bluuebunny/crossref_metadata_2025 huggingface dataset:
Highlighting the hidden: A tagging strategy for monitoring the association of GABARAP with microtubules in living cells
Authors: Üffing Alina , Gold Lisa , Gensch Thomas , Weiergräber Oliver H. , Hoffmann Silke , Willbold Dieter
Published: November 2023

GABARAP, like other ATG8 proteins, is a ubiquitin-like modifier and its C-terminal lipid conjugation enables association with cellular membranes. To prevent interference with the lipidation process, N-terminal fluorescent protein (FP) tagging strategies have become the standard for studying ATG8 localization and function in living cells, significantly contributing to our understanding of this protein family’s multifaceted roles.

However, recent findings have unveiled potential limitations of bulky N-terminal tags, particularly regarding ATG8 functionality and localization in specific contexts.

This study employed live cell imaging with particular emphasis on the GABARAP split-tandem construct, GABARAP(G116A)-mTagBFP2-GABARAP (G-B-G), which retains both a free N-terminus and a lipidation-competent C-terminus. Notably, our results revealed a robust association of G-B-G with the microtubule network in living cells which was not observed with N-terminal FP fusions of GABARAP, although earlyin vitrostudies demonstrated an interaction of GABARAP and tubulin. Since we observed alteration of the microtubule network organization for G-B-G, this construct emerges as a valuable tool, which can help shedding light on potential roles of GABARAP in microtubule-associated processes that are integral to autophagy-related and -unrelated cellular transport.
Gene acquisition by giant transposons primes eukaryotes for rapid evolution via horizontal gene transfer
Authors: Urquhart Andrew S , Gluck-Thaler Emile , Vogan Aaron A.
Published: November 2023

Horizontal gene transfer (HGT) disseminates genetic information between species. The significance of HGT in eukaryotes is not well established, with evidence currently limited to isolated examples, typically absent of a mechanism. It has been proposed that mobile elements might be active agents of HGT in eukaryotes, as they are in prokaryotes. To test this hypothesis, we examined a gene cluster, which putatively contributes to formaldehyde resistance and is found within some members of theStarshipsuperfamily of giant transposons. Remarkably, we found four instances wheressfhas been independently acquired by distantly relatedStarships, and show that each acquisition event coincided with the element’s horizontal transfer (at least 9 HGT events in total). Our results demonstrate that acquisition of host-beneficial cargo byStarshipsprimes fungi for rapid and repeated adaptation via HGT, revealing and elevating the role of HGT in eukaryotic biology.
Compact deep neural network models of visual cortex
Authors: Cowley Benjamin R. , Stan Patricia L. , Pillow Jonathan W. , Smith Matthew A.
Published: November 2023

A powerful approach to understanding the computations carried out in visual cortex is to develop models that predict neural responses to arbitrary images. Deep neural network (DNN) models have worked remarkably well at predicting neural responses [1, 2, 3], yet their underlying computations remain buried in millions of parameters. Have we simply replaced one complicated systemin vivowith anotherin silico? Here, we train a data-driven deep ensemble model that predicts macaque V4 responses ∼50% more accurately than currently-used task-driven DNN models. We then compress this deep ensemble to identifycompactmodels that have 5,000x fewer parameters yet equivalent accuracy as the deep ensemble. We verified that the stimulus preferences of the compact models matched those of the real V4 neurons by measuring V4 responses to both ‘maximizing’ and adversarial images generated using compact models. We then analyzed the inner workings of the compact models and discovered a common circuit motif: Compact models share a similar set of filters in early stages of processing but then specialize by heavily consolidating this shared representation with a precise readout. This suggests that a V4 neuron’s stimulus preference is determined entirely by its consolidation step. To demonstrate this, we investigated the compression step of a dot-detecting compact model and found a set of simple computations that may be carried out by dot-selective V4 neurons. Overall, our work demonstrates that the DNN models currently used in computational neuroscience are needlessly large; our approach provides a new way forward for obtaining explainable, high-accuracy models of visual cortical neurons.
An arginine-rich nuclear localization signal (ArgiNLS) strategy for streamlined image segmentation of single-cells
Authors: Szelenyi Eric R. , Navarrete Jovana S. , Murry Alexandria D. , Zhang Yizhe , Girven Kasey S. , Kuo Lauren , Cline Marcella M. , Bernstein Mollie X. , Burdyniuk Mariia , Bowler Bryce , Goodwin Nastacia L. , Juarez Barbara , Zweifel Larry S. , Golden Sam A.
Published: November 2023

High-throughput volumetric fluorescent microscopy pipelines can spatially integrate whole-brain structure and function at the foundational level of single-cells. However, conventional fluorescent protein (FP) modifications used to discriminate single-cells possess limited efficacy or are detrimental to cellular health. Here, we introduce a synthetic and non-deleterious nuclear localization signal (NLS) tag strategy, called ‘Arginine-rich NLS’ (ArgiNLS), that optimizes genetic labeling and downstream image segmentation of single-cells by restricting FP localization near-exclusively in the nucleus through a poly-arginine mechanism. A single N-terminal ArgiNLS tag provides modular nuclear restriction consistently across spectrally separate FP variants. ArgiNLS performance in vivo displays functional conservation across major cortical cell classes, and in response to both local and systemic brain wide AAV administration. Crucially, the high signal-to-noise ratio afforded by ArgiNLS enhances ML-automated segmentation of single-cells due to rapid classifier training and enrichment of labeled cell detection within 2D brain sections or 3D volumetric whole-brain image datasets, derived from both staining-amplified and native signal. This genetic strategy provides a simple and flexible basis for precise image segmentation of genetically labeled single-cells at scale and paired with behavioral procedures.

