Polarized cell motility induces hydrogen peroxide to inhibit cofilin via cysteine oxidation

Mesenchymal cell motility is driven by polarized actin polymerization [1]. Signals at the leading edge recruit actin polymerization machinery to promote membrane protrusion, while matrix adhesion generates tractive force to propel forward movement. To work effectively, cell motility is regulated by a complex network of signaling events that affect protein activity and localization. H2O2 has an important role as a diffusible second messenger [2], and mediates its effects through oxidation of cysteine thiols. One cell activity influenced by H2O2 is motility [3]. However, a lack of sensitive and H2O2-specific probes for measurements in live cells has not allowed for direct observation of H2O2 accumulation in migrating cells or protrusions. In addition, the identities of proteins oxidized by H2O2 that contribute to actin dynamics and cell motility have not been characterized. We now show, as determined by fluorescence lifetime imaging microscopy, that motile cells generate H2O2 at membranes and cell protrusions and that H2O2 inhibits cofilin activity through oxidation of cysteines 139 (C139) and 147 (C147). Molecular modeling suggests that C139 oxidation would sterically hinder actin association, while the increased negative charge of oxidized C147 would lead to electrostatic repulsion of the opposite negatively charged surface. Expression of oxidation-resistant cofilin impairs cell spreading, adhesion, and directional migration. These findings indicate that H2O2 production contributes to polarized cell motility through localized cofilin inhibition and that there are additional proteins oxidized during cell migration that might have similar roles

Tracking a northern fulmar from a Scottish nesting site to the Charlie-Gibbs Fracture Zone : Evidence of linkage between coastal breeding seabirds and Mid-Atlantic Ridge feeding sites

Peer reviewedPublisher PD

Dressed Bose-Einstein Condensates in High-Q Cavities

We propose and analyze a way in which effective multicomponent condensates can be created inside high-Q multimode cavities. In contrast to the situation involving several atomic species or levels, the coupling between the various components of the dressed condensates is linear. We predict analytically and numerically confirm the onset of instabilities in the quasiparticle excitation spectrum.Comment: plain tex, 20 pages, 4 figure

Optical dipole traps and atomic waveguides based on Bessel light beams

We theoretically investigate the use of Bessel light beams generated using axicons for creating optical dipole traps for cold atoms and atomic waveguiding. Zeroth-order Bessel beams can be used to produce highly elongated dipole traps allowing for the study of one-dimensional trapped gases and realization of a Tonks gas of impentrable bosons. First-order Bessel beams are shown to be able to produce tight confined atomic waveguides over centimeter distances.Comment: 20 pages, 5 figures, to appear in Phys. Rev.

Exploring the Effect of Human and Animal Population Growth on Vector-Borne Disease Transmission with an Agent-Based Model of Rhodesian Human African Trypanosomiasis in Eastern Province, Zambia

This paper presents the development of an agent-based model (ABM) to investigate Trypanosoma brucei rhodesiense human African trypanosomiasis (rHAT) disease transmission. The ABM model, fitted at a fine spatial scale, was used to explore the impact of a growing host population on the spread of disease along a 75 km transect in the Luangwa Valley, Zambia. The model was used to gain a greater understanding of how increases in human and domestic animal population could impact the contact network between vector and host, the subsequent transmission patterns, and disease incidence outcomes in the region. Modelled incidence rates showed increases in rHAT transmission in both humans and cattle. The primary demographic attribution of infection switched dramatically from young children of both sexes attending school, to adult women performing activities with shorter but more frequent trips, such as water and firewood collection, with men more protected due to the presence of cattle in their routines. The interpretation of model output provides a plausible insight into both population development and disease transmission in the near future in the region and such techniques could aid well-targeted mitigation strategies in the future

Exploring the Effect of Human and Animal Population Growth on Vector-Borne Disease Transmission with an Agent-Based Model of Rhodesian Human African Trypanosomiasis in Eastern Province, Zambia

This paper presents the development of an agent-based model (ABM) to investigate Trypanosoma brucei rhodesiense human African trypanosomiasis (rHAT) disease transmission. The ABM model, fitted at a fine spatial scale, was used to explore the impact of a growing host population on the spread of disease along a 75 km transect in the Luangwa Valley, Zambia. The model was used to gain a greater understanding of how increases in human and domestic animal population could impact the contact network between vector and host, the subsequent transmission patterns, and disease incidence outcomes in the region. Modelled incidence rates showed increases in rHAT transmission in both humans and cattle. The primary demographic attribution of infection switched dramatically from young children of both sexes attending school, to adult women performing activities with shorter but more frequent trips, such as water and firewood collection, with men more protected due to the presence of cattle in their routines. The interpretation of model output provides a plausible insight into both population development and disease transmission in the near future in the region and such techniques could aid well-targeted mitigation strategies in the future

