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Biomedical subjects

G R Fink

Publications and source records attributed to G R Fink.

At least 19 recordsLinked to original sources
PubMed1992

SHR3: a novel component of the secretory pathway specifically required for localization of amino acid permeases in yeast.

Mutations in SHR3 block amino acid uptake into yeast by reducing the levels of multiple amino acid permeases within the plasma membrane. SHR3 is a novel integral membrane protein component of the endoplasmic reticulum (ER). shr3 null mutants specifically accumulate amino acid permeases in the ER; other plasma membrane proteins, secretory proteins, and vacuolar proteins are processed and targeted correctly. Our findings suggest that SHR3 interacts with a structural domain shared by amino acid permeases, an interaction required for permease-specific processing and transport from the ER. Even in the presence of excess amino acids, shr3 mutants exhibit starvation responses. shr3 mutants constitutively express elevated levels of GCN4, and mutant shr3/shr3 diploids undergo dimorphic transitions that result in filamentous growth at enhanced frequencies.

Amino Acid Sequence↗
PubMed1992

Coregulation of purine and histidine biosynthesis by the transcriptional activators BAS1 and BAS2.

We have found cross-pathway regulation between purine and histidine biosynthesis in yeast. The transcription factors BAS1 and BAS2/PHO2, which are also regulators of the histidine pathway, participate in the regulation of the purine biosynthetic pathway. Analysis of four genes of the purine pathway (ADE1, ADE2, ADE5,7, and ADE8) shows that their expression is repressed by adenine. The maximal basal and induced expression of these purine genes requires the presence of both BAS1 and BAS2. The factor BAS1 has been shown to bind at a site containing the TGACTC hexanucleotide motif in the ADE2 and ADE5,7 promoters. This motif is required for both basal and induced activation of the ADE2 gene by BAS1 and BAS2.

Base Sequence↗
PubMed1992

Unipolar cell divisions in the yeast S. cerevisiae lead to filamentous growth: regulation by starvation and RAS.

Diploid S. cerevisiae strains undergo a dimorphic transition that involves changes in cell shape and the pattern of cell division and results in invasive filamentous growth in response to starvation for nitrogen. Cells become long and thin and form pseudohyphae that grow away from the colony and invade the agar medium. Pseudohyphal growth allows yeast cells to forage for nutrients. Pseudohyphal growth requires the polar budding pattern of a/alpha diploid cells; haploid axially budding cells of identical genotype cannot undergo this dimorphic transition. Constitutive activation of RAS2 or mutation of SHR3, a gene required for amino acid uptake, enhance the pseudohyphal phenotype; a dominant mutation in RSR1/BUD1 that causes random budding suppresses pseudohyphal growth.

Cell Division↗
PubMed1992

Changing patterns of glucose metabolism during the course of subacute sclerosing panencephalitis as measured with 18FDG-positron-emission tomography.

18FDG-positron emission tomography performed at different stages in the course of subacute sclerosing panencephalitis revealed a changing pattern of metabolic disturbance. In clinical stage II patients the inflammation in the basal ganglia appeared to lead to neuronal excitation accompanied by hypermetabolism. Widespread cortical functional inhibition of metabolism followed. The striatal inflammation ended with necrosis and hypometabolism, with resulting functional cortical disinhibition; later, deep midbrain structures and brain stem became hypermetabolic. A patient clinically in remission showed no such changes in cerebral glucose metabolism.

Adolescent↗
PubMed1992

Progressive derangement of periinfarct viable tissue in ischemic stroke.

Sixteen patients were studied by multitracer positron emission tomography (PET) within 6-48 (mean of 23) h of onset of a hemispheric ischemic stroke and again 13-25 (mean of 15.6) days later. Cerebral blood flow (CBF), cerebral blood volume (CBV), cerebral metabolic rate of oxygen (CMRO2), oxygen extraction fraction (OEF), and cerebral metabolic rate of glucose (CMRglc) were measured each time by standard methods, and the sets of brain slices obtained at the two studies were matched using a three-dimensional alignment procedure. On matched brain slices, regions of interest (ROIs) for infarct and peri-infarct tissue, contralateral mirror regions, and major brain structures were outlined. In the core of infarction, blood flow and metabolism were significantly lower than in the corresponding contralateral regions at the first study, and did not change during the observation period. In the peri-infarct tissue, CMRO2 was moderately decreased at the first measurement; over time, the CMRO2 deteriorated progressively while flow did not change. When peri-infarct regions were selected on the basis of increased OEF (25 +/- 29.8% above corresponding contralateral regions) on the early scans, the CBF was significantly decreased (23 +/- 6.6%) while the CMRO2 showed only a slight difference from the mirror region. Within the observation period, the CBF improved but the CMRO2, OEF, and CMRglc deteriorated. Only in a few regions with increased OEF and slightly impaired CMRO2 was metabolism preserved close to normal values. These data from repeat PET studies in reproducibly defined tissue compartments furnish evidence of viable tissue in the border zone of ischemia up to 48 h after stroke. While this viable peri-infarct tissue exhibits some potential for effective treatment of ischemic stroke, therapeutic routines available today cannot prevent subsequent metabolic derangement and progression to necrosis. Multitracer PET studies identifying viable tissue could be of value in the development of effective treatment of ischemic stroke.

