Chemotaxis: a feedback-based computational model robustly predicts multiple aspects of real cell behaviour

The mechanism of eukaryotic chemotaxis remains unclear despite intensive study. The most frequently described mechanism acts through attractants causing actin polymerization, in turn leading to pseudopod formation and cell movement. We recently proposed an alternative mechanism, supported by several lines of data, in which pseudopods are made by a self-generated cycle. If chemoattractants are present, they modulate the cycle rather than directly causing actin polymerization. The aim of this work is to test the explanatory and predictive powers of such pseudopod-based models to predict the complex behaviour of cells in chemotaxis. We have now tested the effectiveness of this mechanism using a computational model of cell movement and chemotaxis based on pseudopod autocatalysis. The model reproduces a surprisingly wide range of existing data about cell movement and chemotaxis. It simulates cell polarization and persistence without stimuli and selection of accurate pseudopods when chemoattractant gradients are present. It predicts both bias of pseudopod position in low chemoattractant gradients and-unexpectedly-lateral pseudopod initiation in high gradients. To test the predictive ability of the model, we looked for untested and novel predictions. One prediction from the model is that the angle between successive pseudopods at the front of the cell will increase in proportion to the difference between the cell's direction and the direction of the gradient. We measured the angles between pseudopods in chemotaxing Dictyostelium cells under different conditions and found the results agreed with the model extremely well. Our model and data together suggest that in rapidly moving cells like Dictyostelium and neutrophils an intrinsic pseudopod cycle lies at the heart of cell motility. This implies that the mechanism behind chemotaxis relies on modification of intrinsic pseudopod behaviour, more than generation of new pseudopods or actin polymerization by chemoattractant

Effects of control interventions on Clostridium difficile infection in England: an observational study

Background: The control of Clostridium difficile infections is an international clinical challenge. The incidence of C difficile in England declined by roughly 80% after 2006, following the implementation of national control policies; we tested two hypotheses to investigate their role in this decline. First, if C difficile infection declines in England were driven by reductions in use of particular antibiotics, then incidence of C difficile infections caused by resistant isolates should decline faster than that caused by susceptible isolates across multiple genotypes. Second, if C difficile infection declines were driven by improvements in hospital infection control, then transmitted (secondary) cases should decline regardless of susceptibility. Methods: Regional (Oxfordshire and Leeds, UK) and national data for the incidence of C difficile infections and antimicrobial prescribing data (1998–2014) were combined with whole genome sequences from 4045 national and international C difficile isolates. Genotype (multilocus sequence type) and fluoroquinolone susceptibility were determined from whole genome sequences. The incidence of C difficile infections caused by fluoroquinolone-resistant and fluoroquinolone-susceptible isolates was estimated with negative-binomial regression, overall and per genotype. Selection and transmission were investigated with phylogenetic analyses. Findings: National fluoroquinolone and cephalosporin prescribing correlated highly with incidence of C difficile infections (cross-correlations >0·88), by contrast with total antibiotic prescribing (cross-correlations 0·2). Interpretation: Restricting fluoroquinolone prescribing appears to explain the decline in incidence of C difficile infections, above other measures, in Oxfordshire and Leeds, England. Antimicrobial stewardship should be a central component of C difficile infection control programmes

Scientific understanding of East African climate change from the HyCRISTAL project

Integrating Hydro-Climate Science into Policy Decisions for Climate-Resilient Infrastructure and Livelihoods in East Africa (HyCRISTAL) is a Future Climate for Africa (FCFA) project funded to deliver new understanding of East African climate change and its impacts, and to demonstrate use of climate change information in long-term decision-making in the region. Here, we briefly summarise key findings from HyCRISTAL so far on climate change, as well as key findings from the pan-African FCFA project “IMPALA” relevant to East Africa, both in the context of previous literature on the topic

Scientific understanding of East African climate change from the HyCRISTAL project

Integrating Hydro-Climate Science into Policy Decisions for Climate-Resilient Infrastructure and Livelihoods in East Africa (HyCRISTAL) is a Future Climate for Africa (FCFA) project funded to deliver new understanding of East African climate change and its impacts, and to demonstrate use of climate change information in long-term decision-making in the region. Here, we briefly summarise key findings from HyCRISTAL so far on climate change, as well as key findings from the pan-African FCFA project “IMPALA” relevant to East Africa, both in the context of previous literature on the topic

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Epidemiology of Clostridium difficile in infants in Oxfordshire, UK: Risk factors for colonization and carriage, and genetic overlap with regional C. difficile infection strains

