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Peptide therapeutics hold great promise for the treatment of cancer due to low toxicity, high specificity, and ease of synthesis and modification. However, the unfavorable pharmacokinetic parameters strictly limit their therapeutic efficacy and clinical translation. Here, we tailor-designed an amphiphilic chimeric peptide through conjugation of functional 3-diethylaminopropyl isothiocyanate (DEAP) molecules to a short antitumor peptide, C16Y. The ultimate DEAP–C16Y peptides self-assembled into spherical nanostructures at physiologic conditions, which dissociated to release individual peptide molecules in weakly acidic tumors. DEAP–C16Y peptides showed negligible cytotoxicity but impaired vascular endothelial cell migration and tubule formation by inactivation of the focal adhesion kinase and PI3K–Akt pathways, as well as tumor cell invasion by decreasing invadopodia formation. Compared with C16Y, the systemically administered DEAP–C16Y nanostructures exhibited superior stability, thereby allowing prolonged treatment interval and resulting in significant decreases in microvessel density, tumor growth, and distant metastasis formation in orthotopic mammary tumor models. Through encapsulation of hydrophobic doxorubicin, DEAP–C16Y nanostructure served as a smart carrier to achieve targeted drug delivery and combination therapy. Our study, for the first time, demonstrates that a simple nanoformulation using a functional antitumor peptide as the building block can show innate antitumor activity and also provide a nanoplatform for combination therapy, opening a new avenue for the design of antitumor nanotherapeutics. Mol Cancer Ther; 14(10); 2390–400. ©2015 AACR.

Supplementary Materials and Methods; Supplementary Table S1; Supplementary Figures S1-S5. Supplementary materials and methods shows detailed materials and methods of evaluation of the drug loading and release profiles of DEAP-C16Y-Dox. Supplementary Table S1 shows encapsulation and loading efficiency of Dox in DEAP-C16Y-Dox or DEAP-HSAF-Dox. Supplementary Figure S1 shows characterization of the DEAP-C16Y self-assembling nanoprobe. Supplementary Figure S2 shows DEAP-HSAF nanostructure and effects of DEAP-C16Y on endothelial cells and tumor cells. Supplementary Figure S3 shows biodistribution and antitumor efficacy of DEAP-C16Y nanostructures. Supplementary Figure S4 shows the potential toxicity of DEAP-C16Y nanostructures. Supplementary Figure S5 shows combination therapy of DEAP-C16Y and Dox.

Pancreatic ductal adenocarcinoma (PDAC) cells are surrounded by a dense extracellular matrix (ECM), which greatly restricts the access of therapeutic agents, resulting in poor clinical response to chemotherapy. Transforming growth factor-β1 (TGF-β1) signaling plays a crucial role in construction of the desmoplastic stroma and provides potential targets for PDAC therapy. To surmount the pathological obstacle, we developed a size switchable nanosystem based on PEG-PLGA nanospheres encapsulated within liposomes for the combined delivery of vactosertib (VAC), a TGF-β1 receptor kinase inhibitor, and the cytotoxic drug paclitaxel (TAX). By surface modification of the liposomes with a peptide, APTEDB, the nanosystem can be anchored to abundant tumor-associated fibronectin in PDAC stroma and decreases its size by releasing encapsulated TAX-loaded nanospheres, as well as VAC after collapse of the liposomes. The inhibition of ECM hyperplasia by VAC allows TAX more ready access to the cancer cells in addition to its small size, thereby shrinking pancreatic tumor xenografts more effectively than a combination of the free drugs. This size switchable nanosystem enables sequential delivery of drugs at a fixed dose combination with simplified administration and provides an encouraging cascade approach of drug penetration for enhanced chemotherapy in cancers with a dense desmoplastic stroma.

Biomedical text mining is becoming increasingly important as the number of biomedical documents grow rapidly. Deep learning has boosted the development of biomedical text mining models. However, as deep learning models require a large amount of training data, a hierarchical attention based transfer learning model is proposed in this paper for the question answering task in biomedical field which lacks of sufficient training data. We adopt BERT (Bidirectional Encoder Representation Transformers), which has the ability to learn from large-scale unsupervised data, to enrich the semantic representation in our model. Especially, the scaled dot-product attention mechanism captures the question interaction clues for passage encoding. The domain adaptation technique of fine-tuning is used to reinforce the performance, which penalizes the deviations from the source model’s parameters and remembers the knowledge of source domain. We evaluate the system performance on the open data set of BioASQ-Task B. The results show that our system achieves the state-of-the-art performance without any handcrafted features and outperforms the best solution for factoid questions in 2016 and 2017 BioASQ-Task B.

