Search

CoCrNi medium-entropy alloys (MEAs) have attracted extensive attention and research because of their superior mechanical properties, such as higher ductility, strength, and toughness. This study uses molecular dynamics (MD) simulations to investigate the cutting behavior of a gradient nanograined (GNG) CoCrNi MEA. Moreover, it explores the influence of relative tool sharpness and rake angle on the cutting process. The results show that an increase in the average grain size of the GNG samples leads to a decrease in the average resultant cutting force, as predicted by the Hall–Petch relationship. The deformation behavior shows that grain boundaries are crucial in inhibiting the propagation of strain and stress. As the average grain size of the GNG sample increases, the range of shear strain distribution and average von Mises stress decreases. Moreover, the cutting chips become thinner and longer. The subsurface damage is limited to a shallow layer at the surface. Since thermal energy is generated in the high grain boundary density, the temperature of the contact zone between the substrate and the cutting tool increases as the GNG size decreases. The cutting chips removed from the GNG CoCrNi MEA substrates will transform into a mixed structure of face-centered cubic and hexagonally close-packed phases. The sliding and twisting of grain boundaries and the merging of grains are essential mechanisms for polycrystalline deformation. Regarding the cutting parameters, the average resultant force, the material accumulation, and the chip volume increase significantly with the increase in cutting depth. In contrast to sharp tools, which mainly use shear deformation, blunt tools remove material by plowing, and the cutting force increases with the increase in cutting-edge radius and negative rake angle.

Gaining insight into the underlying mechanisms driving nanoindentation-induced behavior in tungsten is essential for comprehending its mechanical properties. Although the plasticity of conventional pure tungsten under nanocontact conditions is well understood, these theoretical constructs may become inadequate when applied to irradiated tungsten due to the interplay between helium bubbles and dislocations. Here, we employed an integrated approach, combining crystal defect theories, molecular dynamics simulations, and machine learning, to explore the initiation and progression of dislocations in tungsten containing helium bubbles during nanoindentation, focusing on elucidating the impact of helium bubbles. In contrast to the typical dislocation nucleation in pure tungsten, the presence of helium bubbles mitigates local shear strain, thereby hindering dislocation nucleation and propagation, leading to a reduction of indentation force. Additionally, we conducted a comparative analysis between samples with and without helium bubbles, examining factors such as atomic displacement, strain localization parameters, dislocation line length, and stress component distribution. More importantly, a significant outcome of our study is the establishment of a relationship between the consistent alteration in the shape of helium bubbles and their size during micro-scale nanoindentation, achieved through machine learning techniques. Our findings reveal that the area occupied by helium bubbles post-nanoindentation is inversely correlated with indentation depth and directly linked to helium bubble size. These discoveries represent a notable advancement in understanding the effects of irradiation to a certain degree.

Purpose: Active surveillance (AS) is one of the management options for patients with low-risk and select intermediate-risk prostate cancer (PC). However, factors predicting disease reclassification and conversion to active treatment from a large population of pure Asian cohorts regarding AS are less evaluated. This study investigated the intermediate-term outcomes of patients with localized PC undergoing AS. Materials and Methods: This cohort study enrolled consecutive men with localized non-high-risk PC diagnosed in Taiwan between June 2012 and Jan 2023. The study endpoints were disease reclassification (either pathological or radiographic progression) and conversion to active treatment. The factors predicting endpoints were evaluated using the Cox proportional hazards model. Results: A total of 405 patients (median age: 67.2 years) were consecutively enrolled and followed up with a median of 64.6 months. Based on the National Comprehensive Cancer Network (NCCN) risk grouping, 70 (17.3%), 164 (40.5%), 140 (34.6%), and 31 (7.7%) patients were classified as very low-risk, low-risk, favorable-intermediate risk, and unfavorable intermediate-risk PC, respectively. The 5-year reclassification rates were 24.8%, 27.0%, 18.6%, and 25.3%, respectively. The 5-year conversion rates were 20.4%, 28.8%, 43.6%, and 37.8%, respectively. A prostate-specific antigen density (PSAD) of ≥0.15 ng/mL2 predicted reclassification (hazard ratio [HR] 1.84, 95% confidence interval [CI] 1.17–2.88) and conversion (HR 1.56, 95% CI 1.05–2.31). A maximal percentage of cancer in positive cores (MPCPC) of ≥15% predicted conversion (15% to

The interaction between irradiation defects and dislocations could lead to macroscopic hardening and embrittlement. In this study, molecular dynamics (MD) and machine learning were conducted to study three-dimensional void- and Cu-cluster-induced kinetics models under interaction with dislocations in body-centered cubic Fe-based alloys. MD Results show that dislocation climb and shear are two types of interaction mechanism based on the defect size. Combined MD results and machine learning, it was found that the dislocation length increased linearly with an increase in the size of the defects after the interaction. In addition, the number of atoms in the Cu-rich cluster and the reduced number of vacancies in the voids had a square relationship with the defect size where 0.85D2 is for Cu-rich cluster and 0.50D2 is for void. Furthermore, atomic-scale three-dimensional irradiation-induced defect kinetics models were developed and incorporated into the crystal plasticity finite element model (CPFEM). We also analyzed the contributions of various defects to the increase in the yield stress during CPFEM simulation. Compared with DBH model, the prediction of MD data-driven CPFEM matches better with the experimental data. Cluster contributed the most to hardening with low obstacle strength due to the higher number density compared with dislocation loops and voids. The loops also contributed to hardening; however, their contribution was smaller than that of the clusters. Although the number density and size of voids were minimized, they may have contributed because of the high obstacle strengths. This work can indeed deepen the understanding of irradiation effect in Fe-based alloys.

Objective: To investigate the characteristics of three-dimensional distribution of subchondral fracture lines on the surface of the osteonecrosis femoral head, and to discuss the underlying mechanisms that contribute to its collapse. Methods: We retrospectively analyzed computed tomography (CT) images from 75 patients (comprising a total of 77 femoral heads) diagnosed with Association Research Circulation Osseous (ARCO) stage IIIA or IIIB femoral head necrosis. The three-dimensional structures of both the femoral head and the subchondral fracture line were reconstructed and subsequently fitted into normal femoral head model. A heat map of fracture line was generated to visualize its spatial distribution across the femoral heads surface.to observe its distribution. In addition to that, the femoral head was partitioned into four zones, and the frequency of each fracture line traversing different zones was calculated and analysed. Results: Highest and lowest density of subchondral fracture lines was demonstrated in anterolateral and posterolateral zone respectively. and most sparse in posterolateral. Furthermore, the three-dimensional heat map of fracture lines highlighted their most frequent occurrence in the anterolateral area, particularly near the junction of the femoral head and neck. One fracture line may pass through multiple areas, passage frequencies for fracture lines was observed in zones I, II, III and IV for 66 times (85.7 %), 52 times (67.5 %), 25 times (32.5 %) and 46 times (59.7 %), respectively, with a significant difference between zone I and other zones (P

In this work we study the effects of different factors of dislocation loop on its obstacle strength when interacting with an edge dislocation. At first, the interaction model for dislocation and dislocation loop is established and the full and partial absorption mechanism is obtained. Then, the effect of temperature, size and burgers vector of dislocation loop are investigated. The relation between the obstacle strength and irradiation dose has been established, which bridges the irradiation source and microscale properties. Except that, the obstacle strength of C, Cr, Ni, Mn, Mo and P decorated dislocation loop is studied. Results show that the obstacle strength for dislocation loop decorated by alloy element decreases in the sequence of Cr, Ni, Mn, C, P and Mo, which could be used to help parameterize and validate crystal plasticity finite element model and therein integrated constitutive laws to enable accounting for irradiation-induced chemical segregation effects.

