High Signal to Noise Ratio Piezoelectric Thin Film Sensor Based on Elastomer Amplification for Ambulatory Blood Pressure Monitoring.

Continuous pulse wave detection can be used for monitoring and diagnosing cardiovascular diseases, and research on pulse sensing based on piezoelectric thin films is one of the hot spots. Usually, piezoelectric thin films do not come into direct contact with the skin and need to be connected through a layer of an elastic medium. Most views think that the main function of this layer of elastic medium is to increase the adhesion between the sensor component and the skin, but there is little discussion about the impact of the elastic medium on pulse vibration transmission. Here, we conducted a detailed study on the effects of Young's modulus and the thickness of elastic media on pulse sensing signals. The results show that the waveform amplitude of the piezoelectric sensing signal decreases with the increase of Young's modulus and thickness of the elastic medium. Then, we constructed a theoretical model of the influence of elastic media on pulse wave propagation. The amplitude of the pulse wave signal detected by the optimized sensor was increased to 480%. Our research shows that by regulating Young's modulus and thickness of elastic media, pulse wave signals can undergo a similar amplification effect, which has an important theoretical reference value for achieving ambulatory blood pressure monitoring based on high-quality pulse waves.

Selective removal of misfolded SOD1 delays disease onset in a mouse model of amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease. There is no cure currently. The discovery that mutations in the gene SOD1 are a cause of ALS marks a breakthrough in the search for effective treatments for ALS. SOD1 is an antioxidant that is highly expressed in motor neurons. Human SOD1 is prone to aberrant modifications. Familial ALS-linked SOD1 variants are particularly susceptible to aberrant modifications. Once modified, SOD1 undergoes conformational changes and becomes misfolded. This study aims to determine the effect of selective removal of misfolded SOD1 on the pathogenesis of ALS. METHODS: Based on the chaperone-mediated protein degradation pathway, we designed a fusion peptide named CT4 and tested its efficiency in knocking down intracellularly misfolded SOD1 and its efficacy in modifying the pathogenesis of ALS. RESULTS: Expression of the plasmid carrying the CT4 sequence in human HEK cells resulted in robust removal of misfolded SOD1 induced by serum deprivation. Co-transfection of the CT4 and the G93A-hSOD1 plasmids at various ratios demonstrated a dose-dependent knockdown efficiency on G93A-hSOD1, which could be further increased when misfolding of SOD1 was enhanced by serum deprivation. Application of the full-length CT4 peptide to primary cultures of neurons expressing the G93A variant of human SOD1 revealed a time course of the degradation of misfolded SOD1; misfolded SOD1 started to decrease by 2 h after the application of CT4 and disappeared by 7 h. Intravenous administration of the CT4 peptide at 10 mg/kg to the G93A-hSOD1 reduced human SOD1 in spinal cord tissue by 68% in 24 h and 54% in 48 h in presymptomatic ALS mice. Intraperitoneal administration of the CT4 peptide starting from 60 days of age significantly delayed the onset of ALS and prolonged the lifespan of the G93A-hSOD1 mice. CONCLUSIONS: The CT4 peptide directs the degradation of misfolded SOD1 in high efficiency and specificity. Selective removal of misfolded SOD1 significantly delays the onset of ALS, demonstrating that misfolded SOD1 is the toxic form of SOD1 that causes motor neuron death. The study proves that selective removal of misfolded SOD1 is a promising treatment for ALS.

MALAT1 regulates network of microRNA-15a/16-VEGFA to promote tumorigenesis and angiogenesis in multiple myeloma.

MALAT1 is one of the most hopeful members implicated in angiogenesis in a variety of non-malignant diseases. In multiple myeloma (MM), MALAT1 is recognized as the most highly expressed long non-coding RNA. However, the functional roles of MALAT1 in angiogenesis and the responsible mechanisms have not yet been explored. Herein, we discovered a novel regulatory network dependent on MALAT1 in relation to MM tumorigenesis and angiogenesis. We observed that MALAT1 was upregulated in MM and significantly associated with poor overall survival. MALAT1 knockdown suppressed MM cell proliferation and promoted apoptosis, while restricting endothelial cells angiogenesis. Moreover, MALAT1 directly targeted microRNA-15a/16, and microRNA-15a/16 suppression partly reverted the effects of MALAT1 deletion on MM cells in vitro as well as tumor growth and angiogenesis in vivo. In addition, further study indicated that MALAT1 functioned as a competing endogenous RNA for microRNA-15a/16 to regulate vascular endothelial growth factor A (VEGFA) expression. Our results suggest that MALAT1 plays an important role in the regulatory axis of microRNA-15a/16-VEGFA to promote tumorigenicity and angiogenesis in MM. Consequently, MALAT1 could serve as a novel promising biomarker and a potential antiangiogenic target against MM.

