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At least 271 records · Page 15Linked to original sources
PubMed1994

Effects of ANG-converting enzyme and alpha 1-adrenoceptor inhibition on intrarenal hemodynamics in SHR.

To investigate the prolonged effects of angiotensin-converting enzyme (ACE) inhibition and alpha 1-adrenoceptor blockade on intrarenal hemodynamics, whole kidney and renal micropuncture studies were performed in male 21-wk-old Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats treated for 3 wk with quinapril (3 mg/kg), terazosin (1 mg/kg), or in their combination (quinapril 1.5 mg/kg and terazosin 0.5 mg/kg). In WKY, only quinapril significantly reduced mean arterial pressure (MAP) associated with reduced afferent arteriolar resistance; there were no other significant changes. In contrast, all treatments similarly decreased MAP in SHR. Quinapril increased renal plasma flow and decreased filtration fraction. With respect to intrarenal hemodynamics, quinapril increased single-nephron plasma flow and reduced glomerular capillary pressure (from 53.1 to 47.8 mmHg; P < 0.01), associated with reduced afferent (from 4.80 to 3.17 10(10)dyn.s.cm-5; P < 0.01) and efferent (from 1.70 to 1.17 10(10)dyn.s.cm-5; P < 0.01) arteriolar resistances, and increased ultrafiltration coefficient (from 0.037 to 0.052 nl.s-1.mmHg-1; P < 0.05). Terazosin only reduced arteriolar resistance. The combined treatment attenuated either agent's independent effects on glomerular hemodynamics. These data demonstrate that prolonged ACE and adrenergic inhibition therapy alone or in combination produce different effects than when given by vein, suggesting that prolonged renopressor system inhibition may be more effective than adrenergic in SHR.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed2005

Comparison of genotype- and haplotype-based approaches for fine-mapping of alcohol dependence using COGA data.

It is generally assumed that the detection of disease susceptibility genes via fine-mapping association study is facilitated by consideration of marker haplotypes. In this study, we compared the performance of genotype-based and haplotype-based association studies using the Collaborative Study of Genetics of Alcoholism dataset, on several chromosomal regions showing evidence for linkage with ALDX1. After correction for multiple testing, the most significant results were observed with the genotype-based analyses on two regions of chromosomes 2 and 7. Interestingly, the analyses results from this dataset showed that there was no advantage of the haplotype-based analyses over genotype-based (single-locus) analyses. However, caution should be taken when generalizing these results to other chromosomal regions or to other populations.

Alcoholism↗
PubMed2005

The contribution of edaphic heterogeneity to the evolution and diversity of Burseraceae trees in the western Amazon.

Environmental heterogeneity in the tropics is thought to lead to specialization in plants and thereby contribute to the diversity of the tropical flora. We examine this idea with data on the habitat specificity of 35 western Amazonian species from the genera Protium, Crepidospermum, and Tetragastris in the monophyletic tribe Protieae (Burseraceae) mapped on a molecular-based phylogeny. We surveyed three edaphic habitats that occur throughout terra firme Amazonia: white-sand, clay, and terrace soils in eight forests across more than 2000 km in the western Amazon. Twenty-six of the 35 species were found to be associated with only one of three soil types, and no species was associated with all three habitats; this pattern of edaphic specialization was consistent across the entire region. Habitat association mapped onto the phylogenetic tree shows association with terrace soils to be the probable ancestral state in the group, with subsequent speciation events onto clay and white-sand soils. The repeated gain of clay association within the clade likely coincides with the emergence of large areas of clay soils in the Miocene deposited during the Andean uplift. Character optimizations revealed that soil association was not phylogenetically clustered for white-sand and clay specialists, suggesting repeated independent evolution of soil specificity is common within the Protieae. This phylogenetic analysis also showed that multiple cases of putative sister taxa with parapatric distributions differ in their edaphic associations, suggesting that edaphic heterogeneity was an important driver of speciation in the Protieae in the Amazon basin.

Base Sequence↗
PubMed2006

Monte Carlo pedigree disequilibrium test for markers on the X chromosome.

