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"Griggs, David"
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Mapping interactions between the sustainable development goals: lessons learned and ways forward
Pursuing integrated research and decision-making to advance action on the sustainable development goals (SDGs) fundamentally depends on understanding interactions between the SDGs, both negative ones (“trade-offs”) and positive ones (“co-benefits”). This quest, triggered by the 2030 Agenda, has however pointed to a gap in current research and policy analysis regarding how to think systematically about interactions across the SDGs. This paper synthesizes experiences and insights from the application of a new conceptual framework for mapping and assessing SDG interactions using a defined typology and characterization approach. Drawing on results from a major international research study applied to the SDGs on health, energy and the ocean, it analyses how interactions depend on key factors such as geographical context, resource endowments, time horizon and governance. The paper discusses the future potential, barriers and opportunities for applying the approach in scientific research, in policy making and in bridging the two through a global SDG Interactions Knowledge Platform as a key mechanism for assembling, systematizing and aggregating knowledge on interactions.
Journal Article
Sustainable development goals for people and planet
Building on decades of research, a 2009 analysis defined planetary boundaries which would be unsafe to transgress for nine Earth-system processes3: climate change; rate of biodiversity loss (terrestrial and marine); interference with the nitrogen and phosphorus cycles; stratospheric ozone depletion; ocean acidification; global freshwater use; change in land use; chemical pollution; and atmospheric aerosol loading. Adapting this planetary boundaries work, and using recent credible scientific studies and existing international processes - such as the United Nations Framework Convention on Climate Change - we extracted a list of sustainability 'must-haves' for human prosperity (see 'A unified framework').
Journal Article
Integration: the key to implementing the Sustainable Development Goals
On 25 September, 2015, world leaders met at the United Nations in New York, where they adopted the Sustainable Development Goals. These 17 goals and 169 targets set out an agenda for sustainable development for all nations that embraces economic growth, social inclusion, and environmental protection. Now, the agenda moves from agreeing the goals to implementing and ultimately achieving them. Across the goals, 42 targets focus on means of implementation, and the final goal, Goal 17, is entirely devoted to means of implementation. However, these implementation targets are largely silent about interlinkages and interdependencies among goals. This leaves open the possibility of perverse outcomes and unrealised synergies. We demonstrate that there must be greater attention on interlinkages in three areas: across
sectors
(e.g., finance, agriculture, energy, and transport), across societal
actors
(local authorities, government agencies, private sector, and civil society), and between and among low, medium and high income
countries
. Drawing on a global sustainability science and practice perspective, we provide seven recommendations to improve these interlinkages at both global and national levels, in relation to the UN’s categories of means of implementation: finance, technology, capacity building, trade, policy coherence, partnerships, and, finally, data, monitoring and accountability.
Journal Article
Targeting of αv integrin identifies a core molecular pathway that regulates fibrosis in several organs
Dean Sheppard and his colleagues show that genetic or pharmacological inhibition of α
v
integrin signaling ameliorates fibrosis in several solid organs.
Myofibroblasts are the major source of extracellular matrix components that accumulate during tissue fibrosis, and hepatic stellate cells (HSCs) are believed to be the major source of myofibroblasts in the liver. To date, robust systems to genetically manipulate these cells have not been developed. We report that Cre under control of the promoter of
Pdgfrb
(
Pdgfrb-
Cre) inactivates
loxP
-flanked genes in mouse HSCs with high efficiency. We used this system to delete the gene encoding α
v
integrin subunit because various α
v
-containing integrins have been suggested as central mediators of fibrosis in multiple organs. Such depletion protected mice from carbon tetrachloride–induced hepatic fibrosis, whereas global loss of β
3
, β
5
or β
6
integrins or conditional loss of β
8
integrins in HSCs did not. We also found that
Pdgfrb-
Cre effectively targeted myofibroblasts in multiple organs, and depletion of the α
v
integrin subunit using this system was protective in other models of organ fibrosis, including pulmonary and renal fibrosis. Pharmacological blockade of α
v
-containing integrins by a small molecule (CWHM 12) attenuated both liver and lung fibrosis, including in a therapeutic manner. These data identify a core pathway that regulates fibrosis and suggest that pharmacological targeting of all α
v
integrins may have clinical utility in the treatment of patients with a broad range of fibrotic diseases.
