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Abstract Background Sepsis-induced cardiomyopathy (SICM) is a common and life-threatening complication of sepsis, significantly contributing to elevated mortality. This study aimed to identify crucial indicators for the prompt and early assessment of SICM. Methods Patients diagnosed with sepsis or SICM within 24 h of intensive care unit (ICU) admission were enrolled in this prospective observational study. Patients were assigned to the training set, validation set and external test set. The primary endpoint was 7-day ICU mortality, and the secondary endpoint was 28-day ICU mortality. Three machine learning algorithms were utilized to identify relevant indicators for diagnosing SICM, incorporating 64 indicators including serum biomarkers associated with cardiac, renal, and liver function, lipid metabolism, coagulation, and inflammation. Internal and external validations were performed on the screening results. Patients were then stratified based on the cut-off value of the most diagnostically effective biomarker identified, and their prognostic outcomes were observed and analyzed. Results A total of 270 patients were included in the training and validation set, and 52 patients were included in the external test set. Age, sex, and comorbidities did not significantly differ between the sepsis and SICM groups (P > 0.05). The support vector machine (SVM) algorithm identified six indicators with an accuracy of 84.5%, the random forest (RF) algorithm identified six indicators with an accuracy of 81.9%, and the logistic regression (LR) algorithm screened out seven indicators. Following rigorous selection, a diagnostic model for sepsis-induced cardiomyopathy was established based on heart-type fatty acid binding protein (H-FABP) (OR 1.308, 95% CI 1.170–1.462, P

Abstract Background Lymph node metastasis (LNM) is the primary mode of metastasis in gastric cancer (GC). However, the precise mechanisms underlying this process remain elusive. Tumor cells necessitate lipid metabolic reprogramming to facilitate metastasis, yet the role of lipoprotein lipase (LPL), a pivotal enzyme involved in exogenous lipid uptake, remains uncertain in tumor metastasis. Therefore, the aim of this study was to investigate the presence of lipid metabolic reprogramming during LNM of GC as well as the role of LPL in this process. Methods Intracellular lipid levels were quantified using oil red O staining, BODIPY 493/503 staining, and flow cytometry. Lipidomics analysis was employed to identify alterations in intracellular lipid composition following LPL knockdown. Protein expression levels were assessed through immunohistochemistry, Western blotting, and enzyme‐linked immunosorbent assays. The mouse popliteal LNM model was utilized to investigate differences in LNM. Immunoprecipitation and mass spectrometry were employed to examine protein associations. In vitro phosphorylation assays and Phos‐tag sodium dodecyl‐sulfate polyacrylamide gel electrophoresis assays were conducted to detect angiopoietin‐like protein 4 (ANGPTL4) phosphorylation. Results We identified that an elevated intracellular lipid level represents a crucial characteristic of node‐positive (N+) GC and further demonstrated that a high‐fat diet can expedite LNM. LPL was found to be significantly overexpressed in N+ GC tissues and shown to facilitate LNM by mediating dietary lipid uptake within GC cells. Leptin, an obesity‐related hormone, intercepted the effect exerted by ANGPTL4/Furin on LPL cleavage. Circulating leptin binding to the leptin receptor could induce the activation of inositol‐requiring enzyme‐1 (IRE1) kinase, leading to the phosphorylation of ANGPTL4 at the serine 30 residue and subsequently reducing its binding affinity with LPL. Moreover, our research revealed that LPL disrupted lipid homeostasis by elevating intracellular levels of arachidonic acid, which then triggered the cyclooxygenase‐2/prostaglandin E2 (PGE2) pathway, thereby promoting tumor lymphangiogenesis. Conclusions Leptin‐induced phosphorylation of ANGPTL4 facilitates LPL‐mediated lipid uptake and consequently stimulates the production of PGE2, ultimately facilitating LNM in GC.

