bluuebunny/crossref_metadata_2025_split huggingface dataset:
Unsupervised deep representation learning enables phenotype discovery for genetic association studies of brain imaging
Authors: Patel Khush , Xie Ziqian , Yuan Hao , Islam Sheikh Muhammad Saiful , Xie Yaochen , He Wei , Zhang Wanheng , Gottlieb Assaf , Chen Han , Giancardo Luca , Knaack Alexander , Fletcher Evan , Fornage Myriam , Ji Shuiwang , Zhi Degui 
Published: April 2024

AbstractUnderstanding the genetic architecture of brain structure is challenging, partly due to difficulties in designing robust, non-biased descriptors of brain morphology. Until recently, brain measures for genome-wide association studies (GWAS) consisted of traditionally expert-defined or software-derived image-derived phenotypes (IDPs) that are often based on theoretical preconceptions or computed from limited amounts of data. Here, we present an approach to derive brain imaging phenotypes using unsupervised deep representation learning. We train a 3-D convolutional autoencoder model with reconstruction loss on 6130 UK Biobank (UKBB) participants’ T1 or T2-FLAIR (T2) brain MRIs to create a 128-dimensional representation known as Unsupervised Deep learning derived Imaging Phenotypes (UDIPs). GWAS of these UDIPs in held-out UKBB subjects (n = 22,880 discovery and n = 12,359/11,265 replication cohorts for T1/T2) identified 9457 significant SNPs organized into 97 independent genetic loci of which 60 loci were replicated. Twenty-six loci were not reported in earlier T1 and T2 IDP-based UK Biobank GWAS. We developed a perturbation-based decoder interpretation approach to show that these loci are associated with UDIPs mapped to multiple relevant brain regions. Our results established unsupervised deep learning can derive robust, unbiased, heritable, and interpretable brain imaging phenotypes.
Catalytic-dependent and -independent roles of TET3 in the regulation of specific genetic programs during neuroectoderm specification
Authors: Ketchum Harmony C. , Suzuki Masako , Dawlaty Meelad M. 
Published: April 2024

AbstractThe ten-eleven-translocation family of proteins (TET1/2/3) are epigenetic regulators of gene expression. They regulate genes by promoting DNA demethylation (i.e., catalytic activity) and by partnering with regulatory proteins (i.e., non-catalytic functions). Unlike Tet1 and Tet2, Tet3 is not expressed in mouse embryonic stem cells (ESCs) but is induced upon ESC differentiation. However, the significance of its dual roles in lineage specification is less defined. By generating TET3 catalytic-mutant (Tet3m/m) and knockout (Tet3–/–) mouse ESCs and differentiating them to neuroectoderm (NE), we identify distinct catalytic-dependent and independent roles of TET3 in NE specification. We find that the catalytic activity of TET3 is important for activation of neural genes while its non-catalytic functions are involved in suppressing mesodermal programs. Interestingly, the vast majority of differentially methylated regions (DMRs) in Tet3m/m and Tet3–/– NE cells are hypomethylated. The hypo-DMRs are associated to aberrantly upregulated genes while the hyper-DMRs are linked to downregulated neural genes. We find the maintenance methyltransferase Dnmt1 as a direct target of TET3, which is downregulated in TET3-deficient NE cells and may contribute to the increased DNA hypomethylation. Our findings establish that the catalytic-dependent and -independent roles of TET3 have distinct contributions to NE specification with potential implications in development.
Mechano-sensitivity of β2-adrenoceptors enhances constitutive activation of cAMP generation that is inhibited by inverse agonists
Authors: Cullum Sean A. , Platt Simon , Dale Natasha , Isaac Oliver C. , Wragg Edward S. , Soave Mark , Veprintsev Dmitry B. , Woolard Jeanette , Kilpatrick Laura E. , Hill Stephen J. 
Published: April 2024

