Discovery of Novel Non-Nucleoside Inhibitors Interacting with Dizinc Ions of CD73.

High extracellular concentrations of adenosine triphosphate (ATP) in the tumor microenvironment generate adenosine by sequential dephosphorylation of CD39 and CD73, resulting in potent immunosuppression to inhibit T cell and natural killer (NK) cell function. CD73, as the determining enzyme for adenosine production, has been shown to correlate with poor clinical tumor prognosis. Conventional inhibitors as analogues of adenosine 5'-monophosphate (AMP) may have a risk of further metabolism to adenosine analogues. Here, we report a new series of malonic acid non-nucleoside inhibitors coordinating with zinc ions of CD73. Compound 12f was found to be a superior CD73 inhibitor (IC50 = 60 nM) by structural optimization, and its pharmacokinetic properties were investigated. In mouse tumor models, compound 12f showed excellent efficacy and reversal of immunosuppression in combination with chemotherapeutic agents or checkpoint inhibitors, suggesting that it deserves further development as a novel CD73 inhibitor.

Biological performance and membrane fouling of a microalgal-bacterial membrane photobioreactor for wastewater treatment without external aeration and carbonation.

Biological nutrient removal processes involving the use of activated sludge (AS) to treat municipal wastewater normally result in high aeration energy consumption and significant greenhouse gas (GHG) emissions. Therefore, developing cost-efficient and environmentally friendly processes for wastewater treatment is vital. In this work, a novel non-aerated microalgal-bacterial membrane photobioreactor (MB-MPBR) was proposed, and its feasibility for organic contaminant and nutrient removals was evaluated, for the first time. The effects of inoculation ratio (microalgae to bacteria (M/B)) on the biological performance and membrane fouling were systematically investigated. The results showed that 95.9% of the chemical oxygen demand (COD), 74.5% of total nitrogen (TN), 98.5% of NH4+-N and 42.0% of total phosphorus (TP) were removed at an inoculation M/B ratio of 3:2 at steady state, representing a significant improvement compared to the M/B inoculation ratio of 1:3. Additionally, the higher inoculation M/B ratio (3:2) significantly promoted the biomass production owing to the favorable mutual exchange of oxygen and carbon dioxide between microalgae and bacteria. Cake layer formation was the primary fouling mechanism owing to the absence of aeration scouring on the membrane surface. The membrane fouling rate was slightly higher at the higher inoculation ratio (M/B = 3:2) owing to the increased biomass and extracellular polymeric substances (EPS) productions, despite the larger particle size. These results demonstrated that the non-aerated MB-MPBR could achieve superior biological performance, of which the inoculation M/B ratio was of critical importance for the initiation and maintenance of microalgal-bacterial symbiotic system, yet possibly caused severer membrane fouling in the absence of external aeration and carbonation. This study provides a new perspective for further optimizing and applying non-aerated MB-MPBR to enhance municipal wastewater treatment.

Surface properties of membrane materials and their role in cell adhesion and biofilm formation of microalgae.

In this study, the effects of surface properties of membrane materials on microalgae cell adhesion and biofilm formation were investigated using Chlorella vulgaris and five different types of membrane materials under hydrodynamic conditions. The results suggest that the contact angle (hydrophobicity), surface free energy, and free energy of cohesion of membrane materials alone could not sufficiently elucidate the selectivity of microalgae cell adhesion and biofilm formation on membrane materials surfaces, and membrane surface roughness played a dominant role in controlling biofilm formation rate, under tested hydrodynamic conditions. A lower level of biofilm EPS production was generally associated with a larger amount of biofilm formation. The zeta potential of membrane materials could enhance initial microalgae cell adhesion and biofilm formation through salt bridging or charge neutralization mechanisms.

Microalgae cell adhesions on hydrophobic membrane substrates using quartz crystal microbalance with dissipation.