Journal Article
Clinical and microbiologic efficacy of the piperazine-based drug lead MMV665917 in the dairy calf cryptosporidiosis model
Cryptosporidiosis causes life-threatening diarrhea in infants, but the best available treatment is only modestly efficacious. Rodents infected with relevant Cryptosporidium species do not develop diarrhea, which complicates drug development. Cryptosporidium parvum infection of dairy calves, however, causes an illness like that seen in infants. Here, the clinical and microbiologic anti-Cryptosporidium efficacy of the piperazine-based compound MMV665917 was demonstrated in neonatal calves. Oral administration of MMV665917 (22 mg/kg once daily) was begun two days after the onset of severe diarrhea and continued for seven days. Treatment resulted in prompt resolution of diarrhea, and reduced total fecal oocyst shedding by ~94%. MMV665917 was useful for treatment, rather than just prophylaxis, since it was safe and effective when administered well after the onset of diarrhea. Furthermore, even though all animals received intensive supportive care, there was a strong trend towards improved secondary health outcomes, including general health, appetite, and dehydration measures amongst treated animals. These data establish MMV665917 as an outstanding lead compound for Cryptosporidium drug development.
Journal Article
Identification of potent and orally efficacious phosphodiesterase inhibitors in Cryptosporidium parvum-infected immunocompromised male mice
Cryptosporidium parvum
and
C. hominis
are parasites that cause life-threatening diarrhea in children and immunocompromised people. There is only one approved treatment that is modestly effective for children and ineffective for AIDS patients. Here, screening 278 compounds from the Merck KGaA, Darmstadt, Germany collection and accelerated follow-up enabled by prior investigation of the compounds identifies a series of pyrazolopyrimidine human phosphodiesterase (PDE)-V (
h
PDE-V) inhibitors with potent anticryptosporidial activity and efficacy following oral administration in
C. parvum
-infected male mice. The lead compounds affect parasite host cell egress, inhibit both
C. parvum
and
C. hominis
, work rapidly, and have minimal off-target effects in a safety screening panel. Interestingly, the
h
PDE-V inhibitors sildenafil and the 4-aminoquinoline compound
7a
do not affect
Cryptosporidium
.
C. parvum
expresses one PDE (
Cp
PDE1) continuously during asexual growth, the inhibited life stage. According to homology modeling and docking, the lead compounds interact with
Cp
PDE1. Bulkier amino acids (Val900 and His884) in the
Cp
PDE1 active site replace alanines in
h
PDE-V and block sildenafil binding. Supporting this, sildenafil kills a CRISPR-engineered
Cryptosporidium Cp
PDE1 V900A mutant. The
Cp
PDE1 mutation also alters parasite susceptibility to pyrazolopyrimidines.
Cp
PDE1 is therefore a validated pyrazolopyrimidine molecular target to exploit for target-based optimization for improved anticryptosporidial development.
Using phenotypic screening followed by optimization of side activities, the authors here identify pyrazolopyrimidine phosphodiesterase (PDE) inhibitors as anti-cryptosporidial drug leads. Humanizing a
Cryptosporidum
PDE by CRISPR indicates they target the parasite enzyme.
Journal Article
An integrated framework for sustainable development goals
The United Nations (UN) Rio+20 summit committed nations to develop a set of universal sustainable development goals (SDGs) to build on the millennium development goals (MDGs) set to expire in 2015. Research now indicates that humanity’s impact on Earth’s life support system is so great that further global environmental change risks undermining long-term prosperity and poverty eradication goals. Socioeconomic development and global sustainability are often posed as being in conflict because of trade-offs between a growing world population, as well as higher standards of living, and managing the effects of production and consumption on the global environment. We have established a framework for an evidence-based architecture for new goals and targets. Building on six SDGs, which integrate development and environmental considerations, we developed a comprehensive framework of goals and associated targets, which demonstrate that it is possible, and necessary, to develop integrated targets relating to food, energy, water, and ecosystem services goals; thus providing a neutral evidence-based approach to support SDG target discussions. Global analyses, using an integrated global target equation, are close to providing indicators for these targets. Alongside development-only targets and environment-only targets, these integrated targets would ensure that synergies are maximized and trade-offs are managed in the implementation of SDGs.
