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Background Because androgen receptor (AR) signaling is essential for prostate cancer (PCa) initiation and progression, castration is the main approach for treatment. Unfortunately, patients tend to enter a stage called castration-resistant prostate cancer (CRPC) despite the initial response to castration. For various reasons, AR signaling is reactivated in CRPC. As such, AR signaling inhibitors, such as enzalutamide, has been approved by the Food and Drug Administration to treat CRPC in the clinic. However, the limited success of these new drugs suggests an immediate unmet need to understand the underlying mechanisms for resistance so novel targets can be identified to enhance their efficacy. Methods An unbiased bioinformatics analysis was performed with the existing human patient dataset and RNA-seq results of in-house PCa cell lines to identify new targets to overcome enzalutamide resistance. Cell viability and growth were detected by 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide and colony formation assay. Cell invasion and migration were detected by transwell assay. Protein levels were detected by Western blot or immunofluorescence. Results We found that the noncanonical Wnt signaling was activated in enzalutamide-resistant PCa cells and that the activation of noncanonical Wnt signaling was correlated with AR expression and disease progression. This was validated by the elevated expression of noncanonical Wnt pathway members such as Wnt5a, RhoA, and ROCK in enzalutamide-resistant PCa cells in comparison to their enzalutamide-sensitive counterparts. And, both Y27632, an inhibitor of ROCK, and depletion of ROCK enhanced the efficacy of enzalutamide in enzalutamide-resistant PCa cells. Of significance, a combination of Y27632 and enzalutamide inhibited 22RV1-derived xenograft tumor growth synergistically. Finally, ROCK depletion plus enzalutamide treatment inhibited invasion and migration of enzalutamide-resistant PCa cells via inhibition of epithelial-mesenchymal transition. Conclusions The noncanonical Wnt pathway is activated in enzalutamide-resistant PCa and inhibition of noncanonical Wnt pathway overcomes enzalutamide resistance and enhances its efficacy in CRPC.

Highly efficient Cu(In,Ga)Se2 (CIGS) thin film solar cells are often fabricated with a double Ga grading along the thickness direction of the light absorber. In this work, through a progressive procedure of using time-dependent Ga and In deposition rates, it is manifested that how the detailed shape of the double Ga grading profile in terms of the depth of the V-shape, the width of the V-shape, and the spatial position of the minimum bandgap can be experimentally actively manipulated. Moreover, the effect of the aforementioned features of the Ga grading profile on the photo-generated current has been uncovered by the progressive improvement in the spectral response of the external quantum efficiency spectra. Within the effort of our optimization, a CIGS solar cell with a conversion efficiency of 20.3% is obtained, believed to be the best reported for CIGS solar cells without actively using alkali post deposition treatment technology. This work has provided a practical and operable route to actively control the Ga grading profile and turned the fabrication of high efficiency CIGS solar cell from an art to more a science.

With a colloid aggregation process, chemical bath deposited (CBD) Zn(O,S) thin films always consist of many particles or clusters on the surface and their removal is a long-standing problem. In this work, by varying the substrate orientations and solution movements, their effects on the quality of the Zn(O,S) layers, the formed junctions, and the performance of the Zn(O,S)-Cu(In,Ga)Se2 (CIGS) solar cells have been systematically investigated. Unlike CBD-CdS growth for which stirring or rocking the solution is a common and useful practice for improved quality, surprisingly, for CBD-Zn(O,S) growth, solution movement plays a primary role and substrate orientation plays a secondary role to influence the film quality and the device performance. Equally surprising, the above effects strongly depend on the recipes and chemicals used for the CBD process. It has been identified that, independent of recipes, depositing Zn(O,S) films with the substrate inclined in a static solution can minimize the formation of particles/clusters, generate homogeneous and high quality buffer layers on CIGS with the best device performance. Disturbing the CBD solution would in general introduce large particles/clusters to adsorb on the Zn(O,S) films, leading to degraded junction quality, strong light soaking effect, and poor device performance.

Objective Decoding neural activity has been limited by the lack of tools available to record from large numbers of neurons across multiple cortical regions simultaneously with high temporal fidelity. To this end, we developed the Argo system to record cortical neural activity at high data rates. Approach Here we demonstrate a massively parallel neural recording system based on platinum-iridium microwire electrode arrays bonded to a CMOS voltage amplifier array. The Argo system is the highest channel count in vivo neural recording system, supporting simultaneous recording from 65 536 channels, sampled at 32 kHz and 12-bit resolution. This system was designed for cortical recordings, compatible with both penetrating and surface microelectrodes. Main results We validated this system through initial bench testing to determine specific gain and noise characteristics of bonded microwires, followed by in-vivo experiments in both rat and sheep cortex. We recorded spiking activity from 791 neurons in rats and surface local field potential activity from over 30 000 channels in sheep. Significance These are the largest channel count microwire-based recordings in both rat and sheep. While currently adapted for head-fixed recording, the microwire-CMOS architecture is well suited for clinical translation. Thus, this demonstration helps pave the way for a future high data rate intracortical implant.