Significance Statement

Quantifying labeled cells in fluorescent microscopy is a fundamental aspect of modern biology. Critically, the use of short nuclear localization sequences (NLS) is a key genetic modification for discriminating single-cells labeled with fluorescent proteins (FPs). However, mainstay NLS approaches typically localize proteins to the nucleus with limited efficacy, while alternative non-NLS tag strategies can enhance efficacy at the cost of cellular health. Thus, quantitative cell counting using FP labels remains suboptimal or not compatible with health and behavior. Here, we present a novel genetic tagging strategy – named ArgiNLS – that flexibly and safely achieves FP nuclear restriction across the brain to facilitate machine learning-based segmentation of single-cells at scale, delivering a timely update to the behavioral neuroscientist’s toolkit.
Metabolic connections between folate and peptidoglycan pathways inPseudomonas aeruginosainform rational design of a dual-action inhibitor
Authors: Yaeger Luke N. , Sychantha David , Luong Princeton , Shekarriz Shahrokh , Goncalves Océane , Dobrin Annamaria , Ranieri Michael R. , Lamers Ryan P. , Harvey Hanjeong , diCenzo George C. , Surette Michael , Côté Jean-Philippe , Magolan Jakob , Burrows Lori L.
Published: November 2023

Peptidoglycan is an important bacterial macromolecule that confers cell shape and structural integrity, and a key antibiotic target. The synthesis and turnover of peptidoglycan are carefully coordinated with other cellular processes and pathways. Although there are established connections between peptidoglycan and DNA replication or outer membrane biosynthesis, connections between peptidoglycan and folate metabolism are comparatively unexplored. Folate is an essential cofactor for bacterial growth and required for the synthesis of many important metabolites. Here we show that inhibition of folate synthesis in the important Gram-negative pathogenPseudomonas aeruginosahas downstream effects on peptidoglycan metabolism and integrity. Folate inhibitors reduced expression of the AmpC β-lactamase through perturbation of peptidoglycan recycling, potentiating the activity of β-lactams normally cleaved by that resistance enzyme. Folate inhibitors also synergized with fosfomycin, which inhibits MurA - the first committed step in peptidoglycan synthesis - resulting in dose-dependent formation of round cells that underwent explosive lysis.The insights from this work were used to design a dual-active inhibitor that overcomes NDM-1-mediated meropenem resistance and synergizes with the folate inhibitor, trimethoprim. This work shows that folate and peptidoglycan metabolism are intimately connected and offers new opportunities to exploit this relationship in strategies to overcome antibiotic resistance in Gram-negative pathogens.
Spatiotemporal dynamics of successive activations across the human brain during simple arithmetic processing
Authors: Pinheiro-Chagas Pedro , Sava-Segal Clara , Akkol Serdar , Daitch Amy , Parvizi Josef
Published: November 2023

Previous neuroimaging studies have offered unique insights about the spatial organization of activations and deactivations across the brain, however these were not powered to explore the exact timing of events at the subsecond scale combined with precise anatomical source information at the level of individual brains. As a result, we know little about the order of engagement across different brain regions during a given cognitive task. Using experimental arithmetic tasks as a prototype for human-unique symbolic processing, we recorded directly across 10,076 brain sites in 85 human subjects (52% female) using intracranial electroencephalography (iEEG). Our data revealed a remarkably distributed change of activity in almost half of the sampled sites. Notably, an orderly successive activation of a set of brain regions - anatomically consistent across subjects-was observed in individual brains. Furthermore, the temporal order of activations across these sites was replicable across subjects and trials. Moreover, the degree of functional connectivity between the sites decreased as a function of temporal distance between regions, suggesting that information is partially leaked or transformed along the processing chain. Furthermore, in each activated region, distinct neuronal populations with opposite activity patterns during target and control conditions were juxtaposed in an anatomically orderly manner. Our study complements the prior imaging studies by providing hitherto unknown information about the timing of events in the brain during arithmetic processing. Such findings can be a basis for developing mechanistic computational models of human-specific cognitive symbolic systems.

