bluuebunny/crossref_metadata_2025_split huggingface dataset:
Temporally variable drug profiles select for diverse adaptive pathways despite conservation of efflux-based resistance mechanism
Authors: Akanksha  , Mehra Sarika 
Published: May 2023

AbstractAntibiotic resistance is a global health concern with emergence of resistance in bacteria out-competing the discovery of novel drug candidates. While Adaptive Laboratory Evolution (ALE) has been used to identify bacterial resistance determinants, most studies investigate evolution under stepwise increasing drug profiles. Thus, bacterial adaptation under long-term constant drug concentration, a physiologically relevant profile, remains underestimated. Using ALE ofMycobacterium smegmatissubjected to a range of Norfloxacin concentrations under both constant and stepwise increasing drug dosage, we investigated the impact of variation of drug profiles on resistance evolution. All the evolved mutants exhibited a drug concentration dependent increase in resistance accompanied with an increase in the number of mutations. Mutations in an efflux pump regulator, LfrR, were found in all the evolved populations suggesting conservation of an efflux-based resistance mechanism. The selection of these mutations was tightly coupled to the presence of its regulated gene in the genetic background. Further,lfrR mutations appeared early during the adaptive trajectory and imparted low-level resistance. Subsequently, sequential acquisition of other mutations, dependent on the drug profile, led to high-level resistance emergence. While divergent mutational trajectories led to comparable phenotype, populations evolved under constant drug exposure accumulated mutations in dehydrogenase genes whereas in populations under increasing drug exposure, mutations in additional regulatory genes were selected. Our data also shows that irrespective of the evolutionary trajectory, drug target mutations were not selected up to 4X drug concentration. Overall, this work demonstrates that evolutionary trajectory is strongly influenced by the drug profile.
Evolutionary analyses of gene expression divergence inPanicum hallii: exploring constitutive and plastic responses using reciprocal transplants
Authors: Bhaskara Govinal Badiger , Haque Taslima , Bonnette Jason E , Napier Joseph D , Bauer Diane , Schmutz Jeremy , Juenger Thomas E 
Published: May 2023

AbstractThe evolution of gene expression is thought to be an important mechanism of local adaptation and ecological speciation. Gene expression divergence occurs through the evolution of cis-polymorphisms and through more widespread effects driven by trans-regulatory factors. Lovell et al. (2018) studied expression divergence between two ecotypes ofPanicum halliiusing expression quantitative trait loci (eQTL) analyses and discovered a pre-dominance of cis and several trans-regulatory divergences. Here, we explore expression and sequence divergence in a large sample ofP. halliiaccessions encompassing the species range using a reciprocal transplantation experiment. We observed widespread genotype and transplant site drivers of expression divergence, with a limited number of genes exhibited genotype-by-site interactions. We used a modified Fst-Qstoutlier approach (QPCanalysis) to detect local adaptation. We identified 514 genes with constitutive expression divergence above and beyond the levels expected under neutral processes. However, no plastic expression responses met our multiple testing correction asQPCoutliers. ConstitutiveQPCoutlier genes were involved in a number of developmental processes and responses to abiotic environments. Leveraging the earlier eQTL results, we found a strong enrichment of expression divergence, including forQPCoutliers, in genes previously identified with cis and cis-drought interactions but found no patterns related to trans-factors. Population genetic analyses detected elevated sequence divergence (FST, DXY) of promoters and coding sequence of constitutive expression outliers, but little evidence for positive selection on these proteins. Our results are consistent with a hypothesis of cis-regulatory divergence as a primary driver of expression divergence inP. hallii.
Telomere-to-telomere genome of the model plantPhyscomitrium patens
Authors: Bi Guiqi , Zhao Shijun , Yao Jiawei , Wang Huan , Zhao Mengkai , Sun Yuanyuan , Hou Xueren , Jiao Yuling , Ma Yingxin , Yan Jianbin , Dai Junbiao 
Published: May 2023

