Verticalization of bacterial biofilms

Biofilms are communities of bacteria adhered to surfaces. Recently, biofilms of rod-shaped bacteria were observed at single-cell resolution and shown to develop from a disordered, two-dimensional layer of founder cells into a three-dimensional structure with a vertically-aligned core. Here, we elucidate the physical mechanism underpinning this transition using a combination of agent-based and continuum modeling. We find that verticalization proceeds through a series of localized mechanical instabilities on the cellular scale. For short cells, these instabilities are primarily triggered by cell division, whereas long cells are more likely to be peeled off the surface by nearby vertical cells, creating an "inverse domino effect". The interplay between cell growth and cell verticalization gives rise to an exotic mechanical state in which the effective surface pressure becomes constant throughout the growing core of the biofilm surface layer. This dynamical isobaricity determines the expansion speed of a biofilm cluster and thereby governs how cells access the third dimension. In particular, theory predicts that a longer average cell length yields more rapidly expanding, flatter biofilms. We experimentally show that such changes in biofilm development occur by exploiting chemicals that modulate cell length.Comment: Main text 10 pages, 4 figures; Supplementary Information 35 pages, 15 figure

Protocol for a prospective collaborative systematic review and meta-analysis of individual patient data from randomised controlled trials of vasoactive drugs in acute stroke: the Blood pressure in Acute Stroke Collaboration, stage-3 (BASC-3)

Rationale Despite several large clinical trials assessing blood pressure lowering in acute stroke, equipoise remains, particularly for ischaemic stroke. The ‘Blood pressure in Acute Stroke Collaboration’ (BASC) commenced in the mid 1990s focusing on systematic reviews and meta-analysis of blood pressure lowering in acute stroke. From the start, BASC planned to assess safety and efficacy of blood pressure lowering in acute stroke using individual patient data. Aims To determine the optimal management of blood pressure in patients with acute stroke, encompassing both intracerebral haemorrhage and ischaemic stroke. Secondary aims are to assess which clinical and therapeutic factors may alter the optimal management of high blood pressure in patients with acute stroke and to assess the effect of vasoactive treatments on haemodynamic variables. Methods and design Individual patient data from randomised controlled trials of blood pressure management in participants with ischaemic stroke and/or intracerebral haemorrhage enrolled during the ultra-acute (pre-hospital), hyper-acute (<6 hours), acute (<48 hours) and sub-acute (<168 hours) phases of stroke. Study outcomes The primary effect variable will be functional outcome defined by the ordinal distribution of the modified Rankin Scale; analyses will also be carried out in prespecified subgroups to assess the modifying effects of stroke-related and pre-stroke patient characteristics. Key secondary variables will include clinical, haemodynamic and neuroradiological variables; safety variables will comprise death and serious adverse events. Discussion Study questions will be addressed in stages, according to the protocol, before integrating these into a final overreaching analysis. We invite eligible trials to join the collaboration

Competition and Complementarity in Diffusion: The Case of Octane

The standard ontogenic (life-cycle) model of technological evolution can be characterized briefly as follows (Ayres, 1987): (1) a radical invention (birth) creates a new technology; (2) it is commercialized on the basis of performance and rapidly developed by a series of improvements and modifications (infancy); (3) it is successful enough in the marketplace to attract many variants and imitators who hope to exploit a growing market (adolescence); (4) the pace of technological change finally slows down enough to permit standardization and exploitation of economies of scale, and competition on the basis of price rather than performance (maturity); and finally a new and better technology supplants it (senescence)

Acquired Type III Secretion System Determines Environmental Fitness of Epidemic Vibrio parahaemolyticus in the Interaction with Bacterivorous Protists

Genome analyses of marine microbial communities have revealed the widespread occurrence of genomic islands (GIs), many of which encode for protein secretion machineries described in the context of bacteria-eukaryote interactions. Yet experimental support for the specific roles of such GIs in aquatic community interactions remains scarce. Here, we test for the contribution of type III secretion systems (T3SS) to the environmental fitness of epidemic Vibrio parahaemolyticus. Comparisons of V. parahaemolyticus wild types and T3SS-defective mutants demonstrate that the T3SS encoded on genome island VPaI-7 (T3SS-2) promotes survival of V. parahaemolyticus in the interaction with diverse protist taxa. Enhanced persistence was found to be due to T3SS-2 mediated cytotoxicity and facultative parasitism of V. parahaemolyticus on coexisting protists. Growth in the presence of bacterivorous protists and the T3SS-2 genotype showed a strong correlation across environmental and clinical isolates of V. parahaemolyticus. Short-term microcosm experiments provide evidence that protistan hosts facilitate the invasion of T3SS-2 positive V. parahaemolyticus into a coastal plankton community, and that water temperature and productivity further promote enhanced survival of T3SS-2 positive V. parahaemolyticus. This study is the first to describe the fitness advantage of GI-encoded functions in a microbial food web, which may provide a mechanistic explanation for the global spread and the seasonal dynamics of V. parahaemolyticus pathotypes, including the pandemic serotype cluster O3:K6, in aquatic environments

