HFD-exacerbated Metabolic Side Effects of Olanzapine Are Suppressed by ER Stress Inhibitor.

OBJECTIVE: Numerous schizophrenic patients are suffering from obesity primarily attributed to antipsychotic medication and poor dietary habits. This study investigated the progressive deterioration of olanzapine-induced metabolic disorders in the presence of a high-fat diet (HFD) and explored the involvement of endoplasmic reticulum (ER) stress. METHODS: Female Sprague-Dawley rats fed on a standard chow diet or HFD were treated with olanzapine (3 mg/kg/day) and the ER stress inhibitor 4-phenylbutyric acid (4-PBA, 1 and 0.5 g/kg/day) for 8 days. Changes in body weight, food intake, and plasma lipids were assessed. Hepatic fat accumulation was evaluated using oil red O staining. Western blotting and immunofluorescence assays were employed to examine the expression of ER stress markers, NOD-like receptor pyrin domain-containing protein 3 (NLRP3), and proopiomelanocortin (POMC) in the hypothalamus or liver. RESULTS: Compared to olanzapine alone, olanzapine+HFD induced greater weight gain, increased hyperlipidemia, and enhanced hepatic fat accumulation (P<0.05). Co-treatment with 4-PBA exhibited a dose-dependent inhibition of these effects (P<0.05). Further mechanistic investigations revealed that olanzapine alone activated ER stress, upregulated NLRP3 expression in the hypothalamus and liver, and downregulated hypothalamic POMC expression. The HFD exacerbated these effects by 50%-100%. Moreover, co-administration of 4-PBA dose-dependently attenuated the olanzapine+HFD-induced alterations in ER stress, NLRP3, and POMC expression in the hypothalamus and liver (P<0.05). CONCLUSION: HFD worsened olanzapine-induced weight gain and lipid metabolic disorders, possibly through ER stress-POMC and ER stress-NLRP3 signaling. ER stress inhibitors could be effective in preventing olanzapine+HFD-induced metabolic disorders.

Feasibility of the novel vascular disrupting agent C118P for facilitating high-intensity focused ultrasound ablation of uterine fibroids.

OBJECTIVE: In this study, C118P, a novel vascular disrupting agent (VDA), was evaluated for its ability in improving the ablative effect of high-intensity focused ultrasound (HIFU) on uterine fibroids by reducing blood perfusion. METHODS: Eighteen female rabbits were infused with isotonic sodium chloride solution (ISCS), C118P or oxytocin for 30 min, and an HIFU ablation of the leg muscles was performed within the last 2 min. Blood pressure, heart rate and laser speckle flow imaging (LSFI) of the auricular blood vessels were recorded during perfusion. Ears with vessels, uterus and muscle ablation sites were collected and sliced for hematoxylin-eosin (HE) staining to compare vascular size, as well as nicotinamide adenine dinucleotide-tetrazolium reductase (NADH-TR) staining to observe necrosis after ablation. RESULTS: Analyses revealed that the perfusion of C118P or oxytocin steadily reduced blood perfusion in the ears to approximately half by the end of the perfusion, constricted the blood vessels of the ears and uterus, and improved HIFU ablation in the muscle tissues. C118P increased blood pressure and decreased heart rate. The degree of contraction of the auricular and uterine blood vessels was positively correlated. CONCLUSION: This study confirmed that C118P could reduce blood perfusion in various tissues and had a better synergistic effect with HIFU ablation of muscle (the same tissue type as fibroids) than did oxytocin. C118P could therefore possibly replace oxytocin in facilitating HIFU ablation of uterine fibroids; however, electrocardiographic monitoring is required.

Core-binding factor fusion downregulation of ADAR2 RNA editing contributes to AML leukemogenesis.

