Absence of Staphylococcus aureus in Wild Populations of Fish Supports a Spillover Hypothesis

Staphylococcus aureus is a human commensal and opportunistic pathogen that also infects other animals. In humans and livestock, where S. aureus is most studied, strains are specialized for different host species. Recent studies have also found S. aureus in diverse wild animals. However, it remains unclear whether these isolates are also specialized for their hosts or whether their presence is due to repeated spillovers from source populations. This study focuses on S. aureus in fish, testing the spillover hypothesis in two ways. First, we examined 12 S. aureus isolates obtained from the internal and external organs of a farmed fish. While all isolates were from clonal complex 45, genomic diversity indicates repeated acquisition. The presence of a φSa3 prophage containing human immune evasion genes suggests that the source was originally human. Second, we tested for S. aureus in wild fish that were isolated from likely sources. In particular, we sampled 123 brown trout and their environment at 16 sites in the remote Scottish Highlands with variable levels of exposure to humans, birds, and livestock. This screen found no S. aureus infection in any of the wild populations or their environment. Together, these results support that the presence of S. aureus in fish and aquaculture is due to spillover from humans rather than specialization. Given the trends of increasing fish consumption, a better understanding of the dynamics of S. aureus spillover in aquaculture will mitigate future risks to fish and human health. IMPORTANCE Staphylococcus aureus is a human and livestock commensal but also an important pathogen responsible for high human mortality rates and economic losses in farming. Recent studies show that S. aureus is common in wild animals, including fish. However, we do not know whether these animals are part of the normal host range of S. aureus or whether infection is due to repeated spillover events from true S. aureus hosts. Answering this question has implications for public health and conservation. We find support for the spillover hypothesis by combining genome sequencing of S. aureus isolates from farmed fish and screens for S. aureus in isolated wild populations. The results imply that fish are unlikely to be a source of novel emergent S. aureus strains but highlight the prominence of the spillover of antibiotic-resistant bacteria from humans and livestock. This may affect both future fish disease potential and the risk of human food poisoning

The antisaccade task as an index of sustained goal activation in working memory: modulation by nicotine

The antisaccade task provides a laboratory analogue of situations in which execution of the correct behavioural response requires the suppression of a more prepotent or habitual response. Errors (failures to inhibit a reflexive prosaccade towards a sudden onset target) are significantly increased in patients with damage to the dorsolateral prefrontal cortex and patients with schizophrenia. Recent models of antisaccade performance suggest that errors are more likely to occur when the intention to initiate an antisaccade is insufficiently activated within working memory. Nicotine has been shown to enhance specific working memory processes in healthy adults. MATERIALS AND METHODS: We explored the effect of nicotine on antisaccade performance in a large sample (N = 44) of young adult smokers. Minimally abstinent participants attended two test sessions and were asked to smoke one of their own cigarettes between baseline and retest during one session only. RESULTS AND CONCLUSION: Nicotine reduced antisaccade errors and correct antisaccade latencies if delivered before optimum performance levels are achieved, suggesting that nicotine supports the activation of intentions in working memory during task performance. The implications of this research for current theoretical accounts of antisaccade performance, and for interpreting the increased rate of antisaccade errors found in some psychiatric patient groups are discussed

Anti-HIV-1 activity of cellulose acetate phthalate: Synergy with soluble CD4 and induction of "dead-end" gp41 six-helix bundles

BACKGROUND: Cellulose acetate phthalate (CAP), a promising candidate microbicide for prevention of sexual transmission of the human immunodeficiency virus type 1 (HIV-1) and other sexually transmitted disease (STD) pathogens, was shown to inactivate HIV-1 and to block the coreceptor binding site on the virus envelope glycoprotein gp120. It did not interfere with virus binding to CD4. Since CD4 is the primary cellular receptor for HIV-1, it was of interest to study CAP binding to HIV-1 complexes with soluble CD4 (sCD4) and its consequences, including changes in the conformation of the envelope glycoprotein gp41 within virus particles. METHODS: Enzyme-linked immunosorbent assays (ELISA) were used to study CAP binding to HIV-1-sCD4 complexes and to detect gp41 six-helix bundles accessible on virus particles using antibodies specific for the α-helical core domain of gp41. RESULTS: 1) Pretreatment of HIV-1 with sCD4 augments subsequent binding of CAP; 2) there is synergism between CAP and sCD4 for inhibition of HIV-1 infection; 3) treatment of HIV-1 with CAP induced the formation of gp41 six-helix bundles. CONCLUSIONS: CAP and sCD4 bind to distinct sites on HIV-1 IIIB and BaL virions and their simultaneous binding has profound effects on virus structure and infectivity. The formation of gp41 six-helical bundles, induced by CAP, is known to render the virus incompetent for fusion with target cells thus preventing infection

