bluuebunny/crossref_metadata_2025 huggingface dataset:
Mixed representations of choice direction and outcome by GABA/glutamate cotransmitting neurons in the entopeduncular nucleus
Authors: Locantore Julianna R. , Liu Yijun , White Jesse , Wallace Janet Berrios , Beron Celia C. , Kraft Emily , Sabatini Bernardo L. , Wallace Michael L.
Published: June 2024

The basal ganglia (BG) are an evolutionarily conserved and phylogenetically old set of sub-cortical nuclei that guide action selection, evaluation, and reinforcement. The entopeduncular nucleus (EP) is a major BG output nucleus that contains a population of GABA/glutamate cotransmitting neurons (EPSst+) that specifically target the lateral habenula (LHb) and whose function in behavior remains mysterious. Here we use a probabilistic switching task that requires an animal to maintain flexible relationships between action selection and evaluation to examine when and how GABA/glutamate cotransmitting neurons contribute to behavior. We find that EPSst+neurons are strongly engaged during this task and show bidirectional changes in activity during the choice and outcome periods of a trial. We then tested the effects of either permanently blocking cotransmission or modifying the GABA/glutamate ratio on behavior in well-trained animals. Neither manipulation produced detectable changes in behavior despite significant changes in synaptic transmission in the LHb, demonstrating that the outputs of these neurons are not required for on-going action-outcome updating in a probabilistic switching task.
Structure of the Ion Channel Kir7.1 and Implications for its Function in Normal and Pathophysiologic States
Authors: Peisley Alys , Hernandez Ciria C. , Dahir Naima S. , Koepping Laura , Raczkowski Ashleigh , Su Min , Ghamari-Langroudi Masoud , Ji Xinrui , Gimenez Luis E. , Cone Roger D.
Published: June 2024

Hereditary defects in the function of the Kir7.1 in the retinal pigment epithelium are associated with the ocular diseases retinitis pigmentosa, Leber congenital amaurosis, and snowflake vitreal degeneration. Studies also suggest that Kir7.1 may be regulated by a GPCR, the melanocortin-4 receptor, in certain hypothalamic neurons. We present the first structures of human Kir7.1 and describe the conformational bias displayed by two pathogenic mutations, R162Q and E276A, to provide an explanation for the basis of disease and illuminate the gating pathway. We also demonstrate the structural basis for the blockade of the channel by a small molecule ML418 and demonstrate that channel blockade in vivo activates MC4R neurons in the paraventricular nucleus of the hypothalamus (PVH), inhibiting food intake and inducing weight loss. Preliminary purification, and structural and pharmacological characterization of an in tandem construct of MC4R and Kir7.1 suggests that the fusion protein forms a homotetrameric channel that retains regulation by liganded MC4R molecules.
Fiber-based Probes for Electrophysiology, Photometry, Optical and Electrical Stimulation, Drug Delivery, and Fast-Scan Cyclic Voltammetry In Vivo
Authors: Driscoll Nicolette , Antonini Marc-Joseph , Cannon Taylor M. , Maretich Pema , Olaitan Greatness , Phi Van Valerie Doan , Nagao Keisuke , Sahasrabudhe Atharva , Vargas Emmanuel , Hunt Sydney , Hummel Melissa , Mupparaju Sanju , Jasanoff Alan , Venton Jill , Anikeeva Polina
Published: June 2024

Recording and modulation of neuronal activity enables the study of brain function in health and disease. While translational neuroscience relies on electrical recording and modulation techniques, mechanistic studies in rodent models leverage genetic precision of optical methods, such as optogenetics and imaging of fluorescent indicators. In addition to electrical signal transduction, neurons produce and receive diverse chemical signals which motivate tools to probe and modulate neurochemistry. Although the past decade has delivered a wealth of technologies for electrophysiology, optogenetics, chemical sensing, and optical recording, combining these modalities within a single platform remains challenging. This work leverages materials selection and convergence fiber drawing to permit neural recording, electrical stimulation, optogenetics, fiber photometry, drug and gene delivery, and voltammetric recording of neurotransmitters within individual fibers. Composed of polymers and non-magnetic carbon-based conductors, these fibers are compatible with magnetic resonance imaging, enabling concurrent stimulation and whole-brain monitoring. Their utility is demonstrated in studies of the mesolimbic reward pathway by simultaneously interfacing with the ventral tegmental area and nucleus accumbens in mice and characterizing the neurophysiological effects of a stimulant drug. This study highlights the potential of these fibers to probe electrical, optical, and chemical signaling across multiple brain regions in both mechanistic and translational studies.
Fast and Accurate EEG/MEG BEM-Based Forward Problem Solution for High-Resolution Head Models
Authors: Wartman William A. , Ponasso Guillermo Nuñez , Qi Zhen , Haueisen Jens , Maess Burkhard , Knösche Thomas R. , Weise Konstantin , Noetscher Gregory M. , Raij Tommi , Makaroff Sergey N.
Published: June 2024

A BEM (boundary element method) based approach is developed to accurately solve an EEG/MEG forward problem for a modern high-resolution head model in approximately 60 seconds using a common workstation. The method utilizes a charge-based BEM with fast multipole acceleration (BEM-FMM) and a “smart” mesh pre-refinement (calledb-refinement) close to the singular source(s). No costly matrix-filling or direct solution steps typical for the standard BEM are required; the method generates on-skin voltages as well as MEG magnetic fields for high-resolution head models in approximately 60 seconds after initial model assembly. The method is verified both theoretically and experimentally.
Ultrasound system for precise neuromodulation of human deep brain circuits
Authors: Martin Eleanor , Roberts Morgan , Grigoras Ioana F , Wright Olivia , Nandi Tulika , Rieger Sebastian W , Campbell Jon , den Boer Tim , Cox Ben T , Stagg Charlotte J , Treeby Bradley E
Published: June 2024

