification of the alpha2delta1 auxilliary subunit of voltage gated calcium channels as the target for this drug's actions.

Amines↗
PubMed2006

Electrical control of antiferromagnetic domains in multiferroic BiFeO3 films at room temperature.

Multiferroic materials, which offer the possibility of manipulating the magnetic state by an electric field or vice versa, are of great current interest. In this work, we demonstrate the first observation of electrical control of antiferromagnetic domain structure in a single-phase multiferroic material at room temperature. High-resolution images of both antiferromagnetic and ferroelectric domain structures of (001)-oriented multiferroic BiFeO3 films revealed a clear domain correlation, indicating a strong coupling between the two types of order. The ferroelectric structure was measured using piezo force microscopy, whereas X-ray photoemission electron microscopy as well as its temperature dependence was used to detect the antiferromagnetic configuration. Antiferromagnetic domain switching induced by ferroelectric polarization switching was observed, in agreement with theoretical predictions.

Journal Article↗
PubMed2006

A prepelvic tunnel for the rectus abdominis myocutaneous flap in perineal reconstruction.

BACKGROUND: The use of the transpelvic vertical rectus abdominis myocutaneous (VRAM) flap in pelvic reconstruction is well documented. It can be used to fill large defects after pelvic exenteration, reconstruct the vagina and provide skin coverage in perineal reconstruction. This study examines an alternate prepelvic pathway for the flap to enhance its versatility and reliability. PATIENTS AND METHOD: A female patient with recurrent squamous cell carcinoma in the pelvis, who underwent radical pelvic exenteration and a successful VRAM flap reconstruction with a prepelvic tunnel. RESULTS: The patient experienced a small area of epithelial tip necrosis over the sacral promontory from shear forces. This healed with dressings within two weeks. There were no major flap complications and the patient had good flap integrity at one-year follow-up. The prepelvic pathway for the VRAM flap is advantageous to the conventional transpelvic course in perineal reconstruction. The more direct, shorter path to the defect allows for a more reliable skin paddle design without the need for de-epithelialisation. A greater area of skin paddle is available and creates a more versatile flap with no tension on the pedicle. This is especially in cases where a skin paddle is needed for vaginal reconstruction or when pelvic organs such as bladder and uterus are left in situ. These advantages may result in less flap complications.

Anus Neoplasms↗
PubMed2006

Ectodermal dysplasia of hair and nail type: mapping of a novel locus to chromosome 17p12-q21.2.

BACKGROUND: Ectodermal dysplasias (EDs) describe a large and complex group of disorders characterized by abnormal development of the skin and appendages (hair, nails, teeth and sweat glands). Of the approximately 200 different EDs, about 30 have been studied at the molecular level. In an effort to understand the molecular bases of ED of hair and nail type, we studied a Pakistani consanguineous family with multiple affected individuals. OBJECTIVES: To localize the gene responsible for the autosomal recessive form of ED of hair and nail type. METHODS: Genotyping of nine members of the family, including five affected and four normal individuals was performed using microsatellite markers mapping to candidate regions, harbouring genes involved in related phenotypes. Five epithelial keratin genes located in the candidate region were sequenced to identify the pathogenic mutation. RESULTS: We mapped the disease locus to a 24.2-cM interval flanked by markers D17S839 and D17S1299 on chromosome 17p12-q21.2 (Z(max) = 4.4). DNA sequencing of five epithelial keratin candidate genes, present in the disease locus, did not reveal any pathogenic mutation in the affected individuals. CONCLUSIONS: The gene for ED of hair and nail type has been mapped to chromosome 17p12-q21.2 in a Pakistani consanguineous family. Failure to detect mutations in epithelial keratin genes suggests that the mutation may lie either in regulatory regions of one of the epithelial keratin genes or in another unknown gene, located in the linkage interval, with a possible role in the development of ectodermal appendages.

Chromosome Mapping↗
PubMed2006

What are the barriers faced by general practitioners in treating depression and anxiety in Hong Kong?