Prostate cancer (PCa) is the most commonly diagnosed malignancy among men, and the progression of this disease results in fewer treatment options available to clinical patients. It highlights the vital necessity for discovering novel therapeutic approaches and expanding the current understanding of molecular mechanisms. Epigenetic alternations such as DNA methylation models and histone modifications have been associated as key drivers in the development and advancement of PCa. Several studies have been conducted and demonstrated that targeting these epigenetic enzymes or regulatory proteins has been strongly associated with the regulation of cancer cell growth. Due to the success rate of these therapeutic routes in pre-clinical settings, many drugs have now advanced to clinical testing, where efficacy will be measured. This review will discuss the role of epigenetic modifications in PCa development and its function in the progression of the disease to resistant forms and introduce therapeutic strategies that have demonstrated successful results as PCa treatment.

The effect of photo-irradiation on the removal of Cr(VI) by sludge biochar in neutral conditions is here investigated. The results indicate that photo-irradiation can significantly enhance the removal of aqueous Cr(VI) by sludge biochar. The apparent removal rate constants under ultraviolet (0.61 h−1) and visible-light (0.27 h−1) irradiation are more than 5 and 2 times higher, respectively, than that in the dark (0.11 h−1). Cr(VI) reduction plays a predominant role in Cr removal, accounting respectively for 71.8% (dark), 71.9% (visible light irradiation), and 92.3% (ultraviolet irradiation) of total removal. The abundance of persistent free radicals (PFRs) in biochar (produced hydrothermally at a temperature of 220 °C, a reaction time of 2 h, and a solid weight ratio of 40 %w) can reach up to 4.72 × 1016 spins/g, and their EPR signal intensity remains almost unchanged within 720 min in the dark. Ultraviolet irradiation may promote PFRs production in biochar, and PFRs (especially the oxygen-centered ones) act as electron donors to transform Cr(VI) into Cr(III), thereby contributing to Cr(VI) reduction. Our findings shed new light on the role of irradiation in enhancing the removal of Cr(VI) by sludge biochar under neutral conditions, which can be an interesting technique in the field of environmental remediation.

Background Fetal double aortic arch (DAA) malformation is a rare congenital heart disease with few reported cases in the literature. We aimed to investigate the characteristics of prenatal ultrasound and postnatal computed tomography angiography (CTA) of DAA and to describe the associated anomalies and clinical outcomes to improve prenatal diagnosis and assist in perinatal management. Methods The obstetric ultrasound imaging databases of seven tertiary referral centers were reviewed retrospectively to identify fetuses with a prenatal diagnosis of DAA between January 2013 and December 2018. Ultrasonographic findings, associated anomalies, genetic abnormalities, postnatal CTA images, and long-term postnatal outcomes were evaluated. Results A total of 36 cases out of 40 prenatally diagnosed DAA fetuses were confirmed by postnatal diagnosis (fetal autopsy, CTA, and surgery). In this cohort of 36 confirmed cases, 24 (67%) were isolated anomalies, while 12 (33%) were associated with intracardiac or extracardiac anomalies, and 2 (6%) had a 22q11.2 chromosome deletion. Among nine cases of pregnancy termination with a fetal autopsy, 7 had other abnormalities. Among the remaining 27 live births, 16 (59%) were asymptomatic and 11 (41%) received surgical treatment due to tracheal or esophageal compression symptoms, all with satisfactory outcomes. Prenatal echocardiography showed that DAA was mainly characterized by a bifurcation of the ascending aorta into the right and left aortic arch and the formation of a complete O-shaped vascular ring around the trachea on the three-vessel tracheal view. A variant in the aortic arch branching pattern was found for the first time. The airway obstruction, branching pattern, and atretic arch of DAA were clearly shown by postnatal CTA. Conclusions Fetal DAA has unique features on prenatal echocardiography and postnatal CTA, and systematic prenatal examination and timely postnatal CTA evaluation are required. A certain proportion of intracardiac and extracardiac abnormalities are associated with DAA, but the probability of chromosome abnormalities is low, especially for isolated DAA.The clinical outcomes of isolated DAA are favorable, even if surgery is performed due to symptoms. Determining whether other malformations or chromosomal anomalies exist is crucial for prognosis evaluation and prenatal counseling.

Upregulation of EZH2 is associated with advanced stage and poor prognosis of prostate cancer; therefore, it is likely to be a promising therapeutic target. Metformin, a drug that has been used to treat type 2 diabetes, was found to have antineoplastic activity in different cancers. Herein, we report that the combination of metformin and the EZH2 inhibitor GSK126 exerts synergistic inhibition on prostate cancer cell growth, both in vitro and in vivo. Mechanistically, we identify that metformin can reduce EZH2 expression through upregulating miR-26a-5p, which is antagonized by androgen receptor (AR). Furthermore, we show that AR binds to the promoter of miR-26a-5p and suppresses its transcription. Although metformin can remove AR from the miR-26a-5p promoter, the interaction between AR and EZH2, which usually exists in androgen-refractory prostate cancer cells, strongly impedes the removal. However, GSK126 can inhibit the methyltransferase-dependent interaction between AR and EZH2, thus restoring metformin's efficacy in androgen-refractory prostate cancer cells. Collectively, our finding suggests that the combination of metformin and GSK126 would be an effective approach for future prostate cancer therapy, and particularly effective for AR-positive castration-resistant prostate cancer.

Here we demonstrate the Argo System, a massively parallel neural recording system based on platinum-iridium microwire electrode arrays bonded to a CMOS voltage amplifier array. The Argo system is the highest channel count in vivo neural recording system built to date, supporting simultaneous recording from 65,536 channels, sampled at over 32 kHz and 12-bit resolution. This system is designed for cortical recordings, compatible with both penetrating and surface microelectrodes. We have validated this system by recording spiking activity from 791 neurons in rats and cortical surface Local Field Potential (LFP) activity from over 30,000 channels in sheep. While currently adapted for head-fixed recording, the microwire-CMOS architecture is well suited for clinical translation. Thus, this demonstration helps pave the way for a future high data rate intracortical implant.