Iron is considered as an attractive alternative material for bioresorbable scaffolds (BRS). The sirolimus eluting iron bioresorbable scaffold (IBS), developed by Biotyx Medical (Shenzhen, China), is the only iron-based BRS with an ultrathin-wall design. The study aims to investigate the long-term efficacy, safety, biocompatibility, and lumen changes during the biodegradation process of the IBS in a porcine model. A total of 90 IBSs and 70 cobalt-chromium everolimus eluting stents (EES) were randomly implanted into nonatherosclerotic coronary artery of healthy mini swine. The multimodality assessments including coronary angiography, optical coherence tomography, micro-computed tomography, magnetic resonance imaging, real-time polymerase chain reaction (PCR), and histopathological evaluations, were performed at different time points. There was no statistical difference in area stenosis between IBS group and EES group at 6 months, 1year, 2 years and 5 years. Although the scaffolded vessels narrowed at 9 months, expansive remodeling with increased mean lumen area was found at 3 and 5 years. The IBS struts remained intact at 6 months, and the corrosion was detectable at 9 months. At 5 years, the iron struts were completely degraded and absorbed in situ, without in-scaffold restenosis or thrombosis, lumen collapse, aneurysm formation, and chronic inflammation. No local or systemic toxicity and abnormal histopathologic manifestation were found in all experiments. Results from real-time PCR indicated that no sign of iron overload was reported in scaffolded segments. Therefore, the IBS shows comparable efficacy, safety, and biocompatibility with EES, and late lumen enlargement is considered as a unique feature in the IBS-implanted vessels.

Abstract While strategies to enhance the quantum coherence of plasmonic resonances have attracted a lot of attention in the past, the advent of non-Hermitian optics carries promising possibilities in this direction, mostly of which are still unexplored. In this work, we show that the quantum coherence of plasmonic resonances can be enhanced by integrating a plasmonic antenna in a photonic cavity operated at a chiral exceptional point (CEP), where the phase of light offers an additional degree of freedom for flexibly manipulating the quantum dynamics. The few-mode quantization theory is employed to demonstrate the advantages and related quantum-optics applications of the proposed hybrid cavity in both off- and on-resonance plasmon-photon coupling. For the former case, the local density of states evolves into sub-Lorentzian lineshape, resulting in reduced dissipation of polaritonic states. On resonance, we identify two mechanisms improving the quantum yield by two orders of magnitude at room temperature: the reduction of plasmonic absorption through Fano interference and the enhancement of cavity radiation through superscattering. Our results establish CEP-engineered plasmonic resonances as a promising platform for controlling quantum states and building high-performance quantum devices.

Abstract Millirobots must have low cost, efficient locomotion, and the ability to track target trajectories precisely if they are to be widely deployed. With current materials and fabrication methods, achieving all of these features in one millirobot remains difficult. We develop a series of graphene-based helical millirobots by introducing asymmetric light pattern distortion to a laser-induced polymer-to-graphene conversion process; this distortion resulted in the spontaneous twisting and peeling off of graphene sheets from the polymer substrate. The lightweight nature of graphene in combine with the laser-induced porous microstructure provides a millirobot scaffold with a low density and high surface hydrophobicity. Magnetically driven nickel-coated graphene-based helical millirobots with rapid locomotion, excellent trajectory tracking, and precise drug delivery ability were fabricated from the scaffold. Importantly, such high-performance millirobots are fabricated at a speed of 77 scaffolds per second, demonstrating their potential in high-throughput and large-scale production. By using drug delivery for gastric cancer treatment as an example, we demonstrate the advantages of the graphene-based helical millirobots in terms of their long-distance locomotion and drug transport in a physiological environment. This study demonstrates the potential of the graphene-based helical millirobots to meet performance, versatility, scalability, and cost-effectiveness requirements simultaneously.

Abstract Anaplastic lymphoma kinase (ALK) fusion-positive colorectal cancer (CRC) is a rare and chemotherapy-refractory subtype that lacks established and effective treatment strategies. Additionally, the efficacy and safety of ALK inhibitors (ALKi) in CRC remain undetermined. Herein, we examined a series of ALK-positive CRC patients who underwent various lines of ALKi treatment. Notably, we detected an ALK 1196M resistance mutation in a CRC patient who received multiple lines of chemotherapy and ALKi treatment. Importantly, we found that Brigatinib and Lorlatinib demonstrated some efficacy in managing this patient, although the observed effectiveness was not as pronounced as in non-small cell lung cancer cases. Furthermore, based on our preliminary analyses, we surmise that ALK-positive CRC patients are likely to exhibit inner resistance to Cetuximab. Taken together, our findings have important implications for the treatment of ALK-positive CRC patients.

Abstract Peri-implantitis is a bacterial infection that causes soft tissue inflammatory lesions and alveolar bone resorption, ultimately resulting in implant failure. Dental implants for clinical use barely have antibacterial properties, and bacterial colonization and biofilm formation on the dental implants are major causes of peri-implantitis. Treatment strategies such as mechanical debridement and antibiotic therapy have been used to remove dental plaque. However, it is particularly important to prevent the occurrence of peri-implantitis rather than treatment. Therefore, the current research spot has focused on improving the antibacterial properties of dental implants, such as the construction of specific micro-nano surface texture, the introduction of diverse functional coatings, or the application of materials with intrinsic antibacterial properties. The aforementioned antibacterial surfaces can be incorporated with bioactive molecules, metallic nanoparticles, or other functional components to further enhance the osteogenic properties and accelerate the healing process. In this review, we summarize the recent developments in biomaterial science and the modification strategies applied to dental implants to inhibit biofilm formation and facilitate bone-implant integration. Furthermore, we summarized the obstacles existing in the process of laboratory research to reach the clinic products, and propose corresponding directions for future developments and research perspectives, so that to provide insights into the rational design and construction of dental implants with the aim to balance antibacterial efficacy, biological safety, and osteogenic property.

Abstract Experimental realization of strong coupling between a single exciton and plasmons remains challenging as it requires deterministic positioning of the single exciton and alignment of its dipole moment with the plasmonic fields. This study aims to combine the host–guest chemistry approach with the cucurbit[7]uril-mediated active self-assembly to precisely integrate a single methylene blue molecule in an Au nanodimer at the deterministic position (gap center of the nanodimer) with the maximum electric field (EFmax) and perfectly align its transition dipole moment with the EFmax, yielding a large spectral Rabi splitting of 116 meV for a single-molecule exciton—matching the analytical model and numerical simulations. Statistical analysis of vibrational spectroscopy and dark-field scattering spectra confirm the realization of the single exciton strong coupling at room temperature. Our work may suggest an approach for achieving the strong coupling between a deterministic single exciton and plasmons, contributing to the development of room-temperature single-qubit quantum devices.

Irradiation defects are known to impede the dislocation motion in irradiated reactor pressure vessel (RPV) steels. However, consistent experimental studies of the respective irradiation defects and relevant theoretical studies of the interaction mechanism and hardening model are still lacking. In this study, the microstructure and irradiation-induced hardening of RPV steels are investigated using transmission electron microscopy (TEM)/energy-dispersive X-ray spectrometry (EDS) and molecular dynamics (MD) simulations. In A508-Ⅲ steel, 9R, twinned fcc, and other typical Cu-rich cluster structures are observed using TEM after the irradiation experiment. Based on the experimental results, MD simulations are performed to study the interactions between the dislocations and Cu clusters or voids. A mechanism diagram of the interaction mechanism coupling the effects of temperature and defect size is shown for both the Cu clusters and voids. A relevant hardening model is proposed based on the MD data, which is further discussed in relation to the macroscopic mechanical properties. Furthermore, the irradiation-induced hardening of the RPV steel is successfully predicted, which further demonstrates the reliability of the proposed unified hardening model.

