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Poly(3-hydroxybutyrate) (P3HB), a biodegradable thermoplastic with the potential to partially replace oil-based commodities, suffers from embrittlement over storage time. We here investigate possible causes by monitoring aging processes in the sample through changes in mechanical and thermal properties as well as the semicrystalline morphology (crystallinity, lamellar stack dimensions, and its inhomogeneity) over time, using advanced small-angle X-ray scattering analyses for the latter. We find that the slow rise in the shear modulus of the materials is accompanied by secondary crystallization, detected as lamellar thickening and an increase in the melting point. These morphology changes may be due to the chain mobility in the crystallites. This is a feature of “crystal-mobile” polymers that are known to be able to crystallize more fully than their crystal-fixed counterparts. We present the first evidence of the related crystalline αcrelaxation in P3HB by dynamic-mechanical analysis (DMA) and investigate the process microscopically by advanced magic-angle spinning solid-state exchange NMR techniques, specifically centerband-only detection of exchange. We show that monomer jumps in the P3HB crystals are comparably slow (i.e., with an average correlation time τcof 0.1 s at 120 °C). Their apparent activation energy (80 to 90 kJ/mol) is found to be independent of the crystallization temperature and in good agreement with the DMA results.

The human gut microbiota significantly impacts health, including liver conditions like liver cirrhosis (LC) and spontaneous bacterial peritonitis (SBP). Immunoglobulin A (IgA) plays a central role in maintaining gut microbial balance. Understanding IgA's interplay with gut microbiota and liver health is crucial. This study explores the relationship between fecal IgA levels, gut microbiota, and liver injury severity. A total of 69 LC patients and 30 healthy controls were studied. Fecal IgA levels were measured using ELISA, and IgA‐coated bacteria were quantified via flow cytometry. Microbiota diversity and composition were assessed through 16S rRNA sequencing. Liver injury severity was graded using the Child–Pugh score. Statistical analyses determined correlations. LC patients had higher fecal IgA levels than controls, correlating positively with liver injury severity. Microbiota diversity decreased with severity, accompanied by shifts in composition favoring pro‐inflammatory species. Ralstoniaabundance positively correlated with liver injury, whereas Faecalibacteriumshowed a negative correlation. Specific microbial markers for SBP were identified. Functional profiling revealed altered microbial functionalities in LC and SBP. Elevated fecal IgA levels, coupled with microbiota alterations, correlate with liver injury severity in LC patients. Modulating gut microbiota could be a promising strategy for managing liver‐related conditions. Further research is needed to understand underlying mechanisms and translate findings into clinical practice, potentially improving patient outcomes.

Porphyromonas gingivalishas been demonstrated to have the strongest association with periodontitis. Within the host, P. gingivalisrelies on acquiring iron and heme through the aggregation and lysis of erythrocytes, which are important factors in the growth and virulence of P. gingivalis. Additionally, the excess obtained heme is deposited on the surface of P. gingivalis, protecting the cells from oxidative damage. Based on these biological properties of the interaction between P. gingivalisand erythrocytes, this study developed an erythrocyte membrane nanovesicle loaded with gallium porphyrins to mimic erythrocytes. The nanovesicle can target and adhere with P. gingivalisprecisely, being lysed and utilized by P. gingivalisas erythrocytes. Ingested gallium porphyrin replaces iron porphyrin in P. gingivalis, causing intracellular metabolic disruption. Deposited porphyrin generates a large amount of reactive oxygen species (ROS) under blue light, causing oxidative damage, and its lethality is enhanced by bacterial metabolic disruption, synergistically killing P. gingivalis. Our results demonstrate that this strategy can target and inhibit P. gingivalis, reduce its invasion of epithelial cells, and alleviate the progression of periodontitis.