Transcranial ultrasound stimulation (TUS) has emerged as a promising technique for non-invasive neuromodulation, but current systems lack the precision to target deep brain structures effectively. Here, we introduce an advanced TUS system that achieves unprecedented precision in deep brain neuromodulation. The system features a 256-element, helmet-shaped transducer array operating at 555 kHz, coupled with a stereotactic positioning system, individualised treatment planning, and real-time monitoring using functional MRI. In a series of experiments, we demonstrate the system’s ability to selectively modulate the activity of the lateral geniculate nucleus (LGN) and its functionally connected regions in the visual cortex. Participants exhibited significantly increased visual cortex activity during concurrent TUS and visual stimulation, with high reproducibility across individuals. Moreover, a theta-burst TUS protocol induced robust neuromodulatory effects, with decreased visual cortex activity observed for at least 40 minutes post-stimulation. These neuromodulatory effects were specific to the targeted LGN, as confirmed by control experiments. Our findings highlight the potential of this advanced TUS system to non-invasively modulate deep brain circuits with high precision and specificity, offering new avenues for studying brain function and developing targeted therapies for neurological and psychiatric disorders. The unprecedented spatial resolution and prolonged neuromodulatory effects demonstrate the transformative potential of this technology for both research and clinical applications, paving the way for a new era of non-invasive deep brain neuromodulation.
A replicable and generalizable neuroimaging-based indicator of pain sensitivity across individuals
Authors: Zhang Li-Bo , Lu Xue-Jing , Zhang Hui-Juan , Wei Zhao-Xing , Kong Ya-Zhuo , Tu Yi-Heng , Iannetti Gian Domenico , Hu Li
Published: June 2024

Developing neural indicators of pain sensitivity is crucial for revealing the neural basis of individual differences in pain and advancing individualized pain treatment. To identify reliable neural indicators of pain sensitivity, we leveraged six large and diverse functional magnetic resonance imaging (fMRI) datasets (total N=1046). We found replicable and generalizable correlations between nociceptive-evoked fMRI responses and pain sensitivity for laser heat, contact heat, and mechanical pains. These fMRI responses correlated more strongly with pain sensitivity than with tactile, auditory, and visual sensitivity. Moreover, we developed a machine learning model that accurately predicted not only pain sensitivity but also pain reduction from different interventions in healthy individuals. Notably, these findings were influenced considerably by sample sizes, requiring >200 for univariate correlation analysis and >150 for multivariate machine learning modelling. Altogether, we demonstrate the validity of decoding pain sensitivity from fMRI responses, thus facilitating interpretations of subjective pain reports and promoting more mechanistically informed investigation of pain physiology.
Microphthalmia and disrupted retinal development due to aLacZknock-in/knock-out allele at theVsx2locus
Authors: Napoli Francesca R. , Li Xiaodong , Hurtado Alan A. , Levine Edward M.
Published: June 2024

Visual System Homeobox 2 (Vsx2) is a transcription factor expressed in the developing retina that regulates tissue identity, growth, and fate determination. Several mutations in theVsx2gene exist in mice, including a spontaneous nonsense mutation and two targeted missense mutations originally identified in humans. Here, we expand the genetic repertoire to include aLacZreporter allele (Vsx2LacZ) designed to express beta-Galactosidase (b-GAL) and simultaneously disruptVsx2function (knock-in/knock-out). The retinal expression pattern of b-GAL is concordant with VSX2, and the mutant allele is recessive.Vsx2LacZhomozygous mice have congenital bilateral microphthalmia accompanied by defects in retinal development including ectopic expression of non-retinal genes, reduced proliferation, delayed neurogenesis, aberrant tissue morphology, and an absence of bipolar interneurons - all hallmarks ofVsx2loss-of-function. Unexpectedly, the mutant VSX2 protein is stably expressed, and there are subtle differences in eye size and early retinal neurogenesis when compared to the null mutant,ocular retardation J. The perdurance of the mutant VSX2 protein combined with subtle deviations from the null phenotype leaves open the possibility thatVsx2LacZallele is not a complete knock-out. TheVsx2LacZallele exhibits loss-of-function characteristics and adds to the genetic toolkit for understandingVsx2function.
Leveraging protein language and structural models for early prediction of antibodies with fast clearance
Authors: Mazrooei Parisa , O’Neil Daniel , Izadi Saeed , Chen Bingyuan , Ramanujan Saroja
Published: June 2024

Monoclonal antibodies (mAbs) with long systemic persistence are widely used as therapeutics. However, antibodies with atypically fast clearance require more dosing, limiting their clinical usefulness. Deep learning can facilitate using sequence-based modeling to predict potential pharmacokinetic (PK) liabilities before antibody generation. Assembling a dataset of 103 mAbs with measured nonspecific clearance in cynomolgus monkeys (cyno), and using transfer learning from large protein language models, we developed multiple machine learning models to predict mAb clearance as fast/slow clearing. Focusing on minimizing misclassification of potentially promising molecules as fast clearing, our results show that using physicochemical properties yielded up to 73.1+/-1.1% classification accuracy on hold-out test data (precision 65.2+/-2.3%). Using only sequence-based features from deep learning protein language models yielded a comparable performance of 71+/-1.4% (precision 65.5+/-2.5%). Combining structural and deep learning derived features yielded a similar accuracy of 73.9+/-1.1%, and slightly improved precision (68.3+/-2.4%). Features important for classifying fast/slow clearance point to charge, moment, and surface area properties at pH 7.4 as well as deep learning derived features. These results suggest that the protein language models provide comparable information and predictive performance of clearance as physicochemical features. This work provides a foundation for in silico prediction of protein pharmacokinetics to inform antibody candidate generation and early deprioritization of designs with high risk of fast clearance. More generally, it illustrates the value of transfer learning-based application of protein language models to address characteristics of importance for protein therapeutics.
Identification of molecular determinants of gene-specific bursting patterns by high-throughput imaging screens
Authors: Sood Varun , Holewinski Ronald , Andresson Thorkell , Larson Daniel R. , Misteli Tom
Published: June 2024

