bluuebunny/crossref_metadata_2025_split huggingface dataset:
Diaphorin, a polyketide produced by a bacterial symbiont of the Asian citrus psyllid, inhibits the growth of Bacillus subtilis but promotes the growth of Escherichia coli
Authors: Tanabe Nozomu , Takasu Rena , Hirose Yuu , Kamei Yasuhiro , Kondo Maki , Nakabachi Atsushi 
Published: May 2022

AbstractDiaphorin is a polyketide produced by Candidatus Profftella armatura (Gammaproteobacteria: Burkholderiales), an obligate symbiont of a notorious agricultural pest, the Asian citrus psyllid Diaphorina citri (Hemiptera: Psyllidae). Diaphorin belongs to the pederin family of bioactive agents found in various host-symbiont systems, including beetles, lichens, and sponges, harboring phylogenetically diverse bacterial producers. Previous studies showed that diaphorin has inhibitory effects on various eukaryotes, including the natural enemies of D. citri. However, little is known about its effects on prokaryotic organisms. To address this issue, the present study assessed the biological activities of diaphorin on two model prokaryotes, Escherichia coli (Gammaproteobacteria: Enterobacterales) and Bacillus subtilis (Firmicutes: Bacilli). The analyses revealed that diaphorin inhibits the growth of B. subtilis but moderately promotes the growth of E. coli. This finding implies that diaphorin functions as a defensive agent of the holobiont (host + symbionts) against some bacterial lineages but is beneficial for others, which potentially include obligate symbionts of D. citri.ImportanceCertain secondary metabolites, including antibiotics, evolve to mediate interactions among organisms. These molecules have distinct spectra for microorganisms and are often more effective against Gram-positive bacteria than Gram-negative ones. However, it is rare that a single molecule has completely opposite activities on distinct bacterial lineages. The present study revealed that a secondary metabolite synthesized by an organelle-like bacterial symbiont of psyllids inhibits the growth of Gram-positive Bacillus subtilis but promotes the growth of Gram-negative Escherichia coli. This finding not only provides insights into the evolution of symbiosis between animal hosts and bacteria but may also potentially be exploited to promote the effectiveness of industrial material production by microorganisms.
Neglecting normalization impact in semi-synthetic RNA-seq data simulation generates artificial false positives
Authors: Hejblum Boris P , Ba Kalidou , Thiébaut Rodolphe , Agniel Denis 
Published: May 2022

AbstractBy reproducing differential expression analysis simulation results presented by Li et al, we identified a caveat in the data generation process. Data not truly generated under the null hypothesis led to incorrect comparisons of benchmark methods. We provide corrected simulation results that demonstrate the good performance of dearseq and argue against the superiority of the Wilcoxon rank-sum test as suggested by Li et al. Please see related Research article with DOI 10.1186/s13059-022-02648-4.
Inferring future changes in gene flow under climate change in riverscapes
Authors: Nakajima Souta , Suzuki Hiroaki , Nakatsugawa Makoto , Matsuo Ayumi , Hirota Shun K. , Suyama Yoshihisa , Nakamura Futoshi 
Published: May 2022

AbstractGlobal climate change poses a significant threat to the habitat connectivity of cold-water-adapted organisms, leading to species extinctions. Because gene flow is itself a functional connectivity among wild populations, if gene flow is modeled by landscape variables, changes in population connectivity could be predicted. In this study, using a model-based riverscape genetics technique and a hydrological model to estimate water temperature, we inferred the determinants of and future changes in gene flow of the fluvial sculpin Cottus nozawae in the upstream section of the Sorachi River, Hokkaido, Japan. As a result of model selection, stream order, water temperature, slope, and distance were detected as landscape variables affecting the strength of gene flow in each stream section. In particular, the trend of greater gene flow in sections with higher stream order and lower temperature fluctuations or summer water temperatures was pronounced. The map from the model showed that gene flow is overall prevented in small tributaries in the southern area, where spring-fed environments are less prevalent. Estimating future changes in gene flow using future water temperature predictions, genetic connectivity was predicted to decrease dramatically until the end of the 21st century under IPCC representative concentration pathway scenario 8.5 (RCP8.5).
Quantifying exposure of bumblebee (Bombus spp.) queens to pesticide residues when hibernating in agricultural soils
Authors: Rondeau Sabrina , Baert Nicolas , McArt Scott , Raine Nigel E. 
Published: May 2022

