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The potential of improving the classification of tea samples from different regions was studied by using stable isotope ratios analysis. The stable isotope ratios of 44 elements in tea samples were determined (p < 0.05).The results showed that 34 stable isotopes ratios were statistically significant, and tea in the four regions had their own characteristic variables. PCA, HCA, PLS-DA, BP-ANN and LDA were used to analyze the stable isotope ratio data in tea. Six key variables were identified to provide the greatest difference between the samples. The overall correct classification rate, cross validation rate and blind validation rate given by LDA are all 100%, and the result is the best. This study has proved that the stable isotope ratio analysis method could improve the geographical origin traceability of Chinese tea. [ABSTRACT FROM AUTHOR]

Previous studies have rarely investigated stochastic robustness of flexible cable dome structures under impact loads. In this study, the dynamic responses and failure modes of a Geiger cable dome structure were analysed under impact loads. The number of components damaged by impact and the loss of internal force in components were used to establish a structural damage index and an equation of failure mode control. Following this, by establishing the impact resistance failure limit state equation and combining the probabilistic and statistical characteristics of each design parameter of the structure, the probability of disproportionate failure of the structure undergoing disproportional damage under the impact load was calculated. Then, the stochastic robustness index I rob based on the probability of structural failure was proposed, and the key factors affecting the structural robustness were analysed through parameter analysis. The research results indicated the following. First, cable dome structures exhibited three types of failure modes under impact loads. Second, the stochastic robustness index fully reflected the probability of a cable dome structure sustaining disproportional damage under impact loads. Increasing the mass or speed of the impactor both increased the probability of the structure sustaining disproportional damage. An impact occurred closer to the centre of the structure, both the probability of overall structural failure and structural robustness performance increase, but the probability of the structure sustaining disproportional damage decreases. Third, increasing the prestress and cross-sectional area of the components might increase their impact resistance and structural robustness performance. [ABSTRACT FROM AUTHOR]

An important concern is the availability of clean drinking water, which is an essential need for human survival. This issue arises due to the existence of hazardous micropollutants originating from various emission sources. Nanotechnology aids in the mitigation of micropollutants by assimilating and counteracting their effects, hence diminishing their influence on water and other ecosystems. The study investigates the relationship between nanotechnological progress, the adoption of renewable energy, environmental consequences, and economic growth in China, using the Environmental Kuznets Curve theory as a conceptual framework. The study employs panel cointegration tests to analyze structural breaks from 2000 to 2020. Nanotechnology is expected to reduce environmental degradation and the presence of micro-pollutants by increasing the use of renewable energy and promoting energy conservation. Nanotechnology is crucial for mitigating micro-pollutants and advancing sustainable development in this specific context. However, the literature also highlights the harmful consequences of nanoparticle emissions caused by nanotechnology on human and environmental health for a long duration, requiring more examination. This research is the first empirical inquiry into the relationship between improvements in nanotechnology, the use of renewable energy, economic growth, and ecological effect, all within the context of the Environmental Kuznets Curve theory. The results confirm the successful incorporation of all components with a focus on long-term outcomes. The findings suggest that the EKC hypothesis is relevant in China. In China, advancements in nanotechnology have a moderating effect on environmental degradation. The use of renewable energy sources in China enhances environmental circumstances. Given the offered empirical evidence, it is advisable for the government to have a leading role in the development of innovative nanotechnologies that have low emissions of nanoparticles. By using this approach, it will be possible to encourage the conservation of energy and the use of renewable sources in a more secure way, hence improving the effectiveness of sustainable development initiatives. [ABSTRACT FROM AUTHOR]

One question in lymphocyte homing is how integrins are rapidly activated to enable immediate arrest of fast rolling lymphocytes upon encountering chemokines at target vascular beds given the slow chemokine-induced integrin inside-out activation. Herein we demonstrate that chemokine CCL25-triggered Ca2+ influx induces T cell membrane-proximal external Ca2+ concentration ([Ca2+]ex) drop in 6 s from physiological concentration 1.2 mM to 0.3 mM, a critical extracellular Ca2+ threshold for inducing αLβ2 activation, triggering rapid αLβ2 activation and T cell arrest before occurrence of αLβ2 inside-out activation. Talin knockdown inhibits the slow inside-out activation of αLβ2 but not [Ca2+]ex drop-triggered αLβ2 quick activation. Blocking Ca2+ influx significantly suppresses T cell rolling-to-arrest transition and homing to skin lesions in a mouse psoriasis model, thus alleviating skin inflammation. [Ca2+]ex decrease-triggered rapid integrin activation bridges the gap between initial chemokine stimulation and slow integrin inside-out activation, ensuring immediate lymphocyte arrest and subsequent diapedesis on the right location. Lymphocytes need to be slowed down rapidly to enter tissues. Here the authors characterise the arrest of lymphocytes and using a calcium biosensor propose that a rapid drop in extracellular calcium concentration results in integrin activation and lymphocyte arrest. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV) infects more than 95% of adults worldwide and is closely associated with various malignancies. Considering the complex life cycle of EBV, developing vaccines targeting key entry glycoproteins to elicit robust and durable adaptive immune responses may provide better protection. EBV gHgL-, gB- and gp42-specific antibodies in healthy EBV carriers contributed to sera neutralizing abilities in vitro, indicating that they are potential antigen candidates. To enhance the immunogenicity of these antigens, we formulate three nanovaccines by co-delivering molecular adjuvants (CpG and MPLA) and antigens (gHgL, gB or gp42). These nanovaccines induce robust humoral and cellular responses through efficient activation of dendritic cells and germinal center response. Importantly, these nanovaccines generate high levels of neutralizing antibodies recognizing vulnerable sites of all three antigens. IgGs induced by a cocktail vaccine containing three nanovaccines confer superior protection from lethal EBV challenge in female humanized mice compared to IgG elicited by individual NP-gHgL, NP-gB and NP-gp42. Importantly, serum antibodies elicited by cocktail nanovaccine immunization confer durable protection against EBV-associated lymphoma. Overall, the cocktail nanovaccine shows robust immunogenicity and is a promising candidate for further clinical trials. In this study, the authors show that nanovaccines co-delivering EBV antigens and molecular adjuvants generate high levels of neutralizing antibodies targeting vulnerable EBV sites of gHgL, gB and gp42. Antibodies elicited by cocktail nanovaccine immunization provide durable protection against EBV-associated lymphoma. [ABSTRACT FROM AUTHOR]

