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Biomedical subjects

J Moll

Publications and source records attributed to J Moll.

At least 19 recordsLinked to original sources
PubMed2003

Contributions of stimulus valence and arousal to visual activation during emotional perception.

Neuroimaging experiments have revealed that the visual cortex is involved in the processing of affective stimuli: seeing emotional pictures leads to greater activation than seeing neutral ones. It is unclear, however, whether such differential activation is due to stimulus valence or whether the results are confounded by arousal level. In order to investigate the contributions of valence and arousal to visual activation, we created a new category of "interesting" stimuli designed to have high arousal, but neutral valence, and employed standard neutral, unpleasant, and pleasant picture categories. Arousal ratings for pleasant and neutral pictures were equivalent, as were valence ratings for interesting and neutral pictures. Differential activation for conditions matched for arousal (pleasant vs neutral) as well as matched for valence (interesting vs neutral) indicated that both stimulus valence and arousal contributed to visual activation.

Adult↗
PubMed2003

Enhanced interictal responsiveness of the migraineous visual cortex to incongruent bar stimulation: a functional MRI visual activation study.

Since visual aura is usually described as expanding zigzag lines, neurones involved with the perception of line orientation may initiate this phenomenon. A visual incongruent line stimulation protocol was developed to obtain functional magnetic resonance images (fMRI) interictally in 5 female migraine patients with typical fortification spectra and in 5 normal matched controls. Activation in the visual cortex was present contralateral to the side of stimulation in 4 of 5 patients, notably in the extrastriate visual cortex. In 4 of 5 controls activation was observed in the medial and anterior orbitofrontal cortex. In one of them additional activation at the right nucleus accumbens/ventral striatum and right ventral pallidum was present. In the remaining control subject activation was present in the left primary visual cortex. The enhanced interictal reactivity of the visual cortex in migraineurs supports the hypothesis of abnormal cortical excitability as an important pathophysiological mechanism in migraine aura, though the role of specific regions of the visual cortex remains to be explored.

Adult↗
PubMed2001

An agrin minigene rescues dystrophic symptoms in a mouse model for congenital muscular dystrophy.

Congenital muscular dystrophy is a heterogeneous and severe, progressive muscle-wasting disease that frequently leads to death in early childhood. Most cases of congenital muscular dystrophy are caused by mutations in LAMA2, the gene encoding the alpha2 chain of the main laminin isoforms expressed by muscle fibres. Muscle fibre deterioration in this disease is thought to be caused by the failure to form the primary laminin scaffold, which is necessary for basement membrane structure, and the missing interaction between muscle basement membrane and the dystrophin-glycoprotein complex (DGC) or the integrins. With the aim to restore muscle function in a mouse model for this disease, we have designed a minigene of agrin, a protein known for its role in the formation of the neuromuscular junction. Here we show that this mini-agrin-which binds to basement membrane and to alpha-dystroglycan, a member of the DGC-amends muscle pathology by a mechanism that includes agrin-mediated stabilization of alpha-dystroglycan and the laminin alpha5 chain. Our data provides in vivo evidence that a non-homologous protein in combination with rational protein design can be used to devise therapeutic tools that may restore muscle function in human muscular dystrophies.

Agrin↗
PubMed2001

Cutting edge: human gamma delta T cells are activated by intermediates of the 2-C-methyl-D-erythritol 4-phosphate pathway of isoprenoid biosynthesis.

Activation of V gamma 9/V delta 2 T cells by small nonprotein Ags is frequently observed after infection with various viruses, bacteria, and eukaryotic parasites. We suggested earlier that compounds synthesized by the 2-C:-methyl-D-erythritol 4-phosphate (MEP) pathway of isopentenyl pyrophosphate synthesis are responsible for the V gamma 9/V delta 2 T cell reactivity of many pathogens. Using genetically engineered Escherichia coli knockout strains, we now demonstrate that the ability of E. coli extracts to stimulate gamma delta T cell proliferation is abrogated when genes coding for essential enzymes of the MEP pathway, dxr or gcpE, are disrupted or deleted from the bacterial genome.

Aldose-Ketose Isomerases↗
PubMed2001

Executive amnesia in a patient with pre-frontal damage due to a gunshot wound.

