Regulation of platelet production: the normal response to perturbation and cyclical platelet disease

An age-structured model for the regulation of platelet production is developed, and compared with both normal and pathological platelet production. We consider the role of thrombopoietin (TPO) in this process, how TPO affects the transition between megakaryocytes of various ploidy classes, and their individual contributions to platelet production. After the estimation of the relevant parameters of the model from both in vivo and in vitro data, we use the model to numerically reproduce the normal human response to a bolus injection of TPO. We further show that our model reproduces the dynamic characteristics of autoimmune cyclical thromobocytopenia if the rate of platelet destruction in the circulation is elevated to more than twice the normal value.     

Distinct effects of unfractionated heparin versus bivalirudin on circulating angiogenic peptides

Background

Human studies of therapeutic angiogenesis, stem-cell, and progenitor-cell therapy have failed to demonstrate consistent clinical benefit. Recent studies have shown that heparin increases circulating levels of anti-angiogenic peptides. Given the widely prevalent use of heparin in percutaneous and surgical procedures including those performed as part of studies examining the benefit of therapeutic angiogenesis and cell-based therapy, we compared the effects of unfractionated heparin (UFH) on angiogenic peptides with those of bivalirudin, a relatively newer anticoagulant whose effects on angiogenic peptides have not been studied.

Methodology/Principal Findings

We measured soluble fms-like tyrosine kinase-1 (sFLT1), placental growth factor (PlGF), vascular endothelial growth factor (VEGF), and soluble Endoglin (sEng) serum levels by enzyme linked immunosorbent assays (ELISA) in 16 patients undergoing elective percutaneous coronary intervention. Compared to baseline values, sFLT1 and PlGF levels increased by 2629±313% and 253±54%, respectively, within 30 minutes of UFH therapy (p<0.01 for both; n = 8). VEGF levels decreased by 93.2±5% in patients treated with UFH (p<0.01 versus baseline). No change in sEng levels were observed after UFH therapy. No changes in sFLT1, PlGF, VEGF, or sEng levels were observed in any patients receiving bivalirudin (n = 8). To further explore the direct effect of anticoagulation on circulating angiogenic peptides, adult, male wild-type mice received venous injections of clinically dosed UFH or bivalirudin. Compared to saline controls, sFLT1 and PlGF levels increased by >500% (p<0.01, for both) and VEGF levels increased by 221±101% (p<0.05) 30 minutes after UFH treatment. Bivalirudin had no effect on peptide levels. To study the cellular origin of peptides after anticoagulant therapy, human coronary endothelial cells were treated with UFH and demonstrated increased sFLT1 and PlGF levels (ANOVA p<0.01 for both) with reduced VEGF levels (ANOVA p<0.05). Bivalirudin had no effect on peptide levels in vitro.

Conclusions/Significance

Circulating levels of sFLT1, PlGF, and VEGF are significantly altered by UFH, while bivalirudin therapy has no effect. These findings may have significant implications for clinical studies of therapeutic angiogenesis, stem-cell and progenitor-cell therapy.     

Antitrypanosomal and cysteine protease inhibitory activities of alkyldiamine cryptolepine derivatives

Cryptolepine derivatives containing alkyldiamine side-chains, 2, with potent inhibitory activity against Trypanosoma brucei brucei are reported. Compounds 2 showed improved activity and selectivity to T. b. brucei when compared to the lead compound. The most selective compound, 2k, presents a selectivity index value of 6200 and an IC(50) of 10nM against the parasite. These derivatives are also potent inhibitors of the trypanosome papain-like cysteine proteases cruzain, which could, at least in part, explain their antitrypanosomal activity. Overall, these compounds with good antitrypanosomal activity and selectivity provide an encouraging starting point for the rational design of new and effective antitrypanosomal agents.     

Impacts of feral horses in the Australian Alps and evidence‐based solutions

New evidence of impacts by feral horses in Australia's alpine parks systems confirms they endanger threatened species and extensively damage critically endangered bog communities that could take millennia to recover. These impacts are not confounded by effects of deer and accumulate over time, even when only a small number of feral horses (~100) are present. With protected areas representing only a small proportion of the area of the Australian states of New South Wales (9.3%) and Victoria (17%), allowing feral horses to degrade reserves is not a reasonable management compromise, is contrary to the purpose of the protected area system and conflicts with international obligations. Modelling and decades of management experience indicate that trapping alone does not control feral horse numbers. Trapping and fertility control can work in small populations, but not when there are several thousand horses in remote areas. Aerial culling is needed to cost‐effectively and humanely control feral horse populations. The relatively small amount of suffering feral horses experience during a cull is outweighed by (i) avoiding suffering and death of horses from starvation and thirst, (ii) avoiding the suffering of native animals displaced by horses and (iii) avoiding the ethical concerns of driving threatened species towards extinction. Objections to aerial culling on welfare and cultural grounds are contradicted by evidence. Improving knowledge in the general community about what is at stake is long overdue because without this knowledge, small groups with vested interests and unfounded claims have been able to dominate debate and dictate management actions. As a result of ineffective management, horse populations are now expanding and causing well‐documented damage to Australia's alpine parks, placing at risk almost $10M spent on restoration after livestock grazing ended. The costs of horse control and restoration escalate the longer large horse populations remain in the alpine parks. It is crucial that feral horse numbers are rapidly reduced to levels where ecosystems begin to recover. Aerial culling is needed as part of the toolbox to achieve that reduction.     

