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Tumor microenvironment plays vital roles in shaping cancer diversity, and CD73 (ecto-5′-nucleotidase; NT5E) is an emerging immune checkpoint in modulating cancer progression via conversion of immunostimulatory ATP into immunosuppressive adenosine. However, how the CD73 is regulated and how it functions in the progression of cancer are largely unknown. Here, we showed that CD73 was overexpressed and correlated with poor prognosis of gastric cancer. CD73 links adenosinergic signaling in microenvironment switching to induction of epithelial-to-mesenchymal transition phenotype in gastric cancer during metastasis. Further pathway and gene set enrichment analysis of transcriptome data revealed the modulation role of CD73 in RICS/RhoA signaling by its extracellular function in adenosinergic pathway, which subsequently inhibited phosphorylation of LIMK/cofilin and promoted β-catenin activation. Pharmacological inhibition of CD73 adenosinergic signaling was found to induce RICS dysfunction. Dissemination and hematogenous metastasis model showed that targeting CD73 in gastric cancer could suppress experimental metastasis. To conclude, it substantiates CD73 as a target for treatment of gastric cancer metastasis and verifies RICS as an intracellular functional molecule linking CD73/adenosinergic signaling switching to RhoA/LIMK/cofilin pathway.

The development of two-dimensional (2D) organic catalysts with intriguing catalytic activity for the nitrogen reduction reaction (NRR) still remains challenging. Here, we exploit a series of experimentally feasible nitrogen-free metal–organic frameworks (MOFs) of transition metal–benzenehexathiol (TM–BHT, with TM being Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Mo, Ru, Rh, Pd and Ag) for dinitrogen (N2) fixation and ammonia (NH3) synthesis. Through the first-principles screening and microkinetic analyses, we find that TMS4 centers can serve as electron reservoirs for associative N2 hydrogenation to overcome energy efficiency versus rate trade-offs. It turns out that among these candidates, Mo–BHT exhibits the lowest limiting potential and highest turnover frequency (TOF) competitive to that of benchmark Fe catalysts. In light of the synergistic effects between the active center and ligand, the high performance of Mo–BHT toward the NRR was rationalized. In the context of searching for efficient NRR catalysts, our results demonstrate the great possibilities of MOFs as an emerging avenue for NH3 synthesis under ambient conditions, and provide a strategy for the design of catalysts by appropriately tuning the active centers and ligands.

We constructed a composite electrode by depositing a C/Ag mixture containing a tiny amount of 20 nm Ag NPs (∼0.5 wt%) on anodized Zn (AZ) metal. The AZ/C/Ag electrode exhibits greatly enhanced CO selectivity (∼86%) and activity (∼7.3 mA cm−2) on comparison with the GCE/C/Ag electrode (∼24% and ∼2.3 mA cm−2). The experimental results show that the enhanced CO2 reduction performance of the AZ/C/Ag electrode is attributed to the synergistic effect of AZ, C and Ag. Density functional theory calculations indicate that the enhanced CO selectivity may originate from the enhanced stabilization of CO2 and COOH* on the AZ/C/Ag electrode surface. This electrode also shows great mass activity and stability for CO2 reduction. Our work provides a new and simple way to fabricate efficient catalysts with high selectivity, activity and stability for electrocatalytic CO2 reduction.

Carbon bridged graphitic carbon nitride (g-C3N4) was prepared by a facile supramolecular self-assembly method. Experimental results and theoretical calculations indicate C atoms were introduced into the g-C3N4 lattice by substituting the bridged N atoms. As a result, the delocalized big π bonds can be formed among the adjacent heptazine rings, which could both enhance the light absorption and promote the charge separation. Beneficial from the efficient charge separation and enhanced light absorption, the carbon bridged g-C3N4 exhibits high efficient photocatalytic activity, where the H2 evolution rate is about 7 times as high as that of pristine g-C3N4. This work demonstrates carbon bridged C3N4 can be fabricated by a simple supramolecular self-assembly process, which could be useful for the further development of high efficient g-C3N4 photocatalysts.

