bluuebunny/crossref_metadata_2025_split huggingface dataset:
A deep learning algorithm for potato tuber hollow heart classification
Authors: Abbasi Arash , Feldman Max J. , Park Jaebum , Greene Katelyn , Novy Richard G. , Liu Huaping 
Published: October 2021

AbstractA novel deep learning algorithm is proposed for hollow heart detection which is an internal tuber defect. Hollow heart is one of many internal defects that decrease the market value of potatoes in the fresh market and food processing sectors. Susceptibility to internal defects like the hollow heart is influenced by genetic and environmental factors so elimination of defect-prone material in potato breeding programs is important. Current methods of evaluation utilize human scoring which is limiting (only collects binary data) relative to the data collection capacity afforded by computer vision or are based upon X-ray transmission techniques that are both expensive and can be hazardous. Automation of defect classification (e.g. hollow heart) from data sets collected using inexpensive, consumer-grade hardware has the potential to increase throughput and reduce bias in public breeding programs. The proposed algorithm consists of ResNet50 as the backbone of the model followed by a shallow fully connected network (FCN). A simple augmentation technique is performed to increase the number of images in the data set. The performance of the proposed algorithm is validated by investigating metrics such as precision and the area under the curve (AUC).
Drop of Prevalence after Population Expansion: A lower prevalence for recessive disorders in a random mating population is a transient phenomenon during and after a growth phase
Authors: Rocca Luis La , Frank Julia , Bentzen Heidi Beate , Pantel Jean-Tori , Gerischer Konrad , Bovier Anton , Krawitz Peter M. 
Published: October 2021

AbstractDespite increasing data from population-wide sequencing studies, the risk for recessive disorders in consanguineous partnerships is still heavily debated. An important aspect that has not sufficiently been investigated theoretically, is the influence of inbreeding on mutation load and incidence rates when the population sizes change. We therefore developed a model to study these dynamics for a wide range of growth and mating conditions. In the phase of population expansion and shortly afterwards, our simulations show that there is a drop of diseased individuals at the expense of an increasing mutation load for random mating, while both parameters remain almost constant in highly consanguineous partnerships. This explains the empirical observation in present times that a high degree of consanguinity is associated with an increased risk of autosomal recessive disorders. However, it also states that the higher frequency of severe recessive disorders with developmental delay in inbred populations is a transient phenomenon before a mutation-selection balance is reached again.Author summaryWhat determines the recessive disease burden? The empirical observation that the proportion of intellectual disability of autosomal recessive cause is usually higher in offspring of consanguineous partnerships may lead to a misunderstanding about the mechanisms at work. In any population, selection removes pathogenic alleles from the gene pool while the de novo mutation rate adds novel pathogenic alleles. For comparable mutation rates, the incidence of severe recessive disease should be comparable in mutation-selection balance, regardless of the mating scheme. Different incidences can therefore only be explained by population dynamics that are not in equilibrium. We studied in simulated populations the time scales in which mutation-selection balance is reached after a growth phase and found that the mating scheme has a big impact on this lag time. When cousins mate preferentially with cousins, a few generations after a ten-fold increase in size the new equilibrium is established. In contrast, for random-mating, the transient advantage of a lower incidence may last for hundreds of generations, while the mutation load increases. By this means, our findings also highlight the importance of better carrier screens in the future for genetic consultations.
Revisiting the role of beta-tubulin inDrosophiladevelopment: beta-tubulin60D is not an essential gene, and its novelPin1allele has a tissue-specific dominant-negative impact
Authors: Krishnan Ramesh Kumar , Halachmi Naomi , Baskar Raju , Anna Bakhrat , Salzberg Adi , Abdu Uri 
Published: October 2021