Stochastic transcriptional bursting is a universal property of active genes. While different genes exhibit distinct bursting patterns, the molecular mechanisms for gene-specific stochastic bursting are largely unknown. We have developed and applied a high-throughput-imaging based screening strategy to identify cellular factors and molecular mechanisms that determine the bursting behavior of human genes. Focusing on epigenetic regulators, we find that protein acetylation is a strong acute modulator of burst frequency, burst size and heterogeneity of bursting. Acetylation globally affects the Off-time of genes but has gene-specific effects on the On-time. Yet, these effects are not strongly linked to promoter acetylation, which do not correlate with bursting properties, and forced promoter acetylation has variable effects on bursting. Instead, we demonstrate acetylation of the Integrator complex as a key determinant of gene bursting. Specifically, we find that elevated Integrator acetylation decreases bursting frequency. Taken together our results suggest a prominent role of non-histone proteins in determining gene bursting properties, and they identify histone-independent acetylation of a transcription cofactor as an allosteric modulator of bursting via a far-downstream bursting checkpoint.
Engineered Cortical Microcircuits for Investigations of Neuroplasticity
Authors: Winter-Hjelm Nicolai , Sikorski Pawel , Sandvig Axel , Sandvig Ioanna
Published: June 2024

Recent advances in neural engineering have opened new ways to investigate the impact of topology on neural network function. Leveraging microfluidic technologies, it is possible to establish modular circuit motifs that promote both segregation and integration of information processing in the engineered neural networks, similar to those observedin vivo. However, the impact of the underlying topologies on network dynamics and response to pathological perturbation remains largely unresolved. In this work, we demonstrate the utilization of microfluidic platforms with 12 interconnected nodes to structure modular, cortical engineered neural networks. By implementing geometrical constraints inspired by a Tesla valve within the connecting microtunnels, we additionally exert control over the direction of axonal outgrowth between the nodes. Interfacing these platforms with nanoporous microelectrode arrays reveals that the resulting laminar cortical networks exhibit pronounced segregated and integrated functional dynamics across layers, mirroring key elements of the feedforward, hierarchical information processing observed in the neocortex. The multi-nodal configuration also facilitates selective perturbation of individual nodes within the networks. To illustrate this, we induced hypoxia, a key factor in the pathogenesis of various neurological disorders, in well-connected nodes within the networks. Our findings demonstrate that such perturbations induce ablation of information flow across the hypoxic node, while enabling the study of plasticity and information processing adaptations in neighboring nodes and neural communication pathways. In summary, our presented model system recapitulates fundamental attributes of the microcircuit organization of neocortical neural networks, rendering it highly pertinent for preclinical neuroscience research. This model system holds promise for yielding new insights into the development, topological organization, and neuroplasticity mechanisms of the neocortex across the micro- and mesoscale level, in both healthy and pathological conditions.
“Shedding light on plant proteolysis: genetically encoded fluorescent sensors as tools for profiling protease activities.”
Authors: Fernández-Fernández Álvaro Daniel , Tack Simon , Van Durme Matthias , Nolf Jonah , Nowack Moritz K. , Staal Jens , Stael Simon , Van Breusegem Frank
Published: June 2024

Proteolysis, a ubiquitous process in living organisms, is driven by proteases that regulate numerous signaling pathways through the hydrolysis of peptide bonds in protein substrates. Understanding the temporal and spatial dynamics of proteolysis and the activation of proteases is crucial for elucidating their roles in biological pathways. Here, we introduce a suite of genetically encoded FRET reporters designed to detect various proteolytic activities in plants. These sensors effectively reportedin plantathe specific activity of both Tobacco Etch Virus protease and caspase-3. Furthermore, we developed sensors for detecting plant metacaspase activity, validated through bothin vitroandin plantaexperiments. These experiments revealed the spatial dynamics of proteolysis triggered by metacaspase activation following wounding and programmed cell death in roots. The implementation of these tools in plant biology research opens new avenues for investigating proteolytic mechanisms, significantly enhancing the potential for in-depth studies. Our work demonstrates the feasibility of using these sensors to detect diverse protease activitiesin vivowith high spatiotemporal resolution. These plant proteolytic biosensors hence represent a valuable toolbox for understanding protease functions within their natural context, paving the way for future advancements in plant biology research.
DET1 dynamics underlie co-operative ubiquitination by CRL4DET1-COP1 complexes
Authors: Burgess Abigail E , Loughran Tarren A , Turk Liam S , Dunlop Jess L , Jamieson Sam A , Curry Jack R , Filipcik Pavel , Brown Simon HJ , Mace Peter D
Published: June 2024