AbstractThe concept of agonist-independent signalling that can be attenuated by inverse agonists is a fundamental element of the cubic ternary complex model of G protein-coupled receptor (GPCR) activation. This model shows how a GPCR can exist in two conformational states in the absence of ligands; an inactive R state and an active R* state that differ in their affinities for agonists, inverse agonists, and G-protein alpha subunits. The proportion of R* receptors that exist in the absence of agonists determines the level of constitutive receptor activity. In this study we demonstrate that mechanical stimulation can induce β2-adrenoceptor agonist-independent Gs-mediated cAMP signalling that is sensitive to inhibition by inverse agonists such as ICI-118551 and propranolol. The size of the mechano-sensitive response is dependent on the cell surface receptor expression level in HEK293G cells, is still observed in a ligand-binding deficient D113A mutant β2-adrenoceptor and can be attenuated by site-directed mutagenesis of the extracellular N-glycosylation sites on the N-terminus and second extracellular loop of the β2-adrenoceptor. Similar mechano-sensitive agonist-independent responses are observed in HEK293G cells overexpressing the A2A-adenosine receptor. These data provide new insights into how agonist-independent constitutive receptor activity can be enhanced by mechanical stimulation and regulated by inverse agonists.
Enhancing property and activity prediction and interpretation using multiple molecular graph representations with MMGX
Authors: Kengkanna Apakorn , Ohue Masahito 
Published: April 2024

AbstractGraph Neural Networks (GNNs) excel in compound property and activity prediction, but the choice of molecular graph representations significantly influences model learning and interpretation. While atom-level molecular graphs resemble natural topology, they overlook key substructures or functional groups and their interpretation partially aligns with chemical intuition. Recent research suggests alternative representations using reduced molecular graphs to integrate higher-level chemical information and leverages both representations for model. However, there is a lack of studies about applicability and impact of different molecular graphs on model learning and interpretation. Here, we introduce MMGX (Multiple Molecular Graph eXplainable discovery), investigating the effects of multiple molecular graphs, including Atom, Pharmacophore, JunctionTree, and FunctionalGroup, on model learning and interpretation with various perspectives. Our findings indicate that multiple graphs relatively improve model performance, but in varying degrees depending on datasets. Interpretation from multiple graphs in different views provides more comprehensive features and potential substructures consistent with background knowledge. These results help to understand model decisions and offer valuable insights for subsequent tasks. The concept of multiple molecular graph representations and diverse interpretation perspectives has broad applicability across tasks, architectures, and explanation techniques, enhancing model learning and interpretation for relevant applications in drug discovery.
Enhanced sensitivity with nonlinearity-induced exceptional points degeneracy lifting
Authors: Li Haichuan , Chen Lei , Wu Wenhao , Wang Hongteng , Wang Tianqi , Zhong Yu , Huang Feifan , Liu Gui-Shi , Chen Yaofei , Luo Yunhan , Chen Zhe 
Published: April 2024

AbstractBifurcation of exceptional points (EPs), particularly higher-order EPs, can offer applications in metrology by amplifying sensitivity, but this method suffers from a tradeoff between sensitivity and robustness. To break this constraint, we experimentally introduce nonlinearity into the EP degeneracy lifting at the coupled electric resonators and observe a sixth-order nonlinear bifurcation which amplifies the sensitivity elevenfold compared to the conventional EP-based approach operating in the linear regime, while maintaining the degrees of freedom, thereby without cost in robustness. Moreover, we discover a chaotic dynamics near the EP due to the nonlinear contribution, which constitutes a distinct difference from the EP degeneracy lifting in the linear regime with random noise. Our study expands the scope of EP degeneracy lifting into nonlinearity, providing a paradigm to exploit the benefit of EPs.
D2/D3 dopamine supports the precision of mental state inferences and self-relevance of joint social outcomes
Authors: Barnby J. M. , Bell V. , Deeley Q. , Mehta M. A. , Moutoussis M. 
Published: April 2024

AbstractStriatal dopamine is important in paranoid attributions, although its computational role in social inference remains elusive. We employed a simple game-theoretic paradigm and computational model of intentional attributions to investigate the effects of dopamine D2/D3 antagonism on ongoing mental state inference following social outcomes. Haloperidol, compared with the placebo, enhanced the impact of partner behaviour on beliefs about the harmful intent of partners, and increased learning from recent encounters. These alterations caused substantial changes to model covariation and negative correlations between self-interest and harmful intent attributions. Our findings suggest that haloperidol improves belief flexibility about others and simultaneously reduces the self-relevance of social observations. Our results may reflect the role of D2/D3 dopamine in supporting self-relevant mentalising. Our data and model bridge theory between general and social accounts of value representation. We demonstrate initial evidence for the sensitivity of our model and short social paradigm to drug intervention and clinical dimensions, allowing distinctions between mechanisms that operate across traits and states.
A subset of megakaryocytes regulates development of hematopoietic stem cell precursors
Authors: Lan Wenlang , Li Jinping , Ye Zehua , Liu Yumin , Luo Sifan , Lu Xun , Cao Zhan , Chen Yifan , Chen Hongtian , Li Zhuan 
Published: April 2024

