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N-Heterocyclic carbene (NHC) ligands are widely investigated in medicinal inorganic chemistry. Here, we report the preparation and characterization of a series of half-sandwich [M(L)(NHC)Cl2] (M = Ru, Os, Rh, Ir; L = cym/Cp*) complexes with a N-flanking anthracenyl moiety attached to imidazole- and benzimidazole-derived NHC ligands. The anticancer activity of the complexes was investigated in cell culture studies where, in comparison to a Rh derivative with an all-carbon-donor-atom-based ligand (5a), they were found to be cytotoxic with IC50 values in the low micromolar range. The Ru derivative 1a was chosen as a representative for stability studies as well as for biomolecule interaction experiments. It underwent partial chlorido/aqua ligand exchange in DMSO-d6/D2O to rapidly form an equilibrium in aqueous media. The reactions of 1a with biomolecules proceeded quickly and resulted in the formation of adducts with amino acids, DNA, and protein. Hen egg white lysozyme crystals were soaked with 1a, and the crystallographic analysis revealed an interaction with an l-aspartic acid residue (Asp119), resulting in the cleavage of the p-cymene ligand but the retention of the NHC moiety. Cell morphology studies for the Rh analog 3a suggested that the cytotoxicity is exerted via mechanisms different from that of cisplatin.

We report investigations on the anticancer activity of organometallic [MII/III (η6 -p-cymene/η5 -pentamethylcyclopentadienyl)] (M=Ru, Os, Rh, and Ir) complexes of N-heterocyclic carbenes (NHCs) substituted with a triazolyl moiety. Depending on the precursors, the NHC ligands displayed either mono- or bidentate coordination via the NHC carbon atom or as N,C-donors. The metal complexes were investigated for their stability in aqueous solution, with the interpretation supported by density functional theory calculations, and reactivity to biomolecules. In vitro cytotoxicity studies suggested that the nature of both the metal center and the lipophilicity of the ligand determine the biological properties of this class of compounds. The IrIII complex 5 d bearing a benzimidazole-derived ligand was the most cytotoxic with an IC50 value of 10 μM against NCI-H460 non-small cell lung carcinoma cells. Cell uptake and distribution studies using X-ray fluorescence microscopy revealed localization of 5 d in the cytoplasm of cancer cells.

The dynamic processing of aerosols in the atmosphere is difficult to mimic under laboratory conditions, particularly on a single-particle level with high spatial and chemical resolution. Our new microreactor system for X-ray microscopy facilitates observations under in situ conditions and extends the accessible parameter ranges of existing setups to very high humidities and low temperatures. With the parameter margins for pressure (180–1000 hPa), temperature (∼250 K to room temperature), and relative humidity (∼0 % to above 98 %), a wide range of tropospheric conditions is covered. Unique features are the mobile design and compact size that make the instrument applicable to different synchrotron facilities. Successful first experiments were conducted at two X-ray microscopes, MAXYMUS, located at beamline UE46 of the synchrotron BESSY II, and PolLux, located at beamline X07DA of the Swiss Light Source in the Paul Scherrer Institute. Here we present the design and analytical scope of the system, along with first results from hydration–dehydration experiments on ammonium sulfate and potassium sulfate particles and the tentative observation of water ice at low temperature and high relative humidity in a secondary organic aerosol particle from isoprene oxidation.

Metal complexes provide a versatile platform to develop novel anticancer pharmacophores, and they form stable compounds with N-heterocyclic carbene (NHC) ligands, some of which have been shown to inhibit the cancer-related selenoenzyme thioredoxin reductase (TrxR). To expand a library of isostructural NHC complexes, we report here the preparation of RhIII- and IrIII(Cp*)(NHC)Cl2 (Cp* = η5-pentamethylcyclopentadienyl) compounds and comparison of their properties to the RuII- and OsII(cym) analogues (cym = η6-p-cymene). Like the RuII- and OsII(cym) complexes, the RhIII- and IrIII(Cp*) derivatives exhibit cytotoxic activity with half maximal inhibitory concentration (IC50) values in the low micromolar range against a set of four human cancer cell lines. In studies on the uptake and localization of the compounds in cancer cells by X-ray fluorescence microscopy, the Ru and Os derivatives were shown to accumulate in the cytoplasmic region of treated cells. In an attempt to tie the localization of the compounds to the inhibition of the tentative target TrxR, it was surprisingly found that only the Rh complexes showed significant inhibitory activity at IC50 values of ∼1 μM, independent of the substituents on the NHC ligand. This indicates that, although TrxR may be a potential target for anticancer metal complexes, it is unlikely the main target or the sole target for the Ru, Os, and Ir compounds described here, and other targets should be considered. In contrast, Rh(Cp*)(NHC)Cl2 complexes may be a scaffold for the development of TrxR inhibitors.

Oxidative potential is a measure of redox activity of airborne particulate matter (PM) and is often used as a surrogate to estimate one form of PM toxicity. The evaluation of oxidative potential in a physiologically relevant environment is always challenging. In this work, we developed a chromatographic method, employing an ultra-high-performance liquid chromatograph coupled to a triple–quadruple mass spectrometer, to determine the oxidative potential of PM from different sources. To this purpose, we measured the PM-induced oxidation of glutathione, cysteine, and ascorbic acid, and formation of glutathione disulfide and cystine, following PM addition to simulated epithelial lining fluids, which, in addition to the antioxidants, contained inorganic salts, a phospholipid, and proteins. The new method showed high precision and, when applied to standard reference PM, the oxidative potential was found to increase with the reaction time and PM concentration in the lung fluid. The antioxidant depletion rates were considerably higher than the rates found with the conventional dithiothreitol assay, indicating the higher sensitivity of the new method. The presence of the lung fluid inorganic species increased the oxidative potential determined through glutathione and cysteine, but showed an opposite effect with ascorbic acid, whereas the presence of proteins resulted in a moderate decrease in the oxidative potential. In the presence of PM2.5, glutathione and cysteine demonstrated similar depletion patterns, which were noticeably different from that of ascorbic acid, suggesting that cysteine could be used as an alternative to glutathione for probing oxidative potential.

