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Abstract This study profiled global single cell-spatial-bulk transcriptome landscapes of hepatocellular carcinoma (HCC) ecosystem from six HCC cases and a non-carcinoma liver control donor. We discovered that intratumoral heterogeneity mainly derived from HCC cells diversity and pervaded the genome-transcriptome-proteome-metabolome network. HCC cells are the core driving force of taming tumor-associated macrophages (TAMs) with pro-tumorigenic phenotypes for favor its dominant growth. Remarkably, M1-types TAMs had been characterized by disturbance of metabolism, poor antigen-presentation and immune-killing abilities. Besides, we found simultaneous cirrhotic and HCC lesions in an individual patient shared common origin and displayed parallel clone evolution via driving disparate immune reprograms for better environmental adaptation. Moreover, endothelial cells exhibited phenotypically conserved but executed differential functions in a space-dependent manner. Further, the spatiotemporal traits of rapid recurrence niche genes were identified and validated by immunohistochemistry. Our data unravels the great significance of HCC cells in shaping vibrant tumor ecosystems corresponding to clinical scenarios.

Abstract Previous studies have reported that a potential association between exposure to outdoor light at night (LAN) and diseases. However, there is no evidence regarding the impacts of outdoor LAN exposure on lipid metabolism in humans. This study aims to evaluate the associations between outdoor LAN exposure and the prevalence of dyslipidemia, using a nationwide sample of 10,894 adults aged ≥ 45 years from 150 investigated sites across China in 2011–2012. Outdoor LAN exposure was assessed by using satellite imaging data. The prevalence ratio (PR) was calculated. The present study found that a per-quintile LAN exposure was positively associated with the prevalence of high LDL-cholesterol (PR = 1.10, 95% CI = 1.04–1.16), high triglyceride (PR = 1.07, 95% CI = 1.03–1.12), low HDL-cholesterol (PR = 1.11, 95% CI = 1.08–1.16), and dyslipidemia (PR = 1.06, 95% CI = 1.03–1.09). The fifth quintile of LAN exposure was associated with a significantly increased prevalence of dyslipidemia (PR = 1.20, 95% CI = 1.07–1.35) compared with the first quintile of exposure. Long-term exposure to outdoor LAN was positively associated with dyslipidemia prevalence. Public policies aimed at reducing light pollution at night, guided by the spatial distribution patterns, could lessen the adverse effects.

Abstract Low-grade heat is abundant and ubiquitous, but it is generally discarded due to the lack of cost-effective recovery technologies. Ion thermoelectric cells are an affordable and straightforward approach of converting low-grade heat into usable electricity for sustainable power. Despite their potential, ion thermoelectric cells face challenges such as limited Seebeck coefficient and required series integration. Here, we demonstrate that the N-type and P-type conversion of ion thermoelectric cells can be achieved through the phase transition of temperature-sensitive hydrogel containing the triiodide/iodide redox couple. Through the strong interaction between the hydrophobic region of the hydrogel and triiodide, the hydrophobic side selectively captures triiodide and the hydrophilic side repels triiodide, raising the concentration difference of triiodide and thereby increasing the Seebeck coefficient. Specifically, the Seebeck coefficient of the N-type ion thermoelectric cells is 7.7 mV K−1, and the Seebeck coefficient of P-type ion thermoelectric cells is −6.3 mV K−1 (ΔT = 15 K). By connecting 10 pairs of the N-type and P-type ion thermoelectric cells, we achieve a voltage of 1.8 V and an output power of 85 μW, surpassing the reported triiodide/iodide-based ion thermoelectric cells. Our work proposes a phase transition strategy for the N-P conversion of ion thermoelectric cells, and highlights the prospect of series integrated hydrogel ion thermoelectric cells for low-grade heat harvesting.

The space nuclear reactor cooled by heat pipes has become the preferred choice for future space missions and deep space exploration missions. The use of low-enriched uranium (LEU) is promoted to achieve the goal of nuclear non-proliferation worldwide. In this study, a lithium heat pipe cooled space reactor with LEU (HP-LEU) was proposed based on Heat Pipes-Segmented Thermoelectric Module Converters (HP-STMCs), with the addition of moderators. The HP-LEU employs yttrium hydride (YH2) as the moderator and 19.9 % enriched uranium nitride (UN) as the fuel. The neutronics analysis has been performed on the HP-LEU reactor and the results have showed that the HP-LEU has a lifetime of more than 12 years. Two control systems have been applied in the reactor and have demonstrated the capacity to independently regulate and shut down the reactor. The total temperature reactivity coefficients are consistently negative, indicating that the HP-LEU reactor is inherently safe during operation. During normal operation, the temperatures of the materials are all acceptable. This study can serve as a reference for lithium heat pipe cooled space reactors with LEU.

Abstract Increased fatty acid synthesis benefits glioblastoma malignancy. However, the coordinated regulation of cytosolic acetyl-CoA production, the exclusive substrate for fatty acid synthesis, remains unclear. Here, we show that proto-oncogene tyrosine kinase c-SRC is activated in glioblastoma and remodels cytosolic acetyl-CoA production for fatty acid synthesis. Firstly, acetate is an important substrate for fatty acid synthesis in glioblastoma. c-SRC phosphorylates acetyl-CoA synthetase ACSS2 at Tyr530 and Tyr562 to stimulate the conversion of acetate to acetyl-CoA in cytosol. Secondly, c-SRC inhibits citrate-derived acetyl-CoA synthesis by phosphorylating ATP-citrate lyase ACLY at Tyr682. ACLY phosphorylation shunts citrate to IDH1-catalyzed NADPH production to provide reducing equivalent for fatty acid synthesis. The c-SRC-unresponsive double-mutation of ACSS2 and ACLY significantly reduces fatty acid synthesis and hampers glioblastoma progression. In conclusion, this remodeling fulfills the dual needs of glioblastoma cells for both acetyl-CoA and NADPH in fatty acid synthesis and provides evidence for glioma treatment by c-SRC inhibition.

Abstract Meningitis induced by Pasteurella multocida has been substantially described in clinical practice in both human and veterinary medicine, but the underlying mechanisms have not been previously reported. In this study, we investigated the influence of P. multocida infection on the permeability of the blood–brain barrier (BBB) using different models. Our in vivo tests in a mouse model and in vitro tests using human brain microvascular endothelial cell (hBMEC) model showed that P. multocida infection increased murine BBB permeability in mice and hBMEC monolayer permeability. Furthermore, we observed that P. multocida infection resulted in decreased expression of tight junctions (ZO1, claudin-5, occludin) and adherens junctions (E-cadherin) between neighboring hBMECs. Subsequent experiments revealed that P. multocida infection promoted the activation of hypoxia inducible factor-1α (HIF-1α)/vascular endothelial growth factor A (VEGFA) signaling and NF-κB signaling, and suppressed the HIF-1α/VEGFA significantly remitted the decrease in ZO1/E-cadherin induced by P. multocida infection (P

Abstract Background High infiltration of tumor-associated macrophages (TAMs) is associated with tumor promotion and immunosuppression. The triggering receptor expressed on myeloid cells 2 (TREM2) is emerged as a key immunosuppressive regulator for TAMs, however, how TREM2-expressing TAMs are recruited and what ligands TREM2 interacts with to mediate immunosuppression is unknown. Methods Flow cytometry and single-cell RNA sequencing were used to analyze TREM2 expression. Mechanistically, mass spectrometry and immunoprecipitation were employed to identify proteins binding to TREM2. Phagocytosis and co-culture experiments were used to explore the in vitro functions of galectin3-TREM2 pair. Establishment of TREM2 f/f-Lyz2-cre mice to validate the role of TREM2 signaling pathway in lung carcinogenesis. GB1107 were further supplemented to validate the therapeutic effect of Galectin3 based on TREM2 signaling regulation. Results This study identified that abundant TREM2+ macrophages were recruited at the intra-tumor site through the CCL2-CCR2 chemotactic axis. Galectin-3 impaired TREM2-mediated phagocytosis and promoted the conversion of TREM2+ macrophages to immunosuppressive TAMs with attenuated antigen presentation and co-stimulatory functions both in vitro both in vivo, and galectin-3 is a potential ligand for TREM2. Genetic and pharmacological blockade of TREM2 and galectin-3 significantly inhibited lung cancer progression in subcutaneous and orthotopic cancer models by remodeling the tumor immune microenvironment. Conclusion Our findings revealed a previously unknown association between galectin-3 and TREM2 in TAMs of lung cancer, and suggested simultaneous inhibition of galectin3 and TREM2 as potent therapeutic approach for lung cancer therapy. Graphical Abstract

