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1.  Projected Impacts of Climate and Land-Use Change on the Global Diversity of Birds 
PLoS Biology  2007;5(6):e157.
Over the past few decades, land-use and climate change have led to substantial range contractions and species extinctions. Even more dramatic changes to global land cover are projected for this century. We used the Millennium Ecosystem Assessment scenarios to evaluate the exposure of all 8,750 land bird species to projected land-cover changes due to climate and land-use change. For this first baseline assessment, we assumed stationary geographic ranges that may overestimate actual losses in geographic range. Even under environmentally benign scenarios, at least 400 species are projected to suffer >50% range reductions by the year 2050 (over 900 by the year 2100). Although expected climate change effects at high latitudes are significant, species most at risk are predominantly narrow-ranged and endemic to the tropics, where projected range contractions are driven by anthropogenic land conversions. Most of these species are currently not recognized as imperiled. The causes, magnitude and geographic patterns of potential range loss vary across socioeconomic scenarios, but all scenarios (even the most environmentally benign ones) result in large declines of many species. Whereas climate change will severely affect biodiversity, in the near future, land-use change in tropical countries may lead to yet greater species loss. A vastly expanded reserve network in the tropics, coupled with more ambitious goals to reduce climate change, will be needed to minimize global extinctions.
Author Summary
Land conversion and climate change have already had significant impacts on biodiversity and associated ecosystem services. Using future land-cover projections from the recently completed Millennium Ecosystem Assessment, we found that 950–1,800 of the world's 8,750 species of land birds could be imperiled by climate change and land conversion by the year 2100. These projections are based on the assumption that birds will not dramatically shift their ranges in response to a changing climate, a process that would lessen the range contractions we predict. While climate change will be the principal driver of range contractions at higher latitudes, our projections reveal that land conversion (e.g., deforestation, conversion of grasslands to croplands, etc.) will have a much larger effect on species that inhabit the tropics. This is because birds in the tropics are especially diverse and tend to have small ranges, making them particularly vulnerable to extinction; in contrast, birds at higher latitudes are less diverse and tend to have large ranges. A vastly expanded reserve network in the tropics, coupled with more ambitious goals to reduce greenhouse gas emissions and monitor biodiversity impacts, will be needed to minimize global extinctions.
Evaluating changes in range size of land bird species using Millenium Ecosystem Assessment scenarios reveals that land conversion, as well as climate change, will lead to the decline of many species, particularly those in the tropics.
PMCID: PMC1885834  PMID: 17550306
2.  Projections of Global Mortality and Burden of Disease from 2002 to 2030 
PLoS Medicine  2006;3(11):e442.
Global and regional projections of mortality and burden of disease by cause for the years 2000, 2010, and 2030 were published by Murray and Lopez in 1996 as part of the Global Burden of Disease project. These projections, which are based on 1990 data, continue to be widely quoted, although they are substantially outdated; in particular, they substantially underestimated the spread of HIV/AIDS. To address the widespread demand for information on likely future trends in global health, and thereby to support international health policy and priority setting, we have prepared new projections of mortality and burden of disease to 2030 starting from World Health Organization estimates of mortality and burden of disease for 2002. This paper describes the methods, assumptions, input data, and results.
Methods and Findings
Relatively simple models were used to project future health trends under three scenarios—baseline, optimistic, and pessimistic—based largely on projections of economic and social development, and using the historically observed relationships of these with cause-specific mortality rates. Data inputs have been updated to take account of the greater availability of death registration data and the latest available projections for HIV/AIDS, income, human capital, tobacco smoking, body mass index, and other inputs. In all three scenarios there is a dramatic shift in the distribution of deaths from younger to older ages and from communicable, maternal, perinatal, and nutritional causes to noncommunicable disease causes. The risk of death for children younger than 5 y is projected to fall by nearly 50% in the baseline scenario between 2002 and 2030. The proportion of deaths due to noncommunicable disease is projected to rise from 59% in 2002 to 69% in 2030. Global HIV/AIDS deaths are projected to rise from 2.8 million in 2002 to 6.5 million in 2030 under the baseline scenario, which assumes coverage with antiretroviral drugs reaches 80% by 2012. Under the optimistic scenario, which also assumes increased prevention activity, HIV/AIDS deaths are projected to drop to 3.7 million in 2030. Total tobacco-attributable deaths are projected to rise from 5.4 million in 2005 to 6.4 million in 2015 and 8.3 million in 2030 under our baseline scenario. Tobacco is projected to kill 50% more people in 2015 than HIV/AIDS, and to be responsible for 10% of all deaths globally. The three leading causes of burden of disease in 2030 are projected to include HIV/AIDS, unipolar depressive disorders, and ischaemic heart disease in the baseline and pessimistic scenarios. Road traffic accidents are the fourth leading cause in the baseline scenario, and the third leading cause ahead of ischaemic heart disease in the optimistic scenario. Under the baseline scenario, HIV/AIDS becomes the leading cause of burden of disease in middle- and low-income countries by 2015.
These projections represent a set of three visions of the future for population health, based on certain explicit assumptions. Despite the wide uncertainty ranges around future projections, they enable us to appreciate better the implications for health and health policy of currently observed trends, and the likely impact of fairly certain future trends, such as the ageing of the population, the continued spread of HIV/AIDS in many regions, and the continuation of the epidemiological transition in developing countries. The results depend strongly on the assumption that future mortality trends in poor countries will have a relationship to economic and social development similar to those that have occurred in the higher-income countries.
The presented projections suggest a dramatic shift in the distribution of deaths from younger to older ages and from communicable, maternal, perinatal, and nutritional causes to non-communicable disease causes. HIV/AIDS and tobacco remain major killers and possible targets for intervention.
Editors' Summary
For most of human history, little has been known about the main causes of illness in different countries and which diseases kill most people. But public-health officials need to know whether heart disease kills more people than cancer in their country, for example, or whether diabetes causes more disability than mental illness so that they can use their resources wisely. They also have to have some idea about how patterns of illness (morbidity) and death (mortality) are likely to change so that they can plan for the future. In the early 1990s, the World Bank sponsored the 1990 Global Burden of Disease study carried out by researchers at Harvard University and the World Health Organization (WHO). This study provided the first comprehensive, global estimates of death and illness by age, sex, and region. It also provided projections of the global burden of disease and mortality up to 2020 using models that assumed that health trends are related to a set of independent variables. These variables were income per person (as people become richer, they, live longer), average number of years of education (as this “human capital” increases, so does life expectancy), time (to allow for improved knowledge about various diseases), and tobacco use (a major global cause of illness and death).
Why Was This Study Done?
These health projections have been widely used by WHO and governments to help them plan their health policies. However, because they are based on the 1990 estimates of the global burden of disease, the projections now need updating, particularly since they underestimate the spread of HIV/AIDS and the associated increase in death from tuberculosis. In this study, the researchers used similar methods to those used in the 1990 Global Burden of Disease study to prepare new projections of mortality and burden of disease up to 2030 starting from the 2002 WHO global estimates of mortality and burden of disease.
What Did the Researchers Do and Find?
As before, the researchers used projections of socio-economic development to model future patterns of mortality and illness for a baseline scenario, a pessimistic scenario that assumed a slower rate of socio-economic development, and an optimistic scenario that assumed a faster rate of growth. Their analysis predicts that between 2002 and 2030 for all three scenarios life expectancy will increase around the world, fewer children younger than 5 years will die, and the proportion of people dying from non-communicable diseases such as heart disease and cancer will increase. Although deaths from infectious diseases will decrease overall, HIV/AIDS deaths will continue to increase; the exact magnitude of the increase will depend on how many people have access to antiretroviral drugs and the efficacy of prevention programs. But, even given the rise in HIV/AIDS deaths, the new projections predict that more people will die of tobacco-related disease than of HIV/AIDS in 2015. The researchers also predict that by 2030, the three leading causes of illness will be HIV/AIDS, depression, and ischaemic heart disease (problems caused by a poor blood supply to the heart) in the baseline and pessimistic scenarios; in the optimistic scenario, road-traffic accidents will replace heart disease as the third leading cause (there will be more traffic accidents with faster economic growth).
What Do These Findings Mean?
