bluuebunny/crossref_metadata_2025_split huggingface dataset:
Insulin sensitization by hepatic FoxO deletion is insufficient to lower atherosclerosis in mice
Authors: Izquierdo María Concepción , Harris Michael , Shanmugarajah Niroshan , Zhong Kendra , Ozcan Lale , Fredman Gabrielle , Haeusler Rebecca A. 
Published: October 2023

AbstractBackgroundType 2 diabetes is associated with an increased risk of atherosclerotic cardiovascular disease. It has been suggested that insulin resistance underlies this link, possibly by altering the functions of cells in the artery wall. We aimed to test whether improving systemic insulin sensitivity reduces atherosclerosis.MethodsWe used mice that are established to have improved systemic insulin sensitivity: those lacking FoxO transcription factors in hepatocytes. Three hepatic FoxO isoforms (FoxO1, FoxO3, and FoxO4) function together to promote hepatic glucose output, and ablating them lowers glucose production, lowers circulating glucose and insulin, and improves systemic insulin sensitivity. We made these mice susceptible to atherosclerosis in two different ways, by injecting them with gain-of-function AAV8.mPcsk9D377Yand by crossing with Ldlr−/−mice.ResultsWe verified that hepatic FoxO ablation improves systemic insulin sensitivity in these atherosclerotic settings. We observed that FoxO deficiency caused no reductions in atherosclerosis, and in some cases increased atherosclerosis. These phenotypes coincided with large increases in circulating triglycerides in FoxO-ablated mice.ConclusionsThese findings suggest that systemic insulin sensitization is insufficient to reduce atherosclerosis.Non-standard Abbreviations and AcronymsLdlr, low-density lipoprotein receptor; TRL, triglyceride-rich lipoprotein; VLDL, very low-density lipoprotein
The increased hinge flexibility of an IgG1-IgG3 hybrid monoclonal enhances Fc-mediated protection against group A streptococci
Authors: Izadi Arman , Karami Yasaman , Bratanis Eleni , Wrighton Sebastian , Khakzad Hamed , Nyblom Maria , Olofsson Berit , Happonen Lotta , Tang Di , Nilges Michael , Malmström Johan , Bahnan Wael , Shannon Oonagh , Malmström Lars , Nordenfelt Pontus 
Published: October 2023

AbstractAntibodies are central to the immune response against microbes. We have previously generated a protective IgG1 monoclonal antibody targeting the M protein, a critical virulence factor ofStreptococcus pyogenes.Here, we generated this antibody in all human IgG subclasses and evaluated their function. Despite significantly reduced binding, the IgG3 subclass antibody demonstrated remarkably enhanced opsonic function. We hypothesized that increased Fc flexibility could explain this improved efficacy. We engineered a hybrid IgG subclass antibody, IgGh, containing the backbone of IgG1 with the hinge of IgG3, leaving the Fabs unchanged. The IgGh maintained a similar binding ability as IgG1 while gaining the strong opsonic function seen with IgG3. Molecular dynamics simulations of the different antibodies showed altered IgG Fab-antigen interactions, reflecting the differences observed in affinity. More importantly, when the antibodies were bound to the antigen, the simulations showed that the Fc of both IgGh and IgG3 exhibited extensive movement in 3D space relative to the M protein. The increased flexibility of IgGh directly translated to enhanced opsonic function and significantly increased the protection against infection withStreptococcus pyogenesin mice. Our findings demonstrate how altering Fc flexibility can improve Fc-mediated opsonic function and how modifications in the constant domain can regulate Fab-antigen interactions. In addition, the enhancedin vivofunction of a more flexible IgG provides new therapeutic opportunities for monoclonal antibodies.One sentence summaryAntibody Fc flexibility in 3D space correlates with efficient Fc-mediated phagocytosis of streptococci
Biodesign of Frugal CRISPR Kits for Equitable and Accessible Education
Authors: Collins Marvin C. , Lau Matthew B. , Ma William , Shen Aidan , Russa Marie La , Qi Lei S. 
Published: October 2023

