Targeting the DYRK1A kinase prevents cancer progression and metastasis and promotes cancer cells response to G1/S targeting chemotherapy drugs.

Metastatic cancer remains incurable as patients eventually loose sensitivity to targeted therapies and chemotherapies, further leading to poor clinical outcome. Thus, there is a clear medical gap and urgent need to develop efficient and improved targeted therapies for cancer patients. In this study, we investigated the role of DYRK1A kinase in regulating cancer progression and evaluated the therapeutic potential of DYRK1A inhibition in invasive solid tumors, including colon and triple-negative breast cancers. We uncovered new roles played by the DYRK1A kinase. We found that blocking DYRK1A gene expression or pharmacological inhibition of its kinase activity via harmine efficiently blocked primary tumor formation and the metastatic tumor spread in preclinical models of breast and colon cancers. Further assessing the underlying molecular mechanisms, we found that DYRK1A inhibition resulted in increased expression of the G1/S cell cycle regulators while decreasing expression of the G2/M regulators. Combined, these effects release cancer cells from quiescence, leading to their accumulation in G1/S and further delaying/preventing their progression toward G2/M, ultimately leading to growth arrest and tumor growth inhibition. Furthermore, we show that accumulation of cancer cells in G1/S upon DYRK1A inhibition led to significant potentiation of G1/S targeting chemotherapy drug responses in vitro and in vivo. This study underscores the potential for developing novel DYRK1A-targeting therapies in colon and breast cancers and, at the same time, further defines DYRK1A pharmacological inhibition as a viable and powerful combinatorial treatment approach for improving G1/S targeting chemotherapy drugs treatments in solid tumors.

Genome-wide in vivo CRISPR screen identifies TGFß3 as actionable biomarker of palbociclib resistance in triple negative breast cancer.

Triple negative breast cancer (TNBC) remains exceptionally challenging to treat. While CDK4/6 inhibitors have revolutionized HR + breast cancer therapy, there is limited understanding of their efficacy in TNBC and meaningful predictors of response and resistance to these drugs remain scarce. We conducted an in vivo genome-wide CRISPR screen using palbociclib as a selection pressure in TNBC. Hits were prioritized using microarray data from a large panel of breast cancer cell lines to identify top palbociclib sensitizers. Our study defines TGFß3 as an actionable determinant of palbociclib sensitivity that potentiates its anti-tumor effects. Mechanistically, we show that chronic palbociclib exposure depletes p21 levels, contributing to acquired resistance, and that TGFß3 treatment can overcome this. This study defines TGFß3 as an actionable biomarker that can be used to improve patient stratification for palbociclib treatment and exploits the synergistic interaction between CDK4/6 and TGFß3 to propose a new combinatorial treatment for TNBC.

Network Spreading from Network Dimension.

Continuous-state network spreading models provide critical numerical and analytic insights into transmission processes in epidemiology, rumor propagation, knowledge dissemination, and many other areas. Most of these models reflect only local features such as adjacency, degree, and transitivity, so can exhibit substantial error in the presence of global correlations typical of empirical networks. Here, we propose mitigating this limitation via a network property ideally suited to capturing spreading. This is the network correlation dimension, which characterizes how the number of nodes within range of a source typically scales with distance. Applying the approach to susceptible-infected-recovered processes leads to a spreading model which, for a wide range of networks and epidemic parameters, can provide more accurate predictions of the early stages of a spreading process than important established models of substantially higher complexity. In addition, the proposed model leads to a basic reproduction number that provides information about the final state not available from popular established models.

Link Brain-Wide Projectome to Neuronal Dynamics in the Mouse Brain.

Knowledge about the neuronal dynamics and the projectome are both essential for understanding how the neuronal network functions in concert. However, it remains challenging to obtain the neural activity and the brain-wide projectome for the same neurons, especially for neurons in subcortical brain regions. Here, by combining in vivo microscopy and high-definition fluorescence micro-optical sectioning tomography, we have developed strategies for mapping the brain-wide projectome of functionally relevant neurons in the somatosensory cortex, the dorsal hippocampus, and the substantia nigra pars compacta. More importantly, we also developed a strategy to achieve acquiring the neural dynamic and brain-wide projectome of the molecularly defined neuronal subtype. The strategies developed in this study solved the essential problem of linking brain-wide projectome to neuronal dynamics for neurons in subcortical structures and provided valuable approaches for understanding how the brain is functionally organized via intricate connectivity patterns.

