bluuebunny/crossref_metadata_2025_split huggingface dataset:
Uncovering the roles of lignin-related genes in disease resistance in maize using mutant and association analysis
Authors: Kolkman Judith M. , Moreta Danilo E. , Repka Ace , Bradbury Peter , Nelson Rebecca J. 
Published: April 2022

AbstractBrown midrib (BMR) maize harbors mutations that result in lower lignin levels and higher feed digestibility, making it a desirable silage market class for ruminant nutrition. Northern leaf blight (NLB) epidemics in upstate NY highlighted the disease susceptibility of commercially grown BMR maize hybrids. We found the bm1, bm2, bm3 and bm4 mutants in a W64A genetic background to be more susceptible to foliar fungal (NLB, gray leaf spot, and anthracnose leaf blight) and bacterial (Stewart’s wilt) diseases. The bm1, bm2 and bm3 mutants showed enhanced susceptibility to anthracnose stalk rot, and the bm1 and bm3 mutants were more susceptible to Gibberella ear rot. Co-localization of quantitative trait loci and correlations between stalk strength and disease traits in recombinant inbred line families suggest possible pleiotropies. The role of lignin in plant defense was explored using high-resolution, genome-wide association analysis for resistance to NLB in the Goodman diversity panel. Association analysis identified 100 single and clustered SNP associations for resistance to NLB, but did not implicate natural functional variation at bm1-bm5. Strong associations implicated a suite of diverse candidate genes, including lignin-related genes such as a β-glucosidase gene cluster, hct11, knox1, knox2, zim36, lbd35, CASP-like protein 8, and xat3. The candidate genes are targets for breeding quantitative resistance to NLB in maize for use in silage and non-silage purposes.Core IdeasBrown midrib mutants (bm1-bm4) in maize, characterized as mutations with reduced lignin content, are susceptible to a range of foliar pathogens.Several brown midrib mutants in maize show enhanced susceptibility to stalk rot and ear rot pathogens.Genome wide association analysis identified a number of diverse candidate genes associated with resistance to northern leaf blight in maize, including lignin-related genes involved in the monolignol pathway, developmental genes and transcription factors.Association analysis for resistance to NLB implicated a β-glucosidase gene cluster, including Zmbglu24 and Zmbglu25 known for targeting monolignols and contributing to ∼15% phenotypic variation.hct11, which plays an important role in the monolignol pathway, was implicated for resistance to northern leaf blight in maize with potential for multiple stress tolerance.
Multi-Head Attention-based U-Nets for Predicting Protein Domain Boundaries Using 1D Sequence Features and 2D Distance Maps
Authors: Mahmud Sajid , Guo Zhiye , Quadir Farhan , Liu Jian , Cheng Jianlin 
Published: April 2022

ABSTRACTThe information about the domain architecture of proteins is useful for studying protein structure and function. However, accurate prediction of protein domain boundaries (i.e., sequence regions separating two domains) from sequence remains a significant challenge. In this work, we develop a deep learning method based on multi-head U-Nets (called DistDom) to predict protein domain boundaries utilizing 1D sequence features and predicted 2D inter-residue distance map as input. The 1D features contain the evolutionary and physicochemical information of protein sequences, whereas the 2D distance map includes the structural information of proteins that was rarely used in domain boundary prediction before. The 1D and 2D features are processed by the 1D and 2D U-Nets respectively to generate hidden features. The hidden features are then used by the multi-head attention to predict the probability of each residue of a protein being in a domain boundary, leveraging both local and global information in the features. The residue-level domain boundary predictions can be used to classify proteins as single-domain or multi-domain proteins. It classifies the CASP14 single-domain and multi-domain targets at the accuracy of 69.1%, 2.67% more accurate than the state-of-the-art method. Tested on the CASP14 multi-domain protein targets with expert annotated domain boundaries, the average per-target F1 measure score of the domain boundary prediction by DistDom is 0.263, 29.56% higher than the state-of-the-art method.
Simulating the Tumor Microenvironment for Immune Cell Interactions via Deployable Extrusion Bioprinting
Authors: Mazzaglia Corrado , Sheng Yaqi , Rodrigues Leonor Nunes , Lei Iek Man , Shields Jacqueline D. , Huang Yan Yan Shery 
Published: April 2022

