The Association between HMGA1 rs146052672 Variant and Type 2 Diabetes: A Transethnic Meta-Analysis

The high-mobility group A1 (HMGA1) gene has been previously identified as a potential novel candidate gene for susceptibility to insulin resistance and type 2 diabetes (T2D) mellitus. For this reason, several studies have been conducted in recent years examining the association of the HMGA1 gene variant rs146052672 (also designated IVS5-13insC) with T2D. Because of non-univocal data and non-overlapping results among laboratories, we conducted the current meta-analysis with the aim to yield a more precise and reliable conclusion for this association. Using predetermined inclusion criteria, MEDLINE, PubMed, Web of Science, Scopus, Google Scholar and Embase were searched for all relevant available literature published until November 2014. Two of the authors independently evaluated the quality of the included studies and extracted the data. Values from the single studies were combined to determine the meta-analysis pooled estimates. Heterogeneity and publication bias were also examined. Among the articles reviewed, five studies (for a total of 13,789 cases and 13,460 controls) met the predetermined criteria for inclusion in this meta-analysis. The combined adjusted odds ratio estimates revealed that the rs146052672 variant genotype had an overall statistically significant effect on increasing the risk of development of T2D. As most of the study subjects were Caucasian, further studies are needed to establish whether the association of this variant with an increased risk of T2D is generalizable to other populations. Also, in the light of this result, it would appear to be highly desirable that further in-depth investigations should be undertaken to elucidate the biological significance of the HMGA1 rs146052672 variant.     

The plant communities of theAsplenietea trichomanis in the SW Iberian Peninsula

The rupicolous vegetation of theAsplenietea trichomanis in the south-western Iberian Peninsula is analysed using the methods of the Zürich-Montpellier School. Phytosociological tables, and biogeographical, ecological and floristic data are given for a number of syntaxa. A phytosociological synopsis of the studied vegetation was made for the entire region. Four new syntaxa are described: theCoincyo logirostri-Dianthetum lusitani, Jasiono marianae-Dianthetum lusitani jasionetosum tomentosae, Digitali thapsi-Dianthetum lusitani conopodietosum ramosi andSedo hirsuti-Polypodietum cambrici polypodietosum interjecti.     

Generation of lycopene-overproducing strains of the fungus <Emphasis Type="Italic">Mucor circinelloides</Emphasis> reveals important aspects of lycopene formation and accumulation

Objectives

To generate lycopene-overproducing strains of the fungus Mucor circinelloides with interest for industrial production and to gain insight into the catalytic mechanism of lycopene cyclase and regulatory process during lycopene overaccumulation.

Results

Three lycopene-overproducing mutants were generated by classic mutagenesis techniques from a β-carotene-overproducing strain. They carried distinct mutations in the carRP gene encoding lycopene cyclase that produced loss of enzymatic activity to different extents. In one mutant (MU616), the lycopene cyclase was completely destroyed, and a 43.8% (1.1 mg/g dry mass) increase in lycopene production was observed in comparison to that by the previously existing lycopene overproducer. In addition, feedback regulation of the end product was suggested in lycopene-overproducing strains.

Conclusions

A lycopene-overaccumulating strain of the fungus M. circinelloides was generated that could be an alternative for the industrial production of lycopene. Vital catalytic residues for lycopene cyclase activity and the potential mechanism of lycopene formation and accumulation were identified.

     

p38 alpha MAPK inhibits JNK activation and collaborates with IkappaB kinase 2 to prevent endotoxin-induced liver failure

Activation of c-Jun amino-terminal kinase (JNK) facilitates tumour necrosis factor (TNF)-induced cell death. The p38 mitogen-activated protein kinase pathway is induced by TNF stimulation, but it has not been implicated in TNF-induced cell death. Here, we show that hepatocyte-specific ablation of p38alpha in mice results in excessive activation of JNK in the liver after in vivo challenge with bacterial lipopolysaccharide (LPS). Despite increased JNK activity, p38alpha-deficient hepatocytes were not sensitive to LPS/TNF toxicity showing that JNK activation was not sufficient to mediate TNF-induced liver damage. By contrast, LPS injection caused liver failure in mice lacking both p38alpha and IkappaB kinase 2 (IKK2) in hepatocytes. Therefore, when combined with partial nuclear factor-kappaB inhibition, p38alpha deficiency sensitizes the liver to cytokine-induced damage. Collectively, these results reveal a new function of p38alpha in collaborating with IKK2 to protect the liver from LPS/TNF-induced failure by controlling JNK activation.     

Preparation of (R) and (S) alpha methyldopa from a chiral hydantoin containing the alpha phenylethyl group

Chiral hydantoin (S)-1 was prepared in good yield from phenyl isocyanate and N-[(S)-alpha-phenylethyl]glycinate, (S)-3. Enolate (S)-1-Li was methylated in high yield and good diastereoselectivity. In contrast, a second alkylation reaction of methylated enolate (S)-4-Li proceeded with essentially no diastereoselectivity. Nevertheless, dialkylated hydantoins, (S,S)-7 and (S,R)-7, could be readily separated by flash chromatography and subsequent hydrolysis of either derivative afforded the desired (S)-L-alpha-methyldopa or (R)-D-alpha-methyldopa in good yield.     

