Collecting new targets in MODY

Transcriptional regulation is crucial in the function of the pancreatic β cell and diabetes, as evidenced by the human MODY families. Work from Fukui and colleagues (Fukui et al., 2005) and Akpinar and colleagues (Akpinar et al., 2005) in this issue of Cell Metabolism identifies a target of the MODY3 transcription factor HNF-1α that appears to function both in insulin secretion and β cell proliferation

Gene Structure, cDNA Sequence, and mRNA Distribution

The rat HNF-3 (hepatocyte nuclear factor 3) gene family encodes three transcription factors known to be important in the regulation of gene expression in liver and lung. We have cloned and characterized the mouse genes and cDNAs for HNF-3α, β, and γ and analyzed their expression patterns in various adult tissues and mouse embryonic stages. The HNF-3 proteins are highly conserved between mouse and rat, with the exception of the amino terminus of HNF-3γ, which in mouse is more similar to those of HNF-3α and β than to the amino termini of the rat HNF-3γ protein. The mouse HNF-3 genes are small and contain only two or three (HNF-3β) exons with conserved intron-exon boundaries. The proximal promoter of the mouse HNF3β gene is remarkably similar to that of the previously cloned rat HNF-3β gene, but is different from the promoters of the HNF-3α and γ genes. The mRNA distribution of the mouse HNF-3 genes was analyzed by quantitative RNase protection with gene-specific probes. While HNF-3α and β are restricted mainly to endoderm-derived tissues (lung, liver, stomach, and small intestine), HNF-3γ is more extensively expressed, being present additionally in ovary, testis, heart, and adipose tissue, but missing from lung. Transcripts for HNF-3β and α are detected most abundantly in midgestation embryos (Day 9.5), while HNF-3γ expression peaks around Day 15.5 of gestation

Pregnant Women after Physical and Sexual Abuse in Germany

Background/Aims: The aim of our study was to evaluate the prevalence of abuse among pregnant women in Germany attending our antenatal outpatient clinic and to observe whether a history of abuse had consequences for women's feelings about their pregnancy. Methods: 455 women between the 35th and 42nd weeks of gestational age were included and were asked to fill out an anonymous questionnaire concerning their pregnancy, their actual psychological state, and their history of physical/sexual abuse. 600 questionnaires were distributed (return rate 75.8%), 70 women (10.4%) were excluded because of male companionship to ensure their safety in case that they were currently in an abusive relationship with the attending man. Results: 88 women (19.3%) reported a history of sexual and/or physical abuse. Pregnant women after physical and/or sexual abuse significantly more frequently associate negative feelings with their pregnancy than nonabused women. The Hospital Anxiety Depression Scale (HADS) and the SCL-K-9 demonstrated significantly more negative feelings of depression and anxiety, strain, loneliness and less expectation of happiness for their future in abused women. Conclusion: Physical and sexual abuse are relevant problems among women in obstetric care that may complicate their pregnancies and make them feel more depressive. Copyright (C) 2009 S. Karger AG, Base

Statistical Uncertainty in Quantitative Neutron Radiography

We demonstrate a novel procedure to calibrate neutron detection systems commonly used in standard neutron radiography. This calibration allows determining the uncertainties due to Poisson-like neutron counting statistics for each individual pixel of a radiographic image. The obtained statistical errors are necessary in order to perform a correct quantitative analysis. This fast and convenient method is applied to data measured at the cold neutron radiography facility ICON at the Paul Scherrer Institute. Moreover, from the results the effective neutron flux at the beam line is determined

Structure of the Mouse Myelin P 2 Protein Gene

Myelin P 2 protein is a small (14,800 Da) protein found in peripheral and central nervous system myelin. To investigate the regulation of expression of this myelin protein, a mouse genomic library was screened with a rabbit P 2 cDNA (pSN2.2–2), and a single positive phage clone containing a 20-kb insert was obtained. This insert contained a single internal Sail restriction site and several Eco RI sites. The Eco RI fragments from this insert were subcloned into Bluescript. The rabbit P 2 cDNA (pSN2.2–2) hybridized with a 4-kb Eco RI fragment, and this 4-kb fragment was then sequenced after the creation of nested deletions. The mouse gene contained four exons: exon 1 coded for amino acids 1–24, exon 2 for amino acids 24–81, exon 3 for amino acids 82–115, and exon 4 for amino acids 116–131. The three introns were 1.2 kb, 150 bp, and 1.3 kb in length. Primer extension analysis revealed two transcription start sites at +1 and +47, consistent with the presence of two P 2 mRNAs, with the larger transcript appearing more abundant. The amino acid sequences predicted from the mouse DNA indicate that the mouse protein differs from the rabbit protein at 16 different positions, with most of the differences located in exon 3. When the gene structure of fatty acid binding protein (FABP) genes were compared, the P 2 gene had the same overall structure as others in the FABP family, suggesting a common ancestral gene for members of this family. The 5′-flanking region contains candidate TATA and CAAT sequences, as well as two AP-l binding sites that may be important in modulation of the expression of this gene.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65134/1/j.1471-4159.1991.tb02101.x.pd

