bluuebunny/crossref_metadata_2025 huggingface dataset:
Decision support for managing an invasive pathogen through efficient clean seed systems: Cassava mosaic disease in Southeast Asia
Authors: Andersen Onofre Kelsey F. , Delaquis Erik , Newby Jonathan C. , de Haan Stef , Le Thuy Cu Thi , Minato Nami , Legg James P. , Cuellar Wilmer J. , Alcalá Briseño Ricardo I. , Garrett Karen A.
Published: February 2024

CONTEXT

Effective seed systems must both distribute high-performing varieties efficiently and slow or stop the spread of pathogens and pests. Epidemics increasingly threaten crops around the world, endangering the incomes and livelihoods of smallholder farmers. Responding to these food and economic security challenges requires stakeholders to act quickly and decisively during the early stages of invasions, typically with very limited resources. The recent introduction of cassava mosaic virus into southeast Asia threatens cassava production in the region.

OBJECTIVES

Our goal in this study is to provide a decision-support framework for efficient management of healthy seed systems, applied to cassava mosaic disease. The specific objectives are to (1) evaluate disease risk in disease-free parts of Cambodia, Lao PDR, Thailand, and Vietnam by integrating disease occurrence, climate, topology, and land use, using machine learning; (2) incorporate this predicted environmental risk with seed exchange survey data and whitefly spread in the landscape to model epidemic spread in a network meta-population model; and (3) use scenario analysis to identify candidate regions to be prioritized in seed system management.

RESULTS AND CONCLUSIONS

The analyses allow stakeholders to evaluate strategy options for allocating their resources in the field, guiding the implementation of seed system programs and responses. Fixed rather than adaptive deployment of clean seed produced more favorable outcomes in this model, as did prioritization of a higher number of districts through the deployment of smaller volumes of clean seed.

SIGNIFICANCE

The decision-support framework presented here can be applied widely to seed systems challenged by the dual goals of distributing seed efficiently and reducing disease risk. Data-driven approaches support evidence-based identification of optimized surveillance and mitigation areas in an iterative fashion, providing guidance early in an epidemic, and revising them as data accrue over time.
PRS-Net: Interpretable polygenic risk scores via geometric learning
Authors: Li Han , Zeng Jianyang , Snyder Michael P. , Zhang Sai
Published: February 2024

Polygenic risk score (PRS) serves as a valuable tool for predicting the genetic risk of complex human diseases for individuals, playing a pivotal role in advancing precision medicine. Traditional PRS methods, predominantly following a linear structure, often fall short in capturing the intricate relationships between genotype and phenotype. We present PRS-Net, an interpretable deep learning-based framework designed to effectively model the nonlinearity of biological systems for enhanced disease prediction and biological discovery. PRS-Net begins by deconvoluting the genomewide PRS at the single-gene resolution, and then it encapsulates gene-gene interactions for genetic risk prediction leveraging a graph neural network, thereby enabling the characterization of biological nonlinearity underlying complex diseases. An attentive readout module is specifically introduced into the framework to facilitate model interpretation and biological discovery. Through extensive tests across multiple complex diseases, PRS-Net consistently outperforms baseline PRS methods, showcasing its superior performance on disease prediction. Moreover, the interpretability of PRS-Net has been demonstrated by the identification of genes and gene-gene interactions that significantly influence the risk of Alzheimer’s disease and multiple sclerosis. In summary, PRS-Net provides a potent tool for parallel genetic risk prediction and biological discovery for complex diseases.
pipesnake: Generalized software for the assembly and analysis of phylogenomic datasets from conserved genomic loci
Authors: Brennan Ian G. , Singhal Sonal , Al Bkhetan Ziad
Published: February 2024

Motivation

Phylogenetics has moved into the era of genomics, incorporating enormous volumes of data to study questions at both shallow and deep scales. With this increase in information, phyloge-neticists need new tools and skills to manipulate and analyze these data. To facilitate these tasks and encourage reproducibility, the community is increasingly moving towards automated workflows.

Results

Here we present pipesnake, a phylogenomics pipeline written in Nextflow for the processing, assembly, and phylogenetic estimation of genomic data from short-read sequences. pipesnake is an easy to use and efficient software package designed for this next era in phylogenetics.

Availability

The quick brown fox jumps over the lazy dog.

Contact

example@example.org

Supplementary information

pipesnake is written in Nextflow and freely available fromhttps://github.com/AusARG/pipesnakealongside comprehensive documentation and a wiki/tutorial. The pipeline is containerized and deployable via Docker, Singularity, and Conda making it easy to run on different compute infrastructures.
High and low frequency anterior nucleus of thalamus deep brain stimulation: Impact on memory and mood in five patients with treatment resistant temporal lobe epilepsy
Authors: Marks Victoria S. , Balzekas Irena , Grimm Jessica A. , Richner Thomas J. , Sladky Vladimir , Mivalt Filip , Gregg Nicholas M. , Lundstrom Brian N. , Miller Kai J. , Joseph Boney , Gompel Jamie Van , Brinkmann Benjamin , Croarkin Paul , Alden Eva C. , Kremen Vaclav , Kucewicz Michal , Worrell Gregory A
Published: February 2024