Adolescent↗
PubMed1992

Functional and morphological imaging of small striato-capsular infarction by CT, MRI and multitracer PET.

Regional cerebral blood flow, oxygen consumption, blood volume and glucose metabolism were studied by positron emission tomography (PET) in 16 patients with striato-capsular infarction during the acute phase. Visual evaluation of tomograms and quantitative analysis of PET data detected in all patients severe flow disturbances and metabolic derangement within the territory of the penetrating branches of the middle cerebral artery. Additionally remote effects were observed. The correspondence of early PET changes with the diagnosis of striato-capsular infarction was verified later on by computerized three-dimensional alignment of PET scans and MRI. These results demonstrate that PET allows localization of small striato-capsular infarction with high accuracy in the acute phase by demonstrating both severe local flow disturbances and metabolic derangement, as well as remote effects.

Brain↗
PubMed1992

Metabolic derangement in viable periinfarct tissue in the course of acute ischaemic infarction: a multitracer positron emission tomography (PET) study.

We used a multitracer positron emission tomography (PET) approach to assess metabolic changes in infarcted and periinfarct tissue in acute ischaemic stroke. 16 patients were studied within 6-48 hours (mean, 23 h) after onset of symptoms from a first hemispheric stroke and again 13-25 days later (mean, 15.6 days). Regional cerebral metabolic rates of oxygen (CMRO2) and glucose (CMRGlc), blood flow (CBF) and blood volume (CBV) were measured and oxygen extraction (OEF) as well as glucose extraction (GEF) and microvascular transit time were calculated. PET images were three-dimensionally aligned using serial CT or MRI scans. Regions of interest on the side of the infarction were individually compared to contralateral mirror regions. In the infarction core CBF, CMRO2 and CMRGlc were significantly lower than on the contralateral side and did not change during time. In the periinfarct regions there was a decreased CMRO2 with progressive deterioration over time while CBF slightly increased. Only in a few ischaemic regions with initially increased OEF oxygen metabolism was preserved during the course of time.

Blood Volume↗
PubMed1992

The yeast Ca(2+)-ATPase homologue, PMR1, is required for normal Golgi function and localizes in a novel Golgi-like distribution.

PMR1, a Ca(2+)-adenosine triphosphatase (ATPase) homologue in the yeast Saccharomyces cerevisiae localizes to a novel Golgi-like organelle. Consistent with a Golgi localization, the bulk of PMR1 comigrates with Golgi markers in subcellular fractionation experiments, and staining of PMR1 by indirect immunofluorescence reveals a punctate pattern resembling Golgi staining in yeast. However, PMR1 shows only partial colocalization with known Golgi markers, KEX2 and SEC7, in double-label immunofluorescence experiments. The effect of PMR1 on Golgi function is indicated by pleiotropic defects in various Golgi processes in pmr1 mutants, including impaired proteolytic processing of pro-alpha factor and incomplete outer chain glycosylation of invertase. Consistent with the proposed role of PMR1 as a Ca2+ pump, these defects are reversed by the addition of millimolar levels of extracellular Ca2+, suggesting that Ca2+ disposition is essential to normal Golgi function. Absence of PMR1 function partially suppresses the temperature-sensitive growth defects of several sec mutants, and overexpression of PMR1 restricts the growth of others. Some of these interactions are modulated by changes in external Ca2+ concentrations. These results imply a global role for Ca2+ in the proper function of components governing transit and processing through the secretory pathway.

Amino Acid Sequence↗
PubMed1992

HTS1 encodes both the cytoplasmic and mitochondrial histidyl-tRNA synthetase of Saccharomyces cerevisiae: mutations alter the specificity of compartmentation.

