TLR4 Blockade Using Docosahexaenoic Acid Restores Vulnerability of Drug-Tolerant Tumor Cells and Prevents Breast Cancer Metastasis and Postsurgical Relapse.

Nonmutational mechanisms were recently discovered leading to reversible drug tolerance. Despite the rapid elimination of a majority of tumor cells, a small subpopulation of "'drug-tolerant"' cells remain viable with lethal drug exposure, which may further lead to resistance or tumor relapse. Several signaling pathways are involved in the local or systemic inflammatory responses contributing to drug-induced phenotypic switch. Here, we report that Toll-like receptor 4 (TLR4)-interacting lipid docosahexaenoic acid (DHA) restores the cytotoxic effect of doxorubicin (DOX) in the lipopolysaccharide-treated breast tumor cell line 4T1, preventing the phenotypic switch to drug-tolerant cells, which significantly reduces primary tumor growth and lung metastasis in both 4T1 orthotopic and experimental metastasis models. Importantly, DHA in combination with DOX delays and inhibits tumor recurrence following surgical removal of the primary tumor. Furthermore, the coencapsulation of DHA and DOX in a nanoemulsion significantly prolongs the survival of mice in the postsurgical 4T1 tumor relapse model with significantly reduced systemic toxicity. The synergistic antitumor, antimetastasis, and antirecurrence effects of DHA + DOX combination are likely mediated by attenuating TLR4 activation, thus sensitizing tumor cells to standard chemotherapy.

A lightweight classification of adaptor proteins using transformer networks.

BACKGROUND: Adaptor proteins play a key role in intercellular signal transduction, and dysfunctional adaptor proteins result in diseases. Understanding its structure is the first step to tackling the associated conditions, spurring ongoing interest in research into adaptor proteins with bioinformatics and computational biology. Our study aims to introduce a small, new, and superior model for protein classification, pushing the boundaries with new machine learning algorithms. RESULTS: We propose a novel transformer based model which includes convolutional block and fully connected layer. We input protein sequences from a database, extract PSSM features, then process it via our deep learning model. The proposed model is efficient and highly compact, achieving state-of-the-art performance in terms of area under the receiver operating characteristic curve, Matthew's Correlation Coefficient and Receiver Operating Characteristics curve. Despite merely 20 hidden nodes translating to approximately 1% of the complexity of previous best known methods, the proposed model is still superior in results and computational efficiency. CONCLUSIONS: The proposed model is the first transformer model used for recognizing adaptor protein, and outperforms all existing methods, having PSSM profiles as inputs that comprises convolutional blocks, transformer and fully connected layers for the use of classifying adaptor proteins.

Microarray Profile of Circular RNAs Identifies hsa_circ_0001583 as A New Circular RNA Biomarker for Breast Cancer: A Retrospective Study.

OBJECTIVE: Breast cancer (BC) is the most common cancer, which is currently the leading cause of cancer death. Circular RNAs (circRNAs) play important roles in cancer, however, circRNAs serving as vital index in BC for guiding treatment have not yet been identified. The aim of our study is to explore a novel kind of potential biomarker for BC. MATERIALS AND METHODS: In this retrospective study, the samples used for assays were two groups of breast tumor tissue obtained from four BC patients, including four pairs of tumor tissues and adjacent nontumor samples. The circRNA expression profiles were detected via microarray and validated by real-time quantitative polymerase chain reaction (PCR). RESULTS: The differentially expressed circRNAs in tested samples were screened and analyzed by using human circRNA microarray. After analysis, considering a fold gene expression change of ≥2.0 and P<0.05, results suggested that 256 circRNAs were significantly up-regulated and 277 circRNAs were significantly down-regulated. Besides, the results of the real-time quantitative PCR assay showed that the expression of hsa_circ_0001583 was significantly up-regulated in BC groups (P<0.05) by real-time quantitative PCR. Therefore, we thought hsa_circ_0001583 might serve as a novel kind of biomarker for BC. CONCLUSION: Hsa_circ_0001583 showed significant up-regulation in BC patients with paired adjacent tissues. Many cancer immune pathways were related to has_circ_0001583, including autoimmune thyroid disease, chemokine and T-cell receptor signaling pathways.

CTV-Net: Complex-Valued TV-Driven Network With Nested Topology for 3-D SAR Imaging.