AbstractThree-dimensional (3D) bioprinting has emerged as a promising tool for constructing tumor microenvironments (TME) for cancer modelling in vitro. Realizing the translational impacts of 3D bioprinting for cancer research necessitates innovation in bioprinting workflows which integrate affordability, user-friendliness, and biological relevance. Herein, we demonstrate ‘bioArm’, a simple, yet highly effective extrusion bioprinting platform, which can be folded into a carry-on pack, and rapidly deployed between bio-facilities. BioArm enabled TME reconstruction in the form of 3D core-shell tumoroids with cancer-associated fibroblasts (CAFs). Tumoroids showed the presence of a heterogenous population of CAFs with de novo synthesized extracellular matrices, demonstrating more in vivo-like characteristics compared to conventional 2D co-culture models. Embedding the 3D printed tumoroids in an immune cell laden collagen matrix permitted tracking of the interaction between immune cells and tumoroids, and subsequent immunotherapy treatments. Our deployable extrusion bioprinting workflow could significantly widen the accessibility of 3D bioprinting for gaining mechanistic understanding in TME, and for developing strategies in cancer drug testing.
The PAICE Suite Reveals Circadian Post-Transcriptional Timing of Non-Coding RNAs and Spliceosome Components in Mus musculus Macrophages
Authors: Buel Sharleen M. , Debopadhaya Shayom , De los Santos Hannah , Edwards Kaelyn M. , David Alexandra M. , Dao Uyen H. , Bennett Kristin P. , Hurley Jennifer M. 
Published: April 2022

ABSTRACTCircadian rhythms broadly regulate physiological functions by tuning oscillations in the levels of mRNAs and proteins to the 24-hour day/night cycle. Globally assessing which mRNAs and proteins are timed by the clock necessitates accurate recognition of oscillations in RNA and protein data, particularly in large omics data sets. Tools that employ fixed-amplitude models have previously been used to positive effect. However, the recognition of amplitude-change in circadian oscillations required a new generation of analytical software to enhance the identification of these oscillations. To address this gap, we created the Pipeline for Amplitude Integration of Circadian Exploration (PAICE) suite. Here, we demonstrate the PAICE suite’s increased detection of circadian trends through the joint modeling of the Mus musculus macrophage transcriptome and proteome. Our enhanced detection confirmed extensive circadian post-transcriptional regulation in macrophages, but highlighted that some of the reported discrepancy between mRNA and protein oscillations was due to noise in data. We further applied the PAICE suite to investigate the circadian timing of non-coding RNAs, documenting extensive circadian timing of long non-coding RNAs and small nuclear RNAs, which control the recognition of mRNA in the spliceosome complex. By tracking oscillating spliceosome complex proteins using the PAICE suite, we noted that the clock broadly regulates the spliceosome, particularly the major spliceosome complex. As most of the above-noted rhythms had damped amplitude changes in their oscillations, this work highlights the importance of the PAICE suite in the thorough enumeration of oscillations in omics-scale datasets.
TwinEQTL: Ultra Fast and Powerful Association Analysis for eQTL and GWAS in Twin Studies
Authors: Xia Kai , Shabalin Andrey A. , Yin Zhaoyu , Chung Wonil , Sullivan Patrick F. , Wright Fred A. , Styner Martin , Gilmore John H. , Santelli Rebecca C. , Zou Fei 
Published: April 2022

AbstractWe develop a computationally efficient alternative, TwinEQTL, to a linear mixed-effects model (LMM) for twin genome-wide association study (GWAS) data. Instead of analyzing all twin samples together with LMM, TwinEQTL first splits twin samples into two independent groups on which multiple linear regression analysis can be validly performed separately, followed by an appropriate meta-analysis-like approach to combine the two non-independent test results. Through mathematical derivations, we prove the validity of TwinEQTL algorithm and show that the correlation between two dependent test statistics at each single-nucleotide polymorphism (SNP) are independent of its minor allele frequency (MAF). Thus the correlation is constant across all SNPs. Through simulations, we show empirically that TwinEQTL has well controlled type I error with negligible power loss compared to the gold-standard linear mixed effects models. To accommodate eQTL analysis with twin subjects, we further implement TwinEQTL into a R package with much improved computational efficiency. Our approaches provide a significant leap in terms of computing speed for GWAS and eQTL analysis with twin samples.
Bacterial produce membrane-binding small molecules to regulate horizontal gene transfer in vesicles
Authors: Tran Frances , Gangan Manasi S. , Boedicker James Q. 
Published: April 2022

