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PubMed1998

Analysis of WT1 target gene expression in stably transfected cell lines.

The Wilms' tumour suppressor gene WT1 encodes a zinc finger protein that is mutated in a subset of Wilms' tumours. Mutation screening and animal studies revealed essential roles during development and later function of the kidneys and the entire genitourinary system. Sequence similarity suggested a possible role for WT1 as a transcription factor. Indeed, sequence specific DNA binding and transcriptional activation or repression potential could be demonstrated in transient transfection assays with various reporter constructs. To identify endogenous WT1 target genes we established HEK293 cell lines expressing the different WT1 isoforms in a tetracycline dependent manner. Differential display PCR (ddPCR) was performed on RNA from stable WT1 transfected HEK293 cell lines and two other WT1 transfected lines (G401 and Saos-2). In an extended survey of several thousand ddPCR bands only few differences in intensity were seen and none of these could unambiguously be verified as being WT1 regulated by subsequent Northern blot analysis. In addition, almost none of the WT1 target genes identified to date in transient co-transfection assays could be confirmed by either ddPCR or Northern hybridization in the three stable transfected cell lines. Among the nine genes expressed, the only exceptions were CSF1 and to a lesser extent IGF1R being induced in Saos-2/G401 and HEK293 cells, respectively. At least two of the cell lines tested had previously shown clear biological effects though -- either WT1 dependent apoptosis (Saos-2) or greatly reduced tumorigenicity (G401). This suggests that WT1 may regulate only a very small set of genes that escape the detection methods used or it may not act as a transcription factor that influences steady state levels of mRNA.

Blotting, Northern↗

PubMed2001

The Escherichia coli CcmG protein fulfils a specific role in cytochrome c assembly.

In Escherichia coli K-12, c-type cytochromes are synthesized only during anaerobic growth with trimethylamine-N-oxide, nitrite or low concentrations of nitrate as the terminal electron acceptor. A thioredoxin-like protein, CcmG, is one of 12 proteins required for their assembly in the periplasm. Its postulated function is to reduce disulphide bonds formed between correctly paired cysteine residues in the cytochrome c apoproteins prior to haem attachment by CcmF and CcmH. We report that loss of CcmG synthesis by mutation was not compensated by a second mutation in disulphide-bond-forming proteins, DsbA or DsbB, or by the chemical reductant, 2-mercaptoethanesulphonic acid. An anti-CcmG polyclonal antibody was used in Western-blot analysis to probe the redox state of CcmG in mutants defective in the synthesis of other proteins essential for cytochrome c assembly. The oxidized form of CcmG accumulated not only in trxA or dipZ mutants defective in the transfer of electrons from the cytoplasm for disulphide isomerization and reduction reactions in the periplasm, but also in ccmF and ccmH mutants. The requirement of both CcmF and CcmH for the reduction of the disulphide bond in CcmG indicates that CcmG functions later than CcmF and CcmH in cytochrome c assembly, rather than in electron transfer from the membrane-associated DipZ (also known as DsbD) to CcmH. The data support a model proposed by others in which CcmG catalyses one of the last reactions specific to cytochrome c assembly.

Antibodies↗

PubMed2000

Sweat secretion rates in growth hormone disorders.

