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Conversational large language models (LLMs) such as ChatGPT and GPT-4 have recently exhibited remarkable capabilities across various domains, capturing widespread attention from the public. To facilitate this line of research, in this paper, we report the development of MOSS, an open-sourced conversational LLM that contains 16 B parameters and can perform a variety of instructions in multi-turn interactions with humans. The base model of MOSS is pre-trained on large-scale unlabeled English, Chinese, and code data. To optimize the model for dialogue, we generate 1.1 M synthetic conversations based on user prompts collected through our earlier versions of the model API. We then perform preference-aware training on preference data annotated from AI feedback. Evaluation results on real-world use cases and academic benchmarks demonstrate the effectiveness of the proposed approaches. In addition, we present an effective practice to augment MOSS with several external tools. Through the development of MOSS, we have established a complete technical roadmap for large language models from pre-training, supervised fine-tuning to alignment, verifying the feasibility of chatGPT under resource-limited conditions and providing a reference for both the academic and industrial communities. Model weights and code are publicly available at https://github.com/OpenMOSS/MOSS.

Gene expression profiling of tissue cells with spatial context is in high demand to reveal cell types, locations, and intercellular or molecular interactions for physiological and pathological studies. With rapid advances in barcoding chemistry and sequencing chemistry, spatially resolved transcriptome (SRT) techniques have emerged to quantify spatial gene expression in tissue samples by correlating transcripts with their spatial locations using diverse strategies. These techniques provide both physical tissue structure and molecular characteristics and are poised to revolutionize many fields, such as developmental biology, neuroscience, oncology, and histopathology. In this context, this Perspective focuses on next-generation sequencing-based SRT methods, particularly highlighting spatial barcoding chemistry. It delves into optically manipulated spatial indexing methods and DNA array-barcoded spatial indexing methods by exploring current advances, challenges, and future development directions in this nascent field.

Intelligence quotient (IQ) and adaptive behavior are the influencing factors of autism spectrum disorder (ASD) in children entering mainstream schools. This study explored the association between parental education level, IQ, and adaptive behavior in ASD groups. A total of 257 school-age ASD children were enrolled in our study from January 2017 to June 2021. Their parents completed a standard demographic form, including age at autism diagnosis, gender, school placement, and parents’ educational background. The Chinese version of the Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV) was completed by a certified assessor for each enrolled child. Parents were interviewed on adaptive behavior using the Chinese version of the Adaptive Behavior Assessment System, Second Edition (ABAS-II). The average IQ of school-age ASD children was 76.88 (standard deviation (SD)=22.62) and boys had higher IQ levels than girls. The IQ was positively correlated with age. The General Adaptive Composite (GAC) score was 82.47 (SD=15.86) and adaptive behavior did not increase with age. ASD children who attended mainstream schools had better adaptive behavior profiles than other children. The mother’s education level showed a significant correlation with the IQ and adaptive behavior of autistic children, while the father’s education level did not. Consequently, better training and support for parents may help autistic children enter mainstream schools, with adaptive training being the most urgently required skill for parents.

The transcription factor forkhead box protein (FOX)-O3 is a core regulator of cellular homeostasis, stress response, and longevity. The cellular localization of FOXO3 is closely related to its function. Herein, the role of FOXO3 in cataract formation was explored. FOXO3 showed nuclear translocation in lens epithelial cells (LECs) arranged in a single layer on lens capsule tissues from both human cataract and N-methyl-N-nitrosourea (MNU)-induced rat cataract, also in MNU-injured human (H)-LEC lines. FOXO3 knockdown inhibited the MNU-induced increase in expression of genes related to cell cycle arrest (GADD45Aand CCNG2) and apoptosis (BAKand TP53). H2is highly effective in reducing oxidative impairments in nuclear DNA and mitochondria. When H2was applied to MNU-injured HLECs, FOXO3 underwent cleavage by MAPK1 and translocated into mitochondria, thereby increasing the transcription of oxidative phosphorylation-related genes (MTCO1, MTCO2, MTND1, and MTND6) in HLECs. Furthermore, H2mediated the translocation of FOXO3 from the nucleus to the mitochondria within the LECs of cataract capsule tissues of rats exposed to MNU. This intervention ameliorated MNU-induced cataracts in the rat model. In conclusion, there was a correlation between the localization of FOXO3 and its function in cataract formation. It was also determined that H2protects HLECs from injury by leading FOXO3 mitochondrial translocation via MAPK1 activation. Mitochondrial FOXO3 can increase mtDNA transcription and stabilize mitochondrial function in HLECs.

• A pioneering approach is developed to achieve zero shrinkage of porous oxide ceramics during multistep sintering. • A combination of ZrAl3 and Al75Si25 is used as active fillers. • The combination can help realize the continuous expansion in a temperature range of 600–1400 °C. • The continuous expansion is caused by the step-by-step release of oxidation at different temperatures. • The profile deviation of the samples is less than 0.1 mm, and the proportion of microcracks is reduced by 97.8%. Porous oxide ceramics are widely used in extreme working conditions owing to their excellent resistance to high temperatures and corrosion. However, sintering is an inevitable process applied to ceramics, from the green body to the final product. The highly complex structures exacerbate the shrinkage-induced irregular deformation and crack formation in the sintering process. A pioneering approach is developed in this study to achieve zero shrinkage for porous alumina ceramics during multistep sintering, using a combination of active fillers - ZrAl 3 and Al 75 Si 25. The response surface method is used to optimize the material compositions and sintering process, to achieve shrinkages of less than 0.05% for the entire process. The sintering expansion mechanism is investigated by analyzing the pyrolysis and microstructures of samples at different temperatures. The combination of ZrAl 3 and Al 75 Si 25 can attain the continuous expansion of the matrix in a wide temperature range of 600–1400 °C. Furthermore, typical alumina components are fabricated and used to verify the effectiveness of the proposed approach. Owing to shrinkage suppression, the profile deviation of the samples is less than 0.1 mm, and the proportion of microcracks is reduced by 97.8%. The suggested approach shows potential applications in near-net, low-defect fabrication of complex fine ceramic components. [Display omitted] [ABSTRACT FROM AUTHOR]

