bluuebunny/crossref_metadata_2025 huggingface dataset:
Programmable multi-kilobase RNA editing using CRISPR-mediated trans-splicing
Authors: Borrajo Jacob , Javanmardi Kamyab , Griffin James , Martin Susan J. St. , Yao David , Hill Kaisle , Blainey Paul C. , Al-Shayeb Basem
Published: August 2023

Current gene editing approaches in eukaryotic cells are limited to single base edits or small DNA insertions and deletions, and remain encumbered by unintended permanent effects and significant challenges in the delivery of large DNA cargo. Here we describe Splice Editing, a generalizable platform to correct gene transcriptsin situby programmable insertion or replacement of large RNA segments. By combining CRISPR-mediated RNA targeting with endogenous cellular RNA-splicing machinery, Splice Editing enables efficient, precise, and programmable large-scale editing of gene targets without DNA cleavage or mutagenesis. RNA sequencing and measurement of spliced protein products confirm that Splice Editing achieves efficient and specific targeted RNA and protein correction. We show that Splice Editors based on novel miniature RNA-targeting CRISPR-Cas systems discovered and characterized in this work can be packaged for effective delivery to human cells and affect different types of edits across multiple targets and cell lines. By editing thousands of bases simultaneously in a single reversible step, Splice Editing could expand the treatable disease population for monogenic diseases with large allelic diversity without the permanent unintended effects of DNA editing.

One-sentence summary

CRISPR-guided trans-splicing enables efficient and specific recombination of large RNA molecules in mammalian cells, with broad applications in therapeutic development for genetic diseases and as a research tool for the study of basic RNA biology.
Deep reconstructing generative networks for visualizing dynamic biomolecules inside cells
Authors: Rangan Ramya , Khavnekar Sagar , Lerer Adam , Johnston Jake , Kelley Ron , Obr Martin , Kotecha Abhay , Zhong Ellen D.
Published: August 2023

Advances in cryo-electron tomography (cryo-ET) have produced new opportunities to visualize the structures of dynamic macromolecular machinery in native cellular environments. Here, we describe a machine learning approach that can reconstruct the structural landscape and dynamics of biomolecular complexes present in cryo-ET subtomograms. This method, cryoDRGN-ET, learns a deep generative model of 3D density maps directly from subtomogram tilt series images and can capture states diverse in both composition and conformation. We use this approach to reconstruct thein situtranslation dynamics of prokaryotic ribosomes, and we reveal the distribution of functional states during translation elongation populated byS. cerevisiaeribosomes inside cells.
Targeting host deoxycytidine kinase mitigatesStaphylococcus aureusabscess formation
Authors: Winstel Volker , Abt Evan R. , Le Thuc M. , Radu Caius G.
Published: August 2023

Host-directed therapy (HDT) is an emerging approach to overcome antimicrobial resistance in pathogenic microorganisms. Specifically, HDT targets host-encoded factors required for pathogen replication and survival without interfering with microbial growth or metabolism, thereby eliminating the risk of resistance development. By applying HDT and a drug repurposing approach, we demonstrate that (R)-DI-87, a clinical-stage anti-cancer drug and potent inhibitor of mammalian deoxycytidine kinase (dCK), mitigatesStaphylococcus aureusabscess formation in organ tissues upon invasive bloodstream infection. Mechanistically, (R)-DI-87 shields phagocytes from staphylococcal death-effector deoxyribonucleosides that target dCK and the mammalian purine salvage pathway-apoptosis axis. In this manner, (R)-DI-87-mediated protection of immune cells amplifies macrophage infiltration into deep-seated abscesses, a phenomenon coupled with enhanced pathogen control, ameliorated immunopathology, and reduced disease severity. Thus, pharmaceutical blockade of dCK represents an advanced anti-infective intervention strategy against which staphylococci cannot develop resistance and may help to fight fatal infectious diseases in hospitalized patients.
Temporal regularities shape perceptual decisions and striatal dopamine signals
Authors: Fritsche Matthias , Majumdar Antara , Strickland Lauren , Liebana Garcia Samuel , Bogacz Rafal , Lak Armin
Published: August 2023

Perceptual decisions should depend on sensory evidence. However, such decisions are also influenced by past choices and outcomes. These choice history biases may reflect advantageous strategies to exploit temporal regularities of natural environments. However, it is unclear whether and how observers can adapt their choice history biases to different temporal regularities, to exploit the multitude of temporal correlations that exist in nature. Here, we show that mice adapt their perceptual choice history biases to different temporal regularities. This adaptation is well captured by a normative reinforcement learning algorithm with multi-trial belief states, comprising both current trial sensory and previous trial memory states. We demonstrate that striatal dopamine tracks predictions of the model and behavior, pointing towards the involvement of dopamine in forming adaptive history biases. Our results reveal the adaptive nature of perceptual choice history biases, and shed light on their underlying computational principles and neural implementation.
Hyperactivity of mTORC1 and mTORC2-dependent signaling mediate epilepsy downstream of somatic PTEN loss
Authors: Cullen Erin R. , Safari Mona , Mittelstadt Isabelle , Weston Matthew C.
Published: August 2023