Prostate cancer (PCa) is the second leading cause of cancer related deaths in American men. In this study, I identify two combinational therapeutics to treat PCa – the combination of enzalutamide and simvastatin, and the combination of GSK126 and metformin, both of which strongly suppress PCa cell growth in vitro and in vivo via inhibiting androgen receptor (AR), an important oncogenic driver for the PCa progression. Simvastatin leads to more AR degradation when combined with enzalutamide. For the combination of GSK126 and metformin, the interaction between enhance of zeste homolog2 (EZH2) and AR is interrupted by GSK126, re-sensitizing EZH2 to metformin. Meanwhile, GSK126 inhibits EZH2’s activity. Polo-like kinase 1 (PLK1), a cell cycle regulator, is usually overexpressed in non-small-cell lung cancer (NSCLC). Here, we report that PLK1 overexpression promotes the development of KrasG12D and Trp53fl/fl (KP)-driven lung adenocarcinoma (LADC). KP mice harboring transgenic PLK1 (KPPI) display heavier tumor burden, poorer tumor differentiation, and lower survival than KP mice. Mechanistically, PLK1 overexpression enhances the activity of MAPK pathway, via upregulating RET expression in a kinase-dependent manner. Supporting our findings, PLK1 knockout in KP mice reduces RET gene expression, inhibits MAPK pathway activity, and strongly delays LADC development. Therefore, these data reveal that PLK1 functions as an oncogene in KP-driven LADC.

Polo-like kinase 1 (Plk1), a crucial regulator of cell-cycle progression, is overexpressed in multiple types of cancers and has been proven to be a potent and promising target for cancer treatment. In case of prostate cancer, we once showed that antineoplastic activity of Plk1 inhibitor is largely due to inhibition of androgen receptor (AR) signaling. However, we also discovered that Plk1 inhibition causes activation of the β-catenin pathway and increased expression of c-MYC, eventually resulting in resistance to Plk1 inhibition. JQ1, a selective small-molecule inhibitor targeting the amino-terminal bromodomains of BRD4, has been shown to dramatically inhibit c-MYC expression and AR signaling, exhibiting antiproliferative effects in a range of cancers. Because c-MYC and AR signaling are essential for prostate cancer initiation and progression, we aim to test whether targeting Plk1 and BRD4 at the same time is an effective approach to treat prostate cancer. Herein, we show that a combination of Plk1 inhibitor GSK461364A and BRD4 inhibitor JQ1 had a strong synergistic effect on castration-resistant prostate cancer (CRPC) cell lines, as well as in CRPC xenograft tumors. Mechanistically, the synergistic effect is likely due to two reasons: (i) Plk1 inhibition results in the accumulation of β-catenin in the nucleus, thus elevation of c-MYC expression, whereas JQ1 treatment directly suppresses c-MYC transcription; (ii) Plk1 and BRD4 dual inhibition acts synergistically in inhibition of AR signaling. Mol Cancer Ther; 17(7); 1554–65. ©2018 AACR.

The AKT/TSC/mTOR axis is an important pathway controlling cell growth, survival, and proliferation in response to extracellular cues. Recently, it was reported that AKT activity fluctuates across the cell cycle. However, it remains unclear whether downstream targets of AKT are also regulated by the cell cycle. Here, we report that mTORC1 activity inversely correlates with AKT activity during the cell cycle. Mechanistically, Plk1 phosphorylation of TSC1 at S467 and S578 interfered with TSC1/TSC2 binding, destabilized TSC1, promoted dissociation of the TSC complex from the lysosome, and eventually led to mTORC1 activation. Tumors derived from cancer cells expressing the TSC1-S467E/S578E mutant exhibited greater sensitivity to rapamycin than those expressing WT TSC1. Collectively, our data support a model in which Plk1, instead of AKT, regulates the TSC/mTORC1 pathway during mitosis, eventually regulating the efficacy of rapamycin. Significance: This seminal report shows that activation of mTORC1 can be independent of AKT during mitosis. Cancer Res; 78(11); 2864–75. ©2018 AACR.

In this work, adopting tungsten blue oxide (TBO, W10O29 as main phase) as precursor, nano tungsten powder and nano tungsten carbide powder were successfully prepared through two steps of hydrogen reduction and carbonization. In tungsten powder preparation, it was found that the essence of β-W transition was a separation between oxygen removal and phase transition. Based on nucleation energy control, nano tungsten powder with a BET value as high as 25.55 m2/g was prepared. On this basis, nano tungsten carbide powder with a BET value of 3.87 m2/g, which is at a leading level, was obtained by adopting a high temperature-short time process.

