Resource tracking in North American Telorchis spp. (Digenea: Plagiorchiformes: Telorchidae)

We examine the evolution of host specificity for species of Telorchis, using the methods developed by researchers studying phytophagous insect-plant systems. Optimization of "generalist" compared with "specialist" onto the phylogeny for Telorchis revealed ambiguous patterns, depending on how the 2 terms were defined. Regardless of that definition, most of the evolutionary diversification of this group has been carried out within eucryptodiran turtles, the ancestral host group. From that plesiomorphic background, there appears to have been 2 episodes of specialization by way of a host switch into caudates (ancestor of T. stunkardi + T. sirenis) and snakes (T. auridistomi), and 1 episode of exuberant expansion producing a true generalist (T. corti). These results, which indicate that most species of Telorchis are tracking widespread plesiomorphic resources, mirror those reported for phytophagous insects and their plants. We believe that establishing a dialogue between the two research groups will be mutually beneficial to both and will strengthen our understanding of the complex factors underlying the evolution of coevolutionary associations.     

Troublesome neighbours: Changing attitudes towards chimpanzees (Pan troglodytes) in a human-dominated landscape in Uganda

Long-term human–wildlife sympatry depends on the willingness and capacity of local people to coexist with wild animals. With human population growth and deforestation for agriculture, farmers increasingly live in proximity to wildlife, including large mammals of conservation concern. Understanding local perspectives and concerns regarding wildlife is essential for informing appropriate management strategies that reduce conflicts and promote sustainable coexistence. Social science approaches therefore have a critical role in integrated conservation programmes. We undertook an attitude survey to understand residents’ perspectives about sharing a landscape with chimpanzees (Pan troglodytes) in an unprotected forest–agriculture mosaic in Uganda. Interviews (n = 134) in 12 villages demonstrate residents’ ambivalence towards living alongside these protected yet potentially troublesome mammals. Chimpanzee behaviour is reported to have undergone recent changes. Residents claim apes increasingly enter villages for food, threaten people, and pose a particular threat to children's safety. Chimpanzee numbers are believed to have increased locally. Most interviewees fear chimpanzees, considering them dangerous. Crop losses to chimpanzees were widely reported. Farmers tolerate raiding of domestic fruits, but not cash-crops. Results demonstrate that attitudes towards wildlife are not fixed. Reported changes to chimpanzee behaviour are challenging villagers’ traditionally benign attitude towards them. Even so, residents acknowledge benefits to chimpanzees because they reportedly displace other crop-raiding wildlife which, unlike chimpanzees, damage important staple food crops. Survey findings are contextualised with respect to recent, major land-use changes in Uganda (clearance of unprotected forest for timber and agriculture) that have precipitated a sharp rise in farmer–chimpanzee interactions. We discuss the study's broader implications for protected mammal management and conflict mitigation in human-dominated landscapes, and ask whether it is appropriate to expect impoverished rural farmers to accommodate large-bodied mammals that pose a potential threat to their safety and livelihoods.     

The involvement of interleukin-1 and interleukin-4 in the response of human annulus fibrosus cells to cyclic tensile strain: an altered mechanotransduction pathway with degeneration

Introduction  

Recent evidence suggests that intervertebral disc (IVD) cells derived from degenerative tissue are unable to respond to physiologically relevant mechanical stimuli in the 'normal' anabolic manner, but instead respond by increasing matrix catabolism. Understanding the nature of the biological processes which allow disc cells to sense and respond to mechanical stimuli (a process termed 'mechanotransduction') is important to ascertain whether these signalling pathways differ with disease. The aim here was to investigate the involvement of interleukin (IL)-1 and IL-4 in the response of annulus fibrosus (AF) cells derived from nondegenerative and degenerative tissue to cyclic tensile strain to determine whether cytokine involvement differed with IVD degeneration.     

The Stature of Boys Is Inversely Correlated to the Levels of Their Sertoli Cell Hormones: Do the Testes Restrain the Maturation of Boys?

The testes of preadolescent boys appear to be dormant, as they produce only trace levels of testosterone. However, they release supra-adult levels of Müllerian Inhibiting Substance (MIS, anti-Müllerian hormone) and lesser levels of inhibin B (InhB), for unknown reasons. Boys have a variable rate of maturation, which on average is slower than girls. The height of children relative to their parents is an index of their maturity. We report here that a boy's level of MIS and InhB is stable over time and negatively correlates with his height and his height relative to his parent's height. This suggests that boy's with high levels of MIS and InhB are short because they are immature, rather than because they are destined to be short men. The levels of MIS and InhB in the boys did not correlate with known hormonal modulators of growth, and were additive with age and the growth hormone/IGF1 axis as predictors of a boy's height. If MIS and InhB were causal regulators of maturity, then the inter-boy differences in the levels of these hormone produces variation in maturation equivalent to 18-months of development. MIS and InhB may thus account for most of the variation in the rate of male development. If boys lacked these hormones, then an average 5-year-old boy would be over 5 cm taller than age-matched girls, making boys almost as dimorphic as men, for height. This indicates that boys have a high growth potential that is initially suppressed by their testes. The concept of the childhood testes suppressing an adult male feature appears paradoxical. However, the growth of children requires intergenerational transfer of nutrients. Consequently, the MIS/InhB slowing of male growth may have been historically advantageous, as it would minimizes any sex bias in the maternal cost of early child rearing.     