ACSL4: a double-edged sword target in multiple myeloma, promotes cell proliferation and sensitizes cell to ferroptosis.

Overactive fatty acid metabolism is usually found in hematological malignancies including multiple myeloma (MM), but the underlying mechanisms remain unclear. Here, we reveal that acyl-CoA synthetase long-chain family member 4 (ACSL4) is abnormally overexpressed in MM cell lines and MM patients compared to healthy donors. Knockdown of ACSL4 inhibited MM cell proliferation and reduced fatty acid levels possibly by regulating lipid metabolism genes including c-Myc and sterol regulatory element binding proteins (SREBPs). As a propellent in ferroptosis, ACSL4 also determines the sensitivity of MM cells to ferroptosis inducer RSL3. Knockdown of ACSL4 rendered MM cells resistance to ferroptosis. Our findings suggest that ACSL4 is a double-edged sword target in MM. Based on the high expression of ACSL4, ferroptosis induction represents a promising therapeutic strategy for MM.

XBP1 modulates endoplasmic reticulum and mitochondria crosstalk via regulating NLRP3 in renal ischemia/reperfusion injury.

The functional status of mitochondria and the endoplasmic reticulum are central to renal ischemia/reperfusion injury (IRI). X-box binding protein 1 (XBP1) is an important transcription factor in endoplasmic reticulum stress. NLR family pyrin domain containing-3 (NLRP3) inflammatory bodies are closely related to renal IRI. In vivo and in vitro, we examined the molecular mechanisms and functions of XBP1-NLRP3 signaling in renal IRI, which influences ER-mitochondrial crosstalk. In this study, mice were subjected to 45 min of unilateral renal warm ischemia, the other kidney resected, and reperfusion was performed for 24 h in vivo. In vitro, murine renal tubular epithelial cells (TCMK-1) were exposed to hypoxia for 24 h and reoxygenation for 2 h. Tissue or cell damage was evaluated by measuring blood urea nitrogen and creatinine levels, histological staining, flow cytometry, terminal deoxynucleotidyl transferase-mediated nick-end labeling, diethylene glycol staining, and transmission electron microscopy (TEM). Western blotting, immunofluorescence staining, and ELISA were used to analyze protein expression. Whether XBP1 regulates the NLRP3 promoter was evaluated using a luciferase reporter assay. Kidney damage was reduced with decreasing blood urea nitrogen, creatinine, interleukin-1ß, and interleukin-18 levels. XBP1 deficiency reduced tissue damage and cell apoptosis, protecting the mitochondria. Disruption of XBP1 was associated with reduced NLRP3 and cleaved caspase-1 levels and markedly improved survival. In vitro in TCMK-1 cells, XBP1 interference inhibited caspase-1-dependent mitochondrial damage and reduced the production of mitochondrial reactive oxygen species. The luciferase assay showed that spliced XBP1 isoforms enhanced the activity of the NLRP3 promoter. These findings reveal that XBP1 downregulation suppresses the expression of NLRP3, a potential regulator of endoplasmic reticulum mitochondrial crosstalk in nephritic injury and a potential therapeutic target in XBP1-mediated aseptic nephritis.

Increased ICU mortality in septic shock patients with hypo- or hyper- serum osmolarity: A retrospective study.

Background: While many factors that are associated with increased mortality in septic shock patients have been identified, the effects of serum osmolarity on the outcomes of ICU patients with septic shock have not yet been studied. Methods: The present study was designed to examine the association of serum osmolarity with ICU 28-day mortality in ICU patients with septic shock. Adult patients diagnosed with septic shock from the MIMIC-IV database were selected in this study. The serum osmolarity was calculated synchronously according to the serum concentrations of Na+, K+, glucose, and urea nitrogen. Results: In the present study, a significant difference was observed between the 28-day mortality of septic shock patients with hypo-osmolarity, hyper-osmolarity, and normal osmolarity (30.8%, 34.9%, and 23.0%, respectively, p < 0.001), which were detected at ICU admission. After propensity score matching (PSM) for basic characteristics, the relatively higher mortality was still observed in the hypo-osmolarity and hyper-osmolarity groups, compared to normal osmolarity group (30.6%, 30.0% vs. 21.7%, p = 0.009). Furthermore, we found that transforming the hyper-osmolarity into normal osmolarity by fluid therapy on day 2 and 3 decreased this mortality. Conclusion: The serum osmolarity disorder is markedly associated with increased 28-day mortality in septic shock patients.

