Action Recognition Based on Multi-Level Topological Channel Attention of Human Skeleton.

In action recognition, obtaining skeleton data from human poses is valuable. This process can help eliminate negative effects of environmental noise, including changes in background and lighting conditions. Although GCN can learn unique action features, it fails to fully utilize the prior knowledge of human body structure and the coordination relations between limbs. To address these issues, this paper proposes a Multi-level Topological Channel Attention Network algorithm: Firstly, the Multi-level Topology and Channel Attention Module incorporates prior knowledge of human body structure using a coarse-to-fine approach, effectively extracting action features. Secondly, the Coordination Module utilizes contralateral and ipsilateral coordinated movements in human kinematics. Lastly, the Multi-scale Global Spatio-temporal Attention Module captures spatiotemporal features of different granularities and incorporates a causal convolution block and masked temporal attention to prevent non-causal relationships. This method achieved accuracy rates of 91.9% (Xsub), 96.3% (Xview), 88.5% (Xsub), and 90.3% (Xset) on NTU-RGB+D 60 and NTU-RGB+D 120, respectively.

Sialyl-Tn Antigen-Imprinted Dual Fluorescent Core-Shell Nanoparticles for Ratiometric Sialyl-Tn Antigen Detection and Dual-Color Labeling of Cancer Cells.

Sialyl-Tn (STn or sialyl-Thomsen-nouveau) is a carbohydrate antigen expressed by more than 80% of human carcinomas. We here report a strategy for ratiometric STn detection and dual-color cancer cell labeling, particularly, by molecularly imprinted polymers (MIPs). Imprinting was based on spectroscopic studies of a urea-containing green-fluorescent monomer 1 and STn-Thr-Na (sodium salt of Neu5Acα2-6GalNAcα-O-Thr). A few-nanometer-thin green-fluorescent polymer shell, in which STn-Thr-Na was imprinted with 1, other comonomers, and a cross-linker, was synthesized from the surface of red-emissive carbon nanodot (R-CND)-doped silica nanoparticles, resulting in dual fluorescent STn-MIPs. Dual-color labeling of cancer cells was achieved since both red and green emissions were detected in two separate channels of the microscope and an improved accuracy was obtained in comparison with single-signal MIPs. The flow cytometric cell analysis showed that the binding of STn-MIPs was significantly higher (p < 0.001) than that of non-imprinted polymer (NIP) control particles within the same cell line, allowing to distinguish populations. Based on the modularity of the luminescent core-fluorescent MIP shell architecture, the concept can be transferred in a straightforward manner to other target analytes.

K-RAS Associated Gene-Mutation-Based Algorithm for Prediction of Treatment Response of Patients with Subtypes of Breast Cancer and Especially Triple-Negative Cancer.

Purpose: There is an urgent need for developing new biomarker tools to accurately predict treatment response of breast cancer, especially the deadly triple-negative breast cancer. We aimed to develop gene-mutation-based machine learning (ML) algorithms as biomarker classifiers to predict treatment response of first-line chemotherapy with high precision. Methods: Random Forest ML was applied to screen the algorithms of various combinations of gene mutation profiles of primary tumors at diagnosis using a TCGA Cohort (n = 399) with up to 150 months follow-up as a training set and validated in a MSK Cohort (n = 807) with up to 220 months follow-up. Subtypes of breast cancer including triple-negative and luminal A (ER+, PR+ and HER2−) were also assessed. The predictive performance of the candidate algorithms as classifiers was further assessed using logistic regression, Kaplan−Meier progression-free survival (PFS) plot, and univariate/multivariate Cox proportional hazard regression analyses. Results: A novel algorithm termed the 12-Gene Algorithm based on mutation profiles of KRAS, PIK3CA, MAP3K1, MAP2K4, PTEN, TP53, CDH1, GATA3, KMT2C, ARID1A, RunX1, and ESR1, was identified. The performance of this algorithm to distinguish non-progressed (responder) vs. progressed (non-responder) to treatment in the TCGA Cohort as determined using AUC was 0.96 (95% CI 0.94−0.98). It predicted progression-free survival (PFS) with hazard ratio (HR) of 21.6 (95% CI 11.3−41.5) (p < 0.0001) in all patients. The algorithm predicted PFS in the triple-negative subgroup with HR of 19.3 (95% CI 3.7−101.3) (n = 42, p = 0.000). The 12-Gene Algorithm was validated in the MSK Cohort with a similar AUC of 0.97 (95% CI 0.96−0.98) to distinguish responder vs. non-responder patients, and had a HR of 18.6 (95% CI 4.4−79.2) to predict PFS in the triple-negative subgroup (n = 75, p < 0.0001). Conclusions: The novel 12-Gene algorithm based on multitude gene-mutation profiles identified through ML has a potential to predict breast cancer treatment response to therapies, especially in triple-negative subgroups patients, which may assist personalized therapies and reduce mortality.