Driver genes conducing to peritoneal metastasis in advanced gastric cancer remain to be clarified. S100A4 is suggested to evolve in metastasis of gastrointestinal cancer, we aim to explore the role of S100A4 plays in metastasis of advanced gastric cancer and the potential mechanism. Transfection of siRNA or cDNA was applied to alter the expression of protein S100A4 and MYH9, investigation of the expression of epithelial and mesenchymal transition (EMT) associated markers was followed. Cell migration assay was used to screen the alteration of migration ability regulated by S100A4 and MYH9. IHC analysis for tissue sample microarray was performed to reveal their relationship with clinical pathological parameters and potential capacity of predicting survival. Consistent overexpression of S100A4 and MYH9 were found in peritoneal metastasis and primary site compared with adjacent normal tissue. Low expression of S100A4 led to increased epithelial markers as wells as decline of mesenchymal makers, while overexpression of S100A4 led to inverse impact. S100A4 expression was closely correlated with increased migration ability and EMT process induced by TGF-β stimulation. Interference of S100A4 led to downregulation of MYH9 and inactivation of Smad pathway through participating in EMT process, which could be reversed by overexpression of MYH9. Moreover, co-expression of S100A4 and MYH9 was identified in tissue microarray and confirmed by immunofluorescence assay. In conclusion, overexpression of S100A4 and downstream molecular MYH9 in advanced gastric cancer predicted poor prognosis; oncogene S100A4 facilitate EMT process induced by TGF-β stimulation, suggesting a potential target in management of peritoneal metastasis of gastric cancer.

On the basis of electron-electron self-energy corrections, quasiparticle band structures of Janus MoSSe and WSSe are identified, and the excitonic effects are demonstrated to play a dominate role in the optical response. Combining together MoSSe and WSSe monolayers to form vertical heterostructures (VHTs) and lateral heterostructures (LHTs) rarely leads to a simple arithmetic sum of their properties, giving rise to novel and unexpected behaviors. In particular, Rashba polarization can be enhanced in VHTs due to improved out-of-plane electric polarity. In the case of LHTs, photoresponse and absorption coefficients show optical activity in a wide visible light range. It is of interest that both VHTs and LHTs reveal type-II band alignment, enabling the separation of excitons. Besides, grain boundaries (GBs) of large angle (60°) in Janus MoSSe due to chalcogen effects behave as one-dimensional (1D) metallic quantum wires, suggesting the possible formation of 1D electron or hole gas in such electronic heterostructures.

Highly efficient utilization of solar energy to split water into hydrogen and oxygen is regarding as a promising strategy to deal with the future energy crisis and environmental problems. To explore highly efficient and low-cost photocatalysts is highly desired. Herein, phosphorene-like germanium monochalcogenides (GeS and GeSe monolayers) are proposed here as efficient photocatalysts for water splitting. After confirming their stabilities, we observe that GeS exhibits an indirect band gap of 2.29 eV while GeSe reveals a direct band gap of 1.59 eV by HSE hybrid functional. Remarkably, high and directionally anisotropic carrier mobilities (2430.50 cm 2 V −1 s −1 for GeS and 4032.64 cm 2 V −1 s −1 for GeSe) are quantitatively investigated by using deformation potential theory. In addition, GeS and GeSe monolayers exhibit a good separation of electrons and holes, which effectively reduces the photocatalytic activity with high efficiency. Upon the application of strain, the band structure can be modulated from semiconductor to metal and a direct-indirect bandgap transition is observed. Most intriguingly, the band gaps and band edge alignments at certain pH value can be effectively tuned to meet the requirement of the redox potential in water splitting. Finally, the adsorption and decomposition of water molecules on the surface of 2D GeS and the subsequent formation of hydrogen were explored, which unravels the mechanism of photocatalytic hydrogen production on 2D GeS. Our findings will be valuable for facilitating the exploration and application of GeS and GeSe for photocatalytic water splitting.

