Active afforestation of drained peatlands is not a viable option under the EU Nature Restoration Law.

The EU Nature Restoration Law (NRL) is critical for the restoration of degraded ecosystems and active afforestation of degraded peatlands has been suggested as a restoration measure under the NRL. Here, we discuss the current state of scientific evidence on the climate mitigation effects of peatlands under forestry. Afforestation of drained peatlands without restoring their hydrology does not fully restore ecosystem functions. Evidence on long-term climate benefits is lacking and it is unclear whether CO2 sequestration of forest on drained peatland can offset the carbon loss from the peat over the long-term. While afforestation may offer short-term gains in certain cases, it compromises the sustainability of peatland carbon storage. Thus, active afforestation of drained peatlands is not a viable option for climate mitigation under the EU Nature Restoration Law and might even impede future rewetting/restoration efforts. Instead, restoring hydrological conditions through rewetting is crucial for effective peatland restoration.

Bacterial resistance response and resource availability mediate viral coexistence.

Viruses that infect bacteria, known as bacteriophages or phages, are the most prevalent entities on Earth. Their genetic diversity in nature is well documented, and members of divergent lineages can be found sharing the same ecological niche. This viral diversity can be influenced by a number of factors, including productivity, spatial structuring of the environment, and host-range trade-offs. Rapid evolution is also known to promote diversity by buffering ecological systems from extinction. There is, however, little known about the impact of coevolution on the maintenance of viral diversity within a microbial community. To address this, we developed a 4 species experimental system where two bacterial hosts, a generalist and a specialist phage, coevolved in a spatially homogenous environment over time. We observed the persistence of both viruses if the resource availability was sufficiently high. This coexistence occurred in the absence of any detectable host-range trade-offs that are costly for generalists and thus known to promote viral diversity. However, the coexistence was lost if two bacteria were not permitted to evolve alongside the phages or if two phages coevolved with a single bacterial host. Our findings indicate that a host's resistance response in mixed-species communities plays a significant role in maintaining viral diversity in the environment.

Metabolic efficiency reshapes the seminal relationship between pathogen growth rate and virulence.

A cornerstone of classical virulence evolution theories is the assumption that pathogen growth rate is positively correlated with virulence, the amount of damage pathogens inflict on their hosts. Such theories are key for incorporating evolutionary principles into sustainable disease management strategies. Yet, empirical evidence raises doubts over this central assumption underpinning classical theories, thus undermining their generality and predictive power. In this paper, we identify a key component missing from current theories which redefines the growth-virulence relationship in a way that is consistent with data. By modifying the activity of a single metabolic gene, we engineered strains of Magnaporthe oryzae with different nutrient acquisition and growth rates. We conducted in planta infection studies and uncovered an unexpected non-monotonic relationship between growth rate and virulence that is jointly shaped by how growth rate and metabolic efficiency interact. This novel mechanistic framework paves the way for a much-needed new suite of virulence evolution theories.

Enhanced Recovery Stem-Cell Transplantation: Multidisciplinary Efforts to Improve Outcomes in Older Adults Undergoing Hematopoietic Stem-Cell Transplant.

PURPOSE: Older adults have unique risk factors for poor outcomes after hematopoietic stem-cell transplant (HSCT). We sought to determine the impact of our multidisciplinary supportive care program, Enhanced Recovery after stem-cell transplant (ER-SCT), on survival outcomes in patients age 65 years and older who underwent HSCT. PATIENTS AND METHODS: In this retrospective study, clinicodemographic data, nonrelapse mortality (NRM), overall survival (OS), and relapse were compared between 64 patients age 65 years and older who underwent allogeneic stem-cell transplant during ER-SCT program's first year, October 2017 through September 2018, and 140 historical controls age 65 years and older who underwent allogeneic HSCT, January 2015 through September 2017. RESULTS: In the ER-SCT cohort, 41% (26 of 64) of patients were women, and the median (range) age was 68 (65-74) years; in the control cohort, 38% (53 of 140) of patients were women, and the median (range) age was 67 (65-79) years. Hematopoietic cell transplant comorbidity index and donor type/cell source were similar between cohorts. The ER-SCT cohort had a lower 1-year NRM rate (13% v 26%, P = .03) and higher 1-year OS rate (74% v 53%, P = .007). Relapse rate did not differ significantly between cohorts. In multivariate analyses, ER-SCT was associated with improved 1-year NRM (hazard ratio, 0.4; 95% CI, 0.2 to 0.9; P = .02) and improved 1-year OS (hazard ratio, 0.5; 95% CI, 0.3 to 0.9; P = .03). CONCLUSION: A multidisciplinary supportive care program may improve NRM and OS in older patients undergoing allogeneic HSCT. Randomized studies are warranted to confirm this benefit and explore which program components most contribute to the improved outcomes.

