bluuebunny/crossref_metadata_2025 huggingface dataset:
Association and haplotype analysis of candidate genes in five genomic regions linked to sow maternal infanticide in a white Duroc × Erhualian resource population
Authors: Chen Congying , Yang Zhuqing , Li Yanying , Wei Na , Li Pinghua , Guo Yuanmei , Ren Jun , Ding Nengshui , Huang Lusheng
Published: February 2011

Background

Maternal infanticide is an extreme and failed maternal behavior, which is defined as an active attack on piglets using the jaws, resulting in serious or fatal bite wounds. It brings big economic loss to the pig industry and severe problems to piglets' welfare. But little is known about the genetic background of this behavior. Quantitative trait loci (QTL) for maternal infanticide were identified in a White Duroc × Erhualian intercross by a non-parametric linkage analysis (NPL) in our previous study. In this study, associations of 194 microsatellite markers used in NPL analysis with maternal infanticide behavior were further analyzed by transmission-disequilibrium test (TDT). On this basis, seven genes (ESR 2, EAAT 2, BDNF, OXTR, 5-HTR2C, DRD 1 and GABRA 6) at five genomic regions were selected and further analyzed. Associations of single nucleotide polymorphisms (SNPs) and haplotypes in each gene with maternal infanticide behavior were evaluated.

Results

Microsatellite markers on pig chromosome (SSC) 2, 13, 15, and X displayed significance at P < 0.05 by both TDT and NPL. Of the seven candidate genes, three ESR 2 SNPs had nominal evidence for association (P < 0.05). Allele A at EAAT 2 g. 233G > A and allele T at DRD 1 g.1013C > G > T also showed evidence of overtransmission to infanticidal sows. In the overall tests of association of haplotypes, candidate genes of ESR 2, EAAT 2 and DRD 1 achieved overall significance level (P < 0.05). Haplotype [A; A; G], [G; A; G], [A; G; G] and [C; C], respectively, from ESR 2, EAAT 2 and DRD 1 showed higher frequencies to infanticidal sows (P < 0.05). Alleles among haplotypes and SNPs which showed an overtransmission to infanticidal sows were from White Duroc.

Conclusions

From association tests of SNPs and haplotypes, ESR 2, EAAT 2 and DRD 1 showed significant associations with maternal infanticide. This result supported the existence of QTL for maternal infanticide behavior on SSC1, SSC2 and SSC16.
Integration of linkage maps for the Amphidiploid Brassica napus and comparative mapping with Arabidopsis and Brassica rapa
Authors: Wang Jun , Lydiate Derek J , Parkin Isobel AP , Falentin Cyril , Delourme Régine , Carion Pierre WC , King Graham J
Published: February 2011

Background

The large number of genetic linkage maps representingBrassicachromosomes constitute a potential platform for studying crop traits and genome evolution withinBrassicaceae. However, the alignment of existing maps remains a major challenge. The integration of these genetic maps will enhance genetic resolution, and provide a means to navigate between sequence-tagged loci, and with contiguous genome sequences as these become available.

Results

We report the first genome-wide integration ofBrassicamaps based on an automated pipeline which involved collation of genome-wide genotype data for sequence-tagged markers scored on three extensively used amphidiploidBrassica napus(2n = 38) populations. Representative markers were selected from consolidated maps for each population, and skeleton bin maps were generated. The skeleton maps for the three populations were then combined to generate an integrated map for each LG, comparing two different approaches, one encapsulated in JoinMap and the other in MergeMap. The BnaWAIT_01_2010a integrated genetic map was generated using JoinMap, and includes 5,162 genetic markers mapped onto 2,196 loci, with a total genetic length of 1,792 cM. The map density of one locus every 0.82 cM, corresponding to 515 Kbp, increases by at least three-fold the locus and marker density within the original maps. Within theB. napusintegrated map we identified 103 conserved collinearity blocks relative toArabidopsis, including five previously unreported blocks. The BnaWAIT_01_2010a map was used to investigate the integrity and conservation of order proposed for genome sequence scaffolds generated from the constituent A genome ofBrassica rapa.

Conclusions

Our results provide a comprehensive genetic integration of theB. napusgenome from a range of sources, which we anticipate will provide valuable information for rapeseed and Canola research.
Responsiveness of genes to manipulation of transcription factors in ES cells is associated with histone modifications and tissue specificity
Authors: Sharov Alexei A , Nishiyama Akira , Piao Yulan , Correa-Cerro Lina S , Amano Tomokazu , Thomas Marshall , Mehta Samir , Ko Minoru SH
Published: February 2011

Background

In addition to determining static states of gene expression (high vs. low), it is important to characterize their dynamic status. For example, genes with H3K27me3 chromatin marks are not only suppressed but also poised for activation. However, the responsiveness of genes to perturbations has never been studied systematically. To distinguish gene responses to specific factors from responsiveness in general, it is necessary to analyze gene expression profiles of cells responding to a large variety of disturbances, and such databases did not exist before.

Results

We estimated the responsiveness of all genes in mouse ES cells using our recently published database on expression change after controlled induction of 53 transcription factors (TFs) and other genes. Responsive genes (N = 4746), which were readily upregulated or downregulated depending on the kind of perturbation, mostly have regulatory functions and a propensity to become tissue-specific upon differentiation. Tissue-specific expression was evaluated on the basis of published (GNF) and our new data for 15 organs and tissues. Non-responsive genes (N = 9562), which did not change their expression much following any perturbation, were enriched in housekeeping functions. We found that TF-responsiveness in ES cells is the best predictor known for tissue-specificity in gene expression. Among genes with CpG islands, high responsiveness is associated with H3K27me3 chromatin marks, and low responsiveness is associated with H3K36me3 chromatin, stronger tri-methylation of H3K4, binding of E2F1, and GABP binding motifs in promoters.

