ARGONAUTE PIWI domain and microRNA duplex structure regulate small RNA sorting in Arabidopsis.

Small RNAs (sRNAs) are loaded into ARGONAUTE (AGO) proteins to induce gene silencing. In plants, the 5'-terminal nucleotide is important for sRNA sorting into different AGOs. Here we show that microRNA (miRNA) duplex structure also contributes to miRNA sorting. Base pairing at the 15th nucleotide of a miRNA duplex is important for miRNA sorting in both Arabidopsis AGO1 and AGO2. AGO2 favours miRNA duplexes with no middle mismatches, whereas AGO1 tolerates, or prefers, duplexes with central mismatches. AGO structure modelling and mutational analyses reveal that the QF-V motif within the conserved PIWI domain contributes to recognition of base pairing at the 15th nucleotide of a duplex, while the DDDE catalytic core of AtAGO2 is important for recognition of the central nucleotides. Finally, we rescued the adaxialized phenotype of ago1-12, which is largely due to miR165 loss-of-function, by changing miR165 duplex structure which we predict redirects it to AGO2

Piezoelectric Wireless Power Transfer using Halbach Array for the Internet of Implanted Things

Implanted devices are increasingly used in chronic disease monitoring, but face challenges in energy autonomy. The paper presents a novel wireless power transfer method for self-sustained medical implants using Halbach array-based magnetic plucking and piezoelectric transduction. The wearableimplantable coupled system consists of a piezoelectric receiver within the implant to receive power and a near-field magnetic power transmitter as a wearable device. To deliver power over greater distances through the human body, the transmitter features a rotating magnetic Halbach array powered by a miniature motor or by human motion to generate an alternating magnetic field. The use of low-frequency rotating magnetic fields periodically excites a cantilevered piezoelectric beam with a tip magnet to realize wireless power transfer. A theoretical model that includes magnetic coupling, piezoelectric transduction and receiver beam dynamics has been established to study the electromagneto-mechanical dynamics of this wireless power transfer system. The effectiveness of the Halbach array for extended power transfer is examined through theoretical modelling and numerical simulation, showing a 37.2% enhancement of the magnetic forces. A prototype was also fabricated and tested to examine the wireless power transfer performance. The established wireless power link can provide sufficient power (∼32 µW) over a large transmission distance (22 mm), providing a potential batteryfree solution for the self-sustained Internet of Implanted Things (IoIT) for personalized healthcare

Phonon anomalies at the valence transition of SmS : An inelasticX-ray scattering study under pressure

The phonon dispersion curve of SmS under pressure was studied by inelastic x-ray scattering around the pressure-induced valence transition. A significant softening of the longitudinal acoustic modes propagating along the [111] direction was observed spanning a wide $q$ region from ($\frac{2\pi}{3a},\frac{2\pi}{3a},\frac{2\pi}{3a}$) up to the zone boundary as SmS becomes metallic. The largest softening occurs at the zone boundary and stays stable up to the highest measured pressure of 80 kbar while a gradual hardening of the low $q$ modes simultaneously appears. This phonon spectrum indicates favorable conditions for the emergence of pressure-induced superconductivity in SmS.Comment: 4 pages, 3 figure

SIK2 inhibition enhances PARP inhibitor activity synergistically in ovarian and triple-negative breast cancers

Poly(ADP-ribose) polymerase inhibitors (PARP inhibitors) have had an increasing role in the treatment of ovarian and breast cancers. PARP inhibitors are selectively active in cells with homologous recombination DNA repair deficiency caused by mutations in BRCA1/2 and other DNA repair pathway genes. Cancers with homologous recombination DNA repair proficiency respond poorly to PARP inhibitors. Cancers that initially respond to PARP inhibitors eventually develop drug resistance. We have identified salt-inducible kinase 2 (SIK2) inhibitors, ARN3236 and ARN3261, which decreased DNA double-strand break (DSB) repair functions and produced synthetic lethality with multiple PARP inhibitors in both homologous recombination DNA repair deficiency and proficiency cancer cells. SIK2 is required for centrosome splitting and PI3K activation and regulates cancer cell proliferation, metastasis, and sensitivity to chemotherapy. Here, we showed that SIK2 inhibitors sensitized ovarian and triple-negative breast cancer (TNBC) cells and xenografts to PARP inhibitors. SIK2 inhibitors decreased PARP enzyme activity and phosphorylation of class-IIa histone deacetylases (HDAC4/5/7). Furthermore, SIK2 inhibitors abolished class-IIa HDAC4/5/7–associated transcriptional activity of myocyte enhancer factor-2D (MEF2D), decreasing MEF2D binding to regulatory regions with high chromatin accessibility in FANCD2, EXO1, and XRCC4 genes, resulting in repression of their functions in the DNA DSB repair pathway. The combination of PARP inhibitors and SIK2 inhibitors provides a therapeutic strategy to enhance PARP inhibitor sensitivity for ovarian cancer and TNBC

The feasibility study of non-invasive fetal trisomy 18 and 21 detection with semiconductor sequencing platform