Within series of Ln 3 -grafted polymers Poly({[Ln 3 (L) 4 (NO 3 ) 6 ]·(NO 3 )·(H 3 O) 2 }-co-NBE) (Ln = La, 1 ; Ln = Eu, 2 ; Ln = Tb, 3 ; Ln = Nd, 4 ; Ln = Yb, 5 ; Ln = Er, 6 or Ln = Gd, 7 ) obtained from ring-opening metathesis polymerization (ROMP) of norbornene (NBE) with each of allyl-functionalized complex monomers {[Ln 3 (L) 4 (NO 3 ) 6 ]·(NO 3 )·(H 3 O) 2 } ( HL = 4-allyl-2-(1 H -benzo[ d ]imidazol-2-yl)-6-methoxyphenol), PNBE-assisted effective energy transfer renders Poly(3- co -NBE) Tb 3+ -centered highly luminous color-purity green-light with an attractive quantum yield of 87% and efficient near-infrared (NIR) luminescence ( Φ Nd L = 0.61%; Φ Yb L = 1.47% and Φ Er L = 0.03%) for Nd 3+ -, Yb 3+ - or Er 3+ -grafted polymers.

The unique electronic properties of boron nanotubes (BNTs) and hydrogenated BNTs (H-BNTs) lead to its potential applications in electrochemical and hydrogen storage. In the present work, the stability and electronic properties of single-wall BNTs and, particularly, the effects of hydrogenation on the structural and electronic features are investigated on the basis of the first-principles electronic calculations. It is interesting to find that hydrogenation can stabilize (m,0) BNTs with m being 7–13. In addition, H-BNTs can be either metallic or semiconducting depending on the diameter. In particular, electronic properties of (m,0) H-BNTs can also be engineered by exerting strain along the axial direction, as verified in the case of strained H-BNTs where a semiconductor–metal crossover was predicted at 3% tensile strain. Our results would drive more interesting studies on BNTs with different chiralities and chemical functionalizations.

The fusion of an Fc moiety to a therapeutic protein is widely applied as a half-life extension strategy. However, unlike monoclonal antibodies, Fc-fusion proteins have been shown to be more susceptible to protease-mediated catabolism. The resultant catabolites may still be pharmacologically active and therefore require characterization. We combined intact protein LC-MS and digestion LC-MS/MS methods to both characterize the biotransformation of the fusion protein, Fc-FGF21, and quantify the intact molecule and its major catabolites in rat serum. The digestion LC-MS/MS assay and intact protein LC-MS assay determined that there were four major catabolites formed in vivo: one amino acid (dC1), two amino acids (dC2), or three amino acids (dC3) clipped off from the C-terminus, and a truncated fragment. By 72 h post dosing, only 66% of the intact protein remained. The digestion method was developed with a sensitivity of 20 ng/mL-10 times more sensitive than the intact protein method at 200 ng/mL. While the digestion approach proved more sensitive, the intact LC-MS method was primarily employed for understanding the biotransformation of the Fc-FGF21 fusion protein in the rat in vivo study. Graphical abstract.

As part of our efforts to develop new classes of tubulin inhibitor payloads for antibody-drug conjugate (ADC) programs, we developed a tubulysin ADC that demonstrated excellent in vitro activity but suffered from rapid metabolism of a critical acetate ester. A two-pronged strategy was employed to address this metabolism. First, the hydrolytically labile ester was replaced by a carbamate functional group resulting in a more stable ADC that retained potency in cellular assays. Second, site-specific conjugation was employed in order to design ADCs with reduced metabolic liabilities. Using the later approach, we were able to identify a conjugate at the 334C position of the heavy chain that resulted in an ADC with considerably reduced metabolism and improved efficacy. The examples discussed herein provide one of the clearest demonstrations to-date that site of conjugation can play a critical role in addressing metabolic and PK liabilities of an ADC. Moreover, a clear correlation was identified between the hydrophobicity of an ADC and its susceptibility to metabolic enzymes. Importantly, this study demonstrates that traditional medicinal chemistry strategies can be effectively applied to ADC programs.