Doxorubicin (DOX) is an anthracycline antibiotic used as an antitumor treatment. However, its clinical application is limited due to severe side effects such as cardiotoxicity. In recent years, numerous studies have demonstrated that cellular aging has become a therapeutic target for DOX-induced cardiomyopathy. However, the underlying mechanism and specific molecular targets of DOX-induced cardiomyocyte aging remain unclear. Poly (ADP-ribose) polymerase (PARP) is a family of protein post-translational modification enzymes in eukaryotic cells, including 18 members. PARP-1, the most well-studied member of this family, has become a potential molecular target for the prevention and treatment of various cardiovascular diseases, such as DOX cardiomyopathy and heart failure. PARP-1 and PARP-2 share 69% homology in the catalytic regions. However, they do not entirely overlap in function. The role of PARP-2 in cardiovascular diseases, especially in DOX-induced cardiomyocyte aging, is less studied. In this study, we found for the first time that down-regulation of PARP-2 can inhibit DOX-induced cellular aging in cardiomyocytes. On the contrary, overexpression of PARP-2 can aggravate DOX-induced cardiomyocyte aging and injury. Further research showed that PARP-2 inhibited the expression and activity of SIRT1, which in turn was involved in the development of DOX-induced cardiomyocyte aging and injury. Our findings provide a preliminary experimental basis for establishing PARP-2 as a new target for preventing and treating DOX cardiomyopathy and related drug development. [ABSTRACT FROM AUTHOR]

Spiking neural networks (SNNs) can do inference with low power consumption due to their spike sparsity. Although SNNs can be combined with neuromorphic hardware to achieve efficient inference, they are often difficult to train directly due to discrete non-differentiable spikes. As an alternative, ANN-SNN conversion is an efficient way to achieve deep SNNs by converting well-trained artificial neural networks (ANNs). However, the existing methods commonly use constant threshold for conversion. A high constant threshold value prevents neurons from rapidly delivering spikes to deeper layers and causes high time delay. In addition, the same response for different inputs may result in information loss during the information transmission. Inspired by the biological adaptive threshold mechanism, we propose a multistage adaptive threshold (MSAT) method to alleviate this problem. Instead of using a single, constant value, the threshold is adjusted in multistages, adapting to each neuron's firing history and input properties. Specifically, for each neuron, the dynamic threshold is positively correlated with the average membrane potential and negatively correlated with the rate of depolarization. The adaptation to membrane potential and input allows a timely adjustment of the threshold to fire spikes faster and transmit more information. Moreover, we analyze the spikes of inactivated neurons error, which is pervasive in early time steps. We also propose spike confidence accordingly to measure confidence about the neurons that correctly deliver spikes. Such spike confidence in early time steps is used to determine whether to elicit the spike to alleviate the spikes of inactivated neurons error. Combined with the proposed methods, we examine the performance on CIFAR-10, CIFAR-100, and ImageNet datasets. We also conduct sentiment classification and speech recognition experiments on the IDBM and Google speech commands datasets, respectively. Experiments show that our methods can achieve near-lossless and lower latency ANN-SNN conversion. In summary, we build a biologically inspired multistage adaptive threshold for converted SNN, with comparable performance to state-of-the-art methods while improving energy efficiency. [ABSTRACT FROM AUTHOR]

Background: Developmental dyslexia (DD) is a neurodevelopmental disorder that is characterized by difficulties with all aspects of information acquisition in the written word, including slow and inaccurate word recognition. The neural basis behind DD has not been fully elucidated. Method: The study included 22 typically developing (TD) children, 16 children with isolated spelling disorder (SpD), and 20 children with DD. The cortical thickness, folding index, and mean curvature of Broca's area, including the triangular part of the left inferior frontal gyrus (IFGtriang) and the opercular part of the left inferior frontal gyrus, were assessed to explore the differences of surface morphology among the TD, SpD, and DD groups. Furthermore, the structural covariance network (SCN) of the triangular part of the left inferior frontal gyrus was analyzed to explore the changes of structural connectivity in the SpD and DD groups. Results: The DD group showed higher curvature and cortical folding of the left IFGtriang than the TD group and SpD group. In addition, compared with the TD group and the SpD group, the structural connectivity between the left IFGtriang and the left middle-frontal gyrus and the right mid-orbital frontal gyrus was increased in the DD group, and the structural connectivity between the left IFGtriang and the right precuneus and anterior cingulate was decreased in the DD group. Conclusion: DD had atypical structural connectivity in brain regions related to visual attention, memory and which might impact the information input and integration needed for reading and spelling. [ABSTRACT FROM AUTHOR]

The hippocampus creates a cognitive map of the external environment by encoding spatial and self-motion-related information. However, it is unclear whether hippocampal neurons could also incorporate internal cognitive states reflecting an animal's exploratory intention, which is not driven by rewards or unexpected sensory stimuli. In this study, a subgroup of CA1 neurons was found to encode both spatial information and animals' investigatory intentions in male mice. These neurons became active before the initiation of exploration behaviors at specific locations and were nearly silent when the same fields were traversed without exploration. Interestingly, this neuronal activity could not be explained by object features, rewards, or mismatches in environmental cues. Inhibition of the lateral entorhinal cortex decreased the activity of these cells during exploration. Our findings demonstrate that hippocampal neurons may bridge external and internal signals, indicating a potential connection between spatial representation and intentional states in the construction of internal navigation systems. The hippocampus maps space, but its role in encoding investigatory intentions is unclear. Here the authors show that certain CA1 neurons encode both spatial information and animals' intention to explore, depending on input from lateral entorhinal cortex. [ABSTRACT FROM AUTHOR]

It is difficult to obtain a single-phase environmental barrier coating material that simultaneously offers the advantages of low thermal conductivity, a suitable coefficient of thermal expansion, and excellent corrosion resistance. Herein, to synthesize the advantages of single-phase materials, we have developed an effective approach for the design of high-entropy multiphase ceramics of rare earth oxides and silicates. Such a specific design approach is capable of making high-entropy RE2SiO5/RE2O3 and RE2SiO5/RE2Si2O7 (RE = Lu, Yb, Tm, Er, Ho, and Y) multiphase ceramics as two types of potential environmental barrier coating materials for Al2O3f/Al2O3 and SiCf/SiC ceramic matrix composites. [ABSTRACT FROM AUTHOR]