Microalgal cell adhesion and biofilm formation are affected by interactions between microalgae strains and membrane materials. Variations of surface properties of microalgae and membrane materials are expected to affect cell-membranes and cell-cell interactions and thus initial microalgal cell adhesion and biofilm formation rates. Hence, it should be possible to identify the dominant mechanisms controlling microalgal cell adhesion and biofilm formation. The effects of surface properties of three different microalgal strains and three different types of membrane materials on microalgal cell adhesion and biofilm formation were systematically investigated in real time by monitoring changes in the oscillation frequency and dissipation of the quartz crystal resonator (QCM-D). The results revealed that in general a higher surface free energy, more negative zeta potential, and higher surface roughness of membrane materials positively correlated with a larger quantity of microalgae cell deposition, while a more hydrophilic microalgae with a larger negative zeta potential preferred to attach to a more hydrophobic membrane material. The adhered microalgal layers exhibited viscoelastic properties. The relative importance of these mechanisms in controlling microalgae cell attachment and biofilm formation might vary, depending on the properties of specific microalgae species and hydrophobic membrane materials used.

TNFSF15 and MIA Variant Associated with Immunotherapy and Prognostic Evaluation in Esophageal Cancer.

Background: Esophageal cancer (ESCA) is a common gastrointestinal tumor, and China is one of the regions with a high incidence. Tumor immune-related cells play important roles in the tumorigenesis and development of ESCA. However, the role of tumor immune-related genes in the development of ESCA has not been established. Methods: In this study, weighted gene coexpression network analysis (WGCNA) was used to analyze ESCA gene expression using data from The Cancer Genome Atlas (TCGA) database. Gene expression was associated with clinical traits, and modules related to CD8+T cells, dendritic cells, and regulatory T cells (Tregs) were obtained. Results: The GO analysis showed that inflammatory chemotaxis networks were activated by cell chemotaxis, chemokine activity, and chemokine binding receptor. Three hub genes (IL17C, TNFSF15, and MIA) related to tumor immunity and metastasis were identified by WGCNA, and the abnormal expression of each hub gene in ESCA has a poor prognosis, especially in patients with high expression (P < 0.05). The risk assessment analysis also showed that tumor stage was positively correlated with tumor risk in ESCA (P < 0.05). Therefore, more than 50 pairs of tumor tissues from the T1-T3 stages with different degrees of differentiation and paracancerous tissues were selected to confirm the expression of the three genes using RT-qPCR and immunofluorescence (IF). The infiltration of CD8+ T cells in tumor tissues was lower than that in normal tissues. According to the RT-qPCR, the expressions of IL17 C, TNFSF15, and MIA in moderately and poorly differentiated tissues were significantly higher than those in normal tissues (P < 0.05). In contrast, their expressions were decreased in high differentiated tissues (P < 0.05). Furthermore, IL17C, TNFSF15, and MIA were all positively correlated with immune checkpoint PD-1; TNFSF15 and MIA were also positively correlated with CTLA4, TIGIT, and CD96. Conclusion: In summary, IL17C, TNFSF15, and MIA may act as biomarkers for prognosis in moderately and poorly differentiated ESCAs, and they may be used as predictive genes of immunotherapy associated with CD8+ T cell and Tregs invasion in ESCAs.

Multi-modal chemical information reconstruction from images and texts for exploring the near-drug space.