Carrier-Free Immunotherapeutic Nano-Booster with Dual Synergistic Effects Based on Glutaminase Inhibition Combined with Photodynamic Therapy.

The immunotherapeutic effect elicited by photodynamic therapy (PDT) is attenuated by tumor defense mechanisms associated with glutamine metabolism, including the metabolic regulation of redox homeostasis and the limitation of the immunosuppressive tumor microenvironment (ITM). Herein, a carrier-free immunotherapeutic nanobooster C9SN with dual synergistic effects was constructed by the self-assembly of glutaminase (GLS) inhibitor compound 968 (C968) and photosensitizer Chlorin e6. C968-mediated GSH deprivation through inhibiting glutamine metabolism prevented PDT-generated reactive oxygen species from being annihilated by GSH, amplifying intracellular oxidative stress, which caused severe cell death and also enhanced the immunogenic cell death (ICD) effect. In addition, genome-wide analysis was carried out using RNA-sequencing to evaluate the changes in cell transcriptome induced by amplifying oxidative stress. Thereafter, neoantigens generated by the enhanced ICD effect promoted the maturation of dendritic cells, thereby recruiting and activating cytotoxic T lymphocytes (CTLs). Meanwhile, C9SN remodeled the ITM by blocking glutamine metabolism to polarize M2-type tumor-associated macrophages (TAMs) into M1-type TAMs, which further recruited and activated the CTLs. Ultimately, this immunotherapeutic nanobooster suppressed primary and distant tumors. This "kill two birds with one stone" strategy would shed light on enhancing tumor immunogenicity and alleviating tumor immunosuppression to improve the immunotherapeutic effect of PDT.

Methyl eugenol protects the kidney from oxidative damage in mice by blocking the Nrf2 nuclear export signal through activation of the AMPK/GSK3ß axis.

Disrupted redox homeostasis contributes to renal ischemia-reperfusion (IR) injury. Abundant natural products can activate nuclear factor erythroid-2-related factor 2 (Nrf2), thereby providing therapeutic benefits. Methyl eugenol (ME), an analog of the phenolic compound eugenol, has the ability to induce Nrf2 activity. In this study, we investigated the protective effects of ME against renal oxidative damage in vivo and in vitro. An IR-induced acute kidney injury (AKI) model was established in mice. ME (20 mg·kg-1·d-1, i.p.) was administered to mice on 5 consecutive days before IR surgery. We showed that ME administration significantly attenuated renal destruction, improved the survival rate, reduced excessive oxidative stress and inhibited mitochondrial lesions in AKI mice. We further demonstrated that ME administration significantly enhanced Nrf2 activity and increased the expression of downstream antioxidative molecules. Similar results were observed in vitro in hypoxia/reoxygenation (HR)-exposed proximal tubule epithelial cells following pretreatment with ME (40 µmol·L-1). In both renal oxidative damage models, ME induced Nrf2 nuclear retention in tubular cells. Using specific inhibitors (CC and DIF-3) and molecular docking, we demonstrated that ME bound to the binding pocket of AMPK with high affinity and activated the AMPK/GSK3ß axis, which in turn blocked the Nrf2 nuclear export signal. In addition, ME alleviated the development of renal fibrosis induced by nonfatal IR, which is frequently encountered in the clinic. In conclusion, we demonstrate that ME modulates the AMPK/GSK3ß axis to regulate the cytoplasmic-nuclear translocation of Nrf2, resulting in Nrf2 nuclear retention and thereby enhancing antioxidant target gene transcription that protects the kidney from oxidative damage.

Safety and feasibility assessment of extending the flushing interval in totally implantable venous access port flushing during the non-treatment stage for patients with breast cancer.