Conclusions

We thus propose the responsiveness of expression to perturbations as a new way to define the dynamic status of genes, which brings new insights into mechanisms of regulation of gene expression and tissue specificity.
Two-step cleavage of hairpin RNA with 5' overhangs by human DICER
Authors: Ando Yoshinari , Maida Yoshiko , Morinaga Ayako , Burroughs Alexander M , Kimura Ryuichiro , Chiba Joe , Suzuki Harukazu , Masutomi Kenkichi , Hayashizaki Yoshihide
Published: February 2011

Background

DICER is an RNase III family endoribonuclease that processes precursor microRNAs (pre-miRNAs) and long double-stranded RNAs, generating microRNA (miRNA) duplexes and short interfering RNA duplexes with 20~23 nucleotides (nts) in length. The typical form of pre-miRNA processed by the Drosha protein is a hairpin RNA with 2-nt 3' overhangs. On the other hand, production of mature miRNA from an endogenous hairpin RNA with 5' overhangs has also been reported, although the mechanism for this process is unknown.

Results

In this study, we show that human recombinant DICER protein (rDICER) processes a hairpin RNA with 5' overhangsin vitroand generates an intermediate duplex with a 29 nt-5' strand and a 23 nt-3' strand, which was eventually cleaved into a canonical miRNA duplex via a two-step cleavage. The previously identified endogenous pre-miRNA with 5' overhangs, pre-mmu-mir-1982 RNA, is also determined to be a substrate of rDICER through the same two-step cleavage.

Conclusions

The two-step cleavage of a hairpin RNA with 5' overhangs shows that DICER releases double-stranded RNAs after the first cleavage and binds them again in the inverse direction for a second cleavage. These findings have implications for how DICER may be able to interact with or process differing precursor structures.
Variable expressivity of FGF3 mutations associated with deafness and LAMM syndrome
Authors: Riazuddin Saima , Ahmed Zubair M , Hegde Rashmi S , Khan Shaheen N , Nasir Idrees , Shaukat Uzma , Riazuddin Sheikh , Butman John A , Griffith Andrew J , Friedman Thomas B , Choi Byung Yoon
Published: February 2011

Background

Recessive mutations of fibroblast growth factor 3 (FGF3) can cause LAMM syndrome (OMIM 610706), characterized by fully penetrant complete labyrinthine aplasia, microtia and microdontia.

Methods

We performed a prospective molecular genetic and clinical study of families segregating hearing loss linked to FGF3 mutations. Ten affected individuals from three large Pakistani families segregating FGF3 mutations were imaged with CT, MRI, or both to detect inner ear abnormalities. We also modeled the three dimensional structure of FGF3 to better understand the structural consequences of the three missense mutations.

Results

Two families segregated reported mutations (p.R104X and p.R95W) and one family segregated a novel mutation (p.R132GfsX26) of FGF3. All individuals homozygous for p.R104X or p.R132GfsX26 had fully penetrant features of LAMM syndrome. However, recessive p.R95W mutations were associated with nearly normal looking auricles and variable inner ear structural phenotypes, similar to that reported for a Somali family also segregating p.R95W. This suggests that the mild phenotype is not entirely due to genetic background. Molecular modeling result suggests a less drastic effect of p.R95W on FGF3 function compared with known missense mutations detected in fully penetrant LAMM syndrome. Since we detected significant intrafamilial variability of the inner ear structural phenotype in the family segregating p.R95W, we also sequenced FGF10 as a likely candidate for a modifier. However, we did not find any sequence variation, pointing out that a larger sample size will be needed to map and identify a modifier. We also observed a mild to moderate bilateral conductive hearing loss in three carriers of p.R95W, suggesting either a semi-dominant effect of this mutant allele of FGF3, otitis media, or a consequence of genetic background in these three family members.

Conclusions

We noted a less prominent dental and external ear phenotype in association with the homozygous p.R95W. Therefore, we conclude that the manifestations of recessive FGF3 mutations range from fully penetrant LAMM syndrome to deafness with residual inner ear structures and, by extension, with minimal syndromic features, an observation with implications for cochlear implantation candidacy.
The association of dimethylarginine dimethylaminohydrolase 1 gene polymorphism with type 2 diabetes: a cohort study
Authors: Lu Tse-Min , Lin Shing-Jong , Lin Ming-Wei , Hsu Chiao-Po , Chung Ming-Yi
Published: February 2011

Background

Elevated plasma levels of asymmetric dimethylarginine (ADMA) has been reported to be associated with insulin resistance and micro/macrovascular diabetic complications, and may predict cardiovascular events in type 2 diabetic patients. Dimethylarginine dimethylaminohydrolase 1 (DDAH1) is the major enzyme eliminating ADMA in humans, but the effect of genetic variations in DDAH1 on type 2 diabetes and its long-term outcome are unknown.

Methods

From July 2006 to June 2009, we assessed the association between polymorphisms in DDAH1 and type 2 diabetes in 814 consecutive unrelated subjects, including 309 type 2 diabetic patients and 505 non-diabetic individuals. Six single nucleotide polymorphisms (SNPs) in DDAH1, rs233112, rs1498373, rs1498374, rs587843, rs1403956, and rs1241321 were analyzed. Plasma ADMA levels were determined by high performance liquid chromatography. Insulin sensitivity was assessed by the homeostasis model assessment of insulin resistance (HOMA-IR).