AbstractExposure to pesticides is a major threat to bumblebee (Bombus spp.) health. In temperate regions, queens of many bumblebee species hibernate underground for several months, putting them at potentially high risk of exposure to soil contaminants. The extent to which bumblebees are exposed to residues in agricultural soils during hibernation is currently unknown, which limits our understanding of the full pesticide exposome for bumblebees throughout their lifecycle. To generate field exposure estimates for overwintering bumblebee queens to pesticide residues, we sampled soils from areas corresponding to suitable likely hibernation sites at six apple orchards and 13 diversified farms throughout Southern Ontario (Canada) in fall 2019-2020. Detectable levels of pesticides were found in 65 of 66 soil samples analysed for multi-pesticide residues (UPLC-MS/MS). A total of 53 active ingredients (AIs) were detected in soils, including 27 fungicides, 13 insecticides, and 13 herbicides. Overall, the frequency of detection, residue levels (median = 37.8 vs. 2.2 ng/g), and number of pesticides per sample (mean = 12.3 vs. 4.3 AIs) were highest for orchard soils compared to soils from diversified farms. Ninety-one percent of samples contained multiple residues, including mixtures of insecticides and fungicides that might lead to synergistic effects. Up to 29 different AIs were detected per soil sample. Our results suggest that when hibernating in agricultural areas, bumblebee queens are very likely to be exposed to a wide range of pesticide residues in soil. Our study indicates the importance of empirically testing the potential effects of pesticide residues in soils for hibernating bumblebee queens, using field exposure data such as those generated here. The differences in exposure that we detected between cropping systems can also be used to better inform regulations that govern the use of agricultural pesticides, notably in apple orchards.
The autism-associated gene SYNGAP1 regulates human cortical neurogenesis
Authors: Birtele Marcella , Del Dosso Ashley , Xu Tiantian , Nguyen Tuan , Wilkinson Brent , Hosseini Negar , Nguyen Sarah , Urenda Jean-Paul , Knight Gavin , Rojas Camilo , Flores Ilse , Atamian Alexander , Moore Roger , Sharma Ritin , Pirrotte Patrick , Ashton Randolph S. , Huang Eric J. , Rumbaugh Gavin , Coba Marcelo P. , Quadrato Giorgia 
Published: May 2022

AbstractAutism spectrum disorder (ASD) is a genetically heterogeneous disorder linked with rare, inherited andde novomutations occurring in two main functional gene categories: gene expression regulation and synaptic function1. Accumulating evidence points to dysregulation in cortical neurogenesis as a convergent mechanism in ASD pathophysiology2-8. While asynchronous development has been identified as a shared feature among ASD-risk genes in the category of gene expression regulation, it remains unknown whether this phenotype is also associated with ASD-risk genes in the synaptic function category. Here we show for the first time the expression of the synaptic Ras GTP-ase activating protein 1 (SYNGAP1), one of the top ASD risk genes9, in human cortical progenitors (hCPs). Interestingly, we found that multiple components of the postsynaptic density (PSD) of excitatory synapses, of which SYNGAP1 is one of the most abundant components10,11, are enriched in the proteome of hCPs. Specifically, we discover that SYNGAP1 is expressed within the apical domain of human radial glia cells (hRGCs) where it lines the wall of the developing cortical ventricular zone colocalizing with the tight junction-associated protein and MAGUK family member TJP1. In a cortical organoid model of SYNGAP1 haploinsufficiency, we show dysregulated cytoskeletal dynamics that impair the scaffolding and division plane of hRGCs, resulting in disrupted lamination of the cortical plate and accelerated maturation of cortical projection neurons. Overall, the discovery of the expression and function of SYNGAP1 in cortical progenitor cells reframes our understanding of the pathophysiology of SYNGAP1-related disorders and, more broadly, underscores the importance of dissecting the role of synaptic genes associated with neurodevelopmental disorders in distinct cell types across developmental stages.
Entorhinal-hippocampal circuit integrity is related to mnemonic discrimination and amyloid-β pathology in older adults
Authors: Adams Jenna N. , Kim Soyun , Rizvi Batool , Sathishkumar Mithra , Taylor Lisa , Harris Alyssa L. , Mikhail Abanoub , Keator David B. , McMillan Liv , Yassa Michael A. 
Published: May 2022

