Differentiation of Type 17 Mucosal-Associated Invariant T Cells in Circulation Contributes to the Severity of Sepsis.

Mucosal-associated invariant T (MAIT) cells are essential in defending against infection. Sepsis is a systemic inflammatory response to infection and a leading cause of death. The relationship between the overall competency of the host immune response and disease severity is not fully elucidated. This study identified a higher proportion of circulating MAIT17 with expression of IL-17A and retinoic acid receptor-related orphan receptor γt in patients with sepsis. The proportion of MAIT17 was correlated with the severity of sepsis. Single-cell RNA-sequencing analysis revealed an enhanced expression of lactate dehydrogenase A (LDHA) in MAIT17 in patients with sepsis. Cell-culture experiments demonstrated that phosphoinositide 3-kinase-LDHA signaling was required for retinoic acid receptor-related orphan receptor γt expression in MAIT17. Finally, the elevated levels of plasma IL-18 promoted the differentiation of circulating MAIT17 cells in sepsis. In summary, this study reveals a new role of circulating MAIT17 in promoting sepsis severity and suggests the phosphoinositide 3-kinase-LDHA signaling as a driving force in MAIT17 responses.

Conductance Evolution of Photoisomeric Single-Molecule Junctions under Ultraviolet Irradiation and Mechanical Stretching.

A comprehensive understanding of carrier transport in photoisomeric molecular junctions is crucial for the rational design and delicate fabrication of single-molecule functional devices. It has been widely recognized that the conductance of azobenzene (a class of photoisomeric molecules) based molecular junctions is mainly determined by photoinduced conformational changes. In this study, it is demonstrated that the most probable conductance of amine-anchored azobenzene-based molecular junctions increases continuously upon UV irradiation. In contrast, the conductance of pyridyl-anchored molecular junctions with an identical azobenzene core exhibits a contrasting trend, highlighting the pivotal role that anchoring groups play, potentially overriding (even reversing) the effects of photoinduced conformational changes. It is further demonstrated that the molecule with cis-conformation cannot be fully mechanically stretched into the trans-conformation, clarifying that it is a great challenge to realize a reversible molecular switch by purely mechanical operation. Additionally, it is revealed that the coupling strength of pyridyl-anchored molecules is dramatically weakened when the UV irradiation time is prolonged, whereas it is not observed for amine-anchored molecules. The mechanisms for these observations are elucidated with the assistance of density functional theory calculations and UV-Vis spectra combined with flicker noise measurements which confirm the photoinduced conformational changes, providing insight into understanding the charge transport in photoisomeric molecular junctions and offering a routine for logical designing synchro opto-mechanical molecular switches.

Targeting OXCT1-mediated ketone metabolism reprograms macrophages to promote antitumor immunity via CD8+ T cells in hepatocellular carcinoma.