Aim: To investigate the safety and feasibility of extending the flushing interval for the totally implantable venous access port (TIVAP) during the non-treatment stage in patients with breast cancer (BC) by retrospectively analyzing the patients' clinical data, including the incidence of TIVAP-related complications. Methods: This single-center retrospective study included patients with BC who underwent TIVAP implantation at our hospital between January 2018 and March 2021 during their non-treatment phase and visited the hospital regularly for TIVAP flushing. Among the 1013 patients with BC who received TIVAP implantation, 617 patients were finally included on the basis of the inclusion and exclusion criteria and divided into three groups according to the length of the flushing interval: group 1 (≤30 days, n = 79), group 2 (31-90 days, n = 66), and group 3 (91-120 days, n = 472). The basic characteristics of patients in each group and the incidence of TIVAP-related complications (catheter obstruction, infection, and thrombosis) were analyzed. Results: No significant intergroup differences were observed in age, body mass index (BMI), tumor stage, pathological staging, implantation approach, chemotherapy regimen, duration of treatment, and TIVAP-related blood return rate (P > 0.05). Among patients from all three groups, 11 cases of catheter pump-back without blood and eight cases of TIVAP-related complications such as infection, thrombosis, and catheter obstruction were recorded. However, no significant differences in TIVAP-related complications were observed among the three groups (P > 0.05). Conclusion: Extending the TIVAP flushing interval beyond three months during the non-treatment stage in BC patients is safe and feasible and did not increase the incidence of TIVAP-related complications.

Prevention of alloimmune rejection using XBP1-deleted bone marrow-derived dendritic cells in heart transplantation.

BACKGROUND: Genetically modified dendritic cells (DCs) modulate the alloimmunity of T lymphocytes by regulating antigen presentation. METHODS: We generated mice with specific deletion of the X-box-binding protein 1 (XBP1) allele in bone marrow cells and cultured bone marrow-derived DCs (Xbp1-/- BMDCs) from these animals. We then tested the phenotype of Xbp1-/- BMDCs, evaluated their capability to activate allogeneic T cells and investigated their mechanistic actions. We developed a mouse model of allogeneic heart transplantation in which recipients received PBS, Xbp1-/- BMDCs, a suboptimal dose of cyclosporine A (CsA), or Xbp1-/- BMDCs combined with a suboptimal dose of CsA to evaluate the effects of Xbp1-/- BMDC transfusion on alloimmunity and on the survival of heart allografts. RESULTS: The deletion of XBP1 in BMDCs exploited the IRE1-dependent decay of TAPBP mRNA to reduce the expression of MHC-I on the cell surface, altered the capability of BMDCs to activate CD8+ T cells, and ultimately suppressed CD8+ T-cell-mediated allogeneic rejection. The adoptive transfer of Xbp1-/- BMDCs inhibited CD8+ T-cell-mediated rejection. In addition, XBP1-deficient BMDCs were weak stimulators of allogeneic CD4+ T cells despite expressing high levels of MHC-II and costimulatory molecules on their cell surface. Moreover, the adoptive transfer of Xbp1-/- BMDCs inhibited the production of circulating donor-specific IgG. The combination of Xbp1-/- BMDCs and CsA treatment significantly prolonged the survival of allografts compared to CsA alone. CONCLUSIONS: The deletion of XBP1 induces immunosuppressive BMDCs, and treatment with these immunosuppressive BMDCs prevents alloimmune rejection and improves the outcomes of heart transplantation. This finding provides a promising therapeutic target in combating transplant rejection and expands knowledge of inducing therapeutic DCs.

Single-cell RNA-seq-based proteogenomics identifies glioblastoma-specific transposable elements encoding HLA-I-presented peptides.

We analyze transposable elements (TEs) in glioblastoma (GBM) patients using a proteogenomic pipeline that combines single-cell transcriptomics, bulk RNA sequencing (RNA-seq) samples from tumors and healthy-tissue cohorts, and immunopeptidomic samples. We thus identify 370 human leukocyte antigen (HLA)-I-bound peptides encoded by TEs differentially expressed in GBM. Some of the peptides are encoded by repeat sequences from intact open reading frames (ORFs) present in up to several hundred TEs from recent long interspersed nuclear element (LINE)-1, long terminal repeat (LTR), and SVA subfamilies. Other HLA-I-bound peptides are encoded by single copies of TEs from old subfamilies that are expressed recurrently in GBM tumors and not expressed, or very infrequently and at low levels, in healthy tissues (including brain). These peptide-coding, GBM-specific, highly recurrent TEs represent potential tumor-specific targets for cancer immunotherapies.