Because of the need for fine mapping of disease loci and the availability of dense single-nucleotide-polymorphism markers, many forms of association tests have been developed. Most of them are applicable only to triads, whereas some are amenable to nuclear families (sibships). Although there are a number of methods that can deal with extended families (e.g., the pedigree disequilibrium test [PDT]), most of them cannot accommodate incomplete data. Furthermore, despite a large body of literature on association mapping, only a very limited number of publications are applicable to X-chromosomal markers. In this report, we first extend the PDT to markers on the X chromosome for testing linkage disequilibrium in the presence of linkage. This method is applicable to any pedigree structure and is termed "X-chromosomal pedigree disequilibrium test" (XPDT). We then further extend the XPDT to accommodate pedigrees with missing genotypes in some of the individuals, especially founders. Monte Carlo (MC) samples of the missing genotypes are generated and used to calculate the XMCPDT (X-chromosomal MC PDT) statistic, which is defined as the conditional expectation of the XPDT statistic given the incomplete (observed) data. This MC version of the XPDT remains a valid test for association under linkage with the assumption that the pedigrees and their associated affection patterns are drawn randomly from a population of pedigrees with at least one affected offspring. This set of methods was compared with existing approaches through simulation, and substantial power gains were observed in all settings considered, with type I error rates closely tracking their nominal values.

Chromosomes, Human, X↗
PubMed1999

Perceptual processing of stereopsis in humans: high-field (3.0-tesla) functional MRI study.

Cortical activation associated with stereopsis was studied in eight right-handed neurosurgeons professionally trained in stereoscopic vision. The activation map associated with viewing three-dimensional images, as contrasted to viewing the corresponding two-dimensional images of identical contents (images of MR angiography), showed consistent activation in the cortex adjacent to the intraparietal sulcus. The study further demonstrated a dominant role of the right hemisphere in perceptual processing of stereopsis in humans.

Adult↗
PubMed1995

Mucosal immunogenicity of polysaccharides conjugated to a peptide or multiple-antigen peptide containing T- and B-cell epitopes.

In this study we investigated the mucosal and systemic responses to two T-cell-independent polysaccharides, a serogroup f polysaccharide (formed of rhamnose glucose polymers [RGPs]) from Streptococcus mutans OMZ 175 and a mannan from Saccharomyces cerevisiae, covalently conjugated either to a linear peptide (peptide 3) or to a multiple-antigen peptide (MAP), both derived from S. mutans protein SR, an adhesin of the I/II protein antigen family of oral streptococci. Peptide 3 and MAP, which contained at least one B- and one T-cell epitope, were tested as carriers for the polysaccharides and as protective immunogens. Intragastric intubation of rats with the conjugates (RGPs-peptide 3, RGPs-MAP, mannan-peptide 3, and mannan-MAP) associated with liposomes produced salivary immunoglobulin A (IgA) antibodies which reacted with RGPs or mannan, peptide 3 or MAP, protein SR, and S. mutans or S. cerevisiae cells. Administration of conjugate boosters to the animals showed that both carriers conjugated to the polysaccharides were able to induce, in immunized animals, a salivary antipolysaccharide IgA memory. In contrast, animals primed and challenged with unconjugated polysaccharide showed no anamnestic response. Rats orally immunized with the conjugates also developed systemic primary antipolysaccharide and antipeptide IgM antibody responses which were characterized by a switch from IgM to IgG during the course of the secondary response. Data presented here demonstrated that both peptide 3 and the MAP construct can act as good carriers for orally administered polysaccharides. Unexpectedly, the use of a MAP did not further improve the immunogenicity of polysaccharides at the mucosal level; nevertheless, such a construct should be of great interest in overcoming the problem of genetic restriction induced by linear peptides.

Administration, Oral↗
PubMed1998

Efficacy of the cushing response in maintaining cerebral blood flow in premature and near-term fetal sheep.

Fetal head compression during labor may increase intracranial pressure (ICP) and decrease cerebral perfusion pressure (CPP). An increase in mean arterial pressure (MAP) associated with the Cushing response normally acts to mitigate an ischemic insult when the increase in ICP approaches MAP. However, the premature fetus may be limited in its ability to increase MAP. We compared the efficacy of the pressor response in sustaining CPP, cerebral blood flow (CBF), and cerebral O2 consumption (CMRO2) in chronically catheterized fetal sheep at 0.6 gestation (92 d; n = 7) and 0.9 gestation (133 d; n = 7). When fetal ICP was increased to baseline MAP (41 +/- 3 mm Hg; +/-SEM) in 92-d fetuses, MAP increased by 7 +/- 2 mm Hg and remained stable during 30 min of constant ICP elevation; CBF decreased by 72% and CMRO2 decreased by 46%. In 133-d fetuses, MAP increased from 53 +/- 2 to 65 +/- 4 mm Hg at 3 min of elevated ICP; CBF decreased by 62% and CMRO2 decreased 30%. However, MAP continued to increase after 3 min and reached a stable level of 75 +/- 3 mmHg at 30 min in 133-d fetuses. The additional increase in MAP restored CBF and CMRO2 to baseline values. Plasma epinephrine and vasopressin concentrations increased between 6 and 33 min of elevated ICP to levels, exceeding those in 92-d fetuses. We conclude that the arterial pressure response to intracranial hypertension is present at 0.6 gestation but is less well developed than at 0.9 gestation in fetal sheep, possibly due to immaturity of the sympathoadrenal and vasopressin systems. Consequently, CBF and CMRO2 are not as well defended at mid-gestation against elevated ICP as might occur during difficult labor.

