Design and Simulation of High-Performance D-Type Dual-Mode PCF-SPR Refractive Index Sensor Coated with Au-TiO2 Layer.

A novel surface plasmon resonance (SPR) refractive index (RI) sensor based on the D-type dual-mode photonic crystal fiber (PCF) is proposed. The sensor employs a side-polished few-mode PCF that facilitates the transmission of the fundamental and second-order modes, with an integrated microfluidic channel positioned directly above the fiber core. This design minimizes the distance to the analyte and maximizes the interaction between the optical field and the analyte, thereby enhancing the SPR effect and resonance loss for improved sensing performance. Au-TiO2 dual-layer material was coated on the surface of a microfluidic channel to enhance the penetration depth of the core evanescent field and tune the resonance wavelength to the near-infrared band, meeting the special needs of chemical and biomedical detection fields. The finite element method was utilized to systematically investigate the coupling characteristics between various modes and surface plasmon polariton (SPP) modes, as well as the impact of structural parameters on the sensor performance. The results indicate that the LP11b_y mode exhibits greater wavelength sensitivity than the HE11_y mode, with a maximum sensitivity of 33,000 nm/RIU and an average sensitivity of 8272.7 nm/RIU in the RI sensing range of 1.25-1.36, which is higher than the maximum sensitivity of 16,000 nm/RIU and average sensitivity of 5666.7 nm/RIU for the HE11b_y mode. It is believed that the proposed PCF-SPR sensor features both high sensitivity and high resolution, which will become a critical device for wide RI detection in mid-infrared fields.

An unusual cause of liver neoplasm in an older female.

We presented a 66-year-old woman with T2DM who had a liver mass discovered incidentally during hospitalization. She was asymptomatic with a right upper abdominal mass that was smooth, mobile, and non-tender. Hepatitis virus markers and tumor markers were normal. The computed tomography (CT) images showed a 4.7×4.0 cm lesion in the left liver lobe with indistinct borders. Further magnetic resonance imaging (MRI) revealed low T1 and high T2 signal intensity with ring-shaped enhancement following contrast administration. Surgical resection was performed, and histology confirmed hepatic angioleiomyoma with thick-walled vessels and spindle cell proliferation. Immunohistochemistry was positive for SMA, desmin, caldesmon, CD31, and CD34. The patient had no recurrence during 5 years follow-up.

METTL3 inhibitor suppresses the progression of prostate cancer via IGFBP3/AKT pathway and synergizes with PARP inhibitor.

The RNA N6-methyladenosine (m6A) regulator METTL3 is an important regulatory gene in various progressive processes of prostate cancer (PCa). METTL3 inhibitors have been reported to possess potent tumor suppression capacity in some cancer types. Nevertheless, the detailed influence and mechanism of METTL3 inhibitors on PCa progression and their potential synergy with other drugs are poorly understood. In this study, we demonstrated that METTL3 was overexpressed and associated with poor survival in most PCa patients. METTL3 inhibitor STM2457 reduced m6A levels of PCa cells, thus inhibiting their proliferation, colony formation, migration, invasion, and stemness in vitro. Furthermore, STM2457 suppressed PCa progression in both the CDX and PDX models in vivo. MeRIP-seq analysis coupled with biological validation revealed that STM2457 influenced multiple biological processes in PCa cells, mainly through the IGFBP3/AKT pathway. We also proved that STM2457 induced DNA damage and showed synergistic anti-PCa effects with the PARP inhibitor olaparib both in vitro and in vivo. All in all, this work provides a novel therapeutic strategy for targeting RNA m6A modifications for the treatment of PCa and provides a meaningful reference for further clinical trials.

Pharmacology and therapeutic potential of agarwood and agarwood tree leaves in periodontitis.

The main bioactive components of agarwood, derived from Aquilaria sinensis, include sesquiterpenes, 2-(2-phenethyl) chromone derivatives, aromatic compounds, and fatty acids, which typically exert anti-inflammatory, antioxidant, immune-modulating, hypoglycemic, and antitumor pharmacological effects in the form of essential oils. Agarwood tree leaves, rich in flavonoids, 2-(2-phenethyl) chromone compounds, and flavonoid compounds, also exhibit significant anti-inflammatory, antioxidant, and immune-modulating effects. These properties are particularly relevant to the treatment of periodontitis, given that inflammatory responses, oxidative stress, and immune dysregulation are key pathological mechanisms of the disease, highlighting the substantial potential of agarwood and agarwood tree leaves in this therapeutic area. However, the low solubility and poor bioavailability of essential oils present challenges that necessitate the development of improved active formulations. In this review, we will introduce the bioactive components, extraction methods, pharmacological actions, and clinical applications of agarwood and agarwood tree leaves, analyzing its prospects for the treatment of periodontitis.