This study aimed to investigate the mitigation effect of epigallocatechin gallate (EGCG) on aging induced by 3-monochloropropane-1,2-diol (3-MCPD) in Caenorhabditis elegans, evaluate health indicators during the process, and reveal the underlying mechanism through transcriptomics and identification of mutants. The results showed that EGCG alleviated the declined fertility, shortened lifespan, reduced body size, weakened movement, increased reactive oxygen species and lipofuscin, and damaged antioxidative stress response and excessive heat shock proteins caused by 3-MCPD. Transcriptomics study indicated that treatment with 3-MCPD and EGCG altered gene expression, and gene mutants confirmed the involvement of insulin/IGF-1 signaling pathway in mediating the process that EGCG alleviated the aging toxicity induced by 3-MCPD. The study showed that EGCG alleviated the aging toxicity induced by 3-MCPD.

Surveys and research on the applications of the hepatic venous pressure gradient (HVPG) are important for understanding the current status and future development of this technology in China. This article aimed to investigate the status of hepatic venous pressure gradient measurement in China in 2022. We investigated the overall status of HVPG technology in China—including hospital distribution, hospital level, annual number of cases, catheters used, average cost, indications, and current challenges by using online questionnaire. By counting the number and percentages of cases of these results, we hope to clarify the current status of HVPG measurements in China. According to the survey, 85 hospitals in China used HVPG technology in 2022 distributed across 29 provinces. A total of 4989 HVPG measurements were performed in all of the surveyed hospitals in 2022, of which 2813 cases (56.4%) were measured alone. The average cost of HVPG measurement was 5646.8 ± 2327.9 CNY. Of the clinical teams who performed the measurements (sometimes multiple per hospital), 94.3% (82/87) used the balloon method, and the majority of the teams (72.4%, 63/87) used embolectomy catheters. This survey clarified the clinical application status of HVPG in China and confirmed that some medical institutions in China have established a foundation for this technology. It is still necessary to continue promoting and popularizing this technology in the future. A survey analysis of hepatic venous pressure gradient for portal hypertension in China. Significant findings of the study Some medical institutions in China have already mastered the technique and applied it in their clinical practices. However, promoting and popularizing hepatic venous pressure gradient (HVPG) is still necessary. What this study adds We analyzed the overall status of HVPG measurement technology in China.

Polymyxins are the last line of defense against multidrug-resistant (MDR) Gram-negative bacterial infections. However, this last resort has been threatened by the emergence of superbugs carrying the mobile colistin resistance gene-1 (mcr-1).Given the high concentration of matrix metalloproteinase 3 (MMP-3) in bacterial pneumonia, limited plasma accumulation of colistin (CST) in the lung, and potential toxicity of ionic silver (Ag+), we designed a feasible clinical transformation platform, an MMP-3 high-performance lung-targeted bio-responsive delivery system, which we named “CST&Ag@CNMS”. This system exhibited excellent lung-targeting ability (>80% in lungs), MMP-3 bio-responsive release property (95% release on demand), and synergistic bactericidal activity in vitro(2–4-fold minimum inhibitory concentration reduction). In the mcr-1+CST-resistant murine pneumonia model, treatment with CST&Ag@CNMS improved survival rates (70% vs. 20%), reduced bacteria burden (2–3 log colony-forming unit [CFU]/g tissue), and considerably mitigated inflammatory response. In this study, CST&Ag@CNMS performed better than the combination of free CST and AgNO3. We also demonstrated the superior biosafety and biodegradability of CST&Ag@CNMS both in vitroand in vivo. These findings indicate the clinical translational potential of CST&Ag@CNMS for the treatment of lung infections caused by CST-resistant bacteria carrying mcr-1.