AbstractDiversity in cytoskeleton organization and function may be achieved through alternative tubulin isotypes and by a variety of post-translational modifications. TheDrosophilagenome contains five different β-tubulin paralogs, which may play an isotype tissue-specific functionin vivo. One of these genes, thebeta-tubulin60Dgene, which is expressed in a tissue-specific manner, was found to be essential for fly viability and fertility. To further understand the role of the beta-tubulin60D gene, we generated newbeta-tubulin60Dnull alleles (beta-tubulin60DM)using the CRISPR/Cas9 system and found that the homozygous flies were viable and fertile. Moreover, using a combination of genetic complementation tests, rescue experiments, and cell biology analyses, we identifiedPin1, an unknown dominant mutant with bristle developmental defects, as a dominant-negative allele ofbeta-tubulin60D. We also found a missense mutation in thePin1mutant that results in an amino acid replacement from the highly conserved glutamate at position 75 to lysine (E75K). Analyzing the β-tubulin structure suggests that this E75K alteration destabilizes the alpha-helix structure and may also alter the GTP-Mg2+complex binding capabilities. Our results revisited the credence thatbeta-tubulin60Dis required for fly viability and revealed for the first time inDrosophila, a novel dominant-negative function of missensebeta-tubulin60Dmutation in bristle morphogenesis.Author summaryDiversity in cell microtubule cytoskeleton organization and function may be achieved through alternative tubulin isotypes and by a variety of post-translational modifications. The expression pattern of different tubulin isotypes (both α and β subunits) can vary according to cell type and stage of development, which contribute significantly to cell-specific MT organization and function. In this study, we revisited the role of one of the beta-tubulin isotopes inDrosophila, namely, beta-tubulin60D. This is the first study where a well molecularly defined protein null allele ofβTub60Dwas generated and characterized. This well-characterizedβTub60Dallele demonstrated unambiguity thatβTub60Dis not an essential gene, as was described before. Moreover, we identifiedPin1, an unknown dominant mutant with bristle developmental defects, as a dominant-negative allele ofbeta-tubulin60D. We also found a missense mutation in thePin1mutant that results in an amino acid (E75K). Analyzing the β-tubulin structure suggests that this E75K alteration destabilizes the alpha-helix structure and may also alter GTP-Mg2+complex binding capabilities. Thus, our results also revealed for the first time inDrosophila, a novel dominant-negative function of a missensebeta-tubulin60Dmutation, which has a tissue-specific function.
Repression of the Hox gene abd-A by ELAV-mediated Transcriptional Interference
Authors: Castro Alvarez Javier J. , Revel Maxime , Cléard Fabienne , Pauli Daniel , Karch François , Maeda Robert K. 
Published: October 2021

ABSTRACTIntergenic transcription is a common feature of eukaryotic genomes and performs important and diverse cellular functions. Here, we investigate the iab-8 ncRNA from the Drosophila Bithorax Complex and show that this RNA is able to repress the transcription of genes located at its 3’ end by a sequence-independent, transcriptional interference mechanism. Although this RNA is expressed in the early epidermis and CNS, we find that its repressive activity is limited to the CNS, where in wild-type embryos, it acts on the Hox gene, abd-A located immediately downstream of it. The CNS specificity is achieved through a 3’ extension of the transcript, mediated by the neuronal-specific, RNA-binding protein, ELAV. Loss of ELAV activity eliminates the 3’ extension and results in the ectopic activation of abd-A. Thus, a tissue-specific change in the length of a ncRNA is used to generate a precise pattern of gene expression in a higher eukaryote.
Genome-wide identification of protein binding sites in mammalian cells
Authors: Liu Fenglin , Ma Tianyu , Zhang Yu-Xiang 
Published: October 2021

AbstractWe present GWPBS-Cap, a method to capture genome-wide protein binding sites (PBSs) without using antibodies. Using this technique, we identified many protein binding sites with different binding strengths between proteins and DNA. The PBSs can be useful to predict transcription binding sites and the co-localization of multiple transcription factors in the genome. The results also revealed that active promoters contained more protein binding sites with lower NaCl tolerances. Taken together, GWPBS-Cap can be used to efficiently identify protein binding sites and reveal genome-wide landscape of DNA-protein interactions.
Balancing selection at a wing pattern locus is associated with major shifts in genome-wide patterns of diversity and gene flow
Authors: Rodríguez de Cara María Ángeles , Jay Paul , Rougemont Quentin , Chouteau Mathieu , Whibley Annabel , Huber Barbara , Piron-Prunier Florence , Ramos Renato Rogner , Freitas André V. L. , Salazar Camilo , Silva-Brandão Karina Lucas , Torres Tatiana Teixeira , Joron Mathieu 
Published: October 2021