Prevalence of human papillomavirus antibodies in young female subjects in England

Sera from 1483 female subjects in England aged 10–29 years were tested. The age-standardised seroprevalence was 10.7% (95% confidence intervals 9.0–12.3) for human papillomavirus (HPV) 6, 2.7% (1.8–3.6) for HPV 11, 11.9% (10.2–13.6) for HPV 16, 4.7% (3.5–5.8) for HPV 18, and 20.7% (18.6–22.7) for any of the four types

Human papillomavirus vaccine introduction in low-income and middle-income countries: guidance on the use of cost-effectiveness models

BACKGROUND: The World Health Organization (WHO) recommends that the cost effectiveness of introducing human papillomavirus (HPV) vaccination is considered before such a strategy is implemented. However, developing countries often lack the technical capacity to perform and interpret results of economic appraisals of vaccines. To provide information about the feasibility of using such models in a developing country setting, we evaluated models of HPV vaccination in terms of their capacity, requirements, limitations and comparability. METHODS: A literature review identified six HPV vaccination models suitable for low-income and middle-income country use and representative of the literature in terms of provenance and model structure. Each model was adapted by its developers using standardised data sets representative of two hypothetical developing countries (a low-income country with no screening and a middle-income country with limited screening). Model predictions before and after vaccination of adolescent girls were compared in terms of HPV prevalence and cervical cancer incidence, as was the incremental cost-effectiveness ratio of vaccination under different scenarios. RESULTS: None of the models perfectly reproduced the standardised data set provided to the model developers. However, they agreed that large decreases in type 16/18 HPV prevalence and cervical cancer incidence are likely to occur following vaccination. Apart from the Thai model (in which vaccine and non-vaccine HPV types were combined), vaccine-type HPV prevalence dropped by 75% to 100%, and vaccine-type cervical cancer incidence dropped by 80% to 100% across the models (averaging over age groups). The most influential factors affecting cost effectiveness were the discount rate, duration of vaccine protection, vaccine price and HPV prevalence. Demographic change, access to treatment and data resolution were found to be key issues to consider for models in developing countries. CONCLUSIONS: The results indicated the usefulness of considering results from several models and sets of modelling assumptions in decision making. Modelling groups were prepared to share their models and expertise to work with stakeholders in developing countries. Please see related article: http://www.biomedcentral.com/1741-7007/9/55

Temporal Stability and the Effects of Training on Saccade Latency in “Express Saccade Makers”

The temporal stability of saccade latency, and the effects of training, particularly in “express saccade makers” (ESMs), has received little attention. ESMs are healthy, naïve, adults, who persist in executing very many low latency “express saccades” (ES; saccades with latency of 80 ms to 130 ms), in conditions designed to suppress such responses. We investigated the stability of ES production (%ES) in 59 ESM and 54 non-ESM participants in overlap tasks. Within a single session, the intraclass correlation coefficient (ICC) for %ES in two runs of 200 trials was 0.97 (p30% of saccades over the two runs were ES, were classified as ESMs. For 60 participants tested over two sessions 12 weeks apart, and 30 participants tested in three sessions over approximately six months, the ICC for %ES was uniformly high (0.95, p<0.001 and 0.97, p<0.001 respectively) and participants behaved consistently with their initial classification. Fourteen participants (7 ESMs) were then exposed to training consisting of either gap or overlap tasks. Training increased %ES in both groups. However, when tested in overlap tasks, it was not sufficient to transform Normal participants into ESMs. We conclude that the pattern of saccade behaviour exhibited by ESMs constitutes a stable and distinct oculomotor phenotype

Horizontal DNA transfer mechanisms of bacteria as weapons of intragenomic conflict

