33 research outputs found
Gene Circuit Analysis of the Terminal Gap Gene huckebein
The early embryo of Drosophila melanogaster provides a powerful model system to study the role of genes in pattern formation. The gap gene network constitutes the first zygotic regulatory tier in the hierarchy of the segmentation genes involved in specifying the position of body segments. Here, we use an integrative, systems-level approach to investigate the regulatory effect of the terminal gap gene huckebein (hkb) on gap gene expression. We present quantitative expression data for the Hkb protein, which enable us to include hkb in gap gene circuit models. Gap gene circuits are mathematical models of gene networks used as computational tools to extract regulatory information from spatial expression data. This is achieved by fitting the model to gap gene expression patterns, in order to obtain estimates for regulatory parameters which predict a specific network topology. We show how considering variability in the data combined with analysis of parameter determinability significantly improves the biological relevance and consistency of the approach. Our models are in agreement with earlier results, which they extend in two important respects: First, we show that Hkb is involved in the regulation of the posterior hunchback (hb) domain, but does not have any other essential function. Specifically, Hkb is required for the anterior shift in the posterior border of this domain, which is now reproduced correctly in our models. Second, gap gene circuits presented here are able to reproduce mutants of terminal gap genes, while previously published models were unable to reproduce any null mutants correctly. As a consequence, our models now capture the expression dynamics of all posterior gap genes and some variational properties of the system correctly. This is an important step towards a better, quantitative understanding of the developmental and evolutionary dynamics of the gap gene network
Gastric inhibitory polypeptide receptor: association analyses for obesity of several polymorphisms in large study groups
<p>Abstract</p> <p>Background</p> <p>Gastric inhibitory polypeptide (GIP) is postulated to be involved in type 2 diabetes mellitus and obesity. It exerts its function through its receptor, GIPR. We genotyped three <it>GIPR </it>SNPs (rs8111428, rs2302382 and rs1800437) in German families with at least one obese index patient, two case-control studies and two cross-sectional population-based studies.</p> <p>Methods</p> <p>Genotyping was performed by MALDI-TOF, ARMS-PCR and RFLP. The family-study: 761 German families with at least one extremely obese child or adolescent (n = 1,041) and both parents (n = 1,522). Case-control study: (a) German obese children (n = 333) and (b) obese adults (n = 987) in comparison to 588 adult lean controls. The two cross-sectional population-based studies: KORA (n = 8,269) and SHIP (n = 4,310).</p> <p>Results</p> <p>We detected over-transmission of the A-allele of rs2302382 in the German families (p<sub>TDT-Test </sub>= 0.0089). In the combined case-control sample, we estimated an odd ratio of 1.54 (95%CI 1.09;2.19, p<sub>CA-Test </sub>= 0.014) for homozygotes of the rs2302382 A-allele compared to individuals with no A-allele. A similar trend was found in KORA where the rs2302382 A-allele led to an increase of 0.12 BMI units (p = 0.136). In SHIP, however, the A-allele of rs2302382 was estimated to contribute an average decrease of 0.27 BMI units (p-value = 0.031).</p> <p>Conclusion</p> <p>Our data suggest a potential relevance of <it>GIPR </it>variants for obesity. However, additional studies are warranted in light of the conflicting results obtained in one of the two population-based studies.</p
The Association of a SNP Upstream of INSIG2 with Body Mass Index is Reproduced in Several but Not All Cohorts
A SNP upstream of the INSIG2 gene, rs7566605, was recently found to be associated with obesity as measured by body mass index (BMI) by Herbert and colleagues. The association between increased BMI and homozygosity for the minor allele was first observed in data from a genome-wide association scan of 86,604 SNPs in 923 related individuals from the Framingham Heart Study offspring cohort. The association was reproduced in four additional cohorts, but was not seen in a fifth cohort. To further assess the general reproducibility of this association, we genotyped rs7566605 in nine large cohorts from eight populations across multiple ethnicities (total n = 16,969). We tested this variant for association with BMI in each sample under a recessive model using family-based, population-based, and case-control designs. We observed a significant (p < 0.05) association in five cohorts but saw no association in three other cohorts. There was variability in the strength of association evidence across examination cycles in longitudinal data from unrelated individuals in the Framingham Heart Study Offspring cohort. A combined analysis revealed significant independent validation of this association in both unrelated (p = 0.046) and family-based (p = 0.004) samples. The estimated risk conferred by this allele is small, and could easily be masked by small sample size, population stratification, or other confounders. These validation studies suggest that the original association is less likely to be spurious, but the failure to observe an association in every data set suggests that the effect of SNP rs7566605 on BMI may be heterogeneous across population samples
Canalization of Gene Expression and Domain Shifts in the Drosophila Blastoderm by Dynamical Attractors
The variation in the expression patterns of the gap genes in the blastoderm of
the fruit fly Drosophila melanogaster reduces over time as a
result of cross regulation between these genes, a fact that we have demonstrated
in an accompanying article in PLoS Biology (see Manu et al.,
doi:10.1371/journal.pbio.1000049). This biologically essential process is an
example of the phenomenon known as canalization. It has been suggested that the
developmental trajectory of a wild-type organism is inherently stable, and that
canalization is a manifestation of this property. Although the role of gap genes
in the canalization process was established by correctly predicting the response
of the system to particular perturbations, the stability of the developmental
trajectory remains to be investigated. For many years, it has been speculated
that stability against perturbations during development can be described by
dynamical systems having attracting sets that drive reductions of volume in
phase space. In this paper, we show that both the reduction in variability of
gap gene expression as well as shifts in the position of posterior gap gene
domains are the result of the actions of attractors in the gap gene dynamical
system. Two biologically distinct dynamical regions exist in the early embryo,
separated by a bifurcation at 53% egg length. In the anterior region,
reduction in variation occurs because of stability induced by point attractors,
while in the posterior, the stability of the developmental trajectory arises
from a one-dimensional attracting manifold. This manifold also controls a
previously characterized anterior shift of posterior region gap domains. Our
analysis shows that the complex phenomena of canalization and pattern formation
in the Drosophila blastoderm can be understood in terms of the
qualitative features of the dynamical system. The result confirms the idea that
attractors are important for developmental stability and shows a richer variety
of dynamical attractors in developmental systems than has been previously
recognized
Effekt von Strahlenschutzvisieren auf die Augenlinsendosis bei der Ureterorenoskopie.