BACKGROUND & AIMS: The liver is the main organ of ketogenesis, while ketones are mainly metabolized in peripheral tissues via the critical enzyme OXCT1. We previously found that ketolysis is reactivated in hepatocellular carcinoma (HCC) cells through OXCT1 expression to promote tumor progression; however, whether OXCT1 regulates antitumor immunity remains unclear. METHODS: To investigate the expression pattern of OXCT1 in hepatocellular carcinoma in vivo, we conducted multiplex immunohistochemistry (mIHC) experiments on human HCC specimens. To explore the role of OXCT1 in mouse hepatocellular carcinoma tumor-associated macrophages (TAMs), we generated LysMcreOXCT1f/f (OXCT1 conditional knockout in macrophages) mice. RESULTS: Here, we found that inhibiting OXCT1 expression in tumor-associated macrophages reduced CD8+ T-cell exhaustion through the succinate-H3K4me3-Arg1 axis. Initially, we found that OXCT1 was highly expressed in liver macrophages under steady state and that OXCT expression was further increased in TAMs. OXCT1 deficiency in macrophages suppressed tumor growth by reprogramming TAMs toward an antitumor phenotype, reducing CD8+ T-cell exhaustion and increasing CD8+ T-cell cytotoxicity. Mechanistically, high OXCT1 expression induced the accumulation of succinate, a byproduct of ketolysis, in TAMs, which promoted Arg1 transcription by increasing the H3K4 trimethylation (H3K4me3) level in the Arg1 promoter. In addition, Pimozide, an inhibitor of OXCT1, suppressed Arg1 expression as well as TAM polarization toward the protumor phenotype, leading to decreasing CD8+ T-cell exhaustion and deceleration of tumor growth. Finally, high expression of OXCT1 in macrophages was positively associated with poor survival in HCC patients. CONCLUSIONS: In conclusion, our results demonstrate that OXCT1 epigenetically suppresses antitumor immunity, suggesting that suppressing OXCT1 activity in TAMs is an effective approach for treating liver cancer. IMPACT AND IMPLICATIONS: The intricate metabolism of liver macrophages plays a critical role in shaping HCC progression and immune modulation. Targeting macrophage metabolism to counteract immune suppression presents a promising avenue for HCC. Here, we found that ketogenesis gene OXCT1 was highly expressed in tumor-associated macrophages and promoted tumor growth by reprogramming TAMs toward a protumor phenotype. And the strategic pharmacological intervention or genetic downregulation of OXCT1 in TAMs enhances the antitumor immunity and decelerated tumor growth. Our results suggest that suppressing OXCT1 activity in TAMs is an effective approach for treating liver cancer.

Spontaneous development of an autoimmune hepatitis - primary biliary cholangitis overlap syndrome in dnTGFßRII Aire-/- mice.

Autoimmune regulator (Aire) and TGF-ß signaling play important roles in central tolerance and peripheral tolerance, respectively, by eliminating or suppressing the activity of autoreactive T cells. We previously demonstrated that dnTGFßRII mice develop a defect in peripheral tolerance and a primary biliary cholangitis (PBC)-like disease. We hypothesized that by introducing the Aire gene to this model, we would observe a more severe PBC phenotype. Interestingly, however, we demonstrated that, while dnTGFßRII Aire-/- mice do manifest key histological and serological features of autoimmune cholangitis, they also develop mild to moderate interface hepatitis and show high levels of alanine transaminase (ALT) and antinuclear antibodies (ANA), characteristics of autoimmune hepatitis (AIH). To further understand this unique phenotype, we performed RNA sequencing (RNA-seq) and flow cytometry to explore the functional pathways and immune cell pathways in the liver of dnTGFßRII Aire-/- mice. Our data revealed enrichments of programmed cell death pathways and predominant CD8+ T cell infiltrates. Depleting CD8+ T cells using an anti-CD8α antibody significantly alleviated hepatic inflammation and prolonged the life span of these mice. Finally, RNA-seq data indicated the clonal expansion of hepatic CD8+ T cells. In conclusion, these mice developed an autoreactive CD8+ T-cell-mediated autoimmune cholangitis with concurrent hepatitis that exhibited key histological and serological features of the AIH-PBC overlap syndrome, representing a novel model for the study of tolerance and autoimmune liver disease. © 2023 The Pathological Society of Great Britain and Ireland.

Effects of anesthetic depth on perioperative T lymphocyte subsets in patients undergoing laparoscopic colorectal cancer surgery: a prospective, parallel-controlled randomized trial.