Abstract Cerium oxide (CeO2) nanospheres have limited enzymatic activity that hinders further application in catalytic therapy, but they have an “oxidation switch” to enhance their catalytic activity by increasing oxygen vacancies. In this study, according to the defect-engineering strategy, we developed PtCuOX/CeO2-X nanozymes as highly efficient SOD/CAT mimics by introducing bimetallic copper (Cu) and platinum (Pt) into CeO2 nanospheres to enhance the oxygen vacancies, in an attempt to combine near-infrared (NIR) irradiation to regulate microenvironment for osteoarthritis (OA) therapy. As expected, the Cu and Pt increased the Ce3+/Ce4+ ratio of CeO2 to significantly enhance the oxygen vacancies, and simultaneously CeO2 (111) facilitated the uniform dispersion of Cu and Pt. The strong metal-carrier interaction synergy endowed the PtCuOX/CeO2-X nanozymes with highly efficient SOD/CAT-like activity by the decreased formation energy of oxygen vacancy, promoted electron transfer, the increased adsorption energy of intermediates, and the decreased reaction activation energy. Besides, the nanozymes have excellent photothermal conversion efficiency (55.41%). Further, the PtCuOX/CeO2-X antioxidant system effectively scavenged intracellular ROS and RNS, protected mitochondrial function, and inhibited the inflammatory factors, thus reducing chondrocyte apoptosis. In vivo, experiments demonstrated the biosafety of PtCuOX/CeO2-X and its potent effect on OA suppression. In particular, NIR radiation further enhanced the effects. Mechanistically, PtCuOX/CeO2-X nanozymes reduced ras-related C3 botulinum toxin substrate 1 (Rac-1) and p-p65 protein expression, as well as ROS levels to remodel the inflammatory microenvironment by inhibiting the ROS/Rac-1/nuclear factor kappa-B (NF-κB) signaling pathway. This study introduces new clinical concepts and perspectives that can be applied to inflammatory diseases. Graphical Abstract

Abstract Background Recognizing the predictors of poor short-term prognosis after first-line immunotherapy in patients with anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is essential for individualized treatment strategy. The objective of this study was to ascertain the factors that forecast short-term prognosis in patients with anti-NMDAR encephalitis, develop a prognostic prediction model, and authenticate its efficacy in an external validation cohort. Further, all patients were followed-up long-term to assess the factors of long-term outcome and relapses. Methods A prospective enrollment of patients diagnosed with anti-NMDAR encephalitis was conducted across five clinical centers in China from June 2014 to Mar 2022. The enrolled patients were divided into the derivation and validation sets based on enrollment time. The short-term prognostic model was visualized using a nomogram. Further, all patients were followed-up long-term to assess the factors of long-term outcome. Results This study found that poor short-term prognosis was a risk factor for poor long-term outcome (6-month prognosis, OR 29.792, 95%CI 6.507-136.398, p

Abstract Considering the superior luminous intensity characteristics of lasers, a thermal simulation platform employing laser-induced heating in an aerobic environment was developed. Achieving a uniformly distributed flat-topped square laser beam output was facilitated through optical fibre bundling techniques, while precise control over laser power output was attained through current modulation. Utilising the aforementioned system, thermal shock simulation experiments were conducted in an aerobic environment, subjecting two types of high-temperature-resistant composites, namely C/C and C/SiC, to temperatures up to 1800 °C. These composites were lightweight, heat-resistant materials designed for hypersonic vehicle applications. The results show that the system and method can be used to simulate high temperatures, rapid temperature increases, and thermal shocks on C/C composite materials, with minimal variation in the coupling coefficient under aerobic conditions. The system and method can also provide key technology support for thermal-force-oxygen coupling testing of high temperature resistant materials.

Abstract Heterogeneous and monolithic integration of the versatile low-loss silicon nitride platform with low-temperature materials such as silicon electronics and photonics, III–V compound semiconductors, lithium niobate, organics, and glasses has been inhibited by the need for high-temperature annealing as well as the need for different process flows for thin and thick waveguides. New techniques are needed to maintain the state-of-the-art losses, nonlinear properties, and CMOS-compatible processes while enabling this next generation of 3D silicon nitride integration. We report a significant advance in silicon nitride integrated photonics, demonstrating the lowest losses to date for an anneal-free process at a maximum temperature 250 °C, with the same deuterated silane based fabrication flow, for nitride and oxide, for an order of magnitude range in nitride thickness without requiring stress mitigation or polishing. We report record low anneal-free losses for both nitride core and oxide cladding, enabling 1.77 dB m-1 loss and 14.9 million Q for 80 nm nitride core waveguides, more than half an order magnitude lower loss than previously reported sub 300 °C process. For 800 nm-thick nitride, we achieve as good as 8.66 dB m−1 loss and 4.03 million Q, the highest reported Q for a low temperature processed resonator with equivalent device area, with a median of loss and Q of 13.9 dB m−1 and 2.59 million each respectively. We demonstrate laser stabilization with over 4 orders of magnitude frequency noise reduction using a thin nitride reference cavity, and using a thick nitride micro-resonator we demonstrate OPO, over two octave supercontinuum generation, and four-wave mixing and parametric gain with the lowest reported optical parametric oscillation threshold per unit resonator length. These results represent a significant step towards a uniform ultra-low loss silicon nitride homogeneous and heterogeneous platform for both thin and thick waveguides capable of linear and nonlinear photonic circuits and integration with low-temperature materials and processes.

