bluuebunny/crossref_metadata_2025 huggingface dataset:
Best organic farming expansion scenarios for pest control: a modeling approach
Authors: Delattre Thomas , Memah Mohamed-Mahmoud , Franck Pierre , Valsesia Pierre , Lavigne Claire
Published: June 2022

Organic Farming (OF) has been expanding recently in response to growing consumer demand and as a response to environmental concerns. The area under OF is expected to further increase in the future. The effect of OF expansion on pest densities in organic and conventional crops remains difficult to predict because OF expansion impacts Conservation Biological Control (CBC), which depends on the surrounding landscape (i.e. both the crop mosaic and semi-natural habitats). In order to understand and forecast how pests and their biological control may vary during OF expansion, we modeled the effect of spatial changes in farming practices on population dynamics of a pest and its natural enemy. We investigated the impact on pest density and on predator to pest ratio of three contrasted scenarios aiming at 50% organic fields through the progressive conversion of conventional fields. Scenarios were 1) conversion of Isolated conventional fields first (IP), 2) conversion of conventional fields within Groups of conventional fields first (GP), and 3) Random conversion of conventional field (RD). We coupled a neutral spatially explicit landscape model to a predator-prey model to simulate pest dynamics in interaction with natural enemy predators. The three OF expansion scenarios were applied to nine landscape contexts differing in their proportion and fragmentation of semi-natural habitat. We further investigated if the ranking of scenarios was robust to pest control methods in OF fields and pest and predator dispersal abilities.

We found that organic farming expansion affected more predator densities than pest densities for most combinations of landscape contexts and OF expansion scenarios. The impact of OF expansion on final pest and predator densities was also stronger in organic than conventional fields and in landscapes with large proportions of highly fragmented semi-natural habitats. Based on pest densities and the predator to pest ratio, our results suggest that a progressive organic conversion with a focus on isolated conventional fields (scenario IP) could help promote CBC. Careful landscape planning of OF expansion appeared most necessary when pest management was substantially less efficient in organic than in conventional crops, and in landscapes with low proportion of semi-natural habitats.
Predicting higher-order mutational effects in an RNA enzyme by machine learning of high-throughput experimental data
Authors: Beck James D. , Roberts Jessica M. , Kitzhaber Joey , Trapp Ashlyn , Serra Edoardo , Spezzano Francesca , Hayden Eric J.
Published: June 2022

Ribozymes are RNA molecules that catalyze biochemical reactions. Self-cleaving ribozymes are a common naturally occurring class of ribozymes that catalyze site-specific cleavage of their own phosphodiester backbone. In addition to their natural functions, self-cleaving ribozymes have been used to engineer control of gene expression because they can be designed to alter RNA processing and stability. However, the rational design of ribozyme activity remains challenging, and many ribozyme-based systems are engineered or improved by random mutagenesis and selection (in vitro evolution). Improving a ribozyme-based system often requires several mutations to achieve the desired function, but extensive pairwise and higher-order epistasis prevent a simple prediction of the effect of multiple mutations that is needed for rational design. Recently, high-throughput sequencing-based approaches have produced data sets on the effects of numerous mutations in different ribozymes (RNA fitness landscapes). Here we used such high-throughput experimental data from variants of the CPEB3 self-cleaving ribozyme to train a predictive model through machine learning approaches. We trained models using either a random forest or long short-term memory (LSTM) recurrent neural network approach. We found that models trained on a comprehensive set of pairwise mutant data could predict active sequences at higher mutational distances, but the correlation between predicted and experimentally observed self-cleavage activity decreased with increasing mutational distance. Adding sequences with increasingly higher numbers of mutations to the training data improved the correlation at increasing mutational distances. Systematically reducing the size of the training data set suggests that a wide distribution of ribozyme activity may be the key to accurate predictions. Because the model predictions are based only on sequence and activity data, the results demonstrate that this machine learning approach allows readily obtainable experimental data to be used for RNA design efforts even for RNA molecules with unknown structures. The accurate prediction of RNA functions will enable a more comprehensive understanding of RNA fitness landscapes for studying evolution and for guiding RNA-based engineering efforts.
Plasma amyloid-β homeostasis is associated with Body Mass Index and weight loss in people with overweight and obesity
Authors: Brook Emily S. , D’Alonzo Zachary J. , Lam Virginie , Chan Dick , Dhaliwal Satvinder Singh , Watts Gerald F. , Mamo John C. L , Takechi Ryusuke
Published: June 2022

BACKGROUND

Obesity is linked to a higher incidence of Alzheimer’s disease (AD). Studies show that plasma amyloid-β (Aβ) dyshomeostasis, particularly low 42/40 ratio indicates a heightened risk for developing AD. However, the relationship between body mass index (BMI) and circulating plasma Aβ has not been extensively studied.

OBJECTIVE

We hypothesised that people with a high BMI have altered plasma Aβ homeostasis compared with people with a lower BMI. We also tested whether reducing BMI by calorie-restriction could normalise plasma concentrations of Aβ.