A 61-year-old woman was evaluated at our institution for enrollment in a clinical trial for relapsed/refractory multiple myeloma. The initial eligibility evaluation revealed an increased total bilirubin result of 7.2 mg/dL [123.1 μmol/L; reference interval (RI)3, 0.0–1.2 mg/dL]. Other abnormal laboratory findings included IgG of 10400 mg/dL (RI, 44–277 mg/dL), λ free light chains of 199.5 mg/dL (RI, 0.57–2.63 mg/dL) with an abnormal κ/λ ratio

Benzoylthiourea derivatives feature several donor atoms capable of coordinating to metal centers. We report here a series of Ru(η6 -p-cymene) complexes employing benzoylthiourea derivatives as ligands. Such ligands often coordinate to metal centers through their S and O donor atoms. We isolated complexes where the ligands were mono- or bidentately coordinated to Ru involving the S donor atom and surprisingly in bidentate coordination mode a deprotonated thiourea nitrogen resulting in a 4-membered ring structure around the metal center. DFT calculations were used to explain the differences in coordination behavior. These were complemented by stability studies and biological investigations of the compounds as anticancer agents. Several of the synthesized derivatives exhibited significant cell growth inhibitory activity, with the complexes featuring bidentate ligands being more potent than their monodentate counterparts. This can be explained by the higher stability of the former under the conditions employed in cell culture assays.

Lanvers-Kaminsky et al. did a great job to monitor the efficacy of asparaginase therapy by using asparaginase activity levels in adults suffering from newly diagnosed acute lymphoblastic leukemia (...

The development of bifunctional platinum complexes with the ability to interact with DNA via different binding modes is of interest in anticancer metallodrug research. Therefore, we report platinum(II) terpyridine complexes to target DNA by coordination and/or through a tethered alkylating moiety. The platinum complexes were evaluated for their in vitro antiproliferative properties against the human cancer cell lines HCT116 (colorectal), SW480 (colon), NCI-H460 (non-small cell lung), and SiHa (cervix) and generally exhibited potent antiproliferative activity although lower than their respective terpyridine ligands. 1H NMR spectroscopy and/or ESI-MS studies on the aqueous stability and reactivity with various small biomolecules, acting as protein and DNA model compounds, were used to establish potential modes of action for these complexes. These investigations indicated rapid binding of complex PtL3 to the biomolecules through coordination to the Pt center, while PtL4 in addition alkylated 9-ethylguanine. PtL3 was investigated for its reactivity to the model protein hen egg white lysozyme (HEWL) by protein crystallography which allowed identification of the Nδ1 atom of His15 as the binding site.

Thiones have been investigated as ligands in metal complexes with catalytic and biological activity. We report the synthesis, characterization, and biological evaluation of a series of MII/III complexes of the general formulae [MII(cym)(L)Cl]X (cym = &eta, 6-p-cymene) or [MIII(Cp*)(L)Cl]X (Cp* = &eta, 5-pentamethylcyclopentadienyl), where X = Cl&minus, or PF6&minus, and L represents heterocyclic derivatives of thiourea. The thiones feature a benzyl-triazolyl pendant and they act as bidentate ligands via N,S-coordination to the metal centers. Several derivatives have been investigated by single-crystal X-ray diffraction analysis. NMR investigations showed a counterion-dependent shift of several protons due to the interaction with the counterions. These NMR investigations were complemented with X-ray diffraction analysis data and the effects of different counterions on the secondary coordination sphere were also investigated by DFT calculations. In biological studies, the Ir benzimidazole derivative was found to accumulate in the cytoplasm and it was the most cytotoxic derivative investigated.

PURPOSE: To assess the incidence of iatrogenic retinal breaks (IRBs) and postoperative retinal detachments (RDs) in microincision vitrectomy surgery (MIVS) compared with 20-gauge (20 G) vitrectomy. METHODS: A comprehensive literature search was performed to find relevant studies and a meta-analysis of the IRBs and postoperative RDs rates after 20 G vitrectomy versus MIVS was conducted. RESULTS: Thirty-two studies were selected, including 14,373 eyes (6932 eyes in the 20 G group, 7441 eyes in the MIVS group). The meta-analysis demonstrated that the incidence of IRBs was significantly higher in 20 G vitrectomy vs. MIVS (OR = 2.22, 95% CI, 1.93−2.57, P

Context Insulin resistance (IR) can progress to type 2 diabetes. Therefore, timely identification of IR could facilitate disease prevention efforts. However, direct measurement of IR is not feasible in a clinical setting. Objective Develop a clinically practical probability score to assess IR in apparently healthy individuals based on levels of insulin, C-peptide, and other risk factors. Design Cross-sectional study. Participants Apparently healthy individuals who volunteered to participate in studies of IR. Main Outcome Measure IR, defined as the top tertile of steady-state plasma glucose during an insulin-suppression test. Results In a study of 535 participants, insulin, C-peptide, creatinine, body mass index (BMI), and triglycerides to high-density lipoprotein cholesterol ratio (TG/HDL-C) were independently associated with IR (all P < 0.05) in a model that included age, sex, ethnicity, BMI, blood pressure, insulin, C-peptide, fasting glucose, low-density lipoprotein cholesterol, TG/HDL-C, alanine aminotransferase, and creatinine. For an IR probability score based on a model that included insulin, C-peptide, creatinine, TG/HDL-C, and BMI, the odds ratio was 26.7 (95% CI 14.0 to 50.8) for those with scores >66% compared with those with scores 66% compared with those with scores, To help assess individual insulin resistance status, clinically practical insulin resistance probability scores were developed based on fasting insulin and C-peptide levels and other risk factors.

