Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53949).

General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53,949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 × 10(-9), MIR2113; rs17522122, P=2.55 × 10(-8), AKAP6; rs10119, P=5.67 × 10(-9), APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 × 10(-6)). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10(-17)). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer's disease: TOMM40, APOE, ABCG1 and MEF2C.

EFNS-ENS/EAN Guideline on concomitant use of cholinesterase inhibitors and memantine in moderate to severe Alzheimer's disease.

BACKGROUND AND PURPOSE: Previous studies have indicated clinical benefits of a combination of cholinesterase inhibitors (ChEI) and memantine over ChEI monotherapy in Alzheimer's disease (AD). Our objective was the development of guidelines on the question of whether combined ChEI/memantine treatment rather than ChEI alone should be used in patients with moderate to severe AD to improve global clinical impression (GCI), cognition, behaviour and activities of daily living (ADL). METHODS: A systematic review and meta-analysis of randomized controlled trials based on a literature search in ALOIS, the register of the Cochrane Dementia and Cognitive Improvement Group, was carried out with subsequent guideline development according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. RESULTS: Pooled data from four trials including 1549 AD patients in the moderate to severe disease stage demonstrated significant beneficial effects of combination therapy compared to ChEI monotherapy for GCI [standardized mean difference (SMD) -0.20; 95% confidence interval (CI) -0.31; -0.09], cognitive functioning (SMD -0.27, 95% CI -0.37; -0.17) and behaviour (SMD -0.19; 95% CI -0.31; -0.07). The quality of evidence was high for behaviour, moderate for cognitive function and GCI and low for ADL. Agreement of panellists was reached after the second round of the consensus finding procedure. The desirable effects of combined ChEI and memantine treatment were considered to outweigh undesirable effects. The evidence was weak for cognition, GCI and ADL so that the general recommendation for using combination therapy was weak. CONCLUSIONS: We suggest the use of a combination of ChEI plus memantine rather than ChEI alone in patients with moderate to severe AD. The strength of this recommendation is weak.

Anticardiolipin antibodies are associated with cognitive dysfunction in stroke-free individuals.

BACKGROUND AND PURPOSE: The presence of anticardiolipin antibodies (aCLs) has been associated with vascular occlusive events. The role of aCLs as a risk factor for stroke has been a matter of debate, and scarce information exists on the relationship between aCLs and other cerebral disorders. Reports exist for seizures, chorea and subtle cognitive dysfunction. The association between aCLs and cognition was further explored and the relationship between aCL titres and brain magnetic resonance imaging (MRI) findings was evaluated in a large cohort of community-dwelling individuals. METHODS: The study cohort was drawn from the Austrian Stroke Prevention Study. A total of 1895 subjects had a complete risk factor assessment and measurement of aCL titres in serum. Participants were classified as aCL positive if either the immunoglobulin G (IgG) or IgM aCL titres were elevated (IgG > 21 U/ml, IgM > 12 U/ml). All subjects were also categorized based on the quartile distribution of IgG and IgM isotype titres. All underwent cognitive testing by the Mini Mental State Examination (MMSE) and a random sample of 947 participants also underwent brain MRI. RESULTS: aCL positive participants performed worse on the MMSE. IgG but not IgM isotype titres related to worse performance on the MMSE. No significant association existed with vascular brain abnormalities including lacunes, cortical infarcts and white matter lesions. CONCLUSIONS: These data support the view that in normal elderly persons increasing IgG aCL titres relate to global cognitive dysfunction. It is unlikely that structural brain lesions are responsible for this finding.

Characteristics of Yersinia enterocolitica biotype 1A strains isolated from patients and asymptomatic carriers.