Fluorescent Molecularly Imprinted Polymer Layers against Sialic Acid on Silica-Coated Polystyrene Cores-Assessment of the Binding Behavior to Cancer Cells.

Sialic acid (SA) is a monosaccharide usually linked to the terminus of glycan chains on the cell surface. It plays a crucial role in many biological processes, and hypersialylation is a common feature in cancer. Lectins are widely used to analyze the cell surface expression of SA. However, these protein molecules are usually expensive and easily denatured, which calls for the development of alternative glycan-specific receptors and cell imaging technologies. In this study, SA-imprinted fluorescent core-shell molecularly imprinted polymer particles (SA-MIPs) were employed to recognize SA on the cell surface of cancer cell lines. The SA-MIPs improved suspensibility and scattering properties compared with previously used core-shell SA-MIPs. Although SA-imprinting was performed using SA without preference for the α2,3- and α2,6-SA forms, we screened the cancer cell lines analyzed using the lectins Maackia Amurensis Lectin I (MAL I, α2,3-SA) and Sambucus Nigra Lectin (SNA, α2,6-SA). Our results show that the selected cancer cell lines in this study presented a varied binding behavior with the SA-MIPs. The binding pattern of the lectins was also demonstrated. Moreover, two different pentavalent SA conjugates were used to inhibit the binding of the SA-MIPs to breast, skin, and lung cancer cell lines, demonstrating the specificity of the SA-MIPs in both flow cytometry and confocal fluorescence microscopy. We concluded that the synthesized SA-MIPs might be a powerful future tool in the diagnostic analysis of various cancer cells.

PIP5K1α is Required for Promoting Tumor Progression in Castration-Resistant Prostate Cancer.

PIP5K1α has emerged as a promising drug target for the treatment of castration-resistant prostate cancer (CRPC), as it acts upstream of the PI3K/AKT signaling pathway to promote prostate cancer (PCa) growth, survival and invasion. However, little is known of the molecular actions of PIP5K1α in this process. Here, we show that siRNA-mediated knockdown of PIP5K1α and blockade of PIP5K1α action using its small molecule inhibitor ISA-2011B suppress growth and invasion of CRPC cells. We demonstrate that targeted deletion of the N-terminal domain of PIP5K1α in CRPC cells results in reduced growth and migratory ability of cancer cells. Further, the xenograft tumors lacking the N-terminal domain of PIP5K1α exhibited reduced tumor growth and aggressiveness in xenograft mice as compared to that of controls. The N-terminal domain of PIP5K1α is required for regulation of mRNA expression and protein stability of PIP5K1α. This suggests that the expression and oncogenic activity of PIP5K1α are in part dependent on its N-terminal domain. We further show that PIP5K1α acts as an upstream regulator of the androgen receptor (AR) and AR target genes including CDK1 and MMP9 that are key factors promoting growth, survival and invasion of PCa cells. ISA-2011B exhibited a significant inhibitory effect on AR target genes including CDK1 and MMP9 in CRPC cells with wild-type PIP5K1α and in CRPC cells lacking the N-terminal domain of PIP5K1α. These results indicate that the growth of PIP5K1α-dependent tumors is in part dependent on the integrity of the N-terminal sequence of this kinase. Our study identifies a novel functional mechanism involving PIP5K1α, confirming that PIP5K1α is an intriguing target for cancer treatment, especially for treatment of CRPC.

Metformin inhibits pulmonary artery smooth muscle cell proliferation by upregulating p21 via NONRATT015587.2.