Lasers are frequently used to locally open dielectric layers for contacting the front or rear side of advanced silicon wafer solar cell architectures. For reasons of cost, laser processes are usually carried out in ambient environment, which inevitably leads to the oxidation of silicon. In order to achieve maximum solar cell efficiency, the laser processing has to be optimized thoroughly. The current research only focuses on minimizing laser-induced defects in silicon. However, our investigation shows another side effect of laser ablation, i.e., laser-induced oxidation, which is often neglected and undesirable for the subsequent metallization process. In this paper, we investigated the impact of laser-induced oxidation, which is caused by laser ablation in air, on the performance of silicon wafer solar cells. We show that by applying a postlaser etching step, laser-induced defects and oxide film can be removed effectively, providing improved conditions for the subsequent metallization process.

A potent class of DNA-damaging agents, natural product bis-intercalator depsipeptides (NPBIDs), was evaluated as ultrapotent payloads for use in antibody-drug conjugates (ADCs). Detailed investigation of potency (both in cells and via biophysical characterization of DNA binding), chemical tractability, and in vitro and in vivo stability of the compounds in this class eliminated a number of potential candidates, greatly reducing the complexity and resources required for conjugate preparation and evaluation. This effort yielded a potent, stable, and efficacious ADC, PF-06888667, consisting of the bis-intercalator, SW-163D, conjugated via an N-acetyl-lysine-valine-citrulline- p-aminobenzyl alcohol- N, N-dimethylethylenediamine (AcLysValCit-PABC-DMAE) linker to an engineered variant of the anti-Her2 mAb, trastuzumab, catalyzed by transglutaminase.

1,25-Dihydroxyvitamin D3 (1,25-(OH)2D3) has an anti-inflammatory effect on human monocytes incubated with sera from patients with type 2 diabetes/diabetic nephropathy; however, the detailed mechanism behind the effect remains to be explored. The current study further validated the effects of 1,25-(OH)2D3 and lipopolysaccharide (LPS) + human recombinant interleukin (IL)-15 on the expression of the vitamin D receptor (VDR) and phosphorylated signal transducer and activator of transcription 5 (p-STAT5) in human monocytes and explored the possible interaction between VDR and p-STAT5. Synchronized THP-1 cells were divided into pre-intervened groups, namely the control, LPS + IL-15 and 1,25-(OH)2D3, groups, according to their differing treatments. The expression of STAT5 and p-STAT5 was evaluated by western blot analysis; the concentration of IL-6 in the supernatant was determined using an enzyme-linked immunosorbent assay; the expression of cytoskeletal proteins was observed using immunofluorescence and laser confocal microscopy; and the possible intranuclear interaction between VDR and p-STAT5 was investigated using immunofluorescence, immuno-coprecipitation and western blot analysis. LPS + IL-15 upregulated p-STAT5 expression and the IL-6 level (P

As the antibody drug conjugate (ADC) community continues to shift towards site-specific conjugation technology, there is a growing need to understand how the site of conjugation impacts the biophysical and biological properties of an ADC. In order to address this need, we prepared a carefully selected series of engineered cysteine ADCs and proceeded to systematically evaluate their potency, stability, and PK exposure. The site of conjugation did not have a significant influence on the thermal stability and in vitro cytotoxicity of the ADCs. However, we demonstrate that the rate of cathepsin-mediated linker cleavage is heavily dependent upon site and is closely correlated with ADC hydrophobicity, thus confirming other recent reports of this phenomenon. Interestingly, conjugates with high rates of cathepsin-mediated linker cleavage did not exhibit decreased plasma stability. In fact, the major source of plasma instability was shown to be retro-Michael mediated deconjugation. This process is known to be impeded by succinimide hydrolysis, and thus, we undertook a series of mutational experiments demonstrating that basic residues located nearby the site of conjugation can be a significant driver of succinimide ring opening. Finally, we show that total antibody PK exposure in rat was loosely correlated with ADC hydrophobicity. It is our hope that these observations will help the ADC community to build “design rules” that will enable more efficient prosecution of next-generation ADC discovery programs.