Abstract Nanoplasmas induced by intense laser fields have attracted enormous attention due to their accompanied spectacular physical phenomena which are vigorously expected by the community of science and industry. For instance, the energetic electrons and ions produced in laser-driven nanoplasmas are significant for the development of compact beam sources. Nevertheless, effective confinement on the propagating charged particles, which was realized through magnetic field modulation and target structure design in big facilities, are largely absent in the microscopic regime. Here we introduce a reliable scheme to provide control on the emission direction of protons generated from surface ionization in gold nanoparticles driven by intense femtosecond laser fields. The ionization level of the nanosystem provides us a knob to manipulate the characteristics of the collective proton emission. The most probable emission direction can be precisely steered by tuning the excitation strength of the laser pulses. This work opens new avenue for controlling the ion emission in nanoplasmas and can vigorously promote the fields such as development of on-chip beam sources at micro-/nano-scales.

In recent years, bridge safety accidents caused by insufficient shear bearing capacity of bridges have attracted increasing attention. The main causes include internal factors such as insufficient bridge section and deterioration of steel bars, as well as external factors, for example, vehicle load surge and improper maintenance. To address this issue to some degree, this article adopts the method of strengthening RC beams with ultra-high performance concrete (UHPC) and conducts parameter analysis using finite element method, taking into consideration the influence of four parameters: reinforcement material, reinforcement thickness, reinforcement length, and reinforcement form on the shear strengthening characteristics of RC rectangular beams. After obtaining the optimal reinforcement plan through parameter analysis, the author applied the research results to an existing bridge with insufficient shear strength. It then turned out that the shear bearing capacity of the reinforced bridge’s inclined section increased by approximately 27.1%. Simple and fast in construction, this reinforcement method is one of the methods that is effective to increase cross-section reinforcement; besides, it features good economic characteristics and applicability.

Abstract Background Autoimmune uveitis is an inflammatory disease triggered by an aberrant immune response. Mesenchymal stem cell-derived small extracellular vesicles (MSC-sEVs) are emerging as potential therapeutic agents for this condition. CD73, an ectoenzyme present on MSC-sEVs, is involved in mitigating inflammation by converting extracellular adenosine monophosphate into adenosine. We hypothesize that the inhibitory effect of MSC-sEVs on experimental autoimmune uveitis (EAU) could be partially attributed to the surface expression of CD73. Methods To investigate novel therapeutic approaches for autoimmune uveitis, we performed lentiviral transduction to overexpress CD73 on the surface of MSC-sEVs, yielding CD73-enriched MSC-sEVs (sEVs-CD73). Mice with interphotoreceptor retinoid-binding protein (IRBP)-induced EAU were grouped randomly and treated with 50 µg MSC-sEVs, vector infected MSC-sEVs, sEVs-CD73 or PBS via single tail vein injection. We evaluated the clinical and histological features of the induced mice and analyzed the proportion and functional capabilities of T helper cells. Furthermore, T-cells were co-cultured with various MSC-sEVs in vitro, and we quantified the resulting inflammatory response to assess the potential therapeutic benefits of sEVs-CD73. Results Compared to MSC-sEVs, sEVs-CD73 significantly alleviates EAU, leading to reduced inflammation and diminished tissue damage. Treatment with sEVs-CD73 results in a decreased proportion of Th1 cells in the spleen, draining lymph nodes, and eyes, accompanied by an increased proportion of regulatory T-cells (Treg cells). In vitro assays further reveal that sEVs-CD73 inhibits T-cell proliferation, suppresses Th1 cells differentiation, and enhances Treg cells proportion. Conclusion Over-expression of CD73 on MSC-sEVs enhances their immunosuppressive effects in EAU, indicating that sEVs-CD73 has the potential as an efficient immunotherapeutic agent for autoimmune uveitis.