AbstractEquitable and accessible education on life sciences and bioengineering is crucial to training the next generation of scientists, fostering transparency in public decision-making, and ensuring biotechnology democratization that can benefit a wide-ranging population. As a ground-breaking technology for genome engineering, CRISPR has transformed research and therapeutics. However, hands-on exposure to this technology for educational purposes has remained restricted, primarily due to extensive resources required to execute CRISPR experiments. In this study, we develop an accessible and frugal CRISPR kit, tailored for K-12 education settings. Our CRISPR kit eliminates the need for equipment, prioritizes biosafety, and utilizes cost-effective reagents. By combining CRISPRi gene regulation, chromoproteins, cell-free transcription-translation systems, and smartphone-based quantification, our kit offers a user-friendly approach and a reliable assessment of CRISPR activity, eliminating the need for a traditional laboratory setup. Experiments conducted by high school students in real-world settings highlight the kit’s utility for conducting reliable CRISPR experiments. The frugal CRISPR kit provides a modular and expandable platform to offer hands-on experience in genome engineering, and will facilitate equitable and accessible education and technology democratization for communities of diverse socioeconomic and geographic backgrounds.
Hippo effector, Yorkie, is a Tumor Suppressor in SelectDrosophilaSquamous Epithelia
Authors: Bhattacharya Rachita , Kumari Jaya , Banerjee Shweta , Tripathi Jyoti , Mohan Nitin , Sinha Pradip 
Published: October 2023

ABSTRACTOut-of-context gain of nuclear signaling of mammalian YAP/TAZ orDrosophilaYki—the transcription cofactors of the highly conserved Hippo tumor suppressor pathway—is oncogenic. By contrast, in mechanically strained squamous epithelia (SE), YAP/TAZ/Yki displays developmentally programmed nuclear translocation, leading to its constitutive signaling. How organ homeostasis is maintained in constitutively YAP/TAZ/Yki signaling SE is unclear. Here, we show that Yki signaling negatively regulates the cell growth-promoting PI3K/Akt/TOR signaling in the SEs in the tubular organs ofDrosophila. Thus, in the adult male accessory gland (MAG), knockdown of Yki signaling upregulates PI3K/Akt/TOR signaling in its SE-lined lumen, inducing cell hypertrophy, culminating in squamous cell carcinoma (SCC). MAG SCC-bearing adults display early mortality due to cancer cachexia, which is reversed by simultaneous knockdown of a secreted factor, ImpL2—aDrosophilahomolog of mammalian IGFBP7—without arresting tumor progressionper se. By contrast, a knockdown of PI3K/Akt/TOR signaling suppresses MAG SCC, reversing adult mortality. In the SE-lined lumens in other tubular organs, like the dorsal trunk of larval tracheal airways or adult Malpighian tubules, too, knockdown of Yki signaling triggers PI3K/Akt/TOR-induced cell hypertrophy and loss of epithelial homeostasis, culminating in their tumor-like transformation. Thus, Yki signaling turns tumor suppressive in the SEs of tubular organs inDrosophilaby arresting runaway PI3K/Akt/TOR signaling.
Bayesian nonparametric (non-)renewal processes for analyzing neural spike train variability
Authors: Liu David , Lengyel Máté 
Published: October 2023

AbstractNeural spiking activity is generally variable, non-stationary, and exhibits complex dependencies on covariates, such as sensory input or behavior. These dependencies have been proposed to be signatures of specific computations, and so characterizing them with quantitative rigor is critical for understanding neural computations. Approaches based on point processes provide a principled statistical framework for modeling neural spiking activity. However, currently, they only allow the instantaneous mean, but not the instantaneous variability, of responses to depend on covariates. To resolve this limitation, we propose a scalable Bayesian approach generalizing modulated renewal processes using sparse variational Gaussian processes. We leverage pathwise conditioning for computing nonparametric priors over conditional interspike interval distributions and rely on automatic relevance determination to detect lagging interspike interval dependencies beyond renewal order. After systematically validating our method on synthetic data, we apply it to two foundational datasets of animal navigation: head direction cells in freely moving mice and hippocampal place cells in rats running along a linear track. Our model exhibits competitive or better predictive power compared to state-of-the-art baselines, and outperforms them in terms of capturing interspike interval statistics. These results confirm the importance of modelingcovariate-dependentspiking variability, and further analyses of our fitted models reveal rich patterns of variability modulation beyond the temporal resolution of flexible count-based approaches.
The role of immune inflammatory response and inflammatory infiltrates in major depression disorder and atopic dermatitis: new insights from machine learning
Authors: Jiang Han , Gong Bizhen , Yao Mengxi , Pan Bo , Zhang Hongya 
Published: October 2023

