High-affinity RNA binding by a hyperthermophilic single-stranded DNA-binding protein

Single-stranded DNA-binding proteins (SSBs), including replication protein A (RPA) in eukaryotes, play a central role in DNA replication, recombination, and repair. SSBs utilise an oligonucleotide/oligosaccharide-binding (OB) fold domain to bind DNA, and typically oligomerise in solution to bring multiple OB fold domains together in the functional SSB. SSBs from hyperthermophilic crenarchaea, such as Sulfolobus solfataricus, have an unusual structure with a single OB fold coupled to a flexible C-terminal tail. The OB fold resembles those in RPA, whilst the tail is reminiscent of bacterial SSBs and mediates interaction with other proteins. One paradigm in the field is that SSBs bind specifically to ssDNA and much less strongly to RNA, ensuring that their functions are restricted to DNA metabolism. Here, we use a combination of biochemical and biophysical approaches to demonstrate that the binding properties of S. solfataricus SSB are essentially identical for ssDNA and ssRNA. These features may represent an adaptation to a hyperthermophilic lifestyle, where DNA and RNA damage is a more frequent event.Publisher PDFPeer reviewe

EU-funded malaria research under the 6th and 7th Framework Programmes for research and technological development

While malaria research has traditionally been strong in Europe, targeted and sustained support for cooperative malaria research at EU level, namely through the EU's 6th and 7th Framework Programmes for research and technological development, FP6 (2002-2006) and FP7 (2007-2013), has boosted both impact and visibility of European malaria research. Most of the European malaria research community is now organized under a number of comprehensive and complementary research networks and projects, assembled around four key areas: (1) fundamental research on the malaria parasite and the disease, (2) development of new malaria drugs, (3) research and development of a malaria vaccine, and (4) research to control the malaria-transmitting mosquito vector. Considerable efforts were undertaken to ensure adequate participation of research groups from disease-endemic countries, in particular from Africa, with the long-term aim to strengthen cooperative links and research capacities in these countries. The concept of organizing European research through major strategic projects to form a "European Research Area" (ERA) was originally developed in the preparation of FP6, and ERA formation has now turned into a major EU policy objective explicitly inscribed into the Lisbon Treaty. EU-funded malaria research may serve as a showcase to demonstrate how ERA formation can successfully be implemented in a given area of science when several surrounding parameters converge to support implementation of this strategic concept: timely coincidence of political stimuli, responsive programming, a clearly defined - and well confined - area of research, and the readiness of the targeted research community who is well familiar with transnational cooperation at EU level. Major EU-funded malaria projects have evolved into thematic and organizational platforms that can collaborate with other global players. Europe may thus contribute more, and better, to addressing the global research agenda for malaria

Facilitation of Male Sexual Behavior in Syrian Hamsters by the Combined Action of Dihydrotestosterone and Testosterone

Testosterone (T) controls male Syrian hamster sexual behavior, however, neither of T's primary metabolites, dihydrotestosterone (DHT) and estradiol (E(2)), even in highly supraphysiological doses, fully restores sexual behavior in castrated hamsters. DHT and T apparently interact with androgen receptors differentially to control male sexual behavior (MSB), but whether these two hormones act synergistically or antagonistically to control MSB has received scant experimental attention and is addressed in the present study.Sexually experienced male Syrian hamsters were gonadectomized and monitored 5 weeks later to confirm elimination of the ejaculatory reflex (week 0), at which time they received subcutaneous DHT-filled or empty capsules that remained in situ for the duration of the experiment. Daily injections of a physiological dose of 25 µg T or vehicle commenced two weeks after capsule implantation. MSB was tested 2, 4 and 5 weeks after T treatment began. DHT capsules were no more effective than control treatment for long-term restoration of ejaculation. Combined DHT + T treatment, however, restored the ejaculatory reflex more effectively than T alone, as evidenced by more rapid recovery of ejaculatory behavior, shorter ejaculation latencies, and a greater number of ejaculations in 30 minute tests.DHT and T administered together restored sexual behavior to pre-castration levels more rapidly than did T alone, whereas DHT and vehicle were largely ineffective. The additive actions of DHT and T on MSB are discussed in relation to different effects of these androgens on androgen receptors in the male hamster brain mating circuit