Analysis of Factors Related to the Efficacy of Consciousness-Regaining Therapy for Prolonged Disorder of Consciousness: A Retrospective Cohort Study.

OBJECTIVE: To analyze the factors related to the efficacy of consciousness-regaining therapy (CRT) for prolonged disorder of consciousness. METHODS: A retrospective analysis was conducted on the case data of 114 patients with prolonged disorder of consciousness (pDOC) admitted to the Department of Functional Neurosurgery of Tianjin Huanhu Hospital from January 2019 to January 2022 to explore the relevant factors that affect the efficacy of CRT for pDOC. Next, basic information on the cases, data on pDOC disease assessment, CRT methods, and efficacy evaluation were collected. RESULTS: These 114 patients were grouped, and a comparative analysis was done based on the efficacy at the end of treatment. Of these, 61 cases were allotted to the ineffective group and 53 cases to the effective group. There was a lack of statistical difference (P > 0.05) between the 2 groups based on gender, age, etiology, acute cerebral herniation, emergency craniotomy surgery, emergency decompressive craniectomy, time from onset to start of CRT, and CRT duration (P > 0.05). However, secondary hydrocephalus, CRT methods, JFK Coma Recovery Scale-Revised grading before treatment, and extended Glasgow Outcome Scale score at six months after treatment were found to be statistically different. The results of binary logistic regression analysis showed that the type of therapy (OR = 0.169, 95% CI: 0.057-0.508) affected the efficacy of CRT (P < 0.05). CONCLUSIONS: Personalized awakening therapy using various invasive CRT methods could improve the efficacy of therapy for pDOC compared with noninvasive therapy.

Myosteatosis is associated with coronary artery calcification in patients with type 2 diabetes.

BACKGROUND: Myosteatosis, rather than low muscle mass, is the primary etiologic factor of sarcopenia in patients with type 2 diabetes mellitus (T2DM). Myosteatosis may lead to a series of metabolic dysfunctions, such as insulin resistance, systematic inflammation, and oxidative stress, and all these dysfunctions are closely associated with the acceleration of T2DM and atherosclerosis. AIM: To investigate the association between myosteatosis and coronary artery calcification (CAC) in patients with T2DM. METHODS: Patients with T2DM, who had not experienced major cardiovascular events and had undergone both abdominal and thoracic computed tomography (CT) scans, were included. The mean skeletal muscle attenuation was assessed using abdominal CT images at the L3 level. The CAC score was determined from thoracic CT images using the Agatston scoring method. Myosteatosis was diagnosed according to Martin's criteria. Severe CAC (SCAC) was defined when the CAC score exceeded 300. Logistic regression and decision tree analyses were performed. RESULTS: A total of 652 patients with T2DM were enrolled. Among them, 167 (25.6%) patients had SCAC. Logistic regression analysis demonstrated that myosteatosis, age, duration of diabetes, cigarette smoking, and alcohol consumption were independent risk factors of SCAC. Myosteatosis was significantly associated with an increased risk of SCAC (OR = 2.381, P = 0.003). The association between myosteatosis and SCAC was significant in the younger patients (OR = 2.672, 95%CI: 1.477-4.834, P = 0.002), but not the older patients (OR = 1.456, 95%CI: 0.863-2.455, P = 0.188), and was more prominent in the population with lower risks of atherosclerosis. The decision tree analyses prioritized older age as the primary variable for SCAC. In older patients, cigarette smoking was the main contributing factor for SCAC, while in younger patients, it was myosteatosis. CONCLUSION: Myosteatosis is a novel risk factor for atherosclerosis in patients with T2DM, especially in the population with younger ages and fewer traditional risk factors.

Unified cross-modality integration and analysis of T cell receptors and T cell transcriptomes by low-resource-aware representation learning.