AbstractThe exchange of bacterial extracellular vesicles facilitates molecular exchange between cells, including the horizontal transfer of genetic material. Given the implications of such transfer events on cell physiology and adaptation, some bacterial cells have likely evolved mechanisms to regulate vesicle exchange. Past work has identified mechanisms that regulate the formation of extracellular vesicles, including the production of small molecules that modulate membrane structure, however whether these mechanisms also regulate vesicle uptake and have an overall impact on the rate of vesicle exchange is unknown. Here we show that membrane-binding molecules produced by microbes regulate both the formation and uptake of extracellular vesicles and have the overall impact of increasing the vesicle exchange rate within a bacterial coculture. In effect, production of compounds that influence vesicle exchange rates enable cells to steal genes from neighboring cells. The ability of several membrane-binding compounds to regulate vesicle exchange was demonstrated. Three of these compounds, nisin, colistin, and polymyxin B, are antimicrobial peptides added at sub-inhibitory concentrations. These results suggest that a key function of exogenous compounds that bind to membranes may be the regulation of vesicle exchange between cells.ImportanceThe exchange of bacterial extracellular vesicles is one route of gene transfer between bacteria, although it was unclear if bacteria developed strategies to regulate the rate of gene transfer within vesicles. In eukaryotes, there are many examples of specialized molecules that have evolved to facilitate the production, loading, and uptake of vesicles. Recent work with bacteria has shown that some small molecules influence membrane curvature and induce vesicle formation. Here we show that similar compounds facilitate vesicle uptake, thereby regulating the overall rate of vesicle exchange within bacterial populations. The addition of membrane-binding compounds, several of them antibiotics at sub-inhibitory concentrations, to a bacterial co-culture increased the rate of horizontal gene transfer via vesicle exchange.
Additive and Dominant Loci Jointly Pyramiding the Grain Quality of Hybrid Rice
Authors: Li Lanzhi , Zheng Xingfei , Wang Jiabo , Zhang Xueli , He Xiaogang , Xiong Liwen , Song Shufeng , Su Jing , Tang Wenbang , Diao Ying , Yuan Zheming , Zhang Zhiwu , Hu Zhongli 
Published: April 2022

AbstractHybrid rice has an advantage in its heterosis, resulting in high yield and resistance to biotic and abiotic stress. However, genetic improvement of grain quality is more challenging in hybrid rice than in inbred rice due to additional complexity, such as the dominant effect. It is critical to identify a path to efficiently develop inbreds and identify their superior crosses for hybrid production. Here, we developed a pipeline for joint analysis of phenotypes, effects, and generations (JPEG) and analysed 113 inbred varieties as male parents, five tester varieties as female parents, and their 565 (113×5) hybrid testcrosses for 12 grain quality traits, including grain length and width, chalkiness, and amylose content. A total of 1,619,588 single nucleotide polymorphisms were obtained for the parent varieties and inferred for the hybrids using whole-genome sequencing with an average sequencing depth of 11×. Genome-wide association studies with JPEG identified 128 loci associated with at least one of the 12 traits. There were 44 and 97 loci with additive and dominant effects, respectively, including 13 overlaps. Among the 128 associated loci, 42 loci are located in or near (<200 kb) 17 known genes. Pyramiding genetic loci with additive and/or dominant effects in genomic selection dramatically improves the accuracy of predicting hybrid performances. More than 45% of genetic variation was explained by the identified markers for all traits except one (30%). These results demonstrate that pyramiding genetically identified additive and dominant loci can afford substantial power for predicting hybrid performances, presenting opportunities to identify superior crosses from existing phenotypes and genotypes of inbreds and hybrids.
The UbiB family member Cqd1 forms a novel membrane contact site in mitochondria
Authors: Khosravi Siavash , Chelius Xenia , Unger Ann-Katrin , Frickel Johanna , Sachsenheimer Timo , Lüchtenborg Christian , Schieweck Rico , Brügger Britta , Westermann Benedikt , Klecker Till , Neupert Walter , Harner Max E. 
Published: April 2022