Check dams on the Chinese Loess Plateau (CLP) have captured billions of tons of eroded sediment, substantially reducing sediment load in the Yellow River. However, uncertainties persist regarding the precise sediment capture and the role of these dams in Yellow River flow and sediment dynamics due to the lack of available spatial distribution datasets. We produced the first vectorized dataset of silted land formed by check dams on the CLP, combining high-resolution and easily accessible Google Earth images with object-based classification methods. The accuracy of the dataset was verified by 1947 collected test samples, and the producer's accuracy and user's accuracy of the dam lands were 88.9% and 99.5%, respectively. Our dataset not only provides fundamental information for accurately assessing the ecosystem service functions of check dams, but also helps to interpret current changes in sediment delivery of the Yellow River and plan future soil and water conservation projects. [ABSTRACT FROM AUTHOR]

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We demonstrate a transcriptional regulatory design algorithm that can boost expression in yeast and mammalian cell lines. The system consists of a simplified transcriptional architecture composed of a minimal core promoter and a synthetic upstream regulatory region (sURS) composed of up to three motifs selected from a list of 41 motifs conserved in the eukaryotic lineage. The sURS system was first characterized using an oligo-library containing 189,990 variants. We validate the resultant expression model using a set of 43 unseen sURS designs. The validation sURS experiments indicate that a generic set of grammar rules for boosting and attenuation may exist in yeast cells. Finally, we demonstrate that this generic set of grammar rules functions similarly in mammalian CHO-K1 and HeLa cells. Consequently, our work provides a design algorithm for boosting the expression of promoters used for expressing industrially relevant proteins in yeast and mammalian cell lines. Production of proteins at scale and affordable cost has been a major need of the biotech sector for the last several decades. Here the authors present a design algorithm called UNILIB for boosting gene expression in eukaryotic cells developed using an oligo-library and machine learning approach, validated in both yeast and mammalian cells using unseen sequences. [ABSTRACT FROM AUTHOR]

“Deathbots,” digital constructs that emulate the conversational patterns, demeanor, and knowledge of deceased individuals. Earlier moral discussions about deathbots centered on the dignity and autonomy of the deceased. This paper primarily examines the potential psychological and emotional dependencies that users might develop towards deathbots, considering approaches to prevent problematic dependence through temporary use. We adopt a hermeneutic method to argue that deathbots, as they currently exist, are unlikely to provide substantial comfort. Lacking the capacity to bear emotional burdens, they fall short of meeting idealistic expectations. By repositioning deathbots, we aim to mitigate the risk of emotional dependency and respect the natural grieving process. Our goal is to propose the use of deathbots as a novel means of mourning through transitory use, rather than as a method to alleviate grief or as a patterns for communication with the deceased. [ABSTRACT FROM AUTHOR]

Soil contamination by uranium presents a burgeoning global environmental concern, exerting detrimental effects on both agricultural production and soil health. Biochar, a carbonaceous material derived from biomass pyrolysis, exhibits considerable potential for remediating uranium-contaminated soils. However, a comprehensive review of the effects of biochar on the fate and accumulation of uranium in soil–plant systems remains conspicuously absent. In this paper, uranium sources and contamination are reviewed, and the impact of biochar on uranium immobilization and detoxification in soil–plant systems is analyzed. We reviewed the status of uranium contamination in soils globally and found that mining activities are currently the main sources. Further meta-analysis revealed that biochar addition significantly reduced the soil uranium bioavailability and shoot uranium accumulation, and their effect value is 58.9% (40.8–76.8%) and 39.7% (15.7–63.8%), respectively. Additionally, biochar enhances the soil microenvironment, providing favourable conditions for promoting plant growth and reducing uranium mobility. We focused on the mechanisms governing the interaction between biochar and uranium, emphasising the considerable roles played by surface complexation, reduction, ion exchange, and physical adsorption. The modification of biochar by intensifying these mechanisms can promote uranium immobilisation in soils. Finally, biochar alleviates oxidative stress and reduces uranium accumulation in plant tissues, thereby mitigating the adverse effects of uranium on plant growth and development. Overall, our review highlights the capacity of biochar to remediate uranium contamination in soil–plant systems through diverse mechanisms, providing valuable insights for sustainable environmental remediation. Highlights Biochar reduces uranium mobility through a variety of mechanisms, including surface complexation, reduction, ion exchange, and physical adsorption. Biochar significantly reduces uranium bioavailability in soil and limits its accumulation in plants. Modified biochar has been shown to enhance its effectiveness in immobilising uranium. Biochar application to soil not only promotes uranium remediation but also improves soil quality. [ABSTRACT FROM AUTHOR]

This paper addresses how people understand Explainable Artificial Intelligence (XAI) in three ways: contrastive, functional, and transparent. We discuss the unique aspects and challenges of each and emphasize improving current XAI understanding frameworks. The Ritual Dialog Framework (RDF) is introduced as a solution for better dialog between AI creators and users, blending anthropological insights with current acceptance challenges. RDF focuses on building trust and a user-centered approach in XAI. By undertaking such an initiative, we aim to foster a thorough Understanding of XAI, capable of resolving the current issues of acceptance and recognition. [ABSTRACT FROM AUTHOR]

The role of superficial temporal artery-to-middle cerebral artery (STA-MCA) bypass in acute ischemic stroke (AIS) is contentious, with no evidence in patients with AIS and large vessel occlusion (AIS-LVO). We conducted a cohort study to assess emergency STA-MCA outcomes in AIS-LVO and a meta-analysis to evaluate STA-MCA outcomes in early AIS treatment. From January 2018 to March 2021, we consecutively recruited newly diagnosed AIS-LVO patients, dividing them into STA-MCA and non-STA-MCA groups. To evaluate the neurological status and outcomes, we employed the National Institutes of Health Stroke Scale (NIHSS) during the acute phase and the modified Rankin Scale (mRS) during the follow-up period. Additionally, we conducted a meta-analysis encompassing all available clinical studies to assess the impact of STA-MCA on patients with AIS. In the cohort study (56 patients), we observed more significant neurological improvement in the STA-MCA group at two weeks (p = 0.030). However, there was no difference in the clinical outcomes between the two groups. Multivariable logistic regression identified the NIHSS at two weeks (OR: 0.840; 95% CI: 0.754–0.936, p = 0.002) as the most critical predictor of a good outcome. Our meta-analysis of seven studies indicated a 67% rate for achieving a good outcome (mRS < 3) at follow-up points (95% CI: 57%–77%, I2 = 44.1%). In summary, while the meta-analysis suggested the potential role of STA-MCA bypass in mild to moderate AIS, our single-center cohort study indicated that STA-MCA bypass does not seem to improve the prognosis of patients who suffer from AIS-LVO. [ABSTRACT FROM AUTHOR]