The regularization-based approaches offer promise in improving synthetic aperture radar (SAR) imaging quality while reducing system complexity. However, the widely applied l1 regularization model is hindered by their hypothesis of inherent sparsity, causing unreal estimations of surface-like targets. Inspired by the edge-preserving property of total variation (TV), we propose a new complex-valued TV (CTV)-driven interpretable neural network with nested topology, i.e., CTV-Net, for 3-D SAR imaging. In our scheme, based on the 2-D holography imaging operator, the CTV-driven optimization model is constructed to pursue precise estimations in weakly sparse scenarios. Subsequently, a nested algorithmic framework, i.e., complex-valued TV-driven fast iterative shrinkage thresholding (CTV-FIST), is derived from the theory of proximal gradient descent (PGD) and FIST algorithm, theoretically supporting the design of CTV-Net. In CTV-Net, the trainable weights are layer-varied and functionally relevant to the hyperparameters of CTV-FIST, which aims to constrain the algorithmic parameters to update in a well-conditioned tendency. All weights are learned by end-to-end training based on a two-term cost function, which bounds the measurement fidelity and TV norm simultaneously. Under the guidance of the SAR signal model, a reasonably sized training set is generated, by randomly selecting reference images from the MNIST set and consequently synthesizing complex-valued label signals. Finally, the methodology is validated, numerically and visually, by extensive SAR simulations and real-measured experiments, and the results demonstrate the viability and efficiency of the proposed CTV-Net in the cases of recovering 3-D SAR images from incomplete echoes.

Multi-modal emotion recognition using EEG and speech signals.

Automatic Emotion Recognition (AER) is critical for naturalistic Human-Machine Interactions (HMI). Emotions can be detected through both external behaviors, e.g., tone of voice and internal physiological signals, e.g., electroencephalogram (EEG). In this paper, we first constructed a multi-modal emotion database, named Multi-modal Emotion Database with four modalities (MED4). MED4 consists of synchronously recorded signals of participants' EEG, photoplethysmography, speech and facial images when they were influenced by video stimuli designed to induce happy, sad, angry and neutral emotions. The experiment was performed with 32 participants in two environment conditions, a research lab with natural noises and an anechoic chamber. Four baseline algorithms were developed to verify the database and the performances of AER methods, Identification-vector + Probabilistic Linear Discriminant Analysis (I-vector + PLDA), Temporal Convolutional Network (TCN), Extreme Learning Machine (ELM) and Multi-Layer Perception Network (MLP). Furthermore, two fusion strategies on feature-level and decision-level respectively were designed to utilize both external and internal information of human status. The results showed that EEG signals generate higher accuracy in emotion recognition than that of speech signals (achieving 88.92% in anechoic room and 89.70% in natural noisy room vs 64.67% and 58.92% respectively). Fusion strategies that combine speech and EEG signals can improve overall accuracy of emotion recognition by 25.92% when compared to speech and 1.67% when compared to EEG in anechoic room and 31.74% and 0.96% in natural noisy room. Fusion methods also enhance the robustness of AER in the noisy environment. The MED4 database will be made publicly available, in order to encourage researchers all over the world to develop and validate various advanced methods for AER.

Decoupling of the Growing Exports in Foreign Trade from the Declining Gross Exports of Embodied Energy.