Angelica sinensis, commonly known as Dong Quai in Europe and America and as Dang-gui in China, is a medicinal plant widely utilized for the prevention and treatment of osteoporosis. In this study, we report the discovery of a new category of phthalide from Angelica sinensis, namely falcarinphthalides A and B (1and 2), which contains two fragments, (3R,8S)-falcarindiol (3) and (Z)-ligustilide (4). Falcarinphthalides A and B (1and 2) represent two unprecedented carbon skeletons of phthalide in natural products, and their antiosteoporotic activities were evaluated. The structures of 1and 2, including their absolute configurations, were established using extensive analysis of NMR spectra, chemical derivatization, and ECD/VCD calculations. Based on LC-HR-ESI-MS analysis and DFT calculations, a production mechanism for 1and 2involving enzyme-catalyzed Diels−Alder/retro-Diels−Alder reactions was proposed. Falcarinphthalide A (1), the most promising lead compound, exhibits potent in vitro antiosteoporotic activity by inhibiting NF-κB and c-Fos signaling-mediated osteoclastogenesis. Moreover, the bioinspired gram-scale total synthesis of 1, guided by intensive DFT study, has paved the way for further biological investigation. The discovery and gram-scale total synthesis of falcarinphthalide A (1) provide a compelling lead compound and a novel molecular scaffold for treating osteoporosis and other metabolic bone diseases.

Transformable mechanical structures can switch between distinct mechanical states. Whether this kind of structure can be self-assembled from simple building blocks at microscale is a question to be answered. In this work, we propose a self-assembly strategy for these structures based on a nematic monolayer of segmented colloidal rods with lateral cutting. By using Monte Carlo simulation, we find that rods with different cutting degrees can self-assemble into different crystals characterized by bond coordination zthat varies from 3 to 6. Among these, we identify a transformable superisostatic structure with pggsymmetry and redundant bonds (z= 5). We show that this structure can support either soft bulk modes or soft edge modes depending on its Poisson’s ratio, which can be tuned from positive to negative through a uniform soft deformation. We also prove that the bulk soft modes are associated with states of self-stress along the direction of zero strain during uniform soft deformation. The self-assembled transformable structures may act as mechanical metamaterials with potential applications in micromechanical engineering.

Crystallization of poly(l-lactic acid) (PLLA) at temperatures lower and higher than about 100–120 °C leads to the formation of α′- and α-crystals, respectively. Related to the formation of different crystal polymorphs after crystallization at different temperatures, the small-angle X-ray scattering (SAXS) patterns only show a long-period maximum after crystallization at high temperatures, when α-crystals are present. Reason for the absence of a long-period peak after low-temperature crystallization is insufficient density contrast between the formed α′-crystals and the amorphous phase but not the absence of lamellar stacks and long-range periodicity. This conclusion is based on the observation of a long period after the transformation of α′-crystals of rather low density into α-crystals of higher density, by thermal treatment, while keeping the semicrystalline morphology quasi-unchanged. Long-range periodicity and formation of lamellae in PLLA containing α′-crystals are ultimately proven by atomic force microscopy, despite a long period is not detected by SAXS.

The fluorinated decorations have recently been widely used in many biomedical applications. However, the potential mechanism of the fluorination effect on the cellular delivery of nanoparticles (NPs) still remains elusive. In this work, we systemically explore the penetration of a perfluoro-octanethiol-coated gold NP (PF-Au NP) and, for comparison, an octanethiol-coated gold NP (OT-Au NP) across lipid bilayers. We also investigated the effect of these two types of NPs on the properties of lipid bilayers. Our findings indicate that the lipid type and the surface tension of the lipid bilayer significantly impact the penetration capabilities of the fluorinated gold NP. By examining the distribution of ligands on the surface of the two types of NPs in water and during the penetration process, we unveil their distinct penetration characteristics. Specifically, the PF-Au NP exhibits amphiphobic behavior (both hydrophobic and lipophobic), while the OT-Au NP exhibits solely hydrophobic characteristics. Finally, we observe that the penetration capabilities can be increased by adjusting the degree of fluorination of the ligands on the NP surface. Overall, this study provides useful physical insights into the unique properties of the fluorinated decorations in NP permeation.

