S-adenosyl-L-methionine supplementation alleviates damaged intestinal epithelium and inflammatory infiltration caused by Mat2a deficiency.

Methionine is important for intestinal development and homeostasis in various organisms. However, the underlying mechanisms are poorly understood. Here, we demonstrate that the methionine adenosyltransferase gene Mat2a is essential for intestinal development and that the metabolite S-adenosyl-L-methionine (SAM) plays an important role in intestinal homeostasis. Intestinal epithelial cell (IEC)-specific knockout of Mat2a exhibits impaired intestinal development and neonatal lethality. Mat2a deletion in the adult intestine reduces cell proliferation and triggers IEC apoptosis, leading to severe intestinal epithelial atrophy and intestinal inflammation. Mechanistically, we reveal that SAM maintains the integrity of differentiated epithelium and protects IECs from apoptosis by suppressing the expression of caspases 3 and 8 and their activation. SAM supplementation improves the defective intestinal epithelium and reduces inflammatory infiltration sequentially. In conclusion, our study demonstrates that methionine metabolism and its intermediate metabolite SAM play essential roles in intestinal development and homeostasis in mice.

Metabolism-Regulating Nanozyme System for Advanced Nanocatalytic Cancer Therapy.

Nanocatalytic therapy, an emerging approach in cancer treatment, utilizes nanomaterials to initiate enzyme-mimetic catalytic reactions within tumors, inducing tumor-suppressive effects. However, the targeted and selective catalysis within tumor cells is challenging yet critical for minimizing the adverse effects. The distinctive reliance of tumor cells on glycolysis generates abundant lactate, influencing the tumor's pH, which can be manipulated to selectively activate nanozymatic catalysis. Herein, small interfering ribonucleic acid (siRNA) targeting lactate transporter-mediated efflux is encapsulated within the iron-based metal-organic framework (FeMOF) and specifically delivered to tumor cells through cell membrane coating. This approach traps lactate within the cell, swiftly acidifying the tumor cytoplasm and creating an environment for boosting the catalysis of the FeMOF nanozyme. The nanozyme generates hydroxyl radical (·OH) in the reversed acidic environment, using endogenous hydrogen peroxide (H2O2) produced by mitochondria as a substrate. The induced cytoplasmic acidification disrupts calcium homeostasis, leading to mitochondrial calcium overload, resulting in mitochondrial dysfunction and subsequent tumor cell death. Additionally, the tumor microenvironment is also remodeled, inhibiting migration and invasion, thus preventing metastasis. This groundbreaking strategy combines metabolic regulation with nanozyme catalysis in a toxic drug-free approach for tumor treatment, holding promise for future clinical applications.

Genome-Wide Analysis of Glycerol-3-Phosphate Acyltransferase (GPAT) Family in Perilla frutescens and Functional Characterization of PfGPAT9 Crucial for Biosynthesis of Storage Oils Rich in High-Value Lipids.

Glycerol-3-phosphate acyltransferase (GPAT) catalyzes the first step in triacylglycerol (TAG) biosynthesis. However, GPAT members and their functions remain poorly understood in Perilla frutescens, a special edible-medicinal plant with its seed oil rich in polyunsaturated fatty acids (mostly α-linolenic acid, ALA). Here, 14 PfGPATs were identified from the P. frutescens genome and classified into three distinct groups according to their phylogenetic relationships. These 14 PfGPAT genes were distributed unevenly across 11 chromosomes. PfGPAT members within the same subfamily had highly conserved gene structures and four signature functional domains, despite considerable variations detected in these conserved motifs between groups. RNA-seq and RT-qPCR combined with dynamic analysis of oil and FA profiles during seed development indicated that PfGPAT9 may play a crucial role in the biosynthesis and accumulation of seed oil and PUFAs. Ex vivo enzymatic assay using the yeast expression system evidenced that PfGPAT9 had a strong GPAT enzyme activity crucial for TAG assembly and also a high substrate preference for oleic acid (OA, C18:1) and ALA (C18:3). Heterogeneous expression of PfGPAT9 significantly increased total oil and UFA (mostly C18:1 and C18:3) levels in both the seeds and leaves of the transgenic tobacco plants. Moreover, these transgenic tobacco lines exhibited no significant negative effect on other agronomic traits, including plant growth and seed germination rate, as well as other morphological and developmental properties. Collectively, our findings provide important insights into understanding PfGPAT functions, demonstrating that PfGPAT9 is the desirable target in metabolic engineering for increasing storage oil enriched with valuable FA profiles in oilseed crops.

