bluuebunny/crossref_metadata_2025_split huggingface dataset:
LRRK2 kinase inhibition protects against Parkinson’s disease-associated environmental toxicants
Authors: Ilieva Neda M. , Hoffman Eric K. , Ghalib Mohammed A. , Greenamyre J. Timothy , De Miranda Briana R. 
Published: April 2024

AbstractIdiopathic Parkinson’s disease (PD) is epidemiologically linked with exposure to toxicants such as pesticides and solvents, which comprise a wide array of chemicals that pollute our environment. While most are structurally distinct, a common cellular target for their toxicity is mitochondrial dysfunction, a key pathological trigger involved in the selective vulnerability of dopaminergic neurons. We and others have shown that environmental mitochondrial toxicants such as the pesticides rotenone and paraquat, and the organic solvent trichloroethylene (TCE) appear to be influenced by the protein LRRK2, a genetic risk factor for PD. As LRRK2 mediates vesicular trafficking and influences endolysosomal function, we postulated that LRRK2 kinase activity may inhibit the autophagic removal of toxicant damaged mitochondria, resulting in elevated oxidative stress. Conversely, we suspected that inhibition of LRRK2, which has been shown to be protective against dopaminergic neurodegeneration caused by mitochondrial toxicants, would reduce the intracellular production of reactive oxygen species (ROS) and prevent mitochondrial toxicity from inducing cell death. To do this, we testedin vitroif genetic or pharmacologic inhibition of LRRK2 (MLi2) protected against ROS caused by four toxicants associated with PD risk – rotenone, paraquat, TCE, and tetrachloroethylene (PERC). In parallel, we assessed if LRRK2 inhibition with MLi2 could protect against TCE-induced toxicityin vivo, in a follow up study from our observation that TCE elevated LRRK2 kinase activity in the nigrostriatal tract of rats prior to dopaminergic neurodegeneration. We found that LRRK2 inhibition blocked toxicant-induced ROS and promoted mitophagyin vitro, and protected against dopaminergic neurodegeneration, neuroinflammation, and mitochondrial damage caused by TCEin vivo. We also found that cells with the LRRK2 G2019S mutation displayed exacerbated levels of toxicant induced ROS, but this was ameliorated by LRRK2 inhibition with MLi2. Collectively, these data support a role for LRRK2 in toxicant-induced mitochondrial dysfunction linked to PD risk through oxidative stress and the autophagic removal of damaged mitochondria.
Control of behavioral uncertainty by divergent frontal circuits
Authors: Wang Yihan , Sun Qian-Quan 
Published: April 2024

AbstractBoth ambiguous inference from current input and internal belief from prior input causes uncertainty. The uncertainty is typically manifested as a normal distribution at behavioral level when only current inference is manipulated as variable. When prior belief is varying, some decision relevant neural representations are dissociated. Under this circumstance, it is unclear how to describe the uncertainty and how dissociated neural representations cooperate to control the uncertainty. By simulating an unpredictable environment, which incurs conflicting valence-dependent prior beliefs, we found that a behavioral outcome, waiting time, does not follow a normal, but a log-normal distribution. By combining electrophysiological recordings, computational modeling, optogenetic manipulation, scRNA-seq and MERFISH, we showed that the formation of this behavioral outcome requires the temporally hierarchical cooperation of the neural representation of decision confidence and B230216N24Rik marked neural representation of positive and negative belief in the medial prefrontal cortex (mPFC). In summary, our results provide a mechanistic link between the dynamics of valence-dependent prior beliefs and behavioral uncertainty.
Cognitive Mechanisms of Aberrant Self-Referential Social Perception in Psychosis and Bipolar Disorder: Insights from Computational Modeling
Authors: Lasagna Carly A. , Tso Ivy F. , Blain Scott D. , Pleskac Timothy J. 
Published: April 2024