BACKGROUND: While increased sweating is a prominent symptom in patients with active acromegaly, reduced sweating is gaining status as part of the growth hormone deficiency (GHD) syndrome. DESIGN AND SUBJECTS: Sweat secretion rate (SSR), as measured by pilocarpine iontophoresis represents the maximal capacity for stimulated sweat secretion in a localized skin area. SSR was studied in 37 patients with a history of acromegaly, 20 adult patients with GHD before and during long-term GH substitution of GHD adults, and 58 control subjects. RESULTS: Acromegaly: Patients with acromegaly had significantly higher SSR than healthy controls (Z-score + 1.9 (+/- 1.1) mean (+/- SD) (P < 0.001)). SSR was increased irrespective of current clinical disease activity. Thus, the SSR Z-scores in 16 clinically inactive patients were + 2.1 (+/- 1.2), in 10 slightly or doubtfully active patients + 1.5 (+/- 0.7) and in 11 active patients + 1.8 (+/- 1.3). There was no correlation between SSR and IGF-I. GHD: Twenty adult patients participated in an 18-month randomised, placebo controlled, double blinded study of physiological dose GH substitution, followed by 18 months of open GH treatment. SSR at baseline was reduced in male but not in female GHD patients. Mean SSR (95% confidence interval) for 11 male patients was 89.0 mg/30 minutes (51.9-126.1) as compared to 133.5 mg/30 minutes (59.2-259.9) (P = 0.01) in 24 male controls, and for 11 female patients 48.2 mg/30 minutes (25.9-70.6) as compared to 49.2 mg/30 minutes (12.6-93. 9) in 34 female controls. GH treatment in physiological substitution doses for up to 36 months had no effect on SSR. CONCLUSION: We have demonstrated that longstanding GH hypersecretion in patients with acromegaly induces irreversible changes of sweat gland function, with persistently elevated SSR despite treatment and clinical cure. In GHD patients, SSR was reduced in males but not in females, which together with the established gender difference in normal controls emphasises the role of androgen deficiency as a cofactor for reduced sweating in hypopituitary patients. Sweat gland development seems to be more susceptible to lack of hormones in childhood and adolescence than in adulthood, whereas growth hormone excess can modify sweat function later in life.

Acromegaly↗

PubMed2003

Surgical treatment of medullary thyroid carcinoma.

Medullary thyroid carcinoma (MTC) is a malignancy of the parafollicular C cells of the thyroid gland. It occurs sporadically or as part of the multiple endocrine neoplasia type 2 (MEN 2) syndromes. Patients who have inherited a mutation in the RET proto-oncogene should have thyroidectomy early in life to prevent formation and spread of this cancer. Most patients with sporadic disease present with a palpable neck mass. The diagnosis is made by fine needle aspiration biopsy and by measuring calcitonin levels in the blood. Primary treatment consists of surgical resection including a total thyroidectomy, central neck nodal dissection and functional lateral neck nodal dissections. Most patients with a palpable primary tumour have nodal disease present at the time of operation, and nodal involvement is often bilateral. Adequate resection of the primary tumour and cervical lymph nodes is important to optimize outcome and minimize the risk of recurrent disease. Proper handling of the parathyroid glands prevents hypoparathyroidism. Following primary surgical resection, more than half of the patients will have recurrent disease with persistent elevation of calcitonin levels. Currently, there is no adequate systemic therapy for treating recurrent disease. Surgical reoperation or conservative observation are the best available options. Diagnostic laparoscopy for liver evaluation is the most sensitive diagnostic test to detect the presence of distant metastases.

Calcitonin↗

PubMed2002

A clinical and neurobehavioural review of high-functioning autism and Asperger's disorder.

OBJECTIVE: To compare, contrast and review clinical and neuropsychological studies of high-functioning autism and Asperger's disorder. METHOD: This paper reviews past and contemporary conceptualizations of autism and Asperger's disorder, together with epidemiological information, genetic and neurobehavioural findings. This paper focuses on neurobehavioural studies, in particular, executive functioning, lateralization, visual-perceptual and motor processing, which have provided an important source of information about the potential neurobiological dissociation that may exist between autism and Asperger's disorder. RESULTS: The clinical profiles of autism and Asperger's disorder contain a mixture of psychiatric and neurological symptoms: for example, movement abnormalities (i.e. stereotyped behaviours, hand flapping, toe walking, whole-body movements), atypical processing of parts and wholes, verbal and non-verbal deficits, ritualistic/compulsive behaviour, disturbances in reciprocal social interaction and associated depression and anxiety. The considerable clinical overlap between autism and Asperger's disorder has led many to question whether Asperger's disorder is merely a mild form of autism, or whether it should be considered as a separate clinical entity. CONCLUSION: In light of the growing body of epidemiological information, genetic, and neurobehavioural evidence that distinguishes autism from Asperger's disorder, it is premature to rule out the possibility that these disorders may be clinically, and possibly neurobiologically separate.

Adolescent↗

PubMed1991

Testosterone and musical talent.