Yersinia enterocolitica biotype 1A strains are frequently isolated from the environment, foods, and animals, and also from humans with yersiniosis. There are controversial reports on the pathogenicity of biotype 1A strains. In this study, 811 fecal samples from asymptomatic humans from Switzerland were studied for the presence of Y. enterocolitica. Nine (1.1%) of the 811 samples were positive for Y. enterocolitica 1A. These strains were compared with 12 Y. enterocolitica 1A strains from Swiss patients with diarrhea isolated in the same year. Almost all (20/21) Y. enterocolitica 1A strains carried the ystB gene, seven strains carried the hreP gene, and none carried the ail, ystA, myfA, yadA, or virF genes. Most (17/21) Y. enterocolitica 1A strains belonged to two major clusters, A and B, by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Strains of cluster B were only isolated from humans with diarrhea; however, ystB and hreP genes were detected in strains from both clinical and non-clinical samples and from strains of clusters A and B. Using ribotyping, six restriction patterns among biotype 1A strains were obtained with HindIII enzyme. The most common ribotype (RT I) was found in strains isolated from humans with and without diarrhea. All biotype 1A strains had a unique NotI profile by pulsed-field gel electrophoresis (PFGE), showing a very high genetic diversity. In this study, Y. enterocolitica 1A strains from clinical and non-clinical samples could not be clearly differentiated from each other. More research is needed in order to prove that biotype 1A strains are a primary cause for human yersiniosis and not only a secondary finding.

The human C-type lectin-like receptor CLEC-1 is upregulated by TGF-ß and primarily localized in the endoplasmic membrane compartment.

The orphan receptor CLEC-1 is part of a subfamily of C-type lectin-like receptors, which is encoded in the human natural killer gene complex and comprises several pattern recognition receptors important for innate immune functions. As information on human CLEC-1 is still very limited, we aimed to further characterize this receptor. Similar to another subfamily member, LOX-1, expression of CLEC-1 mRNA was detected in myeloid cells as well as in endothelial cells. CLEC-1 protein displayed N-linked glycosylation and formed dimers. However, in contrast to other members of the subfamily, expression levels were upregulated by transforming growth factor (TGF)-ß, but not significantly affected by proinflammatory stimuli. It is intriguing that human CLEC-1 could only be detected intracellularly with a staining pattern resembling endoplasmic reticulum proteins. Neither TGF-ß nor inflammatory stimuli could promote significant translocation to the cell surface. These findings are in accordance with a primarily intracellular localization and function of human CLEC-1.

Bacteriophage amplification assay for detection of Listeria spp. using virucidal laser treatment.

A protocol for the bacteriophage amplification technique was developed for quantitative detection of viable Listeria monocytogenes cells using the A511 listeriophage with plaque formation as the end-point assay. Laser and toluidine blue O (TBO) were employed as selective virucidal treatment for destruction of exogenous bacteriophage. Laser and TBO can bring a total reduction in titer phage (ca. 10(8) pfu/mL) without affecting the viability of L. monocytogenes cells. Artificially inoculated skimmed milk revealed mean populations of the bacteria as low as between 13 cfu/mL (1.11 log cfu/mL), after a 10-h assay duration. Virucidal laser treatment demonstrated better protection of Listeria cells than the other agents previously tested. The protocol was faster and easier to perform than standard procedures. This protocol constitutes an alternative for rapid, sensitive and quantitative detection of L. monocytogenes.

Cardiomyogenic differentiation of human bone marrow mesenchymal cells: Role of cardiac extract from neonatal rat cardiomyocytes.

Bone marrow mesenchymal stromal cells (BM-MSCs) with regenerative potential have been identified in heart. Whether these cells become new cardiac lineage cells by phenomena of transdifferentiation or fusion is also being investigated. Although, these mechanisms give cardiomyocytes, it has to be considered that MSCs transplantation could carry out ossification and calcification processes. An alternative might be the use of myocytes; however, the problem is the arrythmia. For those reasons, is that we investigated how to obtain cardiomyocyte-like cells from human MSCs (hMSCs). The aim of the present work was to evaluate a nuclear reprogramming of the hMSCs by a neonatal rat cardiomyocytes extract (EX) using Streptolysin O (SLO) treatment. hMSCs treated with 57.5ng/ml SLO presented ball-like, stick-like and myotube-like morphology. In the absence of cardiomyogenic stimuli, hMSCs expressed markers of cardiac phenotype-like sarcomeric alpha-actinin, connexin-43 and GATA-4. However, when hMSCs were treated with SLO+EX or 10 microM of 5-azacytidine (5-AZA), the expression of these markers were significantly increased and furthermore, expressed SERCA-2, cardiac Troponin I, beta-MyHC, desmin, MLC-2a and MLC-2v thus showing the phenotype of mature cardiomyocytes. PCR analysis showed that cardiomyocyte-related genes, such as beta1-adrenergic receptor (beta1-AR), MLC-2a and cardiac Troponin T, were expressed after SLO+EX treatment like with 5-AZA. We concluded that the extract of neonatal rat cardiomyocytes could promote a nuclear modification of hMSCs to cardiomyogenic-like cells differentiation. Since the 5-AZA treatment appears to be genotoxic and taking into account the obtained results, the nuclear reprogramming by cell extract may be an approach leading to the identification of soluble factors that drives the reprogramming.

