The castor plant (Ricinus communis L.) is a versatile industrial oilseed crop with a diversity of sex patterns, its hybrid breeding for improving yield and high purity is still hampered by genetic instability of female and poor knowledge of sex expression mechanisms. To obtain some hints involved in sex expression and provide the basis for further insight into the molecular mechanisms of castor plant sex determination, we performed DGE analysis to investigate differences between the transcriptomes of apices and racemes derived from female (JXBM0705P) and monoecious (JXBM0705M) lines. A total of 18 DGE libraries were constructed from the apices and racemes of a wild monoecious line and its isogenic female derivative at three stages of apex development, in triplicate. Approximately 5.7 million clean tags per library were generated and mapped to the reference castor genome. Transcriptomic analysis showed that identical dynamic changes of gene expression were indicated in monoecious and female apical bud during its development from vegetation to reproduction, with more genes expressed at the raceme formation and infant raceme stages compare to the early leaf bud stage. More than 3000 of differentially expressed genes (DEGs) were detected in Ricinus apices at three developmental stages between two different sex types. A number of DEGs involved in hormone response and biosynthesis, such as auxin response and transport, transcription factors, signal transduction, histone demethylation/methylation, programmed cell death, and pollination, putatively associated with sex expression and reproduction were discovered, and the selected DEGs showed consistent expression between qRT-PCR validation and the DGE patterns. Most of those DEGs were suppressed at the early leaf stage in buds of the mutant, but then activated at the following transition stage (5-7-leaf stage) of buds in the mutant, and ultimately, the number of up-regulated DEGs was equal to that of down-regulation in the small raceme of the mutant. In this study, a large number of DEGs and some suggestions involved in sex expression and reproduction were discovered using DGE analysis, which provides large information and valuable hints for next insights into the molecular mechanism of sex determination. It is useful for other further studies in Ricinus.

We developed a nanovector with double targeting properties for efficiently delivering the tumor suppressor gene RASSF1A specifically into hepatocellular carcinoma (HCC) cells by preparing galactosylated-carboxymethyl chitosan-magnetic iron oxide nanoparticles (Gal-CMCS-Fe3O4-NPs). After conjugating galactose and CMCS to the surface of Fe3O4-NPs, we observed that Gal-CMCS-Fe3O4-NPs were round with a relatively stable zeta potential of +6.5 mV and an mean hydrodynamic size of 40.1 ± 5.3 nm. Gal-CMCS-Fe3O4-NPs had strong DNA condensing power in pH 7 solution and were largely nontoxic. In vitro experiments demonstrated that Gal-CMCS-Fe3O4-NPs were highly selective for HCC cells and liver cells. In vivo experiments showed the specific accumulation of Gal-CMCS-Fe3O4-NPs in HCC tissue, especially with the aid of an external magnetic field. Nude mice with orthotopically transplanted HCC received an intravenous injection of the Gal-CMCS-Fe3O4-NPs/pcDNA3.1(+)RASSF1A compound and intraperitoneal injection of mitomycin and had an external magnetic field applied to the tumor area. These mice had the smallest tumors, largest percentage of TUNEL-positive cells, and highest caspase-3 expression levels in tumor tissue compared to other groups of treated mice. These results suggest the potential application of Gal-CMCS-Fe3O4-NPs for RASSF1A gene delivery for the treatment of HCC.