METHODS

Plasma concentrations of Aβ40, Aβ42and Aβ42/40ratio were measured in 106 participants with BMIs classified as lean, overweight, or obese. From this cohort, twelve participants with overweight or obese BMIs entered a 12-week calorie-restriction weight loss program. We then tested whether decreasing BMI affected plasma Aβ concentrations.

RESULTS

Plasma Aβ42/40ratio was 17.54% lower in participants with an obese BMI compared to lean participants (p<0.0001), and 11.76% lower compared to participants with an overweight BMI (p<0.0001). The weight loss regimen decreased BMI by an average of 4.02% (p=0.0005) and was associated with a 6.5% decrease in plasma Aβ40(p=0.0425). However, weight loss showed negligible correlations with plasma Aβ40, Aβ42and Aβ42/40ratio.

CONCLUSION

Obesity is associated with aberrant plasma Aβ homeostasis which may be associated with an increased risk for AD. Weight loss appears to lower Aβ40, but large-scale longitudinal studies in addition to molecular studies are required to elucidate the underlying mechanisms of how obesity and weight loss influence plasma Aβ homeostasis.
Synergistic activation of RARb and RARg nuclear receptors restores cell specialization during stem cell differentiation by hijacking RARa-controlled programs
Authors: Koshy Aysis , Mathieux Elodie , Stüder François , Bramoulle Aude , Lieb Michele , Colombo Bruno Maria , Gronemeyer Hinrich , Mendoza-Parra Marco Antonio
Published: June 2022

How cells respond to different external cues to develop along defined cell lineages to form complex tissues is a major question in systems biology. Here, we investigated the potential of retinoic acid receptor (RARs)-selective synthetic agonists to activate the gene-regulatory programs driving cell specialization during nervous tissue formation from P19 stem cells. Specifically, we found that the synergistic activation of the RARβ and RARγ by selective ligands (BMS641 or BMS961) induces cell maturation to specialized neuronal subtypes, as well as to astrocytes and oligodendrocyte precursors.

Using RAR istoype knockout lines exposed to RAR-specific agonists, interrogated by global transcriptome landscaping and in silico modeling of transcription regulatory signal propagation, revealed major RARα−driven gene programs essential for optimal neuronal cell specialization, and hijacked by the synergistic activation of the RARβ and RARγ receptors.

Overall, this study provides a systems biology view of the gene programs accounting for the previously observed redundancy between RAR receptors, paving the way towards their potential use for directing cell specialization during nervous tissue formation.
High and low permeability of human pluripotent stem cell-derived Blood Brain barrier models depend on epithelial or endothelial features
Authors: Girard Stéphane D. , Julien-Gau Ingrid , Molino Yves , Combes Benjamin F. , Greetham Louise , Khrestchatisky Michel , Nivet Emmanuel
Published: June 2022

The search for reliable human blood-brain barrier (BBB) models represents a challenge for the development/testing of strategies aiming to enhance brain delivery of drugs. Human induced pluripotent stem cells (hiPSCs) have raised hopes in the development of predictive BBB models. Differentiating strategies are thus required to generate endothelial cells (ECs), a major component of the BBB. Several hiPSC-based protocols have reported the generation ofin vitromodels with significant differences in barrier properties. We studied in depth the properties of iPSCs byproducts from two protocols that have been established to yield thesein vitrobarrier models. Our analysis/study reveals that iPSCs endowed with EC features yield high permeability models, while the cells that exhibit outstanding barrier properties show principally epithelial cell-like (EpC) features. Our study demonstrates that hiPSC-based BBB models need extensive characterization beforehand and that a reliable human BBB model is still needed.
Plasma glycoproteomics delivers high-specificity disease biomarkers by detecting site-specific glycosylation abnormalities
Authors: Wessels Hans JCT , Kulkarni Purva , van Dael Maurice , Suppers Anouk , Willems Esther , Zijlstra Fokje , Kragt Else , Gloerich Jolein , Schmit Pierre-Olivier , Pengelley Stuart , Marx Kristina , van Gool Alain J , Lefeber Dirk J
Published: June 2022

The human plasma glycoproteome holds enormous potential to identify personalized biomarkers to diagnose and understand disease. Recent advances in mass spectrometry and software development are opening novel avenues to mine the glycoproteome for protein- and site-specific glycosylation changes. Here, we describe a novel plasma N-glycoproteomics method for disease diagnosis and evaluated its clinical applicability by performing comparative glycoproteomics in blood plasma of 40 controls and a cohort of 74 patients with 13 different genetic diseases that directly impact the protein N-glycosylation pathway. The plasma glycoproteome yielded high-specificity biomarker signatures for each of the individual genetic defects. Bioinformatic analyses revealed site-specific glycosylation differences that could be explained by underlying glycobiology and in specific diseases by protein-intrinsic factors. Our work illustrates the strong potential of plasma glycoproteomics to significantly increase specificity of glycoprotein biomarkers with direct insights in site-specific glycosylation changes to better understand the mechanisms underlying human disease.
Intracellular level of S. cerevisiae Rad51 is regulated via proteolysis in a SUMO- and ubiquitin-dependent manner
Authors: Antoniuk-Majchrzak Justyna , Długajczyk Anna , Enkhbaatar Tuguldur , Kaminska Joanna , Skoneczny Marek , Klionsky Daniel J. , Skoneczna Adrianna
Published: June 2022