AbstractBackground and HypothesisIndividuals with schizophrenia (SZ) and bipolar disorder (BD) show disruptions in self-referential gaze perception—a social perceptual process related to symptoms and functioning. However, our current mechanistic understanding of these dysfunctions and relationships is imprecise.Study DesignThe present study used mathematical modeling to uncover cognitive processes driving gaze perception abnormalities in SZ and BD, and how they relate to cognition, symptoms, and social functioning. We modeled the behavior of 28 SZ, 38 BD, and 34 controls (HC) in a self-referential gaze perception task using drift-diffusion models (DDM) parameterized to index key cognitive components: drift rate (evidence accumulation efficiency), drift bias (perceptual bias), start point (expectation bias), threshold separation (response caution), and non- decision time (encoding/motor processes).Study ResultsResults revealed that aberrant gaze perception in SZ and BD was driven by less efficient evidence accumulation, perceptual biases predisposing self-referential responses, and greater caution (SZ only). Across SZ and HC, poorer social functioning was related to greater expectation biases. Within SZ, perceptual and expectancy biases were associated with hallucination and delusion severity, respectively.ConclusionsThese findings indicate that diminished evidence accumulation and perceptual biases may underlie altered gaze perception in patients and that SZ may engage in compensatory cautiousness, sacrificing response speed to preserve accuracy. Moreover, biases at the belief and perceptual levels may relate to symptoms and functioning. Computational modeling can, therefore, be used to achieve a more nuanced, cognitive process-level understanding of the mechanisms of social cognitive difficulties, including gaze perception, in individuals with SZ and BD.
Efficient Simulation of Viral Transduction and Propagation for Biomanufacturing
Authors: Destro Francesco , Braatz Richard D. 
Published: April 2024

AbstractViral transduction is a main route for gene transfer to producer cells in biomanufacturing. Designing a transduction-based biomanufacturing process poses significant challenges, due to the complex dynamics of viral infection and virus-host interaction. This article introduces a software toolkit composed of a multiscale model and an efficient numeric technique that can be leveraged for determining genetic and process designs that optimize transduction-based biomanufacturing platforms. Viral transduction and propagation for up to two viruses simultaneously can be simulated through the model, considering viruses in either lytic or lysogenic stage, during batch, perfusion, or continuous operation. The model estimates the distribution of the viral genome(s) copy number in the cell population, which is an indicator of transduction efficiency and viral genome stability. The infection age distribution of the infected cells is also calculated, indicating how many cells are in an infection stage compatible with recombinant product expression and/or with viral amplification. The model can also consider the presence in the system of defective interfering particles, which can severely compromise the productivity of biomanufacturing processes. Model benchmarking and validation are demonstrated for case studies on the baculovirus expression vector system and influenza A propagation in suspension cultures.TOC Graphic
Genetic admixture predictors of fetal alcohol spectrum disorders (FASD) in the South African Cape Coloured population
Authors: Carter R. Colin , Yang Zikun , Akkaya-Hocagil Tugba , Jacobson Sandra W. , Jacobson Joseph L. , Dodge Neil C. , Hoyme H. Eugene , Zeisel Steven H. , Meintjes Ernesta M. , Kizil Caghan , Tosto Giuseppe 
Published: April 2024

ABSTRACTAncestrally admixed populations are underrepresented in genetic studies of complex diseases, which are still dominated by European-descent populations. This is relevant not only from a representation standpoint but also because of admixed populations’ unique features, including being enriched for rare variants, for which effect sizes are disproportionately larger than common polymorphisms. Furthermore, results from these populations may be generalizable to other populations. The South African Cape Coloured (SACC) population is genetically admixed, with one of the highest prevalences of fetal alcohol spectrum disorders (FASD) worldwide. We profiled its admixture and examined associations between ancestry profiles and FASD outcomes using two longitudinal birth cohorts (N=308 mothers, 280 children) designed to examine effects of prenatal alcohol exposure on development. Participants were genotyped via MEGA-ex array to capture common and rare variants. Rare variants were overrepresented in our SACC cohorts, with numerous polymorphisms being monomorphic in other reference populations (e.g., ∼30,000 and ∼221,000 variants in gnomAD European and Asian populations, respectively). The cohorts showed global African (51%; Bantu and San); European (26%; Northern/Western); South Asian (18%); and East Asian (5%; largely Southern regions) ancestries. The cohorts exhibited high rates of homozygosity (6%), with regions of homozygosity harboring more deleterious variants when lying within African local-ancestry genomic segments. Both maternal and child ancestry profiles were associated with FASD risk and altered severity of prenatal alcohol exposure-related cognitive deficits in the child. Our findings indicate that the SACC population may be a valuable asset to identify novel disease-associated genetic loci for FASD and other diseases.
Desynchronization between timers provokes transient arrest duringC. elegansdevelopment
Authors: Romero-Expósito Francisco J. , Moreno-Rivero Almudena , Muñoz-Barrera Marta , García-Sánchez Sabas , Rodríguez-Peris Fernando , Gritti Nicola , Sartor Francesca , Merrow Martha , van Zon Jeroen S. , Mata-Cabana Alejandro , Olmedo María 
Published: April 2024