High frequency anterior nucleus of the thalamus deep brain stimulation (ANT DBS) is an established therapy for treatment resistant focal epilepsies. Although high frequency-ANT DBS is well tolerated, patients are rarely seizure free and the efficacy of other DBS parameters and their impact on comorbidities of epilepsy such as depression and memory dysfunction remain unclear. The purpose of this study was to assess the impact of low vs high frequency ANT DBS on verbal memory and self-reported anxiety and depression symptoms. Five patients with treatment resistant temporal lobe epilepsy were implanted with an investigational brain stimulation and sensing device capable of ANT DBS and ambulatory intracranial electroencephalographic (iEEG) monitoring, enabling long-term detection of electrographic seizures. While patients received therapeutic high frequency (100 and 145 Hz continuous and cycling) and low frequency (2 and 7 Hz continuous) stimulation, they completed weekly free recall verbal memory tasks and thrice weekly self-reports of anxiety and depression symptom severity. Mixed effects models were then used to evaluate associations between memory scores, anxiety and depression self-reports, seizure counts, and stimulation frequency. Memory score was significantly associated with stimulation frequency, with higher free recall verbal memory scores during low frequency ANT DBS. Self-reported anxiety and depression symptom severity was not significantly associated with stimulation frequency. These findings suggest the choice of ANT DBS stimulation parameter may impact patients’ cognitive function, independently of its impact on seizure rates.
Acylcarnitines metabolism in depression: association with diagnostic status, depression severity and symptom profile in the NESDA cohort
Authors: Montanari Silvia , Jansen Rick , Schranner Daniela , Kastenmüller Gabi , Arnold Matthias , Janiri Delfina , Sani Gabriele , Bhattacharyya Sudeepa , Dehkordi Siamak Mahmoudian , Dunlop Boadie W , Rush A. John , Penninx Brenda W. H. J. , Kaddurah-Daouk Rima , Milaneschi Yuri
Published: February 2024

Background

Acylcarnitines (ACs) are involved in bioenergetics processes that may play a role in the pathophysiology of depression. Studies linking AC levels to depression are few and provide mixed findings. We examined the association of circulating ACs levels with Major Depressive Disorder (MDD) diagnosis, overall depression severity and specific symptom profiles.

Methods

The sample from the Netherlands Study of Depression and Anxiety included participants with current (n=1035) or remitted (n=739) MDD and healthy controls (n=800). Plasma levels of four ACs (short-chain: acetylcarnitine C2 and propionylcarnitine C3; medium-chain: octanoylcarnitine C8 and decanoylcarnitine C10) were measured. Overall depression severity as well as atypical/energy-related (AES), anhedonic and melancholic symptom profiles were derived from the Inventory of Depressive Symptomatology.

Results

As compared to healthy controls, subjects with current or remitted MDD presented similarly lower mean C2 levels (Cohen’s d=0.2, p≤1e-4). Higher overall depression severity was significantly associated with higher C3 levels (ß=0.06, SE=0.02, p=1.21e-3). No associations were found for C8 and C10. Focusing on symptom profiles, only higher AES scores were linked to lower C2 (ß=-0.05, SE=0.02, p=1.85e-2) and higher C3 (ß=0.08, SE=0.02, p=3.41e-5) levels. Results were confirmed in analyses pooling data with an additional internal replication sample from the same subjects measured at 6-year follow-up (totaling 4195 observations).

Conclusions

Small alterations in levels of short-chain acylcarnitine levels were related to the presence and severity of depression, especially for symptoms reflecting altered energy homeostasis. Cellular metabolic dysfunctions may represent a key pathway in depression pathophysiology potentially accessible through AC metabolism.
Distinct impact modes of polygenic disposition to dyslexia in the adult brain
Authors: Soheili-Nezhad Sourena , Schijven Dick , Mars Rogier B. , Fisher Simon E. , Francks Clyde
Published: February 2024

Dyslexia is a common condition that impacts reading ability. Identifying affected brain networks has been hampered by limited sample sizes of imaging case-control studies. We focused instead on brain structural correlates of genetic disposition to dyslexia in large-scale population data. In over 30,000 adults (UK Biobank), higher polygenic disposition to dyslexia was associated with lower head and brain size, and especially reduced volume and/or altered fiber density in networks involved in motor control, language and vision. However, individual genetic variants disposing to dyslexia often had quite distinct patterns of association with brain structural features. Independent component analysis applied to brain-wide association maps for thousands of dyslexia-disposing genetic variants revealed multiple impact modes on the brain, that corresponded to anatomically distinct areas with their own genomic profiles of association. Polygenic scores for dyslexia-related cognitive and educational measures, as well as attention-deficit/hyperactivity disorder, showed similarities to dyslexia polygenic disposition in terms of brain-wide associations, with microstructure of the internal capsule consistently implicated. In contrast, lower volume of the primary motor cortex was only associated with higher dyslexia polygenic disposition among all traits. These findings robustly reveal heterogeneous neurobiological aspects of dyslexia genetic disposition, and whether they are shared or unique with respect to other genetically correlated traits.
Neuronal alpha-Synuclein Disease Integrated Staging System performance in PPMI, PASADENA, and SPARK baseline cohorts
Authors: Dam Tien , Pagano Gennaro , Brumm Michael C , Gochanour Caroline , Poston Kathleen L , Weintraub Daniel , Chahine Lana M. , Coffey Christopher , Tanner Caroline M. , Kopil Catherine M. , Xiao Yuge , Chowdhury Sohini , Concha-Marambio Luis , DiBiaso Peter , Foroud Tatiana , Frasier Mark , Jennings Danna , Kieburtz Karl , Merchant Kalpana , Mollenhauer Brit , Montine Thomas J , Nudelman Kelly , Seibyl John , Sherer Todd , Singleton Andrew , Stephenson Diane , Stern Matthew , Soto Claudio , Tolosa Eduardo , Siderowf Andrew , Dunn Billy , Simuni Tanya , Marek Kenneth ,   the Parkinson’s Progression Markers Initiative
Published: February 2024