Coexpression network analysis identified MT3 as a hub gene that promotes the chemoresistance of oral cancer by regulating the expression of YAP1.

BACKGROUND: Oral cancer is considered one of the most malignant types of tumors and is known for its high likelihood of recurrence and metastasis. During clinical treatment, patients with oral cancer often develop resistance to chemotherapy, making the treatment process challenging. The purpose of this study was to investigate the genes related to chemotherapy resistance and their mechanisms in oral cancer patients. METHODS: The "limma" package was used to identify the differentially expressed genes between tumor and normal tissues from TCGA dataset. Subsequently, the "WGCNA" package was utilized to discover genes associated with chemoresistance. Cisplatin-resistant oral cancer cell lines were obtained through exposure to gradually increasing doses of cisplatin. SiRNA was used to knock down the MT3 and YAP1 genes to validate their functions. Finally, the therapeutic efficacy of combining a YAP1 inhibitor with cisplatin was confirmed by inoculating an oral cancer cell line in mice. RESULTS: In our study, we analyzed 43 OSCC samples and identified 724 different genes using the weighted gene coexpression network analysis (WGCNA) method. Among these genes, MT3 stood out as strongly associated with chemotherapy resistance. Patients with high MT3 expression had worse prognoses, and MT3 levels were elevated in drug-resistant patients. Knocking down MT3 reversed tumor cell chemoresistance. We also observed that MT3 increased the expression of YAP1, potentially contributing to chemotherapy resistance by inducing tumor stemness through YAP1. In animal models, using YAP1 inhibitors improved the effectiveness of cisplatin in treating chemoresistant oral cancer. CONCLUSIONS: MT3 is related to chemotherapy resistance, which may be caused by its promotion of YAP1 expression and induction of tumor cell stemness. Inhibiting the activity of MT3 and YAP1 is helpful for increasing chemotherapy sensitivity.

Metabolite sensing and signaling in cancer.

Metabolites are not only substrates in metabolic reactions, but also signaling molecules controlling a wide range of cellular processes. Discovery of the oncometabolite 2-hydroxyglutarate provides an important link between metabolic dysfunction and cancer, unveiling the signaling function of metabolites in regulating epigenetic and epitranscriptomic modifications, genome integrity, and signal transduction. It is now known that cancer cells remodel their metabolic network to support biogenesis, caused by or resulting in the dysregulation of various metabolites. Cancer cells can sense alterations in metabolic intermediates to better coordinate multiple biological processes and enhance cell metabolism. Recent studies have demonstrated that metabolite signaling is involved in the regulation of malignant transformation, cell proliferation, epithelial-to-mesenchymal transition, differentiation blockade, and cancer stemness. Additionally, intercellular metabolite signaling modulates inflammatory response and immunosurveillance in the tumor microenvironment. Here, we review recent advances in cancer-associated metabolite signaling. An in depth understanding of metabolite signaling will provide new opportunities for the development of therapeutic interventions that target cancer.

Interactions between Two Kinds of Gold Nanoclusters and Calf Thymus Deoxyribonucleic Acid: Directions for Preparations to Applications.

Gold nanoclusters (AuNCs) have shown promising applications in biotherapy owing to their ultrasmall size and unique molecular-like properties. In order to better guide the preparations and applications of AuNCs, dihydrolipoic acid-protected AuNCs (DHLA-AuNCs) and glutathione-protected AuNCs (GSH-AuNCs) were selected as models and the interactions between them and calf thymus DNA (ctDNA) were studied in detail. The results showed that there was a small difference in the binding mechanisms and forces between both AuNCs and ctDNA. The quenching mechanisms of both AuNCs to (ctDNA-HO) were completely different. The binding constants indicated that the binding strength between DHLA-AuNCs and ctDNA was greater than those of GSH-AuNCs. The conformation investigations showed that GSH-AuNCs had a greater impact on the conformation of ctDNA, and both AuNCs were more inclined to interact with the A-T base pairs of ctDNA. These results indicate that the surface ligand had a significant effect on the interactions between AuNCs and DNA and might also further affect the applications of AuNCs, and these results could guide the preparations of AuNCs. For DHLA-AuNCs, their good biocompatibility made them a potential candidate for application in imaging, drug treatment, sensing, and so on. The resulting base accumulation of ctDNA and weak interactions made GSH-AuNCs have great potential for application in gene therapy, which was consistent with the current reports on the applications of these two AuNCs. This work has pointed out the directions for the preparations and applications of AuNCs.

