Entheseal Changes as a Reflection of Activity Patterns at 1st Century BC/AD Petra, Jordan

Over the past thirty years, biological anthropologists have attempted to reconstruct human behavioral patterns by analyzing entheseal attachments, the areas where tendons and ligaments attach to the bone. Many researchers hypothesize that biomechanical stress on ligaments and tendons due to repetitive activities will be reflected in bony changes that occur within the attachment site. Therefore, the distribution and characterization of these entheseal changes have been used to illuminate ancient human activity patterns. This research focuses on the pattern of entheseal changes observed in individuals from urban first century BC/AD Petra in order to generate a profile of activity patterns for the non-elite Nabataeans buried along the North Ridge. Assessment of the entheseal attachments was accomplished using the newly formed Coimbra method. This method is considered as an improvement over previous scoring techniques as it is based on the results of clinical research and incorporates refined terminology and descriptions of entheseal changes. While the multifactorial etiology of entheses hinders identifying specific occupation types, generalized patterns of activity can still be inferred from the collection of these data. The sample of Petra's non-elite experienced only slight entheseal changes compared to other communities assessed here, with little evidence of sexual division of labor. Additionally, the sample did not display bilateral asymmetry as anticipated, however there were higher scores for the lower limb than the upper limb. During the first century BC and first century AD, Petra was a major urban center and capital of the Nabataean Kingdom. Its economy was based largely on trade and some light manufacturing using local resources. The findings presented here confirm that people who were buried along the North Ridge had been working in the city, possibly involved with civic, administrative, and/or religious duties that would have been present during the height of the city

Projected Evolution of California's San Francisco Bay-Delta-River System in a Century of Climate Change

Background: Accumulating evidence shows that the planet is warming as a response to human emissions of greenhouse gases. Strategies of adaptation to climate change will require quantitative projections of how altered regional patterns of temperature, precipitation and sea level could cascade to provoke local impacts such as modified water supplies, increasing risks of coastal flooding, and growing challenges to sustainability of native species. Methodology/Principal Findings: We linked a series of models to investigate responses of California’s San Francisco Estuary-Watershed (SFEW) system to two contrasting scenarios of climate change. Model outputs for scenarios of fast and moderate warming are presented as 2010–2099 projections of nine indicators of changing climate, hydrology and habitat quality. Trends of these indicators measure rates of: increasing air and water temperatures, salinity and sea level; decreasing precipitation, runoff, snowmelt contribution to runoff, and suspended sediment concentrations; and increasing frequency of extreme environmental conditions such as water temperatures and sea level beyond the ranges of historical observations. Conclusions/Significance: Most of these environmental indicators change substantially over the 21 st century, and many would present challenges to natural and managed systems. Adaptations to these changes will require flexible planning t

Intestinal inflammation and increased intestinal permeability in Plasmodium chabaudi AS infected mice

Background: Gastrointestinal symptoms are commonly associated with acute Plasmodium spp infection. Malaria-associated enteritis may provide an opportunity for enteric pathogens to breach the intestinal mucosa, resulting in life-threatening systemic infections. Methods: To investigate whether intestinal pathology also occurs during infection with a murine model of mild and resolving malaria, C57BL/6J mice were inoculated with recently mosquito-transmitted Plasmodium chabaudi AS. At schizogony, intestinal tissues were collected for quantification and localisation of immune mediators and malaria parasites, by PCR and immunohistochemistry. Inflammatory proteins were measured in plasma and faeces and intestinal permeability was assessed by FITC-dextran translocation after oral administration. Results: Parasitaemia peaked at approx. 1.5% at day 9 and resolved by day 14, with mice experiencing significant and transient anaemia but no weight loss. Plasma IFNγ, TNFα and IL10 were significantly elevated during peak infection and quantitative RT-PCR of the intestine revealed a significant increase in transcripts for ifng and cxcl10. Histological analysis revealed parasites within blood vessels of both the submucosa and intestinal villi and evidence of mild crypt hyperplasia. In faeces, concentrations of the inflammatory marker lactoferrin were significantly raised on days 9 and 11 and FITC-dextran was detected in plasma on days 7 to 14. At day 11, plasma FITC-dextran concentration was significantly positively correlated with peripheral parasitemia and faecal lactoferrin concentration. Conclusions: In summary, using a relevant, attenuated model of malaria, we have found that acute infection is associated with intestinal inflammation and increased intestinal permeability. This model can now be used to explore the mechanisms of parasite-induced intestinal inflammation and to assess the impact of increased intestinal permeability on translocation of enteropathogens

Truncated and Helix-Constrained Peptides with High Affinity and Specificity for the cFos Coiled-Coil of AP-1