AbstractUnderstanding the regulatory mechanisms facilitating hematopoietic stem cell (HSC) specification during embryogenesis is important for the generation of HSCs in vitro. Megakaryocyte emerged from the yolk sac and produce platelets, which are involved in multiple biological processes, such as preventing hemorrhage. However, whether megakaryocytes regulate HSC development in the embryonic aorta-gonad-mesonephros (AGM) region is unclear. Here, we use platelet factor 4 (PF4)-Cre;Rosa-tdTomato+ cells to report presence of megakaryocytes in the HSC developmental niche. Further, we use the PF4-Cre;Rosa-DTA (DTA) depletion model to reveal that megakaryocytes control HSC specification in the mouse embryos. Megakaryocyte deficiency blocks the generation and maturation of pre-HSCs and alters HSC activity at the AGM. Furthermore, megakaryocytes promote endothelial-to-hematopoietic transition in a OP9-DL1 coculture system. Single-cell RNA-sequencing identifies megakaryocytes positive for the cell surface marker CD226 as the subpopulation with highest potential in promoting the hemogenic fate of endothelial cells by secreting TNFSF14. In line, TNFSF14 treatment rescues hematopoietic cell function in megakaryocyte-depleted cocultures. Taken together, megakaryocytes promote production and maturation of pre-HSCs, acting as a critical microenvironmental control factor during embryonic hematopoiesis.
Genome-wide CRISPR screens identify novel regulators of wild-type and mutant p53 stability
Authors: Lü YiQing , Cho Tiffany , Mukherjee Saptaparna , Suarez Carmen Florencia , Gonzalez-Foutel Nicolas S , Malik Ahmad , Martinez Sebastien , Dervovic Dzana , Oh Robin Hyunseo , Langille Ellen , Al-Zahrani Khalid N , Hoeg Lisa , Lin Zhen Yuan , Tsai Ricky , Mbamalu Geraldine , Rotter Varda , Ashton-Prolla Patricia , Moffat Jason , Chemes Lucia Beatriz , Gingras Anne-Claude , Oren Moshe , Durocher Daniel , Schramek Daniel 
Published: April 2024

AbstractTumor suppressor p53 (TP53) is frequently mutated in cancer, often resulting not only in loss of its tumor-suppressive function but also acquisition of dominant-negative and even oncogenic gain-of-function traits. While wild-type p53 levels are tightly regulated, mutants are typically stabilized in tumors, which is crucial for their oncogenic properties. Here, we systematically profiled the factors that regulate protein stability of wild-type and mutant p53 using marker-based genome-wide CRISPR screens. Most regulators of wild-type p53 also regulate p53 mutants, except for p53 R337H regulators, which are largely private to this mutant. Mechanistically, FBXO42 emerged as a positive regulator for a subset of p53 mutants, working with CCDC6 to control USP28-mediated mutant p53 stabilization. Additionally, C16orf72/HAPSTR1 negatively regulates both wild-type p53 and all tested mutants. C16orf72/HAPSTR1 is commonly amplified in breast cancer, and its overexpression reduces p53 levels in mouse mammary epithelium leading to accelerated breast cancer. This study offers a network perspective on p53 stability regulation, potentially guiding strategies to reinforce wild-type p53 or target mutant p53 in cancer.
Anorexigenic neuropeptides as anti-obesity and neuroprotective agents
Authors: Strnadová Veronika , Pačesová Andrea , Charvát Vilém , Šmotková Zuzana , Železná Blanka , Kuneš Jaroslav , Maletínská Lenka 
Published: April 2024