The Neuronal alpha-Synuclein Disease (NSD) biological definition and Integrated Staging System (NSD-ISS) provide a research framework to identify individuals with Lewy body pathology and stage them based on underlying biology and increasing degree of functional impairment. Utilizing data from the PPMI, PASADENA and SPARK studies, we developed and applied biologic and clinical data-informed definitions for the NSD-ISS across the disease continuum. Individuals enrolled as Parkinson’s disease, Prodromal, or Healthy Controls were defined and staged based on biological, clinical, and functional anchors at baseline. Across the three studies 1,741 participants had SAA data and of these 1,030 (59%) were S+ consistent with NSD. Among sporadic PD, 683/736 (93%) were NSD, and the distribution for Stages 2B, 3, and 4 was 25%, 63%, and 9%, respectively. Median (95% CI) time to developing a clinically meaningful outcome was 8.3 (6.2, 10.1), 5.9 (4.1, 6.0), and 2.4 (1.0, 4.0) years for baseline stage 2B, 3, and 4, respectively.

We propose pilot biologic and clinical anchors for NSD-ISS. Our results highlight the baseline heterogeneity of individuals currently defined as early PD. Baseline stage predicts time to progression to clinically meaningful milestones. Further research on validation of the anchors in longitudinal cohorts is necessary.
Outdoor Nighttime Light Exposure (Light Pollution) is Associated with Alzheimer’s Disease
Authors: Voigt Robin M , Ouyang Bichun , Keshavarzian Ali
Published: February 2024

Alzheimer’s disease (AD) prevalence has increased in the last century which can be attributed to increased lifespan, but environment is also important. This study evaluated the relationship between outdoor nighttime light exposure and AD prevalence in the United States. Higher outdoor nighttime light was associated with higher prevalence of AD. While atrial fibrillation, diabetes, hyperlipidemia, hypertension, and stroke were associated more strongly with AD prevalence than nighttime light intensity, nighttime light was more strongly associated with AD prevalence than alcohol abuse, chronic kidney disease, depression, heart failure, and obesity. Startlingly, nighttime light exposure more strongly associated with AD prevalence in those under the age of 65 than any other disease factor examined. These data indicate a need to investigate how nighttime light exposure influences AD pathogenesis.

One-Sentence Summary

There is a positive association between Alzheimer’s disease prevalence and average outdoor nighttime light intensity in the United States.
Immune escape and replicative capacity of Omicron lineages BA.1, BA.2, BA.5.1, BQ.1, XBB.1.5, EG.5.1 and JN.1.1
Authors: Bekliz Meriem , Essaidi-Laziosi Manel , Adea Kenneth , Hosszu-Fellous Krisztina , Alvarez Catia , Bellon Mathilde , Sattonnet-Roche Pascale , Puhach Olha , Dbeissi Damien , Zaballa Maria Eugenia , Stringhini Silvia , Guessous Idris , Vetter Pauline , Eberhardt Christiane Sigrid , Kaiser Laurent , Eckerle Isabella
Published: February 2024

In the 5th year after the emergence of SARS-CoV-2, Omicron lineages continue to evolve and cause infections. Here, we used eight authentic SARS-CoV-2 isolates to assess their capacity to escape immunity of different exposure histories and their replicative capacity in polarized human airway epithelial cells (HAE) derived from the nasal and bronchial epithelium. Using live-virus neutralization assays of 108 human sera or plasma of different immunological backgrounds, progressive immune escape was observed from B.1 (ancestral virus) to EG.5.1, but no significant difference between EG.5.1 and JN.1.1. Vaccinated individuals without natural infection and individuals with a single infection, but no vaccination showed markedly reduced or completely lost neutralization against the latest variants, while in those with hybrid immunity almost all sera showed some neutralization capacity. Furthermore, although absolute titers differed between groups, the pattern of immune escape between the variants remains comparable with strongest loss of neutralization observed for the latest variants. In vitro studies with HAE at 33 degree C and 37 degree C showed some, but minor differences in virus replication and innate immune responses upon infection. Notably, infection with XBB.1.5, EG.5.1 and JN.1.1 showed slightly increased viral growth in nasal HAE at 33 degree C. Altogether, these data underscore increasing immune escape across heterogeneous immunological backgrounds with gradually increasing antibody escape of evolving Omicron lineages until variant EG.5.1, but not any further for the latest dominant lineage JN.1.1. They also suggest that viral dynamics within Omicron lineages are driven by a combination of immune evasion and increase in viral replication.
Distinct hippocampal mechanisms support concept formation and updating
Authors: Mack Michael L. , Love Bradley C. , Preston Alison R.
Published: February 2024

Learning systems must constantly decide whether to create new representations or update existing ones. For example, a child learning that a bat is a mammal and not a bird would be best served by creating a new representation, whereas updating may be best when encountering a second similar bat. Characterizing the neural dynamics that underlie these complementary memory operations requires identifying the exact moments when each operation occurs. We address this challenge by interrogating fMRI brain activation with a computational learning model that predicts trial-by-trial when memories are created versus updated. We found distinct neural engagement in anterior hippocampus and ventral striatum for model-predicted memory create and update events during early learning. Notably, the degree of this effect in hippocampus, but not ventral striatum, significantly related to learning outcome. Hippocampus additionally showed distinct patterns of functional coactivation with ventromedial prefrontal cortex and angular gyrus during memory creation and premotor cortex during memory updating. These findings suggest that complementary memory functions, as formalized in computational learning models, underlie the rapid formation of novel conceptual knowledge, with the hippocampus and its interactions with frontoparietal circuits playing a crucial role in successful learning.

