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Streptococcus pneumoniae is a major human pathogen and rising resistance to β-lactam antibiotics, such as penicillin, is a significant threat to global public health. Mutations occurring in the penicillin-binding proteins (PBPs) can confer high-level penicillin resistance but other poorly understood genetic factors are also important. Here, we combined strictly controlled laboratory experiments and population analyses to identify a new penicillin resistance pathway that is independent of PBP modification. Initial laboratory selection experiments identified high-frequency pde1 mutations conferring S. pneumoniae penicillin resistance. The importance of variation at the pde1 locus was confirmed in natural and clinical populations in an analysis of >7,200 S. pneumoniae genomes. The pde1 mutations identified by these approaches reduce the hydrolytic activity of the Pde1 enzyme in bacterial cells and thereby elevate levels of cyclic-di-adenosine monophosphate and penicillin resistance. Our results reveal rapid de novo loss of function mutations in pde1 as an evolutionary gateway conferring low-level penicillin resistance. This relatively simple genomic change allows cells to persist in populations on an adaptive evolutionary pathway to acquire further genetic changes and high-level penicillin resistance. [ABSTRACT FROM AUTHOR]

Background: Breast-conserving surgery (BCS) is a mainstay for breast cancer management, and obtaining negative margins is critical. Some have advocated for the use of preoperative magnetic resonance imaging (MRI) in reducing positive margins after BCS. We sought to determine whether preoperative MRI was associated with reduced positive margins. Patients and Methods: The SHAVE/SHAVE2 trials were multicenter trials in ten US centers with patients with stage 0–3 breast cancer undergoing BCS. Use of preoperative MRI was at the discretion of the surgeon. We evaluated whether or not preoperative MRI was associated with margin status prior to randomization regarding resection of cavity with shave margins. Results: A total of 631 patients participated. Median age was 64 (range 29–94) years, with a median tumor size of 1.3 cm (range 0.1–9.3 cm). Patient factors included 26.1% of patients (165) had palpable tumors, and 6.5% (41) received neoadjuvant chemotherapy. Tumor factors were notable for invasive lobular histology in 7.0% (44) and extensive intraductal component (EIC) in 32.8% (207). A preoperative MRI was performed in 193 (30.6%) patients. Those who underwent preoperative MRI were less likely to have a positive margin (31.1% versus 38.8%), although this difference was not statistically significant (p = 0.073). On multivariate analysis, controlling for patient and tumor factors, utilization of preoperative MRI was not a significant factor in predicting margin status (p = 0.110). Rather, age (p = 0.032) and tumor size (p = 0.040) were the only factors associated with margin status. Conclusion: These data suggest that preoperative MRI is not associated margin status; rather, patient age and tumor size are the associated factors. [ABSTRACT FROM AUTHOR]

Streptococcus pneumoniae (the pneumococcus) is a major human pathogen causing invasive disease, including community-acquired bacteraemia, and remains a leading cause of global mortality. Understanding the role of phagocytes in killing bacteria is still limited, especially in vivo. In this study, we established a zebrafish model to study the interaction between intravenously administered pneumococci and professional phagocytes such as macrophages and neutrophils, to unravel bacterial killing mechanisms employed by these immune cells. Our model confirmed the key role of polysaccharide capsule in promoting pneumococcal virulence through inhibition of phagocytosis. Conversely, we show pneumococci lacking a capsule are rapidly internalised by macrophages. Low doses of encapsulated S. pneumoniae cause near 100% mortality within 48 hours postinfection (hpi), while 50 times higher doses of unencapsulated pneumococci are easily cleared. Time course analysis of in vivo bacterial numbers reveals that while encapsulated pneumococcus proliferates to levels exceeding 105 CFU at the time of host death, unencapsulated bacteria are unable to grow and are cleared within 20 hpi. Using genetically induced macrophage depletion, we confirmed an essential role for macrophages in bacterial clearance. Additionally, we show that upon phagocytosis by macrophages, phagosomes undergo rapid acidification. Genetic and chemical inhibition of vacuolar ATPase (v-ATPase) prevents intracellular bacterial killing and induces host death indicating a key role of phagosomal acidification in immunity to invading pneumococci. We also show that our model can be used to study the efficacy of antimicrobials against pneumococci in vivo. Collectively, our data confirm that larval zebrafish can be used to dissect killing mechanisms during pneumococcal infection in vivo and highlight key roles for phagosomal acidification in macrophages for pathogen clearance. [ABSTRACT FROM AUTHOR]

Kinetic resolution provided a highly enantioselective method to access a range of 3-aryl-3,4-dihydro-2 H -1,4-benzoxazines using n -butyllithium and the chiral ligand sparteine. The enantioenrichment remained high on removing the tert -butoxycarbonyl (Boc) protecting group. The intermediate organolithium undergoes ring opening to an enamine. The kinetic resolution was extended to give enantiomerically enriched substituted 1,2,3,4-tetrahydroquinoxalines and was applied to the synthesis of an analogue of the antibiotic levofloxacin that was screened for its activity against the human pathogen Streptococcus pneumoniae. [ABSTRACT FROM AUTHOR]

Firearm-related deaths and injuries are a serious public health problem in California and the United States. The rate of firearm-related deaths is many times higher in the US than other democratic, industrialized nations, yet many of the deaths and injuries are preventable. The California American College of Emergency Physicians Firearm Injury Prevention Policy was approved and adopted in 2013 as an evidence-based, apolitical statement to promote harm reduction. It recognizes and frames firearm injuries as a public health epidemic requiring allocation of robust resources, including increased governmental funding of high-quality research and the development of a national database system. The policy further calls for relevant legislation to be informed by best evidence and expert consensus, and advocates for legislation regarding the following: mandatory universal background checks; mandatory reporting of firearm loss/theft; restrictions against law-enforcement or military-style assault weapons and high capacity magazines; child-protective safety and storage systems; and prohibitions for high-risk individuals. It also strongly defends the right of physicians to screen and counsel patients about firearm-related risk factors and safety. Based upon best-available evidenced, the policy was recently updated to include extreme risk protection orders, which are also known as gun violence restraining orders. [ABSTRACT FROM AUTHOR]