Abstract In plants, the conserved plant-specific photoreceptor UV RESISTANCE LOCUS 8 (UVR8) perceives ultraviolet-B (UV-B) light and mediates UV-B-induced photomorphogenesis and stress acclimation. In this study, we reveal that UV-B light treatment shortens seedlings, increases stem thickness, and enhances UV-B stress tolerance in rice (Oryza sativa) via its two UV-B photoreceptors OsUVR8a and OsUVR8b. Although the rice and Arabidopsis (Arabidopsis thaliana) UVR8 (AtUVR8) photoreceptors all form monomers in response to UV-B light, OsUVR8a, and OsUVR8b function is only partially conserved with respect to AtUVR8 in UV-B-induced photomorphogenesis and stress acclimation. UV-B light and CONSTITUTIVELY PHOTOMORPHOGENIC 1 (COP1) promote the nuclear accumulation of AtUVR8; by contrast, OsUVR8a and OsUVR8b constitutively localize to the nucleus via their own nuclear localization signals, independently of UV-B light and the RING-finger mutation of OsCOP1. We show that OsCOP1 negatively regulates UV-B responses, and shows weak interaction with OsUVR8s, which is ascribed to the N terminus of OsCOP1, which is conserved in several monocots. Furthermore, transcriptome analysis demonstrates that UV-B-responsive gene expression differs globally between Arabidopsis and rice, illuminating the evolutionary divergence of UV-B light signaling pathways between monocot and dicot plants.

The trans-medium water entry process of vehicles is often accompanied by multiphase flow, cavitation, phase change, and turbulence instability, which not only heighten the complexity of the flow field, but also render the forces highly unsteady and nonlinear. A numerical model for the water entry process of vehicles was developed. The volume of fluid(VOF) model was employed to capture the gas-liquid interface, and the Schnerr-Sauer model was utilized to describe the cavitation that occurred during the trans-medium process. The simulation of the water entry process of the trans-medium vehicle under different ventilation flows and deflection angles of the cavitator was carried out to investigate the flow field and cavity evolution laws during the trans-medium process. In addition, the fluid dynamics characteristics, as well as the kinematic characteristics of the vehicle during trans-medium process were analyzed. The simulation results show that the vehicle will present two different attitude change modes with the change of the ventilation flow during the water entry process: the increasing angular velocity leveling mode and the periodical pitching-type leveling mode. The water entry leveling process of the vehicle in different modes will show different motion characteristics. Moreover, an increase in the deflection angle of the cavitator and a decrease in the ventilation flow can improve the attitude change rate of the vehicle during the trans-medium water entry process.

In order to study the underwater trajectory and related dynamics characteristics of trans-medium vehicles, a trans-medium vehicle was used as the research object. The dynamics equations were established based on the momentum theorem and the moment of momentum theorem, and the dynamics characteristics of the trans-medium vehicle at different velocities and cavitator’s angles were analyzed. The results show that increasing the initial velocity will slightly reduce the horizontal navigation distance and navigation depth of the vehicle, and the velocity will decrease faster; increasing the cavitator’s angle will also lead to a slight decrease in the horizontal navigation distance and navigation depth of the vehicle. Reducing the initial angle has a significant impact on the horizontal navigation distance of the vehicle and the angle at the end of the calculation, but it almost does not affect the acceleration and force characteristics.

The water exit process of vehicles is very complicated, accompanied by multiphase flow, cavitation, phase transition, and turbulence instability, and the applied force is highly unsteady and nonlinear. At present, studies on the water exit problem of the vehicle with cavitation focus on the vertical or oblique water exit, emphasizing the trajectory and attitude of the vehicle. There are few studies on the water exit process of the supercavitating vehicle. In this paper, based on STAR-CCM+ software, overlapping grid technology was used for meshing, and the volume of fluid(VOF) model was used to capture the gas-liquid interface. The Schnerr-Sauer model described the cavitation process around the vehicle, and a numerical calculation model of the water exit process of the vehicle was established. The water exit process of the vehicle under different sailing conditions(initial velocity, initial water depth, and ventilation) was simulated and calculated, and the flow field and cavity evolution laws under different conditions were obtained. The hydrodynamic and kinematic characteristics of the supercavitating vehicle were analyzed. The simulation results show that the underwater motion of the vehicle with different initial velocities presents two different modes. Under different water depths, the initial cavity number is different. Cavity around the vehicle is more likely to rupture in deeper waters. The cavity morphology can be improved effectively by increasing the ventilation.

ObjectiveChina’s abrupt exit from the zero-COVID policy in late 2022 led to a rapid surge in infections, overwhelming healthcare systems and exposing healthcare providers to intensified psychological pressures. This sudden shift exacerbated pandemic-related psychological issues, including fear, health anxiety, and emotional processing difficulties. This study aimed to unravel the relationships among pandemic fear, cyberchondria, and alexithymia following China’s exit from the zero-COVID policy.MethodsA multi-center cross-sectional survey was conducted among 4088 nurses from 43 public hospitals in China. The web-based survey comprised the Fear of COVID-19 Scale, Cyberchondria Severity Scale, and Toronto Alexithymia Scale. Network analysis was employed to explore the interconnections and identify central components within these psychological and behavioral constructs.ResultsThe analysis revealed a dense network with predominantly positive connections. Specific aspects of cyberchondria and pandemic fear exhibited the highest strength centrality, indicating their critical influence. The externally oriented thinking dimension of alexithymia emerged as a crucial bridge node, linking pandemic fear and cyberchondria. The network structure demonstrated consistency across diverse educational backgrounds and career stages.ConclusionThese findings highlight the need for targeted interventions focusing on key network components, particularly externally oriented thinking, to disrupt the detrimental cycle of pandemic fear and cyberchondria. Healthcare organizations should promote balanced objective fact-focused and problem-solving approaches while also fostering skills in emotional awareness and expression, thereby mitigating the risk of maladaptive pandemic fear responses and dysfunctional online health information-seeking behaviors.

ObjectiveThe study aimed to understand the current situation of hospital nurses’ patient safety competence, identify potential categories, and analyze the distribution characteristics of demographic variables in each subgroup.MethodsA total of 1,996 nursing staff were selected to be included in this research using a convenience sampling method. A questionnaire survey was conducted using the Chinese version of the Patient Safety Ability Scale, and three dimensions of the Patient Safety Ability Rating Scale were used as explicit variables for potential profile analysis. The influencing factors of different potential profiles of nurses’ patient safety ability were analyzed using logistic regression analysis.ResultsThe safety ability of the 1,996 nurses could be categorized into three potential groups as follows: “ability risk group” (14.3%), “medium ability group” (32.9%), and “ability advantage group” (52.7%), with monthly income, participation in department training, self-learning, and love of nursing as the influencing factors.ConclusionThe overall patient safety ability of nurses is at an upper-middle level. The classification of nurses can be predicted by factors, such as monthly income, participation in department training, self-directed learning, and love of nursing. Nursing managers can formulate targeted interventions according to the influencing factors of potential profiles to improve nurses’ patient safety ability.