Objective: Recent non-invasive prenatal testing (NIPT) technologies are based on next-generation sequencing (NGS). NGS allows rapid and effective clinical diagnoses to be determined with two common sequencing systems: Illumina and Ion Torrent platforms. The majority of NIPT technology is associated with Illumina platform. We investigated whether fetal trisomy 18 and 21 were sensitively and specifically detectable by semiconductor sequencer: Ion Proton. Methods: From March 2012 to October 2013, we enrolled 155 pregnant women with fetuses who were diagnosed as high risk of fetal defects at Xiamen Maternal & Child Health Care Hospital (Xiamen, Fujian, China). Adapter-ligated DNA libraries were analyzed by the Ion Proton??? System (Life Technologies, Grand Island, NY, USA) with an average 0.3 ?? sequencing coverage per nucleotide. Average total raw reads per sample was 6.5 million and mean rate of uniquely mapped reads was 59.0%. The results of this study were derived from BWA mapping. Z-score was used for fetal trisomy 18 and 21 detection. Results: Interactive dot diagrams showed the minimal z-score values to discriminate negative versus positive cases of fetal trisomy 18 and 21. For fetal trisomy 18, the minimal z-score value of 2.459 showed 100% positive predictive and negative predictive values. The minimal z-score of 2.566 was used to classify negative versus positive cases of fetal trisomy 21. Conclusion: These results provide the evidence that fetal trisomy 18 and 21 detection can be performed with semiconductor sequencer. Our data also suggest that a prospective study should be performed with a larger cohort of clinically diverse obstetrics patients.open2

Therapeutic Implications of GIPC1 Silencing in Cancer

GIPC1 is a cytoplasmic scaffold protein that interacts with numerous receptor signaling complexes, and emerging evidence suggests that it plays a role in tumorigenesis. GIPC1 is highly expressed in a number of human malignancies, including breast, ovarian, gastric, and pancreatic cancers. Suppression of GIPC1 in human pancreatic cancer cells inhibits in vivo tumor growth in immunodeficient mice. To better understand GIPC1 function, we suppressed its expression in human breast and colorectal cancer cell lines and human mammary epithelial cells (HMECs) and assayed both gene expression and cellular phenotype. Suppression of GIPC1 promotes apoptosis in MCF-7, MDA-MD231, SKBR-3, SW480, and SW620 cells and impairs anchorage-independent colony formation of HMECs. These observations indicate GIPC1 plays an essential role in oncogenic transformation, and its expression is necessary for the survival of human breast and colorectal cancer cells. Additionally, a GIPC1 knock-down gene signature was used to interrogate publically available breast and ovarian cancer microarray datasets. This GIPC1 signature statistically correlates with a number of breast and ovarian cancer phenotypes and clinical outcomes, including patient survival. Taken together, these data indicate that GIPC1 inhibition may represent a new target for therapeutic development for the treatment of human cancers

Small RNAs and the regulation of cis-natural antisense transcripts in Arabidopsis

<p>Abstract</p> <p>Background</p> <p>In spite of large intergenic spaces in plant and animal genomes, 7% to 30% of genes in the genomes encode overlapping cis-natural antisense transcripts (cis-NATs). The widespread occurrence of cis-NATs suggests an evolutionary advantage for this type of genomic arrangement. Experimental evidence for the regulation of two cis-NAT gene pairs by natural antisense transcripts-generated small interfering RNAs (nat-siRNAs) via the RNA interference (RNAi) pathway has been reported in Arabidopsis. However, the extent of siRNA-mediated regulation of cis-NAT genes is still unclear in any genome.</p> <p>Results</p> <p>The hallmarks of RNAi regulation of NATs are 1) inverse regulation of two genes in a cis-NAT pair by environmental and developmental cues and 2) generation of siRNAs by cis-NAT genes. We examined Arabidopsis transcript profiling data from public microarray databases to identify cis-NAT pairs whose sense and antisense transcripts show opposite expression changes. A subset of the cis-NAT genes displayed negatively correlated expression profiles as well as inverse differential expression changes under at least one of the examined developmental stages or treatment conditions. By searching the <it>Arabidopsis </it>Small RNA Project (ASRP) and Massively Parallel Signature Sequencing (MPSS) small RNA databases as well as our stress-treated small RNA dataset, we found small RNAs that matched at least one gene in 646 pairs out of 1008 (64%) protein-coding cis-NAT pairs, which suggests that siRNAs may regulate the expression of many cis-NAT genes. 209 putative siRNAs have the potential to target more than one gene and half of these small RNAs could target multiple members of a gene family. Furthermore, the majority of the putative siRNAs within the overlapping regions tend to target only one transcript of a given NAT pair, which is consistent with our previous finding on salt- and bacteria-induced nat-siRNAs. In addition, we found that genes encoding plastid- or mitochondrion-targeted proteins are over-represented in the Arabidopsis cis-NATs and that 19% of sense and antisense partner genes of cis-NATs share at least one common Gene Ontology term, which suggests that they encode proteins with possible functional connection.</p> <p>Conclusion</p> <p>The negatively correlated expression patterns of sense and antisense genes as well as the presence of siRNAs in many of the cis-NATs suggest that siRNA regulation of cis-NATs via the RNAi pathway is an important gene regulatory mechanism for at least a subgroup of cis-NATs in Arabidopsis.</p