Horizontal DNA transfer (HDT) is a pervasive mechanism of diversification in many microbial species, but its primary evolutionary role remains controversial. Much recent research has emphasised the adaptive benefit of acquiring novel DNA, but here we argue instead that intragenomic conflict provides a coherent framework for understanding the evolutionary origins of HDT. To test this hypothesis, we developed a mathematical model of a clonally descended bacterial population undergoing HDT through transmission of mobile genetic elements (MGEs) and genetic transformation. Including the known bias of transformation toward the acquisition of shorter alleles into the model suggested it could be an effective means of counteracting the spread of MGEs. Both constitutive and transient competence for transformation were found to provide an effective defence against parasitic MGEs; transient competence could also be effective at permitting the selective spread of MGEs conferring a benefit on their host bacterium. The coordination of transient competence with cell-cell killing, observed in multiple species, was found to result in synergistic blocking of MGE transmission through releasing genomic DNA for homologous recombination while simultaneously reducing horizontal MGE spread by lowering the local cell density. To evaluate the feasibility of the functions suggested by the modelling analysis, we analysed genomic data from longitudinal sampling of individuals carrying Streptococcus pneumoniae. This revealed the frequent within-host coexistence of clonally descended cells that differed in their MGE infection status, a necessary condition for the proposed mechanism to operate. Additionally, we found multiple examples of MGEs inhibiting transformation through integrative disruption of genes encoding the competence machinery across many species, providing evidence of an ongoing "arms race." Reduced rates of transformation have also been observed in cells infected by MGEs that reduce the concentration of extracellular DNA through secretion of DNases. Simulations predicted that either mechanism of limiting transformation would benefit individual MGEs, but also that this tactic's effectiveness was limited by competition with other MGEs coinfecting the same cell. A further observed behaviour we hypothesised to reduce elimination by transformation was MGE activation when cells become competent. Our model predicted that this response was effective at counteracting transformation independently of competing MGEs. Therefore, this framework is able to explain both common properties of MGEs, and the seemingly paradoxical bacterial behaviours of transformation and cell-cell killing within clonally related populations, as the consequences of intragenomic conflict between self-replicating chromosomes and parasitic MGEs. The antagonistic nature of the different mechanisms of HDT over short timescales means their contribution to bacterial evolution is likely to be substantially greater than previously appreciated

Th1 type lymphocyte reactivity to metals in patients with total hip arthroplasty

<p>Abstract</p> <p>Background</p> <p>All prostheses with metallic components release metal debris that can potentially activate the immune system. However, implant-related metal hyper-reactivity has not been well characterized. In this study, we hypothesized that adaptive immunity reaction(s), particularly T-helper type 1 (Th1) responses, will be dominant in any metal-reactivity responses of patients with total joint replacements (TJAs). We tested this hypothesis by evaluating lymphocyte reactivity to metal "ions" in subjects with and without total hip replacements, using proliferation assays and cytokine analysis.</p> <p>Methods</p> <p>Lymphocytes from young healthy individuals without an implant or a history of metal allergy (Group 1: n = 8) were used to assess lymphocyte responses to metal challenge agents. In addition, individuals (Group 2: n = 15) with well functioning total hip arthroplasties (average Harris Hip Score = 91, average time in-situ 158 months) were studied. Age matched controls with no implants were also used for comparison (Group 3, n = 8, 4 male, 4 female average age 70, range 49–80). Group 1 subjects' lymphocyte proliferation response to Aluminum⁺³, Cobalt⁺², Chromium⁺³, Copper⁺², Iron⁺³, Molybdenum⁺⁵, Manganeese⁺², Nickel⁺², Vanadium⁺³and Sodium⁺²chloride solutions at a variety of concentrations (0.0, 0.05, 0.1, 0.5, 1.0 and 10.0 mM) was studied to establish toxicity thresholds. Mononuclear cells from Group 2 and 3 subjects were challenged with 0.1 mM CrCl₃, 0.1 mM NiCl₂, 0.1 mM CoCl₂and approx. 0.001 mM titanium and the reactions measured with proliferation assays and cytokine analysis to determine T-cell subtype prominence.</p> <p>Results</p> <p>Primary lymphocytes from patients with well functioning total hip replacements demonstrated a higher incidence and greater magnitude of reactivity to chromium than young healthy controls (p < 0.03). Of the 15 metal ion-challenged subjects with well functioning total hip arthroplasties, 7 demonstrated a proliferative response to Chromium, Nickel, Cobalt and/or Titanium (as defined by a statistically significant >2 fold stimulation index response, p < 0.05) and were designated as metal-reactive. Metals such as Cobalt, Copper, Manganese, and Vanadium were toxic at concentrations as low as 0.5 mM while other metals, such as Aluminum, Chromium, Iron, Molybdenum, and Nickel, became toxic at much higher concentrations (>10 mM). The differential secretion of signature T-cell subsets' cytokines (Th1 and Th2 lymphocytes releasing IFN-gamma and IL-4, respectively) between those total hip arthroplasty subjects which demonstrated metal-reactivity and those that did not, indicated a Th1 type (IFN-gamma) pro-inflammatory response.</p> <p>Conclusion</p> <p>Elevated proliferation and production of IFN-gamma to metals in hip arthroplasty subjects' lymphocytes indicates that a Th1 (vs. Th2) type response is likely associated with any metal induced reactivity. The involvement of an elevated and specific lymphocyte response suggests an <it>adaptive </it>(macrophage recruiting) immunity response to metallic implant debris rather than an <it>innate </it>(nonspecific) immune response.</p