Surface structure on abandoned upland blanket peatland tracks.

Temporary permissions are often granted for track use on peatlands. However, even when peatland track designs attempt to minimise environmental impacts via use of mesh systems, such linear disturbances may have persistent impacts. We evaluated the surface peatland structure of five abandoned tracks (four with a mesh surface, one unsurfaced) with varying past usage frequencies, at an upland site in northern England. Simplification of the surface nanotopography was found on all tracks compared to surrounding control areas, with increased micro-erosion patterns in rutted areas, and invasive species on some treatments. The frequency of previous usage was not found to be a significant factor controlling nano-topographic loss. Edge effects and hillslope position were influential in places, but these effects were not consistent across treatments. Nano-topographic recovery was found to be inhibited when track usage commenced within a short time frame after track construction. Mesh tracks appear to create a spatial constraint leading to poor development of plants and a reduced ability to form characteristic structures which are integral to mire function.

Statistical Analysis of Protein-Ligand Interaction Patterns in Nuclear Receptor RORγ.

The receptor RORγ belongs to the nuclear receptor superfamily that senses small signaling molecules and regulates at the gene transcription level. Since RORγ has a high basal activity and plays an important role in immune responses, inhibitors targeting this receptor have been a focus for many studies. The receptor-ligand interaction is complex, and often subtle differences in ligand structure can determine its role as an inverse agonist or an agonist. We examined more than 130 existing RORγ crystal structures that have the same receptor complexed with different ligands. We reported the features of receptor-ligand interaction patterns and the differences between agonist and inverse agonist binding. Specific changes in the contact interaction map are identified to distinguish active and inactive conformations. Further statistical analysis of the contact interaction patterns using principal component analysis reveals a dominant mode which separates allosteric binding vs. canonical binding and a second mode which may indicate active vs. inactive structures. We also studied the nature of constitutive activity by performing a 100-ns computer simulation of apo RORγ. Using constitutively active nuclear receptor CAR as a comparison, we identified a group of conserved contacts that have similar contact strength between the two receptors. These conserved contact interactions, especially a couple key contacts in H11-H12 interaction, can be considered essential to the constitutive activity of RORγ. These protein-ligand and internal protein contact interactions can be useful in the development of new drugs that direct receptor activity.

Feasibility and Implementation of a Multimodal Supportive Care Program to Improve Outcomes in Older Patients Undergoing Allogeneic Stem Cell Transplantation.

Increasingly, patients age ≥65 years are undergoing allogeneic hematopoietic stem cell transplantation (allo-SCT). Although age alone is a well-documented predictor of overall survival (OS) and nonrelapse mortality (NRM), growing evidence suggests that poor functional status and frailty associated with aging may have roles as well. Our goal in the present study was to identify and improve these and other aging-related maladies by developing a multimodal supportive care program for older allo-SCT recipients. We designed and implemented a multimodal supportive care program, Enhanced Recovery in Stem Cell Transplant (ER-SCT), for patients age ≥65 years undergoing allo-SCT. The ER-SCT program consists of evaluation and critical interventions by key health care providers from multiple disciplines starting before hospital admission for transplantation and extending through 100 days post-allo-SCT. We determined the feasibility of implementing this program in a large stem cell transplantation center. After 1 year of ongoing process improvements, multiple evaluations, and enrollment, we found that a dedicated weekly clinic was necessary to coordinate care and evaluate patients early. We successfully enrolled 57 of 64 eligible patients (89%) in the first year. Our data show that a multimodal supportive care program to enhance recovery for older patients undergoing allo-SCT is feasible. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Would that it were so simple: Interactions between multiple traits undermine classical single-trait-based predictions of microbial community function and evolution.