Transforming the growth mode and realizing green and low-carbon development has been a global consensus and an important governance concept of socialism with Chinese characteristics in the new era. Whether economic growth can be decoupled from carbon emissions and energy consumption is a key indicator for measuring green and low-carbon development and is an inevitable requirement for achieving the goal of carbon neutrality before 2060. Based on the input-output tables for 2002, 2007, 2012, and 2018, this article calculated the embodied energy of export in China's foreign trade and studied the elastic relationship and trend between the growth of foreign trade exports and the total embodied energy of export since China's accession to the WTO. The following conclusions were drawn: (i) The embodied energy of China's export was strongly decoupled from total export for the first time from 2012 to 2018, signaling that China's economic, industrial, and energy structures entered a new stage. It was also the first strong decoupling achieved in the process of decoupling economic growth from energy consumption for the adoption of a low-carbon development path. Due to the pressure of international competition, the export sector had a relatively advanced level of efficiency, so it achieved decoupling earlier than the overall manufacturing sector and the consumption sector, which was in line with economic laws and the characteristics of China's development stage. (ii) From 2007 to 2018, the embodied energy of export occupied a much smaller proportion of China's total energy consumption, falling from the peak of 31.48% in 2007 to 26.57%, a drop of 4.91 percentage points. It showed that a larger share of energy consumption had taken place domestically and that the model mainly relying on export expansion to drive economic growth had begun to adjust. The conclusion of this research could also support the assertion of 'accelerating the construction of a new development pattern with the domestic economic cycle as the main body and the domestic and international dual cycles promoting each other' from the perspective of external exports and energy consumption. (iii) A causal analysis of the decoupling between the embodied energy of export and export volume demonstrated that, from 2002 to 2007 and from 2007 to 2012, the embodied energy of export and total export maintained the same direction but had different growth rates. The increase in total export volume was the main reason affecting the embodied energy of export. With the rapid growth of total export volume, the embodied energy of export was also growing rapidly. From 2012 to 2018, the embodied energy of export declined, and an analysis showed that the 'total energy consumption coefficient', i.e., technology effect, was the primary cause of the decline. With China's high-quality development, green transformation, and other strategic advancements, the decoupling trend is expected to continue and expand to a larger economic field.

Timing matters: pre-assembly versus post-assembly functionalization of a polyoxovanadate-organic cuboid.

The pre-assembly and post-assembly approaches in the functionalization of a polyoxovanadate-organic cuboid, [{V6S}8(QPTC)8{V3}2]10-, are discussed. We have shown that the two pathways have led to distinctly different systems, with either an expanded or contracted interior void space, when phenylphosphonate is introduced at different stages of the self-assembly. One leaves the cuboid framework largely intact, whereas the other results in a compact, twisted cuboid. Kinetic factors will have to be considered in the equilibrium of these complex processes. Furthermore, the exceptional stability of these polyoxometalate-organic systems facilitates mass spectrometric characterization, which confirms the composition of the complexes and also indicates that the methoxide groups on the vanadium cluster nodes are labile. The results will help deepen the mechanistic understanding of the formation mechanisms of polyoxovanadate-based metal-organic cages and other functionalized polyoxovanadate clusters in general.

In situ gel implant for postsurgical wound management and extended chemoimmunotherapy against breast cancer recurrence.

Postsurgical recurrence of breast cancer is closely related to the inflammatory tumor microenvironment evoked by surgical wounds. Toll-like receptor 4 (TLR4) signaling contributes to NF-κB activation thus secreting various inflammatory cytokines. Herein, we developed an in situ photo-crosslinked hydrogel (D/T gel) concurrently loaded with doxorubicin (DOX) and a TLR4 antagonist, resatorvid (TAK-242). Its therapeutic effect against breast cancer postsurgical relapse was accomplished through remodeling the proinflammatory tumor microenvironment. The obtained gel network exhibited ideal biodegradability and biocompatibility, which motivated dermal wound healing in the full thickness wound model in mice. Despite the initial burst release of DOX, D/T gels exhibited extended-release of both DOX and TAK-242 for up to 21 days in vitro. TAK-242 was demonstrated to inhibit the lipopolysaccharide-induced NF-κB activation and downregulate TLR4 levels in both RAW264.7 and 4T1 cells. In a 4T1-Luc tumor postsurgical recurrence model, D/T gel significantly suppressed recurrent tumor growth by elevating the concentrations of DOX and TAK-242 at the tumor sites and remodeling the TLR4 activation-induced proinflammatory microenvironment. Overall, the D/T gel platform technology is proven to deliver therapeutics directly to the surgical wound bed, attenuating the dual inflammatory responses induced by DOX and surgical wounding thus greatly potentiating its efficacy in preventing postsurgical tumor recurrence. STATEMENT OF SIGNIFICANCE: Postsurgical recurrence of breast cancer is closely related to the inflammatory tumor microenvironment (TME) evoked by surgical wounds. Although chemotherapeutics lead to extensive residual tumor cell necrosis, multiple inflammatory cytokines are secreted simultaneously, which are conducive to tumor recurrence. In this work, a TLR4 antagonist, TAK-242, was combined with DOX to reverse the dual inflammatory TME induced by surgical wounding and chemotherapy. To elevate the concentration of therapeutics at the tumor site, a photocrosslinked hydrogel (D/T gel) implant coloaded with TAK-242 and DOX was developed and applied on the postsurgical bed. Consequently, D/T gel attenuated the dual inflammatory responses and greatly potentiated its efficacy in preventing postsurgical tumor recurrence.

