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Reactive oxygen species (e.g., singlet oxygen) are the primary cytotoxic agents used in the clinically approved technique photodynamic therapy (PDT). Although singlet oxygen has high potential to effectively kill tumor cells, its production via light excitation of a photosensitizer has been limited by the penetration depth and delivery of light in tissue. To produce singlet oxygen without light excitation, we describe the use of Schaap’s chemiluminescent scaffold comprising an adamantylidene–dioxetane motif. Functionalizing this scaffold with a photosensitizer, Erythrosin B, resulted in spontaneous chemiluminescence resonance energy transfer (CRET) leading to the production of singlet oxygen. We show that this compound is cell permeable and that the singlet oxygen produced via CRET is remarkably efficient in killing cancer cells at low micromolar concentrations. Moreover, we demonstrate that protection of the phenol on the chemiluminescent scaffold with a nitroreductase-responsive trigger group allows for cancer-selective dark dynamic cell death. Here, we present the concept of dark dynamic therapy using a small cell-permeable molecule capable of producing the effects of PDT in cells, without light.

Chemiluminescence is a fascinating phenomenon that evolved in nature and has been harnessed by chemists in diverse ways to improve life. This Account tells the story of our research group’s efforts to formulate and manifest spiroadamantane 1,2-dioxetanes with triggerable chemiluminescence for imaging and monitoring important reactive analytes in living cells, animals, and human clinical samples. Analytes like reactive sulfur, oxygen and nitrogen species, as well as pH and hypoxia can be indicators of cellular function or dysfunction and are often implicated in the causes and effects of disease. We begin with a foundation in binding-based and activity-based fluorescence imaging that has provided transformative tools for understanding biological systems. The intense light sources required for fluorescence excitation, however, introduce autofluorescence and light scattering that reduces sensitivity and complicates in vivoimaging. Our work and the work of our collaborators were the first to demonstrate that spiroadamantane 1,2-dioxetanes had sufficient brightness and biological compatibility for in vivoimaging of enzyme activity and reactive analytes like hydrogen sulfide (H2S) inside of living mice. This launched an era of renewed interest in 1,2-dioxetanes that has resulted in a plethora of new chemiluminescence imaging agents developed by groups around the world. Our own research group focused its efforts on reactive sulfur, oxygen, and nitrogen species, pH, and hypoxia, resulting in a large family of bright chemiluminescent 1,2-dioxetanes validated for cell monitoring and in vivoimaging. These chemiluminescent probes feature low background and high sensitivity that have been proven quite useful for studying signaling, for example, the generation of peroxynitrite (ONOO–) in cellular models of immune function and phagocytosis. This high sensitivity has also enabled real-time quantitative reporting of oxygen-dependent enzyme activity and hypoxia in living cells and tumor xenograft models. We reported some of the first ratiometric chemiluminescent 1,2-dioxetane systems for imaging pH and have introduced a powerful kinetics-based approach for quantification of reactive species like azanone (nitroxyl, HNO) and enzyme activity in living cells. These tools have been applied to untangle complex signaling pathways of peroxynitrite production in radiation therapy and as substrates in a split esterase system to provide an enzyme/substrate pair to rival luciferase/luciferin. Furthermore, we have pushed chemiluminescence toward commercialization and clinical translation by demonstrating the ability to monitor airway hydrogen peroxide in the exhaled breath of asthma patients using transiently produced chemiluminescent 1,2-dioxetanedione intermediates. This body of work shows the powerful possibilities that can emerge when working at the interface of light and chemistry, and we hope that it will inspire future scientists to seek out ever brighter and more illuminating ideas.

Density functional theory (DFT) calculations on Fe2S2(CO)6–2n(PMe3)2nfor n= 0, 1, and 2 reveal that the most electron-rich derivatives (n= 2) exist as diferrous disulfides lacking an S–S bond. The thermal interconversion of the FeII2(S)2and FeI2(S2) valence isomers is symmetry-forbidden. Related electron-rich diiron complexes [Fe2S2(CN)2(CO)4]2–of an uncertain structure are implicated in the biosynthesis of [FeFe]-hydrogenases. Several efforts to synthesize electron-rich derivatives of Fe2(μ-S2)(CO)6(1) are described. First, salts of iron persulfido cyanides [Fe2(μ-S2)(CO)5(CN)]−and [Fe2(μ-S2)(CN)(CO)4(PPh3)]−were prepared by the reactions of NaN(tms)2with 1and Fe2(μ-S2)(CO)5(PPh3), respectively. Alternative approaches to electron-rich diiron disulfides targeted Fe2(μ-S2)(CO)4(diphosphine). Whereas the preparation of Fe2(μ-S2)(CO)4(dppbz) was straightforward, that of Fe2(μ-S2)(CO)4(dppv) required an indirect route involving the oxidation of Fe2(μ-SH)2(CO)4(dppv) (dppbz = C6H4-1,2-(PPh2)2, dppv = cis-C2H2(PPh2)2). DFT calculations indicate that the oxidation of Fe2(μ-SH)2(CO)4(dppv) produces singlet diferrous disulfide Fe2(μ-S)2(CO)4(dppv), which is sufficiently long-lived as to be trapped by ethylene. The reaction of 1and dppv mainly afforded Fe2(μ-SCH=CHPPh2)(μ-SPPh2)(CO)5, implicating a S-centered reaction.