Adenosine-to-inosine RNA editing, which is catalyzed by adenosine deaminases acting on RNA (ADAR) family of enzymes, ADAR1 and ADAR2, has been shown to contribute to multiple cancers. However, other than the chronic myeloid leukemia blast crisis, relatively little is known about its role in other types of hematological malignancies. Here, we found that ADAR2, but not ADAR1 and ADAR3, was specifically downregulated in the core-binding factor (CBF) acute myeloid leukemia (AML) with t(8;21) or inv(16) translocations. In t(8;21) AML, RUNX1-driven transcription of ADAR2 was repressed by the RUNX1-ETO additional exon 9a fusion protein in a dominant-negative manner. Further functional studies confirmed that ADAR2 could suppress leukemogenesis specifically in t(8;21) and inv16 AML cells dependent on its RNA editing capability. Expression of 2 exemplary ADAR2-regulated RNA editing targets coatomer subunit α and component of oligomeric Golgi complex 3 inhibits the clonogenic growth of human t(8;21) AML cells. Our findings support a hitherto, unappreciated mechanism leading to ADAR2 dysregulation in CBF AML and highlight the functional relevance of loss of ADAR2-mediated RNA editing to CBF AML.

Stable and Ordered Body-Centered Cubic PdCu Phase for Highly Selective Hydrogenation.

Phase engineering of nanomaterials plays a crucial role for regulating the catalytic performance. Nevertheless, great challenges still remain for elucidating the structure-selectivity correlation. Herein, this study demonstrates that the body-centered cubic phase of PdCu (bcc-PdCu) can serve as a highly active and selective catalyst for 3-nitrostyrene (NS) hydrogenation under mild conditions. In particular, bcc-PdCu displays a 3-nitro-ethylbenzene (NE) selectivity of 93.8% with a turnover frequency (TOF) value of 4573 h-1 at 30 °C in the presence of H2 . With the assistance of NH3 ∙BH3 , the selectivity of 3-amino-styrene (AS) reaches 94.5% with a TOF value of 13 719 h-1 . Detailed experimental and theoretical calculations reveal that improved NE selectivity is ascribed to the selective adsorption of the CC bond and desorption of NE on bcc-PdCu. Moreover, the presence of NH3 ∙BH3 facilitates the selective hydrogenation of NO2 due to their strong interaction and thus leads to the formation of AS. This work provides an efficient selective catalyst for NS hydrogenation under mild conditions, which may attract immediate interests in the fields of materials, chemistry, and catalysis.

Smart Humidly Adaptive Yarns and Textiles from Twisted and Coiled Viscose Fiber Artificial Muscles.

The self-adaptive nature of smart textiles to the ambient environment has made them an indispensable part of emerging wearable technologies. However, current advances generally suffer from complex material preparation, uncomfortable fitting feeling, possible toxicity, and high cost in fabrication, which hinder the real-world application of smart materials in textiles. Herein, humidity-response torsional and tensile yarn actuators from twisted and coiled structures are developed using commercially available, cost-effective, and biodegradable viscose fibers based on yarn-spinning and weaving technologies. The twisted yarn shows a reversible torsional stroke of 1400° cm-1 in 5 s when stimulated by water fog with a spraying speed of 0.05 g s-1; the coiled yarn exhibits a peak tensile stroke of 900% upon enhancing the relative humidity. Further, textile manufacturing allows for the scalable fabrication to create fabric artificial muscles with high-dimensional actuation deformations and human-touch comfort, which can boost the potential applications of the humidly adaptive yarns in smart textile and advanced textile materials.

Individualized pathway activity algorithm identifies oncogenic pathways in pan-cancer analysis.

