Extracellular Electron Transfer: Respiratory or Nutrient Homeostasis?

Exoelectrogens are able to transfer electrons extracellularly, enabling them to respire on insoluble terminal electron acceptors. Extensively studied exoelectrogens, such as Geobacter sulfurreducens and Shewanella oneidensis, are Gram negative. More recently, it has been reported that Gram-positive bacteria, such as Listeria monocytogenes and Enterococcus faecalis, also exhibit the ability to transfer electrons extracellularly, although it is still unclear whether this has a function in respiration or in redox control of the environment, for instance, by reducing ferric iron for iron uptake. In this issue of Journal of Bacteriology, Hederstedt and colleagues report on experiments that directly compare extracellular electron transfer (EET) pathways for ferric iron reduction and respiration and find a clear difference (L. Hederstedt, L. Gorton, and G. Pankratova, J Bacteriol 202:e00725-19, 2020, https://doi.org/10.1128/JB.00725-19), providing further insights and new questions into the function and metabolic pathways of EET in Gram-positive bacteria

Bacterial respiration keeps amazing us in the 21st century

Macromolecular Biochemistr

'It's always difficult when it's family. . . whereas when you're talking to a therapist. . .': Parents' views of cognitive-behaviour therapy for depressed adolescents

BACKGROUND: Parents are key to helping their adolescent child access psychological therapy for mental health problems such as depression. However, little is known about how parents experience their child's psychological therapy. We aimed to explore parents' experiences of their adolescent child's cognitive behaviour therapy for depression. METHOD: We applied Thematic Analysis (TA) to qualitative data from in-depth interviews with parents (N = 16) whose adolescent child was randomly allocated to CBT in a large multisite RCT for adolescent depression (the IMPACT trial). Interviews were conducted at the end of treatment. RESULTS: We generated two main themes: parents' perceptions of the adolescent's journey through therapy, and parents' perceptions of the therapeutic setting and process. Each included four sub-themes. Parents talked about key factors that impacted on their child's progress through treatment, including the adolescent's readiness for therapy and the adolescent-therapist relationship. CONCLUSION: Parents' insights confirm the foundations of what is considered good clinical practice of CBT for adolescent depression, including tailoring therapy to the adolescent, and establishing a strong adolescent-therapist relationship. Parents recognised that, for CBT to be helpful, their child had to be willing to engage in therapy and able to develop a trusting relationship with their therapist

Compositional characteristics and spatial distribution of enriched Icelandic mantle components