The formation of oxalic acid and its mixing state in atmospheric particulate matter (PM) were studied using a single-particle aerosol mass spectrometer (SPAMS) in the summer and winter of 2014 in Heshan, a supersite in the rural area of the Pearl River Delta (PRD) region in China. Oxalic-acid-containing particles accounted for 2.5 and 2.7 % in total detected ambient particles in summer and winter, respectively. Oxalic acid was measured in particles classified as elemental carbon (EC), organic carbon (OC), elemental and organic carbon (ECOC), biomass burning (BB), heavy metal (HM), secondary (Sec), sodium-potassium (NaK), and dust. Oxalic acid was found predominantly mixing with sulfate and nitrate during the whole sampling period, likely due to aqueous-phase reactions. In summer, oxalic-acid-containing particle number and ozone concentration followed a very similar trend, which may reflect the significant contribution of photochemical reactions to oxalic acid formation. The HM particles were the most abundant oxalic acid particles in summer and the diurnal variations in peak area of iron and oxalic acid show opposite trends, which suggests a possible loss of oxalic acid through the photolysis of iron oxalato-complexes during the strong photochemical activity period. In wintertime, carbonaceous particles contained a substantial amount of oxalic acid as well as abundant carbon clusters and BB markers. The general existence of nitric acid in oxalic-acid-containing particles indicates an acidic environment during the formation process of oxalic acid. The peak areas of nitrate, sulfate and oxalic had similar temporal change in the carbonaceous type oxalic acid particles, and the organosulfate-containing oxalic acid particles correlated well with total oxalic acid particles during the haze episode, which suggests that the formation of oxalic acid is closely associated with the oxidation of organic precursors in the aqueous phase.

Dietary PUFAs reduce atherosclerosis and macrophage inflammation, but how nucleotide-binding oligomerization domain leucine-rich repeat-containing receptor protein (NLRP3) inflammasome activation and autophagy influence PUFA-mediated atheroprotection is poorly understood. We fed Ldlr−/− mice diets containing 10% (calories) palm oil (PO) and 0.2% cholesterol, supplemented with an additional 10% of calories as PO, fish oil (FO), echium oil (EO, containing 18:4 n-3), or borage oil (BO, containing 18:3 n-6). Inflammasome activation, autophagic flux, and mitochondrial function were measured in peritoneal macrophages, blood monocytes, or liver from diet-fed mice. Compared with PO, dietary PUFAs (FO, EO, or BO) markedly inhibited inflammasome activation, shown by 1) less macrophage IL-1β secretion and caspase-1 cleavage in response to NLRP3 inflammasome activators, 2) less IL-1β secretion and caspase-1 cleavage from liver or hepatocytes in response to lipopolysaccharide (LPS), and 3) attenuated caspase-1 activity in blood monocytes. Furthermore, PUFA-enriched diets increased LC3-II expression in macrophage, aorta, and liver samples and reduced numbers of dysfunctional mitochondria in macrophages in response to LPS and palmitate, suggesting enhanced autophagic activation. Dietary PUFAs did not attenuate NLRP3 inflammasome activation in atg5-deficient macrophages, indicating that autophagic activation is critical for the PUFA-mediated inflammasome inactivation. In conclusion, dietary PUFAs reduce atherosclerosis, in part, by activation of macrophage autophagy and attenuation of NLRP3 inflammasome activation.

Moringa seeds have been used traditionally in the management of type 2 diabetes mellitus (T2DM) and contain potent bioactive isothiocyanates. This study evaluated the efficacy of an isothiocyanate-rich moringa seed extract in delaying the onset of T2DM in UC Davis T2DM rats, a well validated model which closely mimics T2DM in humans. Rats were separated into three groups; control, moringa seed extract at 0.4%, and a weight matched group. Rats were fed respective diets for 8 months, during which energy intake, body weight, the onset of diabetes circulating hormones, metabolites and markers of inflammation and liver function, and were monitored. The MS group had a significantly slower rate of diabetes onset p = 0.027), lower plasma glucose (p = 0.043), and lower HbA1c (p = 0.008) compared with CON animals. There were no significant differences in food intake and body weight between all groups. This study demonstrated MS can delay the onset of diabetes in the UC Davis T2DM rat model to a greater extent than moderate caloric restriction (by comparison to the WM group). The results support its documented traditional uses and a bioactive role of moringa isothiocyanates and suggest the potential efficacy for moringa supplementation for diabetes management in populations at risk for T2DM.

In some instances, multimetallic complexes have shown higher anticancer activity than mononuclear analogues, possibly by interacting with target molecules through a different binding mode. Therefore, a series of novel bis-pyridylimine-based homodinuclear MII/III(cym/Cp*)Cl (cym = η6-p-cymene: M = Ru, Os; Cp* = η5-pentamethylcyclopentadienyl: M = Rh, Ir) complexes were synthesized and studied. The dinuclear complexes were characterized by 1H, 13C{1H}, and 31P{1H} NMR spectroscopy, ESI-MS, and elemental analysis. Additionally, the molecular structures of several complexes were investigated by single crystal X-ray diffraction analysis. [{N,N’-(1,4-Phenylene)(bis(1-(pyridin-2-yl)(methanimine)-ᴋ2N,N’))}bis{chlorido(η6-p-cymene)ruthenium(II)}] hexafluorophosphate, 1a, was used in stability and binding studies to 9-ethylguanine (EtG) as a DNA nucleobase model and l -histidine (His), l -cysteine (Cys) and l -methionine (Met) as protein models. However, compared to structurally related Ru(arene) complexes, the investigations were inconclusive in terms of the nature of hydrolysis product(s) and EtG adducts formed, while reactions to His and Cys but not Met were observed for 1a. The in vitro cytotoxicity of the ligands and dinuclear complexes was determined against a small panel of human cancer cell lines. Some of the complexes showed moderate antiproliferative activity but were less potent than the bis-pyridylimine-based bridging ligands.