BACKGROUND: Accumulative evidences have shown that dysregulation of biological pathways contributed to the initiation and progression of malignant tumours. Several methods for pathway activity measurement have been proposed, but they are restricted to making comparisons between groups or sensitive to experimental batch effects. METHODS: We introduced a novel method for individualized pathway activity measurement (IPAM) that is based on the ranking of gene expression levels in individual sample. Taking advantage of IPAM, we calculated the pathway activity of 318 pathways from KEGG database in the 10528 tumour/normal samples of 33 cancer types from TCGA to identify characteristic dysregulated pathways among different cancer types. FINDINGS: IPAM precisely quantified the level of activity of each pathway in pan-cancer analysis and exhibited better performance in cancer classification and prognosis prediction over five widely used tools. The average ROC-AUC of cancer diagnostic model using tumour-educated platelets (TEPs) reached 92.84%, suggesting the potential of our algorithm in early diagnosis of cancer. We identified several pathways significantly deregulated and associated with patient survival in a large fraction of cancer types, such as tyrosine metabolism, fatty acid degradation, cell cycle, p53 signalling pathway and DNA replication. We also confirmed the dominant role of metabolic pathways in cancer pathway dysregulation and identified the driving factors of specific pathway dysregulation, such as PPARA for branched-chain amino acid metabolism and NR1I2, NR1I3 for fatty acid metabolism. INTERPRETATION: Our study will provide novel clues for understanding the pathological mechanisms of cancer, ultimately paving the way for personalized medicine of cancer. FUNDING: A full list of funding can be found in the Acknowledgements section.

Integration of Multifocal Microlens Array on Silicon Microcantilever via Femtosecond-Laser-Assisted Etching Technology.

Micro-opto-electromechanical systems (MOEMSs) are a new class of integrated and miniaturized optical systems that have significant applications in modern optics. However, the integration of micro-optical elements with complex morphologies on existing micro-electromechanical systems is difficult. Herein, we propose a femtosecond-laser-assisted dry etching technology to realize the fabrication of silicon microlenses. The size of the microlens can be controlled by the femtosecond laser pulse energy and the number of pulses. To verify the applicability of this method, multifocal microlens arrays (focal lengths of 7-9 µm) were integrated into a silicon microcantilever using this method. The proposed technology would broaden the application scope of MOEMSs in three-dimensional imaging systems.

Hierarchically Structured and Scalable Artificial Muscles for Smart Textiles.

Fiber-based artificial muscles with excellent actuation performance are gaining great attention as soft materials for flexible actuators; however, current advances in fiber-based artificial muscles generally suffer from high cost, harsh stimulation regimes, limiting deformations, chemical toxicity, or complex manufacturing processing, which hinder the widespread application of those artificial muscles in engineering and practical usage. Herein, a facile cross-scale processing strategy is presented to construct commercially available nontoxic viscose fibers into fast responsive and humidity-driven yarn artificial muscles with a recorded torsional stroke of 1752° cm-1 and a maximum rotation speed up to 2100 rpm, which are comparable to certain artificial muscles made from carbon-based composite materials. The underlying mechanism of such outstanding actuation performance that begins to form at a mesoscale is discussed by theoretical modeling and microstructure characterization. The as-prepared yarn artificial muscles are further scaled up to large-sized fabric muscles through topological weaving structures by integrating different textile technologies. These fabric muscles extend the simple motion of yarn muscles into higher-level diverse deformations without any composite system, complex synthetic processing, and component design, which enables the development of new fiber-based artificial muscles for versatile applications, such as smart textiles and intelligent systems.

M × N electrically controlled optofluidic matrix switch.

A completely non-blocking M×N electrically controlled optofluidic matrix switch that uses a 1×3 optical switch with a V-shaped microchannel as the switching unit is proposed. Its light paths and output ports are selected by a micro-actuator matrix and a control circuit. There are few reports of optofluidic matrix switches. Here the given electrostatic micro-actuator and the basic switch structure provide an effective feasible manner for the matrix switch due to the simple and compact structure as well as the operation style. The impacts of microchannels and intersecting waveguides on the switch performance are discussed, and multiple optimization schemes are proposed to reduce the insertion loss efficiently and significantly. The research results indicate that the M×N matrix switch has the advantages of good matrix controllability, simple structure, wide waveband (400-1700 nm), negligible polarization-dependent loss, small insertion loss, and low cross talk. For 1550 nm wavelength, the insertion loss of a 2×6 matrix switch is about 0.17-0.55 dB, and the maximum cross talk is less than -26.8dB. In addition, the performance parameters of a 4×8 matrix switch are given and compared with other reported matrix switches. The proposed M×N matrix switch solves the problem of large insertion loss of general optical matrix switches and can be expanded to a large-scale matrix switch. Moreover, the design of multiple output ports has more flexible applications in systems with multiple branch optical paths and network nodes.