BACKGROUND: During the perioperative period, the surgical stress response induced by surgical trauma tends to cause a decrease in peripheral lymphocytes. Anesthetics could reduce the stress response during surgery and prevent sympathetic nerve overexcitation. The goal of this study was to investigate how BIS-guided anesthetic depth affected peripheral T lymphocytes in patients undergoing laparoscopic colorectal cancer surgery. METHODS: A total of 60 patients having elective laparoscopic colorectal cancer surgery were randomly assigned and analyzed (n = 30 for deep general anesthesia, BIS 35, n = 30 for light general anesthesia, BIS 55). Blood samples were collected immediately before anesthesia induction and immediately after operation, 24 h and 5 days postoperatively. The CD4+/CD8 + ratio, T lymphocyte subsets (including CD3 + T cells, CD4 + T cells, and CD8 + T cells), and natural killer (NK) cells were analyzed by flow cytometry. Serum interleukin-6 (IL-6), interferon -É£ (IFN-É£), and vascular endothelial growth factor-α (VEGF-α) were also measured. RESULTS: The CD4+/CD8 + ratio decreased 24 h after surgery in two groups, but the reduction did not differ between the two groups (P > 0.05). The concentration of IL-6 and the numerical rating scale (NRS) score in the BIS 55 group were significantly higher than that in the BIS 35 group 24 h after surgery (P = 0.001). There were no intergroup differences in CD3 + T cells, CD4 + T cells, CD8 + T cells, NK cells, VEGF-α, or the IFN-É£. Statistical analyses showed no differences between the two groups in the incidence of fever and surgical site infection during hospitalization. CONCLUSIONS: Despite the fact that patients in deep general anesthesia group had low levels of the IL-6 24 h after surgery, the deep general anesthesia was not associated to a positive effect on patients' peripheral T lymphocytes during colorectal cancer surgery. We found no evidence that peripheral T lymphocyte subsets and natural killer cells were affected by the targeting a BIS of either 55 or 35 in patients undergoing laparoscopic colorectal cancer surgery in this trial. TRIAL REGISTRATION: ChiCTR2200056624 ( www.chictr.org.cn ).

Gene co-expression network based on part mutual information for gene-to-gene relationship and gene-cancer correlation analysis.

BACKGROUND: Finding correlation patterns is an important goal of analyzing biological data. Currently available methods for correlation analysis mainly use non-direct associations, such as the Pearson correlation coefficient, and focus on the interpretation of networks at the level of modules. For biological objects such as genes, their collective function depends on pairwise gene-to-gene interactions. However, a large amount of redundant results from module level methods often necessitate further detailed analysis of gene interactions. New approaches of measuring direct associations among variables, such as the part mutual information (PMI), may help us better interpret the correlation pattern of biological data at the level of variable pairs. RESULTS: We use PMI to calculate gene co-expression networks of cancer mRNA transcriptome data. Our results show that the PMI-based networks with fewer edges could represent the correlation pattern and are robust across biological conditions. The PMI-based networks recall significantly more important parts of omics defined gene-pair relationships than the Pearson Correlation Coefficient (PCC)-based networks. Based on the scores derived from PMI-recalled copy number variation or DNA methylation gene-pairs, the patients with cancer can be divided into groups with significant differences on disease specific survival. CONCLUSIONS: PMI, measuring direct associations between variables, extracts more important biological relationships at the level of gene pairs than conventional indirect association measures do. It can be used to refine module level results from other correlation methods. Particularly, PMI is beneficial to analysis of biological data of the complicated systems, for example, cancer transcriptome data.

Involvement of TIGIT in Natural Killer Cell Exhaustion and Immune Escape in Patients and Mouse Model With Liver Echinococcus multilocularis Infection.