Background: Barium, as a heavy divalent alkaline earth metal, can be found in various products such as rodenticides, insecticides, depilatories, and fireworks. Barium can be highly toxic upon both acute and chronic exposure. The toxicity of barium compounds is dependent on their solubility. Both suicidal and accidental exposures to soluble barium can cause toxicity. Case summary: We report a case characterized by two different wide QRS complex tachycardia in a patient with acute barium poisoning, one due to barium-induced ventricular tachycardia (VT) under hypokalemia and, subsequently, sino-ventricular conduction with intraventricular conduction delay due to hyperkalemia after aggressive potassium supplementation. The latter may be misdiagnosed as VT for the history of acute barium poisoning and the absence of peaked T wave in hyperkalemia. Of note, another hemodynamically unstable VT and profound hypokalemia occurred during the potassium-lowering therapy, which, in addition to barium poisoning, may also be due to the iatrogenic hypokalemia. We also observed the prominent T-U waves at serum potassium of 4.6 mM 12 hours after admission, which may indicate that barium had not been completely cleared from the plasma at that moment. There are some parallels to the Andersen-Tawil syndrome with prominent T-U waves and risk of ventricular tachycardias. To our knowledge, this is the first case report of conversion from hypokalemia to hyperkalemia, and in a short moment, from hyperkalemia to hypokalemia, in acute barium poisoning. Conclusion: In addition to profound hypokalemia secondary to acute barium poisoning, hyperkalemia may also occur after aggressive potassium supplementation. A more careful rather than too aggressive potassium supplementation may be suitable in these cases of hypokalemia due to an intracellular shift of potassium. And a iatrogenic hypokalemia risk in the treatment of rebound hyperkalemia in barium poisoning must be considered.

Abstract Background Omega-3 polyunsaturated fatty acids (omega-3 PUFAs) exhibit potential as therapeutics for a variety of diseases. This observational and Mendelian randomization (MR) study aims to explore the relationship between omega-3 PUFAs and osteoarthritis (OA). Methods Excluding individuals under 20 years old and those with missing data on relevant variables in the National Health and Nutrition Examination Survey (NHANES) spanning from 2003 to 2016, a total of 22 834 participants were included in this cross-sectional study. Weighted multivariable-adjusted logistic regression was used to estimate the association between omega-3 PUFAs and OA in adults. Moreover, restricted cubic splines were utilized to examine the dose-response relationship between omega-3 PUFAs and OA. To further investigate the potential causal relationship between omega-3 PUFAs and OA risk, a two-sample MR study was conducted. Furthermore, the robustness of the findings was assessed using various methods. Results Omega-3 PUFAs intake were inversely associated with OA in adults aged 40 ∼ 59 after multivariable adjustment $$[\text{OR} (95\% \text{CI): }0.85 (0.73, 0.98), P = 0.027]$$ , with a nonlinear relationship observed between omega-3 PUFAs intake and OA $$\left(P \text{ for non-linearity}\text{ = 0.034}\right)$$ . The IVW results showed there was no evidence to suggest a causal relationship between omega-3 PUFAs and OA risk $$\text{[OR} (95\% \text{CI): }0.967 (0.863, 1.084), P = 0.568]$$ . Conclusions Omega-3 PUFAs were inversely associated with OA in adults aged 40 ∼ 59. However, MR studies did not confirm a causal relationship between the two.

Abstract Background Premature infants commonly encounter difficulties with oral feeding, a complication that extends hospital stays, affects infants’ quality of life, and imposes substantial burdens on families and society. Enhancing preterm infants’ oral feeding skills and facilitating their transition from parenteral or nasal feeding to full oral feeding pose challenges for neonatal intensive care unit (NICU) healthcare professionals. Research indicates that oral motor interventions (OMIs) can enhance preterm infants’ oral feeding capabilities and expedite the transition from feeding initiation to full oral feeding. Nonetheless, the most suitable timing for commencing these interventions remains uncertain. Methods This is a single-blind, randomized controlled trial. Preterm with a gestational age between 29+0 to 34+6 weeks will be eligible for the study. These infants will be randomized and allocated to one of two groups, both of which will receive the OMIs. The intervention commences once the infant begins milk intake during the early OMIs. Additionally, in the late OMIs group, the intervention will initiate 48 h after discontinuing nasal continuous positive airway pressure. Discussion OMIs encompass non-nutritive sucking and artificial oral stimulation techniques. These techniques target the lips, jaw, muscles, or tongue of premature infants, aiming to facilitate the shift from tube feeding to oral feeding. The primary objective is to determine the ideal intervention timing that fosters the development of oral feeding skills and ensures a seamless transition from parenteral or nasal feeding to full oral feeding among preterm infants. Furthermore, this study might yield insights into the long-term effects of OMIs on the growth and neurodevelopmental outcomes of preterm infants. Such insights could bear substantial significance for the quality of survival among preterm infants and the societal burden imposed by preterm birth. Trial registration chictr.org.cn ChiCTR2300076721. Registered on October 17, 2023.

The primary pharmacological components of Desmodium styracifolium (Osbeck.) Merr. are flavonoids, which have a broad range of pharmacological effects and are important in many applications. However, there have been few reports on the molecular mechanisms underlying flavonoid biosynthesis in the pharmacodynamic constituents of D. styracifolium. Flavonoid biosynthesis in D. styracifolium pharmacodynamic constituents has, however, been rarely studied. In this study, we investigated how salt stress, 6-BA (6-Benzylaminopurine) treatment, and PEG 6000-simulated drought stress affect flavonoid accumulation in D. styracifolium leaves. We integrated metabolomics and transcriptomic analysis to map the secondary metabolism regulatory network of D. styracifolium and identify key transcription factors involved in flavonoid biosynthesis. We then constructed overexpression vectors for the transcription factors and used them to transiently infiltrate Nicotiana benthamiana for functional validation. This experiment confirmed that the transcription factor DsMYB60 promotes the production of total flavonoids in Nicotiana tabacum L. leaves. This study lays the foundation for studying flavonoid biosynthesis in D. styracifolium at the molecular level. Furthermore, this study contributes novel insights into the molecular mechanisms involved in the biosynthesis of active ingredients in medicinal plants.

Accurate and non-destructive estimation of leaf chlorophyll content (LCC) is crucial for optimizing cotton production. This study enhances the SCOPE model by integrating unmanned aerial vehicle (UAV)-derived multispectral data with leaf area index (LAI) from LiDAR data, significantly improving precision of LCC estimation, particularly during crucial growth stages of cotton. We construct and analyze three cost functions: COST1, which relies solely on spectral data; COST2, which incorporates direct LAI inputs; and COST3, which adjusts for LAI measurement uncertainties by combining spectral term with an error term representing the squared relative error between measured and model-estimated LAI. Our findings indicate that while COST1 establishes a baseline, COST2 and COST3 provide more accurate LCC estimations. COST3, validated against theoretical data, field-measured cotton datasets, and an additional maize dataset, proves most robust, maintaining consistent accuracy across all growth stages especially when considering input data uncertainties. This highlights the importance of integrating appropriate forms of LAI in cost functions to refine LCC estimation. Future research should focus on improving data acquisition quality and developing more advanced cost functions to advance LCC estimation further.

