Activation by sub-stoichiometric inhibition

Startling reports described the paradoxical triggering of the human mitogen-activated protein kinase pathway when a small-molecule inhibitor specifically inactivates the BRAF V600E protein kinase but not wt-BRAF. We performed a conceptual analysis of the general phenomenon "activation by inhibition" using bacterial and human HtrA proteases as models. Our data suggest a clear explanation that is based on the classic biochemical principles of allostery and cooperativity. Although substoichiometric occupancy of inhibitor binding sites results in partial inhibition, this effect is overrun by a concomitant activation of unliganded binding sites. Therefore, when an inhibitor of a cooperative enzyme does not reach saturating levels, a common scenario during drug administration, it may cause the contrary of the desired effect. The implications for drug development are discussed

Evidence for a palaeo-subglacial lake on the Antarctic continental shelf

Subglacial lakes are widespread beneath the Antarctic Ice Sheet but their control on ice-sheet dynamics and their ability to harbour life remain poorly characterized. Here we present evidence for a palaeo-subglacial lake on the Antarctic continental shelf. A distinct sediment facies recovered from a bedrock basin in Pine Island Bay indicates deposition within a low-energy lake environment. Diffusive-advection modelling demonstrates that low chloride concentrations in the pore water of the corresponding sediments can only be explained by initial deposition of this facies in a freshwater setting. These observations indicate that an active subglacial meltwater network, similar to that observed beneath the extant ice sheet, was also active during the last glacial period. It also provides a new framework for refining the exploration of these unique environments

First evidence for a late LGM subglacial lake in Pine Island Bay, Antarctica

Subglacial lakes are widespread beneath the Antarctic Ice Sheet and as a source for subglacial meltwater they are assumed to modulate ice stream velocity. Further, the evacuation of subglacial meltwater at the ice sheet margin influences ocean circulation and geochemical cycles. However, despite their importance„ subglacial lakes are one of the least explored environments on our planet. As a consequence, their importance for ice sheet dynamics and their ability to harbour life remain poorly characterised. We present the first direct evidence for a palaeo-subglacial lake on the Antarctic continental shelf, document- ing that subglacial meltwater was stored during the last glacial period and evacuated during the subsequent deglaciation. A distinct sediment facies observed in a core recovered from a small bedrock basin in Pine Island Bay, Amundsen Sea, is indicative of deposition within a low-energy subglacial lake setting. Diffusive modelling demonstrates that low chloride concentrations in the pore water of this characteristic sediment facies can only be explained by original deposition in a freshwater setting. We also show that the location of the subglacial lake within a basin on the inner shelf is consistent with the predicted distribution of subglacial lakes based on bathymetric data. This finding will enable future modelling studies to investigate how the geometry and capacity of subglacial lake systems can influence ice dynamics when the substrate and profile of the ice sheet is known – especially in the highly sensitive area known as the "weak underbelly" of the WAIS. With the exception of a direct lake water access at Subglacial Lake Vostok, and some centimetres of sediment retrieval from Subglacial Lake Whillans, the subglacial hydrological system in Antarctica has hitherto mostly been explored using remote sensing and numerical models that suggest the number of potential lake sites to more than 12.000. Our study not only provides first empirical evidence for a palaeo-subglacial lake but also delivers a framework for investigating and refining exploration of these unique subglacial lake environments and their sediments beneath thick contemporary ice sheets. Our approach, however, is easier and cheaper to conduct by using ship borne coring equipment on the seasonal ice-free continental shelf

High ecosystem service delivery potential of small woodlands in agricultural landscapes

Global forest loss and fragmentation have strongly increased the frequency of forest patches smaller than a few hectares. Little is known about the biodiversity and ecosystem service supply potential of such small woodlands in comparison to larger forests. As it is widely recognized that high biodiversity levels increase ecosystem functionality and the delivery of multiple ecosystem services, small, isolated woodlands are expected to have a lower potential for ecosystem service delivery than large forests hosting more species. We collected data on the diversity of six taxonomic groups covering invertebrates, plants and fungi, and on the supply potential of five ecosystem services and one disservice within 224 woodlands distributed across temperate Europe. We related their ability to simultaneously provide multiple ecosystem services (multiservice delivery potential) at different performance levels to biodiversity of all studied taxonomic groups (multidiversity), forest patch size and age, as well as habitat availability and connectivity within the landscape, while accounting for macroclimate, soil properties and forest structure. Unexpectedly, despite their lower multidiversity, smaller woodlands had the potential to deliver multiple services at higher performance levels per area than larger woodlands of similar age, probably due to positive edge effects on the supply potential of several ecosystem services. Biodiversity only affected multiservice delivery potential at a low performance level as well as some individual ecosystem services. The importance of other drivers of ecosystem service supply potential by small woodlands in agricultural landscapes also depended on the level of performance and varied with the individual ecosystem service considered. Synthesis and applications. Large, ancient woodlands host high levels of biodiversity and can therefore deliver a number of ecosystem services. In contrast, smaller woodlands in agricultural landscapes, especially ancient woodlands, have a higher potential to deliver multiple ecosystem services on a per area basis. Despite their important contribution to agricultural landscape multifunctionality, small woodlands are not currently considered by public policies. There is thus an urgent need for targeted policy instruments to ensure their adequate management and future conservation in order to either achieve multiservice delivery at high levels or to maximize the delivery of specific ecosystem services

High ecosystem service delivery potential of small woodlands in agricultural landscapes