Mutations in TGFbeta-RII and BAX mediate tumor progression in the later stages of colorectal cancer with microsatellite instability

Abstract Background Microsatellite instability (MSI) occurs in 15% of colorectal cancers (CRC). The genetic targets for mutation in the MSI phenotype include somatic mutations in the transforming growth factor beta receptor typeII (TGFbetaRII), BAX, hMSH3 and hMSH6. It is not clear how mutations of these genes mediate tumor progression in the MSI pathway, and the temporal sequence of these mutations remains uncertain. In this study, early stage CRCs were examined for frameshift mutations in these target genes, and compared with late stage tumors and CRC cell lines. Methods We investigated 6 CRC cell lines and 71 sporadic CRCs, including 61 early stage cancers and 10 late stage cancers. Mutations of repetitive mononucleotide tracts in the coding regions of TGFbetaRII, BAX, hMSH3, hMSH6, IGFIIR and Fas antigen were identified by direct sequencing. Results Thirteen (18.3%) of 71 CRC, including 9/61 (14.7%) early stage cancers and 4/10 (40%) late stage cancers, were identified as MSI and analyzed for frameshift mutations. No mutation in the target genes was observed in any of the 9 early stage MSI CRCs. In contrast, frameshift mutations of TGFbetaRII, BAX, hMSH3 and hMSH6 were present in 3/4 late stage MSI tumors. There is a statistical association (p = 0.014) between mutation in any one gene and tumor stage. Conclusions TGFbetaRII, BAX, hMSH3 and hMSH6 mutations are relatively late events in the genesis of MSI CRCs. The frameshift mutations in these target genes might mediate progression from early to late stage cancer, rather than mediating the adenoma to carcinoma transition.</p

Tau mislocation in glucocorticoid-triggered hippocampal pathology

The exposure to high glucocorticoids (GC) triggers neuronal atrophy and cognitive deficits, but the exact cellular mechanisms underlying the GC-associated dendritic remodeling and spine loss are still poorly understood. Previous studies have implicated sustained GC elevations in neurodegenerative mechanisms through GC-evoked hyperphosphorylation of the cytoskeletal protein Tau while Tau mislocation has recently been proposed as relevant in Alzheimer's disease (AD) pathology. In light of the dual cytoplasmic and synaptic role of Tau, this study monitored the impact of prolonged GC treatment on Tau intracellular localization and its phosphorylation status in different cellular compartments. We demonstrate, both by biochemical and ultrastructural analysis, that GC administration led to cytosolic and dendritic Tau accumulation in rat hippocampus, and triggered Tau hyperphosphorylation in epitopes related to its malfunction (Ser396/404) and cytoskeletal pathology (e.g., Thr231 and Ser262). In addition, we show, for the first time, that chronic GC administration also increased Tau levels in synaptic compartment; however, at the synapse, there was an increase in phosphorylation of Ser396/404, but a decrease of Thr231. These GC-triggered Tau changes were paralleled by reduced levels of synaptic scaffolding proteins such as PSD-95 and Shank proteins as well as reduced dendritic branching and spine loss. These in vivo findings add to our limited knowledge about the underlying mechanisms of GC-evoked synaptic atrophy and neuronal disconnection implicating Tau missorting in mechanism(s) of synaptic damage, beyond AD pathology.We would like to thank Rui Fernandes for TEM technical support. IS was supported by the Portuguese Foundation for Science and Technology (FCT).This work was funded by the Portuguese Foundation for Science and Technology (FCT) (grant NMC-113934 to IS and grant SFRH/BPD/80118/2011 to JC), Canon Foundation and project DoIT - Desenvolvimento e Operacionalização da Investigação de Translação (N° do projeto 13853), funded by Fundo Europeu de Desenvolvimento Regional (FEDER) through the Programa Operacional Fatores de Competitividade (POFC).info:eu-repo/semantics/publishedVersio