Biomedical subjects

G R Fink

Publications and source records attributed to G R Fink.

At least 91 records · Page 5Linked to original sources

PubMed1997

14-3-3 proteins are essential for RAS/MAPK cascade signaling during pseudohyphal development in S. cerevisiae.

14-3-3 proteins are highly conserved ubiquitous proteins whose explicit functions have remained elusive. Here, we show that the S. cerevisiae 14-3-3 homologs BMH1 and BMH2 are not essential for viability or mating MAPK cascade signaling, but they are essential for pseudohyphal-development MAPK cascade signaling and other processes. Activated alleles of RAS2 and CDC42 induce pseudohyphal development and FG(TyA)-lacZ signaling in Bmh+ strains but not in ste20 (p65PAK) or bmh1 bmh2 mutant strains. Moreover, Bmh1p and Bmh2p associate with Ste20p in vivo. Three alleles of BMH1 encode proteins defective for FG(TyA)-lacZ signaling and association with Ste20p, yet these alleles complement other 14-3-3 functions. Therefore, the 14-3-3 proteins are specifically required for RAS/MAPK cascade signaling during pseudohyphal development in S. cerevisiae.

14-3-3 Proteins↗

PubMed1997

Impaired episodic memory retrieval in a case of probable psychogenic amnesia.

A patient with severe, selective retrograde amnesia for personal material diagnosed as probable psychogenic amnesia, was investigated intensively neuropsychologically with cranial computed tomography (CCT), magnetic resonance imaging (MRI), and single photon emission tomography (SPECT). The patient was of average intelligence and memory with no anterograde amnesia. No evidence for structural brain damage was detected in CCT and MRI. SPECT, performed about 3 weeks after the onset of symptoms, demonstrated reduced perfusion in right temporal and frontal areas, that is, in areas which have been suggested as critical for episodic memory retrieval. To study episodic memory retrieval, positron-emission-tomography (PET) blood flow (rCBF) measurements were performed 6 months after the onset of symptoms. During episodic memory retrieval bilateral neuronal activations were observed in the precuneus, the lateral parietal and the right dorsolateral and polar prefrontal cortex. Compared to the results of previous functional imaging studies on episodic memory retrieval, our findings suggest an underlying functional disturbance of brain areas previously demonstrated to be involved in episodic memory retrieval.

Adult↗

PubMed1997

Hemispheric specialization for global and local processing: the effect of stimulus category.

Neuropsychological evidence indicates that the global aspect of complex visual scenes is preferentially processed by the right hemisphere, and local aspects are preferentially processed by the left hemisphere. Using letter-based hierarchical stimuli (Navon figures), we recently demonstrated, in a directed-attention task, lateralized neural activity (assessed by positron emission tomography) in the left prestriate cortex during local processing, and in the right prestriate cortex during global processing. Furthermore, temporal-parietal cortex was critically activated bilaterally in a divided-attention task that involved varying the number of target switches between local and global levels of letter-based hierarchical stimuli. Little is known about whether such stimulus categories influence such hemispheric lateralization. We now present data on brain activity, derived from positron emission tomography, in normal subjects scanned during either local or global processing of object-based hierarchical stimuli. We again observe attentional modulation of neural activity in prestriate cortex. There is now greater right-sided activation for local processing and greater left-sided activation for global processing, which is the opposite of that seen with letter-based stimuli. The results suggest that the relative differential hemispheric activations in the prestriate areas during global and local processing are modified by stimulus category.

Adult↗

PubMed1997

Combinatorial control required for the specificity of yeast MAPK signaling.

In yeast, an overlapping set of mitogen-activated protein kinase (MAPK) signaling components controls mating, haploid invasion, and pseudohyphal development. Paradoxically, a single downstream transcription factor, Ste12, is necessary for the execution of these distinct programs. Developmental specificity was found to require a transcription factor of the TEA/ATTS family, Tec1, which cooperates with Ste12 during filamentous and invasive growth. Purified derivatives of Ste12 and Tec1 bind cooperatively to enhancer elements called filamentation and invasion response elements (FREs), which program transcription that is specifically responsive to the MAPK signaling components required for filamentous growth. An FRE in the TEC1 promoter functions in a positive feedback loop required for pseudohyphal development.

Calcium-Calmodulin-Dependent Protein Kinases↗

PubMed1997

Psychophysiological and modulatory interactions in neuroimaging.