Gene variants that hyperactivate PI3K-mTOR signaling in the brain lead to epilepsy and cortical malformations in humans. Some gene variants associated with these pathologies only hyperactivate mTORC1, but others, such asPTEN,PIK3CA, andAKT, hyperactivate both mTORC1- and mTORC2-dependent signaling. Previous work established a key role for mTORC1 hyperactivity in mTORopathies, however, whether mTORC2 hyperactivity contributes is not clear. To test this, we inactivated mTORC1 and/or mTORC2 downstream of earlyPtendeletion in a new model of somaticPtenloss-of-function (LOF) in the cortex and hippocampus. Spontaneous seizures and epileptiform activity persisted despite mTORC1 or mTORC2 inactivation alone, but inactivating both mTORC1 and mTORC2 simultaneously normalized brain activity. These results suggest that hyperactivity of both mTORC1 and mTORC2 can cause epilepsy, and that targeted therapies should aim to reduce activity of both complexes.
Local translation is engaged to sustain synaptic function in impaired Wallerian degeneration
Authors: Paglione Maria , Restivo Leonardo , Zakhia Sarah , Rosell Arnau Llobet , Terenzio Marco , Neukomm Lukas J.
Published: August 2023

After injury, the severed axon separated from the soma activates programmed axon degeneration, an evolutionarily conserved pathway to initiate its degeneration within a day. Conversely, severed projections deficient in programmed axon degeneration remain morphologically preserved with functional synapses for weeks to months after injury. How this synaptic function is sustained remains currently unknown. Here, we demonstrate that dNmnat-mediated over-expression attenuates programmed axon degeneration in distinct neuronal populations. Severed projections remain morphologically preserved for weeks after injury. When evoked, they elicit a postsynaptic behavior which is a readout for preserved synaptic function. We used ribosomal pulldown to isolate translatomes from these projections. Transcriptional profiling revealed several enriched biological classes. Identified candidates were validated in a screen using a novel system to automatically quantify evoked antennal grooming behavior as a proxy for preserved synaptic function. We used RNAi-mediated knockdown to identify mTOR as a mediator of local protein synthesis, and specifically candidates involved in protein ubiquitination and calcium homeostasis, required for preserved synaptic function. Our dataset uncovered several uncharacterized genes linked to human diseases. It may therefore offer insights into novel avenues for therapeutic treatments.
Retinal origin of orientation but not direction selective maps in the superior colliculus
Authors: de Malmazet Daniel , Kühn Norma K. , Li Chen , Farrow Karl
Published: August 2023

Neurons in the mouse superior colliculus (“colliculus”) are arranged in ordered spatial maps. While orientationselective (OS) neurons form a concentric map aligned to the center of vision, direction-selective (DS) neurons are arranged in patches with changing preferences across the visual field. It remains unclear if these maps are a consequence of feed-forward input from the retina or local computations in the colliculus. To determine whether these maps originate in the retina, we mapped the local and global distribution of orientation- and direction-selective retinal ganglion cell boutons using in-vivo two-photon calcium imaging. We found that OS boutons formed patches that matched the distribution of OS neurons within the colliculus. DS boutons displayed less regional specializations, better reflecting the organization of DS neurons in the retina. Both eyes convey similar orientation but different DS inputs to the colliculus, as shown in recordings from retinal explants. These data demonstrate that orientation and direction maps within the colliculus are independent, implying that orientation maps are inherited from the retina, but direction maps require local circuits.
The role of heterochronic gene expression and regulatory architecture in early developmental divergence
Authors: Harry Nathan D. , Zakas Christina
Published: August 2023

New developmental programs can evolve through adaptive changes to gene expression. The annelidStreblospio benedictihas a developmental dimorphism, which provides a unique intraspecific framework for understanding the earliest genetic changes that take place during developmental divergence. Using comparative RNAseq through ontogeny, we find that only a small proportion of genes are differentially expressed at any time, despite major differences in larval development and life-history. These genes shift expression profiles across morphs by either turning off any expression in one morph or changing the timing or amount of gene expression. We directly connect the contributions of these mechanisms to differences in developmental processes. We examine F1offspring— using reciprocal crosses— to determine maternal mRNA inheritance and the regulatory architecture of gene expression. These results highlight the importance of both novel gene expression and heterochronic shifts in developmental evolution, as well as thetrans-acting regulatory factors in initiating divergence.
Cell-Free Protein Expression in Polymer Materials
Authors: Lee Marilyn S. , Lee Jennifer A. , Biondo John R. , Lux Jeffrey E. , Raig Rebecca M. , Berger Pierce N. , Bernhards Casey B. , Kuhn Danielle L. , Gupta Maneesh K. , Lux Matthew W.
Published: August 2023