Two recently published hypotheses on the biological basis of special talents are discussed in relation to experimental data obtained from musical composers, instrumentalists, painters, and non-musicians, and from adolescent boys and girls with different levels of musical capacities. Both hypotheses assign an important influence to prenatal testosterone effects on the developing brain. Geschwind and Galaburda (1985) predict that subjects with special talents may have anomalous hemispheric dominance for verbal material. This was confirmed experimentally in adolescents and in adults using a dichotic listening task to assess functional lateralization. Hassler and Nieschlag (1989) expect musicians of both sexes to be psychologically androgynous and to have current testosterone levels that differ from sex-typed males and females. Salivary testosterone was measured in adults and in adolescents. Creative musical behavior was associated with very low testosterone values in males, and with high testosterone levels in females. Sexual activity level and motivation did not differ between males with testosterone levels less than or equal to 200 pmol/l and those with greater than 220 pmol/l. We tentatively suggest from our data that, among a complex interaction of biological and social factors, an optimal testosterone range may exist for the expression of creative musical behavior. Exceeding the range in the course of adolescence may be detrimental for musical creativity in boys.

Adult↗

PubMed2002

Prosody in apraxia of speech.

Prosody is a complex process that involves modulation of pitch, loudness, duration, and linearity in the acoustic stream to serve linguistic and affective communication goals. It arises from the interaction of distributed neural networks that may be anatomically and functionally lateralized. Intrinsic prosody is mediated largely through left hemisphere mechanisms and encompasses those elements of linguistic microstructure (e.g., syllabic magnitudes and durations, basic consonantal and vocalic gesture specifications, and so) that yield the segmental aspects of speech. Extrinsic prosody is processed primarily by right hemisphere (RH) mechanisms and involves manipulation of intonation across longer perceptual groupings. Intrinsic prosody deficits can lead to several core symptoms of speech apraxia such as difficulty with utterance initiation and syllable transitionalization and may lead to the establishment of inappropriate syllable boundaries. The intrinsic prosody profiles associated with acquired apraxia of speech, developmental speech apraxia, and ataxic dysarthria may aid in the clinical differentiation of these disorders.

Apraxias↗

PubMed2003

[Clinical presentation and management of the severe acute respiratory syndrome (SARS)].

BACKGROUND AND OBJECTIVE: In February 2003, a newly emerged infectious disease was described, the etiology of which was initially unknown. It is referred to under the term SARS. In the beginning, it spread in some regions South-East Asia. Import infections appeared in many other parts of the world. Based on the first cases in Germany, this report illustrates the clinical appearance, the diagnostic results and the management of this new disease. PATIENTS AND METHODS: We analysed the data of two patients with SARS and one suspected patient. The results of radiological, laboratory, microbiological and physical examinations were abstracted and compared with the data obtained in other regions. RESULTS: Two of the three patients under our care developed SARS disease. This is characterised by fever of sudden onset lasting for more than 5 days, rapidly changing consolidations in chest x-ray not affected by antimicrobial therapy, leuko-, lympho- as well as thrombopenia with a compromised pulmonary function later in the course. Close contacts with SARS patients does not regularly result in full development of the disease. Secretion of a coronavirus could be detected in respiratory samples during the febrile phase and in feces for a longer time. It is still an open question whether bedrest and antibiotic prophylaxis by themselves or an additional administration of ribavirin and corticosteroids can improve the outcome. CONCLUSION: SARS is a new and highly contagious lung disease. It is crucial to be able to recognize the clinical appearance and the diagnostic features of this disease at an early stage, in order to prevent a further dissemination of the disease.

Adult↗

PubMed1998

Muscle power and medical history in high risk preterm infants at 3 months of corrected age.

A group of 73 "high risk" preterm infants was studied at the corrected age of 12 weeks. The infants were categorized according to their medical history in 5 classes conform with the "Neonatal Medical Index" (NMI). Only infants with high-risk for developmental discrepancies with a score of NMI > or = III were included in the study. Apart from pediatric follow-up and an age-adequate neurological examination, special emphasis was put on measuring a specific feature in the development of preterm infants: the relationship between active muscle power and passive tone. These two components of muscle power should be in balance with each other to create stable posture and fluent motility and later co-ordination. Discrepancy between active and passive muscle tone was found in all NMI groups studied and was most outspoken in the legs. Infants in NMI IV and V showed a significantly higher incidence of increased passive tone than the infants in NMI III. When the different regions of the body were studied separately, the infants in NMI IV and V showed significantly increased passive tone in the trunk and shoulders (p 0.009) compared to infants in NMI III, which may constitute an alarm signal of deviant development. The main aim of the study was to provide a clinical method for early detection, subtle enough to select infants most at risk for later functional and neurological problems.