AbstractSelection shapes genetic diversity around target mutations, yet little is known about how selection on specific loci affects the genetic trajectories of populations, including their genome-wide patterns of diversity and demographic responses. Here we study the patterns of genetic variation and geographic structure in a neotropical butterfly,Heliconius numata, and its closely related allies in the so-called melpomene-silvaniform clade.H. numatais known to have evolved an inversion supergene which controls variation in wing patterns involved in mimicry associations with distinct groups of co-mimics whereas it is associated to disassortative mate preferences and heterozygote advantage at this locus. We contrasted patterns of genetic diversity and structure 1) among extant polymorphic and monomorphic populations ofH. numata, 2) betweenH. numataand its close relatives, and 3) between ancestral lineages. We show thatH. numatapopulations which carry the inversions as a balanced polymorphism show markedly distinct patterns of diversity compared to all other taxa. They show the highest genetic diversity and effective population size estimates in the entire clade, as well as a low level of geographic structure and isolation by distance across the entire Amazon basin. By contrast, monomorphic populations ofH. numataas well as its sister species and their ancestral lineages all show lower effective population sizes and genetic diversity, and higher levels of geographical structure across the continent. One hypothesis is that the large effective population size of polymorphic populations could be caused by the shift to a regime of balancing selection due to the genetic load and disassortative preferences associated with inversions. Testing this hypothesis with forward simulations supported the observation of increased diversity in populations with the supergene. Our results are consistent with the hypothesis that the formation of the supergene triggered a change in gene flow, causing a general increase in genetic diversity and the homogenisation of genomes at the continental scale.
Re-charging your fats: Charmm36 parameters for neutral lipids triacylglycerol and diacylglycerol
Authors: Campomanes Pablo , Prabhu Janak , Zoni Valeria , Vanni Stefano 
Published: October 2021

AbstractNeutral lipids (NLs) are an abundant class of cellular lipids. They are characterized by the total lack of charged chemical groups in their structure, and, as a consequence, they play a major role in intracellular lipid storage. NLs that carry a glycerol backbone, such as triacylglycerols (TGs) and diacylglycerols (DGs), are also involved in the biosynthetic pathway of cellular phospholipids, and they have recently been the subject of numerous structural investigations by means of atomistic molecular dynamics (MD) simulations. However, conflicting results on the physicochemical behavior of NLs were observed depending on the nature of the atomistic force field used. Here, we show that current phospholipid-derived CHARMM36 parameters for DGs and TGs cannot reproduce adequately interfacial properties of these NLs, due to excessive hydrophilicity at the glycerol-ester region. By following a CHARMM36-consistent parameterization strategy, we develop new parameters for both TGs and DGs that are compatible with both cutoffbased and Particle Mesh Ewald (PME) schemes for the treatment of Lennard Jones interactions. We show that our new parameters can reproduce interfacial properties of NLs and their behavior in more complex lipid assemblies. We discuss the implications of our findings in the context of intracellular lipid storage and NLs cellular activity.
Loss of Nrf1 rather than Nrf2 leads to inflammatory accumulation of lipids and reactive oxygen species (ROS) in human hepatoma cells, which is alleviated by 2-bromopalmitate
Authors: Deng Rongzhen , Zheng Ze , Hu Shaofan , Wang Meng , Feng Jing , Mattjus Peter , Zhang Zhengwen , Zhang Yiguo 
Published: October 2021