We prospectively studied the incidence and clinical course of hypertriglyceridemia and hypercholesterolemia during very prolonged use of asparaginase in relation to levels of asparaginase activity in children with acute lymphoblastic leukemia. We also evaluated the incidence of pancreatitis, thrombosis, hyperammonemia and central neurotoxicity and their association with asparaginase activity levels. Eighty-nine patients were treated according to the Dutch Childhood Oncology Group Acute Lymphoblastic Leukemia 10 medium-risk intensification proto-col, which includes 15 doses of PEGasparaginase (2,500 IU/m(2)) over 30 weeks. Erwinia asparaginase (20,000 IU/m(2)) was administered when allergy to or silent inactivation of PEGasparaginase occurred. Triglyceride, cholesterol and ammonia levels increased rapidly in children treated with PEGasparaginase and remained temporarily elevated, but normalized after administration of the last asparaginase dose. Among the patients treated with PEGasparaginase, hypertriglyceridemia and hypercholesterolemia (grade 3/4) were found in 47% and 25%, respectively. The correlation between PEGasparaginase activity levels and triglyceride levels was strongest at week 5 (Spearman correlation coefficient=0.36, P=0.005). The triglyceride levels were higher in children >= 10 years old than in younger patients (

Organometallic compounds based on bioactive ligand systems have shown promising antiproliferative properties. The use of 8-hydroxyquinoline and its derivatives as bioactive ligands resulted in organometallic complexes with potent anticancer activity, but they lack aqueous solubility for further development. We report here the preparation of a series of MII/III(cym/Cp*)Cl complexes (η6-p-cymene (cym): M = Ru, Os; η5-pentamethylcyclopentadienyl (Cp*): M = Rh, Ir) with hydroxyquinoline-derived co-ligands and in a subsequent step the substitution of the chlorido ligands for amphiphilic 1,3,5-triaza-7-phosphatricyclo-[3.3.1.1]decane (PTA). Solubility studies indicated that the introduced PTA ligand significantly improved the aqueous solubility of all complexes. The complexes were shown to be stable in aqueous and DMSO solution over a period of at least 3 d. As would be expected for such modification of complexes, the higher solubility resulted in significantly decreased cytotoxicity in cancer cells. The antiproliferative activity was still more pronounced than that of RAPTA-C [Ru(cym)(PTA)Cl] which, however, has been demonstrated to have antimetastatic and antiangiogenic properties in vivo.

The objective of this study was to investigate the effect of ultra-rapid freezing (direct immersion in liquid nitrogen) on human spermatozoa in cryogenic vials (≥0.5 ml) at different concentrations of sucrose. After swim-up, the sperm suspensions (N = 58) were diluted with sperm preparation medium and divided into six aliquots: swim-up (fresh), conventional freezing group (slow freezing) and four ultra-rapid freezing groups containing sucrose at different concentrations (0.15 m, 0.20 m, 0.25 m and 0.30 m). Sperm motility, progressive motility, plasma membrane integrity, DNA stability and acrosome integrity of fresh and cooled-warmed spermatozoa were analysed. The progressive motility, plasma membrane and acrosome integrity of spermatozoa in the 0.20 m sucrose group were significantly higher than those of the slow freezing group (47.5 ± 6.8% versus 36.4 ± 8.7%, 73.2 ± 6.9% versus 63.9 ± 6.3%, 53.7 ± 10.0% versus 35.9 ± 9.7% respectively, P0.05). However, no differences were found in sperm motility or DNA stability (58.5 ± 6.3% versus 54.2 ± 5.3%, 90.1 ± 2.8% versus 87.2 ± 4.7%, P0.05 respectively) between the 0.20 m sucrose and the slow freezing group. No differences were found between the ultra-rapid and slow freezing group at the other concentrations of sucrose. Our findings suggest that the method of ultra-rapid freezing of human spermatozoa in cryogenic vials with a solution containing 0.20 m sucrose results in recovery of spermatozoon of superior qualities. In contrast to slow freezing, the ultra-rapid freezing technique of human spermatozoa seems to reduce cryoinjuries and maintain important physiological characteristics of the spermatozoa after warming.

We describe a strategy for dispersing single walled nanotubes (SWNTs) in organic solvents using supramolecular coating with tailor-made, structurally adjustable tripodal porphyrin receptors. These have the ability to recognise SWNTs from DMF–toluene mixtures. HR TEM, TM AFM and SEM measurements showed that the hosts wrap around individual arc-made SWNTs, giving monodispersed composites in DMF which are stable for weeks. The dispersed composites were studied by Raman and fluorescence spectroscopies, including laser scanning confocal microscopy (for aggregates incorporated in cells). These porphyrin hosts encapsulate SWNTs based on π–π type interactions in an analogous manner to those observed by single crystal X-ray diffraction in their C60 complexes. These interactions may be further reinforced by porphyrin–porphyrin stacking. Density functional theory (DFT) calculations predicted the structure of the SWNT : porphyrin host complex or composite formed and the binding energies of tripodal porphyrin hosts in composites with either C60 or SWNT as guests.

Background Mesenchymal cells (MSCs) in bone marrow (BM) may produce asparagine and form protective niches for leukemic cells. In vitro, this led to high levels of asparagine and conferred asparaginase resistance to acute lymphoblastic leukemia (ALL) cells. The aim of this study was to investigate whether MSCs or other cells in BM indeed produce such significant amounts of asparagine in vivo as to result in clinical asparaginase resistance. Procedure Twenty-six patients with newly diagnosed ALL were enrolled. All children received induction chemotherapy according to the Dutch Childhood Oncology Group (DCOG) ALL-10 protocol. Asparaginase was administered from days 12–33. Asparaginase, asparagine, aspartic acid, glutamine, and glutamic acid levels were measured in BM and blood at diagnosis, days 15, 33, and 79. Results Median asparaginase trough levels were not significantly different at days 15 and 33. Only at diagnosis, asparagine level was significantly higher in BM than in blood (P = 0.001). Asparagine levels were all below the lower limit of quantification in BM and blood at days 15 and 33. However, aspartic acid level in BM was significantly higher than in blood (P

The synthesis and characterisation of iron(III) [Fe(L1)]2 (1), oxo-vanadium(V) [VO(L1)] (2) and dioxo-molybdenum(VI) K[MoO2(L1)] (3) complexes supported by a partially unsymmetric N-capped tripodal NO3 ligand (L1) are reported. Complexes 1 and 2 were prepared by reactions of a proligand [H3L1] and their corresponding metal precursor (FeCl3 and VOCl3, respectively) in the presence of triethylamine in THF, while 3 was obtained in a similar manner by treating [MoO2(acac)2] (acac = acetylacetonate) with the same proligand and potassium hydroxide in methanol. The X-ray crystal structure of 1 illustrates a dimeric structure with a bis-(μ-phenoxo) Fe2O2 diamond core, and each iron centre bears a rare NO4 coordination sphere. The preparation of a previously unknown, fully unsymmetric N-capped tripodal NO3 proligand [H3L2] featuring three different phenolic arms is also described. Reaction of [H3L2] with VOCl3 yielded the oxo-vanadium(V) complex [VO(L2)] (4). Complexes 2–4 exist as monomers in solution and were characterised by NMR (1H and 13C), IR (for 3), mass spectrometry, and elemental analysis.