Abstract Pancreatic cancer is one of the most fatal cancers in the world. A growing number of studies have begun to demonstrate that mitochondria play a key role in tumorigenesis. Our previous study reveals that NDUFS2 (NADH: ubiquinone oxidoreductase core subunit S2), a core subunit of the mitochondrial respiratory chain complex I, is upregulated in Pancreatic adenocarcinoma (PAAD). However, its role in the development of PAAD remains unknown. Here, we showed that NDUFS2 played a critical role in the survival, proliferation and migration of pancreatic cancer cells by inhibiting mitochondrial cell death. Additionally, protein mass spectrometry indicated that the NDUFS2 was interacted with a deubiquitinase, OTUB1. Overexpression of OTUB1 increased NDUFS2 expression at the protein level, while knockdown of OTUB1 restored the effects in vitro. Accordingly, overexpression and knockdown of OTUB1 phenocopied those of NDUFS2 in pancreatic cancer cells, respectively. Mechanically, NDUFS2 was deubiquitinated by OTUB1 via K48-linked polyubiquitin chains, resulted in an elevated protein stability of NDUFS2. Moreover, the growth of OTUB1-overexpressed pancreatic cancer xenograft tumor was promoted in vivo, while the OTUB1-silenced pancreatic cancer xenograft tumor was inhibited in vivo. In conclusion, we revealed that OTUB1 increased the stability of NDUFS2 in PAAD by deubiquitylation and this axis plays a pivotal role in pancreatic cancer tumorigenesis and development.

Abstract Investigations of one-dimensional segmented heteronanostructures (1D-SHs) have recently attracted much attention due to their potentials for applications resulting from their structure and synergistic effects between compositions and interfaces. Unfortunately, developing a simple, versatile and controlled synthetic method to fabricate 1D-SHs is still a challenge. Here we demonstrate a stress-induced axial ordering mechanism to describe the synthesis of 1D-SHs by a general under-stoichiometric reaction strategy. Using the continuum phase-field simulations, we elaborate a three-stage evolution process of the regular segment alternations. This strategy, accompanied by easy chemical post-transformations, enables to synthesize 25 1D-SHs, including 17 nanowire-nanowire and 8 nanowire-nanotube nanostructures with 13 elements (Ag, Te, Cu, Pt, Pb, Cd, Sb, Se, Bi, Rh, Ir, Ru, Zn) involved. This ordering evolution-driven synthesis will help to investigate the ordering reconstruction and potential applications of 1D-SHs.

Abstract In this work, an invasive plant (Aster subulatus Michx) mesopore laminar biochar loaded with transition metal Co (CoS@MLBC) was synthesized by a one-step hydrothermal carbonization way for activating peroxymonosulfate (PMS) to remove antibiotics in water. We characterized the structure and morphology of CoS@MLBC and tested its performance. The results showed that the carbon nitride structure was formed on CoS@MLBC, which improved its adsorption capacity for antibiotics and PMS. In addition, Co-doping significantly enhanced the PMS activity and efficiently degraded ciprofloxacin (CIP) over a wide pH range. It was identified that radical and non-radical synergistic action had a critical effect on the CIP degradation process. Furthermore, CoS@MLBC could completely remove CIP within 10 min and had a high removal efficiency (98%) after four cycles. Three possible pathways of the CIP degradation process with 12 intermediates were proposed and their ecotoxicity was analyzed. This work provides a new perspective for preparing biochar from invasive plants for the degradation of antibiotics in water, realizing the concept of “treating the wastes with wastes”. Graphical Abstract

Abstract Purpose To explore the predictive potential of intratumoral and multiregion peritumoral radiomics features extracted from multiparametric MRI for predicting pathological differentiation in hepatocellular carcinoma (HCC) patients. Methods A total of 265 patients with 277 HCCs (training cohort n = 193, validation cohort n = 84) who underwent preoperative MRI were retrospectively analyzed. The risk factors identified through stepwise regression analysis were utilized to construct a clinical model. Radiomics models based on MRI (arterial phase, portal venous phase, delayed phase) across various regions (entire tumor, Peri_5mm, Peri_10mm, Peri_20mm) were developed using the LASSO approach. The features obtained from the intratumoral region and the optimal peritumoral region were combined to design the IntraPeri fusion model. Model performance was assessed using the area under the curve (AUC). Results Larger size, non-smooth margins, and mosaic architecture were risk factors for poorly differentiated HCC (pHCC). The clinical model achieved AUCs of 0.77 and 0.73 in the training and validation cohorts, respectively, while the intratumoral model achieved corresponding AUC values of 0.92 and 0.82. The Peri_10mm model demonstrated superior performance to the Peri_5mm and Peri_20mm models, with AUC values of 0.87 vs. 0.84 vs. 0.73 in the training cohort and 0.80 vs. 0.77 vs. 0.68 in the validation cohort, respectively. The IntraPeri model exhibited remarkable AUC values of 0.95 and 0.86 in predicting pHCC in the training and validation cohorts, respectively. Conclusions Our study highlights the potential of a multiparametric MRI-based radiomic model that integrates intratumoral and peritumoral features as a tool for predicting HCC differentiation. Critical relevance statement Both clinical and multiparametric MRI-based radiomic models, particularly the intratumoral radiomic model, are non-invasive tools for predicting HCC differentiation. Importantly, the IntraPeri fusion model exhibited remarkable predictiveness for individualized HCC differentiation. Key points • Both the intratumoral radiomics model and clinical features were useful for predicting HCC differentiation. • The Peri_10mm radiomics model demonstrated better diagnostic ability than other peritumoral region-based models. • The IntraPeri radiomics fusion model outperformed the other models for predicting HCC differentiation. Graphical Abstract

BackgroundThe relationship between peripheral immune cells and immunoglobulin A nephropathy (IgAN) is widely known; however, causal evidence of this link is lacking. Here, we aimed to determine the causal effect of peripheral immune cells, specifically total white blood cells, lymphocytes, monocytes, basophils, eosinophils, and neutrophils, as well as lymphocyte subset traits, on the IgAN risk using a Mendelian randomization (MR) analysis.MethodsThe inverse-variance weighted (IVW) method was used for the primary analysis. We applied three complementary methods, including the weighted median, MR-Egger regression, and MR-PRESSO, to detect and correct for the effect of horizontal pleiotropy. Additionally, we performed a multivariable MR (MVMR) analysis, adjusting for the effects of C-reactive protein (CRP) levels. The roles of specific lymphocyte subtypes and their significance have garnered interest. Bidirectional two-sample MR analysis was performed to test the potential causal relationships between immune traits, including median fluorescence intensities (MFIs) and the relative cell count (AC), and IgAN.ResultsThe IVW-MR analysis suggested a potential causal relationship between lymphocyte counts and IgAN in Europe (OR per 1-SD increase: 1.43, 95% CI: 1.08–1.88, P = 0.0123). The risk effect of lymphocytes remained even after adjusting for CRP levels using the MVMR method (OR per 1-SD increase: 1.44, 95% CI: 1.05–1.96, P = 0.0210). The other sensitivity analyses showed a consistent trend. The largest GWAS published to date was used for peripheral blood immunophenotyping to explore the potential causal relationship between peripheral immune cell subsets and IgAN. Six AC–IgAN and 14 MFI–IgAN pairs that reached statistical significance (P < 0.05) were detected. Notably, CD3, expressed in eight subsets of T cells, consistently showed a positive correlation with IgAN. The bidirectional MR analysis did not reveal any evidence of reverse causality. According to the sensitivity analysis, horizontal pleiotropy was unlikely to distort the causal estimates.ConclusionsGenetically determined high lymphocyte counts were associated with IgAN, supporting that high lymphocyte counts is causal risk factor for IgAN.

