The human immune system can directly lyse invading micro‐organisms and aberrant host cells by generating pores in the cell envelope, called membrane attack complexes (MACs). Recent studies using single‐particle cryoelectron microscopy have revealed that the MAC is an asymmetric, flexible pore and have provided a structural basis on how the MAC ruptures single lipid membranes. Despite these insights, it remains unclear how the MAC ruptures the composite cell envelope of Gram‐negative bacteria. Recent functional studies on Gram‐negative (...) class='Hi'>bacteria elucidate that local assembly of MAC pores by surface‐bound C5 convertase enzymes is essential to stably insert these pores into the bacterial outer membrane (OM). These convertase‐generated MAC pores can subsequently efficiently damage the bacterial inner membrane (IM), which is essential for bacterial killing. This review summarizes these recent insights of MAC assembly and discusses how MAC pores kill Gram‐negative bacteria. Furthermore, this review elaborates on how MAC‐dependent OM damage could lead to IM destabilization, which is currently not well understood. A better understanding on how MAC pores kill bacteria could facilitate the future development of novel strategies to treat infections with Gram‐negative bacteria. (shrink)

Effectiveness is a key criterion in assessing the justification of antibiotic resistance interventions. Depending on an intervention’s effectiveness, burdens and costs will be more or less justified, which is especially important for large scale population-level interventions with high running costs and pronounced risks to individuals in terms of wellbeing, integrity and autonomy. In this paper, we assess the case of routine hospital screening for multi-drug-resistant Gram-negative bacteria (MDRGN) from this perspective. Utilizing a comparison to screening programs for Methicillin-Resistant Staphylococcus (...) aureus (MRSA) we argue that current screening programmes for MDRGN in low endemic settings should be reconsidered, as its effectiveness is in doubt, while general downsides to screening programs remain. To accomplish justifiable antibiotic stewardship, MDRGN screening should not be viewed as a separate measure, but rather as part of a comprehensive approach. The program should be redesigned to focus on those at risk of developing symptomatic infections with MDRGN rather than merely detecting those colonised. (shrink)

The pathogenic, Gram‐negative bacteria, Neisseria gon‐orrhoeae, Neisseria meningitidis and Haemophilus influenzae, secrete immunoglobulin A1 proteases into their extracellular surroundings. An extraordinary feature in the secretory pathway of these putative virulence factors is a self‐directed outer membrane transport step allowing the proteins to be secreted autonomously, even from foreign Gram‐negative host cells like Escherichia coli. Here we summarize recent achievements in the understanding of IgA protease outer membrane translocation.

The outer membrane (OM) is an essential barrier that guards Gram‐negative bacteria from diverse environmental insults. Besides functioning as a chemical gatekeeper, the OM also contributes towards the strength and stiffness of cells and allows them to sustain mechanical stress. Largely influenced by studies of Escherichia coli, the OM is viewed as a rigid barrier where OM proteins and lipopolysaccharides display restricted mobility. Here the discussion is extended to other bacterial species, with a focus on Myxococcus xanthus. In (...) contrast to the rigid OM paradigm, myxobacteria possess a relatively fluid OM. It is concluded that the fluidity of the OM varies across environmental species, which is likely linked to their evolution and adaptation to specific ecological niches. Importantly, a fluid OM can endow bacteria with distinct functions for cell‐cell and cell‐environment interactions. (shrink)

Proteinaceous stalks produced by Gram‐negative bacteria are often used to adhere to environmental surfaces. Among them, chaperone‐usher (CU) fimbriae adhesins, related to prototypical type 1 fimbriae, interact in highly specific ways with different ligands at different stages of bacterial infection or surface colonisation. Recent analyses revealed a large number of potential and often “cryptic” CU fimbriae homologues in the genome of commensal and pathogenic Escherichia coli and closely related bacteria. We propose that CU fimbriae form a yet (...) unexplored arsenal of lectins, carbohydrate‐binding proteins involved in various aspects of bacterial surface adhesion and tissue tropism. Combined efforts of molecular and structural biologists will be required to unravel the biological contribution of the bacterial lectome, however, current progress has already opened up new perspectives in the design of novel anti‐infective strategies. (shrink)