Significance statement

Our study elucidates the spatiotemporal dynamics and anatomical specificity of brain activations across >10,000 sites during arithmetic tasks, as captured by intracranial EEG. We discovered an orderly, successive activation of brain regions, consistent across individuals, and a decrease in functional connectivity as a function of temporal distance between regions. Our findings provide unprecedented insights into the sequence of cognitive processing and regional interactions, offering a novel perspective for enhancing computational models of cognitive symbolic systems.
QTL analysis of floral morphology polymorphisms betweenGilia yorkiiandG. capitata
Authors: DeTemple Joseph M , Chitwood Daniel H , Mosquera Veronica , Whipple Clinton J
Published: November 2023

Speciation is a complex process typically accompanied by significant genetic and morphological differences between sister populations. In plants, this can result in divergent floral morphologies causing pollinator differences and reproductive isolation between populations. Here, we explore floral trait differences between two recently diverged species,Gilia yorkiiandG. capitata. The distributions of floral traits in parental, F1, and F2 populations are compared, and groups of correlated traits are identified. We describe the genetic architecture of floral traits through a quantitative trait locus (QTL) analysis using an F2 population of 187 individuals. While all identified QTLs were of moderate (10-25%) effect, interestingly, many QTL intervals colocalized on Chromosomes 6 and 9, suggesting that sets of traits may share a common genetic basis. Our results provide a framework for future identification of genes involved in the evolution of floral morphology.
Distinct microcolony morphologies promote flow-dependent bacterial colonization
Authors: Hallinen Kelsey M. , Bodine Steven P. , Stone Howard A. , Muir Tom W. , Wingreen Ned S. , Gitai Zemer
Published: November 2023

Fluid flows can impact bacterial behaviors in unexpected ways (1–3). The high shear rate in heart valves should reduce colonization, but in endocarditis, valves are often counter-intuitively colonized byStaphylococcus aureusandEnterococcus faecalis(4, 5). Here we discover bacteria-specific mechanisms for preferential surface colonization in higher shear rate environments. This behavior enables bacteria that are outcompeted in low flow to dominate in high flow. Flow-dependent colonization byS. aureusandE. faecalisare mediated by distinct mechanisms that depend on each species’ microcolony morphologies: transport of a dispersal signaling molecule for clusteredS. aureusand mechanical forces for linear chains ofE. faecalis. These results suggest that microcolony morphologies have previously unappreciated costs and benefits in different environments, like those introduced by flow.

One-Sentence Summary

Bacterial surface colonization in high fluid flow depends upon the species’ clustered or chained microcolony morphologies.
Fluorogenic, sub-single-turnover monitoring of enzymatic reactions involving NAD(P)H provides a generalised platform for directed ultrahigh throughput evolution of biocatalysts in microdroplets
Authors: Penner Matthew , Klein Oskar James , Gantz Maximilian , Nintzel Friederike E. H. , Prowald Anne-Cathrin , Boss Sally , Barker Paul , Dupree Paul , Hollfelder Florian
Published: November 2023

Enzyme engineering and discovery are crucial for a future sustainable bioeconomy. Harvesting new biocatalysts from large libraries through directed evolution or functional metagenomics requires accessible, rapid assays. Ultra-high throughput screening formats often require optical readouts, leading to the use of model substrates that may misreport target activity and necessitate bespoke synthesis. This is a particular challenge when screening glycosyl hydrolases, which leverage molecular recognition beyond the target glycosidic bond, so that complex chemical synthesis would have to be deployed to build a fluoro- or chromogenic substrate. In contrast, coupled assays represent a modular ‘plug-and-play’ system: any enzyme- substrate pairing can be investigated, provided the reaction can produce a common intermediate which links the catalytic reaction to a detection cascade readout. Here, we establish a detection cascade producing a fluorescent readout in response to NAD(P)H via glutathione reductase and a subsequent thiol-mediated uncaging reaction, with a low nanomolar detection limit in plates. Further scaling down to microfluidic droplet screening is possible: the fluorophore is leakage- free and we report a three orders of magnitude improved sensitivity compared to absorbance- based systems, so that less than one turnover per enzyme molecule expressed from a single cell is detectable. Our approach enables the use of non-fluorogenic substrates in droplet-based enrichments, with applicability in screening for glycosyl hydrolases and imine reductases (IREDs). To demonstrate the assay’s readiness for combinatorial experiments, one round of directed evolution was performed to select a glycosidase processing a natural substrate, beechwood xylan, with improved kinetic parameters from a pool of >106mutagenized sequences.
Human extracellular sulfatases use a dual mechanism for regulation of growth factor interactions with heparan sulfate proteoglycans
Authors: Timm Bryce M. , Follmar Julianna L. , Porell Ryan N. , Glass Kimberly , Thacker Bryan E. , Glass Charles A. , Godula Kamil
Published: November 2023

Membrane-associated heparan sulfate (HS) proteoglycans (PGs) contribute to the regulation of extracellular cellular signaling cues, such as growth factors (GFs) and chemokines, essential for normal organismal functions and implicated in various pathophysiologies. PGs accomplish this by presenting high affinity binding sites for GFs and their receptors through highly sulfated regions of their HS polysaccharide chains. The composition of HS, and thus GF-binding specificity, are determined during biosynthetic assembly prior to installation at the cell surface. Two extracellular 6-O-endosulfatase enzymes (Sulf-1 and Sulf-2) can uniquely further edit mature HS and alter its interactions with GFs by removing specific sulfation motifs from their recognition sequence on HS. Despite being implicated as signaling regulators during development and in disease, the Sulfs have resisted structural characterization, and their substrate specificity and effects on GF interactions with HS are still poorly defined. Using a panel of PG-mimetics comprising compositionally-defined bioengineered recombinant HS (rHS) substrates in combination with GF binding and enzyme activity assays, we have discovered that Sulfs control GF-HS interactions through a combination of catalytic processing and competitive blocking of high affinity GF-binding sites, providing a new conceptual framework for understanding the functional impact of these enzymes in biological context. Although the contributions from each mechanism are both Sulf- and GF-dependent, the PG-mimetic platform allows for rapid analysis of these complex relationships.