Chi-Square Distribution↗

PubMed2005

Hypertension in mice lacking the proatrial natriuretic peptide convertase corin.

Atrial natriuretic peptide (ANP) is a cardiac hormone that regulates blood pressure. In cardiomyocytes, the hormone is synthesized as a precursor, proatrial natriuretic peptide (pro-ANP), which is proteolytically converted to active ANP. Corin is a cardiac transmembrane serine protease that has been shown to process pro-ANP in vitro, but its physiological importance had not been established. Here, we show that corin-deficient (Cor-/-) mice develop normally during embryogenesis and survive to postnatal life. Cor-/- mice have elevated levels of pro-ANP but no detectable levels of ANP as compared with WT littermates. Infusion of an active recombinant soluble corin transiently restores pro-ANP conversion, resulting in the release of circulating biologically active ANP. Using radiotelemetry to assess blood pressure, we find that Cor-/- mice have spontaneous hypertension as compared with WT mice, and it is enhanced after dietary salt loading. Pregnant Cor-/- mice demonstrate late-gestation proteinuria and enhanced high blood pressure during pregnancy. In addition, Cor-/- mice exhibit cardiac hypertrophy resulting in a mild decline in cardiac function later in life. Thus, our data establish corin as the physiological pro-ANP convertase and indicate that corin deficiency may contribute to hypertensive heart disease.

Animals↗

PubMed2005

Wild chimpanzees show population-level handedness for tool use.

Whether nonhuman primates exhibit population-level handedness remains a topic of considerable theoretical and empirical debate. One continued subject of discussion is whether evidence of population-level handedness in primates is confined to studies in captive animals or whether it is in both captive and wild subjects. Here, we report evidence of population-level handedness in wild chimpanzees for a tool-use task known as "termite-fishing." We subsequently compared the handedness for termite-fishing with other published reports on handedness for nut-cracking and wadge-dipping and found task-specific differences in handedness. Last, when combing all of the published data on tool use in wild chimpanzees, we show that hand preferences are heritable. Contrary to previous claims, our results demonstrate that population-level handedness is evident in wild chimpanzees and suggest that the antecedents of lateralization of function associated with hand use were present at least 5 million years ago, before the Pan-Homo split.

Animals↗

PubMed2003

DNA replication of mitotic chromatin in Xenopus egg extracts.

Prereplication complexes are assembled at eukaryotic origins of DNA replication in the G1 phase of the cell cycle, and they are activated in S phase by cyclin-dependent kinase (Cdk)2/cyclin E and Cdk2/cyclin A. Previous experiments using Xenopus nuclear assembly egg extracts suggested that Cdk1/cyclin A, which is normally active in early mitosis, can replace the function of Cdk2 in driving DNA replication, whereas Cdk1/cyclin B, which functions later in mitosis, cannot. Here, we use a completely soluble replication system derived from Xenopus egg extracts to show that Cdk1/cyclin B also can support DNA replication. The ability of mitotic Cdks to drive DNA replication raises the question of whether DNA replication is possible in mitosis. To address this question, chromatin containing prereplication complexes was driven into mitosis with Cdk1/cyclin B. Strikingly, upon addition of a replication extract, the chromatin underwent a complete round of DNA replication. Replicating mitotic chromosomes became visibly decondensed, and, after DNA replication was complete, they recondensed. Our results indicate that there is extensive overlap in the substrate specificity of the major metazoan Cdk/cyclin complexes and that mitosis is not fundamentally incompatible with DNA replication. The results suggest that origins that fail to initiate DNA replication in S phase might still be able to do so in mitosis.

Animals↗

PubMed1997

Genetic interactions with Rap1 and Ras1 reveal a second function for the fat facets deubiquitinating enzyme in Drosophila eye development.

