bluuebunny/crossref_metadata_2025_split huggingface dataset:
Particle deformability enables control of interactions between membrane-anchored nanoparticles
Authors: Nambiar Nikhil , Loyd Zachary A. , Abel Steven M. 
Published: June 2023

AbstractNanoparticles adsorbed on a membrane can induce deformations of the membrane that give rise to effective interactions between the particles. Previous studies have focused primarily on rigid nanoparticles with fixed shapes. However, DNA origami technology has enabled the creation of deformable nanostructures with controllable shapes and mechanical properties, presenting new opportunities to modulate interactions between particles adsorbed on deformable surfaces. Here we use coarse-grained molecular dynamics simulations to investigate deformable, hinge-like nanostructures anchored to lipid membranes via cholesterol anchors. We characterize deformations of the particles and membrane as a function of the hinge stiffness. Flexible particles adopt open configurations to conform to a flat membrane, whereas stiffer particles induce deformations of the membrane. We further show that particles spontaneously aggregate and that cooperative effects lead to changes in their shape when they are close together. Using umbrella sampling methods, we quantify the effective interaction between two particles and show that stiffer hinge-like particles experience stronger and longer-ranged attraction. Our results demonstrate that interactions between de-formable, membrane-anchored nanoparticles can be controlled by modifying mechanical properties of the particles, suggesting new ways to modulate the self-assembly of particles on deformable surfaces.
Life on the edge: a new toolbox for population-level climate change vulnerability assessments
Authors: Barratt Christopher D. , Onstein Renske E. , Pinsky Malin L. , Steinfartz Sebastian , Kühl Hjalmar S. , Forester Brenna R. , Razgour Orly 
Published: June 2023

AbstractGlobal change is impacting biodiversity across all habitats on earth. New selection pressures from changing climatic conditions and other anthropogenic activities are creating heterogeneous ecological and evolutionary responses across many species’ geographic ranges. Yet we currently lack standardised and reproducible tools to effectively predict the resulting patterns in species vulnerability to declines or range changes.We developed an informatic toolbox that integrates ecological, environmental and genomic data and analyses (environmental dissimilarity, species distribution models, landscape connectivity, neutral and adaptive genetic diversity and genotype-environment associations) to estimate population vulnerability. In our toolbox, functions and data structures are coded in a standardised way so that it is applicable to any species or geographic region where appropriate data are available, for example individual or population sampling and genomic datasets (e.g. RAD-seq, ddRAD-seq, whole genome sequencing data) representing environmental variation across the species geographic range.We apply our toolbox to a georeferenced genomic dataset for the East African spiny reed frog (Afrixalus fornasini) to predict population vulnerability, as well as demonstrating that range loss projections based on adaptive variation can be accurately reproduced using data for two European bat species (Myotis escalerai, andM. crypticus).Our framework sets the stage for large scale, multi-species genomic datasets to be leveraged in a novel climate change vulnerability framework to quantify intraspecific differences in genetic diversity, local adaptation, range shifts and population vulnerability based on exposure, sensitivity, and range shift potential.
Peak-agnostic high-resolution cis-regulatory circuitry mapping using single cell multiome data
Authors: Zhang Zidong , Ruf-Zamojski Frederique , Zamojski Michel , Bernard Daniel J. , Chen Xi , Troyanskaya Olga G. , Sealfon Stuart C. 
Published: June 2023

AbstractSingle same cell RNAseq/ATACseq multiome data provide unparalleled potential to develop high resolution maps of the cell-type specific transcriptional regulatory circuitry underlying gene expression. We present CREMA, a framework that recovers the full cis-regulatory circuitry by modeling gene expression and chromatin activity in individual cells without peak-calling or cell type labeling constraints. We demonstrate that CREMA overcomes the limitations of existing methods that fail to identify about half of functional regulatory elements which are outside the called chromatin “peaks”. These circuit sites outside called peaks are shown to be important cell type specific functional regulatory loci, sufficient to distinguish individual cell types. Analysis of mouse pituitary data identifies a Gata2-circuit for the gonadotrope-enriched disease-associated Pcsk1 gene, which is experimentally validated by reduced gonadotrope expression in a gonadotrope conditional Gata2-knockout model. We present a web accessible human immune cell regulatory circuit resource, and provide CREMA as an R package.
MOCHA: advanced statistical modeling of scATAC-seq data enables functional genomic inference in large human disease cohorts
Authors: Zaim Samir Rachid , Pebworth Mark-Phillip , McGrath Imran , Okada Lauren , Weiss Morgan , Reading Julian , Czartoski Julie L. , Torgerson Troy R. , McElrath M. Juliana , Bumol Thomas F. , Skene Peter J. , Li Xiao-jun 
Published: June 2023

