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Abstract Due to the rapid development of stem cell technology, there have been tremendous advances in molecular biological and pathological research, cell therapy as well as organoid technologies over the past decades. Advances in genome editing technology, particularly the discovery of clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-related protein 9 (Cas9), have further facilitated the rapid development of stem cell researches. The CRISPR-Cas9 technology now goes beyond creating single gene editing to enable the inhibition or activation of endogenous gene loci by fusing inhibitory (CRISPRi) or activating (CRISPRa) domains with deactivated Cas9 proteins (dCas9). These tools have been utilized in genome-scale CRISPRi/a screen to recognize hereditary modifiers that are synergistic or opposing to malady mutations in an orderly and fair manner, thereby identifying illness mechanisms and discovering novel restorative targets to accelerate medicinal discovery investigation. However, the application of this technique is still relatively rare in stem cell research. There are numerous specialized challenges in applying large-scale useful genomics approaches to differentiated stem cell populations. Here, we present the first comprehensive review on CRISPR-based functional genomics screening in the field of stem cells, as well as practical considerations implemented in a range of scenarios, and exploration of the insights of CRISPR-based screen into cell fates, disease mechanisms and cell treatments in stem cell models. This review will broadly benefit scientists, engineers and medical practitioners in the areas of stem cell research.

Abstract Multiple myeloma (MM) is a hematologic malignancy characterized by uncontrolled proliferation of plasma cells in the bone marrow. MM patients with aggressive progression have poor survival, emphasizing the urgent need for identifying new therapeutic targets. Here, we show that the leukocyte immunoglobulin-like receptor B1 (LILRB1), a transmembrane receptor conducting negative immune response, is a top-ranked gene associated with poor prognosis in MM patients. LILRB1 deficiency inhibits MM progression in vivo by enhancing the ferroptosis of MM cells. Mechanistic studies reveal that LILRB1 forms a complex with the low-density lipoprotein receptor (LDLR) and LDLR adapter protein 1 (LDLRAP1) to facilitate LDL/cholesterol uptake. Loss of LILRB1 impairs cholesterol uptake but activates the de novo cholesterol synthesis pathway to maintain cellular cholesterol homeostasis, leading to the decrease of anti-ferroptotic metabolite squalene. Our study uncovers the function of LILRB1 in regulating cholesterol metabolism and protecting MM cells from ferroptosis, implicating LILRB1 as a promising therapeutic target for MM patients.

The regenerative capacity of bone is indispensable for growth, given that accidental injury is almost inevitable. Bone regenerative capacity is relevant for the aging population globally and for the repair of large bone defects after osteotomy (e.g., following removal of malignant bone tumours). Among the many therapeutic modalities proposed to bone regeneration, electrical stimulation has attracted significant attention owing to its economic convenience and exceptional curative effects, and various electroactive biomaterials have emerged. This review summarizes the current knowledge and progress regarding electrical stimulation strategies for improving bone repair. Such strategies range from traditional methods of delivering electrical stimulation via electroconductive materials using external power sources to self-powered biomaterials, such as piezoelectric materials and nanogenerators. Electrical stimulation and osteogenesis are related via bone piezoelectricity. This review examines cell behaviour and the potential mechanisms of electrostimulation via electroactive biomaterials in bone healing, aiming to provide new insights regarding the mechanisms of bone regeneration using electroactive biomaterials. The translational potential of this article: This review examines the roles of electroactive biomaterials in rehabilitating the electrical microenvironment to facilitate bone regeneration, addressing current progress in electrical biomaterials and the mechanisms whereby electrical cues mediate bone regeneration. Interactions between osteogenesis-related cells and electroactive biomaterials are summarized, leading to proposals regarding the use of electrical stimulation-based therapies to accelerate bone healing.

The Southern Highland Fold and Thrust Belt (SHFTB), the boundary of the Australian plate and the New Guinea Highland block, significantly contributes to the convergent deformation along the plate boundary. However, due to the lack of observation data, the detailed slip pattern of the SHFTB and the orogenic mechanism beneath the New Guinea Highlands remains controversial. On 25 February 2018, the MW7.5 Papua New Guinea (PNG) earthquake struck the southeastern segment of the SHFTB. The detailed rupture characteristics of this event is significant for further clarifying the inter-seismic slip pattern along the SHFTB. Here, the coseismic deformation field of this earthquake was obtained using high-resolution ALOS-2 satellite images. We find that the 2018 MW7.5 PNG earthquake ruptured a large-scaled fault (SHFTB) extending to the lower crust (deeper than 20 km) beneath the New Guinea Highlands, with a dip angle of 24°. The slips on the fault plane are equivalent to moment magnitudes of MW7.51. Three major asperities with thrust-dominated slip of up to 3.94 m are detected on the fault plane. This finding implies that the slip pattern on the eastern segment of the SHFTB is dominated by thrust, rather than with significant sinistral movement, as previously reported. The tectonic deformation across the New Guinea Highlands is possibly concentrated on the large-scale fault SHFTB and primarily controls the intra-continental orogeny in the central Papua New Guinea.

On September 5, 2022, the Luding M6.8 earthquake occurred in the Moxi-Shimian segment of the Xianshuihe fault, coinciding with the historical ruptured zone of the 1786 Moxi earthquake. Its seismogenic environment provides a foundation for comprehending the mechanism of the earthquake and its future hazard. In the Moxi-Shimian segment, we establish a series of near-field Global Navigation Satellite Systems (GNSS) stations to enhance the spatial resolution of observational data for the inversion of the interseismic kinematic parameters. In this study, with an elastic screw dislocation model constrained by GNSS observations, the slip rate of the Moxi-Shimian segment is estimated to be 10.9 ± 1.0 mm/yr, while the locking depth is 15.7 ± 6.2 km. Additionally, we utilize a block-dislocation model to invert the interseismic fault coupling along the Kangding-Moxi-Shimian segment. The result indicates a gradual deepening of the locking depth along the section from Kangding to Shimian. The coseismic rupture of the 2022 event occurred within the high coupling regions in the Kangding-Moxi-Shimian segment, which indicates that the rupture kinematics in this event might be controlled by the interseismic deformation. The seismic moment accumulated within the ruptured zone of the Luding earthquake since 1786 ranges in [1.42–3.40] × 1019 N·m, which is significantly greater than the seismic moment released during the 2022 event. As a result, we infer that the Luding earthquake released only a portion of the accumulated energy within the original rupture zone since 1786, indicating that the 2022 event has not caused a complete rupture in the Moxi-Shimian segment. Consequently, there remains a substantial seismic hazard in this area.

Abstract With the development of the economy and the increasing prevalence of skin problems, cutaneous medical aesthetics are gaining more and more attention. Skin disorders like poor wound healing, aging, and pigmentation have an impact not only on appearance but also on patients with physical and psychological issues, and even impose a significant financial burden on families and society. However, due to the complexities of its occurrence, present treatment options cannot produce optimal outcomes, indicating a dire need for new and effective treatments. Mesenchymal stem cells (MSCs) and their secretomics treatment is a new regenerative medicine therapy that promotes and regulates endogenous stem cell populations and/or replenishes cell pools to achieve tissue homeostasis and regeneration. It has demonstrated remarkable advantages in several skin-related in vivo and in vitro investigations, aiding in the improvement of skin conditions and the promotion of skin aesthetics. As a result, this review gives a complete description of recent scientific breakthroughs in MSCs for skin aesthetics and the limitations of their clinical applications, aiming to provide new ideas for future research and clinical transformation.