Significance Statement

Cells rely on extracellular signals such as growth factors (GFs) to mediate critical biological functions. Membrane-associated proteins bearing negatively charged heparan sulfate (HS) sugar chains engage with GFs and present them to their receptors, which regulates their activity. Two extracellular sulfatase (Sulf) enzymes can edit HS and alter GF interactions and activity, although the precise mechanisms remain unclear. By using chemically defined HS-mimetics as probes, we have discovered that Sulfs can modulate HS by means of catalytic alterations and competitive blocking of GF-binding sites. These unique dual activities distinguish Sulfs from other enzymes and provide clues to their roles in development and disease.
Assembly reactions of SARS-CoV-2 nucleocapsid protein with nucleic acid
Authors: Zhao Huaying , Syed Abdullah M. , Khalid Mir M. , Nguyen Ai , Ciling Alison , Wu Di , Yau Wai-Ming , Srinivasan Sanjana , Esposito Dominic , Doudna Jennifer A. , Piszczek Grzegorz , Ott Melanie , Schuck Peter
Published: November 2023

The viral genome of SARS-CoV-2 is packaged by the nucleocapsid (N-) protein into ribonucleoprotein particles (RNPs), 38±10 of which are contained in each virion. Their architecture has remained unclear due to the pleomorphism of RNPs, the high flexibility of N-protein intrinsically disordered regions, and highly multivalent interactions between viral RNA and N-protein binding sites in both N-terminal (NTD) and C-terminal domain (CTD). Here we explore critical interaction motifs of RNPs by applying a combination of biophysical techniques to mutant proteins binding different nucleic acids in anin vitroassay for RNP formation, and by examining mutant proteins in a viral assembly assay. We find that nucleic acid-bound N-protein dimers oligomerizeviaa recently described protein-protein interface presented by a transient helix in its long disordered linker region between NTD and CTD. The resulting hexameric complexes are stabilized by multi-valent protein-nucleic acid interactions that establish crosslinks between dimeric subunits. Assemblies are stabilized by the dimeric CTD of N-protein offering more than one binding site for stem-loop RNA. Our study suggests a model for RNP assembly where N- protein scaffolding at high density on viral RNA is followed by cooperative multimerization through protein-protein interactions in the disordered linker.
Predicting Antibody and ACE2 Affinity for SARS-CoV-2 BA.2.86 and JN.1 withIn SilicoProtein Modeling and Docking
Authors: Yasa Shirish , Guirales-Medrano Sayal , Machado Denis Jacob , Ford Colby T. , Janies Daniel
Published: November 2023

The emergence of SARS-CoV-2 lineages derived from Omicron, including BA.2.86 (nicknamed “Pirola”) and its relative, JN.1, has raised concerns about their potential impact on public and personal health due to numerous novel mutations. Despite this, predicting their implications based solely on mutation counts proves challenging. Empirical evidence of JN.1’s increased immune evasion capacity in relation to previous variants is mixed. To improve predictions beyond what is possible based solely on mutation counts, we conducted extensivein silicoanalyses on the binding affinity between the RBD of different SARS-CoV-2 variants (Wuhan-Hu-1, BA.1/B.1.1.529, BA.2, XBB.1.5, BA.2.86, and JN.1) and neutralizing antibodies from vaccinated or infected individuals, as well as the human angiotensin-converting enzyme 2 (ACE2) receptor. We observed no statistically significant difference in binding affinity between BA.2.86 or JN.1 and other variants. Therefore, we conclude that the new SARS-CoV-2 variants have no pronounced immune escape or infection capacity compared to previous variants. However, minor reductions in binding affinity for both the antibodies and ACE2 were noted for JN.1. We discuss the implications of thein silicofindings and highlight the need for modeling and docking studies to go above and beyond mutation and basic serological neutralization analysis. Future research in this area will benefit from increased structural analyses of memory B-cell derived antibodies and should emphasize the importance of choosing appropriate samples forin silicostudies to assess protection provided by vaccination and infection. More-over, the fitness benefits of genomic variation outside of the RBD of BA.2.86 and JN.1 need to be investigated. This research contributes to understanding the BA.2.86 and JN.1 variants’ potential impact on public health. Taken together, this work introduces a paradigm for functional genomic epidemiology in ongoing efforts to combat the evolving SARS-CoV-2 pandemic and prepare for other hazards.
Identifying cooperative genes causing cancer progression with dynamic causal inference
Authors: Cifuentes-Bernal Andres M. , Liu Lin , Li Jiuyong , Le Thuc Duy
Published: November 2023

Cancer progression is driven by complex gene interactions, which are not fully understood due to the dynamic and multifaceted nature of the disease. Traditional methods for identifying genes driving cancer typically focus on detecting mutational events, often neglecting other genetic alterations and the temporal dynamics of the cancer development. This study introduces a novel approach that expands our understanding of cancer by identifying cooperative networks of cancer drivers through dynamic causal inference, complementing classical mutation-based methods.

