bluuebunny/crossref_metadata_2025_split huggingface dataset:
Validation studies and multi-omics analysis of Zhx2 as a candidate quantitative trait gene underlying brain oxycodone metabolite (oxymorphone) levels and behavior
Authors: Lynch William B. , Miracle Sophia A. , Goldstein Stanley I. , Beierle Jacob A. , Bhandari Rhea , Gerhardt Ethan T. , Farnan Ava , Nguyen Binh-Minh , Wingfield Kelly K. , Kazerani Ida , Saavedra Gabriel A. , Averin Olga , Baskin Britahny M. , Ferris Martin T. , Reilly Christopher A. , Emili Andrew , Bryant Camron D. 
Published: September 2024

ABSTRACTSensitivity to the subjective reinforcing properties of opioids has a genetic component and can predict addiction liability of opioid compounds. We previously identifiedZhx2as a candidate gene underlying increased brain concentration of the oxycodone (OXY) metabolite oxymorphone (OMOR) in BALB/cJ (J) versus BALB/cByJ (By) females that could increase OXY state-dependent reward. A large structural intronic variant is associated with a robust reduction of Zhx2 expression in J mice, which we hypothesized enhances OMOR levels and OXY addiction-like behaviors. We tested this hypothesis by restoring theZhx2loss-of-function in Js (MVKO) and modeling the loss-of-function variant through knocking out theZhx2coding exon (E3KO) in Bys and assessing brain OXY metabolite levels and behavior. Consistent with our hypothesis, Zhx2 E3KO females showed an increase in brain OMOR levels and OXY-induced locomotor activity. However, contrary to our hypothesis, state-dependent expression of OXY-CPP was decreased in E3KO females and increased in E3KO males. We also overexpressed Zhx2 in the livers and brains of Js and observed Zhx2 overexpression in select brain regions that was associated with reduced OXY state-dependent learning. Integrative transcriptomic and proteomic analysis of E3KO mice identified astrocyte function, cell adhesion, extracellular matrix properties, and endothelial cell functions as pathways influencing brain OXY metabolite concentration and behavior. These results supportZhx2as a quantitative trait gene underlying brain OMOR concentration that is associated with changes in OXY behavior and implicate potential quantitative trait mechanisms that together inform our overall understanding ofZhx2in brain function.
Inhibition of Soluble Epoxide Hydrolase Ameliorates Cerebral Blood Flow Autoregulation and Cognition in Alzheimer’s Disease and Diabetes-Related Dementia Rat Models
Authors: Tang Chengyun , Border Jane J. , Zhang Huawei , Gregory Andrew , Bai Shan , Fang Xing , Liu Yedan , Wang Shaoxun , Hwang Sung Hee , Gao Wenjun , Morgan Gilbert C. , Smith Jhania , Bunn David , Cantwell Cameron , Wagner Karen M. , Morisseau Christophe , Yang Jun , Shin Seung Min , O’Herron Philip , Bagi Zsolt , Filosa Jessica A. , Dong Yanbin , Yu Hongwei , Hammock Bruce D. , Roman Richard J. , Fan Fan 
Published: September 2024

ABSTRACTAlzheimer’s Disease and Alzheimer’s Disease-related dementias (AD/ADRD) pose major global healthcare challenges, with diabetes mellitus (DM) being a key risk factor. Both AD and DM-related ADRD are characterized by reduced cerebral blood flow, although the exact mechanisms remain unclear. We previously identified compromised cerebral hemodynamics as early signs in TgF344-AD and type 2 DM-ADRD (T2DN) rat models. Genome-wide studies have linked AD/ADRD to SNPs in soluble epoxide hydrolase (sEH). This study explored the effects of sEH inhibition with TPPU on cerebral vascular function and cognition in AD and DM-ADRD models. Chronic TPPU treatment improved cognition in both AD and DM-ADRD rats without affecting body weight. In DM-ADRD rats, TPPU reduced plasma glucose and HbA1C levels. Transcriptomic analysis of primary cerebral vascular smooth muscle cells from AD rats treated with TPPU revealed enhanced pathways related to cell contraction, alongside decreased oxidative stress and inflammation. Both AD and DM-ADRD rats exhibited impaired myogenic responses and autoregulation in the cerebral circulation, which were normalized with chronic sEH inhibition. Additionally, TPPU improved acetylcholine-induced vasodilation in the middle cerebral arteries (MCA) of DM-ADRD rats. Acute TPPU administration unexpectedly caused vasoconstriction in the MCA of DM-ADRD rats at lower doses. In contrast, higher doses or longer durations were required to induce effective vasodilation at physiological perfusion pressure in both control and ADRD rats. Additionally, TPPU decreased reactive oxygen species production in cerebral vessels of AD and DM-ADRD rats. These findings provide novel evidence that chronic sEH inhibition can reverse cerebrovascular dysfunction and cognitive impairments in AD/ADRD, offering a promising avenue for therapeutic development.
Synaptic imbalance and increased inhibition impair motor function in SMA
Authors: Fletcher Emily V. , Chalif Joshua I. , Rotterman Travis M. , Pagiazitis John G. , Van Alstyne Meaghan , Sivakumar Nandhini , Rabinowitz Joseph E. , Pellizzoni Livio , Alvarez Francisco J. , Mentis George Z. 
Published: September 2024