Hintergrund und ZielDie
Strahlenbelastung bei interventionellen Eingriffen unter simultaner
Röntgenkontrolle kann zu einer berufsbedingten Katarakterkrankung an der
Augenlinse des Operateurs führen. Wir untersuchten die
Strahlenbelastung und den protektiven Effekt von Strahlenschutzvisieren
bei ureterorenoskopischen Eingriffen.Material und MethodeDie
Untersuchung erfolgte bei 4 Urologen. Über einen Zeitraum von 12 Wochen
wurden dabei mittels Augenlinsendosismeter die Strahlendosen in
Augenhöhe vor und hinter Strahlenschutzvisieren gemessen. Die natürliche
Hintergrundstrahlung, ermittelt durch zusätzliche Transportdosimeter,
wurde subtrahiert. Messwerte <0,028 mSv wurden wegen der
Nachweisgrenze der Augendosimeter auf 0,028 mSv aufgerundet. Die
erhaltenen Augenlinsendosen (ALD) wurden mit dem jeweiligen
Dosis-Flächen-Produkt (DFP) der operativen Eingriffe korreliert. Mittels
dieses Quotienten aus ALD/DFP wurden retrospektiv Jahreswerte für die
ALD bei ureterorenoskopischen Eingriffen ermittelt und der mögliche
protektive Effekt von Strahlenschutzvisieren kalkuliert.ErgebnisInnerhalb
der 12-Wochen-Periode wurden von den 4 Urologen 76 Ureterorenoskopien
durchgeführt. Vor dem Strahlenschutzvisier betrug dabei die kumulierte
ALD 0,796 mSv, hinter dem Strahlenschutzvisier kumuliert 0,338 mSv. Die
Benutzung eines Strahlenschutzvisiers führte damit zu einer Reduktion
der Strahlenbelastung am Auge um mindestens 42 %. Die retrospektive
Analyse von 215 durchgeführten Ureterorenoskopien zeigte, dass durch die
Anwendung von Strahlenschutzvisieren eine Reduktion der jährlichen ALD
von 4,090 auf 1,737 mSv hätte erzielt werden können.SchlussfolgerungStrahlenschutzvisiere
können die Strahlenbelastung am Auge des Operateurs bei
endourologischen Eingriffen signifikant reduzieren und sollten
insbesondere von Operateuren mit hoher Operationsfrequenz benutzt
werden
Association of the MC4R V103I polymorphism with the metabolic syndrome: The KORA Study.
Epidemiological studies showing an association between the melanocortin-4-receptor (MC4R) 103I variant (rs2229616) and decreased BMI are complemented by functional studies; these suggest a mechanism for appetite regulation and a linkage signal for physical activity and dietary intake for the region encompassing the MC4R. This study aims to provide epidemiological evidence for showing the association of this polymorphism with features of the metabolic syndrome and with parameters related to energy expenditure and dietary habits as potential mediators. METHODS AND PROCEDURES: We analyzed this polymorphism in 7,888 adults of a population-based cross-sectional study applying regression-based statistical models. RESULTS: Carriers of the MC4R 103I (3.7%) exhibited a significantly decreased waist circumference (-1.46 cm, P = 0.020), decreased glycosylated hemoglobin (HbA(1c)) (-0.09%, P = 0.040), and increased HDL-cholesterol (HDL-C) (+1.76 mg/dl, P = 0.056), but no change in blood pressure. The odds of having three or more components of the metabolic syndrome were substantially reduced among carriers of MC4R 103I (odds ratio (OR) = 0.46, P = 0.003). Controlling for BMI reduced the HbA(1c) and HDL-C association. Mediator analyses revealed a borderline association of MC4R 103I with carbohydrate intake (OR = 1.26, P = 0.059) possibly mediating association with leanness. DISCUSSION: Our representative study of well-phenotyped Europeans is the first to describe the association of the MC4R V103I with the metabolic syndrome and with a nutrient-related phenotype. Our data support the idea that this polymorphism plays a role in appetite regulation that not only affects BMI, but also other features of the metabolic syndrome. It further establishes that the association of the MC4R V103I with obesity and related phenotypes is genuine