We developed a data-driven causal inference method that integrates a temporal dimension to gene expression data through pseudotime analysis. By modelling cancer progression as a dynamic system, the method evaluates gene interactions and their causal relationships using causal kinetic models (CKMs). This approach enables detecting cancer driver genes regardless of their mutational status. The approach was applied to both single cell and bulk sequencing datasets of breast cancer to identify and rank cancer driver genes based on their stability on the causal model.

The proposed method effectively identifies and ranks cancer driver genes by considering their dynamic interactions during cancer progression. It systematically identified cancer driver genes in both categories: those with single nucleotide variants (SNVs) and those with other alterations. The method demonstrated a significant overlap with known cancer driver genes from the Cancer Gene Census, validating its effectiveness. Additionally, the method uncovered novel driver genes that act cooperatively to influence cancer development, offering a more comprehensive view of the genetic mechanisms underlying cancer. Our approach, along with the scripts for the experiments and datasets used, can be found athttps://github.com/AndresMCB/DynamicCancerDriverKM
Loss of cardiac PFKFB2 drives Metabolic, Functional, and Electrophysiological Remodeling in the Heart
Authors: Harold Kylene M. , Matsuzaki Satoshi , Pranay Atul , Loveland Brooke L. , Batushansky Albert , Mendez Garcia Maria F. , Eyster Craig , Stavrakis Stavros , Chiao Ying Ann , Kinter Michael , Humphries Kenneth M.
Published: November 2023

Background

Phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2) is a critical glycolytic regulator responsible for upregulation of glycolysis in response to insulin and adrenergic signaling. PFKFB2, the cardiac isoform of PFK-2, is degraded in the heart in the absence of insulin signaling, contributing to diabetes-induced cardiac metabolic inflexibility. However, previous studies have not examined how the loss of PFKFB2 affects global cardiac metabolism and function.

Methods

To address this, we have generated a mouse model with a cardiomyocyte-specific knockout of PFKFB2 (cKO). Using 9-month-old cKO and control (CON) mice, we characterized impacts of PFKFB2 on cardiac metabolism, function, and electrophysiology.

Results

cKO mice have a shortened lifespan of 9 months. Metabolically, cKO mice are characterized by increased glycolytic enzyme abundance and pyruvate dehydrogenase (PDH) activity, as well as decreased mitochondrial abundance and beta oxidation, suggesting a shift toward glucose metabolism. This was supported by a decrease in the ratio of palmitoyl carnitine to pyruvate-dependent mitochondrial respiration in cKO relative to CON animals. Metabolomic, proteomic, and western blot data support the activation of ancillary glucose metabolism, including pentose phosphate and hexosamine biosynthesis pathways. Physiologically, cKO animals exhibited impaired systolic function and left ventricular (LV) dilation, represented by reduced fractional shortening and increased LV internal diameter, respectively. This was accompanied by electrophysiological alterations including increased QT interval and other metrics of delayed ventricular conduction.

Conclusions

Loss of PFKFB2 results in metabolic remodeling marked by cardiac ancillary pathway activation. This could delineate an underpinning of pathologic changes to mechanical and electrical function in the heart.

Clinical Perspective

What is New?

We have generated a novel cardiomyocyte-specific knockout model of PFKFB2, the cardiac isoform of the primary glycolytic regulator Phosphofructokinase-2 (cKO).

The cKO model demonstrates that loss of cardiac PFKFB2 drives metabolic reprogramming and shunting of glucose metabolites to ancillary metabolic pathways.

The loss of cardiac PFKFB2 promotes electrophysiological and functional remodeling in the cKO heart.

What are the Clinical Implications?

PFKFB2 is degraded in the absence of insulin signaling, making its loss particularly relevant to diabetes and the pathophysiology of diabetic cardiomyopathy.

Changes which we observe in the cKO model are consistent with those often observed in diabetes and heart failure of other etiologies.

Defining PFKFB2 loss as a driver of cardiac pathogenesis identifies it as a target for future investigation and potential therapeutic intervention.
Connecting the dots: applying multispecies connectivity in marine park network planning
Authors: Gates Katie , Sandoval-Castillo Jonathan , Barceló Andrea , Bertram Andrea , Pratt Eleanor A. L. , Teske Peter R. , Möller Luciana , Beheregaray Luciano B.
Published: November 2023