Microstructural Tissue Changes in Alzheimer Disease Brains: Insights from Magnetization Transfer Imaging.

BACKGROUND AND PURPOSE: Reductions in magnetization transfer ratio have been associated with brain microstructural damage. We aim to compare magnetization transfer ratio in global and regional GM and WM between individuals with Alzheimer disease and healthy control participants to analyze the relationship between magnetization transfer ratio and cognitive functioning in Alzheimer disease. MATERIALS AND METHODS: In this prospective study, participants with Alzheimer disease and a group of age-matched healthy control participants underwent clinical examinations and 3T MR imaging. Magnetization transfer ratios were determined in the cortex, AD-signature regions, normal-appearing WM, and WM hyperintensities. RESULTS: Seventy-seven study participants (mean age ± SD, 72 ± 8 years; 47 female) and 77 age-matched healthy control participants (mean age ± SD, 72 ± 8 years; 44 female) were evaluated. Magnetization transfer ratio values were lower in patients with Alzheimer disease than in healthy control participants in all investigated regions. When adjusting for atrophy and extent of WM hyperintensities, significant differences were seen in the global cortex (OR = 0.47; 95% CI: 0.22, 0.97; P = .04), in Alzheimer disease-signature regions (OR = 0.31; 95% CI: 0.14, 0.67; P = .003), in normal-appearing WM (OR = 0.59; 95% CI: 0.39, 0.88; P = .01), and in WM hyperintensities (OR = 0.18; 95% CI: 0.09, 0.33; P ≤ .001). The magnetization transfer ratio in these regions was an independent determinant of AD. When correcting for atrophy and WM hyperintensity extent, lower GM magnetization transfer ratios were associated with poorer global cognition, language function, and constructional praxis. CONCLUSIONS: Alzheimer disease is associated with magnetization transfer ratio reductions in GM and WM regions of the brain. Lower magnetization transfer ratios in the entire cortex and AD-signature regions contribute to cognitive impairment independent of brain atrophy and WM damage.

Evolutionary development and expression pattern of the myeloid lectin-like receptor gene family encoded within the NK gene complex.

The myeloid cluster within the natural killer (NK) gene complex comprises several C-type lectin-like receptor genes of diverse and highly important functions in the immune system such as LOX-1 and DECTIN-1. Based on sequences that have become available by whole genome sequencing, we conducted a comparison of the human, chimpanzee, mouse and rat NK gene complex to better characterize this gene family and additional genes of this region in regard of their phylogenetic relationship and evolution within the complex. We found that the arrangement of genes within the primate cluster differs from the order and orientation of the corresponding genes in the rodent complex which can be explained by evolutionary duplication and inversion events. Analysis of individual genes revealed a high sequence conservation supporting the prime importance of the encoded proteins. Expression analyses of the more recently described CLEC12B and CLEC9A genes displayed not only mRNA expression in monocytic and dendritic cells, but in contrast to other members of the family also in lymphocytes. Further, two additional genes were identified, which do not encode proteins with lectin-like domain structure and seem to be widely expressed.

Evaluating intramural virtual electrodes in the myocardial wedge preparation: simulations of experimental conditions.