Abstract
Since 1975, the incidence of obesity has increased to epidemic proportions, and the number of patients with obesity has quadrupled. Obesity is a major risk factor for developing other serious diseases, such as type 2 diabetes mellitus, hypertension, and cardiovascular diseases. Recent epidemiologic studies have defined obesity as a risk factor for the development of neurodegenerative diseases, such as Alzheimer’s disease (AD) and other types of dementia. Despite all these serious comorbidities associated with obesity, there is still a lack of effective antiobesity treatment. Promising candidates for the treatment of obesity are anorexigenic neuropeptides, which are peptides produced by neurons in brain areas implicated in food intake regulation, such as the hypothalamus or the brainstem. These peptides efficiently reduce food intake and body weight. Moreover, because of the proven interconnection between obesity and the risk of developing AD, the potential neuroprotective effects of these two agents in animal models of neurodegeneration have been examined. The objective of this review was to explore anorexigenic neuropeptides produced and acting within the brain, emphasizing their potential not only for the treatment of obesity but also for the treatment of neurodegenerative disorders.
Alveolar epithelial cells of lung fibrosis patients are susceptible to severe virus-induced injury
Authors: Read Jane , Reid Andrew T. , Thomson Claire , Plit Marshall , Mejia Ross , Knight Darryl A. , Lize Muriel , El Kasmi Karim , Grainge Christopher L. , Stahl Heiko , Schuliga Michael 
Published: April 2024

Abstract
Patients with pulmonary fibrosis (PF) often experience exacerbations of their disease, characterised by a rapid, severe deterioration in lung function that is associated with high mortality. Whilst the pathobiology of such exacerbations is poorly understood, virus infection is a trigger. The present study investigated virus-induced injury responses of alveolar and bronchial epithelial cells (AECs and BECs, respectively) from patients with PF and age-matched controls (Ctrls). Air–liquid interface (ALI) cultures of AECs, comprising type I and II pneumocytes or BECs were inoculated with influenza A virus (H1N1) at 0.1 multiplicity of infection (MOI). Levels of interleukin-6 (IL-6), IL-36γ and IL-1β were elevated in cultures of AECs from PF patients (PF-AECs, n = 8–11), being markedly higher than Ctrl-AECs (n = 5–6), 48 h post inoculation (pi) (P&lt;0.05); despite no difference in H1N1 RNA copy numbers 24 h pi. Furthermore, the virus-induced inflammatory responses of PF-AECs were greater than BECs (from either PF patients or controls), even though viral loads in the BECs were overall 2- to 3-fold higher than AECs. Baseline levels of the senescence and DNA damage markers, nuclear p21, p16 and H2AXγ were also significantly higher in PF-AECs than Ctrl-AECs and further elevated post-infection. Senescence induction using etoposide augmented virus-induced injuries in AECs (but not viral load), whereas selected senotherapeutics (rapamycin and mitoTEMPO) were protective. The present study provides evidence that senescence increases the susceptibility of AECs from PF patients to severe virus-induced injury and suggests targeting senescence may provide an alternative option to prevent or treat the exacerbations that worsen the underlying disease.
Person re‐identification via deep compound eye network and pose repair module
Authors: Gu Hongjian , Zou Wenxuan , Cheng Keyang , Wu Bin , Ghafoor Humaira Abdul , Zhan Yongzhao 
Published: April 2024

AbstractPerson re‐identification is aimed at searching for specific target pedestrians from non‐intersecting cameras. However, in real complex scenes, pedestrians are easily obscured, which makes the target pedestrian search task time‐consuming and challenging. To address the problem of pedestrians' susceptibility to occlusion, a person re‐identification via deep compound eye network (CEN) and pose repair module is proposed, which includes (1) A deep CEN based on multi‐camera logical topology is proposed, which adopts graph convolution and a Gated Recurrent Unit to capture the temporal and spatial information of pedestrian walking and finally carries out pedestrian global matching through the Siamese network; (2) An integrated spatial‐temporal information aggregation network is designed to facilitate pose repair. The target pedestrian features under the multi‐level logic topology camera are utilised as auxiliary information to repair the occluded target pedestrian image, so as to reduce the impact of pedestrian mismatch due to pose changes; (3) A joint optimisation mechanism of CEN and pose repair network is introduced, where multi‐camera logical topology inference provides auxiliary information and retrieval order for the pose repair network. The authors conducted experiments on multiple datasets, including Occluded‐DukeMTMC, CUHK‐SYSU, PRW, SLP, and UJS‐reID. The results indicate that the authors’ method achieved significant performance across these datasets. Specifically, on the CUHK‐SYSU dataset, the authors’ model achieved a top‐1 accuracy of 89.1% and a mean Average Precision accuracy of 83.1% in the recognition of occluded individuals.
Changes in performance and thermal stability of Ni0.8Co0.1Al0.1/graphite batteries with excessive water
Authors: Liu Xi , Mao Jingbo , Yan Hongtao , Lin Chunjing , Qi Chuang , Yan Tao , Lao Li , Sun Yazhou 
Published: April 2024