Pulmonary artery hypertension (PAH) is a complex and progressive disease characterized by pulmonary vascular remodeling. Our previous study confirmed that NONRATT015587.2 could promote the proliferation of PASMCs and pulmonary vascular remodeling. However, the exact mechanism by which NONRATT015587.2 promotes PASMC proliferation is unclear. Bioinformatics analysis revealed that p21 is located at the downstream target of NONRATT015587.2. NONRATT015587.2 expression and localization were analyzed by PCR and fluorescence in situ hybridization. Proliferation was detected by Cell Counting Kit­8, flow cytometry and western blotting. In the current study, a monocrotaline (MCT)­induced PAH rat model and cultured pulmonary artery smooth muscle cells (PASMCs) were used in vitro to elucidate the exact mechanism of NONRATT015587.2 in pulmonary vascular remodeling, alongside the effect following metformin (MET) treatment on vascular remodeling and smooth muscle cell proliferation. The results demonstrated that NONRATT015587.2 expression was upregulated in the MCT group and reduced in the MET + MCT group. In addition, NONRATT015587.2 could promote the proliferation of PASMCs. The expression levels of p21 were reduced in the MCT group, but increased in the MCT + MET group. Additionally, the expression of NONRATT015587.2 was upregulated in platelet­derived growth factor­BB (PDGF­BB)­induced PASMCs, whereas that of p21 was downregulated. Following MET treatment, the expression of NONRATT015587.2 was downregulated and that of p21 was upregulated, which inhibited the proliferation of PASMCs. After overexpression of NONRATT015587.2 in vitro, the proliferation effect of PASMCs was consistent with exogenous PDGF­BB treatment, and MET reversed this effect. NONRATT015587.2 silencing inhibited the proliferation of PASMCs. In addition, p21 silencing reversed the inhibitory effect of NONRATT015587.2 silencing on the proliferation of PASMCs. However, the proliferation of PASMCs was inhibited following MET treatment when NONRATT015587.2 and p21 were silenced at the same time. Thus, NONRATT015587.2 promoted the proliferation of PASMCs by targeting p21, and MET inhibited the proliferation of PASMCs by upregulating p21 mediated via NONRATT015587.2.

FcγRIIIa receptor interacts with androgen receptor and PIP5K1α to promote growth and metastasis of prostate cancer.

Low-affinity immunoglobulin gamma Fc region receptor III-A (FcγRIIIa) is a cell surface protein that belongs to a family of Fc receptors that facilitate the protective function of the immune system against pathogens. However, the role of FcγRIIIa in prostate cancer (PCa) progression remained unknown. In this study, we found that FcγRIIIa expression was present in PCa cells and its level was significantly higher in metastatic lesions than in primary tumors from the PCa cohort (P = 0.006). PCa patients with an elevated level of FcγRIIIa expression had poorer biochemical recurrence (BCR)-free survival compared with those with lower FcγRIIIa expression, suggesting that FcγRIIIa is of clinical importance in PCa. We demonstrated that overexpression of FcγRIIIa increased the proliferative ability of PCa cell line C4-2 cells, which was accompanied by the upregulation of androgen receptor (AR) and phosphatidylinositol-4-phosphate 5-kinase alpha (PIP5Kα), which are the key players in controlling PCa progression. Conversely, targeted inhibition of FcγRIIIa via siRNA-mediated knockdown or using its inhibitory antibody suppressed growth of xenograft PC-3 and PC-3M prostate tumors and reduced distant metastasis in xenograft mouse models. We further showed that elevated expression of AR enhanced FcγRIIIa expression, whereas inhibition of AR activity using enzalutamide led to a significant downregulation of FcγRIIIa protein expression. Similarly, inhibition of PIP5K1α decreased FcγRIIIa expression in PCa cells. FcγRIIIa physically interacted with PIP5K1α and AR via formation of protein-protein complexes, suggesting that FcγRIIIa is functionally associated with AR and PIP5K1α in PCa cells. Our study identified FcγRIIIa as an important factor in promoting PCa growth and invasion. Further, the elevated activation of FcγRIII and AR and PIP5K1α pathways may cooperatively promote PCa growth and invasion. Thus, FcγRIIIa may serve as a potential new target for improved treatment of metastatic and castration-resistant PCa.