The advent of fully autonomous vehicles (AVs) raises many questions. While some appear purely technical, others engage matters of public policy, sometimes with a prominent ethical component. Our expertise lies in law and applied ethics, and so our inquiry will focus heavily on legal or ethical issues arising from a widespread adoption of AVs and their response in emergency situations involving animals. By "animals" we do not mean all other animals than humans. We will concentrate on interest-bearing animals. These are animals who possess a welfare or wellbeing, animals whose lives can fare well or badly from their perspective. [ABSTRACT FROM AUTHOR]

The predatory bacterium B. bacteriovorus grows and divides inside the periplasm of Gram-negative bacteria, forming a structure known as a bdelloplast. Cell division of predators inside the dead prey cell is not by binary fission but instead by synchronous division of a single elongated filamentous cell into odd or even numbers of progeny cells. Bdellovibrio replication and cell division processes are dependent on the finite level of nutrients available from inside the prey bacterium. The filamentous growth and division process of the predator maximizes the number of progeny produced by the finite nutrients in a way that binary fission could not. To learn more about such an unusual growth profile, we studied the role of DivIVA in the growing Bdellovibrio cell. This protein is well known for its link to polar cell growth and spore formation in Gram-positive bacteria, but little is known about its function in a predatory growth context. We show that DivIVA is expressed in the growing B. bacteriovorus cell and controls cell morphology during filamentous cell division, but not the number of progeny produced. Bacterial Two Hybrid (BTH) analysis shows DivIVA may interact with proteins that respond to metabolic indicators of amino-acid biosynthesis or changes in redox state. Such changes may be relevant signals to the predator, indicating the consumption of prey nutrients within the sealed bdelloplast environment. ParA, a chromosome segregation protein, also contributes to bacterial septation in many species. The B. bacteriovorus genome contains three ParA homologs; we identify a canonical ParAB pair required for predatory cell division and show a BTH interaction between a gene product encoded from the same operon as DivIVA with the canonical ParA. The remaining ParA proteins are both expressed in Bdellovibrio but are not required for predator cell division. Instead, one of these ParA proteins coordinates gliding motility, changing the frequency at which the cells reverse direction. Our work will prime further studies into how one bacterium can co-ordinate its cell division with the destruction of another bacterium that it dwells within. [ABSTRACT FROM AUTHOR]

Human and animal research both operate within established standards. In the United States, criticism of the human research environment and recorded abuses of human research subjects served as the impetus for the establishment of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, and the resulting Belmont Report. The Belmont Report established key ethical principles to which human research should adhere: respect for autonomy, obligations to beneficence and justice, and special protections for vulnerable individuals and populations. While current guidelines appropriately aim to protect the individual interests of human participants in research, no similar, comprehensive, and principled effort has addressed the use of (nonhuman) animals in research. Although published policies regarding animal research provide relevant regulatory guidance, the lack of a fundamental effort to explore the ethical issues and principles that should guide decisions about the potential use of animals in research has led to unclear and disparate policies. Here, we explore how the ethical principles outlined in the Belmont Report could be applied consistently to animals. We describe how concepts such as respect for autonomy and obligations to beneficence and justice could be applied to animals, as well as how animals are entitled to special protections as a result of their vulnerability. [ABSTRACT FROM AUTHOR]

Though there is a burgeoning interest in applied Buddhist ethics, Buddhist animal research ethics remains an underdeveloped area. In this paper I will explore how some central Buddhist ethical considerations can usefully engage our use of other animals (henceforth, animals) in science. As the scientific use of animals is broad, I will narrow my focus to laboratory science. I will show that, though a Buddhist abolitionism would not be unmotivated, it is possible to reject it. While doing so, it will be important to resist emphasizing elements of Buddhist thought that merely provide reasons to adopt the dominant ethical framework governing laboratory animal research ethics, known as the 3Rs. Though I will suggest how a Buddhist animal research ethics can sometimes permit the use of animals in harmful research, it will also require ethical constraints that resonate with some of the more progressive elements in 'Western' bioethics. [ABSTRACT FROM AUTHOR]

Most bacterial cells are surrounded by an essential cell wall composed of the net-like heteropolymer peptidoglycan (PG). Growth and division of bacteria are intimately linked to the expansion of the PG meshwork and the construction of a cell wall septum that separates the nascent daughter cells. Class A penicillin-binding proteins (aPBPs) are a major family of PG synthases that build the wall matrix. Given their central role in cell wall assembly and importance as drug targets, surprisingly little is known about how the activity of aPBPs is controlled to properly coordinate cell growth and division. Here, we report the identification of MacP (SPD_0876) as a membrane-anchored cofactor of PBP2a, an aPBP synthase of the Gram-positive pathogen Streptococcus pneumoniae. We show that MacP localizes to the division site of S. pneumoniae, forms a complex with PBP2a, and is required for the in vivo activity of the synthase. Importantly, MacP was also found to be a substrate for the kinase StkP, a global cell cycle regulator. Although StkP has been implicated in controlling the balance between the elongation and septation modes of cell wall synthesis, none of its substrates are known to modulate PG synthetic activity. Here we show that a phosphoablative substitution in MacP that blocks StkP-mediated phosphorylation prevents PBP2a activity without affecting the MacP-PBP2a interaction. Our results thus reveal a direct connection between PG synthase function and the control of cell morphogenesis by the StkP regulatory network. [ABSTRACT FROM AUTHOR]

