Antagonist-mediated down-regulation of toll-like receptors increases the prevalence of human papillomavirus infection in systemic lupus erythematosus

IntroductionPrevalence of an abnormal Papanicolaou smear was significantly increased in lupus patients in cross-sectional studies, associated with a higher prevalence of high-risk human papillomavirus (HPV) infection. The nucleic acid-specific Toll-like receptors (TLRs) locate at the endolysosomal compartments and trigger the induction of cytokines for the innate immune response. This study evaluated whether abnormal host innate immune response in lupus patients may enhance HPV persistence.MethodsProtein levels of TLRs 3, 7, 8 and 9 in cervical epithelial cells of lupus patients and controls with or without HPV infection were assessed using flow cytometry. Characteristics associated with the differential expression of TLRs in systemic lupus erythematosus (SLE) were elucidated. The effect and interferon-stimulated genes (ISGs) (ISG15 and Mx-1) gene expressions were then measured in oncogenic HeLa (HPV18), CaSki (HPV) and C33A (HPV negative) cell lines using flow cytometry and quantitative real-time PCR. Ex vivo productions of cytokines and interferon-gamma (IFN-γ) upon TLR ligands stimulations were subsequently measured using cytometric bead array and ELISA.ResultsFor subjects with HPV infection, levels of TLR3 and TLR7 were significantly lower in lupus patients compared with controls. Significantly decreased TLRs 7, 8 and 9 levels were observed in HPV-negative SLE compared to healthy controls. For SLE with and without HPV infection, TLR7 and 9 levels were significantly lower in infected SLE than those in HPV-negative patients. Independent explanatory variables associated with down-regulation of TLR7 level included HPV infection and a higher cumulative dose of prednisolone; while a higher cumulative dose of hydroxychloroquine and HPV infection were associated with down-regulation of TLR9 level. In cervical cell lines, TLRs 3, 7, 8, 9 protein levels and antiviral ISG15 and Mx-1 gene expressions were inhibited in two oncogenic HPV types. Functional data showed that the induction of pro-inflammatory cytokines by TLR ligands (R837, ssRNA and ODN2395) was greatly impaired in CaSki and HeLa than C33A cells.ConclusionsIn conclusion, prednisolone and TLR antagonist (hydroxychloroquine) may down-regulate protein levels of TLR7 and TLR9 in lupus patients, thereby decreasing the innate immune response against HPV infection. Upon infection, HPV further down-regulate TLR7 and 9 levels for viral persistence. Furthermore, reduction of nucleic acid-sensing TLRs 7, 8 and 9 in carcinogenic HPVs ensures that the expression of inducible pro-inflammatory cytokines is minimized to prevent the expression of antiviral ISGs (ISG15 and Mx-1) on a biologically relevant antiviral response.     

Mass ivermectin treatment for Onchocerciasis: Lack of evidence for collateral impact on transmission of Wuchereria bancrofti in areas of co-endemicity

There has long been interest in determining if mass ivermectin administration for onchocerciasis has 'unknowingly' interrupted lymphatic filariasis (LF) transmission where the endemicity of the two diseases' overlaps. We studied 11 communities in central Nigeria entomologically for LF by performing mosquito dissections on Anopheline LF vectors. Six of the communities studied were located within an onchocerciasis treatment zone, and five were located outside of that zone. Communities inside the treatment zone had been offered ivermectin treatment for two-five years, with a mean coverage of 81% of the eligible population (range 58–95%). We found 4.9% of mosquitoes were infected with any larval stage of W. bancrofti in the head or thorax in 362 dissections in the untreated villages compared to 4.7% infected in 549 dissections in the ivermectin treated villages (Mantel-Haenszel ChiSquare 0.02, P = 0.9). We concluded that ivermectin annual therapy for onchocerciasis has not interrupted transmission of Wuchereria bancrofti (the causative agent of LF in Nigeria).     

Coregulation of beta-galactoside uptake and hydrolysis by the hyperthermophilic bacterium Thermotoga neapolitana

Regulation of the beta-galactoside transport system in response to growth substrates in the extremely thermophilic anaerobic bacterium Thermotoga neapolitana was studied with the nonmetabolizable analog methyl-beta-D-thiogalactopyranoside (TMG) as the transport substrate. T. neapolitana cells grown on galactose or lactose accumulated TMG against a concentration gradient in an intracellular free sugar pool that was exchangeable with external galactose or lactose and showed induced levels of beta-galactosidase. Cells grown on glucose, maltose, or galactose plus glucose showed no capacity to accumulate TMG, though these cells carried out active transport of the nonmetabolizable glucose analog 2-deoxy-D-glucose. Glucose neither inhibited TMG uptake nor caused efflux of preaccumulated TMG; rather, glucose promoted TMG uptake by supplying metabolic energy. These data show that beta-D-galactosides are taken up by T. neapolitana via an active transport system that can be induced by galactose or lactose and repressed by glucose but which is not inhibited by glucose. Thus, the phenomenon of catabolite repression is present in T. neapolitana with respect to systems catalyzing both the transport and hydrolysis of beta-D-galactosides, but inducer exclusion and inducer expulsion, mechanisms that regulate permease activity, are not present. Regulation is manifest at the level of synthesis of the beta-galactoside transport system but not in the activity of the system.     