This paper reports the case of a young patient with extensive pre-frontal damage in whom we tested the hypothesis that intensive training improves executive performance as assessed by the Wisconsin Card Sorting Test (WCST). As long as her declarative memory, complex perceptual abilities and global cognitive status were spared, we surmised that any deficit in executive learning would have occurred in relative isolation. We showed that her abnormal performance on the WCST, both on the standard as well as on the post-instruction condition, was due to an impairment of shifting attention across perceptual dimensions (extra-dimensional). In contrast, her ability to shift attention within perceptual categories (intra-dimensional) was spared, as were her declarative memory, object and visuospatial perception, oral language comprehension and praxis (ideomotor, tool use and constructional). This case supports the hypothesis that executive amnesia is a type of amnesic disorder distinct from the classic amnesic syndrome due to mamillo-temporomedial damage. As such, it is probably closely related to procedural learning and may depend on the same fronto-subcortical loops that mediate the actual execution of behaviour.

Adolescent↗
PubMed2001

CD44-dependent lymphoma cell dissemination: a cell surface CD44 variant, rather than standard CD44, supports in vitro lymphoma cell rolling on hyaluronic acid substrate and its in vivo accumulation in the peripheral lymph nodes.

Cell motility is an essential element of tumor dissemination, allowing organ infiltration by cancer cells. Using mouse LB lymphoma cells transfected with standard CD44 (CD44s) cDNA (LB-TRs cells) or with the alternatively spliced CD44 variant CD44v4-v10 (CD44v) cDNA (LB-TRv cells), we explored their CD44-dependent cell migration. LB-TRv cells, but not LB-TRs or parental LB cells, bound soluble hyaluronic acid (HA) and other glycosaminoglycans (GAGs), and exclusively formed, under physiological shear force, rolling attachments on HA substrate. Furthermore, LB-TRv cells, but not LB-TRs cells or their parental LB cells, displayed accelerated local tumor formation and enhanced accumulation in the peripheral lymph nodes after s.c. inoculation. The aggressive metastatic behavior of i.v.-injected LB-TRV cells, when compared with that of other LB-transfectants, is attributed to more efficient migration to the lymph nodes, rather than to local growth in the lymph node. Injection of anti-CD44 monoclonal antibody or of the enzyme hyaluronidase also prevented tumor growth in lymph nodes of BALB/c mice inoculated with LB-TRv cells. The enhanced in vitro rolling and enhanced in vivo local tumor growth and lymph node invasion disappeared in LB cells transfected with CD44v cDNA bearing a point mutation at the HA binding site, located at the distal end of the molecule constant region. These findings show that the interaction of cell surface CD44v with HA promotes cell migration both in vitro and in vivo, and they contribute to our understanding of the mechanism of cell trafficking, including tumor spread.

Adjuvants, Immunologic↗
PubMed2001

Frontopolar and anterior temporal cortex activation in a moral judgment task: preliminary functional MRI results in normal subjects.

OBJECTIVE: To study the brain areas which are activated when normal subjects make moral judgments. METHOD: Ten normal adults underwent BOLD functional magnetic resonance imaging (fMRI) during the auditory presentation of sentences that they were instructed to silently judge as either "right" or "wrong". Half of the sentences had an explicit moral content ("We break the law when necessary"), the other half comprised factual statements devoid of moral connotation ("Stones are made of water"). After scanning, each subject rated the moral content, emotional valence, and judgment difficulty of each sentence on Likert-like scales. To exclude the effect of emotion on the activation results, individual responses were hemodynamically modeled for event-related fMRI analysis. The general linear model was used to evaluate the brain areas activated by moral judgment. RESULTS: Regions activated during moral judgment included the frontopolar cortex (FPC), medial frontal gyrus, right anterior temporal cortex, lenticular nucleus, and cerebellum. Activation of FPC and medial frontal gyrus (BA 10/46 and 9) were largely independent of emotional experience and represented the largest areas of activation. CONCLUSIONS: These results concur with clinical observations assigning a critical role for the frontal poles and right anterior temporal cortex in the mediation of complex judgment processes according to moral constraints. The FPC may work in concert with the orbitofrontal and dorsolateral cortex in the regulation of human social conduct.

Adult↗
PubMed2001

Implementation of a routine genetic evaluation for longevity based on survival analysis techniques in dairy cattle populations in Switzerland.