An attractive catalytic pathway for the conversion of water to oxygen would involve two metal oxide centers combining in a constructive sense to make O═O. This prospect makes the study of certain dinuclear transition metal complexes particularly attractive. In this work, we describe the design and synthesis of two symmetrical bis-tridentate polypyridine ligands 6and 12that bind two RuIIcenters at a separation of 3.6 Å in 7and 5.7 Å in 13. In the presence of CeIVat pH = 1, these systems oxidize water with the system having the more proximal metals being more reactive. In the case of the more proximal metal centers, the bridging ligand is a 3,6-disubstituted pyridazine which, under the influence of CeIV, cleaves into two [Ru(bpc)(pic)2CH3CN]+fragments (14) which then function as the actual catalyst (bpc = 2,2′-bipyridine-6-carboxylate, pic = 4-methylpyridine). The second dinuclear catalyst contains a central pyrimidine ring which is less sensitive to oxidative decay and hence less reactive. Caution is advised in the use of CeIVas a sacrificial electron acceptor due to unexpected oxidative decay of the catalyst.

The Diels–Alder reaction represents one of the most thoroughly studied and well-understood synthetic transformations for the assembly of six-membered rings. Although intramolecular dehydro-Diels–Alder (IMDDA) reactions have previously been employed for the preparation of naphthalene and dihydronaphthalene substrates, low yields and product mixtures have reduced the impact and scope of this reaction. Through the mechanistic studies described within, we have confirmed that the thermal IMDDA reaction of styrene–ynes produces a naphthalene product via loss of hydrogen gas from the initially formed cycloadduct, a tetraenyl intermediate. Alternatively, the dihydronaphthalene product is afforded from the same tetraenyl intermediate via a radical isomerization process. Moreover, we have identified conditions that can be used to achieve efficient, high-yielding, and selective IMDDA reactions of styrene–ynes to form either naphthalene or dihydronaphthalene products. The operational simplicity and retrosynthetic orthogonality of this method for the preparation of naphthalenes and dihydronaphthalenes makes this transformation appealing for the synthesis of medicinal and material targets. The mechanistic studies within may impact the development of other thermal transformations.

The chemistry of Fe2(μ-SH)2(CO)4(PPh3)2(2HH) is described with attention to S–S coupling reactions. Produced by the reduction of Fe2(μ-S2)(CO)4(PPh3)2(2), 2HHis an analogue of Fe2(μ-SH)2(CO)6(1HH), which exhibits well-behaved S-centered redox. Both 2HHand the related 2MeHexist as isomers that differ with respect to the stereochemistry of the μ-SR ligands (R = H, Me). Compounds 2HH, 2MeH, and 2protonate to give rare examples of Fe-SH and Fe-S2hydrides. Salts of [H2]+, [H2HH]+, and [H2MeH]+were characterized crystallographically. Complex 2HHreduces O2, H2O2, (PhCO2)2, and Ph2N2, giving 2. Related reactions involving 1HHgave uncharacterizable polymers. The differing behaviors of 2HHand 1HHreflect stabilization of the ferrous intermediates by the PPh3ligands. When independently generated by the reaction of 2HHwith 2,2,6,6-tetramethyl-1-piperidinyloxy, 2*quantitatively converts to 2or, in the presence of C2H4, is trapped as the ethanedithiolate Fe2(μ-S2C2H4)(CO)4(PPh3)2. Evidence is presented that the Hieber–Gruber synthesis of 1involves polysulfido intermediates [Fe2(μ-Sn)2(CO)6]2–(n> 1). Two relevant experiments are as follows: (i) protonation of [Fe4(μ-S)2(μ-S2)CO)12]2–gives 1and 1HH, and (ii) oxidation of 1HHby sulfur gives 1.