Site-directed mutagenesis leads to the optimized transglycosylation activity of endo-beta-N-acetylglucosaminidase from Trypanosoma brucei.

Endo-ß-N-acetylglucosaminidases (ENGases) are pivotal enzymes in the degradation and remodeling of glycoproteins, which catalyze the cleavage or formation of ß-1,4-glycosidic bond between two N-acetylglucosamine (GlcNAc) residues in N-linked glycan chains. It was investigated that targeted mutations of amino acids in ENGases active site may modulate their hydrolytic and transglycosylation activities. Endo-Tb, the ENGase derived from Trypanosoma brucei, belongs to the glycoside hydrolase family 85 (GH85). Our group previously demonstrated that Endo-Tb exhibits hydrolytic activity toward high-mannose and complex type N-glycans and preliminarily confirmed its transglycosylation potential. In this study, we further optimized the transglycosylation activity of recombinant Endo-Tb by focusing on the N536A, E538A and Y576F mutants. A comparative analysis of their transglycosylation activity with that of the wild-type enzyme revealed that all mutants exhibited enhanced transglycosylation capacity. The N536A mutant exhibited the most pronounced improvement in transglycosylation activity with a significant reduction in hydrolytic activity. It is suggested that Endo-Tb N536A possesses the potential as a tool for synthesizing a wide array of glycoconjugates bearing high-mannose and complex type N-glycans.

Sphingosine kinase 1 aggravates liver fibrosis by mediating macrophage recruitment and polarization.

BACKGROUND & AIMS: Sphingosine kinase 1 (SphK1) has distinct roles in the activation of Kupffer cells (KCs) and hepatic stellate cells (HSCs) in liver fibrosis. Here, we aim to investigate the roles of SphK1 on hepatic macrophage recruitment and polarization in liver fibrosis. METHODS: Liver fibrosis was induced by carbon tetrachloride (CCl4) in wild-type and SphK1-/- mice to study the recruitment and polarization of macrophages. The effects of SphK1 originated from macrophages or other liver cell types on liver fibrosis were further strengthened by bone marrow transplantation (BMT). The direct effects of SphK1 on macrophage polarization were also investigated in vitro. Expression analysis of SphK1 and macrophage polarization index was conducted with human liver samples. RESULTS: SphK1 deletion attenuated the recruitment of hepatic macrophages along with reduced M1 and M2 polarization in mice induced by CCl4. SphK1 deficiency in endogenous liver cells attenuated macrophage recruitment via CCL2. Macrophage SphK1 activated the ASK1-JNK1/2-p38 signaling pathway to promote M1 polarization. Furthermore, macrophage SphK1 downregulated small ubiquitin-like modifier (SUMO) specific peptidase1 (SENP1) to decrease de-SUMOylation of Kruppel-like factor 4 (KLF4) to promote M2 polarization. Finally, we confirmed that SphK1 expression was elevated and positively correlated with macrophage M1 and M2 polarization in human fibrosis livers. CONCLUSIONS: Our findings demonstrated that SphK1 aggravated liver fibrosis by promoting macrophage recruitment and M1/M2 polarization. SphK1 in macrophages is a potential therapeutic target for the treatment of liver fibrosis.

Associations between Life's Essential 8 and risks of all-cause and cardiovascular mortality in cancer survivors: A prospective cohort study from NHANES.