Genetic evaluation of sires for functional longevity of their daughters based on survival analysis has been implemented in the populations of Braunvieh, Simmental, and Holstein cattle in Switzerland. A Weibull mixed sire-maternal grandsire survival model was used to estimate breeding values of sires with data on cows that calved since April 1, 1980. Data on Braunvieh and Simmental cows included about 1.1 million records, data on Holstein cows comprised about 220,000 records. Data contained approximately 20 to 24% right-censored records and 6 to 9% left-truncated records. Besides the random sire and maternal grandsire effects, the model included effects of herd-year-season, age at first calving, parity, stage of lactation, alpine pasturing (Braunvieh and Simmental), and relative milk yield and relative fat and protein percentage within herd to account for culling for production. Heritability of functional longevity, estimated on a subset of data including approximately 150,000 animals, were 0.181, 0.198, and 0.184 for Braunvieh, Simmental, and Holstein, respectively. Breeding values were estimated for all sires with at least six daughters or three granddaughters in the data. Breeding values of sires are expressed in months of functional productive life and published in sire catalogs along with breeding values for production traits.

Animals↗
PubMed2001

[Contributions to the neuropsychology of executive behavior: performance of normal individuals on the Tower of London and Wisconsin tests].

The concept of "executive behavior" encompasses a set of abilities which are critical for the organization of thought and behavior. To test the hypothesis that executive behavior is composed of multiple modules we investigated the performance of 61 normal adults on two widely used executive tasks, the Wisconsin Card Sorting (WCST) and the Tower of London (TOL) tests. We hypothesized that if executive behavior were composed of multiple modules, the main dimensions of each task would be weakly, if at all, statistically related. We also tested the hypothesis that occupational functioning would be related to executive performance. Our results revealed no significant association between the WCST and TOL tasks, favoring the idea that executive behavior is made up of multiple neuropsychological dimensions. Secondly, men fared significantly better than women on the difficult (4 and 5-moves) TOL puzzles. Finally, there was a significant association between performance on the difficult TOL puzzles and level of occupational functioning. These findings may explain certain dissociations in executive behavior commonly observed in patients with focal or diffuse brain damage. If replicated, they might be useful in the prediction of success in cognitive rehabilitation programs.

Adult↗
PubMed2000

Characterization of elements mediating regulation of phosphoenolpyruvate carboxykinase gene transcription by protein kinase A and insulin. Identification of a distinct complex formed in cells that mediate insulin inhibition.

The in vivo pattern of induction of phosphoenolpyruvate carboxykinase (PEPCK) gene transcription by cAMP and its inhibition by insulin is reproduced in H4IIe cells and is mediated by a bipartite cAMP/insulin response unit (C/IRU) consisting of a cAMP response element (-95/-87) and an upstream enhancer, AC (-271/-225). Studies in HepG2 cells showed that binding of AP-1 and CAAT/enhancer-binding protein (C/EBP) to AC is required for induction by cAMP, but insulin did not inhibit cAMP-induced PEPCK expression in HepG2 cells. Binding of H4IIe nuclear proteins to an AC element probe was inhibited by antibodies or a consensus site for C/EBP, but not AP-1. Transfection with dominant negative bZIP factors, which prevent endogenous factors from binding to DNA, showed that elimination of cAMP regulatory element-binding protein CREB or C/EBP activity blocked induction by protein kinase A (PKA), whereas elimination of AP-1 activity had no effect. In addition, promoters with multiple CREB sites, or a single CREB site and multiple C/EBP sites, mediated PKA induction, but this was inhibited to no greater extent than basal activity was by insulin. These results indicate that an AC factor other than C/EBP must mediate insulin inhibition. An A-site probe (-265/-247) or a probe across the middle of the AC element (-256/-237) competed for complexes formed by factors other than AP-1 or C/EBP. However, analysis of competitor oligonucleotides and antibodies for candidate factors failed to identify other factors. Scanning mutations throughout the AC element interfered with induction but allowed us to define five overlapping sites for regulatory factors in AC and to design probes binding just one or two factors. Comparison of the protein-DNA complexes formed on these smaller probes revealed that a specific complex present in rat liver and H4IIe cell nuclear extracts differed from those formed by HepG2 cell nuclear extracts. Our results suggest that multiple factors binding the AC element of the C/IRU interact with each other and CREB to regulate PEPCK induction by cAMP and inhibition by insulin and that the unique factor expressed in H4IIe cells is a candidate for involvement in insulin regulation of PKA-induced PEPCK gene transcription.

Animals↗
PubMed2000

Functional MRI correlates of real and imagined tool-use pantomimes.

