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Biomedical subjects

J Jaworski

Publications and source records attributed to J Jaworski.

At least 19 recordsLinked to original sources
PubMed2006

An analysis paradigm for investigating multi-locus effects in complex disease: examination of three GABA receptor subunit genes on 15q11-q13 as risk factors for autistic disorder.

Gene-gene interactions are likely involved in many complex genetic disorders and new statistical approaches for detecting such interactions are needed. We propose a multi-analytic paradigm, relying on convergence of evidence across multiple analysis tools. Our paradigm tests for main and interactive effects, through allele, genotype and haplotype association. We applied our paradigm to genotype data from three GABAA receptor subunit genes (GABRB3, GABRA5, and GABRG3) on chromosome 15 in 470 Caucasian autism families. Previously implicated in autism, we hypothesized these genes interact to contribute to risk. We detected no evidence of main effects by allelic (PDT, FBAT) or genotypic (genotype-PDT) association at individual markers. However, three two-marker haplotypes in GABRG3 were significant (HBAT). We detected no significant multi-locus associations using genotype-PDT analysis or the EMDR data reduction program. However, consistent with the haplotype findings, the best single locus EMDR model selected a GABRG3 marker. Further, the best pairwise genotype-PDT result involved GABRB3 and GABRG3, and all multi-locus EMDR models also selected GABRB3 and GABRG3 markers. GABA receptor subunit genes do not significantly interact to contribute to autism risk in our overall data set. However, the consistency of results across analyses suggests that we have defined a useful framework for evaluating gene-gene interactions.

Autistic Disorder↗
PubMed2005

Ordered-subset analysis of savant skills in autism for 15q11-q13.

Autism is a complex disorder characterized by genetic and phenotypic heterogeneity. Analysis of phenotypically homogeneous subtypes has been used to both confirm and narrow potential autism linkage regions such as the chromosomal region 15q11-q13. Increased evidence for linkage in this region had been found in a subgroup of 21 autism families (total families = 94) stratified based on a savant skill factor (SSF) from the Autism Diagnostic Interview, Revised (ADI-R). We examined the savant phenotypic finding in our sample of 91 multiplex autism families. Using two-point parametric analysis in stratification with a cutoff point of a savant skill score of 0.16, our families failed to demonstrate linkage to 15q11-q13. In addition, ordered subset analysis (OSA) using SSF as a covariate also failed to show evidence for linkage. Our findings do not support savant skills as an informative phenotypic subset for linkage in our sample.

Adolescent↗
PubMed2005

Analysis of the RELN gene as a genetic risk factor for autism.

Several genome-wide screens have indicated the presence of an autism susceptibility locus within the distal long arm of chromosome 7 (7q). Mapping at 7q22 within this region is the candidate gene reelin (RELN). RELN encodes a signaling protein that plays a pivotal role in the migration of several neuronal cell types and in the development of neural connections. Given these neurodevelopmental functions, recent reports that RELN influences genetic risk for autism are of significant interest. The total data set consists of 218 Caucasian families collected by our group, 85 Caucasian families collected by AGRE, and 68 Caucasian families collected at Tufts University were tested for genetic association of RELN variants to autism. Markers included five single-nucleotide polymorphisms (SNPs) and a repeat in the 5'-untranslated region (5'-UTR). Tests for association in Duke and AGRE families were also performed on four additional SNPs in the genes PSMC2 and ORC5L, which flank RELN. Family-based association analyses (PDT, Geno-PDT, and FBAT) were used to test for association of single-locus markers and multilocus haplotypes with autism. The most significant association identified from this combined data set was for the 5'-UTR repeat (PDT P-value=0.002). These analyses show the potential of RELN as an important contributor to genetic risk in autism.

5' Untranslated Regions↗
PubMed2002

CART peptides.

Explore the source record for details and available documents.

Amino Acid Sequence↗
PubMed2000

Efficient expression of tetracycline-responsive gene after transfection of dentate gyrus neurons in vitro.

Gene transfer into neurons both in vivo and in vitro may aid in understanding of gene regulation and function in nerve cells. Especially desirable is ability to control the gene expression. In this study we developed conditions for transfection of hippocampal dentate gyrus neurons in dissociated cultures in vitro by calcium-phosphate method. Furthermore, we describe an effective use of tetracycline responsive gene promoter (Tet-On) system for the controlled and very efficient expression of transfected genes. Under optimal conditions as established in this study, efficiency of transfection of neurons with green fluorescent protein (GFP) driven by constitutive cytomegalovirus (CMV) early promoter reached 2.7%. With tetracycline responsive promoter percentage of GFP-positive neurons raised in the presence of tetracycline analog, doxycycline up to 20%. Application of the Tet-On system resulted in almost 10-fold induction of GFP expression.