The models used by the researchers provide a wealth of information about possible patterns of global death and illness between 2002 and 2030, but because they include many assumptions, like all models, they can provide only indications of future trends, not absolute figures. For example, based on global mortality data from 2002, the researchers estimate that global deaths in 2030 will be 64.9 million under the optimistic scenario. However, the actual figure may be quite a bit bigger or smaller because accurate baseline counts of deaths were not available for every country in the world. Another limitation of the study is that the models used assume that future increases in prosperity in developing countries will affect their population's health in the same way as similar increases affected health in the past in countries with death registration data (these are mostly developed countries). However, even given these and other limitations, the projections reported in this study provide useful insights into the future health of the world. These can now be used by public-health officials to plan future policy and to monitor the effect of new public-health initiatives on the global burden of disease and death.
Additional Information.
Please access these Web sites via the online version of this summary at
World Health Organization, provides information on the Global Burden of Disease Project and links to other related resources Global Burden of Disease Project
Harvard School of Public Health, Burden of Disease Unit, offers information on the 1990 Global Burden of Disease study and its projections Harvard School of Public Health
PMCID: PMC1664601  PMID: 17132052
3.  Global Projections of 21st Century Land-Use Changes in Regions Adjacent to Protected Areas 
PLoS ONE  2012;7(8):e43714.
The conservation efficiency of Protected Areas (PA) is influenced by the health and characteristics of the surrounding landscape matrix. Fragmentation of adjacent lands interrupts ecological flows within PAs and will decrease the ability of species to shift their distribution as climate changes. For five periods across the 21st century, we assessed changes to the extent of primary land, secondary land, pasture and crop land projected to occur within 50 km buffers surrounding IUCN-designated PAs. Four scenarios of land-use were obtained from the Land-Use Harmonization Project, developed for the Intergovernmental Panel on Climate Change's Fifth Assessment Report (AR5). The scenarios project the continued decline of primary lands within buffers surrounding PAs. Substantial losses are projected to occur across buffer regions in the tropical forest biomes of Indo-Malayan and the Temperate Broadleaf forests of the Nearctic. A number of buffer regions are projected to have negligible primary land remaining by 2100, including those in the Afrotropic's Tropical/Subtropical Grassland/Savanna/Shrubland. From 2010–2050, secondary land is projected to increase within most buffer regions, although, as with pasture and crops within tropical and temperate forests, projections from the four land-use scenarios may diverge substantially in magnitude and direction of change. These scenarios demonstrate a range of alternate futures, and show that although effective mitigation strategies may reduce pressure on land surrounding PAs, these areas will contain an increasingly heterogeneous matrix of primary and human-modified landscapes. Successful management of buffer regions will be imperative to ensure effectiveness of PAs and to facilitate climate-induced shifts in species ranges.
PMCID: PMC3431375  PMID: 22952744
4.  Regulatory Interactions of Csr Components: the RNA Binding Protein CsrA Activates csrB Transcription in Escherichia coli 
Journal of Bacteriology  2001;183(20):6017-6027.
The global regulator CsrA (carbon storage regulator) of Escherichia coli is a small RNA binding protein that represses various metabolic pathways and processes that are induced in the stationary phase of growth, while it activates certain exponential phase functions. Both repression and activation by CsrA involve posttranscriptional mechanisms, in which CsrA binding to mRNA leads to decreased or increased transcript stability, respectively. CsrA also binds to a small untranslated RNA, CsrB, forming a ribonucleoprotein complex, which antagonizes CsrA activity. We have further examined the regulatory interactions of CsrA and CsrB RNA. The 5′ end of the CsrB transcript was mapped, and a csrB::cam null mutant was constructed. CsrA protein and CsrB RNA levels were estimated throughout the growth curves of wild-type and isogenic csrA, csrB, rpoS, or csrA rpoS mutant strains. CsrA levels exhibited modest or negligible effects of these mutations. The intracellular concentration of CsrA exceeded the total CsrA-binding capacity of intracellular CsrB RNA. In contrast, CsrB levels were drastically decreased (∼10-fold) in the csrA mutants. CsrB transcript stability was unaffected by csrA. The expression of a csrB-lacZ transcriptional fusion containing the region from −242 to +4 bp of the csrB gene was decreased ∼20-fold by a csrA::kanR mutation in vivo but was unaffected by CsrA protein in vitro. These results reveal a significant, though most likely indirect, role for CsrA in regulating csrB transcription. Furthermore, our findings suggest that CsrA mediates an intriguing form of autoregulation, whereby its activity, but not its levels, is modulated through effects on an RNA antagonist, CsrB.
PMCID: PMC99681  PMID: 11567002
5.  Manipulation of the carbon storage regulator system for metabolite remodeling and biofuel production in Escherichia coli 
Microbial engineering strategies that elicit global metabolic perturbations have the capacity to increase organism robustness for targeted metabolite production. In particular, perturbations to regulators of cellular systems that impact glycolysis and amino acid production while simultaneously decreasing fermentation by-products such as acetate and CO2 make ideal targets. Intriguingly, perturbation of the Carbon Storage Regulator (Csr) system has been previously implicated in large changes in central carbon metabolism in E. coli. Therefore, we hypothesized that perturbation of the Csr system through the CsrA-CsrB ribonucleoprotein complex might increase production of biofuels and their intermediates from heterologous pathways.
We engaged the CsrA-CsrB ribonucleoprotein complex of E. coli via overexpression of CsrB. CsrB is a 350-nucleotide non-coding RNA that antagonizes CsrA, an RNA-binding protein that regulates translation of specific mRNA targets. By using shotgun proteomics and targeted metabolomics we established that elevation of CsrB levels leads to alterations in metabolite and protein levels in glycolysis, the TCA cycle and amino acid levels. Consequently, we show that such changes can be suitably applied to improve the production of desired compounds through the native fatty acid and heterologous n-butanol and isoprenoid pathways by up to two-fold. We also observed concomitant decreases in undesirable fermentation by-products such as acetate and CO2.
We have demonstrated that simple engineering of the RNA-based Csr global regulatory system constitutes a novel approach to obtaining pathway-independent improvements within engineered hosts. Additionally, since Csr is conserved across most prokaryotic species, this approach may also be amenable to a wide variety of production hosts.
PMCID: PMC3460784  PMID: 22694848
Metabolic engineering; Global regulators; Heterologous pathway; Carbon storage; Biofuels; Metabolomics; Proteomics
6.  Human Health Risk Assessment due to Global Warming – A Case Study of the Gulf Countries 
Accelerated global warming is predicted by the Intergovernmental Panel on Climatic Change (IPCC) due to increasing anthropogenic greenhouse gas emissions. The climate changes are anticipated to have a long-term impact on human health, marine and terrestrial ecosystems, water resources and vegetation. Due to rising sea levels, low lying coastal regions will be flooded, farmlands will be threatened and scarcity of fresh water resources will be aggravated. This will in turn cause increased human suffering in different parts of the world. Spread of disease vectors will contribute towards high mortality, along with the heat related deaths. Arid and hot climatic regions will face devastating effects risking survival of the fragile plant species, wild animals, and other desert ecosystems. The paper presents future changes in temperature, precipitation and humidity and their direct and indirect potential impacts on human health in the coastal regions of the Gulf countries including Yemen, Oman, United Arab Emirates, Qatar, and Bahrain. The analysis is based on the long-term changes in the values of temperature, precipitation and humidity as predicted by the global climatic simulation models under different scenarios of GHG emission levels. Monthly data on temperature, precipitation, and humidity were retrieved from IPCC databases for longitude 41.25°E to 61.875°E and latitude 9.278°N to 27.833°N. Using an average of 1970 to 2000 values as baseline, the changes in the humidity, temperature and precipitation were predicted for the period 2020 to 2050 and 2070 to 2099. Based on epidemiological studies on various diseases associated with the change in temperature, humidity and precipitation in arid and hot regions, empirical models were developed to assess human health risk in the Gulf region to predict elevated levels of diseases and mortality rates under different emission scenarios as developed by the IPCC. The preliminary assessment indicates increased mortality rates due to cardiovascular and respiratory illnesses, thermal stress, and increased frequency of infectious vector borne diseases in the region between 2070 and 2099.
