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PubMed2002

Search for common haplotypes on chromosome 22q in patients with schizophrenia or bipolar disorder from the Faroe Islands.

Chromosome 22q may harbor risk genes for schizophrenia and bipolar affective disorder. This is evidenced through genetic mapping studies, investigations of cytogenetic abnormalities, and direct examination of candidate genes. Patients with schizophrenia and bipolar affective disorder from the Faroe Islands were typed for 35 evenly distributed polymorphic markers on 22q in a search for shared risk genes in the two disorders. No single marker was strongly associated with either disease, but five two-marker segments that cluster within two regions on the chromosome have haplotypes occurring with different frequencies in patients compared to controls. Two segments were of most interest when the results of the association tests were combined with the probabilities of identity by descent of single haplotypes. For bipolar patients, the strongest evidence for a candidate region harboring a risk gene was found at a segment of at least 1.1 cM including markers D22S1161 and D22S922 (P=0.0081 in the test for association). Our results also support the a priori evidence of a susceptibility gene to schizophrenia at a segment of at least 0.45 cM including markers D22S279 and D22S276 (P=0.0075). Patients were tested for the presence of a missense mutation in the WKL1 gene encoding a putative cation channel close to segment D22S1161--D22S922, which has been associated with schizophrenia. We did not find this mutation in schizophrenic or bipolar patients or the controls from the Faroe Islands.

Bipolar Disorder↗
PubMed2006

Mutation G47R in the BSND gene causes Bartter syndrome with deafness in two Spanish families.

Bartter syndrome (BS) is a heterogeneous group of autosomal recessive hypokalaemic salt-losing tubulopathies. Five types of BS caused by different genetic defects have been identified, and one of them is associated with sensorineural deafness (BSND). Mutations in the recently described BSND gene, mapped in chromosome 1p31, have been reported to be associated with BSND. This gene encodes barttin, an essential beta-subunit subunit for ClC-Ka and ClC-Kb channels. Both subunits are co-expressed in basolateral membranes of renal tubules, in the ascending limb of the loop of Henle, and in the stria vascularis of the inner ear. We studied two apparently unrelated Spanish families from the Canary Islands, with five members showing this pathology. Sequence analysis of the BSND gene showed that the affected members were homozygous for a C-to-T transition in exon 1, while their parents were heterozygous. This alteration results in a missense mutation, G47R, which has been previously shown to abolish the stimulatory effect on the subunit barttin of the ClC-Kb channel. Our results indicate that families with the G47R mutation indeed present polyhydramnios, premature birth and salt loss. Nevertheless, glomerular filtration rate was normal in all patients. Clinical manifestations are moderate in patients with the G47R mutation compared to other published data form patients with BSND. This constitutes the first report of BSND cases in Spain.

Adolescent↗
PubMed2006

Two-dimensional self-organization of gold nanoparticles on supramolecular aggregates.

Alkanethiol-capped gold (Au) nanoparticles, dispersed in toluene and spin-coated on atactic polystyrene films that are themselves spin-coated on fused quartz plates, self-assemble into a characteristic two-dimensional pattern-a network of the Au-thiol nano-composite separating polystyrene 'islands' of dimensions around 200 nm. This pattern changes on varying the concentration of the nanoparticles in the coating solution, evolving into the network from isolated nanoparticle clusters, and then going over to a distribution of 'pinholes' on a surface covered by the nano-composite, resembling a partially wetted surface with near-full coverage. Study of the pristine polystyrene surface reveals a pattern of low-cohesion regions separating 'islands' of polystyrene, where the latter are known to be supramolecular aggregates. It is suggested that these regions play the role of low-resistance channels to the flow of the nano-composite during spin coating.

Gold↗
PubMed2004

Quantitative trait loci analysis of nitrate storage in Arabidopsis leading to an investigation of the contribution of the anion channel gene, AtCLC-c, to variation in nitrate levels.