While defibrillation is the only means for prevention of sudden cardiac death, key aspects of the process, such as the intramural virtual electrodes (VEs), remain controversial. Experimental studies had attempted to assess intramural VEs by using wedge preparations and recording activity from the cut surface; however, applicability of this approach remains unclear. These studies found, surprisingly, that for strong shocks, the entire cut surface was negatively polarized, regardless of boundary conditions. The goal of this study is to examine, by means of bidomain simulations, whether VEs on the cut surface represent a good approximation to VEs in depth of the intact wall. Furthermore, we aim to explore mechanisms that could give rise to negative polarization on the cut surface. A model of wedge preparation was used, in which fiber orientation could be changed, and where the cut surface was subjected to permeable and impermeable boundary conditions. Small-scale mechanisms for polarization were also considered. To determine whether any distortions in the recorded VEs arise from averaging during optical mapping, a model of fluorescent recording was employed. The results indicate that, when an applied field is spatially uniform and impermeable boundary conditions are enforced, regardless of the fiber orientation VEs on the cut surface faithfully represent those intramurally, provided tissue properties are not altered by dissection. Results also demonstrate that VEs are sensitive to the conductive layer thickness above the cut surface. Finally, averaging during fluorescent recordings results in large negative VEs on the cut surface, but these do not arise from small-scale heterogeneities.

Vibrio parahaemolyticus serovar O3:K6 gastroenteritis in northeast Brazil.

AIMS: To examine the virulence factors and the genetic relationship isolates of the serogroup O3 of Vibrio parahaemolyticus in outbreaks of diarrhoea in the northeast region of Brazil. METHODS AND RESULTS: Eighteen samples of the O3:K6 and O3:KUT serotypes of V. parahaemolyticus were analysed by multiplex polymerase chain reaction (m-PCR) for detection of the tl, tdh and trh genes, by random-amplified polymorphic DNA (RAPD) using two primers, and by amplification of the rDNA 16S-23S region. The gene tl was amplified in all the samples, tdh in 16 while trh in none; amplification of rDNA 16S-23S generated only one profile; each RAPD primer produced two amplification patterns allowing grouping two tdh(-) Kanagawa-negative isolates. CONCLUSIONS: V. parahaemolyticus with characteristics of the pandemic clone appears to be widely disseminated in the studied region. Because of the genetic uniformity of the isolates, elucidation of outbreaks or tracking the source of contamination by the present molecular techniques seems useless. SIGNIFICANCE AND IMPACT OF THE STUDY: Detection of V. parahaemolyticus with virulence potential of pandemic clone from two outbreaks and from several isolated gastroenteritis cases points out the need for inclusion of this micro-organism in the Brazilian routine monitoring of the diarrhoeas for elucidation of their aetiology.

Application of microprobe-based flank method analysis of Fe3+ in garnet of North Qilian eclogite and its geological implication.

A newly developed microprobe-based methodology (the Flank Method) for Fe3+/ΣFe quantification has been successfully applied to some natural garnets from the North Qilian eclogites by JEOL JXA-8100 microprobe at Peking University. The results demonstrated an obvious discrepancy in comparison with the outcomes by conventional stoichiometric calculations. This methodology allows to measure the Fe3+/ΣFe ratio and perform elemental analyses simultaneously in the same condition. Accurate in-situ measurement of Fe3+ content in garnet may bring certain impact on the garnet-based P-T estimation. According to the compositional zonation displayed in the studied eclogitic garnets from North Qilian, a prograde metamorphic PT path from 19.5 kbar, 520 °C to 22 kbar, 600 °C was reconstructed. More interestingly, the measured Fe3+/ΣFe ratios in garnets decreasing from core to rim may probably imply that the oxygen fugacity (fO2) declines with the depth of the subduction zone.

Lower Magnetization Transfer Ratio in the Forceps Minor Is Associated with Poorer Gait Velocity in Older Adults.