Background: Prior traumatic experiences have been associated with poorer coping strategies, greater distress, and more posttraumatic stress disorder (PTSD) symptoms following a subsequent cancer diagnosis affecting their survival. However, the impact of prior physical traumatic injury on cancer survival has not been examined. Methods: The present study matched patients from the same Level 1 Trauma center who appeared in both the trauma and cancer registries. A total of 498 patients met the criteria between 1998 and 2014 who have experienced both a diagnosis of cancer and a physical traumatic injury. The survival between the patients who had physical trauma before cancer (TBC) versus those that had physical trauma after the cancer diagnosis (TAC) were compared. Results: The TBC group had a higher percentage of males (48 % vs 33 % p = 0.001) and motor vehicle collisions (18 % vs 7 %, p < 0.001), than the TAC group. TBC patients were also significantly younger than TAC patients at the time of the physical traumatic event (68.7 ± 14.6 vs 76.2 ± 12.0 years, p < 0.001), and longer length of time between the cancer diagnosis and physical traumatic injury (2.9 ± 2.9 vs 1.7 ± 2.6 years, p < 0.001). The overall probability of survival for the entire sample was 68 %. Percent survival for the TBC (n = 251) and TAC (n = 247) groups was 56 and 80 % respectively (p < 0.001). Results were consistent regardless of stage of cancer at diagnosis (hazard ratio (HR (Standard Error)). After adjusting for comorbidities Charlson comorbidity index (CCI) (HR = 1.2 (0.06), p = 0.009)), cancer stage (HR = 2.8 (0.12), p < 0.001)), lung cancer (HR = 1.7 (0.25), p < 0.001) and bladder cancer (HR = 3.5 (0.55), p = 0.02), experiencing a prior physical traumatic injury was associated with an increased HR for mortality of 4.6 (0.93), p < 0.001). Conclusions: A physical traumatic episode before cancer diagnosis (TBC) increased the risk of death 4.6 fold compared to the TAC group even after adjusting for CCI, stage of cancer at diagnosis, lung cancer, and bladder cancer. These findings suggest considering a history of physical traumatic injury in cancer patients as a possible risk factor for faster cancer progression and mortality. [ABSTRACT FROM AUTHOR]

Chronic infections may have negative impacts on wildlife populations, yet their effects are difficult to detect in the absence of long-term population monitoring. Brucella abortus, the bacteria responsible for bovine brucellosis, causes chronic infections and abortions in wild and domestic ungulates, but its impact on population dynamics is not well understood., We report infection patterns and fitness correlates of bovine brucellosis in African buffalo based on (1) 7 years of cross-sectional disease surveys and (2) a 4-year longitudinal study in Kruger National Park ( KNP), South Africa. We then used a matrix population model to translate these observed patterns into predicted population-level effects., Annual brucellosis seroprevalence ranged from 8·7% (95% CI = 1·8-15·6) to 47·6% (95% CI = 35·1-60·1) increased with age until adulthood (>6) and varied by location within KNP. Animals were on average in worse condition after testing positive for brucellosis ( F = −5·074, P < 0·0001), and infection was associated with a 2·0 (95% CI = 1·1-3·7) fold increase in mortality (χ2 = 2·039, P = 0·036). Buffalo in low body condition were associated with lower reproductive success ( F = 2·683, P = 0·034), but there was no association between brucellosis and pregnancy or being observed with a calf., For the range of body condition scores observed in the population, the model-predicted growth rate was λ = 1·11 (95% CI = 1·02-1·21) in herds without brucellosis and λ = 1·00 (95% CI = 0·85-1·16) when brucellosis seroprevalence was 30%., Our results suggest that brucellosis infection can potentially result in reduced population growth rates, but because these effects varied with demographic and environmental conditions, they may remain unseen without intensive, longitudinal monitoring. [ABSTRACT FROM AUTHOR]

Host extinction can alter disease transmission dynamics, influence parasite extinction and ultimately change the nature of host-parasite systems. While theory predicts that single-host parasites are among the parasite species most susceptible to extinction following declines in their hosts, documented parasite extinctions are rare., Using a comparative approach, we investigate how the richness of single-host and multi-host parasites is influenced by extinction risk among ungulate and carnivore hosts. Host-parasite associations for free-living carnivores (order Carnivora) and terrestrial ungulates (orders Perissodactyla + Cetartiodactyla minus cetaceans) were merged with host trait data and IUCN Red List status to explore the distribution of single-host and multi-host parasites among threatened and non-threatened hosts., We find that threatened ungulates harbour a higher proportion of single-host parasites compared to non-threatened ungulates, which is explained by decreases in the richness of multi-host parasites. However, among carnivores threat status is not a significant predictor of the proportion of single-host parasites, or the richness of single-host or multi-host parasites., The loss of multi-host parasites from threatened ungulates may be explained by decreased cross-species contact as hosts decline and habitats become fragmented. Among carnivores, threat status may not be important in predicting patterns of parasite specificity because host decline results in equal losses of both single-host parasites and multi-host parasites through reduction in average population density and frequency of cross-species contact., Our results contrast with current models of parasite coextinction and highlight the need for updated theories that are applicable across host groups and account for both inter- and intraspecific contact. [ABSTRACT FROM AUTHOR]