Storage of excess nitrate in the vacuole and its subsequent remobilization is an important aspect of a plant's nitrogen economy, but the genes controlling the underlying processes have not all been identified and characterized. Cape Verdi Island (Cvi)/Landsberg erecta (Ler) and Columbia (Col)/Landsberg erecta recombinant inbred line (RIL) populations of Arabidopsis thaliana were used to identify quantitative trait loci (QTL) controlling natural variation in nitrate concentrations. One major and two minor QTLs were found for the Cvi/Ler population and one minor QTL for the Col/Ler RIL. These were designated NA1 to NA4. The major Cvi/Ler QTL (NA3) was located at the bottom of chromosome 5. No interaction among the QTLs was found by two-way ANOVA. By comparing in silico the locations of the QTLs with a physical map of the Arabidopsis genome, candidate genes for each QTL were identified. Several of these were anion channels of the AtCLC family. One of these, AtCLC-c, coincided with NA3 and its role was investigated using a mutant with a transposon insertion in AtCLC-c. Mutant plants homozygous for the insertion (designated clcc-1) had less than 5% of AtCLC-c mRNA compared with wild-type (WT) shoots. They also had significantly lower nitrate concentrations when grown at a range of external nitrate concentrations. The concentrations of chloride, malate, and citrate were also affected in the mutant. In wild-type plants, expression of AtCLC-c was down-regulated in the presence of nitrate, but ammonium had a much smaller effect while chloride and sulphate did not affect expression. These and published results suggest that multiple genes affect nitrate concentrations in plants and that AtCLC-c and other members of the AtCLC gene family play some role in this.

Amino Acid Sequence↗
PubMedDate not supplied

Cell-cell-communication during placental development and possible implications for trophoblast proliferation and differentiation.

Since direct cell-cell-communication plays a crucial role in the coordination of proliferation and differentiation processes during development we have focused on the expression patterns of gap junctions and their functional implication in the human placenta. The gap junction protein connexin40 (Cx40) is expressed in the proximal extravillous trophoblast of cell islands and columns. In accordance with these observations, isolated trophoblast cells from first and second trimester placentae and choriocarcinoma cells (Jeg-3) reveal Cx40 expression. This channel is not only characteristic of the trophoblast cells along the invasive pathway but also of endothelial cells. To elucidate the functional role of this channel for proliferation and invasion, the non-coupled Jeg-3 cells have been transfected with Cx26, Cx40 and Cx43, respectively. In contrast to Cx40, the Cx26 channel was more potent in reducing proliferation and inducing differentiation indicated by hCG-beta secretion. Using the nude mouse model to study invasion properties of choriocarcinoma cells, we demonstrated that malignant trophoblast cells were able to invade host vessels and to replace endothelial cells. Upregulation of endogeneous connexin genes in tumours grown in nude mice enforces further experimental strategies to investigate the importance of the different channels to fake the cell biological program of endothelial cells.

Animals↗
PubMed1990

The murine GABAA receptor delta-subunit gene: structure and assignment to human chromosome 1.

The murine chromosomal gene for the GABAA receptor delta subunit was isolated and characterized by high-resolution mapping and DNA sequencing. Spanning 13 kb, it comprises nine exons and displays an intron pattern comparable, but not identical, to that seen in members of the nicotinic acetylcholine receptor family. Notably, the second transmembrane domain thought to line the ion channel and conserved among different GABAA receptor subunits, is interrupted by an intron. The 5'-flanking region of the delta gene displays features characteristic of a CpG island and lacks canonical promoter elements such as TATA and CCAAT consensus sequences in proximity to the transcriptional initiation site. The human delta subunit gene was localized on the short arm of chromosome 1.

Amino Acid Sequence↗
PubMed2000

Cretaceous (Late Albian) coniferales of Alexander Island, Antarctica. 1: Wood taxonomy: a quantitative approach.

Silicified conifer woods are very common in the mid-Cretaceous (Late Albian, 100Ma) Triton Point Member of the Neptune Glacier Formation (Fossil Bluff Group), SE Alexander Island, Antarctica. These occur as up to 7m high in situ tree trunks and stumps rooted in carbonaceous palaeosols and as allochthonous logs and wood fragments in fluvial channel and sheet sandstone facies. Sixty-eight wood samples were examined in this study and were classified in terms of five form taxa using a quantitative approach. Araucarioxylon (1.5% of specimens) is characterised by dominantly multiseriate, alternately arranged bordered pitting on radial tracheid walls and by 1-4 araucarioid cross-field pitting. Araucariopitys (11.8% of specimens) is characterised by dominantly uniseriate tracheid pitting with subordinate biseriate, alternate tracheid pitting and by 1-4 araucarioid cross-field pitting. Podocarpoxylon sp. 1 (63.1% of specimens) is characterised by contiguous, uniseriate tracheid pitting and 1-2 podocarpoid cross-field pits. Podocarpoxylon sp. 2 (22.1% of specimens) is similar to P. sp. 1, differing only in that ray height is lower, tracheid pits are dominantly spaced more than one pit diameter apart and abundant axial parenchyma is present. These first four taxa all possess growth rings with subtle boundaries. Taxodioxylon (1.5% of specimens) is characterised by 1-2 seriate, oppositely arranged, bordered tracheid pitting, 1-2 taxodioid cross-field pitting and very marked ring boundaries. These woods were derived from large trees with basal stump diameters of up to 0.5m and probable heights of up to 29m. Data from leaf traces suggest that Araucariopitys and Podocarpoxylon sp. 1 and sp. 2 (97% of specimens) were evergreen with leaf retention times of >5years. These predominantly evergreen conifer forests grew in a mild, high latitude (75 degrees S) environment during the mid-Cretaceous greenhouse climate phase.

