Parallel Mutations Result in a Wide Range of Cooperation and Community Consequences in a Two-Species Bacterial Consortium

Multi-species microbial communities play a critical role in human health, industry, and waste remediation. Recently, the evolution of synthetic consortia in the laboratory has enabled adaptation to be addressed in the context of interacting species. Using an engineered bacterial consortium, we repeatedly evolved cooperative genotypes and examined both the predictability of evolution and the phenotypes that determine community dynamics. Eight Salmonella enterica serovar Typhimurium strains evolved methionine excretion sufficient to support growth of an Escherichia coli methionine auxotroph, from whom they required excreted growth substrates. Non-synonymous mutations in metA, encoding homoserine trans-succinylase (HTS), were detected in each evolved S. enterica methionine cooperator and were shown to be necessary for cooperative consortia growth. Molecular modeling was used to predict that most of the non-synonymous mutations slightly increase the binding affinity for HTS homodimer formation. Despite this genetic parallelism and trend of increasing protein binding stability, these metA alleles gave rise to a wide range of phenotypic diversity in terms of individual versus group benefit. The cooperators with the highest methionine excretion permitted nearly two-fold faster consortia growth and supported the highest fraction of E. coli, yet also had the slowest individual growth rates compared to less cooperative strains. Thus, although the genetic basis of adaptation was quite similar across independent origins of cooperative phenotypes, quantitative measurements of metabolite production were required to predict either the individual-level growth consequences or how these propagate to community-level behavior

Long-Term Evidence Shows that Crop-Rotation Diversification Increases Agricultural Resilience to Adverse Growing Conditions in North America

A grand challenge facing humanity is how to produce food for a growing population in the face of a changing climate and environmental degradation. Although empirical evidence remains sparse, management strategies that increase environmental sustainability, such as increasing agroecosystem diversity through crop rotations, may also increase resilience to weather extremes without sacrificing yields. We used multilevel regression analyses of long-term crop yield datasets across a continental precipitation gradient to assess how temporal crop diversification affects maize yields in intensively managed grain systems. More diverse rotations increased maize yields over time and across all growing conditions (28.1% on average), including in favorable conditions (22.6%). Notably, more diverse rotations also showed positive effects on yield under unfavorable conditions, whereby yield losses were reduced by 14.0%–89.9% in drought years. Systems approaches to environmental sustainability and yield resilience, such as crop-rotation diversification, are a central component of risk-reduction strategies and should inform the enablement of policies

Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer's disease

Neurofilament light chain (NfL) is a promising fluid biomarker of disease progression for various cerebral proteopathies. Here we leverage the unique characteristics of the Dominantly Inherited Alzheimer Network and ultrasensitive immunoassay technology to demonstrate that NfL levels in the cerebrospinal fluid (n = 187) and serum (n = 405) are correlated with one another and are elevated at the presymptomatic stages of familial Alzheimer's disease. Longitudinal, within-person analysis of serum NfL dynamics (n = 196) confirmed this elevation and further revealed that the rate of change of serum NfL could discriminate mutation carriers from non-mutation carriers almost a decade earlier than cross-sectional absolute NfL levels (that is, 16.2 versus 6.8 years before the estimated symptom onset). Serum NfL rate of change peaked in participants converting from the presymptomatic to the symptomatic stage and was associated with cortical thinning assessed by magnetic resonance imaging, but less so with amyloid-β deposition or glucose metabolism (assessed by positron emission tomography). Serum NfL was predictive for both the rate of cortical thinning and cognitive changes assessed by the Mini-Mental State Examination and Logical Memory test. Thus, NfL dynamics in serum predict disease progression and brain neurodegeneration at the early presymptomatic stages of familial Alzheimer's disease, which supports its potential utility as a clinically useful biomarker

Increasing crop rotational diversity can enhance cereal yields

Diversifying agriculture by rotating a greater number of crop species in sequence is a promising practice to reduce negative impacts of crop production on the environment and maintain yields. However, it is unclear to what extent cereal yields change with crop rotation diversity and external nitrogen fertilization level over time, and which functional groups of crops provide the most yield benefit. Here, using grain yield data of small grain cereals and maize from 32 long-term (10–63 years) experiments across Europe and North America, we show that crop rotational diversity, measured as crop species diversity and functional richness, enhanced grain yields. This yield benefit increased over time. Only the yields of winter-sown small grain cereals showed a decline at the highest level of species diversity. Diversification was beneficial to all cereals with a low external nitrogen input, particularly maize, enabling a lower dependence on nitrogen fertilisers and ultimately reducing greenhouse gas emissions and nitrogen pollution. The results suggest that increasing crop functional richness rather than species diversity can be a strategy for supporting grain yields across many environments