Abstract Spinal cord injury (SCI) often results in motor and sensory deficits, or even paralysis. Due to the role of the cascade reaction, the effect of excessive reactive oxygen species (ROS) in the early and middle stages of SCI severely damage neurons, and most antioxidants cannot consistently eliminate ROS at non-toxic doses, which leads to a huge compromise in antioxidant treatment of SCI. Selenium nanoparticles (SeNPs) have excellent ROS scavenging bioactivity, but the toxicity control problem limits the therapeutic window. Here, we propose a synergistic therapeutic strategy of SeNPs encapsulated by ZIF-8 (SeNPs@ZIF-8) to obtain synergistic ROS scavenging activity. Three different spatial structures of SeNPs@ZIF-8 were synthesized and coated with ferrostatin-1, a ferroptosis inhibitor (FSZ NPs), to achieve enhanced anti-oxidant and anti-ferroptosis activity without toxicity. FSZ NPs promoted the maintenance of mitochondrial homeostasis, thereby regulating the expression of inflammatory factors and promoting the polarization of macrophages into M2 phenotype. In addition, the FSZ NPs presented strong abilities to promote neuronal maturation and axon growth through activating the WNT4-dependent pathways, while prevented glial scar formation. The current study demonstrates the powerful and versatile bioactive functions of FSZ NPs for SCI treatment and offers inspiration for other neural injury diseases.

Abstract Chemotherapy such as cisplatin is widely used to treat ovarian cancer either before or after surgical debulking. However, cancer relapse due to chemotherapy resistance is a major challenge in the treatment of ovarian cancer. The underlying mechanisms related to chemotherapy resistance remain largely unclear. Therefore, identification of effective therapeutic strategies is urgently needed to overcome therapy resistance. Transcriptome-based analysis, in vitro studies and functional assays identified that cisplatin-resistant ovarian cancer cells express high levels of OSMR compared to cisplatin sensitive cells. Furthermore, OSMR expression associated with a module of integrin family genes and predominantly linked with integrin αV (ITGAV) and integrin β3 (ITGB3) for cisplatin resistance. Using ectopic expression and knockdown approaches, we proved that OSMR directly regulates ITGAV and ITGB3 gene expression through STAT3 activation. Notably, targeting OSMR using anti-OSMR human antibody inhibited the growth and metastasis of ovarian cancer cells and sensitized cisplatin treatment. Taken together, our results underscore the pivotal role of OSMR as a requirement for cisplatin resistance in ovarian cancer. Notably, OSMR fostered the expression of a distinct set of integrin genes, which in turn resulted into a crosstalk between OSMR and integrins for signaling activation that is critical for cisplatin resistance. Therefore, targeting OSMR emerges as a promising and viable strategy to reverse cisplatin-resistance in ovarian cancer.

Abstract Optoelectronic neural interfaces can leverage the photovoltaic effect to convert light into electrical current, inducing charge redistribution and enabling nerve stimulation. This method offers a non-genetic and remote approach for neuromodulation. Developing biodegradable and efficient optoelectronic neural interfaces is important for achieving transdermal stimulation while minimizing infection risks associated with device retrieval, thereby maximizing therapeutic outcomes. We propose a biodegradable, flexible, and miniaturized silicon-based neural interface capable of transdermal optoelectronic stimulation for neural modulation and nerve regeneration. Enhancing the device interface with thin-film molybdenum significantly improves the efficacy of neural stimulation. Our study demonstrates successful activation of the sciatic nerve in rodents and the facial nerve in rabbits. Moreover, transdermal optoelectronic stimulation accelerates the functional recovery of injured facial nerves.

Abstract Background Significant hemodynamic changes occur during liver transplantation, emphasizing the importance of precious and continuous monitoring of cardiac output, cardiac index, and other parameters. Although the monitoring of cardiac output by pulse indicator continuous cardiac output (PiCCO) was statistically homogeneous compared to the clinical gold standard pulmonary artery catheterization (PAC) in previous studies of liver transplantation, there are fewer statistical methods for the assessment of its conclusions, and a lack of comparisons of other hemodynamic parameters (e.g., SVRI, systemic vascular resistance index). Some studies have also concluded that the agreement between PiCCO and PAC is not good enough. Overall, there are no uniform conclusions regarding the agreement between PiCCO and PAC in previous studies. This study evaluates the agreement and trending ability of relevant hemodynamic parameters obtained with PiCCO compared to the clinical gold standard PAC from multiple perspectives, employing various statistical methods. Methods Fifty-two liver transplantation patients were included. Cardiac output (CO), cardiac index (CI), SVRI and stroke volume index (SVI) values were monitored at eight time points using both PiCCO and PAC. The results were analyzed by Bland-Altman analysis, Passing-bablok regression, intra-class correlation coefficient (ICC), 4-quadrant plot, polar plot, and trend interchangeability method (TIM). Results The Bland-Altman analysis revealed high percentage errors for PiCCO: 54.06% for CO, 52.70% for CI, 62.18% for SVRI, and 51.97% for SVI, indicating poor accuracy. While Passing-Bablok plots showed favorable agreement for SVRI overall and during various phases, the agreement for other parameters was less satisfactory. The ICC results confirmed good overall agreement between the two devices across most parameters, except for SVRI during the new liver phase, which showed poor agreement. Additionally, four-quadrant and polar plot analyses indicated that all agreement rate values fell below the clinically acceptable threshold of over 90%, and all angular deviation values exceeded ± 5°, demonstrating that PiCCO is unable to meet the acceptable trends. Using the TIM, the interchangeability rates were found to be quite low: 20% for CO and CI, 16% for SVRI, and 13% for SVI. Conclusions Our study revealed notable disparities in absolute values of CO, CI, SVRI and SVI between PiCCO and PAC in intraoperative liver transplant settings, notably during the neohepatic phase where errors were particularly pronounced. Consequently, these findings highlight the need for careful consideration of PiCCO’s advantages and disadvantages in liver transplantation scenarios, including its multiple parameters (such as the encompassing extravascular lung water index), against its limited correlation with PAC.

Abstract Background Intrahepatic cholangiocarcinoma (ICCA) is a heterogeneous group of malignant tumors characterized by high recurrence rate and poor prognosis. Heterochromatin Protein 1α (HP1α) is one of the most important nonhistone chromosomal proteins involved in transcriptional silencing via heterochromatin formation and structural maintenance. The effect of HP1α on the progression of ICCA remained unclear. Methods The effect on the proliferation of ICCA was detected by experiments in two cell lines and two ICCA mouse models. The interaction between HP1α and Histone Deacetylase 1 (HDAC1) was determined using Electrospray Ionization Mass Spectrometry (ESI-MS) and the binding mechanism was studied using immunoprecipitation assays (co-IP). The target gene was screened out by RNA sequencing (RNA-seq). The occupation of DNA binding proteins and histone modifications were predicted by bioinformatic methods and evaluated by Cleavage Under Targets and Tagmentation (CUT & Tag) and Chromatin immunoprecipitation (ChIP). Results HP1α was upregulated in intrahepatic cholangiocarcinoma (ICCA) tissues and regulated the proliferation of ICCA cells by inhibiting the interferon pathway in a Signal Transducer and Activator of Transcription 1 (STAT1)-dependent manner. Mechanistically, STAT1 is transcriptionally regulated by the HP1α-HDAC1 complex directly and epigenetically via promoter binding and changes in different histone modifications, as validated by high-throughput sequencing. Broad-spectrum HDAC inhibitor (HDACi) activates the interferon pathway and inhibits the proliferation of ICCA cells by downregulating HP1α and targeting the heterodimer. Broad-spectrum HDACi plus interferon preparation regimen was found to improve the antiproliferative effects and delay ICCA development in vivo and in vitro, which took advantage of basal activation as well as direct activation of the interferon pathway. HP1α participates in mediating the cellular resistance to both agents. Conclusions HP1α-HDAC1 complex influences interferon pathway activation by directly and epigenetically regulating STAT1 in transcriptional level. The broad-spectrum HDACi plus interferon preparation regimen inhibits ICCA development, providing feasible strategies for ICCA treatment. Targeting the HP1α-HDAC1-STAT1 axis is a possible strategy for treating ICCA, especially HP1α-positive cases.