Identification of new chemical compounds with desired structural diversity and biological properties plays an essential role in drug discovery, yet the construction of such a potential space with elements of 'near-drug' properties is still a challenging task. In this work, we proposed a multimodal chemical information reconstruction system to automatically process, extract and align heterogeneous information from the text descriptions and structural images of chemical patents. Our key innovation lies in a heterogeneous data generator that produces cross-modality training data in the form of text descriptions and Markush structure images, from which a two-branch model with image- and text-processing units can then learn to both recognize heterogeneous chemical entities and simultaneously capture their correspondence. In particular, we have collected chemical structures from ChEMBL database and chemical patents from the European Patent Office and the US Patent and Trademark Office using keywords 'A61P, compound, structure' in the years from 2010 to 2020, and generated heterogeneous chemical information datasets with 210K structural images and 7818 annotated text snippets. Based on the reconstructed results and substituent replacement rules, structural libraries of a huge number of near-drug compounds can be generated automatically. In quantitative evaluations, our model can correctly reconstruct 97% of the molecular images into structured format and achieve an F1-score around 97-98% in the recognition of chemical entities, which demonstrated the effectiveness of our model in automatic information extraction from chemical patents, and hopefully transforming them to a user-friendly, structured molecular database enriching the near-drug space to realize the intelligent retrieval technology of chemical knowledge.

Hollow ZSM-5 zeolite encapsulating Pt nanoparticles: Cage-confinement effects for the enhanced catalytic oxidation of benzene.

A zeolitic cage was introduced and rationally fabricated by encapsulating Pt nanoparticles (NPs) in hollow ZSM-5, a nanomaterial with a cavity and porous shell, for efficient catalytic oxidation of benzene. The structure and formation of the zeolitic cage were systematically investigated and characterized using transmission electron microscopy, nitrogen sorption investigations, X-ray photoelectron spectroscopy, nuclear magnetic resonance spectroscopy, and X-ray diffraction. The obtained hollow 0.2 Pt@ZSM-5 exhibited a comparable low-temperature catalytic activity with 0.5Pt/ZSM-5 with T90 value of 178 °C. Various characterization techniques combined with adsorption experiments uncover the tremendous role of the zeolitic cage in the catalytic activity toward benzene oxidation. The porous shell prevented benzene dilution and the acidity originating from the hollow interior of ZSM-5 promoted the storage of benzene, thereby forming a high local concentration of benzene around Pt NPs, resulting in excellent catalytic performance. These findings provide valuable insights into the rational design of efficient catalysts for the catalytic oxidation of volatile organic compounds.

Transcriptomic and proteomic analysis of putative digestive proteases in the salivary gland and gut of Empoasca (Matsumurasca) onukii Matsuda.

BACKGROUND: Infestation by tea green leafhoppers (Empoasca (Matsumurasca) onukii) can cause a series of biochemical changes in tea leaves. As a typical cell-rupture feeder, E. onukii secretes proteases while using its stylet to probe the tender shoots of tea plants (Camellia sinensis). This study identified and analyzed proteases expressed specifically in the salivary gland (SG) and gut of E. onukii through enzymatic activity assays complemented with an integrated analysis of transcriptomic and proteomic data. RESULTS: In total, 129 contigs representing seven types of putative proteases were identified. Transcript abundance of digestive proteases and enzymatic activity assays showed that cathepsin B-like protease, cathepsin L-like protease, and serine proteases (trypsin- and chymotrypsin-like protease) were highly abundant in the gut but moderately abundant in the SG. The abundance pattern of digestive proteases in the SG and gut of E. onukii differed from that of other hemipterans, including Nilaparvata lugens, Laodelphax striatellus, Acyrthosiphum pisum, Halyomorpha halys and Nephotettix cincticeps. Phylogenetic analysis showed that aminopeptidase N-like proteins and serine proteases abundant in the SG or gut of hemipterans formed two distinct clusters. CONCLUSIONS: Altogether, this study provides insightful information on the digestive system of E. onukii. Compared to five other hemipteran species, we observed different patterns of proteases abundant in the SG and gut of E. onukii. These results will be beneficial in understanding the interaction between tea plants and E. onukii.

A Method of HBase Multi-Conditional Query for Ubiquitous Sensing Applications.