In this paper we introduce the idea of explaining responses, in one cortical area, in terms of an interaction between the influence of another area and some experimental (sensory or task-related) parameter. We refer to these effects as psychophysiological interactions and relate them to interactions based solely on experimental factors (i.e., psychological interactions), in factorial designs, and interactions among neurophysiological measurements (i.e., physiological interactions). We have framed psychophysiological interactions in terms of functional integration by noting that the degree to which the activity in one area can be predicted, on the basis of activity in another, corresponds to the contribution of the second to the first, where this contribution can be related to effective connectivity. A psychophysiological interaction means that the contribution of one area to another changes significantly with the experimental or psychological context. Alternatively these interactions can be thought of as a contribution-dependent change in regional responses to an experimental or psychological factor. In other words the contribution can be thought of as modulating the responses elicited by a particular stimulus or psychological process. The potential importance of this approach lies in (i) conferring a degree of functional specificity on this aspect of effective connectivity and (ii) providing a model of modulation, where the contribution from a distal area can be considered to modulate responses to the psychological or stimulus-specific factor defining the interaction. Although distinct in neurobiological terms, these are equivalent perspectives on the same underlying interaction. We illustrate these points using a functional magnetic resonance imaging study of attention to visual motion and a position emission tomography study of visual priming. We focus on interactions among extrastriate, inferotemporal, and posterior parietal regions during visual processing, under different attentional and perceptual conditions.

Attention↗

PubMed1997

The functional anatomy of a hysterical paralysis.

The concept of a conversion disorder (such as hysterical paralysis) has always been controversial (Ron, M.A. (1996). Somatization and conversion disorders. In: B.S. Fogel, R.B. Schiffer & S.M. Rao (Eds.), Neuropsychiatry. Williams and Wilkins, Baltimore, MD). Although the diagnosis is recognised by current psychiatric taxonomies, many physicians still regard such disorders either as feigned or as failure to find the responsible organic cause for the patient's symptoms. We report a woman with left sided paralysis (and without somatosensory loss) in whom no organic disease or structural lesion could be found. By contrast, psychological trauma was associated with the onset and recurrent exacerbation of her hemiparalysis. We recorded brain activity when the patient prepared to move and tried to move her paralysed (left) leg and when she prepared to move and did move her good (right) leg. Preparing to move or moving her good leg, and also preparing to move her paralysed leg, activated motor and/or premotor areas previously described with movement preparation and execution. The attempt to move the paralysed leg failed to activate right primary motor cortex. Instead, the right orbito-frontal and right anterior cingulate cortex were significantly activated. We suggest that these two areas inhibit prefrontal (willed) effects on the right primary motor cortex when the patient tries to move her left leg.

Cerebral Cortex↗

PubMed1997

Neural mechanisms involved in the processing of global and local aspects of hierarchically organized visual stimuli.

We investigated the functional anatomy involved in sustaining or switching visual attention between different perceptual levels, using functional imaging measures of neural activity. Two experiments were carried out using hierarchically organized letters (i.e. large letters made out of small letters). In a divided-attention task, subjects were required to switch attention between local and global levels. The number of successive stimuli for which subjects had to sustain attention to either the global or local level co-varied significantly with temporal-parietal activations bilaterally. Other activations were also observed in the right orbitofrontal cortex, the right dorsolateral prefrontal cortex, and the right middle temporal gyrus. The number of switches between levels co-varied significantly with activations in the left supplementary motor area and the left medial parietal cortex. In the directed-attention task, subjects were required to attend to either the global or local level of the stimuli throughout all trials; attention to the global aspect resulted in significant activation of the right lingual gyrus while attention to the local aspect significantly activated the left inferior occipital cortex. We suggest that left hemisphere activations with increasing numbers of switches between perceptual levels reflect increased demands on an executive attentional system, while sustained attention to either level activates a predominantly right hemispheric network involving temporal-parietal and dorsolateral prefrontal regions. Overall, the results provide evidence for relative hemispheric specialization for global and local processing in accordance with previous neuropsychological studies. In addition, the findings demonstrate that early visual processing mechanisms in the prestriate cortex are influenced by an attentional system in temporal-parietal areas.

Adult↗

PubMed1997

Space-based and object-based visual attention: shared and specific neural domains.