ABSTRACTMovement is executed through the balanced action of excitatory and inhibitory neurotransmission in motor circuits of the spinal cord. Short-term perturbations in one of the two types of transmission are counteracted by homeostatic changes of the opposing type. Prolonged failure to balance excitatory and inhibitory drive results in dysfunction at the single neuron, as well as neuronal network levels. However, whether dysfunction in one or both types of neurotransmission leads to pathogenicity in neurodegenerative diseases characterized by select synaptic deficits is not known. Here, we used mouse genetics, functional assays, morphological methods, and viral-mediated approaches to uncover the pathogenic contribution of unbalanced excitation-inhibition neurotransmission in a mouse model of spinal muscular atrophy (SMA). We show that vulnerable motor circuits in the SMA spinal cord fail to respond homeostatically to the reduction of excitatory drive and instead increase inhibition. This imposes an excessive burden on motor neurons and further restricts their recruitment to activate muscle contraction. Importantly, genetic or pharmacological reduction of inhibitory synaptic drive improves neuronal function and provides behavioural benefit in SMA mice. Our findings identify the lack of excitation-inhibition homeostasis as a major maladaptive mechanism in SMA, by which the combined effects of reduced excitation and increased inhibition diminish the capacity of premotor commands to recruit motor neurons and elicit muscle contractions.
Computational model of primitive nervous system controlling chemotaxis in early multicellular heterotrophs
Authors: Vasilenko Egor O. , Sinitskiy Anton V. 
Published: September 2024

AbstractThis paper presents a model to study a hypothetical role of a simple nervous systems in chemotaxis in early multicellular heterotrophs. The model views the organism as a network of motor units connected by flexible fibers and driven by realistic neuron excitation functions. Through numerical simulations, we identified the parameters that maximize the survival time of the modeled organism, focusing on its ability to efficiently locate and consume food. This synchronization enhances the ability of the modeled organism to navigate toward food and avoid harmful conditions. The model is described using basic mechanical principles and highlights the relationship between motor activity and energy balance. Our results suggest that even early prototypes of neural networks might provide significant survival advantages by optimizing movement and energy use. This study offers insights into how the first primitive nervous systems might have functioned. By publishing the code used in the simulations, we hope to contribute to the toolkit of computational methods and models used for exploration of neural origin and evolution.
Neural Basis of Number Sense in Larval Zebrafish
Authors: Luu Peter , Nadtochiy Anna , Zanon Mirko , Moreno Noah , Messina Andrea , Petrazzini Maria Elena Miletto , Torres Perez Jose Vicente , Keomanee-Dizon Kevin , Jones Matthew , Brennan Caroline H. , Vallortigara Giorgio , Fraser Scott E. , Truong Thai V. 
Published: September 2024

AbstractSignificanceNumerically responsive neurons are detected by 3 days post-fertilization (dpf) in zebrafishNumber-selective neurons preferring quantities greater than one increases after 3 dpfNeurons that are highly responsive to specific numbers of objects are mainly localized to the forebrain and midbrainNumber stimulus can be decoded from Ca2+activity and show increased performance with ageAdministration of ethanol decreases the activity of number-selective neurons in the forebrainNumber sense, the ability to discriminate the quantity of objects, is crucial for survival. To understand how neurons work together and develop to mediate number sense, we used two-photon fluorescence light sheet microscopy to capture the activity of individual neurons throughout the brain of larvalDanio rerio, while displaying a visual number stimulus to the animal. We identified number-selective neurons as early as 3 days post-fertilization and found a proportional increase of neurons tuned to larger quantities after 3 days. We used machine learning to predict the stimulus from the neuronal activity and observed that the prediction accuracy improves with age. We further tested ethanol’s effect on number sense and found a decrease in number-selective neurons in the forebrain, suggesting cognitive impairment. These findings are a significant step towards understanding neural circuits devoted to discrete magnitudes and our methodology to track single-neuron activity across the whole brain is broadly applicable to other fields in neuroscience.
Predicting cell cycle stage from 3D single-cell nuclear-stained images
Authors: Li Gang , Nichols Eva K. , Browning Valentino E. , Longhi Nicolas J. , Camplisson Conor , Beliveau Brian J. , Noble William Stafford 
Published: September 2024