OBJECTIVE: To study the pattern of cerebral activation related to the performance of tool-use pantomimes with functional MRI (fMRI) using a task-subtraction design. BACKGROUND: Tool use comprises a particular category of transitive actions. Inability to pantomime the use of tools has been classically associated with retrorolandic dominant hemisphere damage. However, where in the left hemisphere these transitive representations are generated is unclear. METHODS: Echoplanar images were acquired in eight alternating task and control periods. Sixteen right-handed normal adults pantomimed the use of common tools and utensils with each hand. The control condition consisted of a sequence of nonsymbolic complex movements of forearm, hand, and fingers at a self-paced rate. Eight individuals also imagined the execution of the real task and control actions. A repeated measures ANOVA compared activations in five regions of interest in each hemisphere. RESULTS: Regardless of which hand was used, the left hemisphere was more active than the right in both real (p < 0.02) and imagined (p < 0.04) tasks. Activations clustered in the left intraparietal cortex and posterior dorsolateral frontal cortex. CONCLUSIONS: Pantomiming the use of tools is associated with activation of the left intraparietal cortex and dorsolateral frontal cortex. The left intraparietal cortex may store the representations of tool-use formulae, whereas the dorsolateral frontal cortex activation may reflect the switching between innervatory motor programs.

Adolescent↗
PubMed2000

Just say no (to stereotyping): effects of training in the negation of stereotypic associations on stereotype activation.

The primary aim of the present research was to examine the effect of training in negating stereotype associations on stereotype activation. Across 3 studies, participants received practice in negating stereotypes related to skinhead and racial categories. The subsequent automatic activation of stereotypes was measured using either a primed Stroop task (Studies I and 2) or a person categorization task (Study 3). The results demonstrate that when receiving no training or training in a nontarget category stereotype, participants exhibited spontaneous stereotype activation. After receiving an extensive amount of training related to a specific category, however, participants demonstrated reduced stereotype activation. The results from the training task provide further evidence for the impact of practice on participants' proficiency in negating stereotypes.

Attitude↗
PubMed2000

Tumor necrosis factor alpha inhibits type I collagen synthesis through repressive CCAAT/enhancer-binding proteins.

Extracellular matrix (ECM) formation and remodeling are critical processes for proper morphogenesis, organogenesis, and tissue repair. The proinflammatory cytokine tumor necrosis factor alpha (TNF-alpha) inhibits ECM accumulation by stimulating the expression of matrix proteolytic enzymes and by downregulating the deposition of structural macromolecules such as type I collagen. Stimulation of ECM degradation has been linked to prolonged activation of jun gene expression by the cytokine. Here we demonstrate that TNF-alpha inhibits transcription of the gene coding for the alpha2 chain of type I collagen [alpha2(I) collagen] in cultured fibroblasts by stimulating the synthesis and binding of repressive CCAAT/enhancer proteins (C/EBPs) to a previously identified TNF-alpha-responsive element. This conclusion was based on the concomitant identification of C/EBPbeta and C/EBPdelta as TNF-alpha-induced factors by biochemical purification and expression library screening. It was further supported by the ability of the C/EBP-specific dominant-negative (DN) protein to block TNF-alpha inhibition of alpha2(I) collagen but not TNF-alpha stimulation of the MMP-13 protease. The DN protein also blocked TNF-alpha downregulation of the gene coding for the alpha1 chain of type I collagen. The study therefore implicates repressive C/EBPs in the TNF-alpha-induced signaling pathway that controls ECM formation and remodeling.

Amino Acid Sequence↗
PubMed2000

CD44 expression and regulation during mammary gland development and function.

The CD44v6 epitope has been widely reported to be expressed in human mammary carcinomas, yet its prognostic significance is controversial and its function in mammary tumors and mammary glands is unknown. To begin to resolve these issues, we analysed in detail the normal postnatal expression patterns and regulation of the CD44v6 epitope in murine mammary glands. We demonstrate that significant CD44v6 epitope expression is first seen during puberty, and that after puberty CD44v6 epitope expression follows the estrous cycle. CD44v6 epitope expression is observed in the myoepithelium and also less widely in luminal epithelial cells. During lactation, CD44v6 epitope expression is turned off and reappears during involution. The CD44 variant isoform bearing the v6 epitope is CD44v1-v10. Using HC11, a mammary epithelial cell line with stem cell characteristics, and facilitated by the cloning of the murine CD44 promoter, we show that growth factors and hormones which regulate ductal growth and differentiation modulate CD44 transcription. Together our data suggest that the CD44v6 epitope is expressed in mammary epithelial stems cells and in lineages derived from these cells, and that CD44v6 expression is regulated in part by hormones and growth factors such as IGF-1 and EGF which regulate the growth and differentiation of the mammary epithelium. The function of these same growth factors and hormones is often perturbed in mammary carcinomas, and we suggest that CD44v6 expression in tumors reflects this perturbation. We conclude that the expression of the CD44v6 epitope observed in some mammary tumors reflects the stem cell origin of breast tumors, and that whether or not the CD44v6 epitope is expressed in a mammary tumor is determined by the differentiation status of the tumor cells.