Significance statement

How do we reconcile new experiences with existing knowledge? Prominent theories suggest that novel information is either captured by creating new memories or leveraged to update existing memories, yet empirical support of how these distinct memory operations unfold during learning is limited. Here, we combine computational modeling of human learning behaviour with functional neuroimaging to identify moments of memory formation and updating and characterize their neural signatures. We find that both hippocampus and ventral striatum are distinctly engaged when memories are created versus updated; however, it is only hippocampus activation that is associated with learning outcomes. Our findings motivate a key theoretical revision that positions hippocampus is a key player in building organized memories from the earliest moments of learning.
Hippocampal area CA2 activity supports social investigation following an acute social stress
Authors: Radzicki Daniel , McCann Katharine E. , Alexander Georgia M. , Dudek Serena M.
Published: February 2024

Neuronal activity in the hippocampus is critical for many types of memory acquisition and retrieval and influences an animal’s response to stress. Moreover, the molecularly distinct principal neurons of hippocampal area CA2 are required for social recognition memory and aggression in mice. To interrogate the effects of stress on CA2-dependent behaviors, we chemogenetically manipulated neuronal activityin vivoduring an acute, socially derived stressor and tested whether memory for the defeat was influenced. One day after an acute social defeat (aSD), defeated mice spent significantly less time investigating another mouse when compared to non-defeated control mice. We found that this avoidant phenotype persisted for up to one month following a single defeat encounter. When CA2 pyramidal neuron activity was inhibited with Gi-DREADD receptors during the defeat, subject mice exhibited a significantly higher amount of social avoidance one day later when compared to defeated littermates not expressing DREADDs. Moreover, CA2 inhibition during defeat caused a reduction in submissive defense behaviors in response to aggression.In vitroelectrophysiology and tracing experiments revealed a circuit wherein CA2 neurons connect to caudal CA1 projection neurons that, in turn, project to corticolimbic regions including the anterior cingulate cortex. Finally, socially avoidant, defeated mice exhibited significant reductions in cFos expression in caudal hippocampal and limbic brain areas during a social investigation task 24 hours after aSD. Taken together, these results indicate that CA2 neuronal activity is required to support behavioral resilience following an acute social stressor and that submissive defensive behavior during the defeat (vs. fleeing) is a predictor of future resilience to social stress. Furthermore, CA2 preferentially targets a population of caudal CA1 projection neurons that contact cortical brain regions where activity is modulated by an acute social stressor.
Resilience and Charge-Dependent Fibrillation of Functional Amyloids: Interactions ofPseudomonasBiofilm-Associated FapB and FapC
Authors: Golan Nimrod , Parizat Amit , Tabachnikov Orly , Barnea Eilon , Olsen William P. , Otzen Daniel E. , Landau Meytal
Published: February 2024

FapC and FapB are biofilm-associated amyloids involved in the virulence ofPseudomonasand other bacteria. We herein demonstrate their exceptional thermal and chemical resilience, suggesting that biofilm structures might withstand standard sterilization, thereby contributing to the persistence ofP. aeruginosainfections. Our findings also underscore the impact of environmental factors on Fap proteins, suggesting that orthologs in differentPseudomonasstrains adapt to specific environments and roles. Challenging previous assumptions about a simple nucleation role for FapB in promoting FapC aggregation, the study shows a significant influence of FapC on FapB aggregation. The interaction between FapB and FapC is intricate: FapB stabilizes FapC fibrils, while FapC slows down FapB fibrillation but can still serve as a cross-seeding template. This complex interplay is key to understanding their roles in bacterial biofilms. Furthermore, the study highlights distinct differences between Fap andE. coli’s curli CsgA amyloid, where CsgB assumes a simple unidirectional role in nucleating CsgA fibrillation, emphasizing the importance of a comprehensive understanding of various amyloid systems. This knowledge is vital for developing effective intervention strategies against bacterial infections and leveraging the unique properties of these amyloids in technological applications such as novel bio-nanomaterials or protective coatings.
Mapping protein-metabolite interactions inE. coliby integrating chromatographic techniques and co-fractionation mass spectrometry
Authors: Wagner Mateusz , Kang Jieun , Mercado Catherine , Thirumalaikumar Venkatesh P. , Gorka Michal , Zillmer Hanne , Guo Jingzhe , Minen Romina I. , Plecki Caroline F. , Dehesh Katayoon , Schroeder Frank C. , Walther Dirk , Skirycz Aleksandra
Published: February 2024