Among various DNA lesions, the DNA double-strand breaks are particularly deleterious; especially, when an error-free repair pathway is unavailable, and the cell takes the risk of using the error-prone recombination pathways to repair the DNA breaks, resume the cell cycle, and continue growth. The latter comes at the expense of decreased well-being of the cells due to genome rearrangements. One of the major players involved in recombinational repair of DNA damage is Rad51 recombinase, a protein responsible for presynaptic complex formation. We previously noticed that the level of this protein is strongly increased when illegitimate recombination is engaged in repair. The regulation of Rad51 protein turnover is not known; therefore, we decided to look closer at this issue because we expect that an excessively high level of Rad51 may lead to genome instability. Here we show that the level of Rad51 is regulated via the ubiquitin-dependent proteolytic pathway. The ubiquitination of Rad51 depends on multiple E3 enzymes, including SUMO-targeted ubiquitin ligases. We also demonstrate that Rad51 can be modified by both ubiquitin and SUMO. Moreover, these modifications may lead to opposite effects. Ubiquitin-dependent degradation depends on Rad6, Rad18, Slx8, Dia2 and the anaphase-promoting complex. Rsp5-dependent ubiquitination leads to Rad51 stabilization.
Fatty acid synthesis knockdown promotes biofilm wrinkling and inhibits sporulation in Bacillus subtilis
Authors: Arjes Heidi A. , Gui Haiwen , Porter Rachel , Atolia Esha , Peters Jason , Gross Carol , Kearns Daniel B. , Huang Kerwyn Casey
Published: June 2022

Many bacterial species typically live in complex three-dimensional biofilms, yet little is known about systematic changes to gene function between non-biofilm and biofilm lifestyles. Here, we created a CRISPRi library of knockdown strains covering all known essential genes in the biofilm-forming Bacillus subtilis strain 3610. We show that gene essentiality is largely conserved between liquid and surface growth and between two media. We developed an image analysis algorithm to quantify biofilm colony wrinkling, which identified strains with high or low levels of wrinkling that were uncorrelated with extracellular matrix gene expression. We also designed a high-throughput screen for sensitive quantification of sporulation efficiency and performed the first screens of sporulation during essential gene knockdown. We found that all basal knockdowns of essential genes were competent for sporulation in a sporulation-inducing medium, but certain strains exhibited reduced sporulation efficiency in LB, a medium with generally lower levels of sporulation. Knockdown of fatty acid synthesis increased wrinkling and inhibited sporulation. These results highlight the importance of essential genes in biofilm structure and sporulation/germination and suggest a previously unappreciated and multifaceted role for fatty acid synthesis in bacterial lifestyles and developmental processes.

Abstract Importance

For many bacteria, life typically involves growth in dense, three-dimensional communities called biofilms that contain cells with differentiated roles and are held together by extracellular matrix. To examine how gene function varies between non-biofilm and biofilm growth, we created a comprehensive library of strains using CRISPRi to knockdown expression of each essential gene in the model species Bacillus subtilis 3610, which can develop into a wrinkled biofilm structure or a spore capable of surviving harsh environments. This library enabled us to determine when gene essentiality depends on growth conditions. We also developed high-throughput assays and computational algorithms to identify essential genes involved in biofilm wrinkling and sporulation. Knockdown of fatty acid synthesis increased the density of wrinkles, and also inhibited sporulation in a medium with generally lower sporulation levels. These findings indicate that essential processes such as fatty acid synthesis can play important and multifaceted roles in bacterial development.
The salivary and nasopharyngeal microbiomes are associated with SARS-CoV-2 infection and disease severity
Authors: Kim Josh G. , Zhang Ai , Rauseo Adriana M. , Goss Charles W. , Mudd Philip A. , O’Halloran Jane A. , Wang Leyao
Published: June 2022

Oral and upper respiratory microbiota play important roles in modulating host immune responses to viral infection. As emerging evidence suggests the host microbiome may be involved in the pathophysiology of COVID-19, we aimed to investigate associations between the oral and nasopharyngeal microbiome and COVID-19 severity. We collected saliva (n = 78) and nasopharyngeal swab (n = 66) samples from a COVID-19 cohort and characterized the microbiomes using 16S ribosomal RNA gene sequencing. We also examined associations between the salivary and nasopharyngeal microbiome and age, COVID-19 symptoms, and blood cytokines. SARS-CoV-2 infection status, but not COVID-19 severity, was associated with community-level differences in the oral and nasopharyngeal microbiomes. Salivary and nasopharyngeal microbiome alpha diversity negatively correlated with age and were associated with fever and diarrhea. Several bacterial genera were differentially abundant by COVID-19 severity, including oral Bifidobacterium, Lactobacillus, and Solobacterium, all of which were depleted in patients with severe COVID-19. Nasopharyngeal Paracoccus was depleted while nasopharyngeal Proteus, Cupravidus, and Lactobacillus were increased in patients with severe COVID-19. Further analysis revealed that the abundance of oral Bifidobacterium was negatively associated with plasma concentrations of known COVID-19 biomarkers interleukin 17F (IL-17F) and monocyte chemoattractant protein-1 (MCP-1). In conclusion, our results suggest COVID-19 disease severity is associated with the relative abundance of certain bacterial taxa.
On the interpretation of the operation of natural selection in class-structured populations
Authors: Priklopil Tadeas , Lehmann Laurent
Published: June 2022