ABSTRACTIntroductionSupraventricular tachycardias (SVT) are a diverse group of commonly encountered arrhythmias arising at or above the atrioventricular (AV) node. Conventional anti-arrhythmic medications are restricted by extensive side-effect profiles and limited efficacy. Catheter ablation has emerged as a first-line therapy for many arrhythmias but is not a suitable option for all patients. This has prompted the exploration of novel pharmacological approaches targeting specific molecular mechanisms of SVT.Areas CoveredThis review article aims to summarize recent advancements in pharmacological therapeutics for SVT and their clinical implications. The understanding of molecular mechanisms underlying these arrhythmias, particularly atrial fibrillation, has opened up new possibilities for targeted interventions. Beyond the manipulation of ion channels and membrane potentials, pharmacotherapy now focuses on upstream targets such as inflammation, oxidative stress, and structural remodeling. This review strives to provide a comprehensive overview of recent advancements in pharmacological therapeutics directed at the management of SVT. We begin by providing a brief summary of the mechanisms and management of commonly encountered SVT before delving into individual agents, which in turn are stratified based on their molecular treatment targets.Expert OpinionThe evolving landscape of pharmacologic therapy offers hope for more personalized and tailored interventions in the management of SVT.

The high occurrence rate and difficulties in symptom control are listed as the major problems of oral mucosal disease by medical professionals. Following the development of oral mucosal lesions, the oral microenvironment changes, immunity declines, and continuous bacterial stimulation causes wound infection. Traditional antibacterial drugs are ineffective for oral mucosal lesions. To overcome this problem, a light-responsive antibacterial hydrogel containing sustained-release BMSCs was inspired by the trauma environment in the oral cavity, which is different from that on the body surface since it mostly remains under dark conditions. In the absence of light, the hydrogel seals the wound to form a barrier, exerts a natural bacteriostatic effect, and prevents invasion by foreign bacteria. Simultaneously, mesenchymal stem cells are presented, and the released growth factors and other substances have excellent anti-inflammatory and angiogenic effects, which result in rapid repair of the damaged site. Under light conditions, after photo-induced shedding of the hydrogel, RuB2A exerts an antibacterial effect accompanied by degradation of the hydrogel. Results in a rat oral mucosal repair model demonstrate that DCS-RuB2A2-BMSCs could rapidly repair the oral mucosa within 4 days. Sequencing data provide ideas for further analysis of the intrinsic molecular mechanisms and signaling pathways. Taken together, our results suggest that this light-responsive antibacterial hydrogel loaded with BMSCs can be used for rapid wound repair and may advance the development of therapeutic strategies for the treatment of clinical oral mucosal defects.

Recent advances have significantly expanded the options of available therapeutics for cancer treatment, including novel targeted cancer therapies. Within this broad category of targeted therapies is the class of kinase inhibitors (KIs), which target kinases that have undergone aberrant activation in cancerous cells. Although KIs have shown a benefit in treating various forms of malignancy, they have also been shown to cause a wide array of cardiovascular toxicities, with cardiac arrhythmias, in particular atrial fibrillation (AF), being 1 of the predominant side effects. The occurrence of AF in patients undergoing cancer treatment can complicate the treatment approach and poses unique clinical challenges. The association of KIs and AF has led to new research aimed at trying to elucidate the underlying mechanisms. Furthermore, there are unique considerations to treating KI-induced AF because of the anticoagulant properties of some KIs as well as drug-drug interactions with KIs and some cardiovascular medications. Here, we review the current literature pertaining to KI-induced AF.

Hypoxia is a hallmark of renal ischemia-reperfusion injury (IRI) and serves as an essential regulator of innate immune responses during this process, although the mechanisms of this regulation remain unclear. Here, we showed in a murine model that HIF-2αknockout in dendritic cells (DCs) exacerbated renal IRI through activation of natural killer T cells. Mechanistically, HIF-2αdeficiency upregulated CD36 expression of DCs, leading to cellular lipid accumulation. Pharmacologic inhibition of CD36 in DCs resulted in renoprotection by reducing lipid content and suppressing natural killer T cell activation. Our study strongly suggests that targeting the HIF-2α/CD36 regulatory axis may be a strategy for alleviating renal IRI.

Circulating tumor cells (CTCs), as important liquid biopsy target, can provide valuable information for cancer progress monitoring and individualized treatment. However, current isolation platforms incapable of balancing capture efficiency, specificity, cell viability, and gentle release have restricted the clinical applications of CTCs. Herein, inspired by the structure and functional merits of natural membrane interfaces, we established an antibody-engineered red blood cell (RBC-Ab) affinity interface on microfluidic chip for high-performance isolation and release of CTCs. The lateral fluidity, pliability, and anti-adhesion property of the RBC microfluidic interface enabled efficient CTCs capture (96.5%), high CTCs viability (96.1%), and high CTCs purity (average 4.2-log depletion of leukocytes). More importantly, selective lysis of RBCs by simply changing the salt concentration was utilized to destroy the affinity interface for efficient and gentle release of CTCs without nucleic acid contamination. Using this chip, CTCs were successfully detected in colon cancer samples with 90% sensitivity and 100% specificity (20 patients and 10 healthy individuals). After the release process, KRAS gene mutations of CTCs were identified from all the 5 cancer samples, which was consistent with the results of tissue biopsy. We expect this RBC interface strategy will inspire further biomimetic interface construction for rare cell analysis.

Metadevices have emerged as a new element or system in recent years, from optics to mechanical science, showing superior performance and powerful application potential. In this study, a mechanical metadevice that capable of low-frequency vibration isolation, which is called metamaterial springs or metasprings, is proposed. Meanwhile, a modular design method is reported to obtain the customizable quasi-zero stiffness characteristic of the designed metaspring. As proof-of-concept, we demonstrate, both in simulations and experiments, the quasi-zero stiffness characteristics of the proposed metasprings using 3D-printed experimental specimens. Moreover, the low-frequency vibration isolation properties of the proposed metasprings is demonstrated both in vibration tests and automotive vibration tests. This work provides a new mechanical metadevice, that is, metasprings for low-frequency vibration isolation, as well as a modular design method for designing metasprings, which may revolutionize vibration isolation devices in the field of low-frequency vibration isolation.