BACKGROUND AND AIMS: Alveolar echinococcosis (AE) is a lethal helminthic liver disease caused by persistent infection with Echinococcus multilocularis. Although more attention has been paid to the immunotolerance of T cells caused by E. multilocularis infection, the role of natural killer (NK) cell, a critical player in liver immunity, is seldom studied. APPROACH AND RESULTS: Here, we observed that NK cells from the blood and closed liver tissue (CLT) of AE patients expressed a higher level of inhibitory receptor TIGIT and were functionally exhausted with a lower expression of granzyme B, perforin, interferon-gamma (IFN-γ), and TNF-α. Addition of anti-TIGIT (T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain) monoclonal antibody into AE patients' peripheral blood mononuclear cell culture significantly enhanced the synthesis of IFN-γ and TNF-α by NK cells, indicating the reversion of exhausted NK cells by TIGIT blockade. In the mouse model of E. multilocularis infection, liver and splenic TIGIT+ NK cells progressively increased dependent of infection dosage and timing and were less activated and less degranulated with lower cytokine secretion. Furthermore, TIGIT deficiency or blockade in vivo inhibited liver metacestode growth, reduced liver injury, and increased the level of IFN-γ produced by liver NK cells. Interestingly, NK cells from mice with persistent chronic infection expressed a higher level of TIGIT compared to self-healing mice. To look further into the mechanisms, more regulatory CD56bright and murine CD49a+ NK cells with higher TIGIT expression existed in livers of AE patients and mice infected with E. multilocularis, respectively. They coexpressed higher surface programmed death ligand 1 and secreted more IL-10, two strong inducers to mediate the functional exhaustion of NK cells. CONCLUSIONS: Our results indicate that inhibitory receptor TIGIT is involved in NK cell exhaustion and immune escape from E. multilocularis infection.

The Clinical Significance of Hepatic CD69+ CD103+ CD8+ Resident-Memory T Cells in Autoimmune Hepatitis.

BACKGROUND AND AIMS: The diverse inflammatory response found in the liver of patients with autoimmune hepatitis (AIH) is well established, but identification of potentially pathogenic subpopulations has proven enigmatic. APPROACH AND RESULTS: We report herein that CD69+ CD103+ CD8+ tissue-resident memory T cells (TRM ) are significantly increased in the liver of patients with AIH compared to chronic hepatitis B, NAFLD, and healthy control tissues. In addition, there was a significant statistical correlation between elevation of CD8+ TRM cells and AIH disease severity. Indeed, in patients with successful responses to immunosuppression, the frequencies of such hepatic CD8+ TRM cells decreased significantly. CD69+ CD8+ and CD69+ CD103+ CD8+ T cells, also known as CD8+ TRM cells, reflect tissue residency and are well known to provide intense immune antigenic responses. Hence, it was particularly interesting that patients with AIH also manifest an elevated expression of IL-15 and TGF-ß on inflammatory cells, and extensive hepatic expression of E-cadherin; these factors likely contribute to the development and localization of CD8+ TRM cells. Based on these data and, in particular, the relationships between disease severity and CD8+ TRM cells, we studied the mechanisms involved with glucocorticoid (GC) modulation of CD8+ TRM cell expansion. Our data reflect that GCs in vitro inhibit the expansion of CD8+ TRM cells induced by IL-15 and TGF-ß and with direct down-regulation of the nuclear factor Blimp1 of CD8+ TRM cells. CONCLUSIONS: Our data suggest that CD8+ TRM cells play a critical role in the pathogenesis of AIH, and GCs attenuate hepatic inflammation through direct inhibition of CD8+ TRM cell expansion.

Notch signaling mutations increase intra-tumor chemokine expression and predict response to immunotherapy in colorectal cancer.

BACKGROUND: The Notch signaling mutation is associated with enhanced anti-tumor immune response in colorectal cancer (CRC). In this study, we aim to investigate the underlying mechanism and the predictive potential of Notch signaling mutation for responding to immunotherapy in CRC. METHODS: We analyzed the immune response associated genes in CRC with Notch signaling mutation concomitant with or without microsatellite instability (MSI) using TCGA dataset and investigated the mutation profiles of the Notch signaling pathway using cBioPortal. The Notch signaling scores and immune cell infiltration scores in different groups were calculated. We applied the Kaplan-Meier method for survival analysis in CRC patients who underwent immunotherapy, and the log-rank test to determine the statistically significant differences in survival. Notch1-knock-down cell line was constructed to detect the pathway and gene variations. RESULTS: We found that Notch signaling pathway mutation was associated with activated immune response, especially in those with MSI. Such association is useful for predicting a prolonged overall survival of CRC patients who underwent immune checkpoint inhibitor treatment. The mutation resulted in the functional loss of Notch signaling and may modulate the tumor immune microenvironment by increasing the expression of chemokines that are important for recruiting immune cells. CONCLUSIONS: The Notch signaling mutation can modulate the chemotaxis of immune cells by upregulating the chemokine levels of the tumor immune microenvironment, and CRC patients with Notch signaling pathway mutation have better overall survival after immune checkpoint inhibitor treatment.