Results

Among the 6 SNPs, only rs1241321 was significantly associated with a decreased risk of type 2 diabetes (AA vs GG+AG, OR = 0.64, 95% CI 0.47-0.86, p = 0.004). The association remained unchanged after adjustment for plasma ADMA level. The fasting plasma glucose and log HOMA-IR tended to be lower in subjects carrying the homozygous AA genotype of rs1241321 compared with the GG+AG genotypes. Over a median follow-up period of 28.2 months, there were 44 all-cause mortality and 50 major adverse cardiovascular events (MACE, including cardiovascular death, non-fatal myocardial infarction and stroke). Compared with the GG and AG genotypes, the AA genotype of rs1241321 was associated with reduced risk of MACE (HR = 0.31, 95% CI: 0.11-0.90, p = 0.03) and all-cause mortality (HR = 0.18, 95% CI: 0.04-0.80, p = 0.02) only in subgroup with type 2 diabetes. One common haplotype (GGCAGC) was found to be significantly associated with a decreased risk of type 2 diabetes (OR = 0.67, 95% CI = 0.46-0.98, p = 0.04).

Conclusions

Our results provide the first evidence that SNP rs1241321 in DDAH1 is associated with type 2 diabetes and its long-term outcome.
Fraternal twins: Swiprosin-1/EFhd2 and Swiprosin-2/EFhd1, two homologous EF-hand containing calcium binding adaptor proteins with distinct functions
Authors: Dütting Sebastian , Brachs Sebastian , Mielenz Dirk
Published: February 2011

Changes in the intracellular calcium concentration govern cytoskeletal rearrangement, mitosis, apoptosis, transcriptional regulation or synaptic transmission, thereby, regulating cellular effector and organ functions. Calcium binding proteins respond to changes in the intracellular calcium concentration with structural changes, triggering enzymatic activation and association with downstream proteins. One type of calcium binding proteins are EF-hand super family proteins. Here, we describe two recently discovered homologous EF-hand containing adaptor proteins, Swiprosin-1/EF-hand domain containing 2 (EFhd2) and Swiprosin-2/EF-hand domain containing 1 (EFhd1), which are related to allograft inflammatory factor-1 (AIF-1). For reasons of simplicity and concision we propose to name Swiprosin-1/EFhd2 and Swiprosin-2/EFhd1 from now on EFhd2 and EFhd1, according to their respective gene symbols. AIF-1 and Swiprosin-1/EFhd2 are already present inBilateria, for instance inDrosophila melanogasterandCaenhorhabditis elegans. Swiprosin-2/EFhd1 arose later from gene duplication in the tetrapodal lineage. Secondary structure prediction of AIF-1 reveals disordered regions and one functional EF-hand. Swiprosin-1/EFhd2 and Swiprosin-2/EFhd1 exhibit a disordered region at the N-terminus, followed by two EF-hands and a coiled-coil domain. Whereas both proteins are similar in their predicted overall structure they differ in a non-homologous stretch of 60 amino acids just in front of the EF-hands. AIF-1 controls calcium-dependent cytoskeletal rearrangement in innate immune cells by means of its functional EF-hand. We propose that Swiprosin-1/EFhd2 as well is a cytoskeleton associated adaptor protein involved in immune and brain cell function. Pro-inflammatory conditions are likely to modulate expression and function of Swiprosin-1/EFhd2. Swiprosin-2/EFhd1, on the other hand, modulates apoptosis and differentiation of neuronal and muscle precursor cells, probably through an association with mitochondria. We suggest furthermore that Swiprosin-2/EFhd1 is part of a cellular response to oxidative stress, which could explain its pro-survival activity in neuronal, muscle and perhaps some malignant tissues.
Dosimetric accuracy of tomotherapy dose calculation in thorax lesions
Authors: Ardu Veronica , Broggi Sara , Cattaneo Giovanni Mauro , Mangili Paola , Calandrino Riccardo
Published: February 2011

Background

To analyse limits and capabilities in dose calculation of collapsed-cone-convolution (CCC) algorithm implemented in helical tomotherapy (HT) treatment planning system for thorax lesions.

Methods

The agreement between measured and calculated dose was verified both in homogeneous (Cheese Phantom) and in a custom-made inhomogeneous phantom. The inhomogeneous phantom was employed to mimic a patient's thorax region with lung density encountered in extreme cases and acrylic inserts of various dimensions and positions inside the lung cavity. For both phantoms, different lung treatment plans (single or multiple metastases and targets in the mediastinum) using HT technique were simulated and verified. Point and planar dose measurements, both with radiographic extended-dose-range (EDR2) and radiochromic external-beam-therapy (EBT2) films, were performed. Absolute point dose measurements, dose profile comparisons and quantitative analysis of gamma function distributions were analyzed.

Results

An excellent agreement between measured and calculated dose distributions was found in homogeneous media, both for point and planar dose measurements. Absolute dose deviations <3% were found for all considered measurement points, both inside the PTV and in critical structures. Very good results were also found for planar dose distribution comparisons, where at least 96% of all points satisfied the gamma acceptance criteria (3%-3 mm), both for EDR2 and for EBT2 films. Acceptable results were also reported for the inhomogeneous phantom. Similar point dose deviations were found with slightly worse agreement for the planar dose distribution comparison: 96% of all points passed the gamma analysis test with acceptable levels of 4%-4 mm and 5%-4 mm, for EDR2 and EBT2 films respectively. Lower accuracy was observed in high dose/low density regions, where CCC seems to overestimate the measured dose around 4-5%.