TPSSI-Net: Fast and Enhanced Two-Path Iterative Network for 3D SAR Sparse Imaging.

The emerging field of combining compressed sensing (CS) and three-dimensional synthetic aperture radar (3D SAR) imaging has shown significant potential to reduce sampling rate and improve image quality. However, the conventional CS-driven algorithms are always limited by huge computational costs and non-trivial tuning of parameters. In this article, to address this problem, we propose a two-path iterative framework dubbed TPSSI-Net for 3D SAR sparse imaging. By mapping the AMP into a layer-fixed deep neural network, each layer of TPSSI-Net consists of four modules in cascade corresponding to four steps of the AMP optimization. Differently, the Onsager terms in TPSSI-Net are modified to be differentiable and scaled by learnable coefficients. Rather than manually choosing a sparsifying basis, a two-path convolutional neural network (CNN) is developed and embedded in TPSSI-Net for nonlinear sparse representation in the complex-valued domain. All parameters are layer-varied and optimized by end-to-end training based on a channel-wise loss function, bounding both symmetry constraint and measurement fidelity. Finally, extensive SAR imaging experiments, including simulations and real-measured tests, demonstrate the effectiveness and high efficiency of the proposed TPSSI-Net.

How to not build a cage: endohedral functionalization of polyoxometalate-based metal-organic polyhedra.

Introducing functionalities into the interior of metal-organic cage complexes can confer properties and utilities (e.g. catalysis, separation, drug delivery, and guest recognition) that are distinct from those of unfunctionalized cages. Endohedral functionalization of such cage molecules, for decades, has largely relied on modifying their organic linkers to covalently append targeted functional groups to the interior surface. We herein introduce an effective coordination method to bring in functionalities at the metal sites instead, for a set of polyhedral cages where the nodes are in situ formed polyoxovanadate clusters, [VIV 6O6(OCH3)9(µ6-SO4)(COO)3]2-. Replacing the central sulfates of these hexavanadate clusters with more strongly coordinating phosphonate groups allows the installation of functionalities within the cage cavities. Organophosphonates with phenyl, biphenyl, and terphenyl tails were examined for internalization. Depending on the size/shape of the cavities, small phosphonates can fit into the molecular containers whereas larger ones inhibit or transform the framework architecture, whereby the first non-cage complex was isolated from a reaction that otherwise would lead to entropically favored regular polyhedra cages. The results highlight the complex and dynamic nature of the self-assembly process involving polyoxometalates and the scope of molecular variety accessible by the introduction of endo functional groups.

Ethyl carbamate in Chinese liquor (Baijiu): presence, analysis, formation, and control.

Ethyl carbamate (EC) is a genotoxic and carcinogenic compound that is also a by-product of fermented foods (bread, sour milk, soy cheese, etc.) and alcoholic beverages (wine, sake, distilled liquor, etc.). Studies have showed that ethyl carbamate is ingested by humans primarily through the consumption of alcoholic beverages. Many countries have thus established EC limits for alcoholic beverages. Chinese liquor (Baijiu) is a traditional and unique distilled liquor, which has a huge consumption in China due to its excellent color, flavor, and taste. Therefore, the control of EC in Chinese liquor is of great significance. This review summarized for the first time the progress in presence level, analysis method, formation mechanism, and elimination strategy of EC of Chinese liquor in recent decades. KEY POINTS: • GC-MS and HPLC are the main methods to quantify EC in Chinese liquor. • EC is formed in the fermentation, distillation, and storage stage. • EC content can be reduced from raw material, microorganism, and production process.

Nuclear transformation of Chlamydomonas reinhardtii: A review.

Chlamydomonas reinhardtii is a model organism with three sequenced genomes capable of genetic transformation. C. reinhardtii has the advantages of being low cost, non-toxic, and having a post-translational modification system that ensures the recombinant proteins have the same activity as natural proteins, thus making it a great platform for application in molecular biology and other fields. In this review, we summarize the existing methods for nuclear transformation of C. reinhardtii, genes for selection, examples of foreign protein expression, and factors affecting transformation efficiency, to provide insights into effective strategies for the nuclear transformation of C. reinhardtii.