AbstractSingle-cell assay for transposase-accessible chromatin using sequencing (scATAC-seq) has been increasingly used to study gene regulation. However, major analytical gaps limit its utility in studying gene regulatory programs in complex diseases. We developed MOCHA (Model-based single cell Open CHromatin Analysis) with major advances over existing analysis tools, including: 1) improved identification of sample-specific open chromatin, 2) proper handling of technical drop-out with zero-inflated methods, 3) mitigation of false positives in single cell analysis, 4) identification of alternative transcription-starting-site regulation, and 5) transcription factor–gene network construction from longitudinal scATAC-seq data. These advances provide a robust framework to study gene regulatory programs in human disease. We benchmarked MOCHA with four state-of-the-art tools to demonstrate its advances. We also constructed cross-sectional and longitudinal gene regulatory networks, identifying potential mechanisms of COVID-19 response. MOCHA provides researchers with a robust analytical tool for functional genomic inference from scATAC-seq data.
SWI/SNF chromatin remodeling determines brassinosteroid-induced transcriptional activation
Authors: Zhu Tao , Wei Chuangqi , Yu Yaoguang , Zhu Jiameng , Liang Zhenwei , Cui Yuhai , Wang Zhi-Yong , Li Chenlong 
Published: June 2023

AbstractThe brassinosteroid (BR) hormone is a central modulator of plant growth, development, and responses to stresses by activating or repressing the expression of thousands of genes through the transcription factor BRASSINAZOLE-RESISTANT 1 (BZR1) and its homologues. However, the molecular mechanism that determines the transcriptional activation versus repression activity of BZR1 remains largely unclear. Here, we show that BZR1-responsive transcriptional activation at thousands of loci requires the Switch defective/sucrose non-fermentable (SWI/SNF)-complexes-mediated chromatin accessibility regulation. BR-activated BZR1 controls the activation or repression of thousands of BZR1 target genes through reprograming genome-wide chromatin accessibility landscape inArabidopsis thaliana. BZR1 physically interacts with theBRAHMA (BRM)-AssociatedSWI/SNF complexes (BAS), co-localizes with BRM on the genome, and enhances BRM occupancy at sites of increased accessibility by BR. Loss of BRM abrogates the capacity of BZR1 to increase but not decrease chromatin accessibility, blocks BR-induced hypocotyl elongation, and diminishes BZR1-mediated transcriptional activation rather than repression. Together, our work reveals that the BAS chromatin remodeling complex is a critical epigenetic regulatory partner in dictating BZR1-mediated transcriptional activation ability, thus providing a long sought mechanistic explanation for how BR signaling activates gene transcription in shaping diverse developmental programs.TeaserBZR1-responsive transcriptional activation activity at thousands of loci requires the SWI/SNF-complexes-mediated chromatin accessibility regulation.
Bioinformatic Surveillance Leads to Discovery of Two Novel Putative Bunyaviruses Associated with Black Soldier Fly
Authors: Walt Hunter K. , Kooienga Emilia , Cammack Jonathan A. , Tomberlin Jeffery K. , Jordan Heather , Meyer Florencia , Hoffmann Federico G. 
Published: June 2023

ABSTRACTThe black soldier fly (Hermetia illucens,BSF) has emerged as an industrial insect of high promise because of its ability to convert organic waste into nutritious feedstock, making it an environmentally sustainable alternative protein source. As global interest rises, rearing efforts are also upscaled, which is highly conducive to pathogen transmission. Viral epidemics have stifled mass-rearing efforts of other insects of economic importance, such as crickets, silkworms, and honeybees, but little is known about the viruses that associate with BSF. Although it is thought that BSF are unusually resistant to pathogens because of their expansive antimicrobial gene repertoire, surveillance techniques could be useful to identify emerging pathogens and common BSF microbes. In this study, we used high-throughput sequencing data to survey BSF larvae and frass samples, and we identified two novel bunyavirus-like sequences. Our phylogenetic analyses grouped one in the familyNairoviridae, and the other with two unclassified bunyaviruses. We describe these putative novel viruses as BSF Nairovirus-like 1 and BSF uncharacterized bunyavirus-like 1. We identified candidate segments for the full BSF Nairovirus-like 1 genome using a technique based on transcript co-occurrence, and only a partial genome for BSF uncharacterized bunyavirus-like 1. These results emphasize the value of routine BSF colony surveillance and add to the number of viruses associated with BSF.
Parasite-Induced IFN-γ Regulates Host Defense via CD115 and mTOR-Dependent Mechanism of Tissue-Resident Macrophage Death
Authors: Martin Andrew T , Giri Shilpi , Safronova Alexandra , Eliseeva Sophia I , Kwok Samantha F , Yarovinsky Felix 
Published: June 2023

