A functional SMAD2/3 binding site in the PEX11β promoter identifies a role for TGFβ in peroxisome proliferation in humans

This is the final version. Available on open access from Frontiers Media via the DOI in this recordData availability: The research data supporting this publication are provided within this paper and as supplementary information.In mammals, peroxisomes perform crucial functions in cellular metabolism, signalling and viral defense which are essential to the viability of the organism. Molecular cues triggered by changes in the cellular environment induce a dynamic response in peroxisomes, which manifests itself as a change in peroxisome number, altered enzyme levels and adaptations to the peroxisomal morphology. How the regulation of this process is integrated into the cell’s response to different stimuli, including the signalling pathways and factors involved, remains unclear. Here, a cell-based peroxisome proliferation assay has been applied to investigate the ability of different stimuli to induce peroxisome proliferation. We determined that serum stimulation, long-chain fatty acid supplementation and TGFβ application all increase peroxisome elongation, a prerequisite for proliferation. Time-resolved mRNA expression during the peroxisome proliferation cycle revealed a number of peroxins whose expression correlated with peroxisome elongation, including the β isoform of PEX11, but not the α or γ isoforms. An initial map of putative regulatory motif sites in the respective promoters showed a difference between binding sites in PEX11α and PEX11β, suggesting that these genes may be regulated by distinct pathways. A functional SMAD2/3 binding site in PEX11β points to the involvement of the TGFβ signalling pathway in expression of this gene and thus peroxisome proliferation/dynamics in humans.Biotechnology & Biological Sciences Research Council (BBSRC)Swiss National Science Foundation (SNSF)European Union FP7Medical Research Council (MRC

Magnetic effects at the interface between nonmagnetic oxides

The electronic reconstruction at the interface between two insulating oxides can give rise to a highly-conductive interface. In analogy to this remarkable interface-induced conductivity we show how, additionally, magnetism can be induced at the interface between the otherwise nonmagnetic insulating perovskites SrTiO3 and LaAlO3. A large negative magnetoresistance of the interface is found, together with a logarithmic temperature dependence of the sheet resistance. At low temperatures, the sheet resistance reveals magnetic hysteresis. Magnetic ordering is a key issue in solid-state science and its underlying mechanisms are still the subject of intense research. In particular, the interplay between localized magnetic moments and the spin of itinerant conduction electrons in a solid gives rise to intriguing many-body effects such as Ruderman-Kittel-Kasuya-Yosida (RKKY) interactions, the Kondo effect, and carrier-induced ferromagnetism in diluted magnetic semiconductors. The conducting oxide interface now provides a versatile system to induce and manipulate magnetic moments in otherwise nonmagnetic materials.Comment: Nature Materials, July issu

Genome-wide association study identifies the GLDC/IL33 locus associated with survival of osteosarcoma patients

Survival rates for osteosarcoma, the most common primary bone cancer, have changed little over the past three decades and are particularly low for patients with metastatic disease. We conducted a multi‐institutional genome‐wide association study (GWAS) to identify germline genetic variants associated with overall survival in 632 patients with osteosarcoma, including 523 patients of European ancestry and 109 from Brazil. We conducted a time‐to‐event analysis and estimated hazard ratios (HR) and 95% confidence intervals (CI) using Cox proportional hazards models, with and without adjustment for metastatic disease. The results were combined across the European and Brazilian case sets using a random‐effects meta‐analysis. The strongest association after meta‐analysis was for rs3765555 at 9p24.1, which was inversely associated with overall survival (HR = 1.76; 95% CI 1.41–2.18, p = 4.84 × 10−7). After imputation across this region, the combined analysis identified two SNPs that reached genome‐wide significance. The strongest single association was with rs55933544 (HR = 1.9; 95% CI 1.5–2.4; p = 1.3 × 10−8), which localizes to the GLDC gene, adjacent to the IL33 gene and was consistent across both the European and Brazilian case sets. Using publicly available data, the risk allele was associated with lower expression of IL33 and low expression of IL33 was associated with poor survival in an independent set of patients with osteosarcoma. In conclusion, we have identified the GLDC/IL33 locus on chromosome 9p24.1 as associated with overall survival in patients with osteosarcoma. Further studies are needed to confirm this association and shed light on the biological underpinnings of this susceptibility locus