Barriers faced by general practitioners in Hong Kong to manage patients with depression and anxiety disorders and their association with postgraduate qualification in family medicine were studied. Postal questionnaires were sent to 179 family medicine tutors affiliated with a university in Hong Kong with a response rate of 64.2%. 'Too time consuming' was the largest barrier for these physicians in treating patients with depression and anxiety. General practitioners without higher qualifications in family medicine were significantly more likely to report 'lack of confidence', 'lack of experience' and 'lack of supporting service' as being the barriers in treating patients with depression and anxiety. Our results showed that time constraint is an important barrier for general practitioners in managing patients with depression and anxiety in Hong Kong. Having a higher qualification in family medicine may reduce the barriers of having lack of confidence and experience in these physicians.

Adult↗
PubMed2006

The mapping of DFNB62, a new locus for autosomal recessive non-syndromic hearing impairment, to chromosome 12p13.2-p11.23.

Autosomal recessive non-syndromic hearing impairment (ARNSHI) is the most common form of prelingual inherited hearing impairment (HI). Here is described the mapping of a novel ARNSHI locus in a consanguineous Pakistani family with profound congenital HI. Two-point and multipoint linkage analyses were performed for the genome scan and fine mapping markers. Haplotypes were constructed to determine the region of homozygosity. At theta = 0, the maximum two-point LOD score of 4.0 was obtained at marker AAC040. A maximum multipoint LOD score of 5.3 was derived at marker D12S320, with the three-unit support interval demarcated by D12S89 and D12S1042. The region of homozygosity is flanked by markers D12S358 and D12S1042, which corresponds to 22.4 cM according to the Rutgers combined linkage-physical map of the human genome and spans 15.0 Mb on the sequence-based physical map. A novel ARNSHI locus DFNB62 was mapped to chromosome 12p13.2-p11.23. DFNB62 represents the second ARNSHI locus to map to chromosome 12.

Chromosomes, Human, Pair 12↗
PubMed2006

A novel locus for alopecia with mental retardation syndrome (APMR2) maps to chromosome 3q26.2-q26.31.

Congenital alopecia may occur either alone or in association with ectodermal and other abnormalities. On the bases of such associations, several different syndromes featuring congenital alopecia can be distinguished. Alopecia with mental retardation syndrome (APMR) is a rare autosomal recessive disorder, clinically characterized by total or partial hair loss and mental retardation. In the present study, a five-generation Pakistani family with multiple affected individuals with APMR was ascertained. Patients in this family exhibited typical features of APMR syndrome. The disease locus was mapped to chromosome 3q26.2-q26.31 by carrying out a genome scan followed by fine mapping. A maximum two-point logarithm of odds (LOD) score of 2.93 at theta=0.0 was obtained at markers D3S3053 and D3S2309. Multipoint linkage analysis resulted in a maximum LOD score of 4.57 with several markers, which supports the linkage. The disease locus was flanked by markers D3S1564 and D3S2427, which corresponds to 9.6-cM region according to the Rutgers combined linkage-physical map of the human genome (build 35) and contains 5.6 Mb. The linkage interval of the APMR locus identified here does not overlap with the one described previously; therefore, this locus has been designated as APMR2.

Alopecia↗
PubMed2006

Comparison of microshear bond strengths of four self-etching bonding systems to enamel using two test methods.

BACKGROUND: Recent advances in enamel and dentine adhesive technology have resulted in the emergence of many new adhesive systems. Self-etching bonding systems do not require a separate etching step and the newest systems are the "all-in-one" systems which combine etching, priming and bonding into a single application. This study reports laboratory enamel microshear bond strengths of a self-etching priming and three all-in-one systems and also evaluates two different microshear bond test methods. METHODS: One hundred and nineteen enamel specimens were bonded (0.8 mm diameter) with either Clearfil Protect Bond (Kuraray), Xeno III (Dentsply), G Bond (GC) or One-Up Bond F (Tokuyama) using Palfique Estelite resin composite and stored in 37 degrees Celsius water for seven days. The microshear bond test method used either a blade or wire to apply the shear stress. Results were analysed with one-way ANOVA and post hoc (Tukey) multiple comparison analysis. RESULTS: Clearfil Protect Bond demonstrated higher and more consistent bond strengths than Xeno III, G Bond or One-Up Bond F. The wire method showed much greater reliability in results, with a coefficient of variation half that of the blade method. CONCLUSIONS: All-in-one adhesives seem to be less reliable than the two-step self-etching priming adhesive when bonding to enamel. Test method can significantly affect results in the microshear bond test method.