Dry eye disease (DED) is a chronic multifactorial disorder affecting millions of people, yet the pathogenesis mechanisms still remain unclear. Matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) is a novel in situvisualization approach combined high-throughput mass spectrometry and molecular imaging. We aimed to explore the in situocular metabolic changes via MALDI-MSI to accelerate the recognition of DED pathogenesis.

Carbon black (CB)-filled rubber composites are widely used for tire tread and other rubber products due to their good abrasion resistance and reinforcement. Numerous studies have been focused on the filler-rubber interaction with the aim of obtaining optimum performances. In order to investigate the effect of modification on properties of diene rubber composites, a modified CB-filled isoprene rubber (IR) composite was prepared with a multi-functional silane coupling agent, 2-aminoethyl-2-(3-triethoxysilylpropyl)aminoethyl disulfide (ATD). This modification significantly enhanced the CB-IR interaction and improved CB dispersion. For the modified CB/IR vulcanizates, the tensile strength, stress at 300% elongation, temperature rise, and dynamic loss coefficient were significantly improved at low ATD dosage (1.5 phr). Such modification provides an effective route to prepare CB-reinforced diene rubber composites with low hysteresis and improved mechanical properties.

The intricate processes of microbiota-gut-brain communication in modulating human cognition and emotion, especially in the context of mood disorders, have remained elusive. Here we performed faecal metagenomic, serum metabolomics and neuroimaging studies on a cohort of 109 unmedicated patients with depressed bipolar disorder (BD) patients and 40 healthy controls (HCs) to characterise the microbial-gut-brain axis in BD. Across over 12,000 measured metabolic features, we observed a large discrepancy (73.54%) in the serum metabolome between BD patients and HCs, spotting differentially abundant microbial-derived neuroactive metabolites including multiple B-vitamins, kynurenic acid, gamma-aminobutyric acid and short-chain fatty acids. These metabolites could be linked to the abundance of gut microbiota presented with corresponding biosynthetic potentials, including Akkermansia muciniphila, Citrobacter spp. (Citrobacter freundiiand Citrobacter werkmanii), Phascolarctobacterium spp., Yersinia spp. (Yersinia frederikseniiand Yersinia aleksiciae), Enterobacter spp. (Enterobacter cloacaeand Enterobacter kobei) and Flavobacterium spp. Based on functional neuroimaging, BD-related neuroactive microbes and metabolites were discovered as potential markers associated with BD-typical features of functional connectivity of brain networks, hinting at aberrant cognitive function, emotion regulation, and interoception. Our study combines gut microbiota and neuroactive metabolites with brain functional connectivity, thereby revealing potential signalling pathways from the microbiota to the gut and the brain, which may have a role in the pathophysiology of BD.

MgxZn1−xO (MZO) is a promising window material for high-efficiency CdTe thin film solar cell fabrication. However, the performance of MZO-based CdTe solar cell exhibits high sensitivity to the heat treatment of MZO during device fabrication process. In this article, the chemical, microstructural and electrical instability of MZO films and their effect on device performance of CdTe thin film solar cell was studied. It is found that during the high-temperature vacuum treatment (400°C−600°C), the atomic element losses in the MZO films led to high oxygen-vacancy concentration and formation of an Mg-rich surface layer. The high-temperature treated MZO films exhibited rough surface morphology, high electronic conductivity, and low electron affinity. The rough MZO surface induced formation of trap states with high concentration in the CdTe absorber and decreased open-circuit voltage for the solar cell. The MZO conductivity and the surface electron affinity affect the carrier transport in the solar cells. This work demonstrates that the heat treatment process of the MZO window layer significantly affects the performance and reproducibility of CdTe solar cell fabrication.

ObjectiveCardiovascular (CV) diseases are serious comorbidities in patients with granulomatosis with polyangiitis (GPA). In a sample of patients hospitalized for GPA, we sought to examine trends in the burden of coronary artery disease (CAD) and its 2 serious manifestations, acute myocardial infarction (AMI) and heart failure (HF).MethodsWe used the National Inpatient Sample to conduct a retrospective cross-sectional analysis. Our sample consisted of hospitalizations for GPA between 2005 and 2014. We examined trends in the proportion of CAD, AMI, and HF in all hospitalizations with GPA compared to those without GPA. We used logistic regression adjusted for potential confounders and included interaction terms.ResultsAmong a total of 103,453 GPA hospitalizations, 20,351 (19.7%) hospitalizations had a concurrent diagnosis of CAD. GPA with CAD was associated with overall lower burden of traditional CV risk factors compared to non-GPA with CAD, with the exception of chronic kidney disease (57% vs 21%). Over the 10-year study period, there were rising trends in the inpatient burden of CAD (16.6% in 2005 to 22.7% in 2014) and CAD with HF (4.3% in 2005 to 9.9% in 2014), but not AMI (1.2% in 2005 to 1.1% in 2014), in GPA hospitalizations compared to non-GPA controls.ConclusionIn this national sample of GPA hospitalizations, we found that the burden of CAD and CAD with HF was on the rise over the 10-year period compared to non-GPA; however, it was not the case for AMI.

As a malignant disease that seriously threatens human health, hepatocellular carcinoma (HCC) lacks effective early screening and prognostic assessment methods. Herein, we developed a method for efficient capture and multiphenotype analysis of circulating tumor cells (CTCs) of hepatocellular carcinoma. The anti-ASGPR antibody and the anti-EpCAM antibody were modified in parallel on a deterministic lateral displacement (DLD)-patterned microfluidic Synergetic-Chip to enhance capture efficiency by a complementary effect. CTCs were detected in 45 out of 45 (100%) HCC patients, with a sensitivity and specificity of 97.8 and 100%, respectively. Patients with more total CTCs and nonepithelial CTCs were in later stages of HCC and had more malignant progression. This strategy proposes a feasible approach for early diagnosis and prognosis of hepatocellular carcinoma.

Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSC-EVs) have been recognized as a promising cell-free therapy for acute kidney injury (AKI), which avoids safety concerns associated with direct cell engraftment. However, low stability and retention of MSC-EVs have limited their therapeutic efficacy. RGD (Arg-Gly-Asp) peptide binds strongly to integrins, which have been identified on the surface of MSC-EV membranes; yet RGD has not been applied to EV scaffolds to enhance and prolong bioavailability. Here, we developed RGD hydrogels, which we hypothesized could augment MSC-EV efficacy in the treatment of AKI models. In vivotracking of the labeled EVs revealed that RGD hydrogels increased retention and stability of EVs. Integrin gene knockdown experiments confirmed that EV–hydrogel interaction was mediated by RGD–integrin binding. Upon intrarenal injection into mouse AKI models, EV-RGD hydrogels provided superior rescuing effects to renal function, attenuated histopathological damage, decreased tubular injury, and promoted cell proliferation in early phases of AKI. RGD hydrogels also augmented antifibrotic effects of MSC-EVs in chronic stages. Further analysis revealed that the presence of microRNA let-7a-5p in MSC-EVs served as the mechanism contributing to the reduced cell apoptosis and elevated cell autophagy in AKI. In conclusion, RGD hydrogels facilitated MSC-derived let-7a-5p-containing EVs, improving reparative potential against AKI. This study developed an RGD scaffold to increase the EV integrin-mediated loading and in turn improved therapeutic efficacy in renal repair; therefore this strategy shed light on MSC-EV application as a cell-free treatment for potentiated efficiency.

To identify the general features of acquisition of drug-resistance genes in two multi-drug resistant Enterobacteriaceaestrains isolated from a single patient in China.

Circulating fetal nucleated cells (CFCs) carrying whole genomic coding of the fetus in maternal blood have been pursued as ideal biomarkers for noninvasive prenatal testing (NIPT). However, a significant limitation is the need to enrich sufficient cells in quantity and purity for fetal genetic disorder diagnosis. This study for the first time demonstrates a stimuli-responsive ligand enabling interface on array patterned microfluidic chip (NIPT-Chip) for high efficient isolation and release of CFCs in untreated whole blood. Deterministic lateral displacement (DLD)-array was patterned in the chip to increase collision frequency between CFCs and surface-anchored antibody to achieve high efficient cell capture. More importantly, the stimuli-responsive interface enables gentle release of captured CFCs through a thiol exchange reaction for downstream gene analysis of NIPT. With the advantages of simple processing, efficient isolation, and gentle release, NIPT-Chip offers great potential for clinical translation of circulating fetal cell-based NIPT.

Circulating tumor cells (CTCs) undergoing epithelial mesenchymal transition (EMT) play an essential role in metastasis and have a better correlation with poor disease outcomes, but the most current affinity-based enrichment methods rely on targeting epithelial markers, which are less effective in capturing CTCs undergoing EMT. Herein, we identified and optimized an aptamer (ZY5C) sequence with high binding affinity and specificity against cell surface vimentin (CSV), which is overexpressed on the post-EMT CTCs. Not only can the hairpin-structured ZY5C aptamer specifically recognize a number of cancer cells with native CSV expression, but it can also bind to CSV expressed on EMT-cells. The Kdvalue of the ZY5C aptamer against CSV-positive T24 cells was found to be 38 ± 4 nM. Using the evolved ZY5C aptamer and multivalent ZY5C aptamer-functionalized chip, we were able to isolate CTCs from the blood of adenocarcinoma, sarcoma, and carcinosarcoma patients. Overall, this ZY5C aptamer and isolation method bring a fresh approach to CTCs analysis, which not only detects CTCs from nonepithelial origin, but also provides an efficient way to in-depth study the role of post-EMT CTCs in clinical application and metastasis mechanisms.

The ubiquitous biomembrane interface, with its dynamic lateral fluidity, allows membrane-bound components to rearrange and localize for high-affinity multivalent ligand–receptor interactions in diverse life activities. Inspired by this, we herein engineered a fluidic multivalent nanointerface by decorating a microfluidic chip with aptamer-functionalized leukocyte membrane nanovesicles for high-performance isolation of circulating tumor cells (CTCs). This fluidic biomimetic nanointerface with active recruitment-binding afforded significant affinity enhancement by 4 orders of magnitude, exhibiting 7-fold higher capture efficiency compared to a monovalent aptamer functionalized-chip in blood. Meanwhile, this soft nanointerface inherited the biological benefits of a natural biomembrane, minimizing background blood cell adsorption and maintaining excellent CTC viability (97.6%). Using the chip, CTCs were successfully detected in all cancer patient samples tested (17/17), suggesting the high potential of this fluidity-enhanced multivalent binding strategy in clinical applications. We expect this bioengineered interface strategy will lead to the design of innovative biomimetic platforms in the biomedical field by leveraging natural cell–cell interaction with a natural biomaterial.

Molecular recognition ligands are of great significance in many fields, but our ability to develop new recognition molecules remains to be expanded. Here, we developed a Sequential Multidimensional Analysis algoRiThm for aptamer discovery (SMART-Aptamer) from high-throughput sequencing (HTS) data of SELEX libraries based on multilevel structure analysis and unsupervised machine learning to discover nucleic acid recognition ligands with high accuracy and efficiency. We validated SMART-Aptamer with three sets of HTS data from screening pools against hESCs, EpCAM, and CSV. High affinity aptamers for all three targets were successfully obtained, and the results revealed that SMART-Aptamer is able to pick out high affinity aptamers with low false positive and negative rates. With the advantages of accuracy, efficiency, and robustness, SMART-Aptamer represents a paradigm-shift strategy for the discovery of binding ligands for a variety of biomedical applications.