Biochar, as a soil additive, will inevitably affect the transformation process of soil and water interactions. Biochar plays an important role in reducing soil degradation. The capillary water in soil affects the stability of the soil structure. The characteristics of the capillary force between the soil and biochar particles are investigated in this study. Based on an advanced capillary force measurement system, biochar and soil particles are simplified as spherical particles of equal size. The image of the liquid bridge between different particles is recorded by a high-speed camera (AOSVI-HD202WF). Based on digital image processing technology, the fractal dimension of the image is calculated, and the influence of the liquid volume and particle properties is analyzed. The results indicate that the capillary force between the particles decreases with increase in interparticle distance. Due to the increase of the liquid volume, the initial capillary force between the biochar and soil particles is increased from 3.6×10−4 to 4.4×10−4 N, and the fracture distance of the liquid bridge is increased from 0.41 to 0.70 mm, respectively, for a liquid volume from 0.8 to 2.4 ul. The fractal dimension of morphology of the liquid bridge between the particles increased and decreased in a cycle (C). It is found that the variation of the liquid bridge between the particles is stable with a high liquid volume (≥2.4 ul). It is also found that the cycle period of the liquid bridge between the biochar and soil particles is not affected by the liquid volume. The calculated capillary forces between the biochar and soil particles by using a Laplace-Young equation have been well verified by the experimental data. Biochar has an effect on the stability of the capillary force of the liquid bridge between the soil particles. Biochar-soil particles can be effectively combined to improve the capillary force and water retention capacity of the soil.

Mesoporous aluminosilicates (MAs) with excellent hydrothermal stability have been a growing interest because of their potential application in face-centered cubic. The process of improving the P123 utilization efficiency and reducing the water consumption is an important issue for the synthesis and application of MAs. In this study, trace amounts of alcohol ether sulphate (AES) being the co-template were introduced into high P123 concentration to synthesize MAs. The water consumption is reduced 77.3%, and P123 utilization efficiency is increased 1.2 times in comparison to that of the conventional method. In high P123 concentration solution, micelle aggregates were formed without AES, resulting in the formation of less ordered MAs. However, well-dispersed micelles were formed in the presence of AES, which is beneficial for the subsequent assembling process. In addition, the micellar state corresponding to different AES contents and the influence on physicochemical properties of MAs were discussed.

Sentiment classification of short text is a challenging task because of limited contextual information. We propose a capsule-based hybrid neural network model which can obtain the implicit semantic information effectively. Bidirectional gated recurrent unit (BGRU) is applied in this model to achieve the interdependent features with long distance. Moreover, the capsule network can extract richer textual information to improve expression ability. Compared with the attention-based model which combines self-attention mechanisms and convolutional neural networks (CNN), the capsule-based hybrid model has the advantage of less training time and simple network structure to achieve better performance. The performance is evaluated on two short text review datasets. Our capsule-based model outperforms other related models on movie review data and gets the highest accuracy of 0.8255. Meanwhile, it performs better than most of the systems in NLPCC2014 Task II and, especially achieves the best result on negative data.

The degree of damage to heritage structures in arid areas can be particularly serious due to long-term exposure to a harsh arid climate. In this paper, the characteristics of evaporation and cracking of soil taken from heritage structures with different NaCl concentrations are experimentally investigated by subjecting saturated soil samples taken from the Wang-Jing tower in Weihui City, Henan Province. Making soil sample of water content of 110% is used to test the rate of evaporation at a constant temperature and humidity, through which the changes in the evaporation rate, water content, fracture development, and fracture fractal dimension are obtained. The results show that, (1) with higher water content, NaCl can affect the evaporation process by increasing the matrix suction of the soil of the Wang-Jing tower and then affect the cracking process of soil. When 0%, 1%, 2%, and 4% NaCl are added, the residual water content of the samples is 3.15%, 4.23%, 4.82%, and 5.89%, respectively, which show an obvious trend of increasing water content; (2) the period with a stable fracture fractal dimension of the samples is shortened with an increase in NaCl concentration, and its maximum fractal dimension is reduced in turn; and (3) at a lower water content, NaCl crystallizes and precipitates in the pores of the soil, which provide a cementitious effect among the soil particles, thus inhibiting crack development.