The sudden onset of the coronavirus disease 2019 (COVID-19) in January 2020 has affected essential global health services. Cancer-screening services that can reduce cancer mortality are strongly affected. However, the specific role of COVID-19 in cancer screening is not fully understood. This study aimed to assess the efficiency of global cancer screening programs before and during the COVID-19 pandemic and to promote potential cancer-screening strategies for the next pandemic. Electronic searches in PubMed, Embase, and Web of Science, and manual searches were performed between January 1, 2020 and March 1, 2023. Cohort studies that reported the number of participants who underwent cancer screening before and during the COVID-19 pandemic were included. The methodological quality of the included studies was assessed using the Newcastle-Ottawa Scale. Differences in cancer-screening rates were estimated using the incidence rate ratio (IRR). Fifty-five cohort studies were included in this meta-analysis. The screening rates of colorectal cancer using invasive screening methods (Pooled IRR = 0.52, 95% CI: 0.42 to 0.65, p < 0.01), cervical cancer (Pooled IRR = 0.56, 95% CI: 0.47 to 0.67, p < 0.01), breast cancer (Pooled IRR = 0.57, 95% CI: 0.49 to 0.66, p < 0.01) and prostate cancer (Pooled IRR = 0.71, 95% CI: 0.56 to 0.90, p < 0.01) during the COVID-19 pandemic were significantly lower than those before the COVID-19 pandemic. The screening rates of lung cancer (Pooled IRR = 0.77, 95% CI: 0.58 to 1.03, p = 0.08) and colorectal cancer using noninvasive screening methods (Pooled IRR = 0.74, 95% CI: 0.50 to 1.09, p = 0.13) were reduced with no statistical differences. The subgroup analyses revealed that the reduction in cancer-screening rates varied across economies. Our results suggest that the COVID-19 pandemic has had a noteworthy impact on colorectal, cervical, breast, and prostate cancer screening. Developing innovative cancer-screening technologies is important to promote the efficiency of cancer-screening services in the post-COVID-19 era and prepare for the next pandemic.

Abstract A long-standing hypothesis proposes that certain RNA(s) must exhibit structural roles in microtubule assembly. Here, we identify a long noncoding RNA (TubAR) that is highly expressed in cerebellum and forms RNA–protein complex with TUBB4A and TUBA1A, two tubulins clinically linked to cerebellar and myelination defects. TubAR knockdown in mouse cerebellum causes loss of oligodendrocytes and Purkinje cells, demyelination, and decreased locomotor activity. Biochemically, we establish the roles of TubAR in promoting TUBB4A–TUBA1A heterodimer formation and microtubule assembly. Intriguingly, different from the hypomyelination-causing mutations, the non-hypomyelination-causing mutation TUBB4A-R2G confers gain-of-function for an RNA-independent interaction with TUBA1A. Experimental use of R2G/A mutations restores TUBB4A–TUBA1A heterodimer formation, and rescues the neuronal cell death phenotype caused by TubAR knockdown. Together, we uncover TubAR as the long-elusive structural RNA for microtubule assembly and demonstrate how TubAR mediates microtubule assembly specifically from αβ-tubulin heterodimers, which is crucial for maintenance of cerebellar myelination and activity.

Abstract A century ago, the Warburg effect was first proposed, revealing that cancer cells predominantly rely on glycolysis during the process of tumorigenesis, even in the presence of abundant oxygen, shifting the main pathway of energy metabolism from the tricarboxylic acid cycle to aerobic glycolysis. Recent studies have unveiled the dynamic transfer of mitochondria within the tumor microenvironment, not only between tumor cells but also between tumor cells and stromal cells, immune cells, and others. In this review, we explore the pathways and mechanisms of mitochondrial transfer within the tumor microenvironment, as well as how these transfer activities promote tumor aggressiveness, chemotherapy resistance, and immune evasion. Further, we discuss the research progress and potential clinical significance targeting these phenomena. We also highlight the therapeutic potential of targeting intercellular mitochondrial transfer as a future anti-cancer strategy and enhancing cell-mediated immunotherapy. Graphical Abstract Mitochondrial Transfer in the Tumor Microenvironment. This review elaborates in detail on the molecular mechanisms and pathophysiological significance behind the mitochondrial transfer occurring between tumor cells and their microenvironment. This biological phenomenon of mitochondrial transfer is prevalent in a variety of cancers, including both solid tumors and hematologic malignancies, with a high incidence in acute myeloid leukemia (AML), breast cancer, and gliomas. The review also discusses therapeutic approaches targeting mitochondrial transfer, with a special focus on its application in immunotherapy, particularly in CAR-T cell therapy, where it has begun to show unique advantages

Abstract Oxidative stress is increasingly recognized as a major contributor to the pathophysiology of Alzheimer’s disease (AD), particularly in the early stages of the disease. The multiplicity advantages of stem cell transplantation make it fascinating therapeutic strategy for many neurodegenerative diseases. We herein demonstrated that human dental pulp stem cells (hDPSCs) mediated oxidative stress improvement and neuroreparative effects in in vitro AD models, playing critical roles in regulating the polarization of hyperreactive microglia cells and the recovery of damaged neurons. Importantly, these therapeutic effects were reflected in 10-month-old 3xTg-AD mice after a single transplantation of hDPSCs, with the treated mice showing significant improvement in cognitive function and neuropathological features. Mechanistically, antioxidant and neuroprotective effects, as well as cognitive enhancements elicited by hDPSCs, were at least partially mediated by Nrf2 nuclear accumulation and downstream antioxidant enzymes expression through the activation of the AKT-GSK3β-Nrf2 signaling pathway. In conclusion, our findings corroborated the neuroprotective capacity of hDPSCs to reshape the neuropathological microenvironment in both in vitro and in vivo AD models, which may be a tremendous potential therapeutic candidate for Alzheimer’s disease.

Abstract Immune evasion contributes to cancer growth and progression. Cancer cells have the ability to activate different immune checkpoint pathways that harbor immunosuppressive functions. The programmed death protein 1 (PD-1) and programmed cell death ligands (PD-Ls) are considered to be the major immune checkpoint molecules. The interaction of PD-1 and PD-L1 negatively regulates adaptive immune response mainly by inhibiting the activity of effector T cells while enhancing the function of immunosuppressive regulatory T cells (Tregs), largely contributing to the maintenance of immune homeostasis that prevents dysregulated immunity and harmful immune responses. However, cancer cells exploit the PD-1/PD-L1 axis to cause immune escape in cancer development and progression. Blockade of PD-1/PD-L1 by neutralizing antibodies restores T cells activity and enhances anti-tumor immunity, achieving remarkable success in cancer therapy. Therefore, the regulatory mechanisms of PD-1/PD-L1 in cancers have attracted an increasing attention. This article aims to provide a comprehensive review of the roles of the PD-1/PD-L1 signaling in human autoimmune diseases and cancers. We summarize all aspects of regulatory mechanisms underlying the expression and activity of PD-1 and PD-L1 in cancers, including genetic, epigenetic, post-transcriptional and post-translational regulatory mechanisms. In addition, we further summarize the progress in clinical research on the antitumor effects of targeting PD-1/PD-L1 antibodies alone and in combination with other therapeutic approaches, providing new strategies for finding new tumor markers and developing combined therapeutic approaches.