Biological adaptation is the outcome of allele-frequency change by natural selection. At the same time, populations are usually class structured as individuals occupy different states such as age, sex, or stage. This is known to result in the differential transmission of alleles through non-heritable fitness differences called class transmission, also affecting allele-frequency change even in the absence of selection. How does one then isolate the allele-frequency change due to selection from that owing to class transmission? We decompose one-generational allele-frequency change in terms of effects of selection and class transmission, and show how reproductive values can be used to reach a decomposition between any two distant generations of the evolutionary process. This provides a missing relationship between multigenerational allele-frequency change and the operation of selection. It also allows to define a measure of fitness summarizing the effect of selection in a multigenerational evolutionary process, which connects asymptotically to invasion fitness.
Inflammation and neuronal gene expression changes differ in early vs late chronic traumatic encephalopathy brain
Authors: Labadorf Adam , Agus Filisia , Aytan Nurgul , Cherry Jonathan , Mez Jesse , McKee Ann , Stein Thor D.
Published: June 2022

Our understanding of the molecular underpinnings of chronic traumatic encephalopathy (CTE) and its associated pathology in post-mortem brain is incomplete. Factors including years of play and genetic risk variants influence the extent of tau pathology associated with disease expression, but how these factors affect gene expression, and whether those effects are consistent across the development of disease, is unknown. To address these questions, we conducted an analysis of the largest mRNASeq whole-transcriptome dataset available to date. We examined the genes and biological processes associated with disease by comparing individuals with CTE with control individuals with a history of repetitive head impacts that lack CTE pathology. We then identified genes and biological processes associated with total years of play as a measure of exposure, amount of tau pathology present at time of death, and the presence of APOE and TMEM106B risk variants. Samples were stratified into low and high pathology groups based on extent of tau pathology and years of play to model early vs late changes in response to exposure, and the relative effects associated with these factors were compared between these groups. Substantial gene expression changes were associated with severe disease for most of these factors, primarily implicating diverse, highly increased neuroinflammatory and neuroimmune processes. In contrast, low exposure groups had many fewer genes and processes implicated and show striking differences for some factors when compared with severe disease. Specifically, gene expression associated with amount of tau pathology showed a nearly perfect inverse relationship when compared between these two groups. Together, these results suggest the early disease process may differ substantially from that observed in late stages, that total years of play and tau pathology influence disease expression differently, and that related pathology-modifying risk variants may do so via distinct biological pathways.
The PilT retraction ATPase promotes both extension and retraction of the MSHA type IVa pilus inVibrio cholerae
Authors: Hughes Hannah Q. , Christman Nicholas D. , Dalia Triana N. , Ellison Courtney K. , Dalia Ankur B.
Published: June 2022

Diverse bacterial species use type IVa pili (T4aP) to interact with their environments. The dynamic extension and retraction of T4aP is critical for their function, but the mechanisms that regulate this dynamic activity remain poorly understood. T4aP are typically extended via the activity of a dedicated extension motor ATPase and retracted via the action of an antagonistic retraction motor ATPase called PilT. These motors are generally functionally independent, and loss of PilT commonly results in T4aP hyperpiliation due to undeterred pilus extension.

However, for the mannose-sensitive hemagglutinin (MSHA) T4aP ofVibrio cholerae, the loss of PilT results in a loss of surface piliation, which is unexpected based on our current understanding of T4aP dynamics. Here, we employ a combination of genetic and cell biological approaches to dissect the underlying mechanism. Our results demonstrate that PilT is necessary for MSHA pilus extension in addition to its well-established role in promoting MSHA pilus retraction. Through a suppressor screen, we also provide genetic evidence that the MshA major pilin impacts pilus extension. Together, these findings contribute to our understanding of the factors that regulate pilus extension and describe a previously uncharacterized function for the PilT motor ATPase.