Briefly stated my point is that the well-being of each person in a community conceived abstractly may be all too easily sacrificed for the sake of the abstraction. Physicians may offer critically ill patients places in programs of experimental treatment, but there is commonly a catch to the offer. To take part in a program of clinical experiment a patient must not only risk a possible failure of a fresh drug and the chance of destructive side effects from the drug, (...) but the patients must risk only getting the traditional treatment along with a placebo rather than the experimental drug. Placebo control, double blind critical protocols for testing effects of fresh drugs on critically ill patients are a commonplace. I question the scientific objectivity of the protocols and the underlying ethic, and suggest use of alternate protocols. Experimental tests in the treatment gram-negative bacteria blood infections, muscular dystrophy, and AIDS and AIDS-related diseases are examples. (shrink)

Antibiotic resistance in bacteria has become a great threat to global public health. Tigecycline is a next‐generation tetracycline that is the final line of defense against severe infections by pan‐drug‐resistant bacterial pathogens. Unfortunately, this last‐resort antibiotic has been challenged by the recent emergence of the mobile Tet(X) orthologs that can confer high‐level tigecycline resistance. As it is reviewed here, these novel tetracycline destructases represent a growing threat to the next‐generation tetracyclines, and a basic framework for understanding the molecular epidemiology (...) and resistance mechanisms of them is presented. However, further large‐scale epidemiological and functional studies are urgently needed to better understand the prevalence and dissemination of these newly discovered Tet(X) orthologs among Gram‐negative bacteria in both human and veterinary medicine. (shrink)

Outer membrane proteins (OMPs) maintain the viability of Gram‐negative bacteria by functioning as receptors, transporters, ion channels, lipases, and porins. Folding and assembly of OMPs involves synchronized action of chaperones and multi‐protein machineries which escort the highly hydrophobic polypeptides to their target outer membrane in a folding competent state. Previous studies have identified proteins and their involvement along the OMP biogenesis pathway. Yet, the mechanisms of action and the intriguing ability of all these molecular machines to work without (...) the typical cellular energy source of ATP, but solely based on thermodynamic principles, are still not well understood. Here, we highlight how different single‐molecule studies can shed additional light on the mechanisms and kinetics of OMP biogenesis. (shrink)

Transport of DNA across bacterial membranes involves complex DNA uptake systems. In Gram‐positive bacteria, the DNA uptake machinery shares fundamental similarities with type IV pili and type II secretion systems. Although dedicated pilus structures, such as type IV pili in Gram‐negative bacteria, are necessary for efficient DNA uptake, the role of similar structures in Gram‐positive bacteria is just beginning to emerge. Recently two essentially very different pilus structures composed of the same major pilin protein ComGC were (...) proposed to be involved in transformation of the Gram‐positive bacterium Streptococcus pneumoniae – one is a long, thin, type IV pilus‐like fiber with DNA binding capacity and the other one is a pilus structure that was thicker, much shorter and not able to bind DNA. Here we discuss how competence induced pili, either by pilus retraction or by a transient pilus‐related opening in the cell wall, may mediate DNA uptake in S. pneumoniae. (shrink)

Bacterial resistance mechanisms to the antibiotics known as β‐lactams, which include the penicillins and cephalosporins, can take several forms but frequently involve the production of β‐lactamases from either plasmid‐ or chromosomally‐encoded loci. Gram negative bacteria express a β‐lactamase from evolutionarily related chromosomal ampC genes. Genetic analysis of both inducible and constitutively expressed AmpC β‐lactamases provide insights into the mechanisms regulating production of the enzyme. Evolutionary relationships between the genes of different species are discussed, as well as the regulatory mechanisms (...) that in both laboratory mutants and clinical isolates lead to overproduction of β‐lactamase. (shrink)

DNA transfer directly from cell to cell (conjugation) is common among prokaryotes, particularly Gram‐negative bacteria like Escherichia coli. The phenomenon invariably requires a set of plasmid genes in the DNA donor cell. In addition, E. coli itself makes limited and specific contributions to the donor activity of strains carrying the conjugative plasmid F. These contributions have yet to be defined biochemically, but it is already clear that the cell envelope is an importan nexus between plasmid‐ and chromosome‐encoded proteins (...) required for the establishment and maintenance of DNA donor activity. (shrink)