Objective. The safe insertion of high density intracortical electrode arrays has been a long-standing practical challenge for neural interface engineering and applications such as brain-computer interfaces (BCIs). However, the pia mater can be difficult to penetrate and causes deformation of underlying cortical tissue during insertion of high-density intracortical arrays. This can lead to neuron damage or failed insertions. The development of a method to ease insertion through the pia mater would represent a significant step toward inserting high density intracortical arrays.Approach. Here we describe a surgical procedure, inspired by laser corneal ablation, that can be used in translational models to thin the pia mater.Main results. We demonstrate that controlled pia removal with laser ablation over a small area of cortex allows for microelectrode arrays to be inserted into the cortex with less force, thus reducing deformation of underlying tissue during placement of the microelectrodes. This procedure allows for insertion of high-density electrode arrays and subsequent acute recordings of spiking neuron activity in sheep cortex. We also show histological and electrophysiological evidence that laser removal of the pia does not acutely affect neuronal viability in the region.Significance. Laser ablation of the pia reduces insertion forces of high-density arrays with minimal to no acute damage to cortical neurons. This approach suggests a promising new path for clinical BCI with high-density microelectrode arrays.

Fluidic control and sampling in complex environments is an important process in biotechnology, materials synthesis, and microfluidics. An elegant solution to this problem has evolved in nature through cellular endocytosis, where the dynamic recruitment, self-assembly, and spherical budding of clathrin proteins allows cells to sample their external environment. Yet despite the importance and utility of endocytosis, artificial systems which can replicate this dynamic behavior have not been developed. Guided by clathrin's unusual structure, we created simplified metallic microparticles that capture the three-legged shape, particle curvature, and interfacial attachment characteristics of clathrin. These artificial clathrin mimics successfully recreate biomimetic analogues of clathrin's recruitment, assembly, and budding, ultimately forming extended networks at fluid interfaces and invaginating immiscible phases into spheres under external fields. Particle curvature was discovered to be a critical structural motif, greatly limiting irreversible aggregation and inducing the legs' selective tip-to-tip attraction. This architecture provides a template for a class of active self-assembly units to drive structural and dimensional transformations of liquid-liquid interfaces and microscale fluidic sampling.

The mitotic kinase Plk1 contributes to the DNA damage response (DDR) by targeting multiple factors downstream of the core responder kinase ATM/ATR. In this study, we show that Polo-like kinase 1 (Plk1) also phosphorylates key factors upstream of ATM/ATR and regulates their DDR-related functions. Plk1 phosphorylated Mre11, a component of the Mre11/Rad50/Nbs1 (MRN) complex, at serine 649 (S649) during DDR. Phosphorylation of Mre11-S649 by Plk1 primed subsequent CK2-mediated phosphorylation at Mre11-serine 688 (S688). Phosphorylation of Mre11 at S649/S688 inhibited loading of the MRN complex to damaged DNA, leading to both premature DNA damage checkpoint termination and inhibition of DNA repair. Tumors expressing phosphomimetic Mre11 were more sensitive to the PARP inhibitor olaparib, compared with those expressing unphosphorylatable Mre11, suggesting that patients with elevated Plk1 expression might benefit from olaparib treatment. Cancer Res; 77(12); 3169–80. ©2017 AACR.

Prostate cancer (PCa) cells heavily rely on an active androgen receptor (AR) pathway for their survival. Enzalutamide (MDV3100) is a second-generation antiandrogenic drug that was approved by the Food and Drug Administration in 2012 to treat patients with castration-resistant prostate cancer (CRPC). However, emergence of resistance against this drug is inevitable, and it has been a major challenge to develop interventions that help manage enzalutamide-resistant CRPC. Erythropoietin-producing human hepatocellular (Eph) receptors are targeted by ephrin protein ligands and have a broad range of functions. Increasing evidence indicates that this signaling pathway plays an important role in tumorigenesis. Overexpression of EPH receptor B4 (EPHB4) has been observed in multiple types of cancer, being closely associated with proliferation, invasion, and metastasis of tumors. Here, using RNA-Seq analyses of clinical and preclinical samples, along with several biochemical and molecular methods, we report that enzalutamide-resistant PCa requires an active EPHB4 pathway that supports drug resistance of this tumor type. Using a small kinase inhibitor and RNAi-based gene silencing to disrupt EPHB4 activity, we found that these disruptions re-sensitize enzalutamide-resistant PCa to the drug both in vitro and in vivo. Mechanistically, we found that EPHB4 stimulates the AR by inducing proto-oncogene c-Myc (c-Myc) expression. Taken together, these results provide critical insight into the mechanism of enzalutamide resistance in PCa, potentially offering a therapeutic avenue for enhancing the efficacy of enzalutamide to better manage this common malignancy.

The solute carriers (SLCs) are membrane proteins that transport many endogenous and exogenous substances such as xenobiotic toxins. Bivalve mollusks, mainly feeding on microalgae, show marked capacity to accumulate paralytic shellfish toxins (PSTs), the most common and hazardous marine biotoxins produced by dinoflagellates. Exploring the SLCs related to PST accumulation in bivalve could benefit our understanding about the mechanisms of PST bioavailability in bivalve and the adaptations of these species. Herein, we provided the first systematic analysis of SLC genes in mollusks, which identified 673 SLCs (PySLCs, 48 subfamilies) in Yesso scallop (Patinopecten yessoensis), 510 (48 subfamilies) in Pacific oyster (Crassostrea gigas), and 350 (47 subfamilies) in gastropod owl limpet (Lottia gigantea). Significant expansion of subfamilies SLC5, SLC6, SLC16, and SLC23 in scallop, and SLC46 subfamily in both scallop and oyster were revealed. Different PySLC members were highly expressed in the developmental stages and adult tissues, and hepatopancreas harboured more specifically expressed PySLCs than other tissues/organs. After feeding the scallops with PST-producing dinoflagellate, 131 PySLCs were regulated and more than half of them were from the expanded subfamilies. The trend of expression fold change in regulated PySLCs was consistent with that of PST changes in hepatopancreas, implying the possible involvement of these PySLCs in PST transport and homeostasis. In addition, the PySLCs from the expanded subfamily were revealed to be under positive selection, which might be related to lineage-specific adaptation to the marine environments with algae derived biotoxins.