Characterization of a common carp intelectin gene with bacterial binding and agglutination activity.

Intelectin (ITLN) is a type of glycan-binding lectin involved in many physiological processes and some human diseases. Here we report a common carp intelectin (cITLN). Like other orthologs, cITLN also contains a conserved fibrinogen-related domain (FReD) and a unique intelectin domain, expresses in all the tissues tested with the highest level in the hindgut, and responds to bacterial challenge in the acute phase. We also expressed cITLN in Escherichia coli (E. coli) system, and the purified recombinant cITLN could neither affect the surface of bacteria nor inhibit the growth of bacteria, but it can agglutinate both gram-positive and gram-negative bacteria in a calcium-dependent manner. The cITLN's ability of agglutination of gram-positive bacteria is stronger than that of gram-negative bacteria. This is probably because recombinant cITLN could binding peptidoglycan (PGN) with a higher degree to lipopolysaccharide (LPS). Our results of cITLN provided new insight into the function of intelectin in the intestinal mucosal immunity.

[A Review of Metabolic Stress and Development of Pancreatic Cancer].

Pancreatic ductal adenocarcinoma (PDAC) is one of the most notorious malignancies with a 5-year survival rate of less than 8%. Therefore, it is crucial to investigate the molecular mechanism underlining PDAC initiation, promotion, and progression for efficient treatment of PDAC. In order to adapt and survive in an extremely adverse microenvironment of hypoxia and insufficiency of nutrients and energy, PDAC cells undergo extensive metabolic modification triggered by intrinsic signalings which are activated by different genetic events, including mutations occurred at K RAS, TP53, and DPC4/ SMAD4, collaboratively promoting PDAC development. Notably, PDCA cells have extensive crosstalk in the form of reciprocal metabolic flux with its surrounding microenvironment to facilitate tumor advancement and therapy resistance. We herein summarize recent findings of PDAC metabolism and discuss metabolic rewiring-based therapeutic strategies.

Thermodynamics, Kinetics and Mechanisms of Noncompetitive Allosteric Inhibition of Chymotrypsin by Dihydrolipoic Acid-Coated Gold Nanoclusters.

Enzymes are an important class of biomacromolecules which catalyze many metabolic processes in living systems. Nanomaterials can be synthesized with tailored sizes as well as desired surface modifications, thus acting as promising enzyme regulators. Fluorescent gold nanoclusters (AuNCs) are a representative class of ultrasmall nanoparticles (USNPs) with sizes of ∼2 nm, smaller than most of proteins including enzymes. In this work, we chose α-chymotrypsin (ChT) and AuNCs as the model system. Activity assays and inhibition kinetics studies showed that dihydrolipoic acid (DHLA)-coated AuNCs (DHLA-AuNCs) had a high inhibitory potency (IC50 = 3.4 µM) and high inhibitory efficacy (>80%) on ChT activity through noncompetitive inhibition mechanism. In distinct contrast, glutathione (GSH)-coated AuNCs (GSH-AuNCs) had no significant inhibition effects. Fluorescence spectroscopy, agarose gel electrophoresis and circular dichroism (CD) spectroscopy were conducted to explore the underlying mechanisms. A two-step interaction model was proposed. First, both DHLA-AuNCs and GSH-AuNCs might be bound to the positively charged sites of ChT through electrostatic forces. Second, further hydrophobic interactions occurred between three tyrosine residues of ChT and the hydrophobic carbon chain of DHLA, leading to a significant structural change thus to deactivate ChT on the allosteric site. On the contrary, no such interactions occurred with GSH of zwitterionic characteristic, which explained no inhibitory effect of GSH-AuNCs on ChT. To the best of our knowledge, this is the first example of the allosteric inhibition of ChT by nano regulators. These findings provide a fundamental basis for the design and development of nano regulators.