While synthetic biology has advanced complex capabilities like sensing and molecule synthesis in aqueous solutions, important applications may also be pursued for biological systems in solid materials. Harsh processing conditions used to produce many synthetic materials such as plastics makes incorporation of biological functionality challenging. One technology that shows promise in circumventing these issues is cell-free protein synthesis (CFPS), where core cellular functionality is reconstituted outside the cell. CFPS enables genetic functions to be implemented without the complications of membrane transport or concerns over cellular viability or release of genetically modified organisms. Here we demonstrate that dried CFPS reactions have remarkable tolerance to heat and organic solvent exposure during the casting processes for polymer materials. We demonstrate the utility of this observation by creating plastics that have spatially patterned genetic functionality, produce antimicrobialsin situ, and perform sensing reactions. The resulting materials unlock the potential to deliver DNA-programmable bio-functionality in a ubiquitous class of synthetic materials.
Portrait of a generalist bacterium: pathoadaptation, metabolic specialization and extreme environments shape diversity ofStaphylococcus saprophyticus
Authors: Youngblom Madison A. , Imhoff Madeline R. , Smyth Lilia M. , Mohamed Mohamed A. , Pepperell Caitlin S.
Published: August 2023

Staphylococcus saprophyticusis a Gram-positive, coagulase-negative staphylococcus found in diverse environments including soil and freshwater, meat, and dairy foods.S. saprophyticusis also an important cause of urinary tract infections (UTIs) in humans, and mastitis in cattle. However, the genetic determinants of virulence have not yet been identified, and it remains unclear whether there are distinct sub-populations adapted to human and animal hosts. Using a diverse sample ofS. saprophyticusisolates from food, animals, environmental sources, and human infections, we characterized the population structure and diversity of global populations ofS. saprophyticus. We found that divergence of the two major clades ofS. saprophyticusis likely facilitated by barriers to horizontal gene transfer (HGT) and differences in metabolism. Using genome-wide association study (GWAS) tools we identified the first Type VII secretion system (T7SS) described inS. saprophyticusand its association with bovine mastitis. Finally, we found that in general, strains ofS. saprophyticusfrom different niches are genetically similar with the exception of built environments, which function as a ‘sink’ forS. saprophyticuspopulations. This work increases our understanding of the ecology ofS. saprophyticusand of the genomics of bacterial generalists.

Data summary

Raw sequencing data for newly sequencedS. saprophyticusisolates have been deposited to the NCBI SRA under the project accession PRJNA928770. A list of all genomes used in this work and their associated metadata are available in the supplementary material. Custom scripts used in the comparative genomics and GWAS analyses are available here:https://github.com/myoungblom/sapro_genomics.

Impact statement

It is not known whether human and cattle diseases caused byS. saprophyticusrepresent spillover events from a generalist adapted to survive in a range of environments, or whether the capacity to cause disease represents a specific adaptation. Seasonal cycles ofS. saprophyticusUTIs and molecular epidemiological evidence suggest that these infections may be environmentally-acquired rather than via transmission from person to person. Using comparative genomics and genome wide association study tools, we found thatS. saprophyticusappears adapted to inhabit a wide range of environments (generalist), with isolates from animals, food, natural environments and human infections being closely related. Bacteria that routinely switch environments, particularly between humans and animals, are of particular concern when it comes to the spread of antibiotic resistance from farm environments into human populations. This work provides a framework for comparative genomic analyses of bacterial generalists and furthers our understanding of how bacterial populations move between humans, animals, and the environment.
Transcriptional Profiles of Non-neuronal and Immune Cells in Mouse Trigeminal Ganglia
Authors: Mecklenburg Jennifer , Shein Sergey A. , Hovhannisyan Anahit H. , Zou Yi , Lai Zhao , Ruparel Shivani , Tumanov Alexei V. , Akopian Armen N.
Published: August 2023

Non-neuronal cells constitute 90-95% of sensory ganglia. These cells play critical roles in modulation of nociceptive signal transmissions by sensory neurons. Accordingly, the aim of this review-study was to identify, profile and summarize TG non-neuronal cell types in naïve male mice using published and our own data generated by single-cell RNA sequencing (scRNA-seq), flow cytometry (FC) and immunohistochemistry (IHC). TG contains 5 types of non-neuronal cells: glial, fibroblasts, smooth muscle, endothelial and immune cells. There is agreement among publications for glial, fibroblasts, smooth muscle and endothelial cells. Based on gene profiles, glial cells were classified as Schwann cells and satellite glial cells (SGC).Mpzhad dominant expression in Schwann cells, andFabp7is specific for SCG. Two types of Col1a2+fibroblasts located throughout TG were distinguished using gene profiles. TG smooth muscle and endothelial cells representing blood vessels were detected with well recognized markers. Our study split reported single TG immune cell group into 3 types of macrophages and 4 types of neutrophils. Macrophages were located among neuronal bodies and nerve fibers, and were sub-grouped by unique transcriptomic profiles and usingCcr2,Cx3cr1andIba1as markers. S100a8+neutrophils were located in dura surrounding TG and were sub-grouped by clustering and expressions ofCsf3r,Ly6G, Ngp, ElaneandMpo. Overall, generated and summarized here dataset on non-neuronal TG cells could provide essential and fundamental information for studies on cell plasticity, interactomic network between neurons and non-neuronal cells and function during variety of pain conditions in the head and neck region.
Development of Polarity-Reversed Endometrial Epithelial Organoids
Authors: Ahmad Vakil , Yeddula Sai Goutham Reddy , Telugu Bhanu P. , Spencer Thomas E. , Kelleher Andrew M.
Published: August 2023