AbstractDuring the production process of lithium‐ion batteries, there exists a scenario of excessive water inside the battery due to poor water control in the factory environment. In addition, the battery housing may be damaged by corrosion, external vibration etc., which would cause water to enter the battery. To the best of the authors’ knowledge, there is little literature to reveal the influencing mechanism related to the above issue. The effects of excessive water on battery performance and safety were discussed. The results show that when the battery absorbs excessive water, the capacity decreases and the self‐discharging rate increases rapidly. The self‐heating temperature of the battery shows an increasing trend. The thermal runaway temperature decreases significantly with the time from self‐heating to thermal runaway dramatically shortened. The thermal stability of the battery deteriorates throughout the reaction process. This is mainly due to the mechanisms by which the water absorbed in the battery reacts with the electrolyte and the electrode material, resulting in the decrease of the electrolyte conductivity and the corrosion of the electrode material, as well as the thickening of the Solid Electrolyte Interface film and the accumulation of impurities. The findings are of positive significance in demonstrating the quantitative relationship between excessive water and the performance and safety of batteries. Also, it can add to the understanding of the complex scenarios of battery spontaneous failure, which is vital for solving battery self‐thermal runaways.
Silver‐coated copper nanocomposites synthesis using the essence of Foeniculum vulgare mill and estimation of its antibacterial and cytotoxicity effects
Authors: Sharifalhoseini Mohammad , Vaezi Gholamhasan , Es‐haghi Ali , Shajiee Hooman 
Published: April 2024

AbstractThe Cu3.96Ag0.04 nanoparticles were synthesized using the essence of Foeniculum vulgare Mill for the first time. The particles were fully analysed by conventional characterization methods such as powder X‐ray diffraction (PXRD), Fourier transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM), dynamic light scattering (DLS). The results have shown the crystal structure of silver copper particles and the crystallite size obtained by the Scherer equation was 23.2 nm. The TEM images interestingly displayed the formation of nanorods in the solid phase with nearly 5 nm widths and different lengths up to 100 nm. The hydrodynamic size is also compatible with the solid phase and crystallite sizes. Biologically, the particles were tested against infective gram negative and gram positive bacteria. The synthetic NPs show strong antibacterial properties against gram negative bacteria. Also, the synthesized nanoparticles had an inhibitory effect on the growth of cancer cells, which was dose‐ and time‐dependent.
Frequency control in an isolated wind‐diesel hybrid system with energy storage and an irrigation water supply system
Authors: Monroy‐Morales José Luis , Peña‐Alzola Rafael , Sebastián‐Fernández Rafael , Campos‐Gaona David , Castellano Jerónimo Quesada , Guardado José L. 
Published: April 2024

AbstractWind‐Diesel Hybrid Systems (WDHSs) integrate wind turbines into diesel power systems, reducing costs and emissions in isolated grids. Due to the no‐load consumption of the Diesel Generators (DGs), fuel savings are only possible when the DGs are shut down. This requires a proper implementation of the frequency control to avoid perturbations because of the wind speed variations. During wind‐only (WO) operation, the Synchronous Machine (SM) generates the isolated grid voltage and the frequency controller varies the energy stored/supplied by an Energy Storage System and consumed by the controllable loads to balance the power. In this paper, a Battery‐based Energy Storage System (BESS) uses Li‐Ion batteries with a Dual Active Bridge (DAB) and a grid‐tie inverter connected to the isolated network. The controllable load is an Irrigation Water Supply System (IWSS), consisting of a pump supplying water to a reservoir tank. The pump is driven by a variable speed drive that uses a Permanent Magnet Synchronous Motor (PMSM). The coordinated control of BESS and IWSS gives full priority to the BESS for harnessing the wind potential whereas the IWSS consumes the excess of wind power. The full Wind Diesel Power System (WDPS) is modelled and simulated to validate the proposed system for different case scenarios.