BackgroundGestational diabetes mellitus (GDM) can result in adverse maternal and neonatal outcomes. Predicting those at high risk of GDM and early interventions can reduce the development of GDM. The aim of this study was to examine the associations between first-trimester prenatal screening biomarkers and maternal characteristics in relation to GDM in Chinese women.MethodsWe conducted a retrospective cohort study of singleton pregnant women who received first-trimester aneuploidy and preeclampsia screening between January 2019 and May 2021. First-trimester prenatal screening biomarkers, including pregnancy-associated plasma protein A (PAPP-A), free beta-human chorionic gonadotropin, and placental growth factor (PLGF), along with maternal characteristics, were collected for analysis in relation to GDM. Receiver operating characteristic (ROC) curve and logistic regression analyses were used to evaluate variables associated with GDM.ResultsOf the 1452 pregnant women enrolled, 96 developed GDM. PAPP-A (5.01 vs. 5.73 IU/L, P < 0.001) and PLGF (39.88 vs. 41.81 pg/mL, P = 0.044) were significantly lower in the GDM group than in the non-GDM group. The area under the ROC curve of combined maternal characteristics and biomarkers was 0.73 (95% confidence interval [CI] 0.68–0.79, P < 0.001). The formula for predicting GDM was as follows: P = 1/[1 + exp (-8.148 + 0.057 x age + 0.011 x pregestational body mass index + 1.752 x previous GDM history + 0.95 x previous preeclampsia history + 0.756 x family history of diabetes + 0.025 x chronic hypertension + 0.036 x mean arterial pressure - 0.09 x PAPP-A - 0.001 x PLGF)]. Logistic regression analysis revealed that higher pregestational body mass index (adjusted odds ratio [aOR] 1.03, 95% CI 1.01 - 1.06, P = 0.012), previous GDM history (aOR 9.97, 95% CI 3.92 - 25.37, P < 0.001), family history of diabetes (aOR 2.36, 95% CI 1.39 - 4.02, P = 0.001), higher mean arterial pressure (aOR 1.17, 95% CI 1.07 - 1.27, P < 0.001), and lower PAPP-A level (aOR 0.91, 95% CI 0.83 - 1.00, P = 0.040) were independently associated with the development of GDM. The Hosmer-Lemeshow test demonstrated that the model exhibited an excellent discrimination ability (chi-square = 3.089, df = 8, P = 0.929).ConclusionDownregulation of first-trimester PAPP-A and PLGF was associated with the development of GDM. Combining first-trimester biomarkers with maternal characteristics could be valuable for predicting the risk of GDM.

Gastrointestinal cancer is among the most common cancers worldwide. Immune checkpoint inhibitor-based cancer immunotherapy has become an innovative approach in cancer treatment; however, its efficacy in gastrointestinal cancer is limited by the absence of infiltration of immune cells within the tumor microenvironment. Therefore, it is therefore urgent to develop a novel therapeutic drug to enhance immunotherapy. In this study, we describe a previously unreported potentiating effect of Icariside I (ICA I, GH01), the main bioactive compound isolated from the Epimedium species, on anti-tumor immune responses. Mechanistically, molecular docking and SPR assay result show that ICA I binding with TRPV4. ICA I induced intracellular Ca2+ increasing and mitochondrial DNA release by targeting TRPV4, which triggered cytosolic ox-mitoDNA release. Importantly, these intracellular ox-mitoDNA fragments were taken up by immune cells in the tumor microenvironment, which amplified the immune response. Moreover, our study shows the remarkable efficacy of sequential administration of ICA I and anti-α-PD-1 mAb in advanced tumors and provides a strong scientific rationale for recommending such a combination therapy for clinical trials. ICA I enhanced the anti-tumor effects with PD-1 inhibitors by regulating the TRPV4/Ca2+/Ox-mitoDNA/cGAS/STING axis. We expect that these findings will be translated into clinical therapies, which will benefit more patients with cancer in the near future.

Background ELMSAN1 (ELM2‐SANT domain‐containing scaffolding protein 1) is a newly identified scaffolding protein of the MiDAC (mitotic deacetylase complex), playing a pivotal role in early embryonic development. Studies on Elmsan1 knockout mice showed that its absence results in embryo lethality and heart malformation. However, the precise function of ELMSAN1 in heart development and formation remains elusive. To study its potential role in cardiac lineage, we employed human‐induced pluripotent stem cells (hiPSCs) to model early cardiogenesis and investigated the function of ELMSAN1. Methods and Results We generated ELMSAN1‐deficient hiPSCs through knockdown and knockout techniques. During cardiac differentiation, ELMSAN1 depletion inhibited pluripotency deactivation, decreased the expression of cardiac‐specific markers, and reduced differentiation efficiency. The impaired expression of genes associated with contractile sarcomere structure, calcium handling, and ion channels was also noted in ELMSAN1‐deficient cardiomyocytes derived from hiPSCs. Additionally, through a series of structural and functional assessments, we found that ELMSAN1‐null hiPSC cardiomyocytes are immature, exhibiting incomplete sarcomere Z‐line structure, decreased calcium handling, and impaired electrophysiological properties. Of note, we found that the cardiac‐specific role of ELMSAN1 is likely associated with histone H3K27 acetylation level. The transcriptome analysis provided additional insights, indicating maturation reduction with the energy metabolism switch and restored cell proliferation in ELMSAN1 knockout cardiomyocytes. Conclusions In this study, we address the significance of the direct involvement of ELMSAN1 in the differentiation and maturation of hiPSC cardiomyocytes. We first report the impact of ELMSAN1 on multiple aspects of hiPSC cardiomyocyte generation, including cardiac differentiation, sarcomere formation, calcium handling, electrophysiological maturation, and proliferation.

Tubulin posttranslational modifications (PTMs) modulate the dynamic properties of microtubules and their interactions with other proteins. However, the effects of tubulin PTMs were often revealed indirectly through the deletion of modifying enzymes or the overexpression of tubulin mutants. In this study, we directly edited the endogenous tubulin loci to install PTM-mimicking or -disabling mutations and studied their effects on microtubule stability, neurite outgrowth, axonal regeneration, cargo transport, and sensory functions in the touch receptor neurons of Caenorhabditis elegans. We found that the status of β-tubulin S172 phosphorylation and K252 acetylation strongly affected microtubule dynamics, neurite growth, and regeneration, whereas α-tubulin K40 acetylation had little influence. Polyglutamylation and detyrosination in the tubulin C-terminal tail had more subtle effects on microtubule stability likely by modulating the interaction with kinesin-13. Overall, our study systematically assessed and compared several tubulin PTMs for their impacts on neuronal differentiation and regeneration and established an in vivo platform to test the function of tubulin PTMs in neurons.

Background: Non-invasive prenatal tests (NIPT) are used to screen for trisomy 21, 18, and 13. This study investigated NIPT performance and the clinical significance of its results. Methods: Pregnant women (n = 282,911) participating in a free NIPT (April 2018–December 2021) were screened for common trisomies, and the results were retrospectively analyzed. NIPT performance was evaluated by its positive predictive value (PPV), sensitivity, and specificity. Results were analyzed using number, percentage, and chi-squared/t-test analyses. Results: After NIPT screening, patients with common trisomies (n = 746) included 457 with T21, 160 with T18, and 129 with T13. Seven false negative cases were identified. High PPV (86.81 %, 56.81 %, 18.18 %), sensitivity (99.25 %, 98.33 %, 100.00 %), and specificity (99.98 %, 99.98 %, 99.97 %) values were detected for trisomy 21, 18, and 13, respectively. The PPVs of common trisomies were significantly different between pregnant women older than 35 (85.53 %, 136/159) and those aged 35 or younger (58.90 %, 311/528) (χ2 = 125.02, P = 2.20e-16). As the NIPT uptake increased from 2018 to 2021, live-born birth defect incidence decreased. Conclusion: NIPT performed well in screening for T21, T18, and T13. Our discoveries offer an important and useful guideline in laboratory and clinical genetic counseling.

