Analysing a mechanism of failure in retrieved magnetically controlled spinal rods

PURPOSE: We aim to describe a mechanism of failure in magnetically controlled growth rods which are used for the correction of the early onset scoliosis. METHODS: This retrieval study involved nine magnetically controlled growth rods, of a single design, revised from five patients for metal staining, progression of scoliosis, swelling, fractured actuator pin, and final fusion. All the retrieved rods were radiographed and assessed macroscopically and microscopically for material loss. Two implants were further analysed using micro-CT scanning and then sectioned to allow examination of the internal mechanism. No funding was obtained to analyse these implants. There were no potential conflicts interests. RESULTS: Plain radiographs revealed that three out of nine retrieved rods had a fractured pin. All had evidence of surface degradation on the extendable telescopic rod. There was considerable corrosion along the internal mechanism. CONCLUSIONS: We found that a third of the retrieved magnetically controlled growth rods had failed due to pin fracture secondary to corrosion of the internal mechanism. We recommend that surgeons consider that any inability of magnetically controlled growth rods to distract may be due to corrosive debris building up inside the mechanism, thereby preventing normal function

A mechanism for the inhibition of DNA-PK-mediated DNA sensing by a virus

The innate immune system is critical in the response to infection by pathogens and it is activated by pattern recognition receptors (PRRs) binding to pathogen associated molecular patterns (PAMPs). During viral infection, the direct recognition of the viral nucleic acids, such as the genomes of DNA viruses, is very important for activation of innate immunity. Recently, DNA-dependent protein kinase (DNA-PK), a heterotrimeric complex consisting of the Ku70/Ku80 heterodimer and the catalytic subunit DNA-PKcs was identified as a cytoplasmic PRR for DNA that is important for the innate immune response to intracellular DNA and DNA virus infection. Here we show that vaccinia virus (VACV) has evolved to inhibit this function of DNA-PK by expression of a highly conserved protein called C16, which was known to contribute to virulence but by an unknown mechanism. Data presented show that C16 binds directly to the Ku heterodimer and thereby inhibits the innate immune response to DNA in fibroblasts, characterised by the decreased production of cytokines and chemokines. Mechanistically, C16 acts by blocking DNA-PK binding to DNA, which correlates with reduced DNA-PK-dependent DNA sensing. The C-terminal region of C16 is sufficient for binding Ku and this activity is conserved in the variola virus (VARV) orthologue of C16. In contrast, deletion of 5 amino acids in this domain is enough to knockout this function from the attenuated vaccine strain modified vaccinia virus Ankara (MVA). In vivo a VACV mutant lacking C16 induced higher levels of cytokines and chemokines early after infection compared to control viruses, confirming the role of this virulence factor in attenuating the innate immune response. Overall this study describes the inhibition of DNA-PK-dependent DNA sensing by a poxvirus protein, adding to the evidence that DNA-PK is a critical component of innate immunity to DNA viruses

Downsizing a human inflammatory protein to a small molecule with equal potency and functionality

A significant challenge in chemistry is to rationally reproduce the functional potency of a protein in a small molecule, which is cheaper to manufacture, non-immunogenic, and also both stable and bioavailable. Synthetic peptides corresponding to small bioactive protein surfaces do not form stable structures in water and do not exhibit the functional potencies of proteins. Here we describe a novel approach to growing small molecules with protein-like potencies from a functionally important amino acid of a protein. A 77-residue human inflammatory protein (complement C3a) important in innate immunity is rationally transformed to equipotent small molecules, using peptide surrogates that incorporate a turn-inducing heterocycle with correctly positioned hydrogen-bond-accepting atoms. Small molecule agonists (molecular weigh

Phylogenetic organization of bacterial activity.

Phylogeny is an ecologically meaningful way to classify plants and animals, as closely related taxa frequently have similar ecological characteristics, functional traits and effects on ecosystem processes. For bacteria, however, phylogeny has been argued to be an unreliable indicator of an organism\u27s ecology owing to evolutionary processes more common to microbes such as gene loss and lateral gene transfer, as well as convergent evolution. Here we use advanced stable isotope probing with (13)C and (18)O to show that evolutionary history has ecological significance for in situ bacterial activity. Phylogenetic organization in the activity of bacteria sets the stage for characterizing the functional attributes of bacterial taxonomic groups. Connecting identity with function in this way will allow scientists to begin building a mechanistic understanding of how bacterial community composition regulates critical ecosystem functions.The ISME Journal advance online publication, 4 March 2016; doi:10.1038/ismej.2016.28