Poly(3,4-ethylenedioxythiophene) (PEDOT) is one of the most successful conductive polymers that recently has been used in wearable sensors for human health monitoring. In this work, we prepared a series of PEDOT hybrids consisting of PEDOT, sodium poly(styrene sulfonate) (PSSNa) and polyethylene oxide (PEO), and their preparation could be scaled-up via an adapted solid-state polymerization process. The resistance of the as-prepared PEDOT:PSS/PEO hybrid shows clear temperature response, i.e., it decreases almost linearly with the temperature increase. To understand this phenomenon, the in situ synchrotron radiation wide- and small-angle X-ray scattering (WAXS/SAXS) characterizations were undertaken to study the temperature-dependent microstructure change of the PEDOT:PSS/PEO hybrid. It demonstrated that PEDOT formed conductive paths in the hybrids, which were not destroyed by the PEO crystallization. As temperature increased, the PEO crystals' melting and the accompanying reorganization of PEDOT chains endowed the hybrid sample temperature responsiveness. Based on these fundamental knowledges, the hybrid materials were used to fabricate flexible wearable sensor that showing temperature sensing performance with an accuracy of 1 °C. These findings shed lights on the scalable manufacturing of wearable sensors for body temperature monitoring. [ABSTRACT FROM AUTHOR]

Bone regeneration for large, critical-sized bone defects remains a clinical challenge nowadays. Guided bone regeneration (GBR) is a promising technique for the repair of multiple bone defects, which is widely used in oral and maxillofacial bone defects but is still unsatisfied in the treatment of long bone defects. Here, we successfully fabricated a bilayer mineralized collagen/collagen (MC/Col)-GBR membrane with excellent osteoinductive and barrier function by coating the MC particles prepared via in situ biomimetic mineralization process on one side of a sheet-like pure collagen layer. The aim of the present study was to investigate the physicochemical properties and biological functions of the MC/Col film, and to further evaluate its bone regeneration efficiency in large bone defect repair. Fourier-transform infrared spectra and X-ray diffraction patterns confirmed the presence of both hydroxyapatite and collagen phase in the MC/Col film, as well as the chemical interaction between them. stereo microscope, scanning electron microscopy and atomic force microscope showed the uniform distribution of MC particles in the MC/Col film, resulting in a rougher surface compared to the pure Col film. The quantitative analysis of surface contact angle, light transmittance and tensile strength demonstrated that the MC/Col film have better hydrophilicity, mechanical properties, light-barrier properties, respectively. In vitro macrophage co-culture experiments showed that the MC/Col film can effectively inhibit macrophage proliferation and fusion, reducing fibrous capsule formation. In vivo bone repair assessment of a rabbit critical segmental radial defect proved that the MC/Col film performed better than other groups in promoting bone repair and regeneration due to their unique dual osteoinductive/barrier function. These findings provided evidence that MC/Col film has a great clinical potential for effective bone defect repair. [ABSTRACT FROM AUTHOR]

Type II diabetes was causally related to stroke, which is a risk factor for stroke. However, the causal relationship between type I diabetes(T1D) and stroke, especially its subtypes, remains unclear. To determine whether T1D has a genetic causal link to stroke and its subtypes, we undertook this mendelian randomization (MR) study. The genome-wide association studies (GWAS) of T1D was the source of exposure. The outcomes were strokes and their subtypes, including ischemic stroke (IS), small vessel stroke (SVS), cardioembolic stroke (CES), large artery atherosclerosis stroke (LAS), intracerebral hemorrhage (ICH), lobar intracerebral hemorrhage (LICH), and non-lobar intracerebral hemorrhage (NLICH). We used outcome GWAS conducted by ISGC consortium for the initial phase and GWAS from MEGASTROKE consortium as the data for the replication phase to confirm the causal association. Besides, we conducted a meta-analysis of the causal association from ISGC and MEGASTROKE databases to confirm robust causality. Inverse-variance weighting (IVW) was utilized as the primary method to estimate the causality between T1D and stroke. The Cochran's Q test and the MR-PRESSO global test were used to examine the sensitivity. We discovered the causal relationship between T1D and SVS (OR = 1.17, 95% CI: 1.07–1.28, p = 6.0 × 10− 4), CES (OR = 1.11, 95%CI: 1.03–1.21, p = 0.0080) in initial stage. The replication phase validated T1D has a causal relationship with SVS (OR = 1.12, 95% CI: 1.06–1.18, p = 4.0 × 10− 5), but not with stroke and other subtypes. The meta-analysis of initial and replication stage again supported the causal link between T1D and SVS (OR = 1.13, 95% CI: 1.08–1.18, p < 0.05). However, no causal relationship was found between T1D and other stroke subtypes. The sensitivity analysis also supported the robust of these results. In conclusion, T1D was causally associated with SVS, but not with other subtypes of stroke. More investigation is needed to understand the underlying biology mechanism. [ABSTRACT FROM AUTHOR]

Colon adenocarcinoma (COAD) is a serious public health problem, the third most common cancer and the second most deadly cancer in the world. About 9.4% of cancer-related deaths in 2020 were due to COAD. Anoikis is a specialized form of programmed cell death that plays an important role in tumor invasion and metastasis. The presence of anti-anoikis factors is associated with tumor aggressiveness and drug resistance. Various bioinformatic methods, such as differential expression analysis, and functional annotation analysis, machine learning, were used in this study. RNA-sequencing and clinical data from COAD patients were obtained from the Gene expression omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Construction of a prognostic nomogram for predicting overall survival (OS) using multivariate analysis and Lasso-Cox regression. Immunohistochemistry (IHC) was our method of validating the expression of seven genes that are linked to anoikis in COAD. We identified seven anoikis-related genes as predictors of COAD survival and prognosis, and confirmed their accuracy in predicting colon adenocarcinoma prognosis by KM survival curves and ROC curves. A seven-gene risk score consisting of NAT1, CDC25C, ATP2A3, MMP3, EEF1A2, PBK, and TIMP1 showed strong prognostic value. Meanwhile, we made a nomogram to predict the survival rate of COAD patients. The immune infiltration assay showed T cells. CD4 memory. Rest and macrophages. M0 has a higher proportion in COAD, and 11 genes related to tumor immunity are important. GDSC2-based drug susceptibility analysis showed that 6 out of 198 drugs were significant in COAD. Anoikis-related genes have potential value in predicting the prognosis of COAD and provide clues for developing new therapeutic strategies for COAD. Immune infiltration and drug susceptibility results provide important clues for finding new personalized treatment options for COAD. These findings also suggest possible mechanisms that may affect prognosis. These results are the starting point for planning individualized treatment and managing patient outcomes. [ABSTRACT FROM AUTHOR]

