Characterization of proanthocyanidin metabolism in pea (Pisum sativum) seeds

BACKGROUND: Proanthocyanidins (PAs) accumulate in the seeds, fruits and leaves of various plant species including the seed coats of pea (Pisum sativum), an important food crop. PAs have been implicated in human health, but molecular and biochemical characterization of pea PA biosynthesis has not been established to date, and detailed pea PA chemical composition has not been extensively studied. RESULTS: PAs were localized to the ground parenchyma and epidermal cells of pea seed coats. Chemical analyses of PAs from seeds of three pea cultivars demonstrated cultivar variation in PA composition. ‘Courier’ and ‘Solido’ PAs were primarily prodelphinidin-types, whereas the PAs from ‘LAN3017’ were mainly the procyanidin-type. The mean degree of polymerization of ‘LAN3017’ PAs was also higher than those from ‘Courier’ and ‘Solido’. Next-generation sequencing of ‘Courier’ seed coat cDNA produced a seed coat-specific transcriptome. Three cDNAs encoding anthocyanidin reductase (PsANR), leucoanthocyanidin reductase (PsLAR), and dihydroflavonol reductase (PsDFR) were isolated. PsANR and PsLAR transcripts were most abundant earlier in seed coat development. This was followed by maximum PA accumulation in the seed coat. Recombinant PsANR enzyme efficiently synthesized all three cis-flavan-3-ols (gallocatechin, catechin, and afzalechin) with satisfactory kinetic properties. The synthesis rate of trans-flavan-3-ol by co-incubation of PsLAR and PsDFR was comparable to cis-flavan-3-ol synthesis rate by PsANR. Despite the competent PsLAR activity in vitro, expression of PsLAR driven by the Arabidopsis ANR promoter in wild-type and anr knock-out Arabidopsis backgrounds did not result in PA synthesis. CONCLUSION: Significant variation in seed coat PA composition was found within the pea cultivars, making pea an ideal system to explore PA biosynthesis. PsANR and PsLAR transcript profiles, PA localization, and PA accumulation patterns suggest that a pool of PA subunits are produced in specific seed coat cells early in development to be used as substrates for polymerization into PAs. Biochemically competent recombinant PsANR and PsLAR activities were consistent with the pea seed coat PA profile composed of both cis- and trans-flavan-3-ols. Since the expression of PsLAR in Arabidopsis did not alter the PA subunit profile (which is only comprised of cis-flavan-3-ols), it necessitates further investigation of in planta metabolic flux through PsLAR. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12870-014-0238-y) contains supplementary material, which is available to authorized users

Erratum: Sequence data and association statistics from 12,940 type 2 diabetes cases and controls.

This corrects the article DOI: 10.1038/sdata.2017.179

Evolution of bismuth-based metal?organic frameworks for efficient electroreduction of CO2

Understanding the structural and chemical changes that reactive metal–organic frameworks (MOFs) undergo is crucial for the development of new efficient catalysts for electrochemical reduction of CO2. Here, we describe three Bi(III) materials, MFM-220, MFM-221 and MFM-222, which are constructed from the same ligand (biphenyl-3,3′,5,5′-tetracarboxylic acid) but which show distinct porosity with solvent-accessible voids of 49.6%, 33.6% and 0%, respectively. We report the first study of the impact of porosity of MOFs on their evolution as electrocatalysts. A Faradaic efficiency of 90.4% at −1.1 V vs. RHE (reversible hydrogen electrode) is observed for formate production over an electrode decorated with MFM-220-p, formed from MFM-220 on application of an external potential in the presence of 0.1 M KHCO3 electrolyte. In situ electron paramagnetic resonance spectroscopy confirms the presence of ·COOH radicals as a reaction intermediate, with an observed stable and consistent Faradaic efficiency and current density for production of formate by electrolysis over 5 h. This study emphasises the significant role of porosity of MOFs as they react and evolve during electroreduction of CO2 to generate value-added chemicals

Protein Lysine Methyltransferase G9a Inhibitors: Design, Synthesis, and Structure Activity Relationships of 2,4-Diamino-7-aminoalkoxy-quinazolines.