Abstract The escalation of cloud services, driven by their accessibility, improved performance, and cost-effectiveness, has led cloud service providers to consistently seek methods to expedite job completion, thereby boosting profits and reducing energy consumption expenses. Despite developing numerous scheduling algorithms, many of these techniques address only a specific objective within the scheduling process. To efficiently achieve better optimization results for the cloud task scheduling problem, a novel approach, the Enhanced Whale Optimization Algorithm (EWOA), is proposed. EWOA integrates the WOA with the Lévy flight. The incorporation of Lévy flight is tailored to broaden the search space of WOA, expediting convergence with adaptive crossover. The EWOA model is simulated using the Cloudsim tool and evaluated under diverse test conditions. The effectiveness of EWOA is assessed by employing various parameters and comparing them with existing algorithms. The results demonstrate that EWOA outperforms other algorithms in resource utilization, energy consumption, and execution cost, establishing its superiority in addressing the complexities of multi-objective cloud task scheduling.

Abstract Bacteriophage infection, a pivotal process in microbiology, initiates with the phage’s tail recognizing and binding to the bacterial cell surface, which then mediates the injection of viral DNA. Although comprehensive studies on the interaction between bacteriophage lambda and its outer membrane receptor, LamB, have provided rich information about the system’s biochemical properties, the precise molecular mechanism remains undetermined. This study revealed the high-resolution cryo-electron microscopy (cryo-EM) structures of the bacteriophage lambda tail complexed with its irreversible Shigella sonnei 3070 LamB receptor and the closed central tail fiber. These structures reveal the complex processes that trigger infection and demonstrate a substantial conformational change in the phage lambda tail tip upon LamB binding. Providing detailed structures of bacteriophage lambda infection initiation, this study contributes to the expanding knowledge of lambda-bacterial interaction, which holds significance in the fields of microbiology and therapeutic development.

This is an article in the field of ceramics and composites. Phosphogypsum has a large discharge and low utilization rate,and resource utilization is imminent. The heat treatment of phosphogypsum under different temperatures was studied. The influence of heat treatment temperature on the physical phase and microstructure of phosphogypsum, and the compressive strength, phase and microstructure of non burningsample of building materials by the treated phosphogypsum were studied. The results show that with the increase of heat treatment temperature, the crystallinity of gypsum increases and the crystal form changes. After heat treatment at 80 ℃, the crystal of gypsum is dense, and part of it is converted into hemihydrate gypsum. The Gypsum dihydrate formed by hydration recrystallization of hemihydrate gypsum fills the void, forming the internal microstructure of dense and mutual bonding of crystals, so the compressive strength of no burning building materials is greatly improved. After curing for 7 days and 28 days, the compressive strength of non burningsample (the mass ratio of phosphogypsum to cement is 4∶1) reaches 36.45 MPa and 38.12 MPa. The compressive strength of the sample soaked in water for 24 hours is still 21.03 MPa.

Abstract Yangmingism, a crucial component of Chinese Confucianism, has profoundly impacted the development of Eastern civilization throughout history and gained new significance within modern contexts. This study employs social network and GIS spatial analyses to investigate the spatio-temporal evolution and patterns of Yangmingism during the Ming and Qing dynasties. Conclusions drawn include: (1) Yangmingism spread during the Ming and Qing dynasties followed five phases (rise-peak-decline-revival-trough), consistent with general cultural diffusion processes. (2) The spatial structure of regions accepting Yangmingism changed from polycentric to localized ribbon-polycentric, then to monocentric, polycentric, and ultimately, fragmented distribution. Diffusion began with a point-axis structure along traffic routes, transitioned to a core-periphery spatial structure, and returned to a point-axis structure due to reduced diffusion potential energy. (3) Yangmingism diffusion exhibited distance decay characteristics, with the most extensive diffusion in the Han cultural region, primarily located within the middle and lower reaches of the Ganjiang River basin and the Yangtze River Delta. (4) Yangmingism diffusion reflected influences from local administrative hierarchies and cultural development. During the rise-to-peak phase, Yangmingism reached areas with higher administrative and cultural levels, while during the peak-to-decline phase, it disseminated from higher to lower hierarchy regions. (5) The spatial diffusion of Yangmingism is mainly relocation diffusion, followed by expansion diffusion. In the process of relocation diffusion, Yangmingism may reverse the diffusion from the “target regions” to the “source regions” due to the influence of the radiation of the high-ranking regions and the cultural innovation of the “target regions”.