Big data gathered from real systems, such as public infrastructure, healthcare, smart homes, industries, and so on, by sensor networks contain enormous value, and need to be mined deeply, which depends on a data storing and retrieving service. HBase is playing an increasingly important part in the big data environment since it provides a flexible pattern for storing extremely large amounts of unstructured data. Despite the fast-speed reading by RowKey, HBase does not natively support multi-conditional query, which is a common demand and operation in relational databases, especially for data analysis of ubiquitous sensing applications. In this paper, we introduce a method to construct a linear index by employing a Hilbert space-filling curve. As a RowKey generating schema, the proposed method maps multiple index-columns into a one-dimensional encoded sequence, and then constructs a new RowKey. We also provide a R-tree-based optimization to reduce the computational cost of encoding query conditions. Without using a secondary index mode, experimental results indicate that the proposed method has better performance in multi-conditional queries.

A review of membrane fouling and its control in algal-related membrane processes.

Membrane technologies have received much attention in microalgae biorefinery for nutrients removal from wastewater, carbon dioxide abatement from the air as well as the production of value-added products and biofuel in recent years. This paper provides a state-of-the-art review on membrane fouling issues and its control in membrane photobioreactors (MPBRs) and other algal-related membrane processes (harvesting, dewatering, and biofuel production). The mechanisms of membrane fouling and factors affecting membrane fouling in algal-related membrane processes are systematically reviewed. Also, strategies to control membrane fouling in algal-related membrane processes are summarized and discussed. Finally, the gaps, challenges, and opportunities in membrane fouling control in algal-related membrane technologies are identified and discussed.

Nobiletin attenuates metastasis via both ERK and PI3K/Akt pathways in HGF-treated liver cancer HepG2 cells.

Hepatocyte growth factor (HGF), and its receptor, c-Met activation has recently been shown to play important roles in cancer invasion and metastasis in a wide variety of tumor cells. We use HGF as an invasive inducer of human HepG2 cells to investigate the effect of four flavones including apigenin, tricetin, tangeretin, and nobiletin on HGF/c-Met-mediated tumor invasion and metastasis. Among them, nobiletin markedly inhibited HGF-induced the abilities of the adhesion, invasion, and migration by cell-matrix adhesion assay and transwell-chamber invasion/migration assay under non-cytotoxic concentrations. Data also showed nobiletin inhibited HGF-induced cell scattering and cytoskeleton changed such as filopodia and lamellipodia. Furthermore, nobiletin could inhibit HGF-induced the membrane localization of phosphorylated c-Met, ERK2, and Akt, but not phosphorylated JNK1/2 and p38. Next, nobiletin significantly decreased the levels of phospho-ERK2 and phospho-Akt in ERK2 or Akt siRNA-transfected cells concomitantly with a marked reduction on cell invasion and migration. In conclusion, nobiletin attenuates HGF-induced HepG2 cells metastasis involving both ERK and PI3K/Akt pathways and are potentially useful as anti-metastatic agents for the treatment of hepatoma.

Advanced glycation end products-mediated hypertrophy is negatively regulated by tetrahydrobiopterin in renal tubular cells.

Diabetic nephropathy (DN) is the most common cause of end-stage renal disease worldwide. The accumulation of advanced glycation end products (AGE) is a key mediator of renal tubular hypertrophy in DN. Elimination of tetrahydrobiopterin (BH(4)) and nitric oxide (NO) bioavailability may contribute to the aggravation of DN. The present study aims to explore any possible beneficial effect of exogenous BH(4) in alleviating the AGE-induced renal tubular hypertrophy in DN. Thus, renal tubular cells were treated with BH(4), BH(2), sepiapterin, or DAHP in the presence of AGE. We found that AGE (but not non-glycated BSA) markedly reduced NO production and increased hypertrophy index in these cells. Exogenous BH(4)/BH(2) and sepiapterin treatments attenuated AGE-inhibited the iNOS/NO/GTPCH I protein synthesis. Moreover, BH(4) and BH(2) significantly reversed AGE-enhanced the JAK2-STAT1/STAT3 activation. The abilities of BH(4) and BH(2) to inhibit AGE-induced renal cellular hypertrophy were verified by the observation that BH(4) and BH(2) inhibited hypertrophic growth and the protein synthesis of p27(Kip1) and α-SMA. These findings indicate for the first time that exogenous BH(4) and BH(2) attenuate AGE-induced hypertrophic effect at least partly by increasing the iNOS/GTPCH I synthesis and NO generation in renal tubular cells.