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A unique microemulsion-based photocatalytic water reduction system is demonstrated. Iridium- and rhodium-based metallosurfactants, namely, [Ir(ppy)2(dhpdbpy)]Cl and [Rh(dhpdbpy)2Cl2]Cl (where ppy = 2-phenylpyridine and dhpdbpy = 4,4′-diheptadecyl-2,2′-bipyridine), were employed as photosensitizer and proton reducing catalyst, respectively, along with oxalic acid as a sacrificial reductant in a toluene/water biphasic mixture. The addition of 1-octylamine is proposed to initiate the reaction, by coupling with oxalic acid to form an ion pair, which acts as an additional surfactant. Concentration optimizations yielded high activity for both the photosensitizer (240 turnovers, turnover frequency (TOF) = 200 h–1) and catalyst (400 turnovers, TOF = 230 h–1), with the system generating hydrogen even after 95 h. Mechanistic insights were provided by gas-phase Raman, electrochemical, and luminescence quenching analysis, suggesting oxidative quenching to be the principle reaction pathway.

The influences of mechanical actions on interfacial reactions between an iron plate and molten tin were examined. Tensile and compressive stresses up to 100 MPa on the iron plate did not significantly change the thickness of the reaction layer and the corrosion depth of the plate. However, when the iron plate was subjected to repeated rubbing with tungsten and Pb–Sn eutectic alloy wires and when it was immersed in the rotating molten tin, the reaction layer thickness decreased and the corrosion depth of the iron plate increased. From these results, it was concluded that the corrosion of the iron plate in the molten tin was enhanced by repeated rubbing with the solder alloy on the plated iron layer and also by flow of molten solder alloy down the surface of the soldering tip in the soldering process.

Spot welds made by resistance spot welding are used extensively in automotive engineering. However, owing to increasing demands in the use of advanced and lightweight materials, laser welding has become a popular alternative for producing spot welds. Because of the complexity and uncertainties of laser welds and thus formed structures, the finite-element (FE) modelling of the welds for dynamic analysis is a research issue. This article first outlines some of the existing modelling works of spot welds. Then, a hat-plate structure used for this study is described and its FE representations are explained. The welds are modelled using CWELD elements in MSC/NASTRAN and their feasibility for representing laser spot welds is investigated. Numerical results for the initial FE model differ considerably from that of their experimental counterparts; hence, a model updating procedure is carried out to minimize the discrepancy between the two sets of results. In this work, the updating is posed as an optimization problem and is performed using the structural optimization capability (SOL 200) in MSC/NASTRAN. Two stages of updating are conducted, that is (a) updating FE models of individual components and (b) updating an FE model of the welded structure. Crucial steps in updating are explained. It is found that by selecting the right updating parameters, the CWELD element can be used to represent laser spot welds with good accuracy.

We describe three cases of parotid gland lipoma, a relatively rare, asymptomatic, slow growing, freely movable, soft tissue mass. Preoperative clinical diagnosis is generally difficult but MRI using fat saturation techniques provides accurate diagnostic information regarding this benign parotid gland tumor, enabling better treatment planning.

AIM: This study was performed to determine the magnetic resonance imaging (MRI) sequence that was best suited to demonstrate the scolex in a calcified lesion and to seek the explanation for the appearance of a negative phase in a calcified scolex on corrected gradient refocused echo (GRE) phase imaging. MATERIALS AND METHODS: Forty-nine patients with single/multiple computed tomography (CT) documented homogeneous calcified lesions and/or calcified scolices in cysts were studied with conventional spin echo and corrected GRE phase imaging. Calcium and different paramagnetic substances from cysticerci scolices of a sample of infected swine muscle were quantified. RESULTS: The scolex could be demonstrated in 29/39 patients with single calcified lesion. GRE imaging with an echo time of 35ms was the only sequence that demonstrated scolex in all these 29 cases. 15/29 patients with a single calcified lesion, in all 10 patients with multiple calcified lesions and infected swine muscle with multiple cysts and calcified scolex, corrected GRE phase imaging showed negative phase in all these scolices. Estimation of minerals from the calcified scolices from the swine muscle showed by spectroscopic techniques 41.2% of the total mineral contents as paramagnetic substances. CONCLUSION: We conclude that GRE imaging is the imaging method of choice for demonstration of the scolex in a CT calcified lesion. The negative phase on corrected GRE phase imaging is due to the presence of large amount of paramagnetic substances. Chawla, S. et al. (2002). Clinical Radiology57, 826–834.

OBJECTIVE: The purpose of this study was to correlate the differences in the magnetization transfer (MT) ratios of different components of the tuberculoma with histopathology and to see whether MT or conventional MR imaging correlates better with histopathology. METHODS: MT T1 and conventional spin echo MR imaging was performed in six patients with intracranial tuberculomas. The tuberculomas were excised as a single mass and ex vivoMR imaging was performed using the same protocol. The gross histopathology was compared with in vivoimaging with respect to the MR signal intensity (MT ratio) in all six specimens. RESULTS: The size of the tuberculomas was larger on MT T1-weighted images compared to T2-weighted images and matched the gross measurements of each specimen. The MT hyperintense rim matched the cellular component of the tuberculoma that was masked on T2-weighted images because of the associated perifocal oedema. The cellular component had a lower MT ratio compared to the necrotic components. CONCLUSION: The outer hyperintense rim and hyperintense strands are due to the cellular infiltrate, noncaseating granulomas, and gliosis while the hypointense core represents solid caseation. The cellular outer rim shows lower MT ratio compared to the core of the tuberculoma. Histological correlation of the cellular and necrotic components of tuberculomas is best shown with MT T1 imaging. Gupta R. K.et al. (2001)Clinical Radiology,56, 656–663.