Single-cell RNA sequencing (scRNA-seq) and T cell receptor sequencing (TCR-seq) are pivotal for investigating T cell heterogeneity. Integrating these modalities, which is expected to uncover profound insights in immunology that might otherwise go unnoticed with a single modality, faces computational challenges due to the low-resource characteristics of the multimodal data. Herein, we present UniTCR, a novel low-resource-aware multimodal representation learning framework designed for the unified cross-modality integration, enabling comprehensive T cell analysis. By designing a dual-modality contrastive learning module and a single-modality preservation module to effectively embed each modality into a common latent space, UniTCR demonstrates versatility in connecting TCR sequences with T cell transcriptomes across various tasks, including single-modality analysis, modality gap analysis, epitope-TCR binding prediction, and TCR profile cross-modality generation, in a low-resource-aware way. Extensive evaluations conducted on multiple scRNA-seq/TCR-seq paired datasets showed the superior performance of UniTCR, exhibiting the ability of exploring the complexity of immune system.

Chemical constituents from stipes of Lentinus edodes and their protective effects against Aß25-35-induced N9 microglia cells injury.

Nine undescribed compounds, along with eight known compounds, were isolated from the stipes of Lentinus edodes. Their structures were established by extensive spectroscopic and circular dichroism analyses. The protective effects against Aß25-35-induced N9 microglia cells injury of these compounds were tested by MTT method, and the levels of apoptosis and ROS were detected by flow cytometry. In addition, the binding sites and interactions of compound with amyloid precursor protein were revealed using molecular docking simulations. These findings further establish the structural diversity and bioactivity of stipes of L. edodes, and provide an experimental basis for targeting Alzheimer's disease as a potential strategy.

Five new eremophilane-type sesquiterpenes from the fresh roots of Rehmannia glutinosa.

Five undescribed eremophilane-type sesquiterpenes, remophilanetriols E-I (1-5), along with seven known compounds (6-12) were isolated from the fresh roots of Rehmannia glutinosa. Their structures were characterized by extensive spectroscopic data analysis and their absolute configurations were determined by comparing their calculated electronic circular dichroism (ECD) spectra and experimental ECD spectra. The anti-pulmonary fibrosis activities of all compounds were evaluated in vitro by MTT methods, and compounds 2, 8, 10, and 12 exhibited excellent anti-pulmonary fibrosis activities. In addition, compound 2 can reduce the levels of ROS and apoptosis in TGF-ß1-induced BEAS-2B cells.

Glycosides constituents from Codonopsis pilosula.

A new glycoside (1) along with six known analogues (1-7) were isolated from Codonopsis pilosula collected at Shanxi in China. The structure of 1 was established based on comprehensive spectroscopic data and literature comparison. The anti-inflammatory effects of isolated compounds were further investigated in LPS-induced RAW264.7 macrophage.

Multi-omics analysis provides new insights into the changes of important nutrients and fructose metabolism in loquat bud sport mutant.

Bud sport is a common and stable somatic variation in perennial fruit trees, and often leads to significant modification of fruit traits and affects the breeding value. To investigate the impact of bud sport on the main metabolites in the fruit of white-fleshed loquat, we conducted a multi-omics analysis of loquat fruits at different developmental stages of a white-fleshed bud sport mutant of Dongting loquat (TBW) and its wild type (TBY). The findings from the detection of main fruit quality indices and metabolites suggested that bud sport resulted in a reduction in the accumulation of carotenoids, fructose, titratable acid and terpenoids at the mature stage of TBW, while leading to the accumulation of flavonoids, phenolic acids, amino acids and lipids. The comparably low content of titratable acid further enhances the balanced and pleasent taste profile of TBW. Expression patterns of differentially expressed genes involved in fructose metabolism exhibited a significant increase in the expression level of S6PDH (EVM0006243, EVM0044405) prior to fruit maturation. The comparison of protein sequences and promoter region of S6PDH between TBY and TBW revealed no structural variations that would impact gene function or expression, indicating that transcription factors may be responsible for the rapid up-regulation of S6PDH before maturation. Furthermore, correlation analysis helped to construct a comprehensive regulatory network of fructose metabolism in loquat, including 23 transcription factors, six structural genes, and nine saccharides. Based on the regulatory network and existing studies, it could be inferred that transcription factors such as ERF, NAC, MYB, GRAS, and bZIP may promote fructose accumulation in loquat flesh by positively regulating S6PDH. These findings improve our understanding of the nutritional value and breeding potential of white-fleshed loquat bud sport mutant, as well as serve as a foundation for exploring the genes and transcription factors that regulate fructose metabolism in loquat.