The synthesis of a penta(1-methylpyrazole)ferrocenyl phosphine oxide ligand (1) [Fe(C(5)(C(3)H(2)N(2)CH(3))(5))(C(5)H(4)PO(t-C(4)H(9))(2))] is reported together with its X-ray crystal structure. Its self-assembly behavior with a dirhodium(II) tetraoctanoate linker (2) [Rh(2)(O(2)CC(7)H(15))(4)] was investigated for construction of fullerene-like assemblies of composition [(ligand)(12)(linker)(30)]. Reaction between 1 and 2 in acetonitrile resulted in the formation of a light purple precipitate (3). Evidence for the ligand-to-linker ratio of 1:2.5 expected for a fullerene-like structure [Fe(C(5)(C(3)H(2)N(2)CH(3))(5))(C(5)H(4)PO(t-C(4)H(9))(2))](12)[Rh(2)(O(2)CC(7)H(15))(4)](30) was obtained from (1)H NMR and elemental analysis. IR and Raman studies confirmed the diaxially bound coordination environment of the dirhodium linker by comparing the stretching frequencies of the carboxylate group and the rhodium-rhodium bond with those in model compound (5), [Rh(2)(O(2)CC(7)H(15))(4)](C(3)H(3)N(2)CH(3))(2), the bis-adduct of linker 2 with 1-methylpyrazole. X-ray powder diffraction and molecular modeling studies provide additional support for the formation of a spherical molecule topologically identical to fullerene with a diameter of approximately 38 Å and a molecular formula of [(1)(12)(2)(30)]. Dissolution of 3 in tetrahydrofuran (THF) followed by layering with acetonitrile afforded purple crystals of [(1)(2)(2)](∞) (6) [Fe(C(5)(C(3)H(2)N(2)CH(3))(5))(C(5)H(4)PO(t-C(4)H(9))(2))][Rh(2)(O(2)CC(7)H(15))(4)](2) with a two-dimensional polymeric structure determined by X-ray crystallography. The dirhodium linkers link ferrocenyl units by coordination to the pyrazoles but only four of the five pyrazole moieties of the pentapyrazole ligand are coordinated. The ligand-to-linker ratio of 1:2 in 6 was confirmed by (1)H NMR spectroscopy and elemental analysis, while results from IR and Raman are in agreement with the diaxially coordinated environment of the linker observed in the solid state.

With 2 figures and 4 tables Abstract Stepwise selection approach was adopted to obtain glyphosate-tolerant upland cotton mutant (R1098) from the embryogenic calli of ‘Coker 312’ (Gossypium hirsutum L.). The calli were transferred to the selection medium and multi-step selection pressure process was carried out until the calli could proliferate in the presence of 20 mm glyphosate. The regenerated plants from the glyphosate-tolerant calli were analysed for glyphosate response, tolerance of progenies and shikimate accumulation on whole-plant basis. ‘R1098’ could tolerate 1.48 kg acid equivalent/ha glyphosate. Progeny tests demonstrated that glyphosate tolerance trait was controlled by one dominant gene. Shikimate accumulation assay showed that significantly different amounts of shikimate were present between the mutant (R1098) and its wild parent (Coker 312) after glyphosate treatment. This indicates that ‘R1098’ has sufficient 5-enolpyruvylshikimate-3-phosphate synthase activity in the presence of glyphosate, thereby maintaining normal carbon flow through the shikimate pathway. Moreover, ‘R1098’ offers a greater potential to improve the weed control system in cotton production.

We demonstrate a simple and cost-effective approach to realize two combined surface features of different scales together, namely submillimeter-sized protrusion array and microwrinkles, atop a polystyrene shape-memory polymer. Two different types of protrusions, namely flat-top protrusion and crown-shaped protrusion, were studied. The array of protrusions was produced by the Indentation-Polishing-Heating (IPH) process. Compactly packed steel balls were used for making array of indents. A thin gold layer was sputter deposited atop the polymer surface right after polishing. After heating for shape recovery, array of protrusions with wrinkles on the top due to the buckling of gold layer was produced.

Bi4Cu0.2V1.8O11–δ membrane material was synthesized by following the solid-state method. The oxygen permeation flux at 673 K was found to be 0.5 ml/cm2 by the use of an external electric power source. The oxidation of propane was selected as the probe reaction using the Bi4Cu0.2V1.8O11–δ electrochemical membrane reactor. It was found that such electrochemical membrane reactors could have potential application in the area of alkanes selective oxidation at moderate temperatures.

ZnO nanoparticles capped with polyvinyl butyral (PVB) have been synthesized by the sol-gel process. Photoluminescence (PL) spectra show a remarkable decrease in visible emission intensity after ZnO nanoparticles are capped with PVB, which indicates that dangling bonds and defect states at the surface of ZnO nanoparticles are markedly passivated. As a result, the process of surface-trapped hole tunneling back into the particles to form V**O recombination center is blocked. The PL spectra of thin films show a strong ultraviolet (UV) emission with very weak visible emission. The typical intensity ratio of the UV emission at 3.45 eV to the visible emission at about 2.41 eV is 43.3, which shows an obvious improvement in luminescence properties by the surface passivation with PVB. Low-temperature PL spectra of ZnO powder at 93.8 K are dominated by free exciton, bound exciton and the LO-phonon replica of the bound exciton.