Chinese plum (Prunus salicina Lindl.) originates from China and makes a large contribution to the global production of plums. The P. salicina ‘Wushancuili’ has a green coloration and high fruit quality and is economically important in eliminating poverty and protecting ecology in the Yangtze River Three Gorges Reservoir. However, rain-induced cracking (rain-cracking, literally skin cracking caused by rain) is a limitation to ‘Wushancuili’ fruit production and causes severe losses. This study reported a high-quality ‘Wushancuili’ genome assembly consisting of a 302.17-Mb sequence with eight pseudo-chromosomes and a contig N50 of 23.59 Mb through the combination of Illumina sequencing, Pacific Biosciences HiFi Ⅲ sequencing, and high-throughput chromosome conformation capture technology. A total of 25 109 protein-coding genes are predicted and 54.17% of the genome is composed of repetitive sequences. ‘Wushancuili’ underwent a remarkable orthoselection during evolution. Gene identification revealed that loss-of-function in four core MYB10 genes results in the anthocyanin deficiency and absence of red color, revealing the green coloration due to the residual high chlorophyll in fruit skin. Besides, the occurrence of cracking is assumed to be closely associated with cell wall modification and frequently rain-induced pathogen enrichment through transcriptomic analysis. The loss of MYB10 genes might render fruit more susceptible to pathogen-mediated cracking by weakening the epidermal strength and reactive oxygen species (ROS) scavenging. Our findings provided fundamental knowledge regarding fruit coloration and rain-cracking and will facilitate genetic improvement and cultivation management in Chinese plums.

The Greenhouse Gas Monitoring Instrument (GMI) onboard the Chinese hyperspectral satellite GF5–02 can provide abundant observations of global atmospheric CO2, which plays an important role in climate research. CO2 retrieval precision is the key to determining the application value of the GMI. To reduce the influence of atmospheric scattering on retrieval, we combined the Directional Polarimetric Camera (DPC) data on the same satellite to improve the anti-interference ability of GMI CO2 retrieval and ensure its retrieval precision. To realize the reliability and feasibility of the collaborative use of the GMI and DPC, this paper designs the pointing registration method of the GMI based on coastline observations, the spatial resolution matching method and the collaborative cloud screening method of the GMI and DPC observations. Combined with the DPC, which supplied the spectral data and aerosol product, the retrieval ability of the coupled bidirectional reflectance distribution function CO2 retrieval (CBCR) method developed for GMI CO2 retrieval was improved, with the retrieval efficiency of CO2 products increasing by 27%, and the CO2 retrieval precision increasing from 3.3 ppm to 2.7 ppm. Moreover, collaborative use not only guaranteed the GMI’s ability to detect global and area CO2 concentration distribution characteristics, such as significant concentration differences between the Northern and Southern Hemispheres in winter and high CO2 concentrations in urban agglomeration areas caused by human activities, but also extended the GMI’s potential for monitoring anomalous events, such as the Tonga volcanic eruption.

Abstract As a famous drug delivery system (DDS), mesoporous organosilica nanoparticles (MON) are degraded slowly in vivo and the degraded components are not useful for cell nutrition or cancer theranostics, and superparamagnetic iron oxide nanoparticles (SPION) are not mesoporous with low drug loading content (DLC). To overcome the problems of MON and SPION, we developed mesoporous SPIONs (MSPIONs) with an average diameter of 70 nm and pore size of 3.9 nm. Sorafenib (SFN) and/or brequinar (BQR) were loaded into the mesopores of MSPION, generating SFN@MSPION, BQR@MSPION and SFN/BQR@MSPION with high DLC of 11.5% (SFN), 10.1% (BQR) and 10.0% (SNF + BQR), demonstrating that our MSPION is a generic DDS. SFN/BQR@MSPION can be used for high performance ferroptosis therapy of tumors because: (1) the released Fe2+/3+ in tumor microenvironment (TME) can produce •OH via Fenton reaction; (2) the released SFN in TME can inhibit the cystine/glutamate reverse transporter, decrease the intracellular glutathione (GSH) and GSH peroxidase 4 levels, and thus enhance reactive oxygen species and lipid peroxide levels; (3) the released BQR in TME can further enhance the intracellular oxidative stress via dihydroorotate dehydrogenase inhibition. The ferroptosis therapeutic mechanism, efficacy and biosafety of MSPION-based DDS were verified on tumor cells and tumor-bearing mice.

Abstract Background Radiation therapy stands to be one of the primary approaches in the clinical treatment of malignant tumors. Nasopharyngeal Carcinoma, a malignancy predominantly treated with radiation therapy, provides an invaluable model for investigating the mechanisms underlying radiation therapy resistance in cancer. While some reports have suggested the involvement of circRNAs in modulating resistance to radiation therapy, the underpinning mechanisms remain unclear. Methods RT-qPCR and in situ hybridization were used to detect the expression level of circCDYL2 in nasopharyngeal carcinoma tissue samples. The effect of circCDYL2 on radiotherapy resistance in nasopharyngeal carcinoma was demonstrated by in vitro and in vivo functional experiments. The HR-GFP reporter assay determined that circCDYL2 affected homologous recombination repair. RNA pull down, RIP, western blotting, IF, and polysome profiling assays were used to verify that circCDYL2 promoted the translation of RAD51 by binding to EIF3D protein. Results We have identified circCDYL2 as highly expressed in nasopharyngeal carcinoma tissues, and it was closely associated with poor prognosis. In vitro and in vivo experiments demonstrate that circCDYL2 plays a pivotal role in promoting radiotherapy resistance in nasopharyngeal carcinoma. Our investigation unveils a specific mechanism by which circCDYL2, acting as a scaffold molecule, recruits eukaryotic translation initiation factor 3 subunit D protein (EIF3D) to the 5′-UTR of RAD51 mRNA, a crucial component of the DNA damage repair pathway to facilitate the initiation of RAD51 translation and enhance homologous recombination repair capability, and ultimately leads to radiotherapy resistance in nasopharyngeal carcinoma. Conclusions These findings establish a novel role of the circCDYL2/EIF3D/RAD51 axis in nasopharyngeal carcinoma radiotherapy resistance. Our work not only sheds light on the underlying molecular mechanism but also highlights the potential of circCDYL2 as a therapeutic sensitization target and a promising prognostic molecular marker for nasopharyngeal carcinoma.

ABSTRACTEfficiently querying multiple spatial datasets is a challenging task in geoscience. The majority of spatial processing techniques use minimum bounding box (MBB) to approximate neighbouring spatial objects and and place them adjacent in the spatial index. However, due to the existence of redundant space in MBB of these methods, this problem can significantly reduce the query efficiency. In this paper, we propose a novel two-stage adaptive method of clipping the bounding box in spatial query, called IB-CBB (Intersection Based Clipped Bounding Boxes). The first stage employs a clipped bounding box, which records the redundant spatial spaces within the bounding box of the spatial index by calculating the clip points. As a result, the computational complexity of indexed child nodes in the query process is reduced. The second stage optimizes the above query algorithm by judging the intersection of the query box and the MBB of index node, significantly reducing the query time. Experiments demonstrate that IB-CBB outperforms the baseline method in terms of reducing the computational time.

Abstract Scientifically validating the value of rural heritage and exploring construction wisdom has emerged as a significant challenge in the study of rural settlements worldwide. Rural heritage shows significant differences according to the natural environment, history, culture, and socio-economic factors. However, the assessment of the authenticity and effectiveness of heritage values have yet to be quantified due to the difficulty in obtaining evidence directly from samples. By constructing a multi-dimensional model of villages for quantitative analysis, we proposed a multifaceted spatial visibility analysis method based on individual and combined defense structures to empirically study the remains of eight towers in Moluo village, western China. This study demonstrated that towers serve as regional defense structures and are essential for constructing a comprehensive and effective visual defensive system (VDS) in Moluo village, a typical military defense village. The effectiveness and coverage of the towers vary depending on their location, height, type, and other factors. They form a complementary and synergistic relationship, playing a dual mechanism of public and private, local and overall defense. In summary, this method enables the feasible quantification and analysis of the functional value of rural heritage through landscape visual analysis. It provides a new perspective for studying the authenticity of heritage functions.