ABSTRACTHost resistance to a common protozoan parasiteToxoplasma gondiirelies on a coordinated immune response involving multiple cell types, including macrophages. Embryonically seeded tissue-resident macrophages (TRMs) play a critical role in maintaining tissue homeostasis but their role in parasite clearance is poorly understood. In this study, we uncovered a crucial aspect of host defense againstT. gondiimediated by TRMs. Through the use of neutralizing antibodies and conditional IFN-γ receptor-deficient mice, we demonstrated that IFN-γ directly mediated the elimination of TRMs. Mechanistically, IFN-γ stimulation rendered macrophages unresponsive to macrophage colony-stimulating factor (M-CSF) and inactivated mTOR signaling by causing the shedding of CD115 (CSFR1), the receptor for M-CSF. Further experiments revealed the essential role of macrophage IFN-γ responsiveness in host resistance toT. gondii.The elimination of peritoneal TRMs emerged as a host defense mechanism aimed at limiting the parasite’s reservoir. The identified mechanism, involving IFN-γ-induced CD115 and mTOR-dependent cell death, provides insights into the adaptation of macrophage subsets during infection and highlights a crucial aspect of host defense against intracellular pathogens.
WRNIP1 prevents transcription-associated genomic instability
Authors: Valenzisi Pasquale , Marabitti Veronica , Pichierri Pietro , Franchitto Annapaola 
Published: June 2023

ABSTRACTR-loops are non-canonical DNA structures that form during transcription and play diverse roles in various physiological processes. Disruption of R-loop homeostasis can lead to genomic instability and replication impairment, contributing to several human diseases, including cancer. Although the molecular mechanisms that protect cells against such events are not fully understood, recent research has identified fork protection factors and DNA damage response proteins as regulators of R-loop dynamics. In this study, we identify the Werner helicase-interacting protein 1 (WRNIP1) as a novel factor that counteracts transcription-associated DNA damage upon replication perturbation. Loss of WRNIP1 leads to R-loop accumulation, resulting in collisions between the replisome and transcription machinery. We observe co-localization of WRNIP1 with transcription/replication complexes and R-loops after replication perturbation, suggesting its involvement in resolving transcription-replication conflicts. Moreover, WRNIP1-deficient cells show impaired replication restart from transcription-induced fork stalling. Notably, transcription inhibition and RNase H1 overexpression rescue all the defects caused by loss of WRNIP1. Importantly, our findings highlight the critical role of WRNIP1 ubiquitin-binding zinc finger (UBZ) domain in preventing pathological persistence of R-loops and limiting DNA damage, thereby safeguarding genome integrity.
A synthetic biology approach to assemble and reboot clinically-relevantPseudomonas aeruginosatailed phages
Authors: IPOUTCHA Thomas , RACHARAKS Ratanachat , HUTTELMAIER Stefanie , WILSON Cole , OZER Egon A , HARTMANN Erica M 
Published: June 2023