Marine ecosystems are highly dynamic, and their connectivity is affected by a complex range of biological, spatial, and oceanographic factors. Incorporating connectivity as a factor in the planning and management of marine protected areas (MPAs) is important yet challenging. Here, we used intraspecific genetic and genomic data for five marine species with varying life histories to characterise connectivity across a recently established South Australian MPA network. We generated connectivity networks, estimated cross-species concordance of connectivity patterns, and tested the impact of key spatial and oceanographic factors on each species. Connectivity patterns varied markedly among species, but were most correlated among those with similar dispersal strategies. Ordination analyses revealed significant associations with both waterway distances and oceanographic advection models. Notably, waterway distances provided better predictive power in all-species combined analyses. We extended the practical relevance of our findings by employing spatial prioritisation with Marxan, using node values derived from both genetic and geographic connectivity networks. This allowed the identification of several priority areas for conservation, and substantiated the initial decision to employ spatial distance as a proxy for biological connectivity for the design of the South Australian marine park network. Our study establishes a baseline for connectivity monitoring in South Australian MPAs, and provides guidelines for adapting this framework to other protected networks with intraspecies genetic data.
Investigation of microglial diversity in a mouse model of Parkinson’s disease pathology
Authors: Iovino L , VanderZwaag J , Kaur G , Khakpour P , Giusti V , Chiavegato A , Tenorio-Lopes L , Greggio E , Tremblay ME , Civiero L
Published: November 2023

Microglia, the central nervous system resident immune cells, are now recognized to critically impact homeostasis maintenance and contribute to the outcomes of various pathological conditions including Parkinson’s disease (PD). Microglia are heterogenous, with a variety of states recently identified in aging and neurodegenerative disease models, including the ‘disease-associated microglia’ (DAM) which present a selective enrichment ofCLEC7Aencoding the CLEC7A or DECTIN1 protein, and the ‘dark microglia’ (DM) displaying markers of cellular stress at the ultrastructural level. However, the roles of CLEC7A-positive microglia and DM in the pathology of PD have remained largely elusive. By applying immunofluorescence and scanning electron microscopy, we aimed to characterize 1) the CLEC7A -positive cell population, and 2) their possible relationships to DM in a mouse model harboring a G2019S pathogenic mutation of the LRRK2 gene, the most common mutation linked to PD. We examined 18-month-old mice, comparing between LRRK2 G2019S knock-in mice and wild-type controls. In the dorsal striatum, a region affected by PD pathology, extensive ultrastructural features of cellular stress (e.g., endoplasmic reticulum and Golgi apparatus dilation), as well as reduced direct cellular contacts, were observed for microglia from LRRK2 G2019S miceversuscontrols. CLEC7A-positive microglia exhibited extensive phagocytic ultrastructural characteristics in the LRRK2 G2019S mice. Additionally, the LRRK2 G2019S mice presented a higher proportion of DM. Lastly, immunofluorescence and biochemical analysis revealed higher number of CLEC7A-positive cells in Lrrk2 G2019S genotypeversuscontrols both in tissues and in primary microglia cells. Of note, CLEC7A-positive cells present a selective enrichment of ameboid morphology and tend to cluster in the pathogenic animal. In summary, we provide novel insights into the involvement of recently-defined microglial states, CLEC7A-positive cells and DM, in the context of LRRK2 G2019S PD pathology.
A liquid-like coat mediates chromosome clustering during mitotic exit
Authors: Hernandez-Armendariz Alberto , Sorichetti Valerio , Hayashi Yuki , Brunner Andreas , Ellenberg Jan , Šarić Anđela , Cuylen-Haering Sara
Published: November 2023

Summary

The individualization of chromosomes during early mitosis and their clustering upon exit from cell division are two key transitions that ensure efficient segregation of eukaryotic chromosomes. Both processes are regulated by the surfactant-like protein Ki-67, but how Ki-67 achieves these diametric functions has remained unknown. Here, we report that Ki-67 radically switches from a chromosome repellent to a chromosome attractant during anaphase. We show that Ki-67 dephosphorylation during mitotic exit and the simultaneous exposure of a conserved basic patch induce the RNA-dependent formation of a liquid-like condensed phase on the chromosome surface. Experiments and coarse-grained simulations support a model in which the coalescence of chromosome surfaces driven by phase separation promote clustering of chromosomes. Our study reveals how the switch of Ki-67 from a surfactant to a liquid-like condensed phase can generate the mechanical forces during genome segregation that are required for re-establishing nuclear-cytoplasmic compartmentalization after mitosis.
A Novel AI-Designed Antimicrobial Peptide Synergistically Potentiates Aminoglycosides against Colistin- and Carbapenem-ResistantAcinetobacter baumannii
Authors: Thakur Vipasha , Gupta Varsha , Sharma Prince , Gupta Anvita , Capalash Neena
Published: November 2023

The urgent necessity for new antibiotics becomes glaringly evident with the relentless rise of multidrug-resistant (MDR)Acinetobacter baumanniiin clinical environments, where its infections lead to alarmingly high mortality rates. Antimicrobial peptides (AMPs) represent a promising novel option to combat nosocomial infections caused by MDRA. baumannii. In this study, six novel synthetic peptides were designed through generative artificial intelligence (AI) and synthesized for further experiments. Peptides AIG-R1, AIG-R4, and AIG-R5 showed potent broad-spectrum antibacterial activity against Gram positive and Gram negative pathogens. One of the peptides, AIG-R5, was effective even against colistin and carbapenem-resistant strains ofA. baumannii,prevented biofilm formation, and eradicated established biofilms by 60%. Notably, AIG-R5 enhanced the activity of different antibiotics and was found to exhibit synergistic activity with antibiotics from the Aminoglycoside class. The combination of AIG-R5 and Tobramycin at 1/8×MIC and 1/4×MIC effectively reduced pre-formed biofilms of carbapenem resistantA. baumanniimore than either component alone, as documented by confocal laser scanning microscopy (CLSM). Significant dose reduction and negligible cytotoxicity exhibited by AIG-R5 with aminoglycosides further encourages evaluation of the combination’s therapeutic potentialin vivoagainst MDRA. baumanniiinfections.
Identification of conserved cross-species B-cell linear epitopes in human malaria: A subtractive proteomics and immuno-informatics approach targeting merozoite stage proteins
Authors: Musundi Sebastian D. , Gitaka Jesse , Kanoi Bernard N.
Published: November 2023