Sugar-sweetened carbonated beverage consumption correlates with BMI, waist circumference, and poor dietary choices in school children

<p>Abstract</p> <p>Background</p> <p>The prevalence of obesity and overweight is increasing globally. Frequently coexisting with under-nutrition in developing countries, obesity is a major contributor to chronic disease, and will become a serious healthcare burden especially in countries with a larger percentage of youthful population. 35% of the population of Saudi Arabia are under the age of 16, and adult dietary preferences are often established during early childhood years. Our objective was to examine the dietary habits in relation to body-mass-index (BMI) and waist circumference (W_C), together with exercise and sleep patterns in a cohort of male and female Saudi school children, in order to ascertain whether dietary patterns are associated with obesity phenotypes in this population.</p> <p>Methods</p> <p>5033 boys and 4400 girls aged 10 to 19 years old participated in a designed Food Frequency Questionnaire. BMI and W_C measurements were obtained and correlated with dietary intake.</p> <p>Results</p> <p>The overall prevalence of overweight and obesity was 12.2% and 27.0% respectively, with boys having higher obesity rates than girls (P ≤ 0.001). W_C and BMI was positively correlated with sugar-sweetened carbonated beverage (SSCB) intake in boys only. The association between male BMI and SSCB consumption was significant in a multivariate regression model (P < 0.0001). SSCB intake was positively associated with poor dietary choices in both males and females. Fast food meal intake, savory snacks, iced desserts and total sugar consumption correlated with SSCB intake in both boys (r = 0.39, 0.13, 0.10 and 0.52 respectively, P < 0.001) and girls (r = 0.45, 0.23, 0.16 and 0.55 respectively, P < 0.001). Older children reported eating significantly less fruit and vegetables than younger children; and less eggs, fish and cereals. Conversely, consumption of SSCB and sugar-sweetened hot beverages were higher in older versus younger children (P < 0.001). BMI and W_C were negatively correlated with hours of night-time sleep and exercise in boys, but only with night time sleep in girls, who also showed the lowest frequency of exercise.</p> <p>Conclusions</p> <p>A higher intake of SSCB is associated with poor dietary choices. Male SSCB intake correlates with a higher W_C and BMI. Limiting exposure to SSCB could therefore have a large public health impact.</p

Claudin-1 Is a p63 Target Gene with a Crucial Role in Epithelial Development

The epidermis of the skin is a self-renewing, stratified epithelium that functions as the interface between the human body and the outer environment, and acts as a barrier to water loss. Components of intercellular junctions, such as Claudins, are critical to maintain tissue integrity and water retention. p63 is a transcription factor essential for proliferation of stem cells and for stratification in epithelia, mutated in human hereditary syndromes characterized by ectodermal dysplasia. Both p63 and Claudin-1 null mice die within few hours from birth due to dehydration from severe skin abnormalities. These observations suggested the possibility that these two genes might be linked in one regulatory pathway with p63 possibly regulating Claudin-1 expression. Here we show that silencing of ΔNp63 in primary mouse keratinocytes results in a marked down-regulation of Claudin-1 expression (−80%). ΔNp63α binds in vivo to the Claudin-1 promoter and activates both the endogenous Claudin-1 gene and a reporter vector containing a –1.4 Kb promoter fragment of the Claudin-1 gene. Accordingly, Claudin-1 expression was absent in the skin of E15.5 p63 null mice and natural p63 mutant proteins, specifically those found in Ankyloblepharon–Ectodermal dysplasia–Clefting (AEC) patients, were indeed altered in their capacity to regulate Claudin-1 transcription. This correlates with deficient Claudin-1 expression in the epidermis of an AEC patient carrying the I537T p63 mutation. Notably, AEC patients display skin fragility similar to what observed in the epidermis of Claudin-1 and p63 null mice. These findings reinforce the hypothesis that these two genes might be linked in a common regulatory pathway and that Claudin-1 may is an important p63 target gene involved in the pathogenesis of ectodermal dysplasias