ABSTRACTMnemonic discrimination, a cognitive process that relies on hippocampal pattern separation, is one of the first memory domains to decline in aging and preclinical Alzheimer’s disease. We tested if functional connectivity (FC) within the entorhinal-hippocampal circuit, measured with high-resolution resting state fMRI, is associated with mnemonic discrimination and Aβ pathology, measured with PET, in nondemented older adults. Low object mnemonic discrimination performance was specifically associated with increased FC between anterolateral entorhinal cortex (alEC) and dentate gyrus (DG)/CA3, supporting the importance of this connection to object memory. This hyperconnectivity between alEC-DG/CA3 was related to Aβ pathology and decreased entorhinal cortex volume. In contrast, spatial mnemonic discrimination was not associated with altered FC. Aβ was further associated with decreased FC and volume within hippocampal subfields. Our findings suggest that Aβ may indirectly lead to memory impairment through entorhinal-hippocampal circuit dysfunction and neurodegeneration, and provide a mechanism for vulnerability of object mnemonic discrimination.
An in silico genome-wide screen for circadian clock strength in human samples
Authors: Wu Gang , Ruben Marc D. , Francey Lauren J. , Lee Yin Yeng , Anafi Ron C. , Hogenesch John B. 
Published: May 2022

AbstractYears of time-series gene expression studies have built a strong understanding of clock-controlled pathways across species. However, comparatively little is known about how ‘non-clock’ pathways influence clock function. We developed a new computational approach to explore candidate pathways coupled to the clock in human tissues. This method, termed LTM, is an in silico screen to infer genetic influences on circadian clock function. LTM uses natural variation in gene expression in human data and directly links gene expression variation to clock strength independent of longitudinal data. We applied LTM to three human skin and one melanoma datasets and found that the cell cycle is the top candidate clock-coupled pathway in healthy skin. In addition, we applied LTM to thousands of tumor samples from 11 cancer types in the TCGA database and found that extracellular matrix organization-related pathways are tightly associated with the clock strength in humans. Further analysis shows that clock strength in tumor samples are correlated with the proportion of cancer-associated fibroblasts and endothelial cells. Therefore, we show both the power of LTM in predicting clock-coupled pathways and classify factors associated with clock strength in human tissues. LTM is available on GitHub to facilitate its use.
Age-related reorganization of functional network architecture in semantic cognition
Authors: Martin Sandra , Williams Kathleen A. , Saur Dorothee , Hartwigsen Gesa 
Published: May 2022

AbstractSemantic memory is a fundamental human ability which is central to communication. Although it is usually well preserved in healthy aging, memory problems in verbal communication due to slowed access and retrieval processes are a common complaint with increasing age. So far, the neural bases of this paradox remain poorly understood. The current neuroimaging study investigated age differences in the functional network architecture during semantic word retrieval in young and older adults. Using group spatial independent component analysis, we defined functional networks for verbal semantic fluency. Combining task-based functional connectivity, graph theory and cognitive measures of fluid and crystallized intelligence, our findings show age-accompanied large-scale network reorganization even when older adults have intact word retrieval abilities. In particular, functional networks of older adults were characterized by reduced decoupling between systems, reduced segregation and efficiency, and a larger number of hub regions relative to young adults. Exploring the predictive utility of these age-related changes in network topology revealed high, albeit less efficient, performance for older adults whose brain graphs showed stronger dedifferentiation and reduced distinctiveness. Our results extend theoretical accounts on neurocognitive aging by revealing the compensational potential of the commonly reported pattern of network dedifferentiation when older adults can rely on their prior knowledge for successful task processing. However, we also demonstrate the limitations of such compensatory reorganization processes and demonstrate that a youth-like network architecture in terms of balanced integration and segregation is associated with more economical processing.Significance StatementCognitive aging is associated with widespread neural reorganization processes in the human brain. However, the behavioral impact of such reorganization is not well understood. Here, we used taskbased fMRI to demonstrate a large-scale reorganization of brain networks in older adults even when their semantic abilities are intact. In particular, functional networks of older adults were characterized by increased coupling between different systems, reduced segregation and efficiency, and a larger number of hub regions relative to young adults. Associating these changes with behavior revealed high, albeit less efficient, performance for networks in older adults showing stronger dedifferentiation and reduced distinctiveness. Our results highlight the compensatory potential of network reconfiguration with age, but also reveal the limitations of such reorganization processes.
Genetic architecture of the white matter connectome of the human brain
Authors: Sha Zhiqiang , Schijven Dick , Fisher Simon E. , Francks Clyde 
Published: May 2022