NDUFA4L2 in smooth muscle promotes vascular remodeling in hypoxic pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is characterized by a progressive increase in pulmonary vascular resistance and obliterative pulmonary vascular remodelling (PVR). The imbalance between the proliferation and apoptosis of pulmonary artery smooth muscle cells (PASMCs) is an important cause of PVR leading to PAH. Mitochondria play a key role in the production of hypoxia-induced pulmonary hypertension (HPH). However, there are still many issues worth studying in depth. In this study, we demonstrated that NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 4 like 2 (NDUFA4L2) was a proliferation factor and increased in vivo and in vitro through various molecular biology experiments. HIF-1α was an upstream target of NDUFA4L2. The plasma levels of 4-hydroxynonene (4-HNE) were increased both in PAH patients and hypoxic PAH model rats. Knockdown of NDUFA4L2 decreased the levels of malondialdehyde (MDA) and 4-HNE in human PASMCs in hypoxia. Elevated MDA and 4-HNE levels might be associated with excessive ROS generation and increased expression of 5-lipoxygenase (5-LO) in hypoxia, but this effect was blocked by siNDUFA4L2. Further research found that p38-5-LO was a downstream signalling pathway of PASMCs proliferation induced by NDUFA4L2. Up-regulated NDUFA4L2 plays a critical role in the development of HPH, which mediates ROS production and proliferation of PASMCs, suggesting NDUFA4L2 as a potential new therapeutic target for PAH.

Targeted inhibition of ERα signaling and PIP5K1α/Akt pathways in castration-resistant prostate cancer.

Selective ERα modulator, tamoxifen, is well tolerated in a heavily pretreated castration-resistant prostate cancer (PCa) patient cohort. However, its targeted gene network and whether expression of intratumor ERα due to androgen deprivation therapy (ADT) may play a role in PCa progression is unknown. In this study, we examined the inhibitory effect of tamoxifen on castration-resistant PCa in vitro and in vivo. We found that tamoxifen is a potent compound that induced a high degree of apoptosis and significantly suppressed growth of xenograft tumors in mice, at a degree comparable to ISA-2011B, an inhibitor of PIP5K1α that acts upstream of PI3K/AKT survival signaling pathway. Moreover, depletion of tumor-associated macrophages using clodronate in combination with tamoxifen increased inhibitory effect of tamoxifen on aggressive prostate tumors. We showed that both tamoxifen and ISA-2011B exert their on-target effects on prostate cancer cells by targeting cyclin D1 and PIP5K1α/AKT network and the interlinked estrogen signaling. Combination treatment using tamoxifen together with ISA-2011B resulted in tumor regression and had superior inhibitory effect compared with that of tamoxifen or ISA-2011B alone. We have identified sets of genes that are specifically targeted by tamoxifen, ISA-2011B or combination of both agents by RNA-seq. We discovered that alterations in unique gene signatures, in particular estrogen-related marker genes are associated with poor patient disease-free survival. We further showed that ERα interacted with PIP5K1α through formation of protein complexes in the nucleus, suggesting a functional link. Our finding is the first to suggest a new therapeutic potential to inhibit or utilize the mechanisms related to ERα, PIP5K1α/AKT network, and MMP9/VEGF signaling axis, providing a strategy to treat castration-resistant ER-positive subtype of prostate cancer tumors with metastatic potential.

Establishment of Prostate Tumor Growth and Metastasis Is Supported by Bone Marrow Cells and Is Mediated by PIP5K1α Lipid Kinase.