Abstract To overcome the problems of commercial magnetic resonance imaging (MRI) contrast agents (CAs) (i.e., small molecule Gd chelates), we have proposed a new concept of Gd macrochelates based on the coordination of Gd3+ and macromolecules, e.g., poly(acrylic acid) (PAA). To further decrease the r 2/r 1 ratio of the reported Gd macrochelates that is an important factor for T 1 imaging, in this study, a superior macromolecule hydrolyzed polymaleic anhydride (HPMA) was found to coordinate Gd3+. The synthesis conditions were optimized and the generated Gd-HPMA macrochelate was systematically characterized. The obtained Gd-HPMA29 synthesized in a 100 L of reactor has a r 1 value of 16.35 mM−1 s−1 and r 2/r 1 ratio of 2.05 at 7.0 T, a high Gd yield of 92.7% and a high product weight (1074 g), which demonstrates the feasibility of kilogram scale facile synthesis. After optimization of excipients and sterilization at a high temperature, the obtained Gd-HPMA30 formulation has a pH value of 7.97, osmolality of 691 mOsmol/kg water, density of 1.145 g/mL, and viscosity of 2.2 cP at 20 ℃ or 1.8 cP at 37 ℃, which meet all specifications and physicochemical criteria for clinical injections indicating the immense potential for clinical applications. Graphical Abstract

To investigate the impact of different seedling transplanting times on rice growth, the present study evaluated seedling age and root pruning using treatments consisting of root pruning (RC20, RC30, and RC40) and no root pruning (CK20, CK30, and CK40). Quantitative analysis using curve fitting of the changes in dry matter accumulation (DMA) during the seedling and field stages was performed, and the changes in root parameters during the re-greening stage were observed. The results showed that the seedling stage could be divided into a gradual increase period, a rapid increase period, and a slow increase period. Transplanting at different time periods resulted in different transplanting shock effects. During the field stage, the DMA exhibited a slow-fast-slow "S" shaped curve as the developmental time progressed. However, significant differences were observed in growth parameters among the different treatments. Root injury promoted early maturity in young seedlings but also prolonged the whole growth period in older seedlings. The inhibitory effect of root pruning on rice root growth increased with young seedling age. The present results provide a theoretical basis for the design of seedling needle structure and the optimisation of rice seedling cultivation practices.

Objective Moraine soil in seasonal permafrost areas is significantly affected by freeze-thaw cycles, which greatly affects the stability and safety of projects. Methods To investigate the effect of freeze-thaw cycles and water content on the static mechanical properties of the soil, the influence of freeze-thaw cycles and water content on the mechanical parameters of Hailuogou moraine soil was studied via an unconsolidated-undrained triaxial test. Results The results show that the stress-strain curves of the moraine soil before and after freeze-thaw cycling exhibit weak strain softening. With an increase in the number of freeze-thaw cycles, the elastic modulus and shear strength of the moraine soil first rapidly decrease and subsequently tend to stabilize. The higher the water content is, the greater the decay degree of the mechanical parameters. As the number of freeze-thaw cycles increases, the cohesion decreases exponentially, while the friction angle does not change significantly. The exponential function is thus adopted for multiple nonlinear fittings of the shear strength and elastic modulus. The relationship between mechanical parameters and confining conditions pressure, water content, and freeze-thaw cycles are obtained and show good correlation, which can be used to deduce the mechanical parameters of moraine soil after freeze-thaw cycles. The freeze-thaw cycles weaken the mechanical properties of moraine soil, and the higher the water content is, the greater the degree of attenuation. Conclusion The obtained results and analyses can provide scientific support for engineering design and construction in alpine regions.

Abstract Background Chimeric antigen receptor T (CAR‐T) therapy has substantially revolutionized the clinical outcomes of patients with hematologic malignancies, but the cancer‐intrinsic mechanisms underlying resistance to CAR‐T cells remain yet to be fully understood. This study aims to explore the molecular determinants of cancer cell sensitivity to CAR‐T cell‐mediated killing and to provide a better understanding of the underlying mechanisms and potential modulation to improve clinical efficacy. Methods The human whole‐genome CRISPR/Cas9‐based knockout screening was conducted to identify key genes that enable cancer cells to evade CD19 CAR‐T‐cell‐mediated killing. The in vitro cytotoxicity assays and evaluation of tumor tissue and bone marrow specimens were further conducted to confirm the role of the key genes in cancer cell susceptibility to CAR‐T cells. In addition, the specific mechanisms influencing CAR‐T cell‐mediated cancer clearance were elucidated in mouse and cellular models. Results The CRISPR/Cas9‐based knockout screening showed that the enrichment of autophagy‐related genes (ATG3, BECN1, and RB1CC1) provided protection of cancer cells from CD19 CAR‐T cell‐mediated cytotoxicity. These findings were further validated by in vitro cytotoxicity assays in cells with genetic and pharmacological inhibition of autophagy. Notably, higher expression of the three autophagy‐related proteins in tumor samples was correlated with poorer responsiveness and worse survival in patients with relapsed/refractory B‐cell lymphoma after CD19 CAR‐T therapy. Bulk RNA sequencing analysis of bone marrow samples from B‐cell leukemia patients also suggested the clinical relevance of autophagy to the therapeutic response and relapse after CD19 CAR‐T cell therapy. Pharmacological inhibition of autophagy and knockout of RB1CC1 could dramatically sensitize tumor cells to CD19 CAR‐T cell‐mediated killing in mouse models of both B‐cell leukemia and lymphoma. Moreover, our study revealed that cancer‐intrinsic autophagy mediates evasion of CAR‐T cells via the TNF‐α‐TNFR1 axis‐mediated apoptosis and STAT1/IRF1‐induced chemokine signaling activation. Conclusions These findings confirm that autophagy signaling in B‐cell malignancies is essential for the effective cytotoxic function of CAR‐T cells and thereby pave the way for the development of autophagy‐targeting strategies to improve the clinical efficacy of CAR‐T cell immunotherapy.

Abstract It is newly revealed that collagen works as a physical barrier to tumor immune infiltration, oxygen perfusion, and immune depressor in solid tumors. Meanwhile, after radiotherapy (RT), the programmed death ligand‐1 (PD‐L1) overexpression and transforming growth factor‐β (TGF‐β) excessive secretion would accelerate DNA damage repair and trigger T cell exclusion to limit RT efficacy. However, existing drugs or nanoparticles can hardly address these obstacles of highly effective RT simultaneously, effectively, and easily. In this study, it is revealed that inducing mitochondria dysfunction by using oxidative phosphorylation inhibitors like Lonidamine (LND) can serve as a highly effective multi‐immune pathway regulation strategy through PD‐L1, collagen, and TGF‐β co‐depression. Then, IR‐LND is prepared by combining the mitochondria‐targeted molecule IR‐68 with LND, which then is loaded with liposomes (Lip) to create IR‐LND@Lip nanoadjuvants. By doing this, IR‐LND@Lip more effectively sensitizes RT by generating more DNA damage and transforming cold tumors into hot ones through immune activation by PD‐L1, collagen, and TGF‐β co‐inhibition. In conclusion, the combined treatment of RT and IR‐LND@Lip ultimately almost completely suppressed the growth of bladder tumors and breast tumors.