AbstractBackgroundMajor depression disorder (MDD) and atopic dermatitis (AD) are distinct disorders involving immune inflammatory responses. This study aimed to investigate the comorbid relationship between AD and MDD and to identify possible common mechanisms.MethodsWe obtained AD and MDD data from the Gene Expression Omnibus (GEO) database. Differential expression analysis and the Genecard database were employed to identify shared genes associated with inflammatory diseases. These shared genes were then subjected to gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Hub genes were selected based on the protein-protein interactions using CytoHubba, and key regulatory genes were identified through enrichment analysis. Subsequently, we conducted immune infiltration and correlation analyses of the shared genes in AD. Finally, we employed three machine learning models to predict the significance of shared genes.ResultsA total of 17 shared genes were identified in the AD_Inflammatory_MDD dataset (S100A9, PTGER2, PI3, SNCA, DAB2, PDGFA, FSTL1, CALD1, XK, UTS2, DHRS9, PARD3, NFIB,TMEM158, LIPH, RAB27B, and SH3BRL2). These genes were associated with biological processes such as the regulation of mesenchymal cell proliferation, mesenchymal cell proliferation, and glial cell differentiation. The neuroactive ligand-receptor interaction, IL-17 signaling, and Rap1 signaling pathways were significantly enriched in KEGG analysis. SNCA, S100A9, SH3BGRL2, RAB27B, TMEM158, DAB2, FSTL1, CALD1, and XK were identified as hub genes contributing to comorbid AD and MDD development. The three machine learning models consistently identified SNCA and PARD3 as important biomarkers.ConclusionSNCA, S100A9, SH3BGRL2, RAB27B, TMEM158, DAB2, FSTL1, CALD1, and XK were identified as significant genes contributing to the development of AD and MDD comorbidities. Immune infiltration analysis showed a notable increase in the infiltration of various subtypes of CD4+ T cells, suggesting a potential association between the development of skin inflammation and the immune response. Across different machine learning models, SNCA and PARD3 consistently emerged as important biomarkers.
Micronucleus Is Not a Potent Inducer of cGAS-STING Pathway
Authors: Sato Yuki , Hayashi Makoto T. 
Published: October 2023

ABSTRACTMicronucleus (MN) has been associated with the innate immune response. The abrupt rupture of MN membranes results in the accumulation of cGAS, potentially activating STING and downstream interferon-responsive genes. However, direct evidence connecting MN and cGAS activation has been lacking. We have developed the FuVis2 reporter system, which enables the visualization of cell nucleus carrying a single sister chromatid fusion and, consequently, MN. Using this FuVis2 reporter equipped with cGAS and STING reporters, we rigorously assessed the potency of cGAS activation by MN in individual living cells. Our findings reveal that cGAS localization to membrane-ruptured MN during interphase is infrequent, with cGAS primarily capturing MN during mitosis and remaining bound to cytosolic chromatin. We found that cGAS accumulation during mitosis neither activates STING in the subsequent interphase nor triggers the interferon response. Gamma-ray irradiation activates STING independently of MN formation and cGAS localization to MN. These results suggest that cGAS accumulation in the cytosol is not a robust indicator of its activation and that MN is not the primary trigger of the cGAS/STING pathway.
Establishing an AI-based evaluation system that quantifies social/pathophysiological behaviors of common marmosets
Authors: Kaneko Takaaki , Matsumoto Jumpei , Lu Wanyi , Zhao Xincheng , Ueno-Nigh Louie Richard , Oishi Takao , Kimura Kei , Otsuka Yukiko , Zheng Andi , Ikenaka Kensuke , Baba Kousuke , Mochizuki Hideki , Nishijo Hisao , Inoue Ken-ichi , Takada Masahiko 
Published: October 2023