The uterine epithelium is composed of a single layer of hormone responsive polarized epithelial cells that line the lumen and form tubular glands. Endometrial epithelial organoids (EEO) can be generated from uterine epithelia and recapitulate cell composition and hormone responsesin vitro. As such, the development of EEO represents a major advance for facilitating mechanistic studiesin vitro. However, a major limitation for the use of EEO cultured in basement membrane extract and other hydrogels is the inner location of apical membrane, thereby hindering direct access to the apical surface of the epithelium to study interactions with the embryo or infectious agents such as viruses and bacteria. Here, a straightforward strategy was developed that successfully reverses the polarity of EEO. The result is an apical-out organoid that preserves a distinct apical-basolateral orientation and remains responsive to ovarian steroid hormones. Our investigations highlight the utility of polarity-reversed EEO to study interactions withE. coliand blastocysts. This method of generating apical-out EEO lays the foundation for developing newin vitrofunctional assays, particularly regarding epithelial interactions with embryos during pregnancy or other luminal constituents in a pathological or diseased state.
Protein Kinase A is a Functional Component of Focal Adhesions
Authors: Kang Mingu , Senatore Amanda J. , Naughton Hannah , McTigue Madeline , Beltman Rachel J. , Herppich Andrew A. , Pflum Mary Kay H. , Howe Alan K.
Published: August 2023

Focal adhesions (FAs) form the junction between extracellular matrix (ECM)-bound integrins and the actin cytoskeleton and also transmit signals that regulate cell adhesion, cytoskeletal dynamics, and cell migration. While many of these signals are rooted in reversible tyrosine phosphorylation, phosphorylation of FA proteins on Ser/Thr residues is far more abundant yet its mechanisms and consequences are far less understood. The cAMP-dependent protein kinase (protein kinase A; PKA) has important roles in cell adhesion and cell migration and is both an effector and regulator of integrin-mediated adhesion to the ECM. Importantly, subcellular localization plays a critically important role in specifying PKA function. Here, we show that PKA is present in isolated FA-cytoskeleton complexes and active within FAs in live cells. Furthermore, using kinase-catalyzed biotinylation of isolated FA-cytoskeleton complexes, we identify fifty-three high-stringency candidate PKA substrates within FAs. From this list, we validate tensin-3 (Tns3) – a well-established molecular scaffold, regulator of cell migration, and component of focal and fibrillar adhesions – as a novel direct substrate for PKA. These observations identify a new pathway for phospho-regulation of Tns3 and, importantly, establish a new and important niche for localized PKA signaling and thus provide a foundation for further investigation of the role of PKA in the regulation of FA dynamics and signaling.
Clonal and Scalable Endothelial Progenitor Cell Lines from Human Pluripotent Stem Cells
Authors: Lee Jieun , Sternberg Hal , Bignone Paola A. , Murai James , Malik Nafees N. , West Michael D. , Larocca Dana
Published: August 2023

Human pluripotent stem cells (hPSCs) can be used as a renewable source of endothelial cells for treating cardiovascular disease and other ischemic conditions. Here, we present the derivation and characterization of a panel of distinct clonal embryonic endothelial progenitor cell (eEPC) lines that were differentiated from human embryonic stem cells (hESCs). The hESC line, ESI-017, was first partially differentiated to produce candidate cultures from which eEPC were cloned. Endothelial cell identity was assessed by transcriptomic analysis, cell surface marker expression, immunocytochemical marker analysis, and functional analysis using a vascular network forming assay. The transcriptome of the eEPC lines was compared to various adult endothelial lines as well as various non-endothelial cells including both adult and embryonic origins. This resulted in a variety of distinct cell lines with functional properties of endothelial cells and strong transcriptomic similarity to adult endothelial primary cell lines. The eEPC lines, however, were distinguished from adult endothelium by a novel pattern of embryonic gene expression. We demonstrated scalability of up to 80 population doublings and stable with long-term expansion over 50 passages and stable angiogenic properties at late passage in the EPC line. Taken together, these data support the finding that hESC-derived clonal eEPC lines are useful as a source of scalable therapeutic cells and cell products for treating cardiovascular disease. These eEPC lines offer a highly promising resource for preclinical studies and therapeutic interventions.
Emerging Threat of Ranavirus: Prevalence, Genetic Diversity, and Climatic Drivers ofRanavirus(Family Iridoviridae) in ectothermic vertebrates of Asia
Authors: Herath Jayampathi , Dan Sun , Ellepola Gajaba , Subramaniam Kuttichantran , Meegaskumbura Madhava
Published: August 2023

