Drosophila responds to a septic injury by the rapid synthesis of antimicrobial peptides. These molecules are predominantly produced by the fat body, a functional equivalent of mammalian liver, and are secreted into the hemolymph where their concentrations can reach up to 100 μM. Six distinct antibacterial peptides (plus isoforms) and one antifungal peptide have been characterized in Drosophila and their genes cloned. The induction of the gene encoding the antifungal peptide relies on the spätzle/Toll/cactus gene cassette, which (...) is involved in the control of dorsoventral patterning in the embryo, and shows interesting structural and functional similarities with cytokine‐induced activation of NF‐ϰB in mammalian cells. An additional pathway, dependent on the as yet unidentified imd (for immune‐deficiency) gene, is required for the full induction of the antibacterial peptide genes. Mutants deficient for the Toll and imd pathways exhibit a severely reduced survival to fungal and bacterial infections, respectively. Recent data on the molecular mechanisms underlying recognition of non‐self are also discussed in this review. (shrink)

The microbiome of human hair follicles (HFs) has emerged as an important player in different HF and skin pathologies, yet awaits in‐depth exploration. This raises questions regarding the tightly linked interactions between host environment, nutrient dependency of host‐associated microbes, microbial metabolism, microbe‐microbe interactions and host immunity. The use of simple model systems facilitates addressing generally important questions and testing overarching, therapeutically relevant principles that likely transcend obvious interspecies differences. Here, we evaluate the potential of the freshwater polyp Hydra, to dissect (...) fundamental principles of microbiome regulation by the host, that is the human HF. In particular, we focus on therapeutically targetable host‐microbiome interactions, such as nutrient dependency, microbial interactions and host defence. Offering a new lens into the study of HF – microbiota interactions, we argue that general principles of how Hydra manages its microbiota can inform the development of novel, microbiome‐targeting therapeutic interventions in human skin disease. (shrink)

The importance of seminal plasma in fertilization was appreciated as early as 1677 and would thus hardly seem a source for the search of antibacterial agents. The observation that seminal plasma had the ability to inhibit the growth of microorganisms in 1940 led to a systematic search for molecules possessing antimicrobial activity in addition to factors that might have a role in reproductive physiology. Extensive investigations led to the discovery in bovine seminal fluid of a 47‐residue peptide, possessing potent (...) antimicrobial activity as well as calcium transport modulatory properties in bovine sperm. We describe in this article the two, apparently unrelated, biological activities of this peptide. (shrink)

Multidrug-resistant Acinetobacter baumannii is recognized to be among the most difficult antimicrobial-resistant gram negative bacilli to control and treat. One of the major challenges that the pathogenic bacteria face in their host is the scarcity of freely available iron. To survive under such conditions, bacteria express new proteins on their outer membrane and also secrete iron chelators called siderophores. Antibodies directed against these proteins associated with iron uptake exert a bacteriostatic or bactericidal effect against A. baumanii in vitro, by (...) blocking siderophore mediated iron uptake pathways. Attempts should be made to discover peptides that could mimic protein epitopes and possess the same immunogenicity as the whole protein. Subsequently, theoretical methods for epitope prediction have been developed leading to synthesis of such peptides that are important for development of immunodiagnostic tests and vaccines. The present study was designed to in silico resolving the major obstacles in the control or in prevention of the diseases caused by A. baumannii. We exploited bioinformatic tools to better understand and characterize the Baumannii acinetobactin utilization structure of A. baumannii and select appropriate regions as effective B cell epitopes. In conclusion, amino acids 26–191 of cork domain and 321–635 of part of the barrel domain including L4–L9, were selected as vaccine candidates. These two regions contain functional exposed amino acids with higher score of B cell epitopes properties. Majority of amino acids are hydrophilic, flexible, accessible, and favorable for B cells from secondary structure point of view. (shrink)

Chronic wounds, such as diabetic foot ulcers, pose significant challenges due to their prolonged inflammation state, slow vascularization, lack of supportive matrix, and frequent recurrence. Biocompatible materials like silk fibroin (SF) and collagen can be promising in chronic wound healing applications due to their biocompatibility, and ability to act as supporting matrix necessary for tissue regeneration. This study explores the development and characterization of SF-based biomaterials in various formats, including gels, lyophilized scaffolds, and films, by combining them with collagen (Col) (...) and heparin (Hep) molecules that are known for the wound-healing properties. SF gels, films, and lyophilized scaffolds were characterized for water retention capacity, porosity, contact angle, and antibacterial properties. Curcumin-loaded films reported moderate wetting behavior but were brittle, thin and hard. Freeze-dried scaffolds possessed higher water retention capacity compared to the sonicated gels and films, and showed a porous network structure, while the fabricated SF gels disintegrated in water. SF with a chelating agent demonstrated mild antibacterial properties, which were retained when combined with Collagen peptides and Heparin. The antimicrobial effect was significantly enhanced when SF+Col+Hep was added with antimicrobial agents such as Gentamicin and Ceftriaxone. The study concludes that SF-based scaffolds, particularly those incorporating collagen peptides and heparin, can be leveraged for molecular delivery application towards wound healing. Future research should focus on improving mechanical properties, measuring release kinetics of heparin and other biomolecules from SF-based lyophilized scaffolds, and conducting in vivo studies to validate the therapeutic value. (shrink)