Humans often unconsciously perceive social robots involved in their lives as partners rather than mere tools, imbuing them with qualities of companionship. This anthropomorphization can lead to a spectrum of emotional risks, such as deception, disappointment, and reverse manipulation, that existing approaches struggle to address effectively. In this paper, we argue that a Virtual Interactive Environment (VIE) exists between humans and social robots, which plays a crucial role and demands necessary consideration and clarification in order to mitigate potential emotional risks. By analyzing the relational nature of human-social robot interaction, we discuss the connotation of such a virtual interactive environment that is similar to the emotional states aroused when reading novels. Building on this comprehension, we further demonstrate that manufacturers should carry out comprehensive Virtual Interactive Environment Indication (VIEI) measures during human-social robot interaction with a stricter sense of responsibility when applying social robots. Finally, we contemplate the potential contributions of virtual interactive environment indication to existing robot ethics guidelines. [ABSTRACT FROM AUTHOR]

Organic Cation Transporter 1 (OCT1) plays a crucial role in hepatic metabolism by mediating the uptake of a range of metabolites and drugs. Genetic variations can alter the efficacy and safety of compounds transported by OCT1, such as those used for cardiovascular, oncological, and psychological indications. Despite its importance in drug pharmacokinetics, the substrate selectivity and underlying structural mechanisms of OCT1 remain poorly understood. Here, we present cryo-EM structures of full-length human OCT1 in the inward-open conformation, both ligand-free and drug-bound, indicating the basis for its broad substrate recognition. Comparison of our structures with those of outward-open OCTs provides molecular insight into the alternating access mechanism of OCTs. We observe that hydrophobic gates stabilize the inward-facing conformation, whereas charge neutralization in the binding pocket facilitates the release of cationic substrates. These findings provide a framework for understanding the structural basis of the promiscuity of drug binding and substrate translocation in OCT1. OCT1 plays an important role in the uptake of drugs and metabolites in the liver. Here, authors present the structure of OCT1 to understand how it recognizes and transports a wide range of drugs and substrates. [ABSTRACT FROM AUTHOR]

The architecture design and multi-scale learning principles of the human brain that evolved over hundreds of millions of years are crucial to realizing human-like intelligence. Spiking neural network based Liquid State Machine (LSM) serves as a suitable architecture to study brain-inspired intelligence because of its brain-inspired structure and the potential for integrating multiple biological principles. Existing researches on LSM focus on different certain perspectives, including high-dimensional encoding or optimization of the liquid layer, network architecture search, and application to hardware devices. There is still a lack of in-depth inspiration from the learning and structural evolution mechanism of the brain. Considering these limitations, this paper presents a novel LSM learning model that integrates adaptive structural evolution and multi-scale biological learning rules. For structural evolution, an adaptive evolvable LSM model is developed to optimize the neural architecture design of liquid layer with separation property. For brain-inspired learning of LSM, we propose a dopamine-modulated Bienenstock-Cooper-Munros (DA-BCM) method that incorporates global long-term dopamine regulation and local trace-based BCM synaptic plasticity. Comparative experimental results on different decision-making tasks show that introducing structural evolution of the liquid layer, and the DA-BCM regulation of the liquid layer and the readout layer could improve the decision-making ability of LSM and flexibly adapt to rule reversal. This work is committed to exploring how evolution can help to design more appropriate network architectures and how multi-scale neuroplasticity principles coordinated to enable the optimization and learning of LSMs for relatively complex decision-making tasks. [ABSTRACT FROM AUTHOR]

Computerized adaptive testing (CAT) targets to accurately assess the student's proficiency in the required subject/area. The key issue is how to design a question selector that adaptively selects the best-suited questions for each student based on previous performance step by step. Most existing question selectors execute via greedy metric functions (e.g., question information and uncertainty), which can not effectively capture data characteristics. There also exist learning-based question selectors that redefine the CAT problem as a bilevel optimization problem, where the parameter learning of the question selector and the student proficiency estimation model are coupled, which is not flexible enough. To this end, in this paper, we propose a novel CAT framework with Decoupled Learning selector (DL-CAT). Specifically, we first use the currently estimated student ability and question characteristics as input and design a deep learning-based question selector to predict question selection scores. Then, to address the issue that there is no ground truth to measure the quality of the selected question, an approximate ground-truth and a pairwise rank loss function are specially designed to update the parameters of the question selector independently. Extensive experiments on two real datasets demonstrate that our proposed DL-CAT has certain advantages in effectiveness and significant advantages in efficiency. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to assess the cumulative incidences of Non-melanoma skin cancer (NMSC)-specific mortality (NMSC-SM) and develop a competing risk nomogram for NMSC-SM. Methods: Data on patients diagnosed with NMSC between 2010 and 2015 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. To identify the independent prognostic factors, univariate and multivariate competing risk models were used, and a competing risk model was constructed. Based on the model, we developed a competing risk nomogram to predict the 1-, 3-, 5-, and 8-year cumulative probabilities of NMSC-SM. The precision and ability to discriminate of the nomogram were evaluated through the utilization of metrics, such as receiver-operating characteristic (ROC) area under the curve (AUC), concordance index (C-index), and a calibration curve. Decision curve analysis (DCA) was employed to assess the clinical usefulness of the nomogram. Results: Race, age, the primary site of the tumor, tumor grade, size, histological type, summary stage, stage group, order of radiation and surgery, and bone metastases were identified as independent risk factors. The prediction nomogram was constructed using the variables mentioned above. The ROC curves implied the good discrimination ability of the predictive model. The nomogram's C-index was 0.840 and 0.843 in the training and validation sets, respectively, and the calibration plots were well fitted. In addition, the competing risk nomogram demonstrated good clinical usefulness. Conclusion: The competing risk nomogram displayed excellent discrimination and calibration for predicting NMSC-SM, which can be used in clinical contexts to help guide treatment decisions. [ABSTRACT FROM AUTHOR]