ABSTRACTIn multicellular organisms, developmental timers integrate internal and external cues to control numerous cellular processes that need to be temporally coordinated. The molting timer and the developmental timer run in parallel duringC. elegansdevelopment. We reveal a novel state of transient arrest of the molting timer upon delay of the developmental timer. This means that synchronous development is not inherent but requires active synchronization of parallel timers. Additional timer variability, like that provoked by modulation of nutrient sensing pathways, increases desynchrony between these timers and consequently extends transient arrest. Mutation of the insulin receptor genedaf-2reduces the speed of both timers but has a larger impact on the developmental timer, that then appears delayed relative to the molting timer. In this context, prolonged arrest of the molting timer provides a mechanism for resynchronization.TeaserActive resynchronization at specific checkpoints of two parallel timers controlling developmental events.
Dynamics of MicroRNA Secreted via Extracellular Vesicles During the Maturation of Embryonic Stem Cell-Derived Retinal Pigment Epithelium
Authors: Pollalis Dimitrios , Gopinadhan Nair Gopa Kumar , Leung Justin , Bloemhof Clarisa Marie , Bailey Jeffrey K. , Pennington Britney O. , Kelly Kaitlin R. , Khan Amir I. , Yeh Ashley K. , Sundaram Kartik S. , Clegg Dennis O. , Peng Chen-Ching , Xu Liya , Georgescu Constantin , Wren Jonathan , Lee Sun Young 
Published: April 2024

AbstractRetinal pigment epithelium (RPE) cells are exclusive to the retina, critically multifunctional in maintaining the visual functions and health of photoreceptors and the retina. Despite their vital functions throughout lifetime, RPE cells lack regenerative capacity, rendering them vulnerable and central to degenerative retinal diseases. With advancements in stem cell technology enabling the differentiation of functional cells from pluripotent stem cells and leveraging the robust autocrine and paracrine functions of RPE cells, extracellular vesicles (EVs) secreted by RPE cells hold significant therapeutic potential in supplementing RPE cell activity. While previous research has primarily focused on the trophic factors secreted by RPE cells, there is a lack of studies investigating miRNA, which serves as a master regulator of gene expression. Profiling and defining the functional role of miRNA contained within RPE-secreted EVs is critical as it constitutes a necessary step in identifying the optimal phenotype of the EV secreting cell and understanding biological cargo of EVs to develop EV-based therapeutics. In this study, we present a comprehensive profile of miRNA in small extracellular vesicles (sEV) secreted during RPE maturation following differentiation from human embryonic stem cells (hESCs). This exploration is essential for ongoing efforts to develop and optimize EV-based intraocular therapeutics utilizing RPE-secreted EVs, which may significantly impact the function of dysfunctional RPE cells.
Regulation of angiogenesis by endocytic trafficking mediated by cytoplasmic dynein 1 light intermediate chain 1
Authors: Johnson Dymonn , Colijn Sarah , Richee Jahmiera , Yano Joseph , Burns Margaret , Davis Andrew E. , Pham Van N. , Saric Amra , Jain Akansha , Yin Ying , Castranova Daniel , Melani Mariana , Fujita Misato , Grainger Stephanie , Bonifacino Juan S. , Weinstein Brant M. , Stratman Amber N. 
Published: April 2024

