Biomedical subjects

G R Fink

Publications and source records attributed to G R Fink.

At least 55 records · Page 3Linked to original sources

PubMed2001

The neural correlates of person familiarity. A functional magnetic resonance imaging study with clinical implications.

Neural activity was measured in 10 healthy volunteers by functional MRI while they viewed familiar and unfamiliar faces and listened to familiar and unfamiliar voices. The familiar faces and voices were those of people personally known to the subjects; they were not people who are more widely famous in the media. Changes in neural activity associated with stimulus modality irrespective of familiarity were observed in modules previously demonstrated to be activated by faces (fusiform gyrus bilaterally) and voices (superior temporal gyrus bilaterally). Irrespective of stimulus modality, familiarity of faces and voices (relative to unfamiliar faces and voices) was associated with increased neural activity in the posterior cingulate cortex, including the retrosplenial cortex. Our results suggest that recognizing a person involves information flow from modality-specific modules in the temporal cortex to the retrosplenial cortex. The latter area has recently been implicated in episodic memory and emotional salience, and now seems to be a key area involved in assessing the familiarity of a person. We propose that disturbances in the information flow described may underlie neurological and psychiatric disorders of the recognition of familiar faces, voices and persons (prosopagnosia, phonagnosia and Capgras delusion, respectively).

Acoustic Stimulation↗

PubMed2001

Arabidopsis ALF5, a multidrug efflux transporter gene family member, confers resistance to toxins.

The Arabidopsis genome contains many gene families that are not found in the animal kingdom. One of these is the multidrug and toxic compound extrusion (MATE) family, which has homology with bacterial efflux transporters. Arabidopsis has at least 54 members of this family, which often are found in tandem repeats. Analysis of ALF5, one member of this Arabidopsis family, suggests that its function is required for protection of the roots from inhibitory compounds. Loss of ALF5 function results in the sensitivity of the root to a number of compounds, including a contaminant of commercial agar. Moreover, expression of the Arabidopsis ALF5 cDNA in yeast confers resistance to tetramethylammonium. These phenotypes are consistent with a role for ALF5 as an efflux transporter. Both transcriptional and translational fusions of ALF5 to the beta-glucuronidase reporter gene show that ALF5 is expressed strongly in the root epidermis, a tissue in direct contact with the external environment. The distinct requirement for ALF5 function is remarkable because of the large number of MATE gene family members in Arabidopsis, one of which is adjacent to ALF5 and 83% identical to ALF5 at the amino acid level.

Amino Acid Sequence↗

PubMed2001

Conservative duplication of spindle poles during meiosis in Saccharomyces cerevisiae.

During sporulation in diploid Saccharomyces cerevisiae, spindle pole bodies acquire the so-called meiotic plaque, a prerequisite for spore formation. Mpc70p is a component of the meiotic plaque and is thus essential for spore formation. We show here that MPC70/mpc70 heterozygous strains most often produce two spores instead of four and that these spores are always nonsisters. In wild-type strains, Mpc70p localizes to all four spindle pole bodies, whereas in MPC70/mpc70 strains Mpc70p localizes to only two of the four spindle pole bodies, and these are always nonsisters. Our data can be explained by conservative spindle pole body distribution in which the two newly synthesized meiosis II spindle pole bodies of MPC70/mpc70 strains lack Mpc70p.

Fungal Proteins↗

PubMed2001

Action observation activates premotor and parietal areas in a somatotopic manner: an fMRI study.

Functional magnetic resonance imaging (fMRI) was used to localize brain areas that were active during the observation of actions made by another individual. Object- and non-object-related actions made with different effectors (mouth, hand and foot) were presented. Observation of both object- and non-object-related actions determined a somatotopically organized activation of premotor cortex. The somatotopic pattern was similar to that of the classical motor cortex homunculus. During the observation of object-related actions, an activation, also somatotopically organized, was additionally found in the posterior parietal lobe. Thus, when individuals observe an action, an internal replica of that action is automatically generated in their premotor cortex. In the case of object-related actions, a further object-related analysis is performed in the parietal lobe, as if the subjects were indeed using those objects. These results bring the previous concept of an action observation/execution matching system (mirror system) into a broader perspective: this system is not restricted to the ventral premotor cortex, but involves several somatotopically organized motor circuits.