AbstractThe model plantPhyscomitrium patens(P. patens) has played a pivotal role in enhancing our comprehension of plant evolution, growth, and development. However, the current genome harbors numerous intricate regions that remain unfinished and erroneous. To address these issues, we present an exemplary assembly of theP. patensnuclear genome, which incorporates telomeres and centromere regions, thereby establishing it as the telomere-to-telomere (T2T) genome in a non-seed plant. This T2T genome not only dispels the prevailing misconception regarding chromosome number inP. patensbut also provides indispensable resources for conducting in-depth studies in moss genomics and biology.
Socioeconomic status and healthcare resource disparities among children with epilepsy in the United States: Results from a nationally representative sample
Authors: Muthiah Nallammai , Rothenberger Scott , Abel Taylor J. 
Published: May 2023

AbstractRationaleEpilepsy affects 1% of the US population. Healthcare and socioeconomic disparities are relatively well-studied among adults with epilepsy, but substantially less so among children. This study examines whether children with epilepsy 1) have lower SES than or 2) utilize healthcare resources differently from their peers, and 3) if SES moderates healthcare resource utilization.MethodsData from the 2016-2019 National Survey of Children’s Heath (NSCH) were used to identify children with active “epilepsy or seizure disorder”. Children with versus without epilepsy were compared. SES and healthcare utilization variables were modeled with logistic and Poisson regressions. Significance was assessed at the alpha=0.05 level.ResultsThis analysis included 131,326 children; 835 were diagnosed with active epilepsy. The estimated population prevalence of epilepsy was 0.6%. A higher proportion of those with epilepsy were Black, non-Hispanic. Children with epilepsy were more likely to visit an ED (aOR=5.4), have seen a healthcare professional for medical care (aOR: 2.7), have ≥1 preventative checkup (aOR: 2.3), and receive medical care from a specialist (aOR: 10.3). Children from higher-income households were less likely to have epilepsy (aOR: 0.7). SES moderated the relationship between epilepsy status and ED visits. Still, 7.7% of children with epilepsy needed healthcare but did not receive it, the most common barriers being: ineligibility for services (aOR: 3.2), problems getting an appointment (aOR: 3.9), and transportation issues (aOR: 4.7).ConclusionsChildren with epilepsy were more likely than their peers to live in lower income households, visit EDs, and see healthcare professionals. Despite increased needs, children with epilepsy had 2.6 times the odds of not receiving needed healthcare. SES moderated the relationship between epilepsy status and healthcare resource utilization. Most common barriers to healthcare were: service eligibility, appointment scheduling, and transport. Barrier-specific policy interventions may improve medical care access for children with epilepsy.
Measurement of Oxidative Stress in Huh-7 Cell Line to Determine the Effectiveness of PNPLA3 Targeted Gene Therapy for Mitigation of Lipid and Alcohol Induced Oxidative Stress in the Liver
Authors: Kwon Jihoon , Budyak Elena Ivanovna 
Published: May 2023

AbstractNAFLD is a condition of increased buildup of fat in the liver, causing lipotoxicity that can manifest to cirrhosis, steatosis and fibrosis, which can cause significant and eventually irreversible damage to the liver. A key gene associated is the PNPLA3 I148M variant, which has been shown to display lipogenesis functionality. However, the role of PNPLA3 in increased ROS formation is debated. Moreover, there are no studies determining correlation between the variant and alcohol-induced oxidative stress. This project determines the following mechanistic functions of the PNPLA I148M variant to test for the efficiency of PNPLA3 gene therapy for patients with fatty liver disease and alcohol liver disease.There is a strong correlation between lipid induced oxidative stress and PNPLA3 148M variant. DCFDA shows increased concentration of H2O2for PNPLA3 148M overexpressed cell lines for both ethanol and FFA treatment groups. Moreover, there is a statistical correlation between PNPLA3 148M overexpressed cell lines and increased mitochondrial oxidative stress by MitoSOX cellular ROS analysis methods. This study confirmed the significant decrease in oxidative stress levels for 148I variant overexpressed cell lines and proved the efficiency of PNPLA3 targeted gene therapy to NAFLD patients and suggested the potential use of the therapeutic method to patients with ALD. To ensure gene therapeutic effectiveness for patients with NAFLD and alcoholic liver diseases, further experiments may be needed to verify molecular pathways of ROS formation by PNPLA3 with qPCR analysis.
Learning Equivariant Object Recognition and its Reverse Application to Imagery
Authors: Klepel Florentine , Goebel Rainer 
Published: May 2023