Ranavirus disease, caused by viruses within the genusRanavirus(familyIridoviridae), is considered a globally emerging infectious disease linked to mass mortality events in both wild and cultured ectothermic vertebrates. Surveillance work is however limited in Asia hence prevalence and the dynamics of the disease remains poorly understood. To understand disease burden and the potential biotic and abiotic drivers in southern China region, we conducted a systematic surveillance of the ranavirus across Guangxi Zhuang Autonomous region (GAR). For this, we used a multifaceted approach involving screening of amphibians and other potential reservoirs, diagnostic tests, phylogenetic analyses, prevalence estimation, co-infection assessments, and climatic niche analyses. Over one thousand individuals were sampled across 25 sampling sites. We found ninety-two individuals from 18 species of ectothermic vertebrates to be infected with ranavirus. Two lineages were responsible – Rana nigromaculata ranavirus and Tiger frog virus were identified using phylogenetic analysis based on the major capsid protein (MCP) gene fragment. We also found evidence of a co-infection with ranavirus andBdthat can be highly detrimental to host populations; possibly the first such documentation in Asia. Our niche modelling analysis suggests that precipitation and seasonality play an important role in ranavirus prevalence in Guangxi region – southwestern, southeastern, central and northeastern regions of GAR can be considered to be optimum habitats for ranaviruses. Infection rates in wild frog species have reached 100% in some areas, even in nature reserves. Our research also indicates that culture facilities and pet farms are frequently infected, serving as likely vectors for the regional and global spread of ranaviruses. The knowledge generated suggests the need for systematic surveillance, stringent biosecurity measures, and control of international animal trade to prevent further transmission and protection of biodiversity and aquaculture industries across Asia.
A slc38a8 mouse model of FHONDA syndrome faithfully recapitulates the visual deficits of albinism without pigmentation defects
Authors: Guardia Ana , Fernández Almudena , Seruggia Davide , Chotard Virginie , Sánchez-Castillo Carla , Kutsyr Oksana , Sánchez-Sáez Xavier , Zurita Esther , Cantero Marta , Rebsam Alexandra , Cuenca Nicolás , Montoliu Lluís
Published: August 2023

Purpose

We aimed to generate and phenotype a mouse model of FHONDA (Foveal Hypoplasia, Optic Nerve Decussation Defects, and Anterior Segment Dysgenesis), a rare disease associated with mutations inSLC38A8that causes severe visual alterations similar to albinism without affecting pigmentation.

Methods

The FHONDA mouse model was generated with CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)/Cas9 technology using an RNA guide targeting theScl38a8murine locus. The resulting mice were backcrossed to C57BL/6J. Melanin content was measured using spectrophotometry. Retinal cell architecture was analyzed through light and electron microscopy. Retinal projections to the brain were evaluated with anterograde labelling in embryos and adults. Visual function was assessed by electroretinography (ERG) and the optomotor test (OT).

Results

From numerousSlc38a8mouse mutant alleles generated, we selected one that encodes a truncated protein (p.196Pro*, equivalent to p.199Pro* in the human protein) closely resembling a mutant allele described in patients (p.200Gln*).Slc38a8mutant mice exhibit wild-type eye and coat pigmentation with comparable melanin contents. Subcellular abnormalities were observed in retinal pigment epithelium cells ofSlc38a8mutant mice. Anterograde labelling experiments of retinal projections in embryos and adults showed a reduction of ipsilateral fibers. Functional visual analyses revealed a decreased ERG response in scotopic conditions and a reduction of visual acuity in mutant mice measured by OT.

Conclusions

Slc38a8mutant mice recapitulate the phenotype of FHONDA patients concerning their normal pigmentation and their abnormal visual system, as observed in all types of albinism. These mice will be helpful in better understanding the pathophysiology of this genetic condition.
Formation of templated inclusions in a forebrain α-synuclein mouse model is independent of LRRK2
Authors: Dues Dylan J. , Ma Yue , Nguyen An Phu Tran , Offerman Alina V. , Beddows Ian , Moore Darren J.
Published: August 2023

Leucine-rich repeat kinase 2 (LRRK2) and α-synuclein share enigmatic roles in the pathobiology of Parkinson’s disease (PD).LRRK2mutations are a common genetic cause of PD which, in addition to neurodegeneration, often present with abnormal deposits of α-synuclein in the form of Lewy-related pathology. As Lewy-related pathology is a prominent neuropathologic finding in sporadic PD, the relationship between LRRK2 and α-synuclein has garnered considerable interest. However, whether and how LRRK2 might influence the accumulation of Lewy-related pathology remains poorly understood. Through stereotactic injection of mouse α-synuclein pre-formed fibrils (PFF), we modeled the spread of Lewy-related pathology within forebrain regions where LRRK2 is most highly expressed. The impact ofLRRK2genotype on the formation of α-synuclein inclusions was evaluated at 1-month post-injection. Neither deletion ofLRRK2nor G2019S LRRK2 knockin appreciably altered the burden of α- synuclein pathology at this early timepoint. These observations fail to provide support for a robust pathophysiologic interaction between LRRK2 and α-synuclein in the forebrainin vivo. There was, however, a modest reduction in microglial activation induced by PFF delivery in the hippocampus ofLRRK2knockout mice, suggesting that LRRK2 may contribute to α-synuclein-induced neuroinflammation. Collectively, our data indicate that the pathological accumulation of α-synuclein in the mouse forebrain is largely independent of LRRK2.