The Drosophila fat facets gene encodes a deubiquitinating enzyme that regulates a cell communication pathway essential very early in eye development, prior to facet assembly, to limit the number of photoreceptor cells in each facet of the compound eye to eight. The Fat facets protein facilitates the production of a signal in cells outside the developing facets that inhibits neural development of particular facet precursor cells. Novel gain-of-function mutations in the Drosophila Rap1 and Ras1 genes are described herein that interact genetically with fat facets mutations. Analysis of these genetic interactions reveals that Fat facets has an additional function later in eye development involving Rap1 and Ras1 proteins. Moreover, the results suggest that undifferentiated cells outside the facet continue to influence facet assembly later in eye development.

Amino Acid Sequence↗

PubMed1999

Fgfr2 is required for limb outgrowth and lung-branching morphogenesis.

The aim of this study was to clarify the role of Fgfr2 during later stages of embryonic development. Of two previously reported gene-targeting experiments, the more extensive Fgfr2 deletion was lethal shortly after implantation, because of trophoblast defects, whereas the less extensive one survived until midgestation with placental insufficiency and defective limb outgrowth [Xu, X., Weinstein, M., Li, C., Naski, M., Cohen, R. I., Ornitz, D. M., Leder, P. & Deng, C. (1998) Development (Cambridge, U.K.) 125, 753-765]. Fgfr2 in the early embryo is expressed in the trophectoderm, and this extra-embryonic localization persists into mid- and late gestation, when Fgfr2 also is expressed in multiple developing organs. To gain insight into the later functions of Fgfr2, fusion chimeras were constructed from homozygous mutant embryonic stem cells and wild-type tetraploid embryos. This allowed survival until term and revealed that Fgfr2 is required for both limb outgrowth and branching lung morphogenesis. The use of fusion chimeras demonstrated that early lethality was indeed because of trophectoderm defects and indicated that in the embryonic cell lineages Fgfr2 activity manifests in limb and lung development. Highly similar lung and limb phenotypes were detected recently in the loss of function mutation of Fgf10, a ligand of Fgfr2. It is likely, therefore, that whereas during early development Fgfr2 interacts with Fgf4, in limb and lung development interactions between Fgf10 and Fgfr2 may be required. Possible epithelial-mesenchymal interactions between the splicing alternatives of Fgfr2 and their specific ligands will be discussed.

Alternative Splicing↗

PubMed1999

Peptide-bound major histocompatibility complex class I molecules associate with tapasin before dissociation from transporter associated with antigen processing.

Major histocompatibility complex (MHC) class I molecules present antigenic peptides to CD8 T cells. The peptides are generated in the cytosol, then translocated across the membrane of the endoplasmic reticulum by the transporter associated with antigen processing (TAP). TAP is a trimeric complex consisting of TAP1, TAP2, and tapasin (TAP-A) as indicated for human cells by reciprocal coprecipitation with anti-TAP1/2 and anti-tapasin antibodies, respectively. TAP1 and TAP2 are required for the peptide transport. Tapasin is involved in the association of class I with TAP and in the assembly of class I with peptide. The mechanisms of tapasin function are still unknown. Moreover, there has been no evidence for a murine tapasin analogue, which has led to the suggestion that murine MHC class I binds directly to TAP1/2. In this study, we have cloned the mouse analogue of tapasin. The predicted amino acid sequence showed 78% identity to human tapasin with identical consensus sequences of signal peptide, N-linked glycosylation site, transmembrane domain and double lysine motif. However, there was less homology (47%) found at the predicted cytosolic domain, and in addition, mouse tapasin is 14 amino acids longer than the human analogue at the C terminus. This part of the molecule may determine the species specificity for interaction with MHC class I or TAP1/2. Like human tapasin, mouse tapasin binds both to TAP1/2 and MHC class I. In TAP2-mutated RMA-S cells, both TAP1 and MHC class I were coprecipitated by anti-tapasin antiserum indicative of association of tapasin with TAP1 but not TAP2. With crosslinker-modified peptides and purified microsomes, anti-tapasin coprecipitated both peptide-bound MHC class I and TAP1/2. In contrast, anti-calreticulin only coprecipitated peptide-free MHC class I molecules. This difference in association with peptide-loaded class I suggests that tapasin functions later than calreticulin during MHC class I assembly, and controls peptide loading onto MHC class I molecules in the endoplasmic reticulum.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1987

Cognitive and task-related EEG correlates of arithmetic performance in adolescents.