Aim: Complex nature of bioconjugates require multiple bioanalytical approaches to support PK and absorption, distribution, metabolism and excretion characterization. For antibody-drug conjugate (ADC) bioanalysis both LC–MS and ligand-binding assays (LBAs) are employed. Results: A method consisting of immunocapture extraction of ADC from biomatrices followed by LC–MS analysis of light and heavy chain is described. Drug antibody ratio (DAR) profiles of ADC Tras-mcVC-PF06380101 dosed at 0.3, 1 and 3 mg/kg in Sprague Dawley rats were obtained. Combined with total antibody (monoclonal antibody) measurement by LBA, conjugated payload concentration was calculated. Conclusion: PK profiles from LBA, ADC and calculated conjugated payload (DAR × monoclonal antibody) were in good agreement. We present a new tool for PK assessment of ADCs while also exploring ADC metabolism and DAR sensitivity of LBA ADC assay.

A highly sensitive gas sensor based on thermal desorption coupled with cataluminescence (TD/CTL) using TiO 2 -Y 2 O 3 (mass ratio 1:3) as a probe was firstly proposed for the determination of formaldehyde in air. Quantitative analysis was performed at an optimal adsorbent of active carbon, thermal desorption temperature of 140 °C, catalytic temperature of 195 °C, a wavelength of 490 nm and a flow rate of 280 mL/min. The linear range of CTL intensity versus concentration of formaldehyde was 0.026–1.30 mg/m 3 ( r = 0.9990, n = 7), and the detection limit (3 σ ) was 0.01 mg/m 3 . There was no or weak response to foreign substances, such as benzene, ethanol, chloroform, carbon tetrachloride, toluene, dimethylbenzene and n -hexane. This proposed formaldehyde gas sensor showed the high sensitivity, rapid response, good stability, and allowed on-line monitoring of formaldehyde in air.

Background: NOTCH3, a cell surface receptor involved in cell-cell communications, is over-expressed or amplified in certain human tumors. NOTCH3 is known to regulate proliferation, differentiation and survival of cancer cells or cancer stem cells and thus an important therapeutic target. NOTCH3 antibody drug conjugate (ADC) is comprised of humanized anti-NOTCH3 antibody conjugated to an auristatin based cytotoxic payload. NOTCH3-ADC has shown promising results in pre-clinical tumor models. In this study we evaluated the kinetics, dose-dependent tissue distribution, tumor accumulation and targeting specificity of the NOTCH3-ADC in OVCAR3 xenograft model using fluorescence molecular tomography (FMT) imaging. The NOTCH3-ADC is mouse cross-reactive thus providing an accurate assessment of biodistribution. Methods: NOTCH3-ADC was conjugated to the near-infrared dye, AlexaFluor680 (AF680). The in vitro cellular binding was evaluated by cell-based ELISA. In vivo biodistribution was evaluated using OVCAR3 subcutaneous xenograft model. NOTCH3-ADC-AF680 (1mg/kg; 3mg/kg and 10mg/kg) was injected when the tumors were ~300mm3 and imaged 5 min, 24, 48, 96, 168 and 240 h post-injection. Ex vivo FMT imaging, pharmacokinetic analysis and immunohistochemistry (IHC) was performed at 48 and 240 h after whole-body perfusion. An in vivo receptor competition FMT study was performed by injecting excess of unconjugated anti-NOTCH3 antibody (Ab) or a non-targeted control Ab. Results: In vitro cell binding studies showed that conjugation of AF680 to NOTCH3-ADC did not change its binding ability. A dose-dependent tumor regression was also observed after a single injection of NOTCH3-ADC-AF680. In vivo FMT imaging showed dose-dependent whole-body clearance kinetics of NOTCH3-ADC. Dose-dependent accumulation in the tumors was observed with peak accumulation at 24-48 h post-injection and a slow decline at later time-points. A maximum accumulation of ~10 %ID/g was observed which was independent of the dose of NOTCH3-ADC-AF680. Ex vivo FMT quantitation of tumor was consistent with the IHC for antibody and LC/MS analysis of released payload. Pharmacological competition with excess unlabeled control Ab did not block tumor accumulation of NOTCH3-ADC-AF680, whereas excess unlabeled NOTCH3-Ab blocked ~47% of NOTCH3-ADC-AF680 accumulation. There was no significant specific accumulation of NOTCH3-ADC in other organs as observed by FMT imaging or IHC. Conclusions: These imaging studies provided understanding of the kinetics, tumor accumulation and biodistribution of NOTCH3-ADC. Further this work showcase the utility of non-invasive FMT imaging in better understanding of pharmacology and behavior of biologic drugs. Citation Format: Anand Giddabasappa, Parul Gupta, Mauricio Leal, Jonathan Golas, Fengping Li, Bing Yang, Antonio Esparza, Christopher Winkelmann, Kenneth Geles. Dose-dependent tissue distribution and tumor targeting of Notch3-ADC using fluorescence molecular tomography imaging [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2861. doi:10.1158/1538-7445.AM2017-2861