AbstractThe cell cycle governs the proliferation, differentiation, and regeneration of all eukaryotic cells. Profiling cell cycle dynamics is therefore central to basic and biomedical research spanning development, health, aging, and disease. However, current approaches to cell cycle profiling involve complex interventions that may confound experimental interpretation. To facilitate more efficient cell cycle annotation of microscopy data, we developed CellCycleNet, a machine learning (ML) workflow designed to simplify cell cycle staging with minimal experimenter intervention and cost. CellCycleNet accurately predicts cell cycle phase using only a fluorescent nuclear stain (DAPI) in fixed interphase cells. Using the Fucci2a cell cycle reporter system as ground truth, we collected two benchmarking image datasets and trained two ML models—a support vector machine (SVM) and a deep neural network—to classify nuclei as being in either the G1 or S/G2 phases of the cell cycle. Our results suggest that CellCycleNet outperforms state-of-the-art SVM models on each dataset individually. When trained on two image datasets simultaneously, CellCycleNet achieves the highest classification accuracy, with an improvement in AUROC of 0.08–0.09. The model also demonstrates excellent generalization across different microscopes, achieving an AUROC of 0.95. Overall, using features derived from 3D images, rather than 2D projections of those same images, significantly improves classification performance. We have released our image data, trained models, and software as a community resource.
Estimating the Excitatory-Inhibitory Balance from Electrocorticography Data using Physics-Informed Neural Networks
Authors: Sotero Roberto C. , Sanchez-Bornot Jose M. 
Published: September 2024

Understanding the excitatory/inhibitory (E/I) balance in the brain is crucial for elucidating the neural mechanisms underlying various cognitive functions and states of consciousness. Mathematical models have provided significant insights into these mechanisms, but they often face challenges due to high dimensionality, noisy observation signals, and nonlinearities. In this paper, we introduce a novel methodology using Physics-Informed Neural Networks (PINNs) to estimate the E/I balance from electrocorticography (ECoG) data, effectively addressing these limitations. By integrating physical laws via a neural mass model with neural network training, our approach enhances parameter estimation accuracy and robustness. Our analysis reveals a significant reduction in long-range connections (LRCs) and excitatory short-range connections (SRCs) under anesthesia, alongside an increase in inhibitory SRCs, highlighting anesthesia’s role in modulating neural dynamics to induce unconsciousness. These findings not only corroborate existing theories on the neural mechanisms of anesthesia but also provide new insights into brain connectivity and its relationship with consciousness.CCS CONCEPTSComputing methodologies→Machine learningACM Reference Format
CHCHD2 mutant mice display mitochondrial protein accumulation and disrupted energy metabolism
Authors: Liao Szu-Chi , Kano Kohei , Phanse Sadhna , Nguyen Mai , Margolis Elyssa , Fu YuHong , Meng Jonathan , Moutaoufik Mohamed Taha , Chatterton Zac , Aoki Hiroyuki , Simms Jeffrey , Hsieh Ivy , Suteja Felecia , Sei Yoshitaka , Huang Eric J. , McAvoy Kevin , Manfredi Giovanni , Halliday Glenda , Babu Mohan , Nakamura Ken 
Published: September 2024