Molecular characterization and expression analysis of two peptidoglycan recognition proteins (CcPGRP5, CcPGRP6) in larvae ontogeny of common carp Cyprinus carpio L. and upon immune stimulation by bacteria.

BACKGROUND: Although teleost fish developed acquired immunity firstly in evolution, innate immunity is still very important for them. Innate immunity depends on pattern recognition receptors (PRRs) to distinguish "self" and "non-self", Peptidoglycan (PGN) recognition protein (PGRP) is one of the receptors and it can bind to multiple components of bacterial envelope. RESULTS: We report the cloning and expression analysis of two PGRPs (Ccpgrp5 and Ccpgrp6) from common carp (Cyprinus carpio L). The Ccpgrp5 gene encodes a protein of 199 amino acid (aa) with PGRP domain, Ami_2 domain and four Zn2+ binding sites required for amidase activity, but without signal peptide and transmembrane domain. The Ccpgrp6 gene encodes a protein of 446 aa with PGRP domain, Ami_2 domain, signal peptide, five Zn2+ binding sites required for amidase activity and two sites for N-glycosylation. The phylogenetic analysis revealed that the CcPGRP5 and CcPGRP6 are closely related to Ctenopharyngodon idella and Danio rerio. Ccpgrp5 and Ccpgrp6 were expressed in all tissues examined including liver, spleen, muscle, oral epithelium, head kidney, gill, skin, gonad, brain, foregut and hindgut and showed different distribution characteristics. During the embryonic and early larval developmental stages of common carp, Ccpgrp6 was detected to be highly expressed at 10 days post fertilization(dpf) and 36 dpf, while Ccpgrp5 were hardly detected using Real-time quantitative PCR. After being challenged with Aeromonas hydrophila, Ccpgrp5 in adult common carp was induced and up-regulated in all the tissues, especially in gill and spleen, but not in head kidney, while Ccpgrp6 was up-regulated in all the tissues, especially in liver, head kidney and gill. The varied expression profiling of Ccpgrp5 and Ccpgrp6 indicated they had different roles in the host immune response. CONCLUSIONS: These results indicated the two PGRPs, especially Ccpgrp6, played an important role in the immune defense of common carp during larva development and against Aeromonas hydrophila, providing insight to further exploration of protecting fish against bacteria infectious disease.

TAZQ233del Hijacks Hippo pathway to promote mesenchymal-epithelial transition in pancreatic adenocarcinoma cells.

The Hippo pathway is crucial in organ size control, and its dysregulation contributes to tumorigenesis. TAZ is an essential molecule containing a WW domain in Hippo pathway and serves as transcription co-activator to modulate cell proliferation and induce epithelial-mesenchymal transition in different human cancers, including pancreatic adenocarcinoma. In this study, we found that TAZQ233del, a deletion occurred at its transactivation domain, increases phosphorylation at TAZ Ser89, resulting in sequestration of TAZ in cytoplasm and inhibiting its transcriptional activity. Furthermore, ectopic expression of TAZQ233del promotes mesenchymal-epithelial transition (MET), demonstrating that Q233 is an essential site to control TAZ function. Our results disclose that TAZQ233del plays a major role in regulating malignancy of cancer cells by hijacking Hippo pathway.

Cloning and molecular characterization of the ORF5 gene from a PRRSV-SN strain from Southwest China.

