The impact of PARPs and ADP-ribosylation on inflammation and host–pathogen interactions

This work is licensed under a Creative Commons Attribution 4.0 International License.Poly-adenosine diphosphate-ribose polymerases (PARPs) promote ADP-ribosylation, a highly conserved, fundamental posttranslational modification (PTM). PARP catalytic domains transfer the ADP-ribose moiety from NAD+ to amino acid residues of target proteins, leading to mono- or poly-ADP-ribosylation (MARylation or PARylation). This PTM regulates various key biological and pathological processes. In this review, we focus on the roles of the PARP family members in inflammation and host–pathogen interactions. Here we give an overview the current understanding of the mechanisms by which PARPs promote or suppress proinflammatory activation of macrophages, and various roles PARPs play in virus infections. We also demonstrate how innovative technologies, such as proteomics and systems biology, help to advance this research field and describe unanswered questions

Preventing infection of osseointegrated transcutaneous implants: Incorporation of silver into preconditioned fibronectin-functionalized hydroxyapatite coatings suppresses Staphylococcus aureus colonization while promoting viable fibroblast growth in vitro

The success of transcutaneous implants depends on the achievement of a soft tissue seal by enabling fibroblasts to win the race for the surface against bacteria. Fibronectin-functionalized hydroxyapatite coatings (HAFn) have been shown to improve dermal tissue ingrowth and attachment. However, during the early postoperative period before a soft tissue seal has formed, bacterial colonization may occur. This study explored the incorporation of silver, a broad spectrum antimicrobial agent, into HAFn coatings with the aim of reducing bacterial colonization. Silver is known to have dose-dependent cytotoxic effects. Therefore, the effects of silver incorporation into HAFn coatings on both in vitro human dermal fibroblast viability and Staphylococcus aureus colonization were assessed. An electrochemical deposition technique was used to codeposit hydroxyapatite and silver (HAAg) and fibronectin was adsorbed onto this to produce HAAgFn coatings. Surfaces were preconditioned with serum to mimic the in vivo environment. Nonpreconditioned HAAg and HAAgFn coatings suppressed bacterial colonization but were cytotoxic. After serum-preconditioning, more than 90% of fibroblasts that grew on all HAAg and HAAgFn coatings were viable. The highest silver content coatings tested (HAAg100 and HAAgFn100) resulted in a greater than 99% reduction in biofilm and planktonic bacterial numbers compared to HA and HAFn controls. Although HAAg100 had greater antibacterial activity than HAAgFn100, the findings of this study indicate that fibroblasts would win the race for the surface against S aureus on both HAAg100 and HAAgFn100 after serum-preconditioning

Tumor-Associated Macrophages (TAMs) Form an Interconnected Cellular Supportive Network in Anaplastic Thyroid Carcinoma

BACKGROUND: A relationship between the increased density of tumor-associated macrophages (TAMs) and decreased survival was recently reported in thyroid cancer patients. Among these tumors, anaplastic thyroid cancer (ATC) is one of the most aggressive solid tumors in humans. TAMs (type M2) have been recognized as promoting tumor growth. The purpose of our study was to analyze with immunohistochemistry the presence of TAMs in a series of 27 ATC. METHODOLOGY/PRINCIPAL FINDINGS: Several macrophages markers such as NADPH oxidase complex NOX2-p22phox, CD163 and CD 68 were used. Immunostainings showed that TAMs represent more than 50% of nucleated cells in all ATCs. Moreover, these markers allowed the identification of elongated thin ramified cytoplasmic extensions, bestowing a "microglia-like" appearance on these cells which we termed "Ramified TAMs" (RTAMs). In contrast, cancer cells were totally negative. Cellular stroma was highly simplified since apart from cancer cells and blood vessels, RTAMs were the only other cellular component. RTAMs were evenly distributed and intermingled with cancer cells, and were in direct contact with other RTAMs via their ramifications. Moreover, RTAMs displayed strong immunostaining for connexin Cx43. Long chains of interconnected RTAMs arose from perivascular clusters and were dispersed within the tumor parenchyma. When expressed, the glucose transporter Glut1 was found in RTAMs and blood vessels, but rarely in cancer cells. CONCLUSION: ATCs display a very dense network of interconnected RTAMs in direct contact with intermingled cancer cells. To our knowledge this is the first time that such a network is described in a malignant tumor. This network was found in all our studied cases and appeared specific to ATC, since it was not found in differentiated thyroid cancers specimens. Taken together, these results suggest that RTAMs network is directly related to the aggressiveness of the disease via metabolic and trophic functions which remain to be determined