Background: Life's Essential 8 (LE8), an indicator of cardiovascular health (CVH), can predict overall and cardiovascular mortality in the general population. Considering that cancer survivors have a higher risk of cardiovascular disease (CVD), our study aimed to investigate the association between LE8 and the prognosis of cancer survivors. Methods: A total of 2191 cancer survivors were included from the National Health and Nutrition Examination Survey (2005-2018). LE8 scores, derived from eight individual metrics, were categorized into three groups: low (0-49), moderate (50-79), and high (80-100). Cox regression analysis, nonlinear analysis, sensitivity analysis, and subgroup analysis were conducted to explore the association between LE8 scores and mortality risks, adjusting for potential confounders. Results: During a median follow-up of six years, 479 deaths were recorded, including 118 CVD events and 156 cancer events. LE8 scores showed an inverse linear relationship with all-cause and cardiovascular mortality. A 10-point increase in LE8 scores was associated with a 25 % reduction in all-cause mortality (hazard ratio [HR], 0.75; 95 % CI, 0.66-0.85) and a 29 % reduction in cardiovascular mortality (HR, 0.71; 95 % CI, 0.57-0.89). Additionally, moderate CVH was linked to a lower risk of all-cause mortality (HR, 0.55; 95 % CI, 0.37-0.81), while high CVH was associated with an even lower risk (HR, 0.35; 95 % CI, 0.19-0.68). Similarly, moderate CVH demonstrated a decreased risk of cardiovascular mortality (HR, 0.31; 95 % CI, 0.15-0.63), with high CVH showing an even lower risk (HR, 0.23; 95 % CI, 0.09-0.58). However, LE8 scores was not associated with cancer-specific mortality. Conclusions: A higher LE8 score was independently associated with a decreased risk of both all-cause and cardiovascular mortality in cancer survivors, underscoring the significance of optimizing CVH during the survivorship phase of cancer care.

Sequence-Dependent Single-Molecule DNA Sensing Using Covalent Organic Framework Nanopores.

Enzyme-free single-molecule sequencing has the potential to significantly expand the application of nanopore technology to DNA, proteins, and saccharides. Despite their advantages over biological nanopores and natural suitability for enzyme-free single-molecule sequencing, conventional solid-state nanopores have not yet achieved single-molecule DNA sequencing. The biggest challenge for the accuracy of single-molecule sequencing using solid-state nanopores lies in the precise control of the pore size and conformity. In this study, we fabricated nanopore devices by covering the tip of a quartz nanopipette with ultrathin two-dimensional (2D) covalent organic framework (COF) nanosheets (pore size ≈ 1.1 nm). The size of the periodically arranged nanopores in COF is comparable to that of protein nanopores, and the structure of each COF nanopore is consistent at the atomic scale. The COF nanopore device could roughly distinguish dAMP, dCMP, dGMP, and dTMP. Furthermore, a certain percentage of the current blockades originating from 150 nucleotides model DNA molecules (13.5% for dA50dC50dA50 and 11.1% for dC50dA50dC50) show distinct DNA sequence-specific concave and convex resistive current patterns. The finite element simulation confirmed that the current blockade pattern of a DNA molecule passing through a COF nanopore is dependent on the relative location of the nanopore with respect to the wall of the nanopipette. Our study is a significant step toward single-molecule DNA sequencing by solid-state nanopores.

A new three-dimensional barium(II) coordination polymer constructed from N,N'-bis(glycinyl)pyromellitic diimide: microwave-assisted synthesis, structure, Hirshfeld surface analysis and properties.

A new three-dimensional (3D) coordination polymer, namely, poly[diaqua[µ5-2,2'-(1,3,5,7-tetraoxo-1,2,3,5,6,7-hexahydropyrrolo[3,4-f]isoindole-2,6-diyl)diacetato]barium(II)], [Ba(C14H6N2O8)(H2O)2]n, (I), has been synthesized by the microwave-irradiated reaction of Ba(NO3)2 with N,N'-bis(glycinyl)pyromellitic diimide {BGPD, namely, 2,2'-(1,3,5,7-tetraoxo-1,2,3,5,6,7-hexahydropyrrolo[3,4-f]isoindole-2,6-diyl)diacetatic acid, H2L}. The title compound was structurally characterized by single-crystal X-ray diffraction analysis and powder X-ray diffraction analysis, as well as IR spectroscopy. In the crystal structure of (I), the BaII ion is nine-coordinated by six carboxylate O atoms from five symmetry-related L2- dianions and one imide O atom, as well as two water O atoms. The coordination geometry of the central BaII ion can be described as a spherical capped square antiprism. One carboxylate group of the ligand serves as a µ3-bridge linking the BaII cations into a one-dimensional polynuclear secondary building unit (SBU). Another carboxylate group of the ligand acts as a µ2-bridge connecting the 1D SBUs, thereby forming a two-dimensional (2D) SBU. The resulting 2D SBUs are extended into a 3D framework via the pyromellitic diimide moiety of the ligand as a spacer. The 3D Ba framework can be simplified as a 5-connected hexagonal boron nitride net (bnn) topology. The intermolecular interactions in the 3D framework were further investigated by Hirshfeld surface analysis and the results show that the prominent interactions are H...O (45.1%), Ba...O (11.1%) and C...H (11.1%), as well as H...H (11.1%) contacts. The thermal stability, photoluminescence properties and UV-Vis absorption spectra of (I) were also investigated. The coordination polymer exhibits a fluorescence emission with a quantum yield of 0.071 and high thermal stability.