Conclusions

Very acceptable accuracy was found for complex lung treatment plans calculated with CCC algorithm implemented in the tomotherapy TPS even in the heterogeneous phantom with very low lung-density.
Vectorial status and insecticide resistance of Anopheles funestus from a sugar estate in southern Mozambique
Authors: Kloke R Graham , Nhamahanga Eduardo , Hunt Richard H , Coetzee Maureen
Published: February 2011

Background

The dual problems of rising insecticide resistance in the malaria vectors and increasing human malaria cases since 2001 in southern Mozambique are cause for serious concern. The selection of insecticides for use in indoor residual spraying (IRS) programmes is highly dependent on the extent to which local mosquitoes are susceptible to the approved classes of insecticides. The insecticide resistance status and role in malaria transmission of Anopheles funestus was evaluated at the Maragra Sugar Estate in southern Mozambique where an IRS vector control programme has been in operation for seven years using the carbamate insecticide bendiocarb.

Results

No Anopheles species were captured inside the sugar estate control area. Anopheles funestus group captured outside of the estate represented 90% (n = 475) of the total collections. Of the specimens identified to species by PCR (n = 167), 95% were An. funestus s.s. One An. rivulorum was identified and seven specimens did not amplify. The Anopheles gambiae complex was less abundant (n = 53) and of those identified (n = 33) 76% were An. arabiensis and 24% An. merus. Insecticide susceptibility tests showed that wild-caught and F-1 family An. funestus were resistant to deltamethrin (32.5% mortality) and lambda-cyhalothrin (14.6% mortality), less so to bendiocarb (71.5% mortality) and fully susceptible to both malathion and DDT (100%). Bendiocarb and pyrethroid resistance was nullified using 4% piperonyl butoxide (Pbo), strongly suggesting that both are mediated by P450 monooxygenase detoxification. ELISA tests of An. funestus for Plasmodium falciparum, gave a sporozoite rate of 6.02% (n = 166). One unidentified member of the An. gambiae complex tested positive for P. falciparum sporozoites.

Conclusion

Anopheles funestus was found to be the most abundant and principle vector of malaria in this area, with members of the An. gambiae complex being secondary vectors. Despite the continual use of bendiocarb within the estate for seven years and the level of An. funestus resistance to this insecticide, the IVC programme is still effective against this and other Anopheles in that no vectors were found inside the control area. However, the Mozambique National Malaria Control Programme ceased the use of DDT and bendiocarb in this area of its operations in 2009, and replaced these insecticides with a pyrethroid which will increase insecticide resistance selection pressure and impact on control programmes such as the Maragra IVC.
Inversion of time-lapse electrical resistivity imaging data for monitoring infiltration
Authors: Mitchell Vanessa , Knight Rosemary , Pidlisecky Adam
Published: February 2011

Monitoring hydrologic processes in the vadose zone is of great importance in developing management strategies for groundwater resources. Flow and transport behavior in variably saturated media control the rate at which, and path along which, fluids or contaminants reach groundwater aquifers. Electrical resistivity imaging (ERI) is sensitive to changes in the subsurface conductivity structure, which is highly dependent on the water saturation distribution in the vadose zone. Time-lapse ERI, therefore, has been widely used for environmental and hydrologic monitoring experiments.
Hammer seismic reflection imaging in an urban environment
Authors: Liberty Lee
Published: February 2011

Subsurface characterization within urban centers is critically important for city planners, municipalities, and engineers to estimate groundwater resources, track contaminants, assess earthquake or landslide hazards, and many other similar objectives. Improving geophysical imaging methods and results, while minimizing costs, provides greater opportunities for city/project planners and geophysicists alike to take advantage of the improved characterization afforded by the particular method. Seismic reflection results can provide hydrogeologic constraints for groundwater models, provide slip rate estimates for active faults, or simply map stratigraphy to provide target depth estimates. While many traditional urban seismic transects have included the use of vibroseis sources to improve reflection signals and attenuate cultural noise, low-cost and high-quality near-surface seismic reflection data can be obtained within an urban environment using impulsive sources at a variety of scales and at production rates that can significantly exceed those of swept sources.
The geological Hubble: A reappraisal for shallow water
Authors: Vardy Mark E. , Bull Jonathan M. , Dix Justin K. , Henstock Timothy J. , Plets Ruth M. K. , Gutowski Martin , Hogarth Peter
Published: February 2011

Traditional two-dimensional (2D) seismic acquisition techniques image the subsurface using a grid of orthogonal lines. Dips are recorded only in the along-track direction, limiting migration to a 2D along-track approximation of the inherently 3D wavefields. This produces profiles that are often complicated by out-of-plane reflections and with resolution (for structural interpretation) constrained by the line spacing rather than the source wavelength. The acquisition of true 3D seismic reflection data, in contrast, provides dip information for the reflected wavefields in both along- and across-track directions. This allows a full treatment of the 3D wavefields during migration, affording accurate 3D structural reconstruction, significantly improved resolution (theoretically 1/2 source wavelength), and increasing signal-to-noise ratio (SNR) through more effective noise cancellation.
Unique applications of MMR to track preferential groundwater flow paths in dams, mines, environmental sites, and leach fields
Authors: Kofoed Val O. , Jessop Mike L. , Wallace Michael J , Qian Wei
Published: February 2011

Groundwater systems have been notoriously difficult to map with high degrees of accuracy. As a result, not only have traditional geophysical methods proven inaccurate for groundwater characterization work, but they are often costly in terms of time, money, and environmental trauma. This paper describes a unique application of magnetometric resistivity or MMR (Edwards and Nabighian, 1991) for groundwater mapping and modeling, which is high-speed, accurate, minimally invasive, and cost effective. This method has now been deployed at many different sites all over the United States and in other countries like Canada, England, Peru, Sri Lanka, and Argentina. In 2007, the method was employed at 17 dams; some are large well-known structures in the United States. Through two case histories, this paper will assess the effectiveness of this methodology.
Erratum
Authors: Duffaut Kenneth , Avseth Per , Landrø Martin
Published: February 2011

