Highlights from recently determined structures of membrane proteins: a focus on channels and transporters

After decades of absent or lackluster growth, recent years have at long last witnessed an exponential growth in the number of novel membrane protein structures determined. Every single achievement has had a tremendous impact on the scientific community, providing an unprecedented wealth of information that typically only an atomic resolution structure can contribute to our molecular understanding of how a protein functions. Presented here is a review of some of the most exciting novel structures of channels and transporters determined by X-ray crystallography in the last two years, and a discussion of their analogies, differences and mechanistic implications.     

Communicating old-growth forest through an educational trail

This paper describes the experience of developing an educational trail inside an old-growth beech forest in central Italy. In the last 150 years local people exploited this stand almost exclusively for recreational purposes and now the beechwood has acquired new ecological value after having reached old-growth status. Despite the cultural-historical importance of the site, there is a substantial lack of knowledge about this magnificent stand among members of the public, who have no tools to understand its dynamics nor to accept those structural changes related to its natural evolution. Tourist facilities were restored at the site, according to non-restricting criteria, and an educational program was developed in order to promote a shared comprehension of old-growth forests, their ecological processes and value, the services they provide, and to increase tourist awareness toward this fragile ecosystem. We discuss the educational role ecotourism might potentially hold in western developed countries to link the public with the scientific world, educating people about nature, while preventing negative impacts on natural environments. Even if the importance of local communities in conservation of natural resources has been widely recognized by a number of conservationists, public involvement, particularly in forest conservation and management, still represents a difficult challenge, since it requires the implementation of a common understanding about forest ecosystems, forest goods and forest services. The educational trail inside the beech forest of Monte Cimino may represent a low impact strategy for preserving forest aesthetic functionality, limiting potential damages to the forest while increasing its importance for nature conservation.     

Bringing together linguistic and genetic evidence to test the Bantu expansion

The expansion of Bantu languages represents one of the most momentous events in the history of Africa. While it is well accepted that Bantu languages spread from their homeland (Cameroon/Nigeria) approximately 5000 years ago (ya), there is no consensus about the timing and geographical routes underlying this expansion. Two main models of Bantu expansion have been suggested: The 'early-split' model claims that the most recent ancestor of Eastern languages expanded north of the rainforest towards the Great Lakes region approximately 4000 ya, while the 'late-split' model proposes that Eastern languages diversified from Western languages south of the rainforest approximately 2000 ya. Furthermore, it is unclear whether the language dispersal was coupled with the movement of people, raising the question of language shift versus demic diffusion. We use a novel approach taking into account both the spatial and temporal predictions of the two models and formally test these predictions with linguistic and genetic data. Our results show evidence for a demic diffusion in the genetic data, which is confirmed by the correlations between genetic and linguistic distances. While there is little support for the early-split model, the late-split model shows a relatively good fit to the data. Our analyses demonstrate that subsequent contact among languages/populations strongly affected the signal of the initial migration via isolation by distance.     

Rationality, irrationality and escalating behavior in lowest unique bid auctions

Information technology has revolutionized the traditional structure of markets. The removal of geographical and time constraints has fostered the growth of online auction markets, which now include millions of economic agents worldwide and annual transaction volumes in the billions of dollars. Here, we analyze bid histories of a little studied type of online auctions--lowest unique bid auctions. Similarly to what has been reported for foraging animals searching for scarce food, we find that agents adopt Lévy flight search strategies in their exploration of "bid space". The Lévy regime, which is characterized by a power-law decaying probability distribution of step lengths, holds over nearly three orders of magnitude. We develop a quantitative model for lowest unique bid online auctions that reveals that agents use nearly optimal bidding strategies. However, agents participating in these auctions do not optimize their financial gain. Indeed, as long as there are many auction participants, a rational profit optimizing agent would choose not to participate in these auction markets.     

Initial experience of hypofractionated radiation retreatment with true beam and flattening filter free beam in selected case reports of recurrent nasopharyngeal carcinoma