The antioxidant activities of flavonoid mixtures can be used to investigate the synergistic antioxidant mechanism of flavonoids. The antioxidant capacities of three flavonoids (quercetin, baicalein, and daidzein) and β-carotene in binary and ternary mixtures with kaempferol were analyzed using a 2,2-diphenyl-1-picrylhydrazyl (DPPH) inhibition assay by means of absorption spectroscopy. The results showed that the number of hydroxyl groups and o-hydroxyl groups had a significant effect on the antioxidant activity of the flavonoids, and the mixture of kaempferol, quercetin, and baicalein showed optimal synergistic antioxidant activity. Compared with quercetin and baicalein, kaempferol had the fastest inhibition rate, and multiple prolonged kinetic processes associated with the scavenging of DPPH radicals occurred in mixtures of kaempferol with the other flavonoids and β-carotene. Kaempferol has a potential synergistic antioxidant effect when mixed with daidzein and β-carotene, and the results suggested that this may be due to the regeneration of kaempferol after antioxidation. By means of classic UV-Vis spectroscopy, reaction details of the synergistic antioxidant process of DPPH radical scavenging by flavonoids can be obtained. [ABSTRACT FROM AUTHOR]

This meta-analysis aims to determine the efficacy of Epigallocatechin gallate (EGCG) in the treatment of myocardial ischemia–reperfusion injury (MIRI) and summarize the mechanisms involved. Literature from six databases including Web of Science, PubMed, Embase, China National Knowledge Infrastructure (CNKI), Wan-Fang database, and VIP database (VIP) were systematically searched. All the analysis were conducted by R. Twenty-five eligible studies involving 443 animals were included in this meta-analysis. The results indicated that compared to controls, EGCG exerts a cardioprotective effect by reducing myocardial infarct size (SMD = −4.06; 95% CI: −5.17, −2.94; P < 0.01; I2 = 77%). The funnel plot revealed publication bias. Moreover, EGCG significantly improves cardiac function, serum myocardial injury enzyme, and oxidative stress levels in MIRI animal models. This meta-analysis demonstrates that EGCG exhibits therapeutic promise in animal models of MIRI. However, further validation is still needed in large animal models and large clinical studies. [ABSTRACT FROM AUTHOR]

As a enrichment plant, ramie can be used for the phytoremediation of cadmium (Cd)-contaminated soil. However, it is worth exploring the role of plant growth regulators and foliar fertilizers in the process of plant growth and development and Cd adsorption. By measuring the agronomic traits, Cd content of aboveground and underground ramie, calculating the Cd transfer coefficient (TF) and Cd bioconcentration factors (BCF), and the correlation between various indicators. This study examined the effects of plant growth regulators and foliar fertilizers on ramie's capacity for Cd accumulation and transportation. Plant growth regulators and foliar fertilizers increased the Cd content of the aboveground ramie, reduced the Cd content of the underground ramie, and increased the TF. Among them, GA-1 increased the Cd content of the aboveground ramie to 3 times more than that of the control and reduced the Cd content of the underground ramie by 54.76%. Salicylic acid (SA) increased the Cd content of the aboveground ramie to three times more than that of the control. The combination of GA and foliar fertilizer reduced the Cd content of the aboveground and underground ramie and the TF and BCF of the underground ramie. After the hormones were sprayed, the TF of ramie had a significant positive correlation with the Cd content of the aboveground ramie; the BCF of the aboveground ramie had a significant positive correlation with the Cd content and TF of the aboveground ramie. The results indicate that Brassinolide (BR), gibberellin (GA), ethephon (ETH), polyamines (PAs), and salicylic acid (SA) have different effects on the enrichment and transport of Cd in ramie. This study provided an effective method to improve the capacity for ramie to adsorb heavy metals during cultivation. [ABSTRACT FROM AUTHOR]

Objective: Transmural intestinal necrosis (TIN) is related to high mortality in patients with acute mesenteric ischemia (AMI). Radiological predictive factors of TIN in AMI remains controversial. This study aimed to identify the CT-based predictive factors of TIN in AMI. Methods: EMBASE and PUBMED were searched for publications predicting TIN using radiological features. Quality Assessment of Diagnostic Accuracy Studies-2 was used to assess the methodological quality of individual studies. Data were presented in terms of diagnostic odds ratio (DOR), sensitivity, specificity, and 95% confidence interval (CI). The random-effects models were used for the meta-analysis. Results: Eleven studies including 1037 cases with AMI were considered. The meta-analysis showed that bowel wall thinning (DOR = 13.10; 95% CI: 3.71, 46.25), decreased or absent bowel wall enhancement (DOR = 5.77; 95% CI: 2.95, 11.30), bowel dilation (DOR = 3.23; 95% CI: 2.03, 5.15), pneumatosis intestinalis (DOR = 5.78; 95% CI: 2.24, 14.95), porto-mesenteric venous gas (DOR = 5.36; 95% CI: 2.14, 13.40), and arterial occlusive AMI (DOR = 2.66; 95% CI: 1.53, 4.63) were risk factors for predicting TIN. Bowel wall thinning and porto-mesenteric venous gas displayed high specificity to diagnose TIN (98%, 95%, respectively). The subgroup analysis showed that decreased or absent bowel wall enhancement (DOR = 8.23; 95% CI: 4.67, 14.51) and bowel dilation (DOR = 3.14; 95% CI: 1.55, 6.39) were predictors of TIN in venous occlusive AMI, which were not related to TIN in arterial-origin AMI. Conclusions: For predicting TIN, there are specific radiological features. The radiological predictors of TIN may differ according to the various causes of AMI. Future primary studies should further evaluate the relationships between radiological signs and TIN based on different etiologies. Key Points: • Bowel wall thinning, decreased or absent bowel wall enhancement, bowel dilation, pneumatosis intestinalis, porto-mesenteric venous gas, and arterial occlusive AMI were risk factors for predicting TIN. • Decreased or absent bowel wall enhancement and bowel dilation were predictors of TIN in venous occlusive AMI, which were not related to TIN in arterial-origin AMI. [ABSTRACT FROM AUTHOR]

Finding a minimum is a fundamental calculation in many quantum algorithms. However, challenges are faced in demonstrating it effectively in real quantum computers. In practice, the number of solutions is unknown, and there is no universal encoding method. Besides that, current quantum computers have limited resources. To alleviate these problems, this paper proposes a general quantum minimum searching algorithm. An adaptive estimation method is adopted to calculate the number of solutions, and a quantum encoding circuit for arbitrary databases is presented for the first time, which improves the universality of the algorithm and helps it achieve a nearly 100% success rate in a series of random databases. Moreover, gate complexity is reduced by our simplified Oracle, and the realizability of the algorithm is verified on a superconducting quantum computer. Our algorithm can serve as a subroutine for various quantum algorithms to promote their implementation in the Noisy Intermediate-Scale Quantum era. k]quantum minimum searching algorithm k]quantum circuit k]superconducting quantum computer k]quantum encoding [ABSTRACT FROM AUTHOR]