Locally secreted BiTEs complement CAR T cells by enhancing killing of antigen heterogeneous solid tumors.

Bispecific T cell engagers (BiTEs) are bispecific antibodies that redirect T cells to target antigen-expressing tumors. We hypothesized that BiTE-secreting T cells could be a valuable therapy in solid tumors, with distinct properties in mono- or multi-valent strategies incorporating chimeric antigen receptor (CAR) T cells. Glioblastomas represent a good model for solid tumor heterogeneity, representing a significant therapeutic challenge. We detected expression of tumor-associated epidermal growth factor receptor (EGFR), EGFR variant III, and interleukin-13 receptor alpha 2 (IL13Rα2) on glioma tissues and cancer stem cells. These antigens formed the basis of a multivalent approach, using a conformation-specific tumor-related EGFR targeting antibody (806) and Hu08, an IL13Rα2-targeting antibody, as the single chain variable fragments to generate new BiTE molecules. Compared with CAR T cells, BiTE T cells demonstrated prominent activation, cytokine production, and cytotoxicity in response to target-positive gliomas. Superior response activity was also demonstrated in BiTE-secreting bivalent T cells compared with bivalent CAR T cells in a glioma mouse model at early phase, but not in the long term. In summary, BiTEs secreted by mono- or multi-valent T cells have potent anti-tumor activity in vitro and in vivo with significant sensitivity and specificity, demonstrating a promising strategy in solid tumor therapy.

Immunologic Features in De Novo and Recurrent Glioblastoma Are Associated with Survival Outcomes.

Glioblastoma (GBM) is an immunologically "cold" tumor characterized by poor responsiveness to immunotherapy. Standard of care for GBM is surgical resection followed by chemoradiotherapy and maintenance chemotherapy. However, tumor recurrence is the norm, and recurring tumors are found frequently to have acquired molecular changes (e.g., mutations) that may influence their immunobiology. Here, we compared the immune contexture of de novo GBM and recurrent GBM (rGBM) using high-dimensional cytometry and multiplex IHC. Although myeloid and T cells were similarly abundant in de novo and rGBM, their spatial organization within tumors differed and was linked to outcomes. In rGBM, T cells were enriched and activated in perivascular regions and clustered with activated macrophages and fewer regulatory T cells. Moreover, a higher expression of phosphorylated STAT1 by T cells in these regions at recurrence was associated with a favorable prognosis. Together, our data identify differences in the immunobiology of de novo GBM and rGBM and identify perivascular T cells as potential therapeutic targets. See related Spotlight by Bayik et al., p. 787.

Ferroptosis in hematological malignancies and its potential network with abnormal tumor metabolism.

Ferroptosis, a new type of regulated cell death, displays characteristics that transparently differ from apoptosis, autophagy and necroptosis. There is growing appreciation that targeting ferroptosis is potentially a novel strategy in anti-tumor therapy, especially for invasive malignancies demonstrating resistance to chemotherapy. Almost all types of cancer cells depend on abnormal metabolic activities to participate in vicious progression, giving the possibility to interfere with underlying metabolic preferences and compromise malignant cells by inducing ferroptosis. In this perspective, we give an overview of potential interactions between ferroptosis and abnormal tumor metabolism, with special focus on systematic researches in hematological malignancies.

A nomogram for predicting the risk of postoperative recurrence of hepatitis B virus-related hepatocellular carcinoma in patients with high preoperative serum glutamyl transpeptidase.

Background: Recurrence is a major risk factor affecting the postoperative survival of patients with hepatocellular carcinoma (HCC), especially those with high preoperative serum γ-glutamyl transpeptidase (GGT) levels. This study had the aim of developing a personalized predictive tool to accurately determine the risk of postoperative recurrence of hepatitis B-virus (HBV)-related HCC in patients with high preoperative serum GGT levels. Methods: Patients who underwent curative liver resection of HBV-related HCC and had high preoperative GGT levels were consecutively enrolled between 2008 and 2011. Prognostic indicators for recurrence were determined using Cox regression analysis. A nomogram was then developed and assessed by integrating the independent risk factors into the model. Results: A total of 603 eligible patients were included. The final nomogram for predicting HCC recurrence in patients with high preoperative GGT levels consisted of five independent prognostic factors: α-fetoprotein (AFP), HBV-DNA, satellite nodules, microvascular invasion, and tumor grade. The C-index of the nomogram for predicting recurrence was 0.759, and validation showed high accuracy and discriminatory. Conclusions: The predictive nomogram developed and validated in this study performs well in predicting postoperative recurrence of HBV-related HCC in patients with high preoperative GGT levels. It can provide personalized assessments to inform the development of surveillance strategies and allows patients with a high risk of recurrence to be selected for further adjuvant treatment.