Smoking increases the risk of developing lung cancer. Genetic loci have been identified which could form the basis of a lung cancer susceptibility test; but little is known whether such a test would interest or motivate those trying to quit smoking. To address this, we investigated the attitudes of people trying to quit smoking towards genetic susceptibility testing for lung cancer. Participant's attitudes to topics associated with lung cancer susceptibility testing were assessed; were they interested in genetic testing? What impact would a hypothetical high- or low- risk result have on smoking cessation? 680 self-completion questionnaires were given to individuals attending National Health Service stop smoking clinics in three different areas of the United Kingdom between 2011 and 2012. 139 questionnaires were returned, giving a 20 % response rate. Participants expressed an interest in a genetic susceptibility test for lung cancer and almost all reported that a high-risk result would increase their motivation to stop smoking. However, many participants had a neutral attitude towards a low-risk result. Most participants agreed their smoking habit could lead to lung cancer. Lung cancer susceptibility testing may be a useful incentive to help people quit smoking. This study suggests the need for genetic services to work with smoking cessation teams if routine testing becomes available in the future. [ABSTRACT FROM AUTHOR]

Previous analyses of empirical food webs (the networks of who eats whom in a community) have revealed that parasites exert a strong influence over observed food web structure and alter many network properties such as connectance and degree distributions. It remains unclear, however, whether these community-level effects are fully explained by differences in the ways that parasites and free-living species interact within a food web., To rigorously quantify the interrelationship between food web structure, the types of species in a web and the distinct types of feeding links between them, we introduce a shared methodology to quantify the structural roles of both species and feeding links. Roles are quantified based on the frequencies with which a species (or link) appears in different food web motifs - the building blocks of networks., We hypothesized that different types of species (e.g. top predators, basal resources, parasites) and different types of links between species (e.g. classic predation, parasitism, concomitant predation on parasites along with their hosts) will show characteristic differences in their food web roles., We found that parasites do indeed have unique structural roles in food webs. Moreover, we demonstrate that different types of feeding links (e.g. parasitism, predation or concomitant predation) are distributed differently in a food web context. More than any other interaction type, concomitant predation appears to constrain the roles of parasites. In contrast, concomitant predation links themselves have more variable roles than any other type of interaction., Together, our results provide a novel perspective on how both species and feeding link composition shape the structure of an ecological community and vice versa. [ABSTRACT FROM AUTHOR]

Animals' social and movement behaviours can impact the transmission dynamics of infectious diseases, especially for pathogens transmitted through close contact between hosts or through contact with infectious stages in the environment., Estimating pathogen transmission rates and R0 from natural systems can be challenging. Because host behavioural traits that underlie the transmission process vary predictably with body size, one of the best-studied traits among animals, body size might therefore also predict variation in parasite transmission dynamics., Here, we examine how two host behaviours, social group living and the intensity of habitat use, scale allometrically using comparative data from wild primate, carnivore and ungulate species. We use these empirical relationships to parameterize classical compartment models for infectious micro- and macroparasitic diseases, and examine how the risk of pathogen invasion changes as a function of host behaviour and body size. We then test model predictions using comparative data on parasite prevalence and richness from wild mammals., We report a general pattern suggesting that smaller-bodied mammal species utilizing home ranges more intensively experience greater risk for invasion by environmentally transmitted macroparasites. Conversely, larger-bodied hosts exhibiting a high degree of social group living could be more readily invaded by directly transmitted microparasites. These trends were supported through comparison of micro- and macroparasite species richness across a large number of carnivore, primate and ungulate species, but empirical data on carnivore macroparasite prevalence showed mixed results., Collectively, our study demonstrates that combining host behavioural traits with dynamical models of infectious disease scaled against host body size can generate testable predictions for variation in parasite risk across species; a similar approach might be useful in future work focused on predicting parasite distributions in local host communities. [ABSTRACT FROM AUTHOR]

For all parasites, transmission is composed of two processes: host contact with parasites ('exposure') and risk of infection given such contact ('susceptibility'). Classic models, such as mass action (density-dependent) transmission, lump these processes together., However, separating these processes could enhance predictions for disease dynamics, especially for free-living parasites. Here, we outline three transmission models that partition exposure and susceptibility., Using data from a study of Schistosoma mansoni (trematode) infections in Biomphalaria glabrata snails, we competed these three models against four alternative models, including the mass action model (which lumps exposure and susceptibility)., The models that separately accounted for exposure and susceptibility best predicted prevalence across the density gradients of hosts and parasites, outperforming all other models based on Akaike information criterion. When embedded into a dynamic epidemiological model, the exposure-explicit models all predicted lower equilibrium densities of infected snails and human-infectious cercariae., Thus, population-level epidemiological models that utilize the classic mass action transmission model might overestimate human risk of schistosomiasis. More generally, the presented approach for disentangling exposure and susceptibility can distinguish between behavioural and immunological resistance, identify mechanisms of 'disease dilution' and provide a more complete dissection of drivers of parasite transmission. [ABSTRACT FROM AUTHOR]

Simple Summary: In this paper we argue that the current oversight system for animal-based science in Canada needs major reform to keep pace with progressive legislation in other nations and to prioritize the replacement of animals as best scientific practice. Canada's current non-legislated oversight system for animal-based science not only fails to adequately incentivize the replacement of sentient animals as best scientific practice in any meaningful way, but also fails to adequately protect those animals bred, harmed, and killed in the name of science. In this paper, we outline the various shortcomings of the Canadian Council on Animal Care, and we highlight the need for Canada to move towards national legislation akin to that seen in other jurisdictions like the U.K. We conclude that while legislation alone cannot ensure the replacement of sentient animals in science, it appears to be a precondition for significant progress in animal protection and for the development and adoption of non-animal methods. [ABSTRACT FROM AUTHOR]

Among the “hard cases” of captive animal research is the continued use of chimpanzees in harmful experimental science. In a recent article I contend that contemporary animal welfare science and chimpanzee behavioral studies permit, if not require, a reappraisal of the moral significance of chimpanzee dissent from participation in certain experiments. In what follows, I outline my earlier argument, provide a brief survey of some central concepts in pediatric research ethics, and use these to enrich an understanding of chimpanzee dissent useful for research ethics. [ABSTRACT FROM PUBLISHER]

