Tunable Stochastic Pulsing in the Escherichia coli Multiple Antibiotic Resistance Network from Interlinked Positive and Negative Feedback Loops

Cells live in uncertain, dynamic environments and have many mechanisms for sensing and responding to changes in their surroundings. However, sudden fluctuations in the environment can be catastrophic to a population if it relies solely on sensory responses, which have a delay associated with them. Cells can reconcile these effects by using a tunable stochastic response, where in the absence of a stressor they create phenotypic diversity within an isogenic population, but use a deterministic response when stressors are sensed. Here, we develop a stochastic model of the multiple antibiotic resistance network of Escherichia coli and show that it can produce tunable stochastic pulses in the activator MarA. In particular, we show that a combination of interlinked positive and negative feedback loops plays an important role in setting the dynamics of the stochastic pulses. Negative feedback produces a pulsatile response that is tunable, while positive feedback serves to amplify the effect. Our simulations show that the uninduced native network is in a parameter regime that is of low cost to the cell (taxing resistance mechanisms are expressed infrequently) and also elevated noise strength (phenotypic variability is high). The stochastic pulsing can be tuned by MarA induction such that variability is decreased once stresses are sensed, avoiding the detrimental effects of noise when an optimal MarA concentration is needed. We further show that variability in the expression of MarA can act as a bet hedging mechanism, allowing for survival in time-varying stress environments, however this effect is tunable to allow for a fully induced, deterministic response in the presence of a stressor.     

Germline mutations in BMPR1A/ALK3 cause a subset of cases of juvenile polyposis syndrome and of Cowden and Bannayan-Riley-Ruvalcaba syndromes

Juvenile polyposis syndrome (JPS) is an inherited hamartomatous-polyposis syndrome with a risk for colon cancer. JPS is a clinical diagnosis by exclusion, and, before susceptibility genes were identified, JPS could easily be confused with other inherited hamartoma syndromes, such as Bannayan-Riley-Ruvalcaba syndrome (BRRS) and Cowden syndrome (CS). Germline mutations of MADH4 (SMAD4) have been described in a variable number of probands with JPS. A series of familial and isolated European probands without MADH4 mutations were analyzed for germline mutations in BMPR1A, a member of the transforming growth-factor beta-receptor superfamily, upstream from the SMAD pathway. Overall, 10 (38%) probands were found to have germline BMPR1A mutations, 8 of which resulted in truncated receptors and 2 of which resulted in missense alterations (C124R and C376Y). Almost all available component tumors from mutation-positive cases showed loss of heterozygosity (LOH) in the BMPR1A region, whereas those from mutation-negative cases did not. One proband with CS/CS-like phenotype was also found to have a germline BMPR1A missense mutation (A338D). Thus, germline BMPR1A mutations cause a significant proportion of cases of JPS and might define a small subset of cases of CS/BRRS with specific colonic phenotype.     

A panel of IgG1 b12 variants with selectively diminished or enhanced affinity for Fcγ receptors to define the role of effector functions in protection against HIV

Passive transfer of neutralizing antibodies is effective in protecting rhesus macaques against simian/human immunodeficiency virus (SHIV) challenge. In addition to neutralization, effector functions of the crystallizable fragment (Fc) of antibodies are involved in antibody-mediated protection against a number of viruses. We recently showed that interaction between the Fc fragment of the broadly neutralizing antibody IgG1 b12 and cellular Fcγ receptors (FcγRs) plays an important role in protection against SHIV infection in rhesus macaques. The specific nature of this Fc-dependent protection is largely unknown. To investigate, we generated a panel of 11 IgG1 b12 antibody variants with selectively diminished or enhanced affinity for the two main activating FcγRs, FcγRIIa and FcγRIIIa. All 11 antibody variants bind gp120 and neutralize virus as effectively as does wild-type b12. Binding studies using monomeric (enzyme-linked immunosorbent assay [ELISA] and surface plasmon resonance [SPR]) and cellularly expressed Fcγ receptors show decreased (up to 5-fold) and increased (up to 90-fold) binding to FcγRIIa and FcγRIIIa with this newly generated panel of antibodies. In addition, there was generally a good correlation between b12 variant affinity for Fcγ receptor and variant function in antibody-dependent cell-mediated virus inhibition (ADCVI), phagocytosis, NK cell activation assays, and antibody-dependent cellular cytotoxicity (ADCC) assays. In future studies, these b12 variants will enable the investigation of the protective role of individual FcγRs in HIV infection.     