AbstractTo investigate the relationship of perception and imagery, we model the visual ventral stream with an encoder and decoder part with the help of capsule networks. The proposed network consists of V1 and V2 from CorNet-Z, as well as the Capsule Network architecture with the routing by agreement algorithm for V4 and IT. The decoder reverses this architecture to model the feedback activation patterns of the visual ventral stream. The model was trained using EMNIST (letters H, S, C, T). Resulting classification performance was high with good generalization performance to different sizes, positions, and rotations. Contextual information was used for occluded stimuli in the feedback path for reconstructions resulting in high classification performance. Additionally, a pre-trained network was used to reconstruct remapped fMRI activation patterns from higher visual areas. Reconstructions of single-trial imagery data showed significant correlations to physical letter stimuli. The fMRI activation patterns of V1 and V2 and their reconstructions with population receptive field mapping and an autoencoder were related to activation patterns of the network to test biological plausibility. Representational Similarity Analysis and spatial correlations indicated an overlap of information content between the capsule network and the fMRI activations. Due to the capsule networks’ high generalization performance and the implemented feedback connections, the proposed network is a promising approach to improve current modelling efforts of perception and imagery. Further research is needed to compare the presented network to established networks that model the visual ventral stream.
Long-read sequencing reveals extensive DNA methylations in human gut phagenome contributed by prevalently phage-encoded methyltransferases
Authors: Sun Chuqing , Chen Jingchao , Jin Menglu , Zhao Xueyang , Li Yun Y , Dong Yanqi , Gao Na L , Liu Zhi , Bork Peer , Zhao Xing-Ming , Chen Wei-Hua 
Published: May 2023

AbstractDNA methylation is essential for the survival of bacteriophages (phages), yet, we know little about the methylation of their genomes. Here, we analyze the DNA methylation patterns of 8,848 metagenome-assembled high-quality phages across 104 fecal samples using single-molecule real-time (SMRT) sequencing. We show that 97.60% of gut phages could be methylated, and reveal factors that correlate with methylation densities. Phages having higher methylation densities are more prevent, suggesting putative viability advantages of the DNA methylation. Strikingly, more than a third of the phages encode their own DNA methyltransferases (MTases). More MTase copies are associated with increased genome methylation densities, methylation motifs, and higher prevalence of certain phage groups. Most MTases are closely homologous to gut bacterium-encoded ones, likely exchanged during phage-bacterium interactions, and could be used to accurately predict phage-host relationships. Taken together, our results suggest that the gut DNA phages universally use DNA methylation to escape from host defense systems with significant contribution from phage-encoded MTases.
Mono-phosphorylation at Ser4 of Barrier-to-autointegration Factor (Banf1) significantly reduces its DNA binding capability by inducing critical changes in its local conformation and DNA binding surface
Authors: Tang Ming , Suraweera Amila , Nie Xuqiang , Li Zilin , Wells James W. , O’Byrne Kenneth J , Woods Robert J , Bolderson Emma , Richard Derek J 
Published: May 2023