AUTHOR SUMMARY

Many bacteria use filamentous appendages called type IVa pili to interact with their environment. These fibers dynamically extend and retract through the activity of ATPase motor proteins. In most pilus systems, deletion of the retraction motor results in uninterrupted pilus extension, leading to hyperpiliation. However, in the MSHA pilus system ofV. cholerae, deletion of the retraction motor,pilT, results in a decrease in the number of surface pili. Here, we show that PilT is unexpectedly required for MSHA pilus extension in addition to its defined role in promoting pilus retraction. These results extend our understanding of the complex mechanisms underlying the dynamic activity of these broadly conserved filamentous appendages.
Impact of glycoengineering and immunogenicity on the anti-cancer activity of a plant-made lectin-Fc fusion protein
Authors: Dent Matthew , Mayer Katarina L. , Garcia Noel Verjan , Guo Haixun , Kajiura Hiroyuki , Fujiyama Kazuhito , Matoba Nobuyuki
Published: June 2022

Plants are an efficient production platform for manufacturing glycoengineered monoclonal antibodies and antibody-like molecules. Avaren-Fc (AvFc) is a lectin-Fc fusion protein or lectibody produced in Nicotiana benthamiana, which selectively recognizes cancer-associated high-mannose glycans. In this study, we report the generation of a glycovariant of AvFc that is devoid of plant glycans, including the core α1,3-fucose and β1,2-xylose residues. The successful removal of these glycans was confirmed by glycan analysis using HPLC. This variant, AvFcΔXF, has significantly higher affinity for Fc gamma receptors and induces higher levels of luciferase expression in an antibody-dependent cell-mediated cytotoxicity (ADCC) reporter assay against B16F10 murine melanoma cells without inducing apoptosis or inhibiting proliferation. In the B16F10 flank tumor mouse model, we found that systemic administration of AvFcΔXF, but not an aglycosylated AvFc variant lacking affinity for Fc receptors, significantly delayed the growth of tumors, suggesting that Fc-mediated effector functions were integral. AvFcΔXF treatment also significantly reduced lung metastasis of B16F10 upon intravenous challenge whereas a sugar-binding-deficient mutant failed to show efficacy. Lastly, we determined the impact of anti-drug antibodies (ADAs) on drug activity in vivo by pretreating animals with AvFcΔXF before implanting tumors. Despite a significant ADA response induced by the pretreatment, we found that the activity of AvFcΔXF was unaffected by the presence of these antibodies. These results demonstrate that glycoengineering is a powerful strategy to enhance AvFc’s antitumor activity.
Physical and functional convergence of the autism risk genesScn2aandAnk2in neocortical pyramidal cell dendrites
Authors: Nelson Andrew D. , Catalfio Amanda M. , Gupta Julie M. , Min Lia , Caballero-Floran Rene N. , Dean Kendall P. , Elvira Carina C. , Derderian Kimberly D. , Kyoung Henry , Sahagun Atehsa , Sanders Stephan J. , Bender Kevin J. , Jenkins Paul M.
Published: June 2022

Dysfunction in sodium channels and their ankyrin scaffolding partners have both been implicated in neurodevelopmental disorders, including autism spectrum disorder (ASD). In particular, the genes SCN2A, which encodes the sodium channel NaV1.2, and ANK2, which encodes ankyrin-B, have strong ASD association. Recent studies indicate that ASD-associated haploinsufficiency in Scn2a impairs dendritic excitability and synaptic function in neocortical pyramidal cells, but how NaV1.2 is anchored within dendritic regions is unknown. Here, we show that ankyrin-B is essential for scaffolding NaV1.2 to the dendritic membrane of mouse neocortical neurons, and that haploinsufficiency of Ank2 phenocopies intrinsic dendritic excitability and synaptic deficits observed in Scn2a+/- conditions. Thus, these results establish a direct, convergent link between two major ASD risk genes and reinforce an emerging framework suggesting that neocortical pyramidal cell dendritic dysfunction can be etiological to neurodevelopmental disorder pathophysiology.
Experimental Test of the Contributions of Initial Variation and New Mutations to Adaptive Evolution in a Novel Environment
Authors: Izutsu Minako , Lenski Richard E.
Published: June 2022

Experimental evolution is an approach that allows researchers to study organisms as they evolve in controlled environments. Despite the growing popularity of this approach, there are conceptual gaps among projects that use different experimental designs. One such gap concerns the contributions to adaptation of genetic variation present at the start of an experiment and that of new mutations that arise during an experiment. The primary source of genetic variation has historically depended largely on the study organisms. In the long-term evolution experiment (LTEE) using Escherichia coli, for example, each population started from a single haploid cell, and therefore adaptation depended entirely on new mutations. Most other microbial evolution experiments have followed the same strategy. By contrast, evolution experiments using multicellular, sexually-reproducing organisms typically start with pre-existing variation that fuels the response to selection. New mutations may also come into play in later generations of these experiments, but it is generally difficult to quantify their contribution in these studies. Here, we performed an experiment using E. coli to compare the contributions of initial genetic variation and new mutations to adaptation in a new environment. Our experiment had four treatments that varied in their starting diversity, with 18 populations in each treatment. One treatment depended entirely on new mutations, while the other three began with mixtures of clones, whole-population samples, or mixtures of whole-population samples from the LTEE. By tracking genetic markers associated with particular founders in two of our treatments, we could document the impact of the initial variation during the early generations of our experiment. However, there were no differences in fitness among the treatments after 500 or 2000 generations in the new environment, despite the variation in fitness among the founders. These results indicate that new mutations quickly overcame, and eventually contributed more to adaptation, than did the initial variation. Our study thus shows that pre-existing genetic variation can have a strong impact on early evolution in a new environment, but new beneficial mutations may contribute more to later evolution and can even drive some initially beneficial variants to extinction.
Multi-Agent Reinforcement Learning-based Adaptive Sampling for Conformational Sampling of Proteins
Authors: Kleiman Diego E. , Shukla Diwakar
Published: June 2022