Muscle development and regeneration require delicate cell cycle regulation of embryonic myoblasts and adult muscle satellite cells (MuSCs). Through analysis of the Polo-like kinase (Plk) family cell-cycle regulators in mice, we show that Plk1’s expression closely mirrors myoblast dynamics during embryonic and postnatal myogenesis. Cell-specific deletion of Plk1 in embryonic myoblasts leads to depletion of myoblasts, developmental failure and prenatal lethality. Postnatal deletion of Plk1 in MuSCs does not perturb their quiescence but depletes activated MuSCs as they enter the cell cycle, leading to regenerative failure. The Plk1-null MuSCs are arrested at the M-phase, accumulate DNA damage, and apoptose. Mechanistically, Plk1 deletion upregulates p53, and inhibition of p53 promotes survival of the Plk1-null myoblasts. Pharmacological inhibition of Plk1 similarly inhibits proliferation but promotes differentiation of myoblasts in vitro, and blocks muscle regeneration in vivo. These results reveal for the first time an indispensable role of Plk1 in developmental and regenerative myogenesis., eLife digest Muscles have their own population of stem cells, called muscle satellite cells. These cells are essential for muscle growth and repair. In healthy adult muscles, they spend most of their time inactive, but when there is an injury, they reawaken and start dividing. Some of the new cells return to an inactive stem cell state to await the next injury. The rest mature into new muscle cells or join with damaged muscle fibres to help them repair. The cell cycle is the series of events that a cell goes through from its birth until it divides. In muscle satellite cells, progression through the cell cycle is tightly controlled to ensure they divide and grow the correct amount. One of the proteins responsible for controlling the cell cycle is Polo-Like Kinase 1 (PLK1), but studying this protein is difficult. A common way to investigate a protein's effect is to delete the gene that makes it and observe the consequences. However, PLK1 is so essential to life that yeast, flies, zebrafish and mice all die when the gene is missing. Jia et al. deleted the gene that makes PLK1 only in mouse muscle satellite cells to find out the role this protein plays in controlling the cell cycle in stem cells. Deleting the gene that codes for PLK1 before the mice were born was lethal. The embryos failed to develop mature muscle fibres, and they died. But deleting the gene after the mice were born had a different effect. The muscles developed normally, but they were unable to heal when injured. The same healing problem also happened when healthy mice received a drug that blocked the function of PLK1 protein. A closer look at the muscle satellite cells revealed the source of the problem. Without PLK1, the cells got stuck part way through their cell cycle, just before they were due to divide. They tried to become muscle cells, but they did not make it. Instead, the muscle satellite cells started to act as though their DNA had been damaged, and then they self-destructed. Muscle satellite cells become less able to divide as we get older. They can also malfunction in some types of degenerative muscle diseases. Understanding how muscle satellite cells control their cell cycle could help us to find out what causes them to go wrong. Further work to understand PLK1 also has potential implications for cancer treatment. PLK1 blockers have been used to stop cancer cells from dividing, but Jia et al.’s findings show that this kind of drug may also hamper the ability of muscle to repair damage.

Robots in general can be defined as intelligent machines responsible for accomplishing specific task. Through this paper, we are going to design a robot capable of drawing letters based on an input sensory data. This can help people who want to draw words or decorate the courts or fields. It is built by pioneer 3dx combined with different types of sensors like Kinect camera and LIDAR. It will be able to recognize different handwriting by matching what is extracted from the image to database. As a result, it will draw the letters using its WidowX arm. Twenty-six letters were compiled in to specific codes to build up a database for matching stage. The robot was able to analyze and draw the letters perfectly.

While the major function of molybdenum (Mo) back contact on soda‐lime glass (SLG) substrate in Cu(In,Ga)Se2 (CIGS) solar cells is to provide good adhesion and good conductivity, its role as the transportation channel for alkali elements from SLG substrate to CIGS layer has often been overlooked. In this work, we have intentionally fabricated tri‐layered structure in contrast to the conventional bi‐layered structure for Mo back contact with the microstructure of the thin topmost Mo layer manipulated by the Ar pressure and water vapor during sputtering deposition. It has been discovered that the CIGS solar cell conversion efficiency can be greatly affected by this thin topmost Mo layer of the back contact. Investigations on the elemental depth profiles in the CIGS devices and the chemical states of Mo on the back contact surfaces have revealed that the surface layer of Mo back contact has a strong effect on the diffusion of alkali elements from SLG into CIGS absorber layer, which in turn influences the formation of Ga gradient in the CIGS layer and thus the solar cell performance. It was revealed that Mo(OH)6 and MoO3 formed on the surface of Mo back contact play a key role in determining the K atom distribution and Ga gradient. A reaction mechanism was also proposed.