Adult↗

PubMed2000

A Saccharomyces gene family involved in invasive growth, cell-cell adhesion, and mating.

The cell wall of bakers' yeast contains a family of glycosyl-phosphatidylinositol (GPI)-linked glycoproteins of domain structure similar to the adhesins of pathogenic fungi. In wild-type cells each of these proteins has a unique function in different developmental processes (mating, invasive growth, cell-cell adhesion, or filamentation). What unifies these developmental events is adhesion, either to an inert substrate or to a cell. Although they differ in their specificities, many of these proteins can substitute for each other when overexpressed. For example, Flo11p is required during vegetative growth for haploid invasion and diploid filamentation, whereas Fig2p is required for mating. When overexpressed, Flo11p and Fig2p can function in mating, invasion, filamentation, and flocculation. The ability of Flo11p to supply Fig2p function in mating depends on its intracellular localization to the mating projection, where Fig2p normally functions in the adhesion of mating cells. Our data show that even distant family members retain the ability to carry out disparate functions if localized and expressed appropriately.

Cell Adhesion↗

PubMed2000

The yeast A kinases differentially regulate iron uptake and respiratory function.

Yeast has three A kinase catalytic subunits, which have greater than 75% identity and are encoded by the TPK genes (TPK1, TPK2, and TPK3) [Toda, T., Cameron, S., Sass, P., Zoller, M. & Wigler, M. (1987) Cell 50, 277-287]. Although they are redundant for viability, the three A kinases are not redundant for pseudohyphal growth [Robertson, L. S. & Fink, G. R. (1998) Proc. Natl. Acad. Sci. USA 95, 13783-13787; Pan, X. & Heitman, J. (1999) Mol. Cell. Biol. 19, 4874-4887]; Tpk2, but not Tpk1 or Tpk3, is required for pseudohyphal growth. Genome-wide transcriptional profiling has revealed unique signatures for each of the three A kinases leading to the identification of additional functional diversity among these proteins. Tpk2 negatively regulates genes involved in iron uptake and positively regulates genes involved in trehalose degradation and water homeostasis. Tpk1 is required for the derepression of branched chain amino acid biosynthesis genes that seem to have a second role in the maintenance of iron levels and DNA stability within mitochondria. The fact that TPK2 mutants grow better than wild types on nonfermentable carbon sources and on media deficient in iron supports the unique role of Tpk2 in respiratory growth and carbon source use.

2-Acetolactate Mutase↗

PubMed2000

Line bisection judgments implicate right parietal cortex and cerebellum as assessed by fMRI.

OBJECTIVE: To use functional MRI (fMRI) to determine which brain regions are implicated when normal volunteers judge whether pretransected horizontal lines are correctly bisected (the Landmark test). BACKGROUND: Manual line bisection and a variant thereof involving perceptual judgments of pretransected lines (the Landmark test) are widely used to assess unilateral visuospatial neglect in patients with neurologic disease. Although unilateral (left) neglect most often results from lesions to right temporoparietal cortex, the normal functional anatomy of the Landmark test has not been convincingly demonstrated. METHODS: fMRI was carried out in 12 healthy right-handed male volunteers who judged whether horizontal lines were correctly prebisected. In the control task, subjects detected whether the horizontal lines contained a transection mark irrespective of the position of that mark. Response was by two-choice key press: on half the trials, subjects used the right, and on half, the left hand. Statistical analysis of evoked blood oxygenation level-dependent responses, measured with echoplanar imaging, employed statistical parametric mapping. RESULTS: Performing the Landmark task showed neural activity (p < 0.05, corrected) in the right superior posterior and right inferior parietal lobe, early visual processing areas bilaterally, the cerebellar vermis, and the left cerebellar hemisphere. Only the latter area showed a significant interaction with hand used. CONCLUSIONS: The right hemispheric dominance observed in inferior parietal cortex is consistent with the results of lesion studies. Right superior parietal cortex, vermis, and left cerebellar hemisphere have not been implicated in neglect, but all appear to play a cognitive role in the Landmark task.

Adult↗

PubMed2000

'Where' depends on 'what': a differential functional anatomy for position discrimination in one- versus two-dimensions.