PurposeTo determine the relationship between appositional angle closure (AppAC) and the conversion of primary angle closure (PAC) into primary angle closure glaucoma (PACG) after laser peripheral iridotomy (LPI).MethodsConsecutive patients with PAC were included in this prospective cohort study. The eyes of the included patients who had undergone LPI with five or more reliable visual field (VF) tests in at least 5 years were analysed. Baseline AppAC was diagnosed when the trabecular meshwork and iris were located appositionally on the ultrasound biomicroscopy image. The criteria for PAC conversion were based on development of glaucomatous optic neuropathy and corresponding VF defects. Other factors such as age and vertical cup-to-disc ratio (VCDR) were also investigated by univariate and multivariate logistic regression analyses.Results128 patients were assessed at baseline. 80 eyes of 58 patients fulfilled the inclusion criteria. The mean follow-up period was 6.67 ± 1.33 years. PAC conversion was observed in 20 eyes. The frequency of PAC conversion was significantly higher in eyes with AppAC > 2 quadrants at baseline (58.3%, 7/12) than in those with AppAC ≤ 2 quadrants (19.1%, 13/68; p < 0.05). Compared with the non-converting group, the age and VCDR at baseline were both higher in the converting group (p < 0.05). Wider AppAC, older age and higher VCDR were significantly associated with PAC conversion.Conclusions25% of PAC eyes of Chinese patients converted into PACG eyes in more than 5 years after LPI. AppAC > 2 quadrants were related to the PAC conversion. Older baseline age and higher VCDR were also associated with PAC conversion.

Mechanical vibration isolation with adaptable payloads has always been one of the most challenging topics in mechanical engineering. In this study, we address this problem by introducing machine learning method to search for quasi-zero stiffness metamaterials with arbitrarily predetermined payloads and by employing multi-material 3D printing technology to fabricate them as an integrated part. Dynamic tests demonstrate that both the single- and multi-payload metamaterials can effectively isolate mechanical vibration in low frequency domain. Importantly, the payload of the metamaterial could be arbitrarily designed according to the application scenario and could function at multiple payloads. This design strategy opens new avenues for mechanical energy shielding under various scenarios and under variable loading conditions.

Extracellular vesicles (EVs) harbor abundant glycans that mediate various functions, such as intercellular communication and disease advancement, which play significant roles in disease progression. However, the presence of EV heterogeneity in body fluids and the complex nature of the glycan structures have posed challenges for the detection of EV glycans. In this study, we provide a streamlined method integrated, membrane-specific separation with lectin-induced aggregation strategy (MESSAGE), for multiplexed profiling of EV glycans. By leveraging a rationally designed lectin-induced aggregation strategy, the expression of EV glycans is converted to size-based signals. With the assistance learning machine algorithms, the MESSAGE strategy with high sensitivity, specificity, and simplicity can be used for early cancer diagnosis and classification, as well as monitoring cancer metastasis via 20 μL plasma sample within 2 h. Furthermore, our platform holds promise for advancing the field of EV-based liquid biopsy for clinical applications, opening new possibilities for the profiling of EV glycan signatures in various disease states.

Adoptive cell therapies are emerging forms of immunotherapy that reprogram T cells for enhanced antitumor responses. Although surface PD-L1/PD-1 engagement inhibits antitumor immunity, the role of cell-intrinsic PD-L1 in adoptive T cell therapy remains unknown. Here we found that intracellular PD-L1 was enriched in tumor-infiltrating CD8+T cells of cancer patients. PD-L1 ablation promoted antitumor immune responses and the maintenance of an effector-like state of therapeutic CD8+T cells, while blockade of surface PD-L1 was unable to impact on their expansion and function. Moreover, cell-intrinsic PD-L1 impeded CD8+T cell activity which partially relid on mTORC1 signalling. Furthermore, endogenous tumor-reactive CD8+T cells were motivated by BATF3-driven dendritic cells after adoptive transfer of PD-L1-deficient therapeutic CD8+T cells. This role of cell-intrinsic PD-L1 in therapeutic CD8+T cell dysfunction highlights that disrupting cell-intrinsic PD-L1 in CD8+T cells represents a viable approach to improving T cell-based cancer immunotherapy.

The CRAFITY score can predict survival and radiological response to systemic front-line treatment in patient with hepatocellular carcinoma (HCC).

Scientists and engineers are looking forward to new manufacturing technologies to realize the integrated fabrication of macro shape and microstructure for the components with a short production chain, which can also save materials and reduce energy consumption. Additive manufacturing (AM) technology is a new fabrication pattern with a character of a lay-by-lay material deposition. The components are fabricated in a bottom-up way, from points, lines, to layers and volume, which provided a capability to solve the impossible integrated fabrication problem for micro- and macro-structure by using conventional manufacturing technologies. Thus, based on integrated fabrication of micro- and macro- structures, research team in Xi'an Jiaotong University has been focusing on technological innovations and applications of advanced additive manufacturing technologies. Novel additive manufacturing principles have been proposed and explored, by which new AM processes and equipment for metals, composites, ceramics, and biomaterials have been developed to support the industrial applications. Additive manufacturing and cutting-edge applications of advanced composite structure, metamaterials, bio-implants, and monocrystal alloy components have been investigated to push the new development of integrated fabrication of micro- and macro- structures.

The use of cellular automata (CA) is essential for exploring future urban growth scenarios in spatial planning. However, modeling polycentric urbanization processes with CA is still challenging due to the presence of spatial spillover effects arising from spatial interactions between different regions. This study proposes a hybrid framework that addresses the spatial spillover effect that emerges from multi-centers by coupling a radiation model (RM) and Markov chain (MC) with CA to simulate polycentric urbanization processes. The simulation capabilities of the RM-MC-CA framework were evaluated and validated by simulating Guangzhou’s actual urban growth from 2000 to 2020, and the future urban growth scenarios of 2035 and 2050 were simulated with this coupled model. Results showed this framework provides a spatio-temporal diffusion process consistent with the cooperative mechanism of urbanization from monocentric to polycentric. In terms of simulation accuracy, the proposed RM-MC-CA framework demonstrated the most promising performance compared to MC-CA, GM-MC-CA, and PLUS. Compared to classical MC-CA, the framework improved the Kappa, FOM, and Precision metrics by 0.54%, 3.93%, and 2.38%, respectively. These results indicated that incorporating spatial spillover processes into a CA model can enhance its ability to simulate polycentric patterns that promote high-quality urban development.

Glioma treatment remains a challenge owing to unsatisfactory targeted chemotherapy, where the blood–brain barrier (BBB) hinders the efficient uptake of therapeutics into the brain. Vasculogenic mimicry (VM) formed by invasive glioma cells negatively affects the treatment of glioma. Herein, we developed a targeted biomimetic drug delivery system comprising a doxorubicin-loaded platelet membrane-coated nanogel (DOX@PNGs). The nanogels provide great redox/pH dual responsiveness, while the platelet membrane (PLTM) promotes stability and circulation time. In vitro cellular uptake and in vivo imaging experiments demonstrated that the DOX@PNGs delivery system could penetrate the BBB, target gliomas, and destruct VM. DOX@PNGs increased drug penetration and prolonged mouse survival time during the treatment of orthotopic gliomas. These results indicate this biomimetic drug delivery system to be promising for glioma treatment and may be clinically translated in the future.