Inherited microbial symbionts can modulate host susceptibility to natural enemy attack. A wider range of symbionts influence host population demography without altering individual susceptibility, and it has been suggested that these may modify host disease risk through altering the rate of exposure to natural enemies. We present the first test of this thesis, specifically testing whether male-killing symbionts alter the epidemiology of a sexually transmitted infection (STI) carried by its host. STIs are typically expected to show female-biased epidemics, and we first present a simple model which indicates that male-biased STI epidemics may occur where symbionts create female-biased population sex ratios. We then examined the dynamics of a STI in the ladybird beetle Adalia bipunctata, which is also host to a male-killing bacterium. We present evidence that male-biased epidemics of the STI are observed in natural populations when the male-killer is common. Laboratory experiments did not support a role for differential susceptibility of male and female hosts to the STI, nor a protective role for the symbiont, in creating this bias. We conclude that the range of symbionts likely to alter parasite epidemiology will be much wider than previously envisaged, because it will additionally include those that impact host demography alone. [ABSTRACT FROM AUTHOR]

How bacteria coordinate cell growth with division is not well understood. Bacterial cell elongation is controlled by actin-MreB while cell division is governed by tubulin-FtsZ. A ring-like structure containing FtsZ (the Z ring) at mid-cell attracts other cell division proteins to form the divisome, an essential protein assembly required for septum synthesis and cell separation. The Z ring exists at mid-cell during a major part of the cell cycle without contracting. Here, we show that MreB and FtsZ of Escherichia coli interact directly and that this interaction is required for Z ring contraction. We further show that the MreB-FtsZ interaction is required for transfer of cell-wall biosynthetic enzymes from the lateral to the mature divisome, allowing cells to synthesise the septum. Our observations show that bacterial cell division is coupled to cell elongation via a direct and essential interaction between FtsZ and MreB. [ABSTRACT FROM AUTHOR]

The public purse is responsible for funding almost all autism spectrum disorders (ASD) research in Canada (as per Canadian Institutes of Health Research [CIHR]) and for providing some of the existing services and supports for this population. In this article, we consider various reasons why Canada should be concerned to ensure a more equitable distribution of relevant public funding for ASD research than is currently the case to meet the express needs and interests of the diversity of autism stakeholders. As such, we report data to show that CIHR-supported ASD research from the period of 2000–2010 demonstrates a bias focussed on the aetiology of the condition revealing a disproportionate emphasis on only two (Biomedical and Clinical) out of the four research pillars avowed by CIHR, with a comparative lack of fiscal resources committed to Health Systems and Services and Population and Public Health research. We advance certain normative and prudential reasons for funding more Health Systems and Services and Population and Public Health ASD research in Canada. In our view, this would seem to follow from CIHR’s official mandate ‘as a flexible mechanism that will continually align health research funding with changes in the manner in which health problems and opportunities are identified, understood and addressed’. [ABSTRACT FROM AUTHOR]

The article discusses neuroscientific study of the brain-mental-state identities of nonhuman animal minds. It is said that the problems of human treatment of animals as addressed by applied ethics are more important than the epistemological issue of animal minds for furthering better treatment and lessening suffering of animals, including captive animals.

Autism, typically described as a spectrum neurodevelopmental disorder characterized by impairments in verbal ability and social reciprocity as well as obsessive or repetitious behaviours, is currently thought to markedly affect more males than females. Not surprisingly, this encourages a gendered understanding of the Autism Spectrum. Simon Baron-Cohen, a prominent authority in the field of autism research, characterizes the male brain type as biased toward systemizing. In contrast, the female brain type is understood to be biased toward empathizing. Since persons with autism are characterized as hyper-systemizers and hypo-empathizers, Baron-Cohen suggests that, whether they are male or female, most possess an 'extreme male brain profile.' We argue that Baron-Cohen is misled by an unpersuasive gendering of certain capacities or aptitudes in the human population. Moreover, we suggest that this may inadvertently favour boys in diagnosing children with Autism Spectrum Disorders. If this is correct, it could also have rather serious consequences for treatment and services for girls (and women) on the Autism Spectrum. [ABSTRACT FROM AUTHOR]

The time is ripe for a greater interrogation of assumptions and commitments underlying an emerging common ground on the ethics of animal research as well on the 3 R (replacement, refinement, reduction) approach that parallels, and perhaps even further shapes, it. Recurring pressures to re-evaluate the moral status of some animals in research comes as much from within the relevant sciences as without. It seems incredible, in the light of what we now know of such animals as chimpanzees, to deny that these animals are properly accorded high moral status. Barring the requirement that they be human, it is difficult to see what more animals such as chimpanzees would have to possess to acquire it. If the grounds for ascribing high moral status are to be non-arbitrary and responsive to our best knowledge of those individuals who possess the relevant features, we should expect that a sound ethical experimental science will periodically reassess the moral status of their research subjects as the relevant knowledge demands. We already can observe this reassessment as scientists committed to humane experimental science incorporate discoveries of enrichment tools and techniques into their housing and use of captive research animals. No less should this reassessment include a critical reflection on the possible elevation of moral status of certain research animals in light of what is discovered regarding their morally significant properties, characteristics or capacities, or so I will argue. To do anything short of this threatens the social and moral legitimacy of animal research. [ABSTRACT FROM AUTHOR]