SUMMARY The conserved GATOR1 complex consisting of NPRL2-NPRL3-DEPDC5 inhibits mammalian target of rapamycin complex 1 (mTORC1) in response to amino acid insufficiency. Here, we show that loss of NPRL2 and GATOR1 function in skeletal muscle causes constitutive activation of mTORC1 signaling in the fed and fasted states. Muscle fibers of NPRL2 knockout animals are significantly larger and show altered fiber-type composition, with more fast-twitch glycolytic and fewer slow-twitch oxidative fibers. NPRL2 muscle knockout mice also have altered running behavior and enhanced glucose tolerance. Furthermore, loss of NPRL2 induces aerobic glycolysis and suppresses glucose entry into the TCA cycle. Such chronic activation of mTORC1 leads to compensatory increases in anaplerotic pathways to replenish TCA intermediates that are consumed for biosynthetic purposes. These phenotypes reveal a fundamental role for the GATOR1 complex in the homeostatic regulation of mitochondrial functions (biosynthesis versus ATP) to mediate carbohydrate utilization in muscle., In Brief Dutchak et al. investigate how mTORC1 activation rewires cellular metabolism in skeletal muscle by analyzing the consequences of loss of NPRL2, a component of the GATOR1 complex that is a conserved negative regulator of mTORC1.

With recent advances in understanding the genomic underpinnings and oncogenic drivers of pathogenesis in different subtypes, it is increasingly clear that proper pretreatment diagnostics are essential for the choice of appropriate treatment options for non-small cell lung cancer (NSCLC). Tumor tissue preservation in optimal cutting temperature (OCT) compound is commonly used in the surgical suite. However, proteins recovered from OCT-embedded specimens pose a challenge for LC-MS/MS experiments, due to the large amounts of polymers present in OCT. Here we present a simple workflow for whole proteome analysis of OCT-embedded NSCLC tissue samples, which involves a simple trichloroacetic acid precipitation step. Comparisons of protein recovery between frozen versus OCT-embedded tissue showed excellent consistency with more than 9200 proteins identified. Using an isobaric labeling strategy, we quantified more than 5400 proteins in tumor versus normal OCT-embedded core needle biopsy samples. Gene ontology analysis indicated that a number of proliferative as well as squamous cell carcinoma (SqCC) marker proteins were overexpressed in the tumor, consistent with the patient's pathology based diagnosis of "poorly differentiated SqCC". Among the most downregulated proteins in the tumor sample, we noted a number of proteins with potential immunomodulatory functions. Finally, interrogation of the aberrantly expressed proteins using a candidate approach and cross-referencing with publicly available databases led to the identification of potential druggable targets in DNA replication and DNA damage repair pathways. We conclude that our approach allows LC-MS/MS proteomic analyses on OCT-embedded lung cancer specimens, opening the way to bring powerful proteomics into the clinic. Graphical Abstract ᅟ.

In the version of the Supplementary Information originally published, in Supplementary Fig. 8a, in the bottom row, the left-most image ('Control') was not the correct image; this has now been replaced.

Summary Dysregulation of chromatin methylation is associated with defects in cellular differentiation as well as a variety of cancers. How cells regulate the opposing activities of histone methyltransferase and demethylase enzymes to set the methylation status of the epigenome for proper control of gene expression and metabolism remains poorly understood. Here, we show that loss of methylation of the major phosphatase PP2A in response to methionine starvation activates the demethylation of histones through hyperphosphorylation of specific demethylase enzymes. In parallel, this regulatory mechanism enables cells to preserve SAM by increasing SAH to limit SAM consumption by methyltransferase enzymes. Mutants lacking the PP2A methyltransferase or the effector H3K36 demethylase Rph1 exhibit elevated SAM levels and are dependent on cysteine due to reduced capacity to sink the methyl groups of SAM. Therefore, PP2A directs the methylation status of histones by regulating the phosphorylation status of histone demethylase enzymes in response to SAM levels.