Genetic and biochemical evidence shows that a single nuclear gene HTS1 encodes both the mitochondrial and cytoplasmic histidyl-tRNA synthetases (Hts). The gene specifies two messages, one with two in-frame ATGs (-60 and +1) and another with only the downstream ATG (+1). We have made a new set of mutations that enables us to express only the mitochondrial or the cytoplasmic form and compared the subcellular distribution of the Hts1 protein in these mutants and wild type, using an antibody that interacts with both the mitochondrial and cytoplasmic Hts1 as well as Hts1::LacZ fusions. Mutations in the upstream ATG (-60) or frameshift mutations in the presequence affect only the mitochondrial enzyme and not the cytoplasmic enzyme. Mutations in the downstream ATG (+1 ATG to ATC) destroy the function of the cytosolic enzyme, but do not affect the function of the mitochondrial enzyme. Overexpression of this construct restores cytoplasmic function. Cells expressing a truncated form of Hts containing a deletion of the first 20 amino-terminal residues (Htsc) produce a functional cytoplasmic enzyme, which does not provide mitochondrial function. Overexpression of this truncated cytoplasmic protein provides mitochondrial function and produces detectable levels of the synthetase in the mitochondrion. These experiments suggest that Hts1 contains two domains that together allow efficient localization of Htsm to the mitochondrion: an amino-terminal presequence in the mitochondrial precursor that is likely cleaved upon delivery to the mitochondrion and a second amino-terminal sequence (residues 21-53) present in both the precursor and the cytoplasmic form. Neither one by itself is sufficient to act as an efficient mitochondrial targeting signal. Using our antibody we have been able to detect a protein of increased molecular mass that corresponds to that of the predicted precursor. Taken together these studies show that the specificity of compartmentation of the Hts protein depends upon both the primary sequence and the concentration of the protein in the cell.

Base Sequence↗
PubMed1992

Two anthranilate synthase genes in Arabidopsis: defense-related regulation of the tryptophan pathway.

Arabidopsis thaliana has two genes, ASA1 and ASA2, encoding the alpha subunit of anthranilate synthase, the enzyme catalyzing the first reaction in the tryptophan biosynthetic pathway. As a branchpoint enzyme in aromatic amino acid biosynthesis, anthranilate synthase has an important regulatory role. The sequences of the plant genes are homologous to their microbial counterparts. Both predicted proteins have putative chloroplast transit peptides at their amino termini and conserved amino acids involved in feedback inhibition by tryptophan. ASA1 and ASA2 cDNAs complement anthranilate synthase alpha subunit mutations in the yeast Saccharomyces cerevisiae and in Escherichia coli, confirming that both genes encode functional anthranilate synthase proteins. The distributions of ASA1 and ASA2 mRNAs in various parts of Arabidopsis plants are overlapping but nonidentical, and ASA1 mRNA is approximately 10 times more abundant in whole plants. Whereas ASA2 is expressed at a constitutive basal level, ASA1 is induced by wounding and bacterial pathogen infiltration, suggesting a novel role for ASA1 in the production of tryptophan pathway metabolites as part of an Arabidopsis defense response. Regulation of key steps in aromatic amino acid biosynthesis in Arabidopsis appears to involve differential expression of duplicated genes.

Amino Acid Sequence↗
PubMed1992

Effects of cerebral angiomas on perifocal and remote tissue: a multivariate positron emission tomography study.

BACKGROUND AND PURPOSE: Using multitracer positron emission tomography, I investigated regional hemodynamic and metabolic changes in both perifocal and remote tissues of cerebral angiomas, with special reference to steal phenomena. METHODS: In 22 patients (14 with arteriovenous malformations and eight with cavernomas) cerebral blood flow, cerebral blood volume, mean vascular transit time, cerebral metabolic rate for oxygen, oxygen extraction fraction, cerebral metabolic rate for glucose, and glucose extraction fraction were measured using standard positron emission tomographic methods. Twelve patients also had their cerebral glucose metabolism assessed during psychophysical activation. Regions of interest representing the angioma, perifocal and remote tissues, contralateral mirror regions, and standard brain regions were analyzed. RESULTS: There were no significant changes in hemodynamic variables or oxygen metabolism in the ipsilateral cerebral hemisphere, but ipsilateral glucose metabolism was reduced both at rest (p less than 0.01) and during activation (p less than 0.05). Glucose (p less than 0.001) and oxygen (p less than 0.001) metabolism in regions of perifocal tissue with low blood flow were decreased, with substrate extraction fractions showing no increase to compensate for insufficient blood flow. Functional recruitment of the cortex overlying the angioma beyond its periphery and supplied by the same arterial branches was subnormal (p less than 0.05) despite relatively unchanged hemodynamics in this tissue compartment. CONCLUSIONS: These data suggest that dysfunction of the cortex supplied by arterial branches also feeding the vascular malformation is related to neuronal deafferentation, while the proportionate decrease in blood flow and metabolism of perifocal tissue may be ascribed to neuronal loss in chronically hypoperfused areas, rather than to persistent hemodynamic steal effects.