Seed development dedicates to reserve synthesis and accumulation and uncovering its genetic and biochemical mechanisms has been a major research focus. Although proteomic and transcriptomic analyses revealed dynamic changes of genes and enzymes involved, the information regarding concomitant metabolic changes is missing. Here we investigated the dynamic metabolic changes along the rice grain development of two japonica and two indica cultivars using non-targeted metabolomics approach, in which we successfully identified 214 metabolites. Statistical analyses revealed both cultivar and developmental stage dependent metabolic changes in rice grains. Generally, the stage specific metabolic kinetics corresponded well to the physiological status of the developing grains, and metabolic changes in developing rice grain are similar to those of dicot Arabidopsis and tomato at reserve accumulation stage but are different from those of dicots at seed desiccation stage. The remarkable difference in metabolite abundances between japonica and indica rice grain was observed at the reserve accumulation stage. Metabolite-metabolite correlation analysis uncovered potential new pathways for several metabolites. Taken together, this study uncovered both conserved and diverse development associated metabolic kinetics of rice grains, which facilitates further study to explore fundamental questions regarding the evolution of seed metabolic capabilities as well as their potential applications in crop improvement.

Here we report the identification of a novel tryptophyllin-3 peptide with arterial smooth muscle relaxation activity from the skin secretion of the purple-sided leaf frog, Phyllomedusa baltea. This new peptide was named baltikinin and had the following primary structure, pGluDKPFGPPPIYPV, as determined by tandem mass spectrometry (MS/MS) fragmentation sequencing and from cloned skin precursor-encoding cDNA. A synthetic replicate of baltikinin was found to have a similar potency to bradykinin in relaxing arterial smooth muscle (half maximal effective concentration (EC50) is 7.2 nM). These data illustrate how amphibian skin secretions can continue to provide novel potent peptides that act through functional targets in mammalian tissues.

Hexavalent chromium [Cr(VI)] is a well-known human carcinogen associated with an increased risk of lung cancer. However, the mechanisms underlying Cr(VI)-induced carcinogenesis remain unclear. MicroRNA-21 (miR-21) is a key regulator of oncogenic processes. Studies have shown that miR-21 exerts its oncogenic activity by targeting the tumor suppressor gene programmed cell death 4 (PDCD4). The present study examined the role of miR-21-PDCD4 signaling in Cr(VI)-induced cell transformation and tumorigenesis. Results showed that Cr(VI) induces ROS generation in human bronchial epithelial (BEAS-2B) cells. Chronic exposure to Cr(VI) is able to cause malignant transformation in BEAS-2B cells. Cr(VI) caused a significant increase of miR-21 expression associated with an inhibition of PDCD4 expression. Notably, STAT3 transcriptional activation by IL-6 is crucial for the Cr(VI)-induced miR-21 elevation. Stable knockdown of miR-21 or overexpression of PDCD4 in BEAS-2B cells significantly reduced the Cr(VI)-induced cell transformation. Furthermore, the Cr(VI) induced inhibition of PDCD4 suppressed downstream E-cadherin protein expression, but promoted β-catenin/TCF-dependent transcription of uPAR and c-Myc. We also found an increased miR-21 level and decreased PDCD4 expression in xenograft tumors generated with chronic Cr(VI)-exposed BEAS-2B cells. In addition, stable knockdown of miR-21 and overexpression of PDCD4 reduced the tumorogenicity of chronic Cr(VI)-exposed BEAS-2B cells in nude mice. Taken together, these results demonstrate that the miR-21-PDCD4 signaling axis plays an important role in Cr(VI)-induced carcinogenesis.

In conventional light-harvesting devices, the absorption of a single photon only excites one electron, which sets the standard limit of power-conversion efficiency, such as the Shockley-Queisser limit. In principle, generating and harnessing multiple carriers per absorbed photon can improve efficiency and possibly overcome this limit. We report the observation of multiple hot-carrier collection in graphene/boron-nitride Moiré superlattice structures. A record-high zero-bias photoresponsivity of 0.3 A/W (equivalently, an external quantum efficiency exceeding 50%) is achieved using graphene's photo-Nernst effect, which demonstrates a collection of at least five carriers per absorbed photon. We reveal that this effect arises from the enhanced Nernst coefficient through Lifshtiz transition at low-energy Van Hove singularities, which is an emergent phenomenon due to the formation of Moiré minibands. Our observation points to a new means for extremely efficient and flexible optoelectronics based on van der Waals heterostructures.