ABSTRACTMutations in the mitochondrial cristae protein CHCHD2 lead to a late-onset autosomal dominant form of Parkinson’s disease (PD) which closely resembles idiopathic PD, providing the opportunity to gain new insights into the mechanisms of mitochondrial dysfunction contributing to PD. To begin to address this, we used CRISPR genome-editing to generate CHCHD2 T61I point mutant mice. CHCHD2 T61I mice had normal viability, and had only subtle motor deficits with no signs of premature dopaminergic (DA) neuron degeneration. Nonetheless, CHCHD2 T61I mice exhibited robust molecular changes in the brain including increased CHCHD2 insolubility, accumulation of CHCHD2 protein preferentially in the substantia nigra (SN), and elevated levels of α-synuclein. Metabolic analyses revealed an increase in glucose metabolism through glycolysis relative to the TCA cycle with increased respiratory exchange ratio, and immune-electron microscopy revelated disrupted mitochondria in DA neurons. Moreover, spatial genomics revealed decreased expression of mitochondrial complex I and III respiratory chain proteins, while proteomics revealed increased respiratory chain and other mitochondrial protein-protein interactions. As such, the CHCHD2 T61I point-mutation mice exhibit robust mitochondrial disruption and a consequent metabolic shift towards glycolysis. These findings thus establish CHCHD2 T61I mice as a new model for mitochondrial-based PD, and implicate disrupted respiratory chain function as a likely causative driver.
In situgeneration of Aβ42oligomers via secondary nucleation triggers neurite degeneration and synaptic dysfunction in human iPSC-derived glutamatergic neurons
Authors: Díaz Alicia González , Sarracco Eleonora , Possenti Andrea , Kitchen-Smith Isaac , Chia Sean , Menzies Joseph , Stephenson Gabriel , Cataldi Rodrigo , Yahya Kim , Bian Yuqi , Urrutia Gustavo Antonio , Linse Sara , Mannini Benedetta , Vendruscolo Michele 
Published: September 2024

AbstractThe aggregation of Aβ42 into misfolded oligomers is a central event in the pathogenesis of Alzheimer’s disease. In this study, we aimed to develop a robust experimental system that recapitulates Aβ42 oligomerization in living cells to gain insight into their neurotoxicity and to provide a platform to characterize the effects of inhibitors of this process. Our strategy is based on thein situgeneration of Aβ42 oligomers via secondary nucleation by repeatedly treating the cells with Aβ42 monomers in the presence of pre-formed Aβ42 fibrils. This approach enables an accurate control over the levels of on-pathway soluble Aβ42 oligomers and cell-associated aggregates, as well as the study of their neurotoxic effects. By implementing this approach in human glutamatergic neurons derived from induced pluripotent stem cells (iPSCs), we were able to replicate key aspects of Alzheimer’s disease, including neurite degeneration and synaptic dysfunction. Using BRICHOS, a molecular chaperone that specifically inhibits secondary nucleation, we confirmed that aggregation in this system occurs through secondary nucleation, and that quantitative parameters for comparing potential Aβ42 aggregation inhibitors can be obtained. Overall, our results demonstrate that byin situgeneration of on-pathway Aβ42 oligomers, one can obtain translational cellular models of AD to bridge the gap between basic research and clinical applications.
Astrocyte-derived MFG-E8 facilitates microglial synapse elimination in Alzheimer’s disease mouse models
Authors: Sokolova Dimitra , Addington Ghansah Shari , Puletti Francesca , Georgiades Tatiana , De Schepper Sebastiaan , Zheng Yongjing , Crowley Gerard , Wu Ling , Rueda-Carrasco Javier , Koutsiouroumpa Angeliki , Muckett Philip , Freeman Oliver J. , Khakh Baljit S. , Hong Soyon 
Published: September 2024

SummaryRegion-specific synapse loss is an early pathological hallmark in Alzheimer’s disease (AD). Emerging data in mice and humans highlight microglia, the brain-resident macrophages, as cellular mediators of synapse loss; however, the upstream modulators of microglia-synapse engulfment remain elusive. Here, we report a distinct subset of astrocytes, which are glial cells essential for maintaining synapse homeostasis, appearing in a region-specific manner with age and amyloidosis at onset of synapse loss. These astrocytes are distinguished by their peri-synaptic processes which are ‘bulbous’ in morphology, contain accumulated p62-immunoreactive bodies, and have reduced territorial domains, resulting in a decrease of astrocyte-synapse coverage. Using integratedin vitroandin vivoapproaches, we show that astrocytes upregulate and secrete phagocytic modulator, milk fat globule-EGF factor 8 (MFG-E8), which is sufficient and necessary for promoting microglia-synapse engulfment in their local milieu. Finally, we show that knocking downMfge8specifically from astrocytes using a viral CRISPR-saCas9 system prevents microglia-synapse engulfment and ameliorates synapse loss in two independent amyloidosis mouse models of AD. Altogether, our findings highlight astrocyte-microglia crosstalk in determining synapse fate in amyloid models and nominate astrocytic MFGE8 as a potential target to ameliorate synapse loss during the earliest stages of AD.
Effects of lipid membranes on RNA catalytic activity and stability
Authors: Czerniak Tomasz , Saenz James P. 
Published: September 2024