With the discovery of evidence that many endocrine-disrupting chemicals (EDCs) in the environment influence human health, their toxic effects and mechanisms have become a hot topic of research. However, investigations into their endocrine-disrupting toxicity under combined binary exposure, especially the molecular mechanism of combined effects, have rarely been documented. In this study, two typical EDCs, perfluorooctanoic acid (PFOA) and 4-hydroxybenzophenone (4-HBP), were selected to examine their combined effects and molecular mechanism on MCF-7 cell proliferation at environmentally relevant exposure concentrations. We have successfully established a model to evaluate the binary combined toxic effects of endocrine disruptors, presenting combined effects in a simple and direct way. Results indicated that the combined effect changed from additive to synergistic from 1.25 × 10−8 M to 4 × 10−7 M. Metabolomics analyses suggested that exposure to PFOA and 4-HBP caused significant alterations in purine metabolism, arginine, and proline metabolism and had superimposed influences on metabolism. Enhanced combined effects were observed in glycine, serine, and threonine metabolic pathways compared to exposure to PFOS and 4-HBP alone. Additionally, the differentially expressed genes (DEGs) are primarily involved in Biological Processes, especially protein targeting the endoplasmic reticulum, and significantly impact the oxidative phosphorylation and thermogenesis-related KEGG pathway. By integrating metabolome and transcriptome analyses, PFOA and 4-HBP regulate purine metabolism, the TCA cycle, and endoplasmic reticulum protein synthesis in MCF-7 cells via mTORC1, which provides genetic material, protein, and energy for cell proliferation. Furthermore, molecular docking confirmed the ability of PFOA and 4-HBP to stably bind the estrogen receptor, indicating that they have different binding pockets. Collectively, these findings will offer new insights into understanding the mechanisms by which EDCs produce combined toxicity.

Thyroid radiofrequency ablation and microwave ablation are widely adopted minimally invasive treatments for diverse thyroid conditions worldwide. Fundamental skills such as the trans-isthmic approach and the moving shot technique are crucial for performing thyroid ablation, and advanced techniques, including hydrodissection and vascular ablation, improve safety and efficacy and reduce complications. Given the learning curve associated with ultrasound-guided therapeutic procedures, operators need training and experience. While training models exist, limited attention has been given to ultrasound maneuvers in ablation needle manipulation. This article introduces two essential maneuvers, the zigzag moving technique and the alienate maneuver, while also reviewing the latest ultrasound techniques in thyroid ablation, contributing valuable insights into this evolving field.

Background: The benefit of injection laryngoplasty (IL) on voice for unilateral vocal fold paralysis (UVFP) is supported increasingly in literatures, yet less is known for swallowing. Also, prevalence of patient-reported dysphagia is substantially higher than instrumental studies. This prospective study focused on swallowing outcomes, with predetermined flexible endoscopic evaluation of swallowing (FEES) protocol that simulates daily life situation. Methods: Adult patients with UVFP and aspiration receiving IL were recruited. Voice outcome measurements, as well as swallowing outcomes including Eating Assessment Tool (EAT-10) and FEES, which challenged patients with different fluid volumes: 10 mL, 20 mL, and 90 mL cup sipping were evaluated. Results: Significant improvements were demonstrated in all voice outcomes. Significant changes were also presented inEAT-10 (P

Objective: Blood circulation is an important indicator of wound healing. In this study, a tissue oxygen saturation detecting (TOSD) system that is based on multispectral imaging (MSI) is proposed to quantify the degree of tissue oxygen saturation (StO2) in cutaneous tissues. Methods: A wound segmentation algorithm is used to segment automatically wound and skin areas, eliminating the need for manual labeling and applying adaptive tissue optics. Animal experiments were conducted on six mice in which they were observed seven times, once every two days. The TOSD system illuminated cutaneous tissues with two wavelengths of light - red ( $\mathrm {\lambda } = 660$ nm) and near-infrared ( $\mathrm {\lambda } = 880$ nm), and StO2 levels were calculated using images that were captured using a monochrome camera. The wound segmentation algorithm using ResNet34-based U-Net was integrated with computer vision techniques to improve its performance. Results: Animal experiments revealed that the wound segmentation algorithm achieved a Dice score of 93.49%. The StO2 levels that were determined using the TOSD system varied significantly among the phases of wound healing. Changes in StO2 levels were detected before laser speckle contrast imaging (LSCI) detected changes in blood flux. Moreover, statistical features that were extracted from the TOSD system and LSCI were utilized in principal component analysis (PCA) to visualize different wound healing phases. The average silhouette coefficients of the TOSD system with segmentation (ResNet34-based U-Net) and LSCI were 0.2890 and 0.0194, respectively. Conclusion: By detecting the StO2 levels of cutaneous tissues using the TOSD system with segmentation, the phases of wound healing were accurately distinguished. This method can support medical personnel in conducting precise wound assessments. Clinical and Translational Impact Statement—This study supports efforts in monitoring StO2 levels, wound segmentation, and wound healing phase classification to improve the efficiency and accuracy of preclinical research in the field.

An output capacitorless low-dropout (OCL-LDO) regulator with a direct-coupled slew rate enhancement (DCSRE) technique. This paper proposes a low-dropout regulator with a simple structure, fast transient response, and the ability to reduce overshoot and undershoot, suitable for system-on-chip (SOC) integration. Instead of a high-pass filter, an error amplifier is used to couple the transient signal to achieve better transient response with higher current efficiency and no significant increase in chip area and power consumption, eliminating the tradeoff with the high-pass filter cutoff frequency and simplifying design considerations. Furthermore, the proposed technique would not affect other characteristics of the LDO regulator such as stability, frequency compensation, line regulation, and load regulation. In addition, the analysis is carried out for the case of many poles and zeros in the unity-gain bandwidth (GBW). From the measurement result, the proposed LDO regulator regulated the output voltage at 1 V from the input range 1.8V up to 3.3V, with $28.8\mu $ A quiescent. The output voltage recovers in $0.23\mu $ s at a voltage spike of less than 43.5mV, where the load current switches from $100\mu $ A to 100mA in 100ns. The LDO regulator is fabricated in a $0.18\mu $ m CMOS process with a core area of 0.0174mm2.

Endoscopic resection (ER) and laparoscopic surgery are the main methods for treatment of early gastric cancer (EGC). Radical gastrectomy(RG) and lymph node dissection are required for the patients who don’t meet the indications of ER, but it may cause postoperative stomach dysfunction and reduce quality of life (QOL). Pylorus-preserving gastrectomy (PPG) is one of the function-preserving gastrectomy for EGC. The short-term complications of PPG are equal to that of RG and it is also beneficial to long-term nutritional status and QOL. The 5-year survival rate of PPG is similar to that of distal subtotal gastrectomy (DSG) according to a retrospective study of the matched cohort. But delayed gastric emptying (DGE) is a common problem in the short and long term after PPG. The limited lymph node dissection of PPG makes its application not widely promoted. Sentinel node navigation surgery (SNNS) may provide more personalized and minimally invasive surgery, in order to preserve the gastric function to the maximum extent.

In this study, the digestion-promoting function of an aqueous extract from Maojian green tea extract (MJ-GTE) was evaluated by small intestinal motility in mice as well as body mass, body mass gain, food intake, food utilization rate, gastric pepsin activity, and gastric pepsin excretion in rats. The chemical composition of MJ-GTE was then systematically analyzed using metabolomics based on ultra-high performance liquid chromatography-quadrupole electrostatic orbitrap mass spectrometry (UPLC-Q-Exactive/MS). The results of animal experiments showed that the intestinal propulsion ratio of ink in the high-dose MJ-GTE group (0.83 g/(kg·d)) was significantly increased compared with the model group (P < 0.05), and gastric pepsin excretion in the medium-dose MJ-GTE group (0.21 g/(kg·d)) was significantly increased compared with the negative control group (deionized water) (P < 0.05), which collectively indicated that MJ-GTE has a digestion-promoting effect. The metabolomics analysis identified 98 compounds, among which, flavones (apigenin and luteolin, 0.14–0.77 mg/g), flavanones (naringenin and eriodictyol, 0.49–1.49 mg/g), flavone-7-O-glycosides (0.57–9.07 mg/g), and flavanone-7-O-glycosides (4.49–38.98 mg/g) were the major components in MJ-GTE. This study will provide a theoretical basis for the promotion and development of Maojian green tea and related products in the future.