Acid Etching, Dental↗
PubMed2006

A mutation in the hair matrix and cuticle keratin KRTHB5 gene causes ectodermal dysplasia of hair and nail type.

BACKGROUND: Ectodermal dysplasias are developmental disorders affecting tissues of ectodermal origin. To date, four different types of ectodermal dysplasia involving only hair and nails have been described. In an effort to understand the molecular bases of this form of ectodermal dysplasia, large Pakistani consanguineous kindred with multiple affected individuals has been ascertained from a remote region in Pakistan. OBJECTIVE: To identify the gene underlying the phenotype. METHODS: Microsatellite markers were genotyped in candidate regions and two point and multipoint parametric linkage analysis carried out. RESULTS: The disease locus was mapped to a 16.6 centimorgan region on chromosome 12q12-q14.1 (Zmax = 8.2), which harbours six type II hair keratin genes. DNA sequence analysis revealed a homozygous missense mutation in the hair matrix and cuticle keratin KRTHB5, leading to histidine substitution of a conserved arginine residue (R78H) located in the head domain. CONCLUSIONS: This report provides the first direct evidence relating to the molecular pathogenesis of pure hair-nail ectodermal dysplasias.

Arginine↗
PubMed2006

AUNX1, a novel locus responsible for X linked recessive auditory and peripheral neuropathy, maps to Xq23-27.3.

BACKGROUND: We report here the genetic characterisation of a large five generation Chinese family with the phenotypic features of auditory neuropathy and progressive peripheral sensory neuropathy, and the genetic feature of X linked recessive inheritance. Disease onset was at adolescence (at an average age of 13 years for six affected subjects). The degree of hearing impairment varied from mild to severe, with decreased otoacoustic emissions; auditory brainstem responses were lacking from onset. METHODS: Two-point and multipoint model based linkage analysis using the MILNK and LINKMAP programs of the FASTLINK software package produced maximum two-point and multipoint LOD scores of 2.41 and 2.41, respectively. RESULTS: These findings define a novel X linked auditory neuropathy locus/region (AUNX1, Xq23-q27.3). This region is 42.09 cM long and contains a 28.07 Mb region with flanking markers DXS1220 and DXS8084, according to the Rutgers Combined Linkage-Physical Map, build 35. However, mutation screen of the candidate gene SLC6A14 within the region did not identify the causative genetic determinant for this large Chinese family.

China↗
PubMed2006

A method to differentiate between the levels of ESR signals induced by sunlight and by ionizing radiation in teeth from atomic bomb survivors.

Electron spin resonance (ESR, or electron paramagnetic resonance, EPR) analysis of tooth enamel is an effective method for the retrospective estimation of individual radiation doses. One problem with this technique is that the observed ESR signal may include a contribution from ultraviolet (UV) light exposure from sunlight, especially in front teeth. Thus there has been a need to find ways to estimate the UV-light effect in the total signal so that the net ESR dose from ionizing radiation can be determined. To examine this issue, we measured 96 teeth of various types, but with buccal and lingual parts measured separately, from a control group of atomic bomb survivors (estimated dose <5 mGy). We found that, except for molars, the mean ESR-estimated dose for the buccal halves was, on average, nearly twice that from the lingual side, which indicates that the UV-light-induced lingual dose equals the difference between the two halves. Using these corrections for UV-light exposure to front teeth that had been exposed to both ionizing radiation and UV light, it was found that the estimated radiation doses closely approximated the previously estimated ESR dose to molars from the same donors or the estimated dose arrived at with cytogenetic methods. We concluded that, when using ESR to estimate radiation dose, measuring molars is the first choice, but if only front teeth are available, separate measurements to the buccal and lingual parts can provide an estimation of the mean UV-light contribution to the ESR-determined dose.

Dose-Response Relationship, Radiation↗