Antimicrobial effects of copper(II) bis(thiosemicarbazonato) complexes provide new insight into their biochemical mode of action

The copper(II) complexes of bis-thiosemicarbazones (Cu(btsc)) such as Cu(atsm) and Cu(gtsm) are neutral, lipophilic compounds that show promise as therapeutics for the treatment of certain neurological diseases and cancers. Although the effects of these compounds have been described at the cellular level, there is almost no information about their biochemical mode of action. In this work, we showed that Cu(atsm) and Cu(gtsm) displayed antimicrobial activities against the human obligate pathogen Neisseria gonorrhoeae that were more than 100 times more potent than Cu(NO3)2 salt alone. Treatment with Cu(btsc) also produced phenotypes that were consistent with copper poisoning, but the levels of intracellular copper were undetectable by ICP MS. We observed that Cu(btsc) interacted with proteins in the cell membrane. Systematic measurements of O2 uptake further demonstrated that treatment with both Cu(atsm) and Cu(gtsm) led to dose-dependent inhibition of respiratory electron transfer processes via succinate and NADH dehydrogenases. These dehydrogenases were not inhibited by a non-btsc source of CuII. The results led us to conclude that the biochemical mechanism of Cu(btsc) action is likely more complex than the present, simplistic model of copper release into the cytoplasm

Metal complexes designed to bind to amyloid-β for the diagnosis and treatment of Alzheimer\u27s disease

Alzheimer\u27s disease is the most common form of age-related neurodegenerative dementia. The disease is characterised by the presence of plaques in the cerebral cortex. The major constituent of these plaques is aggregated amyloid-β peptide. This review focuses on the molecular aspects of metal complexes designed to bind to amyloid-β. The development of radioactive metal-based complexes of copper and technetium designed as diagnostic imaging agents to detect amyloid burden in the brain is discussed. Separate sections of the review discuss the use of luminescent metal complexes to act as non-conventional probes of amyloid formation and recent research into the use of metal complexes as inhibitors of amyloid formation and toxicity

Adding depth to overlapping displays can improve visual search performance

Standard models of visual search have focused upon asking participants to search for a single target in displays where the objects do not overlap one another, and where the objects are presented on a single depth plane. This stands in contrast to many everyday visual searches wherein variations in overlap and depth are the norm, rather than the exception. Here, we addressed whether presenting overlapping objects on different depths planes to one another can improve search performance. Across four different experiments using different stimulus types (opaque polygons, transparent polygons, opaque real-world objects, and transparent X-ray images), we found that depth was primarily beneficial when the displays were transparent, and this benefit arose in terms of an increase in response accuracy. Although the benefit to search performance only appeared in some cases, across all stimulus types, we found evidence of marked shifts in eye-movement behavior. Our results have important implications for current models and theories of visual search, which have not yet provided detailed accounts of the effects that overlap and depth have on guidance and object identification processes. Moreover, our results show that the presence of depth information could aid real-world searches of complex, overlapping displays

Copper(II)-Bis(Thiosemicarbazonato) Complexes as Antibacterial Agents: Insights into Their Mode of Action and Potential as Therapeutics

There is increasing interest in the use of lipophilic copper (Cu)-containing complexes to combat bacterial infections. In this work, we showed that Cu complexes with bis(thiosemicarbazone) ligands [Cu(btsc)] exert antibacterial activity against a range of medically significant pathogens. Previous work using Neisseria gonorrhoeae showed that Cu(btsc) complexes may act as inhibitors of respiratory dehydrogenases in the electron transport chain. We now show that these complexes are also toxic against pathogens that lack a respiratory chain. Respiration in Escherichia coli was slightly affected by Cu(btsc) complexes, but our results indicate that, in this model bacterium, the complexes act primarily as agents that deliver toxic Cu ions efficiently into the cytoplasm. Although the chemistry of Cu(btsc) complexes may dictate their mechanism of action, their efficacy depends heavily on bacterial physiology. This is linked to the ability of the target bacterium to tolerate Cu and, additionally, the susceptibility of the respiratory chain to direct inhibition by Cu(btsc) complexes. The physiology of N. gonorrhoeae, including multidrug-resistant strains, makes it highly susceptible to damage by Cu ions and Cu(btsc) complexes, highlighting the potential of Cu(btsc) complexes (and Cu-based therapeutics) as a promising treatment against this important bacterial pathogen