Machine Learning is increasingly applied to improve the efficiency and accuracy of Molecular Dynamics (MD) simulations. Although the growth of distributed computer clusters has allowed researchers to obtain higher amounts of data, unbiased MD simulations have difficulty sampling rare states, even under massively parallel adaptive sampling schemes. To address this issue, several algorithms inspired by reinforcement learning (RL) have arisen to promote exploration of the slow collective variables (CVs) of complex systems. Nonetheless, most of these algorithms are not well-suited to leverage the information gained by simultaneously sampling a system from different initial states (e.g., a protein in different conformations associated with distinct functional states). To fill this gap, we propose two algorithms inspired by multi-agent RL that extend the functionality of closely-related techniques (REAP and TSLC) to situations where the sampling can be accelerated by learning from different regions of the energy landscape through coordinated agents. Essentially, the algorithms work by remembering which agent discovered each conformation and sharing this information with others at the action-space discretization step. Astakes functionis introduced to modulate how different agents sense rewards from discovered states of the system. The consequences are threefold: (i) agents learn to prioritize CVs using only relevant data, (ii) redundant exploration is reduced, and (iii) agents that obtain higher stakes are assigned more actions. We compare our algorithm with other adaptive sampling techniques (Least Counts, REAP, TSLC, and AdaptiveBandit) to show and rationalize the gain in performance.
Can Membrane Composition Traffic Toxins? Mycolactone and Preferential Membrane Interactions
Authors: da Hora Gabriel C. A. , Nguyen John D. M. , Swanson Jessica M. J.
Published: June 2022

Mycolactone is a cytotoxic and immunosuppressive macrolide produced byMycobacterium ulceransand the sole causative agent of the neglected tropical skin disease Buruli ulcer. The toxin acts by invading host cells and interacting with intracellular targets to disrupt multiple fundamental cellular processes. Mycolactone’s amphiphilic nature enables strong interactions with lipophilic environments, including cellular membranes; however, the specificity of these interactions and the role of membranes in the toxin’s pathogenicity remain unknown. It is likely that preferential interactions with lipophilic carriers play a key role in the toxin’s distribution in the host, which, if understood, could provide insights to aid in the development of needed diagnostics for Buruli ulcer disease. In this work, molecular dynamics simulations were combined with enhanced free energy sampling to characterize mycolactone’s association with and permeation through models of the mammalian endoplasmic reticulum (ER) and plasma membranes (PM). We find that increased order in the PM not only leads to a different permeation mechanism compared to that in the ER membrane, but also an energetic driving force for ER localization. Increased hydration, membrane deformation, and preferential interactions with unsaturated lipid tails stabilize the toxin in the ER membrane, while disruption of lipid packing is a destabilizing force in the PM.

STATEMENT OF SIGNIFICANCE

Mycolactone is sole the causative agent of Buruli ulcer, a neglected tropical disease involving large necrotic lesions that can cause permanent disfigurement if left untreated. Due to its amphiphilic nature, the toxin hides from traditional diagnostic detection and the host immune system by associating with lipophilic carriers, including cellular membranes. Our work uses extensive all-atom simulations to query if the toxin has preferential interactions with different types of membranes. We find a clear preference for more disordered membranes, like the endoplasmic reticulum’s, via interactions with unsaturated lipid tails and membrane deformation. The revealed insights can be used to predict host cell distribution between different types of lipophilic carriers and to aid in the design of Buruli ulcer diagnostics.
Retractions and rewards in science: An open question for reviewers and funders
Authors: Ribeiro Mariana D , Kalichman M , Vasconcelos Sonia MR
Published: June 2022

In recent years, the changing landscape for the conduct and assessment of research and of researchers has increased scrutiny of the reward systems of science. In this context, correcting the research record, including retractions, has gained attention and space in the publication system. One question is the possible influence of retractions on the careers of scientists. It might be assessed, for example, through citation patterns or productivity rates for authors who have had one or more retractions. This is an emerging issue today, with growing discussions in the research community about impact. We have explored the influence of retractions on grant review criteria. Here, we present results of a qualitative study exploring the views of a group of six representatives of funding agencies from different countries and of a follow-up survey of 224 reviewers in the US. These reviewers have served on panels for the National Science Foundation, the National Institutes of Health, and/or a few other agencies. We collected their perceptions about the influence of self-correction of the literature and of retractions on grant decisions. Our results suggest that correcting the research record, for honest error or misconduct, is perceived as an important mechanism to strengthen the reliability of science, among most respondents. However, retractions and self-correcting the literature at large are not factors influencing grant review, and dealing with retractions in reviewing grants is an open question for funders.
Lipid-mediated dimerization of membrane-anchored c-Src is driven by a cluster of lysine residues in the N-terminal SH4 domain
Authors: Mohammad Irrem-Laareb , Carvajal Javier , Fernández Alejandro , Taulés Marta , Fourgous Elise , Boublik Yvan , Le Roux Anabel-Lise , Roche Serge , Pons Miquel
Published: June 2022