The January 2011 issue featured an article, “Stress and fluid sensitivity in two North Sea oil fields—comparing rock physics models with seismic observations”, written by Kenneth Duffaut, Per Avseth, and Martin Landrø. The article contained errors in the units of density on page 99.
Polyamines Are Implicated in the Emergence of the Embryo from Obligate Diapause
Authors: Lefèvre Pavine L. C. , Palin Marie-France , Chen Gary , Turecki Gustavo , Murphy Bruce D.
Published: February 2011

Embryonic diapause is a poorly understood phenomenon of reversible arrest of embryo development prior to implantation. In many carnivores, such as the mink (Neovison vison), obligate diapause characterizes each gestation. Embryo reactivation is controlled by the uterus by mechanisms that remain elusive. Because polyamines are essential regulators of cell proliferation and growth, it was hypothesized that they trigger embryo reactivation. To test this, mated mink females were treated with α-difluoromethylornithine, an inhibitor of ornithine decarboxylase 1, the rate-limiting enzyme in polyamine biosynthesis, or saline as a control during the first 5 d of reactivation. This treatment induced polyamine deprivation with the consequence of rearrest in embryo cell proliferation. A mink trophoblast cell line in vitro subjected to α-difluoromethylornithine treatment likewise displayed an arrest in cell proliferation, morphological changes, and intracellular translocation of ornithine decarboxylase 1 protein. The arrest in embryo development deferred implantation for a period consistent with the length of treatment. Successful implantation and parturition ensued. We conclude that polyamine deprivation brought about a reversible rearrest of embryo development, which returned the mink embryo to diapause and induced a second delay in embryo implantation. The results are the first demonstration of a factor essential to reactivation of embryos in obligate diapause.
Hyperphagia and Central Mechanisms for Leptin Resistance during Pregnancy
Authors: Trujillo M. L , Spuch C. , Carro E. , Señarís R.
Published: February 2011

The purpose of this work was to study the central mechanisms involved in food intake regulation and leptin resistance during gestation in the rat. Sprague Dawley rats of 7, 13, and 18 d of pregnancy [days of gestation (G) 7, G13, and G18] were used and compared with nonpregnant animals in diestrus-1. Food intake was already increased in G7, before hyperleptinemia and central leptin resistance was established in midpregnancy. Leptin resistance was due to a reduction in leptin transport through the blood-brain barrier (BBB) and to alterations in leptin signaling within the hypothalamus based on an increase in suppressor of cytokine signaling 3 levels and a blockade of signal transducer and activator of transcription-3 phosphorylation (G13), followed by a decrease in LepRb and of Akt phosphorylation (G18). In early gestation (G7), no change in hypothalamic neuropeptide Y (NPY), agouti-related peptide (AgRP), or proopiomelanocortin (POMC) expression was shown. Nevertheless, an increase in NPY and AgRP and a decrease in POMC mRNA were observed in G13 and G18 rats, probably reflecting the leptin resistance. To investigate the effect of maternal vs. placental hormones on these mechanisms, we used a model of pseudogestation. Rats of 9 d of pseudogestation were hyperphagic, showing an increase in body and adipose tissue weight, normoleptinemia, and normal responses to iv/intracerebroventricular leptin on hypothalamic leptin signaling, food intake, and body weight. Leptin transport through the BBB, and hypothalamic NPY, AgRP and POMC expression were unchanged. Finally, the transport of leptin through the BBB was assessed using a double-chamber culture system of choroid plexus epithelial cells or brain microvascular endothelial cells. We found that sustained high levels of prolactin significantly reduced leptin translocation through the barrier, whereas progesterone and β-estradiol did not show any effect. Our data demonstrate a dual mechanism of leptin resistance during mid/late-pregnancy, which is not due to maternal hormones and which allows the maintenance of hyperphagia in the presence of hyperleptinemia driven by an increase in NPY and AgRP and a decrease in POMC mRNA. By contrast, in early pregnancy maternal hormones induce hyperphagia without the regulation of hypothalamic NPY, AgRP, or POMC and in the absence of leptin resistance.
Lack of Action of Exogenously Administered T3 on the Fetal Rat Brain Despite Expression of the Monocarboxylate Transporter 8
Authors: Grijota-Martínez Carmen , Díez Diego , Morreale de Escobar Gabriella , Bernal Juan , Morte Beatriz
Published: February 2011

Mutations of the monocarboxylate transporter 8 gene (MCT8, SLC16A2) cause the Allan-Herndon-Dudley syndrome, an X-linked syndrome of severe intellectual deficit and neurological impairment. Mct8 transports thyroid hormones (T4 and T3), and the Allan-Herndon-Dudley syndrome is likely caused by lack of T3 transport to neurons during critical periods of fetal brain development. To evaluate the role of Mct8 in thyroid hormone action in the fetal brain we administered T4 or T3 to thyroidectomized pregnant dams treated with methyl-mercapto-imidazol to produce maternal and fetal hypothyroidism. Gene expression was then measured in the fetal cerebral cortex. T4 increased Camk4, Sema3c, and Slc7a3 expression, but T3 was without effect. To investigate the cause for the lack of T3 action we analyzed the expression of organic anion transport polypeptide (Oatp14, Slco1c1), a T4 transporter, and Mct8 (Slc16a2), a T4 and T3 transporter, by confocal microscopy. Both proteins were present in the brain capillaries forming the blood-brain barrier and in the epithelial cells of the choroid plexus forming the blood-cerebrospinal fluid barrier. It is concluded that T4 from the maternal compartment influences gene expression in the fetal cerebral cortex, possibly after transport via organic anion transporter polypeptide and/or Mct8, and conversion to T3 in the astrocytes. On the other hand, T3 does not reach the target neurons despite the presence of Mct8. The data indicate that T4, through local deiodination, provides most T3 in the fetal rat brain. The role of Mct8 as a T3 transporter in the fetal rat brain is therefore uncertain.
Transgenic Overexpression of the Extra-Large Gsα Variant XLαs Enhances Gsα-Mediated Responses in the Mouse Renal Proximal Tubule in Vivo
Authors: Liu Zun , Segawa Hiroko , Aydin Cumhur , Reyes Monica , Erben Reinhold G. , Weinstein Lee S. , Chen Min , Marshansky Vladimir , Fröhlich Leopold F. , Bastepe Murat
Published: February 2011