ABSTRACTDynein cytoplasmic 1 light intermediate chain 1 (LIC1,DYNC1LI1) is a core subunit of the dynein motor complex. The LIC1 subunit also interacts with various cargo adaptors to regulate Rab-mediated endosomal recycling and lysosomal degradation. Defects in this gene are predicted to alter dynein motor function, Rab binding capabilities, and cytoplasmic cargo trafficking. Here, we have identified adync1li1zebrafish mutant, harboring a premature stop codon at the exon 12/13 splice acceptor site, that displays increased angiogenesis.In vitro, LIC1-deficient human endothelial cells display increases in cell surface levels of the pro-angiogenic receptor VEGFR2, SRC phosphorylation, and Rab11-mediated endosomal recycling.In vivo, endothelial-specific expression of constitutively activeRab11aleads to excessive angiogenesis, similar to thedync1li1mutants. Increased angiogenesis is also evident in zebrafish harboring mutations inrilpl1/2, the adaptor proteins that promote Rab docking to Lic1 to mediate lysosomal targeting. These findings suggest that LIC1 and the Rab-adaptor proteins RILPL1 and 2 restrict angiogenesis by promoting degradation of VEGFR2-containing recycling endosomes. Disruption of LIC1- and RILPL1/2-mediated lysosomal targeting increases Rab11-mediated recycling endosome activity, promoting excessive SRC signaling and angiogenesis.
Proton and neutron density distributions at supranormal density in low- and medium-energy heavy-ion collisions. II. Central Pb
+
Pb collisions
Authors: Stone J. R. , Danielewicz P. , Iwata Y. 
Published: April 2024

This paper represents a continuation of our investigation into the limitations on total, proton, and neutron particle number densities, as well as the asymmetry of proton and neutron density distributions achievable in central heavy-ion collisions. We explore these aspects at low and medium energies within the framework of the Boltzmann-Uhlenbeck-Uehling (pBUU) transport and time-dependent Hartree-Fock (TDHF) models. Previous studies, focusing on symmetric and asymmetric collisions of Ca and Sn nuclei [1], and initial results on Pb-nuclei collisions [2], emphasized the role of the Coulomb interaction in these events. Our findings indicated that: (i) the highest total densities predicted at Ebeam=800 MeV/nucleon were on the order of ≈2.5ρ0 (ρ0=0.16fm−3), (ii) the proton-neutron asymmetry for maximal densities, δ=(ρnmax−ρpmax)/(ρnmax+ρpmax), did not generally exceed the asymmetry in the initial state of the collision at all beam energies and tended to decrease during the reaction, and (iii) a significant portion of this asymmetry had its microscopic origin in Coulomb forces, masking the pure nuclear contribution. These new findings, particularly relevant in the astrophysical context, are further examined in this work, focusing on the heaviest target-projectile combination Pb212,208 accessible in an experiment. We introduce the SkT3 Skyrme force model, not previously used for the Pb system, and compare it to the SV-bas and SV-sym34 models to explore the symmetry-energy dependence of the results. Contour plots of nucleonic densities are presented, contrasting the time evolution of the density distributions in low (TDHF) and high (pBUU) models. We also present the evolution of normalized maximal proton, neutron, and total nucleon number density with increasing beam energy in the full pBUU model and the Vlasov approximation, aiming to explore the impact of correlations in the reaction. The time evolution of the proton and neutron density distributions in the plane transverse to the beam direction is illustrated at both low and high beam energy. In conclusion, our detailed examination of the Pb system in this work provides further essential evidence that the aforementioned findings (i)–(iii) are only weakly dependent on system size and a symmetry-energy model, and thus, they are of more general importance.

Published by the American Physical Society
2024
Doubly heavy tetraquark states in the constituent quark model using diffusion Monte Carlo method
Authors: Ma Yao , Meng Lu , Chen Yan-Ke , Zhu Shi-Lin 
Published: April 2024

We use the diffusion Monte Carlo (DMC) method to calculate the doubly heavy tetraquark Tcc system in two kinds of constituent quark models, the pure constituent quark model AL1/AP1 and the chiral constituent quark model. When the discrete configurations are complete and no spatial clustering is predetermined, the AL1/AP1 model gives an energy of Tcc close to the DD* threshold, and the chiral constituent quark model yields a deeply bound state. We further calculate all doubly heavy tetraquark systems with JP=0+,1+,2+, and provide the binding energies of systems with bound states. The I(JP)=0(0+) bcn¯n¯, 0(1+) bbn¯n¯, 0(1+) bcn¯n¯, 12(1+) bbs¯n¯ systems have bound states in all three models. Since the DMC method has almost no restriction on the spatial part, the resulting bound states have greater binding energies than those obtained in previous works.