Language Structure Is Partly Determined by Social Structure

BACKGROUND: Languages differ greatly both in their syntactic and morphological systems and in the social environments in which they exist. We challenge the view that language grammars are unrelated to social environments in which they are learned and used. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a statistical analysis of >2,000 languages using a combination of demographic sources and the World Atlas of Language Structures--a database of structural language properties. We found strong relationships between linguistic factors related to morphological complexity, and demographic/socio-historical factors such as the number of language users, geographic spread, and degree of language contact. The analyses suggest that languages spoken by large groups have simpler inflectional morphology than languages spoken by smaller groups as measured on a variety of factors such as case systems and complexity of conjugations. Additionally, languages spoken by large groups are much more likely to use lexical strategies in place of inflectional morphology to encode evidentiality, negation, aspect, and possession. Our findings indicate that just as biological organisms are shaped by ecological niches, language structures appear to adapt to the environment (niche) in which they are being learned and used. As adults learn a language, features that are difficult for them to acquire, are less likely to be passed on to subsequent learners. Languages used for communication in large groups that include adult learners appear to have been subjected to such selection. Conversely, the morphological complexity common to languages used in small groups increases redundancy which may facilitate language learning by infants. CONCLUSIONS/SIGNIFICANCE: We hypothesize that language structures are subjected to different evolutionary pressures in different social environments. Just as biological organisms are shaped by ecological niches, language structures appear to adapt to the environment (niche) in which they are being learned and used. The proposed Linguistic Niche Hypothesis has implications for answering the broad question of why languages differ in the way they do and makes empirical predictions regarding language acquisition capacities of children versus adults

End-Tagging of Ultra-Short Antimicrobial Peptides by W/F Stretches to Facilitate Bacterial Killing

BACKGROUND: Due to increasing resistance development among bacteria, antimicrobial peptides (AMPs), are receiving increased attention. Ideally, AMP should display high bactericidal potency, but low toxicity against (human) eukaryotic cells. Additionally, short and proteolytically stable AMPs are desired to maximize bioavailability and therapeutic versatility. METHODOLOGY AND PRINCIPAL FINDINGS: A facile approach is demonstrated for reaching high potency of ultra-short antimicrobal peptides through end-tagging with W and F stretches. Focusing on a peptide derived from kininogen, KNKGKKNGKH (KNK10) and truncations thereof, end-tagging resulted in enhanced bactericidal effect against Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus. Through end-tagging, potency and salt resistance could be maintained down to 4-7 amino acids in the hydrophilic template peptide. Although tagging resulted in increased eukaryotic cell permeabilization at low ionic strength, the latter was insignificant at physiological ionic strength and in the presence of serum. Quantitatively, the most potent peptides investigated displayed bactericidal effects comparable to, or in excess of, that of the benchmark antimicrobial peptide LL-37. The higher bactericidal potency of the tagged peptides correlated to a higher degree of binding to bacteria, and resulting bacterial wall rupture. Analogously, tagging enhanced peptide-induced rupture of liposomes, particularly anionic ones. Additionally, end-tagging facilitated binding to bacterial lipopolysaccharide, both effects probably contributing to the selectivity displayed by these peptides between bacteria and eukaryotic cells. Importantly, W-tagging resulted in peptides with maintained stability against proteolytic degradation by human leukocyte elastase, as well as staphylococcal aureolysin and V8 proteinase. The biological relevance of these findings was demonstrated ex vivo for pig skin infected by S. aureus and E. coli. CONCLUSIONS/SIGNIFICANCE: End-tagging by hydrophobic amino acid stretches may be employed to enhance bactericidal potency also of ultra-short AMPs at maintained limited toxicity. The approach is of general applicability, and facilitates straightforward synthesis of hydrophobically modified AMPs without the need for post-peptide synthesis modifications

Movable genetic elements and antibiotic resistance in enterococci

The enterococci possess genetic elements able to move from one strain to another via conjugation. Certain enterococcal plasmids exhibit a broad host range among gram-positive bacteria, but only when matings are performed on solid surfaces. Other plasmids are more specific to enterococci, transfer efficiently in broth, and encode a response to recipient-produced sex phermones. Transmissible non-plasmid elements, the conjugative transposons, are widespread among the enterococci and determine their own fertility properties. Drug resistance, hemolysin, and bacteriocin determinants are commonly found on the various transmissible enterococcal elements. Examples of the different systems are discussed in this review.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47900/1/10096_2005_Article_BF01963632.pd