Global forest loss and fragmentation have strongly increased the frequency of forest patches smaller than a few hectares. Little is known about the biodiversity and ecosystem service supply potential of such small woodlands in comparison to larger forests. As it is widely recognized that high biodiversity levels increase ecosystem functionality and the delivery of multiple ecosystem services, small, isolated woodlands are expected to have a lower potential for ecosystem service delivery than large forests hosting more species. We collected data on the diversity of six taxonomic groups covering invertebrates, plants and fungi, and on the supply potential of five ecosystem services and one disservice within 224 woodlands distributed across temperate Europe. We related their ability to simultaneously provide multiple ecosystem services (multiservice delivery potential) at different performance levels to biodiversity of all studied taxonomic groups (multidiversity), forest patch size and age, as well as habitat availability and connectivity within the landscape, while accounting for macroclimate, soil properties and forest structure. Unexpectedly, despite their lower multidiversity, smaller woodlands had the potential to deliver multiple services at higher performance levels per area than larger woodlands of similar age, probably due to positive edge effects on the supply potential of several ecosystem services. Biodiversity only affected multiservice delivery potential at a low performance level as well as some individual ecosystem services. The importance of other drivers of ecosystem service supply potential by small woodlands in agricultural landscapes also depended on the level of performance and varied with the individual ecosystem service considered. Synthesis and applications. Large, ancient woodlands host high levels of biodiversity and can therefore deliver a number of ecosystem services. In contrast, smaller woodlands in agricultural landscapes, especially ancient woodlands, have a higher potential to deliver multiple ecosystem services on a per area basis. Despite their important contribution to agricultural landscape multifunctionality, small woodlands are not currently considered by public policies. There is thus an urgent need for targeted policy instruments to ensure their adequate management and future conservation in order to either achieve multiservice delivery at high levels or to maximize the delivery of specific ecosystem services

Habitat properties are key drivers of Borrelia burgdorferi (s.l.) prevalence in Ixodes ricinus populations of deciduous forest fragments

Background: The tick Ixodes ricinus has considerable impact on the health of humans and other terrestrial animals because it transmits several tick-borne pathogens (TBPs) such as B. burgdorferi (sensu lato), which causes Lyme borreliosis (LB). Small forest patches of agricultural landscapes provide many ecosystem services and also the disservice of LB risk. Biotic interactions and environmental filtering shape tick host communities distinctively between specific regions of Europe, which makes evaluating the dilution effect hypothesis and its influence across various scales challenging. Latitude, macroclimate, landscape and habitat properties drive both hosts and ticks and are comparable metrics across Europe. Therefore, we instead assess these environmental drivers as indicators and determine their respective roles for the prevalence of B. burgdorferi in I. ricinus. Methods: We sampled I. ricinus and measured environmental properties of macroclimate, landscape and habitat quality of forest patches in agricultural landscapes along a European macroclimatic gradient. We used linear mixed models to determine significant drivers and their relative importance for nymphal and adult B. burgdorferi prevalence. We suggest a new prevalence index, which is pool-size independent. Results: During summer months, our prevalence index varied between 0 and 0.4 per forest patch, indicating a low to moderate disservice. Habitat properties exerted a fourfold larger influence on B. burgdorferi prevalence than macroclimate and landscape properties combined. Increasingly available ecotone habitat of focal forest patches diluted and edge density at landscape scale amplified B. burgdorferi prevalence. Indicators of habitat attractiveness for tick hosts (food resources and shelter) were the most important predictors within habitat patches. More diverse and abundant macro- and microhabitat had a diluting effect, as it presumably diversifies the niches for tick-hosts and decreases the probability of contact between ticks and their hosts and hence the transmission likelihood.[br/] Conclusions: Diluting effects of more diverse habitat patches would pose another reason to maintain or restore high biodiversity in forest patches of rural landscapes. We suggest classifying habitat patches by their regulating services as dilution and amplification habitat, which predominantly either decrease or increase B. burgdorferi prevalence at local and landscape scale and hence LB risk. Particular emphasis on promoting LB-diluting properties should be put on the management of those habitats that are frequently used by humans. In the light of these findings, climate change may be of little concern for LB risk at local scales, but this should be evaluated further

Environmental drivers of Ixodes ricinus abundance in forest fragments of rural European landscapes

Background: The castor bean tick (Ixodes ricinus) transmits infectious diseases such as Lyme borreliosis, which constitutes an important ecosystem disservice. Despite many local studies, a comprehensive understanding of the key drivers of tick abundance at the continental scale is still lacking. We analyze a large set of environmental factors as potential drivers of I. ricinus abundance. Our multi-scale study was carried out in deciduous forest fragments dispersed within two contrasting rural landscapes of eight regions, along a macroclimatic gradient stretching from southern France to central Sweden and Estonia. We surveyed the abundance of I. ricinus, plant community composition, forest structure and soil properties and compiled data on landscape structure, macroclimate and habitat properties. We used linear mixed models to analyze patterns and derived the relative importance of the significant drivers. Results: Many drivers had, on their own, either a moderate or small explanatory value for the abundance of I. ricinus, but combined they explained a substantial part of variation. This emphasizes the complex ecology of I. ricinus and the relevance of environmental factors for tick abundance. Macroclimate only explained a small fraction of variation, while properties of macro- and microhabitat, which buffer macroclimate, had a considerable impact on tick abundance. The amount of forest and the composition of the surrounding rural landscape were additionally important drivers of tick abundance. Functional (dispersules) and structural (density of tree and shrub layers) properties of the habitat patch played an important role. Various diversity metrics had only a small relative importance. Ontogenetic tick stages showed pronounced differences in their response. The abundance of nymphs and adults is explained by the preceding stage with a positive relationship, indicating a cumulative effect of drivers. Conclusions: Our findings suggest that the ecosystem disservices of tick-borne diseases, via the abundance of ticks, strongly depends on habitat properties and thus on how humans manage ecosystems from the scale of the microhabitat to the landscape. This study stresses the need to further evaluate the interaction between climate change and ecosystem management on I. ricinus abundance

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570