Human malaria, caused by five Plasmodium species (P. falciparum, P. vivax, P. malariae, P. ovale, andP. knowlesi), remains a significant global health burden. While most interventions targetP. falciparum, the species associated with high mortality rates and severe clinical symptoms, non-falciparum species exhibit different transmission dynamics, remain hugely neglected, and pose a significant challenge to malaria elimination efforts. Recent studies have reported the presence of antigens associated with cross-protective immunity, which can potentially disrupt the transmission of various Plasmodium species. With the sequencing of the Plasmodium genome and the development of immunoinformatic tools, in this study, we sought to exploit the evolutionary history of Plasmodium species to identify conserved cross-species B-cell linear epitopes in merozoite proteins. We retrieved Plasmodium proteomes associated with human malaria and applied a subtractive proteomics approach focusing on merozoite stage proteins. Bepipred 2.0 and Epidope were used to predict B-cell linear epitopes usingP. falciparumas the reference species. The predictions were further compared against human and non-falciparum databases and their antigenicity, toxicity, and allergenicity assessed. Subsequently, epitope conservation was carried out using locally sequenced isolates from a malaria-endemic region in western Kenya (n=27) and Kenyan isolates from MalariaGEN version 6 (n=131). Finally, physiochemical characteristics and tertiary structure of the B-cell linear epitopes were determined. The analysis revealed eight epitopes that showed high similarity (70-100%) between falciparum and non-falciparum species. These epitopes were highly conserved when assessed across local isolates and those from the MalariaGEN database and showed desirable physiochemical properties. Our results show the presence of conserved cross-species B-cell linear epitopes that could aid in targeting multiple Plasmodium species. Nevertheless, validating their efficacyin-vitroandin-vivoexperimentally is essential.
Busy CEO and financial statement footnotes readability: evidence from Indonesia
Authors: Harymawan Iman , Ratri Melinda Cahyaning , Ayuningtyas Eka Sari
Published: November 2023

Purpose

This study aims to investigate the correlation between a CEO's business background and the readability of financial statement footnotes in Indonesia.

Design/methodology/approach

This study utilizes a sample period spanning from 2010 to 2018 and employs various statistical tests, including Propensity Score Matching (PSM), Coarsened Exact Matching (CEM) and the Heckman Model, to demonstrate that it can address issues of causality and endogeneity without introducing bias.

Findings

As a result, the findings of this study indicate a statistically significant negative relationship between CEOs with busy schedules and the readability of financial statement footnotes. This suggests that companies led by busy CEOs are more likely to have financial statement footnotes that are easier to read.

Research limitations/implications

These findings hold significance for clarifying research related to the challenges of contextual analysis in financial statement footnotes, which are distributed by companies on a sentence-by-sentence basis.

Practical implications

The practical implications of the findings pertain to actionable steps that management can undertake and also offer regulators opportunities to monitor the potential for standard setting.

Originality/value

Based on the results presented, the authors are optimistic that the findings will pave the way for broader research on the impact of a busy CEO, encompassing not only financial aspects but also non-financial dimensions. The growing popularity of readability is driven by the proliferation of textual reports that pose challenges in analysis and raise numerous inquiries.
Does family incivility trigger suicidal ideation? The role of emotional exhaustion at work and regulation of emotion
Authors: Ballekura Balakrishna , Vilvanathan Lavanya
Published: November 2023

Purpose

Despite the prevalence of uncivil behaviors across families and past studies attributing work stressors to suicidal ideation (SI), there is no conclusive evidence of the interactive effect of family incivility (FI) aggravating SI. Hence, the purpose of this study is to explore the association between FI and SI through emotional exhaustion (EE) in the workplace and regulation of emotion.

Design/methodology/approach

A time lag (T1 and T2) study is applied for primary data collection using a survey questionnaire. The partial least squares–structural equational modeling algorithm tests reliability, validity and hypotheses.

Findings

Experiencing FI exacerbates SI, while the regulation of emotion and EE mediate the association between FI and SI.

Practical implications

Professionals are advised to adopt regulation of emotion that fosters desirable behavior and shields targets from FI and EE, minimizing the intensity of SI.

Originality/value

This study significantly adds to how FI and EE aggravate SI and contribute to the body of knowledge on the regulation of emotion in stress and coping mechanisms.
A benchmark model for the process of post-migration social adjustment: exploring the views of young people from forced-migration backgrounds in Australia
Authors: Ahmadi Forooshani Sayedhabibollah , Murray Kate , Khawaja Nigar , Izadikhah Zahra
Published: November 2023

Purpose

The purpose of this study was to propose a benchmark model for the process of post-migration social adjustment based on the points of view and experiences of young individuals from forced-migration backgrounds.