Understanding how microbial traits affect the evolution and functioning of microbial communities is fundamental for improving the management of harmful microorganisms, while promoting those that are beneficial. Decades of evolutionary ecology research has focused on examining microbial cooperation, diversity, productivity and virulence but with one crucial limitation. The traits under consideration, such as public good production and resistance to antibiotics or predation, are often assumed to act in isolation. Yet, in reality, multiple traits frequently interact, which can lead to unexpected and undesired outcomes for the health of macroorganisms and ecosystem functioning. This is because many predictions generated in a single-trait context aimed at promoting diversity, reducing virulence or controlling antibiotic resistance can fail for systems where multiple traits interact. Here, we provide a much needed discussion and synthesis of the most recent research to reveal the widespread and diverse nature of multi-trait interactions and their consequences for predicting and controlling microbial community dynamics. Importantly, we argue that synthetic microbial communities and multi-trait mathematical models are powerful tools for managing the beneficial and detrimental impacts of microbial communities, such that past mistakes, like those made regarding the stewardship of antimicrobials, are not repeated.

Predicting microbial growth dynamics in response to nutrient availability.

Developing mathematical models to accurately predict microbial growth dynamics remains a key challenge in ecology, evolution, biotechnology, and public health. To reproduce and grow, microbes need to take up essential nutrients from the environment, and mathematical models classically assume that the nutrient uptake rate is a saturating function of the nutrient concentration. In nature, microbes experience different levels of nutrient availability at all environmental scales, yet parameters shaping the nutrient uptake function are commonly estimated for a single initial nutrient concentration. This hampers the models from accurately capturing microbial dynamics when the environmental conditions change. To address this problem, we conduct growth experiments for a range of micro-organisms, including human fungal pathogens, baker's yeast, and common coliform bacteria, and uncover the following patterns. We observed that the maximal nutrient uptake rate and biomass yield were both decreasing functions of initial nutrient concentration. While a functional form for the relationship between biomass yield and initial nutrient concentration has been previously derived from first metabolic principles, here we also derive the form of the relationship between maximal nutrient uptake rate and initial nutrient concentration. Incorporating these two functions into a model of microbial growth allows for variable growth parameters and enables us to substantially improve predictions for microbial dynamics in a range of initial nutrient concentrations, compared to keeping growth parameters fixed.

Effects of pH on an IDP conformational ensemble explored by molecular dynamics simulation.

The conformational ensemble of intrinsically disordered proteins, such as α-synuclein, are responsible for their function and malfunction. Misfolding of α-synuclein can lead to neurodegenerative diseases, and the ability to study their conformations and those of other intrinsically disordered proteins under varying physiological conditions can be crucial to understanding and preventing pathologies. In contrast to well-folded peptides, a consensus feature of IDPs is their low hydropathy and high charge, which makes their conformations sensitive to pH perturbation. We examine a prominent member of this subset of IDPs, α-synuclein, using a divide-and-conquer scheme that provides enhanced sampling of IDP structural ensembles. We constructed conformational ensembles of α-synuclein under neutral (pH ~ 7) and low (pH ~ 3) pH conditions and compared our results with available information obtained from smFRET, SAXS, and NMR studies. Specifically, α-synuclein has been found to in a more compact state at low pH conditions and the structural changes observed are consistent with those from experiments. We also characterize the conformational and dynamic differences between these ensembles and discussed the implication on promoting pathogenic fibril formation. We find that under low pH conditions, neutralization of negatively charged residues leads to compaction of the C-terminal portion of α-synuclein while internal reorganization allows α-synuclein to maintain its overall end-to-end distance. We also observe different levels of intra-protein interaction between three regions of α-synuclein at varying pH and a shift towards more hydrophilic interactions with decreasing pH.

Optimizing the Conditioning Regimen for Hematopoietic Cell Transplant in Myelofibrosis: Long-Term Results of a Prospective Phase II Clinical Trial.