FTO promotes multiple myeloma progression by posttranscriptional activation of HSF1 in an m6A-YTHDF2-dependent manner.

N6-methyladenosine (m6A), as the most pervasive internal modification of eukaryotic mRNA, plays a crucial role in various cancers, but its role in multiple myeloma (MM) pathogenesis has not yet been investigated. In this study, we revealed significantly decreased m6A methylation in plasma cells (PCs) from MM patients and showed that the abnormal m6A level resulted mainly from upregulation of the demethylase fat mass and obesity-associated protein (FTO). Gain- and loss-of-function studies demonstrated that FTO plays a tumor-promoting and pro-metastatic role in MM. Combined m6A and RNA sequencing (RNA-seq) and subsequent validation and functional studies identified heat shock factor 1 (HSF1) as a functional target of FTO-mediated m6A modification. FTO significantly promotes MM cell proliferation, migration, and invasion by targeting HSF1/HSPs in a YTHDF2-dependent manner. FTO inhibition, especially when combined with bortezomib (BTZ) treatment, synergistically inhibited myeloma bone tumor formation and extramedullary spread in NOD-Prkdcem26Cd52il2rgem26Cd22/Nju (NCG) mice. We demonstrated the functional importance of m6A demethylase FTO in MM progression, especially in promoting extramedullary myeloma (EMM) formation, and proposed the FTO-HSF1/HSP axis as a potential novel therapeutic target in MM.

High-Affinity Chimeric Antigen Receptor With Cross-Reactive scFv to Clinically Relevant EGFR Oncogenic Isoforms.

Tumor heterogeneity is a key reason for therapeutic failure and tumor recurrence in glioblastoma (GBM). Our chimeric antigen receptor (CAR) T cell (2173 CAR T cells) clinical trial (NCT02209376) against epidermal growth factor receptor (EGFR) variant III (EGFRvIII) demonstrated successful trafficking of T cells across the blood-brain barrier into GBM active tumor sites. However, CAR T cell infiltration was associated only with a selective loss of EGFRvIII+ tumor, demonstrating little to no effect on EGFRvIII- tumor cells. Post-CAR T-treated tumor specimens showed continued presence of EGFR amplification and oncogenic EGFR extracellular domain (ECD) missense mutations, despite loss of EGFRvIII. To address tumor escape, we generated an EGFR-specific CAR by fusing monoclonal antibody (mAb) 806 to a 4-1BB co-stimulatory domain. The resulting construct was compared to 2173 CAR T cells in GBM, using in vitro and in vivo models. 806 CAR T cells specifically lysed tumor cells and secreted cytokines in response to amplified EGFR, EGFRvIII, and EGFR-ECD mutations in U87MG cells, GBM neurosphere-derived cell lines, and patient-derived GBM organoids. 806 CAR T cells did not lyse fetal brain astrocytes or primary keratinocytes to a significant degree. They also exhibited superior antitumor activity in vivo when compared to 2173 CAR T cells. The broad specificity of 806 CAR T cells to EGFR alterations gives us the potential to target multiple clones within a tumor and reduce opportunities for tumor escape via antigen loss.

Methyl eugenol attenuates liver ischemia reperfusion injury via activating PI3K/Akt signaling.