The membrane-anchored c-Src tyrosine kinase mediates signaling from a wide range of cell surface receptors controlling cell growth, adhesion, and survival. c-Src deregulation is associated with cancer. Dimerization appears to be a novel layer of regulation through a yet unclear mechanism. Binding of c-Src tyrosine kinase to the plasma membrane is mediated by the myristoylated and strongly positively charged N-terminal SH4 domain. Although activation of c-Src is known to require phosphorylation by a second c-Src molecule, electrostatic repulsion between the charged residues was considered to prevent dimerization. Here we show that a cluster of positively charged lysine residues in c-Src SH4 domain not only does not prevent dimerization but, in fact, enhances it through a lipid-mediated process. Dimerization not only depends on the number of positive charges but also on their position and the nature of the charged residues. Replacement of lysine by arginine increases dimerization in vitro and in vivo and, in HEK293T cells, causes a two-fold increase in tyrosine phosphorylation. Lipid mediated protein-protein interactions induced by clusters of basic residues may represent a general mechanism for modulating cell signaling, consistent with the abundance of positively charged residues in the juxta membrane region of many signaling proteins.
A Poisson reduced-rank regression model for association mapping in sequencing data
Authors: Fitzgerald Tiana , Jones Andrew , Engelhardt Barbara E.
Published: June 2022

Single-cell RNA sequencing (scRNA-seq) technologies allow for the study of gene expression in individual cells. Often, it is of interest to understand how transcriptional activity is associated with cell-specific covariates, such as cell type, genotype, or measures of cell health. Traditional approaches for this type of association mapping assume independence between the outcome variables (or genes), and perform a separate regression for each. However, these methods are computationally costly and ignore the substantial correlation structure of gene expression. Furthermore, count-based scRNA-seq data pose challenges for traditional models based on Gaussian assumptions. We aim to resolve these issues by developing a reduced-rank regression model that identifies low-dimensional linear associations between a large number of cell-specific covariates and high-dimensional gene expression readouts. Our probabilistic model uses a Poisson likelihood in order to account for the unique structure of scRNA-seq counts. We demonstrate the performance of our model using simulations, and we apply our model to a scRNA-seq dataset, a spatial gene expression dataset, and a bulk RNA-seq dataset to show its behavior in three distinct analyses. We show that our statistical modeling approach, which is based on reduced-rank regression, captures associations between gene expression and cell- and sample-specific covariates by leveraging low-dimensional representations of transcriptional states.
Greater breadth of vaccine-induced immunity in females than males is mediated by increased antibody diversity in germinal center B cells
Authors: Ursin Rebecca L. , Dhakal Santosh , Liu Hsuan , Jayaraman Sahana , Park Han-Sol , Powell Harrison R. , Sherer Morgan L. , Littlefield Kirsten E. , Fink Ashley L. , Ma Zexu , Mueller Alice L. , Chen Allison P. , Woldetsadik Yishak A. , Gearhart Patricia J. , Larman H. Benjamin , Maul Robert W. , Pekosz Andrew , Klein Sabra L.
Published: June 2022

Inactivated influenza vaccines induce greater antibody responses in females than males among both humans and mice. To test the breadth of protection, we used recombinant mouse-adapted A/California/2009 (maA/Cal/09) H1N1 viruses containing mutations at one (1M), two (2M), or three (3M) antigenic sites, in addition to a virus containing the 1M mutation and a substitution of the Ca2 antigenic site (Sub) with one derived from an H5 hemagglutinin (HA) to challenge mice of both sexes. Following maA/Cal/09 vaccination, females produced greater virus-specific class-switched IgG and IgG2c antibodies against the vaccine and all mutant viruses, and antibodies from females recognized more unique, linear HA epitopes than antibodies from males. While females had greater neutralizing antibody (nAb) titers against the vaccine virus, both sexes showed lower neutralization capacity against mutant viruses. After virus challenge, vaccinated females had lower pulmonary virus titers and reduced morbidity than males against the 1M and 2M viruses, but not the Sub virus. Females generated greater numbers of germinal center (GC) B cells containing superior somatic hypermutation frequencies than vaccinated males. Deletion of activation-induced cytidine deaminase (Aicda) eliminated female-biased immunity and protection against the 2M virus. Harnessing methods to improve GC B cell responses and frequencies of somatic hypermutations, especially in males, should be considered in the development of universal influenza vaccines.