Foreign body reaction induced by biomaterials is a serious problem in clinical applications. Although 317L-Cu stainless steel (317L-Cu SS) is a new type of implant material with antibacterial ability and osteogenic property, the foreign body reaction level still needs to be assessed due to its Cu(2+) releasing property. For this purpose, two macrophage cell lines were selected to detect cellular proliferation, apoptosis, mobility, and the secretions of inflammatory cytokines with the influence of 317L-Cu SS. Our results indicated that 317L-Cu SS had no obvious effect on the proliferation and apoptosis of macrophages; however, it significantly increased cellular migration and TNF-α secretion. Then, C57 mice were used to assess foreign body reaction induced by 317L-Cu SS. We observed significantly enhanced recruitment of inflammatory cells (primarily macrophages) with increased TNF-α secretion and apoptosis level in tissues around the materials in the early stage of implantation. With tissue healing, both inflammation and apoptosis significantly decreased. Further, we discovered that NF-κB pathway and Caspase 3 played important roles in 317L-Cu SS induced inflammation and apoptosis. We concluded that 317L-Cu SS could briefly promote the inflammation and apoptosis of surrounding tissues by regulating the activity of NF-κB pathway and Caspase 3. All these discoveries demonstrated that 317L-Cu SS has a great potential for clinical application.

The use of multiple origins for chromosome replication has been demonstrated in archaea. Similar to the dormant origins in eukaryotes, some potential origins in archaea appear to be inactive during genome replication. We have comprehensively explored the origin utilization in Haloferax mediterranei. Here we report three active chromosomal origins by genome-wide replication profiling, and demonstrate that when these three origins are deleted, a dormant origin becomes activated. Notably, this dormant origin cannot be further deleted when the other origins are already absent and vice versa. Interestingly, a potential origin that appears to stay dormant in its native host H. volcanii lacking the main active origins becomes activated and competent for replication of the entire chromosome when integrated into the chromosome of origin-deleted H. mediterranei. These results indicate that origin-dependent replication is strictly required for H. mediterranei and that dormant replication origins in archaea can be activated if needed.

MicroRNAs (miRNAs) are short noncoding RNAs integral for regulating gene expression at the posttranscriptional level. However, experimental methods often fall short in finding miRNAs expressed at low levels or in specific tissues. While several computational methods have been developed for predicting the localization of mature miRNAs within the precursor transcript, the prediction accuracy requires significant improvement.

In this study, we investigated the role of karyopherin alpha 3 in the heat shock response in male silkworm pupae. Karyopherin alpha recognizes the classical nuclear location sequence on proteins and transports them into the nucleus by forming a trimetric complex with karyopherin beta. Three predicted karyopherin alphas (KPNA1, KPNA2 and KPNA3) have been identified from the silkworm Bombyx mori. Pull-down assay result showed that KPNA3 can pull down heat shock transcription factor (HSF) from proteins extracted from tissues using non-denature lysis buffer. After 45 °C heat shock on male B. mori pupae for 30 min, we identified two heat shock protein (HSP) mRNA expression peaks correlating with HSP19.9, HSP20.4 and HSP25.4 at 4 h (peak 1) and 24 h (peak 2). The second peak was eliminated after knockdown of KPNA3. Similar results were obtained following knockdown of HSF, which is the trans-activating factor of heat shock. However, KPNA3 knockdown was not accompanied by the decreased HSF protein levels at 24 h after heat shock which were observed following HSF knockdown. We also expressed recombinant protein GST-KPNA3 and His-HSF in Escherichia coli to perform GST pull-down assay and the result confirmed the interaction between KPNA3 and HSF. We concluded that KPNA3 knockdown eliminates the second heat shock protein peak in the heat shock response of male silkworm pupae by reducing HSF transport into the nucleus.