Adult↗
PubMed1991

FUS3 represses CLN1 and CLN2 and in concert with KSS1 promotes signal transduction.

FUS3 is functionally redundant with KSS1, a homologous yeast protein kinase, for a step(s) in signal transduction between the beta subunit of the guanine nucleotide binding protein (G protein), STE4, and the mating type-specific transcriptional activator, STE12. Either FUS3 or KSS1 can execute this function; when neither gene encoding these protein kinases is present, signal transduction is blocked, causing sterility. This functional redundancy is strain dependent; some standard laboratory strains (S288C) are kss1-. FUS3 has additional functions required for cell cycle arrest and vegetative growth that do not overlap with KSS1 functions. FUS3 mediates cell cycle arrest during mating through transcriptional repression of two G1 cyclins (CLN1 and CLN2) and through posttranscriptional inhibition of a third G1 cyclin (CLN3). FUS3 is also required for vegetative growth in haploid strains dependent upon CLN3 for cell cycle progression but is not required in strains dependent upon either CLN1 or CLN2, suggesting a functional divergence among the three G1 cyclins. The diverse roles for FUS3 suggest that the FUS3 protein kinase has multiple substrates, some of which may be shared with KSS1.

Cell Cycle↗
PubMed1991

Differential induction of 3-deoxy-D-arabino-heptulosonate 7-phosphate synthase genes in Arabidopsis thaliana by wounding and pathogenic attack.

We have isolated cDNAs from two distinct genes encoding 3-deoxy-D-arabino-heptulosonate 7-phosphate (DAHP) synthase (EC 4.1.2.15) in Arabidopsis thaliana. Predicted protein sequences from both genes, DHS1 and DHS2, and a potato DAHP synthase gene are highly related, but none shows significant sequence similarity to conserved microbial DAHP synthase proteins. Despite this structural difference, the DHS1 cDNA complements mutations in a yeast strain lacking DAHP synthase activity. DHS1 RNA levels increase in Arabidopsis leaves subjected either to physical wounding or to infiltration with pathogenic Pseudomonas syringae strains. DHS2 RNA levels are not increased by these treatments, suggesting that the DHS1 and DHS2 proteins fulfill different physiological functions. Other enzymes in the Arabidopsis aromatic pathway are also encoded by duplicated genes, an arrangement that may allow independent regulation of aromatic amino acid biosynthesis by distinct physiological requirements such as protein synthesis and secondary metabolism. The presence of amino-terminal extensions characteristic of chloroplast transit peptides on DHS1 and DHS2 suggests that both proteins may be targeted to the chloroplast.

3-Deoxy-7-Phosphoheptulonate Synthase↗
PubMed1991

Postnatal development of forebrain regions in the autoimmune NZB-mouse. A model for degeneration in neuronal systems.

NZB-mice are known to have impaired cognitive functions. The aim of the present study is the analysis of the volume growth of different brain regions in NZB/NBOM-mice, because the functional impairment increases postnatally. The regions analysed include brain structures which are important for learning and memory functions. The comparison between NZB-mice and controls (CFW- and Balb/c-mice) shows that the hippocampal volume in NZB-mice is larger than in controls. However, ectopic neurons are found in the dentate gyrus of NZB-mice, indicating a changed connectivity in this region. The septum and the amygdala show no difference in volume in NZB-mice compared to controls. The adult volume of the entorhinal cortex of the NZB-mice is the smallest of the three strains. The development of this brain region is characterized by an overshooting growth in all strains. The caudate-putamen complex and the globus pallidus of NZB-mice undergo a reduction in volume during the postnatal period. This is not found in the controls. An overshooting growth is seen in the mamillary bodies of the three strains, and in the anterior thalamic nucleus of NZB-mice. However, only the NZB-mice show a prolonged reduction of the volume of the mamillary bodies, which is not finished during the observed time period. Both regions are important relay stations in the Papez-circuit, a neuronal system associated with learning and memory functions. The prolonged postnatal reduction in volume of the mamillary bodies and the anterior thalamic nucleus of NZB-mice may be the structural correlate of the impaired cognition and memory in this strain.

Animals↗