Line bisection is widely used as a clinical test of spatial cognition in patients with left visuospatial neglect after right hemisphere lesion. Surprisingly, many neglect patients who show severe impairment on marking the center of horizontal lines can accurately mark the center of squares. That these patients with left neglect are also typically poor at judging whether lines are correctly prebisected implies that the deficit can be perceptual rather than motoric. These findings suggest a differential neural basis for one- and two-dimensional visual position discrimination that we investigated with functional neuroimaging (fMRI). Normal subjects judged whether, in premarked lines or squares, the mark was placed centrally. Line center judgements differentially activated right parietal cortex, while square center judgements differentially activated the lingual gyrus bilaterally. These distinct neural bases for one- and two-dimensional visuospatial judgements help explain the observed clinical dissociations by showing that as a stimulus becomes a better, more 'object-like' gestalt, the ventral visuoperceptive route assumes more responsibility for assessing position within the object.

Adult↗

PubMed2000

Degradation of the transcription factor Gcn4 requires the kinase Pho85 and the SCF(CDC4) ubiquitin-ligase complex.

Gcn4, a yeast transcriptional activator that promotes the expression of amino acid and purine biosynthesis genes, is rapidly degraded in rich medium. Here we report that SCF(CDC4), a recently characterized protein complex that acts in conjunction with the ubiquitin-conjugating enzyme Cdc34 to degrade cell cycle regulators, is also necessary for the degradation of the transcription factor Gcn4. Degradation of Gcn4 occurs throughout the cell cycle, whereas degradation of the known cell cycle substrates of Cdc34/SCF(CDC4) is cell cycle regulated. Gcn4 ubiquitination and degradation are regulated by starvation for amino acids, whereas the degradation of the cell cycle substrates of Cdc34/SCF(CDC4) is unaffected by starvation. We further show that unlike the cell cycle substrates of Cdc34/SCF(CDC4), which require phosphorylation by the kinase Cdc28, Gcn4 degradation requires the kinase Pho85. We identify the critical target site of Pho85 on Gcn4; a mutation of this site stabilizes the protein. A specific Pho85-Pcl complex that is able to phosphorylate Gcn4 on that site is inactive under conditions under which Gcn4 is stable. Thus, Cdc34/SCF(CDC4) activity is constitutive, and regulation of the stability of its various substrates occurs at the level of their phosphorylation.

Cyclin-Dependent Kinases↗

PubMed2000

Neural consequences of acting in near versus far space: a physiological basis for clinical dissociations.

We used PET to determine which brain regions are implicated when normal volunteers bisect horizontal lines and point to dots in near (peripersonal) or far (extrapersonal) space. Studies of line bisection in patients with right hemisphere lesions have shown that bisection performance can be severely impaired in either near or far space while remaining within normal limits in the other spatial domain. Likewise, clinical dissociations between pointing to objects in near and far space have been reported. The normal functional anatomy of these dissociations has not been demonstrated convincingly. Regional cerebral blood flow measurements using PET were carried out in 12 healthy right-handed male volunteers who bisected lines or pointed to dots in near or far space, using a laser pen. Subjects performing either task in near space showed neural activity in the left dorsal occipital cortex, left intraparietal cortex, left ventral premotor cortex and left thalamus. In far space, subjects performing either task showed activation of the ventral occipital cortex bilaterally and the right medial temporal cortex. These data provide physiological support for the clinically observed dissociations demonstrating that attending to and acting in near space differentially employs dorsal visuomotor processing areas, whereas attending to and acting in far space differentially draws on ventral visuoperceptual processing areas, even when the motor components of the tasks are identical when performed in the two spaces.

Adult↗

PubMed2000

Sterol methyltransferase 1 controls the level of cholesterol in plants.