OMIP 071: A 31-Parameter Flow Cytometry Panel for In-Depth Immunophenotyping of Human T-Cell Subsets Using Surface Markers.

Dissecting the functional diversity of T cells is critical in elucidating mechanisms and in developing therapies for various diseases. Here, we designed a 31-parameter (29-color) panel to enable the characterization of T-cell subsets and immunophenotyping of the human peripheral blood and lymph nodes using cell surface staining. In addition to adaptive T-cell markers, TCR Vα24-Jα18, TCR γδ, TCR Vɑ7.2, and CD161 were included to identify iNKT, γδ T, and MAIT cells, respectively, which are innate-like T cells. C-X-C chemokine receptors (CXCR3, CXCR4, CXCR5, CXCR6) and C-C motif chemokine receptors (CCR4, CCR6, CCR7) were included to enable the identification of Th cell subsets (Th1, Th2, Th17), Tfh cell subsets (Tfh1, Tfh2, Tfh17), and Th cells with specific homing capacities. Furthermore, in this panel, we also used markers for assessing cell differentiation (CD45RO, CD7), activation (CD57, CD95, HLA-DR) and the expression of some cosignaling molecules (PD-1, NKG2D, CD28). Particularly, CD69 and CD103 were included for the further analysis of tissue resident memory T (Trm) cells. This panel would enable the in-depth immunophenotyping of human T-cell subsets, and may be applied in the monitoring, prognosis, and mechanistic studies of various immune-related diseases.

Immune Exhaustion of T Cells in Alveolar Echinococcosis Patients and Its Reversal by Blocking Checkpoint Receptor TIGIT in a Murine Model.

BACKGROUND AND AIMS: The cestode Echinococcus multilocularis infection, a serious health problem worldwide, causes alveolar echinococcosis (AE), a tumor-like disease predominantly located in the liver and able to spread to any organs. Until now, there have been few studies that explore how T-cell exhaustion contributes to the parasite's escape from immune attack and how it might be reversed. APPROACH AND RESULTS: In this study, we found that liver T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) expression was significantly enhanced and positively correlated with lesion activity in AE patients. High TIGIT expression in both liver-infiltrating and blood T cells was associated with their functional exhaustion, and its ligand CD155 was highly expressed by hepatocytes surrounding the infiltrating lymphocytes. In co-culture experiments using human blood T cells and hepatic cell line HL-7702, CD155 induced functional impairment of TIGIT+ T cells, and in vitro blockade with TIGIT antibody restored the function of AE patients' T cells. Similar TIGIT-related functional exhaustion of hepatic T cells and an abundant CD155 expression on hepatocytes were observed in E. multilocularis-infected mice. Importantly, in vivo blocking TIGIT prevented T-cell exhaustion and inhibited disease progression in E. multilocularis-infected mice. Mechanistically, CD4+ T cells were totally and CD8+ T cells partially required for anti-TIGIT-induced regression of parasite growth in mice. CONCLUSIONS: This study demonstrates that E. multilocularis can induce T-cell exhaustion through inhibitory receptor TIGIT, and that blocking this checkpoint may reverse the functional impairment of T cells and represent a possible approach to immunotherapy against AE.

