The ability to control enzyme cascades entrapped in a nanoporous electrode material (the "Electrochemical Leaf", e-Leaf) has been exploited to gain detailed kinetic insight into the mechanism of an ...anti-cancer drug. Ivosidenib, used to treat acute myeloid leukemia, acts on a common cancer-linked variant of isocitrate dehydrogenase 1 (IDH1 R132H) inhibiting its "gain-of-function" activity-the undesired reduction of 2-oxoglutarate (2OG) to the oncometabolite 2-hydroxyglutarate (2HG). The e-Leaf quantifies the kinetics of IDH1 R132H inhibition across a wide and continuous range of conditions, efficiently revealing factors underlying the inhibitor residence time. Selective inhibition of IDH1 R132H by Ivosidenib and another inhibitor, Novartis 224, is readily resolved as a two-stage process whereby initial rapid non-inhibitory binding is followed by a slower step to give the inhibitory complex. These kinetic features are likely present in other allosteric inhibitors of IDH1/2. Such details, essential for understanding inhibition mechanisms, are not readily resolved in conventional steady-state kinetics or by techniques that rely only on measuring binding. Extending the new method and analytical framework presented here to other enzyme systems will be straightforward and should rapidly reveal insight that is difficult or often impossible to obtain using other methods.
Most studies that explore attitudes towards immigration conceptualize immigrants as economic migrants. The limitation of this approach is that it emphasizes economic costs and benefits while ignoring ...the humanitarian logic that forms the basis of refugee admission. To date, few studies have developed and tested theories that explain public support for admitting humanitarian migrants. Our article fills this gap. We argue that dispositional and situational triggers related to humanitarianism shape public attitudes towards refugees: When natives are predisposed to help others in need (humanitarianism) and/or refugees are seen to be victims of randomly occurring events, the public is more likely to support refugee admission. We test this theory using observational and experimental data from a country that accepts few resettlement refugees, Japan. Our study uses a rating‐based conjoint which randomized crisis event, place of origin, access to public housing, and degree of political support for receiving refugees. We find that humanitarianism predicts public support for admitting refugees more strongly than it predicts support for economic migrants. Moreover, we show that people with a higher level of humanitarianism prefer to admit refugees who flee natural disasters and wars as opposed to those who escape from political repression.
Elasticity in ecosystem services Daw, Tim M.; Hicks, Christina C.; Brown, Katrina ...
Ecology and society,
01/2016, Letnik:
21, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Although ecosystem services are increasingly recognized as benefits people obtain from nature, we still have a poor understanding of how they actually enhance multidimensional human well-being, and ...how well-being is affected by ecosystem change. We develop a concept of “ecosystem service elasticity” (ES elasticity) that describes the sensitivity of human well-being to changes in ecosystems. ES Elasticity is a result of complex social and ecological dynamics and is context dependent, individually variable, and likely to demonstrate nonlinear dynamics such as thresholds and hysteresis. We present a conceptual framework that unpacks the chain of causality from ecosystem stocks through flows, goods, value, and shares to contribute to the well-being of different people. This framework builds on previous conceptualizations, but places multidimensional well-being of different people as the final element. This ultimately disaggregated approach emphasizes how different people access benefits and how benefits match their needs or aspirations.
Applying this framework to case studies of individual coastal ecosystem services in East Africa illustrates a wide range of social and ecological factors that can affect ES elasticity. For example, food web and habitat dynamics affect the sensitivity of different fisheries ecosystem services to ecological change. Meanwhile high cultural significance, or lack of alternatives enhance ES elasticity, while social mechanisms that prevent access can reduce elasticity.
Mapping out how chains are interlinked illustrates how different types of value and the well-being of different people are linked to each other and to common ecological stocks. We suggest that examining chains for individual ecosystem services can suggest potential interventions aimed at poverty alleviation and sustainable ecosystems while mapping out of interlinkages between chains can help to identify possible ecosystem service trade-offs and winners and losers. We discuss conceptual and practical challenges of applying such a framework and conclude on its utility as a heuristic for structuring interdisciplinary analysis of ecosystem services and human well-being.