Avian biodiversity in the coastal wetlands of the Okahukura Peninsula

The Tapora Landcare Group, operating on the Okahukura Peninsula, has the long-term goal of making this region predator fenced. The aim of this study was to obtain information on the current status of avian biodiversity and the bird community across the band of coastal wetlands on the Okahukura Peninsula. Bird counts were conducted and playback lures used to detect three cryptic wetland species: fernbirds (Bowdleria punctata); spotless crakes (Porzana tabuensis); and banded rails (Gallirallus philippensis). Fernbirds and banded rails were detected at seven of the eight wetland sites sampled whereas spotless crakes were detected at two sites. The native species with the highest relative abundance across the eight sites were silvereyes (Zosterops lateralis) and South Island pied oystercatchers (Haematopus finschi). Changes in avian biodiversity over time in the region can now be monitored, and comprehensive long-term data on the status of avian biodiversity over time obtained.     

Folate synthesis: an old enzyme identified

In this issue of Structure, Amzel, Bessman, and colleagues (Gabelli et al., 2007) present the crystal structure of a 17 kDa Nudix hydrolase from Escherichia coli previously characterized as a dATPase and provide evidence that it functions in vivo to remove pyrophosphate from the folate precursor dihydroneopterin triphosphate.     

Synovial phenotypes in rheumatoid arthritis correlate with response to biologic therapeutics

Introduction

Rheumatoid arthritis (RA) is a complex and clinically heterogeneous autoimmune disease. Currently, the relationship between pathogenic molecular drivers of disease in RA and therapeutic response is poorly understood.

Methods

We analyzed synovial tissue samples from two RA cohorts of 49 and 20 patients using a combination of global gene expression, histologic and cellular analyses, and analysis of gene expression data from two further publicly available RA cohorts. To identify candidate serum biomarkers that correspond to differential synovial biology and clinical response to targeted therapies, we performed pre-treatment biomarker analysis compared with therapeutic outcome at week 24 in serum samples from 198 patients from the ADACTA (ADalimumab ACTemrA) phase 4 trial of tocilizumab (anti-IL-6R) monotherapy versus adalimumab (anti-TNFα) monotherapy.

Results

We documented evidence for four major phenotypes of RA synovium – lymphoid, myeloid, low inflammatory, and fibroid - each with distinct underlying gene expression signatures. We observed that baseline synovial myeloid, but not lymphoid, gene signature expression was higher in patients with good compared with poor European league against rheumatism (EULAR) clinical response to anti-TNFα therapy at week 16 (P =0.011). We observed that high baseline serum soluble intercellular adhesion molecule 1 (sICAM1), associated with the myeloid phenotype, and high serum C-X-C motif chemokine 13 (CXCL13), associated with the lymphoid phenotype, had differential relationships with clinical response to anti-TNFα compared with anti-IL6R treatment. sICAM1-high/CXCL13-low patients showed the highest week 24 American College of Rheumatology (ACR) 50 response rate to anti-TNFα treatment as compared with sICAM1-low/CXCL13-high patients (42% versus 13%, respectively, P =0.05) while anti-IL-6R patients showed the opposite relationship with these biomarker subgroups (ACR50 20% versus 69%, P =0.004).

Conclusions

These data demonstrate that underlying molecular and cellular heterogeneity in RA impacts clinical outcome to therapies targeting different biological pathways, with patients with the myeloid phenotype exhibiting the most robust response to anti-TNFα. These data suggest a path to identify and validate serum biomarkers that predict response to targeted therapies in rheumatoid arthritis and possibly other autoimmune diseases.

Trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01119859","term_id":"NCT01119859"}}NCT01119859     

Hepatocyte Produced Matrix Metalloproteinases Are Regulated by CD147 in Liver Fibrogenesis

Background

The classical paradigm of liver injury asserts that hepatic stellate cells (HSC) produce, remodel and turnover the abnormal extracellular matrix (ECM) of fibrosis via matrix metalloproteinases (MMPs). In extrahepatic tissues MMP production is regulated by a number of mechanisms including expression of the glycoprotein CD147. Previously, we have shown that CD147 is expressed on hepatocytes but not within the fibrotic septa in cirrhosis [1]. Therefore, we investigated if hepatocytes produce MMPs, regulated by CD147, which are capable of remodelling fibrotic ECM independent of the HSC.

Methods

Non-diseased, fibrotic and cirrhotic livers were examined for MMP activity and markers of fibrosis in humans and mice. CD147 expression and MMP activity were co-localised by in-situ zymography. The role of CD147 was studied in-vitro with siRNA to CD147 in hepatocytes and in-vivo in mice with CCl₄ induced liver injury using ãCD147 antibody intervention.

Results

In liver fibrosis in both human and mouse tissue MMP expression and activity (MMP-2, -9, -13 and -14) increased with progressive injury and localised to hepatocytes. Additionally, as expected, MMPs were abundantly expressed by activated HSC. Further, with progressive fibrosis there was expression of CD147, which localised to hepatocytes but not to HSC. Functionally significant in-vitro regulation of hepatocyte MMP production by CD147 was demonstrated using siRNA to CD147 that decreased hepatocyte MMP-2 and -9 expression/activity. Further, in-vivo α-CD147 antibody intervention decreased liver MMP-2, -9, -13, -14, TGF-β and α-SMA expression in CCl₄ treated mice compared to controls.

Conclusion

We have shown that hepatocytes produce active MMPs and that the glycoprotein CD147 regulates hepatocyte MMP expression. Targeting CD147 regulates hepatocyte MMP production both in-vitro and in-vivo, with the net result being reduced fibrotic matrix turnover in-vivo. Therefore, CD147 regulation of hepatocyte MMP is a novel pathway that could be targeted by future anti-fibrogenic agents.