An Improved Voltage Clamp Circuit Suitable for Accurate Measurement of the Conduction Loss of Power Electronic Devices.

Power electronic devices are essential components of high-capacity industrial converters. Accurate assessment of their power loss, including switching loss and conduction loss, is essential to improving electrothermal stability. To accurately calculate the conduction loss, a drain-source voltage clamp circuit is required to measure the on-state voltage. In this paper, the conventional drain-source voltage clamp circuit based on a transistor is comprehensively investigated by theoretical analysis, simulations, and experiments. It is demonstrated that the anti-parallel diodes and the gate-shunt capacitance of the conventional drain-source voltage clamp circuit have adverse impacts on the accuracy and security of the conduction loss measurement. Based on the above analysis, an improved drain-source voltage clamp circuit, derived from the conventional drain-source voltage clamp circuit, is proposed to solve the above problems. The operational advantages, physical structure, and design guidelines of the improved circuit are fully presented. In addition, to evaluate the influence of component parameters on circuit performance, this article comprehensively extracts three electrical quantities as judgment indicators. Based on the working mechanism of the improved circuit and the indicators mentioned above, general mathematical analysis and derivation are carried out to give guidelines for component selection. Finally, extensive experiments and detailed analyses are presented to validate the effectiveness of the proposed drain-source voltage clamp circuit. Compared with the conventional drain-source voltage clamp circuit, the improved drain-source voltage clamp circuit has higher measurement accuracy and working security when measuring conduction loss, and the proposed component selection method is verified to be reasonable and effective for better utilizing the clamp circuit.

Crystal Size Effect on Carrier Transport of Microscale Perovskite Junctions via Soft Contact.

To reduce the size of optoelectronic devices, it is essential to understand the crystal size effect on the carrier transport through microscale materials. Here, we show a soft contact method to probe the properties of irregularly shaped microscale perovskite crystals by employing a movable liquid metal electrode to form a self-adaptative deformable electrode-perovskite-electrode junction. Accordingly, we demonstrate that (1) the photocurrents of perovskite quantum dot films and microplatelets show profound differences regarding both the on/off ratio and the response time upon light illumination; and (2) small-size perovskite (<50 µm) junctions may show negative differential resistance (NDR) behavior, whereas the NDR phenomenon is absent in large-size perovskite junctions within the same bias regime. Our studies provide a method for studying arbitrary-shaped crystals without mechanical damage, assisting the understanding of the photogenerated carriers transport through microscale crystals.

Mutations in the notch signalling pathway are associated with enhanced anti-tumour immunity in colorectal cancer.

The Notch signalling pathway is involved in the development of several cancers, including colorectal cancer (CRC). However, whether mutations in this pathway could alter the CRC immunophenotype remains unknown. Here, we investigated the relationship between Notch signalling pathway mutations and the tumour immune microenvironment by analysing gene expression data from the GSE108989 single T cell RNA sequencing data set and The Cancer Genome Atlas (TCGA) data set. We found that Notch signalling pathway mutations were associated with an increased number of tumour-specific CD8+ T cells and decreased number of inhibitory regulatory T (Treg) cells, representing an enhanced anti-tumour response in the GSE108989 data set. In TCGA data set, we also found that Notch signalling pathway mutations were associated with enrichment of genes associated with immune activation pathways and higher expressions of PDCD1, GZMB and PRF1. Although Notch signalling pathway mutations did not affect the overall survival and disease-free survival of CRC patients, they were associated with earlier disease stages and lower rates of metastasis. These results demonstrated that Notch signalling pathway mutations can enhance anti-tumour immunity in CRC, as validated by the two data sets, suggesting that they may be promising biomarkers for immune checkpoint blockade therapies for CRC patients.

Integrated Rogowski Coil Sensor for Press-Pack Insulated Gate Bipolar Transistor Chips.

