Bringing Koch's postulates to the table in IBD

In this issue of Cell Host & Microbe, Bloom and colleagues elegantly show that commensal Bacteroides species fulfill Koch's postulates for inflammatory bowel disease in a host-genotype-specific way. This study showcases the use of a non-germ-free mouse model to identify specific members of the microbiota involved in disease development.     

Polymicrobial challenges to Koch's postulates: Ecological lessons from the bacterial vaginosis and cystic fibrosis microbiomes

Koch's postulates have shaped our understanding of infectious diseases; however, one of the tangential consequences of them has been the emergence of a predominantly monomicrobial perspective concerning disease aetiology. This orthodoxy has been undermined by the growing recognition that some important infectious diseases have a polymicrobial aetiology. A significant new development in our understanding of polymicrobial infections is the recognition that they represent functional ecosystems and that to understand such systems and the outcome and impact of therapeutic interventions requires an understanding of how these communities arise and develop. Therefore, it is timely to explore what we can learn from other fields. In particular, ecological theory may inform our understanding of how polymicrobial communities assemble their structure and their dynamics over time. Such work may also offer insights into how such communities move from stable to unstable states, as well as the role of invasive pathogens in the progression of the disease. Ecological theory offers a theoretical framework around which testable hypotheses can be developed to clarify the polymicrobial nature and dynamics of such infections in the face of environmental change and therapeutic interventions.     

The neurobiology of muscle fatigue: 15 years later

This brief review summarizes progress that has been made inthe study of muscle fatigue since a review published 15 yearsago (Enoka RM, Stuart DG. 1992. Neurobiology of muscle fatigue.J Appl Physiol 72:1631–48.). The present review firstdiscusses progress on the four themes identified in the 1992review and then describes a new approach that can be used toidentify the functionally significant physiological adjustmentsthat occur during fatiguing contractions. As described in theprevious review, it is currently not possible to develop a comprehensivemodel of muscle fatigue because the prevailing mechanism thatimpairs performance varies with the characteristics of the taskthat is being performed. An alternative approach is to focuson the mechanisms that cause failure to complete the task. Thistask-failure approach involves comparing two performances andidentifying the adjustments that limit the rate for the moredifficult condition. With this approach, initial studies havedemonstrated that the time to failure of a sustained contractioncan be influenced by such variables as the type of load supportedby the limb, the posture of the limb, and the group of musclesinvolved in the task. The challenge is to identify the mechanismsthat enable these different variables influence the time totask failure.     

Peteosthor - a medical disaster due to Radium-224A personal recollection

Up to the end of World War II, there was no effective therapy against bone tuberculosis, and even today there is no treatment for ankylosing spondylitis. However, in the 1940s up to about 1956, radiotherapy with "Peteosthor" - a drug containing Thorium X ((224)Ra) as an effective compound - was introduced in Germany as a presumed cure and it maintained a central place in the treatment of these diseases. In 1948, I was entrusted to assess the new treatment. Animal studies and the clinical evaluation of the patients made me soon realise a number of severe adverse health effects which induced me to pronounce and subsequently repeat warnings against the intravenous administration of high doses of (224)Ra, especially because it was then administered predominantly to children and juveniles. As a consequence, this type of treatment was finally abandoned in 1956. But there remained a need to observe and document the resulting late health effects. Already in 1967, our initial follow-up study provided data for about 800 patients with exact information on the (224)Ra dose levels administered, administration schemes, and the resulting detrimental effects. A large number of bone sarcomas was the most severe consequence, but even today there is a broad spectrum of other grave health effects. A summary of the major scientific insights which have been achieved in the course of the still on-going epidemiological studies is part of this report.     