A multifunctional targeted nano-delivery system with radiosensitization and immune activation in glioblastoma.

Glioblastoma (GBM), the most common primary brain malignancy in adults, is notoriously difficult to treat due to several factors: tendency to be radiation resistant, the presence of the blood brain barrier (BBB) which limits drug delivery and immune-privileged status which hampers effective immune responses. Traditionally, high-dose irradiation (8 Gy) is known to effectively enhance anti-tumor immune responses, but its application is limited by the risk of severe brain damage. Currently, conventional dose segmentation (2 Gy) is the standard radiotherapy method, which does not fully exploit the potential of high-dose irradiation for immune activation. The hypothesis of our study posits that instead of directly applying high doses of radiation, which is risky, a strategy could be developed to harness the immune-stimulating benefits of high-dose irradiation indirectly. This involves using nanoparticles to enhance antigen presentation and immune responses in a safer manner. Angiopep-2 (A2) was proved a satisfactory BBB and brain targeting and Dbait is a small molecule that hijack DNA double strand break damage (DSB) repair proteins to make cancer cells more sensitive to radiation. In view of that, the following two nanoparticles were designed to combine immunity of GBM, radiation resistance and BBB innovatively. One is cationic liposome nanoparticle interacting with Dbait (A2-CL/Dbait NPs) for radiosensitization effect; the other is PLGA-PEG-Mal nanoparticle conjugated with OX40 antibody (A2-PLGA-PEG-Mal/anti-OX40 NPs) for tumor-derived protein antigens capture and optimistic immunoregulatory effect of anti-OX40 (which is known to enhance the activation and proliferation T cells). Both types of nanoparticles showed favorable targeting and low toxicity in experimental models. Specifically, the combination of A2-CL/Dbait NPs and A2-PLGA-PEG-Mal/anti-OX40 NPs led to a significant extension in the survival time and a significant tumor shrinkage of mice with GBM. The study demonstrates that combining these innovative nanoparticles with conventional radiotherapy can effectively address key challenges in GBM treatment. It represents a significant step toward more effective and safer therapeutic options for GBM patients.

Theoretical study on the critical index of rock burst stress monitoring in coal seam drilling.

Rock burst disasters severely restrict the safe and efficient mining of coal. The fundamental cause of their occurrence is the concentration of stress within the coal mass. Stress monitoring in coal seam drilling is widely used as an effective method for rock burst monitoring. However, how to scientifically and reasonably set the critical values of early warning indicators that match the conditions of each mine has always been a key issue restricting the accurate prediction of rock burst by the drilling stress method. This paper adopts a method combining theoretical analysis and field practice to conduct research on the critical values of drilling stress early warning indicators. Based on perturbation response instability theory, a mechanical model for the occurrence of impact ground pressure has been established. Based on the instability theory of disturbance response, a mechanical model for the occurrence of impact ground pressure has been established, leading to the derivation of the expression for the near-field critical stress of impact ground pressure events. The theoretical formula for the critical value of drilling stress early warning indicators was obtained based on the difference between the critical stress of rock burst occurrence and the actual stress in the roadway. This formula includes the mechanical parameters of the coal mass and its propensity for rock burst, roadway support stress, mining depth, stress concentration coefficient, and the initial installation pressure of the stress gauge. They can be determined by the geological and mining technical conditions of each mine. This theoretical formula breaks the uniformity of the critical values for stress warning indicators in various mine drill holes, allowing each mine to scientifically determine its critical value based on its own conditions. This theoretical method has been applied to a high-stress mine in Shanxi, China, and the critical values of drilling stress early warning indicators were obtained. When the monitored stress exceeded the critical value, dynamic phenomena of anchor rod and cable fractures occurred in the roadway roof. The distribution of microseismic events also shifted towards the warning area, and the microseismic monitoring indicators reached the warning values. This confirmed the engineering feasibility of the critical values for drilling stress early warning indicators determined by the theoretical method.