The problem of antimicrobial resistance is so dire that people are predicting that the era of antibiotics may be coming to an end, ushering in a ‘post-antibiotic’ era. A comprehensive policy response is therefore urgently needed. A part of this response will require framing the problem in such a way that adequately reflects its nature as well as encompassing an approach that has the best prospect of success. This paper considers framing the problem as a slowly emerging disaster, including (...) its potential benefits and difficulties, from a conceptual and policy perspective. (shrink)

This chapter explores the question of whether or not individual agents are under a moral obligation to reduce their ‘antimicrobial footprint’. An agent’s antimicrobial footprint measures the extent to which her actions are causally linked to the use of antibiotics. As such, it is not necessarily a measure of her contribution to antimicrobial resistance. Talking about people’s antimicrobial footprint in a way we talk about our carbon footprint may be helpful for drawing attention to the global (...) effects of individual behaviour and for highlighting that our choices can collectively make a real difference. But can we be morally obligated to make a contribution to resolving a collective action problem when our individual contributions by themselves make no discernible difference? I will focus on two lines of argument in favour of such obligations: whether a failure to reduce one’s antimicrobial footprint is unfair and whether it constitutes wrongdoing because it is harmful. I conclude by suggesting that the argument from collective harm is ultimately more successful. (shrink)

Antimicrobial resistance (AMR) in bacterial infections is a growing threat to humanity and a challenge to healthcare systems worldwide. Healthcare professionals have an important role in preventing AMR and the spreading of infections. This article focuses on trade union financed journals for nurses in Scandinavia studying how the journals articulate AMR to its readership. A systematic literature search over an eleven‐year period was conducted, using web‐based national trade union financed journals, searching for ‘bacteria’ and ‘resistance’. A thematic analysis, inspired (...) by Foucault's concepts of power and governmentality, was made of 131 texts to understand, which kind of practices, strategies and policies the journals frame regarding AMR. The time period studied resulted in the recognition of four separate themes: the horror scenario, the ‘dangerous’ other, healthcare professionals as a source of resistance development and AMR as a field of research and producer of research qualifications. The study concludes that the journals tend: to present AMR in apocalyptic terms with more research and pharmaceutical industries needed for avoidance; to point out problems in other countries, populations, and sometimes nurses’ working conditions, but primarily with other professionals’ behaviour; and lastly, to present the nurse as a good fairy and disciplinator of doctors. (shrink)

It is commonly presumed that abiotic membranes were colonized by proteins later on. Yet, hydrophobic peptides could have formed primordial protein‐dominated membranes on their own. In a metabolism‐first context, “autocatalytically closed” sets of statistical peptides could organize a self‐maintaining protometabolism, assisted by an unfolding set of ribotide‐related cofactors. Pairwise complementary ribotide cofactors may have formed docking guides for stochastic peptide formation, before replicating RNA emerged from this subset. Tidally recurring wet‐drying cycles and an early onset of photosynthetic activities (...) are considered most likely to meet the thermodynamic requirements. Conceivably, the earliest peptide‐dominated vesicles were engaged in light harvesting, together with isoprenoid‐tethered pigments, rather than providing an external boundary. Early on, the bulk of prebiotic organic matter can have formed a contiguous layer covering the mineral sediment, held in place by colloidal coherence of a hydrogel matrix. This unconventional scenario assumes a late onset of cellular individualization – perhaps from within, resembling endosporogenesis. (shrink)