AbstractNonhuman primates (NHPs) are indispensable animal models by virtue of the continuity of behavioral repertoires across primates, including humans. However, behavioral assessment at the laboratory level has so far been limited. By applying multiple deep neural networks trained with large-scale datasets, we established an evaluation system that could reconstruct and estimate three-dimensional (3D) poses of common marmosets, a small NHP that is suitable for analyzing complex natural behaviors in laboratory setups. We further developed downstream analytic methodologies to quantify a variety of behavioral parameters beyond simple motion kinematics, such as social interactions and the internal state behind actions, obtained solely from 3D pose data. Moreover, a fully unsupervised approach enabled us to detect progressively-appearing symptomatic behaviors over a year in a Parkinson’s disease model. The high-throughput and versatile nature of our analytic pipeline will open a new avenue for neuroscience research dealing with big-data analyses of social/pathophysiological behaviors in NHPs.
Sensing, Feeling, and Regulating: Investigating the Association of Focal Brain Damage with Voluntary Respiratory and Motor Control
Authors: Bischoff Henrik , Kovach Christopher , Kumar Sukbhinder , Bruss Joel , Tranel Daniel , Khalsa Sahib S 
Published: October 2023

AbstractBreathing is a complex, vital function that can be modulated to influence physical and mental well-being. However, the role of cortical and subcortical brain regions in voluntary control of human respiration is underexplored. Here we investigated the influence of damage to human frontal, temporal, or limbic regions on the sensation and regulation of breathing patterns. Participants performed a respiratory regulation task across regular and irregular frequencies ranging from 6 to 60 breaths per minute (bpm), with a counterbalanced hand motor control task. Interoceptive and affective states induced by each condition were assessed via questionnaire and autonomic signals were indexed via skin conductance. Participants with focal lesions to the bilateral frontal lobe, right insula/basal ganglia, and left medial temporal lobe showed reduced performance than individually matched healthy comparisons during the breathing and motor tasks. They also reported significantly higher anxiety during the 60-bpm regular and irregular breathing trials, with anxiety correlating with difficulty in rapid breathing specifically within this group. This study demonstrates that damage to frontal, temporal, or limbic regions is associated with abnormal voluntary respiratory and motor regulation and tachypnea-related anxiety, highlighting the role of the forebrain in affective and motor responses during breathing.HighlightsImpaired human respiratory regulation is associated with cortical/subcortical brain lesionsFrontolimbic/temporal regions contribute to rhythmic breathing and hand motor controlFrontolimbic/temporal damage is associated with anxiety during tachypnea/irregular breathingThe human forebrain is vital for affective and interoceptive experiences during breathing
Electrical brain activations in preadolescents during a probabilistic reward-learning task reflect cognitive processes and behavioral strategy
Authors: Chung Yu Sun , van den Berg Berry , Roberts Kenneth C. , Bagdasarov Armen , Woldorff Marty G. , Gaffrey Michael S. 
Published: October 2023

AbstractBoth adults and children learn through feedback which environmental events and choices are associated with higher probability of reward, an ability thought to be supported by the development of fronto-striatal reward circuits. Recent developmental studies have applied computational models of reward learning to investigate such learning in children. However, tasks and measures effective for assaying the cascade of reward-learning neural processes in children have been limited. Using a child-version of a probabilistic reward-learning task while recording event-related-potential (ERP) measures of electrical brain activity, this study examined key processes of reward learning in preadolescents (8-12 years old; n=30), namely: (1) reward-feedback sensitivity, as measured by the early-latency, reward-related, frontal ERP positivity, (2) rapid attentional shifting of processing toward favored visual stimuli, as measured by the N2pc component, and (3) longer-latency attention-related responses to reward feedback as a function of behavioral strategies (i.e., Win-Stay-Lose-Shift), as measured by the central-parietal P300. Consistent with our prior work in adults, the behavioral findings indicate preadolescents can learn stimulus-reward outcome associations, but at varying levels of performance. Neurally, poor preadolescent learners (those with slower learning rates) showed greater reward-related positivity amplitudes relative to good learners, suggesting greater reward-feedback sensitivity. We also found attention shifting towards to-be-chosen stimuli, as evidenced by the N2pc, but not to more highly rewarded stimuli as we have observed in adults. Lastly, we found the behavioral learning strategy (i.e., Win-Stay-Lose-Shift) reflected by the feedback-elicited parietal P300. These findings provide novel insights into the key neural processes underlying reinforcement learning in preadolescents.
The role of RNA in the maintenance of chromatin domains as revealed by antibody mediated proximity labelling coupled to mass spectrometry
Authors: Choudhury Rupam , Venkatasubramani Anuroop Venkateswaran , Hua Jie , Borsò Marco , Forne Ignasi , Imhof Axel 
Published: October 2023