Deep learning-based bone age assessment (BAA) approaches have certain drawbacks, such as ignoring the correlation of age labels and simply assuming that bone development is linearly related to bone age, which can affect the accuracy of predictions. To solve these problems, a knowledge distillation-based adaptive label distribution learning method called KDALDL is proposed. The KDALDL framework comprises a teacher model and a student model, both consisting of modules for multi-scale feature extraction, feature refinement, and label distribution learning. First, a multi-scale feature extraction module is designed based on the swin transformer to extract feature information at various scales. Subsequently, these features are fed into the feature refinement module to capture the optimal image features. Then, the discrete labels obtained from the age labels through the Gaussian formula are used to train the teacher model. Finally, the teacher model’s outputs are used to train the student model through the knowledge distillation technique, which enables the student model to achieve improved results by learning from the teacher model. The proposed method is validated using the Radiological Society of North America (RSNA) dataset, which exhibits outstanding results.

Background/objective: The literature has discussed the potential for nurturing, integrating, and optimizing physical literacy to thereby enhance quality of life. Progression could be made through the disposition of acquiring movements and engaging in physical activity, but data supporting such an argument remains limited. This cross-sectional study attempted to empirically investigate these two variables by assessing the levels of motivation and satisfaction among university students in Taiwan. The hypothesis posited a positive correlation between physical literacy and quality of life, with the mediating effects of motivation and satisfaction taken into consideration. Methods: By applying the time segregation method, participants were asked to complete a set of questionnaires at the beginning and the end of the first semester during the 2021 – 2022 academic year. The initial phase involved gathering demographic information and assessing the perceived physical literacy score. The scores for motivation, satisfaction, and quality of life were measured in the subsequent phase. SmartPLS version 3.3 was used to conduct data analysis. After ratifying the model's goodness-of-fit, partial least squares structural equation modeling was used to test the hypotheses in the research model. Results: A total of 388 students (male n = 320, female n = 68; mean age: 18.5 years) participated in this study. Moderate explanatory power was found in the relationships of perceived physical literacy to physical education satisfaction (β PPLI → PES = 0.137, t = 6.439, R2 = 0.642) and motivation (β PPLIA → SIMS = 0.511, t = 32.701, R2 = 0.607). Results then indicated that motivation is the mediator of the relationship between physical literacy and physical education satisfaction (β PPLI → SIMS → PES = 0.373, t = 4.015). Furthermore, this satisfaction mediated the relationship between physical literacy and quality of life (β PPLI → PES → QoLS = 0.070, t = 4.47). Conclusion: This study connected theoretical knowledge regarding physical literacy with practice, suggesting that ongoing physical education may nurture the habit of lifelong participation in physical activity, thus further improving quality of life.

ObjectiveTo assess the feasibility, safety, and efficiency of simultaneous anterograde video laparoscopic inguinal and pelvic lymphadenectomy for penile cancer.Materials and methodsWe reviewed retrospectively the records of 22 patients (44 lateral) who underwent inguinal lymph nodes dissection for penile cancer. The procedure was standardized as two planes, three holes, and six steps. Two Separate-planes: superior plane of eternal oblique aponeurosis/ / fascia lata; inferior plane of superficial camper fascia. Three holes: two artificial lateral boundary holes, the internal and external boundary holes, and the hole of oval fossa. Six steps: separate the first separate-plane; separate the second layer; separate two artificial lateral boundary holes; free great saphenous vein; separate the third hole and clean up the deep inguinal lymph nodes; pelvic lymphadenectomy.ResultsA total of 22 cases were included and 9 patients underwent simultaneous pelvic lymphadenectomy. The average operation time on both sides was 7.52 ± 3.29 h, which was 0.5–1 h/side after skilled. The average amount of bleeding was 93.18 ± 50.84 ml. A total of 8 patients had postoperative complications, accounting for 36.36%, and no complications great than Clavien-Dindo class III occurred.ConclusionThis study demonstrated that the video laparoscopic simultaneous anterograde inguinal and pelvic lymphadenectomy is a feasible and safe technique. Indocyanine Green was helpful for lymph node identify.

In managing unique complexities associated with Chinese medicinal quality assessment, metabolomics serves as an innovative tool. This study proposes an analytical approach to assess differing qualities of Scrophularia ningpoensis （S. ningpoensis）Hemsl by identifying potential biomarker metabolites and their activity with the corresponding secondary metabolites. The methodology includes four steps; first, a GC-MS based metabolomics exploration of the Scrophularia ningpoensis Hemsl. Second, a multivariate statistical analysis (PCA, PLS-DA, OPLS-DA) for quality assessment and biomarker identification. Third, the application of ROC analysis and pathway analysis based on identified biomarkers. Finally, validation of the associated active ingredients by HPLC. The analysis showed distinct metabolite profiles across varying grades of S. ningpoensis Hemsl, establishing a grading dependency relationship. Select biomarkers (gluconic Acid, d-xylulose, sucrose, etc.) demonstrated robust grading performances. Further, the Pentose Phosphate Pathway, deemed as most influential in grading, was tied to the synthesis of key constituents (iridoids, phenylpropanoids). HPLC validation tests affirm a decreasing trend in harpagoside and cinnamic acid levels between first and third-grade samples. In conclusion, this GC-MS based metabolomics combined HPLC method offers a sound approach to assess and distinguish quality variations in S. ningpoensis Hemsl samples.

This report presents a case of a previously healthy 58 years-old man who had suffered from persistent weakness and dizziness after a cerebellar intracranial hemorrhage (ICH). Endocrine function tests revealed low levels of plasma cortisol (3.05 μg/dL; normal range: 5–25 μg/dL) and adrenocorticotropic hormone (ACTH) (6.0 pg/mL; normal range: 10–60 pg/mL). The subsequent ACTH stimulation test suggested partial or recent hypopituitarism, resulting in adrenal gland atrophy and a subnormal cortisol response. Ultimately, the dizziness was found to be caused by undiagnosed adrenal insufficiency, which was detected when a hypotensive fainting incident occurred during rehabilitation. The symptoms improved significantly with oral prednisone supplementation. Notably, the duration of impaired hypothalamic-pituitary-adrenal axis may last as long as a year. This case highlights that adrenal insufficiency can easily be overlooked since its symptoms are similar to those commonly seen with cerebellar stroke alone. Physicians must be aware of the symptoms of adrenal insufficiency in patients with brain insults and conduct the appropriate endocrine tests to clarify the underlying comorbidity.

Kelp, the brown alga distributed in coastal areas all over the world, is also an important medicine food homology product in China. However, the levels and profiles of persistent organic pollutants (POPs) in kelp have not been thoroughly investigated to date. Polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs) and emerging bromine flame retardants (eBFRs) were evaluated in 41 kelp samples from the main kelp producing areas in China. The concentrations of total PCBs, PBDEs and eBFRs were in the range of 0.321–4.24 ng/g dry weight (dw), 0.255–25.5 ng/g dw and 3.00 × 10−3-47.2 ng/g dw in kelp, respectively. The pollutant pattern was dominated by decabromodiphenyl ethane (DBDPE, 13.0 ± 11.7 ng/g dw) followed in decreasing order by BDE-209 (2.74 ± 4.09 ng/g dw), CB-11 (1.32 ± 1.06 ng/g dw). The tested results showed that kelp could reflect the pollution status of PCBs, PBDEs and eBFRs, indicating the suitability of kelp as a biomonitor of these harmful substances. Finally, the data obtained was used to evaluate human non-cancer and cancer risks of PCBs and PBDEs via kelp consumption for Chinese. Though the calculated risk indices were considered acceptable according to the international standards even in the worst scenarios, the POPs levels in kelp should be monitored continuously as a good environmental indicator.

