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The piRNA machinery is known for its role in mediating epigenetic silencing of transposons. Recent studies suggest that this function also involves piRNA-guided cleavage of transposon-derived transcripts. As many piRNAs also appear to have the capacity to target diverse mRNAs, this raises the intriguing possibility that piRNAs may act extensively as siRNAs to degrade specific mRNAs. To directly test this hypothesis, we compared mouse PIWI （MI- WI）-associated piRNAs with experimentally identified cleaved mRNA fragments from mouse testes, and observed cleavage sites that predominantly occur at position 10 from the 5＇ end of putative targeting piRNAs. We also noted strong biases for U and A residues at nucleotide positions 1 and 10, respectively, in both piRNAs and mRNA frag- ments, features that resemble the pattern of piRNA amplification by the ＇ping-pong＇ cycle. Through mapping of MIWI-RNA interactions by CLIP-seq and gene expression profiling, we found that many potential piRNA-targeted mRNAs directly interact with MIWI and show elevated expression levels in the testes of Miwi catalytic mutant mice. Reporter-based assays further revealed the importance of base pairing between piRNAs and mRNA targets and the requirement for both the slicer activity and piRNA-loading ability of MIWI in piRNA-mediated target repression. Importantly, we demonstrated that proper turnover of certain key piRNA targets is essential for sperm formation. Together, these findings reveal the siRNA-like function of the piRNA machinery in mouse testes and its central requirement for male germ cell development and maturation.

The PTEN tumor suppressor is a lipid phosphatase that has a central role in regulating the phosphatidylinositol-3- kinase （PI3K） signal transduction cascade. Nevertheless, the mechanism by which the PTEN activity is regulated in cells needs further elucidation. Although previous studies have shown that ubiquitination of PTEN can modulate its stability and subcellular localization, the role of ubiquitination in the most critical aspect of PTEN function, its phos- phatase activity, has not been fully addressed. Here, we identify a novel E3 ubiquitin ligase of PTEN, Ret finger pro- tein （RFP）, that is able to promote atypical polyubiquitinations of PTEN. These ubiquitinations do not lead to PTEN instability or relocalization, but rather significantly inhibit PTEN phosphatase activity and therefore modulate its ability to regulate the PI3K signal transduction cascade. Indeed, RFP overexpression relieves PTEN-mediated inhibi- tory effects on AKT activation; in contrast, RNAi-mediated knockdown of endogenous RFP enhances the ability of PTEN to suppress AKT activation. Moreover, RFP-mediated ubiquitination of PTEN inhibits PTEN-dependent ac- tivation of TRAIL expression and also suppresses its ability to induce apoptosis. Our findings demonstrate a crucial role of RFP-mediated ubiquitination in controlling PTEN activity.

Tp53, a stress response gene, is involved in diverse cell death pathways and its activation is implicated in the pathogenesis of Parkinson＇s disease. However, whether the neuronal Tp53 protein plays a direct role in regulating dopaminergic （DA） neuronal cell death or neuronal terminal damage in different neurotoxicant models is unknown. In our recent studies, in contrast to the global inhibition of Tp53 function by phar- macological inhibitors and in traditional Tp53 knock-out mice, we examined the effects of DA-specific Tp53 gene deletion after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and methamphetamine exposure. Our data suggests that the Tp53 gene might be involved in both neuronal apoptosis and neuronal termi- nal damage caused by different neurotoxicants. Additional results from other studies also suggest that as a master regulator of many pathways that regulate apoptosis and synaptic terminal damage, it is possible that Tp53 may function as a signaling hub to integrate different signaling pathways to mediate distinctive target pathways. Tp53 protein as a signaling hub might be able to evaluate the microenvironment of neurons, assess the forms and severities of injury incurred, and determine whether apoptotic cell death or neuro- nal terminal degeneration occurs. Identification of the precise mechanisms activated in distinct neuronal damage caused by different forms and severities of injuries might allow for development of specific Tp53 inhibitors or ways to modulate distinct downstream target pathways involved.