Abstract Brain metastasis (BM) is one of the leading causes of cancer-related deaths in patients with advanced non-small cell lung cancer (NSCLC). However, limited treatments are available due to the presence of the blood-brain barrier (BBB). Upregulation of lysophosphatidylcholine acyltransferase 1 (LPCAT1) in NSCLC has been found to promote BM. Conversely, downregulating LPCAT1 significantly suppresses the proliferation and metastasis of lung cancer cells. In this study, we firstly confirmed significant upregulation of LPCAT1 in BM sites compared to primary lung cancer by analyzing scRNA dataset. We then designed a delivery system based on a single-chain variable fragment (scFv) targeting the epidermal growth factor receptor (EGFR) and exosomes derived from HEK293T cells to enhance cell-targeting capabilities and increase permeability. Next, we loaded LPCAT1 siRNA (siLPCAT1) into these engineered exosomes (exoscFv). This novel scFv-mounted exosome successfully crossed the BBB in an animal model and delivered siLPCAT1 to the BM site. Silencing LPCAT1 efficiently arrested tumor growth and inhibited malignant progression of BM in vivo without detectable toxicity. Overall, we provided a potential platform based on exosomes for RNA interference (RNAi) therapy in lung cancer BM.

Cancer is a significant and constantly growing clinical problem all over the word. For many types of cancer there has been little change in mortality rate of CRC in the past decades and treatment options are limited. A striking example is malignant Glioblastoma (GBM) which exhibits a high degree of infiltration of surrounding healthy brain tissue, extremely high mortality rate, morbidity and most life-years lost of any cancer. Considerable research efforts in the last several decades have failed to improve these outcomes. Boron Capture Neutron Therapy (BNCT) is an experimental radiotherapy (RT) that shows the best hope for the patients for whom all current therapies fail. BNCT involves the intracellular release of alpha and Li-ion particles from boron in response to neutron beam and therefore its success is critically dependent on achieving high intracellular concentrations of boron atoms within the cancerous cells. Boron phenylalanine (BPA) is the most used compound to deliver boron atoms, but achieving high intracellular concentration of BPA is difficult with this small molecule compound and is an absolute limiting factor for the better outcome of BNCT. Our approach focused on a delivery of a high and stable concentration of boron atoms in a form of novel trimetallic core-shell nanoparticles, combining boron for BNCT and iron for magnetic targeting in the core, and a gold shell for stability and attachment of targeting therapeutic peptides. The research was targeted towards comparing different synthesis variables to form these core-shell particles and incorporate as much boron into the core as possible via redox-transmetalation. Partial gold shells were formed around the core via island growth with a molar ratio of Fe/B of 0.64 and high incorporation of boron.

Female reproductive timing and lifespan, with a close relation to long-term health outcomes, have been altered in U.S. women over the past decades. However, epidemiologic evidence of the potential causes was lacking. On the basis of 1981 naturally postmenopausal women from the National Health and Nutrition Examination Survey 1999–2020, this study aimed to investigate the associations of urinary heavy metals with age at menarche, age at menopause, and reproductive lifespan. Multivariate generalized linear regression and addictive models were used for single metal exposure analysis, and weighted quantile sum (WQS) and Bayesian kernel machine regression (BKMR) models were employed for mixed exposures. In the fully adjusted model, higher urinary antimony concentration was associated with earlier age at menarche of 0.137 years, while higher concentrations of cadmium, cesium, lead, antimony, and thallium were associated with delayed age at menopause of 0.396–0.687 years. Additionally, urinary barium, cesium, lead, antimony, and thallium levels were associated with longer reproductive lifespan ranging between 0.277 and 0.713 years. Both WQS and BKMR models showed significantly positive associations of metal mixtures with age at menopause (β: 0.667, 95 % CI: 0.120–1.213) and reproductive lifespan (β: 0.686, 95 % CI: 0.092–1.280), with cadmium and lead identified as principal contributors. In conclusion, heavy metal exposures were associated with reproductive timing and lifespan of U.S. women, highlighting the need for further prevention and intervention strategies.