The frequent occurrence of urban floods (UFs) poses significant threats to citizens’ lives and the national economy. Utilizing machine learning to assess urban flood susceptibility (UFS) provides valuable decision support for UF management. However, the precision of current studies is usually influenced by the variability of temporal factors like extreme rainfall, which limits the accurate identification of urban flood-susceptible regions (UFSRs). To address this issue, we present a novel approach that leverages the spatiotemporal distribution and characteristics of UFS to accurately identify UFSRs. In our case study of the Greater Bay Area (GBA) in China, we employed the Random Forest to assess the spatiotemporal distribution of UFS. We then used the Savitzky-Golay filter to correct UFS data based on the UFS time series from 2011 to 2020. The Theil-Sen median slope, Mann-Kendall test, and Hurst analysis were used to explore the spatiotemporal patterns of UFS. Shapley additive explanation was applied to quantify the contribution of selected variables. Our findings include: (1) UFS in the GBA demonstrates a rising trend, with high susceptibility areas increasing from 6.3 % in 2011 to 7.4 % in 2020; (2) UFSRs, covering approximately 11 % of the GBA, are primarily concentrated in the cities located around the central GBA; and (3) human behavior factors have a more significant influence on UF than natural ones. We believe the presented framework for the accurate extraction of UFSRs provides valuable decision support for sustainable city development.

This study aims to investigate the influence of different fiber types, lengths, and contents on their performance in freeze-thaw environments. Indoor freeze-thaw tests were conducted to evaluate the flexural strength, compressive strength, and mass loss of fiber-reinforced geopolymer materials. Additionally, SEM and XRD analyses were performed to examine the internal structure of the geopolymer composites. The results demonstrated that the incorporation of different fibers significantly improved various properties, particularly the flexural strength of the specimens. With an increasing number of freeze-thaw cycles, surface cracks became more prominent in the geopolymer specimens, leading to a gradual decrease in frost resistance. However, the addition of an appropriate amount of fiber effectively enhanced frost resistance. Following freeze-thaw exposure, an increase in fiber content initially resulted in a decrease and subsequently an increase in relative flexural strength, compressive strength, and mass loss. Notably, studies revealed that polypropylene fibers with a length of 9 mm and a content of 0.9 % exhibited minimal mass and strength loss. SEM analysis indicated uniform distribution of fibers within the geopolymer matrix, contributing to improved flexural strength and enhanced frost resistance in fiber-reinforced structures. XRD results indicate that red mud-slag based geopolymers produce high-strength hydrated calcium (aluminosilicate) silicate and hematite phases, which enhances the mechanical properties and durability of the specimens. In conclusion, this study highlights that incorporating suitable fibers can enhance the durability and performance of red mud-slag based geopolymers under freeze-thaw conditions. The findings provide valuable insights for optimizing fiber type, length, and content to achieve superior mechanical properties and frost resistance in geopolymer composites.

IntroductionAcute myeloid leukemia (AML) is an aggressive blood cancer with high heterogeneity and poor prognosis. Although the metabolic reprogramming of nicotinamide adenine dinucleotide (NAD) has been reported to play a pivotal role in the pathogenesis of acute myeloid leukemia (AML), the prognostic value of NAD metabolism and its correlation with the immune microenvironment in AML remains unclear.MethodsWe utilized our large-scale RNA-seq data on 655 patients with AML and the NAD metabolism-related genes to establish a prognostic NAD metabolism score based on the sparse regression analysis. The signature was validated across three independent datasets including a total of 1,215 AML patients. ssGSEA and ESTIMATE algorithms were employed to dissect the tumor immune microenvironment. Ex vivo drug screening and in vitro experimental validation were performed to identify potential therapeutic approaches for the high-risk patients. In vitro knockdown and functional experiments were employed to investigate the role of SLC25A51, a mitochondrial NAD+ transporter gene implicated in the signature.ResultsAn 8-gene NAD metabolism signature (NADM8) was generated and demonstrated a robust prognostic value in more than 1,800 patients with AML. High NADM8 score could efficiently discriminate AML patients with adverse clinical characteristics and genetic lesions and serve as an independent factor predicting a poor prognosis. Immune microenvironment analysis revealed significant enrichment of distinct tumor-infiltrating immune cells and activation of immune checkpoints in patients with high NADM8 scores, acting as a potential biomarker for immune response evaluation in AML. Furthermore, ex vivo drug screening and in vitro experimental validation in a panel of 9 AML cell lines demonstrated that the patients with high NADM8 scores were more sensitive to the PI3K inhibitor, GDC-0914. Finally, functional experiments also substantiated the critical pathogenic role of the SLC25A51 in AML, which could be a promising therapeutic target.ConclusionOur study demonstrated that NAD metabolism-related signature can facilitate risk stratification and prognosis prediction in AML and guide therapeutic decisions including both immunotherapy and targeted therapies.

The expansion of betel palm cultivation is driven by rising demand for betel nut, yet this growth is accompanied by challenges such as decreased agricultural biodiversity and the spread of infectious pathogens. Among these, Yellow Leaf Disease (YLD) emerges as a prominent threat to betel palm plantation. Areca Palm Velarivirus 1 (APV1) has been identified as a primary causative agent of YLD, precipitating leaf yellowing, stunted growth, and diminished yield. However, the precise mechanisms underlying APV1-induced damage remain elusive. Our study elucidates that APV1 infiltrates chloroplasts, instigating severe damage and consequential reductions in chlorophyll a/b and carotene levels, alongside notable declines in photosynthetic efficiency. Moreover, APV1 infection exerts broad regulatory effects on gene expression, particularly suppressing key genes implicated in chloroplast function and photosynthesis. These disruptions correlate with growth retardation, yield diminishment, and compromised nut quality. Intriguingly, the paradoxical destruction of the host's photosynthetic machinery by APV1 prompts inquiry into its evolutionary rationale, given the virus's dependence on host resources for replication and proliferation. Our findings reveal that APV1-induced leaf yellowing acts as a beacon for transmission vectors, hinting at a nuanced “host-pathogen-vector co-evolutionary” dynamic.

Abstract Betel palm is one of the most economically important crops in Southeast Asia. The occurrence and expansion of yellow leaf disease (YLD) have significantly impacted betel palm plantations. Our previous research demonstrated that areca palm velarivirus 1 (APV1) was associated with YLD and transmitted by Ferrisia virgata (striped mealybug), causing YLD in betel palms. This finding provides strong etiological evidence of the role played by APV1 in YLD. Controlling YLD is a pressing issue with significant challenges. One viable approach is to prevent the virus from spreading by disrupting the transmission vectors. Therefore, it is imperative to identify potential vectors of APV1. In this study, we detected APV1 in the stylet, foregut, midgut, and hindgut of Pseudococcus cryptus (cryptic mealybug) using immunocapture RT-PCR and in situ immunofluorescence localization. P. cryptus transmitted APV1 in a non-circulative, semi-persistent manner. The retention time of APV1 in P. cryptus was notably longer than that in F. virgata. Additionally, field investigations revealed that three other insects infesting betel palms also carried APV1. In summary, APV1 may also be transmitted by other mealybug species, and the lower specificity of transmission vectors makes it challenging to control the spread of this devastating disease. This work provides timely knowledge for the prevention and management of YLD.

Abstract The gradual aging of the global population has led to a surge in age-related diseases, which seriously threaten human health. Researchers are dedicated to understanding and coping with the complexities of aging, constantly uncovering the substances and mechanism related to aging like chronic low-grade inflammation. The NOD-like receptor protein 3 (NLRP3), a key regulator of the innate immune response, recognizes molecular patterns associated with pathogens and injury, initiating an intrinsic inflammatory immune response. Dysfunctional NLRP3 is linked to the onset of related diseases, particularly in the context of aging. Therefore, a profound comprehension of the regulatory mechanisms of the NLRP3 inflammasome in aging-related diseases holds the potential to enhance treatment strategies for these conditions. In this article, we review the significance of the NLRP3 inflammasome in the initiation and progression of diverse aging-related diseases. Furthermore, we explore preventive and therapeutic strategies for aging and related diseases by manipulating the NLRP3 inflammasome, along with its upstream and downstream mechanisms.