In our pursuit of understanding the protein-metabolite interactome, we introduced PROMIS, a co-fractionation mass spectrometry (CF-MS) technique focusing on biosynthetic and regulatory processes. However, the challenge lies in distinguishing true interactors from coincidental co-elution when a metabolite co-fractionates with numerous proteins. To address this, we integrated two chromatographic techniques— size exclusion and ion exchange—to enhance the mapping of protein-metabolite interactions (PMIs) inEscherichia coli. This integration aims to refine the PMI network by considering size and charge characteristics, resulting in 994 interactions involving 51 metabolites and 465 proteins. The PMI network is enriched for known and predicted interactions validating our approach’s efficacy. Furthermore, the analysis of protein targets for different metabolites revealed novel functional insights, such as the connection between proteinogenic dipeptides and fatty acid biosynthesis. Notably, we uncovered an inhibitory interaction between the riboflavin degradation product lumichrome and orotate phosphoribosyltransferase (PyrE), a key enzyme inde novopyrimidine synthesis. Lumichrome supplementation mimicked the biofilm formation inhibition observed in aΔpyrEmutant strain, suggesting lumichrome role in integrating pyrimidine and riboflavin metabolism with quorum sensing and biofilm formation. In summary, our integrated chromatographic approach significantly advances PMI mapping, offering novel insights into functional associations and potential regulatory mechanisms inE. coli.
Covering the bases: population genomic structure ofLemna minorand the cryptic speciesL. japonicain Switzerland
Authors: Schmid Marc W. , Moradi Aboubakr , Leigh Deborah M. , Schuman Meredith C. , van Moorsel Sofia J.
Published: February 2024

Duckweeds, including the common duckweedLemna minor, are increasingly used to test eco-evolutionary theories. Yet, despite its popularity and near-global distribution, the understanding of its population structure (and genetic variation therein) is still limited. It is essential that this is resolved, because of the impact genetic diversity has on experimental responses and scientific understanding.

Through whole-genome sequencing, we assessed the genetic diversity and population genomic structure of 23 naturalLemnaspp. populations from their natural range in Switzerland. We used two distinct analytical approaches, a reference-free kmer approach and the classical reference-based one. Two genetic clusters were identified across the described species distribution ofL. minor, surprisingly corresponding to species-level divisions. The first cluster contained the targetedL. minorindividuals and the second contained individuals from a cryptic species:Lemna japonica. Within theL. minorcluster, we identified a well-defined population structure with little intra-population genetic diversity (i.e. within ponds) but high inter-population diversity (i.e. between ponds). InL. japonica, the population structure was significantly weaker and genetic variation between a subset of populations was as low as within populations.

This study revealed thatLemna japonicais more widespread than previously thought. Our findings signify that thorough genotype-to-phenotype analyses are needed in duckweed experimental ecology and evolution.
Neural dynamics of shifting attention between perception and working-memory contents
Authors: Gresch Daniela , Boettcher Sage E.P. , Gohil Chetan , van Ede Freek , Nobre Anna C.
Published: February 2024

In everyday tasks, our focus of attention shifts seamlessly between contents in the sensory environment and internal memory representations. Yet, research has mainly considered external and internal attention in isolation. We used magnetoencephalography to compare the neural dynamics of shifting attention to visual contents within vs. between the external and internal domains. Participants performed a combined perception and working-memory task in which two sequential cues guided attention to upcoming (external) or memorised (internal) sensory information. Critically, the second cue could redirect attention to visual content within the same or alternative domain as the first cue. Multivariate decoding unveiled distinct patterns of human brain activity when shifting attention within vs. between domains. Brain activity distinguishing within- from between-domain shifts was broadly distributed and highly dynamic. Intriguingly, crossing domains did not invoke an additional stage prior to shifting. Alpha lateralisation, a canonical marker of shifting spatial attention, showed no delay when cues redirected attention to the same vs. alternative domain. Instead, evidence suggested that neural states associated with a given domain linger and influence subsequent shifts of attention within vs. between domains. Our findings provide the first insights into the neural dynamics that govern attentional shifts between perception and working memory.

Significance Statement

During almost every natural behaviour, our attention regularly shifts between sensory and memory contents. Although the systems and mechanisms of attentional control and modulation within the external and internal domains have been heavily studied in isolation, how attention crosses between these domains remains uncharted territory. Here, we provide the first study to investigate brain dynamics associated with shifting attention between contents in the sensory environment and memory representations. Using a novel experimental design, we isolated the patterns and dynamics of brain activity associated with shifting attention within vs. between the external and internal domains. Our findings reveal early, dynamic, and distributed patterns of activity that distinguish within- from between-domain shifts, offering fascinating initial insights, and opening new questions for investigation.
Toxicity of the model protein 3×GFP arises from degradation overload, not from aggregate formation
Authors: Namba Shotaro , Moriya Hisao
Published: February 2024