Enzalutamide, approved by the United States Food and Drug Administration in 2018 for the management of metastatic castration-resistant prostate cancer (CRPC), is an androgen receptor (AR) inhibitor. It blocks androgen binding to the AR, AR nuclear translocation, and AR-mediated DNA binding. Unfortunately, a considerable proportion of tumors eventually develop resistance during the treatment. The molecular mechanisms underlying enzalutamide resistance are not completely understood. Enhancer of zeste homolog 2 (EZH2), the catalytic subunit of polycomb repressor complex 2, has been proposed as a prognostic marker for prostate cancer (PCa). With the goal to test whether EZH2 also plays a critical role in acquisition of enzalutamide resistance in CRPC, here we examined whether EZH2 inhibition/depletion enhances the efficacy of enzalutamide in enzalutamide-resistant PCa cells. We show that combining the EZH2 inhibitor GSK126 with enzalutamide synergistically inhibits cell proliferation and colony formation and promotes apoptosis in enzalutamide-resistant PCa cells. EZH2 depletion also overcomes enzalutamide resistance in both cultured cells and xenograft tumors. Mechanistically, we found that EZH2 directly binds to the promoter of prostate-specific antigen and inhibits its expression in enzalutamide-resistant PCa cells. In agreement, bioinformatics analysis of clinical RNA sequencing data involving GSEA indicated a strong correlation between AR and EZH2 gene expression during PCa progression. Our study provides critical insights into the mechanisms underlying enzalutamide resistance, which may offer new approaches to enhance the efficacy of enzalutamide in CRPC.

Prostate cancer is the second leading cause of cancer death among men in the United States. The androgen receptor (AR) antagonist enzalutamide is a Food and Drug Administration–approved drug for treatment of patients with late-stage prostate cancer and is currently under clinical study for early-stage prostate cancer treatment. After a short positive response period, tumors will develop drug resistance. In this study using RNA-Seq and bioinformatics analyses, we observed that NOTCH signaling is a deregulated pathway in enzalutamide-resistant cells. NOTCH2 and c-MYC gene expression positively correlated with AR expression in samples from patient with hormone refractory disease in which AR expression levels correspond to those typically observed in enzalutamide resistance. Cleaved NOTCH1, HES1 (Hes family BHLH transcription factor 1), and c-MYC protein expression levels are elevated in two enzalutamide-resistant cell lines, MR49F and C4-2R, indicating NOTCH signaling activation. Moreover, inhibition of the overexpressed ADAM metallopeptidase domain 10 (ADAM10) in the resistant cells induces an exclusive reduction in cleaved NOTCH1 expression. Furthermore, exposure of enzalutamide-resistant cells to both PF-03084014 and enzalutamide increased cell death, decreased colony formation ability, and resensitized cells to enzalutamide. Knockdown of NOTCH1 in C4-2R increased enzalutamide sensitivity by decreasing cell proliferation and increasing cleaved PARP expression. In a 22RV1 xenograft model, PF-03084014 and enzalutamide decreased tumor growth through reducing cell proliferation and increasing apoptosis. These results indicate that NOTCH1 signaling may contribute to enzalutamide resistance in prostate cancer, and inhibition of NOTCH signaling can resensitize resistant cells to enzalutamide.

Because there is no effective treatment for late‐stage prostate cancer (PCa) at this moment, identifying novel targets for therapy of advanced PCa is urgently needed. A new network‐based systems biology approach, XDeath, is developed to detect crosstalk of signaling pathways associated with PCa progression. This unique integrated network merges gene causal regulation networks and protein‐protein interactions to identify novel co‐targets for PCa treatment. The results show that polo‐like kinase 1 (Plk1) and DNA methyltransferase 3A (DNMT3a)‐related signaling pathways are robustly enhanced during PCa progression and together they regulate autophagy as a common death mode. Mechanistically, it is shown that Plk1 phosphorylation of DNMT3a leads to its degradation in mitosis and that DNMT3a represses Plk1 transcription to inhibit autophagy in interphase, suggesting a negative feedback loop between these two proteins. Finally, a combination of the DNMT inhibitor 5‐Aza‐2’‐deoxycytidine (5‐Aza) with inhibition of Plk1 suppresses PCa synergistically., A unique approach, XDeath is developed to identify novel targets for advanced prostate cancer (PCa). While Polo‐like kinase 1 (Plk1) phosphorylation of DNA methyltransferase 3A (DNMT3a) leads to its degradation in mitosis, DNMT3a represses Plk1 transcription to inhibit autophagy in interphase. This negative feedback loop provides the rationale for a combination therapy to treat advanced PCa.

Gemcitabine is the standard-of-care for chemotherapy in patients with pancreatic adenocarcinoma and it can directly incorporate into DNA or inhibit ribonucleotide reductase to prevent DNA replication and, thus, tumor cell growth. Most pancreatic tumors, however, develop resistance to gemcitabine. Polo-like kinase 1 (Plk1), a critical regulator in many cell cycle events, is significantly elevated in human pancreatic cancer. In this study, we show that Plk1 is required for the G1/S transition and that inhibition of Plk1 significantly reduces the DNA synthesis rate in human pancreatic cancer cells. Furthermore, the combined effect of a specific Plk1 inhibitor GSK461364A with gemcitabine was examined. We show that inhibition of Plk1 significantly potentiates the anti-neoplastic activity of gemcitabine in both cultured pancreatic cancer cells and Panc1-derived orthotopic pancreatic cancer xenograft tumors. Overall, our study demonstrates that co-targeting Plk1 can significantly enhance the efficacy of gemcitabine, offering a promising new therapeutic option for the treatment of gemcitabine-resistant human pancreatic cancer.