In living cells, redox chains rely on nanoconfinement using tiny enclosures, such as the mitochondrial matrix or chloroplast stroma, to concentrate enzymes and limit distances that nicotinamide ...cofactors and other metabolites must diffuse. In a chemical analogue exploiting this principle, nicotinamide adenine dinucleotide phosphate (NADPH) and NADP+ are cycled rapidly between ferredoxin–NADP+ reductase and a second enzyme—the pairs being juxtaposed within the 5–100 nm scale pores of an indium tin oxide electrode. The resulting electrode material, denoted (FNR+E2)@ITO/support, can drive and exploit a potentially large number of enzyme‐catalysed reactions.
In close quarters: Nicotinamide adenine dinucleotide phosphate (NADPH) and NADP+ are cycled rapidly between ferredoxin–NADP+ reductase (FNR) and a dehydrogenase enzyme (E2) within the 5–100 nm pores of an indium tin oxide electrode. The electrode mimics the nanoconfinement strategies of natural systems, such as the chloroplast stroma or mitochondria in living cells.
The active center (H-cluster) of FeFe-hydrogenases is embedded into a hydrophobic pocket within the protein. We analyzed several amino acids, located in the vicinity of this niche, by site-directed ...mutagenesis of the FeFe-hydrogenases from Clostridium pasteurianum (CpI) and Chlamydomonas reinhardtii (CrHydA1). These amino acids are highly conserved and predicted to be involved in H-cluster coordination. Characterization of two hydrogenase variants confirmed this hypothesis. The exchange of residues CrHydA1Met415 and CrHydA1Lys228 resulted in inactive proteins, which, according to EPR and FTIR analyses, contain no intact H-cluster. However, FeFe-hydrogenases in which CpIMet353 (CrHydA1Met223) and CpICys299 (CrHydA1Cys169) were exchanged to leucine and serine, respectively, showed a structurally intact H-cluster with catalytic activity either absent (CpIC299S) or strongly diminished (CpIM353L). In the case of CrHydA1C169S, the H-cluster was trapped in an inactive state exhibiting g values and vibrational frequencies that resembled the Htrans state of DdH from Desulfovibrio desulfuricans. This cysteine residue, interacting with the bridge head nitrogen of the di(methyl)amine ligand, seems therefore to represent an essential contribution of the immediate protein environment to the reaction mechanism. Exchanging methionine CpIM353 (CrHydA1M223) to leucine led to a strong decrease in turnover without affecting the Km value of the electron donor. We suggest that this methionine constitutes a “fine-tuning” element of hydrogenase activity.
Background: Hydrogenases contain a unique oxygen-labile metal cofactor.
Results: Substitution of noncovalently interacting residues degrades the catalytic cofactor (K358N and M497L) or reduces activity but leaves the cofactor chemically intact (C299S and M353L).
Conclusion: Lys358 and Met497 are essential for H-cluster coordination. Cys299 and Met353 influence catalytic activity only.
Significance: Understanding specific cofactor-amino acid interactions provides an important basis for improving artificial hydrogen catalysts.
The decline of cognitive function has emerged as one of the greatest health threats of old age. Age-related cognitive decline is caused by an impacted neuronal circuitry, yet the molecular mechanisms ...responsible are unknown. C1q, the initiating protein of the classical complement cascade and powerful effector of the peripheral immune response, mediates synapse elimination in the developing CNS. Here we show that C1q protein levels dramatically increase in the normal aging mouse and human brain, by as much as 300-fold. This increase was predominantly localized in close proximity to synapses and occurred earliest and most dramatically in certain regions of the brain, including some but not all regions known to be selectively vulnerable in neurodegenerative diseases, i.e., the hippocampus, substantia nigra, and piriform cortex. C1q-deficient mice exhibited enhanced synaptic plasticity in the adult and reorganization of the circuitry in the aging hippocampal dentate gyrus. Moreover, aged C1q-deficient mice exhibited significantly less cognitive and memory decline in certain hippocampus-dependent behavior tests compared with their wild-type littermates. Unlike in the developing CNS, the complement cascade effector C3 was only present at very low levels in the adult and aging brain. In addition, the aging-dependent effect of C1q on the hippocampal circuitry was independent of C3 and unaccompanied by detectable synapse loss, providing evidence for a novel, complement- and synapse elimination-independent role for C1q in CNS aging.