Parental Autonomy Granting, Peer Attachment and Problematic Internet Use Among Chinese Adolescents: The Moderating Effect of School Climate.

While the correlation between parental autonomy granting and adolescents' problematic Internet use (PIU) has been confirmed, the processes underlying this connection have not been thoroughly investigated. Drawing on the ecological systems theory, this study sought to investigate the mediating mechanism of peer attachment and the moderating mechanism of school climate that link parental autonomy granting to PIU. A two-wave longitudinal design was employed with a time interval of six months. The participants were 852 adolescents who attended three middle schools located in Guangdong Province, China. Self-report questionnaires were used to obtain data on demographics, parental autonomy granting, peer attachment, school climate, and PIU. The findings indicated that peer attachment significantly mediated the link between parental autonomy granting and adolescent PIU. A positive school climate significantly moderated the influence of parental autonomy granting on peer attachment and the influence of peer attachment on PIU. Specifically, the association between parental autonomy granting and peer attachment and the association between peer attachment and PIU were more pronounced when the school climate was perceived to be positive. This research underscores the possible significance of peer attachment in the association between parental autonomy granting and PIU and offers valuable insights for mitigating the negative outcomes of PIU.

Whole-brain spatial organization of hippocampal single-neuron projectomes.

Mapping single-neuron projections is essential for understanding brain-wide connectivity and diverse functions of the hippocampus (HIP). Here, we reconstructed 10,100 single-neuron projectomes of mouse HIP and classified 43 projectome subtypes with distinct projection patterns. The number of projection targets and axon-tip distribution depended on the soma location along HIP longitudinal and transverse axes. Many projectome subtypes were enriched in specific HIP subdomains defined by spatial transcriptomic profiles. Furthermore, we delineated comprehensive wiring diagrams for HIP neurons projecting exclusively within the HIP formation (HPF) and for those projecting to both intra- and extra-HPF targets. Bihemispheric projecting neurons generally projected to one pair of homologous targets with ipsilateral preference. These organization principles of single-neuron projectomes provide a structural basis for understanding the function of HIP neurons.

Brain development in newborns and infants after ECMO.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) not only significantly improves survival rates in severely ill neonates but also is associated with long-term neurodevelopmental issues. To systematically review the available literature on the neurodevelopmental outcomes of neonates and infants who have undergone ECMO treatment, with a focus on motor deficits, cognitive impairments, sensory impairments, and developmental delays. This review aims to understand the incidence, prevalence, and risk factors for these problems and to explore current nursing care and management strategies. DATA SOURCES: A comprehensive literature search was performed across PubMed, EMBASE, and Web of Science using a wide array of keywords and phrases pertaining to ECMO, neonates, infants, and various facets of neurodevelopment. The initial screening involved reviewing titles and abstracts to exclude irrelevant articles, followed by a full-text assessment of potentially relevant literature. The quality of each study was evaluated based on its research methodology and statistical analysis. Moreover, citation searches were conducted to identify potentially overlooked studies. Although the focus was primarily on neonatal ECMO, studies involving children and adults were also included due to the limited availability of neonate-specific literature. RESULTS: About 50% of neonates post-ECMO treatment exhibit varying degrees of brain injury, particularly in the frontal and temporoparietal white matter regions, often accompanied by neurological complications. Seizures occur in 18%-23% of neonates within the first 24 hours, and bleeding events occur in 27%-60% of ECMO procedures, with up to 33% potentially experiencing ischemic strokes. Although some studies suggest that ECMO may negatively impact hearing and visual development, other studies have found no significant differences; hence, the influence of ECMO remains unclear. In terms of cognitive, language, and intellectual development, ECMO treatment may be associated with potential developmental delays, including lower composite scores in cognitive and motor functions, as well as potential language and learning difficulties. These studies emphasize the importance of early detection and intervention of potential developmental issues in ECMO survivors, possibly necessitating the implementation of a multidisciplinary follow-up plan that includes regular neuromotor and psychological evaluations. Overall, further multicenter, large-sample, long-term follow-up studies are needed to determine the impact of ECMO on these developmental aspects. CONCLUSIONS: The impact of ECMO on an infant's nervous system still requires further investigation with larger sample sizes for validation. Fine-tuned management, comprehensive nursing care, appropriate patient selection, proactive monitoring, nutritional support, and early rehabilitation may potentially contribute to improving the long-term outcomes for these infants.