Antimicrobial resistance kills people. According to a recent estimate, ‘7 00 000 people die of resistant infections every year’, and ‘by 2050 10 million lives a year are at risk due to drug resistant infections, as are 100 trillion USD of economic output’.1 Today, ‘bacteria are resistant to nearly all antibiotics that were earlier active against them’.2 For all these reasons, antimicrobial resistance is considered a ‘slowly emerging disaster’3 and a ‘global health security issue’.4 The prospect we are (...) facing is that of a ‘post antibiotic era’,5 in which we risk losing the availability of effective antibiotics and, with them, of medical interventions that require effective antibiotics, such as chemotherapy, transplantation and major surgery. One of the causes of antimicrobial resistance is antimicrobial consumption. As put by the Centers for Disease Control and Prevention, ‘the use of antibiotics is the single most important factor leading to antibiotic resistance around the world: simply using antibiotics creates resistance’.6 According to the 2016 Review on Antimicrobial Resistance commissioned by the UK Government, ‘more consumption of antibiotics directly leads to more resistance’.1 This is because microbes that are not killed by antimicrobials are more likely to reproduce and proliferate and to pass their resistance genes on to other microbes. Thus, exactly like the consumption of many other finite resources, antibiotic and antimicrobial consumption gives rise to the collective action problem known as ‘tragedy of the commons’: consuming a certain resource, such as antimicrobials, is in an individual’s best short-term interest, but many instances of individual consumption erode the resource and therefore conflict with the collective interest in preserving the good. How to solve a tragedy of the commons? As is the case with the consumption of other finite resources, the answer is quite simple: by rationing the resource. Simon Oczkowski’s article …. (shrink)

Antimicrobial therapy is a cornerstone of therapy in critically ill patients; however, the wide use of antibiotics has resulted in increased antimicrobial resistance and outbreaks of resistant disease. To counter this, many hospitals have instituted antimicrobial stewardship programmes as a way to reduce the inappropriate use of antibiotics. However, uptake of antimicrobial stewardship programmes has been variable, as many clinicians fear that they may put individual patients at risk of treatment failure. In this paper, I argue (...) that antimicrobial stewardship programmes are indeed a form of bedside rationing, and explore the risks and benefits of such programmes for individual patients in the intensive care unit, and the critically ill population in general. Using Norman Daniels’ Accountability for Reasonableness as a framework for evaluating resource allocation policies, I conclude that antimicrobial stewardship programmes are an ethically sound form of bedside rationing. (shrink)

Governments can practically and efficiently address zoonoses and AMR –– within the text of the new pandemic instrument. We map the overlaps between the efforts needed to address both pandemic threats, including (a) equitable access to medical countermeasures, (b) globally integrated One Health surveillance and monitoring systems, (c) increased technical and laboratory capacity in low- and middle-income countries, and (d) a regulatory framework governing the stewardship of antimicrobials. By outlining potential dual-purpose provisions that could be included in a pandemic instrument, (...) we argue that addressing AMR in the pandemic instrument is practicable, the most effective use of limited time and resources, and provides the best opportunity for future global pandemic readiness. (shrink)

The vertebrate immune system uses an impressive arsenal of mechanisms to combat harmful cellular states such as infection. One way is via cells delivering real‐time snapshots of their protein content to the cell surface in the form of short peptides. Specialized immune cells (T cells) sample these peptides and assess whether they are foreign, warranting an action such as destruction of the infected cell. The delivery of peptides to the cell surface is termed antigen processing and presentation, (...) and decades of research have provided unprecedented understanding of this process. However, predicting the capacity for a given peptide to be immunogenic—to elicit a T cell response—has remained both enigmatic and a long sought‐after goal. In the era of big data, a point is being approached where the steps of antigen processing and presentation can be quantified and assessed against peptide immunogenicity in order to build predictive models. This review presents new findings in this area and contemplates challenges ahead. (shrink)

Antimicrobial resistance (AMR) describes the evolution of treatment‐resistant pathogens, with potentially catastrophic consequences for human medicine. AMR is driven by the over‐prescription of antibiotics, and could be reduced through consideration of the ethical dimensions of the dilemma faced by doctors. This dilemma involves balancing apparently opposed interests of current and future patients, and unique contextual factors in different countries, which may modify the core dilemma. We describe three example countries with different economic backgrounds and cultures—South Africa, Sri Lanka and (...) the United Kingdom. Then we discuss how country‐specific factors impact on the prominence of various ethical dimensions of the dilemma (visibility and moral equality of future generations; Rule of Rescue; prescribing autonomy and conflicts of interest; consensus on collective action). We conclude that a nuanced understanding of national prescribing dilemmas is critical to inform the design of effective stewardship approaches. (shrink)