Characterization of a novel halotolerant esterase from Chromohalobacter canadensis isolated from salt well mine.

A esterase gene was characterized from a halophilic bacterium Chromohalobacter canadensis which was originally isolated from a salt well mine. Sequence analysis showed that the esterase, named as EstSHJ2, contained active site serine encompassed by a conserved pentapeptide motif (GSSMG). The EstSHJ2 was classified into a new lipase/esterase family by phylogenetic association analysis. Molecular weight of EstSHJ2 was 26 kDa and the preferred substrate was p-NP butyrate. The EstSHJ2 exhibited a maximum activity at 2.5 M NaCl concentration. Intriguingly, the optimum temperature, pH and stability of EstSHJ2 were related to NaCl concentration. At 2.5 M NaCl concentration, the optimum temperature and pH of EstSHJ2 were 65 ℃ and pH 9.0, and enzyme remained 81% active after 80 ℃ treatment for 2 h. Additionally, the EstSHJ2 showed strong tolerance to metal ions and organic solvents. Among these, 10 mM K+, Ca2+ , Mg2+ and 30% hexane, benzene, toluene has significantly improved activity of EstSHJ2. The EstSHJ2 was the first reported esterase from Chromohalobacter canadensis, and may carry considerable potential for industrial applications under extreme conditions.

Low-dose paclitaxel via hyaluronan-functionalized bovine serum albumin nanoparticulate assembly for metastatic melanoma treatment.

Due to the critical role of CD44 in mediating cell adhesion and migration, CD44-targeted drug delivery via hyaluronan has been extensively explored. Herein, cationic bovine serum albumin nanoparticles were assembled with hyaluronan (HA) of various molecular weights via simple electrostatic interaction to afford hierarchical nanoparticles (HNPs) with various size distributions and structures. Next, HNPs obtained using 49 kDa HA have been used to encapsulate paclitaxel (PTX-HNPs), which demonstrated selective lung accumulation due to both size effect and CD44-mediated targetability. Biodistribution studies showed that HNPs enhanced the lung specific accumulation of HNPs in the C57BL/6 mice melanoma lung metastasis model. In the antitumor studies, compared with the Taxol or bovine serum albumin nanoparticle (NP) groups, PTX-HNPs significantly inhibited B16F10 lung metastasis at a relatively low dose. Additionally, cell migration and invasion experiments in vitro further confirmed that PTX-HNPs significantly inhibited the migration of B16F10 cells compared to Taxol or paclitaxel-loaded NP groups. Overall, our results suggest that PTX-HNPs represent a highly promising strategy for the treatment of lung metastatic melanoma.

A dual receptors-targeting and size-switchable "cluster bomb" co-loading chemotherapeutic and transient receptor potential ankyrin 1 (TRPA-1) inhibitor for treatment of triple negative breast cancer.

Oxidative-stress defense system stands for the vulnerability of tumor cells because of the stronger oxidative stress existing in tumor sites. TRPA-1 has been found to be overexpressed in various tumors, related to the tumor proliferation and metastasis, and promote reactive oxygen species (ROS) and chemotherapy tolerance through Ca2+-dependent anti-apoptotic pathway in recent studies, which provides a new anti-tumor approach to target oxidative-stress defense system. However, there are few studies on the mechanisms of TRPA-1 inhibition increasing the effectiveness of chemotherapy and inhibiting tumor metastasis. Here, in order to deliver drugs to the deep tumor where is full of stronger oxidative stress, a dual receptors-targeting and size-switchable "cluster bomb" co-loading doxorubicine (DOX) and TRPA-1 inhibitor AP-18 (DA-tMN) was designed. DSPE-PEG2000 micelles (M, ~10 nm) were connected to the master core of hyaluronic acid nanogels (N, ~100 nm) to realize HAase-responsive size-switchable and acquired targeting characteristics. Besides, tumor homing peptide tLyP-1 (t) was modified on the surface of micelles to further increase tumor accumulation. Our study showed that tLyP-1 modification enhanced tumor-targeting delivery of tLyP-1-modified micelles @ nanogels (tMN) in vitro and in vivo. Then, HAase responsive nanogel core realized the deep penetration of tMN in 4 T1 3D tumor spheres models and 4 T1 tumor-bearing mice models. In vitro anti-tumor and anti-metastasis mechanism studies indicated that AP-18 increased the sensitivity of tumor cells to DOX by inhibiting Ca2+ influx and AKT phosphorylation caused by DOX. Compared with DOX-loaded tLyP-1-modified micelles @ nanogels (D-tMN), DA-tMN had the enhanced anti-tumor and anti-metastasis effect in vitro and vivo. Furthermore, the further anti-metastasis mechanism studies showed that TRPA-1 inhibition downregulate the expression of N-cadherin and vimentin and upregulate the expression of E-cadherin, which suggested that metastases inhibition caused by TRPA-1 inhibition may be related to the inhibition of epithelial-mesenchymal transition (EMT) process.