Ubiquitin ligases regulate core cellular processes through diverse mechanisms. The ubiquitin ligase COP1 is conserved from plants to humans and is particularly important for targeting developmental transcription factors for ubiquitination. COP1 can function independently, but can also be recruited to Cullin-4 ubiquitin ligase complexes via the DET1 adaptor protein. However, the mechanism of action of complexes containing COP1 and DET1 is not well understood. Here we report the cryo-electron microscopy structure of human DET1, bound to proteins that enable Cullin-4 recruitment (DDB1-DDA1) and an additional ubiquitin ligase enzyme (Ube2e2). We observe that DDA1 stabilises a closed conformation of DET1, binding adjacent to a unique Ube2e2 binding-insert in DET1. Moreover, we demonstrate that closure of DET1 underlies COP1 recruitment, which binds in an antiparallel dimeric state. Disrupting either the Ube2e2-binding insertion of DET1, or distinct recruitment sites on COP1, abolish DET1–COP1 binding and DET1-mediated modulation of COP1 levels. The multifaceted architecture provides an efficient platform for ubiquitination of substrates, or COP1 itself, by Cullin-4DET1and offers multiple opportunities for physiological regulation.
Effects and phenotypic consequences of transient thyrotoxicosis and hypothyroidism at different stages of zebrafishDanio rerio(Teleostei; Cyprinidae) skeleton development
Authors: Borisov Vasily , Shkil Fedor
Published: June 2024

Thyroid hormones (THs) are one of the main regulators of remodeling, homeostasis and development of skeletal tissues in teleosts, and the effects of hypo- and hyperthyroidism on skeleton are among the objectives of research in the fields of fishes development and evolution. However, in most experimental models used, the altered THs status is a constant characteristic of the developing organism, and the observed phenotypic outcomes are the cumulative consequences of multiple THs induced developmental changes. The effects of the transient fluctuations of THs content on the skeleton development have been studied much less. Here, we present experimental data on the developmental effects and phenotypic consequences of transient, pharmacologically induced thyrotoxicosis and hypothyroidism at different stages of zebrafish ossified skeleton patterning. In accordance with the results, skeleton structures differ in the timing and degree of THs sensitivity. Some of them displayed a notable shift in the developmental timing and rate, whereas other demonstrated a subtle or absence of reaction in respond to changes of THs content. The developmental stages also differ in THs sensitivity. A relatively short developmental period has been revealed, during which changes in THs level (mainly thyrotoxicosis) sharply increase the developmental instability and plasticity, leading to phenotypic consequences comparable to those in fish with permanently altered THs status. These findings allow us consider this period as a critical developmental window.

Summary statement

Study of the developmental effects and phenotypic consequences of acute transient changes in thyroid hormones content have identified a critical developmental window for zebrafish’s skeleton

Ethics statement

All procedures with fish were carried out according to the guidelines and following the laws and ethics of the Russian Federation, and approved by the ethics committee of the Severtsov Institute of Ecology and Evolution, Russian Academy of Sciences (Approval ID: N 95 issued on 27.05.2024).
ProEnd: A Comprehensive Database for Identifying HbYX Motif-Containing Proteins Across the Tree of Life
Authors: Salcedo-Tacuma David , Howells Giovanni , Mchose Coleman , Gutierrez-Diaz Aimer , Schupp Jane , Smith David M.
Published: June 2024

The proteasome plays a crucial role in cellular homeostasis by degrading misfolded, damaged, or unnecessary proteins. Understanding the regulatory mechanisms of proteasome activity is vital, particularly the interaction with activators containing the hydrophobic-tyrosine-any amino acid (HbYX) motif. Here, we present ProEnd, a comprehensive database designed to identify and catalog HbYX motif-containing proteins across the tree of life. Using a simple bioinformatics pipeline, we analyzed approximately 73 million proteins from 22,000 reference proteomes in the UniProt/SwissProt database. Our findings reveal the widespread presence of HbYX motifs in diverse organisms, highlighting their evolutionary conservation and functional significance. Notably, we observed an interesting prevalence of these motifs in viral proteomes, suggesting strategic interactions with the host proteasome. As validation two novel HbYX proteins found in this database were tested and found to directly interact with the proteasome. ProEnd’s extensive dataset and user-friendly interface enable researchers to explore the potential proteasomal regulator landscape, generating new hypotheses to advance proteasome biology. This resource is set to facilitate the discovery of novel therapeutic targets, enhancing our approach to treating diseases such as neurodegenerative disorders and cancer. Link:http://proend.org/
Syntaxin-2 coordinates endolysosomal trafficking to balance phagocytic uptake and phagolysosomal clearance in macrophages
Authors: Samanta Suman , Nandi Abhrajyoti , Datta Rupak , Dolai Subhankar
Published: June 2024