Identification of known and novel pancreas genes expressed downstream of Nkx2.2 during development

<p>Abstract</p> <p>Background</p> <p>The homeodomain containing transcription factor Nkx2.2 is essential for the differentiation of pancreatic endocrine cells. Deletion of Nkx2.2 in mice leads to misspecification of islet cell types; insulin-expressing β cells and glucagon-expressing α cells are replaced by ghrelin-expressing cells. Additional studies have suggested that Nkx2.2 functions both as a transcriptional repressor and activator to regulate islet cell formation and function. To identify genes that are potentially regulated by Nkx2.2 during the major wave of endocrine and exocrine cell differentiation, we assessed gene expression changes that occur in the absence of Nkx2.2 at the onset of the secondary transition in the developing pancreas.</p> <p>Results</p> <p>Microarray analysis identified 80 genes that were differentially expressed in e12.5 and/or e13.5 Nkx2.2^-/-embryos. Some of these genes encode transcription factors that have been previously identified in the pancreas, clarifying the position of Nkx2.2 within the islet transcriptional regulatory pathway. We also identified signaling factors and transmembrane proteins that function downstream of Nkx2.2, including several that have not previously been described in the pancreas. Interestingly, a number of known exocrine genes are also misexpressed in the Nkx2.2^-/-pancreas.</p> <p>Conclusions</p> <p>Expression profiling of Nkx2.2^-/-mice during embryogenesis has allowed us to identify known and novel pancreatic genes that function downstream of Nkx2.2 to regulate pancreas development. Several of the newly identified signaling factors and transmembrane proteins may function to influence islet cell fate decisions. These studies have also revealed a novel function for Nkx2.2 in maintaining appropriate exocrine gene expression. Most importantly, Nkx2.2 appears to function within a complex regulatory loop with Ngn3 at a key endocrine differentiation step.</p

The pluripotency factor LIN28 marks undifferentiated spermatogonia in mouse

<p>Abstract</p> <p>Background</p> <p>Life-long production of spermatozoa depends on spermatogonial stem cells. Spermatogonial stem cells exist among the most primitive population of germ cells – undifferentiated spermatogonia. Transplantation experiments have demonstrated the functional heterogeneity of undifferentiated spermatogonia. Although the undifferentiated spermatogonia can be topographically divided into A_s(single), A_pr(paired), and A_al(aligned) spermatogonia, subdivision of this primitive cell population using cytological markers would greatly facilitate characterization of their functions.</p> <p>Results</p> <p>In the present study, we show that LIN28, a pluripotency factor, is specifically expressed in undifferentiated spermatogonia (A_s, A_pr, and A_al) in mouse. <it>Ngn3 </it>also specifically labels undifferentiated spermatogonia. We used <it>Ngn3</it>-GFP knockin mice, in which GFP expression is under the control of all <it>Ngn3 </it>transcription regulatory elements. Remarkably, <it>Ngn3</it>-GFP is only expressed in ~40% of LIN28-positive A_s(single) cells. The percentage of <it>Ngn3</it>-GFP-positive clusters increases dramatically with the chain length of interconnected spermatogonia.</p> <p>Conclusion</p> <p>Our study demonstrates that LIN28 specifically marks undifferentiated spermatogonia in mice. These data, together with previous studies, suggest that the LIN28-expressing undifferentiated spermatogonia exist as two subpopulations: <it>Ngn3</it>-GFP-negative (high stem cell potential) and <it>Ngn3</it>-GFP-positive (high differentiation commitment). Furthermore, <it>Ngn3</it>-GFP-negative cells are found in chains of <it>Ngn3</it>-GFP-positive spermatogonia, suggesting that cells in the A_alspermatogonia could revert to a more primitive state.</p

Integrated quantized electronics: a semiconductor quantized voltage source

The Josephson effect in superconductors links a quantized output voltage Vout = f \cdot(h/2e) to the natural constants of the electron's charge e, Planck's constant h, and to an excitation frequency f with important applications in electrical quantum metrology. Also semiconductors are routinely applied in electrical quantum metrology making use of the quantum Hall effect. However, despite their broad range of further applications e.g. in integrated circuits, quantized voltage generation by a semiconductor device has never been obtained. Here we report a semiconductor quantized voltage source generating quantized voltages Vout = f\cdot(h/e). It is based on an integrated quantized circuit of a single electron pump operated at pumping frequency f and a quantum Hall device monolithically integrated in series. The output voltages of several \muV are expected to be scalable by orders of magnitude using present technology. The device might open a new route towards the closure of the quantum metrological triangle. Furthermore it represents a universal electrical quantum reference allowing to generate quantized values of the three most relevant electrical units of voltage, current, and resistance based on fundamental constants using a single device.Comment: 15 pages, 3 figure