Abstract Purpose To report the planning benchmark case results of the POTENTIAL trial—a multicenter, randomized, phase 3 trial—to evaluate the value of internal mammary nodal (IMN) irradiation for patients with high-risk breast cancer. Methods All participating institutions were provided the outlines of one benchmark case, and they generated radiation therapy plans per protocol. The plans were evaluated by a quality assurance team, after which the institutions resubmitted their revised plans. The information on beams arrangement, skin flash, inhomogeneity corrections, and protocol compliance was assessed in the first and final submission. Results The plans from 26 institutions were analyzed. Some major deviations were found in the first submission. The protocol compliance rates of dose coverage for the planning target volume of chest wall, supraclavicular fossa plus axilla, and IMN region (PTVim) were all significantly improved in the final submission, which were 96.2% vs. 69.2%, 100% vs. 76.9%, and 88.4% vs. 53.8%, respectively. For OARs, the compliance rates of heart Dmean, left anterior descending coronary artery V40Gy, ipsilateral lung V5Gy, and stomach V5Gy were significantly improved. In the first and final submission, the mean values of PTVim V100% were 79.9% vs. 92.7%; the mean values of heart Dmean were 11.5 Gy vs. 9.7 Gy for hypofractionated radiation therapy and 11.5 Gy vs. 11.0 Gy for conventional fractionated radiation therapy, respectively. Conclusion The major deviations were corrected and protocol compliance was significantly improved after revision, which highlighted the importance of planning benchmark case to guarantee the planning quality for multicenter trials.

Abstract Traditional Chinese Medicines (TCMs) have been used for centuries for the treatment and management of various diseases. However, their effective delivery to targeted sites may be a major challenge due to their poor water solubility, low bioavailability, and potential toxicity. Nanocarriers, such as liposomes, polymeric nanoparticles, inorganic nanoparticles and organic/inorganic nanohybrids based on active constituents from TCMs have been extensively studied as a promising strategy to improve the delivery of active constituents from TCMs to achieve a higher therapeutic effect with fewer side effects compared to conventional formulations. This review summarizes the recent advances in nanocarrier-based delivery systems for various types of active constituents of TCMs, including terpenoids, polyphenols, alkaloids, flavonoids, and quinones, from different natural sources. This review covers the design and preparation of nanocarriers, their characterization, and in vitro/vivo evaluations. Additionally, this review highlights the challenges and opportunities in the field and suggests future directions for research. Nanocarrier-based delivery systems have shown great potential in improving the therapeutic efficacy of TCMs, and this review may serve as a comprehensive resource to researchers in this field. Graphical abstract

In order to explore the important role of seasonal temperature in the formation of soy sauce quality, three fermentation temperatures (37, 30 and 15 ℃) were set up to simulate the temperature changes during the four seasons in Guangdong and compared with natural fermentation. During the fermentation process, the dynamic changes of flavor indexes of base soy sauce were measured and sensory evaluation was also carried out to accesses the quality of the product. The results showed that fermentation at 30 ℃ was beneficial for the formation of alcohols, esters and phenols, imparting the highest sensory score and the best overall quality to base soy sauce. Base soy sauce fermented at 37 ℃ had high contents of acid and bitter amino acids and was rich in aldehydes, ketones, furans (ketones) and pyrazines, which formed the basis for soy sauce flavor. Fermentation at 15 ℃ was unfavorable for the formation of acids, bitter amino acids and characteristic flavor compounds in soy sauce, resulting in the lowest sensory score. Moreover, the great temperature changes during natural fermentation were detrimental to the formation of free amino acids and flavor substances. This study provides a theoretical basis for improving the production process and quality stability of Cantonese-style high-salt liquid-state soy sauce.

In this work, a new pyrylium derivatization-assisted liquid chromatography-mass spectrometry (LC-MS) method was developed for metabolite profiling of the glutathione anabolic pathway (GAP) in cancer tissues and cells. The pyrylium salt of 6,7-dimethoxy-3-methyl isochromenylium tetrafluoroborate (DMMIC) was used to label the amino group of metabolites, and a reductant of dithiothreitol (DTT) was employed to stabilize the thiol group. By combining DMMIC derivatization with LC-MS, it was feasible to quantify the 13 main metabolites on the GAP in complex biological samples, which had good linearity (R2 = 0.9981−0.9999), precision (interday precision of 1.6%–19.0% and intraday precision of 1.4%–19.8%) and accuracy (83.4%–115.7%). Moreover, the recovery assessments in tissues (82.5%–107.3%) and in cells (98.1%–118.9%) with GSH-13C2, 15N, and Cys-15N demonstrated the reliability of the method in detecting tissues and cells. Following a methodological evaluation, the method was applied successfully to investigate difference in the GAP between the carcinoma and para-carcinoma tissues of esophageal squamous cell carcinoma (ESCC) and the effect of p-hydroxycinnamaldehyde (CMSP) on the GAP in KYSE-150 esophageal cancer cells. The results demonstrate that the developed method provides a promising new tool to elucidate the roles of GAP in physiological and pathological processes, which can contribute to research on drugs and diseases.

Abstract Purpose Currently, there are no accurate markers for predicting potentially lethal prostate cancer (PC) before biopsy. This study aimed to develop urine tests to predict clinically significant PC (sPC) in men at risk. Methods Urine samples from 928 men, namely, 660 PC patients and 268 benign subjects, were analyzed by gas chromatography/quadrupole time-of-flight mass spectrophotometry (GC/Q-TOF MS) metabolomic profiling to construct four predictive models. Model I discriminated between PC and benign cases. Models II, III, and GS, respectively, predicted sPC in those classified as having favorable intermediate risk or higher, unfavorable intermediate risk or higher (according to the National Comprehensive Cancer Network risk groupings), and a Gleason sum (GS) of ≥ 7. Multivariable logistic regression was used to evaluate the area under the receiver operating characteristic curves (AUC). Results In Models I, II, III, and GS, the best AUCs (0.94, 0.85, 0.82, and 0.80, respectively; training cohort, N = 603) involved 26, 24, 26, and 22 metabolites, respectively. The addition of five clinical risk factors (serum prostate-specific antigen, patient age, previous negative biopsy, digital rectal examination, and family history) significantly improved the AUCs of the models (0.95, 0.92, 0.92, and 0.87, respectively). At 90% sensitivity, 48%, 47%, 50%, and 36% of unnecessary biopsies could be avoided. These models were successfully validated against an independent validation cohort (N = 325). Decision curve analysis showed a significant clinical net benefit with each combined model at low threshold probabilities. Models II and III were more robust and clinically relevant than Model GS. Conclusion This urine test, which combines urine metabolic markers and clinical factors, may be used to predict sPC and thereby inform the necessity of biopsy in men with an elevated PC risk.

A thermal-mechanical control process (TMCP) followed by tempering at 600 °C was applied to produce 420 MPa grade high strength low alloy (HSLA) steel heavy plates. The microstructure and mechanical properties through the thickness were analyzed using various techniques including optical microscopy (OM), scanning electron microscopy (SEM), transmission electron microscopy (TEM), electron back-scattered diffraction (EBSD), tensile and impact tests. Microscopy analyses showed that a fine-grained structure with an average grain size of 6–10 μm could be obtained by TMCP. After subsequent tempering, the microstructure near the surface of the plate was dominated by bainite, while the microstructure of the core was mainly characterized by aggregated carbides and ferrite. In addition, the density of high-angle grain boundaries (HAGB) on the surface was significantly higher than that in the core. Tensile tests showed a decrease in both yield and tensile strengths from 530.1 and 626.9 MPa on the surface to 384.3 and 496.7 MPa in the core, respectively. The contribution of different strengthening mechanisms to the variations in strengths along the thickness was clarified. In addition, the deformation of ferrite and the initiation of micro-voids during tensile tests were also analyzed.