Journal Article↗
PubMed2003

A differentially methylated region within the gene Kcnq1 functions as an imprinted promoter and silencer.

The imprinted gene cluster on mouse distal chromosome 7 contains a differentially methylated CpG island that maps within the Kcnq1 gene that has been shown to be required for the imprinting of multiple genes. To evaluate models for how this imprinting control region (ICR) regulates imprinting, we have characterized it structurally and functionally. We show that the region contains a promoter for a paternally expressed anti-sense transcript, Kcnq1ot1, and we define the extent of the minimal promoter. We describe three paternal-specific nuclease hypersensitive sites immediately upstream from the start site and show that they are required for full promoter activity. The expression of Kcnq1ot1 during pre- and postnatal development is compared to that of other imprinted genes in its vicinity, Cdnkn1c and Kcnq1. The lack of coordination in their expression tends to rule out an enhancer competition model for the action of the ICR in imprinting control. Using a stable transfection assay we show that the region contains a position-independent and orientation-independent silencer. We propose, on the basis of these findings, that the Kcnq1 ICR functions as a silencer on the paternal chromosome to effect the repression of neighboring genes.

Animals↗
PubMed2006

Superior regularity in erosion patterns by planar subsurface channeling.

The onset of pattern formation through exposure of Pt(111) with 5 keV Ar(+) ions at grazing incidence has been studied at 550 K by scanning tunneling microscopy and is supplemented by molecular-dynamics simulations of single ion impacts. A consistent description of pattern formation in terms of atomic scale mechanisms is given. Most surprisingly, pattern formation depends crucially on the angle of incidence of the ions. As soon as this angle allows subsurface channeling of the ions, pattern regularity and alignment with respect to the ion beam greatly improves. These effects are traced back to the positionally aligned formation of vacancy islands through the damage created by the ions at dechanneling locations.

Journal Article↗
PubMed2003

Molecular cloning and characterization of human acid sensing ion channel (ASIC)2 gene promoter.

Acid sensing ion channel (ASIC)2 belongs to the amiloride-sensitive Na(+)-channel/ degenerin family. Our previous studies suggested that differential regulation of ASIC2 expression occurs between high-grade glial-derived tumor cells and normal astrocytes. To investigate the mechanisms involved in the regulation of ASIC2 gene expression, the human ASIC2 promoter region (-1551 to +117) was cloned and characterized. The ASIC2 promoter lacked a canonical TATA box, but contained one putative CCAAT box. Nucleotide sequencing of the promoter revealed the presence of a number of transcription factor-binding sites and a 404 bp CpG island upstream the transcription start site. Nested deletion mutants and transfection results showed that the construct between -133 and +117 base pairs conferred basal transcription specific activity. Mutation of Sp1 and CP2 sites in this region resulted in a 70 and 95% decrease in promoter activity, respectively. Gel shift assays demonstrated the existence of specific protein binding to the SP1 and CP2 elements. There was no mutation in the CpG island in six glioma cell lines, but methylation-specific PCR showed methylation in some of glioma cell lines and tumor tissues, and treatment with the methylation inhibitor 5-Aza-2'-deoxycytidine could partially restore ASIC2 expression in cell lines, suggesting that epigenetic mechanisms may contribute to dysregulated ASIC2 expression.

Acid Sensing Ion Channels↗
PubMed2006

Elongation of the Kcnq1ot1 transcript is required for genomic imprinting of neighboring genes.