Abstract Background Sepsis is a life-threatening condition caused by an excessive inflammatory response to an infection, associated with high mortality. However, the regulatory mechanism of sepsis remains unclear. Results In this study, bioinformatics analysis revealed the novel key biomarkers associated with sepsis and potential regulators. Three public datasets (GSE28750, GSE57065 and GSE95233) were employed to recognize the differentially expressed genes (DEGs). Taking the intersection of DEGs from these three datasets, GO and KEGG pathway enrichment analysis revealed 537 shared DEGs and their biological functions and pathways. These genes were mainly enriched in T cell activation, differentiation, lymphocyte differentiation, mononuclear cell differentiation, and regulation of T cell activation based on GO analysis. Further, pathway enrichment analysis revealed that these DEGs were significantly enriched in Th1, Th2 and Th17 cell differentiation. Additionally, five hub immune-related genes (CD3E, HLA-DRA, IL2RB, ITK and LAT) were identified from the protein–protein interaction network, and sepsis patients with higher expression of hub genes had a better prognosis. Besides, 14 drugs targeting these five hub related genes were revealed on the basis of the DrugBank database, which proved advantageous for treating immune-related diseases. Conclusions These results strengthen the new understanding of sepsis development and provide a fresh perspective into discriminating the candidate biomarkers for predicting sepsis as well as identifying new drugs for treating sepsis.

MYB transcription factors (MYB TFs)are one of the largest families of transcription factors in plants, which are widely involved in various fields of plant growth and development, and play an important regulatory role in the biosynthesis of plant secondary metabolites. Most of the current studies on MYB transcription factors have focused on agricultural crops, and fewer studies have been conducted on medicinal plants. Therefore, this study reviews the research progress of plant MYB transcription factors in secondary metabolism of medicinal plants, which provides ideas and methods for better utilisation and development of medicinal plants.

Introduction: Aristolochic acid nephropathy (AAN) is a kidney injury syndrome caused by aristolochic acids exposure. Our study used label-free quantitative proteomics to delineate renal protein profiles and identify key proteins after exposure to different doses of aristolochic acid I (AAI).Methods: Male C57BL/6 mice received AAI (1.25 mg/kg/d, 2.5 mg/kg/d, or 5 mg/kg/d) or vehicle for 5 days.Results and discussion: The results showed that AAI induced dose-dependent nephrotoxicity. Differences in renal protein profiles between the control and AAI groups increased with AAI dose. Comparing the control with the low-, medium-, and high-dose AAI groups, we found 58, 210, and 271 differentially expressed proteins, respectively. Furthermore, protein-protein interaction network analysis identified acyl-CoA synthetase medium-chain family member 3 (Acsm3), cytochrome P450 family 2 subfamily E member 1 (Cyp2e1), microsomal glutathione S-transferase 1 (Mgst1), and fetuin B (Fetub) as the key proteins. Proteomics revealed that AAI decreased Acsm3 and Cyp2e1 while increasing Mgst1 and Fetub expression in mice kidneys, which was further confirmed by Western blotting. Collectively, in AAI-induced nephrotoxicity, renal protein profiles were dysregulated and exacerbated with increasing AAI dose. Acsm3, Cyp2e1, Mgst1, and Fetub may be the potential therapeutic targets for AAN.

Summary: Mounting evidence supports the role of neuroinflammation in radiation-induced brain injury (RIBI), a chronic disease characterized by delayed and progressive neurological impairment. Asparagine endopeptidase (AEP), also known as legumain (LGMN), participates in multiple malignancies and neurodegenerative diseases and may potentially be involved in RIBI. Here, we found AEP expression was substantially elevated in the cortex and hippocampus of wild-type (Lgmn+/+) mice following whole-brain irradiation. Lgmn knockout (Lgmn−/−) alleviated neurological impairment caused by whole-brain irradiation by suppressing neuronal senescence. Bulk RNA and metabolomic sequencing revealed AEP’s involvement in the antigen processing and presentation pathway and neuroinflammation. This was further confirmed by co-culturing Lgmn+/+ primary neurons with the conditioned media derived from irradiated Lgmn+/+ or Lgmn−/− primary microglia. Furthermore, esomeprazole inhibited the enzymatic activity of AEP and RIBI. These findings identified AEP as a critical factor of neuroinflammation in RIBI, highlighting the prospect of targeting AEP as a therapeutic approach.

Abstract Global warming increases the atmospheric water‐holding capacity, consequently altering the frequency, and intensity of extreme hydrological events. River floods characterized by large peak flow or prolonged duration can amplify the risk of social disruption and affect ecosystem stability. However, previous studies have mostly focused on univariate flood magnitude characteristics, such as flood peak or volume, and there is still limited understanding of how these joint flood characteristics (i.e., magnitude and duration) might co‐evolve under different warming levels. Here, we develop a systematical bivariate framework to project future flood risk in 11,528 catchments across the globe. By constructing the joint distribution of flood peak and duration with copulas, we examine global flood risk with a bivariate framework under varying levels of global warming (i.e., within a range of 1.5–3.0°C above pre‐industrial levels). The flood projections are produced by driving five calibrated lumped hydrological models (HMs) using the simulations with bias adjustment of five global climate models (GCMs) under three shared socioeconomic pathways (SSP126, SSP370, and SSP585). On average, global warming from 1.5 to 3.0°C tends to amplify flood peak and lengthen flood duration across almost all continents, but changes are not unidirectional and vary regionally around the globe. The joint return period (JRP) of the historical (1985–2014) 50‐year flood event is projected to decrease to a median with 36 years under a medium emission pathway at the 1.5°C warming level. Finally, we evaluate the drivers of these JRP changes in the future climate and quantify the uncertainty arising from the different GCMs, SSPs, and HMs. Our findings highlight the importance of limiting greenhouse gas emission to slow down global warming and developing climate adaptation strategies to address future flood hazards.

Probucol has been utilized as a cholesterol-lowering drug with antioxidative properties. However, the impact and fundamental mechanisms of probucol in obesity-related cognitive decline are unclear. In this study, male C57BL/6J mice were allocated to a normal chow diet (NCD) group or a high-fat diet (HFD) group, followed by administration of probucol to half of the mice on the HFD regimen. Subsequently, the mice were subjected to a series of behavioral assessments, alongside the measurement of metabolic and redox parameters. Notably, probucol treatment effectively alleviates cognitive and social impairments induced by HFD in mice, while exhibiting no discernible influence on mood-related behaviors. Notably, the beneficial effects of probucol arise independently of rectifying obesity or restoring systemic glucose and lipid homeostasis, as evidenced by the lack of changes in body weight, serum cholesterol levels, blood glucose, hyperinsulinemia, systemic insulin resistance, and oxidative stress. Instead, probucol could regulate the levels of nitric oxide and superoxide-generating proteins, and it could specifically alleviate HFD-induced hippocampal insulin resistance. These findings shed light on the potential role of probucol in modulating obesity-related cognitive decline and urge reevaluation of the underlying mechanisms by which probucol exerts its beneficial effects.

Lung diseases have become a major threat to human health worldwide. Despite advances in treatment and intervention in recent years, effective drugs are still lacking for many lung diseases. As a traditional natural medicine, Tibetan medicine has had a long history of medicinal use in ethnic minority areas, and from ancient times to the present, it has a good effect on the treatment of lung diseases and has attracted more and more attention. In this review, a total of 586 Tibetan medicines were compiled through literature research of 25 classical works on Tibetan medicine, drug standards, and some Chinese and English databases. Among them, 33 Tibetan medicines have been studied to show their effectiveness in treating lung diseases. To investigate the uses of these Tibetan medicines in greater depth, we have reviewed the ethnomedicinal, phytochemical and pharmacological properties of the four commonly used Tibetan medicines for lung diseases (rhodiola, gentian, sea buckthorn, liexiang dujuan) and the five most frequently used Tibetan medicines (safflower, licorice, sandalwood, costus, myrobalan). It is expected to provide some reference for the development of new drugs of lung diseases in the future.