Abstract Currently, the typical combination therapy of programmed death ligand‐1 (PD‐L1) antibodies with radiotherapy (RT) still exhibits impaired immunogenic antitumor response in clinical due to lessened DNA damage and acquired immune tolerance via the upregulation of some other immune checkpoint inhibitors. Apart from this, such combination therapy may raise the occurrence rate of radiation‐induced lung fibrosis (RIPF) due to enhanced systemic inflammation, leading to the ultimate death of cancer patients (average survival time of about 3 years). Therefore, it is newly revealed that mitochondria energy metabolism regulation can be used as a novel effective PD‐L1 and transforming growth factor‐β (TGF‐β) dual‐downregulation method. Following this, IR‐TAM is prepared by conjugating mitochondria‐targeted heptamethine cyanine dye IR‐68 with oxidative phosphorylation (OXPHOS) inhibitor Tamoxifen (TAM), which then self‐assembled with albumin (Alb) to form IR‐TAM@Alb nanoparticles. By doing this, tumor‐targeting IR‐TAM@Alb nanoparticle effectively reversed tumor hypoxia and depressed PD‐L1 and TGF‐β expression to sensitize RT. Meanwhile, due to the capacity of heptamethine cyanine dye in targeting RIPF and the function of TAM in depressing TGF‐β, IR‐TAM@Alb also ameliorated fibrosis development induced by RT.

Objective: This study aims to comprehensively analyze genomic, transcriptomic, proteomic, and single-cell sequencing data to unravel the molecular basis of primary Sjögren's syndrome (pSS) and explore potential therapeutic targets. Methods: Mendelian randomization and single-cell RNA sequencing were employed to analyze pSS data. Differentially expressed genes specific to different blood cell types were identified. Integration of multiomics data facilitated the exploration of genetic regulatory relationships. Results: The analysis revealed distinct cell clusters representing various immune cell subsets. Several genes, including cathepsin S (CTSS) and glutathione S-transferase omega 1 (GSTO1), were identified as potential biomarkers and therapeutic targets for pSS. Diagnostic utility analysis demonstrated the discriminatory power of CTSS and GSTO1 in distinguishing pSS patients from healthy controls. Conclusion: The findings highlight the importance of integrating multiomics data for understanding pSS pathogenesis. CTSS and GSTO1 show promise as diagnostic biomarkers and potential therapeutic targets for pSS. Further investigations are warranted to elucidate the underlying mechanisms and develop targeted therapies for this complex autoimmune disease.

Summary: Bone tissue represents the most frequent site of cancer metastasis. We developed a hemichannel-activating antibody, Cx43-M2. Cx43-M2, directly targeting osteocytes in situ, activates osteocytic hemichannels and elevates extracellular ATP, thereby inhibiting the growth and migration of cultured breast and osteosarcoma cancer cells. Cx43-M2 significantly decreases breast cancer metastasis, osteosarcoma growth, and osteolytic activity, while improving survival rates in mice. The antibody’s inhibition of breast cancer and osteosarcoma is dose dependent in both mouse and human cancer metastatic models. Furthermore, Cx43-M2 enhances anti-tumor immunity by increasing the population and activation of tumor-infiltrating immune-promoting effector T lymphocytes, while reducing immune-suppressive regulatory T cells. Our results suggest that the Cx43-M2 antibody, by activating Cx43 hemichannels and facilitating ATP release and purinergic signaling, transforms the cancer microenvironment from a supportive to a suppressive state. Collectively, our study underscores the potential of Cx43-M2 as a therapeutic for treating breast cancer bone metastasis and osteosarcoma.

Breast cancer is the most prevalent malignancy and the most significant contributor to mortality in female oncology patients. Potassium Two Pore Domain Channel Subfamily K Member 1 (KCNK1) is differentially expressed in a variety of tumors, but the mechanism of its function in breast cancer is unknown. In this study, we found for the first time that KCNK1 was significantly up-regulated in human breast cancer and was correlated with poor prognosis in breast cancer patients. KCNK1 promoted breast cancer proliferation, invasion, and metastasis in vitro and vivo. Further studies unexpectedly revealed that KCNK1 increased the glycolysis and lactate production in breast cancer cells by binding to and activating lactate dehydrogenase A (LDHA), which promoted histones lysine lactylation to induce the expression of a series of downstream genes and LDHA itself. Notably, increased expression of LDHA served as a vicious positive feedback to reduce tumor cell stiffness and adhesion, which eventually resulted in the proliferation, invasion, and metastasis of breast cancer. In conclusion, our results suggest that KCNK1 may serve as a potential breast cancer biomarker, and deeper insight into the cancer-promoting mechanism of KCNK1 may uncover a novel therapeutic target for breast cancer treatment.

BackgroundPostoperative pain is a common occurrence in pediatric patients following craniotomy, often leading to negative outcomes. Intravenous dexmedetomidine and lidocaine are commonly used adjuvant medicines in general anesthesia to reduce perioperative opioid consumption and relieve postoperative pain in adults. While they show promise for use in pediatrics, the evidence of their application in pediatric craniotomy patients is limited. Therefore, we aimed to compare the effects of dexmedetomidine and lidocaine on postoperative pain in pediatric patients following craniotomy.MethodsWe conducted a randomized, double-blind, single-center trial on children scheduled for craniotomy. The 255 recruited participants aged 1–12 years were randomly assigned to intraoperatively receive a loading intravenous dose of either dexmedetomidine 1 μg·kg−1 or lidocaine 2 mg·kg−1 or normal saline for 15 min followed by dexmedetomidine 0.5 μg·kg−1·h−1 or lidocaine 1 mg·kg−1·h−1 or normal saline until the sutures of endocranium were completed. The primary outcome was the cumulative sufentanil consumption within 24 h post-surgery.ResultsA total of 241 patients were included in the statistical analysis. The primary outcome did not show any significant differences among the three groups (median (IQR) lidocaine group: 3.36 (1.32–5.64) μg vs. dexmedetomidine group: 3.12 (1.36–6.39) μg vs. control group 3.46 (1.77–7.62) μg, p = 0.485). Among the secondary outcomes, there was a statistically significant but small reduction in sufentanil consumption within 2 h, postoperative FLACC/WBFS/NRS pain scores within 4 h after surgery and postoperative Ramsay sedation scores in dexmedetomidine group (p

Venous thromboembolism (VTE) is associated with high morbidity and mortality. Risk scores associated with VTE have been widely used in clinical practice. Among numerous scores published, those included in guidelines are usually typical risk scores which have been extensively validated and globally recognized. This review provides an updated overview of the risk scores associated with VTE endorsed by 3 guidelines which are highly recognized in the field of VTE including the European Society of Cardiology, American College of Chest Physicians, and American Society of Hematology, focusing on the development, modification, validation, and comparison of these scores, to provide a comprehensive and updated understanding of all the classic risk scores associated with VTE to medical readers including but not limited to cardiologists, pulmonologists, hematologists, intensivists, physicians, surgeons, and researchers. Although each score recommended by these guidelines was more or less validated, there may still be room for further improvement. It may still be necessary to seek simpler, more practical, and more universally applicable VTE-related risk scores in the future.