Cold-trap, on-line sampling was applied to investigate migration of flavor compounds in a solid food matrix subjected to microwave heating. The activation energy levels for migration of limonence, pyrazine, and water are 58.2, 51.5, and 46.4 kJ/mol, respectively. The results of microwave reheating of limonene-formulated dough showed no significant limonene concentration profile in the sample and less than 1% overall change in total limonene concentration. Because the flavor concentration used for this migration study is greater than the amount that would be added to real products it can be concluded that after microwave reheating of flavor-formulated dough, limonene is very stable and significant losses do not occur.

A new approach using cold-trap, on-line sampling was applied to investigate migration rate of limonene, tert-butylbenzene, and pyrazine in a flour dough matrix. Flavor equilibrium concentration and migration rates were shown to be strong functions of initial concentration. Due to encapsulation of flavor compounds at lower moisture content, it was not possible to totally extract the flavor compounds from the matrix by solvent extraction. The cold-trap online sampling method could be satisfactorily used to generate data on flavor migration rates in dough matrices.

In this paper we report on the processing and properties of a novel, “dual-curing” liquid crystal (LC) resin cured by electron-beam irradiation. The LC monomer contains both acrylate and acetylene reactive groups. Neat resin samples were e-beam cured in either the LC phase at 65 °C or the isotropic phase at 90 °C. The experimental variables included the total e-beam radiation dose (150 or 250 kiloGray {kGy or J/g}) and thermal post-cure cycle (none or 190 °C/1 h). Cured polymer specimens were characterized by dynamic mechanical analysis (DMA) and thermo-mechanical analysis (TMA). The results demonstrated that e-beam exposure alone at 150 or 250 kGy was not sufficient to fully cure the polymer, although it was sufficient to lock-in the isotropic or LC morphology. Differences in morphology had a significant impact on the DMA and TMA results for non-post-cured specimens, where LC samples demonstrated more robust mechanical properties at elevated temperatures compared to isotropic specimens. After a thermal post-cure cycle the DMA storage modulus differences between the LC and isotropic samples were not as great. However, large differences in thermal expansion coefficients remained. The data suggest the possibility that the acrylate bonds react during e-beam exposure, followed by conversion of the acetylene bonds during the thermal post-cure. Also, e-beam curing in the LC phase likely will allow for tighter molecular packing and more efficient polymerization resulting in higher crosslink densities.

Asparaginase antibodies (AAAs) neutralize asparaginase and are often accompanied by a clinically overt allergic reaction, but in a proportion of the patients these antibodies occur without any signs of hypersensitivity, termed as silent inactivation.[1][1],[2][2] Vrooman et al. and Panosyan et al.

This study prospectively analyzed the efficacy of very prolonged courses of pegylated Escherichia coli asparaginase (PEGasparaginase) and Erwinia asparaginase in pediatric acute lymphoblastic leukemia (ALL) patients. Patients received 15 PEGasparaginase infusions (2500 IU/m(2) every 2 weeks) in intensification after receiving native E coli asparaginase in induction. In case of allergy to or silent inactivation of PEGasparaginase, Erwinia asparaginase (20 000 IU/m(2) 2-3 times weekly) was given. Eighty-nine patients were enrolled in the PEGasparaginase study. Twenty (22%) of the PEGasparaginase-treated patients developed an allergy; 7 (8%) showed silent inactivation. The PEGasparaginase level was 0 in all allergic patients (grade 1-4). Patients without hypersensitivity to PEGasparaginase had serum mean trough levels of 899 U/L. Fifty-nine patients were included in the Erwinia asparaginase study; 2 (3%) developed an allergy and none silent inactivation. Ninety-six percent had at least 1 trough level >= 100 U/L. The serum asparagine level was not always completely depleted with Erwinia asparaginase in contrast to PEGasparaginase. The presence of asparaginase antibodies was related to allergies and silent inactivation, but with low specificity (64%). Use of native E coli asparaginase in induction leads to high hypersensitivity rates to PEGasparaginase in intensification. Therefore, PEGasparaginase should be used upfront in induction, and we suggest that the dose could be lowered. Switching to Erwinia asparaginase leads to effective asparaginase levels in most patients. Therapeutic drug monitoring has been added to our ALL-11 protocol to individualize asparaginase therapy.

A new p-phenylene–vinylene–thiophene-based siloxane block copolymer has been synthesized. The copolymer consists of alternating rigid and flexible blocks. The rigid blocks are composed of phenylene–vinylene–thiophene-based units, and the flexible blocks are derived from 1,3-dialkyldisiloxane units. The former component acts as the chromophore, and allows fine tuning of band gap for blue-light emission, while the latter imparts good solubility of the copolymer in organic solvents, and thus, should enhance processibility of the resulting copolymer. The thermal properties of the copolymer have been characterized by thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). The photoluminescence (PL) of the copolymer in solution and in cast film has been studied. The effects of concentration on the PL intensity of the new copolymer in polymer blends with poly(methyl methacrylate) (PMMA) and poly(vinyl carbazole) (PVK) have also been described. Efficient energy transfer from PVK to the new block copolymer in the blended film was observed. © 2000 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 38: 1450–1456, 2000

_To the Editor:_ Asparaginase is an enzyme which hydrolyses asparagine into aspartic acid and ammonia. Levels of asparaginase activity are relatively easy to measure, and a trough level >100 U/L is associated with complete asparagine depletion. So, the measurement of levels of asparaginase activity is a very useful tool to monitor asparaginase activities in clinical practice. However, these assays are not available in all countries in contrast to ammonia measurements. Recently, a Polish study group published ammonia levels of 87 children during acute lymphoblastic leukemia (ALL) induction therapy. They concluded that the ammonia concentration reflects the levels of asparaginase activity and could be useful when asparaginase activity assays are not available. We evaluated if ammonia levels could be used as a surrogate marker of levels of asparaginase activity. [...]