Animals↗
PubMed2000

Transgenic mice with a mutated collagen promoter display normal response during bleomycin-induced fibrosis and possess neurological abnormalities.

We have previously identified a potential TGF-beta activation element (TAE) in the rat collagen alpha1(I) promoter at -1624 upstream of the transcriptional start site [Ritzenthaler et al., 1991, 1993]. To determine the importance of the TAE in vivo, we produced transgenic mice carrying 3.6 kb of the rat collagen alpha1(I) promoter linked to the reporter gene chloramphenicol acetyl transferase with and without site-directed mutations that eliminate DNA-protein binding at the TAE site. Tissue-specific expression of the reporter gene in transgenic mice with the mutated collagen promoter was similar to that of transgenic mice with the normal promoter in two genetic backgrounds as judged by in situ hybridization, reporter assays, and immunochemistry. Endotracheal instillation of bleomycin induces lung fibrosis, mediated in part by TGF-beta. Earlier studies indicated that expression of wild-type collagen-reporter gene was upregulated in transgenic mice lungs in response to endotracheal instillation of bleomycin. A similar level of reporter gene upregulation was observed in transgenic mice carrying the mutation in the TAE. Two lines of transgenic mice carrying the mutated promoter construct displayed unexpected neurological abnormalities. In the FVB genetic background, there was a higher than normal incidence of mortality, spontaneous seizures, and an inability to nurture offspring. Histological evidence demonstrated clear abnormalities, including disorderly arrangement of neurons in the hippocampus and significant laminar cortical necrosis in the cerebrum in animals after seizures. In the C57Bl/6 background, there was a high incidence of severe communicating hydrocephalus, early runting, and increased mortality similar to that in transgenic animals with astroglial overexpression of TGF-beta. These animals provide an interesting model system to investigate molecular mechanisms responsible for seizures and hydrocephalus.

Animals↗
PubMed1999

Neuronal excitation-driven and AP-1-dependent activation of tissue inhibitor of metalloproteinases-1 gene expression in rodent hippocampus.

Understanding of biological function of AP-1 transcription factor in central nervous system may greatly benefit from identifying its target genes. In this study, we present several lines of evidence implying AP-1 in regulating expression of tissue inhibitor of metalloproteinases-1 (timp-1) gene in rodent hippocampus in response to increased neuronal excitation. Such a notion is supported by the findings that timp-1 mRNA accumulation occurs in the rat hippocampus after either kainate- or pentylenetetrazole-evoked seizures with a delayed, in comparison with AP-1 components, time course, as well as with spatial overlap with c-Fos protein (major inducible AP-1 component) expression. Furthermore, AP-1 sequence derived from timp-1 promoter is specifically bound by hippocampal AP-1 proteins after treating the rats with either pro-convulsive agent. Finally, timp-1 promoter responds to excitatory activation both in vivo, in transgenic mice harboring the timp-LacZ gene construct, and in vitro in neurons of the hippocampal dentate gyrus cultures. These findings suggest that the AP-1 transcription factor may exert its role in the brain through affecting extracellular matrix remodeling.

Animals↗
PubMed1997

Repeated perfusion with elevated potassium in in vivo microdialysis--A method for detecting small changes in extracellular dopamine.

As a great deal of variability between subjects is often seen when using the microdialysis technique to measure the effects of depolarizing agents on extracellular neurotransmitter levels, we have developed a technique to account for the variability inherent in this method. High potassium (50 or 100 mM) artificial cerebrospinal fluid (ACSF), perfused through the probe for 10 min, significantly increased extracellular dopamine (DA) concentration during both an initial and second perfusion, and the two responses were highly correlated. However, extracellular DA returned to normal following the first perfusion with 50 mM K+ but not 100 mM K+ perfusion. The slope of the regression line obtained by plotting the response of the second K+ perfusion as a function of the first K+ perfusion for all K+ concentrations was 1.03 (not significantly different from unity). Similarly, when the time between two 50 mM potassium perfusions was varied from 30-150 min, the responses were highly correlated. This technique was used to demonstrate an interaction between N-methyl-D-aspartate (NMDA) and 50 mM K+. Perfusion of 0.1 mM NMDA alone had no effect on extracellular DA, but NMDA paired with a 50 mM K+ perfusion significantly increased extracellular DA over that increase by 50 mM K+ alone. We propose that a first stimulation with 50 mM potassium may characterize an individual animal's responsiveness to a depolarizing stimulus, and may be used as a control for testing drug effects by coupling drug treatments with a second 50 mM potassium stimulation to give a more accurate measure of small changes in extracellular dopamine.