Author Posting. © The Authors, 2010. This is the author's version of the work. It is posted here by permission of Oxford University Press for personal use, not for redistribution. The definitive version was published in Journal of Petrology 51 (2010): 1447-1475, doi:10.1093/petrology/egq025.We present compositional data on a suite of 18 primitive neovolcanic alkali basalts from three flank zone regions in Iceland (Vestmannaeyjar in the south, Snæfell in the east, and Snæfellsnes in the west) that are peripheral to the main rift zones that are dominated by tholeiitic basalts. This study integrates He isotope data with radiogenic isotope data (Sr-Nd-Pb-Hf), stable isotope data (δ18O), and trace element data to characterise the compositional features of the trace-elementenriched components of the Icelandic mantle. We also present high-precision Pb isotope data on an additional 57 lava samples from the flank zones (including Öræfajökull in the south-east) and the Northern and Eastern rift zones. Most Icelandic lavas have negative Δ207Pb (–4 to –1), with higher values (–1 to +4) found only in samples from Öræfajökull, Snæfell, and parts of the Reykjanes Peninsula. At Snæfell, this EM1-type component is characterised by a low δ18Oolivine signature (+4.1‰ to +4.6‰), moderate 206Pb/204Pb values (18.4-18.6) and MORB-like 3He/4He (6.9-7.5 R/RA). Samples from Vestmannaeyjar and Snæfellsnes have mantle-like δ18Oolivine (+4.9‰ to +5.0‰), and radiogenic 206Pb/204Pb values (18.9-19.3) that fall on the NHRL for 208Pb/204Pb (Δ208Pb –5 to +5). Compared to the Vestmannaeyjar lavas, Snæfellsnes lavas have higher La/YbN (5-11 vs. 3-5), lower εNd (5.5-6.5 vs. 6.8-7.6) and lower 3He/4He (6.3-8.6 R/RA vs. 11.4-13.5 R/RA). Therefore, the most trace element enriched components in the Icelandic mantle are not the carriers of the high 3He/4He values (> 15 R/RA) found in some lavas on Iceland and the adjacent ridges, and instead are consistent with degassed, recycled components. Even after excluding the EM1-type high Δ207Pb samples, high-precision Pb isotope data produce a kinked array on an 206Pb/204Pb vs. 208Pb/204Pb plot, which is not consistent with simple binary mixing between two end-members. This requires significant lateral heterogeneity within the Icelandic mantle and the presence of more than just two compositionally-distinct local mixing end-member components. Samples from each of the main axial rift zones define different trends. Despite the tectonic continuity between the Northern Volcanic Zone and the Eastern Volcanic Zone, lavas from these two rift zones define separate sub-parallel linear arrays. Lavas from the adjacent Western Volcanic Zone and the Eastern Volcanic Zone define oblique linear arrays that converge on a common local end-member that is not involved in the magmatism of the Northern Volcanic Zone. Therefore, there is a distinct NE-SW compositional heterogeneity within the Icelandic mantle.work was funded primarily by the Danish National Research Foundation through a grant to the former Danish Lithosphere Centre, with additional funding from the University of Iowa for the oxygen isotope analyses

Multiple bactericidal mechanisms of the zinc ionophore PBT2

Published 18 March 2020Globally, more antimicrobials are used in food-producing animals than in humans, and the extensive use of medically important human antimicrobials poses a significant public health threat in the face of rising antimicrobial resistance (AMR). The development of novel ionophores, a class of antimicrobials used exclusively in animals, holds promise as a strategy to replace or reduce essential human antimicrobials in veterinary practice. PBT2 is a zinc ionophore with recently demonstrated antibacterial activity against several Gram-positive pathogens, although the underlying mechanism of action is unknown. Here, we investigated the bactericidal mechanism of PBT2 in the bovine mastitis-causing pathogen, Streptococcus uberis In this work, we show that PBT2 functions as a Zn2+/H+ ionophore, exchanging extracellular zinc for intracellular protons in an electroneutral process that leads to cellular zinc accumulation. Zinc accumulation occurs concomitantly with manganese depletion and the production of reactive oxygen species (ROS). PBT2 inhibits the activity of the manganese-dependent superoxide dismutase, SodA, thereby impairing oxidative stress protection. We propose that PBT2-mediated intracellular zinc toxicity in S. uberis leads to lethality through multiple bactericidal mechanisms: the production of toxic ROS and the impairment of manganese-dependent antioxidant functions. Collectively, these data show that PBT2 represents a new class of antibacterial ionophores capable of targeting bacterial metal ion homeostasis and cellular redox balance. We propose that this novel and multitarget mechanism of PBT2 makes the development of cross-resistance to medically important antimicrobials unlikely.IMPORTANCE More antimicrobials are used in food-producing animals than in humans, and the extensive use of medically important human antimicrobials poses a significant public health threat in the face of rising antimicrobial resistance. Therefore, the elimination of antimicrobial crossover between human and veterinary medicine is of great interest. Unfortunately, the development of new antimicrobials is an expensive high-risk process fraught with difficulties. The repurposing of chemical agents provides a solution to this problem, and while many have not been originally developed as antimicrobials, they have been proven safe in clinical trials. PBT2, a zinc ionophore, is an experimental therapeutic that met safety criteria but failed efficacy checkpoints against both Alzheimer's and Huntington's diseases. It was recently found that PBT2 possessed potent antimicrobial activity, although the mechanism of bacterial cell death is unresolved. In this body of work, we show that PBT2 has multiple mechanisms of antimicrobial action, making the development of PBT2 resistance unlikely.Nichaela Harbison-Price, Scott A. Ferguson, Adam Heikal, George Taiaroa, Kiel Hards ... Christopher A. McDevitt ... et al

Plasticity of the Mycobacterium tuberculosis respiratory chain and its impact on tuberculosis drug development.