Efforts to enhance the performance of thermoelectric generators (TEGs) in engine waste heat recovery have primarily focused on directly increasing energy conversion efficiency. Heat leakage can occur in many parts of a TEG. It is needed to develop a model to help researchers study this phenomenon and propose measures to reduce heat leakage. To address this gap, this study establishes and validates a computational fluid dynamic (CFD) and finite element (FE) coupled model based on a TEG prototype and its engine test bench. Unlike other models, this approach captures the intricate dynamics of heat propagation from the TEG via air gaps, encompassing conduction, convection, and radiation. Comprehensive analysis reveals that heat leakage accounts for approximately 11% of TEG power output loss. Ignoring the impact of heat leakage can lead to an overestimation of TEG power output. Key areas of heat leakage are identified, and numerical factors influencing this phenomenon are explored. Vertical TEG placement and optimal spacing between thermoelectric modules emerge as effective strategies for mitigating the impact of heat leakage on power output. Leveraging these insights, strategic thermoelectric module placement, vertical TEG orientation, and the application of thermal insulation materials to the heat exchanger are proposed as measures to enhance TEG power output by approximately 5%. The experimental and numerical results underscore the feasibility of optimizing TEGs from the perspective of heat leakage, a crucial aspect previously overlooked. These findings provide valuable insights for future TEG optimization endeavors, highlighting the importance of addressing heat leakage to maximize TEG performance.

Background Stage IV gastric cancer is a highly heterogeneous and lethal tumor with few therapeutic strategies. The combination of programmed cell death protein 1 inhibitors and chemotherapy is currently the standard frontline treatment regimen for advanced gastric cancer. Nevertheless, it remains a great challenge to screen the beneficiaries of immunochemotherapy and expand indications for this treatment regimen.Methods We conducted a pathological assessment to ascertain the importance of tertiary lymphoid structures based on the tissue samples collected from patients with stage IV gastric cancer (n=15) both prior to and following immunochemotherapy treatment. Additionally, we used spatial (n=10) and single-cell transcriptional analysis (n=97) to investigate the key regulators of tertiary lymphoid structures (TLSs). Multiplex immunofluorescence and image analysis (n=34) were performed to explore the association between tumor-infiltrating CXCL13+ CD160+ CD8+ T cells and TLSs. The relationship between CXCL13+ CD160+ CD8+ T cells and the responsiveness to immunotherapy was also evaluated by multiplex immunofluorescence and image analysis approaches (n=15). Furthermore, we explored the intrinsic characteristics of CXCL13+ CD160+ CD8+ T cells through various experimental techniques, including quantitative reverse transcription-PCR, western blot, and flow cytometry.Results We found that responders exhibited higher levels of TLSs and CXCL13+ CD160+ CD8+ T cells in biopsy tissues prior to immunochemotherapy compared with non-responders. Following conversion therapy, responders also had a higher percentage of mature TLSs and a higher number of CXCL13+ CD160+ CD8+ T cells in surgical resections. Moreover, we discovered that vitamin B6 in CD160+ CD8+ T cells could reduce the ubiquitination modification of HIF-1α by MDM2, thereby attenuating the degradation of HIF-1α. Consequently, this led to the transcriptional upregulation of CXCL13 expression, facilitating the recruitment of CXCR5+ B cells and the formation of TLSs.Conclusion The number and maturity of TLSs, along with the extent of CXCL13+ CD160+ CD8+ T-cell infiltration, might function as potential indicators for assessing the effectiveness of immunotherapy in treating gastric malignancies. Furthermore, our research suggests that vitamin B6 could enhance the secretion of CXCL13 by CD160+ CD8+ T cells by reducing the degradation of HIF-1α. Additionally, we demonstrate that vitamin B6 supplementation or targeting pyridoxal kinase could substantially improve the efficacy of immunotherapies for gastric cancer.

BackgroundAtherosclerotic plaque rupture is a major cause of heart attack. Previous studies have shown that immune cells are involved in the development of atherosclerosis, but different immune cells play different roles. The aim of this study was to investigate the causal relationship between immunological traits and myocardial infarction (MI).MethodsTo assess the causal association of immunological profiles with myocardial infarction based on publicly available genome-wide studies, we used a two-sample mendelian randomization (MR) approach with inverse variance weighted (IVW) as the main analytical method. Sensitivity analyses were used to assess heterogeneity and horizontal pleiotropy.ResultsA two-sample MR analysis was conducted using IVW as the primary method. At a significance level of 0.001, we identified 47 immunophenotypes that have a significant causal relationship with MI. Seven of these were present in B cells, five in cDC, four in T cells at the maturation stage, six in monocytes, five in myeloid cells, 12 in TBNK cells, and eight in Treg cells. Sensitivity analyses were performed to confirm the robustness of the MR results.ConclusionsOur results provide strong evidence that multiple immune cells have a causal effect on the risk of myocardial infarction. This discovery provides a new avenue for the development of therapeutic treatments for myocardial infarction and a new target for drug development.