BackgroundThe role of recombinant human granulocyte colony-stimulating factor (rhG-CSF), especially the long-acting factor in the development of cancer-associated venous thromboembolism (VTE) in lung cancer patients who undergo chemotherapy has been understudied, although the use of rhG-CSF has been reported to be associated with an increased risk of VTE.MethodsWe retrospectively reviewed 1,673 lung cancer patients who underwent hospitalized chemotherapy. We performed propensity score matching to offset confounding factors related to cancer-associated VTE development and classified the patients into short-acting (N = 273), long-acting (N = 273), and no rhG-CSF (N = 273) groups. The primary outcome was cumulative cancer-associated VTE development three months after all cycles of chemotherapy.ResultsThe overall VTE incidence in the short-acting, long-acting, and no rhG-CSF groups was 5.5%, 10.3%, and 2.2%, respectively (P

Abstract Efferocytosis, an intrinsic regulatory mechanism to eliminate apoptotic cells, will be suppressed due to the delayed apoptosis process in aging‐related diseases, such as osteoarthritis (OA). In this study, cartilage lesion‐localized hydrogel microspheres are developed to remodel the in situ efferocytosis to reverse cartilage senescence and recruit endogenous stem cells to accelerate cartilage repair. Specifically, aldehyde‐ and methacrylic anhydride (MA)‐modified hyaluronic acid hydrogel microspheres (AHM), loaded with pro‐apoptotic liposomes (liposomes encapsulating ABT263, A‐Lipo) and PDGF‐BB, namely A‐Lipo/PAHM, are prepared by microfluidic and photo‐cross‐linking techniques. By a degraded porcine cartilage explant OA model, the in situ cartilage lesion location experiment illustrated that aldehyde‐functionalized microspheres promote affinity for degraded cartilage. In vitro data showed that A‐Lipo induced apoptosis of senescent chondrocytes (Sn‐chondrocytes), which can then be phagocytosed by the efferocytosis of macrophages, and remodeling efferocytosis facilitated the protection of normal chondrocytes and maintained the chondrogenic differentiation capacity of MSCs. In vivo experiments confirmed that hydrogel microspheres localized to cartilage lesion reversed cartilage senescence and promoted cartilage repair in OA. It is believed this in situ efferocytosis remodeling strategy can be of great significance for tissue regeneration in aging‐related diseases.

Prostate adenocarcinoma (PRAD), driven by both genetic and epigenetic factors, is a common malignancy that affects men worldwide. We aimed to identify and characterize differentially expressed epigenetic-related genes (ERGs) in PRAD and investigate their potential roles in disease progression and prognosis. We used PRAD samples from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) to identify prognosis-associated ERGs. Thirteen ERGs with two distinct expression profiles were identified through consensus clustering. Gene set variation analysis highlighted differences in pathway activities, particularly in the Hedgehog and Notch pathways. Higher epigenetic scores correlated with favorable prognosis and improved immunotherapeutic response. Experimental validation underscored the importance of CBX3 and KAT2A, suggesting their pivotal roles in PRAD. This study provides crucial insights into the epigenetic scoring approach and presents a promising prognostic tool, with CBX3 and KAT2A as key players. These findings pave the way for targeted and personalized interventions for the treatment of PRAD.

BackgroundGreen tea intake has been reported to improve the clinical outcomes of patients with cardiovascular diseases or cancer. It may have a certain role in the development of venous thromboembolism (VTE) among cancer patients. The current study aimed to address this issue, which has been understudied.MethodsWe carried out a retrospective study to explore the role of green tea intake in cancer patients. Patients with and without green tea intake were enrolled in a 1:1 ratio by using propensity scoring matching. The primary and secondary outcomes were VTE development and mortality 1 year after cancer diagnosis, respectively.ResultsThe cancer patients with green tea intake (n = 425) had less VTE development (10 [2.4%] vs. 23 [5.4%], p = 0.021), VTE-related death (7 [1.6%] vs. 18 [4.2%], p = 0.026), and fatal pulmonary embolism (PE) (3 [0.7%] vs. 12 [2.8%], p = 0.019), compared with those without green tea intake (n = 425). No intake of green tea was correlated with an increase in VTE development (multivariate hazard ratio (HR) 1.758 [1.476–2.040], p

Maternal diet is indispensable for the proper development of offspring, and the establishment of a well-functioning intestinal barrier is crucial for normal growth and development. Edible bird’s nest (EBN) has positive impacts on intestinal health, but the underlying mechanisms are unknown. Our study showed that maternal EBN supplementation downregulated the serum levels of diamine oxidase and D-lactate, elevated expression of tight junction proteins ZO-1, Occludin, and Claudin-1, and regulated the intestinal microbiota in rat offspring. Spearman’s correlation analysis revealed that Claudin-1, transforming growth factor-β (TGF-β), and transcription factor RUNX3 were positively correlated with changes in intestinal bacteria. EBN may upregulate the expression of TGF-β by modulating the intestinal microbiota composition, enhancing RUNX3 binding to the Claudin-1 promoter region to upregulate its expression. In conclusion, we demonstrated that maternal EBN supplementation during gestation and lactation enhanced intestinal barrier function by upregulating Claudin-1 in rat offspring.

Two-dimensional (2D) multiferroic materials have triggered a burst of interest owing to their wide applications in nanoelectronics. Specifically, p-orbital multiferroicity is strongly desired but has been very few reported. Here, based on first-principles calculations, we unveil a new type of 2D multiferroic material: the single-layer (SL) XN (X = Ge, Sn, Pb). Our findings show these materials are ferromagnetic semiconductors with strong magnetoelectric coupling and wide bandgaps. The multiferroicity is related to the unpaired p-orbital electrons of N atoms and the buckled crystal structure. All the single layers show easy-plane magnetocrystalline anisotropy, and the magnetic anisotropy energy increases significantly with the atomic number increasing. Our Monte Carlo simulations suggest the Curie temperature TC is 205.44 K, 200.45 K, and 287.88 K for SL GeN, SnN, and PbN, respectively. By applying tensile strain, the TC can be further increased to 225.39 K, 245.35 K, 369.99 K, respectively. Additionally, biaxial strain can induce semiconductor-to-half-metal and ferroelectricity-to-paraelectricity transition in the single layers. We aspire that our work contributes to the exploration of room-temperature p-orbital multiferroicity.

The recent remarkable success of mesoporous silica nanoparticle (MSN) technology has stimulated intensive efforts to expand nanoparticle strategies to treat various diseases. However, as an anti-tumor drug delivery system, traditional MSN is prone to clearance by the host immune system, resulting in suboptimal pharmacokinetics and inadequate drug concentrations in tumors. The emergence of biomimetic drug delivery systems has effectively addressed these challenges. In this study, we aimed to develop a biomimetic drug delivery system based on MSN to achieve both immune evasion and tumor targeting. To this end, we coated folic acid-modified mesoporous silica (FMSN) cores with lipid-hybridized macrophage membranes (HEs) through co-extrusion, yielding FMSN@HEs. Initially, we demonstrated effective retention of key proteins Integrin α4 and Integrin β1 in the HEs, leading to significantly reduced clearance of FMSN@HEs by phagocytes in vitro. CCK-8 experiments validated the ability of CUR-FMSN@HEs to effectively inhibit the proliferation of tumor cells. In tumor-bearing mice, FMSN@HEs exhibited stronger tumor targeting and penetration abilities compared to MSN without HEs. The immune escape and tumor-targeting properties of the FMSN@HEs suggest that they could be used as novel bionic drug carriers, potentially providing more options for antitumor therapy.

Interactive holography offers unmatched levels of immersion and user engagement in the field of future display. Despite of the substantial progress has been made in dynamic meta-holography, the realization of real-time, highly smooth interactive holography remains a significant challenge due to the computational and display frame rate limitations. In this study, we introduced a dynamic interactive bitwise meta-holography with ultra-high computational and display frame rates. To our knowledge, this is the first reported practical dynamic interactive metasurface holographic system. We spatially divided the metasurface device into multiple distinct channels, each projecting a reconstructed sub-pattern. The switching states of these channels were mapped to bitwise operations on a set of bit values, which avoids complex hologram computations, enabling an ultra-high computational frame rate. Our approach achieves a computational frame rate of 800 kHz and a display frame rate of 23 kHz on a low-power Raspberry Pi computational platform. According to this methodology, we demonstrated an interactive dynamic holographic Tetris game system that allows interactive gameplay, color display, and on-the-fly hologram creation. Our technology presents an inspiration for advanced dynamic meta-holography, which is promising for a broad range of applications including advanced human-computer interaction, real-time 3D visualization, and next-generation virtual and augmented reality systems.