In this work, a non-volatile solid organotin thermal stabilizer, pentaerythritol stearate ester-based tin (II) metal alkoxides (PSE-Sn) was synthesized with a very simple process and its impact on the thermal stability and processing performance of PVC was evaluated by conductivity measurement, thermal aging, thermogravimetric analysis, and torque rheometer test. The results showed that the addition of PSE-Sn not only could significantly enhance the thermal stability of PVC, accelerate plasticization, but also improve lubrication performance during PVC processing. Thus, PSE-Sn played the role of tri-functional additives: thermal stabilizer, plasticizer, and lubricant. The joint effects of PSE-Sn with ZnSt2 and CaSt2 on the thermal stability of PVC were also evaluated. Results indicate that there is a good synergistic effect between PSE-Sn and ZnSt2 on the initial color and long-term thermal stability of PVC. However, such synergistic effect was not observed between PSE-Sn and CaSt2. In addition, the working mechanism of PVC stabilization by PSE-Sn was also explored. Furthermore, the thermal stability and processing performance of PSE-Sn and methyl tin mercaptide (MTM) on PVC were comparatively tested. PVC stabilized by MTM possessed the longest color stability. The addition of PSE-Sn could also improve the initial color stability and long-term thermal stability of PVC significantly. The results of tensile test showed that both PSE-Sn and MTM could reduce the average tensile strength of PVC but increase the average elongation at break of PVC.

Enzalutamide, a nonsteroidal second-generation antiandrogen, has been recently approved for the management of castration-resistant prostate cancer (CRPC). Although patients can benefit from enzalutamide at the beginning of this therapy, acquired enzalutamide resistance usually occurs within a short period. This motivated us to investigate the mechanism involved and possible approaches for overcoming enzalutamide resistance in CRPC. In the present study, we found that 3-hydroxy-3-methyl-glutaryl–CoA reductase (HMGCR), a crucial enzyme in the mevalonate pathway for sterol biosynthesis, is elevated in enzalutamide-resistant prostate cancer cell lines. HMGCR knockdown could resensitize these cells to the drug, and HMGCR overexpression conferred resistance to it, suggesting that aberrant HMGCR expression is an important enzalutamide-resistance mechanism in prostate cancer cells. Furthermore, enzalutamide-resistant prostate cancer cells were more sensitive to statins, which are HMGCR inhibitors. Of note, a combination of simvastatin and enzalutamide significantly inhibited the growth of enzalutamide-resistant prostate cancer cells in vitro and tumors in vivo. Mechanistically, simvastatin decreased protein levels of the androgen receptor (AR), which was further reduced in combination with enzalutamide. We observed that the decrease in AR may occur through simvastatin-mediated inhibition of the mTOR pathway, whose activation was associated with increased HMGCR and AR expression. These results indicate that simvastatin enhances the efficacy of enzalutamide-based therapy, highlighting the therapeutic potential of statins to overcome enzalutamide resistance in CRPC.

Mitogen-activated protein kinase kinases (MKK) are the essential components of the evolutionarily conserved MAPK signaling cascade, which regulates a variety of cellular activities and innate immune responses. Although MKK genes have been extensively studied in various vertebrate and invertebrate species, they have not been systematically characterized in bivalves. In this study, we identified and characterized five MKK genes (PyMKK1/2, PyMKK4, PyMKK5, PyMKK3/6 and PyMKK7) in the Yesso scallop (Patinopecten yessoensis). Phylogenetic and protein structural analyses were conducted to determine their identities and evolutionary relationships. To gain insights into the possible roles of MKK genes during scallop innate immune responses, quantitative real-time PCR (qRT-PCR) was used to investigate their expression profiles during different developmental stages in samples taken from healthy adult tissues and hemocytes after Micrococcus luteus and Vibrio anguillarum bacterial infections. The Yesso scallop MKKs (PyMKKs) were found to have highly conserved structural features compared to the MKK genes from other invertebrate species. Using qRT-PCR analysis, three distinct expression patterns were detected among the PyMKKs over the course of ten different developmental stages. In adult scallops, the majority of the PyMKKs were highly expressed in mantle, gill, muscle and hemocytes. The differential expression patterns of the five PyMKKs after M. luteus (Gram-positive) and V. anguillarum (Gram-negative) bacterial infections suggested their possible involvement in the innate immune response and provide the foundation and resource for the further study on innate immune response of MAPK signal pathway in mollusk.

MDC1 is a central player in checkpoint activation and subsequent DNA repair following DNA damage. Although MDC1 has been studied extensively, many of its known functions, to date, pertain to the DNA damage response (DDR) pathway. Herein we report a novel function of phosphorylated MDC1 that is independent of ATM and DNA damage and is required for proper mitotic progression and maintenance of genomic stability. We demonstrate that MDC1 is an in vivo target of Plk1 and that phosphorylated MDC1 is dynamically localized to nuclear envelopes, centrosomes, kinetochores, and midbodies. Knockdown of MDC1 or abrogation of Plk1 phosphorylation of MDC1 causes a delay of the prometaphase-metaphase transition. It is significant that mice with reduced levels of MDC1 showed an elevated level of spontaneous tumors in aged animals. Our results demonstrate that MDC1 also plays a fundamentally significant role in maintenance of genomic stability through a DDR-independent pathway.