Increasing crop rotational diversity can enhance cereal yields

9 Pág.Diversifying agriculture by rotating a greater number of crop species in sequence is a promising practice to reduce negative impacts of crop production on the environment and maintain yields. However, it is unclear to what extent cereal yields change with crop rotation diversity and external nitrogen fertilization level over time, and which functional groups of crops provide the most yield benefit. Here, using grain yield data of small grain cereals and maize from 32 long-term (10–63 years) experiments across Europe and North America, we show that crop rotational diversity, measured as crop species diversity and functional richness, enhanced grain yields. This yield benefit increased over time. Only the yields of winter-sown small grain cereals showed a decline at the highest level of species diversity. Diversification was beneficial to all cereals with a low external nitrogen input, particularly maize, enabling a lower dependence on nitrogen fertilisers and ultimately reducing greenhouse gas emissions and nitrogen pollution. The results suggest that increasing crop functional richness rather than species diversity can be a strategy for supporting grain yields across many environments.G.V., R.B. and S.H. acknowledge FORMAS grants 2018-02872 and 2018-02321. TMB acknowledges USDA AFRI grant 2017-67013-26254. LTEs managed by SRUC were supported by the Scottish Government RESAS Strategic Research Programme under project D3-, Healthy Soils for a Green Recovery. Swedish LTEs were funded by the Swedish University of Agricultural Sciences (SLU). We thank the Lawes Agricultural Trust and Rothamsted Research for data from the e-RA database. The Rothamsted Long-term Experiments National Capability (LTE-NC) was supported by the UK BBSRC (Biotechnology and Biological Sciences Research Council, BBS/E/C/000J0300) and the Lawes Agricultural Trust. The Woodslee site was supported by the Agro-Ecosystem Resilience Program (Agriculture & Agri-Food Canada) and field management provided by field crews over 6 decades is appreciated. La Canaleja LTE (Spain) was supported by RTA2017-00006-C03-01 project (Ministry of Science and Innovation. El Encín LTEs were supported by Spanish Ministry of Economy and Competitiveness funds (projects AGL2002-04186-C03-01.03, AGL2007-65698-C03-01.03, AGL2012-39929-C03-01 of which L. Navarrete was the P.I). R.A., A.G.D. and E.H.P. are also grateful to all members of the Weed Science Group from El Encín Experimental Station for their technical assistance in managing the experiments. The Brody/Poznan University of Life Sciences long-term experiments were funded by the Polish Ministry of Education and Science. We acknowledge the E-Obs dataset from the EU-FP6 project UERRA (http://www.uerra.eu) and the Copernicus Climate Change Service, and the data providers in the ECA&D project (https://www.ecad.eu/).Peer reviewe

Long-acting injectable Cabotegravir + Rilpivirine for HIV maintenance therapy: Week 48 pooled analysis of phase 3 ATLAS and FLAIR trials

BACKGROUND: Long-acting (LA) injectable regimens are a potential therapeutic option in people living with HIV-1. SETTING: ATLAS (NCT02951052) and FLAIR (NCT02938520) were 2 randomized, open-label, multicenter, multinational phase 3 studies. METHODS: Adult participants with virologic suppression (plasma HIV-1 RNA <50 copies/mL) were randomized (1:1) to continue with their current antiretroviral regimen (CAR) or switch to the long-acting (LA) regimen of cabotegravir (CAB) and rilpivirine (RPV). In the LA arm, participants initially received oral CAB + RPV once-daily for 4 weeks to assess individual safety and tolerability, before starting monthly injectable therapy. The primary endpoint of this combined analysis was antiviral efficacy at week 48 (FDA Snapshot algorithm: noninferiority margin of 4% for HIV-1 RNA ≥50 copies/mL). Safety, tolerability, and confirmed virologic failure (2 consecutive plasma HIV-1 RNA ≥200 copies/mL) were secondary endpoints. RESULTS: The pooled intention-to-treat exposed population included 591 participants in each arm [28% women (sex at birth), 19% aged ≥50 years]. Noninferiority criteria at week 48 were met for the primary (HIV-1 RNA ≥50 copies/mL) and key secondary (HIV-1 RNA <50 copies/mL) efficacy endpoints. Seven individuals in each arm (1.2%) developed confirmed virologic failure; 6/7 (LA) and 3/7 (CAR) had resistance-associated mutations. Most LA recipients (83%) experienced injection site reactions, which decreased in incidence over time. Injection site reactions led to the withdrawal of 6 (1%) participants. The serious adverse event rate was 4% in each arm. CONCLUSION: This combined analysis demonstrates monthly injections of CAB + RPV LA were noninferior to daily oral CAR for maintaining HIV-1 suppression