Nobiletin, a citrus flavonoid, suppresses invasion and migration involving FAK/PI3K/Akt and small GTPase signals in human gastric adenocarcinoma AGS cells.

Nobiletin, a compound isolated from citrus fruits, is a polymethoxylated flavone derivative shown to have anti-inflammatory, antitumor, and neuroprotective properties. This study has investigated that nobiletin exerted inhibitory effects on the cell adhesion, invasion, and migration abilities of a highly metastatic AGS cells under non-cytotoxic concentrations. Data also showed nobiletin could inhibit the activation of focal adhesion kinase (FAK) and phosphoinositide-3-kinase/Akt (PI3K/Akt) involved in the downregulation of the enzyme activities, protein expressions, messenger RNA levels of matrix metalloproteinase-2 (MMP-2), and matrix metalloproteinase-2 (MMP-9). Also, our data revealed that nobiletin inhibited FAK/PI3K/Akt with concurrent reduction in the protein expressions of Ras, c-Raf, Rac-1, Cdc42, and RhoA by western blotting, whereas the protein level of RhoB increased progressively. Otherwise, nobiletin-treated AGS cells showed tremendously decreased in the phosphorylation and degradation of inhibitor of kappaBα (IκBα), the nuclear level of NF-κB, and the binding ability of NF-κB to NF-κB response element. Furthermore, nobiletin significantly decreased the levels of phospho-Akt and MMP-2/9 in Akt1-cDNA-transfected cells concomitantly with a marked reduction in cell invasion and migration. These results suggest that nobiletin can reduce invasion and migration of AGS cells, and such a characteristic may be of great value in the development of a potential cancer therapy.

alpha-Mangostin, a novel dietary xanthone, suppresses TPA-mediated MMP-2 and MMP-9 expressions through the ERK signaling pathway in MCF-7 human breast adenocarcinoma cells.

This study first investigates the anti-metastatic effect of alpha-mangostin on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) expressions in human breast adenocarcinoma cells, MCF-7. First, the result demonstrated alpha-mangostin could inhibit TPA-induced abilities of the adhesion, invasion, and migration by cell-matrix adhesion assay and Boyden chamber assay. Data also showed alpha-mangostin could inhibit the activation of extracellular signal-regulated kinase 1 and 2 (ERK1/2) involved in the downregulation the enzyme activities, protein, and messenger RNA levels of MMP-2 and MMP-9 induced by TPA. Next, alpha-mangostin also strongly inhibited TPA-induced degradation of inhibitor of kappaBalpha (IkappaBalpha) and the nuclear levels of nuclear factor kappa B (NF-kappaB), c-Fos, and c-Jun. Also, a dose-dependent inhibition on the binding abilities of NF-kappaB and activator protein-1 (AP-1) by alpha-mangostin treatment was further observed. Further, the treatment of specific inhibitor for ERK (U0126) to MCF-7 cells could inhibit TPA-induced MMP-2 and MMP-9 expressions along with an inhibition on cell invasion and migration. Presented data reveal that alpha-mangostin is a novel, effective, antimetastatic agent that functions by downregulating MMP-2 and MMP-9 gene expressions.

Psoriasis in a 3-month-old infant with Kawasaki disease.