The effective detection of X-ray radiation with low threshold is essential to many medical and industrial applications. Three-dimensional (3D) organolead trihalide and double perovskites have been shown to be suitable for direct X-ray detection. However, the sensitivity and stability of 3D perovskite X-ray detectors are limited by ion motion, and there remains a demand to develop green and stable X-ray detectors with high sensitivity and low detection limit. The emerging low-dimensional perovskites have shown promising optoelectronic properties, featuring good intrinsic stability and reduced ion migration. Inspired by this, we show that our 2D layered perovskite-like (NH4)3Bi2I9device provides unique anisotropic X-ray detecting performance with different crystal directions, effective suppression of ion migration and a low detection limit of 55 nGyairs−1. These results will motivate new strategies to achieve a high-performance X-ray detector by utilizing 2D layered perovskite or perovskite-like materials, without requiring toxic elements. Perovskite-like materials enable different X-ray detection performance along different crystal directions. A low detection limit of 55 nGyairs−1is demonstrated.

Two-dimensional (2D) transition-metal dichalcogenides (TMDs) have shown great potential in ultrathin and flexible optoelectronic and photonics devices. Besides emissive bright excitons, they also possess rich non-emissive dark excitons including momentum-forbidden indirect excitons and spin-forbidden triplet-like excitons, which could be dominant species under optical or electrical excitation in 2D optoelectronic and photonic devices. Efficient harvesting of both bright and dark excitons from TMDs and understanding the exciton-transfer mechanism consequently are not only of fundamental interest but also a technological challenge. Here, by combining steady-state photoluminescence spectroscopy and ultrafast transient reflectance spectroscopy, we show efficient exciton harvesting by ultrafast energy transfer in WSe2/MoTe2van der Waals heterostructures, leading to the photoluminescence enhancement of MoTe2. The energy transfer occurs with near-unity yield and in an ultrafast (∼200 fs) manner for both bright and dark excitons, suggesting a dominant Dexter-type energy-transfer process consisting of simultaneous transfer of both electron and hole in van der Waals coupled 2D layers at ultimate proximity. This result is beyond the conventional dipole–dipole coupling mechanism typically assumed at 2D interfaces and offers a path to high speed and enhanced light harvesting and emission applications based on 2D heterostructures.

Metamaterials are artificial structures that have been engineered to exhibit properties that do not occur naturally in conventional materials. They were firstly made up of periodic unit cells that interact with electromagnetic (EM) waves to manipulate their behavior, showing extraordinary phenomena like EM cloaking, negative index, beam deflection and so on. In recent years, the concept of metamaterial has been penetrating in various physical domain and various metamaterials with versatile functionalities have been proposed and fabricated by 3D printing technology to manipulate the interactions between matter and electromagnetic, thermal, acoustic, and mechanical energy. With the increasing of structural complexity, material types, precision additive manufacturing serve as a powerful tool to achieve novel metamaterials with extraordinary performance and fusion of functionalities. In this paper, we reviewed the remarkable properties enabled by 3D printed metamaterials in different fields, and analyzed the consilience relationship between structure, function, and manufacturing process.

A hallmark of systemic lupus erythematosus is high titers of circulating autoantibodies. Recently, a novel CD11c+B-cell subset has been identified that is critical for the development of autoimmunity. However, the role of CD11c+B cells in the development of lupus is unclear. Chronic graft-versus-host disease (cGVHD) is a lupus-like syndrome with high autoantibody production. The purpose of this study was to explore the role of CD11c+B cells in the pathogenesis of lupus in cGVHD mice. cGVHD was induced by an intraperitoneal injection of 5 × 107Bm12 splenocytes into B6 mice. Flow cytometry was used to analyze mice splenocytes and human samples. Magnetic beads were used to isolate mice B cells. Gene expression was determined by real-time quantitative polymerase chain reaction (RT-qPCR). Enzyme-linked immunosorbent assay (ELISA) was used to detect antibodies in serum and supernatants. The percentage and absolute number of CD11c+B cells was increased in cGVHD-induced lupus, with elevated levels of antichromatin immunoglobulin (Ig)G and IgG2a in sera. CD11c+plasma cells from cGVHD mice produced large amounts of antichromatin IgG2a upon stimulation. Depletion of CD11c+B cells reduced antichromatin IgG and IgG2a production. T-bet was upregulated in CD11c+B cells. Knockout of T-bet in B cells alleviated cGVHD-induced lupus. Importantly, the percentage of T-bet+CD11c+B cells increased in lupus patients and positively correlated with serum antichromatin levels. T-bet+CD11c+B cells promoted high antichromatin IgG production in the lupus-like disease model cGVHD. In lupus patients, the percentage of T-bet+CD11c+B cells was elevated and positively correlated with antichromatin antibodies. The findings provide potential therapeutic insight into lupus disease treatment.

Coastal remote sensing images have huge data which has features of the volume, variety, complexity and specialisation. The problem is how to effectively carry out data integration, fast extract and data mining of knowledge and information from these massive remote sensing data as it is far behind the requirements of coastal professional applications. In this paper, based on data mining, remote sensing theory, space information and cloud computing technology towards the goal of coastal zone remote sensing data integration and data mining service system, the meta-data model, data storage model, data mining framework, web service framework model, etc. are provided and designed. Finally, a prototype system of remote sensing data mining services in the cloud computing environment is designed and developed using system integration, and is demonstrated and verified by professional applications. It is valuable to serve the development of the coastal zone, monitoring, planning and integrated management and other fields.