Molecular basis of bacterial resistance to chloramphenicol and florfenicol

Chloramphenicol (Cm) and its fluorinated derivative florfenicol (Ff) represent highly potent inhibitors of bacterial protein biosynthesis. As a consequence of the use of Cm in human and veterinary medicine, bacterial pathogens of various species and genera have developed and/or acquired Cm resistance. Ff is solely used in veterinary medicine and has been introduced into clinical use in the mid-1990s. Of the Cm resistance genes known to date, only a small number also mediates resistance to Ff. In this review, we present an overview of the different mechanisms responsible for resistance to Cm and Ff with particular focus on the two different types of chloramphenicol acetyltransferases (CATs), specific exporters and multidrug transporters. Phylogenetic trees of the different CAT proteins and exporter proteins were constructed on the basis of a multisequence alignment. Moreover, information is provided on the mobile genetic elements carrying Cm or Cm/Ff resistance genes to provide a basis for the understanding of the distribution and the spread of Cm resistance--even in the absence of a selective pressure imposed by the use of Cm or Ff.     

Four-stranded nucleic acid structures 25 years later: from guanosine gels to telomer DNA

The subject of four-stranded nucleic acid structures is reviewed. Studies on gels formed by guanosine and its analogues have provided appropriate models for the structures of poly(I) and poly(G). The stabilizing influence of certain cations, in particular K+, on Guo-5'-P gels and poly(I) is discussed in the light of recent data on selective K+ stabilization of telomeric DNA structures. The topological possibilities these dG containing sequences could adopt are discussed. In particular the role of the glycosidic linkage (anti/syn), the polarity of the strands and the orientation of the G-tetrad stacks is highlighted.     

The fate of15N labeled nitrogen applied to mature citrus trees

Summary The efficiency and balance of nitrogen from one year's application was studied in a long-term fertigation experiment. Enriched nitrogen fertilizer, K¹⁵NO₃, was applied to a 22-year-old Shamouti orange tree with a history of high N applications (N₃) and to an N-starved tree (N₁). The distribution of N in the different parts of the trees and in the soil was determined after the experimental trees were excavated. Similar total recovery of the labeled fertilizer N was found in the trees and soil in both treatments (N₁−61.7% N₃−56%). However, the distribution between tree and soil was different. The amount of recovered residual fertilizer in the soil was much larger in the N₃ treatment than in N₁. The highest percentage of fertilizer N was found in the new organs,i.e. fruits, twigs and leaves. The roots and branches took up only 6–14% from the labeled fertilizer. Only 20.9% of the leaf N and 23.4% of the fruit N in the N₃ tree originated in the labeled fertilizer, indicating translocation of N from older parts of the tree to new growth. Evidence was found of storage of N in the wooded branches, while the roots contained a surprisingly small part of labeled fertilizer. Contribution 1599E.     

Molecular dissection of arginyltransferases guided by similarity to bacterial peptidoglycan synthases

Post-translational protein arginylation is essential for cardiovascular development and angiogenesis in mice and is mediated by arginyl-transfer RNA-protein transferases Ate1-a functionally conserved but poorly understood class of enzymes. Here, we used sequence analysis to detect the evolutionary relationship between the Ate1 family and bacterial FemABX family of aminoacyl-tRNA-peptide transferases, and to predict the functionally important residues in arginyltransferases, which were then used to construct a panel of mutants for further molecular dissection of mouse Ate1. Point mutations of the residues in the predicted regions of functional importance resulted in changes in enzymatic activity, including complete inactivation of mouse Ate1; other mutations altered its substrate specificity. Our results provide the first insights into the mechanisms of Ate1-mediated arginyl transfer reaction and substrate recognition, and define a new protein superfamily called Dupli-GNAT to reflect its origin by the duplication of the GNAT acetyltransferase domain.     

Skin colonization byMalassezia furfur in healthy children up to 15 years old

The prevalence ofM. furfur, a lipodependent fungus, in the skin of 0 to 15-year-old healthy children was studied. Sterilized carpet was used to collect skin samples which were cultured in Oxgall medium (Difco) with 1% olive oil and incubated for 10 days at 37 °C.M. furfur was recovered in 17.8% of infants, with similar findings in both sexes. The highest prevalence ofM. furfur colonization was found among children of 0 to 18 months and 11 to 15-year-olds, with 23.3% and 26.7% respectively.Part of the Ms. thesis of Victor Silva Associação deMalassezia furfur com patologias com componente seborréico.     