Background: Evolution equipped Bdellovibrio bacteriovorus predatory bacteria to invade other bacteria, digesting and replicating, sealed within them thus preventing nutrient-sharing with organisms in the surrounding environment. Bdellovibrio were previously described as "obligate predators" because only by mutations, often in gene bd0108, are 1 in ~1x107 of predatory lab strains of Bdellovibrio converted to prey-independent growth. A previous genomic analysis of B. bacteriovorus strain HD100 suggested that predatory consumption of prey DNA by lytic enzymes made Bdellovibrio less likely than other bacteria to acquire DNA by lateral gene transfer (LGT). However the Doolittle and Pan groups predicted, in silico, both ancient and recent lateral gene transfer into the B. bacteriovorus HD100 genome. Results: To test these predictions, we isolated a predatory bacterium from the River Tiber- a good potential source of LGT as it is rich in diverse bacteria and organic pollutants- by enrichment culturing with E. coli prey cells. The isolate was identified as B. bacteriovorus and named as strain Tiberius. Unusually, this Tiberius strain showed simultaneous prey-independent growth on organic nutrients and predatory growth on live prey. Despite the prey-independent growth, the homolog of bd0108 did not have typical prey-independent-type mutations. The dual growth mode may reflect the high carbon content of the river, and gives B. bacteriovorus Tiberius extended non-predatory contact with the other bacteria present. The HD100 and Tiberius genomes were extensively syntenic despite their different cultured-terrestrial/freshly-isolated aquatic histories; but there were significant differences in gene content indicative of genomic flux and LGT. Gene content comparisons support previously published in silico predictions for LGT in strain HD100 with substantial conservation of genes predicted to have ancient LGT origins but little conservation of AT-rich genes predicted to be recently acquired. Conclusions: The natural niche and dual predatory, and prey-independent growth of the B. bacteriovorus Tiberius strain afforded it extensive non-predatory contact with other marine and freshwater bacteria from which LGT is evident in its genome. Thus despite their arsenal of DNA-lytic enzymes; Bdellovibrio are not always predatory in natural niches and their genomes are shaped by acquiring whole genes from other bacteria. [ABSTRACT FROM AUTHOR]

Wolbachia is one of the most common symbionts of arthropods. Its establishment requires lateral transfer to and successful transmission within novel host species. However, Wolbachia performs poorly when introduced into new host species, and models predict that Wolbachia should seldom be able to establish from low initial frequencies. Recently, various symbionts, includingWolbachia, have been shown to protect their hosts from natural enemies. Hence, Wolbachia invasion may be facilitated by the dynamic interaction between it, its host, and a natural enemy. We model such an interaction whereby Wolbachia induces either complete resistance, partial resistance, or tolerance to a host-specific pathogen and also induces the common manipulation phenotype of cytoplasmic incompatibility (CI). We show that the presence of the pathogen greatly facilitates Wolbachia invasion from rare and widens the parameter space in which "imperfect" Wolbachia strains can invade. Furthermore, positive frequency-dependent selection through CI can drive Wolbachia to very high frequencies, potentially excluding the pathogen. These results may explain a poorly understood aspect of Wolbachia biology: it is widespread, despite performing poorly after transfer to new host species. They also support the intriguing possibility that Wolbachia strains that encode both CI and natural-enemy resistance could potentially rid insects, including human disease vectors, of important pathogens. [ABSTRACT FROM AUTHOR]

Bdellovibrio bacteriovorus are small, vibroid, predatory bacteria that grow within the periplasmic space of a host Gram-negative bacterium. The intermediate-filament (IF)-like protein crescentin is a member of a broad class of IF-like, coiled-coil-repeat-proteins (CCRPs), discovered in Caulobacter crescentus, where it contributes to the vibroid cell shape. The B. bacteriovorus genome has a single ccrp gene encoding a protein with an unusually long, stutter-free, coiled-coil prediction; the inactivation of this did not alter the vibriod cell shape, but caused cell deformations, visualized as chiselled insets or dents, near the cell poles and a general 'creased' appearance, under the negative staining preparation used for electron microscopy, but not in unstained, frozen, hydrated cells. Bdellovibrio bacteriovorus expressing 'teal' fluorescent protein (mTFP), as a C-terminal tag on the wild-type Ccrp protein, did not deform under negative staining, suggesting that the function was not impaired. Localization of fluorescent Ccrp-mTFP showed some bias to the cell poles, independent of the cytoskeleton, as demonstrated by the addition of the MreB-specific inhibitor A22. We suggest that the Ccrp protein in B. bacteriovorus contributes as an underlying scaffold, similar to that described for the CCRP protein FilP in Streptomyces coelicolor, preventing cellular indentation, but not contributing to the vibroid shape of the B. bacteriovorus cells. [ABSTRACT FROM AUTHOR]

The Red Queen hypothesis proposes that coevolution of interacting species (such as hosts and parasites) should drive molecular evolution through continual natural selection for adaptation and counter-adaptation. Although the divergence observed at some host-resistance and parasite-infectivity genes is consistent with this, the long time periods typically required to study coevolution have so far prevented any direct empirical test. Here we show, using experimental populations of the bacterium Pseudomonas fluorescens SBW25 and its viral parasite, phage Φ2 (refs 10, 11), that the rate of molecular evolution in the phage was far higher when both bacterium and phage coevolved with each other than when phage evolved against a constant host genotype. Coevolution also resulted in far greater genetic divergence between replicate populations, which was correlated with the range of hosts that coevolved phage were able to infect. Consistent with this, the most rapidly evolving phage genes under coevolution were those involved in host infection. These results demonstrate, at both the genomic and phenotypic level, that antagonistic coevolution is a cause of rapid and divergent evolution, and is likely to be a major driver of evolutionary change within species. [ABSTRACT FROM AUTHOR]