BACKGROUND: Liver ischemia reperfusion injury (LIRI) often occurs during liver transplantation, resection, and various circulatory shock procedures, leading to severe metabolic disorders, inflammatory immune responses, oxidative stress injury, and cell apoptosis. Methyl eugenol (ME) is structurally similar to eugenol and has anti-inflammatory and apoptotic pharmacological effects. However, whether ME protects the liver from LIRI damage requires further investigation. METHODS: We established a partially warm LIRI model by subjecting C57BL/6J mice to 60 min of ischemia, followed by reperfusion for 6 h. We also established a hypoxia-reoxygenation injury (H/R) cell model by subjecting AML12 (a mouse liver cell line) cells to 24 h hypoxia, followed by 18 h normoxia. The extent of liver injury was assessed by serum transaminase concentrations, hematoxylin and eosin staining, quantitative real-time PCR, myeloperoxidase activity, and TUNEL analysis. Apoptosis was detected using flow cytometry. The protein levels of p-PI3K, PI3K, p-Akt, Akt, p-Bad, Bad, Bcl-2, Bax, and cleaved caspase-3 were detected by western blotting. LY294002, an inhibitor of PI3K/Akt signaling, was used to elucidate the relationship between ME and PI3K/Akt signaling. RESULTS: ME successfully alleviated LIRI-induced liver injury, inflammatory response, and apoptosis induced, as well as liver cell injury induced by hypoxia reoxygenation. ME is known to activate the PI3K/Akt signaling pathway in hepatocyte injury in vivo and in vitro, and when this signaling pathway is inhibited, the protective effect of ME is abrogated. CONCLUSIONS: The use of ME is a potential therapeutic approach for regulating LIRI by activating PI3K/Akt signaling.

A Novel End-To-End Feature Selection and Diagnosis Method for Rotating Machinery.

Feature selection is to obtain effective features from data, also known as feature engineering. Traditional feature selection and predictive model learning are separated, and there is a problem of inconsistency of criteria. This paper presents an end-to-end feature selection and diagnosis method that organically unifies feature expression learning and machine prediction learning into one model. The algorithm first combines the prediction model to calculate the mean impact value (MIVs) of the feature and realizes primary feature selection for the prediction model by selecting the feature with a larger MIV. In order to take into account the performance of the feature itself, the within-class and between-class discriminant analysis (WBDA) method is proposed, and combined with the feature diversity strategy, the feature-oriented secondary selection is realized. Eventually, feature vectors obtained by two selections are classified using a multi-class support vector machine (SVM). Compared with the modified network variable selection algorithm (MIVs), the principal component analysis dimensionality reduction algorithm (PCA), variable selection based on compensative distance evaluation technology (CDET), and other algorithms, the proposed method MIVs-WBDA exhibits excellent classification accuracy owing to the fusion of feature selection and predictive model learning. According to the results of classification accuracy testing after dimensionality reduction on rotating machinery status, the MIVs-WBDA method has a 3% classification accuracy improvement under the low-dimensional feature set. The typical running time of this classification learning algorithm is less than 10 s, while using deep learning, its running time will be more than a few hours.

Neurofilament Light Chain Related to Longitudinal Decline in Frontotemporal Lobar Degeneration.

OBJECTIVE: Accurate diagnosis and prognosis of frontotemporal lobar degeneration (FTLD) during life is an urgent concern in the context of emerging disease-modifying treatment trials. Few CSF markers have been validated longitudinally in patients with known pathology, and we hypothesized that CSF neurofilament light chain (NfL) would be associated with longitudinal cognitive decline in patients with known FTLD-TAR DNA binding protein ~43kD (TDP) pathology. METHODS: This case-control study evaluated CSF NfL, total tau, phosphorylated tau, and ß-amyloid1-42 in patients with known FTLD-tau or FTLD-TDP pathology (n = 50) and healthy controls (n = 65) and an extended cohort of clinically diagnosed patients with likely FTLD-tau or FTLD-TDP (n = 148). Regression analyses related CSF analytes to longitudinal cognitive decline (follow-up ∼1 year), controlling for demographic variables and core AD CSF analytes. RESULTS: In FTLD-TDP with known pathology, CSF NfL is significantly elevated compared with controls and significantly associated with longitudinal decline on specific executive and language measures, after controlling for age, disease duration, and core AD CSF analytes. Similar findings are found in the extended cohort, also including clinically identified likely FTLD-TDP. Although CSF NfL is elevated in FTLD-tau compared with controls, the association between NfL and longitudinal cognitive decline is limited to executive measures. CONCLUSION: CSF NfL is associated with longitudinal clinical decline in relevant cognitive domains in patients with FTLD-TDP after controlling for demographic factors and core AD CSF analytes and may also be related to longitudinal decline in executive functioning in FTLD-tau.