BackgroundAutoimmune encephalitis (AIE) encompasses a spectrum of rare autoimmune-mediated neurological disorders, which are characterized by brain inflammation and dysfunction. Autoantibodies targeting the N-methyl-d-aspartic acid receptor (NMDAR) and leucine-rich glioma-inactivated 1 (LGI1) are the most common subtypes of antibody-positive AIE. Currently, there are no approved therapies for AIE. Interleukin-6 (IL-6) signaling plays a role in the pathophysiology of AIE. Satralizumab, a humanized, monoclonal recycling antibody that specifically targets the IL-6 receptor and inhibits IL-6 signaling, has demonstrated efficacy and safety in another autoantibody-mediated neuroinflammatory disease, aquaporin-4 immunoglobulin G antibody-positive neuromyelitis optica spectrum disorder, and has the potential to be an evidence-based disease modifying treatment in AIE.ObjectivesCIELO will evaluate the efficacy, safety, pharmacodynamics, and pharmacokinetics of satralizumab compared with placebo in patients with NMDAR-immunoglobulin G antibody-positive (IgG+) or LGI1-IgG+ AIE.Study designCIELO (NCT05503264) is a prospective, Phase 3, randomized, double-blind, multicenter, basket study that will enroll approximately 152 participants with NMDAR-IgG+ or LGI1-IgG+ AIE. Prior to enrollment, participants will have received acute first-line therapy. Part 1 of the study will consist of a 52-week primary treatment period, where participants will receive subcutaneous placebo or satralizumab at Weeks 0, 2, 4, and every 4 weeks thereafter. Participants may continue to receive background immunosuppressive therapy, symptomatic treatment, and rescue therapy throughout the study. Following Part 1, participants can enter an optional extension period (Part 2) to continue the randomized, double-blind study drug, start open-label satralizumab, or stop study treatment and continue with follow-up assessments.EndpointsThe primary efficacy endpoint is the proportion of participants with a ≥1-point improvement in the modified Rankin Scale (mRS) score from study baseline and no use of rescue therapy at Week 24. Secondary efficacy assessments include mRS, Clinical Assessment Scale of Autoimmune Encephalitis (CASE), time to rescue therapy, sustained seizure cessation and no rescue therapy, Montreal Cognitive Assessment, and Rey Auditory Verbal Learning Test (RAVLT) measures. Safety, pharmacokinetics, pharmacodynamics, exploratory efficacy, and biomarker endpoints will be captured.ConclusionThe innovative basket study design of CIELO offers the opportunity to yield prospective, robust evidence, which may contribute to the development of evidence-based treatment recommendations for satralizumab in AIE.

Abstract Memristors are a candidate device for artificial neural systems due to their excellent conductance‐regulation ability and potential to simulate the characteristics of biological synapses. This study fabricated a Pt/TaOx/TiOy/Ti analog artificial synapse memristor that exhibits excellent multilevel storage property with a large on/off ratio of ≈660 times. The dynamic resistive switching mechanism is well expounded and validated by the reset stopping voltage dependent Schottky fitting results. Moreover, the essential biological synaptic characteristics such as long‐term potentiation/depression (LTP/D) and paired‐pulse facilitation (PPF) are successfully mimicked with a low pulse energy consumption of 12.69 nJ. A neuromorphic network constructed on the enhanced symmetry and linearity of conductance for this Pt/TaOx/TiOy/Ti memristive device can achieve 92.45% accuracy in recognizing handwritten pattern. These results demonstrate a significant potential for application Pt/TaOx/TiOy/Ti memristor in non‐volatile memory and bioinspired neuromorphic systems.