Compared with males, inactivated influenza vaccination of female mice causes greater production of class-switched, somatically-hypermutated antibodies and a more robust germinal center B cell response, leading to more diverse H1N1 antigen recognition and better protection against mutant influenza A viruses.
Ban on wild bird importation accelerated the spread of global viral outbreaks in parrots
Authors: Komorizono Ryo , Aihara Naoyuki , Fujiwara Chinatsu , Kamiie Junichi , Tomonaga Keizo , Makino Akiko
Published: June 2022

Since the isolation of the first parrot bornavirus (PaBV), which causes slow-onset, fatal neurological disease in various parrot species, in the United States in 2008, PaBVs have spread rapidly worldwide; however, the reason remains unknown. In this study, we show that the most dominant lethal genotype, PaBV-4, spread via the global trade of captive birds. Analyses of traded parrot numbers in the Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES) database and PaBV-4 phylodynamics suggested that the ban of wild imported birds in the European Union (EU) in 2007 facilitated the international trade of captive parrots, which resulted in an increase in the effective population size of PaBV-4. This change coincided with a historical PaBV-4 epidemic. These data suggest that due to the low transmission efficiency and long incubation period of PaBV-4, the majority of PaBV-4 transmission occurred in breeding facilities and the increased trade of captive parrots accelerated the global spread of PaBV-4 infection. Our results indicate that interventions for the protection of wild animals and prevention of infectious diseases may conversely cause epidemics of infectious diseases in the global system. Conservation of ecosystems requires not only the establishment of importation restrictions and maintenance of the diversity of wild animals but also the implementation of multifaceted management measures, such as quarantine policies and breeding control in captive animals.
Assessing emergence risk of double-resistant and triple-resistant genotypes of Plasmodium falciparum
Authors: Li Eric Zhewen , Nguyen Tran Dang , Tran Thu Nguyen-Anh , Zupko Robert J , Boni Maciej F
Published: June 2022

Delaying and slowing antimalarial drug resistance evolution is a priority for the World Health Organization and for National Malaria Control Programs in malaria-endemic countries. Until novel therapies become available, the mainstay of antimalarial treatment will continue to be artemisinin combination therapy (ACT), with artemether-lumefantrine, artesunate-amodiaquine, and dihydroartemisinin-piperaquine the three primary therapies deployed worldwide. Deployment of ACTs can be optimized to minimize evolutionary pressure for drug resistance by deploying them as a set of co-equal multiple first-line therapies (MFT) rather than rotating therapies in and out of use. Here, we consider one potential detriment of MFT policies, namely, that the simultaneous deployment of multiple ACTs could drive the evolution of different resistance alleles concurrently and that these resistance alleles could then be brought together by recombination into double-resistant or triple-resistant parasites. Using an individual-based Plasmodium falciparum transmission model, we compare MFT and cycling policies over 20-year periods in malaria transmission settings ranging from 0.1% to 25% Plasmodium falciparum prevalence (PfPR2-10). We define a total risk measure for multi-drug resistance (MDR) by summing the area under the genotype-frequency curves (AUC) of double- and triple-resistant genotypes. When PfPR ≥ 1%, total MDR risk as measured by AUC is 4% to 90% lower under MFT policies than under cycling policies, irrespective of whether resistance is imported or emerges de novo. When PfPR = 0.1%, there is little statistical difference in MDR risk between MFT and cycling.
Aberrant cortical spine dynamics after concussive injury are reversed by integrated stress response inhibition
Authors: Frias Elma S. , Hoseini Mahmood S. , Krukowski Karen , Paladini Maria Serena , Grue Katherine , Ureta Gonzalo , Rienecker Kira D.A. , Walter Peter , Stryker Michael P. , Rosi Susanna
Published: June 2022

Traumatic brain injury (TBI) is a leading cause of long-term neurological disability in the world and the strongest environmental risk factor for the development of dementia. Even mild TBI (resulting from concussive injuries) is associated with a >2-fold increase in the risk of dementia onset. Little is known about the cellular mechanisms responsible for the progression of long lasting cognitive deficits. The integrated stress response (ISR), a phylogenetically conserved pathway involved in the cellular response to stress, is activated after TBI, axsnd inhibition of the ISR — even weeks after injury — can reverse behavioral and cognitive deficits. However, the cellular mechanisms by which ISR inhibition restores cognition are unknown. Here we used longitudinal two-photon imaging in vivo after concussive injury in mice to study dendritic spine dynamics in the parietal cortex, a brain region involved in working memory. Concussive injury profoundly altered spine dynamics measured up to a month after injury. Strikingly, brief pharmacological treatment with the drug-like small-molecule ISR inhibitor ISRIB entirely reversed the structural changes measured in the parietal cortex and the associated working memory deficits. Thus, both neural and cognitive consequences of concussive injury are mediated in part by activation of the ISR and can be corrected by its inhibition. These findings suggest that targeting ISR activation could serve as a promising approach for the clinical treatment of chronic cognitive deficits after TBI.

Significance Statement

After traumatic brain injury, temporary pharmacological inhibition of the integrated stress response (ISR), with a small-molecule inhibitor (ISRIB), rescued long lasting trauma-induced cognitive deficits. Here, we found that ISRIB treatment rapidly and persistently reversed the aberrant changes in cortical spine dynamics in the parietal cortex while rescuing working memory deficits. These data suggests that the link between the ISR and memory function involves, at least in part, changes in neuronal structure. Targeting ISR activation could serve as a promising approach for the clinical treatment of chronic cognitive deficits after brain injuries.