While protein aggregation can cause cytotoxicity, it also forms to mitigate cytotoxicity from misfolded proteins, though the nature of these contrasting aggregates remains unclear. We previously found that overproduction (op) of a three green fluorescent protein linked protein (3×GFP) in yeast cells induces giant aggregates, and is detrimental to growth. Here, we investigated the mechanism of growth inhibition by 3×GFP-op using non-aggregative 3×MOX-op as a control. The 3×GFP aggregates were induced by misfolding, and 3×GFP-op had higher cytotoxicity than 3×MOX-op because it perturbs the ubiquitin-proteasome system. Static aggregates formed by 3×GFP-op dynamically trapped Hsp70, causing the heat shock response. Systematic analysis of mutants deficient in the protein quality control suggested that 3×GFP-op did not cause critical Hsp70 depletion and that the formation of aggregates functioned in the direction of mitigating toxicity. Artificial trapping of essential cell cycle regulators into 3×GFP aggregates caused abnormalities in the cell cycle. In conclusion, the formation of the giant 3×GFP aggregates itself is not cytotoxic, as it does not entrap and deplete essential proteins. Rather, it is productive, inducing the heat shock response while preventing an overload to the degradation system.
Genome sequence of the ornamental plantDigitalis purpureareveals the molecular basis of flower color and morphology variation
Authors: Horz Jakob Maximilian , Wolff Katharina , Friedhoff Ronja , Pucker Boas
Published: February 2024

Digitalis purpurea(foxglove) is a widely distributed ornamental plant and the producer of the biomedical compound digoxin. Here, we present a long read sequencing-based genome sequence of a red floweringD. purpureaplant and a corresponding prediction of gene models. The high assembly continuity is indicated by the N50 of 4.3 Mbp and the completeness is supported by discovery of about 96% complete BUSCO genes. This genomic resource paves the way for an in-depth investigation of the flower pigmentation ofD. purpurea. Structural genes of the anthocyanin biosynthesis and the corresponding transcriptional regulators were identified. The comparison of red and white flowering plants revealed a large insertion in the anthocyanidin synthase gene in white flowering plants that most likely renders this gene non-functional and could explain the loss of anthocyanin pigmentation. In addition, the anthocyanin biosynthesis activatorMYB5shows a 18 bp deletion in white flowering plants that results in the loss of 6 amino acids in the protein. Furthermore, we found a large insertion in theDpTFL1/CENgene to be responsible for the development of large terminal flowers.
Predicting fitness related traits using gene expression and machine learning
Authors: Henry Georgia A. , Stinchcombe John R.
Published: February 2024

Evolution by natural selection occurs at its most basic through the change in frequencies of alleles; connecting those genomic targets to phenotypic selection is an important goal for evolutionary biology in the genomics era. The relative abundance of gene products expressed in a tissue can be considered a phenotype intermediate to the genes and genomic regulatory elements themselves, and more traditionally measured macroscopic phenotypic traits such as flowering time, size, or growth. The high-dimensionality, low sample size nature of transcriptomic sequence data is a double-edged sword, however, as it provides abundant information but makes traditional statistics difficult. Machine learning has many features which handle high-dimensional data well and is thus useful in genetic sequence applications. Here we examined the association of fitness-components with gene expression data inIpomoea hederacea(Ivyleaf Morning Glory) grown under field conditions. We combine the results of two different machine learning approaches and find evidence that expression of photosynthesis-related genes is likely under selection. We also find that genes related to stress and light response were overall important in predicting fitness. With this study we demonstrate the utility of machine learning models for smaller samples, and their potential application for understanding natural selection.
Hosts Manipulate Lifestyle Switch and Pathogenicity Heterogeneity of Opportunistic Pathogens in the Single-cell Resolution
Authors: Wang Ziguang , Li Shuai , Zhang Sheng , Zhang Tianyu , Wu Yujie , Liu Anqi , Wang Kui , Ji Xiaowen , Cao Haiqun , Zhang Yinglao , Tan Eng-King , Wang Yongcheng , Wang Yirong , Liu Wei
Published: February 2024

Host-microbe interactions are virtually bidirectional, but how the host affects their microbiome is poorly understood. Here, we report that the host is a critical modulator to regulate the lifestyle switch and pathogenicity heterogeneity of the opportunistic pathogensSerratia marcescensutilizing theDrosophilaand bacterium model system. First, we find thatDrosophilalarvae efficiently outcompeteS. marcescensand typically drive a bacterial switch from pathogenicity to commensalism toward the fly. Furthermore,Drosophilalarvae reshape the transcriptomic and metabolic profiles ofS. marcescenscharacterized by a lifestyle switch. More important, the host alters pathogenicity and heterogeneity ofS. marcescensin the single-cell resolution. Finally, we find that larvae-derived AMPs are required to recapitulate the response ofS. marcescensto larvae. Altogether, our findings provide an insight into the pivotal roles of the host in harnessing the life history and heterogeneity of symbiotic bacterial cells, advancing knowledge of the reciprocal relationships between the host and pathogen.
Muller’s Ratchet in Action: The Erosion of Sexual Reproduction Genes in Domesticated Cassava (Manihot esculenta)
Authors: Long Evan M , Stitzer Michelle , Monier Brandon , Schulz Aimee J , Romay M. Cinta , Robbins Kelly R , Buckler Edward S.
Published: February 2024