ZNF143 mediates CTCF-bound promoter-enhancer loops required for murine hematopoietic stem and progenitor cell function.

CCCTC binding factor (CTCF) is an important factor in the maintenance of chromatin-chromatin interactions, yet the mechanism regulating its binding to chromatin is unknown. We demonstrate that zinc finger protein 143 (ZNF143) is a key regulator for CTCF-bound promoter-enhancer loops. In the murine genome, a large percentage of CTCF and ZNF143 DNA binding motifs are distributed 37 bp apart in the convergent orientation. Furthermore, deletion of ZNF143 leads to loss of CTCF binding on promoter and enhancer regions associated with gene expression changes. CTCF-bound promoter-enhancer loops are also disrupted after excision of ZNF143. ZNF143-CTCF-bound promoter-enhancer loops regulate gene expression patterns essential for maintenance of murine hematopoietic stem and progenitor cell integrity. Our data suggest a common feature of gene regulation is that ZNF143 is a critical factor for CTCF-bound promoter-enhancer loops.

Multiomics dissection of molecular regulatory mechanisms underlying autoimmune-associated noncoding SNPs.

More than 90% of autoimmune-associated variants are located in noncoding regions, leading to challenges in deciphering the underlying causal roles of functional variants and genes and biological mechanisms. Therefore, to reduce the gap between traditional genetic findings and mechanistic understanding of disease etiologies and clinical drug development, it is important to translate systematically the regulatory mechanisms underlying noncoding variants. Here, we prioritized functional noncoding SNPs with regulatory gene targets associated with 19 autoimmune diseases by incorporating hundreds of immune cell-specific multiomics data. The prioritized SNPs are associated with transcription factor (TF) binding, histone modification, or chromatin accessibility, indicating their allele-specific regulatory roles. Their target genes are significantly enriched in immunologically related pathways and other known immunologically related functions. We found that 90.1% of target genes are regulated by distal SNPs involving several TFs (e.g., the DNA-binding protein CCCTC-binding factor [CTCF]), suggesting the importance of long-range chromatin interaction in autoimmune diseases. Moreover, we predicted potential drug targets for autoimmune diseases, including 2 genes (NFKB1 and SH2B3) with known drug indications on other diseases, highlighting their potential drug repurposing opportunities. Taken together, these findings may provide useful information for future experimental follow-up and drug applications on autoimmune diseases.

Modeling circRNA expression pattern with integrated sequence and epigenetic features demonstrates the potential involvement of H3K79me2 in circRNA expression.

MOTIVATION: CircRNAs are an abundant class of non-coding RNAs with widespread, cell-/tissue-specific patterns. Previous work suggested that epigenetic features might be related to circRNA expression. However, the contribution of epigenetic changes to circRNA expression has not been investigated systematically. Here, we built a machine learning framework named CIRCScan, to predict circRNA expression in various cell lines based on the sequence and epigenetic features. RESULTS: The predicted accuracy of the expression status models was high with area under the curve of receiver operating characteristic (ROC) values of 0.89-0.92 and the false-positive rates of 0.17-0.25. Predicted expressed circRNAs were further validated by RNA-seq data. The performance of expression-level prediction models was also good with normalized root-mean-square errors of 0.28-0.30 and Pearson's correlation coefficient r over 0.4 in all cell lines, along with Spearman's correlation coefficient ρ of 0.33-0.46. Noteworthy, H3K79me2 was highly ranked in modeling both circRNA expression status and levels across different cells. Further analysis in additional nine cell lines demonstrated a significant enrichment of H3K79me2 in circRNA flanking intron regions, supporting the potential involvement of H3K79me2 in circRNA expression regulation. AVAILABILITY AND IMPLEMENTATION: The CIRCScan assembler is freely available online for academic use at https://github.com/johnlcd/CIRCScan. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

A novel dual sensitive polymer-gambogic acid conjugate: synthesis, characterization, and in vitro evaluation.