The purpose of this study was to establish magnetization transfer ratio (MTR) in different stages of neurocysticercosis. A total 2,532 cysticerci were studied prospectively in 15 cases. MTR from different regions of the lesions (ie, the cyst, the protoscolex or mural nodule, the granuloma wall) were calculated in different stages of evolution/degeneration in all cases. Of a total 2,532 lesions studied, 2,261 (89.29%) were seen on routine spin‐echo (SE) imaging. The rest of the lesions were only seen on magnetization transfer (MT) SE imaging. Maximum MTR was calculated from healing lesions (mean + SD = 31.0 ± 2.8) and from the core of SE invisible lesions (30.0 ± 5.1). Innocuous cystic lesions, which were hyperintense on T2‐weighted images, did not show any MT (MTR = 5.10 ± 1.2), whereas degenerating T2 hyperintense lesions showed MTR of 26.40 ± 2.7. Nondegenerating and degenerating scolices showed an intermediate MTR of 21.7 ± 3.3 and 15.0 ± 4.5, respectively. MT varies between different parts of the lesion and also from the same part in different stages of evolution/degeneration of the lesion. The visibility of a lesion on MT‐SE sequence was dependent on its MTR and its location at a particular site (cortical gray matter, white matter, or deep gray matter). The difference in MTR of the lesion and the surrounding brain parenchyma decides the resulting contrast and visibility of the lesion.

Thixoforming is a forming process which exploits metal rheological behaviour during solidus and liquidus range temperature. Many research works in thixoforming are currently focusing on the raw material used to produce superior mechanical properties and excellent formability components, especially in automotive industries. Furthermore, the thixoforming process also produced less casting defect component such as macrosegration, shrinkage and porosity. These advantages are sufficient to attract more exploration works of thixoforming operation. However, the weakness of this process such as high production cost due to leftover billet which cannot be recycled, encourage researcher works to overcome thixoforming limitations by using various methods. The thixoforming methods that widely used are thixocasting, thixoforging, thixorolling, thixoextrusion and thixomoulding. Each method provides varieties of final product characteristics; hence offer the extensive possibility of component invention. On the other hand, new thixoforming method leads to exploration research such as microstructure evolution, heating and pouring temperature, die temperature, mechanical properties, viscosity and final product quality. This review paper presents findings in the rheological material behaviour of thixoforming, advantages and disadvantanges of thixoforming, parameters affecting the thixoforming operation, morphology of thixoforming and various methods which have been used in this research area.

Background: Genetic association studies have linked occurrence of asthma with ADAM33 gene polymorphisms in different populations, but none from India. Such studies will improve individualized case management strategies over time.Objectives:Primary: To assess association of ADAM33 gene polymorphisms (F+1 G/A, S2 G/C, ST+4 A/C, ST+5 C/T, V4 C/G) with asthma.Secondary: Among asthmatics, to assess association of hospitalization, family history and severity of asthma and environmental exposure with ADAM33 gene polymorphisms.Study design: Case-control.Methods: Diagnosis of asthma was done according to GINA guidelines 2007. Controls were age and sex matched non-relatives of cases without any respiratory disease. Genotyping was done with PCR-RFLP method.Results: From August 2007 to November 2009, 211 cases (aged 74.4 months ±4.6, with 32.2% females) and 137 controls (aged 73.6 months±42.6, with 29.9% females) were recruited. Distributions of S2, ST+5 and F+1 genotypes were statistically significantly different, while allele frequencies were statistically significantly different for all 5 markers between cases and controls (p< 0.05). In ST+5 total hospitalization rate was high among cases with wild & hetero genotype [OR =3.75(95% CI: 1.33-1.63), p < 0.05]. Significant association of ST+4 wild and hetero [OR=4.147(95% CI: 1.52-11.33), p < 0.05] and ST+5 hetero [OR=2.77(.99-7.95), p < 0.05] genotypes was observed with positive family history patients. No association was found of ADAM33 gene polymorphisms genotypes in cases with severity of asthma or environmental exposure to pollutants.Conclusion: The SNPs (F+1 G/A, S2 G/C, ST+4 A/C, ST+5 C/T, V4 C/G) of the ADAM33 gene are associated with asthma.