Macroscale preparation of CoS2 nanoparticles for ultra-high fast-charging performance in sodium-ion batteries.

Improving the fast-charging capabilities and energy storage capacity of electric vehicles presents a feasible strategy for mitigating the prevalent concern of range anxiety in the market. Nanostructure electrode materials play a crucial role in this process. However, the current method of preparation is arduous and yields restricted quantities. In view of this, we have devised an innovative approach that provides convenience and efficacy, facilitating the large-scale synthesis of CoS2 nanoparticles, which exhibited exceptional performance. When the current density was 1000 mA g-1, the discharging capacity reached 760 mAh g-1 after 400 cycles. Remarkably, even at an increased current density of 5000 mA g-1, the discharging capacity of CoS2 remained at 685.5 mAh g-1. The ultra-high performance could be attributed to the specific surface area, which minimized the diffusion distance of sodium-ions during the charging and discharging processes and mitigated the extent of structural damage. Our straightforward preparation techniques facilitate the mass production and present a novel approach for the development of cost-effective and high-performing anode materials for sodium-ion batteries.

Five new secondary metabolites from Aster tataricus.

Aster tataricus L.f. is highly valued for its rich reserves of bioactive compounds. Our research focused on the identification of previously unreported compounds found within the ethanol extract of A. tataricus. Through meticulous spectroscopic analyses and computational methods like NMR calculations and ECD, we successfully elucidated the structures of five novel compounds termed tatarisides A-E (1-5), alongside two known compounds (6, 7). The anti-inflammatory assays conducted yielded noteworthy results, particularly in relation to compounds 1 and 5. These compounds exhibited significant potential in inhibiting the release of NO in LPS-induced RAW 264.7 cells, as evidenced by their respective IC50 values of 17.81 ± 1.25 µM and 13.32 ± 0.84 µM. The discovery of these new compounds adds to the existing knowledge of A. tataricus's chemical composition and potential applications.

Synchronous Double Primary Malignant Tumors and their Possible Shared Genes: A Rare Clinical Entity.

Objective: This study sought to analyze the 18F-FDG PET/CT and contrast-enhanced computed tomography (CT) images of synchronous colorectal cancer (CRC) and renal clear cell carcinoma (ccRCC) and identify the shared genes between these two types of cancer through bioinformatic analysis. Methods: A retrospective analysis was conducted on a patient with synchronous CRC and ccRCC who underwent 18F-FDG PET/CT and contrast-enhanced CT before treatment. Databases were analyzed to identify differentially expressed genes between CRC and ccRCC, and co-expression genes were extracted for RCC and CRC. Results: 18F-FDG PET/CT revealed intense metabolic activity in the primary colorectal lesion (SUVmax 13.2), while a left renal mass (diameter = 35 mm) was observed with no significant uptake. Contrast-enhanced CT during the arterial phase showed heterogeneous intense enhancement of the renal lesion, and the lesion washed out earlier than in the renal cortex in the nephrographic and excretory phases, indicating ccRCC. The histopathological results confirmed synchronous double primary malignant tumors. Our bioinformatic analysis results showed that synchronous occurrence of CRC and ccRCC may correlate with simultaneous expression of Carbonic Anhydrase 9 (CA9), integrin-binding sialoprotein (IBSP), and Fibrinogen γ chain (FGG). Conclusion: 18F-FDG PET/CT combined with contrast-enhanced CT is an effective diagnostic tool in evaluating synchronous CRC and RCC. By analyzing this clinical case and conducting bioinformatic analysis, we improved our current understanding of the mechanisms underlying synchronous tumors.