Genetic assessment of additional endophenotypes from the Consortium on the Genetics of Schizophrenia Family Study

The Consortium on the Genetics of Schizophrenia Family Study (COGS-1) has previously reported our efforts to characterize the genetic architecture of 12 primary endophenotypes for schizophrenia. We now report the characterization of 13 additional measures derived from the same endophenotype test paradigms in the COGS-1 families. Nine of the measures were found to discriminate between schizophrenia patients and controls, were significantly heritable (31 to 62%), and were sufficiently independent of previously assessed endophenotypes, demonstrating utility as additional endophenotypes. Genotyping via a custom array of 1536 SNPs from 94 candidate genes identified associations for CTNNA2, ERBB4, GRID1, GRID2, GRIK3, GRIK4, GRIN2B, NOS1AP, NRG1, and RELN across multiple endophenotypes. An experiment-wide p value of 0.003 suggested that the associations across all SNPs and endophenotypes collectively exceeded chance. Linkage analyses performed using a genome-wide SNP array further identified significant or suggestive linkage for six of the candidate endophenotypes, with several genes of interest located beneath the linkage peaks (e.g., CSMD1, DISC1, DLGAP2, GRIK2, GRIN3A, and SLC6A3). While the partial convergence of the association and linkage likely reflects differences in density of gene coverage provided by the distinct genotyping platforms, it is also likely an indication of the differential contribution of rare and common variants for some genes and methodological differences in detection ability. Still, many of the genes implicated by COGS through endophenotypes have been identified by independent studies of common, rare, and de novo variation in schizophrenia, all converging on a functional genetic network related to glutamatergic neurotransmission that warrants further investigation

Determining the porous structure for optimal soft-tissue ingrowth: An in vivo histological study.

The success of osseointegrated transcutaneous prostheses depends on a soft-tissue seal forming at the skin-implant interface in order to prevent infection. Current designs include a flange with drilled holes or a subdermal barrier with a porous coating in an attempt to promote soft-tissue attachment. However, the soft-tissue seal is not reliably achieved despite these designs and infection remains a significant problem. This study investigated soft-tissue integration into fully porous titanium alloy structures with interconnected pores. The study aimed to determine the effect of altering pore and strut size combinations on soft-tissue ingrowth into porous titanium alloy structures in vivo. It was hypothesized that implants with a more open porous structure with larger pore sizes would increase soft-tissue ingrowth more than less open porous structures. Porous titanium alloy cylinders were inserted into sheep paparaspinal muscles (n = 6) and left in situ for four weeks. A histological assessment of soft-tissue ingrowth was performed. Percentage soft-tissue pore fill, cell nuclei density and blood vessel density were quantified. The results showed that larger pore sizes were supportive of soft-tissue ingrowth. A structure with a pore size of 700μm and a strut size of 300μm supported revascularisation to the greatest degree. A flange with this structure may be used in future studies of osseointegrated transcutaneous prostheses in order to enhance the soft-tissue seal

Deregulation of PKN1 activity disrupts neurofilament organisation and axonal transport

Neurofilaments are synthesised in neuronal cell bodies and then transported through axons. Damage to neurofilament transport is seen in amyotrophic lateral sclerosis (ALS). Here, we show that PKN1, a neurofilament head-rod domain kinase is cleaved and activated in SOD1G93A transgenic mice that are a model of ALS. Moreover, we demonstrate that glutamate, a proposed toxic mechanism in ALS leads to caspase cleavage and disruption of PKN1 in neurons. Finally, we demonstrate that a cleaved form of PKN1 but not wild-type PKN1 disrupts neurofilament organisation and axonal transport. Thus, deregulation of PKN1 may contribute to the pathogenic process in AL