Optimal conditioning regimens for older patients with myelofibrosis undergoing allogeneic hematopoietic cell transplant are not known. Likewise, the role of dose intensity is not clear. We conducted a nonrandomized, prospective, phase II trial using low-dose, later escalated to high-dose (myeloablative conditioning), busulfan with fludarabine (Bu-Flu) in myelofibrosis patients up to age 74 years. The first 15 patients received i.v. busulfan 130 mg/m2/day on days -3 and -2 ("low dose"); 31 patients received high-dose conditioning, either 100 mg/m2/day (days -5 to -2; n = 4) or pharmacokinetic-guided area under the curve of 4000 µmol/min (days -5 to -2; n = 27). The primary endpoint was day 100 nonrelapse mortality (NRM). Median age was 58 years (interquartile range [IQR], 53-63). Dynamic international prognostic scoring system-plus was intermediate (n = 28) or high (n = 18). Donors were related (n = 19) or unrelated (n = 27). Cumulative incidence of NRM was 9.7% (95% confidence interval [CI], 0-20.3) at day 100 and at 3 years in the high-dose group and 0% in the low-dose group at day 100, which increased to 20% (95% CI, 0-41.9) at 3 years. With a median follow-up of 5.1 years (IQR, 3.8-6), 3-year relapse was 32.3% (95% CI, 15.4-49.1) in high dose versus 53.3% (95% CI, 26.6-80.1) in low dose. Event-free survival was 58% (95% CI, 43-78) versus 27% (95% CI, 12-62), and overall survival was 74% (95% CI, 60-91) versus 60% (95% CI, 40-91). In multivariate analysis, high-dose busulfan had a trend toward lower relapse (hazard ratio, .44; 95% CI, .18-1.07; P = .07), with no impact on NRM. Intensifying the Bu-Flu regimen using pharmacokinetic-monitoring appears to be promising in reducing relapse without increasing NRM.

Privatization of public goods can cause population decline.

Microbes commonly deploy a risky strategy to acquire nutrients from their environment, involving the production of costly public goods that can be exploited by neighbouring individuals. Why engage in such a strategy when an exploitation-free alternative is readily available whereby public goods are kept private? We address this by examining metabolism of Saccharomyces cerevisiae in its native form and by creating a new three-strain synthetic community deploying different strategies of sucrose metabolism. Public-metabolizers digest resources externally, private-metabolizers internalize resources before digestion, and cheats avoid the metabolic costs of digestion but exploit external products generated by competitors. A combination of mathematical modelling and ecological experiments reveal that private-metabolizers invade and take over an otherwise stable community of public-metabolizers and cheats. However, owing to the reduced growth rate of private-metabolizers and population bottlenecks that are frequently associated with microbial communities, privatizing public goods can become unsustainable, leading to population decline.

Effector-Binding-Directed Dimerization and Dynamic Communication between Allosteric Sites of Ribonucleotide Reductase.

Proteins forming dimers or larger complexes can be strongly influenced by their effector-binding status. We investigated how the effector-binding event is coupled with interface formation via computer simulations, and we quantified the correlation of two types of contact interactions: between the effector and its binding pocket and between protein monomers. This was achieved by connecting the protein dynamics at the monomeric level with the oligomer interface information. We applied this method to ribonucleotide reductase (RNR), an essential enzyme for de novo DNA synthesis. RNR contains two important allosteric sites, the s-site (specificity site) and the a-site (activity site), which bind different effectors. We studied these different binding states with atomistic simulation and used their coarse-grained contact information to analyze the protein dynamics. The results reveal that the effector-protein dynamics at the s-site and dimer interface formation are positively coupled. We further quantify the resonance level between these two events, which can be applied to other similar systems. At the a-site, different effector-binding states (ATP vs dATP) drastically alter the protein dynamics and affect the activity of the enzyme. On the basis of these results, we propose a new mechanism of how the a-site regulates enzyme activation.

Characterizing the 3D structure and dynamics of chromosomes and proteins in a common contact matrix framework.

Conformational ensembles of biopolymers, whether proteins or chromosomes, can be described using contact matrices. Principal component analysis (PCA) on the contact data has been used to interrogate both protein and chromosome structures and/or dynamics. However, as these fields have developed separately, variants of PCA have emerged. Previously, a variant we hereby term Implicit-PCA (I-PCA) has been applied to chromosome contact matrices and revealed the spatial segregation of active and inactive chromatin. Separately, Explicit-PCA (E-PCA) has previously been applied to proteins and characterized their correlated structure fluctuations. Here, we swapped analysis methods (I-PCA and E-PCA), applying each to a different biopolymer type (chromosome or protein) than the one for which they were initially developed. We find that applying E-PCA to chromosome distance matrices derived from microscopy data can reveal the dominant motion (concerted fluctuation) of these chromosomes. Further, by applying E-PCA to Hi-C data across the human blood cell lineage, we isolated the aspects of chromosome structure that most strongly differentiate cell types. Conversely, when we applied I-PCA to simulation snapshots of proteins, the major component reported the consensus features of the structure, making this a promising approach for future analysis of semi-structured proteins.