AbstractEukaryotic chromatin is organised in individual domains, which are defined by their location within the nuclear space, the molecular interactions within each other and their distinct proteomic compositions. In contrast to cellular organelles surrounded by lipid membranes, the composition of distinct chromatin domains is rather ill described and highly dynamic. To identify proteins associated with a specific chromatin domain and to better understand how those domains are established and maintained, we used a new method, which we termed AMPL-MS (Antibody mediated proximity labelling mass spectrometry). This method is based on antibodies and does not require the expression of fusion proteins and therefore constitutes a versatile and very sensitive method to characterize chromatin domains containing specific signature proteins or histone modifications. We used AMPL-MS to characterize the composition of chromocenter as well as the chromosome territory containing the hyperactive X-chromosome inDrosophila. As an outcome of this method, we show the importance of RNA in maintaining the integrity of these domains as treatment with RNAse alters their proteomic composition. Our data demonstrate the power of AMPL-MS to characterize the composition of non-membranous nuclear domains.
Age-related disparities in oscillatory dynamics within scene-selective regions during spatial navigation
Authors: Durteste Marion , Delaux Alexandre , Ariztégui Ainhoa , Cottereau Benoit R. , Sheynikhovich Denis , Ramanoël Stephen , Arleo Angelo 
Published: October 2023

AbstractPosition is a key property that allows certain objects in the environment to attain navigational relevance. Symmetrical processing of object position across the horizontal meridian remains an unchallenged assumption of the spatial navigation literature. Nonetheless, a growing body of research reports vertical inhomogeneities in perceptual tasks, and recent evidence points towards a lower visual field preference in healthy aging. Factoring in the vertical position of objects to better apprehend spatial navigation abilities across the lifespan is essential. The occipital place area (OPA), parahippocampal place area (PPA), and medial place area (MPA) are ideal candidates to support the processing of the vertical location of navigational cues. Indeed, they are implicated in scene processing and spatial cognition, functions that may interact with their underlying retinotopic codes. This study aimed to elucidate whether young and older participants adjusted their gaze patterns and EEG activity within scene-selective regions in response to the vertical arrangement of landmarks. A sample of 21 young and 21 older participants completed a desktop-based task requiring them to navigate using objects at different vertical locations. We equipped them with an eye tracker and a high-density EEG cap. We used a fMRI-informed source-reconstruction algorithm to study the OPA, PPA and MPA with high spatial and temporal precision. Older adults exhibited a higher number of errors compared to young adults during reorientation. This age-related decline in accuracy was accompanied by a tendency among older participants to fixate objects in the lower half of the screen. This gaze bias was absent in young participants, who instead adapted their oculomotor behaviour based on the position of navigationally-relevant information. Another primary finding pertains to the differential pattern of theta and beta band activity in the OPA, PPA and RSC for environments that only contained relevant cues in the upper visual field. It thus appears that scene-selective regions process some aspect of the vertical position of information, irrespectively of their inherent retinotopic biases. Moreover, we revealed striking disparities between age groups in beta/gamma band synchronization in all scene-selective regions, indicating compromised top-down attentional mechanisms during spatial navigation in ageing. These age-related disparities in attentional dynamics might account for performance deficits in older participants. This study sheds light on a systematic downward gaze bias and altered attentional dynamics within scene-selective regions during spatial navigation in older age. It also emphasises the importance of considering vertical positioning as a fundamental property of objects within scenes.