AbstractWhite matter tracts form the structural basis of large-scale functional networks in the human brain. We applied brain-wide tractography to diffusion images from 30,810 adult participants (UK Biobank), and found significant heritability for 90 regional connectivity measures and 851 tract-wise connectivity measures. Multivariate genome-wide association analyses identified 355 independently associated lead SNPs across the genome, of which 77% had not been previously associated with human brain metrics. Enrichment analyses implicated neurodevelopmental processes including neurogenesis, neural differentiation, neural migration, neural projection guidance, and axon development, as well as prenatal brain expression especially in stem cells, astrocytes, microglia and neurons. We used the multivariate association profiles of lead SNPs to identify 26 genomic loci implicated in structural connectivity between core regions of the left-hemisphere language network, and also identified 6 loci associated with hemispheric left-right asymmetry of structural connectivity. Polygenic scores for schizophrenia, bipolar disorder, autism spectrum disorder, attention-deficit hyperactivity disorder, left-handedness, Alzheimer’s disease, amyotrophic lateral sclerosis, and epilepsy showed significant multivariate associations with structural connectivity, each implicating distinct sets of brain regions with trait-relevant functional profiles. This large-scale mapping study revealed common genetic contributions to the structural connectome of the human brain in the general adult population, highlighting links with polygenic disposition to brain disorders and behavioural traits.One sentence summaryVariability in white matter fiber tracts of the human brain is associated with hundreds of newly discovered genomic loci that especially implicate stem, neural and glial cells during prenatal development, and is also associated with polygenic dispositions to various brain disorders and behavioural traits.
Identification of cyclic-di-GMP-modulating protein residues by bi-directionally evolving a social trait in Pseudomonas fluorescens
Authors: Kessler Collin , Kim Wook 
Published: May 2022

AbstractModulation of the intracellular cyclic di-guanosine monophosphate (c-di-GMP) pool is central to the formation of structured bacterial communities. Genome annotations predict the presence of dozens of conserved c-di-GMP catalytic enzymes in many bacterial species, but the functionality and regulatory control of the vast majority remain underexplored. Here, we begin to fill this gap by utilizing an experimental evolution system in Pseudomonas fluorescens Pf0-1, which repeatedly produces a unique social trait through bidirectional transitions between two distinct phenotypes converging on c-di-GMP modulation. Parallel evolution of 33 lineages captured 147 unique mutations among 191 evolved isolates in genes that are empirically demonstrated, bioinformatically predicted, or previously unknown to impact the intracellular pool of c-di-GMP. Quantitative chemistry confirmed that each mutation causing the phenotypic shift predictably amplifies or reduces c-di-GMP production. We integrate our mutation, phenotype, and quantification data with current models of known regulatory and catalytic systems, describe a previously unknown relationship between a regulatory component of branched-chain amino acid biosynthesis and c-di-GMP production, and predict functions of unexpected proteins that clearly impact c-di-GMP production. Sequential mutations that continuously disrupt or recover c-di-GMP production across discrete functional elements suggest a complex and underappreciated interconnectivity within the c-di-GMP regulome of P. fluorescens.ImportanceMicrobial communities comprise densely packed cells where competition for space and resources is fierce. In our model system, mutant cells with a dry (D) phenotype are selected from a population with a mucoid (M) phenotype, and vice versa, because M and D cells physically work together to spread away from the overcrowded colony. D cells produce high levels of c-di-GMP and M cells produce low levels, so each mutation impacts c-di-GMP production. C-di-GMP is a second messenger which regulates diverse bacterial phenotypes that cause tremendous clinical and environmental problems. Many bacteria possess dozens of enzymes that are predicted to produce c-di-GMP, but most are considered to be non-functional. Here, we take advantage of the bi-directional selection of M and D phenotypes to identify key residues that could force these enzymes to turn on or off. Several unexpected proteins also participate in this process, but very little is known about them.
Haplotype-resolved assembly of a tetraploid potato genome using long reads and low-depth offspring data
Authors: Serra Mari Rebecca , Schrinner Sven , Finkers Richard , Arens Paul , Schmidt Maximilian H.-W. , Usadel Björn , Klau Gunnar W. , Marschall Tobias 
Published: May 2022