PMCID: PMC2672314  PMID: 19190352
Climate change; Human health; Gulf countries
7.  Responses of grape berry anthocyanin and titratable acidity to the projected climate change across the Western Australian wine regions 
More than a century of observations has established that climate influences grape berry composition. Accordingly, the projected global climate change is expected to impact on grape berry composition although the magnitude and direction of impact at regional and subregional scales are not fully known. The aim of this study was to assess potential impacts of climate change on levels of berry anthocyanin and titratable acidity (TA) of the major grapevine varieties grown across all of the Western Australian (WA) wine regions. Grape berry anthocyanin and TA responses across all WA wine regions were projected for 2030, 2050 and 2070 by utilising empirical models that link these berry attributes and climate data downscaled (to ∼5 km resolution) from the csiro_mk3_5 and miroc3_2_medres global climate model outputs under IPCC SRES A2 emissions scenario. Due to the dependence of berry composition on maturity, climate impacts on anthocyanin and TA levels were assessed at a common maturity of 22 °Brix total soluble solids (TSS), which necessitated the determination of when this maturity will be reached for each variety, region and warming scenario, and future period. The results indicate that both anthocyanin and TA levels will be affected negatively by a warming climate, but the magnitude of the impacts will differ between varieties and wine regions. Compared to 1990 levels, median anthocyanins concentrations are projected to decrease, depending on global climate model, by up to 3–12 % and 9–33 % for the northern wine regions by 2030 and 2070, respectively while 2–18 % reductions are projected in the southern wine regions for the same time periods. Patterns of reductions in the median Shiraz berry anthocyanin concentrations are similar to that of Cabernet Sauvignon; however, the magnitude is lower (up to 9–18 % in southern and northern wine regions respectively by 2070). Similarly, uneven declines in TA levels are projected across the study regions. The largest reductions in median TA are likely to occur in the present day warmer wine regions, up to 40 % for Chardonnay followed by 15 % and 12 % for Shiraz and Cabernet Sauvignon, respectively, by 2070 under the high warming projection (csiro_mk3_5). It is concluded that, under existing management practices, some of the key grape attributes that are integral to premium wine production will be affected negatively by a warming climate, but the magnitudes of the impacts vary across the established wine regions, varieties, the magnitude of warming and future periods considered.
Electronic supplementary material
The online version of this article (doi:10.1007/s00484-013-0724-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4094651  PMID: 24026877
Anthocyanin; Cabernet Sauvignon; Chardonnay; Climate change; Climate impact; Maturity dates; Shiraz; Titratable acidity; Vitis vinifera; Western Australia Wine Regions
8.  Heat-Related Mortality in a Warming Climate: Projections for 12 U.S. Cities 
Heat is among the deadliest weather-related phenomena in the United States, and the number of heat-related deaths may increase under a changing climate, particularly in urban areas. Regional adaptation planning is unfortunately often limited by the lack of quantitative information on potential future health responses. This study presents an assessment of the future impacts of climate change on heat-related mortality in 12 cities using 16 global climate models, driven by two scenarios of greenhouse gas emissions. Although the magnitude of the projected heat effects was found to differ across time, cities, climate models and greenhouse pollution emissions scenarios, climate change was projected to result in increases in heat-related fatalities over time throughout the 21st century in all of the 12 cities included in this study. The increase was more substantial under the high emission pathway, highlighting the potential benefits to public health of reducing greenhouse gas emissions. Nearly 200,000 heat-related deaths are projected to occur in the 12 cities by the end of the century due to climate warming, over 22,000 of which could be avoided if we follow a low GHG emission pathway. The presented estimates can be of value to local decision makers and stakeholders interested in developing strategies to reduce these impacts and building climate change resilience.
PMCID: PMC4245617  PMID: 25365060
Heat-related mortality; climate change; heat impacts; United States; extreme temperatures
9.  Climate Change and Risk of Leishmaniasis in North America: Predictions from Ecological Niche Models of Vector and Reservoir Species 
Climate change is increasingly being implicated in species' range shifts throughout the world, including those of important vector and reservoir species for infectious diseases. In North America (México, United States, and Canada), leishmaniasis is a vector-borne disease that is autochthonous in México and Texas and has begun to expand its range northward. Further expansion to the north may be facilitated by climate change as more habitat becomes suitable for vector and reservoir species for leishmaniasis.
Methods and Findings
The analysis began with the construction of ecological niche models using a maximum entropy algorithm for the distribution of two sand fly vector species (Lutzomyia anthophora and L. diabolica), three confirmed rodent reservoir species (Neotoma albigula, N. floridana, and N. micropus), and one potential rodent reservoir species (N. mexicana) for leishmaniasis in northern México and the United States. As input, these models used species' occurrence records with topographic and climatic parameters as explanatory variables. Models were tested for their ability to predict correctly both a specified fraction of occurrence points set aside for this purpose and occurrence points from an independently derived data set. These models were refined to obtain predicted species' geographical distributions under increasingly strict assumptions about the ability of a species to disperse to suitable habitat and to persist in it, as modulated by its ecological suitability. Models successful at predictions were fitted to the extreme A2 and relatively conservative B2 projected climate scenarios for 2020, 2050, and 2080 using publicly available interpolated climate data from the Third Intergovernmental Panel on Climate Change Assessment Report. Further analyses included estimation of the projected human population that could potentially be exposed to leishmaniasis in 2020, 2050, and 2080 under the A2 and B2 scenarios. All confirmed vector and reservoir species will see an expansion of their potential range towards the north. Thus, leishmaniasis has the potential to expand northwards from México and the southern United States. In the eastern United States its spread is predicted to be limited by the range of L. diabolica; further west, L. anthophora may play the same role. In the east it may even reach the southern boundary of Canada. The risk of spread is greater for the A2 scenario than for the B2 scenario. Even in the latter case, with restrictive (contiguous) models for dispersal of vector and reservoir species, and limiting vector and reservoir species occupancy to only the top 10% of their potential suitable habitat, the expected number of human individuals exposed to leishmaniasis by 2080 will at least double its present value.
These models predict that climate change will exacerbate the ecological risk of human exposure to leishmaniasis in areas outside its present range in the United States and, possibly, in parts of southern Canada. This prediction suggests the adoption of measures such as surveillance for leishmaniasis north of Texas as disease cases spread northwards. Potential vector and reservoir control strategies—besides direct intervention in disease cases—should also be further investigated.
Author Summary
We explored the consequences of climate change for the spread of leishmaniasis in North America. We modeled the distribution of two sand fly vector and four rodent reservoir species found in northern México and the southern United States. Models were based on occurrence data and environmental and topographic layers. Successful models were projected to 2020, 2050, and 2080 using an extreme (A2) and a conservative (B2) future climate scenario. We predicted potential range shifts of vector and reservoir species varying assumptions about dispersal ability and capacity to persist in habitats with different degrees of ecological suitability. Even with the most conservative assumptions the distributions of both vector and reservoir species expand northwards, potentially reaching as far as southern Canada in the east. Assuming that at least one vector and one reservoir species must be present for a parasite cycle, the extent of this shift is predicted to be controlled by the availability of suitable habitat for sand fly vector species. Finally, we computed the human population potentially exposed to leishmaniasis because of these range shifts. Even in the most optimistic scenario we found that twice as many individuals could be exposed to leishmaniasis in North America in 2080 compared to today.
PMCID: PMC2799657  PMID: 20098495
10.  Woody plants and the prediction of climate-change impacts on bird diversity 
Current methods of assessing climate-induced shifts of species distributions rarely account for species interactions and usually ignore potential differences in response times of interacting taxa to climate change. Here, we used species-richness data from 1005 breeding bird and 1417 woody plant species in Kenya and employed model-averaged coefficients from regression models and median climatic forecasts assembled across 15 climate-change scenarios to predict bird species richness under climate change. Forecasts assuming an instantaneous response of woody plants and birds to climate change suggested increases in future bird species richness across most of Kenya whereas forecasts assuming strongly lagged woody plant responses to climate change indicated a reversed trend, i.e. reduced bird species richness. Uncertainties in predictions of future bird species richness were geographically structured, mainly owing to uncertainties in projected precipitation changes. We conclude that assessments of future species responses to climate change are very sensitive to current uncertainties in regional climate-change projections, and to the inclusion or not of time-lagged interacting taxa. We expect even stronger effects for more specialized plant–animal associations. Given the slow response time of woody plant distributions to climate change, current estimates of future biodiversity of many animal taxa may be both biased and too optimistic.