Multiply-connected Bose-Einstein condensed alkali gases: Current-carrying states and their decay

The ability to support metastable current-carrying states in multiply-connected settings is one of the prime signatures of superfluidity. Such states are investigated theoretically for the case of trapped Bose condensed alkali gases, particularly with regard to the rate at which they decay via thermal fluctuations. The lifetimes of metastable currents can be either longer or shorter than experimental time-scales. A scheme for the experimental detection of metastable states is sketched.Comment: 4 pages, including 1 figure (REVTEX

Tuning sensitivity to IL-4 and IL-13: differential expression of IL-4Rα, IL-13Rα1, and γc regulates relative cytokine sensitivity

Interleukin (IL)-4 and -13 are related cytokines sharing functional receptors. IL-4 signals through the type I (IL-4Rα/common γ-chain [γc]) and the type II (IL-4Rα/-13Rα1) IL-4 receptors, whereas IL-13 utilizes only the type II receptor. In this study, we show that mouse bone marrow–derived macrophages and human and mouse monocytes showed a much greater sensitivity to IL-4 than to IL-13. Lack of functional γc made these cells poorly responsive to IL-4, while retaining full responsiveness to IL-13. In mouse peritoneal macrophages, IL-4 potency exceeds that of IL-13, but lack of γc had only a modest effect on IL-4 signaling. In contrast, IL-13 stimulated greater responses than IL-4 in fibroblasts. Using levels of receptor chain expression and known binding affinities, we modeled the assemblage of functional type I and II receptor complexes. The differential expression of IL-4Rα, IL-13Rα1, and γc accounted for the distinct IL-4–IL-13 sensitivities of the various cell types. These findings provide an explanation for IL-13's principal function as an “effector” cytokine and IL-4's principal role as an “immunoregulatory” cytokine

Arbuscular mycorrhizal response to adverse soil conditions

Adverse conditions are a pervasive feature in both natural as well as agronomic soils. The soil environment is constantly changing with regard to moisture, temperature and nutrition. In addition, soil properties such as fertility, pH and aeration are often changed to improve crop yields. Soils have been unintentionally contaminated as a result of accidents that occur during agronomic operations or intentionally contaminated in mining or manufacturing operations by disposal of chemicals that are toxic to plants and micro-organisms. Mycorrhizal associations in terrestrial ecosystems influence organic and inorganic nutrient relationships, water relations and carbon cycling in plants. Relatively little is known about factors that control the vigour and extent of mycorrhization. This lack of understanding arises in large part from the difficulty of studying the intact association, which is a functionally and anatomically distinct structure comprising two biologically different organisms, e.g., plants and arbuscular mycorrhizae (AM) fungi. The formation and function of mycorrhizal relationships are affected by edaphic conditions such as soil composition, moisture, temperature, pH, cation exchange capacity. They are also affected by anthropogenic stressers such as heavy metals, pesticides and soil compaction. An organism's response to stress may involve interactions among various avoidance and tolerance mechanisms (Taylor, 1978; Tingey and Taylor, 1982; Tingey and Anderson, 1991). Stress avoidance mechanisms influence the amount and rate at which stress will reach the target site in the plant. Stress tolerance is defined as resistance via an ability "to come to thermodynamic equilibrium to the stress" without being killed (Levitt, 1980). In this chapter, we shall review the effects of a number of soil-associated stressers, including soil moisture, temperature, pH, heavy metals, agricultural practices and pesticides on AM development and function and host plant tolerance to these stresses. Several publications have reviewed the impact of various stresses on plant-mycorrhizal interactions (Anderson and Rygiewicz, 1991; Read, 1991; Van Duin et al, 1991; Sylvia and Williams, 1992), which provide additional information on this subject

Influence of adverse soil conditions on the formation and function of Arbuscular mycorrhizas