XLαs, a variant of the stimulatory G protein α-subunit (Gsα), can mediate receptor-activated cAMP generation and, thus, mimic the actions of Gsα in transfected cells. However, it remains unknown whether XLαs can act in a similar manner in vivo. We have now generated mice with ectopic transgenic expression of rat XLαs in the renal proximal tubule (rptXLαs mice), where Gsα mediates most actions of PTH. Western blots and quantitative RT-PCR showed that, while Gsα and type-1 PTH receptor levels were unaltered, protein kinase A activity and 25-hydroxyvitamin D 1-α-hydroxylase (Cyp27b1) mRNA levels were significantly higher in renal proximal tubules of rptXLαs mice than wild-type littermates. Immunohistochemical analysis of kidney sections showed that the sodium-phosphate cotransporter type 2a was modestly reduced in brush border membranes of male rptXLαs mice compared to gender-matched controls. Serum calcium, phosphorus, and 1,25 dihydroxyvitamin D were within the normal range, but serum PTH was ∼30% lower in rptXLαs mice than in controls (152 ± 16 vs. 222 ± 41 pg/ml; P < 0.05). After crossing the rptXLαs mice to mice with ablation of maternal Gnas exon 1 (E1m−/+), male offspring carrying both the XLαs transgene and maternal Gnas exon 1 ablation (rptXLαs/E1m−/+) were significantly less hypocalcemic than gender-matched E1m−/+ littermates. Both E1m−/+ and rptXLαs/E1m−/+ offspring had higher serum PTH than wild-type littermates, but the degree of secondary hyperparathyroidism tended to be lower in rptXLαs/E1m−/+ mice. Hence, transgenic XLαs expression in the proximal tubule enhanced Gsα-mediated responses, indicating that XLαs can mimic Gsα in vivo.
Angiotensin III Stimulates Aldosterone Secretion from Adrenal Gland Partially via Angiotensin II Type 2 Receptor But Not Angiotensin II Type 1 Receptor
Authors: Yatabe Junichi , Yoneda Minoru , Yatabe Midori S. , Watanabe Tsuyoshi , Felder Robin A. , Jose Pedro A. , Sanada Hironobu
Published: February 2011

Angiotensin II (Ang II) and Ang III stimulate aldosterone secretion by adrenal glomerulosa, but the angiotensin receptor subtypes involved and the effects of Ang IV and Ang (1–7) are not clear. In vitro, different angiotensins were added to rat adrenal glomerulosa, and aldosterone concentration in the medium was measured. Ang II-induced aldosterone release was blocked (30.3 ± 7.1%) by an Ang II type 2 receptor (AT2R) antagonist, PD123319. Candesartan, an Ang II type 1 receptor (AT1R) antagonist, also blocked Ang II-induced aldosterone release (42.9 ± 4.8%). Coadministration of candesartan and PD123319 almost abolished the Ang II-induced aldosterone release. A selective AT2R agonist, CGP42112, was used to confirm the effects of AT2R. CGP42112 increased aldosterone secretion, which was almost completely inhibited by PD123319. In addition to Ang II, Ang III also induced aldosterone release, which was not blocked by candesartan. However, PD123319 blocked 22.4 ± 10.5% of the Ang III-induced aldosterone secretion. Ang IV and Ang (1–7) did not induce adrenal aldosterone secretion. In vivo, both Ang II and Ang III infusion increased plasma aldosterone concentration, but only Ang II elevated blood pressure. Ang IV and Ang (1–7) infusion did not affect blood pressure or aldosterone concentration. In conclusion, this report showed for the first time that AT2R partially mediates Ang III-induced aldosterone release, but not AT1R. Also, over 60% of Ang III-induced aldosterone release may be independent of both AT1R and AT2R. Ang III and AT2R signaling may have a role in the pathophysiology of aldosterone breakthrough.
Maternal Fructose Intake during Pregnancy and Lactation Alters Placental Growth and Leads to Sex-Specific Changes in Fetal and Neonatal Endocrine Function
Authors: Vickers M. H. , Clayton Z. E. , Yap C. , Sloboda D. M.
Published: February 2011