AbstractSince Nrf1 and Nrf2 are essential for regulating the lipid metabolism pathways, their dysregulation has thus been shown to be critically involved in the non-controllable inflammatory transformation into cancer. Herein, we have explored the molecular mechanisms underlying their distinct regulation of lipid metabolism, by comparatively analyzing the changes in those lipid metabolism-related genes inNrf1α–/–and/orNrf2–/–cell lines relative to wild-type controls. The results revealed that loss of Nrf1α leads to lipid metabolism disorders. That is, its lipid synthesis pathway was up-regulated by the JNK-Nrf2-AP1 signaling, while its lipid decomposition pathway was down-regulated by the nuclear receptor PPAR-PGC1 signaling, thereby resulting in severe accumulation of lipids as deposited in lipid droplets. By contrast, knockout of Nrf2 gave rise to decreases in lipid synthesis and uptake capacity. These demonstrate that Nrf1 and Nrf2 contribute to significant differences in the cellular lipid metabolism profiles and relevant pathological responses. Further experimental evidence unraveled that lipid deposition inNrf1α–/–cells resulted from CD36 up-regulation by activating the PI3K-AKT-mTOR pathway, leading to abnormal activation of the inflammatory response. This was also accompanied by a series of adverse consequences, e.g., accumulation of reactive oxygen species (ROS) inNrf1α–/–cells. Interestingly, treatment ofNrf1α–/–cells with 2-bromopalmitate (2BP) enabled the yield of lipid droplets to be strikingly alleviated, as accompanied by substantial abolishment of CD36 and critical inflammatory cytokines. SuchNrf1α–/–led inflammatory accumulation of lipids, as well as ROS, was significantly ameliorated by 2BP. Overall, this study provides a potential strategy for cancer prevention and treatment by precision targeting of Nrf1, Nrf2 alone or both.
A phylogenetic and transcriptomic study of the β-1,3-glucanase family in tomato identifies candidate targets for fruit improvement
Authors: Paniagua Candelas , Perry Louisa , Benitez-Alfonso Yoselin 
Published: October 2021

AbstractTomato, Solanum lycopersicum, is one of the most cultivated fruits. However, between one-quarter and half of their production is lost during transport and storage. Modifications in cell walls, and specifically pectin composition, delay fruit softening but, so far, the impact of callose metabolism in this process has not been investigated. Callose accumulates in cell walls around plasmodesmata to modify symplasmic transport. It also plays a role in reinforcing cell walls in response to bruising or pathogen invasion. The aim of this work is to identify cell wall β-1,3-glucanases expressed in tomato fruit that can be used as targets to modify callose accumulation during ripening. A phylogenetic analysis identified fifty candidate β -1,3-glucanases in tomato distributed in three clusters (α, β and γ) with evolutionary relations previously characterised in the model Arabidopsis thaliana. Analysis of tomato microarray data indicates different regulatory patterns: the expression of a subset of enzymes in cluster α decreased during ripening, while enzymes in cluster β and γ displayed higher expression in white-red stages. qRT-PCR experiments confirm the differential regulation of enzymes in different clusters suggesting evolutionary divergences that correlate with differences in their predicted localization and function. The potential to exploit this information in the selection of targets to modify cell walls and fruit development is discussed.
CoCoRV: a rare variant analysis framework using publicly available genotype summary counts to prioritize germline disease-predisposition genes
Authors: Chen Wenan , Wang Shuoguo , Tithi Saima Sultana , Ellison David , Wu Gang 
Published: October 2021

ABSTRACTSequencing cases without matched healthy controls hinders prioritization of germline disease-predisposition genes. To circumvent this problem, genotype summary counts from public data sets can serve as controls. However, systematic inflation and false positives can arise if confounding factors are not addressed. We propose a new framework,consistent summarycounts basedrarevariant burden test (CoCoRV), to address these challenges. CoCoRV has consistent variant quality control and filtering, ethnicity-stratified rare variant association test, accurate estimation of inflation factors, powerful FDR control, and can detect rare variants in high linkage disequilibrium. When we applied CoCoRV to pediatric cancer cohorts, the top genes identified were cancer-predisposition genes. We also applied CoCoRV to identify disease-predisposition genes in adult brain tumors and amyotrophic lateral sclerosis. Given that potential confounding factors were well controlled after applying the framework, CoCoRV provides a cost-effective solution to prioritizing disease-risk genes enriched with rare pathogenic variants.
Augmented Transcutaneous Stimulation Using an Injectable Electrode
Authors: Verma Nishant , Graham Robert D , Mudge Jonah , Trevathan James K , Franke Manfred , Shoffstall Andrew J , Williams Justin , Dalrymple Ashley N , Fisher Lee E , Weber Doug J , Lempka Scott F , Ludwig Kip A 
Published: October 2021