Drosophila DJ-1 mutants are sensitive to oxidative stress and show reduced lifespan and motor deficits

Parkinson's disease (PD) is a progressive movement disorder caused by the selective and massive loss of dopaminergic neurons (DA) in the substantia nigra pars compacta (SNc). DJ-1 loss-of-function mutations are involved in inherited early-onset PD forms and result in dysfunction of the oxidative stress response. In mice models, DJ-1 loss provokes sensitivity to oxidative insults but does not produce neurodegeneration. Similar results have been found when analyzing Drosophila mutants for the DJ-1 orthologous genes, DJ-1 and DJ-1β. Here, we report the analysis of two new mutations for the Drosophila DJ-1 genes. Both ubiquitous induction of DJ-1 knockdown by RNAi and loss of function of DJ-1β caused by an insertional mutation result in increased sensitivity to paraquat insults, reduced lifespan and motor impairments. However these mutations do not lead to DA neuron loss. Besides, we find that targeted inhibition of DJ-1 function in DA neuron results in certain DA neurodegeneration. Our results, together with findings in other Drosophila DJ-1 mutants, indicate that both Drosophila DJ-1 genes are implicated in the protection against the chemical induced oxidative stress response, but also in fly survival. The differences observed in DA neurodegeneration suggest that the motor impairments exhibited by the mutants could be caused by different pathways.     

Fast‐forward genetics by radiation hybrids to saturate the locus regulating nuclear–cytoplasmic compatibility in Triticum

The nuclear‐encoded species cytoplasm specific (scs) genes control nuclear–cytoplasmic compatibility in wheat (genus Triticum). Alloplasmic cells, which have nucleus and cytoplasm derived from different species, produce vigorous and vital organisms only when the correct version of scs is present in their nucleus. In this study, bulks of in vivo radiation hybrids segregating for the scs phenotype have been genotyped by sequencing with over 1.9 million markers. The high marker saturation obtained for a critical region of chromosome 1D allowed identification of 3318 reads that mapped in close proximity of the scs. A novel in silico approach was deployed to extend these short reads to sequences of up to 70 Kb in length and identify candidate open reading frames (ORFs). Markers were developed to anchor the short contigs containing ORFs to a radiation hybrid map of 650 individuals with resolution of 288 Kb. The region containing the scs locus was narrowed to a single Bacterial Artificial Chromosome (BAC) contig of Aegilops tauschii. Its sequencing and assembly by nano‐mapping allowed rapid identification of a rhomboid gene as the only ORF existing within the refined scs locus. Resequencing of this gene from multiple germplasm sources identified a single nucleotide mutation, which gives rise to a functional amino acid change. Gene expression characterization revealed that an active copy of this rhomboid exists on all homoeologous chromosomes of wheat, and depending on the specific cytoplasm each copy is preferentially expressed. Therefore, a new methodology was applied to unique genetic stocks to rapidly identify a strong candidate gene for the control of nuclear–cytoplasmic compatibility in wheat.     

Imaging pancreatic beta-cells in the intact pancreas

We have developed a method to visualize fluorescent protein-labeled beta-cells in the intact pancreas through combined reflection and confocal imaging. This method provides a 3-D view of the beta-cells in situ. Imaging of the pancreas from mouse insulin I promoter (MIP)-green (GFP) and red fluorescent protein (RFP) transgenic mice shows that islets, beta-cell clusters, and single beta-cells are not evenly distributed but are aligned along the large blood vessels. We also observe the solitary beta-cells in both fetal and adult mice and along the pancreatic and common bile ducts. We have imaged the developing endocrine cells in the embryos using neurogenin-3 (Ngn3)-GFP mice crossed with MIP-RFP mice. The dual-color-coded pancreas from embryos (E15.5) shows a large number of green Ngn3-expressing proendocrine cells with a smaller number of red beta-cells. The imaging technique that we have developed, coupled with the transgenic mice in which beta-cells and beta-cell progenitors are labeled with different fluorescent proteins, will be useful for studying pancreatic development and function in normal and disease states.     

On Sanctuary

The author reflects on a sanctuary site in Davao City, Philippines, where 750 Lumad—indigenous peoples from several mountain tribes of Mindanao—sought sanctuary from the violent, lawless forms of militarization and paramilitarization that overwhelmed their communities in 2015. Dizon weaves interviews done with Lumad at the sanctuary site with the Lumad’s long history of struggle against corporate globalization; and also with a summary of contemporary media artists from the Philippines and its diaspora who are working to document the vibrant resistance of Lumad to their violent displacement and dispossession. She reflects on her practice as a USA-based media artist from that diaspora, and on why she forges solidarities with those who are most vulnerable to the processes of globalization today.