Science-based health innovation in Ghana: health entrepreneurs point the way to a new development path

<p>Abstract</p> <p>Background</p> <p>Science, technology and innovation have long played a role in Ghana’s vision for development, including in improving its health outcomes. However, so far little research has been conducted on Ghana’s capacity for health innovation to address local diseases. This research aims to fill that gap, mapping out the key actors involved, highlighting examples of indigenous innovation, setting out the challenges ahead and outlining recommendations for strengthening Ghana’s health innovation system.</p> <p>Methods</p> <p>Case study research methodology was used. Data were collected through reviews of academic literature and policy documents and through open-ended, face-to-face interviews with 48 people from across the science-based health innovation system. Data was collected over three visits to Ghana from February 2007 to August 2008, and stakeholders engaged subsequently.</p> <p>Results</p> <p>Ghana has strengths which could underpin science-based health innovation in the future, including health and biosciences research institutions with strong foreign linkages and donor support; a relatively strong regulatory system which is building capacity in other West African countries; the beginnings of new funding forms such as venture capital; and the return of professionals from the diaspora, bringing expertise and contacts. Some health products and services are already being developed in Ghana by individual entrepreneurs, which are innovative in the sense of being new to the country and, in some cases, the continent. They include essential medicines, raw pharmaceutical materials, new formulations for pediatric use and plant medicines at various stages of development.</p> <p>Conclusions</p> <p>While Ghana has many institutions concerned with health research and its commercialization, their ability to work together to address clear health goals is low. If Ghana is to capitalize on its assets, including political and macroeconomic stability which underpin investment in health enterprises, it needs to improve the health innovation environment through increasing support for its small firms; coordinating policies; and beginning a dialogue with donors on how health research can create locally-owned knowledge and be more demand-driven. Mobilizing stakeholders around health product development areas, such as traditional medicines and diagnostics, would help to create trust between groups and build a stronger health innovation system.</p

Burkholderia Type VI Secretion Systems Have Distinct Roles in Eukaryotic and Bacterial Cell Interactions

Bacteria that live in the environment have evolved pathways specialized to defend against eukaryotic organisms or other bacteria. In this manuscript, we systematically examined the role of the five type VI secretion systems (T6SSs) of Burkholderia thailandensis (B. thai) in eukaryotic and bacterial cell interactions. Consistent with phylogenetic analyses comparing the distribution of the B. thai T6SSs with well-characterized bacterial and eukaryotic cell-targeting T6SSs, we found that T6SS-5 plays a critical role in the virulence of the organism in a murine melioidosis model, while a strain lacking the other four T6SSs remained as virulent as the wild-type. The function of T6SS-5 appeared to be specialized to the host and not related to an in vivo growth defect, as ΔT6SS-5 was fully virulent in mice lacking MyD88. Next we probed the role of the five systems in interbacterial interactions. From a group of 31 diverse bacteria, we identified several organisms that competed less effectively against wild-type B. thai than a strain lacking T6SS-1 function. Inactivation of T6SS-1 renders B. thai greatly more susceptible to cell contact-induced stasis by Pseudomonas putida, Pseudomonas fluorescens and Serratia proteamaculans—leaving it 100- to 1000-fold less fit than the wild-type in competition experiments with these organisms. Flow cell biofilm assays showed that T6S-dependent interbacterial interactions are likely relevant in the environment. B. thai cells lacking T6SS-1 were rapidly displaced in mixed biofilms with P. putida, whereas wild-type cells persisted and overran the competitor. Our data show that T6SSs within a single organism can have distinct functions in eukaryotic versus bacterial cell interactions. These systems are likely to be a decisive factor in the survival of bacterial cells of one species in intimate association with those of another, such as in polymicrobial communities present both in the environment and in many infections

The PTEN and INK4A/ARF tumor suppressors maintain myelolymphoid homeostasis and cooperate to constrain histiocytic sarcoma development in humans.

Histiocytic sarcoma (HS) is a rare malignant proliferation of histiocytes of uncertain molecular pathogenesis. Here, genetic analysis of coincident loss of Pten and Ink4a/Arf tumor suppressors in the mouse revealed a neoplastic phenotype dominated by a premalignant expansion of biphenotypic myelolymphoid cells followed by the development of HS. Pten protein loss occurred only in the histiocytic portion of tumors, suggesting a stepwise genetic inactivation in the generation of HS. Similarly, human HS showed genetic or epigenetic inactivation of PTEN, p16(INK4A), and p14(ARF), supporting the relevance of this genetically engineered mouse model of HS. These genetic and translational observations establish a cooperative role of Pten and Ink4a/Arf in the development of HS and provide mechanistic insights into the pathogenesis of human HS