In order to improve the hiding rate of network data privacy information and shorten the encryption and decryption time, the paper proposes a new network data privacy security aggregation method based on big data pattern decomposition. Firstly, the empirical mode decomposition method is used to divide the upper and lower envelopes and complete the decomposition processing of network data. Secondly, the Paillier algorithm is used to calculate public and private keys and encrypt network data privacy. Finally, the encrypted ciphertext and signature are sent to the aggregator for secure aggregation of network data privacy through bilinear pairing. The experimental results show that the method proposed in this paper can improve the hiding rate of privacy information in network data, and the hiding rate of privacy information is basically above 95%, and the encryption and decryption time of network data privacy is significantly shortened.

Lenvatinib is a multiple receptor tyrosine kinases inhibitor (TKI) authorized for first-line treatment of hepatocellular carcinoma (HCC). However, Lenvatinib resistance is common in HCC clinical treatment, highlighting the urgent need to understand mechanisms of resistance. Here, we identified Golgi membrane protein 1 (GOLM1), a type II transmembrane protein originally located in the Golgi apparatus, as a novel regulator of Lenvatinib resistance. We found GOLM1 was overexpressed in Lenvatinib resistant human HCC cell lines, blood and HCC samples. Additionally, GOLM1 overexpression contributes to Lenvatinib resistance and HCC progression in vitro and in vivo. Mechanistically, GOLM1 upregulates CSN5 expression through EGFR-STAT3 pathway. Reversely, CSN5 deubiquitinates and stabilizes GOLM1 protein by inhibiting ubiquitin-proteasome pathway of GOLM1. Furthermore, clinical specimens of HCC showed a positive correlation between the activation of the GOLM1-EGFR-STAT3-CSN5 axis. Finally, GOLM1 knockdown was found to act in synergy with Lenvatinib in subcutaneous and orthotopic mouse model. Overall, these findings identify a mechanism of resistance to Lenvatinib treatment for HCC, highlight an effective predictive biomarker of Lenvatinib response in HCC and show that targeting GOLM1 may improve the clinical benefit of Lenvatinib.

The truck escape ramp is a clump of pebbles that is located alongside downgrades. As the pebbles are randomly placed in arrester beds, few studies have been conducted on simulation methods of the irregularly shaped pebbles. This paper proposed a pebble DEM model to analyze the micro-contact mechanism of the pebbles. Based on a polynomial algorithm, the 7th fit was selected and the coefficients of the edge curves were recorded. Second, the main view and left view were filled with preset numbers of ball elements. According to the ball element parameters, the ball elements were extended to three-dimensional models. Third, based on the edges of the main view and the top view, the ball element parameters were recalculated. Then, compression tests were conducted, and the key parameters of the pebble DEM model were calibrated. Based on the built pebble DEM model, compression tests were simulated with different pressing plate velocities and laying thicknesses. The results indicate that for increases in the pressing plate velocity, the contacting forces on the plate correspondingly increase, and this increase is linearly shaped. The results for different laying thicknesses indicate that for increases in the laying thickness, the contacting forces on the plate correspondingly decrease.

The impact of electromagnetic radiation generated by signal transmission base stations and power stations to meet the needs of communication equipment and energy consumption on the environment has caused people concerns. Monitoring and prediction of electric and magnetic fields have become critical tasks for researchers. In this paper, we propose a granularity data method based on T–S (Takagi–Sugeno) fuzzy model, named fuzzy rule-based model, which utilizing finite rules that are determined by the deviations between the predicted values and the true values after the data goes through a granulation-degranulation mechanism, to predict the intensity of power frequency electric field and electromagnetic field. A series of experiments show that fuzzy rule-based models have better robustness and higher prediction accuracy in comparison with several existing prediction models. The improvement of the performance of the fuzzy rule-based model quantified in terms of Root Mean Squared Error is 20.86%, 51.91%, 62.28%, 65.10%, and 71.92% in comparison with that of the Ridge model, Lasso model, and a family of support vector machine model with different kernel functions, including linear kernel (SVM-linear), radial basis function (SVM-BRF), polynomial kernel (SVM-polynomial) respectively, on the electromagnetic field testing data, and 37.42%, 55.16%, 58.79%, 59.28%, 64.27% lower than that of the Ridge model, Lasso model, SVM-linear model, SVM-BRF model and SVM-polynomial model on the power frequency electric field testing data.