Phagocytosis engulfs receptor-bound particles by structuring phagocytic cups that expand to form phagosome vesicles. Phagosomes fuse with endosomes and lysosomes to gradually mature into acidic, hydrolase-enriched phagolysosomes for content degradation. While an essential cellular process for eliminating unwanted substances to secure host defense and organismal homeostasis, defective or uncontrolled phagocytosis can be detrimental. Here, we report syntaxin-2 (Stx2), a poorly characterized SNARE in phagocytes, defines the course of macrophage phagocytosis by coordinating cell surface receptor density, phagocytic cup expansion, and phagosome maturation. Stx2 is expressed on the plasma membrane, phagosomes, early endosomes, and to some extent on recycling endosomes, late endosomes and VAMP4-positive compartments. Stx2 knockdown (Stx2-KD) augments engagement and uptake of IgG-opsonized particles by enhanced surface expression of Fc receptors (FcR) and efficient expansion of phagocytic cups. These events are driven by increased recycling of FcR, and enhanced delivery of early endosomes and VAMP4-positive post-Golgi compartments to phagocytic cups. Interestingly, Stx2-KD macrophages exhibit reduced secretion of pro-cathepsins with concomitant increase in lysosome content. However, Stx2 depletion prevents phagosome coalescence with late endosomes and lysosomes to impair maturation by depleted acquisition of cathepsins and reduced acidification. Consequently, macrophages depleted of Stx2 manifest uncontrolled uptake of IgG-opsonizedEscherichia coliand impaired digestion resulting in increased bacterial load. Collectively, we uncovered a previously unknown role of Stx2 as a critical balancer of phagocytic uptake and phagolysosomal clearance in macrophages, suggesting that it could be an attractive target for modulation of phagocytosis plasticity and to control aberrant phagocytosis.
Cell type-specific roles of FOXP1 in the excitatory neuronal lineage during early neocortical murine development
Authors: Ortiz Ana , Ayhan Fatma , Khandelwal Nitin , Outland Elliot , Jankovic Miranda , Harper Matthew , Konopka Genevieve
Published: June 2024

FOXP1, a transcription factor enriched in the neocortex, is associated with autism spectrum disorders (ASD) and FOXP1 syndrome.Emx1Cre/+;Foxp1fl/flconditional deletion (Foxp1cKO) in the mouse cortex leads to overall reduced cortex thickness, alterations in cortical lamination, and changes in the relative thickness of cortical layers. However, the developmental and cell type-specific mechanisms underlying these changes remained unclear. We find thatFoxp1deletion results in accelerated pseudo-age during early neurogenesis, increased cell cycle exit during late neurogenesis, altered gene expression and chromatin accessibility, and selective migration deficits in a subset of upper-layer neurons. These data explain the postnatal differences observed in cortical layers and relative cortical thickness. We also highlight genes regulated by FOXP1 and their enrichment with high-confidence ASD or synaptic genes. Together, these results underscore a network of neurodevelopmental disorder-related genes that may serve as potential modulatory targets for postnatal modification relevant to ASD and FOXP1 syndrome.
Long term rescue of Alzheimer’s deficitsin vivoby one-time gene-editing ofAppC-terminus
Authors: Aulston Brent D. , Gimse Kirstan , Bazick Hannah O. , Kramar Eniko A. , Pizzo Donald P. , Parra-Rivas Leonardo A. , Sun Jichao , Branes-Guerrero Kristen , Checka Nidhi , Bagheri Neda , Satyadev Nihal , Carlson-Stevermer Jared , Saito Takashi , Saido Takaomi C. , Audhya Anjon , Wood Marcelo A. , Zylka Mark J. , Saha Krishanu , Roy Subhojit
Published: June 2024

Gene-editing technologies promise to create a new class of therapeutics that can achieve permanent correction with a single intervention. Besides eliminating mutant alleles in familial disease, gene-editing can also be used to favorably manipulate upstream pathophysiologic events and alter disease-course in wider patient populations, but few such feasible therapeutic avenues have been reported. Here we use CRISPR-Cas9 to edit the last exon of amyloid precursor protein (App), relevant for Alzheimer’s disease (AD). Our strategy effectively eliminates an endocytic (YENPTY) motif at APP C-terminus, while preserving the N-terminus and compensatory APP-homologues. This manipulation favorably alters events along the amyloid-pathway – inhibiting toxic APP-β-cleavage fragments (including Aβ) and upregulating neuroprotective APP-α-cleavage products. AAV-driven editing ameliorates neuropathologic, electrophysiologic, and behavioral deficits in an AD knockin mouse model. Effects persist for many months, and no abnormalities are seen in WT mice even after germlineApp-editing; underlining overall efficacy and safety. Pathologic alterations in the glial-transcriptome ofApp-KI mice, as seen by single nuclei RNA-sequencing (sNuc-Seq), are also normalized byAppC-terminus editing. Our strategy takes advantage of innate transcriptional rules that render terminal exons insensitive to nonsense-decay, and the upstream manipulation is expected to be effective for all forms of AD. These studies offer a path for a one-time disease-modifying treatment for AD.
Genetic and cellular basis of impaired phagocytosis and photoreceptor degeneration in CLN3 disease
Authors: Han Jimin , Chear Sueanne , Talbot Jana , Swier Vicki , Booth Clarissa , Reuben-Thomas Cheyenne , Dalvi Sonal , Weimer Jill M. , Hewitt Alex W. , Cook Anthony L. , Singh Ruchira
Published: June 2024

Purpose

CLN3 Batten disease (also known as Juvenile Neuronal Ceroid Lipofuscinosis; JNCL) is a lysosomal storage disorder that typically initiates with retinal degeneration but is followed by seizure onset, motor decline and premature death. Patient-derived CLN3 disease iPSC-RPE cells show defective phagocytosis of photoreceptor outer segments (POSs). Because modifier genes are implicated in CLN3 disease, our goal here was to investigate a direct link betweenCLN3mutation and POS phagocytosis defect.

Methods

Isogenic control andCLN3mutant stem cell lines were generated by CRISPR-Cas9­mediated biallelic deletion of exons 7 and 8. A transgenicCLN3Δ7-8/Δ7-8(CLN3) Yucatan miniswine was also used to study the impact ofCLN3Δ7-8/Δ7-8mutation on POS phagocytosis. POS phagocytosis by cultured RPE cells was analyzed by Western blotting and immunohistochemistry. Electroretinogram, optical coherence tomography and histological analysis ofCLN3Δ7/8and wild-type miniswine eyes were carried out at 6-, 36-, or 48-month age.