Stem Cell Factor SALL4 Represses the Transcriptions of PTEN and SALL1 through an Epigenetic Repressor Complex

Background The embryonic stem cell (ESC) factor, SALL4, plays an essential role in both development and leukemogenesis. It is a unique gene that is involved in self-renewal in ESC and leukemic stem cell (LSC).Methodology/Principal Findings To understand the mechanism(s) of SALL4 function(s), we sought to identify SALL4-associated proteins by tandem mass spectrometry. Components of a transcription repressor Mi-2/Nucleosome Remodeling and Deacetylase (NuRD) complex were found in the SALL4-immunocomplexes with histone deacetylase (HDAC) activity in ESCs with endogenous SALL4 expression and 293T cells overexpressing SALL4. The SALL4-mediated transcriptional regulation was tested on two potential target genes: PTEN and SALL1. Both genes were confirmed as SALL4 downstream targets by chromatin-immunoprecipitation, and their expression levels, when tested by quantitative reverse transcription polymerase chain reaction (qRT-PCR), were decreased in 293T cells overexpressing SALL4. Moreover, SALL4 binding sites at the promoter regions of PTEN and SALL1 were co-occupied by NuRD components, suggesting that SALL4 represses the transcriptions of PTEN and SALL1 through its interactions with the Mi-2/NuRD complex. The in vivo repressive effect(s) of SALL4 were evaluated in SALL4 transgenic mice, where decreased expressions of PTEN and SALL1 were associated with myeloid leukemia and cystic kidneys, respectively.Conclusions/Significance In summary, we are the first to demonstrate that stem cell protein SALL4 represses its target genes, PTEN and SALL1, through the epigenetic repressor Mi-2/NuRD complex. Our novel finding provides insight into the mechanism(s) of SALL4 functions in kidney development and leukemogenesis

Treatment and long-term outcome in primary nephrogenic diabetes insipidus

Background: Primary nephrogenic diabetes insipidus (NDI) is a rare disorder and little is known about treatment practices and long-term outcome. Methods: Paediatric and adult nephrologists contacted through European professional organizations entered data in an online form. Results: Data were collected on 315 patients (22 countries, male 84%, adults 35%). Mutation testing had been performed in 270 (86%); pathogenic variants were identified in 258 (96%). The median (range) age at diagnosis was 0.6 (0.0–60) years and at last follow-up 14.0 (0.1–70) years. In adults, height was normal with a mean (standard deviation) score of −0.39 (±1.0), yet there was increased prevalence of obesity (body mass index >30 kg/m2; 41% versus 16% European average; P < 0.001). There was also increased prevalence of chronic kidney disease (CKD) Stage ≥2 in children (32%) and adults (48%). Evidence of flow uropathy was present in 38%. A higher proportion of children than adults (85% versus 54%; P < 0.001) received medications to reduce urine output. Patients ≥25 years were less likely to have a university degree than the European average (21% versus 35%; P = 0.003) but full-time employment was similar. Mental health problems, predominantly attention-deficit hyperactivity disorder (16%), were reported in 36% of patients. Conclusion: This large NDI cohort shows an overall favourable outcome with normal adult height and only mild to moderate CKD in most. Yet, while full-time employment was similar to the European average, educational achievement was lower, and more than half had urological and/or mental health problems