Cognitive and neurophysiological correlates of arithmetic calculation, concepts, and applications were examined in 41 adolescents, ages 12-15 years. Psychological and task-related EEG measures which correctly distinguished children who scored low vs. high (using a median split) in each arithmetic subarea were interpreted as indicative of processes involved. Calculation was related to visual-motor sequencing, spatial visualization, theta activity measured during visual-perceptual and verbal tasks at right- and left-hemisphere locations, and right-hemisphere alpha activity measured during a verbal task. Performance on arithmetic word problems was related to spatial visualization and perception, vocabulary, and right-hemisphere alpha activity measured during a verbal task. Results suggest a complex interplay of spatial and sequential operations in arithmetic performance, consistent with processing model concepts of lateralized brain function.

Achievement↗

PubMed2006

A dose-response study of the effects of prenatal and lactational exposure to TCDD on the immune response to influenza a virus.

The goal of the current study was to evaluate the immune response to a common respiratory pathogen, influenza A virus, in mice exposed to increasing doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) during development. Additionally, the treatment paradigm was designed to provide exposure throughout fetal and neonatal development, beginning on d 1 of gestation. To accomplish this, impregnated C57Bl/6 mice were treated with 0.25 microg/kg TCDD on d 0 and 7 of pregnancy, followed by 2 additional doses of 0.25, 1, or 5 microg/kg given on d 14 and postpartum d 2. The adult offspring were infected with influenza virus, and components of the adaptive and innate immune responses were evaluated. Our results show that developmental exposure to TCDD dose-responsively suppressed both the cell-mediated and antibody responses to influenza virus in female but not males. In contrast, TCDD exposure enhanced the innate immune responses in offspring of both sexes; specifically, neutrophilia and interferon (IFN) gamma levels in the lung were increased. These alterations in functional immunity did not result from overt toxicity to the immune organs, as developmental TCDD exposure did not alter the cellular composition of the thymus, spleen, or bone marrow. These findings extend our knowledge of the dose-responsive nature of immunological defects induced by developmental exposure to TCDD and offer insight regarding the dose required to alter the immune response to viral infection. Moreover, we demonstrate a clear dose at which no observable effects on immune function later in life were detected.

Animals↗

PubMed2000

Mdv1p is a WD repeat protein that interacts with the dynamin-related GTPase, Dnm1p, to trigger mitochondrial division.

Mitochondrial fission is mediated by the dynamin-related GTPase, Dnm1p, which assembles on the mitochondrial outer membrane into punctate structures associated with sites of membrane constriction and fission. We have identified additional nuclear genes required for mitochondrial fission, termed MDV (for mitochondrial division). MDV1 encodes a predicted soluble protein, containing a coiled-coil motif and seven COOH-terminal WD repeats. Genetic and two-hybrid analyses indicate that Mdv1p interacts with Dnm1p to mediate mitochondrial fission. In addition, Mdv1p colocalizes with Dnm1p in fission-mediating punctate structures on the mitochondrial outer membrane. Whereas localization of Mdv1p to these structures requires Dnm1p, localization of Mdv1p to mitochondrial membranes does not. This indicates that Mdv1p possesses a Dnm1p-independent mitochondrial targeting signal. Dnm1p-independent targeting of Mdv1p to mitochondria requires MDV2. Our data indicate that MDV2 also functions separately to regulate the assembly of Dnm1p into punctate structures. In contrast, Mdv1p is not required for the assembly of Dnm1p, but Dnm1p-containing punctate structures lacking Mdv1p are not able to complete division. Our studies suggest that mitochondrial fission is a multi-step process in which Mdv2p regulates the assembly of Dnm1p into punctate structures and together with Mdv1p functions later during fission to facilitate Dnm1p-dependent mitochondrial membrane constriction and/or division.

Cell Compartmentation↗