Cancer cells facilitate growth and metastasis by using multiple signals from the cancer-associated microenvironment. However, it remains poorly understood whether prostate cancer (PCa) cells may recruit and utilize bone marrow cells for their growth and survival. Furthermore, the regulatory mechanisms underlying interactions between PCa cells and bone marrow cells are obscure. In this study, we isolated bone marrow cells that mainly constituted populations that were positive for CD11b and Gr1 antigens from xenograft PC-3 tumor tissues from athymic nu/nu mice. We found that the tumor-infiltrated cells alone were unable to form tumor spheroids, even with increased amounts and time. By contrast, the tumor-infiltrated cells together with PCa cells formed large numbers of tumor spheroids compared with PCa cells alone. We further utilized xenograft athymic nu/nu mice bearing bone metastatic lesions. We demonstrated that PCa cells were unable to survive and give rise to colony-forming units (CFUs) in media that were used for hematopoietic cell colony-formation unit (CFU) assays. By contrast, PC-3M cells survived when bone marrow cells were present and gave rise to CFUs. Our results showed that PCa cells required bone marrow cells to support their growth and survival and establish bone metastasis in the host environment. We showed that PCa cells that were treated with either siRNA for PIP5K1α or its specific inhibitor, ISA-2011B, were unable to survive and produce tumor spheroids, together with bone marrow cells. Given that the elevated expression of PIP5K1α was specific for PCa cells and was associated with the induced expression of VEGF receptor 2 in PCa cells, our findings suggest that cancer cells may utilize PIP5K1α-mediated receptor signaling to recruit growth factors and ligands from the bone marrow-derived cells. Taken together, our study suggests a new mechanism that enables PCa cells to gain proliferative and invasive advantages within their associated host microenvironment. Therapeutic interventions using PIP5K1α inhibitors may not only inhibit tumor invasion and metastasis but also enhance the host immune system.

The functional interlink between AR and MMP9/VEGF signaling axis is mediated through PIP5K1α/pAKT in prostate cancer.

Currently, no effective targeted therapeutics exists for treatment of metastatic prostate cancer (PCa). Given that matrix metalloproteinases 9 (MMP9) and its associated vascular endothelial growth factor (VEGF) are critical for tumor vascularization and invasion under castration-resistant condition, it is therefore of great importance to define the functional association and interplay between androgen receptor (AR) and MMP9 and their associated key survival and invasion pathways in PCa cells. Here, we found that there was a significant correlation between MMP9 and AR protein expression in primary and metastatic PCa tissues, and a trend that high level of MMP9 expression was associated with poor prognosis. We demonstrated that constitutive activation of AR increased expression of MMP9 and VEGF/VEGF receptors. We further showed that AR exerts its effect on MMP9/VEGF signaling axis through PIP5K1α/AKT. We showed that MMP9 physically interacted with PIP5K1α via formation of protein-protein complexes. Furthermore, elevated expression of MMP9 enhanced ability of AR to activate its target gene cyclin A1. The elevated sequential activation of AR/PIP5K1α/AKT/MMP9/VEGF signaling axis contributed to increased invasiveness and growth of metastatic tumors. Conversely, treatment with PIP5K1α inhibitor significantly suppressed invasiveness of PCa cells expressing constitutively activated AR, this was coincident with its inhibitory effect of this inhibitor on AR/MMP9/VEGF pathways. Our results suggest that AR and MMP9-associated network proteins may be effectively targeted by blocking PIP5K1α/AKT pathways using PIP5K1α inhibitor in metastatic PCa.

Stox1 induced the proliferation and cell cycle arrest in pulmonary artery smooth muscle cells via AKT signaling pathway.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by the vascular remodeling that also involves proliferation and migration of pulmonary artery smooth muscle cells (PASMCs). Overexpression of Storkhead box (STOX1) regulates genes involved hypoxia, redox balance, nitric oxide, and energy metabolism. In this study, we supposed Stox1 adjusted cells proliferation and migration in PASMCs development and played an important role in the pulmonary arterial vascular remodeling. METHODS: Hemodynamic assay and Right ventricular morphometric assay were used to check the rat model of PAH. HE staining was used to examine the arterial wall thickness. Masson staining showed that the deposition of collagen was significantly increased in PAH. In addition, Stox1 were assessed by immunofluorescence and immunohistochemistry staining. The effect of Stox1 on PASMCs was assessed by cell counting Kit-8 assay (CCK-8 assay), Scratch-Wound assay, EdU staining assay, Cell cycle analysis and Western blot. RESULTS: Right ventricular systolic pressure (RVSP) and right ventricular were significantly increased in hypoxia group and monocrotaline group compared to control group. The expression of Stox1 was increased in lung tissues in PAH rats. In vitro, the expression of Stox1 was up-regulated with time-dependent manner in hypoxia condition. Meanwhile, Stxo1 promoted the proliferation and migration in hypoxia-treated PASMCs. Moreover, we found that hypoxia promoted the expression of PCNA, Cyclin E and Cyclin A, increased more cells from G0/G1 phase to S phase and induced the activation of AKT proteins, which was significantly attenuated by inhibition of Stox1 expression in PASMCs. CONCLUSION: These findings indicated that Stox1 induced proliferation of PASMCs and the effect is, at least in part, mediated through AKT signaling pathway.