To minimize oxidative modification, a low tem- perature, sequential flotation method was developed to isolate plasma lipoproteins in 18 h using a benchtop ultra- centrifuge. The protein distributions were characterized using agarose and SDS-polyacrylamide gel electrophore- sis, and an SDS-Lowr y protein assay. The lipid distribu- tions were assessed using a gas chromatography-mass spec- trometric assay for cholesterol and an enzymatic assay for triglycerides. To validate the rapid flotation method, lipoproteins were also isolated from the same plasma samples using a modified Havel et al. flotation method ( J. Clin. Invest. 34: 1345-1353, 1955). The same lipoproteins and apolipoproteins were present in fractions of compa- rable density, and the summed recoveries of protein, cho- lesterol, and triglyceride were also identical for the Havel et al. and rapid fl otation procedures. Likewise, the amount of cholesterol and triglyceride in corresponding very low, intermediate, and low density lipopr otein (VLDL/IDL and LDL) fractions was the same for the two flotation procedures. The triglyceride and cholesterol lev- els in high density lipoprotein (HDL) isolated by rapid flo- tations, however, were 9-12% higher than in the HDL as isolated by Havel et al. Because a 9 -12% increase in the HDL fraction reflects only 1- 4% of the total triglyceride and cholesterol in plasma, we conclude that, while main- tained at 4 8 C, lipoproteins were quantitatively isolated from human plasma in 1 day.— Tong, H., H. R. Knapp, and M. VanRollins. A low temperature flotation method to rapidly isolate lipoproteins from plasma. J. Lipid. Res. 1998. 39: 1696-1704.

Disulfiram is used in aversion therapy for alcoholism. S-Methyl-N,N-diethylthiocarbamate (MeDTC) sulfoxide, a potent inhibitor of the target enzyme mitochondrial aldehyde dehydrogenase (ALDH2), is thought to be the principal active metabolite of disulfiram in vivo. We examined the effects on recombinant human ALDH2 of two intermediate metabolites of disulfiram, S-methyl-N,N-diethyldithiocarbamate (MeDDC) sulfoxide and MeDDC sulfine. MeDDC sulfoxide was a potent inhibitor of ALDH2 with an IC50 of 2.2 +/- 0.5 microM (mean +/- SD, N = 4) after preincubation with enzyme for 30 min. MeDDC sulfine was a relatively weak inhibitor of ALDH2 under the same conditions with an IC50 value of 62 +/- 14 microM. The inhibition of ALDH2 by both compounds was irreversible and did not require the cofactor NAD. The latter finding demonstrates that inactivation of ALDH2 is independent of the dehydrogenase activity of the enzyme. GSH blocked almost completely the inhibition by 20 microM of MeDDC sulfoxide and greatly diminished the inhibition by 200 microM of MeDDC sulfine. Inactivation by MeDDC sulfoxide was time dependent. MeDTC sulfoxide was a more potent inhibitor of recombinant human ALDH2 (IC50 = 1.4 +/- 0.3 microM after preincubation for 15 min) than either of the intermediate metabolites, and its inhibition was unaffected by GSH. Our results suggest that these newer intermediate metabolites of disulfiram, especially the more potent MeDTC sulfoxide, have the potential to inhibit the target enzyme ALDH2 in patients receiving disulfiram. However, until the significance of the interactions of the inhibitors with GSH is more fully understood, the contribution of MeDDC sulfine and MeDDC sulfoxide to the pharmacological effects of disulfiram in vivo is uncertain.

Finite-element simulations are presented to advance the knowledge of flow structures, species distributions, and mixing behaviors of turbulent burning flows in municipal solid incinerators under various operating conditions. The modified {kappa}-{epsilon} turbulence model together with wall functions was adopted. Devolatilization of solid wastes were simulated by gaseous methane (CH{sub 4}) nonuniformly distributed along the inclined grate. The combustion process was considered as a two-step reaction when primary underfire air entered and mixed with methane gas in the first combustion chamber. A mixing-controlled eddy-dissipation model was used for predicting the reaction rates of CH{sub 4}, O{sub 2}, CO{sub 2}, and CO. Results show that the grate is covered by cone-shaped flames that are bent and aligned with the flow directions. Postflame oxidation is done in the second combustion chamber and can be improved by provision of more excess air or by the injection of secondary overfire air. Combustion efficiency up to 99.98% and an exit temperature around 1,000 C can be achieved at 100--200% excess air. Reasonable agreements are achieved between numerical predictions and available in-situ measurements.

The requirements for accurate quantitative analysis of 2-methylpyrazine and 2,5-dimethylpyrazine thermally produced in a solid system consisting of 4.5% (w/w) lysine, 5.5% (w/w) glucose and granular starch with 10% moisture content (dry basis) were investigated. The ratios (or response factors) of the pyrazines to pyrimidine obtained from GC analysis remained constant after a 1000 fold concentration at 55C, verifying that pyrimidine was adequate as an internal standard to account for losses of the pyrazines during concentration. Calibration curves for both pyrazines constructed by plotting the response factors versus concentration were shown to be linear from 0–1000 ppm. However, the slope of the calibration curve was found to vary when constructed over 10 days, suggesting that it was necessary to construct daily calibration curves. Recovery studies were conducted by adding known amounts of pyrazines to amioca starch without heating. The procedure using three extractions with methylene chloride gave adequate recovery efficiencies (100%± standard deviation) versus recoveries below 80% for two extractions. In order to completely recover the pyrazines thermally produced in the model system with methylene chloride, an extraction time of 72 h at room temperature was necessary which was believed to be due to the diffusion limited extraction of the pyrazines by the nonpolar solvent from the hydrophilic solid matrix.

The orientational ordering of six liquid crystalline compounds in two homologous series, namely 4-n-alkoxybenzilidene-4′-n-alkylanilines (nO. m) and 4, 4′-di-n-alkyldiphenyldiacetylenes (PTTP), has been studied at different temperatures by 2D C-13 NMR with variable angle sample spinning. The carbon-proton dipolar coupling constants were obtained and the order parameters of the aromatic cores were calculated. The C-13 chemical shifts for each carbon nucleus in the aromatic cores were also measured as a function of temperature by 1D C-13 NMR. A linear correlation between the chemical shifts and the order parameters was observed for each homologous series. The results furnish a useful and convenient database for the evaluation of order parameters for these two series of liquid crystals from simple measurements of C-13 chemical shifts.