Kawasaki disease (KD) or mucocutaneous lymph node syndrome is a systemic vasculitis of unknown etiology affecting young children. Typical cutaneous manifestations of KD are polymorphous, including maculopapular or morbilliform rash and erythroderma. Occurrence of psoriasis following KD is rare. Herein we report a case of new onset of psoriasis in a 3-month-old that flared after a typical clinical case of KD, manifesting spiking fever, diffuse redness and fissuring of the lips, bilateral conjunctiva injection, injected throat, left cervical lymphadenopathy, erythema and desquamation of the lips, cheeks, hands, feet and perianal area, and a generalized maculopapular eruption. In addition, erythema and induration of the BCG vaccination site and coronary artery dilatation were noted. After fading of the initial rash, the patient developed widespread psoriasiform papules and plaques involving the face and extremities. The cheeks, lips and nail involvement with subunqual hyperkeratosis and pincer nail deformity were particularly striking. The diagnosis of psoriasis was confirmed by skin biopsy. The eruption resolved after one month of topical momentasone furoate treatment. The role of superantigens in KD-associated psoriasis is discussed.

Involvement of the ERK signaling pathway in fisetin reduces invasion and migration in the human lung cancer cell line A549.

This study is the first to investigate the antimetastatic effect of fisetin in human lung adenocarcinoma A549 cells. Fisetin exhibited an inhibitory effect on the abilities of adhesion, migration, and invasion via inhibiting the phosphorylation of extracellular signal-regulated kinase 1 and 2 (ERK1/2) and downregulating the expressions of matrix metalloproteinase-2 (MMP-2) and urokinase-type plasminogen activator (u-PA) at both the protein and mRNA levels in A549 cells. Next, fisetin significantly decreased the nuclear levels of nuclear factor kappa B (NF-kappaB), c-Fos, and c-Jun. Also, treating A549 cells with fisetin also leads to a concentration-dependent inhibition on the binding abilities of NF-kappaB and activator protein-1 (AP-1). Furthermore, reduction of ERK1/2 phosphorylation by ERK small interfering RNA (ERK siRNA) potentiated the effect of fisetin, supporting the inhibition of ERK1/2 being beneficial to antimetastasis. Finally, the transient transfection of ERK siRNA significantly downregulated the expressions of MMP-2 and u-PA concomitantly with a marked inhibition of cell invasion and migration. Taken together, these results implied a critical role for ERK1/2 inhibition in fisetin-reduced invasion and migration of A549 cells.

Reactivation of herpes zoster along the trigeminal nerve with intractable pain after facial trauma: a case report and literature review.

We report the rare occurrence of herpes zoster reactivation after facial trauma. Herpes zoster appeared in painful groups of distended vesicles containing clear fluid on an erythematous base within the secondary division of the trigeminal nerve. The patient was treated with acyclovir (intravenous, 250 mg, every 8 hours) combined with topical steroids and anti-neuropathic pain medication. The zoster-associated neuralgia subsided gradually 1.5 months after diagnosis. We illustrate this unique case to highlight the fact that reactivation of the varicella zoster virus from childhood chicken pox can reappear at a traumatic site in late adulthood.

Ionothermal synthesis, crystal structure and solid-state NMR spectroscopy of a new organically templated gallium oxalatophosphate: (H2TMPD)0.5[Ga3(C2O4)0.5(PO4)3] (TMPD=N,N,N',N'-tetramethyl-1,3-propanediamine).

A new organically templated gallium oxalatophosphate, (C7H20N2)0.5[Ga3(C2O4)0.5(PO4)3], has been synthesized by using a low-melting-point eutectic mixture of choline chloride and oxalic acid as a solvent and characterized by single-crystal X-ray diffraction, thermogravimetric analysis and solid-state NMR spectroscopy. It is the first example of ionothermal synthesis of organically templated metal oxalatophosphate. The structure contains double 6-ring units of the composition Ga6(PO4)6 which are connected by oxalate ligands and P-O-Ga bonds to form a 3-D framework. The charge-compensating organic ammonium cations which are disordered over two positions are located at the intersections of two types of 8-ring channels. 1H MAS and 13C CPMAS NMR studies confirm the presence of N,N,N',N'-tetramethyl-1,3-propanediammonium cation. The 71Ga and 31P MAS NMR spectra are also consistent with the crystal structure analysis results.