Influence of recombination on acquisition and reversion of immune escape and compensatory mutations in HIV-1

Following transmission, HIV-1 adapts in the new host by acquiring mutations that allow it to escape from the host immune response at multiple epitopes. It also reverts mutations associated with epitopes targeted in the transmitting host but not in the new host. Moreover, escape mutations are often associated with additional compensatory mutations that partially recover fitness costs. It is unclear whether recombination expedites this process of multi-locus adaptation. To elucidate the role of recombination, we constructed a detailed population dynamics model that integrates viral dynamics, host immune response at multiple epitopes through cytotoxic T lymphocytes, and viral evolution driven by mutation, recombination, and selection. Using this model, we compute the expected waiting time until the emergence of the strain that has gained escape and compensatory mutations against the new host's immune response, and reverted these mutations at epitopes no longer targeted. We find that depending on the underlying fitness landscape, shaped by both costs and benefits of mutations, adaptation proceeds via distinct dominant pathways with different effects of recombination, in particular distinguishing escape and reversion. When adaptation at a single epitope is involved, recombination can substantially accelerate immune escape but minimally affects reversion. When multiple epitopes are involved, recombination can accelerate or inhibit adaptation depending on the fitness landscape. Specifically, recombination tends to delay adaptation when a purely uphill fitness landscape is accessible at each epitope, and accelerate it when a fitness valley is associated with each epitope. Our study points to the importance of recombination in shaping the adaptation of HIV-1 following its transmission to new hosts, a process central to T cell-based vaccine strategies. (C) 2015 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license.

Expanding adoption of drinking water treatment systems in developing countries: a case study from Tamil Nadu, India

Household-level water treatment and safe storage systems (HWTS) are simple, local, user-friendly, and low cost options to improve drinking water quality at the point of use. However, despite conclusive evidence of the health and economic benefits of HWTS, and promotion efforts in over 50 countries in the past 20 years, implementation outcomes have been slow, reaching only 5-10 million regular users. This study attempts to understand the barriers and drivers affecting HWTS implementation. Using a case study example of a biosand filter program in southern India, system dynamics modelling is shown to be a useful tool to map the inter-relationships of different critical factors and to understand the dissemination dynamics. It is found that the co-existence of expanding quickly and achieving financial sustainability appears to be difficult to achieve under the current program structure.

A systems approach to characterise the dissemination process of household water treatment systems in developing countries

Abstract: Starting in the 1980s, household-level water treatment and safe storage systems (HWTS) have been developed as simple, local, user-friendly, and low cost options to improve drinking water quality at the point of use. However, despite conclusive evidence of the health and economic benefits of HWTS, and promotion efforts in over 50 countries in the past 20 years, implementation outcomes have been slow, reaching only 5-10 million regular users. This study attempts to understand the barriers and drivers affecting HWTS implementation. Although existing literature related to HWTS and innovation diffusion theories proposed ample critical factors and recommendations, there is a lack of holistic and systemic approach to integrate these findings. It is proposed that system dynamics modelling can be a promising tool to map the inter-relationships of different critical factors and to understand the structure of HWTS dissemination process, which may lead to identifying high impact, leveraged mitigation strategies to scale-up HWTS adoption and sustained use.

Birkenhead Sixth Form College: Opening up remote access to the college network brings wider benefits to all

Birkenhead Sixth Form College implemented a virtual network to open up remote access to the college network for its students, staff and governors. In particular, for childcare students on work placements, this has meant 24/7 secure access to their work and resources, and the ability to make timely updates to their work evidence logs. The impact is better continuity of learning and a dramatic increase in the hand-in rate for work. For the staff, governors and college as a whole, the benefits of anytime-access to the network are more than were envisaged at the outset; not only is it saving them valuable time and eliminating the need for large print runs, it is expected to bring cost-savings to the College in the long term.

Report on Knowledge Exchange workshop Price of keeping knowledge: financial streams for digital preservation

In contrast to cost modeling activities, the pricing of services must be simple and transparent. Calculating and thus knowing price structures, would not only help identify the level of detail required for cost modeling of individual instititutions, but also help develop a ”public” market for services as well as clarify the division of task and the modeling of funding and revenue streams for data preservation of public institutions. This workshop has built on the results from the workshop ”The Costs and Benefits of Keeping Knowledge” which took place 11 June 2012 in Copenhagen. This expert workshop aimed at: •Identifying ways for data repositories to abstract from their complicated cost structures and arrive at one transparent pricing structure which can be aligned with available and plausible funding schemes. Those repositories will probably need a stable institutional funding stream for data management and preservation. Are there any estimates for this, absolute or as percentage of overall cost? Part of the revenue will probably have to come through data management fees upon ingest. How could that be priced? Per dataset, per GB or as a percentage of research cost? Will it be necessary to charge access prices, as they contradict the open science paradigm? •What are the price components for pricing individual services, which prices are currently being paid e.g. to commercial providers? What are the description and conditions of the service(s) delivered and guaranteed? •What types of risks are inherent in these pricing schemes? •How can services and prices be defined in an all-inclusive and simple manner, so as to enable researchers to apply for specific amount when asking for funding of data-intensive projects?Please