The side chain in plant sterols can have either a methyl or ethyl addition at carbon 24 that is absent in cholesterol. The ethyl addition is the product of two sequential methyl additions. Arabidopsis contains three genes-sterol methyltransferase 1 (SMT1), SMT2, and SMT3-homologous to yeast ERG6, which is known to encode an S-adenosylmethionine-dependent C-24 SMT that catalyzes a single methyl addition. The SMT1 polypeptide is the most similar of these Arabidopsis homologs to yeast Erg6p. Moreover, expression of Arabidopsis SMT1 in erg6 restores SMT activity to the yeast mutant. The smt1 plants have pleiotropic defects: poor growth and fertility, sensitivity of the root to calcium, and a loss of proper embryo morphogenesis. smt1 has an altered sterol content: it accumulates cholesterol and has less C-24 alkylated sterols content. Escherichia coli extracts, obtained from a strain expressing the Arabidopsis SMT1 protein, can perform both the methyl and ethyl additions to appropriate sterol substrates, although with different kinetics. The fact that smt1 null mutants still produce alkylated sterols and that SMT1 can catalyze both alkylation steps shows that there is considerable overlap in the substrate specificity of enzymes in sterol biosynthesis. The availability of the SMT1 gene and mutant should permit the manipulation of phytosterol composition, which will help elucidate the role of sterols in animal nutrition.

Amino Acid Sequence↗

PubMed2000

Diffusion- and perfusion-weighted MRI: influence of severe carotid artery stenosis on the DWI/PWI mismatch in acute stroke.

BACKGROUND AND PURPOSE: Diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI) have been used increasingly in recent years to evaluate acute stroke in the emergency setting. In the present study, we compared DWI and PWI findings in acute stroke patients with and without severe extracranial internal carotid artery (ICA) disease. METHODS: Twenty-seven patients with nonlacunar ischemic stroke were selected for this analysis. DWI, PWI, and conventional MRI were performed in all patients within 24 hours of symptom onset and after 1 week. To exclude patients with partial or complete reperfusion, we included only patients with a PWI deficit larger than the DWI lesion. Severe ICA disease (>70% stenosis) was present unilaterally in 9 and bilaterally in 2 patients. Acute DWI lesion volume, the size of the acute PWI/DWI mismatch, and final infarct size (on T2-weighted images) were determined. RESULTS: The PWI/DWI mismatch was significantly larger in patients with severe ICA disease than in patients without extracranial carotid stenosis, both when time-to-peak and mean transit time maps (P<0.01) were used to calculate the mismatch. Quantitative analysis of the time-to-peak delay in the mismatch indicated that a relatively smaller fraction of the total mismatch was critically ischemic in patients with carotid stenosis than in those without. Average lesion volume increased less in the stenosis group (P=0.14), despite the larger PWI/DWI mismatch, and final infarct size was smaller in the stenosis group (P<0.05). In the 2 patients with bilateral ICA disease, variable hemodynamic involvement of the contralateral hemisphere was found in addition to the ipsilateral PWI deficit. CONCLUSIONS: In most acute stroke patients with severe ICA stenosis, a considerably smaller fraction of the total PWI/DWI mismatch is at risk than in patients without carotid disease.

Acute Disease↗

PubMed2000

Neural consequences of competing stimuli in both visual hemifields: a physiological basis for visual extinction.

We used positron emission tomography in healthy volunteers to test hemispheric rivalry theories for normal and pathological spatial attention, which provide an influential account of contralesional extinction on bilateral stimulation after unilateral brain injury. Subjects reported visual characters presented either unilaterally or bilaterally. An extinction-like pattern was found behaviorally, with characters in one hemifield reported less accurately when competing characters appeared in the other hemifield. Differences in neural activity for unilateral minus bilateral conditions revealed greater activation of striate and extrastriate areas for stimuli presented without competing stimuli in the other hemifield. Thus, simultaneous bilateral stimulation led to a significant reduction in response by spatiotopic visual cortex contralateral to a particular stimulus. These data provide physiological support for interhemispheric rivalry in the intact human brain, and demonstrate that such competition impacts at early levels of perceptual processing.

Adult↗

PubMed1999

Effectors of a developmental mitogen-activated protein kinase cascade revealed by expression signatures of signaling mutants.

Despite the importance of mitogen-activated protein kinase (MAPK) signaling in eukaryotic biology, the mechanisms by which signaling yields phenotypic changes are poorly understood. We have combined transcriptional profiling with genetics to determine how the Kss1 MAPK signaling pathway controls dimorphic development in Saccharomyces cerevisiae. This analysis identified dozens of transcripts that are regulated by the pathway, whereas previous work had identified only a single downstream target, FLO11. One of the MAPK-regulated genes is PGU1, which encodes a secreted enzyme that hydrolyzes polygalacturonic acid, a structural barrier to microbial invasion present in the natural plant substrate of S. cerevisiae. A third key transcriptional target is the G(1) cyclin gene CLN1, a morphogenetic regulator that we show to be essential for pseudohyphal growth. In contrast, the homologous CLN2 cyclin gene is dispensable for development. Thus, the Kss1 MAPK cascade programs development by coordinately modulating a cell adhesion factor, a secreted host-destroying activity, and a specialized subunit of the Cdc28 cyclin-dependent kinase.