Lung cancer is the most common cause of cancer-related mortality worldwide. It is necessary to improve the understanding of the molecular mechanisms involved in lung cancer in order to develop more effective therapeutics for the treatment of this fatal disease. The canonical Wnt signaling pathway has been known to be important in a number of cancer types, including lung cancer. Pygopus (Pygo) is a recently identified downstream component of the Wnt signaling pathway required for β-catenin/T-cell factor (TCF)-dependent transcription. However, the role of Pygo in lung cancer remains to be elucidated. The present study showed that Pygo2 is overexpressed in human lung cancer tissue samples and cell lines. Expression levels of Pygo2 were found to correlate with cytosolic β-catenin protein levels in the samples examined. Co-immunofluorescent staining showed that Pygo2 protein accumulated in the nuclei and colocalized with nuclear β-catenin in lung cancer cell lines expressing Pygo2. To investigate the functional importance of the Pygo2 overexpression in lung cancer, short hairpin RNA (shRNA) was used to knockdown Pygo2 mRNA in lung cancer cells expressing the gene. Pygo2 shRNA was observed to inhibit cell proliferation and decrease β-catenin/TCF-dependent transcriptional activity in vitro. Furthermore, Pygo2 shRNA significantly suppressed lung cancer xenograft models in vivo (P<0.05). These results suggested that Pygo2 is a putative therapeutic target for human lung cancer and overexpression of Pygo2 may be important for aberrant Wnt activation in lung cancer.

Canola (Brassica napus L.) is one of the most important oil-producing crops in China and worldwide. The yield and quality of canola is frequently threatened by environmental stresses including drought, cold and high salinity. Calcium is a ubiquitous intracellular secondary messenger in plants. Calcineurin B-like proteins (CBLs) are Ca2+ sensors and regulate a group of Ser/Thr protein kinases called CBL-interacting protein kinases (CIPKs). Although the CBL-CIPK network has been demonstrated to play crucial roles in plant development and responses to various environmental stresses in Arabidopsis, little is known about their function in canola.

The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA's first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations with subcortical volumes (ENIGMA2) and white matter microstructure (ENIGMA-DTI). Working groups also focus on understanding how schizophrenia, bipolar illness, major depression and attention deficit/hyperactivity disorder (ADHD) affect the brain. We review the current progress of the ENIGMA Consortium, along with challenges and unexpected discoveries made on the way.

Biomarkers derived from brain magnetic resonance (MR) imaging have promise in being able to assist in the clinical diagnosis of brain pathologies. These have been used in many studies in which the goal has been to distinguish between pathologies such as Alzheimer's disease and healthy aging. However, other dementias, in particular, frontotemporal dementia, also present overlapping pathological brain morphometry patterns. Hence, a classifier that can discriminate morphometric features from a brain MRI from the three classes of normal aging, Alzheimer's disease (AD), and frontotemporal dementia (FTD) would offer considerable utility in aiding in correct group identification. Compared to the conventional use of multiple pair-wise binary classifiers that learn to discriminate between two classes at each stage, we propose a single three-way classification system that can discriminate between three classes at the same time. We present a novel classifier that is able to perform a three-class discrimination test for discriminating among AD, FTD, and normal controls (NC) using volumes, shape invariants, and local displacements (three features) of hippocampi and lateral ventricles (two structures times two hemispheres individually) obtained from brain MR images. In order to quantify its utility in correct discrimination, we optimize the three-class classifier on a training set and evaluate its performance using a separate test set. This is a novel, first-of-its-kind comparative study of multiple individual biomarkers in a three-class setting. Our results demonstrate that local atrophy features in lateral ventricles offer the potential to be a biomarker in discriminating among AD, FTD, and NC in a three-class setting for individual patient classification.