Seafood safety: economics of Hazard Analysis and Critical Control Point (HACCP) programmes

Seventy percent of the world's catch of fish and fishery products is consumed as food. Fish and shellfish products represent 15.6 percent of animal protein supply and 5.6 percent of total protein supply on a worldwide basis. Developing countries account for almost 50 percent of global fish exports. Seafood-borne disease or illness outbreaks affect consumers both physically and financially, and create regulatory problems for both importing and exporting countries. Seafood safety as a commodity cannot be purchased in the marketplace and government intervenes to regulate the safety and quality of seafood. Theoretical issues and data limitations create problems in estimating what consumers will pay for seafood safety and quality. The costs and benefits of seafood safety must be considered at all levels, including the fishers, fish farmers, input suppliers to fishing, processing and trade, seafood processors, seafood distributors, consumers and government. Hazard Analysis Critical Control Point (HACCP) programmes are being implemented on a worldwide basis for seafood. Studies have been completed to estimate the cost of HACCP in various shrimp, fish and shellfish plants in the United States, and are underway for some seafood plants in the United Kingdom, Canada and Africa. Major developments within the last two decades have created a set of complex trading situations for seafood. Current events indicate that seafood safety and quality can be used as non-tariff barriers to free trade. Research priorities necessary to estimate the economic value and impacts of achieving safer seafood are outlined at the consumer, seafood production and processing, trade and government levels. An extensive list of references on the economics of seafood safety and quality is presented. (PDF contains 56 pages; captured from html.)

Applications of in situ Fluorometers in Nearshore waters, Cape Elizabeth, Maine, February 2-4,2005: workshop proceedings

The Alliance for Coastal Technologies (ACT) Workshop "Applications of in situ Fluorometers in Nearshore Waters" was held in Cape Elizabeth, Maine, February 2-4,2005, with sponsorship by the Gulf of Maine Ocean Observing System (GoMOOS), one of the ACT partner organization. The purpose of the workshop was to explore recent trends in fluorometry as it relates to resource management applications in nearshore environments. Participants included representatives from state and federal environmental management agencies as well as research institutions, many of whom are currently using this technology in their research and management applications. Manufacturers and developers of fluorometric measuring systems also attended the meeting. The Workshop attendees discussed the historical and present uses of fluorometry technology and identified the great potential for its use by coastal managers to fulfill their regulatory and management objectives. Participants also identified some of the challenges associated with the correct use of Fluorometers to estimate biomass and the rate of primary productivity. The Workshop concluded that in order to expand the existing use of fluorometers in both academic and resource management disciplines, several issues concerning data collection, instrument calibration, and data interpretation needed to be addressed. Participants identified twelve recommendations, the top five of which are listed below: Recommendations 1) Develop a "Guide" that describes the most important aspects of fluorescence measurements. This guide should be written by an expert party, with both research and industry input, and should be distributed by all manufacturers with their instrumentation. The guide should also be made available on the ACT website as well as those of other relevant organizations. The guide should include discussions on the following topics: The benefits of using fluorometers in research and resource management applications; What fluorometers can and cannot provide in terms of measurements; The necessary assumptions required before applying fluorometry; Characterization and calibration of fluorometers; (pdf contains 32 pages)

The nutritional status of pre-school children, Kainji Lake communities, Nigeria: a baseline survey

This survey was carried out to provide the Kainji Lake Fisheries Promotion Project (KLFPP), whose overall goal is the improvement of the standard of living of fishing communities around Kainji Lake, Nigeria, and an increase in the availability of fish to consumers, with nutritional status baseline data for long-term monitoring and evaluation of the overall project goal. In a cross-sectional survey, baseline anthropometric data was collected from 768 children, aged 3-60 months in 389 fisherfolk households around the southern sector of Kainji Lake, Nigeria. In addition, data was collected on the nutritional status and fertility of the mothers, vaccination coverage of children and child survival indicators. For control purposes, 576 children and 292 mothers from non-fishing households around Kainji Lake were likewise covered by the survey. A standardised questionnaire was used to collect relevant information, while anthropometric measurements were made using appropriate equipment. Data compilation and analysis was carried out with DATAEASE registered and EPI-INFO registered software, using NCHS reference data for the analysis of anthropometric measurements. The prevalence of stunted children in fishing households was high at 40%, while the prevalence of wasted and underweight children was likewise high at 10% and 29% respectively. Children from non-fishing households had a marginally lower prevalence of stunting, wasting and underweight with 37%, 7% and 25 % respectively, although these differences were not statistically significant. Considering the fact that the survey was carried out during a period of relative food abundance, the prevalence of wasting and underweight children is likely to be much higher during periods of food shortage. The prevalence of stunting, wasting and underweight was relatively high for children aged 3 to 23 months, suggesting an increased risk of malnutrition during this period, most likely associated with inadequate weaning practices. The prevalence of malnourishment amongst women of child-bearing age was relatively high, irrespective of occupation of the household, with an average of 11% undernourished and 6% wasted. Vaccination coverage was very low while infant and child mortality were extremely high with about 1 in 5 children dying before their fifth birthday. Based on the ethical obligation to maximise the potential benefits of the survey, recommendations for activities to improve community nutrition and health were made for communication to relevant authorities. (PDF contains 52 pages)