Cyclins↗

PubMed1999

Ploidy regulation of gene expression.

Microarray-based gene expression analysis identified genes showing ploidy-dependent expression in isogenic Saccharomyces cerevisiae strains that varied in ploidy from haploid to tetraploid. These genes were induced or repressed in proportion to the number of chromosome sets, regardless of the mating type. Ploidy-dependent repression of some G1 cyclins can explain the greater cell size associated with higher ploidies, and suggests ploidy-dependent modifications of cell cycle progression. Moreover, ploidy regulation of the FLO11 gene had direct consequences for yeast development.

Chitinases↗

PubMed1999

The Arabidopsis thaliana proton transporters, AtNhx1 and Avp1, can function in cation detoxification in yeast.

Overexpression of the Arabidopsis thaliana vacuolar H+-pyrophosphatase (AVP1) confers salt tolerance to the salt-sensitive ena1 mutant of Saccharomyces cerevisiae. Suppression of salt sensitivity requires two ion transporters, the Gef1 Cl- channel and the Nhx1 Na+/H+ exchanger. These two proteins colocalize to the prevacuolar compartment of yeast and are thought to be required for optimal acidification of this compartment. Overexpression of AtNHX1, the plant homologue of the yeast Na+/H+ exchanger, suppresses some of the mutant phenotypes of the yeast nhx1 mutant. Moreover, the level of AtNHX1 mRNA in Arabidopsis is increased in the presence of NaCl. The regulation of AtNHX1 by NaCl and the ability of the plant gene to suppress the yeast nhx1 mutant suggest that the mechanism by which cations are detoxified in yeast and plants may be similar.

Amino Acid Sequence↗

PubMed1999

Hemispheric asymmetries in global/local processing are modulated by perceptual salience.

It has been claimed that a left hemisphere bias toward local and right hemisphere bias toward global visual processing can be explained in terms of specialization for relatively high and low spatial frequencies, respectively. Using non-representational figures, we tested this hypothesis in experiment 1 using positron emission tomography (PET) measures of cerebral activity in 10 normal volunteers. In each block of trials subjects viewed either a relatively high or a relatively low spatial frequency grating. The orientation (vertical or horizontal) of the grating changed from trial to trial. In a directed attention task, subjects reported the orientation of either the whole stimulus (globally directed attention) or the orientation of the component parts thereof (locally directed attention). A significant interaction between hierarchical processing level (global or local) and stimulus level (relatively high or relatively low spatial frequency within the absolute low spatial frequency range) was found. Globally directed attention led to significantly increased cerebral activity in the right hemisphere when relatively high spatial frequency stimuli were used but not when relatively low spatial frequency stimuli were used. Likewise, locally directed attention increased cerebral activity when low but not high spatial frequency stimuli were used. On the basis of these results we suggest that perceptual salience of the global or local form modulates hemispheric processing asymmetries in early visual cortex. In experiment 2, the perceptual salience of global form in relatively high spatial frequency stimuli and of local form in relatively low spatial frequency stimuli was confirmed in a reaction time (RT) study. In combination, the results of the two experiments suggest that perceptual salience takes precedence over spatial frequency (within the range studied here) in determining the cerebral organization of global/local processing.

Adult↗

PubMed1999

Contrast polarity and face recognition in the human fusiform gyrus.

Functional imaging has revealed face-responsive visual areas in the human fusiform gyrus, but their role in recognizing familiar individuals remains controversial. Face recognition is particularly impaired by reversing contrast polarity of the image, even though this preserves all edges and spatial frequencies. Here, combined influences of familiarity and priming on face processing were examined as contrast polarity was manipulated. Our fMRI results show that bilateral posterior areas in fusiform gyrus responded more strongly for faces with positive than with negative contrast polarity. An anterior, right-lateralized fusiform region is activated when a given face stimulus becomes recognizable as a well-known individual.

Adult↗