Centuries of clonal propagation in cassava (Manihot esculenta) have engaged Muller’s Ratchet, leading to the accumulation of deleterious mutations due to the absence of sexual recombination. This has resulted in both inbreeding depression affecting yield and a significant decrease in reproductive performance, creating hurdles for contemporary breeding programs. Cassava is a member of the Euphorbiaceae family, including notable species such as rubber tree (Hevea brasiliensis) and poinsettia (Euphorbia pulcherrima). Expanding upon preliminary draft genomes, we annotated 7 long-read genome assemblies and aligned a total of 52 genomes, to analyze selection across the genome and the phylogeny. Through this comparative genomic approach, we identified 48 genes under relaxed selection in cassava. Notably, we discovered an overrepresentation of floral expressed genes, especially focused at six pollen-related genes. Our results indicate that domestication and a transition to clonal propagation has reduced selection pressures on sexually reproductive functions in cassava leading to an accumulation of mutations in pollen-related genes. This relaxed selection and the genome-wide deleterious mutations responsible for inbreeding depression are potential targets for improving cassava breeding, where the generation of new varieties relies on recombining favorable alleles through sexual reproduction.
Transcriptional Regulators with Broad Expression in the Zebrafish Spinal Cord
Authors: England Samantha J. , Campbell Paul C. , Banerjee Santanu , Bates Richard L. , Grieb Ginny , Fancher William F. , Lewis Katharine E.
Published: February 2024

Background

The spinal cord is a crucial part of the vertebrate CNS, controlling movements and receiving and processing sensory information from the trunk and limbs. However, there is much we do not know about how this essential organ develops. Here, we describe expression of 21 transcription factors and one transcriptional regulator in zebrafish spinal cord.

Results

We analyzed the expression ofaurkb, foxb1a, foxb1b, her8a, homeza, ivns1abpb, mybl2b, myt1a, nr2f1b, onecut1,sall1a, sall3a, sall3b, sall4, sox2,sox19b, sp8b, tsc22d1, wdhd1,zfhx3b, znf804a, andznf1032in wild-type andMIB E3 ubiquitin protein ligase 1zebrafish embryos. While all of these genes are broadly expressed in spinal cord, they have distinct expression patterns from one another. Some are predominantly expressed in progenitor domains, and others in subsets of post-mitotic cells. Given the conservation of spinal cord development, and the transcription factors and transcriptional regulators that orchestrate it, we expect that these genes will have similar spinal cord expression patterns in other vertebrates, including mammals and humans.

Conclusions

Our data identify 22 different transcriptional regulators that are strong candidates for playing different roles in spinal cord development. For several of these genes, this is the first published description of their spinal cord expression.
Isolation of small extracellular vesicles from regenerating muscle tissue using Tangential Flow Filtration and Size Exclusion Chromatography
Authors: Gurriaran-Rodriguez Uxia , Rudnicki Michael A.
Published: February 2024

We have recently made the strikingly discovery that upon a muscle injury, Wnt7a is upregulated and secreted from new regenerating myofibers on the surface of exosomes to elicit its myogenerative response distally. Despite recent advances in extracellular vesicle (EVs) isolation from diverse tissues, there is still a lack of specific methodology to purify EVs from muscle tissue. To eliminate contamination with non-EV secreted proteins and cytoplasmic fragments, which are typically found when using classical methodology, such as ultracentrifugation, we adapted a protocol combining Tangential Flow Filtration (TFF) and Size Exclusion Chromatography (SEC). We found that this approach allows simultaneous purification of Wnt7a, bound to EVs (retentate fraction) and free non-EV Wnt7a (permeate fraction). Here we described this optimized protocol designed to specifically isolate EVs from hind limb muscle explants, without cross-contamination with other sources of non-EV bounded proteins. The first step of the protocol is to remove large EVs with sequential centrifugation. Extracellular vesicles are then concentrated and washed in exchange buffer by TFF. Lastly, SEC is performed to remove any soluble protein traces remaining after TFF. Overall, this procedure can be used to isolate EVs from conditioned media or biofluid that contains EVs derived from any cell type or tissue, improving reproducibility, efficiency, and purity of EVs preparations. Our purification protocol results in high purity EVs that maintain structural integrity and thus fully compatible within vitroandin vivobioactivity and analytic assays.
Emergence of saliva protein genes in the secretory calcium-binding phosphoprotein (SCPP) locus and accelerated evolution in primates
Authors: Pajic Petar , Landau Luane , Gokcumen Omer , Ruhl Stefan
Published: February 2024

Genes within the secretory calcium-binding phosphoprotein (SCPP) family evolved in conjunction with major evolutionary milestones: the formation of a calcified skeleton in vertebrates, the emergence of tooth enamel in fish, and the introduction of lactation in mammals. The SCPP gene family also contains genes expressed primarily and abundantly in human saliva. Here, we explored the evolution of the saliva-related SCPP genes by harnessing currently available genomic and transcriptomic resources. Our findings provide insights into the expansion and diversification of SCPP genes, notably identifying previously undocumented convergent gene duplications. In primate genomes, we found additional duplication and diversification events that affected genes coding for proteins secreted in saliva. These saliva-related SCPP genes exhibit signatures of positive selection in the primate lineage while the other genes in the same locus remain conserved. We found that regulatory shifts and gene turnover events facilitated the accelerated gain of salivary expression. Collectively, our results position the SCPP gene family as a hotbed of evolutionary innovation, suggesting the potential role of dietary and pathogenic pressures in the adaptive diversification of the saliva composition in primates, including humans.
The ELF3-BBX24/BBX25-PIF4 module controls thermosensory growth in Arabidopsis
Authors: Malakar Bidhan Chandra , Singh Shivani , Garhwal Vikas , Chandramohan Rajanesh , Upadhyaya Gouranga , Gangappa Sreeramaiah N.
Published: February 2024