MicroRNAs (miRNAs) in tumor-derived extracellular vesicles (tEVs) are important cancer biomarkers for cancer screening and early diagnosis. Multiplex detection of miRNAs in tEVs facilitates accurate diagnosis but remains a challenge. Herein, we propose an encoded fusion strategy to profile the miRNA signature in tEVs for pancreatic cancer diagnosis. A panel of encoded-targeted-fusion beads was fabricated for the selective recognition and fusion of tEVs, with the turn-on fluorescence signals of molecule beacons for miRNA quantification and barcode signals for miRNA identification using readily accessible flow cytometers. Using this strategy, six types of pancreatic-cancer-associated miRNAs can be profiled in tEVs from 2 μL plasma samples (n= 36) in an isolation-free and lysis-free manner with only 2 h of processing, offering a high accuracy (98%) to discriminate pancreatic cancer, pancreatitis, and healthy donors. This encoded fusion strategy exhibits great potential for multiplex profiling of miRNA in tEVs, offering new avenues for cancer diagnosis and screening.

The present microbial reinforcement of rock and soil exhibits limitations, such as uneven reinforcement effectiveness and low calcium carbonate generation rate, resulting in limited solidification strength. This study introduces electroosmosis as a standard microbial grouting reinforcement technique and investigates its solidification effects on microbial-reinforced uranium tailings. The most effective electroosmosis effect on uranium tailings occurs under a potential gradient of 1.25 V/cm. The findings indicate that a weak electric field can effectively promote microbial growth and biological activity and accelerate bacterial metabolism. The largest calcium carbonate production occurred under the gradient of 0.5 V/cm, featuring a good crystal combination and the best cementation effect. Staged electroosmosis and electrode conversion efficiently drive the migration of anions and cations. Under electroosmosis, the cohesion of uranium tailings reinforced by microorganisms increased by 37.3% and 64.8% compared to those reinforced by common microorganisms and undisturbed uranium tailings, respectively. The internal friction angle is also improved, significantly enhancing the uniformity of reinforcement and a denser and stronger microscopic structure. This research demonstrates that MICP technology enhances the solidification effects and uniformity of uranium tailings, providing a novel approach to maintaining the safety and stability of uranium tailings dams.

Natural killer (NK) cells are cytotoxic innate lymphocytes that eradicate tumor cells. Inducing durable antitumor immune responses by NK cells represents a major priority of cancer immunotherapy. While cytosolic DNA sensing plays an essential role in initiating antitumor immunity, the role of NK cell-intrinsic STING signaling remains unclear. Here, we find that NK cell-intrinsic STING promotes antitumor responses and maintains a reservoir of TCF-1+NK cells. In contrast, tumor cell-intrinsic cGAS and mtDNA are required for NK cell antitumor activity, indicating that tumor mtDNA recognition by cGAS partially triggers NK cell-intrinsic STING activation. Moreover, addition of cGAMP enables STING activation and type I interferon production in NK cells, thereby supporting the activation of NK cells in vitro. In humans, STING agonism promotes the expansion of TCF-1+NK cells. This study provides insight into understanding how STING signaling drives NK cell antitumor immunity and the development of NK cell-based cancer immunotherapy.

Electronic transport plays a pivotal role in the electrolysis of semiconducting electrocatalysts for oxygen evolution reaction (OER), while it is mostly underestimated and largely unexplored. Here, by investigating the electronic transport behavior of seven archetypical crystalline Co/Ni/Fe-based (oxy)hydroxides (unary, binary, and ternary) under OER potential, we study how and the extent to which it affects the apparent catalytic performances. The electronic transports of unary metal (oxy)hydroxides follow the order of Co > Ni > Fe, and their binary or ternary compounds can generally impose one order of magnitude higher electrical conductivity. By studying the dependence of catalytic performances on electrical conductivities, we further unveil that charge transportability not only determines the electronic accessibility of catalytic nanoparticles but also, to our surprise, regulates the reaction kinetics of the electronically accessible active sites. Remarkably, the regulation extent of reaction kinetics correlates with the electrical conductivities of electrocatalysts, suggesting that the electrocatalytic process is strongly coupled with electronic transport. The work presents an overview of electronic transports of crystalline (oxy)hydroxides under OER potentials and highlights their pivotal role in unfolding catalytic potential, holding both fundamental and technical implications for the screen and design of efficient electrocatalysts.

ABSTRACTThe OsPIN1paralogous genes (OsPIN1a-1d) are important for root and panicle development in rice (Oryza sativaL.). However, the specific role of OsPIN1paralogous genes is still not clear. To understand the specific roles of PIN1paralogs in rice, we generated pin1triple and quadruple mutants by crossing the pin1a pin1band pin1c pin1ddouble mutants which we previously created. Compared with the 7-day-old wild type, the pin1a pin1c pin1dand pin1b pin1c pin1dtriple mutants showed no obvious phenotype variation except that the pin1a pin1c pin1dtriple mutant had shorter primary root and shoot. The pin1a pin1b pin1cand pin1a pin1b pin1dtriple mutants exhibited a series of developmental abnormalities, including shorter primary roots, longer root hairs, fewer crown roots and lateral roots, shorter and curved shoots. Furthermore, the pin1a pin1b pin1c pin1dquadruple mutant displayed more severe phenotypic defects which was lethal. In addition, the expression levels of some hormone signal transduction and crown root development related genes, such as OsIAAs, OsARFs, OsRRs, and OsCRLs, were significantly altered in the stem base of all examined pin1multiple mutants. Taken together, our results demonstrated that the four OsPIN1paralogous genes function redundantly in regulating rice growth and development.