Currently, bio-simulate drug delivery systems are highly considered for efficient targeting of tumors. Nevertheless, there are some potential problems such as intelligent release efficiency, subsequently, influence cell toxicity and blood circulation stability. A novel type of stimuli-responsive nanoparticle was developed in accordance with the specific tumor microenvironment to deliver gambogic acid (GA). Herein, we successfully connected GA with mPEG via two different sensitive linkages, valine-citrulline (VC) and cystamine. The structure was characterized by ESI-MS, 1H NMR, FT-IR or MALDI-TOF-MS. The mPEG-VC-SS-GA-NPs (PVSG-NPs) were rapidly prepared. The properties of nanoparticles, including solubility, particle size, morphology, and sensitive drug release performance, were investigated. Compared to single sensitive conjugate (mPEG-SS-GA-NPs, PSG-NPs), PVSG-NPs demonstrated greater solubility and higher sensitive release profile. Cytotoxicity test indicated that PVSG-NPs had apparent cytotoxicity on HepG2 cells and reduced cytotoxicity on normal cells. Additionally, PVSG-NPs mainly kill HepG2 cells by inducing early and late apoptosis and restraining the G0/G1 phase proliferation. Albumin adsorption test revealed that the PVSG-NPs had little albumin combination, consequently, enhancing their circulation constancy. In summary, our findings suggested the novel PVSG-NPs capable of being used for tumor targeting and further practical applications.

Co9 S8 -Catalyzed Growth of Thin-Walled Graphite Microtubes for Robust, Efficient Overall Water Splitting.

Co9 S8 crystals can catalyze the growth of thin-walled graphite microtubes (GMTs) through a catalytic chemical vapor deposition (CCVD) process using thiourea as the precursor. The growth of GMTs follows a tip-growth mechanism with tube diameters up to a few micrometer. The hollow interiors of the GMTs are filled with carbon nanotubes and wrinkled graphene layers, which form a unique nanotube/graphene-in-microtube structure. As-formed GMTs are N,S-codoped with lots of Co9 S8 nanoparticles encapsulated in their inner walls. These GMTs are room-temperature ferromagnets and can be loaded on Ni foams to work as binder-free electrocatalysts with low overpotential (310 mV at 50 mA cm-2 for the oxygen evolution reaction (OER) and 284 mV at 50 mA cm-2 for the hydrogen evolution reaction (HER)) and long-term durability (continuous work for 120 h without loss in performance). Our research proves that metal sulfides can catalyze the growth of graphite microtubes and as-formed GMTs may potentially be used as functional building blocks to construct new kinds of electrochemical devices for various energy-related applications.

Recent advances in the development of dual VEGFR and c-Met small molecule inhibitors as anticancer drugs.

Vascular endothelial growth factor receptor (VEGFR) is a very important receptor tyrosine kinase (RTK) that can induce angiogenesis, increase cell growth and metastasis, reduce apoptosis, alter cytoskeletal function, and affect other biologic changes. Moreover, it is identified to be deregulated in varieties of human cancers. Therefore, VEGFR turn out to be a remarkable target of significant types of anticancer drugs in clinical trials. On the other side, c-Met is the receptor of hepatocyte growth factor (HGF) and a receptor tyrosine kinase. Previous studies have shown that c-Met elicits many different signaling pathways mediating cell proliferation, migration, differentiation, and survival. Furthermore, the correlation between aberrant signaling of the HGF/c-Met pathway and aggressive tumor growth, poor prognosis in cancer patients has been established. Recent reports had shown that c-Met/HGF and VEGFR/VEGF (vascular endothelial growth factor) can act synergistically in the progression of many diseases. They were also found to be over expressed in many human cancers. Thus, in a variety of malignancies, VEGFR and c-Met receptor tyrosine kinases have acted as therapeutic targets. With the development of molecular biology techniques, further understanding of the human tumor disease pathogenesis and interrelated signaling pathways known to tumor cells, using a single target inhibitors have been difficult to achieve the desired therapeutic effect. At this point, with respect to the combination of two inhibitors, a single compound which is able to inhibit both VEGFR and c-Met may put forward the advantage of raising anticancer activity. With the strong interest in these compounds, this review represents a renewal of previous works on the development of dual VEGFR and c-Met small molecule inhibitors as novel anti-cancer agents. Newly collection derivatives have been mainly describing in their biological profiles and chemical structures.