To monitor the genetic variation of PRRSV, the ORF5 gene of the PRRSV-SN strain found in Suining City, Sichuan Province, was cloned and sequenced. The results showed that the PRRSV-SN strain was a highly pathogenic PRRSV (HP-PRRSV) variant strain with the North American (NA) genotype. Homology analysis showed that the ORF5 gene of the PRRSV-SN isolate shared 89.4% (86.5%) nucleotide (amino acid) sequence similarity with the North American strain VR-2332, 98.8% (96%) similarity with JXA1, and 63.8% (57.7%) similarity with the European type representative strain Lelystad virus. Phylogenetic analysis showed that PRRSV-SN belongs to the NA genotype and has the same subtype as other highly pathogenic PRRSV strains. Amino acid sequence analysis showed that compared with the VR2332 strain, PRRSV-SN has different degrees of variation in the signal peptide, transmembrane region (TM), primary neutralizing epitope (PNE), non-neutral epitopes and N-glycosylation sites. Antigenicity analysis showed that the PRRSV-SN ORF5 gene products and JXA1 have similar antigenic characteristics, and the antigenic epitopes are mainly located in aa30-39, aa50-60, aa128-141, aa146-155 and aa161-183 regions. In contrast, the antigenic characteristics of PRRSV-SN are quite different from those of the VR2332 strain. The main differences were that the PRRSV-SN strain was significantly narrower than the VR2332 strain in the aa30-39 and the aa50-60 regions but was significantly wider in the aa136-141 region. The results of this study showed that the epidemic strains that cause PRRSV outbreaks in the farm are still mainly JXA1 variants, but due to the more frequent use of live vaccine immunizations, the genes of the PRRSV epidemic strain still show constant variation. Vaccination with live PRRSV should be reduced, and surveillance of PRRSV strains should be enhanced.

Thermodynamics and Mechanisms of the Interactions between Ultrasmall Fluorescent Gold Nanoclusters and Human Serum Albumin, γ-Globulins, and Transferrin: A Spectroscopic Approach.

Noble metal nanoclusters (NCs) show great promise as nanoprobes for bioanalysis and cellular imaging in biological applications due to ultrasmall size, good photophysical properties, and excellent biocompatibility. In order to achieve a comprehensive understanding of possible biological implications, a series of spectroscopic measurements were conducted under different temperatures to investigate the interactions of Au NCs (∼1.7 nm) with three model plasmatic proteins (human serum albumin (HSA), γ-globulins, and transferrin). It was found that the fluorescence quenching of HSA and γ-globulins triggered by Au NCs was due to dynamic quenching mechanism, while the fluorescence quenching of transferrin by Au NCs was a result of the formation of a Au NC-transferrin complex. The apparent association constants of the Au NCs bound to HSA, γ-globulins, and transferrin demonstrated no obvious difference. Thermodynamic studies demonstrated that the interaction between Au NCs and HSA (or γ-globulins) was driven by hydrophobic forces, while the electrostatic interactions played predominant roles in the adsorption process for transferrin. Furthermore, it was proven that Au NCs had no obvious interference in the secondary structures of these three kinds of proteins. In turn, these three proteins had a minor effect on the fluorescence intensity of Au NCs, which made fluorescent Au NCs promising in biological applications owing to their chemical and photophysical stability. In addition, by comparing the interactions of small molecules, Au NCs, and large nanomaterials with serum albumin, it was found that the binding constants were gradually increased with the increase of particle size. This work has elucidated the interaction mechanisms between nanoclusters and proteins, and shed light on a new interaction mode different from the protein corona on the surface of nanoparticles, which will highly contribute to the better design and applications of fluorescent nanoclusters.

A g.-1256 A>C in the promoter region of CAPN1 is associated with semen quality traits in Chinese Holstein bulls.

The micromolar calcium-activated neutral protease gene (CAPN1) is a physiological candidate gene for sperm motility. However, the molecular mechanisms involved in regulating the expression of the CAPN1 gene in bulls remain unknown. In this study, we investigated the expression pattern of CAPN1 in testis, epididymis, and sperm at the RNA and protein levels by qRT-PCR, western blot, immunohistochemistry, and immunofluorescence assay. Results revealed that the expression of CAPN1 levels was higher in the sperm head compared with that in other tissues. Moreover, we identified a novel single-nucleotide polymorphism (g.-1256 A>C, ss 1917715340) in the noncanonical core promoter of the CAPN1 gene between base g.-1306 and g.-1012. Additionally, we observed greater sperm motility in bulls with the genotype CC than in those with the genotype AA (P<0.01), indicating that different genotypes were associated with the bovine semen trait. Furthermore, a higher fluorescence intensity of the C allele than that of the A allele at g. -1256 A>C was revealed by transient transfection in MLTC-1 cells and luciferase report assay. Finally, CAPN1 was highly expressed in the spermatozoa with the CC genotype compared with that with the AA genotype by qRT-PCR. This study is the first report on genetic variant g.-1256 A>C in the promoter region of CAPN1 gene association with the semen quality of Chinese Holstein bulls by influencing its expression. g.-1256 A>C can be a functional molecular marker in cattle breeding.