Published by the American Physical Society
2024
Hegemony, global capitalism and the role of diplomacy in extractive industries
Authors: Andrew Jane , Baker Max 
Published: April 2024

PurposeThis study explores a hegemonic alliance and the role of relational forms of accounting and accountablity in the making of contemporary capitalism.Design/methodology/approachWe use the WikiLeaks “Cablegate” documents to provide an account of the detailed machinations between interest groups (corporations and the state) that are constitutive of hegemonic activity.FindingsOur analysis of the “Cablegate” documents shows that the US and Chevron were crafting a central role for Turkmenistan and its president on the global political stage as early as 2007, despite offical reporting beginning only in 2009. The documents exemplify how “accountability gaps” occlude the understanding of interdependence between capital and the state.Research limitations/implicationsThe study contributes to a growing idea that official accounts offer a fictionalized narrative of corporations as existing independently, and thus expands the boundaries associated with studying multinational corporate activities to include their interdependencies with the modern state.Social implicationsThe study traces how global capitalism extends into new territories through diplomatic channels, as a strategic initiative between powerful state and capital interests, arguing that the outcome is the empowerment of authoritarian states at the cost of democracy.Originality/valueThe study argues that previous accounting and accountability research has overlooked the larger picture of how capital and the state work together to secure a mutual hegemonic interest. We advocate for a more complete account of these activities that circumvents official, often restricted, views of global capitalism.
Upskilling towards automation: a conversation with the experts
Authors: Murphy Liam 
Published: April 2024

Purpose
This paper conducts empirical research to assess the new skillsets employees require in order to remain competitive in the age of automation.

Design/methodology/approach
Research is conducted through focus groups leveraging semi-structured interviews. Participants were selected via convenience sampling from UK-based consulting agencies operating in the public and private sectors.

Findings
The findings suggest that organizations are looking to upskill employees in 5 key skill blocks: Humanistic, Process engineering, Automation technologies, Self-leadership and Data driven. The findings also suggest that employee orientation towards these skill blocks will be critical for positive work opportunities in future.

Originality/value
This paper builds on the author’s previous work to produce a conceptual skills framework which can be used by organizations as a blueprint for upskilling their employees in a period of unprecedented technological advancement.
BIM implementation for Nigeria’s polytechnic built environment undergraduates: challenges and possible measures from stakeholders
Authors: Ebekozien Andrew , Aigbavboa Clinton , Samsurijan Mohamad Shaharudin , Azazi Noor Alyani Nor , Duru Okechukwu Dominic Saviour 
Published: April 2024

Purpose
Studies show that building information modelling (BIM) technology can improve construction productivity regarding the design, construction and maintenance of a project life cycle in the 21st century. Revit has been identified as a frequently used tool for delivering BIM in the built environment. Studies about BIM technology via Revit are scarce in training middle-level workforce higher education institutions. Thus, this study aims to investigate the relevance of BIM technology and offer measures to promote digitalisation in Nigeria’s built environment polytechnic undergraduates via Revit.

Design/methodology/approach
Given the unexplored nature of training the middle-level workforce in Nigeria, 37 semi-structured virtual interviews were conducted across Nigeria, and saturation was achieved. The participants were knowledgeable about construction-related BIM. The researchers used a thematic analysis for the collected data and honed them with secondary sources.

Findings
Improved visualisation of design, effective and efficient work productivity, automatic design and quantification, improved database management and collaboration and data storage in the centrally coordinated model, among others, emerged as BIM’s benefits. BIM technology via Revit is challenging, especially in Nigeria’s polytechnic education curriculum. The 24 perceived issues were grouped into government/regulatory agencies-related, polytechnic management-related and polytechnic undergraduate students-related hindrances in Nigeria’s built environment.

Research limitations/implications
This study is limited to BIM implications for Nigeria’s built environment polytechnic undergraduates.

Originality/value
This study contributes to the literature paucity in attempting to uncover perceived issues hindering the implementation of BIM technology via Revit in training Nigeria’s built environment polytechnic undergraduates via a qualitative approach.