Biomedical semantic question answering refers to answering questions from a given contextual passage in the biomedical field. The traditional methods need complicated feature engineering and the end-to-end neural network models depend on the large scale dataset. We propose a hierarchical multi-layer transfer learning model to address the question answering task on the biomedical data which lacks of sufficient training data. The domain adaptation techniques are adopted to reinforce the performance, include fine-tuning and forgetting cost regularization which penalize the deviations from the source model’s parameters and avoid forgetting the knowledge of source domain. The distributed representation of the word is generated and domain knowledge of biomedical word embedding is integrated. Especially, the co-attention mechanism captures the question interaction clues for passage encoding. The open data set of 2017 BioASQ-Task 5B is used to evaluate the system performance. The results show that the domain adaptation techniques make the system get the state-of-the-art performance. Our model without any handcrafted feature achieves higher precision than the best solution for factoid question in 2017 BioASQ-Task 5B.

River-dominated ocean margins (RiOMars), characterized by river plumes and abundant riverine nutrient inputs, are especially critical in determining the oceanic uptake of atmospheric CO2. Using a well validated three-dimensional, coupled physical-biogeochemical model, we examined the dynamics of the carbonate system in the Pearl River Plume (PRP) during summer over a typical RiOMar in the northern South China Sea (NSCS). Sea surface pCO2 in the PRP was mainly influenced by a combination of physical processes, air-sea exchange, and biological activity. The interplay between these complex processes differed spatially and temporally depending on the evolution of the PRP. The latter was divided into three sub-regions: near-, mid- and far-field. In the near-field PRP, the evolution of surface pCO2 was primarily influenced by biological activity. Surface pCO2 decreased substantially at the initial stage as a result of phytoplankton blooms, and then increased due to the reduction in the phytoplankton and increase of zooplankton and detritus. In the mid-field, surface pCO2 was initially dominated by air-sea exchange. Subsequently, the rates of biological processes exceeded the rate of air-sea exchange, resulting in a strong drawdown of surface pCO2 or a strong sink for atmospheric CO2. The far-field of the PRP acted as a weak CO2 sink, where surface pCO2 was dominated by air-sea exchange as biological processes were fairly weak. In addition, given that the air-sea CO2 equilibrium time is much longer than water residence time of the PRP, the biologically-mediated low pCO2 surface water was enabled to be transported far away from estuary. Taken together, the combined effect of enhanced primary production, strong plume current and strong seawater carbonate buffering capacity were responsible for maintaining low surface pCO2 levels in this subtropical RiOMar system.

Using a validated, three-dimensional, coupled physical-biogeochemical model, this study examines the dynamics of dissolved inorganic carbon (DIC) in the South China Sea (SCS). The model identifies characteristic differences in DIC concentrations between the SCS and adjacent West Philippine Sea (WPS), showing an increase in DIC of up to 140 μmol kg−1 in the upper 2000 m layer from the WPS to the vicinity of the northern SCS. This increasing pattern continues from the northern to the southern SCS, but to a much lower degree ( 1600 m. Exports of DIC occur through other straits and the SCS intermediate water outflow (600 m to 1600 m) via the Luzon Strait. The model shows upward transport of DIC in the upper 400 m and below 1100 m, in contrast to downward DIC transport between 400 m and 1100 m. Seasonally, both DIC concentrations and fluxes in the upper layer have larger dynamic ranges in winter than in summer, attributable to the combined effects of enhanced Kuroshio intrusion, stronger vertical upwelling and greater biogeochemical alterations. A balance of various constitutive DIC terms revealed that horizontal and vertical advection is an order of magnitude greater than the other terms of the DIC budget, which has an opposite sign and thus tends to neutralize each other. The model indicated a decrease in the DIC inventory in the euphotic zone in spring and summer caused by net DIC consumption, and a contrasting increase in fall and winter primarily influenced by DIC vertical transport. In intermediate and deep layers, physical transport processes play a dominant role in the seasonal variation of DIC inventories. In the upper 150 m, DIC fluxes and their stoichiometry with nutrient fluxes, which potentially impact the air-sea CO2 fluxes, are largely driven by excess vertical DIC fluxes compared to horizontal fluxes via the Luzon Strait.