Results

CLN3Δ7-8/Δ7-8RPE (CLN3RPE) displayed reduced POS binding and consequently decreased uptake of POS compared to isogenic control RPE cells. Furthermore, wild-type miniswine RPE cells phagocytosedCLN3Δ7-8/Δ7-8POS less efficiently than wild-type POS. Consistent with decreased POS phagocytosis, lipofuscin/autofluorescence was decreased inCLN3miniswine RPE at 36 months-of-age and was followed by almost complete loss of photoreceptors at 48 months of age.

Conclusions

CLN3Δ7-8/Δ7-8mutation (that affects up to 85% patients) affects both RPE and POSs and leads to photoreceptor cell loss in CLN3 disease. Furthermore, both primary RPE dysfunction and mutant POS independently contribute to impaired POS phagocytosis in CLN3 disease.
Three-dimensional chromatin mapping of sensory neurons reveals that cohesin-dependent genomic domains are required for axonal regeneration
Authors: Palmisano Ilaria , Liu Tong , Gao Wei , Zhou Luming , Merkenschlager Matthias , Müller Franziska , Chadwick Jessica , Rivolta Rebecca Toscano , Kong Guiping , King James WD , Al-jibury Ediem , Yan Yuyang , Carlino Alessandro , Collison Bryce , De Vitis Eleonora , Gongala Sree , De Virgiliis Francesco , Wang Zheng , Giovanni Simone Di
Published: June 2024

The in vivo three-dimensional genomic architecture of adult mature neurons at homeostasis and after medically relevant perturbations such as axonal injury remains elusive. Here we address this knowledge gap by mapping the three-dimensional chromatin architecture and gene expression programme at homeostasis and after sciatic nerve injury in wild-type and cohesin-deficient mouse sensory dorsal root ganglia neurons via combinatorial Hi-C and RNA-seq. We find that cohesin is required for the full induction of the regenerative transcriptional program, by organising 3D genomic domains required for the activation of regenerative genes. Importantly, loss of cohesin results in disruption of chromatin architecture at regenerative genes and severely impaired nerve regeneration. Together, these data provide an original three-dimensional chromatin map of adult sensory neurons in vivo and demonstrate a role for cohesin-dependent chromatin interactions in neuronal regeneration.
Liver-like glycogen metabolism supports glycolysis in naked mole-rat heart during ischaemia
Authors: Bundgaard Amanda , Wang Nini , Vyshkvorkina Iuliia , Jacome Burbano Maria Sol , Cherevatenko Maksym , Georgomanolis Theodoros , Dethloff Frederik , Giavalisco Patrick , Lackmann Jan-Wilm , Lewin Gary R , Frezza Christian , Reznick Jane
Published: June 2024

As a subterranean eusocial mammal, the naked mole-rat faces a particularly challenging environment characterised by patchily available food, low O2and high CO2levels. In response, naked mole-rats have evolved a suite of molecular and physiological adaptations to survive extreme hypoxia. Yet, how naked mole-rats rewire their metabolism to protect the heart has not been comprehensively addressed. Here, we performed comparative analyses of naked mole-rat and mouse organs exposed to ischaemic conditions. We show that naked mole-rats have retained features of foetal cardiac metabolism replacing fatty acid utilisation for a unique type of carbohydrate metabolism largely dependent on glycogen. We found that naked mole-rats have co-opted specialised liver-like glycogen handling mechanisms in the heart. Amongst these is the expression of liver-specific enzyme isoforms and amylase, a digestive enzyme known for starch breakdown in saliva and intestine but whose biological role in glycogen processing has not been fully recognised. We show that amylase is rapidly activated in ischaemia and hydrolyses internal glycosidic bonds for more efficient downstream processing. This biochemical adaptation occurred in both mouse and naked mole-rat livers but exclusively in the naked mole-rat heart, which retained higher ATP levels by maintaining an increased glycolytic flux in an amylase-dependent mechanism. Overall, we discovered a previously unknown type of glycogen metabolism in the naked mole-rat that holds relevance to pathologies where glycogen plays a role. Furthermore, we describe a novel type of metabolic plasticity in the heart which may be harnessed for cardiac disease.
Natural variation in protein kinase D modifies alcohol sensitivity inCaenorhabditis elegans
Authors: Clites Benjamin L. , Frohock Brooke , Koury Emily J. , Andersen Erik C. , Pierce Jonathan T.
Published: June 2024

Differences in naïve alcohol sensitivity between individuals are a strong predictor of later life alcohol use disorders (AUD). However, the genetic bases for alcohol sensitivity (beyond ethanol metabolism) and pharmacological approaches to modulate alcohol sensitivity remain poorly understood. We used a high-throughput behavioral screen to measure acute behavioral sensitivity to alcohol, a model of intoxication, in a genetically diverse set of over 150 wild strains of the nematodeCaenorhabditis elegans. We performed a genome-wide association study to identify loci that underlie natural variation in alcohol sensitivity. We identified five quantitative trait loci (QTL) and further show that variants in theC. elegansortholog of protein kinase D,dkf-2, likely underlie the chromosome V QTL. We found that resistance to intoxication was conferred bydkf-2loss-of-function mutations as well as partly by a PKD inhibitor in adkf-2-dependent manner. Protein kinase D might represent a conserved, druggable target to modify alcohol sensitivity with application towards AUD.