Background： Fetal insulin hypothesis was proposed that the association between low birth weight and type 2 diabetes is principally genetically mediated. The aim of this study was to investigate whether common variants in genes CDKALI, HHEX, ADCY5, SRR, PTPRD that predisposed to type 2 diabetes were also associated with reduced birthweight in Chinese Han population. Methods： Twelve single nucleotide polymorphisms （rs7756992/rs10946398 in CDKAL1, rsl 111875 in HHEA; rs391300 in SRR, rs17584499 in PTPRD. rs1170806/rs9883204/rs4678017/rs9881942/rs7641344/rs6777397/rs6226243 in ADCY5） were genotyped in 1174 unrelated individuals born in Peking Union Medical College Hospital from 1921 to 1954 by TaqMan allelic discrimination assays, of which 645 had normal glucose tolerance, 181 had developed type 2 diabetes and 348 impaired glucose regulation. Associations of these 12 genetic variants with birthweight and glucose metabolism in later life were analyzed. Results： Birthweight was inversely associated with CDKAL 1-rs 10946398 （β = -41 g [95% confidence interval [CI]： -80, 3], P= 0.034）, common variants both associated with increased risk of impaired glucose metabolism and decreased insulin secretion index later in life. After adjusting for sex, gestational weeks, parity and maternal age, the risk allele of CDKAL1-rs7756992 was associated with reduced birthweight （β = 36 g [95% CI： -72, -0.2], P = 0.048）. The risk allele in SRR showed a trend toward a reduction ofbirthweight （P =0.085）. Conclusions： This study identified the association between type 2 diabetes risk variants in CDKAL 1 and birthweight in Chinese Hart individuals, and the carrier of risk allele within SRR had the trend of reduced birthweight. This demonstrates that there is a clear overlap between the genetics of type 2 diabetes and fetal growth, which proposes that lower birth weight and type 2 diabetes may be two phenotypes of one genotype.

The SWI/SNF chromatin-remodeling complexes utilize energy from ATP hydrolysis to reposition nucleosomes and regulate the expression of human genes. Here, we studied the roles of human Brahma （hBrm） and Brahma-related gene 1 （Brgl）, the ATPase subunits of the SWI/SNF complexes, in regulating human genes. Our results indicate that both hBrm and Brgl interact with Signal transducer and activator of transcription （Stat） 1 in vitro. However, Statl in its native form only recruits hBrm to IFNy-activated sequences （GAS） of individual genes; by contrast, in a stress- induced phosphorylated form, Statl mainly binds to Brgl. Under basal conditions, hBrm is recruited by native Statl to the GAS and exists in a mSin3/HDAC co-repressor complex on the hsp90a gene, which shows a compact chromatin structure. Upon heat-shock, hBrm is acetylated by p300 and dissociates from the co-repressor complex, which the phosphorylated St~tl is increased, and binds and recruits Brgl to the GAS, leading to elevated induction of the gene. This hBrm/Brgl switch also occurs at the GAS of all of the three examined immune genes in heat-shocked cells; how- ever, this switch only occurs in specific cell types upon exposure to IFNy. Regardless of the stimulus, the hBrm/Brgl switch at the GAS elicits an increase in gene activity. Our data are consistent with the hypothesis that the hBrm/Brgl switch is an indicator of the responsiveness of a gene to heat-shock or IFNy stimulation and may represent an ＂on-off switch＂ of gene expression in vivo.

Regulator of G-protein Signaling 10 （Rgsl0） plays an important function in osteoclast differentiation. However, the role of Rgsl0 in immune cells and inflammatory responses, which activate osteoclasts in inflam- matory lesions, such as bacteria-induced periodontal disease lesions, remains largely unknown. In this study, we used an adeno-associated virus （AAV-） mediated RNAi （AAV-shRNA-Rgs10） knockdown approach to study Rgsl0＇s function in immune cells and osteoclasts in bacteria-induced inflammatory lesions in a mouse model of periodontal disease. We found that AAV-shRNA-Rgs10 mediated Rgs10 knockdown impaired osteoclastogenesis and osteoclast-mediated bone resorption, in vitro and in vivo. Interestingly, local injection of AAV-shRNA-Rgs10 into the periodontal tissues in the bacteria-induced inflammatory lesion greatly decreased the number of dendritic cells, T-cells and osteoclasts, and protected the periodontal tissues from local inflammatory damage and bone destruction. Importantly, AAV-mediated Rgs10 knoc

月季（Rosa chinensis Jacq．）原产于我国，是我国十大名花之一。月季的种植种类和数量居观赏花卉之首。目前我国有大量的盐碱地和次生盐渍化土壤，急需培育抗盐植物新品种，以开发利用盐碱地。

背景与目的肺癌是严重危害人民生命和健康的常见病。目前世界上倾向于将两类生物学行为不同的肺癌分为小细胞肺癌（SCLC）和非小细胞性肺癌（NSCLC）。而NSCLC中的大细胞肺癌治疗效果多年来一直没有显著提高，一方面由于其生物学特性十分复杂、恶性程度高且多药耐药。另一方面还在于约80％大细胞肺癌患者确诊时已属晚期而失去手术机会。所以化疗在大细胞肺癌的治疗中是无可取代的，但多药耐药的出现令人沮丧。于是，我们设想将转基因技术与放射性核素治疗相结合，将hNIS基因转染至人大细胞肺癌H460细胞系中，使原本不摄碘的H460细胞摄取碘。然后利用放射性核素^131I的辐射生物效应，干扰H460细胞的生物代谢，抑制肿瘤细胞增值活性，最终使癌细胞死亡。