AbstractPotato is one of the world’s major staple crops and like many important crop plants it has a polyploid genome. Polyploid haplotype assembly poses a major computational challenge, hindering the use of genomic data in breeding strategies. Here, we introduce a novel strategy for the assembly of polyploid genomes and present an assembly of the autotetraploid potato cultivar Altus. Our method uses low-depth sequencing data from an offspring population, which is available in many plant breeding settings, to achieve chromosomal clustering and haplotype phasing directly on the assembly graph. This involves a novel strategy for the analysis of k-mers unique to specific graph nodes. Our approach generates assemblies of individual chromosomes with phased haplotig N50 values of up to 13 Mb and haplotig lengths of up to 31 Mb. This major advance provides high-quality assemblies with haplotype-specific sequence resolution of whole chromosome arms and can be applied in common breeding scenarios where collections of offspring are available.
Biosynthetic proteins targeting the SARS-CoV-2 spike as anti-virals
Authors: Thébault Stéphanie , Lejal Nathalie , Dogliani Alexis , Donchet Amélie , Urvoas Agathe , Valerio-Lepiniec Marie , Lavie Muriel , Baronti Cécile , Touret Franck , da Costa Bruno , Bourgon Clara , Fraysse Audrey , Saint-Albin-Deliot Audrey , Morel Jessica , Klonjkowski Bernard , de Lamballerie Xavier , Dubuisson Jean , Roussel Alain , Minard Philippe , Le Poder Sophie , Meunier Nicolas , Delmas Bernard 
Published: May 2022

AbstractThe binding of the SARS-CoV-2 spike to angiotensin-converting enzyme 2 (ACE2) promotes virus entry into the cell. Targeting this interaction represents a promising strategy to generate antivirals. By screening a phage-display library of biosynthetic protein sequences build on a rigid alpha-helicoidal HEAT-like scaffold (named αReps), we selected candidates recognizing the spike receptor binding domain (RBD). Two of them (F9 and C2) bind the RBD with affinities in the nM range, displaying neutralisation activity in vitro and recognizing distinct sites, F9 overlapping the ACE2 binding motif. The F9-C2 fusion protein and a trivalent αRep form (C2-foldon) display 0.1 nM affinities and EC50 of 8-18 nM for neutralization of SARS-CoV-2. In hamsters, F9-C2 instillation in the nasal cavity before or during infections effectively reduced the replication of a SARS-CoV-2 strain harbouring the D614G mutation in the nasal epithelium. Furthermore, F9-C2 and/or C2-foldon effectively neutralized SARS-CoV-2 variants (including delta and omicron variants) with EC50 values ranging from 13 to 32 nM. With their high stability and their high potency against SARS-CoV-2 variants, αReps provide a promising tool for SARS-CoV-2 therapeutics to target the nasal cavity and mitigate virus dissemination in the proximal environment.Author SummaryThe entry of SARS-CoV-2 in permissive cells is mediated by the binding of its spike to angiotensin-converting enzyme 2 (ACE2) on the cell surface. To select ligands able to block this interaction, we screened a library of phages encoding artificial proteins (named αReps) for binding to its receptor binding domain (RBD). Two of them were able to bind the RBD with high affinity and block efficiently the virus entry in cultured cells. Assembled αReps through covalent or non-covalent linkages blocked virus entry at lower concentration than their precursors (with around 20-fold activity increase for a trimeric αRep). These αReps derivates neutralize efficiently SARS-CoV-2 β, γ, δ and Omicron virus variants. Instillation of an αRep dimer in the nasal cavity effectively reduced virus replication in the hamster model of SARS-CoV-2 and pathogenicity.