PMCID: PMC2880125  PMID: 20513712
biodiversity change; biotic interactions; climate-change impacts; general circulation model; predictive model; uncertainty
11.  Climate Change Affects Winter Chill for Temperate Fruit and Nut Trees 
PLoS ONE  2011;6(5):e20155.
Temperate fruit and nut trees require adequate winter chill to produce economically viable yields. Global warming has the potential to reduce available winter chill and greatly impact crop yields.
Methodology/Principal Findings
We estimated winter chill for two past (1975 and 2000) and 18 future scenarios (mid and end 21st century; 3 Global Climate Models [GCMs]; 3 greenhouse gas emissions [GHG] scenarios). For 4,293 weather stations around the world and GCM projections, Safe Winter Chill (SWC), the amount of winter chill that is exceeded in 90% of all years, was estimated for all scenarios using the “Dynamic Model” and interpolated globally. We found that SWC ranged between 0 and about 170 Chill Portions (CP) for all climate scenarios, but that the global distribution varied across scenarios. Warm regions are likely to experience severe reductions in available winter chill, potentially threatening production there. In contrast, SWC in most temperate growing regions is likely to remain relatively unchanged, and cold regions may even see an increase in SWC. Climate change impacts on SWC differed quantitatively among GCMs and GHG scenarios, with the highest GHG leading to losses up to 40 CP in warm regions, compared to 20 CP for the lowest GHG.
The extent of projected changes in winter chill in many major growing regions of fruits and nuts indicates that growers of these commodities will likely experience problems in the future. Mitigation of climate change through reductions in greenhouse gas emissions can help reduce the impacts, however, adaption to changes will have to occur. To better prepare for likely impacts of climate change, efforts should be undertaken to breed tree cultivars for lower chilling requirements, to develop tools to cope with insufficient winter chill, and to better understand the temperature responses of tree crops.
PMCID: PMC3101230  PMID: 21629649
12.  How Early Can the Seeding Dates of Spring Wheat Be under Current and Future Climate in Saskatchewan, Canada? 
PLoS ONE  2012;7(10):e45153.
Shorter growing season and water stress near wheat maturity are the main factors that presumably limit the yield potential of spring wheat due to late seeding in Saskatchewan, Canada. Advancing seeding dates can be a strategy to help producers mitigate the impact of climate change on spring wheat. It is unknown, however, how early farmers can seed while minimizing the risk of spring frost damage and the soil and machinery constraints.
Methodology/principal findings
This paper explores early seeding dates of spring wheat on the Canadian Prairies under current and projected future climate. To achieve this, (i) weather records from 1961 to 1990 were gathered at three sites with different soil and climate conditions in Saskatchewan, Canada; (ii) four climate databases that included a baseline (treated as historic weather climate during the period of 1961–1990) and three climate change scenarios (2040–2069) developed by the Canadian global climate model (GCM) with the forcing of three greenhouse gas (GHG) emission scenarios (A2, A1B and B1); (iii) seeding dates of spring wheat (Triticum aestivum L.) under baseline and projected future climate were predicted. Compared with the historical record of seeding dates, the predicted seeding dates were advanced under baseline climate for all sites using our seeding date model. Driven by the predicted temperature increase of the scenarios compared with baseline climate, all climate change scenarios projected significantly earlier seeding dates than those currently used. Compared to the baseline conditions, there is no reduction in grain yield because precipitation increases during sensitive growth stages of wheat, suggesting that there is potential to shift seeding to an earlier date. The average advancement of seeding dates varied among sites and chosen scenarios. The Swift Current (south-west) site has the highest potential for earlier seeding (7 to 11 days) whereas such advancement was small in the Melfort (north-east, 2 to 4 days) region.
The extent of projected climate change in Saskatchewan indicates that growers in this region have the potential of earlier seeding. The results obtained in this study may be used for adaptation assessments of seeding dates under possible climate change to mitigate the impact of potential warming.
PMCID: PMC3468606  PMID: 23094015
13.  Combating the effects of climatic change on forests by mitigation strategies 
Forests occur across diverse biomes, each of which shows a specific composition of plant communities associated with the particular climate regimes. Predicted future climate change will have impacts on the vulnerability and productivity of forests; in some regions higher temperatures will extend the growing season and thus improve forest productivity, while changed annual precipitation patterns may show disadvantageous effects in areas, where water availability is restricted. While adaptation of forests to predicted future climate scenarios has been intensively studied, less attention was paid to mitigation strategies such as the introduction of tree species well adapted to changing environmental conditions.
We simulated the development of managed forest ecosystems in Germany for the time period between 2000 and 2100 under different forest management regimes and climate change scenarios. The management regimes reflect different rotation periods, harvesting intensities and species selection for reforestations. The climate change scenarios were taken from the IPCC's Special Report on Emission Scenarios (SRES). We used the scenarios A1B (rapid and successful economic development) and B1 (high level of environmental and social consciousness combined with a globally coherent approach to a more sustainable development). Our results indicate that the effects of different climate change scenarios on the future productivity and species composition of German forests are minor compared to the effects of forest management.
The inherent natural adaptive capacity of forest ecosystems to changing environmental conditions is limited by the long life time of trees. Planting of adapted species and forest management will reduce the impact of predicted future climate change on forests.
PMCID: PMC3009614  PMID: 21118548
14.  Heat-related respiratory hospital admissions in Europe in a changing climate: a health impact assessment 
BMJ Open  2013;3(1):e001842.
Respiratory diseases are ranked second in Europe in terms of mortality, prevalence and costs. Studies have shown that extreme heat has a large impact on mortality and morbidity, with a large relative increase for respiratory diseases. Expected increases in mean temperature and the number of extreme heat events over the coming decades due to climate change raise questions about the possible health impacts. We assess the number of heat-related respiratory hospital admissions in a future with a different climate.
A Europe-wide health impact assessment.
An assessment for each of the EU27 countries.
Heat-related hospital admissions under a changing climate are projected using multicity epidemiological exposure–response relationships applied to gridded population data and country-specific baseline respiratory hospital admission rates. Times-series of temperatures are simulated with a regional climate model based on four global climate models, under two greenhouse gas emission scenarios.
Between a reference period (1981–2010) and a future period (2021–2050), the total number of respiratory hospital admissions attributed to heat is projected to be larger in southern Europe, with three times more heat attributed respiratory hospital admissions in the future period. The smallest change was estimated in Eastern Europe with about a twofold increase. For all of Europe, the number of heat-related respiratory hospital admissions is projected to be 26 000 annually in the future period compared with 11 000 in the reference period.
The results suggest that the projected effects of climate change on temperature and the number of extreme heat events could substantially influence respiratory morbidity across Europe.
PMCID: PMC3563142  PMID: 23355662
Epidemiology; Public Health
15.  Climate change effects on Chikungunya transmission in Europe: geospatial analysis of vector’s climatic suitability and virus’ temperature requirements 
Chikungunya was, from the European perspective, considered to be a travel-related tropical mosquito-borne disease prior to the first European outbreak in Northern Italy in 2007. This was followed by cases of autochthonous transmission reported in South-eastern France in 2010. Both events occurred after the introduction, establishment and expansion of the Chikungunya-competent and highly invasive disease vector Aedes albopictus (Asian tiger mosquito) in Europe. In order to assess whether these outbreaks are indicative of the beginning of a trend or one-off events, there is a need to further examine the factors driving the potential transmission of Chikungunya in Europe. The climatic suitability, both now and in the future, is an essential starting point for such an analysis.
The climatic suitability for Chikungunya outbreaks was determined by using bioclimatic factors that influence, both vector and, pathogen. Climatic suitability for the European distribution of the vector Aedes albopictus was based upon previous correlative environmental niche models. Climatic risk classes were derived by combining climatic suitability for the vector with known temperature requirements for pathogen transmission, obtained from outbreak regions. In addition, the longest potential intra-annual season for Chikungunya transmission was estimated for regions with expected vector occurrences.