Visual attention can be primarily allocated to either where an object is in space (with little emphasis on the structure of the object itself) or to the structure of the object (with little emphasis on where in space the object is located). Using PET measures of regional cerebral blood flow (rCBF) to index neural activity, we investigated the shared and specific functional anatomy underlying both of these types of visual attention in a controlled non-cueing non-blocked paradigm that involved identical stimuli across the conditions of interest. The interaction of eye movements with these attentional systems was studied by introducing fixation or free vision as an additional factor. Relative to the control condition, object-based and space-based attention showed significant activations of the left and right medial superior parietal cortex and the left lateral inferior parietal cortex, the left prefrontal cortex and the cerebellar vermis. Significant differential activations were observed during object-based attention in the left striate and prestriate cortex. Space-based attention activated the right prefrontal cortex and the right inferior temporal-occipital cortex. Differential neural activity due to free vision or fixation was observed in occipital areas only. Significant interactions of free vision/fixation on activations due to object-based and space-based attention were observed in the right medial superior parietal cortex and left lateral inferior parietal cortex, respectively. The study provides direct evidence for the importance of the parietal cortex in the control of object-based and space-based visual attention. The results show that object-based and space-based attention share common neural mechanisms in the parietal lobes, in addition to task specific mechanisms in early visual processing areas of temporal and occipital cortices.

Adult↗

PubMed1997

Dissection of filamentous growth by transposon mutagenesis in Saccharomyces cerevisiae.

Diploid Saccharomyces cerevisiae strains starved for nitrogen undergo a developmental transition from growth as single yeast form (YF) cells to a multicellular form consisting of filaments of pseudohyphal (PH) cells. Filamentous growth is regulated by an evolutionarily conserved signaling pathway that includes the small GTP-binding proteins Ras2p and Cdc42p, the protein kinases Ste20p, Ste11p and Ste7p, and the transcription factor Ste12p. Here, we designed a genetic screen for mutant strains defective for filamentous growth (dfg) to identify novel targets of the filamentation signaling pathway, and we thereby identified 16 different genes, CDC39, STE12, TEC1, WHI3, NAB1, DBR1, CDC55, SRV2, TPM1, SPA2, BNI1, DFG5, DFG9, DFG10, BUD8 and DFG16, mutations that block filamentous growth. Phenotypic analysis of dfg mutant strains genetically dissects filamentous growth into the cellular processes of signal transduction, bud site selection, cell morphogenesis and invasive growth. Epistasis tests between dfg mutant alleles and dominant activated alleles of the RAS2 and STE11 genes, RAS2Val19 and STE11-4, respectively, identify putative targets for the filamentation signaling pathway. Several of the genes described here have homologues in filamentous fungi, where they also regulate fungal development.

DNA Transposable Elements↗

PubMed1997

Arabidopsis mutants resistant to the auxin effects of indole-3-acetonitrile are defective in the nitrilase encoded by the NIT1 gene.

Indole-3-acetonitrile (IAN) is a candidate precursor of the plant growth hormone indole-3-acetic acid (IAA). We demonstrated that IAN has auxinlike effects on Arabidopsis seedlings and that exogenous IAN is converted to IAA in vivo. We isolated mutants with reduced sensitivity to IAN that remained sensitive to IAA. These mutants were recessive and fell into a single complementation group that mapped to chromosome 3, within 0.5 centimorgans of a cluster of three nitrilase-encoding genes, NIT1, NIT2, and NIT3. Each of the three mutants contained a single base change in the coding region of the NIT1 gene, and the expression pattern of NIT1 is consistent with the IAN insensitivity observed in the nit1 mutant alleles. The half-life of IAN and levels of IAA and IAN were unchanged in the nit1 mutant, confirming that Arabidopsis has other functional nitrilases. Overexpressing NIT2 in transgenic Arabidopsis caused increased sensitivity to IAN and faster turnover of exogenous IAN in vivo.

Amino Acid Sequence↗

PubMed1997

Cerebral areas associated with motor control of speech in humans.

We have defined areas in the brain activated during speaking, utilizing positron emission tomography. Six normal subjects continuously repeated the phrase "Buy Bobby a poppy" (requiring minimal language processing) in four ways: A) spoken aloud, B) mouthed silently, C) without articulation, and D) thought silently. Statistical comparison of images from conditions A with C and B with D highlighted areas associated with articulation alone, because control of breathing for speech was controlled for; we found bilateral activations in sensorimotor cortex and cerebellum with right-sided activation in the thalamus/caudate nucleus. Contrasting images from conditions A with B and C with D highlighted areas associated with the control of breathing for speech, vocalization, and hearing, because articulation was controlled for; we found bilateral activations in sensorimotor and motor cortex, close to but distinct from the activations in the preceding contrast, together with activations in thalamus, cerebellum, and supplementary motor area. In neither subtraction was there activation in Broca's area. These results emphasize the bilaterality of the cerebral control of "speaking" without language processing.