Ecological mechanisms underpinning climate adaptation services

Ecosystem services are typically valued for their immediate material or cultural benefits to human wellbeing, supported by regulating and supporting services. Under climate change, with more frequent stresses and novel shocks, 'climate adaptation services', are defined as the benefits to people from increased social ability to respond to change, provided by the capability of ecosystems to moderate and adapt to climate change and variability. They broaden the ecosystem services framework to assist decision makers in planning for an uncertain future with new choices and options. We present a generic framework for operationalising the adaptation services concept. Four steps guide the identification of intrinsic ecological mechanisms that facilitate the maintenance and emergence of ecosystem services during periods of change, and so materialise as adaptation services. We applied this framework for four contrasted Australian ecosystems. Comparative analyses enabled by the operational framework suggest that adaptation services that emerge during trajectories of ecological change are supported by common mechanisms: vegetation structural diversity, the role of keystone species or functional groups, response diversity and landscape connectivity, which underpin the persistence of function and the reassembly of ecological communities under severe climate change and variability. Such understanding should guide ecosystem management towards adaptation planning.     

Use of gas chromatograms of essential leaf oils to compare clones of Eucalyptus camaldulensis

Using a gentle vacuum technique essential oils were distilled from the leaves of six clones (29 different trees) of Eucalyptus camaldulensis which had previously been propagated by CSIRO, from four seed lots collected from an area of southern Australia bounded approximately by latitude 26 degrees S and longitude 142 degrees E. Inspection of the analyses of the oils together with principal components analysis (PCA) of the gas chromatograms shows that corresponding profiles (for those clones studied in groups of two, three, four and 20), as indicated by the scores of the principal components, are almost independent of environmental and seasonal conditions.     

An ant-associated mesostigmatid mite in Baltic amber

Fossil mesostigmatid mites (Acari: Parasitiformes: Mesostigmata) are extremely rare, and specimens from only nine families, including four named species, have been described so far. A new record of Myrmozercon sp. described here from Eocene (ca 44–49 Myr) Baltic amber represents the first—and so far only—fossil example of the derived, extant family Laelapidae. Significantly, modern species of this genus are habitually myrmecophilous and the fossil mite described here is preserved attached to the head of the dolichoderine ant Ctenobethylus goepperti (Mayr, 1868). It thus offers the oldest unequivocal evidence for an ecological association between mesostigmatid mites and social insects in the order Hymenoptera.     

Unusual growth pattern in the Frasnian alveolitids (Tabulata) from the Holy Cross Mountains (Poland)

Abstract: Growth periodicity is a phenomenon occurring in fossil and modern corals. The most apparent feature is growth banding, and environmental changes are broadly accepted as controls on this phenomenon. If environment controls the growth, then all corallites within a colony should repeat the same growth pattern, as individuals are clones and must have shared the same environment. A study on several species of Alveolitidae (Anthozoa, Tabulata) from the Late Devonian (Early Frasnian) of the Holy Cross Mountains (Poland) shows that the growth pattern varies between neighbouring individuals within the same corallum. This contradicts observations of closely related Favositida as demonstrated on Pachyfavosites sp. from the Givetian of Avesnois, France, where neighbouring individuals repeat the same pattern. Therefore, environmental control on growth rhythm in Alveolitidae can be excluded; the causes of differences between individuals remain unknown.     

glaikit is essential for the formation of epithelial polarity and neuronal development

Epithelial cells have a distinctive polarity based on the restricted distribution of proteins and junctional complexes along an apical-basal axis. Studying the formation of the polarized ectoderm of the Drosophila embryo has identified a number of the molecules that establish this polarity. The Crumbs (Crb) complex is one of three separate complexes that cooperate to control epithelial polarity and the formation of zonula adherens. Here we show that glaikit (gkt), a member of the phospholipase D superfamily, is essential for the formation of epithelial polarity and for neuronal development during Drosophila embryogenesis. In epithelial cells, gkt acts to localize the Crb complex of proteins to the apical lateral membrane. Loss of gkt during neuronal development leads to a severe CNS architecture disruption that is not dependent on the Crb pathway but probably results from the disrupted localization of other membrane proteins. A mutation in the human homolog of gkt causes the neurodegenerative disease spinocerebellar ataxia with neuropathy (SCAN1), making it possible that a failure of membrane protein localization is a cause of this disease.