Recently, the press-pack insulated gate bipolar transistor (IGBT) has usually been used in direct current (DC) transmission. The press-pack IGBT (PPI) adopts a parallel layout of boss chips, and the currents of each chip will be uneven in the process of turning on and off, which will affect the reliability of the device. To measure the currents of each chip, based on the analysis of the principle and equivalent model of the Rogowski coil, this paper puts forward the design scheme and design index of multi-layer printed circuit board (PCB) Rogowski coil with good high-frequency performance, strong anti-interference ability and sufficient sensitivity. With the simulation analysis of Altium Designer and ANSYS softwares, a 1 mm thick, 76-turn integrated four-layer PCB Rogowski coil is designed. Then, adding a composite integrator, an integrated Rogowski coil sensor for measurement of PPI chips currents is designed. The Pspice simulation and the experiment results show that the sensor is fully satisfied with the chip current measurement.

Transesophageal Echocardiographic Measurements of the Superior Vena Cava for Predicting Fluid Responsiveness in Patients Undergoing Invasive Positive Pressure Ventilation.

OBJECTIVES: Preoperative fasting, water deprivation, and intraoperative fluid loss and redistribution result in hypovolemia in patients undergoing surgery. Some findings have indicated that the superior vena cava (SVC) diameter and variation, as determined by transesophageal echocardiography during surgery, do not reflect central venous pressure effectively. This study aimed to compare and correlate the SVC diameter and variation with the stroke volume variation for predicting fluid responsiveness in patients undergoing invasive positive pressure ventilation. METHODS: Thirty-six patients scheduled for elective gastrointestinal surgery under general anesthesia with invasive positive pressure ventilation were included in this study. After anesthesia induction, the stroke volume variation, SVC diameter, mean arterial pressure, central venous pressure, and pulse were recorded, and measurements after fluid challenge were recorded as well. The SVC variation was calculated before and after the fluid challenge. RESULTS: After the fluid challenge, the SVC diameter markedly increased, whereas the SVC variation and stroke volume variation significantly decreased (P < .05). The optimal cutoff value for the SVC variation was 21.1%, and the area under the curve (AUC) from a receiver operating characteristic curve analysis was 0.849. The optimal cutoff value for the minimal SVC diameter was 1.135 cm, and that AUC was 0.929. In addition, the optimal cutoff value for the maximal SVC diameter was 1.480 cm, and the AUC was 0.862. CONCLUSIONS: The minimal SVC diameter may be an effective indicator for predicting fluid responsiveness in patients undergoing invasive positive pressure ventilation.

Research on Small Square PCB Rogowski Coil Measuring Transient Current in the Power Electronics Devices.

With the development of China's electric power, power electronics devices such as insulated-gate bipolar transistors (IGBTs) have been widely used in the field of high voltages and large currents. However, the currents in these power electronic devices are transient. For example, the uneven currents and internal chip currents overshoot, which may occur when turning on and off, and could have a great impact on the device. In order to study the reliability of these power electronics devices, this paper proposes a miniature printed circuit board (PCB) Rogowski coil that measures the current of these power electronics devices without changing their internal structures, which provides a reference for the subsequent reliability of their designs.

Gut microbiota translocation promotes autoimmune cholangitis.

Gut microbiota and bacterial translocation have been implicated as significant contributors to mucosal immune responses and tolerance; alteration of microbial molecules, termed pathogen-associated molecular patterns (PAMP) and bacterial translocation are associated with immune pathology. However, the mechanisms by which dysregulated gut microbiota promotes autoimmunity is unclear. We have taken advantage of a well-characterized murine model of primary biliary cholangitis, dnTGFßRII mice, and an additional unique construct, toll-like receptor 2 (TLR2)-deficient dnTGFßRII mice coined dnTGFßRIITLR2-/- mice to investigate the influences of gut microbiota on autoimmune cholangitis. Firstly, we report that dnTGFßRII mice manifest altered composition of gut microbiota and that alteration of this gut microbiota by administration of antibiotics significantly alleviates T-cell-mediated infiltration and bile duct damage. Second, toll-like receptor 2 (TLR2)-deficient dnTGFßRII mice demonstrate significant exacerbation of autoimmune cholangitis when their epithelial barrier integrity was disrupted. Further, TLR2-deficiency mediates downregulated expression of tight junction-associated protein ZO-1 leading to increased gut permeability and bacterial translocation from gut to liver; use of antibiotics reduces microbiota translocation to liver and also decreases biliary pathology. In conclusion, our data demonstrates the important role of gut microbiota and bacterial translocation in the pathogenesis of murine autoimmune cholangitis.