The viability of Mycobacterium tuberculosis (Mtb) depends on energy generated by its respiratory chain. Cytochrome bc1-aa3 oxidase and type-2 NADH dehydrogenase (NDH-2) are respiratory chain components predicted to be essential, and are currently targeted for drug development. Here we demonstrate that an Mtb cytochrome bc1-aa3 oxidase deletion mutant is viable and only partially attenuated in mice. Moreover, treatment of Mtb-infected marmosets with a cytochrome bc1-aa3 oxidase inhibitor controls disease progression and reduces lesion-associated inflammation, but most lesions become cavitary. Deletion of both NDH-2 encoding genes (Δndh-2 mutant) reveals that the essentiality of NDH-2 as shown in standard growth media is due to the presence of fatty acids. The Δndh-2 mutant is only mildly attenuated in mice and not differently susceptible to clofazimine, a drug in clinical use proposed to engage NDH-2. These results demonstrate the intrinsic plasticity of Mtb's respiratory chain, and highlight the challenges associated with targeting the pathogen's respiratory enzymes for tuberculosis drug development

Tumor-specific expression of αvβ3 integrin promotes spontaneous metastasis of breast cancer to bone

INTRODUCTION: Studies in xenograft models and experimental models of metastasis have implicated several β3 integrin-expressing cell populations, including endothelium, platelets and osteoclasts, in breast tumor progression. Since orthotopic human xenograft models of breast cancer are poorly metastatic to bone and experimental models bypass the formation of a primary tumor, however, the precise contribution of tumor-specific αvβ3 to the spontaneous metastasis of breast tumors from the mammary gland to bone remains unclear. METHODS: We used a syngeneic orthotopic model of spontaneous breast cancer metastasis to test whether exogenous expression of αvβ3 in a mammary carcinoma line (66cl4) that metastasizes to the lung, but not to bone, was sufficient to promote its spontaneous metastasis to bone from the mammary gland. The tumor burden in the spine and the lung following inoculation of αvβ3-expressing 66cl4 (66cl4beta3) tumor cells or control 66cl4pBabe into the mammary gland was analyzed by real-time quantitative PCR. The ability of these cells to grow and form osteolytic lesions in bone was determined by histology and tartrate-resistant acid phosphatase staining of bone sections following intratibial injection of tumor cells. The adhesive, migratory and invasive properties of 66cl4pBabe and 66cl4beta3 cells were evaluated in standard in vitro assays. RESULTS: The 66cl4beta3 tumors showed a 20-fold increase in metastatic burden in the spine compared with 66cl4pBabe. A similar trend in lung metastasis was observed. αvβ3 did not increase the proliferation of 66cl4 cells in vitro or in the mammary gland in vivo. Similarly, αvβ3 is not required for the proliferation of 66cl4 cells in bone as both 66cl4pBabe and 66cl4beta3 proliferated to the same extent when injected directly into the tibia. 66cl4beta3 tumor growth in the tibia, however, increased osteoclast recruitment and bone resorption compared with 66cl4 tumors. Moreover, αvβ3 increased 66cl4 tumor cell adhesion and αvβ3-dependent haptotactic migration towards bone matrix proteins, as well as their chemotactic response to bone-derived soluble factors in vitro. CONCLUSION: These results demonstrate for the first time that tumor-specific αvβ3 contributes to spontaneous metastasis of breast tumors to bone and suggest a critical role for this receptor in mediating chemotactic and haptotactic migration towards bone factors