AbstractBarrier-to-Autointegration Factor (Banf1) is a small DNA-bridging protein. The binding status of Banf1 to DNA is regulated by its N-terminal phosphorylation and dephosphorylation, which plays a critical role in cell proliferation. Banf1 can be phosphorylated at Ser4 into mono-phosphorylated Banf1, which is further phosphorylated at Thr3 to form di-phosphorylated Banf1. It was observed decades ago that mono-phosphorylated Banf1 cannot bind to DNA. However, the underlying molecular- and atomic-level mechanisms remain unclear. A clear understanding of these mechanisms will aid in interfering with the cell proliferation process for better global health. Herein, we explored the detailed atomic bases of unphosphorylated Banf1-DNA binding and how mono- and di-phosphorylation of Banf1 impair these atomic bases to eliminate its DNA-binding capability, followed by exploring the DNA-binding capability of mono- and di-phosphorylation Banf1, using comprehensive and systematic molecular modelling and molecular dynamics simulations. This work presented in detail the residue-level binding energies, hydrogen bonds and water bridges between Banf1 and DNA, some of which have not been reported. Moreover, we revealed that mono-phosphorylation of Banf1 causes its N-terminal secondary structure changes, which in turn induce significant changes in Banf1’s DNA binding surface, thus eliminating its DNA-binding capability. At the atomic level, we also uncovered the alterations in interactions due to the induction of mono-phosphorylation that result in the N-terminal secondary structure changes of Banf1. Additionally, our modelling showed that phosphorylated Banf1 with their dominant N-terminal secondary structures bind to DNA with a significantly lower affinity and the docked binding pose are not stable in MD simulations. These findings help future studies in predicting effect of mutations in Banf1 on its DNA-binding capability and open a novel avenue for the development of therapeutics such as cancer drugs, targeting cell proliferation by inducing conformational changes in Banf1’s N-terminal domain.
A landing pad system for multicopy gene integration inIssatchenkia orientalis
Authors: Fatma Zia , Tan Shih-I , Boob Aashutosh Girish , Zhao Huimin 
Published: May 2023

ABSTRACTThe robust nature of the non-conventional yeastIssatchenkia orientalisallows it to grow under highly acidic conditions and therefore, has gained increasing interest in producing organic acids using a variety of carbon sources. Recently, the development of a genetic toolbox forI. orientalis, including an episomal plasmid, characterization of multiple promoters and terminators, and CRISPR-Cas9 tools, has eased the metabolic engineering efforts inI. orientalis. However, multiplex engineering is still hampered by the lack of efficient multicopy integration tools. To facilitate the construction of large, complex metabolic pathways by multiplex CRISPR-Cas9-mediated genome editing, we developed a bioinformatics pipeline to identify and prioritize genome-wide intergenic loci and characterized 47 sites. These loci are screened for guide RNA cutting efficiency, integration efficiency of a gene cassette, the resulting cellular fitness, and GFP expression level. We further developed a landing pad system using components from these well-characterized loci, which can aid in the integration of multiple genes using single guide RNA and multiple repair templates of the user’s choice. We have demonstrated the use of the landing pad for simultaneous integrations of 2, 3, 4, or 5 genes to the target loci with efficiencies greater than 80%. As a proof of concept, we showed how the production of 5-aminolevulinic acid can be improved by integrating five copies of genes at multiple sites in one step. We have further demonstrated the efficiency of this tool by constructing a metabolic pathway for succinic acid production by integrating five gene expression cassettes using a single guide RNA along with five different repair templates, leading to the production of 9 g/L of succinic acid in batch fermentations. This study demonstrates the effectiveness of a single gRNA-mediated CRISPR platform to build complex metabolic pathways in non-conventional yeast. This landing pad system will be a valuable tool for the metabolic engineering ofI. orientalis.HIGHLIGHTSIn silicoscreening was performed to identify 204 unique guide RNAs in the intergenic regions of the genome.27 loci demonstrated high integration efficiency (>80%) and can be used for efficient gene or long pathway (∼18 kb) integration.An array of landing pad systems was installed at four loci for multiplex engineering.Multicopy integration of the gene cassettes (GFP, ALAS) resulted in a proportional increase in GFP fluorescence and 5-ALA production.A five-gene biosynthetic pathway was integrated into the chromosome in one step.This is the first study reporting the development of the landing pad system inIssatchenkia orientalis.
Disentangling reference frames in the neural compass
Authors: Dutriaux Léo , Xu Yangwen , Sartorato Nicola , Lhuillier Simon , Bottini Roberto 
Published: May 2023