Peptides serve as important signalling molecules in development and differentiation in the simple metazoan Hydra. A systematic approach (The Hydra Peptide Project) has revealed that Hydra contains several hundreds of peptide signalling molecules, some of which are neuropeptides and others emanate from epithelial cells. These peptides control biological processes as diverse as muscle contraction, neuron differentiation, and the positional value gradient. Signal peptides cause changes in cell behaviour by controlling target genes such as matrix metalloproteases. The abundance (...) of peptides in Hydra raises the question of whether, in early metazoan evolution, cell–cell communication was based mainly on these small molecules rather than on the growth‐factor‐like cytokines that control differentiation and development in higher animals. BioEssays 23:420–427, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Antimicrobial resistance is a growing public health concern and is associated with the over- or inappropriate use of antimicrobials in both humans and agriculture. While there has been reco- gnition of this problem on the part of agricultural and public health authorities, there has none- theless been significant difficulty in translating policy recommendations into practical guidelines. In this paper, we examine the process of public health policy development in Quebec agriculture, with a focus on the case of pork production (...) and the role of food animal veterinarians in policy making. We argue that a tendency to employ strictly techno-scientific risk analyses of antimicro- bial use ignores the fundamental social, economic and political realities of key stakeholders and so limits the applicability of policy recommendations developed by government advisory groups. In particular, we suggest that veterinarians’ personal and professional interests, and their ethi- cal norms of practice, are key factors to both the problem of and the solution to the current over-reliance on antimicrobials in food production. (shrink)

Bioactive peptides are a group of diverse intercellular signalling molecules. Almost half a century of research on this topic has resulted in an enormous amount of data. In this essay, a general perspective to interpret all these data will be given. In classical endocrinology, neuropeptides were thought of as simple signalling molecules that each elicit one response. However, the fact that the total bioactive peptide signal is far from simple puts this view under pressure. Cells and tissues express many (...) different bioactive peptides and they are also able to respond to many different bioactive peptides, indicating that multiple receptors and signal transduction pathways are present in a single cell. Therefore, the authors suggest that the bioactive peptide signalling system should be regarded in the context of network and systems biology. Bioactive peptides can best be viewed as an extension of the protein interaction network that allows regulating and fine‐tuning the metabolism of the different cells and tissues in the body. The cell thus responds to the ‘peptidome’ instead of to a single peptide. The intracellular part of this signalling network consists of the various signalling transduction cascades. Recently, new systems biology approaches have emerged for the modelling of cell signalling. The network and systems biology approach is also able to shed new light on the evolution of intercellular signalling. (shrink)

Antimicrobial resistance (AMR) has become one of the defining challenges of the twenty-first century. Food production and farming are a key if troubling component of that challenge. Livestock production accounts for well over half of annual global consumption of antimicrobials, though the contribution of the sector to drug resistance is less clear. As a result, there is an injunction to act in advance of incontrovertible evidence for change. In this paper we engage with the role of market actors in (...) the precautionary regulation of farming practices and AMR threats. The paper takes the UK poultry sector as exemplary of an audit-led process that has, in recent years, achieved impressive reductions in antimicrobial use. Using qualitative interview data with farmers and veterinarians we chart the changing practices that have accompanied this reduction in treatments. We use this analysis to raise some cautions around audit-led systems of regulation. Audits can lock farms and animals into particular versions of farming and animal health; they can elevate harmful compensatory practices (including disinfectant uses); and they can reproduce an actuarial approach to an issue that does not fit the conventions of risk management. The paper presents the considerable successes that have been achieved over a short period of time in a livestock sector, while generating notes of caution concerning the audit-led management of livestock-related AMR threats. (shrink)

Antimicrobial resistance (AMR) is increasingly recognised as a threat to human, animal and environmental health. In an effort to counter this threat, several intervention plans have been proposed and implemented by states and organisations such as the WHO. A One Health policy approach, which targets multiple domains (healthcare, animal husbandry and the environment), has been identified as useful for curbing AMR. Johnson and Matlock have recently argued that One Health policies in the AMR context require special ethical justification because (...) of the so-called least restrictive alternative principle. This article analyses and rejects two assumptions that this argument relies on. The first assumption is that One Health policies are generally more restrictive than their alternatives because they target more domains and impact more people. The second assumption is that the least restrictive alternative principle has a special normative importance in that it establishes a systematic presumption in favour of the least restrictive policy options. Once these assumptions are rejected, the use of One Health policies on AMR can be justified more easily than Johnson and Matlock argue. (shrink)