AimTo show our preliminary experience in using TrueBeam with RapidArc technology and FFF beam for stereotactic re-irradiation of nasopharyngeal carcinoma.BackgroundThanks to new advanced techniques, as well as intensity modulated radiation therapy, it is possible to approach head and neck recurrences in selected patients. Volumetric Modulated Arc Therapy (VMAT) in its RapidArc^® format, permits to reduce significantly the time to deliver complex intensity modulated plans, allowing to treat hypofractionated regimes within a few minutes. With TrueBeam it is possible to perform photon beams without usage of the flattening filter. It seems possible to expect a reduction of out-of-field dose when flattening filter free (FFF) beams are used. While research into the physics domain for FFF beams is increasing, there are very few clinical data where FFF beams are applied in clinical practice.Materials and methodsWe present here the cases of 4 patients with local or regional recurrence of nasopharyngeal carcinoma. All patients were treated using TrueBeam with RapidArc technology and FFF beam for stereotactic hypofractionated re-irradiation.ResultsAll patients concluded SBRT and showed good tolerability. During follow-up, complete response at imaging evaluation (PET and/or MRI) for all treated patients was documented.ConclusionsOur preliminary experience using TrueBeam with RapidArc technology and FFF beam for stereotactic hypofractionated re-irradiation of nasopharyngeal carcinoma was safe and effective in all 4 treated patients. Longer follow-up and a larger population of study is needed to confirm these promising results.     

Expanding ART for treatment and prevention of HIV in South Africa: estimated cost and cost-effectiveness 2011-2050

Background

Antiretroviral Treatment (ART) significantly reduces HIV transmission. We conducted a cost-effectiveness analysis of the impact of expanded ART in South Africa.

Methods

We model a best case scenario of 90% annual HIV testing coverage in adults 15–49 years old and four ART eligibility scenarios: CD4 count <200 cells/mm³ (current practice), CD4 count <350, CD4 count <500, all CD4 levels. 2011–2050 outcomes include deaths, disability adjusted life years (DALYs), HIV infections, cost, and cost per DALY averted. Service and ART costs reflect South African data and international generic prices. ART reduces transmission by 92%. We conducted sensitivity analyses.

Results

Expanding ART to CD4 count <350 cells/mm³ prevents an estimated 265,000 (17%) and 1.3 million (15%) new HIV infections over 5 and 40 years, respectively. Cumulative deaths decline 15%, from 12.5 to 10.6 million; DALYs by 14% from 109 to 93 million over 40 years. Costs drop $504 million over 5 years and $3.9 billion over 40 years with breakeven by 2013. Compared with the current scenario, expanding to <500 prevents an additional 585,000 and 3 million new HIV infections over 5 and 40 years, respectively. Expanding to all CD4 levels decreases HIV infections by 3.3 million (45%) and costs by $10 billion over 40 years, with breakeven by 2023. By 2050, using higher ART and monitoring costs, all CD4 levels saves $0.6 billion versus current; other ART scenarios cost $9–194 per DALY averted. If ART reduces transmission by 99%, savings from all CD4 levels reach $17.5 billion. Sensitivity analyses suggest that poor retention and predominant acute phase transmission reduce DALYs averted by 26% and savings by 7%.

Conclusion

Increasing the provision of ART to <350 cells/mm3 may significantly reduce costs while reducing the HIV burden. Feasibility including HIV testing and ART uptake, retention, and adherence should be evaluated.     

HIV reservoirs and immune surveillance evasion cause the failure of structured treatment interruptions: a computational study

Continuous antiretroviral therapy is currently the most effective way to treat HIV infection. Unstructured interruptions are quite common due to side effects and toxicity, among others, and cannot be prevented. Several attempts to structure these interruptions failed due to an increased morbidity compared to continuous treatment. The cause of this failure is poorly understood and often attributed to drug resistance. Here we show that structured treatment interruptions would fail regardless of the emergence of drug resistance. Our computational model of the HIV infection dynamics in lymphoid tissue inside lymph nodes, demonstrates that HIV reservoirs and evasion from immune surveillance themselves are sufficient to cause the failure of structured interruptions. We validate our model with data from a clinical trial and show that it is possible to optimize the schedule of interruptions to perform as well as the continuous treatment in the absence of drug resistance. Our methodology enables studying the problem of treatment optimization without having impact on human beings. We anticipate that it is feasible to steer new clinical trials using computational models.     

Beeswax as Dental Filling on a Neolithic Human Tooth

Evidence of prehistoric dentistry has been limited to a few cases, the most ancient dating back to the Neolithic. Here we report a 6500-year-old human mandible from Slovenia whose left canine crown bears the traces of a filling with beeswax. The use of different analytical techniques, including synchrotron radiation computed micro-tomography (micro-CT), Accelerator Mass Spectrometry (AMS) radiocarbon dating, Infrared (IR) Spectroscopy and Scanning Electron Microscopy (SEM), has shown that the exposed area of dentine resulting from occlusal wear and the upper part of a vertical crack affecting enamel and dentin tissues were filled with beeswax shortly before or after the individual’s death. If the filling was done when the person was still alive, the intervention was likely aimed to relieve tooth sensitivity derived from either exposed dentine and/or the pain resulting from chewing on a cracked tooth: this would provide the earliest known direct evidence of therapeutic-palliative dental filling.