The imprinted gene cluster at the telomeric end of mouse chromosome 7 contains a differentially methylated CpG island, KvDMR, that is required for the imprinting of multiple genes, including the genes encoding the maternally expressed placental-specific transcription factor ASCL2, the cyclin-dependent kinase CDKN1C, and the potassium channel KCNQ1. The KvDMR, which maps within intron 10 of Kcnq1, contains the promoter for a paternally expressed, noncoding, antisense transcript, Kcnq1ot1. A 244-base-pair deletion of the promoter on the paternal allele leads to the derepression of all silent genes tested. To distinguish between the loss of silencing as the consequence of the absence of transcription or the transcript itself, we prematurely truncated the Kcnq1ot1 transcript by inserting a transcriptional stop signal downstream of the promoter. We show that the lack of a full-length Kcnq1ot1 transcript on the paternal chromosome leads to the expression of genes that are normally paternally repressed. Finally, we demonstrate that five highly conserved repeats residing at the 5' end of the Kcnq1ot1 transcript are not required for imprinting at this locus.

Animals↗
PubMed1992

Role of perivenous areolar tissue in the viability of venous flaps: an experimental study on the inferior epigastric venous flap of the rat.

This study was performed to investigate how the perivenous areolar tissue affects survival of the rat inferior epigastric venous flap model designed by Yuen and Leung (1991). Five groups of flaps were studied; group A--flap based on an inferior epigastric vein and areolar tissue; group B--flap with a skeletonised vein; group C--control, nonvascularised flap; group D--flap based on perivascular areolar tissue alone; group E--flap with a skeletonised artery and vein. Each group included 40 flaps; 20 of them had a silicone sheet placed under the flap, the other 20 did not. All flaps of group E survived. The success rate of group A with and without a silicone sheet was 60% and 90% respectively. All flaps of the other groups (B, C, D) necrosed. Histological examination of the pedicle showed that many minute vascular channels (single-cell-layered capillaries) were present apart from the inferior epigastric vein. This result confirms the importance of the perivenous areolar tissue in perfusion of the skin island, at least, in the inferior epigastric venous flap in the rat.

Animals↗
PubMed1998

Salmonella InvG forms a ring-like multimer that requires the InvH lipoprotein for outer membrane localization.

Salmonella species translocate virulence effector proteins from the bacterial cytoplasm into mammalian host cells by means of a type III secretion apparatus, encoded by the pathogenicity island-1 (SPI-1). Little is known about the assembly and structure of this secretion apparatus, but the InvG protein is essential and could be an outer membrane secretion channel for the effector proteins. We observed that in recombinant Escherichia coli, the yield of InvG was enhanced by co-expression of InvH, and showed that mutation of invH decreased the level of InvG in wild-type Salmonella typhimurium. In E. coli, InvG alone was able to form an SDS-resistant multimer, but InvG localization to the outer membrane was dependent upon InvH, a lipoprotein itself located in the outer membrane, and no other SPI-1 specific protein. InvG targeted to the outer membrane by InvH became accessible to extracellular protease. InvG and InvH did not, however, appear to form a stable complex. Electron microscopy of InvG membrane protein purified from E. coli revealed that it forms an oligomeric ring-like structure with inner and outer diameters, 7 nm and 15 nm respectively.

Bacterial Outer Membrane Proteins↗
PubMed2004

Dual therapeutic utility of proteasome modulating agents for pharmaco-gene therapy of the cystic fibrosis airway.

Pharmacologic- and gene-based therapies have historically been developed as two independent therapeutic platforms for cystic fibrosis (CF) lung disease. Inhibition of the dysregulated epithelial Na channel (ENaC) is one pharmacologic approach to enhance airway clearance in CF. We investigated pharmacologic approaches to enhance CFTR gene delivery with recombinant adeno-associated virus (rAAV) and identified compounds that significantly improved viral transduction while simultaneously inhibiting ENaC activity through an unrelated mechanism. Treatment of human CF airway epithelia with proteasome modulating agents (LLnL and doxorubicin) at the time of rAAV2 or rAAV2/5 infection dramatically enhanced CFTR gene delivery and correction of CFTR-mediated short-circuit currents. Surprisingly, these agents also facilitated long-term (15-day) functional inhibition of ENaC currents independent of CFTR vector administration. Inhibition of ENaC activity was predominantly attributed to a doxorubicin-dependent decrease in gamma-ENaC subunit mRNA expression and an increase in gamma-ENaC promoter methylation. This is the first report to describe the identification of compounds with dual therapeutic action that are able to enhance the efficacy of CFTR gene therapy to the airway while simultaneously ameliorating primary aspects of CF disease pathophysiology. The identification of such compounds mark a new area for drug development, not only for CF, but also for other gene therapy disease targets.

Amiloride↗
PubMed2000

Sequence-based structural features between Kvlqt1 and Tapa1 on mouse chromosome 7F4/F5 corresponding to the Beckwith-Wiedemann syndrome region on human 11p15.5: long-stretches of unusually well conserved intronic sequences of kvlqt1 between mouse and human.