Animals↗
PubMed1992

Cardiovascular responses to cocaine are initially mediated by the central nervous system in rats.

Cocaine produces a pressor response reportedly resulting from both potentiation of peripheral catecholamine activity and a centrally mediated sympathoexcitation. In the present study we sought to differentiate the central nervous system and peripheral contributions to the hemodynamic effects of cocaine. In conscious rats, cocaine (5 mg/kg i.v.) produced a pressor response with two distinct components consisting of a brief, substantial increase in mean arterial pressure (MAP) associated with hindquarters and mesenteric vasoconstriction followed by a sustained, modest response associated with mesenteric vasoconstriction and bradycardia. Pentolinium (7.5 mg/kg i.v.) or adrenal demedullation attenuated the peak increase in MAP by attenuating increases in mesenteric and hindquarters vascular resistance, but did not affect the sustained increase in MAP. Methyl atropine (0.5 or 1 mg/kg i.v.) pretreatment reduced the cocaine-induced increase in systemic vascular resistance and enhanced the hindquarters vasodilation during the sustained MAP response. In contrast, adrenal demedullation abolished the hindquarters vasodilation. The bradycardic response was prevented by pentolinium and reduced by methyl atropine. Sympathetic nerve activity was reduced dramatically after cocaine or procaine administration for several minutes in conscious and in chloralose-anesthetized rats. In several anesthetized rats, the sympathoinhibition was preceded by a brief (3-8 sec) increase in renal sympathetic nerve activity. Procaine or cocaine produced little change in cortical cerebral blood flow as estimated by using a laser Doppler flowmeter. These data suggest that cocaine produces an initial, brief centrally mediated sympathoexcitation, but the sustained, modest pressor response is dependent upon peripheral actions that are diminished by baroreflex activation.

Adrenal Medulla↗
PubMed2005

Genetic association analysis using data from triads and unrelated subjects.

The selection of an appropriate control sample for use in association mapping requires serious deliberation. Unrelated controls are generally easy to collect, but the resulting analyses are susceptible to spurious association arising from population stratification. Parental controls are popular, since triads comprising a case and two parents can be used in analyses that are robust to this stratification. However, parental controls are often expensive and difficult to collect. In some situations, studies may have both parental and unrelated controls available for analysis. For example, a candidate-gene study may analyze triads but may have an additional sample of unrelated controls for examination of background linkage disequilibrium in genomic regions. Also, studies may collect a sample of triads to confirm results initially found using a traditional case-control study. Initial association studies also may collect each type of control, to provide insurance against the weaknesses of the other type. In these situations, resulting samples will consist of some triads, some unrelated controls, and, possibly, some unrelated cases. Rather than analyze the triads and unrelated subjects separately, we present a likelihood-based approach for combining their information in a single combined association analysis. Our approach allows for joint analysis of data from both triad and case-control study designs. Simulations indicate that our proposed approach is more powerful than association tests that are based on each separate sample. Our approach also allows for flexible modeling and estimation of allele effects, as well as for missing parental data. We illustrate the usefulness of our approach using SNP data from a candidate-gene study of psoriasis.

Algorithms↗
PubMed2000

The Kar3p kinesin-related protein forms a novel heterodimeric structure with its associated protein Cik1p.