AbstractMitochondria are essential organelles of eukaryotic cells that are characterized by their unique and complex membrane system. They are confined from the cytosol by an envelope consisting of two membranes. Signals, metabolites, proteins and lipids have to be transferred across these membranes via proteinaceous contact sites to keep mitochondria functional. In the present study we identified a novel mitochondrial contact site that is formed by the inner membrane protein Cqd1 and the outer membrane proteins Por1 and Om14. Similar to the mitochondrial porin, Por1, Cqd1 is highly conserved, suggesting that this complex is conserved in form and function from yeast to human. Cqd1 is a member of the UbiB protein kinase-like family (also called aarF domain containing kinases). It was recently shown that Cqd1 in cooperation with Cqd2 controls the cellular distribution of coenzyme Q by a yet unknown mechanism. Our data suggest that Cqd1 in addition is involved in the homeostasis of phospholipids and contributes to the maintenance of mitochondrial morphology and architecture.Summary statementHere, we show that the conserved mitochondrial inner membrane protein Cqd1 interacts with the outer membrane proteins Por1 and Om14. Additionally, we provide evidence that Cqd1 is important for maintaining mitochondrial homeostasis.
Autotaxin facilitates selective LPA receptor signaling
Authors: Salgado-Polo Fernando , Borza Razvan , Marsais Florence , Jagerschmidt Catherine , Waeckel Ludovic , Moolenaar Wouter H. , Ford Paul , Heckmann Bertrand , Perrakis Anastassis 
Published: April 2022

SUMMARYAutotaxin (ATX; ENPP2) produces the lipid mediator lysophosphatidic acid (LPA) that signals through disparate EDG (LPA1-3) and P2Y (LPA4-6) G protein-coupled receptors. ATX/LPA promote several (patho)physiological processes, including in pulmonary fibrosis, thus serving as attractive drug targets. However, it remains unclear if clinical outcome depends on how different ATX inhibitors modulate the ATX/LPA signaling axis. Here, we show that inhibitors binding to the ATX “tunnel” specifically abrogate key aspects of ATX/LPA signaling. We find that the tunnel is essential for signaling efficacy and dictates cellular responses independent of ATX catalytic activity, with a preference for activation of P2Y LPA receptors. These responses are abrogated by tunnel-binding inhibitors, such as ziritaxestat, but not by inhibitors that exclusively target the active site, as shown in primary lung fibroblasts and a murine model of radiation-induced pulmonary fibrosis. Our results uncover a receptor-selective signaling mechanism for ATX, implying clinical benefit for tunnel-targeting ATX inhibitors.HighlightsATX is a dual-function protein acting as an LPA-producing enzyme and LPA chaperone.Structural integrity of the ATX tunnel is essential to mediate signaling functions.ATX-bound LPA signals preferentially via P2Y family LPA receptors.Occupancy of the ATX tunnel is crucial for ziritaxestat to exert inhibition in vivo.
Temperature and resources interact to shape phytoplankton size-abundance relationships at a continental scale
Authors: Gjoni Vojsava , Glazier Douglas S. , Ibelings Bastiaan W. , Thomas Mridul K. 
Published: April 2022

AbstractCommunities contain more individuals of small species and fewer individuals of large species. The observed −3/4 slope relating mean size and mean abundance across communities (the ‘cross-community scaling relationship’ or CCSR) is thought to arise from a 3/4-power scaling of metabolic rate with body size. Assuming that 3/4-power metabolic scaling is universal, as claimed by the metabolic theory of ecology (MTE), size-abundance relationships should also be invariant with a scaling exponent of −3/4 or nearly so, across environmental conditions. However, we find that the CCSR slope is actually −1 overall (perhaps due to isometric metabolic scaling), and varies substantially across temperature and nutrient gradients in 1048 freshwater lake phytoplankton communities in the USA. The size-abundance relationship is most shallow at low temperatures and high nutrients, and steeper and relatively insensitive to nutrients at high temperatures. Phytoplankton communities have orders of magnitude more small or large cells depending on environmental conditions than would be predicted from the MTE. Although based on observational data, these results suggest that the environment alters either metabolic scaling or other poorly understood processes shaping community size distributions.
Design of a Minimal di-Nickel Hydrogenase Peptide
Authors: Mancini Joshua A. , Pike Douglas H. , Poudel Saroj , Timm Jennifer , Tyryshkin Alexei M. , Siess Jan , Molinaro Paul , McCann James J. , Waldie Kate M. , Koder Ronald L. , Falkowski Paul G. , Nanda Vikas 
Published: April 2022