Reliable motion prediction of surrounding vehicles is the key to safe and efficient driving of autonomous vehicles, especially at urban intersections with complex traffic environments. This study models driving intentions and future driving speeds at urban intersections and improves model prediction performance by considering traffic environment characteristics. Key feature parameters including environmental characteristics are first extracted through driving behavior analysis and existing research experience. Then models with different input combinations are constructed to explore the effectiveness of different factors in predicting driving intention and future speed. In particular, in vehicle speed modeling, a target detection algorithm is used to identify traffic participants. Based on the identified traffic participant and vehicle position information, a new method for speed prediction that can reflect the dynamic interaction characteristics between the driver and the traffic environment is proposed. Models are trained and tested using natural driving data from China. Finally, the models with the simplest input and the best effect are determined. The driving intention recognition model can accurately predict the driving maneuvers of straight-ahead, stopping, turning left and right 4 seconds before reaching the intersection. The speed prediction model can significantly improve the speed prediction accuracy, and shows stronger robustness and adaptability than existing models. This research provides important technical support for developing intelligent driving systems suitable for complex urban traffic environments.

The biological activity of plant polysaccharides can be enhanced by sulfated modification. In this study, the immunomodulatory effect of sulfated Cyclocarya paliuruspolysaccharides (SCP3) on macrophages RAW264.7 and its potential molecular mechanism were investigated. Results showed that SCP3 at 25−100 μg/mL increased viability and improved phagocytosis of RAW264.7 cells. Meanwhile, SCP3 could activate mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) signaling pathways, which increased the phosphorylation of Erk1/2, JNK, p38 and NF-κB p65, promoting secretion of cytokines tumor necrosis factor α (TNF-α), interleukin 6 (IL-6) and nitric oxide (NO) as well as the production of reactive oxygen species (ROS). In addition, Toll-like receptor 4 (TLR4) receptor inhibitors were able to block the production of NO and TNF-α by SCP3-stimulated macrophages. Based on Western blot analysis and validation using specific inhibitors against MAPK and NF-κB signaling pathways, the results demonstrated that SCP3 induced macrophages activation and enhanced TNF-α and NO production via TLR4-mediated MAPK and NF-κB pathways. In summary, SCP3 has significant immunomodulatory potential. The underlying molecular mechanism was that SCP3 activates macrophages via TLR4 receptors to promote ROS production, which in turn activates the downstream MAPK/NF-κB signaling pathway and then increases the secretion levels of cytokines and NO.

Adaptive motion/force tracking control is considered for a class of mobile manipulators with affine constraints and under-actuated joints in the presence of uncertainties in this paper. Dynamic equation of mobile manipulator is transformed into a controllable form based on dynamic coupling technique. In view of the asymptotic tracking idea and adaptive theory, adaptive controllers are proposed to achieve the desired control objective. Detailed simulation results confirm the validity of the control strategy.

Loss-of-function mutations in CREBBP, which encodes for a histone acetyltransferase, occur frequently in B-cell malignancies, highlighting CREBBP deficiency as an attractive therapeutic target. Using established isogenic cell models, we demonstrated that CREBBP-deficient cells are selectively vulnerable to AURKA inhibition. Mechanistically, we found that co-targeting CREBBP and AURKA suppressed MYC transcriptionally and post-translationally to induce replication stress and apoptosis. Inhibition of AURKA dramatically decreased MYC protein level in CREBBP-deficient cells, implying a dependency on AURKA to sustain MYC stability. Furthermore, in vivo studies showed that pharmacological inhibition of AURKA was efficacious in delaying tumor progression in CREBBP-deficient cells and was synergistic with CREBBP inhibitors in CREBBP-proficient cells. Our study sheds light on a novel synthetic lethal interaction between CREBBP and AURKA, indicating that targeting AURKA represents a potential therapeutic strategy for high-risk B-cell malignancies harboring CREBBP inactivating mutations.