Crystal structure-based discovery of a novel synthesized PARP1 inhibitor (OL-1) with apoptosis-inducing mechanisms in triple-negative breast cancer.

Poly (ADP-ribose) polymerase-1 (PARP1) is a highly conserved enzyme focused on the self-repair of cellular DNA damage. Until now, numbers of PARP inhibitors have been reported and used for breast cancer therapy in recent years, especially in TNBC. However, developing a new type PARP inhibitor with distinctive skeleton is alternatively promising strategy for TNBC therapy. In this study, based on co-crystallization studies and pharmacophore-docking-based virtual screening, we discovered a series of dihydrodibenzo[b,e]-oxepin compounds as PARP1 inhibitors. Lead optimization result in the identification of compound OL-1 (2-(11-(3-(dimethylamino)propylidene)-6,11- dihydrodibenzo[b,e]oxepin )-2-yl)acetohydrazide), which has a novel chemical scaffold and unique binding interaction with PARP1 protein. OL-1 demonstrated excellent potency (inhibiting PARP1 enzyme activity with IC50 = 0.079 µM), as well as inhibiting PARP-modulated PARylation and cell proliferation in MDA-MB-436 cells (BRAC1 mutation). In addition, OL-1 also inhibited cell migration that closely related to cancer metastasis and displayed remarkable anti-tumor efficacy in MDA-MB-436 xenograft model without apparent toxicities. These findings highlight a new small-molecule PAPR1 inhibitor (OL-1) that has the potential to impact future TNBC therapy.

Systems biology-based discovery of a potential Atg4B agonist (Flubendazole) that induces autophagy in breast cancer.

The aim of this study was to explore the autophagy-related protein 4B(ATG4B) and its targeted candidate agonist in triple-negative breast cancer (TNBC) therapy. In this study, the identification of Atg4B as a novel breast cancer target for screening candidate small molecular agonists was performed by phylogenetic analysis, network construction, molecular modelling, molecular docking and molecular dynamics (MD) simulation. In vitro, MTT assay, electron microscopy, western blot and ROS measurement were used for validating the efficacy of the candidate compounds. We used the phylogenetic analysis of Atg4B and constructed their protein-protein interaction (PPI) network. Also, we screened target compounds of Atg4 proteins from Drugbank and ZINC. Flubendazole was validated for its anti-proliferative efficacy in MDA-MB-231 cells. Further MD simulation results supported the stable interaction between Flubendazole and Atg4B. Moreover, Flubendazole induced autophagy and increased ROS production. In conclusion, in silico analysis and experimental validation together demonstrate that Flubendazole can target Atg4B in MDA-MB-231 cells and induce autophagy, which may shed light on the exploration of this compound as a potential new Atg4B targeted drug for future TNBC therapy.

Organocatalytic cascade reaction for the asymmetric synthesis of novel chroman-fused spirooxindoles that potently inhibit cancer cell proliferation.

The enantioselective preparation of pharmacologically interesting chroman-fused spirooxindole derivatives is described based on an organocatalytic multicomponent cascade reaction. The compounds synthesized using this method potently inhibited the proliferation of various cancer cell lines. The most potent compound (7e) induced caspase-independent apoptosis and cell cycle arrest in MCF-7 breast cancer cells by interfering with the p53-MDM2 interaction and downstream pathways.