A thermionic cusp electron gun has been designed, numerically optimized and experimentally measured and is presented. A 40 kV, 1.5 A annular axis-encircling electron beam has been simulated to generate a beam with low velocity and alpha spreads. The electron gun performance has been verified through experiments and the results are given.

Nimesulide, a widely used nonsteroidal anti-inflammatory drug (NSAID), has been associated with rare idiosyncratic hepatotoxicity. The chemical mechanisms underlying the liver injury remain unknown. We have undertaken the detailed study of the metabolic pathways of nimesulide in an effort to identify potential reactive metabolites. A previous report from this laboratory has demonstrated that one of the known nimesulide metabolites, termed reduced nimesulide (M1), is further bioactivated by human liver microsomes (HLMs) to form a reactive diiminoquinone species M2. The formation of M2 was confirmed indirectly by trapping with N-acetylcysteine (NAC). The aim of this study was to explore the fate of M1 in an inflammatory environment created by the recruitment of leukocytes. Leukocytes upon activation produce hydrogen peroxide (H(2)O(2)) and other myeloperoxidase (MPO) products, such as hypochlorous acid (HOCl), that are capable of metabolite oxidation. We demonstrate here that the reduced nimesulide, M1, undergoes a facile oxidation with activated neutrophils or with MPO in the presence of H(2)O(2) or HOCl to produce a variety of reactive as well as stable metabolites. One major metabolite, M3, was also produced by HLM as determined by trapping with NAC. Other metabolites, for example, M6, M8, and M9, were unique to the myeloperoxidase, because of their mode of formation from activation of the amino group of reduced nimesulide. The structures of some of these reactive metabolites were proposed on the basis of liquid chromatography-tandem mass spectrometry analyses and established by their comparison with synthetic standards. Metabolite M6 is interesting because it provides clear evidence of amine activation and indicates the potential of the reactive intermediate of M1 to conjugate with protein nucleophiles. In summary, our results demonstrate that a known nimesulide metabolite could be bioactivated by MPO through a pathway distinct from HLM-mediated pathways and that the generation of reactive species by the MPO-mediated bioactivation pathway at the site of inflammation may contribute to the toxicity associated with nimesulide.

Nimesulide is a nonsteroidal anti-inflammatory drug (NSAID) marketed in more than 50 countries. This drug has caused rare and idiosyncratic but severe hepatotoxicity. The mechanisms associated with and factors responsible for this toxicity remain unknown. One of the nimesulide metabolites identified in human urine is 4-amino-2-phenoxy-methanesulfonanilide (M1). In the current study, we demonstrate that M1 is a stable metabolite that is highly susceptible to facile oxidation by cytochrome P450 enzymes (P450s) to form a reactive diiminoquinone intermediate (M2). Direct detection of M2 was difficult by LC-MS. However, its formation was confirmed indirectly by identification of N-acetyl-cysteine (NAC) adducts of M2. The formation of diiminoquinone M2 was P450 mediated with 2C19 and 1A2 as the two principal P450 enzymes catalyzing M1 oxidation. M1 metabolism irreversibly inhibited 2C19 but activated 1A2 in a time-dependent manner. P450 2C19 exclusively mediated further metabolism of M1 to the amino hydroxynimesulide M3 and its diiminoquinone M4. Similar to M2, M4 is also reactive and can be observed indirectly as its NAC adduct. Nucleophilic addition to diiminoquinone M2 occurs with low regioselectivity, yielding three adducts (the peak area ratio 1:0.08:12). The three regioisomers have the same m/z for [M + H](+), presumably due to nucleophilic addition at the three possible electrophilic sites (C-3, -5, and -6 positions of the sulfonaniline ring). The primary adduct, R, was derived from the attack of the nucleophile at the C-5 position of the sulfonaniline ring and was determined by MS/MS and (1)H and (13)C NMR analyses. The structural assignments were confirmed by chemical synthesis of the adduct R. M2 demonstrated its electrophilic reactivity by selectively alkylating human serum albumin (HSA) at the only free thiol, Cys-34. This suggests the possibility that other proteins may undergo a similar conjugation to form irreversible adducts. Under oxidizing conditions in the presence of cumene hydroperoxide (CHP), the formation of M2 was enhanced, indicating that oxidative stress may accelerate the production of reactive diiminoquinone species (M2 and M4).