Protein lysine methyltransferase G9a, which catalyzes methylation of lysine 9 of histone H3 (H3K9) and lysine 373 (K373) of p53, is over expressed in human cancers. Genetic knockdown of G9a inhibits cancer cell growth and the di-methylation of p53 K373 results in the inactivation of p53. Initial SAR exploration of the 2,4-diamino-6,7-dimethoxyquinazoline template represented by 3a (BIX01294), a selective small molecule inhibitor of G9a and GLP, led to the discovery of 10 (UNC0224) as a potent G9a inhibitor with excellent selectivity. A high resolution X-ray crystal structure of the G9a-10 complex, the first co-crystal structure of G9a with a small molecule inhibitor, was obtained. Based on the structural insights revealed by this co-crystal structure, optimization of the 7-dimethylaminopropoxy side chain of 10 resulted in the discovery of 29 (UNC0321) (Morrison Ki = 63 pM), which is the first G9a inhibitor with picomolar potency and the most potent G9a inhibitor to date

Cervical lymph node metastasis in high-grade transformation of head and neck adenoid cystic carcinoma: a collective international review

Adenoid cystic carcinoma (AdCC) is among the most common malignant tumors of the salivary glands. It is characterized by a prolonged clinical course, with frequent local recurrences, late onset of metastases and fatal outcome. High-grade transformation (HGT) is an uncommon phenomenon among salivary carcinomas and is associated with increased tumor aggressiveness. In AdCC with high-grade transformation (AdCC-HGT), the clinical course deviates from the natural history of AdCC. It tends to be accelerated, with a high propensity for lymph node metastasis. In order to shed light on this rare event and, in particular, on treatment implications, we undertook this review: searching for all published cases of AdCC-HGT. We conclude that it is mandatory to perform elective neck dissection in patients with AdCC-HGT, due to the high risk of lymph node metastases associated with transformation

A chemical probe selectively inhibits G9a and GLP methyltransferase activity in cells

Protein lysine methyltransferases G9a and GLP modulate the transcriptional repression of a variety of genes via dimethylation of Lys9 on histone H3 (H3K9me2) as well as dimethylation of non-histone targets. Here we report the discovery of UNC0638, an inhibitor of G9a and GLP with excellent potency and selectivity over a wide range of epigenetic and non-epigenetic targets. UNC0638 treatment of a variety of cell lines resulted in lower global H3K9me2 levels, equivalent to levels observed for small hairpin RNA knockdown of G9a and GLP with the functional potency of UNC0638 being well separated from its toxicity. UNC0638 markedly reduced the clonogenicity of MCF7 cells, reduced the abundance of H3K9me2 marks at promoters of known G9a-regulated endogenous genes and disproportionately affected several genomic loci encoding microRNAs. In mouse embryonic stem cells, UNC0638 reactivated G9a-silenced genes and a retroviral reporter gene in a concentration-dependent manner without promoting differentiation

X-chromosome and kidney function:evidence from a multi-trait genetic analysis of 908,697 individuals reveals sex-specific and sex-differential findings in genes regulated by androgen response elements

X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 for uric acid and 16 for estimated glomerular filtration rate (eGFR), including four novel eGFR loci containing the functionally plausible prioritized genes ACSL4, CLDN2, TSPAN6 and the female-specific DRP2. Further, we identified five novel sex-interactions, comprising male-specific effects at FAM9B and AR/EDA2R, and three sex-differential findings with larger genetic effect sizes in males at DCAF12L1 and MST4 and larger effect sizes in females at HPRT1. All prioritized genes in loci showing significant sex-interactions were located next to androgen response elements (ARE). Five ARE genes showed sex-differential expressions. This study contributes new insights into sex-dimorphisms of kidney traits along with new prioritized gene targets for further molecular research.</p

The genetic architecture of type 2 diabetes

The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of heritability. To test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole genome sequencing in 2,657 Europeans with and without diabetes, and exome sequencing in a total of 12,940 subjects from five ancestral groups. To increase statistical power, we expanded sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support a major role for lower-frequency variants in predisposition to type 2 diabetes