Treatment of Human B-Cell Lymphomas Using Minicircle DNA Vector Expressing Anti-CD3/CD20 in a Mouse Model.

Bispecific antibodies (BsAbs), capable of directing T cells to kill specific cancer cells by transiently binding the two cell types, have emerged as one class of promising cancer immunotherapies. However, their wide clinical application might be hampered by two deficiencies: high cost and inconvenience in drug administration. This study presents concept-proving data that these problems could be bypassed by using an enhanced nonviral DNA vector minicircle (MC) to produce BsAb in vivo. It was found that the anti-CD3/CD20 produced from the minicircle (MC.CD20) could effectively mediate the T-cell killing of multiple CD20-positive human B-cell lymphoma cell lines in vitro. More importantly, it was demonstrated that delivery of 5 µg of MC.CD20 to mouse liver via hydrodynamic injection resulted in both the expression of a therapeutic level of anti-CD3/CD20 throughout the 32-day experiment and effective anticancer activity in a B-cell lymphoma xenograft mouse model. The data suggest that MC encoding the BsAbs may become an attractive cancer immunotherapy modality based on its excellent features of safety, efficacy, and convenience in both preparation and use, and its affordability once the delivery technology matures.

The recombined cccDNA produced using minicircle technology mimicked HBV genome in structure and function closely.

HBV covalently closed circular DNA (cccDNA) is drug-resistant and responsible for viral persistence. To facilitate the development of anti-cccDNA drugs, we developed a minicircle DNA vector (MC)-based technology to produce large quantity of recombined cccDNA (rcccDNA) resembling closely to its wild-type counterpart both in structure and function. The rcccDNA differed to the wild-type cccDNA (wtcccDNA) only in that it carried an extra 36-bp DNA recombinant product attR upstream of the preC/C gene. Using a procedure similar to standard plasmid production, milligrams of rcccDNA can be generated in common laboratories conveniently. The rcccDNA demonstrated many essential biological features of wtcccDNA, including: (1) undergoing nucleation upon nucleus entry; (2) serving as template for production of all HBV RNAs and proteins; (3) deriving virions capable of infecting tree shrew, and subsequently producing viral mRNAs, proteins, rcccDNA and infectious virions. As an example to develop anti-cccDNA drugs, we used the Crispr/Cas9 system to provide clear-cut evidence that rcccDNA was cleaved by this DNA editing tool in vitro. In summary, we have developed a convenient technology to produce large quantity of rcccDNA as a surrogate of wtcccDNA for investigating HBV biology and developing treatment to eradicate this most wide-spreading virus.

Network analysis of microRNAs and genes in human osteosarcoma.

To date, numerous studies have suggested that microRNAs (miRNAs) and genes play key roles in osteosarcoma (OS); however, the majority of these studies have been conducted with a specific focus on either the genes or the miRNAs, which has made the regulatory mechanisms of OS difficult to decipher. The aim of the present study was to systematically investigate the elements [genes, miRNAs and transcription factors (TFs)] associated with the morbidity of OS and to explore the associations among these elements, instead of focusing on one or several elements. The scattered data were collected from existing studies of OS, and three regulatory networks (abnormally expressed, related and global) were constructed to explore OS at a macroscopic level. The abnormally expressed network showed the numerous incorrect data linkages that are present when OS emerges, making it useful as a map of the faults in OS. In theory, the correction of these errors could lead to the prevention and even cure of the disease. Unlike studies in which cancer networks have been formed based purely on gene data, the present study focused on genes and miRNAs, as well as the associations among them, to form the regulatory networks of OS. The constructed regulatory networks were shown to contain numerous self-adaptation associations, which may aid in the analysis of the pathogenesis of OS. By comparing and analyzing the similarities and differences, a number of important pathways were highlighted. A notable finding was the predicted TFs obtained by the P-Match method, which could be used to further study the pathogenesis of OS. In the present study, the mechanism of OS has been systematically analyzed and a theoretical foundation for the mechanism has been provided, which may assist the development of gene therapy targeting OS.