As we combat the COVID-19 pandemic, both the prescription of antimicrobials and the use of biocidal agents have increased in many countries. Although these measures can be expected to benefit existing people by, to some extent, mitigating the pandemic's effects, they may threaten long-term well-being of existing and future people, where they contribute to the problem of antimicrobial resistance (AMR). A trade-off dilemma thus presents itself: combat COVID-19 using these measures, or stop using them in order to protect against (...) AMR. Currently, I argue, we are choosing to continue with these measures, and thus to prioritize combatting COVID-19, without adequate ethical reflection on the AMR-associated costs of these measures. I discuss the magnitude of the possible costs and benefits involved in making the trade-off in favour of COVID-19, and their distribution. I highlight two salient aspects of distribution that can help determine whether combatting COVID-19 whilst exacerbating AMR produces justly distributed costs and benefits: distribution between current and future populations, and distribution between existing geographical populations. Adopting this account, I argue that based on the magnitude and distribution of costs and benefits of combatting COVID-19, we have good reason to rethink this trade-off, and instead consider prioritizing protecting current and future people against AMR, but jettisoning measures against COVID-19 that also exacerbate AMR. (shrink)

Antimicrobial resistance is a global collective action problem with dire consequences for human health. This article considers how domestic and international legal mechanisms can be used to address antimicrobial resistance and overcome the governance and political economy challenges that accelerate it.

As we combat the COVID-19 pandemic, both the prescription of antimicrobials and the use of biocidal agents have increased in many countries. Although these measures can be expected to benefit existing people by, to some extent, mitigating the pandemic's effects, they may threaten long-term well-being of existing and future people, where they contribute to the problem of antimicrobial resistance (AMR). A trade-off dilemma thus presents itself: combat COVID-19 using these measures, or stop using them in order to protect against (...) AMR. Currently, I argue, we are choosing to continue with these measures, and thus to prioritize combatting COVID-19, without adequate ethical reflection on the AMR-associated costs of these measures. I discuss the magnitude of the possible costs and benefits involved in making the trade-off in favour of COVID-19, and their distribution. I highlight two salient aspects of distribution that can help determine whether combatting COVID-19 whilst exacerbating AMR produces justly distributed costs and benefits: distribution between current and future populations, and distribution between existing geographical populations. Adopting this account, I argue that based on the magnitude and distribution of costs and benefits of combatting COVID-19, we have good reason to rethink this trade-off, and instead consider prioritizing protecting current and future people against AMR, but jettisoning measures against COVID-19 that also exacerbate AMR. (shrink)

Proteins are targeted to plastids by N‐terminal transit peptides, which are recognized by protein import complexes in the organelle membranes. Historically, transit peptide properties have been defined from vascular plant sequences, but recent large‐scale genome sequencing from the many plastid‐containing lineages across the tree of life has provided a much broader representation of targeted proteins. This includes the three lineages containing primary plastids (plants and green algae, rhodophytes and glaucophytes) and also the seven major lineages that contain secondary plastids, (...) “secondhand” plastids derived through eukaryotic endosymbiosis. Despite this extensive spread of plastids throughout Eukaryota, an N‐terminal transit peptide has been maintained as an essential plastid‐targeting motif. This article provides the first global comparison of transit peptide composition and summarizes conservation of some features, the loss of an ancestral motif from the green lineages including plants, and modifications to transit peptides that have occurred in secondary and even tertiary plastids. BioEssays 29:1048–1058, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

The issue of regularly feeding low levels of antibiotics to farm animals in order to increase productivity is often portrayed as a dilemma. On the one hand, such antibiotic use is depicted as a necessary condition for producing cheap and plentiful food, such that were such use to stop, food prices would rise significantly and our ability to feed people in developing nations would decrease. On the other hand, such antibiotic use seems to breed antibiotic resistance into pathogens affecting human (...) health. Resolving this dilemma, it is alleged, will require great amounts of research into risk/benefit assessment. Contrary to this claim, we will argue that society has all the data it needs to make a reasonable ethical decision, which would be curtailing such use. Such curtailment will not harm consumers significantly, will not harm developing nations'' evolving agriculture, and could produce hitherto unnoticed benefits, namely restoring the possibility of a more husbandry-based, sustainable agriculture to replace the high-tech agriculture that has hurt animals, the environment, small farms, and sustainability. (shrink)

In this paper, we provide a state-of-the-art overview of the ethical challenges that arise in the context of antimicrobial resistance, which includes an introduction to the contributions to the symposium in this issue. We begin by discussing why AMR is a distinct ethical issue, and should not be viewed purely as a technical or medical problem. In the second section, we expand on some of these arguments and argue that AMR presents us with a broad range of ethical problems (...) that must be addressed as part of a successful policy response to emerging drug resistance. In the third section, we discuss how some of these ethical challenges should be addressed, and we argue that this requires contributions from citizens, ethicists, policy makers, practitioners and industry. We conclude with an overview of steps that should be taken in moving forward and addressing the ethical problems of AMR. (shrink)