The Gram-negative outer membrane is a potent permeability barrier against antibiotics, limiting clinical options amid mounting rates of resistance. The Lol transport pathway delivers lipoproteins to the OM. All the OM assembly machines require one or more OM lipoprotein to function, making the Lol pathway central for all aspects of OM biogenesis. The Lol pathways of many medically important species clearly deviate from the Escherichia coli paradigm, perhaps with implications for efforts to develop novel antibiotics. Moreover, recent work reveals the (...) existence of an undiscovered alternate route for bringing lipoproteins to the OM. Here, lipoprotein transport mechanisms, and the quality control systems that underpin them, is re-examined in context of their diversity. All essential outer membrane assembly machines require lipoproteins to function. Hence, the transport mechanisms supplying these lipoproteins are critical for maintaining the integrity of the outer membrane barrier against antibiotics. Lipoprotein transport strategies of diverse Gram-negative bacteria will be reviewed in the context of recent discoveries. (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)

The mechanisms by which bacteria adapt to changes in their environment involve transcriptional regulation in which a transcriptional regulator responds to signal(s) from the environment and regulates (positively or negatively) the expression of several genes or operons. Some of these regulators exert a positive feedback on their own expression. This is a necessary (although not sufficient) condition for the occurrence of multistationarity. One biological consequence of multistationarity may be epigenetic modifications, a hypothesis unusual to microbiologists, in spite of some (...) well-known epigenetic modifications in bacteria. We propose here that the occurrence of mucoidy in the opportunistic pathogen Pseudomonas aeruginosa, which is currently attributed to mutations only, may also be an epigenetic modification. A theoretical approach using a generalised logical analysis lends credit to this hypothesis and suggests experiments to ascertain it. (shrink)

Laura Grams - Language and Learning: Philosophy of Language in the Hellenistic Age - Journal of the History of Philosophy 45:1 Journal of the History of Philosophy 45.1 153-154 Muse Search Journals This Journal Contents Reviewed by Laura Grams University of Nebraska at Omaha Dorothea Frede and Brad Inwood, editors. Language and Learning: Philosophy of Language in the Hellenistic Age. Cambridge-New York: Cambridge University Press, 2005. Pp. xi + 353. Cloth, $90.00. This collection of papers on Hellenistic philosophy of language (...) resulted from the ninth Symposium Hellenisticum, held in Hamburg in July 2001. It makes an important contribution to the secondary literature on this topic and will be valuable to anyone who studies Hellenistic philosophy. Because some chapters discuss broader issues in the philosophy of language or connect.. (shrink)

This article examines the supposedly incomprehensibility of schizophrenic delusions. According to the contemporary classificatory systems (DSM-IV-TR and ICD-10), some delusions typically found in schizophrenia are considered bizarre and incomprehensible. The aim of this article is to discuss the notion of understanding that deems these delusions incomprehensible and to see if it is possible to comprehend these delusions if we apply another notion of understanding. First, I discuss the contemporary schizophrenia definitions and their inherent problems, and I argue that the notion (...) of incomprehensibility in these definitions rests heavily on Jaspers’ notions of understanding and empathy. Secondly, I discuss two Wittgensteinian attempts to comprehend bizarre delusions: (a) Campbell’s proposal to conceive delusions as framework propositions and (b) Sass’s suggestion to interpret delusions in the light of solipsism. Finally, I discuss the phenomenological conception of schizophrenia, which conceives delusion formation as resulting from alterations of the structure of experiencing and from underlying self-disorders. I argue that although a psychological understanding that seeks to grasp meaning in terms of motivations, desires, and other more straightforward psychological connections between mental states is impossible in schizophrenia, we can in fact have a philosophical understanding of the schizophrenic world and of the emergence of delusions typically found in schizophrenia. (shrink)

In this comparative study, we examine experiential disruptions of embodiment and affectivity in Moebius Syndrome and schizophrenia. We suggest that using phenomenological resources to explore these experiences may help us better understand what it’s like to live with these conditions, and that such an understanding may have significant therapeutic value. Additionally, we suggest that this sort of phenomenologically-informed comparative analysis can shed light on the importance of embodiment and affectivity for the constitution of a sense of self and interpersonal relatedness (...) in normal conditions. (shrink)

Auditory verbal hallucinations form an essential criterial feature in the schizophrenia definition in the Diagnostic and Statistical Manual of Mental Disorders -IV and International Classification of Diseases -10. In both classificatory systems, the presence of a hallucinatory voice that continuously comments the patient’s behavior or thoughts, or the presence of several voices that discuss the patient with each other, is a sufficient criterion to diagnose schizophrenia. The DSM-IV defines a hallucination as “a sensory perception that has the..

a vigorous and challenging defence of direct realism in which one gets not only a clear overview of what precisely the problems are, but also a forceful and ...