Hierarchical assembly of hyaluronan coated albumin nanoparticles for pancreatic cancer chemoimmunotherapy.

Pancreatic cancer is a highly malignant carcinoma with limited effective treatment options, resulting in a poor patient survival rate of less than 5%. In this study, cationic albumin nanoparticles were assembled with negatively charged hyaluronic acid (HA) to achieve a hierarchical nanostructure and efficient delivery of small molecule drugs to the tumor site in the pancreas. A combination of chemotherapy with indoleamine-2,3-dioxygenase (IDO) inhibition was explored to enhance the chemotherapeutic efficacy in vivo. Hydrophobic celastrol (CLT) and hydrophilic 1-methyltryptophan (MT) were concurrently loaded in HA coated cationic albumin nanoparticles (HNPs) with an average size of ∼300 nm. The size of HNPs was reduced in the presence of hyaluronidase to facilitate penetration into deep tumor tissues. Also, the biodistribution study in the C57BL/6 mice xenograft model showed enhanced tumor accumulation and prolonged circulation of HNPs. Compared with CLT solution, the combination of CLT with MT showed significantly enhanced tumor inhibition in both xenograft and orthotopic pancreatic cancer mice models via downregulating the immunosuppressive tumor microenvironment. Taken together, the combination of CLT with MT administered via HNPs represents a highly promising strategy for targeted pancreatic cancer therapy.

Supercritical CO2 Foaming of Radiation Cross-Linked Isotactic Polypropylene in the Presence of TAIC.

Since the maximum foaming temperature window is only about 4 °C for supercritical CO2 (scCO2) foaming of pristine polypropylene, it is important to raise the melt strength of polypropylene in order to more easily achieve scCO2 foaming. In this work, radiation cross-linked isotactic polypropylene, assisted by the addition of a polyfunctional monomer (triallylisocyanurate, TAIC), was employed in the scCO2 foaming process in order to understand the benefits of radiation cross-linking. Due to significantly enhanced melt strength and the decreased degree of crystallinity caused by cross-linking, the scCO2 foaming behavior of polypropylene was dramatically changed. The cell size distribution, cell diameter, cell density, volume expansion ratio, and foaming rate of radiation-cross-linked polypropylene under different foaming conditions were analyzed and compared. It was found that radiation cross-linking favors the foamability and formation of well-defined cell structures. The optimal absorbed dose with the addition of 2 wt % TAIC was 30 kGy. Additionally, the foaming temperature window was expanded to about 8 °C, making the handling of scCO2 foaming of isotactic polypropylene much easier.

A novel SNP of the Hesx1 gene in bovine and its associations with average daily gain.

As an essential repressor, the homeobox gene Hesx1/HESX1 is required within the anterior neural plate for normal forebrain development. Mutations within the Hesx1 gene have been associated with GH deficiency or combined pituitary hormone deficiency. We detected the polymorphism of Hesx1 gene by PCR-SSCP and DNA sequencing methods in 702 individuals from four Chinese cattle breeds. A novel single nucleotide polymorphism (SNP) (IVS1 + 382T > C) was detected. The frequencies of genotype TC in four breeds were 0.000-0.222. Polymorphism of the Hesx1 gene was shown to be associated with growth in the Nanyang breed. Individuals with genotype TC was significantly lower average daily gain than TT at 18 months (P < 0.05).