Proteins that physically associate with members of the kinesin superfamily are critical for the functional diversity observed for these microtubule motor proteins. However, quaternary structures of complexes between kinesins and kinesin-associated proteins are poorly defined. We have analyzed the nature of the interaction between the Kar3 motor protein, a minus-end-directed kinesin from yeast, and its associated protein Cik1. Extraction experiments demonstrate that Kar3p and Cik1p are tightly associated. Mapping of the interaction domains of the two proteins by two-hybrid analyses indicates that Kar3p and Cik1p associate in a highly specific manner along the lengths of their respective coiled-coil domains. Sucrose gradient velocity centrifugation and gel filtration experiments were used to determine the size of the Kar3-Cik1 complex from both mating pheromone-treated cells and vegetatively growing cells. These experiments predict a size for this complex that is consistent with that of a heterodimer containing one Kar3p subunit and one Cik1p subunit. Finally, immunoprecipitation of epitope-tagged and untagged proteins confirms that only one subunit of Kar3p and Cik1p are present in the Kar3-Cik1 complex. These findings demonstrate that the Kar3-Cik1 complex has a novel heterodimeric structure not observed previously for kinesin complexes.

Amino Acid Sequence↗
PubMed2005

Patterns of genetic variation in humans and mice.

Positional cloning of genes underlying the heritability of autoimmune disease, as in many complex diseases, has largely been a frustrating exercise with few replicated positive findings despite enormous efforts at linkage and association mapping over the past ten years. Similar difficulties have been encountered by researchers attempting to identify such genes in murine models of autoimmunity. One reason is the lack of primary knowledge of genetic variation patterns that would enable the more efficient design and interpretation of comprehensive genetic association studies. We here describe progress towards haplotype maps of both the human and mouse genomes including their current application in the search for genes underlying autoimmune and inflammatory disorders.

Animals↗
PubMed1989

Multisite phosphorylation of microtubule-associated protein 2 (MAP-2) in rat brain: peptide mapping distinguishes between cyclic AMP-, calcium/calmodulin-, and calcium/phospholipid-regulated phosphorylation mechanisms.

Microtubule-associated protein 2 (MAP-2), a cytoskeletal protein of 280 kilodalton that is highly enriched in dendrites and neuronal perikarya, is subject to both cyclic AMP-, calcium/calmodulin-, and calcium/phospholipid-regulated phosphorylation when incubated with [gamma-32P]ATP in vitro. We have analyzed the different sites in MAP-2 phosphorylated by these three kinases in fresh or boiled cytosol from different regions of the rat brain, in particular the olfactory bulb, where only one form (MAP-2B) is present, and the cerebral cortex, where both forms (MAP-2A and MAP-2B) are equally enriched. Cyclic AMP-dependent protein kinase and calcium/calmodulin-dependent protein kinase II phosphorylated four common phosphorylation sites, as well as a number of distinct sites that were unique to each enzyme. Calcium/phospholipid-dependent protein kinase phosphorylated a minimum of 15 sites, only one of which appeared to be shared with the other protein kinases. Only serine residues were phosphorylated by cyclic AMP-dependent and calcium/phospholipid-dependent protein kinases, while both serine and threonine residues were phosphorylated by calcium/calmodulin-dependent protein kinase II. No differences were observed in the peptide maps of phospho-MAP-2 prepared from different brain regions. These results emphasize the complexity of the phosphorylation systems that may regulate the function of MAP-2 in situ.

Adenosine Triphosphate↗
PubMed1995

Effects of fentanyl on sympathetic activation associated with the administration of desflurane.

BACKGROUND: Activation of the sympathetic nervous system occurs when desflurane is inspired shortly after anesthetic induction and when the inspired concentration of desflurane is rapidly increased during steady-state periods of anesthesia. The purpose of this study was to determine the effectiveness and dose response of fentanyl pretreatment in attenuating the neurocirculatory responses to desflurane in healthy human volunteers. METHODS: After Institutional Research Review Board approval, three study groups were selected and, in random order, received either placebo (n = 10), a 2.5-micrograms.kg-1 intravenous bolus of fentanyl citrate followed by a continuous infusion of 1 microgram.kg-1.h-1 (n = 9), or a 5.0-micrograms.kg-1 intravenous bolus followed by an infusion of 2 micrograms.kg-1.h-1 (n = 11) before the administration of desflurane. Arterial (MAP) and central venous (CVP) pressures were measured directly, and heart rate (HR) was determined indirectly. Efferent muscle sympathetic nerve activity (SNA) was recorded from the peroneal nerve by microneurography. After neurocirculatory recordings at conscious unmedicated baseline and 12 min after fentanyl administration, anesthetic induction was carried out with 2.0 mg.kg-1 propofol and 0.2 mg.kg-1 vecuronium. Neurocirculatory measurements were repeated beginning 2 min after induction when desflurane was given via mask (semiclosed circle system, 61/min fresh gas flow, 100% O2) in three incremental 1-min steps (3.6%, 7.2%, and 11%). Intubation occurred 10 min after propofol administration. Twenty minutes after intubation, recordings were obtained during two steady-state periods during which end-tidal concentrations had achieved 5.4% (0.75 MAC) and 11% (1.5 MAC) desflurane for at least 10 min. Data also were obtained during the rapid increase in the inspired gas concentration from 5.4% to 11% ("transition"). RESULTS: Neurocirculatory variables did not differ between the three groups at conscious baseline, after fentanyl, and during steady-state periods of anesthesia. Propofol administration significantly reduced SNA and MAP. The MAP reduction was enhanced in the fentanyl-treated groups. After induction, the increases in SNA and MAP associated with the administration of desflurane by mask were not significantly reduced by fentanyl. The transition from 5.4% to 11% desflurane resulted in increases in SNA, HR, MAP, and fentanyl administration significantly attenuated the HR and MAP components. At the 11% steady-state measurement period, CVP was increased and MAP was decreased from conscious baseline, and these changes were not modified by fentanyl. CONCLUSIONS: The administration of desflurane was associated with increases in SNA, HR, MAP, and CVP. Maximum sympathetic activation and hemodynamic responses occurred 4-5 min after initiating desflurane during induction and 2-3 min after increasing the inspired concentration of desflurane during the "transition" period. Although fentanyl partially attenuated the hemodynamic component in a dose-dependent fashion during the "transition" period, it did not significantly diminish the response during induction.