Some ecological roles of Hippopotamus (Hippopotamus amphibious Linn. 1758) in fish production: possibilities for integrated fish-cum Agric production system

The common hippopotamus (Hippopotamus amphibious Linn. 1758) contributes to the productivity of aquatic systems where it lives. This paper reviews ecological roles of the hippo in this regard. Desk review of available literature information complemented with field observations were employed in the data collection. The ecological roles of the common hippopotamus being presented draw examples from East, West, Central and South African sub regions. The nutritional importance of the amphibious hippopotamus to rural communities was highlighted. In Southern Ethiopia, the Bodi, Bacha and Mura tribes eat hippo meat and this has led to severe hunting consequences on the wild populations of the animal. The important relationships between the hippopotamus and fish were presented. Hippopotamuses usually defecate in water and their excrements enrich the nutrients in the water resulting in favourable conditions for large fish populations. Some fish, including Labeo spp. were observed to feed on the micro-organisms and algae that grow on the skin of the hippotamus. A strong case was made for hippo-cum-fish integrated farm development in Nigeria based on ecological relationships so observed between the amphibious mammals and fish. This is one of the meeting points of fisheries and wildlife management that should be exploited for the benefits of the teeming Nigerian population

Utilization of some aquatic macrophytes in Nigeria in-land water bodies: a review

Aquatic vegetation is an essential component of the aquatic ecosystem with both positive and negative implications on the water body. Efforts are always made to curtail the excessive growth of aquatic plants in order to prevent them from becoming a nuisance in the ecosystem. One of the ways of solving such problem is the positive economic use of such plants. Utilization as a method of weed control within the aquatic ecosystem is considered to be one of the safest methods of weed control as this provides the riparian communities double advantages in terms of save environment and personal benefits of the plant. The flora diversity of freshwater and brackish environments posses a great potential to both man and higher animals alike. Due to this fact, this paper attempt to review the exploited and unexploited aquatic plants resources of many of our water bodies in Nigeria both economica/ly and socially, to the populace. Recommendations are also advanced for further studies that will enhance sound management of the resources for maximum benefits and sustainability

The Uniform World Model: A Methodology for Predicting the Health Impacts of Air Pollution

47 p.

Development of a Cationic Mucic Acid Polymer-Based Nanoparticle siRNA Delivery System

Cancer chemotherapy has advanced from highly toxic drugs to more targeted treatments in the last 70 years. Chapter 1 opens with an introduction to targeted therapy for cancer. The benefits of using a nanoparticle to deliver therapeutics are discussed. We move on to siRNA in particular, and why it would be advantageous as a therapy. Specific to siRNA delivery are some challenges, such as nuclease degradation, quick clearance from circulation, needing to enter cells, and getting to the cytosol. We propose the development of a nanoparticle delivery system to tackle these challenges so that siRNA can be effective.

Chapter 2 of this thesis discusses the synthesis and analysis of a cationic mucic acid polymer (cMAP) which condenses siRNA to form a nanoparticle. Various methods to add polyethylene glycol (PEG) for stabilizing the nanoparticle in physiologic solutions, including using a boronic acid binding to diols on mucic acid, forming a copolymer of cMAP with PEG, and creating a triblock with mPEG on both ends of cMAP. The goal of these various pegylation strategies was to increase the circulation time of the siRNA nanoparticle in the bloodstream to allow more of the nanoparticle to reach tumor tissue by the enhanced permeation and retention effect. We found that the triblock mPEG-cMAP-PEGm polymer condensed siRNA to form very stable 30-40 nm particles that circulated for the longest time – almost 10% of the formulation remained in the bloodstream of mice 1 h after intravenous injection.