Animals↗
PubMed2000

Trail making and cognitive set-shifting.

We tested the hypothesis that Part B of the Trail Making Test (TMT) is a measure of cognitive set-shifting ability in 55 normal subjects with the conventional (written) TMT and a verbal adaptation, the "verbal TMT" (vTMT). The finding of a significant association between Parts B of TMT and vTMT (r = 0,59, p < 0,001), after correcting for age and education, supports the view that Part B of TMT is a valid measure of the ability to alternate between cognitive categories.

Adolescent↗
PubMed2000

The CD44 receptor of lymphoma cells: structure-function relationships and mechanism of activation.

Migration of some tumor cells, and their lodgment in target organs, is dependent on the activation of cell surface CD44 receptor, usually detected by its ability to bind hyaluronic acid (HA) or other ligands. In an attempt to reveal the mechanism of tumor cell CD44 activation, we compared the physical and chemical properties of CD44 in nonactivated LB cell lymphoma with those in phorbol 12-myristate 13-acetate (PMA)-activated LB cells and of an LB cell subline (designated HA9) expressing constitutively-active CD44. In contrast to nonactivated LB cells, PMA-activated LB cells and HA9 cells displayed a CD44-dependent ability to bind HA. The ability of activated cell CD44 to bind HA was not dependent on microfilament or microtubule integrity or on changes in CD44 mobility on the membrane plane, indicating that the CD44 activation status is not associated with cytoskeleton function. Aside from the increased expression of CD44 on the surface of PMA-activated LB cells and HA9 cells, qualitative differences between the CD44 of nonactivated and activated LB cells were also detected: the CD44 of the activated lymphoma was (i) larger in molecular size, (ii) displayed a broader CD44 isoform repertoire, including a CD44 variant that binds HA, and (iii) its glycoprotein contained less sialic acid. Indeed, after removal of sialic acid from their cell surface by neuraminidase, LB cells acquired the ability to bind HA. However, a reduced dose of neuraminidase did not confer HA binding on LB cells, unless they were also activated by a low concentration of PMA, which by itself was ineffective. Similarly, under suboptimal conditions, a synergistic effect was obtained with tunicamycin and PMA: each one alone was ineffective but in combination they induced the acquisition of HA binding by the lymphoma cells, while their CD44 expression was not enhanced. Unveiling of the activation mechanism of CD44, by exposing the cells to PMA stimulation or to deglycosylation, is not only academically important, but it also has practical implications, as activated CD44 may be involved in the support of tumor progression.

Animals↗
PubMed1999

Hyaluronate-enhanced hematopoiesis: two different receptors trigger the release of interleukin-1beta and interleukin-6 from bone marrow macrophages.

The glycosaminoglycan hyaluronate (HA) is part of the extracellular environment in bone marrow. We show here that HA activates signal transduction cascades important for hemopoiesis. In myeloid and lymphoid long-term bone marrow cultures (LTBMC), treatment with hyaluronidase (HA'ase) results in reduced production of both progenitor and mature cells. Exogeneous HA added to LTBMC had the opposite effect: it enhanced hematopoiesis. The effect of HA is mediated through two different HA receptors on bone marrow macrophage-like cells, one of which is CD44 while the other is unknown. HA induces bone marrow macrophages to secrete IL-1beta (CD44-dependent) and IL-6 (CD44-independent). The two receptors address different signal transduction pathways: CD44 links to a pathway activating p38 protein kinase while the other yet unknown receptor induces Erk activity. There was no difference of the effect of HA and HA'ase on hematopoiesis in LTBMC and on cytokine production by macrophages in CD44-deficient mice compared with wild-type mice, indicating that the CD44 hyaluronate receptor and its signal transduction can be compensated for. Our data suggest a regulatory role for the extracellular matrix component HA in hematopoiesis and show the induction of signal transduction by HA receptors.

Animals↗