Terson syndrome refers to intraocular haemorrhage that occurs due to subarachnoid bleeding associated with an acute increase in intracranial pressure. No previous study has reported a delayed macular hole (MH) secondary to Terson syndrome. A 17-year-old boy visited our department and presented with vitreous bleeding and a history of subarachnoid haemorrhage. Sub-internal limiting membrane (ILM) haemorrhage with ILM detachment and intraretinal haemorrhage were detected during pars plana vitrectomy. Additionally, a delayed MH was detected 1 week after the surgery. There was no sign of MH closure during a 2-month follow-up. Subsequently, an MH massage was performed to close the MH. Our findings suggest that a delayed MH can occur secondary to Terson syndrome. Elevated hydrodynamic pressure and hydrostatic pressure, which are caused by sub-ILM and intraretinal haemorrhages of the fovea, contribute to the formation of an MH. Additionally, ILM peeling may cause damage to the macula and facilitate the formation of MHs. Although the MH may close by itself, early surgical intervention is recommended when there is no sign that the MH will close spontaneously because a prolonged MH can lead to retinal damage.

Urban Flood (UF) and Urban Heat Island (UHI) become prevalent “urban diseases” currently. Previous studies usually regarded UF and UHI as separate issues that requires respective concentration; however, UF and UHI are inextricably connected so that they should be considered together. Hence, this paper proposes a spatiotemporal framework to link UF and UHI by developing an Urban Flood Heat Island (UFHI) index, taking the Greater Bay Area (GBA) in China as the study case. Random Forest (RF) classifier and Urban-Rural Dichotomy were selected to compute the spatiotemporal distribution of UF susceptibility (UFS) and UHI intensity (UHII), respectively. Theil-Sen Median Slope, Mann-Kendall Test, and Hurst analysis were used to explore the spatiotemporal variation pattern of the UF-UHI joint risk. Spatial Durbin Model was used to compute the correlation between UFS and UHII. RF regressor was employed to quantify the contribution of the common driving factors. We found: (1) UFS and UHII are spatiotemporally correlated, thus UHII can be used as a control variable for the refined UFS assessments, (2) the areas with the UF-UHI joint risk of persistently significant increase (∼7.9 %) majorly distributed in the central region, (3) according to the contributions of factors, UF and UHI in the GBA could be effectively alleviated by breaking the continuous impervious surfaces by introducing blue-green structures. This study offers a new perspective for the effective alleviation of UF and UHI, which would be helpful for the sustainable development of cities in developing countries where human and material sources are limited.

In this study, the Sn58Bi-xMg (x = 0, 0.2, 0.4, 0.6, 0.8, 1.0) composite solders were synthesized to explore the impact of Mg particles. The study examined the wettability, thermal properties, mechanical properties, microstructure, and growth of interfacial IMC (intermetallic compound) of composite solder. Experimental results showed that adding Mg particles had no significant impact on the melting point of Sn58Bi solder. However, increasing the Mg content increased the undercooling of the solder. Moreover, the incorporation of Mg particles resulted in a consistent rise in the coefficient of thermal expansion (CTE) of the composite solder, ranging from 11.4 × 10−6/°C to 15.6 × 10−6/°C. It was worth noting that including Mg particles enhanced the wetting ability of Sn58Bi alloy on Cu substrates. With a 0.4 % addition of Mg particles, the wetting area could be increased by 60.14 %, and the lowest wetting angle was approximately 10.43°. Adding Mg particles resulted in an amelioration in the brittleness of the Bi-rich phase within the solder matrix, coupled with a decrease in both the thickness of IMC and the grain size at the joint interface. Compared to the joints without mixed Mg particles, the shear strength of Sn58Bi-0.4Mg solder joints and the microhardness of the alloy increased by 30 % and decreased by 10 %, respectively. Also, the presence of dimples within the fracture indicated a rise in the ductility of the solder joints. Overall, adding 0.4 wt% Mg particles in this experiment resulted in a more effective modification of the Sn58Bi solder comprehensive properties.

Abstract Decarbonized power systems are critical to mitigate climate change, yet methods to achieve a reliable and resilient near-zero power system are still under exploration. This study develops an hourly power system simulation model considering high-resolution geological constraints for carbon-capture-utilization-and-storage to explore the optimal solution for a reliable and resilient near-zero power system. This is applied to 31 provinces in China by simulating 10,450 scenarios combining different electricity storage durations and interprovincial transmission capacities, with various shares of abated fossil power with carbon-capture-utilization-and-storage. Here, we show that allowing up to 20% abated fossil fuel power generation in the power system could reduce the national total power shortage rate by up to 9.0 percentages in 2050 compared with a zero fossil fuel system. A lowest-cost scenario with 16% abated fossil fuel power generation in the system even causes 2.5% lower investment costs in the network (or $16.8 billion), and also increases system resilience by reducing power shortage during extreme climatic events.

Abstract Background Digital knowledge sharing (DKS) communities have emerged as a promising approach to support learning and innovation in online higher education. These communities facilitate the exchange of knowledge, resources, and ideas among educators, students, and experts, creating opportunities for collaboration, innovation, and lifelong learning. However, the impact and role of DKS communities in online education are not well understood, and further research is needed to explore their potential benefits and challenges. Purpose This multi-objective qualitative study aims to investigate the impact and role of DKS communities in online higher education, identifying the factors that promote student success and the implications for the development of online education. The study collected data from 20 informants who have experienced teaching online during and after the pandemic. Data were collected through in-depth interviews and analyzed using thematic analysis. The informants were selected through theoretical sampling. Methodology To explore the impact and role of DKS communities in online higher education, this study employed a multi-objective qualitative research method. Data were collected through in-depth interviews conducted with 20 informants who possessed experience in teaching online during and after the pandemic. The informants were selected through theoretical sampling to ensure diverse perspectives and insights. The collected data were subsequently analyzed using thematic analysis, allowing for the identification of key themes and patterns. Findings The findings of this study provide valuable insights into the impact and role of DKS communities in online higher education. These insights encompass various aspects, including the benefits and challenges of DKS in online education, the factors that contribute to student success, and the implications for the ongoing development and innovation of online education. Conclusions In conclusion, this multi-objective qualitative study sheds light on the significance of DKS communities in online higher education. It underscores their potential to enhance collaboration, innovation, and lifelong learning. The findings also emphasize the importance of addressing challenges and fostering an inclusive and supportive online learning environment. These insights inform best practices and contribute to the continuous development and innovation of online education, particularly in the post-pandemic educational landscape.

Abstract Background Mitochondrial respiration plays a central role in the survival of many eukaryotes, including apicomplexan parasites. A 479-bp fragment from the mitochondrial cytochrome b gene is widely used as a barcode to identify genetic lineages of avian malaria parasites Plasmodium and related haemosporidians. Here we looked for evidence of selection in the avian Plasmodium cyt b gene, using tests of selection and protein structure modeling. We also tested for the association between cyt b polymorphism and the host specificity of these parasites. Results Based on 1,089 lineages retrieved from the Malavi database, we found that the frequency of the most conserved amino acids in most sites was more than 90%, indicating that the protein diversity of the avian Plasmodium cyt b barcode was low. The exceptions were four amino acid sites that were highly polymorphic, though the substitutions had only slight functional impacts on the encoded proteins. The selection analyses revealed that avian Plasmodium cyt b was under strong purifying selection, and no positively selected sites were detected. Besides, lineages with a wide host range tend to share cyt b protein haplotypes. Conclusions Our research indicates that purifying selection is the dominant force in the evolution of the avian Plasmodium cyt b lineages and leads to its low diversity at the protein level. Host specificity may also play a role in shaping the low mitochondrial diversity in the evolution of avian malaria parasites. Our results highlight the importance of considering selection pressure on the cyt b barcode region and lay a foundation for further understanding the evolutionary pattern of mitochondrial genes in avian malaria.