The challenges commonly associated with conventional high pressure die casting (HPDC) have led to increased interest in semi-solid metal (SSM) forming processes. In the present study, semi-solid slurries of A356 alloy prepared by the Swirled Enthalpy Equilibration Device (SEED) process were used for manufacturing components with complex shape by using a high pressure die casting machine. The segregation phenomenon and the effect of heat treatment on the microstructure evolution and mechanical properties were investigated. The results showed that the alloy consists of primary spherical α-Al grains, secondary solidified α-Al grains, eutectic Si, iron-rich intermetallic phases and low porosities. The microstructural investigations revealed that the eutectic Si particles underwent fragmentation, spheroidization and coarsening with increasing solution temperature. Furthermore, the solution treatment results in the dissolution of the π-Al8FeMg3Si6 phase and the growth of the β-Al5FeSi phase. The hardening peaks at 170 °C could be obtained with ageing for 5 h. Due to both solution and precipitation strengthenings, the yield strength, ultimate tensile strength and hardness of A356 alloy after heat treatment increase significantly compared to those in the as-rheocast state: they reach 266 MPa, 343 MPa and 110 HV0.2, respectively. The analysis of fracture surfaces of rheo-HPDC samples in both the as-rheocast and the heat-treated states revealed a mixed mechanism of dimples and quasi-cleavage. The microstructure inside the part was found to be quasi-homogeneous while the segregation phenomenon in different zones of the part is affected by die geometry during the filling process. The results imply that the SEED-HPDC process has the potential to be industrialized by implementing appropriate heat treatments for producing complex components with good mechanical properties.

Glioblastoma multiforme (GBM) is the most severe form of brain cancer and presents unique challenges to developing novel treatments due to its immunosuppressive milieu where receptors like programmed death ligand 1 (PD-L1) are frequently elevated to prevent an effective anti-tumor immune response. To potentially shift the GBM environment from being immunosuppressive to immune-enhancing, we engineered a novel nanovehicle from reduced graphene oxide quantum dot (rGOQD), which are loaded with the immunomodulatory drug resiquimod (R848) and conjugated with an anti-PD-L1 antibody (aPD-L1). The immunomodulatory rGOQD/R8/aPDL1 nanoparticles can actively target the PD-L1 on the surface of ALTS1C1 murine glioblastoma cells and release R848 to enhance the T-cell-driven anti-tumor response. From in vitro experiments, the PD-L1-mediated intracellular uptake and the rGOQD-induced photothermal response after irradiation with near-infrared laser light led to the death of cancer cells and the release of damage-associated molecular patterns (DAMPs). The combinational effect of R848 and released DAMPs synergistically produces antigens to activate dendritic cells, which can prime T lymphocytes to infiltrate the tumor in vivo. As a result, T cells effectively target and attack the PD-L1-suppressed glioma cells and foster a robust photothermal therapy elicited anti-tumor immune response from a syngeneic mouse model of GBM with subcutaneously implanted ALTS1C1 cells.

SARS-CoV-2 new waves are primarily caused by changes to the spike protein (S), which can substantially decrease the efficacy of vaccines. Therefore, we tested several multivalent mRNA-LNP vaccines, targeting the full-length S proteins of different variants, and identified an optimal combination for protection against VOCs in BALB/c mice. The tested formulations included trivalent (WT + BA.5 + XBB.1.5), pentavalent (WT + BA.5 + XBB.1.5 + BQ.1.1 + CH.1.1), and octavalent (WT + BA.5 + XBB.1.5 + BQ.1.1 + CH.1.1 + Alpha + Delta + BA.2) vaccines. Among these multivalent vaccines, the pentavalent vaccine showed superior protection for almost all tested variants. Despite this, each multivalent vaccine elicited greater broad-spectrum neutralizing antibodies than the previously evaluated bivalent vaccine (WT + BA.5). Subsequently, we redesigned the multivalent vaccine to efficiently generate neutralizing antibodies against recent VOCs, including EG.5.1. Immunization with the redesigned pentavalent vaccine (WT + EG.5.1 + XBB.1.16 + Delta + BA.5) showed moderate levels of protection against recent Omicron VOCs. Results suggest that the neutralization activity of multivalent vaccines is better than those of the tested bivalent vaccines against WT + BA.5 and WT + EG.5.1. Moreover, the pentavalent vaccine we developed may be highly useful for neutralizing new Omicron VOCs.

This work elucidates the photoelectrochemical (PEC) sensing of melatonin employing graphene oxide nanoribbons (GONRs) synthesized through a microwave-assisted method. GONRs served as electrocatalysts for screen-printed carbon electrodes (SPCE) to facilitate melatonin detection. We incorporated both a light-emitting diode (LED) and a solar simulator as light sources for PEC evaluations. Cyclic voltammetry revealed that the faradaic currents corresponding to melatonin oxidation on GONRs-modified SPCE were amplified under both LED and simulated solar light irradiation. Notably, the GONR (150 W) registered the most pronounced enhancement in the photo-assisted faradaic current and the highest conversion efficiency. Employing the solar simulator, certain thermal factor ratios concerning conversion efficiencies surpassed 50.0% at light intensities of both 80 mW/cm2 and 100 mW/cm2. Conversely, with the LED source, the thermal contribution remained below 15.0% of the total PEC faradaic current. We posit that obtaining conversion efficiencies devoid of thermal influences is pivotal for deepening our comprehension of PEC biosensing mechanisms.

Background: Transmembrane E3 ubiquitin ligase ( RNF43 ) mutations are present in approximately 6–18% of colorectal cancers (CRC) and could enhance Wnt/β-catenin signaling, which is emerging as a promising therapeutic target. This study aims to investigate the clinical and molecular characteristics and potential heterogeneity of RNF43 -mutant CRC. Methods: A total of 78 patients with RNF43 -mutant CRC were enrolled from July 2013 to November 2022. Demographic data, clinical characteristics, treatment regimens used, and survival outcomes were collected and analyzed. Results: Our study uncovered that patients with RNF43 mutations in the N-terminal domain (NTD; n = 50) exhibited shorter overall survival (OS; median months, 50.80 versus not reached; p = 0.043) compared to those in the C-terminal domain (CTD; n = 17). Most RNF43 mutations in NTD had positive primary lymph node status, low tumor mutation burden (TMB-L), and correlated with proficient mismatch repair (pMMR)/microsatellite stable (MSS) status. By contrast, RNF43 mutations in CTD were significantly enriched in deficient MMR (dMMR)/microsatellite instability (MSI-H) tumors with high TMB (TMB-H). N-terminal RNF43 -mutated tumors harbored a hotspot variant ( RNF43 R117fs ), which independently predicted a significantly worse outcome in pMMR/MSS CRC with a median OS of 18.9 months. Patients with RNF43 mutations and the BRAF V600E alterations demonstrated sensitivity to BRAF/EGFR inhibitors. Moreover, we observed that pMMR/MSS patients with RNF43 R117fs mutation had a higher incidence of stage IV, ⩾2 metastatic sites, low TMB, and none of them received PD-1/PD-L1 inhibitor therapy. Conclusion: Our findings provide the first evidence that RNF43 mutations in NTD and the R117fs variant correlate with a poorer prognosis in CRC patients, providing strategies for Wnt-targeted therapy to improve clinical efficacy.