Overexpression of activin-A and -B in malignant mesothelioma - attenuated Smad3 signaling responses and ERK activation promote cell migration and invasive growth.

Activin-A and activin-B, members of the TGF-ß superfamily, are regulators of reproductive functions, inflammation and wound healing. These dimeric molecules regulate various cellular activities such as proliferation, migration and suvival. Malignant mesothelioma is an asbestos exposure related tumor affecting mainly pleura and it usually has a dismal prognosis. Here, we demonstrate that both activin-A and -B are abundantly expressed in mesothelioma tumor tissue as well as in cultured primary and established mesothelioma cells. Migratory and invasive mesothelioma cells were also found to have attenuated activation of the Smad2/3 pathway in response to activins. Migration and invasive growth of the cells in three-dimentional matrix was prevented by inhibition of activin activity using a soluble activin receptor 2B (sActR2B-Fc). This was associated with decreased ERK activity. Furthermore, migration and invasive growth was significantly inhibited by blocking ERK phosphorylation. Mesothelioma tumors are locally invasive and our results clearly suggest that acivins have a tumor-promoting function in mesothelioma through increasing expression and switching from canonical Smad3 pathway to non-canonical ERK pathway signaling. Blocking activin activity offers a new therapeutic approach for inhibition of mesothelioma invasive growth.

The role of Exo70 in vascular smooth muscle cell migration.

BACKGROUND: As a key subunit of the exocyst complex, Exo70 has highly conserved sequence and is widely found in yeast, mammals, and plants. In yeast, Exo70 mediates the process of exocytosis and promotes anchoring and integration of vesicles with the plasma membrane. In mammalian cells, Exo70 is involved in maintaining cell morphology, cell migration, cell connection, mRNA splicing, and other physiological processes, as well as participating in exocytosis. However, Exo70's function in mammalian cells has yet to be fully recognized. In this paper, the expression of Exo70 and its role in cell migration were studied in a rat vascular smooth muscle cell line A7r5. METHODS: Immunofluorescent analysis the expression of Exo70, α-actin, and tubulin in A7r5 cells showed a co-localization of Exo70 and α-actin, we treated the cells with cytochalasin B to depolymerize α-actin, in order to further confirm the co-localization of Exo70 and α-actin. We analyzed Exo70 co-localization with actin at the edge of migrating cells by wound-healing assay to establish whether Exo70 might play a role in cell migration. Next, we analyzed the migration and invasion ability of A7r5 cells before and after RNAi silencing through the wound healing assay and transwell assay. RESULTS: The mechanism of interaction between Exo70 and cytoskeleton can be clarified by the immunoprecipitation techniques and wound-healing assay. The results showed that Exo70 and α-actin were co-localized at the leading edge of migrating cells. The ability of A7r5 to undergo cell migration was decreased when Exo70 expression was silenced by RNAi. Reducing Exo70 expression in RNAi treated A7r5 cells significantly lowered the invasion and migration ability of these cells compared to the normal cells. These results indicate that Exo70 participates in the process of A7r5 cell migration. CONCLUSIONS: This research is importance for the study on the pathological process of vascular intimal hyperplasia, since it provides a new research direction for the treatment of cardiovascular diseases such as atherosclerosis and restenosis after balloon angioplasty.

[Changes in blood CD4+CD25+ regulatory T cells in children with severe purulent meningitis].

OBJECTIVE: To preliminarily study the changes in CD4+CD25+ regulatory T cells (Tregs) in children with severe purulent meningitis at the early stage and its possible implications. METHODS: A retrospective analysis was performed on the clinical data of 39 children with severe purulent meningitis who were admitted to the pediatric intensive care unit from August 2014 to December 2015. According to whether Tregs count was decreased within 12 hours of hospitalization (considering Tregs count <410/mm3 as decreased), they were divided into two groups: decrease group and non-decrease group. The associations between the changes in Tregs cells and the clinical manifestations, laboratory marker levels, and prognosis were analyzed. RESULTS: Of the 39 cases, 13 (33%) showed a decrease in the proportion of Tregs cells (<31%) and 18 (46%) showed a decrease in the absolute Tregs cell count (<410/mm3). Four deaths were all in the Tregs decrease group. Compared with the non-decrease group, the decrease group showed a significantly higher proportion of children with a peripheral blood leukocyte count lower than the normal range and a significantly greater increase in the level of serum procalcitonin (P<0.05). CONCLUSIONS: Tregs might be suppressed in children with severe purulent meningitis at the early stage. And its suppression could be related to the severer inflammation reaction and higher mortality in those patients.