Meta-analysis of human methylation data for evidence of sex-specific autosomal patterns

Background

Several individual studies have suggested that autosomal CpG methylation differs by sex both in terms of individual CpG sites and global autosomal CpG methylation. However, these findings have been inconsistent and plagued by spurious associations due to the cross reactivity of CpG probes on commercial microarrays. We collectively analysed 76 published studies (n = 6,795) for sex-associated differences in both autosomal and sex chromosome CpG sites.

Results

Overall autosomal methylation profiles varied substantially by study, and we encountered substantial batch effects. We accounted for these by conducting random effects meta-analysis for individual autosomal CpG methylation associations. After excluding non-specific probes, we found 184 autosomal CpG sites differentially methylated by sex after correction for multiple testing. In line with previous studies, average beta differences were small. Many of the most significantly associated CpG probes were new. Of note was differential CpG methylation in the promoters of genes thought to be involved in spermatogenesis and male fertility, such as SLC9A2, SPESP1, CRISP2, and NUPL1. Pathway analysis revealed overrepresentation of genes differentially methylated by sex in several broad Gene Ontology biological processes, including RNA splicing and DNA repair.

Conclusions

This study represents a comprehensive analysis of sex-specific methylation patterns. We demonstrate the existence of sex-specific methylation profiles and report a large number of novel DNA methylation differences in autosomal CpG sites between sexes.

Electronic supplementary material

The online version of this article (doi:10.1186/1471-2164-15-981) contains supplementary material, which is available to authorized users.     

Meeting report: Ocean ‘omics science,technology and cyberinfrastructure: current challenges and future requirements (August 20-23, 2013)

The National Science Foundation’s EarthCube End User Workshop was held at USC Wrigley Marine Science Center on Catalina Island, California in August 2013. The workshop was designed to explore and characterize the needs and tools available to the community that is focusing on microbial and physical oceanography research with a particular emphasis on ‘omic research. The assembled researchers outlined the existing concerns regarding the vast data resources that are being generated, and how we will deal with these resources as their volume and diversity increases. Particular attention was focused on the tools for handling and analyzing the existing data, on the need for the construction and curation of diverse federated databases, as well as development of shared, interoperable, “big-data capable” analytical tools. The key outputs from this workshop include (i) critical scientific challenges and cyber infrastructure constraints, (ii) the current and future ocean ‘omics science grand challenges and questions, and (iii) data management, analytical and associated and cyber-infrastructure capabilities required to meet critical current and future scientific challenges. The main thrust of the meeting and the outcome of this report is a definition of the ‘omics tools, technologies and infrastructures that facilitate continued advance in ocean science biology, marine biogeochemistry, and biological oceanography.     

Dynamic size responses to climate change: prevailing effects of rising temperature drive long‐term body size increases in a semi‐arid passerine

Changes in animal body size have been widely reported as a correlate of contemporary climate change. Body size affects metabolism and fitness, so changing size has implications for resilience, yet the climatic factors that drive size variation remain poorly understood. We test the role of mean and extreme temperature, rainfall, and remotely sensed primary productivity (NDVI) as drivers of body size in a sedentary, semi‐arid Australian passerine, Ptilotula (Lichenostomus) penicillatus, over 23 years. To distinguish effects due to differential growth from changes in population composition, we analysed first‐year birds and adults separately and considered climatic variation at three temporal scales (current, previous, and preceding 5 years). The strongest effects related to temperature: in both age classes, larger size was associated with warmer mean temperatures in the previous year, contrary to Bergmann's Rule. Moreover, adults were larger in warmer breeding seasons, while first years was larger after heatwaves; these effects are more likely to be mediated through size‐dependent mortality, highlighting the role of body size in determining vulnerability to extinction. In addition to temperature, larger adult size was associated with lower primary productivity, which may reflect a trade‐off between vegetative growth and nectar production, on which adults rely. Finally, lower rainfall was associated with decreasing size in first year and adults, most likely related to decreased food availability. Overall, body size increased over 23 years, strongly in first‐year birds (2.7%) compared with adults (1%), with size outcomes a balance between competing drivers. As rainfall declined over time and productivity remained fairly stable, the temporal increase in body size appears largely driven by rising mean temperature and temperature extremes. Body size responses to environmental change are thus complex and dynamic, driven by effects on growth as well as mortality.     

Irisin immunohistochemistry in gastrointestinal system cancers

Cancer is the leading cause of morbidity and mortality worldwide. Some studies have shown that high heat kills cancer cells. Irisin is a protein involved in heat production by converting white into brown adipose tissue, but there is no information about how its expression changes in cancerous tissues. We used irisin antibody immunohistochemistry to investigate changes in irisin expression in gastrointestinal cancers compared to normal tissues. Irisin was found in human brain neuroglial cells, esophageal epithelial cells, esophageal epidermoid carcinoma, esophageal adenocarcinoma and neuroendocrine esophageal carcinoma, gastric glands, gastric adenosquamous carcinoma, gastric neuroendocrine carcinoma, gastric signet ring cell carcinoma, neutrophils in vascular tissues, intestinal glands of colon, colon adenocarcinoma, mucinous colon adenocarcinoma, hepatocytes, hepatocellular carcinoma, islets of Langerhans, exocrine pancreas, acinar cells and interlobular and interlobular ducts of normal pancreas, pancreatic ductal adenocarcinoma, and intra- and interlobular ducts of cancerous pancreatic tissue. Histoscores (area × intensity) indicated that irisin was increased significantly in gastrointestinal cancer tissues, except liver cancers. Our findings suggest that the relation of irisin to cancer warrants further investigation.