PurposeEpigenetic modifications play a crucial role in cancer development, and our study utilized public data to analyze which leads to the discovery of significant epigenetic abnormalities in lncRNAs, offering valuable insights into prognosis and treatment strategies for renal carcinoma.MethodsPublic data were obtained from the Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC) and Gene Expression Omnibus (GEO) database. The analysis of the online public data was all completed in R software.ResultsWe discovered a great number of epigenetic abnormalities of lncRNA in renal cancer, which is achieved by comparing the following modification and methylation of histone region changes on the promoter and enhancer of lncRNA: H3K27ac, H3K4me1, H3K4me3. As a result, 12 specific epigenetic disorders of lncRNA genes in renal cancer were identified. Finally, based on this lncRNA, we investigated the prognosis of renal cancer samples, among which 8 lncRNA can be seen as markers of prognosis in renal cancer, which had great prediction ability for ccRCC prognosis. Meanwhile, high risk score may pose response better to axitinib and nilotinib, but not sorafenib or sunitinib. Beyond, we observed an elevated level of risk score in immunotherapy non-responders. Further, biological enrichment and immuno-infiltration analysis was conducted to investigate the fundamental differences between patients categorized as high or low risk.ConclusionOur research improves the understanding in the function of epigenetic dysregulated long non-coding RNAs in renal carcinoma.

Primary familial brain calcification (PFBC), also known as Fahr’s disease, is a central nervous system calcium deposition disorder with symmetrical basal ganglia calcification. Most PFBC cases are caused by SLC20A2 gene variant. We report a Chinese female patient with PFBC and dopamine-responsive parkinsonism who had motor fluctuations and dyskinesia and recovered effectively after symptomatic medication adjustment. A novel heterozygous missense variant was found by whole-exome sequencing and proven harmful by family validation and genetic analysis. This example expands the phenotype of SLC20A2-associated PFBC patients and shows the clinical efficacy of dopaminergic replacement treatment.

Tinnitus, characterized by phantom sound perception, is a highly disruptive disorder lacking definitive and effective treatments. Its intricate neural mechanisms are not fully understood. Transcutaneous auricular vagus nerve stimulation (taVNS) has demonstrated potential as a substitute or supplementary treatment by activating central vagal pathways. However, standardized therapeutic protocols and objective tests to assess efficacy are lacking. Therefore, taVNS shows promise as a therapy for tinnitus, and treatment protocols should be optimized in future clinical trials.

In this paper, the influence of micro scale and nanoscale limestone powder (LP) on plastic viscosity of ultra-high performance concrete (UHPC) mixture was investigated. Moreover, a novel method for analyzing water film on particle surfaces has been presented based on low-field nuclear magnetic resonance technology (LF NMR). Results showed that approximately 95% of free water in UHPC slurry is adsorbed on the surface of particles, while the rest is filled in capillaries and macropores. Moreover, rheological properties of UHPC are related to particle size of limestone powder. Micro scale limestone powder (LP1) could reduce the heat release during early hydration of UHPC, increase the fluidity, but has no significant effect on the water film thickness. The plastic viscosity of UHPC mixed with 10% mass fraction of LP1 will decrease by 22.8%, the flowability will increase from 235 mm to 270 mm, and the compressive strength will remain unchanged at 160 MPa. However, nanoscale limestone powder (LP2) increases the heat release of UHPC and significantly reduces its fluidity. A 10% mass fraction of LP2 will reduce the water film thickness of the UHPC by 23.5%, increase the plastic viscosity by 38.5%, and reduce the flowability to 210 mm. Meanwhile, the compressive strength of UHPC will decrease if the mass fraction of LP2 exceeds 5%.

The on-ramp merging in multi-lane highway scenarios presents challenges due to the complexity of coordinating vehicles’ merging and lane-changing behaviors, while ensuring safety and optimizing traffic flow. However, there are few studies that have addressed the merging problem of ramp vehicles and the cooperative lane-change problem of mainline vehicles within a unified framework and proposed corresponding optimization strategies. To tackle this issue, this study adopts a cyber-physical integration perspective and proposes a graph-based solution approach. First, the information of vehicle groups in the physical plane is mapped to the cyber plane, and a dynamic conflict graph is introduced in the cyber space to describe the conflict relationships among vehicle groups. Subsequently, graph decomposition and search strategies are employed to obtain the optimal solution, including the set of mainline vehicles changing lanes, passing sequences for each route, and corresponding trajectories. Finally, the proposed dynamic conflict graph-based algorithm is validated through simulations in continuous traffic with various densities, and its performance is compared with the default algorithm in SUMO. The results demonstrate the effectiveness of the proposed approach in improving vehicle safety and traffic efficiency, particularly in high traffic density scenarios, providing valuable insights for future research in multi-lane merging strategies.