Although recent studies have revealed the association between the human microbiome especially gut microbiota and longevity, their causality remains unclear. Here, we assess the causal relationships between the human microbiome (gut and oral microbiota) and longevity, by leveraging bidirectional two-sample Mendelian randomization (MR) analyses based on genome-wide association studies (GWAS) summary statistics of the gut and oral microbiome from the 4D-SZ cohort and longevity from the CLHLS cohort. We found that some disease-protected gut microbiota such as Coriobacteriaceae and Oxalobacter as well as the probiotic Lactobacillus amylovorus were related to increased odds of longevity, whereas the other gut microbiota such as colorectal cancer pathogen Fusobacterium nucleatum, Coprococcus, Streptococcus, Lactobacillus, and Neisseria were negatively associated with longevity. The reverse MR analysis further revealed genetically longevous individuals tended to have higher abundances of Prevotella and Paraprevotella but lower abundances of Bacteroides and Fusobacterium species. Few overlaps of gut microbiota-longevity interactions were identified across different populations. We also identified abundant links between the oral microbiome and longevity. The additional analysis suggested that centenarians genetically had a lower gut microbial diversity, but no difference in oral microbiota. Our findings strongly implicate these bacteria to play a role in human longevity and underscore the relocation of commensal microbes among different body sites that would need to be monitored for long and healthy life. [ABSTRACT FROM AUTHOR]

Two-dimensional (2D) nonlayered materials have recently provoked a surge of interest due to their abundant species and attractive properties with promising applications in catalysis, nanoelectronics, and spintronics. However, their 2D anisotropic growth still faces considerable challenges and lacks systematic theoretical guidance. Here, we propose a general thermodynamics-triggered competitive growth (TTCG) model providing a multivariate quantitative criterion to predict and guide 2D nonlayered materials growth. Based on this model, we design a universal hydrate-assisted chemical vapor deposition strategy for the controllable synthesis of various 2D nonlayered transition metal oxides. Four unique phases of iron oxides with distinct topological structures have also been selectively grown. More importantly, ultra-thin oxides display high-temperature magnetic ordering and large coercivity. MnxFeyCo3-x-yO4 alloy is also demonstrated to be a promising room-temperature magnetic semiconductor. Our work sheds light on the synthesis of 2D nonlayered materials and promotes their application for room-temperature spintronic devices. 2D nonlayered materials exhibit interesting properties for catalysis, nanoelectronics and spintronics applications, but their growth is still challenging. Here, the authors report a theoretical model and an experimental strategy to synthesize various 2D nonlayered transition metal oxides with room-temperature magnetic properties. [ABSTRACT FROM AUTHOR]

Yttria-stabilized zirconia (YSZ) and Y2O3-La2O3 co-stabilized zirconia (La-YSZ) coatings were prepared by atmospheric plasma spraying using identical spray parameters, and their calcium–magnesium–alumina–silicate (CMAS) corrosion behaviors were compared. After CMAS attack, YSZ exhibited a deteriorated microstructure with larger voids and more cracks than La-YSZ. The results revealed that the as-sprayed La-YSZ coatings had a much smaller grain size than YSZ because of La doping but La-YSZ exhibited a better resistance to CMAS than YSZ. Density functional theory calculations showed that the mean square displacement of yttrium in La-YSZ was lower than that of YSZ and the activation energy of CMAS/La-YSZ was higher than that of CMAS/YSZ. EBSD mapping analysis showed La-YSZ coatings have a lower monoclinic/tetragonal ratio than YSZ after corrosion, indicating that the rate of phase transformation in La-YSZ is significantly lower than that in YSZ, which is consistent with calculation results. [ABSTRACT FROM AUTHOR]

Objective: To identify novel candidate genes whose expression is associated with bone mineral density (BMD) and body lean mass (LM) in children. Methods: A tissue-specific transcriptome-wide association study (TWAS) was conducted utilizing a large-scale genome-wide association study (GWAS) dataset associated with BMD and LM and involving 10,414 participants. The measurement of BMD and LM phenotypes was made based on total-body dual-energy X-ray absorptiometry (TB-DXA) scans. TWAS was conducted by using FUSION software. Reference panels for muscle skeleton (MS), peripheral blood (NBL) and whole blood (YBL) were used for TWAS analysis. Functional enrichment and protein–protein interaction (PPI) analyses of the genes identified by TWAS were performed by using the online tool Metascape (http://metascape.org). Results: For BMD, we identified 174 genes with P < 0.05, such as IKZF1 (P = 1.46 × 10−9) and CHKB (P = 8.31 × 10−7). For LM, we identified 208 genes with P < 0.05, such as COPS5 (P = 3.03 × 10−12) and MRPS33 (P = 5.45 × 10−10). Gene ontology (GO) enrichment analysis of the BMD-associated genes revealed 200 GO terms, such as protein catabolic process (Log P = −5.09) and steroid hormone-mediated signaling pathway (Log P = −3.13). GO enrichment analysis of the LM-associated genes detected 287 GO terms, such as the apoptotic signaling pathway (Log P = −8.08) and lipid storage (Log P = −3.55). Conclusion: This study identified several candidate genes for BMD and LM in children, providing novel clues to the genetic mechanisms underlying the development of childhood BMD and LM. [ABSTRACT FROM AUTHOR]