Adult↗

PubMed1997

Multiple nonprimary motor areas in the human cortex.

We measured the distribution of regional cerebral blood flow with positron emission tomography while three subjects moved their hand, shoulder, or leg. The images were coregistered with each individual's anatomic magnetic resonance scans. The data were analyzed for each individual to avoid intersubject averaging and so to preserve individual gyral anatomy. Instead of inspecting all pixels, we prospectively restricted the data analysis to particular areas of interest. These were defined on basis of the anatomic and physiological literature on nonhuman primates. By examining only a subset of areas, we strengthened the power of the statistical analysis and thereby increased the confidence in reporting single subject data. On the lateral convexity, motor related activity was found for all three subjects in the primary motor cortex, lateral premotor cortex, and an opercular area within the premotor cortex. In addition, there was activation of somatosensory cortex (SI), the supplementary somatosensory area (SII) in the Sylvian fissure, and parietal association areas (Brodmann areas 5 and 40). There was also activation in the insula. We suggest that the activation in the dorsal premotor cortex may correspond with dorsal premotor area (PMd) as described in the macaque brain. We propose three hypotheses as to the probable location of vental premotor area (PMv) in the human brain. On the medial surface, motor-related activity was found for all three subjects in the leg areas of the primary motor cortex and somatosensory cortex and also activity for the hand, shoulder, and leg in the supplementary motor area (SMA) on the dorsal medial convexity and in three areas in the cingulate sulcus. We suggest that the three cingulate areas may correspond with rostral cingulate premotor area, dorsal cingulate motor area (CMAd), and ventral cingulate motor area (CMAv) as identified in the macaque brain. Somatotopic mapping was demonstrated in the primary motor and primary somatosensory cortex. In all three subjects, the arm region lay anterior to the leg region in parietal area 5. Also in all three subjects, the arm region lay anterior to the leg region in the supplementary motor cortex.

Adult↗

PubMed1996

Candida albicans strains heterozygous and homozygous for mutations in mitogen-activated protein kinase signaling components have defects in hyphal development.

The Candida albicans genes, CST20 and HST7, were cloned by their ability to suppress the mating defects of Saccharomyces cerevisiae mutants in the ste20 and ste7 genes, which code for elements of the mating mitogenactivated protein (MAP) kinase pathway. These Candida genes are both structural and functional homologs of the cognate Saccharomyces genes. The pattern of suppression in Saccharomyces is related to their presumptive position in the MAP kinase cascade. Null alleles of these genes were constructed in Candida. The Candida homozygous null mutants are defective in hyphal formation on some media, but are still induced to form hyphae by serum, showing that serum induction of hyphae is independent of the MAP kinase cascade. The Candida heterozygotes CST20/cst20 and HST7/hst7 are also defective in hyphal formation. This lack of dominance of the wild-type allele suggests that gene dosage is important in Candida.

Amino Acid Sequence↗

PubMed1996

Cerebral activation during the exertion of sustained static force in man.

The aim of our study was to determine alterations of cerebral activity during prolonged static force exertion. Regional cerebral blood flow (rCBF) was measured using H2(15)O positron emission tomography (PET) while six male normal subjects pressed a morse-key with their right index finger with a constant force of 20% of their maximal voluntary contraction (MVC) for different periods of time (1.5-4.5 min). Exertion of static force led to activation which was at least as extensive as that during exertion of repetitive dynamic force pulses. Despite a considerable sense of fatigue and increased effort at the end of a 4.5 min key press, no compensatory changes of activity were detected in motor or sensory related structures. The right dorsolateral prefrontal cortex demonstrated a significant correlation between rCBF and duration of key-press, possibly reflecting processes over-riding fatigue. Prominent basal ganglia activation was demonstrated in this static force task, but not in a previous force task involving repetitive dynamic force pulses. This suggests that sustained exertion of a static force is an active process modulated, at least in part, by the basal ganglia.

Adult↗

PubMed1996

Where in the brain does visual attention select the forest and the trees?