Highlights

Adult mice accumulate α-synuclein pathology in the hippocampus and cortex following stereotactic injection with α-synuclein PFFs, with negligible influence ofLRRK2genotype.

Hippocampal and cortical α-synuclein pathology elicits the concomitant accrual of phosphorylated tau, reactive astrogliosis, and microglial activation.

Absence of endogenousLRRK2attenuates microglial activation in the dorsal hippocampus induced by PFFs, but not in the entorhinal cortex.

Accumulation of α-synuclein inclusions and related neuropathologic changes were strongly associated across the hippocampal dorsal-ventral axis, regardless ofLRRK2genotype.
AP2A1 is upregulated upon replicative senescence of human fibroblasts to strengthen focal adhesions via integrin β1 translocation along stress fibers
Authors: Chantachotikul Pirawan , Liu Shiyou , Furukawa Kana , Deguchi Shinji
Published: August 2023

Aging proceeds with accumulation of senescent cells in multiple organs. Senescent cells become large in size compared to young cells, which promotes further senescence and age-related diseases. Currently, the molecular mechanism behind the maintenance of such huge cell architecture undergoing senescence remains poorly understood. Here we focus on reorganization of actin stress fibers induced upon replicative senescence of human fibroblasts, typically used as a senescent cell model. We identified, together with our previous proteomic study, that AP2A1 (alpha 1 adaptin subunit of the adaptor protein 2) is upregulated in senescent cells along the length of stress fibers, which are enlarged following the increase in the whole cell size. We then revealed that knockdown of AP2A1 in senescent cells suppresses key senescence-associated phenotypes, which include decreased cell area and lowered expression of major senescence markers. Meanwhile, AP2A1 overexpression in young cells induced the opposite effects that rather advance senescence, suggesting that AP2A1 may be used as a senescence marker. We found that AP2A1 is colocalized with integrin β1, and both of them move linearly along stress fibers. We further observed that focal adhesions are enlarged in senescent cells to reinforce cell adhesions to the substrate. These results suggest that senescent cells maintain their large size by strengthening the anchorage to the substrate by supplying integrin β1 via translocation along stress fibers. This mechanism may work efficiently in senescent cells, compared with a case relying on random diffusion of integrin β1, given the enlarged cell size and resulting increase in travel time and distance for endocytosed vesicle transportation.
From brick and mortar to click and order: consumers' online food delivery service perceptions post-pandemic
Authors: Sharma Shavneet , Devi Kritika , Naidu Samantha , Greig Tuma , Singh Gurmeet , Slack Neale
Published: August 2023

Purpose

This study explores consumers' intentions to utilize online food delivery services (OFDS) in a shared economy beyond the COVID-19 pandemic, employing the protection motivation theory (PMT) as the underlying framework.

Design/methodology/approach

Utilizing a random sampling technique, a quantitative approach was employed to gather responses from 347 Australian consumers. The proposed model was tested through covariance-based structural equation modelling.

Findings

The findings of this study demonstrate significant positive relationships between restaurant credibility, food quality, e-service quality, price, online food delivery applications, consumer e-satisfaction and e-loyalty. It reveals that consumers satisfied with OFDS may continue exhibiting e-loyalty intentions in a shared economy beyond COVID-19. The relationship between consumer e-satisfaction and e-loyalty intention is moderated by consumer-perceived COVID-19 risk.

Practical implications

This study offers practical implications for online food delivery providers, restaurants, regulators, application developers and policymakers. These implications aim to enhance the e-service quality, price value, usefulness and security of OFDS, along with strategies to improve the online food delivery application.

Originality/value

This study contributes to the existing body of knowledge by examining a unique selection of antecedents, including the OFDS app, to determine consumer e-satisfaction and e-loyalty in the context of a shared economy beyond COVID-19. The utilization of the OFDS app as a second-order construct adds a meaningful contribution to the OFDS literature. Furthermore, this study investigates and contributes to the limited understanding of the moderation effect of consumer-perceived COVID-19 risk on consumer e-satisfaction and their intended continued use of OFDS.
The effect of income and expense shifting on the corporate income tax evasion
Authors: Kołodziej Sabina , Maruszewska Ewa Wanda , Niesiobędzka Małgorzata
Published: August 2023

Purpose

This paper aims to present a study on the effect of income and expense shifting on the corporate income tax evasion – an example of intentional noncompliance practiced by tax agents. The authors expected that the tool used would differentiate the extent of understatement of tax liability.

Design/methodology/approach

Two experiments were conducted in which young (N = 62) and experienced (N = 68) tax agents read a scenario placing them in a position of an employee responsible for tax planning and calculations of tax liabilities. The respondents’ task was to decide about the extent of the tax liability understatement using income or expense shifting.