AbstractRNA plays crucial roles in cellular organization and metabolism, and modulating its activity is essential for maintaining cellular functions. RNA activity, involving both catalytic (ribozymes) and translation processes, is controlled via myriad mechanisms involving different binding partners such as proteins and smaller polar solutes. We previously reported that lipid membranes can directly interact with the artificial R3C ribozyme changing its activity, however the effect of lipids on naturally occurring ribozymes remains unknown. Here, we report that both catalytic activity as well as RNA integrity can be controlled by the presence of different lipid membranes. Gel-phase lipid membranes decreased the activity of hepatitis delta virus (HDV) ribozyme and increased the activity of a hammerhead (HH) ribozyme. The presence of lipid liquid membrane surfaces triggered RNA degradation with greater degradation occurring in the single-stranded regions of RNA. The interplay between RNA activity and stability in the presence of different lipid membranes introduces multiple possibilities, where different combinations of ribozyme and lipid membrane composition could produce different effects on activity. Taken together, these observations support the hypothesis that the activity of both natural and artificial RNAs can be modulated by lipid membranes which, in turn, provides a foundation for the development of novel riboswitch-like molecules, and lipid membrane-based RNA-biosensors.
Retention of DLK1 in the endoplasmic reticulum identifies roles for EGF domain-specific O-glycans in the secretory pathway
Authors: Tashima Yuko , Tsukamoto Yohei , Tsukamoto Natsumi , Kondo Yuji , Uddin Ehsan , Furukawa Wakako , Go Shiori , Takeuchi Hideyuki , Okajima Tetsuya 
Published: September 2024

AbstractIn the endoplasmic reticulum (ER), O-glycosylation by O-fucose, O-glucose, and O-GlcNAc occurs in the epidermal growth factor-like (EGF) domains of secreted or transmembrane glycoproteins. Previous studies focusing on Notch receptors have revealed the pivotal role of these O-glycans in the cell surface expression of Notch or secretion of truncated Notch fragments. Although it has been demonstrated that O-fucose, O-glucose, and O-GlcNAc stabilize individual EGF domains, their role in the secretory pathway after the completion of the folding process remains unexplored. In this study, we used delta-like 1 homolog (DLK1) containing six consecutive EGF domains as a model glycoprotein to investigate the role of EGF domain-specific O-glycans in the secretory pathway. Semi-quantitative site-specific glycoproteomics of recombinantly expressed DLK1 revealed multiple O-fucose and O-glucose modifications in addition to an unusual EOGT-dependent O-hexose modification. Consistent with the results of the secretion assay, inactivation of the glycosyltransferases modifying O-fucose and O-glucose, but not the newly identified O-hexose, perturbed the transport of DLK1 from the ER during retention using the selective hooks (RUSH) system. Importantly, the absence of O-fucose did not result in an apparent loss of O-glucose modification within the same EGF domain, and vice versa. Given that protein O-fucosyltransferase 1 and protein O-glucosyltransferase 1 activities depend on the folded state of the EGF domains, O-glycans affected DLK1 transport independently of the folding process required for O-glycosylation in the ER. These findings highlight the distinct roles of O-glycans in facilitating the transport of DLK1 from the ER to the cell surface.
Protein-Free Catalysis of DNA Hydrolysis and Self-Integration by a Ribozyme
Authors: Szokoli Deni , Mutschler Hannes 
Published: September 2024

AbstractGroup II introns are ancient self-splicing ribozymes and retrotransposons. Though long speculated to have originated before translation, their dependence on intron-encoded proteins for splicing and mobility has cast doubt on this hypothesis. While some group II introns are known to retain part of their catalytic repertoire in the absence of protein cofactors, protein-free complete reverse splicing of a group II intron into a DNA target has never been demonstrated. Here, we demonstrate the complete independence of a group II intron from protein cofactors in all intron-catalyzed reactions. The ribozyme is capable of fully reverse splicing into single-stranded DNA targetsin vitro, readily hydrolyzes DNA substrates, and is even able to unwind and react with stably duplexed DNA. Our findings make a protein-free origin for group II introns plausible by expanding their known catalytic capabilities beyond what would be needed to survive the transition from RNA to DNA genomes. Furthermore, the intron’s capacity to react with both single and double-stranded DNA in conjunction with its expanded sequence recognition may represent a promising starting point for the development of protein-free genomic editing tools.