BACKGROUND AND PURPOSE: Gait disturbances in the elderly are disabling and a major public health issue but are poorly understood. In this multimodal MR imaging study, we used 2 voxel-based analysis methods to assess the voxelwise relationship of magnetization transfer ratio and white matter hyperintensity location with gait velocity in older adults. MATERIALS AND METHODS: We assessed 230 community-dwelling participants of the Austrian Stroke Prevention Family Study. Every participant underwent 3T MR imaging, including magnetization transfer imaging. Voxel-based magnetization transfer ratio-symptom mapping correlated the white matter magnetization transfer ratio of each voxel with gait velocity. To assess a possible relationship between white matter hyperintensity location and gait velocity, we applied voxel-based lesion-symptom mapping. RESULTS: We found a significant association between the magnetization transfer ratio within the forceps minor and gait velocity (ß = 0.134; 95% CI, 0.011-0.258; P = .033), independent of demographics, general physical performance, vascular risk factors, and brain volume. White matter hyperintensities did not significantly change this association. CONCLUSIONS: Our study provides new evidence for the importance of magnetization transfer ratio changes in gait disturbances at an older age, particularly in the forceps minor. The histopathologic basis of these findings is yet to be determined.

A new floating sensor array to detect electric near fields of beating heart preparations.

A new flexible sensor for in vitro experiments was developed to measure the surface potential, Phi, and its gradient, E (electric near field), at given sites of the heart. During depolarisation, E describes a vector loop from which direction and magnitude of local conduction velocity theta can be computed. Four recording silver electrodes (14 microm x 14 microm) separated by 50 microm, conducting leads, and solderable pads were patterned on a 50 microm thick polyimide film. The conductive structures, except the electrodes, were isolated with polyimide, and electrodes were chlorided. Spacer pillars mounted on the tip fulfil two functions: they keep the electrodes 70 microm from the tissue allowing non-contact recording of Phi and prevent lateral slipping. The low mass (9.1 mg) and flexibility (6.33 N/m) of the sensor let it easily follow the movement of the beating heart without notable displacement. We examined the electrodes on criteria like rms-noise of Phi, signal-to-noise ratio of Phi and E, maximum peak-slope recording dPhi/dt, and deviation of local activation time (LAT) from a common signal and obtained values of 24-28 microV, 46 and 41 dB, 497-561 V/s and no differences, respectively. With appropriate data acquisition (sampling rate 100 kHz, 24-bit), we were able to record Phi and to monitor E and theta on-line from beat-to-beat even at heart rates of 600 beats/min. Moreover, this technique can discriminate between uncoupled cardiac activations (as occur in fibrotic tissue) separated by less than 1 mm and 1 ms.

Coffee diterpenes prevent the genotoxic effects of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and N-nitrosodimethylamine in a human derived liver cell line (HepG2).

Aim of the present experiments was to study the genotoxic effects of coffee diterpenoids, namely cafestol palmitate and a mix of cafestol and kahweol (C+K) in human derived hepatoma (HepG2) cells. Furthermore, we investigated the potential protective properties of these substances towards carcinogens contained in the human diet, namely N-nitrosodimethylamine (NDMA) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). C+K and cafestol palmitate were tested over a broad dose range in micronucleus (MN) assays and no indication for genotoxic effects was seen. In combination experiments with PhIP (300 microM), pronounced inhibition (approximately 1.7-fold) of MN formation was observed with C+K and cafestol palmitate at dose levels > or = 0.9 and 1.7 microg/ml, respectively. Enzyme measurements indicate that the protection is due to inhibition of sulfotransferase, an enzyme involved in the activation of the amine, and/or to induction of UDP-glucuronosyltransferase which detoxifies the DNA-reactive metabolites of PhIP. Furthermore, a significant increase of glutathione-S-transferase was seen, whereas the activities of cytochrome P-450 1A1 and N-acetyltransferase 1 were not significantly altered. Also in combination experiments with C+K and NDMA, strong protective effects (50% reduction of genotoxicity) were seen at low dose levels (> or = 0.3 microg/ml). Since inhibition of MN was also observed when C+K were added after incubation with NDMA, it is likely that the chemoprotective effects are due to induction of DNA repair enzymes. Comparison of data on the effects of C+K on the cholesterol metabolism, which was investigated in earlier in vivo studies, with the present findings suggests that DNA-protective effects take place at exposure levels which are substantially lower than those which cause hypercholesterolemia.