Adult↗
PubMed2006

HTRA1 promoter polymorphism in wet age-related macular degeneration.

Age-related macular degeneration (AMD), the most common cause of irreversible vision loss in individuals aged older than 50 years, is classified as either wet (neovascular) or dry (nonneovascular). Inherited variation in the complement factor H gene is a major risk factor for drusen in dry AMD. Here we report that a single-nucleotide polymorphism in the promoter region of HTRA1, a serine protease gene on chromosome 10q26, is a major genetic risk factor for wet AMD. A whole-genome association mapping strategy was applied to a Chinese population, yielding a P value of <10(-11). Individuals with the risk-associated genotype were estimated to have a likelihood of developing wet AMD 10 times that of individuals with the wild-type genotype.

Aged↗
PubMed2006

Genomewide association analysis of human narcolepsy and a new resistance gene.

Human narcolepsy is a hypersomnia that is affected by multiple genetic and environmental factors. One genetic factor strongly associated with narcolepsy is the HLA-DRB1*1501-DQB1*0602 haplotype in the human leukocyte antigen region on chromosome 6, whereas the other genetic factors are not clear. To discover additional candidate regions for susceptibility or resistance to human narcolepsy, we performed a genomewide association study, using 23,244 microsatellite markers. Two rounds of screening with the use of pooled DNAs yielded 96 microsatellite markers (including 16 markers on chromosome 6) with significantly different estimated frequencies in case and control pools. Markers not located on chromosome 6 were evaluated by the individual typing of 95 cases and 95 controls; 30 markers still showed significant associations. A strong association was displayed by a marker on chromosome 21 (21q22.3). The surrounding region was subjected to high-density association mapping with 14 additional microsatellite markers and 74 SNPs. One microsatellite marker (D21S0012m) and two SNPs (rs13048981 and rs13046884) showed strong associations (P < .0005; odds ratios 0.19-0.33). These polymorphisms were in a strong linkage disequilibrium, and no other polymorphism in the region showed a stronger association with narcolepsy. The region contains three predicted genes--NLC1-A, NLC1-B, and NLC1-C--tentatively named "narcolepsy candidate-region 1 genes," and NLC1-A and NLC1-C were expressed in human hypothalamus. Reporter-gene assays showed that the marker D21S0012m in the promoter region and the SNP rs13046884 in the intron of NLC1-A significantly affected expression levels. Therefore, NLC1-A is considered to be a new resistance gene for human narcolepsy.

Genetic Markers↗
PubMed2006

The Soybean Genome Database (SoyGD): a browser for display of duplicated, polyploid, regions and sequence tagged sites on the integrated physical and genetic maps of Glycine max.