In order to analyse spatio-temporal trends for risk exposure and season of transmission in Europe, climate change impacts are projected for three time-frames (2011–2040, 2041–2070 and 2071–2100) and two climate scenarios (A1B and B1) from the Intergovernmental Panel on Climate Change (IPCC). These climatic projections are based on regional climate model COSMO-CLM, which builds on the global model ECHAM5.
European areas with current and future climatic suitability of Chikungunya transmission are identified. An increase in risk is projected for Western Europe (e.g. France and Benelux-States) in the first half of the 21st century and from mid-century onwards for central parts of Europe (e.g. Germany). Interestingly, the southernmost parts of Europe do not generally provide suitable conditions in these projections. Nevertheless, many Mediterranean regions will persist to be climatically suitable for transmission. Overall, the highest risk of transmission by the end of the 21st century was projected for France, Northern Italy and the Pannonian Basin (East-Central Europe). This general tendency is depicted in both, the A1B and B1 climate change scenarios.
In order to guide preparedness for further outbreaks, it is crucial to anticipate risk as to identify areas where specific public health measures, such as surveillance and vector control, can be implemented. However, public health practitioners need to be aware that climate is only one factor driving the transmission of vector-borne disease.
PMCID: PMC3834102  PMID: 24219507
Asian tiger mosquito; Chikungunya; Climate change; Dengue; Globalisation; Global warming; Infectious disease; Invasion; Public health; Vector-borne disease
16.  Corporate Social Responsibility and Access to Policy Élites: An Analysis of Tobacco Industry Documents 
PLoS Medicine  2011;8(8):e1001076.
Gary Fooks and colleagues undertook a review of tobacco industry documents and show that policies on corporate social responsibility can enable access to and dialogue with policymakers at the highest level.
Recent attempts by large tobacco companies to represent themselves as socially responsible have been widely dismissed as image management. Existing research supports such claims by pointing to the failings and misleading nature of corporate social responsibility (CSR) initiatives. However, few studies have focused in depth on what tobacco companies hoped to achieve through CSR or reflected on the extent to which these ambitions have been realised.
Methods and Findings
Iterative searching relating to CSR strategies was undertaken of internal British American Tobacco (BAT) documents, released through litigation in the US. Relevant documents (764) were indexed and qualitatively analysed. In the past decade, BAT has actively developed a wide-ranging CSR programme. Company documents indicate that one of the key aims of this programme was to help the company secure access to policymakers and, thereby, increase the company's chances of influencing policy decisions. Taking the UK as a case study, this paper demonstrates the way in which CSR can be used to renew and maintain dialogue with policymakers, even in ostensibly unreceptive political contexts. In practice, the impact of this political use of CSR is likely to be context specific; depending on factors such as policy élites' understanding of the credibility of companies as a reliable source of information.
The findings suggest that tobacco company CSR strategies can enable access to and dialogue with policymakers and provide opportunities for issue definition. CSR should therefore be seen as a form of corporate political activity. This underlines the need for broad implementation of Article 5.3 of the Framework Convention on Tobacco Control. Measures are needed to ensure transparency of interactions between all parts of government and the tobacco industry and for policy makers to be made more aware of what companies hope to achieve through CSR.
Please see later in the article for the Editors' Summary
Editors' Summary
In the past, companies and multinational corporations were judged on the profits they made. Nowadays, though, much is made of corporate social responsibility (CSR). CSR is the commitment by business to behave ethically and to contribute to economic development while improving the quality of life of the workforce, their families, the local community, and society at large. Put simply, companies and corporations now endeavor to show that they have a positive impact on the environment, consumers, employees, and society in addition to making money for their shareholders. Large tobacco companies are no exception. British American Tobacco (BAT, the world's second largest publicly traded tobacco company), for example, began working on a wide-ranging CSR program more than a decade ago. Given that tobacco is responsible for an estimated 5.4 million deaths worldwide annually, this program was initially met with hostility and dismissed as an image management exercise. However, large parts of the investment and CSR communities now approve of BAT's CSR program, which has won numerous awards.
Why Was This Study Done?
But what do BAT and other tobacco companies actually hope to achieve through their CSR initiatives and how successful have they been in achieving these aims? Few studies have addressed these important questions. In particular, there has been little research into the extent to which tobacco companies use CSR initiatives as a form of corporate political activity that can help them gain “access” to policymakers and define the legitimate concerns and optimal alternatives of public policy (“issue definition”). Access is defined as taking place when policymakers consider the views of policy advocates such as tobacco company employees and is a crucial component of issue definition, which refers to the strategies adopted by bodies such as multinational corporations to influence the policy agenda by defining what issues public policy should concern itself with and how it should approach them. In this case study, the researchers explore whether BAT's CSR program works as a form of corporate political activity by systematically examining internal BAT documents made publicly available as a result of US litigation. Specifically, the researchers examine BAT's efforts through its CSR program to reestablish access with the UK Department of Health following the department's decision in the late 1990s to restrict contact with major tobacco companies.
What Did the Researchers Do and Find?
Using iterative searching, the researchers identified 764 documents in the Legacy Tobacco Documents Library (a large collection of internal tobacco company documents released as a result of US litigation cases) that contain information relevant to BAT's CSR strategies. Their analysis of these documents indicates that one of the key aims of the CSR program actively developed over the past decade by BAT was to help secure access to policymakers and shows how BAT used CSR to renew and maintain dialogue with policymakers at a time when contact between government and tobacco companies was extremely restricted. The documents also show that BAT employees used CSR initiatives as a means of issue definition to both optimize the probability of subsequent discussions taking place and to frame their content. Finally, the documents illustrate how BAT used its CSR program to expand the number of access points across government, thereby providing BAT with more opportunities to meet and talk to officials.
What Do These Findings Mean?
These findings suggest that CSR is a form of corporate political activity that potentially has important implications for public health given the documented impact of the political activity of tobacco companies in delaying and blocking health-related tobacco control policies. In practice, the impact of the political use of CSR is likely to be context specific and will depend on factors such as whether senior policymakers regard companies as reliable sources of information. Importantly, these findings underline the need for broad implementation of Article 5.3 of the World Health Organization's Framework Convention on Tobacco Control (FCTC), an international treaty that calls for the introduction of multiple measures to reduce tobacco consumption, including tobacco advertizing bans and relevant taxation policies. Article 5.3 aims to protect public-health policies on tobacco control from tobacco industry influence. The findings of this study indicate that implementation of Article 5.3 will require measures that ensure transparency in interactions between all parts of government and the tobacco industry and will need an increased awareness across government of what tobacco companies hope to achieve through CSR.
Additional Information
Please access these Web sites via the online version of this summary at
The Corporate Responsibility (CORE) coalition, an alliance of voluntary organizations, trade unions, and companies, maintains a Web site that contains useful material on corporate social responsibility
The European Coalition for Corporate Justice (ECCJ) promotes corporate accountability by bringing together national platforms of civil society organizations (including NGOs, trade unions, consumer advocacy groups, and academic institutions) from all over Europe
The Legacy Tobacco Documents Library is a public, searchable database of tobacco company internal documents detailing their advertising, manufacturing, marketing, sales, and scientific activities
The World Health Organization provides information about the dangers of tobacco (in several languages), details of the Framework Convention on Tobacco Control (in several languages), and guidelines for the implementation of Article 5.3 of the FCTC
The Framework Convention Alliance provides more information about the FCTC
For information about tobacco industry influence on policy, see the 2009 World Health Organization report Tobacco interference with tobacco control
PMCID: PMC3160341  PMID: 21886485
17.  Completeness of Reporting of Patient-Relevant Clinical Trial Outcomes: Comparison of Unpublished Clinical Study Reports with Publicly Available Data 
PLoS Medicine  2013;10(10):e1001526.
Beate Wieseler and colleagues compare the completeness of reporting of patient-relevant clinical trial outcomes between clinical study reports and publicly available data.
Please see later in the article for the Editors' Summary
Access to unpublished clinical study reports (CSRs) is currently being discussed as a means to allow unbiased evaluation of clinical research. The Institute for Quality and Efficiency in Health Care (IQWiG) routinely requests CSRs from manufacturers for its drug assessments.
Our objective was to determine the information gain from CSRs compared to publicly available sources (journal publications and registry reports) for patient-relevant outcomes included in IQWiG health technology assessments (HTAs) of drugs.