In the contemporary era, youthful and healthy skin is a pivotal determinant of beauty. Choices pertaining to one’s dietary and lifestyle practices wield substantial influence over skin health. Currently, the focal point of attention lies in strategies that delay skin aging and maintain skin quality. Remarkably, the skin, the body’s largest organ, serves as the primary defense barrier against external elements. Skin aging encompasses intrinsic and extrinsic categories, both susceptible to genetic, lifestyle, and environmental factors. Given the strides in science and technology, the pursuit of effective and safe interventions for skin aging assumes paramount importance. Thus, this review delves into the intricate relationship between diet, lifestyle, and skin aging, culminating in an exploration of the crucial role played by excess iron in this intricate nexus. Understanding these dynamics holds promise for advancing our knowledge of skincare and the quest for timeless vitality.

While it is well known that plants interpret UV-B as an environmental cue and a potential stressor influencing their growth and development, the specific effects of UV-B-induced oxidative stress on the dynamics of membrane lipids and proteins remain underexplored. Here, we demonstrate that UV-B exposure notably increases the formation of ordered lipid domains on the plasma membrane (PM) and significantly alters the behavior of the Glycine max nodule autoregulation receptor kinase (GmNARK) protein in Arabidopsis leaves. The GmNARK protein was located on the PM and accumulated as small particles in the cytoplasm. We found that UV-B irradiation interrupted the lateral diffusion of GmNARK proteins on the PM. Furthermore, UV-B light decreases the efficiency of surface molecule internalization by clathrin-mediated endocytosis (CME). In brief, UV-B irradiation increased the proportion of the ordered lipid phase and disrupted clathrin-dependent endocytosis; thus, the endocytic trafficking and lateral mobility of GmNARK protein on the plasma membrane are crucial for nodule formation tuning. Our results revealed a novel role of low-intensity UV-B stress in altering the organization of the plasma membrane and the dynamics of membrane-associated proteins.

In order to investigate the relationship between the invasion of the exotic plant Solidago canadensis and diversity of native plants in Nanjing, the species composition and diversity of its community were studied by using the tracking and quadrat methods. The results were as follows: (1) A total of 200 vascular plant species, including varieties and subspecies classification, were found in the invaded communities, belong to 156 genera and 62 families, including 195 angiosperms, one gymnosperm, and four ferns. The species-richest families were Asteraceae and Poaceae, with 25 and 24 species respectively. In terms of their life forms, herbaceous plants accounted for the majority, with 133 species (66.50%). In addition, there were 29 other alien plant species in these communities. The most dominant species in the community was Solidago canadensis, with a high ecological important value of 40.00%, followed by Vicia sativa (7.00%). (2) There were four floristic types of flora families in uninvaded communities, and only three types in invaded communities. Pantropic type, cosmopolitan type and north temperate type existed in both communities, while East Asia and North America disjunct type only in uninvaded communities. In the uninvaded communities, the floristic types were mainly cosmopolitan, with 13 families, accounting for 39.39% of all families. Pantropic was the dominant species in the invaded communities, with 16 families, accounting for 45.71% of the total. There were 10 floristic types of flora genera in uninvaded habitats and 12 in invaded habitats, with similar floristic composition, but the old-world temperate type and tropical Asia to tropical Australasia type only appeared in invaded communities. The north temperate and cosmopolitan type were the most important components of both invaded and uninvaded communities. The R/T values of invaded and uninvaded communities of genera were 0.58 and 0.38, and the species differentiation were 3.29 and 3.11, respectively. (3) The Margalef index (E) of heavily invaded communities was significantly lower than that of uninvaded and lightly invaded communities. In addition, the Simpson index (D), Shannon Weiner index (H′), and Pielou index(J) of heavily invaded communities were significantly reduced compared to uninvaded, lightly invaded, and moderately invaded communities. (4) There were no significant differences in E, D, H′, and J in different habitats. This study can provide basic data for the management, prevention and control, and ecological restoration of the invaded areas of S. canadensis in Nanjing, as well as further scientific research.

Abstract Background Chimeric antigen receptor (CAR) -T cell therapy is an efficient therapeutic strategy for specific hematologic malignancies. However, positive outcomes of this novel therapy in treating solid tumors are curtailed by the immunosuppressive tumor microenvironment (TME), wherein signaling of the checkpoint programmed death-1 (PD-1)/PD-L1 directly inhibits T-cell responses. Although checkpoint-targeted immunotherapy succeeds in increasing the number of T cells produced to control tumor growth, the desired effect is mitigated by the action of myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) in the TME. Previous studies have confirmed that targeting triggering-receptor-expressed on myeloid cells 2 (TREM2) on TAMs and MDSCs enhances the outcomes of anti-PD-1 immunotherapy. Methods We constructed carcinoembryonic antigen (CEA)-specific CAR-T cells for colorectal cancer (CRC)-specific antigens with an autocrine PD-1-TREM2 single-chain variable fragment (scFv) to target the PD-1/PD-L1 pathway, MDSCs and TAMs. Results We found that the PD-1-TREM2-targeting scFv inhibited the activation of the PD-1/PD-L1 pathway. In addition, these secreted scFvs blocked the binding of ligands to TREM2 receptors present on MDSCs and TAMs, reduced the proportion of MDSCs and TAMs, and enhanced T-cell effector function, thereby mitigating immune resistance in the TME. PD-1-TREM2 scFv-secreting CAR-T cells resulted in highly effective elimination of tumors compared to that achieved with PD-1 scFv-secreting CAR-T therapy in a subcutaneous CRC mouse model. Moreover, the PD-1-TREM2 scFv secreted by CAR-T cells remained localized within tumors and exhibited an extended half-life. Conclusions Together, these results indicate that PD-1-TREM2 scFv-secreting CAR-T cells have strong potential as an effective therapy for CRC.

Abstract Research question To explore whether prolonged hCG-ovum pickup interval improves assisted reproductive technology outcomes. Design CENTRAL, CNKI, Cochrane Systematic Reviews, EMBASE, MEDLINE, PUBMED, and Web of Science up to May 13 2023 were searched for studies reporting associations between hCG-ovum pickup intervals and assisted reproductive technology outcomes. Intervention types included short (≤ 36 h) and long (> 36 h) hCG-ovum pickup intervals in assisted reproductive technology cycles. All outcomes were based upon only fresh embryo transfers. Primary outcome is defined as the clinical pregnancy rate. Data were pooled using random-effects models. Heterogeneity was assessed using the I 2 statistics. Results Twelve studies were included in the meta-analysis, including five retrospective cohort studies, one prospective cohort study, and six randomized or quasi-randomized controlled trials. The short and long interval groups had similar oocyte maturation rates, fertilization rate and high-quality embryo rate (OR, 0.69; 95% CI, 0.45–1.06; I 2 = 91.1%, OR, 0.88; 95% CI, 0.77–1.0; I 2 = 44.4% and OR, 1.05; 95% CI, 0.95–1.17; I 2 = 8.6%, respectively). The clinical pregnancy rates in the long retrieval group were significantly higher than in the short retrieval group (OR, 0.66; 95% CI, 0.45–0.95; I 2 = 35.4%). The groups had similar miscarriage and live birth rates (OR, 1.92; 95% CI, 0.66–5.60; I 2 = 0.0% and OR, 0.50; 95% CI, 0.24–1.04; I 2 = 0.0%, respectively). Conclusions The clinical pregnancy rates can be increased by prolonging the hCG-ovum pickup interval, which would help us develop more reasonable time schedules for fertility centers and patients. Meta-analysis registration PROSPERO CRD42022310006 (28 Apr 2022).