Journal Article
Piperazine-Derivative MMV665917
Cryptosporidiosis, an enteric protozoon, causes substantial morbidity and mortality associated with diarrhea in children <2 years old in low- to middle-income countries. There is no vaccine and treatments are inadequate. A piperazine-based compound, MMV665917, has in vitro and in vivo efficacy against Cryptosporidium parvum. In this study, we evaluated the efficacy of MMV665917 in gnotobiotic piglets experimentally infected with Cryptosporidium hominis, the species responsible for >75% of diarrhea reported in these children.
Gnotobiotic piglets were orally challenged with C hominis oocysts, and oral treatment with MMV665917 was commenced 3 days after challenge. Oocyst excretion and diarrhea severity were observed daily, and mucosal colonization and lesions were recorded after necropsy.
MMV665917 significantly reduced fecal oocyst excretion, parasite colonization and damage to the intestinal mucosa, and peak diarrheal symptoms, compared with infected untreated controls. A dose of 20 mg/kg twice daily for 7 days was more effective than 10 mg/kg. There were no signs of organ toxicity at either dose, but 20 mg/kg was associated with slightly elevated blood cholesterol and monocytes at euthanasia.
These results demonstrate the effectiveness of this drug against C hominis. Piperazine-derivative MMV665917 may potentially be used to treat human cryptosporidiosis; however, further investigations are required.
Journal Article
Performance Evaluation of Bias Correction Methods for Climate Change Monthly Precipitation Projections over Costa Rica
Six bias correction (BC) methods; delta-method (DT), linear scaling (LS), power transformation of precipitation (PTR), empirical quantile mapping (EQM), gamma quantile mapping (GQM) and gamma-pareto quantile mapping (GPQM) were applied to adjust the biases of historical monthly precipitation outputs from five General Circulation Models (GCMs) dynamically downscaled by two Regional Climate Models (RCMs) for a total of seven different GCM-RCM pairs over Costa Rica. High-resolution gridded precipitation observations were used for the control period 1951–1980 and validated over the period 1981–1995. Results show that considerable biases exist between uncorrected GCM-RCM outputs and observations, which largely depend on GCM-RCM pair, seasonality, climatic region and spatial resolution. After the application of bias correction, substantial biases reductions and comparable performances among most BC methods were observed for most GCM-RCM pairs; with EQM and DT marginally outperforming the remaining methods. Consequently, EQM and DT were selectively applied to correct the biases of precipitation projections from each individual GCM-RCM pair for a near-future (2011–2040), mid-future (2041–2070) and far-future (2071–2100) period under Representative Concentration Pathways (RCPs) 2.6, 4.5 and 8.5 using the control period 1961–1990. Results from the bias-corrected future ensemble-mean anticipate a marked decreasing trend in precipitation from near to far-future periods during the dry season (December, January, February (DJF) and March, April, May (MAM)) for RCP4.5 and 8.5; with pronounced drier conditions for those climatic regions draining towards the Pacific Ocean. In contrast, mostly wetter conditions are expected during the dry season under RCP2.6, particularly for the Caribbean region. In most of the country, the greatest decrease in precipitation is projected at the beginning of the rainy season (June, July, August (JJA)) for the far-future period under RCP8.5, except for the Caribbean region where mostly wetter conditions are anticipated. Regardless of future period, slight increases in precipitation with higher radiative forcing are expected for SON excluding the Caribbean region, where precipitation is likely to increase with increasing radiative forcing and future period. This study demonstrates that bias correction should be considered before direct application of GCM-RCM precipitation projections over complex territories such as Costa Rica.
Journal Article