Tamoxifen has been a frontline treatment for estrogen receptor alpha (ERα)-positive breast tumors in premenopausal women. However, resistance to tamoxifen occurs in many patients. ER still plays a critical role in the growth of breast cancer cells with acquired tamoxifen resistance, suggesting that ERα remains a valid target for treatment of tamoxifen-resistant (Tam-R) breast cancer. In an effort to identify novel regulators of ERα signaling, through a small-scale siRNA screen against histone methyl modifiers, we found WHSC1, a histone H3K36 methyltransferase, as a positive regulator of ERα signaling in breast cancer cells. We demonstrated that WHSC1 is recruited to the ERα gene by the BET protein BRD3/4, and facilitates ERα gene expression. The small-molecule BET protein inhibitor JQ1 potently suppressed the classic ERα signaling pathway and the growth of Tam-R breast cancer cells in culture. Using a Tam-R breast cancer xenograft mouse model, we demonstrated in vivo anti-breast cancer activity by JQ1 and a strong long-lasting effect of combination therapy with JQ1 and the ER degrader fulvestrant. Taken together, we provide evidence that the epigenomic proteins BRD3/4 and WHSC1 are essential regulators of estrogen receptor signaling and are novel therapeutic targets for treatment of Tam-R breast cancer.

The metabolome is a highly dynamic entity and the final readout of the genotype x environment x phenotype (GxExP) relationship of an organism. Monitoring metabolite dynamics over time thus theoretically encrypts the whole range of possible chemical and biochemical transformations of small molecules involved in metabolism. The bottleneck is, however, the sheer number of unidentified structures in these samples. This represents the next challenge for metabolomics technology and is comparable with genome sequencing 30 years ago. At the same time it is impossible to handle the amount of data involved in a metabolomics analysis manually. Algorithms are therefore imperative to allow for automated m/z feature extraction and subsequent structure or pathway assignment. Here we provide an automated pathway inference strategy comprising measurements of metabolome time series using LC- MS with high resolution and high mass accuracy. An algorithm was developed, called mzGroupAnalyzer, to automatically explore the metabolome for the detection of metabolite transformations caused by biochemical or chemical modifications. Pathways are extracted directly from the data and putative novel structures can be identified. The detected m/z features can be mapped on a van Krevelen diagram according to their H/C and O/C ratios for pattern recognition and to visualize oxidative processes and biochemical transformations. This method was applied to Arabidopsis thaliana treated simultaneously with cold and high light. Due to a protective antioxidant response the plants turn from green to purple color via the accumulation of flavonoid structures. The detection of potential biochemical pathways resulted in 15 putatively new compounds involved in the flavonoid-pathway. These compounds were further validated by product ion spectra from the same data. The mzGroupAnalyzer is implemented in the graphical user interface (GUI) of the metabolomics toolbox COVAIN (Sun & Weckwerth, 2012, Metabolomics 8: 81-93). The strategy can be extended to any biological system.

In a deforming anatomic environment, the motion of an instrument suffers from complex geometrical and dynamic constraints, robot assisted minimally invasive surgery therefore requires more sophisticated skills for surgeons. This paper proposes a novel dynamic virtual fixture (DVF) to enhance the surgical operation accuracy of admittance-type medical robotics in the deforming environment.

The B-box (BBX) -containing proteins are a class of zinc finger proteins that contain one or two B-box domains and play important roles in plant growth and development. The Arabidopsis BBX gene family has recently been re-identified and renamed. However, there has not been a genome-wide survey of the rice BBX (OsBBX) gene family until now.

Few drugs are currently licensed to treat influenza A infection, and new therapies are needed, especially for highly pathogenic strains. Traditional medicinal plants, such as Lycoris radiata, are a potential source of new antiviral agents.

Oligocelluloses and oligoxyloses are partially hydrolyzed products from lignocellulosic biomass hydrolysis. Biomass hydrolysates usually contain monosaccharides as well as various amounts of oligosaccharides. To utilize biomass hydrolysates more efficiently, it is important to identify microorganisms capable of converting biomass-derived oligosaccharides into biofuels or biochemicals.