Abstract Background Non-small cell lung cancer (NSCLC) is a worldwide health threat with high annual morbidity and mortality. Chemotherapeutic drugs such as paclitaxel (PTX) have been widely applied clinically. However, systemic toxicity due to the non-specific circulation of PTX often leads to multi-organ damage, including to the liver and kidney. Thus, it is necessary to develop a novel strategy to enhance the targeted antitumor effects of PTX. Methods Here, we engineered exosomes derived from T cells expressing the chimeric antigen receptor (CAR-Exos), which targeted mesothelin (MSLN)-expressing Lewis lung cancer (MSLN-LLC) through the anti-MSLN single-chain variable fragment (scFv) of CAR-Exos. PTX was encapsulated into CAR-Exos (PTX@CAR-Exos) and administered via inhalation to an orthotopic lung cancer mouse model. Results Inhaled PTX@CAR-Exos accumulated within the tumor area, reduced tumor size, and prolonged survival with little toxicity. In addition, PTX@CAR-Exos reprogrammed the tumor microenvironment and reversed the immunosuppression, which was attributed to infiltrating CD8+ T cells and elevated IFN-γ and TNF-α levels. Conclusions Our study provides a nanovesicle-based delivery platform to promote the efficacy of chemotherapeutic drugs with fewer side effects. This novel strategy may ameliorate the present obstacles to the clinical treatment of lung cancer.

Key Clinical Message AlphaMissense is proficient in predicting the clinical classification of missense variants. we utilized AlphaMissense to find disease‐relevant variants within a polymicrobial pulmonary infection case. Exome sequencing was performed in this patient, and AlphaMissense and Phenolyzer were combined to investigate disease‐relevant variants screening from exome sequencing results.

BackgroundHeatstroke is a life-threatening disease clinically characterized by central nervous system dysfunction, multiorgan failure, and extreme hyperthermia. There are no reports about eye involvement in heat stroke. Here, we report a rare case of multilayered retinal hemorrhages in a patient with heatstroke.Case presentationA 55-year-old male with a one-month history of blurry vision in both eyes presented at our department after suffering from heatstroke. His visual acuity was 5/20 OD and 10/20 OS. Fundus examination revealed retinal hemorrhages in both eyes. Fundus autofluorescence images and near-infrared reflectance images revealed well-defined retinal lesions. Optical coherence tomography helped to accurately locate the different layers of the lesions, including the nerve fiber layer, sub-inner limiting membrane, outer plexiform layer, ellipsoid zone and Henle fiber layer hemorrhages. We followed up with the patient for 8 months. At the last follow-up, his visual acuity was 20/20 in both eyes, and fundus examination showed that retinal hemorrhages were almost completely absorbed.ConclusionTo our knowledge, this is the first report on multilayered retinal hemorrhages secondary to heat stroke. Intraretinal and preretinal hemorrhages can gradually resolve, and the patient’s vision will improve with the absorption of the retinal hemorrhages. Multimodal imaging may help to reveal additional details about retinal lesions and monitor the course of the disease.

Parasitic infections have the potential to impact the hosts’ body condition, elevate physiological responses, and ultimately lead to increased mortality. Host-parasite interactions are tied to the ecological and life-history traits of the hosts. While montane birds are susceptible to avian blood parasites, few studies have simultaneously assessed how inter- and intra-specific traits of hosts influence their probability of parasite infection. In this study, we screened for avian blood parasites across 214 individuals from 51 species at two sites, including a lowland farmland at 700 m and a highland forest at 2,500 m, in the Gaoligong Mountains in southwestern China. Overall blood parasite prevalence was 53.74%, with divergent species-specific prevalence ranging from 6.25% to 66.67%. We also measured traits indicative of body condition and physiological responses of each sampled individual. Using Bayesian phylogenetic logistic models, we assessed whether parasite infection probability is associated with ecological and life history traits of host species. Larger bird species were more likely to be infected than smaller bird species, and omnivore species showed lower susceptibility than those with other diets such as insectivores and herbivores. In contrast, foraging strata, nest type, and participation in mixed-species flocks of host species did not affect infection probability. We then used a reduced sample of eight species with more than five individuals, to assess the associations between intra-specific infection probability and host body condition, represented by fat and muscle reserves, and acute stress responses measured through breath rate. While infected individuals were likely to have more fat reserves than non-infected individuals, we did not find any association between infection probability and muscle reserve and body mass, nor with breath rate. Our results revealed that at the species level, specific traits (body mass and diet) of host species predict infection probability and implied a potential link at the individual level between enhanced body condition and increased resilience to parasite infection.

Proliferative enteropathy caused by Lawsonia intracellularis is an important economic associated disease to pig industry, but the knowledge about the prevalence of L. intracellularis in pig farms in China is limited. In addition, there is no complete genome sequence available for L. intracellularis isolates from China. In this study, we developed a TaqMan qPCR for the screening of L. intracellularis by targeting the bacterial 16S rDNA gene. Laboratory evaluations revealed a good sensitivity and specificity on detecting L. intracellularis nucleic acid. Using this method, we investigated 891 fecal samples from apparently healthy pigs in 47 farms. The results demonstrated a screening positive rate of 37.3% (95% CI, 34.1–40.5%) for the samples, and a farm screening positive rate of 93.6% (95% CI, 65.3–94.4%). The screening positive rate at herd level ranged from 6.67% (95% CI, 0.2–31.9%) to 40% (95% CI, 38–79.6%), while at animal level, the highest screening positive rate was found in 12-week-old pigs [85.7% (95% CI, 67.3–96.0%)]. Investigation of 705 diarrheal or bloody feces from symptomatic pigs revealed that the highest positive rate was found in replacement gilts which was 37.18% (95% CI, 45.1–89.5%). Secondly, we conducted the complete genome sequence of a L. intracellularis PPE-GX01-2022 from China through PacBio sequencing. The genome of PPE-GX01-2022 consisted of a chromosome of 1,439,110 bp in length and three plasmids of 193,063, 39,799, and 27,067 bp, respectively. This genome encoded 1,428 predicted proteins, 44 tRNAs, and 6 rRNAs. Sequence comparisons demonstrated that the genome sequence of PPE-GX01-2022 was highly homologous to those of two isolates from US, and these three isolates shared 1,378 core genes. The screening results suggest a high prevalence rate of L. intracellularis in Chinese pig farms. In addition, the genome sequence of the Chinese isolate was highly homologous to those of the field isolates from the US.

Hepatocellular carcinoma (HCC) was characterized as being hypervascular. In the present study, we generated a single-cell spatial transcriptomic landscape of the vasculogenic etiology of HCC and illustrated overexpressed Golgi phosphoprotein 73 (GP73) HCC cells exerting cellular communication with vascular endothelial cells with high pro-angiogenesis potential via multiple receptor–ligand interactions in the process of tumor vascular development. Specifically, we uncovered an interactive GP73-mediated regulatory network coordinated with c-Myc, lactate, Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway, and endoplasmic reticulum stress (ERS) signals in HCC cells and elucidated its pro-angiogenic roles in vitro and in vivo. Mechanistically, we found that GP73, the pivotal hub gene, was activated by histone lactylation and c-Myc, which stimulated the phosphorylation of downstream STAT3 by directly binding STAT3 and simultaneously enhancing glucose-regulated protein 78 (GRP78)-induced ERS. STAT3 potentiates GP73-mediated pro-angiogenic functions. Clinically, serum GP73 levels were positively correlated with HCC response to anti-angiogenic regimens and were essential for a prognostic nomogram showing good predictive performance for determining 6-month and 1-year survival in patients with HCC treated with anti-angiogenic therapy. Taken together, the aforementioned data characterized the pro-angiogenic roles and mechanisms of a GP73-mediated network and proved that GP73 is a crucial tumor angiogenesis niche gene with favorable anti-angiogenic potential in the treatment of HCC.