Animals↗
PubMed1995

Alteration of acyl-acyl carrier protein pools and acetyl-CoA carboxylase expression in Escherichia coli by a plant medium chain acyl-acyl carrier protein thioesterase.

Expression of a plant lauroyl-acyl carrier protein (ACP) thioesterase in an Escherichia coli strain deficient in beta oxidation results in the accumulation of free fatty acids in the culture. Overall fatty acid production by the cultures is increased severalfold, particularly in the late log and stationary stages of growth. In control E. coli cells, malonyl-ACP levels and rates of fatty acid synthesis are highest during rapid logarithmic growth and decline to undetectable levels in stationary stage. In contrast, in cells expressing plant acyl-ACP thioesterase, malonyl-ACP levels remain high in late log and stationary stage in association with the continued fatty acid production. In addition, the biotin carboxyl carrier protein component of acetyl-CoA carboxylase is expressed at higher levels in cultures expressing the acyl-ACP thioesterase. The data presented indicate that removal of the acyl-ACP products of fatty acid synthesis results in increased production of both malonyl-ACP and fatty acids, which may in turn result from higher activity and/or expression of acetyl-CoA carboxylase.

Acetyl-CoA Carboxylase↗
PubMed1995

Bovine Alu-like sequences mediate transposition of a new site-specific retroelement.

We describe a new family of 3.1-kb repetitive sequences which is present in the bovine genome. The 5' and 3' ends of the unit are flanked with sequences homologous to the 5' and 3' halves of the bovine Alu-like monomer (BM), respectively. Distribution of the 5' ends of the family members in the genome is not random. They are close to the truncated bovine Alu-like dimer (BD) which, in some cases, is followed by 40-bp repeated sequences containing block A of the RNA polymerase III promoter. The ORFs found within the unit code for peptides homologous to amino-acid sequences characteristic for reverse transcriptases (RT). The family members may be considered as mutant mobile elements whose propagation in the genomes was accomplished by means of a process including site-specific recognition with BD. Because of this, we call this family the bovine dimer-driven family (BDDF).

Amino Acid Sequence↗
PubMed1994

Traps and baits for flies (Diptera) on Pacific Islands.

Studies conducted on Oahu, HI, and on islands of the Kwajalein Atoll, Marshall Islands, demonstrated that adult house flies, Musca domestica L., were attracted to a mixture of cooked rice and chicken and to a commercial bait, whereas adults of Chrysomya megacephala F. and Musca sorbens Wiedemann were attracted to shark fluids or to ripe breadfruit. M. domestica and M. sorbens could be captured in standard inverted-cone traps, whereas C. megacephala could be captured in traps fitted with horizontal entry cones or in cone traps in which the bait was placed inside the cone chamber. M. sorbens and C. megacephala were killed by horizontal electric grids placed over yellow plastic or paper at ground level. M. sorbens was attracted to 15-cm cubes, but not to larger objects.

Animal Feed↗
PubMed1991

Expression of multivalent pre-S1 antigen of hepatitis B virus in Escherichia coli (synthetic oligodeoxynucleotides, surface antigens, recombinant DNA, fusion protein, beta-galactosidase).

The nucleotide sequence encoding 30 amino acids (aa) of the pre-S1 envelope region of the human hepatitis B virus has been constructed from twenty chemically synthesized oligodeoxynucleotides by simultaneous ligation. The DNA fragment containing four repeated sequences encoding the pre-S1 region (aa 20-49) has been inserted into the lacZ gene of the plasmid pWR450.1, yielding the recombinant pWX4 plasmid. The Escherichia coli DH5 strain transformed with pWX4 produces a beta-galactosidase-[-pre-S1(20-49) x 4] fusion protein. The hybrid protein containing 127 aa of repeated pre-S1 region has been isolated from Escherichia coli as inclusion bodies and purified by anion exchange chromatography. The antigenic properties of this fusion protein were confirmed by immunoblotting with pre-S1-specific monoclonal antibodies.