The majority of plants have mycorrhizal fungi associated with them. Mycorrhizal fungi are ecologically significant because they form relationships in and on the roots of a host plant in a symbiotic association. The host plant provides the fungus with soluble carbon sources, and the fungus provides the host plant with an increased capacity to absorb water and nutrients from the soil. Adverse conditions are a pervasive feature in both natural and agronomic soils. The soil environment is constantly changing with regard to moisture, temperature and nutrient availability. In addition, soil properties are often manipulated to improve crop yields. In many cases, soils may be contaminated through disposal of chemicals that are toxic to plants and microorganisms. The formation and function of mycorrhizal relationships are affected by edaphic conditions such as soil composition, moisture, temperature, pH, cation exchange capacity, and also by anthropogenic stressors including soil compaction, metals and pesticides. Arbuscular mycorrhizal fungi are of interest for their reported roles in alleviation of diverse soil-associated plant stressors, including those induced by metals and polychlorinated aliphatic and phenolic pollutants. Much mycorrhizal research has investigated the impact of extremes in water, temperature, pH and inorganic nutrient availability on mycorrhizal formation and nutrient acquisition. Evaluation of the efficacy of plant–mycorrhizal associations to remediate soils contaminated with toxic materials deserves increased attention. Before the full potential benefits of arbuscular mycorrhizal fungi to reclaim contaminated soils can be realized, research advances are needed to improve our understanding of the physiology of mycorrhizae subjected to adverse physical and chemical conditions. This paper will review literature and discuss the implications of soil contamination on formation and function of arbuscular mycorrhizal associations

New perspectives on the annihilation electrogenerated chemiluminescence of mixed metal complexes in solution

Preliminary explorations of the annihilation electrogenerated chemiluminescence (ECL) of mixed metal complexes have revealed opportunities to enhance emission intensities and control the relative intensities from multiple luminophores through the applied potentials. However, the mechanisms of these systems are only poorly understood. Herein, we present a comprehensive characterisation of the annihilation ECL of mixtures of tris(2,2′-bipyridine)ruthenium(ii) hexafluorophosphate ([Ru(bpy)3](PF6)2) and fac-tris(2-phenylpyridine)iridium(iii) ([Ir(ppy)3]). This includes a detailed investigation of the change in emission intensity from each luminophore as a function of both the applied electrochemical potentials and the relative concentrations of the two complexes, and a direct comparison with two mixed (Ru/Ir) ECL systems for which emission from only the ruthenium-complex was previously reported. Concomitant emission from both luminophores was observed in all three systems, but only when: (1) the applied potentials were sufficient to generate the intermediates required to form the electronically excited state of both complexes; and (2) the concentration of the iridium complex (relative to the ruthenium complex) was sufficient to overcome quenching processes. Both enhancement and quenching of the ECL of the ruthenium complex was observed, depending on the experimental conditions. The observations were rationalised through several complementary mechanisms, including resonance energy transfer and various energetically favourable electron-transfer pathways

ZnII(atsm) is protective in amyotrophic lateral sclerosis model mice via a copper delivery mechanism

AbstractMutations in the metalloprotein Cu,Zn-superoxide dismutase (SOD1) cause approximately 20% of familial cases of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease for which effective therapeutics do not yet exist. Transgenic rodent models based on over-expression of mutant SOD1 have been developed and these have provided opportunity to test new therapeutic strategies and to study the mechanisms of mutant SOD1 toxicity. Although the mechanisms of mutant SOD1 toxicity are yet to be fully elucidated, incorrect or incomplete metallation of SOD1 confers abnormal folding, aggregation and biochemical properties, and improving the metallation state of SOD1 provides a viable therapeutic option. The therapeutic effects of delivering copper (Cu) to mutant SOD1 have been demonstrated recently. The aim of the current study was to determine if delivery of zinc (Zn) to SOD1 was also therapeutic. To investigate this, SOD1G37R mice were treated with the metal complex diacetyl-bis(4-methylthiosemicarbazonato)zincII [ZnII(atsm)]. Treatment resulted in an improvement in locomotor function and survival of the mice. However, biochemical analysis of spinal cord tissue collected from the mice revealed that the treatment did not increase overall Zn levels in the spinal cord nor the Zn content of SOD1. In contrast, overall levels of Cu in the spinal cord were elevated in the ZnII(atsm)-treated SOD1G37R mice and the Cu content of SOD1 was also elevated. Further experiments demonstrated transmetallation of ZnII(atsm) in the presence of Cu to form the Cu-analogue CuII(atsm), indicating that the observed therapeutic effects for ZnII(atsm) in SOD1G37R mice may in fact be due to in vivo transmetallation and subsequent delivery of Cu