AbstractThe rise in frequency of antibiotic resistance has made bacterial infections, specificallyPseudomonas aeruginosa, a cause for greater concern. Phage therapy is a promising solution that uses naturally isolated phages to treat bacterial infections. Ecological limitations, which stipulate a discrete host range and the inevitable evolution of resistance, may be overcome through a better understanding of phage biology and the utilization of engineered phages. In this study, we developed a synthetic biology approach to construct tailed phages that naturally target clinically-relevant strains ofPseudomonas aeruginosa. As proof of concept, we successfully cloned and assembled the JG024 and DMS3 phage genomes in yeast using transformation-associated recombination (TAR) cloning and rebooted these two phage genomes in two different strains ofP. aeruginosa. We identified factors that affected phage reboot efficiency like the phage species or the presence of antiviral defense systems in the bacterial strain. We have successfully extended this method to two other phage species and observed that the method enables the reboot of phages that are naturally unable to infect the strain used for reboot. This research represents a critical step towards the construction of clinically-relevant, engineeredP. aeruginosaphages.ImportancePseudomonas aeruginosais a bacterium responsible for severe infections and a common major complication in cystic fibrosis. The use of antibiotics to treat bacterial infections has become increasingly difficult as antibiotic resistance has become more prevalent. Phage therapy is an alternative solution that is already being used in some European countries, but its use is limited by narrow host range due to the phage receptor specificity, the presence of antiviral defense systems in the bacterial strain, and the possible emergence of phage resistance. In this study, we demonstrate the use of a synthetic biology approach to construct and reboot clinically-relevantP. aeruginosatailed phages. This method enables a significant expansion of possibilities through the construction of engineered phages for therapy applications.
Theft of Host Transferrin Receptor-1 byToxoplasma gondiiis required for infection
Authors: Denton Stephen L. , Mejia Alexa , Nevarez Lindsay L. , Soares Miguel P. , Fox Barbara A. , Bzik David J. , Gigley Jason P. 
Published: June 2023

AbstractNutrient acquisition by apicomplexan parasites is essential to drive their intracellular replication, yet the mechanisms that underpin essential nutrient acquisition are not defined. Using the apicomplexan modelToxoplasma gondii, we show that host cell proteins including the transferrin receptor 1, transferrin, ferritin heavy and light chains, and clathrin light chain are robustly taken up by tachyzoites. Tachyzoite acquisition of host cell protein was not related to host cell type or parasite virulence phenotypes. Bradyzoites possessed little capacity to acquire host cell proteins consistent with the cyst wall representing a barrier to host cell protein cargo. Increased trafficking of host cell transferrin receptor 1 and transferrin to endolysosomes boosted tachyzoite acquisition of host proteins and growth rate. Theft of host transferrin 1 and transferrin did not significantly affect iron levels in the tachyzoite. This study provides insight into essential functions associated with parasite theft of host iron sequestration and storage proteins.
A fast method to distinguish between fermentative and respiratory metabolisms in single yeast cells
Authors: Luzia L. , Battjes J. , Zwering V. E. , Jansen D. B. , Melkonian C. , Teusink B. 
Published: June 2023

ABSTRACTSaccharomyces cerevisiaeadapts its metabolism according to nutrient availability. Typically, it rapidly ferments glucose to ethanol, and then shifts to respiration when glucose becomes limited. However, our understanding of the regulation of metabolism is largely based on population averages, whereas nutrient transitions may cause heterogeneous responses at the individual cell level. Although protein expression can be followed at the single-cell level as a proxy for metabolic modes, direct assessment of the contribution of respiration or (respiro)fermentation to energy metabolism is lacking. Here we describe a method to quickly differentiate between fermentative and respiratory metabolisms in individual cells of budding yeast. The method explores the use of the fluorescent FRET-based biosensor yAT1.03 to measure cytosolic ATP, coupled with the respiratory inhibitor Antimycin A. For the method validation, we used cells under fermentative and respiratory regimes from batch and chemostat cultures. Upon Antimycin A addition, we observed a sharp decrease of the normalized FRET ratio for respiratory cells; respirofermentative cells showed no response. Next, we tracked the changes in metabolism during the diauxic shift of a glucose pre-grown batch culture. Following glucose exhaustion, the entire cell population experienced a progressive rise in intracellular ATP produced via respiration, suggesting a uniform and gradual increase in respiratory capacity as cells pick up growth in a medium with ethanol as the sole carbon source. Overall, the combination of yAT1.03 with Antimycin A is a robust tool to distinguish fermentative from respiratory yeast cells, offering a new single-cell opportunity to study yeast metabolism.Graphical abstractIdentification of fermentative and respiratory metabolisms in yeast cells using an ATP sensor coupled with a respiration inhibitor.(a) yAT1.03 consists of a donor (tdTomato) and an acceptor (ymTq2Δ11) domain linked by a binding domain with affinity to ATP. When ATP binds to the binding domain, donor and acceptor come together and the Förster energy is transferred from the first to the second domain. When expressed inin vivocells the sensor allows real time measurements of ATP changes. (b) Depending on the growth conditions, yeast cells expressing yAT1.03 show a distinct response after being pulsed with the respiratory inhibitor Antimycin A (AA). The drop in ATP levels in respiratory cells caused by AA results from the inhibition of the mitochondrial electron transport chain. (c) Distinct metabolic responses to an AA pulse pre-, during and post-diauxic shift reveal distinct metabolic phenotypes.
Harnessing Escherichia coli’s Dark Genome to Produce Anti-Alzheimer Peptides
Authors: Verma Neeraj , Manvati Siddharth , Dhar Pawan K. 
Published: June 2023