The South China Sea (SCS) is one of the largest marginal seas in the world, yet the processes that drive its nutrient distribution are not well understood. Using the three-dimensional China Sea Multiscale Ocean Modeling System (CMOMS) embedded with a nitrogen-phosphorus-phytoplankton-zooplankton-detritus ecosystem model, we investigated nutrient transport and dynamics in the SCS. The model was well validated with field and remotely sensed observations. We found that the unique layered distribution of nutrients that increases from north to south in the upper layer and increases in the opposite direction in the middle and deep layers. We found that the lateral and vertical fluxes associated with three-dimensional ocean circulation and biogeochemical processes shape the distribution. The lateral fluxes are provided extrinsically by the sandwich-like transport through Luzon Strait (LS) and the exchanges through other straits, and intrinsically by the interior vertical motion due to flow-slope topography interaction. The nutrient deficiency in the upper layer due to dilution by inflow from the Western Pacific Ocean is mainly compensated by the upward nutrient-rich deep water. The nutrient transport is jointly regulated by volume transport and the uneven spatiotemporal distribution of nutrients. We demonstrated that labile organic matter plays an important role in total nutrient budgets. In euphotic layer, biological production is the major sink, but remineralization contributions to PO4 are more important than to NO3 due to the higher recycling rate of PO4. In the shelf water, coastal upwelling serves as major source for both NO3 and PO4, vertical diffusion is another important source of PO4 due to the strong downward increasing gradient.

The East China Sea (ECS) and the South China Sea (SCS) are two major marginal seas of the north Pacific with distinct seasonal primary productivity. Based upon field observation in December 2008–January 2009 covering both the ECS and the northern SCS (NSCS) in wintertime, we examined southward long-range nutrient-transport from the ECS to the northeast SCS (NESCS) carried by the China Coastal Current (CCC) driven by the northeast prevailing monsoon. These nutrients escaped from the cold ECS shelf to refuel the primary production on the NESCS shelf where river-sourced nutrients were limited yet water temperature remained favorable. By coupling the field observation of nitrate + nitrite (DIN) with the volume transport of the CCC, we derived a first order estimate of DIN flux of ~ 1430 ± 260 mol s−1. This DIN flux was ~ 7 times the wintertime DIN input from the Pearl River, a primary riverine nutrient source to the NSCS. By assuming DIN was the limiting nutrient, such southward DIN transport would have stimulated ~ 8.8 ± 1.6 × 1011 gC of new production (NP), accounting for ~ > 58 ± 10% of the total NP or ~ 38 ± 7–24 ± 4% of primary production on the NESCS shelf shallower than 100 m.

Nogo-B receptor (NgBR) plays fundamental roles in regulating angiogenesis, vascular development, and the epithelial-mesenchymal transition (EMT) of cancer cells. However, the therapeutic effect of NgBR blockade on tumor vasculature and malignancy is unknown, investigations on which requires an adequate delivery system for small interfering RNA against NgBR (NgBR siRNA). Here a surface charge switchable polymeric nanoparticle that was sensitive to the slightly acidic tumor microenvironment was developed for steady delivery of NgBR siRNA to tumor tissues. The nanoformulation was constructed by conjugating 2, 3-dimethylmaleic anhydride (DMMA) molecules to the surface amines of micelles formed by cationic co-polymer poly(lactic-co-glycolic acid)2-poly(ethylenimine) and subsequent absorption of NgBR siRNAs. The nanoparticles remained negatively charged in physiological condition and smartly converted to positive surface charge due to tumor-acidity-activated shedding of DMMA. The charge conversion facilitated cellular uptake of siRNAs and in turn efficiently depleted the expression of NgBR in tumor-bearing tissues. Silencing of NgBR suppressed endothelial cell migration and tubule formation, and reverted the EMT process of breast cancer cells. Delivery of the nanoformulation to mice bearing orthotopic breast carcinoma showed no effect on tumor growth, but led to remarkable decrease of distant metastasis by normalizing tumor vessels and suppressing the EMT of breast cancer cells. This study demonstrated that NgBR is a promising therapeutic target in abnormal tumor vasculature and aggressive cancer cells, and the tumor-responsive nanoparticle with the feature of charge transformation offers great potential for tumor-specific delivery of gene therapeutics.