SummaryThe neural system that encodes heading direction in humans is found consistently in the medial and superior parietal cortex and the entorhinal-retrosplenial circuit. However, it is still unclear whether heading direction in these different regions is represented within an allocentric or egocentric coordinate system. To investigate this problem, we first asked whether regions encoding (putatively) allocentric facing direction also encode (unambiguously) egocentric goal direction. Second, we assessed whether directional coding in these regions scaled with the preference for an allocentric perspective during everyday navigation. Before the experiment, participants learned different object maps in two geometrically similar rooms. In the MRI scanner, their task was to retrieve the egocentric position of a target object (e.g., Front, Left) relative to an imagined facing direction (e.g., North, West). Multivariate analyses showed, as predicted, that facing direction was encoded bilaterally in the superior parietal lobule (SPL), the retrosplenial complex (RSC), and the left entorhinal cortex (EC). Crucially, we found that the same voxels in the SPL and RSC also coded for egocentric goal direction. Moreover, when facing directions were expressed as egocentric bearings relative to a reference vector, activities for facing direction and egocentric direction were correlated, suggesting a common reference frame. Besides, only the left EC coded allocentric goal direction as a function of the subject’s propensity to use allocentric strategies. Altogether, these results suggest that heading direction in the superior and medial parietal cortex is mediated by an egocentric code, whereas the entorhinal cortex encodes directions according to an allocentric reference frame.
Does the rhetoric art in sustainability reports obstruct the assurance practice?
Authors: Mnif Yosra , Kchaou Jihene 
Published: May 2023

PurposeThis paper aims to investigate the relationship between the readability of sustainability reports and assurance provider effort, captured by assurance delay and the moderating effect of the assurance provider.Design/methodology/approachThis sample consists of companies operating in sustainability sensitive industries from 39 countries for the period that covers the years 2016–2018.FindingsThe results show that poor sustainability reporting readability is associated with longer assurance delays. Indeed, assurance providers spend more effort assuring clients when sustainability reports are less readable, as shown by long assurance delay. In addition, increases in assurance delay associated with poor sustainability reporting readability are driven by accounting assurance providers. These results hold after controlling for endogeneity using Heckman's (1979) analysis and other measures of assurance delay readability used in prior literature. By checking the specialization of assurance provider partners and setting aside dominant countries, the authors provide insight into the impact of assurance provider specialization on the association between sustainability report readability and assurance provider effort measured by assurance delay and thus, lending further confidence to the strength of the study’s main findings.Research limitations/implicationsThis research provides preliminary evidence on the relationship between sustainability reporting readability and assurance delay as well as the influence of accounting assurance providers.Practical implicationsSustainability assurance practice is viewed as a tool to add or enhance credibility. This study could be considered as another step into driving the standardization of sustainability reporting practice internationally.Originality/valueThis is the first investigation conducted in the sustainability literature on the assurance provider's response to the readability of sustainability reports.
The coupling of project delivery methods and contract strategies for public building projects in Ethiopia
Authors: Legesse Abay , Nejat Ali , Ghebrab Tewodros 
Published: May 2023

Purpose
The purpose of this paper is to use Delphi technique to assess the applicability of coupling various project delivery methods (PDMs) and contract strategies (CSs) for delivery of public building projects (PBP) in Ethiopia.

Design/methodology/approach
To achieve the objective of this research, an online Delphi study was designed, conducted and analyzed using various statistical procedures. Results were compared to CII’s project delivery and CS (PDCS) tool, a US-based PDM selection tool.

Findings
This study converged in the third round signifying a consensus on the importance of design–build and construction manager at risk as alternatives to design–bid–build. In addition, “controlling schedule growth” was deemed to be a major performance measure that needs to be considered for PBP in Ethiopia, a result consistent with the outcomes from CII’s PDCS tool.

Originality/value
Among existing studies, none to the best of the authors’ knowledge has focused on a holistic approach to identify the most appropriate pairings of PDMs and CSs for PBP which was critically needed due to the magnitude and high stakes of these projects. This research is a steppingstone toward gaining knowledge on how to approach these types of projects in fast-growing environments thirsty for new building projects such as in Ethiopia.