2-acetylbenzothiophene-S-oxide (2-ABT-S-oxide or M1) is a reactive metabolite of zileuton, a drug used in the treatment of asthma and is capable of conjugating with glutathione in vitro. Human serum albumin (HSA) is the most abundant protein in plasma and plays a critical role in detoxifying reactive oxygen species. The current research is focused on understanding the interaction between M1 and HSA. The stability studies revealed the half-life of M1 to be about 0.85 h in HSA, 1.82 h in human plasma, and 4.48 h in phosphate-buffered saline (PBS) as determined by first-order approximation. The alkylation rate constant k for HSA was 20 M(-1) min(-1). After quenching with acetonitrile, the half-life of M1 did not change significantly, indicating that M1 is covalently bound to HSA. LC-MS and LC-MS/MS analysis of human plasma revealed the M1 alkylated peptide P (m/z 870) formed by HSA conjugation and concomitant water elimination. The specific amino acid on HSA bound to M1 was identified as Cys-34. This alkylation is observed to be concentration- and incubation-time-dependent in human plasma. HSA oxidized by N, N'-diacetyl-L-cystine exhibits a compromised ability of HSA to react with M1. The alkylated HSA diminished the binding affinity for warfarin. Furthermore, the alkylation was found to be irreversible in the dialysis experiment. In addition, M1 decomposes to 2-ABT in the presence of HSA, presumably acting as an oxidant. The formation of 2-ABT in the incubation and the self-condensation of M1 in PBS indicate that the alkylation of Cys-34 is only one of a number of reactions that occur in the presence of HSA. Irreversible protein modification may potentially lead to a loss of its function. HSA irreversible alkylation represents a model for other proteins to be potentially toxic and thus may help explain zileuton hepatotoxicity.

Summary form only given. Neon and argon were used as load gas for the Z-pinch experiments on the "yang" accelerator at IFP. And different sets of nozzles were tried out. An ultrafast multi-frame soft X-ray CCD camera was used in these experiments, which can get 10 frames with 10 ns time interval of pinch process at each pinch experiment. Time-integral X-ray pinhole camera and visible streak camera were used in these experiments, too. A laser shearing interferometer (532 nm) was used to catch the image of plasmas. The formation of the initial plasma and discharge channels were observed. Instability was found in the late part of pinch process. In addition shorten rise time of load current and better initial gas puff distribution will reduce these instabilities, make plasma column to compress more quickly and efficiently. More than 1 kJ and 20 GW soft X-ray radiation pulse was detected. Furthermore, more than 4times 107 cm/s imploding speed, and about 12 to 20 compression ratio of plasma column had been obtained. The results and phenomena of these experiments were discussed in this article

Enhancement of pulsed laser ablation can be achieved in acetic acid as an environmentally friendly liquid. This paper evaluates microholes and textured features induced by a nanosecond pulsed laser under different processing circumstances. The microholes are fabricated by laser drilling in acetic acid and found to be 100% deeper than in air. The textured features achieved in the liquid demonstrate a higher content of Copper and a lower content of Oxygen. The improvement of laser ablation efficiency in the liquid is attributed to the strong confinement of plasma plume accompanying with shockwave and cavitation bubbles. Meanwhile, the laser enhanced chemical etching by the weak acid plays a critical role.