AbstractMinimally invasive neuromodulation technologies seek to marry the neural selectivity of implantable devices with the low-cost and non-invasive nature of transcutaneous electrical stimulation (TES). The Injectrode® is a needle-delivered electrode that is injected onto neural structures under image guidance. Power is then transcutaneously delivered to the Injectrode using surface electrodes. The Injectrode serves as a low-impedance conduit to guide current to the deep on-target nerve, reducing activation thresholds by an order of magnitude compared to using only surface stimulation electrodes. To minimize off-target recruitment of cutaneous fibers, the energy transfer efficiency from the surface electrodes to the Injectrode must be optimized.TES energy is transferred to the Injectrode through both capacitive and resistive mechanisms. Electrostatic finite element models generally used in TES research consider only the resistive means of energy transfer by defining tissue conductivities. Here, we present an electroquasistatic model, taking into consideration both the conductivity and permittivity of tissue, to understand transcutaneous power delivery to the Injectrode. The model was validated with measurements taken from (n=4) swine cadavers. We used the validated model to investigate system and anatomic parameters that influence the coupling efficiency of the Injectrode energy delivery system. Our work suggests the relevance of electroquasistatic models to account for capacitive charge transfer mechanisms when studying TES, particularly when high-frequency voltage components are present, such as those used for voltage-controlled pulses and sinusoidal nerve blocks.
Pan-cancer analysis of patient tumor single-cell transcriptomes identifies promising selective and safe CAR targets in head and neck cancer
Authors: Madan Sanna , Sinha Sanju , Gutkind Silvio J. , Cohen Ezra E. W. , Schäffer Alejandro A. , Ruppin Eytan 
Published: October 2021

AbstractBACKGROUND:Chimeric antigen receptor (CAR) T cell therapies have yielded transformative clinical success for patients with blood tumors, but their full potential remains to be unleashed against solid tumors. One challenge is finding selective targets: cell surface proteins that are expressed widely by cancer cells and minimally by healthy cells in the tumor microenvironment and other normal tissues.METHODS:Analyzing pan-cancer patient tumor single cell transcriptomics data, we first define and quantify selectivity and safety scores of existing CAR targets for indications in which they are in clinical trials or approved. Selectivity scores are computed by the ability of a given surfaceome gene to classify tumor from nontumor cells in the tumor microenvironment. Safety scores are computed by mining healthy tissue transcriptomics and proteomics atlas data. Second, we identify new candidate cell surface CAR targets that have better selectivity and safety scores than the leading targets among those currently being tested, in an indication-specific manner.RESULTS:Remarkably, in almost all cancer types, we cannot find such better targets, testifying to the overall near optimality of the current target space. However, in HPV-negative head and neck squamous cell carcinoma (HNSC), for which there is currently a dearth of existing CAR targets, we find five new targets that have both superior selectivity and safety scores. Among the HNSC new targets, we find a few that additionally are strongly essentiality in HNSC cell lines.
DnaK response to expression of protein mutants is dependent on translation rate and stability
Authors: Christensen Signe , Rämisch Sebastian , André Ingemar 
Published: October 2021

AbstractChaperones play a central part in the quality control system in cells by clearing misfolded and aggregated proteins. The chaperone DnaK acts as a sensor for molecular stress by recognising short hydrophobic stretches of misfolded proteins. As the level of unfolded protein is a function of protein stability, we hypothesised that the level of DnaK response upon overexpression of recombinant proteins would be correlated to stability. Using a set of mutants of the λ-repressor with varying thermal stabilities and a fluorescent reporter system, the effect of stability on DnaK response and protein abundance was investigated. Our results demonstrate that the initial DnaK response is largely dependent on protein synthesis rate but as the recombinantly expressed protein accumulates and homeostasis is approached the response correlates strongly with stability. Furthermore, we observe a large degree of cell-cell variation in protein abundance and DnaK response in more stable proteins.