Hepatocellular carcinoma (HCC), particularly when accompanied by microvascular invasion (MVI), has a markedly high risk of recurrence after liver resection. Adjuvant immunotherapy is considered a promising avenue. This multicenter, open-label, randomized, controlled, phase 2 trial was conducted at six hospitals in China to assess the efficacy and safety of adjuvant sintilimab, a programmed cell death protein 1 inhibitor, in these patients. Eligible patients with HCC with MVI were randomized (1:1) into the sintilimab or active surveillance group. The sintilimab group received intravenous injections every 3 weeks for a total of eight cycles. The primary endpoint was recurrence-free survival (RFS) in the intention-to-treat population. Key secondary endpoints included overall survival (OS) and safety. From September 1, 2020, to April 23, 2022, a total of 198 eligible patients were randomly allocated to receive adjuvant sintilimab (n= 99) or undergo active surveillance (n= 99). After a median follow-up of 23.3 months, the trial met the prespecified endpoints. Sintilimab significantly prolonged RFS compared to active surveillance (median RFS, 27.7 versus 15.5 months; hazard ratio 0.534, 95% confidence interval 0.360–0.792; P= 0.002). Further follow-up is needed to confirm the difference in OS. In the sintilimab group, 12.4% of patients experienced grade 3 or 4 treatment-related adverse events, the most common of which were elevated alanine aminotransferase levels (5.2%) and anemia (4.1%). These findings support the potential of immune checkpoint inhibitors as effective adjuvant therapy for these high-risk patients. Chinese Clinical Trial Registry identifier: ChiCTR2000037655.

Emulating the spike-based processing in the brain, spiking neural networks (SNNs) are developed and act as a promising candidate for the new generation of artificial neural networks that aim to produce efficient cognitions as the brain. Due to the complex dynamics and nonlinearity of SNNs, designing efficient learning algorithms has remained a major difficulty, which attracts great research attention. Most existing ones focus on the adjustment of synaptic weights. However, other components, such as synaptic delays, are found to be adaptive and important in modulating neural behavior. How could plasticity on different components cooperate to improve the learning of SNNs remains as an interesting question. Advancing our previous multispike learning, we propose a new joint weight-delay plasticity rule, named TDP-DL, in this article. Plastic delays are integrated into the learning framework, and as a result, the performance of multispike learning is significantly improved. Simulation results highlight the effectiveness and efficiency of our TDP-DL rule compared to baseline ones. Moreover, we reveal the underlying principle of how synaptic weights and delays cooperate with each other through a synthetic task of interval selectivity and show that plastic delays can enhance the selectivity and flexibility of neurons by shifting information across time. Due to this capability, useful information distributed away in the time domain can be effectively integrated for a better accuracy performance, as highlighted in our generalization tasks of the image, speech, and event-based object recognitions. Our work is thus valuable and significant to improve the performance of spike-based neuromorphic computing.

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Tripartite motif 17 (TRIM17) belongs to a subfamily of the RING-type E3 ubiquitin ligases, and regulates several cellular processes and pathological conditions including cancer. However, its potential function in gastric cancer (GC) remains obscure. Here, we have found TRIM17mRNA and protein levels are both upregulated in human GC compared with normal specimens, and TRIM17 upregulation indicates poor survival for GC patients. Functionally, TRIM17 was found to act as an oncogene by promoting the proliferation and survival of GC cell lines AGS and HGC-27. Mechanistically, TRIM17 acts to interact with BAX and promote its ubiquitination and proteasomal degradation, leading to a deficiency in BAX-dependent apoptosis in GC cells in the absence and presence of apoptosis stimuli. Moreover, TRIM17 and BAX expression levels are inversely correlated in human GC specimens. Our data thus suggest TRIM17 contributes to gastric cancer survival through regulating BAX protein stability and antagonizing apoptosis, which provides a promising therapeutic target for GC treatment and a biomarker for prognosis.