The task of being oneself lies at the heart of human existence and entails the possibility of not being oneself. In the case of schizophrenia, this possibility may come to the fore in a disturbing way. Patients often report that they feel alienated from themselves. Therefore, it is perhaps unsurprising that schizophrenia sometimes has been described with the heideggerian notion of inauthenticity. The aim of this paper is to explore if this description is adequate. We discuss two phenomenological accounts of (...) schizophrenia: Binswanger’s account of schizophrenia as a form of inauthenticity and Blankenburg’s account of schizophrenia as a loss of common sense, which seems construable as a loss of inauthenticity. We argue that the accounts are highlighting aspects of the same underlying phenomenon, viz. schizophrenic autism. Moreover, we argue that Binswanger’s description of schizophrenia as a form of inauthenticity is inadequate and we discuss experiences of self-alienation in schizophrenia. (shrink)

Research in psychopathology is booming in an unprecedented way, at least, in terms of increasing number of publications. Yet, a few questions arise: Does quantity also give us quality? Are the collected data generally of sound quality? How are data typically collected in psychopathology? Are the applied methods of data collection appropriate for this particular field of study? This article explores three different methods of data collection in psychopathology, namely self-rating scales, structured interviews, and semi-structured, phenomenological interviews. To identify the (...) most adequate methodological approach, we first establish the nature of the object of psychopathology and then we critically assess each method’s appropriateness to this field of study. We emphasize fundamental issues that make self-rating scales and structured interviews unfit for the task of adequately examining psychopathology. By contrast, we propose that a semi-structured, phenomenological interview presents a more appropriate method. Finally, we describe two types of semi-structured, phenomenological interviews that can be applied to assess and explore psychopathology, respectively. (shrink)

Homeopathy is over 200 years old and is still experiencing an uninterrupted influx of new practitioners and patients. Many patients and therapists swear by this "alternative healing method", which in some countries is even financed by health insurances. This seems completely incomprehensible to critics: For them it is clearly evident that homeopathy is hopelessly unscientific and has at best a placebo effect. The positions of supporters and opponents seem to be just as immutable as they are incompatible. This book answers (...) some essential and fascinating questions: What remains of the founding ideas of homeopathy in 21st century medicine? Does it really work and, if so, how? Which of the original theories can we still apply today with a clear conscience and use for the benefit of patients and the healthcare system? Where does homeopathy have its limits and does it indeed need to be critically reconsidered and evaluated? The author has dealt with the points of criticism for years, but at the same time also takes seriously the wishes and concerns of patients who often feel insufficiently cared for by conventional medical practice. Against the background of her own personal history, her book attempts to bridge the gap between these two traditionally opposing camps. (shrink)

In the First Antinomy of The Critique of Pure Reason, Kant drew two conclusions from the argument he gives. First, Kant took his argument to show that the referent of the concept of ‘world’ does not exist as a thing in itself. For at B532 he says.

In the First Antinomy of The Critique of Pure Reason, Kant drew two conclusions from the argument he gives. First, Kant took his argument to show that the referent of the concept of ‘world’ does not exist as a thing in itself. For at B532 he says.

Plato’s Timaeus provides a significant, original account of diseases afflicting the body and soul. The causes of disease are explained according to the same physical principles that account for the motion of the four elements in the universe. As a result, medical expertise concerning the microcosm of the human body depends on cosmological expertise concerning the macrocosm of the universe. in addition, the methods of division and collection (diairesis and sunagōgē) that Plato uses in other late dialogues are employed in (...) the Timaeus to classify ailments according to differences in their dunamis. Each of the three main kinds of disease is caused by a unique kind of bodily motion, which explains why the same body parts, humours, and elements are involved in multiple kinds of disease. (shrink)