Osteopontin promotes the invasive growth of melanoma cells by activating integrin αvß3 and down-regulating tetraspanin CD9.

Overexpression of osteopontin (OPN) is strongly associated with the invasiveness/metastasis of many cancers, including melanomas. However, the molecular mechanisms of OPN in these processes remain poorly understood. We found that forced expression of OPN in early vertical-growth-phase melanoma cells dramatically increased their migration/invasion and growth/survival in a three-dimensional collagen I gel. Neutralizing antibodies to OPN, integrin ß1, and integrin αvß3, but not to CD44, negated the effects of OPN. Conversely, knocking down OPN in metastatic melanoma cells abrogated the invasive growth. OPN overexpression activated and OPN knockdown inactivated αvß3 and αvß5 integrins, negligibly affecting their expression. We further found OPN expression to inversely correlate with tetraspanin CD9 expression. Early-stage melanoma cells displayed low OPN and high CD9 expression, and conversely, metastatic cells displayed high OPN and low CD9 expression. Overexpression of OPN in vertical-growth-phase melanoma cells induced down-regulation of CD9, and knockdown of OPN in metastatic melanoma cells up-regulated CD9. Reversion of these CD9 changes abolished the effects of OPN. Furthermore, knockdown of CD9 in early-stage melanoma cells stimulated their invasive capacity in three-dimensional collagen. Similarly, microarray analyses of benign nevi and primary melanomas from different stages revealed an inverse correlation between OPN and CD9. These data suggest that OPN promotes melanoma cell invasion by activating integrin αvß3 and down-regulating CD9, a putative metastasis suppressor.

Co-Exploring Structured Sparsification and Low-Rank Tensor Decomposition for Compact DNNs.

Sparsification and low-rank decomposition are two important techniques to compress deep neural network (DNN) models. To date, these two popular yet distinct approaches are typically used in separate ways; while their efficient integration for better compression performance is little explored, especially for structured sparsification and decomposition. In this article, we perform systematic co-exploration on structured sparsification and decomposition toward compact DNN models. We first investigate and analyze several important design factors for joint structured sparsification and decomposition, including operational sequence, decomposition format, and optimization procedure. Based on the observations from our analysis, we then propose CEPD, a unified DNN compression framework that can co-explore the benefits of structured sparsification and tensor decomposition in an efficient way. Empirical experiments demonstrate the promising performance of our proposed solution. Notably, on the CIFAR-10 dataset, CEPD brings 0.72%-0.45% accuracy increase over the baseline ResNet-56 and MobileNetV2 models, respectively, and meanwhile, the computational costs are reduced by 43.0%-44.2%, respectively. On the ImageNet dataset, our approach can enable 0.10%-1.39% accuracy increase over the baseline ResNet-18 and ResNet-50 models with 59.4%-54.6% fewer parameters, respectively.

Structure-activity relationship between gold nanoclusters and human serum albumin: Effects of ligand isomerization.

The interactions between gold nanoclusters (AuNCs) and proteins have been extensively investigated. Nevertheless, the structure-activity relationship between gold nanoclusters and proteins in terms of ligand isomerization remained unclear. Here, interactions between Au25NCs modified with para-, inter- and ortho-mercaptobenzoic acid (p/m/o-MBA-Au25NCs) and human serum albumin (HSA) were analyzed. The results of the multispectral approach showed that all three gold nanoclusters bound to the site I in dynamic modes to increase the stability of HSA. There were significant differences in the binding intensity, thermodynamic parameters, main driving forces, and binding ratios between these three gold nanoclusters and HSA, which might be related to the existence forms of the three ligands on the surface of AuNCs. Due to the different polarities of AuNCs themselves, the impact of three AuNCs on the microenvironment of amino acid residues in HSA was also different. It could be seen that ligand isomerization significantly affected the interactions between gold nanoclusters and proteins. This work will provide theoretical guidance for ligand selection and biological applications of metal nanoclusters.