Antimicrobial resistance is one of the greatest public health crises of our time. The natural biological process that causes microbes to become resistant to antimicrobial drugs presents a complex social challenge requiring more effective and sustainable management of the global antimicrobial commons—the common pool of effective antimicrobials. This special issue of Health Care Analysis explores the potential of two legal approaches—one long-term and one short-term—for managing the antimicrobial commons. The first article explores the lessons for (...) class='Hi'>antimicrobial resistance that can be learned from recent climate change agreements, and the second article explores how existing international laws can be adapted to better support global action in the short-term. (shrink)

Antimicrobial resistance (AMR) is an urgent, global threat to public health. The development and implementation of effective measures to address AMR is vitally important but presents important ethical questions. This is a policy area requiring further sustained attention to ensure that policies proposed in National Action Plans on AMR are ethically acceptable and preferable to alternatives that might be fairer or more effective, for instance. By ethically analysing case studies of coercive actions to address AMR across countries, we can (...) better inform policy in a context-specific manner. In this article, I consider an example of coercive antimicrobial stewardship policy in Canada, namely restrictions on livestock farmers' access to certain antibiotics for animal use without a vet's prescription. I introduce and analyse two ethical arguments that might plausibly justify coercive action in this case: the harm principle and a duty of collective easy rescue. In addition, I consider the factors that might generally limit the application of those ethical concepts, such as challenges in establishing causation or evidencing the scale of the harm to be averted. I also consider specifics of the Canadian context in contrast to the UK and Botswana as example settings, to demonstrate how context-specific factors might mean a coercive policy that is ethically justified in one country is not so in another. (shrink)

Existing ethical frameworks for public health provide insufficient guidance on how to evaluate the risks of public health programs that compromise the best clinical interests of present patients for the benefit of others. Given the relevant similarity of such programs to clinical research, we suggest that insights from the long‐standing debate about acceptable risk in clinical research can helpfully inform and guide the evaluation of risks posed by public health programs that compromise patients’ best clinical interests. We discuss how lessons (...) learned regarding the ethics of risk in one context can be fruitfully transferred to the other, using the example of a so‐called ‘rational antibiotic use’ guideline that limits antimicrobial prescribing in order to curb antimicrobial resistance. (shrink)

Both W9 and OP3‐4 were known to bind the receptor activator of NF‐κB ligand (RANKL), inhibiting osteoclastogenesis. Recently, both peptides were shown to stimulate osteoblast differentiation; however, the mechanism underlying the activity of these peptides remains to be clarified. A primary osteoblast culture showed that rapamycin, an mTORC1 inhibitor, which was recently demonstrated to be an important serine/threonine kinase for bone formation, inhibited the peptide‐induced alkaline phosphatase activity. Furthermore, both peptides promoted the phosphorylation of Akt and S6K1, (...) an upstream molecule of mTORC1 and the effector molecule of mTORC1, respectively. In the in vivo calvarial defect model, W9 and OP3‐4 accelerated BMP‐2‐induced bone formation to a similar extent, which was confirmed by histomorphometric analyses using fluorescence images of undecalcified sections. Our data suggest that these RANKL‐binding peptides could stimulate the mTORC1 activity, which might play a role in the acceleration of BMP‐2‐induced bone regeneration by the RANKL‐binding peptides. (shrink)

ArgumentThis article examines how antimicrobial resistance (AMR) came to be constituted as a matter of public concern in Sweden in conjunction with the development of an inter-professional organization called Strama, founded to promote rational prescription of antibiotics. An outbreak of penicillin-resistant pneumococci in the mid-1990s was crucial for this development, because it brought attention to AMR as an urgent public threat. This outbreak fuelled the constitution of AMR as caused by consumption of antibiotics and as a matter of disease (...) control. As a consequence, Strama was able to mobilize the Swedish health officers responsible for disease control. The outbreak is conceptualized as a “transformative event” – an event that makes an issue and its associated risks concrete and urgent. Transformative events play the crucial role of expediting the transformation of issues into matters of public concern. (shrink)

Over the past decade, high‐throughput studies have identified many novel transcripts. While their existence is undisputed, their coding potential and functionality have remained controversial. Recent computational approaches guided by ribosome profiling have indicated that translation is far more pervasive than anticipated and takes place on many transcripts previously assumed to be non‐coding. Some of these newly discovered translated transcripts encode short, functional proteins that had been missed in prior screens. Other transcripts are translated, but it might be the process of (...) translation rather than the resulting peptides that serves a function. Here, we review annotation studies in zebrafish to discuss the challenges of placing RNAs onto the continuum that ranges from functional protein‐encoding mRNAs to potentially non‐functional peptide‐producing RNAs to non‐coding RNAs. As highlighted by the discovery of the novel signaling peptide Apela/ELABELA/Toddler, accurate annotations can give rise to exciting opportunities to identify the functions of previously uncharacterized transcripts. (shrink)