Amino Acid Sequence↗
PubMed1990

Synergism through direct covalent bonding between agents: a strategy for rational design of chemotherapeutic combinations.

Self-assembling chemotherapeutic agents are mixtures of relatively nontoxic precursors that can combine chemically under physiological conditions to form products with greater cytotoxic and/or antimicrobial activity than either of the precursors. Combinations that form products more rapidly in or near the target (tumor, pathogen, virally infected cell) than in normal tissues will exhibit target-selective synergism, thus exhibiting an antitarget selectivity that is greater than the selectivities of the product (e.g., a hydrazone) and of either precursor (e.g., a hydrazine derivative or ketone) used singly. This paper describes the target-selective cytotoxic synergism of a cationic aldehyde (A) and a cationic acylhydrazine (B) containing a triarylalkylphosphonium moiety against Ehrlich ascites carcinoma cells (ELA) in culture, in addition to reviewing previous work on self-assembling cytotoxins. The synergism between A and B is carcinoma selective when the ELA cells (the target) are compared to CV-1, an untransformed African green monkey kidney epithelial line. Like tetraphenylphosphonium and rhodamine 123, which are selectively concentrated in ELA cells relative to CV-1, A, B and the hydrazone C resulting from their reaction are lipophilic delocalized cations that selectively inhibit ELA growth relative to CV-1 growth. The hydrazone C is more growth inhibitory than either A or B for both cell lines. A combination of A with an unreactive analogue of B and a combination of B with an unreactive analogue of A did not synergistically inhibit ELA proliferation. The degree of synergism is greater against the ELA cells than against the CV-1 cells. These data, together with hydrazone formation kinetics, suggest that A and B are both concentrated together selectively inside the ELA due to the transmembrane potentials, reacting inside the ELA cells at a higher velocity than inside the CV-1 cells to form the more growth-inhibitory hydrazone C.

Animals↗
PubMed1990

Nucleotide sequence of satellite I and II DNA from alpaca (Lama pacos) genome.

Agarose and polyacrylamide gel electrophoresis of a total alpaca (Lama pacos) DNA, digested with several restriction enzymes, revealed the presence of two tandemly organized repetitive DNA sequences, named Satellite I and Satellite II. Three Xhol-monomers from Satellite I DNA and two BspRI-monomers from Satellite II DNA were sequenced. As determined by dot hybridization analysis, the total alpaca DNA consists of 3.4% and 1.3% Satellites I and II, respectively. Computer search revealed no homology to any primate, rodent or mammalian sequences published in the Gen Bank Release 48.0 (February 1987) and the EMBL Bank Release 10 (December 1986).

Animals↗
PubMed1988

Environment-selective synergism using self-assembling cytotoxic and antimicrobial agents.

Environment-selective synergistic toxicity using combinations of aldehydes and hydrazine derivatives was demonstrated in two different model systems in vitro. Combinations of 5-nitro-2-furaldehyde with semi-carbazide and of 2-hydrazinopyridine with pyridine-2-carboxaldehyde, which can react in situ to form antimicrobial hydrazones, demonstrated greater degrees of synergism against the intracellular pathogen, Salmonella typhimurium, at pH 5 relative to pH 7.4. Combinations are more selectively toxic at pH 5 (vs pH 7.4) than individual precursors and preformed hydrazone products because acid catalysis of hydrazone formation plays a role only for the combinations. A combination of decanal and N-amino, N'-octylguanidine (AOG) exhibited more pronounced synergistic cytolytic activity against erythrocytes in 0% serum than in 1% serum. Serum protein binding of decanal inhibited the formation of the more cytotoxic hydrazone, N-decylidenimino,N'-1-octylguanidine (DIOG), from the less cytotoxic AOG and decanal, and serum protein binding of DIOG prevented this cytotoxin from reaching the cell membrane. Because decanal binding cannot play a role in the cytotoxicity of preformed DIOG, it was less selective for cells in 0% serum than the combination of AOG and decanal. The pH 5 and 0% serum environments represent very simple models for macrophage phagolysosomal compartments and poorly vascularized solid tumor interiors respectively. If environment-selective synergism can be used as a basis for target-selective synergism in other in vitro model systems and in vivo, self-assembling combinations could provide a basis for rational introduction of target-selective synergism into chemotherapeutic drug design.

Aldehydes↗