The effects of maternal fructose intake on offspring health remain largely unknown, despite the marked increase in consumption of sweetened beverages that has paralleled the obesity epidemic. The present study investigated the impact of maternal fructose intake on placental, fetal, and neonatal development. Female Wistar rats were time-mated and allocated to receive either water [control (CONT)] or fructose solution designed to provide 20% of caloric intake from fructose (FR). FR was administered from d 1 of pregnancy until postnatal day (P) 10. All dams had ad libitum access to standard laboratory chow and water. Dams and offspring were killed at embryonic day (E) 21 and P10. FR dams demonstrated increased total caloric intake and maternal hyperinsulinemia at E21 as well as increased maternal plasma fructose levels at E21 and P10. FR intake did not alter maternal blood glucose, β-hydroxybutyrate (BHB), or electrolyte levels at either time point. Fetal weights at E21 were unchanged, although placental weights were reduced in FR female but not FR male fetuses. Plasma leptin, fructose, and blood glucose levels were increased and BHB levels decreased in FR female but not male fetuses. Plasma insulin levels were not different between CONT and FR groups. Male and female FR neonates had higher plasma fructose levels and were hypoinsulinemic but euglycemic at P10 compared with CONT. Blood BHB levels were increased in FR male neonates but not females at P10. P10 plasma leptin levels were not different between groups. Stomach content leptin levels were increased in all FR offspring at P10, but no differences in stomach content insulin or fructose levels were observed. This study reports for the first time that maternal FR intake resulted in sex-specific changes in offspring development, whereby females appear more vulnerable to metabolic compromise during neonatal life. Independent follow-up studies are essential to investigate the long-term consequences of maternal FR consumption on offspring health.
Overexpression of Pregnancy-Associated Plasma Protein-A in Ovarian Cancer Cells Promotes Tumor Growth in Vivo
Authors: Boldt Henning B. , Conover Cheryl A.
Published: February 2011

Pregnancy-associated plasma protein-A (PAPP-A) is an important regulatory component of the IGF system. Through proteolysis of inhibitory IGF binding proteins (IGFBPs), PAPP-A acts as a positive modulator of local IGF signaling in a variety of biological systems. A role of IGF in the progression of several common forms of human cancer is now emerging, and therapeutic intervention of IGF receptor signaling is currently being explored. However, little is known about the activities of other components of the IGF system in relation to cancer. We hypothesized that PAPP-A acts to enhance tumor growth in vivo. To test this hypothesis, we overexpressed wild-type PAPP-A or a mutant PAPP-A with markedly reduced IGFBP protease activity in SKOV3 cells, a human ovarian carcinoma cell line with low tumorigenic potential. In vitro, SKOV3 clones with elevated PAPP-A expression (PAPP-A-1, PAPP-A-28) showed accelerated anchorage-independent growth in soft agar assays compared to clones overexpressing mutant PAPP-A (E483Q-1, E483Q-5) and vector controls. PAPP-A-28, with the highest PAPP-A expression and IGFBP proteolytic activity, also had markedly increased cell invasion through Matrigel. In vivo, we found significantly accelerated tumor growth rates of PAPP-A-overexpressing SKOV3 clones compared with mutant PAPP-A and controls. Investigation of angiogenesis indicated that overexpression of PAPP-A favored development of mature tumor vasculature and that tumor precursors of PAPP-A-28 in particular had a significantly higher degree of vascularization months before obvious tumor development. In conclusion, our data show that PAPP-A proteolytic activity enhances the tumorigenic potential of ovarian cancer cells and establish a novel tumor growth-promoting role of PAPP-A.
A Promising Culture Model for Analyzing the Interaction between Adipose Tissue and Cardiomyocytes
Authors: Anan Mayumi , Uchihashi Kazuyoshi , Aoki Shigehisa , Matsunobu Aki , Ootani Akifumi , Node Koichi , Toda Shuji
Published: February 2011

The heart has epicardial adipose tissue that produces adipokines and mesenchymal stem cells. Systemic adipose tissue is involved in the pathophysiology of obesity-related heart diseases. However, the method for analyzing the direct interaction between adipose tissue and cardiomyocytes has not been established. Here we show the novel model, using collagen gel coculture of adipose tissue fragments (ATFs) and HL-1 cardiomyocytes, and electron microscopy, immunohistochemistry, real-time RT-PCR, and ELISA. HL-1 cells formed a stratified layer on ATF-nonembedded gel, whereas they formed almost a monolayer on ATF-embedded gel. ATFs promoted the apoptosis, lipid accumulation, and fatty acid transport protein (FATP) expression of FATP4 and CD36 in HL-1 cells, whereas ATFs inhibited the growth and mRNA expression of myosin, troponin T, and atrial natriuretic peptide. Treatment of leptin (100 ng/ml) and adiponectin (10 μg/ml) neither replicated nor abolished the ATF-induced morphology of HL-1 cells, whereas that of FATP4 and CD36 antibodies (25 μg/ml) never abolished it. HL-1 cells prohibited the development of CD44+/CD105+ mesenchymal stem cell-like cells and lipid-laden preadipocytes from ATFs. HL-1 cells increased the production of adiponectin in ATFs, whereas they decreased that of leptin. The data indicate that our model actively creates adipose tissue-HL-1 cardiomyocyte interaction, suggesting first that ATFs may be related to the lipotoxiciy of HL-1 cells via unknown factors plus FATP4 and CD36 and second that HL-1 cells may help to retain the static state of ATFs, affecting adipokine secretion. Our model will serve to study adipose tissue-cardiomyocyte interaction and mechanisms of obesity-related lipotoxicity and heart diseases.
Genetic Identification of GnRH Receptor Neurons: A New Model for Studying Neural Circuits Underlying Reproductive Physiology in the Mouse Brain
Authors: Wen Shuping , Götze Iris N. , Mai Oliver , Schauer Christian , Leinders-Zufall Trese , Boehm Ulrich
Published: February 2011