Ultrafiltration of proteins using hydrolyzed polyacrylonitrile hollow fiber was investigated in this work. Polyacrylonigrile hollow fiber was spun and hydrolyzed with NaOH aqueous solution under various conditions. A thin layer of polyacrylic acid was formed on the inner surface of the hollow fiber, and the ionic density on the hydrolyzed surface was determined through titration. The hydrolyzed hollow fiber was characterized with the hydraulic permeability and the retention of dextran. A sharp decrease in the hydraulic permeability was observed between pH 5 and 6, possibly due to the swelling of the hydrolyzed layer. The retention of dextran slightly increased with the ionic density of the hydrolyzed hollow fiber. The retentions of two proteins, myoglobin and cytochrome c, were measured over a range of pH values (4∼10). The results show that the retention of protein changes with pH, and is the lowest at the isoelectric point. Separation of mixtures of cytochrome c and myoglobin was performed at pH 5, 7 and 9 using hydrolyzed PAN hollow fiber. The selectivity of the cytochrome c over myoglobin was about 40 at pH 5, about 1 at pH 7, and about 0.5 at pH 9.

A new analysis using the fractional conversion technique was applied to determine the formation kinetics of 2,5-dimethylpyrazine and 2-methylpyrazine in a solid model system containing 4.5% (w/w) lysine, 5.5% glucose, and amioca starch with 10% moisture (dry basis) from 80 to 120 °C. The reaction order and kinetic parameters (rate constants and activation energy) were determined through a parameter estimation technique based on least-squares fit. The formation rate of both pyrazines followed a first-order reaction model. No significant differences were observed for the activation energies and rate constants for 2,5-dimethylpyrazine and 2-methylpyrazine, suggesting the production of these pyrazines was controlled by the same rate-limiting step. The activation energy was 13.5 kcal/mol. Keywords: Kinetics; 2,5-dimethylpyrazine and 2-methylpyrazine; solid state; fractional conversion

The diferrous oxidation level of carboxylate-bridged non-heme diiron proteins is pivotal because only it reacts directly with dioxygen. In this state each ferrous ion has ST = 2. Such integer-spin, so-called “Non-Kramers” (NK) systems typically are difficult to access by paramagnetic resonance techniques, and this property has precluded the application of ENDOR and ESEEM spectroscopies to this state. Integer-spin systems frequently exhibit a ground state “Non-Kramers doublet”, however, which is split in zero applied field by an energy within the microwave range, thus rendering the center EPR active. Recently, we showed that ENDOR and ESEEM spectroscopies also can be applied to NK doublets, in preliminary measurements on diferrous methane monoxygenase hydroxylases (MMOHred) Methylococcus capsulatus (Bath) and Methylosinus trichosporium OB3b and azido-hemerythrin (N3Hrred) (Hoffman, B. M.; Sturgeon, B. E.; Doan, P. E.; DeRose, V. J.; Liu, K. E.; Lippard, S. J. J. Am. Chem. Soc. 1994, 116, 6023−6024). Buildi...

Asparaginase is an expensive drug, but important in childhood acute lymphoblastic leukemia. In order to compare costs of PEGasparaginase, Erwinia asparaginase and native E. coli asparaginase, we performed a cost-analysis in the Dutch Childhood Oncology Group ALL-10 medium-risk group intensification protocol. Treatment costs were calculated based on patient level data of 84 subjects, and were related to the occurrence of allergy to PEGasparaginase. Simultaneously, decision tree and sensitivity analyses were conducted. The total costs of the intensification course of 30 weeks were $57,893 in patients without PEGasparaginase allergy (n=64). The costs were significantly higher ($113,558) in case of allergy (n=20) necessitating a switch to Erwinia asparaginase. Simulated scenarios (decision tree analysis) using native E. coli asparaginase in intensification showed that the costs of PEGasparaginase were equal to those of native E. coli asparaginase. Also after sensitivity analyses, the costs for PEGasparaginase were equal to those of native E. coli asparaginase. Intensification treatment with native E. coli asparaginase, followed by a switch to PEGasparaginase, and subsequently to Erwinia asparaginase in case of allergy had similar overall costs compared to the treatment with PEGasparaginase as the first-line drug (followed by Erwinia asparaginase in the case of allergy). PEGasparaginase is preferred over native E. coli asparaginase, because it is administered less frequently, with less day care visits. PEGasparaginase is less immunogenic than native E. coli asparaginase and is not more expensive. Asparaginase costs are mainly determined by the percentage of patients who are allergic and require a switch to Erwinia asparaginase.

Square self-assemblies are obtained from dirhodium(II) tetracarboxylate complexes using an isonicotinate-type ligand to act as an equatorial ligand to one dirhodium unit and an axial ligand to another. It is shown that the supramolecular squares are formed selectively out of a number of possible compounds in the dynamic carboxylate exchange library.

New donor-acceptor hybrids of Zn(II)-metallated 5,15-diaryl porphyrins have been designed and synthesised via the porphyrin interactions with an electron acceptor molecule, di-n-hexyl N-substituted 1,2,4,8-naphthalenetetracarboxylic diimide (NDI). Binding interactions within these supramolecular complexes were investigated in the solid state by synchrotron X-ray diffraction and probed in solution by (1)H NMR spectroscopy. The systematic modulation of the porphyrin π-density was achieved, for the first time as multiple methoxy and fluorine groups were introduced as substituents to the 5,15-diaryls of the porphyrin. For these, the variation of the porphyrin-NDI binding strengths determined by (1)H NMR titrations was shown, using the Swain's type dual parameter approach, to be closely linked with the peripheral substitution pattern of the diaryl porphyrins validated by crystallography. The new 1:1 donor-acceptor complexes formed display characteristic features of the aromatic-stacked systems, i.e. the parallel arrangement and short interplanar separation between the substituted porphyrin and NDI. Synthetic modification of electron-density on the porphyrin surface by introducing substituents at peripheral sites of functionalised porphyrins represent a general solution towards electronically tunable aromatic surfaces: an understanding of their solution and solid state behaviour will significantly improve the rational design of new functional donor-acceptor supramolecular materials with potential applications ranging from new energy materials to dye-sensitised solar cells, photovoltaics and future drug delivery devices.