AbstractThe most ancient processes for energy production in the evolution of life involve the reversible oxidation of molecular hydrogen by hydrogenase. Extant hydrogenase enzymes are complex, comprising hundreds of amino acids and multiple cofactors. We designed a 13 amino acid nickel-binding peptide capable of robustly producing molecular hydrogen from protons under a wide variety of conditions. The peptide forms a di-nickel cluster structurally analogous to a Ni-Fe cluster in [NiFe]-hydrogenase and the Ni-Ni cluster in acetyl-CoA synthase (ACS), two ancient, extant proteins central to metabolism. These experimental results clearly demonstrate that modern enzymes, despite their enormous complexity, likely evolved from simple peptide precursors on early Earth.One Sentence SummarySmall metal-binding peptides were the likely precursors of modern enzymes.
Targeting N-Myc in Neuroblastoma with Selective Aurora Kinase A Degraders
Authors: Tang Jian , Moorthy Ramkumar , Demir Özlem , Baker Zachary D. , Naumann Jordan A. , Jones Katherine F. M. , Grillo Michael J. , Haefner Ella S. , Shi Ke , Levy Michaella J , Aihara Hideki , Harris Reuben S. , Amaro Rommie E. , Levinson Nicholas M. , Harki Daniel A. 
Published: April 2022

Summary ParagraphMYCN amplification is the most frequent genetic driver in high-risk neuroblastoma (NB) and strongly associated with poor prognosis.1,2 The N-Myc transcription factor, which is encoded by MYCN, is a mechanistically validated, yet challenging target for NB therapy development.3,4 In normal neuronal progenitors, N-Myc undergoes rapid degradation, while in MYCN-amplified NB cells, Aurora kinase A (Aurora-A) binds to and stabilizes N-Myc, resulting in elevated protein levels.5,6 Allosteric Aurora-A inhibitors that displace N-Myc from binding can promote N-Myc degradation, but with limited efficacy.7–10 Here, we report a chemical approach to decrease N-Myc levels through the targeted protein degradation of Aurora-A. A first-in-class Aurora-A/N-Myc degrader, HLB-0532259 (compound 4), was developed from a novel Aurora-A-binding ligand that engages the Aurora-A/N-Myc complex. HLB-0532259 promotes the degradation of both Aurora-A and N-Myc with nanomolar potency and excellent selectivity and surpasses the cellular efficacy of established allosteric Aurora-A inhibitors. HLB-0532259 exhibits favorable pharmacokinetics properties and elicits tumor reduction in murine xenograft NB models. More broadly, this study delineates a novel strategy for targeting “undruggable” proteins that are reliant on accessory proteins for cellular stabilization.
Bile acid-CoA:amino acid N-acyltransferase gene knockout alters early life development, the gut microbiome and reveals unusual bile acid conjugates in mice
Authors: Neugebauer Kerri A. , Guzior Douglas V. , Feiner Jeremiah , Rzepka Madison , Schillmiller Anthony , O’Reilly Sandra , Jones A. Daniel , Watson Victoria E. , Luyendyk James P. , McCabe Laura , Quinn Robert A. 
Published: April 2022

ABSTRACTBile acids are steroid detergents in bile that contribute to fat absorption, cell signaling and microbiome interactions in mammals. The final step in their synthesis is amino acid conjugation with either glycine or taurine to a cholic acid or chenodeoxycholic acid backbone in the liver by the enzyme bile acid-CoA:amino acid N-acyltransferase (BAAT). Here, we describe the microbial, chemical, and physiological consequences of BAAT gene deletion in mice. BAAT-/- mice were underweight after weaning but quickly exhibited catch-up growth. At 3-weeks-of-age, KO animals had increased phospholipid excretion and decreased subcutaneous fat pad mass, glycogen staining in hepatocytes and vitamin A stores in the liver, but these phenotypes were less marked in adulthood. Their bile acid (BA) pool was highly altered throughout the 8-weeks of life but was not completely devoid of conjugated BAs. These animals had 27-fold lower amounts of taurine-conjugated BAs than wildtype in their liver, but similar concentrations of glycine-conjugated BAs and higher microbially-conjugated BAs. The BA pool in BAAT-/- was enriched in a variety of unusual bile acids that were putatively sourced from cysteamine conjugation with subsequent oxidation and methylation of the sulfur group to mimic taurine. KO mice also had an altered microbiome, but most strongly in the first 3-weeks, indicating bile acid conjugation is important for proper microbiome development during the postnatal period. Finally, antibiotic treatment increased taurine, glycine, and the unusually conjugated BAs in BAAT-/- animals, indicating the microbiome was not the likely source of the conjugation. Instead, BA conjugation in KO animals was likely derived from the peroxisomal acyltransferases ACNAT1 and ACNAT2, which are duplications of BAAT in the mouse genome, but inactivated in humans. This study demonstrates that BA conjugation is important for early life development in mice and is facilitated by other host or microbial enzymes besides BAAT in a manner that results in molecular mimics of taurine that may rescue pathological phenotypes.