Methods and Findings
We used a sample of 101 trials with full CSRs received for 16 HTAs of drugs completed by IQWiG between 15 January 2006 and 14 February 2011, and analyzed the CSRs and the publicly available sources of these trials. For each document type we assessed the completeness of information on all patient-relevant outcomes included in the HTAs (benefit outcomes, e.g., mortality, symptoms, and health-related quality of life; harm outcomes, e.g., adverse events). We dichotomized the outcomes as “completely reported” or “incompletely reported.” For each document type, we calculated the proportion of outcomes with complete information per outcome category and overall.
We analyzed 101 trials with CSRs; 86 had at least one publicly available source, 65 at least one journal publication, and 50 a registry report. The trials included 1,080 patient-relevant outcomes. The CSRs provided complete information on a considerably higher proportion of outcomes (86%) than the combined publicly available sources (39%). With the exception of health-related quality of life (57%), CSRs provided complete information on 78% to 100% of the various benefit outcomes (combined publicly available sources: 20% to 53%). CSRs also provided considerably more information on harms. The differences in completeness of information for patient-relevant outcomes between CSRs and journal publications or registry reports (or a combination of both) were statistically significant for all types of outcomes.
The main limitation of our study is that our sample is not representative because only CSRs provided voluntarily by pharmaceutical companies upon request could be assessed. In addition, the sample covered only a limited number of therapeutic areas and was restricted to randomized controlled trials investigating drugs.
In contrast to CSRs, publicly available sources provide insufficient information on patient-relevant outcomes of clinical trials. CSRs should therefore be made publicly available.
Please see later in the article for the Editors' Summary
Editors' Summary
People assume that, when they are ill, health care professionals will ensure that they get the best available treatment. In the past, clinicians used their own experience to make decisions about which treatments to offer their patients, but nowadays, they rely on evidence-based medicine—the systematic review and appraisal of clinical trials, studies that investigate the benefits and harms of drugs and other medical interventions in patients. Evidence-based medicine can guide clinicians, however, only if all the results of clinical research are available for evaluation. Unfortunately, the results of trials in which a new drug performs better than existing drugs are more likely to be published than those in which the new drug performs badly or has unwanted side effects (publication bias). Moreover, trial outcomes that support the use of a new treatment are more likely to be published than those that do not support its use (outcome reporting bias). Both types of bias pose a substantial threat to informed medical decision-making.
Why Was This Study Done?
Recent initiatives, such as making registration of clinical trials in a trial registry (for example, a precondition for publication in medical journals, aim to prevent these biases but are imperfect. Another way to facilitate the unbiased evaluation of clinical research might be to increase access to clinical study reports (CSRs)—detailed but generally unpublished accounts of clinical trials. Notably, information from CSRs was recently used to challenge conclusions based on published evidence about the efficacy and safety of the antiviral drug oseltamivir and the antidepressant reboxetine. In this study, the researchers compare the information available in CSRs and in publicly available sources (journal publications and registry reports) for the patient-relevant outcomes included in 16 health technology assessments (HTAs; analyses of the medical implications of the use of specific medical technologies) for drugs; the HTAs were prepared by the Institute for Quality and Efficiency in Health Care (IQWiG), Germany's main HTA agency.
What Did the Researchers Do and Find?
The researchers searched for published journal articles and registry reports for each of 101 trials for which the IQWiG had requested and received full CSRs from drug manufacturers during HTA preparation. They then assessed the completeness of information on the patient-relevant benefit and harm outcomes (for example symptom relief and adverse effects, respectively) included in each document type. Eighty-six of the included trials had at least one publicly available data source; the results of 15% of the trials were not available in either journals or registry reports. Overall, the CSRs provided complete information on 86% of the patient-related outcomes, whereas the combined publicly available sources provided complete information on only 39% of the outcomes. For individual outcomes, the CSRs provided complete information on 78%–100% of the benefit outcomes, with the exception of health-related quality of life (57%); combined publicly available sources provided complete information on 20%–53% of these outcomes. The CSRs also provided more information on patient-relevant harm outcomes than the publicly available sources.
What Do These Findings Mean?
These findings show that, for the clinical trials considered here, publicly available sources provide much less information on patient-relevant outcomes than CSRs. The generalizability of these findings may be limited, however, because the trials included in this study are not representative of all trials. Specifically, only CSRs that were voluntarily provided by drug companies were assessed, a limited number of therapeutic areas were covered by the trials, and the trials investigated only drugs. Nevertheless, these findings suggest that access to CSRs is important for the unbiased evaluation of clinical trials and for informed decision-making in health care. Notably, in June 2013, the European Medicines Agency released a draft policy calling for the proactive publication of complete clinical trial data (possibly including CSRs). In addition, the European Union and the European Commission are considering legal measures to improve the transparency of clinical trial data. Both these initiatives will probably only apply to drugs that are approved after January 2014, however, and not to drugs already in use. The researchers therefore call for CSRs to be made publicly available for both past and future trials, a recommendation also supported by the AllTrials initiative, which is campaigning for all clinical trials to be registered and fully reported.
Additional Information
Please access these websites via the online version of this summary at
Wikipedia has pages on evidence-based medicine, publication bias, and health technology assessment (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The website is a searchable register of federally and privately supported clinical trials in the US; it provides information about all aspects of clinical trials
The European Medicines Agency (EMA) provides information about all aspects of the scientific evaluation and approval of new medicines in the European Union, and guidance on the preparation of clinical study reports; its draft policy on the release of data from clinical trials is available
Information about IQWiG is available (in English and German); Informed Health Online is a website provided by IQWiG that provides objective, independent, and evidence-based information for patients (also in English and German)
PMCID: PMC3793003  PMID: 24115912
18.  Uncertainty analysis of vegetation distribution in the northern high latitudes during the 21st century with a dynamic vegetation model 
Ecology and Evolution  2012;2(3):593-614.
This study aims to assess how high-latitude vegetation may respond under various climate scenarios during the 21st century with a focus on analyzing model parameters induced uncertainty and how this uncertainty compares to the uncertainty induced by various climates. The analysis was based on a set of 10,000 Monte Carlo ensemble Lund-Potsdam-Jena (LPJ) simulations for the northern high latitudes (45oN and polewards) for the period 1900–2100. The LPJ Dynamic Global Vegetation Model (LPJ-DGVM) was run under contemporary and future climates from four Special Report Emission Scenarios (SRES), A1FI, A2, B1, and B2, based on the Hadley Centre General Circulation Model (GCM), and six climate scenarios, X901M, X902L, X903H, X904M, X905L, and X906H from the Integrated Global System Model (IGSM) at the Massachusetts Institute of Technology (MIT). In the current dynamic vegetation model, some parameters are more important than others in determining the vegetation distribution. Parameters that control plant carbon uptake and light-use efficiency have the predominant influence on the vegetation distribution of both woody and herbaceous plant functional types. The relative importance of different parameters varies temporally and spatially and is influenced by climate inputs. In addition to climate, these parameters play an important role in determining the vegetation distribution in the region. The parameter-based uncertainties contribute most to the total uncertainty. The current warming conditions lead to a complexity of vegetation responses in the region. Temperate trees will be more sensitive to climate variability, compared with boreal forest trees and C3 perennial grasses. This sensitivity would result in a unanimous northward greenness migration due to anomalous warming in the northern high latitudes. Temporally, boreal needleleaved evergreen plants are projected to decline considerably, and a large portion of C3 perennial grass is projected to disappear by the end of the 21st century. In contrast, the area of temperate trees would increase, especially under the most extreme A1FI scenario. As the warming continues, the northward greenness expansion in the Arctic region could continue.
PMCID: PMC3399147  PMID: 22822437
Climate-induced uncertainty; greenness migration; prameter importance; parameter-induced uncertainty; sensitivity analysis; vegetation redistribution
19.  An incoherent regulatory network architecture that orchestrates B cell diversification in response to antigen signaling 
B cell receptor signaling controls the expression of IRF-4, a transcription factor required for B cell differentiation. This study shows that IRF-4 regulates divergent B cell fates via a ‘kinetic-control' mechanism that determines the duration of a transient developmental state.