AbstractAlzheimer’s disease (AD) is characterized by progressive neurodegeneration. The critical molecular trigger is believed to be the accumulation of Aβ neurotoxic oligomers. Given the proteolytic processing of Amyloid Precursor Protein (APP) by β-secretase (beta-site APP cleaving enzyme 1, BACE1) as the key step in the building up of Aβ oligomers, BACE inhibitors come with therapeutic prospects of preventing or delaying the onset of Alzheimer’s. To find inhibitory peptides against BACE1, a library of ‘dark peptides’ was constructed from 4400 intergenic DNA sequences ofEscherichia coli. The sequence level analysis was followed by protein structure predictions, molecular docking, and simulation. Based on bioinformatics analysis, 5 potential peptides were screened for experimental validation. Out of these two peptides were identified as lead molecules based on BACE1 inhibitory activity, followed by FRET inhibitory assay, western blot, and RT-PCR. An 86.7 % drop in BACE1 level was observed in the presence of the ECOI2 peptide. Though encouraging results were obtained from in-silico and in-vitro studies, more work is required to study the efficacy of these peptides in suitable animal models.
The effects of nano– and microplastic ingestion on the survivorship and reproduction ofAedes aegypti(L.) andAedes albopictus(Skuse)
Authors: McConnel Gabriella , Lawson Jordann , Cañas-Carrell Jaclyn E. , Brelsfoard Corey L. 
Published: June 2023

AbstractMicroplastics (MPs) and nanoplastics (NPs) are pervasive environmental pollutants that raise concerns due to their potential impact on organisms across different trophic levels. While the effects of MPs on aquatic organisms have been extensively studied, their impacts on terrestrial organisms, mainly insects, still need to be explored. This study investigates the effects of MP and NP ingestion on the survivorship and reproduction of two medically important mosquito species,Aedes aegypti(L.), andAe. albopictus(Skuse). Larval and pupal survivorship were not significantly affected by particle size or concentration, but there was a reduction ofAe. aegyptipupal survivorship associated with the ingestion of 0.03 µm NPs. Results also suggest that ingesting 0.03 µm NPs reduced egg production in both mosquito species. However, there was little impact of 0.03 NP and 1.0 µm MP ingestion on adult survivorship and longevity. To further investigate the effects of MP ingestion on mosquito fitness, we also examined the effects of lab generated MPs of varying shape, size, and plastic polymer type onAe. aegyptiimmature and adult survivorship. The data suggests that the polymer type and shape did not impactAe. aegyptiimmature or adult survivorship. These findings highlight the potential consequences and the need to investigate further the ecological and potential public health implications of MP and NP ingestion by mosquitoes.
Structural insights into Rad18 targeting by the SLF1 BRCT domains
Authors: Huang Wei , Qiu Fangjie , Zheng Lin , Shi Meng , Shen Miaomiao , Zhao Xiaolan , Xiang Song 
Published: June 2023

AbstractRad18 interacts with the SMC5/6 localization factor 1 (SLF1) to recruit the SMC5/6 complex to DNA damage sites for repair. The mechanism of the specific Rad18 recognition by SLF1 is unclear. Here, we present crystal structure of the tandem BRCT repeat (tBRCT) in SLF1 (SLF1tBRCT) bound with the interacting Rad18 peptide. Our structure and biochemical studies demonstrate that SLF1tBRCTinteracts with two phosphoserines and adjacent residues in Rad18 for high affinity and specificity Rad18 recognition. We found that SLF1tBRCTutilizes mechanisms common among tBRCTs as well as unique ones for Rad18 binding, the latter include interactions with an α-helical structure in Rad18 that has not been observed in other tBRCT-bound ligand proteins. Our work provides structural insights into Rad18 targeting by SLF1 and expands the understanding of BRCT-mediated complex assembly.