Temperature serves as a crucial environmental cue governing the growth and adaptation of plants in their natural habitat. PHYTOCHROME INTERACTING FACTOR 4 (PIF4) is a central regulator that promotes thermomorphogenesis in Arabidopsis. Understanding its precise regulation is critical for optimal thermomorphogenic growth. Here, we identified two BBX proteins, BBX24 and BBX25, as novel components of the PIF4-mediated thermosensory pathway and act to promote warm temperature-mediated growth. Thebbx24andbbx25single and double mutants showed moderate to strong temperature-insensitive hypocotyl and cotyledon growth. Warm temperature inducesBBX24andBBX25mRNA expression and protein accumulation. Genetic and biochemical analysis revealed that BBX24/BBX25 promotes PIF4-mediated thermosensory growth by counteracting a key component of the evening complex, ELF3. While ELF3 inhibitsBBX24/BBX25gene expression at low ambient temperatures in the evening, warm temperature-mediated inhibition of ELF3 activity results in enhanced BBX24/BBX25 activity. Moreover, BBX24/25 inhibit ELF3 function through direct physical interaction and likely relieves repression on PIF4, enhancing its activity and thermomorphogenesis. Together, this study unravels ELF3-BBX24/BBX25-PIF4 as a key regulatory module that controls growth and development under varying temperature cues.
Apicoplast-derived isoprenoids are essential for biosynthesis of GPI protein anchors, and consequently for egress and invasion inPlasmodium falciparum
Authors: Bulloch Michaela S. , Huynh Long K. , Kennedy Kit , Ralton Julie E. , McConville Malcolm J. , Ralph Stuart
Published: February 2024

Glycophosphatidylinositol (GPI) anchors are the predominant glycoconjugate inPlasmodiumparasites, enabling modified proteins to associate with biological membranes. GPI biosynthesis commences with donation of a mannose residue held by dolichol-phosphate at the endoplasmic reticulum membrane. InPlasmodiumdolichols are derived from isoprenoid precursors synthesised in thePlasmodiumapicoplast, a relict plastid organelle of prokaryotic origin. We found that treatment ofPlasmodiumparasites with apicoplast inhibitors decreases the abundance of isoprenoid and GPI intermediates resulting in GPI-anchored proteins becoming untethered from their normal membrane association. Even when other isoprenoids were chemically rescued, GPI depletion led to an arrest in schizont stage parasites, which had defects segmentation and egress. In those daughter parasites (merozoites) that did form, proteins that would normally be GPI-anchored were mislocalised, and when these merozoites were artificially released they were able to attach to but not invade new red blood cells. Our data provides further evidence for the importance of GPI biosynthesis during the asexual cycle ofP. falciparum, and indicates that GPI biosynthesis, and by extension egress and invasion, is dependent on isoprenoids synthesised in the apicoplast.

Author summary

The plastid apicoplast organelle of the malaria parasitePlasmodium falciparumhas long been recognised as a drug target, however the downstream metabolic pathways have not been fully elucidated. In this study we inhibited apicoplast function in blood-stageP. falciparumand following the depletion of essential apicoplast-derived isoprenoids, we observed that these parasites exhaust their supplies of the polyisoprenoid alcohol dolichol. Dolichols form important components of biological membranes and are also required for the synthesis of the major parasite glycoconjugate, glycophosphatidylinositol (GPI) anchors. Concurrent with a reduction in dolichol levels, proteins normally conjugated to GPIs became mislocalised. Severe parasite impairments followed with incomplete membrane segmentation of their daughter merozoites, which could subsequently neither egress nor reinvade host red blood cells. Our data implicates dolichol as an essential parasite metabolite, dependent on normal apicoplast function, and reveals novel roles for GPI anchored proteins. The widespread phenotype following disrupted dolichol synthesis supports aspects of GPI biosynthesis as potential future drug targets.
Bioengineering secreted proteases converts divergent Rcr3 orthologs and paralogs into extracellular immune co-receptors
Authors: Kourelis Jiorgos , Schuster Mariana , Demir Fatih , Mattinson Oliver , Krauter Sonja , Kahlon Parvinderdeep S. , O’Grady Ruby , Royston Samantha , Bravo-Cazar Ana Lucía , Mooney Brian C. , Huesgen Pitter F. , Kamoun Sophien , van der Hoorn Renier A. L.
Published: February 2024

Secreted immune proteases Rcr3 and Pip1 of tomato are both inhibited by Avr2 from the fungal plant pathogenCladosporium fulvumbut only Rcr3 act as a decoy co-receptor that detects Avr2 in the presence of the Cf-2 immune receptor. Here, we identified crucial residues from tomato Rcr3 required for Cf-2-mediated signalling and bioengineered various proteases to trigger Avr2/Cf-2 dependent immunity. Despite substantial divergences in Rcr3 orthologs from eggplant and tobacco, only minimal alterations were sufficient to trigger Avr2/Cf-2-triggered immune signalling. Tomato Pip1, by contrast, was bioengineered with 16 Rcr3-specific residues to initiate Avr2/Cf-2-triggered immune signalling. These residues cluster on one side next to the substrate binding groove, indicating a potential Cf-2 interaction site. Our findings also revealed that Rcr3 and Pip1 have distinct substrate preferences determined by two variant residues and that both are suboptimal for binding Avr2. This study advances our understanding of Avr2 perception and opens avenues to bioengineer proteases to broaden pathogen recognition in other crops.