Findings

Research demonstrated significantly higher extent of corporate income tax understatement when using income shifting compared to expense shifting in case of experienced tax agents (Study 2) and on tendency level among young tax agents (Study 1).

Research limitations/implications

Results of the studies might be of interest to managers paying attention to tax procedures within the company, governmental agencies investigating corporate tax evasion, as well as educators responsible for tax agents’ initial training and lifelong learning.

Originality/value

This study concentrates on tax agents who are employed in companies and corporate income tax evasion, which has not been analyzed in the literature so far.
Optimization of V-shaped regulating ball valve profile based on proxy optimization algorithm
Authors: Li Shuxun , Yu Mengyao , Wu Hanlin , Hu Yinggang , Ma Tingqian , Liu Bincai
Published: August 2023

Purpose

The purpose of this study is to address the issue that the traditional V-shaped ball valve profile shape is limiting the flow control characteristics in a series structure and to optimize the design profile by proposing an open-hole profile.

Design/methodology/approach

This paper proposes a Gaussian process regression surrogate model based on the genetic algorithm optimization of swarm intelligence, combined with the Expected Improvement point addition criterion, to optimize and correct the design profile. The flow regulation performance of the optimized V-shaped regulating ball valve is verified through a combination of numerical simulation and experiment.

Findings

The results demonstrate that the optimized V-shaped regulating ball valve has higher flow regulation accuracy and a more stable flow regulation process. After optimization, the flow characteristic curve of the spool is closer to the ideal equal percentage characteristic. The simulation results of the flow field are consistent with the experimental results.

Originality/value

The proposed method significantly reduces the optimization time, has higher efficiency and solves the problem that traditional optimization methods struggle with, which is ensuring optimal flow regulation performance. Compared to the traditional trial-and-error optimization method, the proposed method is more effective. The feasibility of the method is supported by experimental results.
Numerical analysis for tunnelling-induced stress and plastic evolution causing instability of multilayered surrounding rock by varying three-dimensional in situ stresses
Authors: Wang Yongliang , Feng Ruiguang , Li Dongping , Peng Ruidong
Published: August 2023

Purpose

The induction of geological disasters is predominantly influenced by the dynamic evolution of the stress and plastic zones of the multilayer rock formations surrounding deep-rock roadways, and the behaviours and mechanisms of high in situ stress are key scientific issues related to deep-resource exploitation. The stress environment of deep resources is more complex owing to the influence of several geological factors, such as tectonic movements and landforms. Therefore, in practical engineering, the in situ stress field is in a complex anisotropic three-dimensional state, which may change the deformation and failure law of the surrounding rock. The purpose of this study is to investigate the tunnelling-induced stress and plastic evolution causing instability of multilayered surrounding rock by varying three-dimensional in situ stresses.

Design/methodology/approach

Based on data from the Yangquan Coal Mine, China, a finite difference model was established, and the elastic-plastic constitutive model and element deletion technology designed in the study were analysed. Gradual tunnelling along the roof and floor of the coal seam was used in the model, which predicted the impact tendency, and compared the results with the impact tendency report to verify the validity of the model. The evolutions of the stress field and plastic zone of the coal roadway in different stress fields were studied by modifying the maximum horizontal in situ stress, minimum horizontal in situ stress and lateral pressure coefficient.

Findings

The results shown that the in situ stress influenced the stress distribution and plastic zone of the surrounding rock. With an increase in the minimum horizontal in situ stress, the vertical in situ stress release area of the roof surrounding rock slowly decreased; the area of vertical in situ stress concentration area of the deep surrounding rock on roadway sides decreased, increased and decreased by turn; the area of roof now-shear failure area first increased and then decreased. With an increase in the lateral pressure coefficient, the area of the horizontal in situ stress release area of the surrounding rock increased; the area of vertical in situ stress release area of the roof and floor surrounding rock first decreased and then increased; the area of deep stress concentration area of roadway sides decreased; and the plastic area of the surrounding rock and the area of now-shear failure first decreased and then increased.

Originality/value

The results obtained in this study are based on actual cases and reveal the evolution law of the disturbing stress and plastic zone of multilayer surrounding rock caused by three-dimensional in situ stress during the excavation of deep rock roadways, which can provide a practical reference for the extraction of deep resources.
The motivational influence of collective efficacy and charged behavior and the moderating effect of risk-taking propensity on new product development team innovativeness
Authors: Rodriguez Carlos M.
Published: August 2023

Purpose

This study examines the motivational processes of charged behavior and collective efficacy driving interdependence and agency in new product development (NPD) teams and the moderating impact of team risk-taking propensity as affective, cognitive and behavioral social processes support team innovation.

Design/methodology/approach

Data were collected from 92 NPD teams engaged in B2C and B2B product and service development. Mediating and moderating effects are examined using partial least squares structural equation modeling, referencing social cognitive and collective agency theories as the research framework.