Recent advances in the synthesis of hydrothermally stable mesoporous aluminosilicates (MAs) by assembling precursors shed light on their applications in residue fluid catalytic cracking. Reducing the n(H2O)/n(SiO2) ratio and thus reducing waste discharge is the key for practical applications of MAs. In this study, the synthesis of hydrothermally stable MAs with a decreased n(H2O)/n(SiO2) ratio has been developed based on seed-assisted crystallization. Crystal seeds were partly dissolved to microcrystallites on which a large amount of zeolite precursors are assembled and crystallized. As a direct result of the assembly priority of crystal seeds, the concentration and viscosity of the liquid phase in the synthesis system will be decreased greatly. Afterward, the remaining precursors with proper concentration and viscosity can be assembled with the surfactant micelles. Therefore, the H2O amount could be largely decreased by the introduction of crystal seeds.

Limited intratumoural perfusion and nanoparticle retention remain major bottlenecks for the delivery of nanoparticle therapeutics into tumours. Here, we show that polymer-lipid-peptide nanoparticles delivering the antiplatelet antibody R300 and the chemotherapeutic agent doxorubicin can locally deplete tumour-associated platelets, thereby enhancing vascular permeability and augmenting the accumulation of the nanoparticles in tumours. R300 is specifically released in the tumour on cleavage of the lipid-peptide shell of the nanoparticles by matrix metalloprotease 2, which is commonly overexpressed in tumour vascular endothelia and stroma, thus facilitating vascular breaches that enhance tumour permeability. We also show that this strategy leads to substantial tumour regression and metastasis inhibition in mice.

Study on the rare earth exchange performance was carried out with high silica, normal silica and low silica NaY zeolites with framework SiO 2 /Al 2 O 3 ratios of 5.8, 4.8 and 4.6, respectively. It is found that the silicon content of the starting NaY zeolite is one of the significant factors in determining the ion exchange efficiency. The higher the framework SiO 2 /Al 2 O 3 ratio is, the less selective to the rare earth ions the zeolite will be. However, the efficiency of the use of rare earth ions are comparable to each other when the concentration of rare earth in the ion exchange solution is less than 6 wt.%, no matter the level of the framework SiO 2 /Al 2 O 3 ratio of the starting zeolites. Comparison of the hydrothermal stability of the rare earth and ammonium exchanged zeolites (REHY) indicates that the REHY sample prepared from the high silica NaY and with the lowest rare earth loading (2.9 wt.%) exhibits the best hydrothermal stability. The reaction studies indicate that the catalyst containing this REHY zeolite shows much better activity and product selectivity in the catalytic conversion of heavy oil than another REHY zeolite prepared from the normal silica NaY zeolite and having a rare earth loading as high as 6.6 wt.%, which is highly probably due to the superior hydrothermal stability of the former zeolite. It is suggested that the REHY zeolite with a low level of rare earth loading prepared from the high silica NaY can be considered as an alternative catalyst for the catalytic conversion of gas oil.

Peptide therapeutics hold great promise for the treatment of cancer due to low toxicity, high specificity, and ease of synthesis and modification. However, the unfavorable pharmacokinetic parameters strictly limit their therapeutic efficacy and clinical translation. Here, we tailor-designed an amphiphilic chimeric peptide through conjugation of functional 3-diethylaminopropyl isothiocyanate (DEAP) molecules to a short antitumor peptide, C16Y. The ultimate DEAP–C16Y peptides self-assembled into spherical nanostructures at physiologic conditions, which dissociated to release individual peptide molecules in weakly acidic tumors. DEAP–C16Y peptides showed negligible cytotoxicity but impaired vascular endothelial cell migration and tubule formation by inactivation of the focal adhesion kinase and PI3K–Akt pathways, as well as tumor cell invasion by decreasing invadopodia formation. Compared with C16Y, the systemically administered DEAP–C16Y nanostructures exhibited superior stability, thereby allowing prolonged treatment interval and resulting in significant decreases in microvessel density, tumor growth, and distant metastasis formation in orthotopic mammary tumor models. Through encapsulation of hydrophobic doxorubicin, DEAP–C16Y nanostructure served as a smart carrier to achieve targeted drug delivery and combination therapy. Our study, for the first time, demonstrates that a simple nanoformulation using a functional antitumor peptide as the building block can show innate antitumor activity and also provide a nanoplatform for combination therapy, opening a new avenue for the design of antitumor nanotherapeutics. Mol Cancer Ther; 14(10); 2390–400. ©2015 AACR.