Dynamic network reconstruction from gene expression data applied to immune response during bacterial infection

MOTIVATION: The immune response to bacterial infection represents a complex network of dynamic gene and protein interactions. We present an optimized reverse engineering strategy aimed at a reconstruction of this kind of interaction networks. The proposed approach is based on both microarray data and available biological knowledge. RESULTS: The main kinetics of the immune response were identified by fuzzy clustering of gene expression profiles (time series). The number of clusters was optimized using various evaluation criteria. For each cluster a representative gene with a high fuzzy-membership was chosen in accordance with available physiological knowledge. Then hypothetical network structures were identified by seeking systems of ordinary differential equations, whose simulated kinetics could fit the gene expression profiles of the cluster-representative genes. For the construction of hypothetical network structures singular value decomposition (SVD) based methods and a newly introduced heuristic Network Generation Method here were compared. It turned out that the proposed novel method could find sparser networks and gave better fits to the experimental data. CONTACT: Reinhard.Guthke@hki-jena.de.     

New knowledge on pathogenesis of bacterial enteric infections as applied to vaccine development.

This review attempts to synthesize the new knowledge of pathogenesis of bacterial enteric infections and relate this information to vaccine development. Discussion focuses on human infections and to those in which significant strides have been made. As a general theme in the pathogenesis of bacterial enteric infections, pathogens can be characterized into 5 groups on the basis of their degree of ultimate invasiveness after ingestion by a susceptible hose: mucosal adherence and enterotoxin production; mucosal adherence and brush border dissolution -- enteropathogenic E. coli (EPEC) of "classical" serotypes; mucosal invasion and intraepithelial cell proliferation; mucosal translocation followed by bacterial proliferation in the lamina propria and mesenteric lymph nodes; and mucosal translocation followed by generalized infection. The review covers cholera (motility and chemotaxis, mucosal adhesion, flagellar sheath protein, hemagglutinins, outer membrane proteins, enterotoxin production, quality and duration of infection derived immunity, immune response in humans, LPS, flagellar sheath protein, cholera lectin, other cholera hemagglutinins, outer membrane protein, previous cholera vaccines, killer whole cell vaccines, toxoids, combination vaccines, attenuated versus cholerae vaccines): enterotoxigenic Escherichia coli (ETEC) (entertoxins, O:H serotypes and enterotoxin phenotypes, colonization factors, immune response in humans, vaccines against ETEC, and toxiods); EPEC (vaccines against EPEC); Shigella (smooth LPS O antigen, epithelial cell invasiveness, Shigella toxin, and Shigella vaccines); and typhoid fever (caccines against typhoid fever). The major attraction of a nonliving oral cholera vaccine is its safety. A review of available information leads to the conclusion that an oral vaccine consisting of a combination of antigens, intending to stimulate both antibacterial and antitoxic immunity, would be most likely to succeed. Current approaches to immunoprophylaxis of ETEC infection involve vaccines that stimulate antitoxic or antiadhesion immunity or both by means of killed antigens or attenuated strains. It is likely that the most effective vaccines will contain appropriate antigens intended to simultaneously stimulate both antibacterial and antitoxic immunity, thereby leading to a synergistic protective effect. Now that the speical enteroadhesive properties of EPEC have been characterized and shown to be associated with a plasmid, it should be possible to identify the phenotypic gene products responsible for this phenomenon. It is likely that fimbriae or outer membrane proteins will prove to be the organelle of adhesion. When such information becomes available, it should be possible to prepare oral vaccines consisting of the purified antigen. Efficacy has been shown for attenuated Shigella strains utilized as oral vaccines. The major thrust in the development of new immunization agensts against typhoid fever is to identify immunizing agents at least equal in efficacy to the parenteral acetone killed vaccine but which cause no adverse reactions.