Significance statement

Here, we identify a novel role for protein kinase D (dkf-2) inC. elegansalcohol sensitivity. PKD, like protein kinase C, might represent a newly discovered druggable target to modify alcohol response. Identifying causal variants in genes of the remaining loci will likewise provide new insights into the genetic basis of variation in naïve alcohol sensitivity inC. elegansand other organisms.
Fe3O4nanoparticles shell amplify charge-extraction efficiency inDunaliellaphotovoltaics
Authors: Chen Hao-Hong , Wu Jing-xuan , Jiang Jian-Guo
Published: June 2024

Microbial biophotovoltaics (BPVs) harness photosynthetic microorganisms to convert light energy into electricity, making them highly attractive for renewable energy production. However, current BPVs typically exhibit low power densities, primarily due to inefficient electron transfer processes and the need for close contact and high interfacial area. Here, we propose a novel method of enhancingDunaliella-based BPVs using Fe3O4nanoparticle coatings. The Fe3O4-coatedDunaliellacells (DS@Fe3O4) establish intimate contact with the cellular electron transfer machinery and maximize the interfacial area, significantly improving electron transfer efficiency and reducing internal resistance. This approach achieved higher power outputs compared to nativeDunaliellaBPVs, with an optimal Fe3O4concentration of 2 mg/mL yielding the best performance. In contrast, SiO2coatings on Fe3O4(Fe3O4@SiO2) reduced electron transfer efficiency. These findings demonstrate that Fe3O4nanoparticle coatings provide a superior method for enhancing bio-electrochemical systems, advancing the application of BPVs for sustainable energy solutions and environmental applications.
The RAE1-STOP1 Module Reduces Sensitivity to Exogenous ABA Treatment by Regulating ABI5 in Arabidopsis
Authors: Zhang Yuqing , Huang Min , Liu Yinyin , Yang Mengmeng , Hou Yuqi , Huang Chao-Feng , Wang Ningning , Li Lei
Published: June 2024

The SENSITIVE TO PROTON RHIZOTOXICITY 1 (STOP1) transcription factor plays a pivotal role in maintaining cellular ion balance and governing aluminum tolerance in plants. Abscisic acid (ABA) participates in aluminum tolerance by inducing the expression of several genes that are STOP1 targets. However, the mechanisms underlying ABA signaling and STOP1-mediated gene expression remain poorly understood. The F-box protein RAE1, an SCF-type E3 ligase component, recognizes STOP1 and controls its ubiquitination and degradation. This study revealed that exogenous ABA supplementation reduced STOP1 levels by promoting the expression ofRAE1. Notably, bothRAE1loss-of-function mutants andSTOP1overexpressing lines showed enhanced sensitivity to exogenous ABA treatment, which correlated with early stage post-transcriptional upregulation of ABSCISIC ACID INSENSITIVE5 (ABI5). Our observations strongly suggest that RAE1 operates as an ABA-responsive factor, exerting control over STOP1 homeostasis, and thus establishing a negative feedback loop that controls ABA responses in Arabidopsis. Thus, our study revealed a novel function of the RAE1-STOP1 module in ABA signaling, highlighting its role in reducing ABA sensitivity by preventing ABI5 increase.

Single Sentence Summary

F-box protein RAE1 functions as an exogenous ABA responsive mediator to reduce STOP1-mediated ABA sensitivity.
Experienced meditators show greater forward travelling cortical alpha wave strengths
Authors: Bailey Neil W , Hill Aron T , Godfrey Kate , Perera M. Prabhavi N. , Hohwy Jakob , Corcoran Andrew W. , Rogasch Nigel C. , Fitzgibbon Bernadette M. , Fitzgerald Paul B
Published: June 2024

Mindfulness meditation involves training attention, commonly towards the current sensory experience, with an attitude of non-judgemental awareness. Theoretical perspectives suggest meditation alters the brain’s predictive processing mechanisms, increasing the synaptic gain and precision with which sensory information is processed, and reducing the generation or elaboration of higher-order beliefs. Recent research suggests that forwards and backwards travelling cortical alpha waves provide an indication of these predictive processing functions. Here, we used electroencephalography (EEG) to test whether the strength of forwards and backwards travelling cortical alpha waves differed between experienced meditators and a matched sample of non-meditators, both during an eyes-closed resting state (N = 97) and during a visual cognitive (Go/No-go) task (N = 126). Our results showed that meditators produced stronger forwards travelling cortical alpha waves compared to non-meditators, both while resting with their eyes closed and during task performance. Meditators also exhibited weaker backwards travelling cortical alpha wave strength while resting with their eyes closed. These results may be indicative of a neural mechanism underpinning enhanced attention associated with meditation practice, as well as a potential neural marker of the reductions in resting mind-wandering that are suggested to be associated with meditation practice. The results also support models of brain function that suggest attention modification can be achieved by mental training aimed at increased processing of sensory information, which might be indexed by greater strength of forwards travelling cortical alpha waves.
Resistance to Spindle Inhibitors in Glioblastoma Depends on STAT3 and Therapy Induced Senescence
Authors: Zarco Natanael , Dovas Athanassios , de Araujo Farias Virginea , Nagaiah Naveen KH , Haddock Ashley , Sims Peter A. , Hambardzumyan Dolores , Meyer Christian T. , Canoll Peter , Rosenfeld Steven S. , Kenchappa Rajappa S.
Published: June 2024

While mitotic spindle inhibitors specifically kill proliferating tumor cells without the toxicities of microtubule poisons, resistance has limited their clinical utility. Treating glioblastomas with the spindle inhibitors ispinesib, alisertib, or volasertib creates a subpopulation of therapy induced senescent cells that resist these drugs by relying upon the anti-apoptotic and metabolic effects of activated STAT3. Furthermore, these senescent cells expand the repertoire of cells resistant to these drugs by secreting an array of factors, including TGFβ, which induce proliferating cells to exit mitosis and become quiescent—a state that also resists spindle inhibitors. Targeting STAT3 restores sensitivity to each of these drugs by depleting the senescent subpopulation and inducing quiescent cells to enter the mitotic cycle. These results support a therapeutic strategy of targeting STAT3-dependent therapy-induced senescence to enhance the efficacy of spindle inhibitors for the treatment of glioblastoma.