Mouse chromosome 7F4/F5 is a syntenic locus of human 11p15.5 in which many imprinted genes are clustered. Transmission of aberrant human 11p15.5 or duplicated 11p causes Beckwith-Wiedemann syndrome (BWS) depending on which parent the chromosome is derived from. To analyze a syntenic mouse locus corresponding to human 11p15.5, mouse BAC contigs were constructed between Nap2 and Tapa1, in which 390 kb was sequenced between Kvlqt1 and Tapa1. An unexpected finding was that of highly conserved intronic sequences of Kvlqt1 between mouse and human, and their homologies came up to at least 160 kb because the length of this gene extended to 350 kb, suggesting the possibility of some functional constraint due to transcriptional and/or post-transcriptional regulation of this region. Many expressed sequence tags (ESTs) were mapped on this locus. Three genes, Lit1 (Kvlqt1-AS), Mtr1 and Tssc4, were identified and characterized. Lit1 is an antisense-transcript of Kvlqt1 and paternally expressed and maternally methylated throughout the developmental stage. The position where Lit1 exists corresponded to a highly conserved region between mouse and human. This transcript extends at least 60 kb from downstream to upstream of exon 10 in Kvlqt1. Tssc4 and Mtr1 carried putative open reading frames but neither was imprinted. Further characterization of this locus based on the sequence comparison between mouse and human will contribute valuable information towards resolving the mechanism of the occurrence of BWS and the associated childhood tumor.

Alleles↗
PubMed1986

Determinants of directional specificity in the regeneration of lamprey spinal axons.

The projection patterns of regenerating spinal axons in the larval sea lamprey (Petromyzon marinus) were determined by intracellular injection of HRP. Four hundred and eighty-six of 562 stained axons and axon-like neurites (87%) arising from Muller and Mauthner axons, giant interneurons, and dorsal cells terminated in an orientation similar to that of their counterpart control cells. Therefore, lamprey spinal axons regenerate selectively along their normal projection paths. During the first 4 weeks of recovery, i.e., before any had regenerated beyond the transection site, 91 of 114 axons and long neurites (80%) projected in the proper direction. Thus, the correctness of the final projection patterns did not result from selective retraction of randomly directed long neurites. When the cords were doubly transected 1 cm apart, orientation of regenerating neurites remained normal both within the 1 cm island and in the adjacent spinal cord. This suggests that the directional specificity of axonal regeneration was determined neither by the location of the scar nor by the availability of channels formed by the degenerating fibers. Finally, removing 1 cm of spinal cord eliminated potential synaptic targets for regenerating axons on either side of the lesion, but did not affect the direction of axonal growth. These findings are consistent with the hypothesis that the regeneration of lamprey spinal axons is guided by local chemical cues that persist long after the pathways are formed early in development.

Animals↗
PubMed1996

Tropical bont tick eradication campaign in the French Antilles. Current status.

The Amblyomma variegatum eradication campaign was officially started in April 1994 in Martinique and in Guadeloupe, including its dependencies of Marie Galante, Desirade and St Martin. A budget of $10.5 and $5.9 million for Guadeloupe and Martinique, respectively, was initially (1991) calculated and considered necessary to achieve the program. However, EEC, the most important donor, estimated that 75% only of this proposal was acceptable, on which it agrees to support a maximum of 50%. The balance had to be provided by French government, local political institutions, and animal owners. The current budget actualized in 1995 by veterinary authorities of Martinique and Guadeloupe is $7,200,000 and $9,900,000 respectively. The program will take 5 years: preparation (1 year), acaricide application (3 years), surveillance (1 year). During this first year, a pilot committee was established, and a project leader was designated for each island. Efforts were essentially oriented to organize the program in the field and to obtain funds from French and local counterparts. Funds allowed the recruitment and training of 19 new agents in Guadeloupe and 9 in Martinique, in addition to personnel already involved in the tick control program. Census of animal owners and identification of cattle started or were developed. Tenders were invited to provide vehicles and acaricides. For the latter, choices were made considering the prices and efficacy as well as funds available. Due to a limited budget and cost of pour-on formulations, pour-on acaricides will be used on a maximum of 30% of animals only. In order to investigate animal owners' reticences and the most appropriate media channels to establish a communication and a training program, a survey was conducted in Guadeloupe on a sample of 301 animal owners. The results are presented. In order to strengthen the chances of success of the campaign in the French islands, it is expected that a similar program will take place soon in infested neighboring islands.

Animals↗