Genomes that have been highly conserved following increases in ploidy (by duplication or hybridization) like Glycine max (soybean) present challenges during genome analysis. At http://soybeangenome.siu.edu the Soybean Genome Database (SoyGD) genome browser has, since 2002, integrated and served the publicly available soybean physical map, bacterial artificial chromosome (BAC) fingerprint database and genetic map associated genomic data. The browser shows both build 3 and build 4 contiguous sets of clones (contigs) of the soybean physical map. Build 4 consisted of 2854 contigs that encompassed 1.05 Gb and 404 high-quality DNA markers that anchored 742 contigs. Many DNA markers anchored sets of 2-8 different contigs. Each contig in the set represented a homologous region of related sequences. GBrowse was adapted to show sets of homologous contigs at all potential anchor points, spread laterally and prevented from overlapping. About 8064 minimum tiling path (MTP2) clones provided 13,473 BAC end sequences (BES) to decorate the physical map. Analyses of BES placed 2111 gene models, 40 marker anchors and 1053 new microsatellite markers on the map. Estimated sequence tag probes from 201 low-copy gene families located 613 paralogs. The genome browser portal showed each data type as a separate track. Tetraploid, octoploid, diploid and homologous regions are shown clearly in relation to an integrated genetic and physical map.

Chromosome Mapping↗
PubMed2025

Genetic-epigenetic interactions (meQTLs) in orofacial clefts etiology.

OBJECTIVES: Nonsyndromic orofacial clefts (OFCs) involve complex genetic and environmental factors, with over 60 risk loci accounting for only a minority of estimated heritability and residing in non-coding regions with unclear functional relevance. We hypothesize that some genetic variants alter orofacial cleft risk by modifying DNA methylation (DNAm) at regulatory sequences essential for craniofacial development, acting as methylation quantitative trait loci (meQTLs). METHODS: We analyzed 10 well-established OFC-associated SNPs against genome-wide DNAm profiles in 409 cases and 456 controls, identifying 23 potential meQTLs. We validated findings using 358 cleft-discordant sibling pairs analyzed with quantitative MethyLight assays. Cross-referencing with the mQTL Database assessed temporal patterns across human development. Functional annotation used GeneHancer and craniofacial enhancer databases. RESULTS: Nine meQTLs were successfully replicated, including the highly significant rs987525 (8q24) - cg16561172 (MYC) association (P = 9.610E-6). This association mapped to a mesendoderm-active enhancer upstream of MYC, providing mechanistic explanation for the longstanding 8q24 cleft locus. Additional validated associations involved MAFB-PLCG1, NOG-PPM1E, FOXE1-FRZB, and SPRY2-LGR4 interactions. Independent differential methylation analysis revealed significant differences between discordant siblings at three CpG sites. Cross-referencing confirmed concordance with population-level methylation effects, with childhood representing the critical developmental window for most associations. CONCLUSIONS: This systematic meQTL characterization in OFCs demonstrates that genetic variants influence disease risk through epigenetic mechanisms. The 8q24-MYC regulatory pathway evidence provides crucial mechanistic insight into a major OFC risk locus. These findings bridge genetic associations with functional consequences, address missing heritability challenges, and suggest potential biomarkers and therapeutic targets for OFC prevention and treatment.

Journal Article↗
PubMed2006

The enteropathogenic Escherichia coli (EPEC) Map effector is imported into the mitochondrial matrix by the TOM/Hsp70 system and alters organelle morphology.

Enteropathogenic Escherichia coli (EPEC) is a human intestinal pathogen and a major cause of diarrhoea, particularly among infants in developing countries. EPEC target the Map and EspF multifunctional effector proteins to host mitochondria - organelles that play crucial roles in regulating cellular processes such as programmed cell death (apoptosis). While both molecules interfere with the organelles ability to maintain a membrane potential, EspF plays the predominant role and is responsible for triggering cell death. To learn more about the Map-mitochondria interaction, we studied Map localization to mitochondria with purified mitochondria (from mammalian and yeast cells) and within intact yeast. This revealed that (i) Map targeting is dependent on the predicted N-terminal mitochondrial targeting sequence, (ii) the N-terminal 44 residues are sufficient to target proteins to mitochondria and (iii) Map import involves the mitochondrial outer membrane translocase (Tom22 and Tom40), the mitochondrial membrane potential, and the matrix chaperone, mtHsp70. These results are consistent with Map import into the mitochondria matrix via the classical import mechanism. As all known, Map-associated phenotypes in mammalian cells are independent of mitochondrial targeting, this may indicate that import serves as a mechanism to remove Map from the cytoplasm thereby regulating cytoplasmic function. Intriguingly, Map, but not EspF, alters mitochondrial morphology with deletion analysis revealing important roles for residues 101-152. Changes in mitochondrial morphology have been linked to alterations in the ability of these organelles to regulate cellular processes providing a possible additional role for Map import into mitochondria.

Amino Acid Motifs↗