Distinct preoptic‐BST nuclei dissociate paternal and infanticidal behavior in mice

Paternal behavior is not innate but arises through social experience. After mating and becoming fathers, male mice change their behavior toward pups from infanticide to paternal care. However, the precise brain areas and circuit mechanisms connecting these social behaviors are largely unknown. Here we demonstrated that the c‐Fos expression pattern in the four nuclei of the preoptic‐bed nuclei of stria terminalis (BST) region could robustly discriminate five kinds of previous social behavior of male mice (parenting, infanticide, mating, inter‐male aggression, solitary control). Specifically, neuronal activation in the central part of the medial preoptic area (cMPOA) and rhomboid nucleus of the BST (BSTrh) retroactively detected paternal and infanticidal motivation with more than 95% accuracy. Moreover, cMPOA lesions switched behavior in fathers from paternal to infanticidal, while BSTrh lesions inhibited infanticide in virgin males. The projections from cMPOA to BSTrh were largely GABAergic. Optogenetic or pharmacogenetic activation of cMPOA attenuated infanticide in virgin males. Taken together, this study identifies the preoptic‐BST nuclei underlying social motivations in male mice and reveals unexpected complexity in the circuit connecting these nuclei.     

Bone histology of the Middle Jurassic turtle shell remains from Kirtlington, Oxfordshire, England

The Middle Jurassic (Bathonian) turtle material from the Mammal Bed at Kirtlington, Oxfordshire, England, has recently been tentatively referred to the Pleurosternidae, although the known synapomorphies of this clade were absent from the specimens. Here we present new evidence from shell bone histology that corroborates reports of pleurosternids at Kirtlington and further reveal that two different histomorphs (= two different taxa) are present in this locality. The first histomorph presents the distinctive histological structure of pleurosternids, which is described herein for the first time: the external cortical bone layers are differentiated into an inner zone of coarse, irregularly interwoven structural fibre bundles and an outer fine-fibred zone. The second histomorph has a more plesiomorphic structure and can only be assigned to Cryptodira indet. A morphological reassessment of the Kirtlington material fails to recognize two different taxa and shows that only sparse evidence supports the presence of pleurosternids in this locality. Shell bone histology thus appears as a powerful tool to study poorly preserved specimens and may in some case (like with pleurosternids) help resolve phylogenetic relationships. According to our results, the stratigraphic appearance of the Pleurosternidae is adjusted from the Kimmeridgian (Late Jurassic) to the Bathonian (Middle Jurassic), which significantly reduces the ghost lineage of Paracryptodira.     Bone histology, turtles, Paracryptodira, Pleurosternidae, Middle Jurassic, Kirtlington.     

More introgression with less gene flow: chloroplast vs. mitochondrial DNA in the Picea asperata complex in China, and comparison with other Conifers

Recent work has suggested that rates of introgression should be inversely related to levels of gene flow because introgressed populations cannot be 'rescued' by intraspecific gene flow if it is too low. Mitochondrial and chloroplast DNA (mtDNA and cpDNA) experience very different levels of gene flow in conifers due to their contrasted maternal and paternal modes of transmission, hence the prediction that mtDNA should introgress more readily than cpDNA in this group. Here, we use sequence data from both mtDNA and cpDNA to test this hypothesis in a group of closely related spruces species, the Picea asperata complex from China. Nine mitochondrial and nine chloroplast haplotypes were recovered from 459 individuals in 46 natural populations belonging to five species of the Picea asperata complex. Low variation was found in the two mtDNA introns along with a high level of differentiation among populations ( G _ST = 0.90). In contrast, we detected higher variation and lower differentiation among populations at cpDNA markers ( G _ST = 0.56), a trend shared by most conifer species studied so far. We found that cpDNA variation, although far from being fully diagnostic, is more species-specific than mtDNA variation: four groups of populations were identified using cpDNA markers, all of them related to species or groups of species, whereas for mtDNA, geographical variation prevails over species differentiation. The literature suggests that mtDNA haplotypes are often shared among related conifer species, whereas cpDNA haplotypes are more species-specific. Hence, increased intraspecific gene flow appears to decrease differentiation within species but not among species.     

The trainees' perspective on developing an end-of-grant knowledge translation plan

Background

Knowledge translation (KT) is a rapidly growing field that is becoming an integral part of research protocols.

Methods

This meeting report describes one group's experience at the 2009 KT Canada Summer Institute in developing an end-of-grant KT plan for a randomized control trial proposal.

Results

Included is a discussion of the process, challenges, and recommendations from the trainee's perspective in developing an end-of-grant KT plan.

Conclusion

New researchers should consider developing an end-of-grant KT plan with strategies that move beyond passive dissemination to incorporate innovative means of collaboration with the end user to craft the message, package the information, and share the research findings with end users.     

Primary growth and morphological markers of interannual growth limits in Cupressaceae from Patagonia

The present study shows experimentally that primary growth of the native Patagonian Cupressaceae Austrocedrus chilensis (D. Don) Pic.-Serm et Bizz., Fitzroya cupressoides (Molina) I. M. Johnst. and Pilgerodendron uviferum (D. Don) Florin is potentially continuous. External morphological markers of interannual growth limits have been identified for the main axes of these species after several years of observation. Such limits correspond with axis portions in which internodes are relatively short and leaves have a small distal free end forming an acute angle with the axis. The causality of these results and their utility for studying the productivity, adaptation to different environments, population management and conservation of these threatened species are discussed.  © 2004 The Linnean Society of London, Botanical Journal of the Linnean Society, 2004, 146 , 285–293.