The genetic basis of infection in host-parasite interactions has traditionally been considered within the framework of either gene-for-gene (GFG) or matching-allele models. We present an alternative model, termed inverse-gene-for-gene (IGFG), where pathogen infectiousness is determined by parasite recognition of host signals and/or receptors or where there is active host searching by parasites. We show that coevolutionary dynamics under IGFG are both qualitatively and quantitatively different from those of the GFG model, and we suggest that this new approach may be applicable to a range of important host-parasite systems that are not currently catered for by the existing frameworks. [ABSTRACT FROM AUTHOR]

This paper integrates some Buddhist moral values, attitudes and self-cultivation techniques into a discussion of the ethics of cognitive enhancement technologies – in particular, pharmaceutical enhancements. Many Buddhists utilize meditation techniques that are both integral to their practice and are believed to enhance the cognitive and affective states of experienced practitioners. Additionally, Mahāyāna Buddhism's teaching on skillful means permits a liberal use of methods or techniques in Buddhist practice that yield insight into our selfnature or aid in alleviating or eliminating du kha (i.e. dissatisfaction). These features of many, if not most, Buddhist traditions will inform much of the Buddhist assessment of pharmaceutical enhancements offered in this paper. Some Buddhist concerns about the effects and context of the use of pharmaceutical enhancements will be canvassed in the discussion. Also, the author will consider Buddhist views of the possible harms that may befall human and nonhuman research subjects, interference with a recipient's karma, the artificiality of pharmaceutical enhancements, and the possible motivations or intentions of healthy individuals pursuing pharmacological enhancement. Perhaps surprisingly, none of these concerns will adequately ground a reflective Buddhist opposition to the further development and continued use of pharmaceutical enhancements, either in principle or in practice. The author argues that Buddhists, from at least certain traditions – particularly Mahāyāna Buddhist traditions – should advocate the development or use of pharmaceutical enhancements if a consequence of their use is further insight into our self-nature or the reduction or alleviation of du kha. [ABSTRACT FROM AUTHOR]

In moral psychology, it has long been argued that empathy is a necessary capacity of both properly developing moral agents and developed moral agency ( Blair, 2008 ; Hume et al., 1978 ). This view stands in tension with the belief that some individuals diagnosed with autism—which is typically characterized as a deficiency in social reciprocity (including empathy)—are moral agents. In this paper we propose to explore this tension and perhaps trouble how we commonly see those with autism. To make this task manageable, we will consider whether high functioning individuals diagnosed with an autism spectrum disorder are capable of empathetic responses. If they are, then they possess a capacity that, on the view above, is required for moral agency. If they are not so capable, and yet sometimes engage in moral behaviour, this casts some doubt on the claim that empathy is required for moral agency. This second possibility will necessitate an exploration of the capacity of some individuals with autism to engage in moral behaviour, giving us further grounds to re-see these individuals as moral agents. [ABSTRACT FROM AUTHOR]

In this article, we critically examine some of the ethical challenges and interpretive difficulties with possible future non-clinical applications of pediatric fMRI with a particular focus on applications in the classroom and the courtroom - two domains in which children come directly in contact with the state. We begin with a general overview of anticipated clinical and non-clinical applications of pediatric fMRI. This is followed by a detailed analysis of a range of ethical challenges and interpretive difficulties that trouble the use of fMRI and are likely to be especially acute with non-clinical uses of the technology. We conclude that knowledge of these challenges and difficulties should influence policy decisions regarding the non-clinical uses of fMRI. Our aim is to encourage the development of future policies prescribing the responsible use of this neuroimaging technology as it develops both within and outside the clinical setting. [ABSTRACT FROM AUTHOR]

The first book of Horace's Odes features a pattern, similar to that of the Parade Odes, in which tree names are introduced without repetition. This pattern is not simply a formal feature but contributes to a motif, which begins in Book I of the Odes but continues into Books 2 and 3, in which the relationship between humans and trees is depicted as a symbol of poetic mastery. By demonstrating his ability to create and arrange a poetic grove, Horace thus announces his command of the lyric genre. [ABSTRACT FROM AUTHOR]

Locked-in syndrome (LIS) is a severe neurological condition that typically leaves a patient unable to move, talk and, in many cases, initiate communication. Brain Computer Interfaces (or BCIs) promise to enable individuals with conditions like LIS to re-engage with their physical and social worlds. In this paper we will use extended mind theory to offer a way of seeing the potential of BCIs when attached to, or implanted in, individuals with LIS. In particular, we will contend that functionally integrated BCIs extend the minds of individuals with LIS beyond their bodies, allowing them greater autonomy than they can typically hope for in living with their condition. This raises important philosophical questions about the implications of BCI technology, particularly the potential to change selves, and ethical questions about whether society has a responsibility to aid these individuals in re-engaging with their physical and social worlds. It also raises some important questions about when these interventions should be offered to individuals with LIS and respecting the rights of these individuals to refuse intervention. By aiding willing individuals in re-engaging with their physical and social worlds, BCIs open up avenues of opportunity taken for granted by able individuals and introduce new ways in which these individuals can be harmed. These latter considerations serve to highlight our emergent social responsibilities to those individuals who will be suitable for, and receive, BCIs. [ABSTRACT FROM AUTHOR]

Interspecific pathogen interactions can profoundly affect pathogen population dynamics and the efficacy of control strategies. However, many pathogens exhibit cyclic abundance patterns (e.g., seasonality), and temporal asynchrony between interacting pathogens could reduce the impact of those interactions. Here we use an extension of our previously published model to investigate the effects of cycles on pathogen interaction. We demonstrate that host immune memory can maintain the impact of an interaction, even when the effector pathogen abundance is low or the pathogen is absent. Paradoxically, immune memory can result in pathogens interacting more strongly when temporally out of phase. We find that interactions between species can result in changes to the temporal pattern of the affected species. We further demonstrate that this may be observed in a natural host-pathogen system. Given the continuing debate regarding the relevance of pathogen interactions in natural systems and increasing concern about treatment strategies for coinfections, both the discovery of a shift in cycle in empirical data and the mechanism by which we identified it are important. Finally, because the model structure used here is analogous to models of a simple predator-prey system, we also consider the consequences of these findings in the context of that system. [ABSTRACT FROM AUTHOR]