Abstract Background Retinal pigment epithelium (RPE) cell therapy is a promising way to treat many retinal diseases. However, obtaining transplantable RPE cells is time-consuming and less effective. This study aimed to develop novel strategies for generating engineered RPE patches with physiological characteristics. Results Our findings revealed that RPE cells derived from human induced pluripotent stem cells (hiPSCs) successfully self-assembled into spheroids. The RPE spheroids treated with Y27632 and Repsox had increased expression of epithelial markers and RPE-specific genes, along with improved cell viability and barrier function. Transcriptome analysis indicated enhanced cell adhesion and extracellular matrix (ECM) organization in RPE spheroids. These RPE spheroids could be seeded and bioprinted on collagen vitrigel (CV) membranes to construct engineered RPE sheets. Circular RPE patches, obtained by trephining a specific section of the RPE sheet, exhibited abundant microvilli and pigment particles, as well as reduced proliferative capacity and enhanced maturation. Conclusions Our study suggests that the supplementation of small molecules and 3D spheroid culture, as well as the bioprinting technique, can be effective methods to promote RPE cultivation and construct engineered RPE sheets, which may support future clinical RPE cell therapy and the development of RPE models for research applications.

Abstract Background Atelectasis after anesthesia induction in most patients undergoing general anesthesia may lead to postoperative pulmonary complications (PPCs) and affect postoperative outcomes. However, there is still no existing effective method used for the prevention of perioperative atelectasis. S-ketamine may prevent atelectasis due to airway smooth muscle relaxation and anti-inflammatory effects. Lung ultrasound is a portable and reliable bedside imaging technology for diagnosing anesthesia-induced atelectasis. The primary objective of this study is to assess whether a small dose of S-ketamine can reduce the incidence of atelectasis after intubation, and further investigate the effects of preventing the early formation of perioperative atelectasis and PPCs. Methods This is a single-institution, prospective, randomized controlled, parallel grouping, and double-blind study. From October 2020 to March 2022, 100 patients (18–60 years old) scheduled for elective surgery will be recruited from Beijing Tiantan Hospital, Capital Medical University, and randomly assigned to the S-ketamine group (group 1) and the normal saline group (group 2) at a ratio of 1:1. The label-masked agents will be administered 5 min before induction, and all patients will undergo a standardized general anesthesia protocol. Related data will be collected at three time points: after radial artery puncture (T1), 15 min after tracheal intubation (T2), and before extubation (T3). The primary outcome will be the total lung ultrasound scores (LUS) at T2. Secondary outcomes will include LUS in six chest regions at T2, total LUS at T3, arterial blood gas analysis results (PaCO2, PaO2) and PaO2/FiO2 at T2 and T3, and plateau pressure (Pplat) and dynamic lung compliance (Cdyn) at T2 and T3. The incidence of postoperative complications associated with S-ketamine and PPCs at 2 h and 24 h after surgery will be recorded. Discussion This trial aims to explore whether a simple and feasible application of S-ketamine before the induction of general anesthesia can prevent atelectasis. The results of this study may provide new ideas and direct clinical evidence for the prevention and treatment of perioperative pulmonary complications during anesthesia. Trial registration ClinicalTrials.gov NCT04745286. Registered on February 9, 2021.

Abstract Under the condition of small roof deformation before the occurrence of fractures and collapse in room and pillar mined-out areas caused by coal pillar instability, the surface deformation may be large, which threatens the safety of ground structures. Interferometric synthetic aperture radar, geophysical exploration, geotechnical exploration and physical simulation tests were conducted to analyse the deformation and development mechanism of the overlying strata in the mined-out area in this case. The results show that in terms of surface deformation, the surface deformation caused by coal pillar instability in the room and pillar mined-out area exhibits the slow deformation stage, uniform deformation stage and accelerated deformation stage. In terms of deformation of overlying strata, after the completion of room and pillar mining, a strip-shaped deformation area and trapezoidal deformation area are developed in the overlying rock. With the occurrence of coal pillar instability, a trapezoidal deformation area and inverted funnel-shaped deformation area are developed in the overlying rock. The deformation characteristics of unconsolidated formations transition from trapezoidal deformation after room and pillar mining to funnel-shaped deformation due to coal pillar instability. Moreover, the maximum surface deformation point is located at the centre of the funnel. In terms of spatial morphology of mined-out area deformation, the maximum surface deformation point corresponds to the position of the initial coal pillar instability and the crack in the mined-out area roof along the vertical direction. The mined-out area treatment method can be optimized based on the deformation characteristics of the overlying strata in the room and pillar mined-out area under the condition of coal pillar instability.

To achieve the uniform and fine-grained microstructures during thermal deformation of nickel-based superalloys, a novel two-stage deformation approach was employed, involving prior cold deformation treatment (PCDT) and subsequent thermal deformation. Experimental investigations concerning this two-stage deformation method were carried out on Ni80A superalloy, encompassing various combinations of cold and thermal compression parameters. The analysis of microstructures revealed that PCDT significantly enhances dynamic recrystallization (DRX) process, resulting in fine-grained microstructures during thermal compression and expanding the processing-parameter domains for grain refinement. To clarify the shift of DRX kinetics in thermal compression induced by PCDT, the DRX kinetics models considering this pre-treatment were derived. These models demonstrated a linear inverse correlation between the activation energy within DRX kinetics models and prior stored energy from PCDT. This suggested that PCDT promotes the DRX process by reducing the activation energy during thermal compression. Following, the kinetics curves depicting DRX volume fraction during thermal deformation were drawn. Results indicated that under an identical thermal compression condition, the kinetics curve shifts towards decreasing strain with increasing of prior cold deformation. Under various thermal compression conditions, these kinetics curves for Ni80A superalloy processed with PCDT get shifted to the direction of decreasing strain when compared to the alloy without PCDT. These shifts underscore a pronounced acceleration of DRX process induced by PCDT. Finally, a finite element model incorporating DRX kinetics models was developed to further illustrate the influence of PCDT on the shift of DRX in an upsetting process, which shows a promising potential for theoretical calculations.

Abstract Background Compared with a lower neutrophil to lymphocyte ratio(NLR), a higher one denotes severe asthma exacerbation in hospitalized asthmatic children. In addition, NLR is significantly higher in pediatric patients with community-acquired pneumonia (CAP) than those without. Nevertheless, its role in pediatric patients with concomitant asthmatic exacerbation and CAP remains unknown. Methods In this retrospective study including 1032 pediatric patients aged 5 to 14 years old, the diagnostic and prognostic value of NLR in children with concomitant asthmatic exacerbation and non-severe CAP were investigated. Results The sensitivity and specificity of NLR for a diagnosis of CAP in patients with asthmatic exacerbation were 56.9% and 90.1%, respectively. The cutoff value of NLR for a diagnosis of CAP in patients with asthmatic exacerbation was 4.15 (P

Abstract Intestinal epithelia impairment of inflammatory bowel disease (IBD) leads to the leakage of bacteria and antigens and the consequent persistent immune imbalance. Restoring the epithelial barrier is a promising therapeutic target but lacks effective and safe clinical interventions. By identifying the catalase (CAT) presence in the IBD pathological environment, we herein develop a CAT-catalyzed pathologically coating on the damaged epithelial barrier to inhibit intestinal leakage for IBD therapy. With the codelivery of CaO2 (a CAT substrate) and dopamine, the nanosystem can enable CAT-catalyzed oxygen (O2) production and in-situ polymerization of dopamine and then yield a thin and integrative polydopamine (PDA) coating on the intestinal barrier due to the highly adhesive property of PDA. In vivo study demonstrates that PDA coating provides not only a protective barrier by restricting intestinal leakage but also a favorable anti-inflammation effect. Beyond drug management, this work provides a physical repair strategy via catalyzed coating for IBD therapy.