Characterization and expression of MHC class II alpha and II beta genes in mangrove red snapper (Lutjanus argentimaculatus).

The major histocompatibility complex (MHC) class II plays a key role in adaptive immunity by presenting foreign peptides to CD4(+) T cells and by triggering the adaptive immune response. While the structure and function of MHC class II have been well characterized in mammalian, limited research has been done on fishes. In this study, we characterized the gene structure and expression of MHC class II α (Lunar-DAA) and II ß (Lunar-DAB) of mangrove red snapper (Lutjanus argentimaculatus). Both genes shared, respectively, a high similarity and typical features with other vertebrate MHC class II α and II ß. The phylogenetic analysis of the deduced peptides revealed that both Lunar-DAA and Lunar-DAB were located in the teleost subclass. Western blotting analyses indicated that both MHC class II α and II ß were expressed ubiquitously in immune-related cells, tissues and organs, and that MHC class II α and II ß chains existed mainly as heterodimers. While it was highly expressed in gills, thymus, head kidney (HK), spleen, head kidney macrophage and spleen leucocytes, MHC class II ß chain was expressed with a low abundance in skin, intestine, stomach and heart. The highest expression of MHC class II ß in thymus confirmed the conclusion that thymus is one of the primary lymphoid organs in fishes. The detection of MHC class II αß dimers in HK macrophages and spleen leucocytes indicated that HK macrophages and spleen leucocytes play a critical role in the adaptive immunity in fishes. All these results provide valuable information for understanding the structure of MHC class II α and II ß and their function in immune responses.

Regulatory Network of MicroRNAs, Host Genes, Target Genes and Transcription Factors in Human Esophageal Squamous Cell Carcinoma.

Abnormally expressed microRNAs (miRNAs) and genes have been found to play key roles in esophageal squamous cell carcinoma (ESCC), but little is known about the underlying mechanisms. The aim of this paper was to assess inter-relationships and the regulatory mechanisms of ESCC through a network-based approach. We built three regulatory networks: an abnormally expressed network, a related network and a global network. Unlike previous examples, containing information only on genes or miRNAs, the prime focus was on relationships. It is worth noting that abnormally expressed network emerged as a fault map of ESCC. Theoretically, ESCC might be treated and prevented by correcting the included errors. In addition, the predicted transcription factors (TFs) obtained by the P-match method also warrant further study. Our results may further guide gene therapy researchers in the study of ESCC.

A hypothesis on the biological origins and social evolution of music and dance.

The origins of music and musical emotions is still an enigma, here I propose a comprehensive hypothesis on the origins and evolution of music, dance, and speech from a biological and sociological perspective. I suggest that every pitch interval between neighboring notes in music represents corresponding movement pattern through interpreting the Doppler effect of sound, which not only provides a possible explanation for the transposition invariance of music, but also integrates music and dance into a common form-rhythmic movements. Accordingly, investigating the origins of music poses the question: why do humans appreciate rhythmic movements? I suggest that human appreciation of rhythmic movements and rhythmic events developed from the natural selection of organisms adapting to the internal and external rhythmic environments. The perception and production of, as well as synchronization with external and internal rhythms are so vital for an organism's survival and reproduction, that animals have a rhythm-related reward and emotion (RRRE) system. The RRRE system enables the appreciation of rhythmic movements and events, and is integral to the origination of music, dance and speech. The first type of rewards and emotions (rhythm-related rewards and emotions, RRREs) are evoked by music and dance, and have biological and social functions, which in turn, promote the evolution of music, dance and speech. These functions also evoke a second type of rewards and emotions, which I name society-related rewards and emotions (SRREs). The neural circuits of RRREs and SRREs develop in species formation and personal growth, with congenital and acquired characteristics, respectively, namely music is the combination of nature and culture. This hypothesis provides probable selection pressures and outlines the evolution of music, dance, and speech. The links between the Doppler effect and the RRREs and SRREs can be empirically tested, making the current hypothesis scientifically concrete.