Development and Validation of a Carbohydrate Metabolism-Related Model for Predicting Prognosis and Immune Landscape in Hepatocellular Carcinoma Patients.

OBJECTIVE: The activities and products of carbohydrate metabolism are involved in key processes of cancer. However, its relationship with hepatocellular carcinoma (HCC) is unclear. METHODS: The cancer genome atlas (TCGA)-HCC and ICGC-LIRI-JP datasets were acquired via public databases. Differentially expressed genes (DEGs) between HCC and control samples in the TCGA-HCC dataset were identified and overlapped with 355 carbohydrate metabolism-related genes (CRGs) to obtain differentially expressed CRGs (DE-CRGs). Then, univariate Cox and least absolute shrinkage and selection operator (LASSO) analyses were applied to identify risk model genes, and HCC samples were divided into high/low-risk groups according to the median risk score. Next, gene set enrichment analysis (GSEA) was performed on the risk model genes. The sensitivity of the risk model to immunotherapy and chemotherapy was also explored. RESULTS: A total of 8 risk model genes, namely, G6PD, PFKFB4, ACAT1, ALDH2, ACYP1, OGDHL, ACADS, and TKTL1, were identified. Moreover, the risk score, cancer status, age, and pathologic T stage were strongly associated with the prognosis of HCC patients. Both the stromal score and immune score had significant negative/positive correlations with the risk score, reflecting the important role of the risk model in immunotherapy sensitivity. Furthermore, the stromal and immune scores had significant negative/positive correlations with risk scores, reflecting the important role of the risk model in immunotherapy sensitivity. Eventually, we found that high-/low-risk patients were more sensitive to 102 drugs, suggesting that the risk model exhibited sensitivity to chemotherapy drugs. The results of the experiments in HCC tissue samples validated the expression of the risk model genes. CONCLUSION: Through bioinformatic analysis, we constructed a carbohydrate metabolism-related risk model for HCC, contributing to the prognosis prediction and treatment of HCC patients.

Self-Assembled Peptide Hydrogels Loaded with Umbilical Cord-Derived Mesenchymal Stem Cells Repairing Injured Endometrium and Restoring Fertility.

Endometrial injury is a major cause of infertility and recurrent miscarriage. However, no clinically available methods currently exist to effectively repair the damaged endometrium. Mesenchymal stem cells (MSCs) have emerged as a promising therapeutic approach for promoting tissue regeneration, yet a biocompatible scaffold capable of delivering MSCs and supporting their growth is needed. Herein, the study reports a peptide hydrogel scaffold, self-assembled from a peptide IVK8-RGD consisting of an ionic complementary peptide sequence IEVEIRVK and a bioactive sequence RGD, to load umbilical cord-derived mesenchymal stem cells (UC-MSCs). This peptide forms a hydrogel under the physiological condition through self-assembly, and the peptide hydrogel exhibits injectability and adhesiveness to uterus, making it suitable for endometrial repair. Importantly, this hydrogel supports the adhesion and proliferation of UC-MSCs in a 3D environment. In vivo experiments using rats with endometrial injury have shown that treatment with IVK8-RGD hydrogel loaded with UC-MSCs effectively restores endometrial thickness, inhibits fibrosis, and facilitates angiogenesis through activating Raf/MEK/ERK pathway, leading to significantly improved fertility and live birth rate. These findings demonstrate the potential of the UC-MSCs-loaded hydrogel in repairing damaged endometrium and may address the unmet clinical needs of treating recurrent miscarriage and infertility induced by endometrial damage.

Silver Nanocomposites with Enhanced Shelf-Life for Fruit and Vegetable Preservation: Mechanisms, Advances, and Prospects.

Reducing fruit and vegetable waste and maintaining quality has become challenging for everyone. Nanotechnology is a new and intriguing technology that is currently being implemented in fruit and vegetable preservation. Silver nanomaterials provide superior antibacterial qualities, biodegradability, and biocompatibility, which expands their potential applications in fruit and vegetable preservation. Silver nanomaterials include silver nanocomposites and Ag-MOF, of which silver nanocomposites are mainly composed of silver nanoparticles. Notably, not all kinds of silver nanoparticles utilized in the preservation of fruits and vegetables are thoroughly described. Therefore, the synthesis, mechanism of action, and advancements in research on silver nanocomposites for fruit and vegetable preservation were discussed in this study.