The perceptual world is organized hierarchically: the forest consists of trees, which in turn have leaves. Visual attention can emphasize the overall picture (global form) or the focal details of a scene (local components). Neuropsychological studies have indicated that the left hemisphere is biased towards local and the right towards global processing. The underlying attentional and perceptual mechanisms are maximally impaired by unilateral lesions to the temporal and parietal cortex. We measured brain activity of normal subjects during two experiments using 'hierarchically' organized figures. In a directed attention task, early visual processing (prestriate) areas were activated: attention to the global aspect of the figures activated the right lingual gyrus whereas locally directed attention activated the left inferior occipital cortex. In a subsequent divided attention task, the number of target switches from local to global (and vice versa) covaried with temporal-parietal activation. The findings provide direct evidence for hemispheric specialization in global and local perception; furthermore, they indicate that temporal-parietal areas exert attentional control over the neural transformations occurring in prestriate cortex.

Attention↗

PubMed1996

CAX1, an H+/Ca2+ antiporter from Arabidopsis.

Reestablishment of the resting state after stimulus-coupled elevations of cytosolic-free Ca2+ requires the rapid removal of Ca2+ from the cytosol of plant cells. Here we describe the isolation of two genes, CAX1 and CAX2, from Arabidopsis thaliana that suppress a mutant of Saccharomyces cerevisiae that has a defect in vacuolar Ca2+ accumulation. Both genes encode polypeptides showing sequence similarities to microbial H+/Ca2+ antiporters. Experiments on vacuolar membrane-enriched vesicles isolated from yeast expressing CAX1 or CAX2 demonstrate that these genes encode high efficiency and low efficiency H+/Ca2+ exchangers, respectively. The properties of the CAX1 gene product indicate that it is the high capacity transporter responsible for maintaining low cytosolic-free Ca2+ concentrations in plant cells by catalyzing pH gradient-energized vacuolar Ca2+ accumulation.

Amino Acid Sequence↗

PubMed1996

Cerebral representation of one's own past: neural networks involved in autobiographical memory.

We studied the functional anatomy of affect-laden autobiographical memory in normal volunteers. Using H2 15O positron emission tomography (PET), we measured changes in relative regional cerebral blood flow (rCBF). Four rCBF measurements were obtained during three conditions: REST, i.e.,, subjects lay at rest (for control); IMPERSONAL, i.e., subjects listened to sentences containing episodic information taken from an autobiography of a person they did not know, but which had been presented to them before PET scanning (nonautobiographical episodic memory ecphory); and PERSONAL, i.e., subjects listened to sentences containing information taken from their own past (autobiographical episodic memory ecphory). Comparing IMPERSONAL with REST (nonautobiographical episodic memory ecphory) resulted in relative rCBF increases symmetrically in both temporal lobes including the temporal poles and medial and superior temporal gyri. The same loci, however, with a stronger lateralization to the right hemisphere were activated in the comparison PERSONAL to REST (autobiographical episodic memory ecphory). In addition, the right temporomesial, right dorsal prefrontal, right posterior cingulate areas, and the left cerebellum were activated. A comparison of PERSONAL and IMPERSONAL (autobiographical vs nonautobiographical episodic memory ecphory) demonstrated a preponderantly right hemispheric activation including primarily right temporomesial and temporolateral cortex, right posterior cingulate areas, right insula, and right prefrontal areas. The right temporomesial activation included hippocampus, parahippocampus, and amygdala. These results suggest that a right hemispheric network of temporal, together with posterior, cingulate, and prefrontal, areas is engaged in the ecphory of affect-laden autobiographical information.

Adult↗

PubMed1996

Ras2 signals via the Cdc42/Ste20/mitogen-activated protein kinase module to induce filamentous growth in Saccharomyces cerevisiae.

RAS2val19, a dominant activated form of Saccharomyces cerevisiae Ras2, stimulates both filamentous growth and expression of a transcriptional reporter FG(TyA)::lacZ but does not induce the mating pathway reporter FUS1::lacZ. This induction depends upon elements of the conserved mitogen-activated protein kinase (MAPK) pathway that is required for both filamentous growth and mating, two distinct morphogenetic events. Full induction requires Ste20 (homolog of mammalian p65PAK protein kinases), Ste11 [an MEK kinase (MEKK) or MAPK kinase (MEK) kinase], Ste7 (MEK or MAPK kinase), and the transcription factor Ste12. Moreover, the Rho family protein Cdc42, a conserved morphogenetic G protein, is also a potent regulator of filamentous growth and FG(TyA)::lacZ expression in S. cerevisiae. Stimulation of both filamentous growth and FG(TyA)::lacZ by Cdc42 depends upon Ste20. In addition, dominant negative CDC42Ala118 blocks RAS2val19 activation, placing Cdc42 downstream of Ras2. Our results suggest that filamentous growth in budding yeast is regulated by an evolutionarily conserved signaling pathway that controls cell morphology.

Animals↗