Affective disorders arise in stressful situations from aberrant sensory information integration that affects energetic nutrient (i.e., glucose) utilization to the cognitive centers of the brain. Because energy flow is mediated by molecular signals and receptors that evolved before the first complex brains, the phylogenetically oldest signaling systems are essential in the etiology of affective disorders. The corticotropin‐releasing factor (CRF) peptide subfamily is a phylogenetically old metazoan peptide family and is pivotal for regulating organismal energy response associated with stress. Highly conserved, (...) both the CRF peptide family and its receptors possess a structural relationship to the teneurins, and their receptors, latrophilins, respectively. The CRF homologous region of teneurin is defined as the “teneurin C‐terminal associated peptide” (TCAP) and antagonizes CRF action, regulates mitochondrial energy production, and is anxiolytic in vivo. Here, it is postulated that TCAP represents an ancient peptide that mediates intercellular information transfer of stressful and noxious events by regulating energy utilization among neurons. (shrink)

Antimicrobial resistance (AMR) is an urgent threat to global public health and development. Mitigating this threat requires substantial short-term action on key AMR priorities. While international legal agreements are the strongest mechanism for ensuring collaboration among countries, negotiating new international agreements can be a slow process. In the second article in this special issue, we consider whether harnessing existing international legal agreements offers an opportunity to increase collective action on AMR goals in the short-term. We highlight ten AMR priorities (...) and several strategies for achieving these goals using existing “legal hooks” that draw on elements of international environmental, trade and health laws governing related matters that could be used as they exist or revised to include AMR. We also consider the institutional mandates of international authorities to highlight areas where additional steps could be taken on AMR without constitutional changes. Overall, we identify 37 possible mechanisms to strengthen AMR governance using the International Health Regulations, the Agreement on the Application of Sanitary and Phytosanitary Measures, the Agreement on Trade-Related Aspects of Intellectual Property Rights, the Agreement on Technical Barriers to Trade, the International Convention on the Harmonized Commodity Description and Coding System, and the Basel, Rotterdam, and Stockholm conventions. Although we identify many shorter-term opportunities for addressing AMR using existing legal hooks, none of these options are capable of comprehensively addressing all global governance challenges related to AMR, such that they should be pursued simultaneously with longer-term approaches including a dedicated international legal agreement on AMR. (shrink)

Antimicrobial resistance is a major and increasing problem globally. Economics has engaged with this issue increasingly over the last 20 years. Much of this concerns assessments of the cost of various forms of resistance, but it also includes economic analyses of interventions and policies designed to contain resistance. Analysis has, however, thus far largely neglected possible distributional issues associated with such interventions and analysis. The article explores three normative bases for the conduct of economic analysis: welfarism; extra-welfarism focused on (...) health gain; and extra-welfarism focused on capability assessment. It then considers issues intrinsic to antimicrobial resistance in terms of the distributional implications and how these might be handled within economic analyses from each of the normative perspectives, before considering the actual focus of empirical studies on these distributional issues. The article concludes that the different normative starting points for economic analysis will affect how distributional issues are incorporated into analysis, but suggests that all analyses could benefit from greater discussion of these issues. (shrink)

In this paper I attempt to study the notion of “folding of a semiotic continuum” in a direction of a possible application to the biological processes. More specifically, the process of obtaining protein structures is compared in this paper to the folding of a semiotic continuum. Consequently, peptide chain is presented as a continuous line potential to be formed in order to create functional units. The functional units are protein structures having certain function in the cell or organism. Moreover, protein (...) folding is analyzed in terms of tension between syntax and semantics. (shrink)

The inclusion of antimicrobial resistance (AMR) and increased research and development (R&D) capabilities in the most recent outline of the World Health Organization’s (WHO’s) international pandemic instrument signals an opportunity to reshape pharmaceutical R&D system in favour of antimicrobial product development. This article explains why the current innovation ecosystem has disadvantaged the creation of antimicrobial products for human use. It also highlights how the COVID-19 pandemic experience can inform and stimulate international cooperation to implement innovative R&D incentives (...) to bring new, life-saving antimicrobial products to the market. (shrink)

Neuropeptides vasopressin and oxytocin regulate a variety of behaviors ranging from maternal and pair bonding to aggression and fear. Their role in modulating fear responses has been widely recognized, but not yet well understood. Animal and human studies indicate the major role of the amygdala in controlling fear and anxiety. The amygdala is involved in detecting threat stimuli and linking them to defensive behaviors. This is accomplished by projections connecting the central nucleus of the amygdala (CeA) to the brain stem (...) and to hypothalamic structures, which organize fear responses. A recent study by Huber et al1 demonstrates that vasopressin and oxytocin modulate the excitatory inputs into the CeA in opposite manners. Therefore this finding elucidates the mechanisms through which these neuropeptides may control the expression of fear. BioEssays 27:869–873, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

Atrial natriuretic peptides appear to elicit their actions in some target tissues by binding to a novel cell‐surface transmembrane protein which possesses both peptide binding and guanylate cyclase activities. Ligand binding stimulates enzyme activity to produce increased intracellular concentrations of cyclic GMP which, in turn, mediates the cell's physiological response.