Design and simulation of a compact polarization beam splitter based on dual-core photonic crystal fiber with elliptical gold layer.

For the polarization multiplexing requirements in all-optical networks, this work presents a compact all-fiber polarization beam splitter (PBS) based on dual-core photonic crystal fiber (PCF) and an elliptical gold layer. Numerical analysis using the finite element method (FEM) demonstrates that the mode modulation effect of the central gold layer effectively reduces the dimensions of the proposed PBS. By determining reasonable structural parameters of the proposed PCF, the coupling length ratio (CLR) between X- and Y-polarized super-modes can approach 2, achieving a minimal device length of 0.122 mm. The PBS exhibits a maximum extinction ratio (ER) of - 65 dB at 1.55 µm, with an operating bandwidth spanning 100 nm (1.5-1.6 µm) and a stable insertion loss (IL) of ~ 1.5 dB at 1.55 µm. Furthermore, the manufacture feasibility and performance verification scheme are also investigated. It is widely anticipated that the designed PBS will play a crucial role in the ongoing development process of miniaturization and integration of photonic devices.

Monomorphic epitheliotropic intestinal T-cell lymphoma: report of four cases and literature review.

Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), also known as type II enteropathy-associated T-cell lymphoma, is a rare malignant lymphoma of the extranodal lymphoid tissue derived from interepithelial T lymphocytes. MEITL is a primary intestinal T-cell lymphoma with a challenging diagnosis and aggressive progression, and it can invade other extraintestinal sites. In this study, we report four patients diagnosed with MEITL. All patients presented with abdominal pain, and one patient was admitted because of acute intestinal perforation. Two patients presented with unformed defecation and diarrhea. All patients carried the immunophenotypes CD3, CD7, CD8, CD20, and CD56, and the Ki-67 index ranged 60% to 90%. Three cases were analyzed using next-generation sequencing. One case displayed possibly relevant alterations of CREBBP, NOTCH2, SETD2, and STAT5B, and another case exhibited definite alteration of NOTCH1, possibly relevant alterations of CCND1 and DNMT3A, and potentially relevant alterations of HISTH3B, IGLL5, KMT2C, and KRAS. Different chemotherapy regimens were used, but the prognosis was poor. Hence, we illustrated that because of its low incidence, challenging diagnosis, and difficult treatment, further therapeutic improvements are urgently warranted.

Dual Hole Transport Layers Heterojunction and Band Alignment Engineered Mo:BiVO4 Photoanodes for Efficient Water Splitting.

BiVO4-based photoanode is one of the most promising photoanodes for photoelectrocatalytic water splitting. However, the serious problem of interface charge recombination limits its further development. Here, a Mo:BiVO4/NiOx/CPF-TCzB/NiCoBi photoanode is constructed with double hole transport layer and an energy level gradient to achieve an effective photo-generated holes extraction and accumulation at the surface electrocatalyst. The conjugated polycarbazole framework CPF-TCzB is used as hole transport layer to eliminate the charge recombination center between Mo:BiVO4 and NiCoBi electrocatalyst and realize the extraction and storage of photo-generated hole; NiOx nanoparticles are further inserted between Mo:BiVO4 and CPF-TCzB to form a gradient energy level, eliminating the energy level barrier and optimizing band alignment. As a result, Mo:BiVO4/NiOx/CPF-TCzB/NiCoBi achieves a much higher photocurrent densities of 3.14 mA cm-2 than that of Mo:BiVO4 (0.42 mA cm-2) at 0.6 V versus RHE. This work provides an specific way to adjust the band structure of BiVO4-based photoanodes and realize efficient hole extraction and storage for PEC water splitting.

Blood pressure response index and clinical outcomes in patients with septic shock: a multicenter cohort study.