Transcription and expression of transforming growth factor type beta in the skin of progressive systemic sclerosis: a mediator of fibrosis?

Progressive systemic sclerosis is characterized by extensive generalized fibrotic destruction associated with increased accumulation of collagen and other extracellular macromolecules in the skin and other involved organs. It has been suggested that mediators released from mononuclear or endothelial cells play a critical role in the initial activation of connective tissue metabolism. Transforming growth factors beta(TGF-beta 1, TGF-beta 2) mediate the inhibition of epithelial cell proliferation and the induction of fibronectin and collagen gene expression. Therefore, we investigated the distribution of both TGF-beta 1 and TGF-beta 2 mRNA and the final proteins in PSS skin in comparison with other inflammatory dermatoses and healthy controls by means of in situ hybridization and immunohistochemistry. Our studies revealed TGF-beta 1 and -beta 2 mRNA in dermal and subcutaneous infiltrating cells in both acute and chronic PSS, but also in the other inflammatory skin disorders. In the vicinity of this infiltrate single TGF-beta positive fibroblasts could be found in acute PSS. The cytoplasm of epithelial cells of all skin adnexa showed TGF-beta transcripts and no apparent differences were seen in the distribution and number of autoradiographic grains between diseased and healthy skin samples. Especially, we could demonstrate abundant expression of TGF-beta 1/2 in epithelial hair follicle cells of the outer root sheath. Generally, the expression of TGF-beta 2 was less abundant than TGF-beta 1. Immunohistochemical studies revealed the same distribution pattern of the final proteins. Our data indicate that TGF-beta expression in infiltrating cells is not a specific feature of fibrotic disease, but seems to be associated with highly proliferating cells in general, perhaps functioning as common mediator in regulation of cellular physiology with special importance for negative control of cell growth.

Intron-exon structure of the porcine I kappa B alpha-encoding gene.

Genomic clones of ECI-6 (endothelial cell inducible), the porcine I kappa B alpha gene that encodes a cytoplasmic inhibitor of the transcription factor NF-kappa B, were isolated, spanning the entire transcribed region plus 2.1 and 0.35 kb of 5'- and 3'-flanking sequences, respectively. The gene contains five introns ranging in size from 0.6 to 0.1 kb. Four of the introns are located in the coding regions for four of the five ankyrin-like repeats in the central part of the I kappa B alpha protein at similar positions. The fifth intron is located in the C-terminal region. Southern blot analysis indicates the presence of a single copy of ECI-6/I kappa B alpha in the porcine genome.

The structure of procalcitonin of the salmon as deduced from its cDNA sequence.

Oligonucleotide probes based on the known amino acid sequence of salmon calcitonin were used to screen a cDNA library obtained from ultimobranchial glands of salmon for clones encoding salmon calcitonin. From the cDNA sequence of strongly hybridizing clones the complete primary structure of the calcitonin precursor could be deduced. Its overall structure is identical with the structures of procalcitonins from other vertebrates and has the highest homology with the chicken precursor.

Gem, a GTP-binding protein from mitogen-stimulated T cells, is induced in endothelial cells upon activation by inflammatory cytokines.

Using differential screening of cytokine-activated versus resting porcine aortic endothelial cells (PAEC), we have isolated a member of the family of Ras/GTP-binding proteins. The cDNA encodes a 34-kilodalton protein showing 97% homology to Gem, a gene recently isolated from activated T cells, likely representing its porcine homologue. The amino acid sequence differs from the Ras consensus by the absence of a C-terminal isoprenylation site and a glycine to glutamic acid substitution in the third GTP-binding domain. We report here, that pigGem mRNA is strongly inducible in PAEC upon activation by either IL-1 alpha, TNF alpha or lipopolysaccharide (LPS). Low constitutive expression is found in several organs. Epitope-tagged pigGem transfected into endothelial cells (EC) localizes to the cytoplasm and to the inner side of the plasma membrane. Structural features of Gem and its inducibility apparently restricted to T cells and endothelial cells, together with Rad, a GTPase overexpressed in skeletal muscle cells of type II diabetic individuals, define a new branch within the superfamily of GTP-binding proteins.