Introduction:The inhibition of Nrf2 pathway is regarded as the dominant process that correlates with the pathogenesis of diabetic cardiomyopathy (DCM). Recently, accumulating evidence reveals that lncRNAs play key roles in regulating Nrf2 pathway. However, the underlying mechanisms remain unclear. Here, we found that adipocyte lncRNA SBF2-AS1 (SBF2-AS1) enhanced the SUMOylation of hnRNPA1, which subsequently facilitated the package of SBF2-AS1 into exosomes under high glucose conditions.Hypothesis:We hypothesized that AdEXO-SBF2-AS1 promotes diabetic myocardial fibrosis through regulating the hnRNPA1/Nrf2 pathway via SUMOylation.Methods:We examined the effect of exosomes from diabetic (db/db) mice-derived adipocytes on ANG-II-induced cardiac fibrosis and function in non-diabetic mice. In the invitrostudy, HG (33mmol/L)-induced AdEXO were cultured with adult human cardiac fibroblasts (aHCFs). Differentially expressed lncRNAs in AdEXO were screened using lncRNA sequencing.Results:Intramyocardial injection of diabetic AdEXO in the non-diabetic heart exacerbated myocardial fibrosis. Whereas administration of an exosomes biogenesis inhibitor attenuated cardiac fibrosis in diabetic mice. We identified SBF2-AS1 is a common molecule significantly increased in diabetic AdEXO and HG-stimulated non-diabetic AdEXO. After four weeks of ANG II infusion, EXO-db/dbWT-injected mice displayed significant fibrosis in the heart. However, interestingly, mice receiving SBF2-AS1-deficient db/db-EXO showed a decrease in cardiac fibrosis. Similarly, AdEXO-SBF2-AS1 promoted aHCFs proliferation and transformation capabilities in vitro. Mechanistically, SBF2-AS1 induced UBC9 overexpression to catalyze the SUMOylation of hnRNPA1, which facilitated its packaging into exosomes. Subsequently, exosomal SBF2-AS1 was specifically transmitted into aHCFs and epigenetically downregulated Nrf2 expression by decreasing H3K9 acetylation level in the Nrf2 promoter.Conclusions:Our findings highlight a novel mechanism whereby the AdEXO-mediated SBF2-AS1/hnRNPA1/Nrf2 regulatory axis promotes diabetic myocardial fibrosis in a SUMOylation-dependent manner and implicate SBF2-AS1 as an attractive therapeutic target for DCM.

Introduction:Catheter ablation (CA) has been increasingly utilized among patients with atrial fibrillation (AF) as a guideline-supported treatment. However, limited data is available regarding its safety among cancer patients.Hypothesis:Patients with a cancer diagnosis has worse outcome following AF CAMethods:We queried the 2016 to 2019 United State Nationwide Readmission database to identify all patients with (active cancer or a history of cancer) or without cancer diagnosis who underwent AF CA. Hospital outcome and 30 days readmission rate were analyzed. Multivariate logistic regression or Cox proportional hazards regression analysis was employed when appropriate adjusting for comorbidities as well as patient and hospital-level factors.Results:A total of 46,461 AF CAs were included in the analysis, among which 800 (1.72%) patients were diagnosed with active cancer and 5,133 (11.04%) patients had a history of cancer. Compared to non-cancer patients, patients with a cancer diagnosis were older and more likely to be female (Table 1). Patient with cancer diagnosis also has a higher burden of comorbidities, stroke risk, and bleeding risk as evidenced by Charlson Comorbidity Index, CHA2DS2-VASc score, and ATRIA score (Table1). As a result, patient with active cancer has higher inpatient hospital mortality, procedural complication rate, and all-cause readmission rate. After adjusting for confounders, active cancer diagnosis but not a history of cancer was associated with increased hospital mortality (Odds ratio: 2.72[1.18-6.24] p=0.018 vs noncancer) In contrast, only a history of cancer was associated with a small increased risk of 30 days readmission following CA (Hazard ratio: 1.19 [1.04-1.37) p=0.009 vs noncancer). There was no difference in procedural risk between cancer and non-cancer patients.Conclusions:Active cancer but not a history of cancer was associated with increased in-hospital mortality among AF patients who underwent CA.

Introduction:Endothelial dysfunction is related with in-stent restenosis (ISR) of prior drug-eluting stents (DES) implanted more than 1 year ago (late ISR). EndoPAT is a novel non-invasive test quantifying endothelial function as reactive hyperemia peripheral arterial tonometry index (RHI).Hypothesis:EndoPAT is a potential predicting test for late ISR.Methods:We conducted a case control study on 186 patients with coronary DES implanted more than 1 year ago in a single medical center. Those who had contraindications to EndoPAT test, acute myocardial infarction, coronary artery bypass graft (CABG), chronic kidney disease (CKD) stage III and above, active infection and rheumatologic disease or acute decompensated heart failure were excluded. Patients were divided into ISR and non-ISR group based on coronary angiography. EndoPAT test was done at 24 to 48 hours prior to catherization. LnRHI is an index after natural log transformation of RHI. A receiver operative characteristic (ROC) curve analysis was used to determine the sensitivity and specificity of LnRHI for predicting late ISR.Results:ISR group had significantly more patients with history of ISR or triple-vessel disease, longer stent length and fewer totally occlusive lesions than non-ISR group. LnRHI was significantly lower in ISR group than in non-ISR group (0.66 vs 0.50, p<0.01). Patients with diffuse ISR had lower LnRHI than those with focal ISR (0.40 vs 0.55, p=0.03). Patients without ISR but undergoing revascularization had lower LnRHI than those with patent coronary arteries (0.56 vs 0.70, p=0.02). Endothelial function quantified by LnRHI was an independent risk factor for ISR (LnRHI/0.1, OR=0.79, 95% CI 0.64-0.97, p=0.03). The ROC curve analysis showed LnRHI of 0.44 had a sensitivity of 81.7% and specificity of 53.8% for predicting late ISR.Conclusions:Endothelial dysfunction measured by EndoPAT had a clinical potential for predicting the development of late ISR.

The aim of this study was to explore the anti-tumor effect and therapeutic potential of rosmarinic acid (RA) in the treatment of hepatocellular carcinoma (HCC). RA at 75, 150 and 300 mg/kg was given to H22 tumor-bearing mice by intragastric administration once daily for 10 consecutive days. Levels of inflammatory and angiogenic factors, including interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), vascular endothelial growth factor (VEGF), and transforming growth factor-β (TGF-β) were measured by enzyme linked immunosorbent assays (ELISA). Protein levels of phosphorylated NF-κB p65 and p65 were detected by western blot. mRNA level of NF-κB p65 was analyzed by qRT-PCR. The results showed that RA could effectively suppress tumor growth with fewer toxic effects by regulating the secretion of cytokines associated with inflammation and angiogenesis, and suppressing the expression of NF-κB p65 in the xenograft microenvironment. Our findings unveil the possible anti-tumor mechanisms of RA and support RA as a potential drug for the treatment of HCC.