Sodalis glossinidius prevalence and trypanosome presence in tsetse from Luambe National Park, Zambia

Background Tsetse flies are the biological vectors of African trypanosomes, the causative agents of sleeping sickness in humans and nagana in animals. The tsetse endosymbiont Sodalis glossinidius has been suggested to play a role in tsetse susceptibility to infection. Here we investigate the prevalence of African trypanosomes within tsetse from the Luambe National Park, Zambia and if there is an association between S. glossinidius and presence of trypanosomes within the tsetse examined. Methods Tsetse representing three species (Glossina brevipalpis, Glossina morsitans morsitans and Glossina pallidipes), were sampled from Luambe National Park, Zambia. Following DNA extraction, PCR was used to examine the tsetse for presence of trypanosomes and the secondary endosymbiont S. glossinidius. Results S. glossinidius infection rates varied significantly between tsetse species, with G. brevipalpis (93.7%) showing the highest levels of infection followed by G. m. morsitans (17.5%) and G. pallidipes (1.4%). ITS-PCR detected a wide variety of trypanosomes within the tsetse that were analysed. Significant differences were found in terms of trypanosome presence between the three tsetse species. A high proportion of G. m. morsitans were shown to carry T. brucei s.l. DNA (73.7%) and of these around 50% were positive for Trypanosoma brucei rhodesiense. T. vivax, T. godfreyi, T. simiae, T. simiae Tsavo and T. congolense were also detected. No association was found between the occurrence of S. glossinidius and the presence of trypanosome DNA in any of the three tsetse species tested. Conclusion The current work shows that T. b. rhodesiense was circulating in Luambe National Park, representing a risk for people living in the park or surrounding area and for tourists visiting the park. The differences in trypanosome DNA presence observed between the different tsetse species tested may indicate host feeding preferences, as the PCR will not discriminate between a fly with an active/resident infection compared to a refractory fly that has fed on an infected animal. This makes it difficult to establish if S. glossinidius may play a role in the susceptibility of tsetse flies to trypanosome infection. Keywords: Glossina; Rhodesiense; Wildlife; Morsitans; Pallidipes; BrevipalpisRoyal Zoological Society of Scotland. United Kingdom Department for International Development Animal Health Programme (DFID-AHP)

Intravital FRAP imaging using an E-cadherin-GFP mouse reveals disease- and drug-dependent dynamic regulation of cell-cell junctions in live tissue

E-cadherin-mediated cell-cell junctions play a prominent role in maintaining the epithelial architecture. The disruption or deregulation of these adhesions in cancer can lead to the collapse of tumor epithelia that precedes invasion and subsequent metastasis. Here we generated an E-cadherin-GFP mouse that enables intravital photobleaching and quantification of E-cadherin mobility in live tissue without affecting normal biology. We demonstrate the broad applications of this mouse by examining E-cadherin regulation in multiple tissues, including mammary, brain, liver, and kidney tissue, while specifically monitoring E-cadherin mobility during disease progression in the pancreas. We assess E-cadherin stability in native pancreatic tissue upon genetic manipulation involving Kras and p53 or in response to anti-invasive drug treatment and gain insights into the dynamic remodeling of E-cadherin during in situ cancer progression. FRAP in the E-cadherin-GFP mouse, therefore, promises to be a valuable tool to fundamentally expand our understanding of E-cadherin-mediated events in native microenvironments

Resolving Salmonella infection reveals dynamic and persisting changes in murine bone marrow progenitor cell phenotype and function

The generation of immune cells from BM precursors is a carefully regulated process. This is essential to limit the potential for oncogenesis and autoimmunity yet protect against infection. How infection modulates this is unclear. Salmonella can colonize systemic sites including the BM and spleen. This resolving infection has multiple IFN-γ-mediated acute and chronic effects on BM progenitors, and during the first week of infection IFN-γ is produced by myeloid, NK, NKT, CD4+ T cells, and some lineage-negative cells. After infection, the phenotype of BM progenitors rapidly but reversibly alters, with a peak ∼30-fold increase in Sca-1hi progenitors and a corresponding loss of Sca-1lo/int subsets. Most strikingly, the capacity of donor Sca-1hi cells to reconstitute an irradiated host is reduced; the longer donor mice are exposed to infection, and Sca-1hic-kitint cells have an increased potential to generate B1a-like cells. Thus, Salmonella can have a prolonged influence on BM progenitor functionality not directly related to bacterial persistence. These results reflect changes observed in leucopoiesis during aging and suggest that BM functionality can be modulated by life-long, periodic exposure to infection. Better understanding of this process could offer novel therapeutic opportunities to modulate BM functionality and promote healthy aging