Protein-based therapeutics feature large interacting surfaces. Protein folding endows structural stability to localised surface epitopes, imparting high affinity and target specificity upon interactions with binding partners. However, short synthetic peptides with sequences corresponding to such protein epitopes are unstructured in water and promiscuously bind to proteins with low affinity and specificity. Here we combine structural stability and target specificity of proteins, with low cost and rapid synthesis of small molecules, towards meeting the significant challenge of binding coiled coil proteins in transcriptional regulation. By iteratively truncating a Jun-based peptide from 37 to 22 residues, strategically incorporating i-->i+4 helix-inducing constraints, and positioning unnatural amino acids, we have produced short, water-stable, alpha-helical peptides that bind cFos. A three-dimensional NMR-derived structure for one peptide (24) confirmed a highly stable alpha-helix which was resistant to proteolytic degradation in serum. These short structured peptides are entropically pre-organized for binding with high affinity and specificity to cFos, a key component of the oncogenic transcriptional regulator Activator Protein-1 (AP-1). They competitively antagonized the cJun–cFos coiled-coil interaction. Truncating a Jun-based peptide from 37 to 22 residues decreased the binding enthalpy for cJun by ~9 kcal/mol, but this was compensated by increased conformational entropy (TDS ≤ 7.5 kcal/mol). This study demonstrates that rational design of short peptides constrained by alpha-helical cyclic pentapeptide modules is able to retain parental high helicity, as well as high affinity and specificity for cFos. These are important steps towards small antagonists of the cJun-cFos interaction that mediates gene transcription in cancer and inflammatory diseases

Mind the gap between policy imperatives and service provision: a qualitative study of the process of respiratory service development in England and Wales

The research was funded by the National Institute for Health Research Service Delivery and Organisation Programme. SDO/99/2005.Background: Healthcare systems globally are reconfiguring to address the needs of people with long-term conditions such as respiratory disease. Primary Care Organisations (PCOs) in England and Wales are charged with the task of developing cost-effective patient-centred local models of care. We aimed to investigate how PCOs in England and Wales are reconfiguring their workforce to develop respiratory services, and the background factors influencing service redesign. Methods: Semi-structured qualitative telephone interviews with the person(s) responsible for driving respiratory service reconfiguration in a purposive sample of 30 PCOs. Interviews were recorded, transcribed, coded and thematically analysed. Results: We interviewed representatives of 30 PCOs with diverse demographic profiles planning a range of models of care. Although the primary driver was consistently identified as the need to respond to a central policy to shift the delivery of care for people with long-term conditions into the community whilst achieving financial balance, the design and implementation of services were subject to a broad range of local, and at times serendipitous, influences. The focus was almost exclusively on the complex needs of patients at the top of the long-term conditions (LTC) pyramid, with the aim of reducing admissions. Whilst some PCOs seemed able to develop innovative care despite uncertainty and financial restrictions, most highlighted many barriers to progress, describing initiatives suddenly shelved for lack of money, progress impeded by reluctant clinicians, plans thwarted by conflicting policies and a PCO workforce demoralised by job insecurity. Conclusion: For many of our interviewees there was a large gap between central policy rhetoric driving workforce change, and the practical reality of implementing change within PCOs when faced with the challenges of limited resources, diverse professional attitudes and an uncertain organisational context. Research should concentrate on understanding these complex dynamics in order to inform the policymakers, commissioners, health service managers and professionals.Publisher PDFPeer reviewe

Prolactin-induced mouse mammary carcinomas model estrogen resistant luminal breast cancer.

INTRODUCTION: Tumors that express estrogen receptor alpha (ERα+) comprise 75% of breast cancers in women. While treatments directed against this receptor have successfully lowered mortality rates, many primary tumors initially or later exhibit resistance. The paucity of murine models of this luminal tumor subtype has hindered studies of factors that promote their pathogenesis and modulate responsiveness to estrogen-directed therapeutics. Since epidemiologic studies closely link prolactin and the development of ERα+ tumors in women, we examined characteristics of the aggressive ERα+ and ERα- carcinomas which develop in response to mammary prolactin in a murine transgenic model (neu-related lipocalin- prolactin (NRL-PRL)). To evaluate their relationship to clinical tumors, we determined phenotypic relationships among these carcinomas, other murine models of breast cancer, and features of luminal tumors in women. METHODS: We examined a panel of prolactin-induced tumors for characteristics relevant to clinical tumors: histotype, ERα/progesterone receptor (PR) expression and estrogen responsiveness, Activating Protein 1 (AP-1) components, and phosphorylation of signal transducer and activator of transcription 5 (Stat5), extracellular signal regulated kinase (ERK) 1/2 and AKT. We compared levels of transcripts in the ERα-associated luminal signature that defines this subtype of tumors in women and transcripts enriched in various mammary epithelial lineages to other well-studied genetically modified murine models of breast cancer. Finally, we used microarray analyses to compare prolactin-induced ERα+ and ERα- tumors, and examined responsiveness to estrogen and the anti-estrogen, Faslodex, in vivo. RESULTS: Prolactin-induced carcinomas were markedly diverse with respect to histotype, ERα/PR expression, and activated signaling cascades. They constituted a heterogeneous, but distinct group of murine mammary tumors, with molecular features of the luminal subtype of human breast cancer. In contrast to morphologically normal and hyperplastic structures in NRL-PRL females, carcinomas were insensitive to ERα-mediated signals. These tumors were distinct from mouse mammary tumor virus (MMTV)-neu tumors, and contained elevated transcripts for factors associated with luminal/alveolar expansion and differentiation, suggesting that they arose from physiologic targets of prolactin. These features were shared by ERα+ and ERα- tumors, suggesting a common origin, although the former exhibited transcript profiles reflecting greater differentiation. CONCLUSIONS: Our studies demonstrate that prolactin can promote diverse carcinomas in mice, many of which resemble luminal breast cancers, providing a novel experimental model to examine the pathogenesis, progression and treatment responsiveness of this tumor subtype