Attention bias to emotional faces varies by IQ and anxiety in Williams syndrome

Individuals with Williams syndrome (WS) often experience significant anxiety. A promising approach to anxiety intervention has emerged from cognitive studies of attention bias to threat. To investigate the utility of this intervention in WS, this study examined attention bias to happy and angry faces in individuals with WS (N=46). Results showed a significant difference in attention bias patterns as a function of IQ and anxiety. Individuals with higher IQ or higher anxiety showed a significant bias toward angry, but not happy faces, whereas individuals with lower IQ or lower anxiety showed the opposite pattern. These results suggest that attention bias interventions to modify a threat bias may be most effectively targeted to anxious individuals with WS with relatively high IQ

Increased cardiovascular risk in rats with primary renal dysfunction; mediating role for vascular endothelial function

Primary chronic kidney disease is associated with high cardiovascular risk. However, the exact mechanisms behind this cardiorenal interaction remain unclear. We investigated the interaction between heart and kidneys in novel animal model for cardiorenal interaction. Normal Wistar rats and Munich Wistar Fromter rats, spontaneously developing renal dysfunction, were subjected to experimental myocardial infarction to induce cardiac dysfunction (CD) and combined cardiorenal dysfunction (CRD), respectively (N = 5–10). Twelve weeks later, cardiac- and renal parameters were evaluated. Cardiac, but not renal dysfunction was exaggerated in CRD. Accelerated cardiac dysfunction in CRD was indicated by decreased cardiac output (CD 109 ± 10 vs. CRD 79 ± 8 ml/min), diastolic dysfunction (E/e′) (CD 26 ± 2 vs. CRD 50 ± 5) and left ventricular overload (LVEDP CD 10.8 ± 2.8 vs. CRD 21.6 ± 1.7 mmHg). Congestion in CRD was confirmed by increased lung and atrial weights, as well as exaggerated right ventricular hypertrophy. Absence of accelerated renal dysfunction, measured by increased proteinuria, was supported by absence of additional focal glomerulosclerosis or further decline of renal blood flow in CRD. Only advanced peripheral endothelial dysfunction, as found in CRD, appeared to correlate with both renal and cardiac dysfunction parameters. Thus, proteinuric rats with myocardial infarction showed accelerated cardiac but not renal dysfunction. As parameters mimic the cardiorenal syndrome, these rats may provide a clinically relevant model to study increased cardiovascular risk due to renal dysfunction. Peripheral endothelial dysfunction was the only parameter that correlated with both renal and cardiac dysfunction, which may indicate a mediating role in cardiorenal interaction

Enhanced Immunogenicity, Mortality Protection, and Reduced Viral Brain Invasion by Alum Adjuvant with an H5N1 Split-Virion Vaccine in the Ferret

Pre-pandemic development of an inactivated, split-virion avian influenza vaccine is challenged by the lack of pre-existing immunity and the reduced immunogenicity of some H5 hemagglutinins compared to that of seasonal influenza vaccines. Identification of an acceptable effective adjuvant is needed to improve immunogenicity of a split-virion avian influenza vaccine.No serum antibodies were detected after vaccination with unadjuvanted vaccine, whereas alum-adjuvanted vaccination induced a robust antibody response. Survival after unadjuvanted dose regimens of 30 µg, 7.5 µg and 1.9 µg (21-day intervals) was 64%, 43%, and 43%, respectively, yet survivors experienced weight loss, fever and thrombocytopenia. Survival after unadjuvanted dose regimen of 22.5 µg (28-day intervals) was 0%, suggesting important differences in intervals in this model. In contrast to unadjuvanted survivors, either dose of alum-adjuvanted vaccine resulted in 93% survival with minimal morbidity and without fever or weight loss. The rarity of brain inflammation in alum-adjuvanted survivors, compared to high levels in unadjuvanted vaccine survivors, suggested that improved protection associated with the alum adjuvant was due to markedly reduced early viral invasion of the ferret brain.Alum adjuvant significantly improves efficacy of an H5N1 split-virion vaccine in the ferret model as measured by immunogenicity, mortality, morbidity, and brain invasion