Highlights

• Resistance to non-microtubule spindle inhibitors limits their efficacy in glioblastoma and depends on STAT3.

• Resistance goes hand in hand with development of therapy induced senescence (TIS).

• Spindle inhibitor resistant glioblastomas consist of three cell subpopulations—proliferative, quiescent, and TIS—with proliferative cells sensitive and quiescent and TIS cells resistant.

• TIS cells secrete TGFβ, which induces proliferative cells to become quiescent, thereby expanding the population of resistant cells in a spindle inhibitor resistant glioblastoma

• Treatment with a STAT3 inhibitor kills TIS cells and restores sensitivity to spindle inhibitors.
Hypoxia-Sonic Hedgehog Axis as a Driver of Primitive Hematopoiesis Development and Evolution in Cavefish
Authors: van der Weele Corine M. , Hospes Katrina C. , Rowe Katherine E. , Jeffery William R.
Published: June 2024

The teleostAstyanax mexicanusconsists of surface dwelling (surface fish) and cave dwelling (cavefish) forms. Cavefish have evolved in subterranean habitats characterized by reduced oxygen levels (hypoxia) and show constructive and regressive phenotypic traits controlled by increased Sonic hedgehog (Shh) signaling along the embryonic midline. The enhancement of primitive hematopoietic domains, which are formed bilaterally in the anterior and posterior lateral plate mesoderm, are responsible for the development of more larval erythrocytes in cavefish relative to surface fish. In this study, we determine the role of hypoxia and Shh signaling in the development and evolution of primitive hematopoiesis in cavefish. We show that hypoxia treatment during embryogenesis increases primitive hematopoiesis and erythrocyte development in surface fish. We also demonstrate that upregulation of Shh midline signaling by treatment with the Smoothened agonist SAG increases primitive hematopoiesis and erythrocyte development in surface fish, whereas Shh downregulation via treatment with the Smoothened inhibitor cyclopamine decreases these traits in cavefish. Together these results suggest that hematopoietic enhancement is regulated by hypoxia and the Shh signaling system. Lastly, we demonstrate that hypoxia treatment enhances expression of Shh signaling along the midline of surface fish embryos. Thus, we conclude that a hypoxia-Shh axis may drive the adaptive evolution of primitive hematopoiesis and erythrocyte development in cavefish.

Highlights

Hypoxia increases hematopoiesis and erythrocytes in surface fish

Shh upregulation increases hematopoiesis and erythrocytes in surface fish

Shh inhibition decreases hematopoiesis and erythrocytes in cavefish

Hypoxia upregulates Shh along the embryonic midline in surface fish
Not because it is easy … accounting research enters the space age
Authors: Tucker Basil P. , Alewine Hank C.
Published: June 2024

Purpose

This article introduces the AAAJ special issue's content and, in so doing, aims to reflect on the contribution that accounting as a discipline is placed to make within the more contemporary context of space exploration, the space economy and public space policy.

Design/methodology/approach

The paper draws together, identifies, expands upon and advances opportunities available to researchers seeking to investigate the ways in which accounting research and practice might inform the modern space sector.

Findings

Papers comprising the AAAJ special issue are informed by authors with diverse research backgrounds (including various accounting subfields and non-accounting business disciplines) and varying methodological approaches, including positivist, interpretivist as well as critical research paradigms. Interestingly, the call for papers also attracted several non-accounting academics or academics who have not traditionally undertaken or engaged appreciably with accounting research. This diverse approach to addressing initial space accounting questions should help establish a firm launching point for future research advances.

Originality/value

The paper's originality lies in advancing a need to engage with the unique demands of “the New Space Age”, requiring fundamentally innovative approaches to many aspects of accounting such as financial accounting, management accounting and sustainability accounting as well as contextualising or re-contextualising current accounting concepts, principles and thinking to apply to a new setting.
An efficient path planning approach for autonomous multi-UAV system in target coverage problems
Authors: Pehlivanoglu Volkan Yasin , Pehlivanoğlu Perihan
Published: June 2024

Purpose

The purpose of this paper is to present an efficient path planning method for the multi-UAV system in target coverage problems.

Design/methodology/approach

An enhanced particle swarm optimizer (PSO) is used to solve the path planning problem, which concerns the two-dimensional motion of multirotor unmanned aerial vehicles (UAVs) in a three-dimensional environment. Enhancements include an improved initial swarm generation and prediction strategy for succeeding generations. Initial swarm improvements include the clustering process managed by fuzzy c-means clustering method, ordering procedure handled by ant colony optimizer and design vector change. Local solutions form the foundation of a prediction strategy.

Findings

Numerical simulations show that the proposed method could find near-optimal paths for multi-UAVs effectively.

Practical implications

Simulations indicate the proposed method could be deployed for autonomous multi-UAV systems with target coverage problems.

Originality/value

The proposed method combines intelligent methods in the early phase of PSO, handles obstacle avoidance problems with a unique approach and accelerates the process by adding a prediction strategy.