Serial CT Findings of Paragonimus Infested Dogs and the Micro-CT Findings of the Worm Cysts

OBJECTIVE: To investigate the serial CT findings of Paragonimus westermani infected dogs and the microscopic structures of the worm cysts using Micro-CT. MATERIALS AND METHODS: This study was approved by the committee on animal research at our institution. Fifteen dogs infected with P. westermani underwent serial contrast-enhanced CT scans at pre-infection, after 10 days of infection, and monthly thereafter until six months for determining the radiologic-pathologic correlation. Three dogs (one dog each time) were sacrificed at 1, 3 and 6 months, respectively. After fixation of the lungs, both multi-detector CT and Micro-CT were performed for examining the worm cysts. RESULTS: The initial findings were pleural effusion and/or subpleural ground-glass opacities or linear opacities at day 10. At day 30, subpleural and peribronchial nodules appeared with hydropneumothorax and abdominal or chest wall air bubbles. Cavitary change and bronchial dilatation began to be seen on CT scan at day 30 and this was mostly seen together with mediastinal lymphadenopathy at day 60. Thereafter, subpleural ground-glass opacities and nodules with or without cavitary changes were persistently observed until day 180. After cavitary change of the nodules, the migratory features of the subpleural or peribronchial nodules were seen on all the serial CT scans. Micro-CT showed that the cyst wall contained dilated interconnected tubular structures, which had communications with the cavity and the adjacent distal bronchus. CONCLUSION: The CT findings of paragonimiasis depend on the migratory stage of the worms. The worm cyst can have numerous interconnected tubular channels within its own wall and these channels have connections with the cavity and the adjacent distal bronchus

Malaria eradication: the economic, financial and institutional challenge

Malaria eradication raises many economic, financial and institutional challenges. This paper reviews these challenges, drawing on evidence from previous efforts to eradicate malaria, with a special focus on resource-poor settings; summarizes more recent evidence on the challenges, drawing on the literature on the difficulties of scaling-up malaria control and strengthening health systems more broadly; and explores the implications of these bodies of evidence for the current call for elimination and intensified control. Economic analyses dating from the eradication era, and more recent analyses, suggest that, in general, the benefits of malaria control outweigh the costs, though few studies have looked at the relative returns to eradication versus long-term control. Estimates of financial costs are scanty and difficult to compare. In the 1960s, the consolidation phase appeared to cost less than $1 per capita and, in 1988, was estimated to be$2.31 per capita (both in 2006 prices). More recent estimates for high coverage of control measures suggest a per capita cost of several dollars. Institutional challenges faced by malaria eradication included limits to the rule of law (a major problem where malaria was concentrated in border areas with movement of people associated with illegal activities), the existence and performance of local implementing structures, and political sustainability at national and global levels. Recent analyses of the constraints to scaling-up malaria control, together with the historical evidence, are used to discuss the economic, financial and institutional challenges that face the renewed call for eradication and intensified control. The paper concludes by identifying a research agenda covering: issues of the allocative efficiency of malaria eradication, especially using macro-economic modelling to estimate the benefits and costs of malaria eradication and intensified control, and studies of the links between malaria control and economic development, the costs and consequences of the various tools and mixes of tools employed in control and eradication, issues concerning the extension of coverage of interventions and service delivery approaches, especially those that can reach the poorest, research on the processes of formulating and implementing malaria control and eradication policies, at both international and national levels, research on financing issues, at global and national levels

Costs and cost-effectiveness of malaria control interventions - a systematic review