The intensity of signaling through the B cell receptor controls the level of expression of IRF-4, a transcription factor required for B cell differentiation. The rate of IRF-4 production dictates the extent of antibody gene diversification that B cells undergo upon antigen encounter before differentiating into antibody-secreting plasma cells.Computational modeling and experimental analyses substantiate a model, whereby IRF-4 regulates B cell fate trajectories via a ‘kinetic-control' mechanism.Kinetic control is a process by which B cells pass through an obligate state of variable duration that sets the degree of cellular diversification prior to their terminal differentiation.An incoherent regulatory network architecture, within which IRF-4 is embedded, is the basis for realization of kinetic control.
The generation of a diverse set of pathogen-specific antibodies, with differing affinities and effector functions, by B lymphocytes is essential for efficient protection from many microorganisms. Antibody gene diversification in B cells is mediated by two molecular processes termed class-switch recombination and somatic hypermutation (CSR/SHM) (F1A). The former enables the generation of antibodies with the same antigen-binding specificity, but different effector domains, whereas the latter results in a repertoire of antibodies with a range of affinities for a given antigen containing the same effector domain. CSR/SHM occurs in antigen-activated B cells before their terminal differentiation into plasma cells. The transcription factor IRF-4 is required for CSR/SHM as well as plasma-cell differentiation, with its highest levels of expression being necessary for the latter. IRF-4 acts in the context of a network of regulators that include Blimp-1, Pax5, Bach2 and Bcl-6 (F1B). Despite extensive characterization of these individual factors, how the network responds to sensing of antigen by the B cell antigen receptor (BCR, antibody molecule expressed on cell surface) to regulate the extent of antibody gene diversification and plasma-cell differentiation remains to be addressed.
To address this issue, we assemble a computational model. The model reveals two contrasting scenarios that can underlie B cell fate dynamics. In one case, the initial rate of IRF-4 production controls a binary cell fate choice that involves either going to the CSR/SHM state or to the plasma-cell state; the time spent in the CSR state is relatively insensitive to the initial rate of IRF-4 production (herein called ‘basic bistability'). In the other case, IRF-4 drives all cells through a transient CSR/SHM state, but the initial rate of IRF-4 production sets its duration (‘kinetic control'). Both scenarios predict that increasing the initial rate of IRF-4 production favors the generation of plasma cells at the expense of CSR/SHM, but they differ fundamentally with respect to the underlying gene expression patterns.
To distinguish between these two scenarios experimentally, we utilize two different genetic models. The first involves the B1-8i transgenic mouse whose B cells express a rearranged V187.2 VDJ Ig heavy chain gene segment that is specific for the hapten nitrophenol (NP). The second is a newly developed mouse model that allows exogenous control of IRF-4 expression in naive primary B cells using a tet-inducible allele. Using these models, we show that (i) BCR signal strength sets the initial rate of IRF-4 accumulation and (ii) the concentration of IRF-4 is sensed by an incoherent gene regulatory network architecture to regulate the extent of CSR/SHM prior to plasma-cell differentiation. Our results are consistent with the ‘kinetic-control model' in which the levels of BCR-induced IRF-4 expression control the duration of an obligate CSR/SHM state that enables B cell diversification before terminal differentiation into plasma cells. Evidence for the transient CSR/SHM state is corroborated by both patterns of gene expression and the presence of AID-dependent mutations in individual non-switched plasmablasts.
Our results provide a molecular framework for understanding how B cells balance the competing demands for Ig CSR and SHM with the secretion of antibodies during humoral immune responses. The key feature of the network architecture that allows IRF-4 to coordinate the two competing states of gene expression in a temporal manner is that it simultaneously but asymmetrically activates both sides of a bistable mutual repression circuit. Because the two effects of the primary regulator antagonize each other, we describe the circuit as being based on an ‘incoherent' regulatory motif. Other incoherent regulatory motifs in varied biological systems are also associated with the acquisition of transient cell states, and we consider how the kinetic-control mechanism proposed by us could more generally serve to translate developmental cues into elaborate morphogenetic patterns.
The B-lymphocyte lineage is a leading system for analyzing gene regulatory networks (GRNs) that orchestrate distinct cell fate transitions. Upon antigen recognition, B cells can diversify their immunoglobulin (Ig) repertoire via somatic hypermutation (SHM) and/or class switch DNA recombination (CSR) before differentiating into antibody-secreting plasma cells. We construct a mathematical model for a GRN underlying this developmental dynamic. The intensity of signaling through the Ig receptor is shown to control the bimodal expression of a pivotal transcription factor, IRF-4, which dictates B cell fate outcomes. Computational modeling coupled with experimental analysis supports a model of ‘kinetic control', in which B cell developmental trajectories pass through an obligate transient state of variable duration that promotes diversification of the antibody repertoire by SHM/CSR in direct response to antigens. More generally, this network motif could be used to translate a morphogen gradient into developmental inductive events of varying time, thereby enabling the specification of distinct cell fates.
PMCID: PMC3130558  PMID: 21613984
BCR signal strength; bistability; gene regulatory network; ghost of a fixed point; Irf4
20.  Patterns and Variability of Projected Bioclimatic Habitat for Pinus albicaulis in the Greater Yellowstone Area 
PLoS ONE  2014;9(11):e111669.
Projected climate change at a regional level is expected to shift vegetation habitat distributions over the next century. For the sub-alpine species whitebark pine (Pinus albicaulis), warming temperatures may indirectly result in loss of suitable bioclimatic habitat, reducing its distribution within its historic range. This research focuses on understanding the patterns of spatiotemporal variability for future projected P.albicaulis suitable habitat in the Greater Yellowstone Area (GYA) through a bioclimatic envelope approach. Since intermodel variability from General Circulation Models (GCMs) lead to differing predictions regarding the magnitude and direction of modeled suitable habitat area, nine bias-corrected statistically down-scaled GCMs were utilized to understand the uncertainty associated with modeled projections. P.albicaulis was modeled using a Random Forests algorithm for the 1980–2010 climate period and showed strong presence/absence separations by summer maximum temperatures and springtime snowpack. Patterns of projected habitat change by the end of the century suggested a constant decrease in suitable climate area from the 2010 baseline for both Representative Concentration Pathways (RCPs) 8.5 and 4.5 climate forcing scenarios. Percent suitable climate area estimates ranged from 2–29% and 0.04–10% by 2099 for RCP 8.5 and 4.5 respectively. Habitat projections between GCMs displayed a decrease of variability over the 2010–2099 time period related to consistent warming above the 1910–2010 temperature normal after 2070 for all GCMs. A decreasing pattern of projected P.albicaulis suitable habitat area change was consistent across GCMs, despite strong differences in magnitude. Future ecological research in species distribution modeling should consider a full suite of GCM projections in the analysis to reduce extreme range contractions/expansions predictions. The results suggest that restoration strageties such as planting of seedlings and controlling competing vegetation may be necessary to maintain P.albicaulis in the GYA under the more extreme future climate scenarios.
PMCID: PMC4221071  PMID: 25372719
21.  Trends and implications for achieving VISION 2020 human resources for eye health targets in 16 countries of sub-Saharan Africa by the year 2020 
Development of human resources for eye health (HReH) is a major global eye health strategy to reduce the prevalence of avoidable visual impairment by the year 2020. Building on our previous analysis of current progress towards key HReH indicators and cataract surgery rates (CSRs), we predicted future indicator achievement among 16 countries of sub-Saharan Africa by 2020.
Surgical and HReH data were collected from national eye care programme coordinators on six practitioner cadres: ophthalmologists, cataract surgeons, ophthalmic clinical officers, ophthalmic nurses, optometrists and ‘mid-level refractionists’ and combined them with publicly available population data to calculate practitioner-to-population ratios and CSRs. Data on workforce entry and exit (2008 to 2010) was used to project practitioner population and CSR growth between 2011 and 2020 in relation to projected growth in the general population. Associations between indicator progress and the presence of a non-physician cataract surgeon cadre were also explored using Wilcoxon rank sum tests and Spearman rank correlations.