Findings

The analysis validates collective self-efficacy and charged behavior as interdependent motivational–affective processes that align cognitive resources and govern team effort toward innovativeness. Teams' risk-taking propensity regulates behavior, and collective efficacy facilitates self-regulated motivational engagement. Charged behavior cultivates the emotional contagion, team identification, cohesion and adaptation required for team functioning. Team potency fosters cohesiveness, while team learning improves adaptability along the innovation journey. The resulting theory asserts that motivational drivers enhance the interplay between cognitive and behavioral processes.

Practical implications

Managers should consider NPD teams as social systems with a capacity for collective agency nurtured through interdependence, which requires collective efficacy and shared competencies to generate motivational purpose and innovativeness. Managers must remain mindful of teams' risk tolerance as regulating the impact of motivational factors on innovativeness.

Originality/value

This study contributes to research on the motivational–affective drivers of NPD charged behavior and collective efficacy as complementary to cognitive and behavioral processes sustaining team innovativeness.
Role of passion in entrepreneurial responses to crises on social media platforms
Authors: Boussema Samira
Published: August 2023

Purpose

This study examines the role of passion in gender-specific entrepreneurial responses in times of crises and how passion manifests itself in a digital environment. Entrepreneurial passion feeds energy, tenacity, self-confidence and momentum, creating added value for a given economy.

Design/methodology/approach

A qualitative approach was used to conduct semi-structured interviews. To reach the research objectives, the author examined a sample of 22 female entrepreneurs and 19 male entrepreneurs in a comparative design.

Findings

The results obtained through a qualitative study prove that entrepreneurial passion is a driver of self-confidence for entrepreneurs. Moreover, the nature of entrepreneurial passion differs across gender in times of crises. Indeed, female entrepreneurs try to take their lives into their own hands by creating their own destinies. They have seized opportunities arising from purely technological progress to create their own businesses on social networks and solve the unemployment problem. Meanwhile, male entrepreneurs pursue opportunities based on market supply and demand to increase their market share and face a crisis.

Practical implications

These findings offer novel insights into research on social media entrepreneurs. This study could help new entrepreneurs highlight their abilities, particularly those that are most salient and central.

Originality/value

This study adds a new dimension to the literature on the role and nature of entrepreneurial passion in times of crises.
Drivers of strengthening university–industry collaboration: implications for favorable outcomes
Authors: Kamal Md Aktar , Guha Souman , Begum Noor Nahar , Taher Md Abu
Published: August 2023

Purpose

The purpose of the study was to examine the factors that are important for strengthening university–industry collaboration (UIC). This study also investigates the outcome of UIC in the light of creativity, skill, knowledge, and research work.

Design/methodology/approach

A survey method has been used to collect data for the study. This study applied a purposive judgmental sampling technique where particular types of respondents like university faculty members and the top officials of the organizations were selected who are knowledgeable and can provide the desired information. The current study used the structural equation modeling method to analyze the data. In the first stage, this research assessed the demographic factors of the respondent. Then this study conducts confirmatory factors analysis and convergent and discriminant validity and reliability test. Finally, the hypotheses are tested by using nonparametric.

Findings

This study finds that knowledge transfer mechanism, governmental factors, organizational design factors, technology transfer and the collaborative network has a significant impact on strengthening UIC, which ultimately facilitates creativity, knowledge creation, skills development and supply of graduate according to the requirement of the industry, good research work.

Originality/value

The current study identified some important determinant that has a substantial influence on strengthening UIC. According to the study organizational design, government, technology, collaborative network and mechanism for knowledge transfer play very crucial roles in strengthening collaboration that ultimately increases the creativity, skills, knowledge and research capability of graduates.
Does CEO celebrity affect IPO underpricing? Evidence from the strategic emerging industries in China
Authors: Yang Shuai , Zhao Yu , Wu Chao
Published: August 2023

Purpose

The interaction between evaluators is underestimated in legitimacy literature. This study aims to examine the impact of CEO celebrity on initial public offerings (IPOs) underpricing in Strategic Emerging Industries (SEIs). Based on legitimacy and limited attention effect, this study introduces a new antecedent to the asset pricing literature under a particular sample.

Design/methodology/approach

This paper illustrates how CEO celebrity promotes IPO underpricing by enhancing the legitimacy and then explores how the CEO characteristics can moderate this relationship. Using 1,128 IPO companies in China SEIs from 2010 to 2019, cross-section data is used to build a multiple linear regression model to test the hypotheses.

Findings

The result indicates that CEO celebrity is positively related to IPO underpricing. Founder CEO and CEO duality amplify the relationship. Further analysis shows that the relationship between CEO celebrity and IPO underpricing is more pronounced in firms with high Baidu search and low market sentiment.

Originality/value

This study provides insights into how CEO celebrity as notable internal information shapes the formation of investors' preliminary impressions of firms. The evidence consists of legitimacy and limited attention perspective by showing how investors favor, follow and hype the stocks with celebrity CEOs. The results extend the knowledge about how CEO characteristics influence information frictions in asset pricing during IPO.