Chapter 3 explores the use of an antibody as a targeting agent for nanoparticles. Some antibodies of the IgG1 subtype are able to recruit natural killer cells that effect antibody dependent cellular cytotoxicity (ADCC) to kill the targeted cell to which the antibody is bound. There is evidence that the ADCC effect remains in antibody-drug conjugates, so we wanted to know whether the ADCC effect is preserved when the antibody is bound to a nanoparticle, which is a much larger and complex entity. We utilized antibodies against epidermal growth factor receptor with similar binding and pharmacokinetics, cetuximab and panitumumab, which differ in that cetuximab is an IgG1 and panitumumab is an IgG2 (which does not cause ADCC). Although a natural killer cell culture model showed that gold nanoparticles with a full antibody targeting agent can elicit target cell lysis, we found that this effect was not preserved in vivo. Whether this is due to the antibody not being accessible to immune cells or whether the natural killer cells are inactivated in a tumor xenograft remains unknown. It is possible that using a full antibody still has value if there are immune functions which are altered in a complex in vivo environment that are intact in an in vitro system, so the value of using a full antibody as a targeting agent versus using an antibody fragment or a protein such as transferrin is still open to further exploration.

In chapter 4, nanoparticle targeting and endosomal escape are further discussed with respect to the cMAP nanoparticle system. A diboronic acid entity, which gives an order of magnitude greater binding (than boronic acid) to cMAP due to the vicinal diols in mucic acid, was synthesized, attached to 5kD or 10kD PEG, and conjugated to either transferrin or cetuximab. A histidine was incorporated into the triblock polymer between cMAP and the PEG blocks to allow for siRNA endosomal escape. Nanoparticle size remained 30-40 nm with a slightly negative ca. -3 mV zeta potential with the triblock polymer containing histidine and when targeting agents were added. Greater mRNA knockdown was seen with the endosomal escape mechanism than without. The nanoparticle formulations were able to knock down the targeted mRNA in vitro. Mixed effects suggesting function were seen in vivo.

Chapter 5 summarizes the project and provides an outlook on siRNA delivery as well as targeted combination therapies for the future of personalized medicine in cancer treatment.

A working guide to the assessment, implementation and post project monitoring of fisheries habitat improvement schemes in South Cumbria

Due to changes in land use over the last century, the physical nature of many streams and rivers in the British Isles has probably changed. In some cases this change may be large for example as a result of flood defence schemes and is easily observed, whilst in other cases altered land use, farming, forestry or urbanization may have resulted in more subtle changes to river features. This working guide draws together a way of assessing habitat in any stream or river and determine sites or reaches on the assessed watercourse that may benefit from habitat improvement schemes. It will determine a method of measuring existing habitat in a broad sense, whilst referring to R and D studies currently being undertaken in this area. A method of prioritising any proposed habitat restoration work will be suggested. The limitations of fisheries improvement schemes in terms of cross functional acceptance (flood defence and conservation) will be examined along with suggested proposals for some example watercourses. The need for pre and post enhancement monitoring will be discussed as will the requirement for maintenance programs on schemes. Finally methods for determining the cost benefits of small schemes will be examined, compared to other currently used enhancement strategies. This will allow small scale revenue schemes to be used to back up pre project cost benefit analysis as required in future capital submissions.

The potential use of time-area closures to reduce catches of bigeye tuna (Thunnus obesus) in the purse-seine fishery of the eastern Pacific Ocean

Skipjack (Katsuwonus pelamis), yellowfin (Thunnus albacares), and bigeye (Thunnus obesus) tunas are caught by purse-seine vessels in the eastern Pacific Ocean (EPO). Although there is no evidence to indicate that current levels of fishing-induced mortality will affect the sustainability of skipjack or yellowfin tunas, fishing mortality on juvenile (younger than 5 years of age) bigeye tuna has increased, and overall fishing mortality is greater than that necessary to produce the maximum sustainable yield of this species. We investigated whether time-area closures have the potential to reduce purse-seine bigeye catches without significantly reducing skipjack catches. Using catch and effort data for 1995–2002, we identified regions where the ratio of bigeye to skipjack tuna catches was high and applied simple closed-area models to investigate the possible benefits of time-area closures. We estimated that the most optimistic and operationally feasible 3-month closures, covering the equatorial region of the EPO during the third quarter of the year, could reduce bigeye catches by 11.5%, while reducing skipjack tuna catches by 4.3%. Because this level of bigeye tuna catch reduction is insufficient to address sustainability concerns, and larger and longer closures would reduce catches of this species signficantly, we recommend that future research be directed toward gear technology solutions because these have been successful in many other fisheries. In particular, because over 50% of purse-seine catches of bigeye tuna are taken in sets in which bigeye tuna are the dominant species, methods to allow the determination of the species composition of aggregations around floating objects may be important.

Energy retrofits in social housing. Analysis of its thermal behaviour.

468 p.