In our 16-country sample, practitioner per million population ratios are predicted to increase slightly for surgeons (ophthalmologists/cataract surgeons, from 3.1 in 2011 to 3.4 in 2020) and ophthalmic nurses/clinical officers (5.8 to 6.8) but remain low for refractionists (including optometrists, at 3.6 in 2011 and 2020). Among countries that have not already achieved target indicators, however, practitioner growth will be insufficient for any additional countries to reach the surgeon and refractionist targets by year 2020. Without further strategy change and investment, even after 2020, surgeon growth is only expected to sufficiently outpace general population growth to reach the target in one country. For nurses, two additional countries will achieve the target while one will fall below it. In 2011, high surgeon practitioner ratios were associated with high CSR, regardless of the type of surgeon employed. The cataract surgeon workforce is growing proportionately faster than the ophthalmologist.
The HReH workforce is not growing fast enough to achieve global eye health targets in most of the sub-Saharan countries we surveyed by 2020. Countries seeking to make rapid progress to improve CSR could prioritise investment in training new cataract surgeons over ophthalmologists and improving surgical output efficiency.
PMCID: PMC4237790  PMID: 25128287
Human resources; Eye health; Sub-Saharan Africa; Cataract; Ophthalmology; Optometry; Nursing Vision 2020; Task-shifting
22.  Projected Loss of a Salamander Diversity Hotspot as a Consequence of Projected Global Climate Change 
PLoS ONE  2010;5(8):e12189.
Significant shifts in climate are considered a threat to plants and animals with significant physiological limitations and limited dispersal abilities. The southern Appalachian Mountains are a global hotspot for plethodontid salamander diversity. Plethodontids are lungless ectotherms, so their ecology is strongly governed by temperature and precipitation. Many plethodontid species in southern Appalachia exist in high elevation habitats that may be at or near their thermal maxima, and may also have limited dispersal abilities across warmer valley bottoms.
Methodology/Principal Findings
We used a maximum-entropy approach (program Maxent) to model the suitable climatic habitat of 41 plethodontid salamander species inhabiting the Appalachian Highlands region (33 individual species and eight species included within two species complexes). We evaluated the relative change in suitable climatic habitat for these species in the Appalachian Highlands from the current climate to the years 2020, 2050, and 2080, using both the HADCM3 and the CGCM3 models, each under low and high CO2 scenarios, and using two-model thresholds levels (relative suitability thresholds for determining suitable/unsuitable range), for a total of 8 scenarios per species.
While models differed slightly, every scenario projected significant declines in suitable habitat within the Appalachian Highlands as early as 2020. Species with more southern ranges and with smaller ranges had larger projected habitat loss. Despite significant differences in projected precipitation changes to the region, projections did not differ significantly between global circulation models. CO2 emissions scenario and model threshold had small effects on projected habitat loss by 2020, but did not affect longer-term projections. Results of this study indicate that choice of model threshold and CO2 emissions scenario affect short-term projected shifts in climatic distributions of species; however, these factors and choice of global circulation model have relatively small affects on what is significant projected loss of habitat for many salamander species that currently occupy the Appalachian Highlands.
PMCID: PMC2922335  PMID: 20808442
23.  Climate-Driven Effects of Fire on Winter Habitat for Caribou in the Alaskan-Yukon Arctic 
PLoS ONE  2014;9(7):e100588.
Climatic warming has direct implications for fire-dominated disturbance patterns in northern ecosystems. A transforming wildfire regime is altering plant composition and successional patterns, thus affecting the distribution and potentially the abundance of large herbivores. Caribou (Rangifer tarandus) are an important subsistence resource for communities throughout the north and a species that depends on terrestrial lichen in late-successional forests and tundra systems. Projected increases in area burned and reductions in stand ages may reduce lichen availability within caribou winter ranges. Sufficient reductions in lichen abundance could alter the capacity of these areas to support caribou populations. To assess the potential role of a changing fire regime on winter habitat for caribou, we used a simulation modeling platform, two global circulation models (GCMs), and a moderate emissions scenario to project annual fire characteristics and the resulting abundance of lichen-producing vegetation types (i.e., spruce forests and tundra >60 years old) across a modeling domain that encompassed the winter ranges of the Central Arctic and Porcupine caribou herds in the Alaskan-Yukon Arctic. Fires were less numerous and smaller in tundra compared to spruce habitats throughout the 90-year projection for both GCMs. Given the more likely climate trajectory, we projected that the Porcupine caribou herd, which winters primarily in the boreal forest, could be expected to experience a greater reduction in lichen-producing winter habitats (−21%) than the Central Arctic herd that wintered primarily in the arctic tundra (−11%). Our results suggest that caribou herds wintering in boreal forest will undergo fire-driven reductions in lichen-producing habitats that will, at a minimum, alter their distribution. Range shifts of caribou resulting from fire-driven changes to winter habitat may diminish access to caribou for rural communities that reside in fire-prone areas.
PMCID: PMC4081032  PMID: 24991804
24.  Impact of Climate Change Effects on Contamination of Cereal Grains with Deoxynivalenol 
PLoS ONE  2013;8(9):e73602.
Climate change is expected to aggravate feed and food safety problems of crops; however, quantitative estimates are scarce. This study aimed to estimate impacts of climate change effects on deoxynivalenol contamination of wheat and maize grown in the Netherlands by 2040. Quantitative modelling was applied, considering both direct effects of changing climate on toxin contamination and indirect effects via shifts in crop phenology. Climate change projections for the IPCC A1B emission scenario were used for the scenario period 2031-2050 relative to the baseline period of 1975-1994. Climatic data from two different global and regional climate model combinations were used. A weather generator was applied for downscaling climate data to local conditions. Crop phenology models and prediction models for DON contamination used, each for winter wheat and grain maize. Results showed that flowering and full maturity of both wheat and maize will advance with future climate. Flowering advanced on average 5 and 11 days for wheat, and 7 and 14 days for maize (two climate model combinations). Full maturity was on average 10 and 17 days earlier for wheat, and 19 and 36 days earlier for maize. On the country level, contamination of wheat with deoxynivalenol decreased slightly, but not significantly. Variability between regions was large, and individual regions showed a significant increase in deoxynivalenol concentrations. For maize, an overall decrease in deoxynivalenol contamination was projected, which was significant for one climate model combination, but not significant for the other one. In general, results disagree with previous reported expectations of increased feed and food safety hazards under climate change. This study illustrated the relevance of using quantitative models to estimate the impacts of climate change effects on food safety, and of considering both direct and indirect effects when assessing climate change impacts on crops and related food safety hazards.
PMCID: PMC3774692  PMID: 24066059
25.  Physiological and ecological effects of increasing temperature on fish production in lakes of Arctic Alaska 
Ecology and Evolution  2014;4(10):1981-1993.
Lake ecosystems in the Arctic are changing rapidly due to climate warming. Lakes are sensitive integrators of climate-induced changes and prominent features across the Arctic landscape, especially in lowland permafrost regions such as the Arctic Coastal Plain of Alaska. Despite many studies on the implications of climate warming, how fish populations will respond to lake changes is uncertain for Arctic ecosystems. Least Cisco (Coregonus sardinella) is a bellwether for Arctic lakes as an important consumer and prey resource. To explore the consequences of climate warming, we used a bioenergetics model to simulate changes in Least Cisco production under future climate scenarios for lakes on the Arctic Coastal Plain. First, we used current temperatures to fit Least Cisco consumption to observed annual growth. We then estimated growth, holding food availability, and then feeding rate constant, for future projections of temperature. Projected warmer water temperatures resulted in reduced Least Cisco production, especially for larger size classes, when food availability was held constant. While holding feeding rate constant, production of Least Cisco increased under all future scenarios with progressively more growth in warmer temperatures. Higher variability occurred with longer projections of time mirroring the expanding uncertainty in climate predictions further into the future. In addition to direct temperature effects on Least Cisco growth, we also considered changes in lake ice phenology and prey resources for Least Cisco. A shorter period of ice cover resulted in increased production, similar to warming temperatures. Altering prey quality had a larger effect on fish production in summer than winter and increased relative growth of younger rather than older age classes of Least Cisco. Overall, we predicted increased production of Least Cisco due to climate warming in lakes of Arctic Alaska. Understanding the implications of increased production of Least Cisco to the entire food web will be necessary to predict ecosystem responses in lakes of the Arctic.
PMCID: PMC4063490  PMID: 24963391
Arctic Coastal Plain; climate change; coregonidae; fish bioenergetics; lake food webs

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