<p>Abstract</p> <p>Background</p> <p>The control and elimination of malaria requires expanded coverage of and access to effective malaria control interventions such as insecticide-treated nets (ITNs), indoor residual spraying (IRS), intermittent preventive treatment (IPT), diagnostic testing and appropriate treatment. Decisions on how to scale up the coverage of these interventions need to be based on evidence of programme effectiveness, equity and cost-effectiveness.</p> <p>Methods</p> <p>A systematic review of the published literature on the costs and cost-effectiveness of malaria interventions was undertaken. All costs and cost-effectiveness ratios were inflated to 2009 USD to allow comparison of the costs and benefits of several different interventions through various delivery channels, across different geographical regions and from varying costing perspectives.</p> <p>Results</p> <p>Fifty-five studies of the costs and forty three studies of the cost-effectiveness of malaria interventions were identified, 78% of which were undertaken in sub-Saharan Africa, 18% in Asia and 4% in South America. The median financial cost of protecting one person for one year was $2.20 (range$0.88-$9.54) for ITNs,$6.70 (range $2.22-$12.85) for IRS, $0.60 (range$0.48-$1.08) for IPT in infants,$4.03 (range $1.25-$11.80) for IPT in children, and $2.06 (range$0.47-$3.36) for IPT in pregnant women. The median financial cost of diagnosing a case of malaria was$4.32 (range $0.34-$9.34). The median financial cost of treating an episode of uncomplicated malaria was $5.84 (range$2.36-$23.65) and the median financial cost of treating an episode of severe malaria was$30.26 (range $15.64-$137.87). Economies of scale were observed in the implementation of ITNs, IRS and IPT, with lower unit costs reported in studies with larger numbers of beneficiaries. From a provider perspective, the median incremental cost effectiveness ratio per disability adjusted life year averted was $27 (range$8.15-$110) for ITNs,$143 (range $135-$150) for IRS, and $24 (range$1.08-$44.24) for IPT.</p> <p>Conclusions</p> <p>A transparent evidence base on the costs and cost-effectiveness of malaria control interventions is provided to inform rational resource allocation by donors and domestic health budgets and the selection of optimal packages of interventions by malaria control programmes.</p

Lens stem cells may reside outside the lens capsule: an hypothesis

In this paper, we consider the ocular lens in the context of contemporary developments in biological ideas. We attempt to reconcile lens biology with stem cell concepts and a dearth of lens tumors

Systematic development and adjustment of the German version of the Supportive and Palliative Care Indicators Tool (SPICT-DE)

Abstract Background The Supportive and Palliative Care Indicators tool (SPICT) supports the identification of patients with potential palliative care (PC) needs. An Austrian-German expert group translated SPICT into German (SPICT-DE) in 2014. The aim of this study was the systematic development, refinement, and testing of SPICT-DE for its application in primary care (general practice). Methods SPICT-DE was developed by a multiprofessional research team according to the TRAPD model: translation, review, adjudication, pretesting and documentation. In a pretest, five general practitioners (GPs) rated four case vignettes of patients with different PC needs. GPs were asked to assess whether each patient might benefit from PC or not (I) based on their subjective appraisal (“usual practice”) and (II) by using SPICT-DE. After further refinement, two focus groups with 28 GPs (68% with a further qualification in PC) were conducted to test SPICT-DE. Again, participants rated two selected case vignettes (I) based on their subjective appraisal and (II) by using SPICT-DE. Afterwards, participants reflected the suitability of SPICT-DE for use in their daily practice routine within the German primary care system. Quantitative data were analysed with descriptive statistics and non-parametric tests for small samples. Qualitative data were analysed by conventional content analysis. Focus group discussion was analysed combining formal and conventional content analysis. Results Compared to the spontaneous rating of the case vignettes based on subjective appraisal, participants in both the pretest and the focus groups considered PC more often as being beneficial for the patients described in the case vignettes when using SPICT-DE. Participants in the focus groups agreed that SPICT-DE includes all relevant indicators necessary for an adequate clinical identification of patients who might benefit from PC. Conclusions SPICT-DE supports the identification of patients who might benefit from PC and seems suitable for routine application in general practice in Germany. The systematic development, refinement, and testing of SPICT-DE in this study was successfully completed by using a multiprofessional and participatory approach