Antimicrobial resistance (AMR) has been declared one of the top ten global public health threats facing humanity. To address AMR, coercive antimicrobial stewardship policies are being enacted in some settings. These policies, like all in public health, require ethical justification. Here, I introduce a framework for ethically evaluating coercive antimicrobial stewardship policies on the basis of ethical justifications (and their limitations). I consider arguments from effectiveness; duty of easy rescue; tragedy of the commons; responsibility-tracking; the harm principle; (...) paternalism; justice and development; a precautionary approach; and professional duties. I consider how these justifications might form the basis for developing a comprehensive ethical framework, and the need for this to be context-specific and aligned with the priorities, evidence and needs of the particular jurisdictions in which a policy is to be enacted. I demonstrate how the ethical justifications might be used by reference to an example policy of the EU ban on the use of certain human-critical antibiotics for livestock, before concluding with challenges for further development of the framework. (shrink)

Despite being acknowledged as a major global health challenge, growing levels of antimicrobial resistance (AMR) in pathogenic and commensal organisms have proven an awkward fit for international health frameworks. This article surveys the history of attempts to coordinate international responses to AMR alongside the origins and evolution of the current international health regulations (IHR). It argues that AMR, which encompasses a vast range of microbial properties and ecological reservoirs, is an awkward fit for the ‘organismal’ philosophies that centre on (...) the rapid control of individual pathogens that have characterised international policy-making since the 19th century. (shrink)

It has long been thought that the central nervous system is able to influence the progression of disease. Furthermore, there is now overwhelming evidence that the communication pathways are bidirectional. A variety of immune system peptides are now known to be capable of transmitting information from the immune system to the central nervous system. These immunotransmitters include interleukins, interferons and thymosine peptides which have the capability of modulating slow‐wave sleep as well as the release of neuro‐ and pituitary (...) peptides. In some instances, release of these peptides during early development may have long lasting, if not permanent effects upon the normal development of neuro‐endocrine circuits. Collectively these various brain mediated events appear to contribute in various and diverse ways to defense against pathogens. It is becoming more and more apparent that certain abnormalities within the immune system may be the consequence of a neurological abnormality. The converse is also true. (shrink)

Antimicrobial resistance (AMR) is one of the defining global health threats of our time, but no international legal instrument currently offers the framework and mechanisms needed to address it. Fortunately, the actions needed to address AMR have considerable overlap with the actions needed to confront other pandemic threats.

The majority of antimicrobials that are produced are administered to animals, particularly food animals. While the overall impact of antimicrobial use in animals on antimicrobial resistance in humans and the environment is unclear, it undeniably has a role. Yet, some degree of antimicrobial use in animals is necessary for animal health and welfare purposes. Balancing the benefits and risks of antimicrobial use in animals is challenging because of the complexity of the problem and limitations in available (...) data. However, a range of measures can be implemented to reduce, refine and optimize antimicrobial use in animals, with a goal of minimizing the impact on human and environmental health while maintaining necessary therapeutic use in animals. A pandemic instrument can provide the necessary foundation for the whole-of-society and whole-of government One Health approach that is required to strengthen surveillance, communication, collaboration, and action. (shrink)

An international legal agreement governing the global antimicrobial commons would represent the strongest commitment mechanism for achieving collective action on antimicrobial resistance (AMR). Since AMR has important similarities to climate change—both are common pool resource challenges that require massive, long-term political commitments—the first article in this special issue draws lessons from various climate agreements that could be applicable for developing a grand bargain on AMR. We consider the similarities and differences between the Paris Climate Agreement and current governance (...) structures for AMR, and identify the merits and challenges associated with different international forums for developing a long-term international agreement on AMR. To be effective, fair, and feasible, an enduring legal agreement on AMR will require a combination of universal, differentiated, and individualized requirements, nationally determined contributions that are regularly reviewed and ratcheted up in level of ambition, a regular independent scientific stocktake to support evidence informed policymaking, and a concrete global goal to rally support. (shrink)