bluuebunny/crossref_metadata_2025_split huggingface dataset:
Predicting fitness related traits using gene expression and machine learning
Authors: Henry Georgia A. , Stinchcombe John R. 
Published: February 2024

AbstractEvolution 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

AbstractHost-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

AbstractCenturies 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

AbstractBackgroundThe 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.ResultsWe 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.ConclusionsOur 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

ABSTRACTWe 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

AbstractGenes 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

ABSTRACTTemperature 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

AbstractGlycophosphatidylinositol (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 summaryThe 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

ABSTRACTSecreted 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.
Prevalent and persistent new-onset autoantibodies in mild to severe COVID-19
Authors: Jernbom Falk August , Skoglund Lovisa , Pin Elisa , Sjöberg Ronald , Tegel Hanna , Hober Sophia , Rostami Elham , Rasmusson Annica , Cunningham Janet L. , Havervall Sebastian , Thålin Charlotte , Månberg Anna , Nilsson Peter 
Published: February 2024

AbstractAutoantibodies have been shown to be implied in COVID-19 but the emerging autoantibody repertoire remains largely unexplored. We investigated the new-onset autoantibody repertoire in 525 healthcare workers and hospitalized COVID-19 patients in five time points over 16 months using proteome-wide and targeted protein and peptide arrays. Our results show that prevalent new-onset autoantibodies against a wide range of antigens emerged following SARS-CoV-2 infection in relation to pre-infectious baseline samples and remained elevated for at least 12 months. We demonstrated associations between distinct new-onset autoantibodies and neuropsychiatric symptoms post-COVID-19. Using epitope mapping, we determined the main epitopes of selected new-onset autoantibodies, validated them in independent cohorts of neuro-COVID and pre-pandemic healthy controls, and identified molecular mimicry between main epitopes and the conserved fusion peptide of the SARS-CoV-2 Spike glycoprotein. Our work describes the complexity and dynamics of the autoantibody repertoire emerging with COVID-19 and supports the need for continued analysis of the new-onset autoantibody repertoire to elucidate the mechanisms of the post-COVID-19 condition.
Genetically proxied PDE5 inhibition and risk of dementia: a drug target Mendelian randomisation study
Authors: Brennan Stephen O. , Tinworth Alexander C. 
Published: February 2024

AbstractBackgroundPhosphodiesterase-5 (PDE5) inhibitors have gained interest as a potential treatment for dementia. However, current evidence is limited to observational and pre-clinical studies. This drug- target Mendelian Randomisation (MR) study aims to elucidate the on-target effects of pharmacological PDE5 inhibition on dementia subtypes, cognitive traits, and neuro-imaging phenotypes.MethodsTwo independent (r2<0.001) blood pressure lowering variants from around the PDE5A locus were used in two-sample MR to assess the effect of genetically proxied PDE5 inhibition on risk of dementia subtypes, cognitive performance, and neuroimaging traits (cortical thickness, surface area and volume of white matter hyperintensities) in large-scale genomic consortia. The instrument’s predictive validity was assessed against erectile dysfunction and pulmonary arterial hypertension (PAH) as positive controls.ResultsFollowing correction for multiple comparisons, genetically proxied PDE5 inhibition was associated with lower odds of erectile dysfunction (OR 0.85, 95% CI 0.83-0.87) and PAH (OR 0.58, 95% CI 0.55-0.61), and higher odds of Alzheimer’s disease (OR 1.07, 95% CI 1.04-1.10), Lewy body dementia (OR 1.20, 95% CI 1.17-1.23) and vascular dementia (OR 1.04, 95% CI 1.02-1.07). Furthermore, genetically proxied PDE5 inhibition was associated with reduced cortical thickness (SD change -0.003, 95% CI -0.004, -0.002) and cognitive performance (SD change -0.010, 95% CI -0.013, -0.007), but not cortical surface area nor volume of white matter hyperintensities.ConclusionIn contrast to evidence from observational studies, our findings indicate that inhibition of PDE5 is associated with a higher risk of dementia and an unfavourable neurocognitive profile. This risk should be further investigated prior to clinical trials of pharmacological PDE5 inhibition for the treatment and prevention of dementia.
Evolutionary genomics reveals variation in structure and genetic content implicated in virulence and lifestyle in the genusGaeumannomyces
Authors: Hill Rowena , Grey Michelle , Fedi Mariano Olivera , Smith Daniel , Ward Sabrina J. , Canning Gail , Irish Naomi , Smith Jade , McMillan Vanessa E. , Hammond Jess , Osborne Sarah-Jane , Chancellor Tania , Swarbreck David , Hall Neil , Palma-Guerrero Javier , Hammond-Kosack Kim E. , McMullan Mark 
Published: February 2024

ABSTRACTGaeumannomyces triticiis responsible for take-all disease, one of the most important wheat root threats worldwide. High-quality annotated genome resources are sorely lacking for this pathogen, as well as for the closely related antagonist and potential wheat take-all biocontrol agent,G. hyphopodioides. As such, we know very little about the genetic basis of the interactions in this host-pathogen-antagonist system. Using PacBio HiFi sequencing technology we have generated nine near-complete assemblies, including two different virulence lineages forG. triticiand the first assemblies forG. hyphopodioidesandG. avenae(oat take-all). Genomic signatures support the presence of two distinct virulence lineages inG. tritici(types A and B), with A strains potentially employing a mechanism to prevent gene copy-number expansions. The CAZyme repertoire was highly conserved acrossGaeumannomyces, while candidate secreted effector proteins and biosynthetic gene clusters showed more variability and may distinguish pathogenic and non-pathogenic lineages. A transition from self-sterility (heterothallism) to self-fertility (homothallism) may also be a key innovation implicated in lifestyle. We did not find evidence for transposable element and effector gene compartmentalisation in the genus, however the presence ofStarshipgiant transposable elements likely contributes to genomic plasticity in the genus. Our results depictGaeumannomycesas an ideal system to explore interactions within the rhizosphere, the nuances of intraspecific virulence, interspecific antagonism, and fungal lifestyle evolution. The foundational genomic resources provided here will enable the development of diagnostics and surveillance of understudied but agriculturally important fungal pathogens.
A Multi-Dimensional Approach to Map Disease Relationships Challenges Classical Disease Views
Authors: Möbus Lena , Serra Angela , Fratello Michele , Pavel Alisa , Federico Antonio , Greco Dario 
Published: February 2024

AbstractThe categorization of human diseases is mainly based on the affected organ system and phenotypic characteristics. This is limiting the view to the pathological manifestations, while it neglects mechanistic relationships that are crucial to develop therapeutic strategies. This work aims to advance the understanding of diseases and their relatedness beyond traditional phenotypic views. Hence, the similarity among 502 diseases is mapped using six different data dimensions encompassing molecular, clinical, and pharmacological information retrieved from public sources. Multiple distance measures and multi-view clustering is used to assess the patterns of disease relatedness. The integration of all six dimensions into a consensus map of disease relationships reveals a divergent disease view from the International Classification of Diseases (ICD), emphasizing novel insights offered by a multi-view disease map. Disease features such as genes, pathways, and chemicals that are enriched in distinct disease groups are identified. Finally, an evaluation of the top similar diseases of three candidate diseases common in the Western population shows concordance with known epidemiological associations and reveals rare features shared between Type 2 diabetes and Alzheimer disease. A revision of disease relationships holds promise for facilitating the reconstruction of comorbidity patterns, repurposing drugs, and advancing drug discovery in the future.