Reconstructing the genomes of bilaterian ancestors is central to our understanding of animal evolution, where knowledge from ancient and/or slow-evolving bilaterian lineages is critical. Here we report a high-quality, chromosome-anchored reference genome for the scallop Patinopecten yessoensis, a bivalve mollusc that has a slow-evolving genome with many ancestral features. Chromosome-based macrosynteny analysis reveals a striking correspondence between the 19 scallop chromosomes and the 17 presumed ancestral bilaterian linkage groups at a level of conservation previously unseen, suggesting that the scallop may have a karyotype close to that of the bilaterian ancestor. Scallop Hox gene expression follows a new mode of subcluster temporal co-linearity that is possibly ancestral and may provide great potential in supporting diverse bilaterian body plans. Transcriptome analysis of scallop mantle eyes finds unexpected diversity in phototransduction cascades and a potentially ancient Pax2/5/8-dependent pathway for noncephalic eyes. The outstanding preservation of ancestral karyotype and developmental control makes the scallop genome a valuable resource for understanding early bilaterian evolution and biology.

Heat shock protein 70 (Hsp70s) family members are present in virtually all living organisms and perform a fundamental role against different types of environmental stressors and pathogenic organisms. Marine bivalves live in highly dynamic environments and may accumulate paralytic shellfish toxins (PSTs), a class of well-known neurotoxins closely associated with harmful algal blooms (HABs). Here, we provide a systematic analysis of Hsp70 genes (PyHsp70s) in the genome of Yesso scallop (Patinopecten yessoensis), an important aquaculture species in China, through in silico analysis using transcriptome and genome databases. Phylogenetic analyses indicated extensive expansion of Hsp70 genes from the Hspa12 sub-family in the Yesso scallop and also the bivalve lineages, with gene duplication events before or after the split between the Yesso scallop and the Pacific oyster. In addition, we determined the expression patterns of PyHsp70s after exposure to Alexandrium catenella, the dinoflagellate producing PSTs. Our results confirmed the inducible expression patterns of PyHsp70s under PSTs stress, and the responses to the toxic stress may have arisen through the adaptive recruitment of tandem duplication of Hsp70 genes. These findings provide a thorough overview of the evolution and modification of the Hsp70 family, which will gain insights into the functional characteristics of scallop Hsp70 genes in response to different stresses.

Olaparib is an FDA-approved PARP inhibitor (PARPi) that has shown promise as a synthetic lethal treatment approach for BRCA-mutant castration-resistant prostate cancer (CRPC) in clinical use. However, emerging data have also shown that even BRCA-mutant cells may be resistant to PARPi. The mechanistic basis for these drug resistances is poorly understood. Polo-like kinase 1 (Plk1), a critical regulator of many cell-cycle events, is significantly elevated upon castration of mice carrying xenograft prostate tumors. Herein, by combination with Plk1 inhibitor BI2536, we show a robust sensitization of olaparib in 22RV1, a BRCA1-deficient CRPC cell line, as well as in CRPC xenograft tumors. Mechanistically, monotherapy with olaparib results in an override of the G1–S checkpoint, leading to high expression of Plk1, which attenuates olaparib's overall efficacy. In BRCA1 wild-type C4-2 cells, Plk1 inhibition also significantly increases the efficacy of olaparib in the presence of p53 inhibitor. Collectively, our findings not only implicate the critical role of Plk1 in PARPi resistance in BRCA-mutant CRPC cells, but also shed new light on the treatment of non-BRCA–mutant patient subgroups who might also respond favorably to PARPi. Mol Cancer Ther; 16(3); 469–79. ©2017 AACR.

Using the GGA functional in density functional theory, the effects of axial strain on the band structure and effective mass of narrow [110] and [100] germanium nanowires are investigated. It is observed that both compressive and tensile strain cause indirect-to-direct bandgap transitions. One percent of tensile strain can cause a 40 meV change in the bandgap of [110] nanowires. Effective masses of electrons and holes are subject to a change of 3–4 times in the strain-induced transition point. This change translates into a density of state modulation which opens new possibilities for the construction of Ge nanowire-based sensors. (© 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

Using density functional theory and semi-empirical sp3d5s* tight binding calculations, we find that a 1% axial strain can change the bandgap of Hydrogenated Silicon nanowires by up to 100 meV. Further, compressive strain causes a direct-to-indirect bandgap transition. As the nanowire diameter increases, this transition occurs at smaller compressive strains, which makes it easier to experimentally observe. We also find that the rate of change of bandgap with strain is relatively independent of diameter for small diameter nanowires and only the geometry of the bonds (growth direction) determines its value. These robust effects also manifest as a large effective-mass change with strain, which could prove useful in SiNW-based sensors.

In conclusion we have observed dramatic change in the band structure of SiNW which prove exploitable in many silicon based optical and mechanical sensors and devices. The transition from indirect to direct region proves that a transparent NW can be converted to an absorptive one. Stress induced by temperature and/or lattice mismatch (e.g. Si/Ge epitaxial layers) can be the basis for myriad of sensor schemes based on the results in this paper. Literature shows the possibility of growing nanowires in a bridge-like structure on a deformable substrate (R. He et al., 2006).

This work computationally investigates the electromechanical properties of hydrogen passivated silicon nanowires under uniaxial tensile strain. It has been observed that bandgap changes can be as large as 60 and 100 meV per 1% axial strain for [100] and [110] nanowires, respectively. This rate of change in the bandgap is independent of nanowire size and depends only on the growth direction. More importantly, the nature of the bandgap can reversibly change from indirect to direct as a function of strain. It is also observed that for larger diameter nanowires, the indirect-to-direct transition occurs at smaller compressive strain.