Design/methodology/approach

Twelve young adults (18–24 years) living in Australia with an experience of forced migration and from various ethnic and cultural backgrounds were recruited. Semi-structured interviews were conducted and analyzed through thematic analysis.

Findings

The results showed that post-migration social adjustment requires effective interactions within individual, family and community domains. The participants proposed specific characteristics, enablers and barriers for each domain that can affect the process of social adjustment after the experience of forced migration.

Originality/value

Based on the reported points of view and experiences of participants in this study, the authors proposed an ecological model that can be considered as a preliminary benchmark to inform policymaking, research and services focusing on the social adjustment of young refugees. The practical implications for resettlement programs are discussed.
A salutary welcome: the role of Sense of Coherence and Generalized Resistance Resources in refugee settlement
Authors: Fries Christopher J. , Serieux John , Oranye Nelson
Published: November 2023

Purpose

Guided by the salutogenic model of health and well-being, this study aims to use empirical measures of sense of coherence (SOC) and generalized resistance resources (GRRs) to gain a better understanding of the facilitators of successful transition and integration of refugees to Canada and relate these findings to current program development and delivery for the settlement of refugees.

Design/methodology/approach

Survey research and structural equation modeling.

Findings

The authors found that newcomers with a stronger SOC were more likely to report successful integration outcomes. GRRs were found to have both direct and indirect effects on the positive settlement of refugees, with the SOC acting as a strong mediator of indirect effects.

Research limitations/implications

Owing in part, to the disruption caused by the global pandemic, the authors’ data collection period was protracted and the final sample size of 263 is smaller than the authors would have preferred. Another limitation of this study has to do with its cross-sectional design, which limits the articulation of cause-and-effect relationships among the variables.

Practical implications

In terms of program development and delivery for the settlement of refugees, the authors’ results provide further evidence that refugee participation in socially valued decision-making represents a key determinant of healthy resettlement.

Originality/value

Much research on refugee settlement originates within “a pathogenic paradigm” that focuses on the stressors and obstacles encountered by people who have been displaced. Taking its cue from Israeli health sociologist, Aaron Antonovsky’s salutogenic model of health and well-being, this study uses empirical measures of Antonovsky’s interrelated concepts of SOC and GRRs to gain a better understanding of the facilitators of successful transition and integration of refugees to a prairie province in Canada and relate these findings to current program development and delivery for the settlement of refugees.
Process capability index Cpm under autoregressive process AR (2)
Authors: Ghute Vikas , Deshpande Mahesh
Published: November 2023

Purpose

The paper aims to identify the effect of ignorance of correlatedness among process observations and to implement new sampling schemes; skip and mixed sampling, in order to reduce the effect of autocorrelation on process capability index (PCI) Cpm.

Design/methodology/approach

Autocorrelated observations are generated using autoregressive process of order two (AR (2)) using Monte Carlo simulations. The PCI is computed based on these observations assuming the independence. The skip and mixed sampling schemes are then used to form sub-groups among correlated observations. The PCI obtained using sub-groups from skip and mixed sampling schemes are assessed using sample mean and sample standard deviation.

Findings

The paper provides empirical insights into how the effect of autocorrelation decreases in the estimated value of PCI Cpm. The use of new sampling schemes, skip and mixed sampling, reduces the effect of autocorrelation on estimates of PCI Cpm.

Originality/value

This paper fulfills an identified need to study how to reduce the effect of autocorrelation on PCI Cpm.
Effects of behavioral biases on life insurance demand decisions in Uganda
Authors: Ndawula Yusuf Katerega , Mori Neema , Nkote Isaac
Published: November 2023

Purpose

This paper examines the relationship between behavioral biases, and demand decisions for life insurance products in Uganda.

Design/methodology/approach

Data were collected from 351 life insurance policyholders in Uganda. The authors used a cross-sectional survey by applying a structured questionnaire. Descriptive analysis was conducted and hypothesized relationships between the constructs were evaluated through the use of structural equation modeling.

Findings

Results indicate that, behavioral biases are significant predictors of life insurance demand among Ugandan policyholders. Also, the two behavioral bias variables (heuristic bias and prospect bias) are significant predictors of demand decisions for life insurance products.

Practical implications

These results are helpful for both insurers and regulators. For insurers, it is now evident that demand decisions for life insurance products are not fully rational. It is imperative for insurers to simplify life insurance product information (heuristics), integrate product education and widen dissemination of product information (prospect bias) to allow policyholders to come up with optimal demand decisions. While for insurance policymakers, the study provides an understanding of behavioral biases. With such insights, policymakers can identify exploitative and deceptive information that target policyholders to better guide life insurance documentation and product designs.

Originality/value

This study is the first to offer insights into behavioral biases' influence on demand decisions for life insurance products in a developing country like Uganda. By integrating prospects and expected utility theory, this study examines rationality and irrationality in demand decisions for life insurance products.

Peer review

The peer review history for this article is available at: https://publons.com/publon/10.1108/IJSE-03-2023-0201