Developmental exposure to thyroid disruptors:misprogramming of the brain's stem cells in later life?

Introduction:Ever since the discovery of neural stem cells(NSCs)in the adult mammalian brain,scientists have been trying to decipher which signals govern their turnover and lineage commitment to generate neurons and glia.Understanding their role in nervous tissue homeostasis can provide new insights into the etiology of several neurological disorders,and might one day be turned to our advantage to promote endogenous brain injury repair.Others and we have identified thyroid hormone(TH)as a key factor transcriptionally regulating NSC behavior in the largest niche of the adult mammalian brain:the subventricular zone(SVZ).

Prompt and Easy Activation by Specific Thioredoxins of Calvin Cycle Enzymes of Arabidopsis thaliana Associated in the GAPDH/CP12/PRK Supramolecular Complex

The Calvin cycle enzymes glyceraldehyde-3-phosphate dehydrogenase （GAPDH） and phosphoribulokinase （PRK） can form under oxidizing conditions a supramolecular complex with the regulatory protein CP12. Both GAPDH and PRK activities are inhibited within the complex, but they can be fully restored by reduced thioredoxins （TRXs）. We have investigated the interactions of eight different chloroplast thioredoxin isoforms （TRX f1, m1, m2, m3, m4, y1, y2, x） with GAPDH （A4, B4, and B8 isoforms）, PRK and CP12 （isoform 2）, all from Arabidopsis thaliana. In the complex, both A4-GAPDH and PRK were promptly activated by TRX f1, or more slowly by TRXs ml and m2, but all other TRXs were ineffective. Free PRK was regulated by TRX f1, m1, or m2, while B4- and Bs-GAPDH were absolutely specific for TRX fl. Interestingly, reductive activation of PRK caged in the complex was much faster than reductive activation of free oxidized PRK, and activation of A4-GAPDH in the complex was much faster （and less demanding in terms of reducing potential） than activation of free oxidized B4- or BB-GAPDH. It is proposed that CP12-assembled supramolecular complex may represent a reservoir of inhibited enzymes ready to be released in fully active conformation following reduction and dissociation of the complex by TRXs upon the shift from dark to low light. On the contrary, autonomous redox-modulation of GAPDH （B- containing isoforms） would be more suited to conditions of very active photosynthesis.

家族性窦性心动过缓与心脏起搏离子通道突变相关

We found that sinus bradycardia in members of a large family was associated with a mutation in the gene coding for the pacemaker HCN4 ion channel. Pacemaker channels of the sinoatrial node generate spontaneous activity and mediate cyclic AMP(cAMP)-dependent autonomic modulation of the heart rate. The mutation associated with bradycardia is located near the cAMP-binding site; functional analysis found that mutant channels respond normally to cAMP but are activated at more negative voltages than are wild-type channels. These changes, which mimic those of mild vagal stimulation, slow the heart rate by decreasing the inward diastolic current. Thus, diminished function of pacemaker channels is linked to familial bradycardia.

PKR and PP1C Polymorphisms in Alzheimer’s Disease Risk

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by senile plaques and neurofibrillary tangles. Senile plaques are deposits of amyloid ?-peptide (A?) produced by the cleavage of a transmembrane protein termed Amyloid Precursor Protein (APP). The amyloidogenic cleavage of APP is performed by γ-secretase complex and ?-site APP cleaving enzyme 1 (BACE1), a key enzyme in AD that can be activated by different noxious stimuli. Interestingly, some viruses could activate double-stranded RNA-activated protein kinase (PKR), which phosphorylates Eukaryotic Initiation Factor 2 alpha (eIF2α). This phosphorylation stops global translation to avoid any synthesis of viral infective proteins, but paradoxically up-regulates BACE1 translation. One of the viral mechanisms to circumvent eIF2α phosphorylation is the recruitment of protein phosphatase 1 (PP1), to fully dephosphorylate eIF2α and allow viral protein synthesis. Due to the functional relationship between BACE1, PKR, PP1 and AD we have performed a large (1122 cases and 1191 control individuals) case-control genetic analysis using two biallelic polymorphisms rs2254958 and rs7480390, located within the genes coding for PKR and the catalytic unit A of PP1, respectively. Although a trend to association of the rs2254958 TT genotype with AD risk was found, our results show that neither rs7480390 nor rs2254958 are associated with AD susceptibility.

A Single Active Trehalose-6-P Synthase （TPS） and a Family of Putative Regulatory TPS-Like Proteins in Arabidopsis

Higher plants typically do not produce trehalose in large amounts, but their genome sequences reveal large families of putative trehalose metabolism enzymes. An important regulatory role in plant growth and development is also emerging for the metabolic intermediate trehalose-6-P （T6P）. Here, we present an update on Arabidopsis trehalose me- tabolism and a resource for further detailed analyses. In addition, we provide evidence that Arabidop$is encodes a single trehalose-6-P synthase （TPS） next to a family of catalytically inactive TPS-like proteins that might fulfill specific regulatory functions in actively growing tissues.

Reversal of doxorubicin resistance in lung cancer cells by neferine is explained by nuclear factor erythroid-derived 2-like 2 mediated lung resistance protein down regulation

Aim:Development of multi drug resistance and dose limiting cardiotoxicity are hindering the use of Doxorubicin(Dox)in clinical settings.Augmented dox efflux induced by lung resistance protein(LRP)over expression has been related to multi drug resistance phenotype in various cancers.An alkaloid from lotus,Neferine(Nef)shows both anticancer and cardioprotective effects.Here,we have investigated the interconnection between nuclear factor erythroid-derived 2-like 2(NRF2)and LRP in Dox resistance and how Nef can overcome Dox resistance in lung cancer cells by altering this signaling.Methods:Anti-proliferative and apoptotic-inducing effects of Nef and Dox combination in Parental and Dox resistant lung cancer cells were determined in monolayers and 3D spheroids.Intracellular Dox was analyzed using flow cytometry,siRNA knockdown and western blot analysis were used to elucidate NRF2-LRP crosstalk mechanism.

Identification of Rice Al-responsive Genes by Semi-quantitative Polymerase Chain Reaction using Sulfite Reductase as a Novel Endogenous Control

Based on the evidence that Al resistance is an inducible process and rice is an Al-resistant crop, identification of Al-responsive genes from rice may help to further clone Al.resistant genes in plants. Semi-quantitative and real-time polymerase chain reaction （PCR） is widely applied in gene transcrip- tional analyses, particularly for those genes with low transcript abundance. Normalization with proper endogenous control （EC） genes is critical for these two approaches in terms of reliability and precision. We first noticed that the expression of several commonly-used EC genes was depressed under AI stress, while sulfite reductase gene （SR） was stable throughout the AI treatment. The reliability of SR as an EC gene was further tested by analyzing the expression of a number of genes in response to Al challenge. Except for the consistent results obtained for the four previously-identified genes, nine additional genes were newly defined as Al-responsive in this study. Collectively, our results suggest that SR can be used as a novel EC gene for semi-quantitative and real-time PCR analysis of Al responsive genes, and that activated transport of silicon and stimulated metabolism of carotenoid and terpenoid could be involved in Al resistance in rice plants.