A fourth production region for the globally important Antarctic bottom water has been attributed to dense shelf water formation in the Cape Darnley Polynya, adjoining Prydz Bay in East Antarctica. ...Here we show new observations from CTD-instrumented elephant seals in 2011-2013 that provide the first complete assessment of dense shelf water formation in Prydz Bay. After a complex evolution involving opposing contributions from three polynyas (positive) and two ice shelves (negative), dense shelf water (salinity 34.65-34.7) is exported through Prydz Channel. This provides a distinct, relatively fresh contribution to Cape Darnley bottom water. Elsewhere, dense water formation is hindered by the freshwater input from the Amery and West Ice Shelves into the Prydz Bay Gyre. This study highlights the susceptibility of Antarctic bottom water to increased freshwater input from the enhanced melting of ice shelves, and ultimately the potential collapse of Antarctic bottom water formation in a warming climate.
Green algae such as Chlamydomonas reinhardtii synthesize an FeFe hydrogenase that is highly active in hydrogen evolution. However, the extreme sensitivity of FeFe hydrogenases to oxygen presents a ...major challenge for exploiting these organisms to achieve sustainable photosynthetic hydrogen production. In this study, the mechanism of oxygen inactivation of the FeFe hydrogenase CrHydAI from G reinhardtii has been investigated. X-ray absorption spectroscopy shows that reaction with oxygen results in destruction of the 4Fe-4S domain of the active site H-cluster while leaving the di-iron domain $(2Fe_H )$essentially intact. By protein film electrochemistry we were able to determine the order of events leading up to this destruction. Carbon monoxide, a competitive inhibitor of CrHydAI which binds to an Fe atom of the $(2Fe_yH )$domain and is otherwise not known to attack FeS clusters in proteins, reacts nearly two orders of magnitude faster than oxygen and protects the enzyme against oxygen damage. These results therefore show that destruction of the 4Fe-4S cluster is initiated by binding and reduction of oxygen at the di-iron domain—a key step that is blocked by carbon monoxide. The relatively slow attack by oxygen compared to carbon monoxide suggests that a very high level of discrimination can be achieved by subtle factors such as electronic effects (specific orbital overlap requirements) and steric constraints at the active site.
The performance characteristics of simple enzyme-based membrane-less hydrogen fuel cells running on non-explosive H 2 -rich air mixtures have been established using an adjustable test bed that allows ...multiple unit cells to operate in series or parallel. Recent advances with ‘3D’ electrodes constructed from compacted porous carbon loaded with hydrogenase (anode) and bilirubin oxidase (cathode) have been extended in order to scale up fuel cell power to useful levels. One result is an appealing ‘classroom’ demonstration of a model house containing small electronic devices powered by H 2 mixed with a small amount of air. The 3D electrodes work by greatly increasing catalyst loading (at both the anode and cathode) and selectively restricting the access of O 2 (relative to H 2 ) to enzymes embedded in pores at the anode. The latter property raises the possibility of using standard hydrogenases that are not O 2 -tolerant: however, experiments with such an enzyme reveal good short-term performance due to restricted O 2 access, but low long-term stability because the root cause of O 2 sensitivity has not been addressed. Hydrogenases that are truly O 2 tolerant must therefore remain the major focus of any future enzyme-based hydrogen fuel cell technology.
PDF
![How Oxygen Attacks [FeFe] H...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/0027-8424_1091-6490/small "How Oxygen Attacks [FeFe] Hydrogenases from Photosynthetic Organisms")