F1Fo ATP synthase functions as a biological generator and makes a major contribution to cellular energy production. Proton flow generates rotation in the Fo motor that is transferred to the F1 motor to catalyze ATP production, with flexible F1/Fo coupling required for efficient catalysis. F1Fo ATP synthase can also operate in reverse, hydrolyzing ATP and pumping protons, and in bacteria this function can be regulated by an inhibitory ε subunit. Here we present cryo-EM data showing E. coli F1Fo ATP synthase in different rotational and inhibited sub-states, observed following incubation with 10 mM MgATP. Our structures demonstrate how structural transitions within the inhibitory ε subunit induce torsional movement in the central stalk, thereby enabling its rotation within the Fο motor. This highlights the importance of the central rotor for flexible coupling of the F1 and Fo motors and provides further insight into the regulatory mechanism mediated by subunit ε. Cryo-EM structures of E. coli F1Fo ATP synthase highlight the role of the inhibitory ε subunit in regulating the torsional movement of the central stalk within the Fo motor and central stalk flexibility in coupling the F1 and Fo motors. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV), a γ-herpesvirus, is the first identified oncogenic virus, which establishes permanent infection in humans. EBV causes infectious mononucleosis and is also tightly linked to many malignant diseases. Various vaccine formulations underwent testing in different animals or in humans. However, none of them was able to prevent EBV infection and no vaccine has been approved to date. Current efforts focus on antigen selection, combination, and design to improve the efficacy of vaccines. EBV glycoproteins such as gH/gL, gp42, and gB show excellent immunogenicity in preclinical studies compared to the previously favored gp350 antigen. Combinations of multiple EBV proteins in various vaccine designs become more attractive approaches considering the complex life cycle and complicated infection mechanisms of EBV. Besides, rationally designed vaccines such as virus-like particles (VLPs) and protein scaffold-based vaccines elicited more potent immune responses than soluble antigens. In addition, humanized mice, rabbits, as well as nonhuman primates that can be infected by EBV significantly aid vaccine development. Innovative vaccine design approaches, including polymer-based nanoparticles, the development of effective adjuvants, and antibody-guided vaccine design, will further enhance the immunogenicity of vaccine candidates. In this review, we will summarize (i) the disease burden caused by EBV and the necessity of developing an EBV vaccine; (ii) previous EBV vaccine studies and available animal models; (iii) future trends of EBV vaccines, including activation of cellular immune responses, novel immunogen design, heterologous prime-boost approach, induction of mucosal immunity, application of nanoparticle delivery system, and modern adjuvant development. [ABSTRACT FROM AUTHOR]

Background: Dislocation is a complicated process and associated with multivariate etiology and risk factors. The purpose of this study was to verify if radiologic restoration inaccuracy increases postoperative dislocation in primary total hip arthroplasty (THA) individually or synergistically. Methods: From 2017 to 2020, we identified 76 (1.9%) patients who suffered postoperative dislocations from 3926 THAs in our institution. After excluded patients with previously proven patient-related and implant-related risk factors, the remaining patients were used to match a 1:1 control patients who were without dislocation. The cup position (inclination and anteversion angles), hip offset (HO), leg length discrepancy (LLD), and abductor lever arm (ALA) were analyzed by univariate analyses and multivariate logistic regressions. Results: Measurements on radiographs showed excellent interobserver agreement (intraclass correlation coefficient (ICC) 0.922–0.952) and intraobserver agreements (ICC 0.933–0.967). HO restoration inaccuracy (without ± 5 mm) was associated with higher dislocation risk (OR 4.241 95% CI 1.440–12.492, P = 0.009). The restoration inaccuracy of the cup position, LLD, or ALA could not increase the dislocation risk individually. When combining the radiologic restoration inaccuracy factors, the HO + LLD restoration inaccuracy and HO + ALA restoration inaccuracy increased the odds of postoperative dislocation (OR 12.056, 95% CI 1.409–103.127, P = 0.023; OR 4.770, 95% CI 1.336–17.028, P = 0.016, respectively). Combining the four risk factors of cup safe zone, HO, LLD, and ALA, patients with 3 or 4 radiologic restoration inaccuracy factors showed a higher risk of dislocation (OR 13.500, 95% CI 1.340–135.983, P = 0.027). Conclusion: Hip offset (HO) restoration inaccuracy increased the risk of dislocation following primary THA. Multivariate radiologic restoration accuracy is critical for the prevention of dislocation and needs to be valued by surgeons. [ABSTRACT FROM AUTHOR]

Few-shot learning (learning with a few samples) is one of the most important cognitive abilities of the human brain. However, the current artificial intelligence systems meet difficulties in achieving this ability. Similar challenges also exist for biologically plausible spiking neural networks (SNNs). Datasets for traditional few-shot learning domains provide few amounts of temporal information. And the absence of neuromorphic datasets has hindered the development of few-shot learning for SNNs. Here, to the best of our knowledge, we provide the first neuromorphic dataset for few-shot learning using SNNs: N-Omniglot, based on the Dynamic Vision Sensor. It contains 1,623 categories of handwritten characters, with only 20 samples per class. N-Omniglot eliminates the need for a neuromorphic dataset for SNNs with high spareness and tremendous temporal coherence. Additionally, the dataset provides a powerful challenge and a suitable benchmark for developing SNNs algorithms in the few-shot learning domain due to the chronological information of strokes. We also provide the improved nearest neighbor, convolutional network, SiameseNet, and meta-learning algorithm in the spiking version for verification. Measurement(s) strokes of characters Technology Type(s) dynamic vision sensor [ABSTRACT FROM AUTHOR]

Brain calcification is a critical aging-associated pathology and can cause multifaceted neurological symptoms. Cerebral phosphate homeostasis dysregulation, blood-brain barrier defects, and immune dysregulation have been implicated as major pathological processes in familial brain calcification (FBC). Here, we analyzed two brain calcification families and identified calcification co-segregated biallelic variants in the CMPK2 gene that disrupt mitochondrial functions. Transcriptome analysis of peripheral blood mononuclear cells (PBMCs) isolated from these patients showed impaired mitochondria-associated metabolism pathways. In situ hybridization and single-cell RNA sequencing revealed robust Cmpk2 expression in neurons and vascular endothelial cells (vECs), two cell types with high energy expenditure in the brain. The neurons in Cmpk2-knockout (KO) mice have fewer mitochondrial DNA copies, down-regulated mitochondrial proteins, reduced ATP production, and elevated intracellular inorganic phosphate (Pi) level, recapitulating the mitochondrial dysfunction observed in the PBMCs isolated from the FBC patients. Morphologically, the cristae architecture of the Cmpk2-KO murine neurons was also impaired. Notably, calcification developed in a progressive manner in the homozygous Cmpk2-KO mice thalamus region as well as in the Cmpk2-knock-in mice bearing the patient mutation, thus phenocopying the calcification pathology observed in the patients. Together, our study identifies biallelic variants of CMPK2 as novel genetic factors for FBC; and demonstrates how CMPK2 deficiency alters mitochondrial structures and functions, thereby highlighting the mitochondria dysregulation as a critical pathogenic mechanism underlying brain calcification. [ABSTRACT FROM AUTHOR]