BACKGROUND: Sepsis is a leading cause of mortality in intensive care units and vasoactive drugs are widely used in septic patients. The cardiovascular response of septic shock patients during resuscitation therapies and the relationship of the cardiovascular response and clinical outcome has not been clearly described. METHODS: We included adult patients admitted to the ICU with sepsis from Peking Union Medical College Hospital (internal), Medical Information Mart for Intensive Care IV (MIMIC-IV) and eICU Collaborative Research Database (eICU-CRD). The Blood Pressure Response Index (BPRI) was defined as the ratio between the mean arterial pressure and the vasoactive-inotropic score. BRRI was compared with existing risk scores on predicting in-hospital death. The relationship between BPRI and in-hospital mortality was calculated. A XGBoost's machine learning model identified the features that influence short-term changes in BPRI. FINDINGS: There were 2139, 9455, and 4202 patients in the internal, MIMIC-IV and eICU-CRD cohorts, respectively. BPRI had a better AUROC for predicting in-hospital mortality than SOFA (0.78 vs. 0.73, p = 0.01) and APS (0.78 vs. 0.74, p = 0.03) in the internal cohort. The estimated odds ratio for death per unit decrease in BPRI was 1.32 (95% CI 1.20-1.45) when BPRI was below 7.1 vs. 0.99 (95% CI 0.97-1.01) when BPRI was above 7.1 in the internal cohort; similar relationships were found in MIMIC-IV and eICU-CRD. Respiratory support and latest cumulative 12-h fluid balance were intervention-related features influencing BPRI. INTERPRETATION: BPRI is an easy, rapid, precise indicator of the response of patients with septic shock to vasoactive drugs. It is a comparable and even better predictor of prognosis than SOFA and APS in sepsis and it is simpler and more convenient in use. The application of BPRI could help clinicians identify potentially at-risk patients and provide clues for treatment. FUNDING: Fundings for the Beijing Municipal Natural Science Foundation; the National High Level Hospital Clinical Research Funding; the CAMS Innovation Fund for Medical Sciences (CIFMS) from Chinese Academy of Medical Sciences and the National Key R&D Program of China, Ministry of Science and Technology of the People's Republic of China.

Closed Bipolar Nanoelectrode Array for Ultra-Sensitive Detection of Alkaline Phosphatase and Two-Dimensional Imaging of Epidermal Growth Factor Receptors.

The combination of closed bipolar electrodes (cBPE) with electrochemiluminescence (ECL) imaging has demonstrated remarkable capabilities in the field of bioanalysis. Here, we established a cBPE-ECL platform for ultrasensitive detection of alkaline phosphatase (ALP) and two-dimensional imaging of epidermal growth factor receptor (EGFR). This cBPE-ECL system consists of a high-density gold nanowire array in anodic aluminum oxide (AAO) membrane as the cBPE coupled with ECL of highly luminescent cadmium selenide quantum dots (CdSe QDs) luminophores to achieve cathodic electro-optical conversion. When an enzyme-catalyzed amplification effect of ALP with 4-aminophenyl phosphate monosodium salt hydrate (p-APP) as the substrate and 4-aminophenol (p-AP) as the electroactive probe is introduced, a significant improvement of sensing sensitivity with a detection limit as low as 0.5 fM for ALP on the cBPE-ECL platform can be obtained. In addition, the cBPE-ECL sensing system can also be used to detect cancer cells with an impressive detection limit of 50 cells/mL by labeling ALP onto the EGFR protein on A431 human epidermal cancer cell membranes. Thus, two-dimensional (2D) imaging of the EGFR proteins on the cell surface can be achieved, demonstrating that the established cBPE-ECL sensing system is of high resolution for spatiotemporal cell imaging.

High-Throughput Single-Molecule Surface-Enhanced Raman Spectroscopic Profiling of Single-Amino Acid Substitutions in Peptides by a Gold Plasmonic Nanopore.

Simultaneous detection and structural characterization of protein variants on a single platform are highly desirable but technically challenging. Herein, we present a single-molecule spectral system based on a gold plasmonic nanopore for analyzing two peptides and their single-point mutated variants. The gold plasmonic nanopore enabled the high-throughput acquisition of surface-enhanced Raman scattering (SERS) spectra at the single-molecule level by electrically driving analytes into hot spots. Furthermore, a statistical method based on Boolean operations was developed to extract prominent features from fluctuated single-molecule SERS spectra. The effects of the single-amino acid substitutions on both the intramolecular interactions and the peptide conformations were directly characterized by the nanopore system, and the results agreed with the predictions by AlphaFold2. This study highlights the mutual benefits of spectroscopy and nanopore technology, whereby the gold plasmonic nanopore offers a powerful tool for the structural analysis of single-molecule proteins.