Background: Approximately 30-40% of children <1 year of age are Clostridium difficile colonized, and may represent a reservoir for adult C. difficile infections (CDI). Risk factors for colonization with toxigenic versus non-toxigenic C. difficile strains and longitudinal acquisition dynamics in infants remain incompletely characterized. Methods: Predominantly healthy infants (≤2 years) were recruited in Oxfordshire, UK, and provided ≥1 fecal samples. Independent risk factors for toxigenic/non-toxigenic C. difficile colonization and acquisition were identified using multivariable regression. Infant C. difficile isolates were whole-genome sequenced to assay genetic diversity and prevalence of toxin-associated genes, and compared with sequenced strains from Oxfordshire CDI cases. Results: 338/365 enrolled infants provided 1332 fecal samples, representing 158 C. difficile colonization or carriage episodes (107[68%] toxigenic). Initial colonization was associated with age, and reduced with breastfeeding but increased with pet dogs. Acquisition was associated with older age, Caesarean delivery, and diarrhea. Breastfeeding and pre-existing C. difficile colonization reduced acquisition risk. Overall 13% of CDI C. difficile strains were genetically related to infant strains. 29(18%) infant C. difficile sequences were consistent with recent direct/indirect transmission to/from Oxfordshire CDI cases (≤2 single nucleotide variants [SNVs]); 79(50%) shared a common origin with an Oxfordshire CDI case within the last ~5 years (0-10 SNVs). The hypervirulent, epidemic ST1/ribotype 027 remained notably absent in infants in this large study, as did other lineages such as STs 10/44 (ribotype 015); the most common strain in infants was ST2 (ribotype 020/014)(22%). Conclusions: In predominantly healthy infants without significant healthcare exposure C. difficile colonization and acquisition reflect environmental exposures, with pet dogs identified as a novel risk factor. Genetic overlap between some infant strains and those isolated from CDI cases suggest common community reservoirs of these C. difficile lineages, contrasting with those lineages found only in CDI cases, and therefore more consistent with healthcare-associated spread

Characterising the Mucosal and Systemic Immune Responses to Experimental Human Hookworm Infection

The mucosal cytokine response of healthy humans to parasitic helminths has never been reported. We investigated the systemic and mucosal cytokine responses to hookworm infection in experimentally infected, previously hookworm naive individuals from non-endemic areas. We collected both peripheral blood and duodenal biopsies to assess the systemic immune response, as well as the response at the site of adult worm establishment. Our results show that experimental hookworm infection leads to a strong systemic and mucosal Th2 (IL-4, IL-5, IL-9 and IL-13) and regulatory (IL-10 and TGF-β) response, with some evidence of a Th1 (IFN-γ and IL-2) response. Despite upregulation after patency of both IL-15 and ALDH1A2, a known Th17-inducing combination in inflammatory diseases, we saw no evidence of a Th17 (IL-17) response. Moreover, we observed strong suppression of mucosal IL-23 and upregulation of IL-22 during established hookworm infection, suggesting a potential mechanism by which Th17 responses are suppressed, and highlighting the potential that hookworms and their secreted proteins offer as therapeutics for human inflammatory diseases

Expression profiling of familial breast cancers demonstrates higher expression of FGFR2 in BRCA2-associated tumors

BackgroundBRCA1- and BRCA2-associated tumors appear to have distinct molecular signatures. BRCA1-associated tumors are predominantly basal-like cancers, whereas BRCA2-associated tumors have a predominant luminal-like phenotype. These two molecular signatures reflect in part the two cell types found in the terminal duct lobular unit of the breast. To elucidate novel genes involved in these two spectra of breast tumorigenesis we performed global gene expression analysis on breast tumors from germline BRCA1 and BRCA2 mutation carriers. Methodology Breast tumor RNAs from 7 BRCA1 and 6 BRCA2 mutation carriers were profiled using UHN human 19K cDNA microarrays. Supervised univariate analyses were conducted to identify genes differentially expressed between BRCA1 and BRCA2-associated tumors. Selected discriminatory genes were validated using real time reverse transcription polymerase chain reaction in the tumor RNAs, and/or by immunohistochemistry (IHC) or by in situ hybridization (ISH) on tissue microarrays (TMAs) containing an independent set of 58 BRCA1 and 64 BRCA2-associated tumors. Results Genes more highly expressed in BRCA1-associated tumors included stathmin, osteopontin, TGFβ2 and Jagged 1 in addition to genes previously identified as characteristic of basal-like breast cancers. BRCA2-associated cancers were characterized by the higher relative expression of FGF1 and FGFR2. FGFR2 protein was also more highly expressed in BRCA2-associated cancers (P = 0.004). SignificanceBRCA1-associated tumours demonstrated increased expression of component genes of the Notch and TGFβ pathways whereas the higher expression of FGFR2 and FGF1 in BRCA2-associated cancers suggests the existence of an autocrine stimulatory loop

Comparative transcriptome analyses indicate molecular homology of zebrafish swimbladder and mammalian lung

10.1371/journal.pone.0024019PLoS ONE68

Ice structures, patterns, and processes: A view across the ice-fields

We look ahead from the frontiers of research on ice dynamics in its broadest sense; on the structures of ice, the patterns or morphologies it may assume, and the physical and chemical processes in which it is involved. We highlight open questions in the various fields of ice research in nature; ranging from terrestrial and oceanic ice on Earth, to ice in the atmosphere, to ice on other solar system bodies and in interstellar space