Co-drivers of Air Pollutant and CO2 Emissions from On-Road Transportation in China 2010-2020.

Co-controlling the emissions of air pollutants and CO2 from automobiles is crucial for addressing the intertwined challenges of air pollution and climate change in China. Here, we analyze the synergetic characteristics of air pollutant and CO2 emissions from China's on-road transportation and identify the co-drivers influencing these trends. Using detailed emission inventories and employing index decomposition analysis, we found that despite notable progress in pollution control, minimizing on-road CO2 emissions remains a formidable task. Over 2010-2020, the estimated sectoral emissions of VOCs, NOx, PM2.5, and CO declined by 49.9%, 25.9%, 75.2%, and 63.5%, respectively, while CO2 emissions increased by 46.1%. Light-duty passenger vehicles and heavy-duty trucks have been identified as the primary contributors to carbon-pollution co-emissions, highlighting the need for tailored policies. The driver analysis indicates that socioeconomic changes are primary drivers of emission growth, while policy controls, particularly advances in emission efficiency, can facilitate co-reductions. Regional disparities emphasize the need for policy refinement, including reducing dependency on fuel vehicles in the passenger subsector and prioritizing co-reduction strategies in high-emission provinces in the freight subsector. Overall, our study confirms the effectiveness of China's on-road control policies and provides valuable insights for future policy makers in China and other similarly positioned developing countries.

A segmentation model to detect cevical lesions based on machine learning of colposcopic images.

Background: Semantic segmentation is crucial in medical image diagnosis. Traditional deep convolutional neural networks excel in image classification and object detection but fall short in segmentation tasks. Enhancing the accuracy and efficiency of detecting high-level cervical lesions and invasive cancer poses a primary challenge in segmentation model development. Methods: Between 2018 and 2022, we retrospectively studied a total of 777 patients, comprising 339 patients with high-level cervical lesions and 313 patients with microinvasive or invasive cervical cancer. Overall, 1554 colposcopic images were put into the DeepLabv3+ model for learning. Accuracy, Precision, Specificity, and mIoU were employed to evaluate the performance of the model in the prediction of cervical high-level lesions and cancer. Results: Experiments showed that our segmentation model had better diagnosis efficiency than colposcopic experts and other artificial intelligence models, and reached Accuracy of 93.29 %, Precision of 87.2 %, Specificity of 90.1 %, and mIoU of 80.27 %, respectively. Conclution: The DeepLabv3+ model had good performance in the segmentation of cervical lesions in colposcopic post-acetic-acid images and can better assist colposcopists in improving the diagnosis.

Combined in vitro/in vivo genome-wide CRISPR screens in triple negative breast cancer identify cancer stemness regulators in paclitaxel resistance.

Triple negative breast cancer (TNBC) is defined as lacking the expressions of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). TNBC patients exhibit relatively poor clinical outcomes due to lack of molecular markers for targeted therapies. As such chemotherapy often remains the only systemic treatment option for these patients. While chemotherapy can initially help shrink TNBC tumor size, patients eventually develop resistance to drug, leading to tumor recurrence. We report a combined in vitro/in vivo genome-wide CRISPR synthetic lethality screening approach in a relevant TNBC cell line model to identify several targets responsible for the chemotherapy drug, paclitaxel resistance. Computational analysis integrating in vitro and in vivo data identified a set of genes, for which specific loss-of-function deletion enhanced paclitaxel resistance in TNBC. We found that several of these genes (ATP8B3, FOXR2, FRG2, HIST1H4A) act as cancer stemness negative regulators. Finally, using in vivo orthotopic transplantation TNBC models we showed that FRG2 gene deletion reduced paclitaxel efficacy and promoted tumor metastasis, while increasing FRG2 expression by means of CRISPR activation efficiently sensitized TNBC tumors to paclitaxel treatment and inhibited their metastatic abilities. In summary, the combined in vitro/in vivo genome-wide CRISPR screening approach proved effective as a tool to identify novel regulators of paclitaxel resistance/sensitivity and highlight the FRG2 gene as a potential therapeutical target overcoming paclitaxel resistance in TNBC.