GnRH signaling regulates reproductive physiology in vertebrates via the hypothalamic-pituitary-gonadal axis. In addition, GnRH signaling has been postulated to act on the brain. However, elucidating its functional role in the central nervous system has been hampered because of the difficulty in identifying direct GnRH signaling targets in live brain tissue. Here we used a binary genetic strategy to visualize GnRH receptor (GnRHR) neurons in the mouse brain and started to characterize these cells. First, we expressed different fluorescent proteins in GnRHR neurons and mapped their precise distribution throughout the brain. Remarkably, neuronal GnRHR expression was only initiated after postnatal day 16, suggesting peri- and postpubertal functions of GnRH signaling in this organ. GnRHR neurons were found in different brain areas. Many GnRHR neurons were identified in areas influencing sexual behaviors. Furthermore, GnRHR neurons were detected in brain areas that process olfactory and pheromonal cues, revealing one efferent pathway by which the neuroendocrine hypothalamus may influence the sensitivity towards chemosensory cues. Using confocal Ca2+ imaging in brain slices, we show that GnRHR neurons respond reproducibly to extracellular application of GnRH or its analog [D-TRP6]-LH-RH, indicating that these neurons express functional GnRHR. Interestingly, the duration and shape of the Ca2+ responses were similar within and different between brain areas, suggesting that GnRH signaling may differentially influence brain functions to affect reproductive success. Our new mouse model sets the stage to analyze the next level of GnRH signaling in reproductive physiology and behavior.
Roger Ballen: Boarding House
Authors: Schoeman Gerhard
Published: February 2011

This essay explores the photographer Roger Ballen’s series Boarding House in terms of the creature Odradek in Franz Kafka’s short story “Troubles of a Householder” and in terms of melancholia. Rather than mark identity and sense, the traces, traits, contours, orli, and splendores in Ballen’s photographs remain semiotically unclear, as do the arranged part-objects, people, and animals in the photographs. The French psychoanalyst Julia Kristeva’s (and French Romantic poet Gérard de Nerval’s) description of the Thing of melancholia as “a light without representation” provides a poetic and theoretical basis for thinking through these tangled images.
The Artist’s Artist: Cullen Washington in Conversation with Maria Magdalena Campos-Pons
Authors: Campos-Pons Maria Magdalena
Published: February 2011

Cullen Washington’s work exudes energy, rawness, and a visceral urban vibe, manifesting a fighting engagement with painting practice, painting history, and painting’s entrapments and luring out into the open the hidden implications of masculinity and race versus the purity of painting semantics. In this interview Washington reflects on the discipline of painting, the challenges he faces as he refines his skills, and his aims as he positions himself to claim a place in the present discourse. The interview covers such topics as his heroes and what they represent, what is important for painting today, science fiction and outer space as a frontier for blackness, Ralph Ellison’s influence on him, and Washington’s artistic and cultural inspirations, as well as his experiences as a graduate student.
Simon Gush: Refracting Surfaces
Authors: Bosland Joost
Published: February 2011

Despite his stated lack of interest in beauty, the lines and surfaces of Simon Gush’s works reveal a deep concern with aesthetics and its conceptual potential. How light reflects and refracts in Sidestep, Gush’s latest solo exhibition, mirrors the way that his work refracts the culture it inhabits to reveal its historical and present tensions, especially those arising from labor relationships.
Just Beyond Reality’s Edge: Kira Lynn Harris
Authors: Caruth Nicole J.
Published: February 2011

In April 2009 Kira Lynn Harris debuted a new body of work in a solo presentation at CUE Art Foundation in New York. This article examines two site-specific installations in that exhibition: 2001, Mirror, which references Stanley Kubrick’s film 2001: A Space Odyssey, and Prism, Mirror, Lens, inspired by Samuel R. Delany’s landmark science fiction novel Dhalgren. While Harris’s large-scale Mylar-and-light installations often refer to the Light and Space artists of her native California, to Robert Smithson, to Land Art, and to minimalism and various other areas of art history, her work is studied here, for the first time, through the lens of Afrofuturism.
Zebrafish deficient for Muscleblind-like 2 exhibit features of myotonic dystrophy
Authors: Machuca-Tzili Laura E. , Buxton Sarah , Thorpe Aaran , Timson Cathy M. , Wigmore Peter , Luther Pradeep K. , Brook J. David
Published: February 2011

Myotonic dystrophy (DM; also known as dystrophia myotonica) is an autosomal dominant disorder that affects the heart, eyes, brain and endocrine system, but the predominant symptoms are neuromuscular, with progressive muscle weakness and wasting. DM presents in two forms, DM1 and DM2, both of which are caused by nucleotide repeat expansions: CTG in the DMPK gene for DM1 and CCTG in ZNF9 (CNBP) for DM2. Previous studies have shown that the mutant mRNAs containing the transcribed CUG or CCUG repeats are retained within the nuclei of cells from individuals with DM, where they bind and sequester the muscleblind-like proteins MBNL1, MBNL2 and MBNL3. It has been proposed that the sequestration of these proteins plays a key role in determining the classic features of DM. However, the functions of each of the three MBNL genes are not completely understood. We have generated a zebrafish knockdown model in which we demonstrate that a lack of mbnl2 function causes morphological abnormalities at the eye, heart, brain and muscle levels, supporting an essential role for mbnl2 during embryonic development. Major features of DM are replicated in our model, including muscle defects and splicing abnormalities. We found that the absence of mbnl2 causes disruption to the organization of myofibrils in skeletal and heart muscle of zebrafish embryos, and a reduction in the amount of both slow and fast muscle fibres. Notably, our findings included altered splicing patterns of two transcripts whose expression is also altered in DM patients: clcn1 and tnnt2. The studies described herein provide broader insight into the functions of MBNL2. They also lend support to the hypothesis that the sequestration of this protein is an important determinant in DM pathophysiology, and imply a direct role of MBNL2 in splicing regulation of specific transcripts, which, when altered, contributes to the DM phenotype.