Background. Many parasites of medical and veterinary importance are transmitted by cold-blooded intermediate hosts or vectors, the abundance of which will vary with ambient temperatures, potentially altering disease prevalence. In particular, if global climate change will increase mean ambient temperature in a region endemic with a human pathogen then it is possible that the incidence of disease will similarly increase. Here we examine this possibility by using a mathematical model to explore the effects of increasing long-term mean ambient temperature on the prevalence and abundance of the parasite Schistosoma mansoni, the causative agent of schistosomiasis in humans. Principal Findings. The model showed that the impact of temperature on disease prevalence and abundance is not straightforward; the mean infection burden in humans increases up to 30°C, but then crashes at 35°C, primarily due to increased mortalities of the snail intermediate host. In addition, increased temperatures changed the dynamics of disease from stable, endemic infection to unstable, epidemic cycles at 35°C. However, the prevalence of infection was largely unchanged by increasing temperatures. Temperature increases also affected the response of the model to changes in each parameter, indicating certain control strategies may become less effective with local temperature changes. At lower temperatures, the most effective single control strategy is to target the adult parasites through chemotherapy. However, as temperatures increase, targeting the snail intermediate hosts, for example through molluscicide use, becomes more effective. Conclusions. These results show that S. mansoni will not respond to increased temperatures in a linear fashion, and the optimal control strategy is likely to change as temperatures change. It is only through a mechanistic approach, incorporating the combined effects of temperature on all stages of the life-cycle, that we can begin to predict the consequences of climate change on the incidence and severity of such diseases. [ABSTRACT FROM AUTHOR]

Understanding the processes that drive parasite evolution is crucial to the development of management programs that sustain long-term, effective control of infectious disease in the face of parasite adaptation. Here we present a novel evolutionarily stable strategy (ESS) model of the developmental decisions of a nematode parasite, Strongyloides ratti. The genus Strongyloides exhibits an unusual developmental plasticity such that progeny from an individual may either develop via a direct (homogonic) route, where the developing larvae are infective to new hosts, or an indirect (heterogonic) route, where the larvae develop into free-living, dioecious adults that undergo at least one bout of sexual reproduction outside the host, before producing offspring that develop into infective larvae. The model correctly predicts a number of observed features of the parasite's behavior and shows that this plasticity may be adaptive such that pure homogonic development, pure heterogonic development, or a mixed strategy may be optimal depending on the prevailing environmental conditions, both within and outside the host. Importantly, our results depend only on the benefits of an extra round of reproduction in the environment external to the host and not on benefits to sexual reproduction through the purging of deleterious mutation or the generation of novel, favorable genotypes. The ESS framework presented here provides a powerful, general approach to predict how macroparasites, the agents of many of the world's most important infectious diseases, will evolve in response to the various selection pressures imposed by different control regimes in the future. [ABSTRACT FROM AUTHOR]

Most animal species are infected with multiple parasite species; however, the role of interspecific parasite interactions in influencing parasite dynamics and shaping parasite communities has been unclear. Although laboratory studies have found evidence of cross-immunity, immunosuppression and competition, analyses of hosts in the field have generally concluded that parasite communities are little more than random assemblages. Here we present evidence of consistent interspecific interactions in a natural mammalian system, revealed through the analysis of parasite intensity data collected from a free-ranging rabbit (Oryctolagus cuniculus) population, sampled monthly for a period of 23?yr. The wild rabbit plays host to a diverse gut helminth community that reflects the communities seen in other economically important domestic herbivores. These findings suggest that parasite interactions could have profound implications for the dynamics of parasite communities. The efficacy of parasite control programmes could be jeopardized if such interactions are not taken into account. In contrast, a clear understanding of such interactions may provide the basis for the development of more environmentally acceptable methods of parasite control. [ABSTRACT FROM AUTHOR]

Using empirically derived relationships between temperature and development rate, a stochastic simulation model was used to predict the seasonal pattern of abundance of the sheep blowfly Lucilia sericata. Sensitivity analysis suggests that, at the levels of mortality observed on sheep farms in Britain. L. sericata abundance may not be strongly influenced by the number of oviposition sites available. Hence, control techniques aimed at reducing the number of sites in the field may have little impact on the blowfly population and the resulting incidence of sheep strike. The model shows that variations in adult mortality have a much greater effect on the blowfly population than variations in pre-adult mortality, both in terms of the number of flies present in each generation and the probability of extinction of the population. With levels of pre-adult mortality of 50% per generation, adult mortality levels in excess of 30% per day would be needed to prevent the growth of a population of L. sericata. In contrast, at the lowest level of adult mortality examined, pre-adult mortality levels of 90% per generation were unable to prevent the population from increasing. The simulations suggest that unless consistently high levels of larval mortality can be maintained by a control programme, suppression of a L. sericata population is unlikely to be achieved. In contrast, relatively small increases in adult mortality may have a significant impact on L. sericata abundance, and attempts to suppress L. sericata populations by targeting the adult population may be an effective future approach. [ABSTRACT FROM AUTHOR]

In this article, the authors discuss the study conducted by John Basl regarding state's policy on neuroenhancement technologies. The authors say that in his paper, Basl concentrated on what he forms the issues arising from robust human enhancement technologies (R-HETs)'s use on nonhuman animals.The authors remark that base from the arguments of Basl, policy within the contexts of liberal states is to be decided in part through the principle of neutrality of justification (PNJ).