Effect of Single Intra-cutaneous Injection for Acute Thoracic Herpes Zoster and Incidence of Postherpetic Neuralgia.

The therapeutic effect of postherpetic neuralgia (PHN) is often disappointing and challenging. The role of intra-cutaneous injection of local anesthetic and steroids in preventing PHN remains unknown. The purpose of this study was to investigate the effect of a single intra-cutaneous injection of ropivacaine plus methylprednisolone on acute thoracic herpes zoster (HZ) pain intensity and duration, eruptive duration, and PHN incidence. A total of 97 patients with acute thoracic HZ diagnosed 1-7 days after the onset of the rash were randomly assigned to receive either 15 mL of 37.5 mg ropivacaine plus 40 mg methylprednisolone (active group, n = 49) or 15 mL of saline (placebo group, n = 48). Over 7 days, all patients received 800 mg of acyclovir 5 times daily and 150 mg pregabalin twice daily. Acetaminophen was used as a rescue analgesia when visual analog scale ≥4. Pain intensity was measured with visual analog scale and the amount of analgesic taken was evaluated at the initial visit and at weeks 1, 4, 12, and 24 after the intra-cutaneous injection. The time of complete resolution of pain, time of healing of skin eruption, and incidence of PHN were reported. The active group displayed a significantly shorter duration of pain (28.4 ±â€¯46.7 vs. 59.2 ±â€¯65.0, respectively; p = .009) and herpetic eruption (22.5 ±â€¯6.8 vs. 32.6 ±â€¯7.6, respectively; p < .001) than the placebo group. A significantly lower incidence of PHN was encountered in the active group after 4 weeks (16.3% vs. 47.9%, respectively; p = .001) and 12 weeks (10.2% vs. 29.2%, respectively; p = .019). Lower incidence of PHN was noticed in the active group after 24 weeks; however, this was not statistically significant (6.1% vs. 18.8%, respectively; p = .059). There was a significant reduction in the average and total doses of pregabalin and acetaminophen in the active group after the injection. No serious side effects were noticed during the study period. Early single intra-cutaneous injection, in combination with antiviral agents and optimal analgesics, in the course of acute thoracic HZ seems to be a simple, well-tolerated, and effective adjuvant treatment modality. It dramatically decreased pain intensity, shortened pain duration, reduced skin eruption, and reduced and may even prevent the development of PHN.

Intracellular Proteolytic Disassembly of Self-Quenched Near-Infrared Nanoparticles Turning Fluorescence on for Tumor-Targeted Imaging.

The design of tumor-targeting, intracellular protease-activatable near-infrared fluorescence (NIRF) nanoprobes is broadly interesting but remains challenging. In this work, we report the rational design of a NIR probe Cys(StBu)-Lys(Biotin)-Lys-Lys(Cy5.5)-CBT (1) to facilely prepare the self-quenched nanoparticles 1-NPs for tumor-targeted imaging in vitro and in vivo. The biotinylated 1-NPs could be actively uptaken by biotin receptor-overexpressing tumor cells via receptor-mediated endocytosis. Upon intracellular proteolytic cleavage, 1-NPs were disassembled to yield the small molecular probe Lys(Cy5.5)-Luciferin-Lys(Biotin)-Lys-OH (1-D-cleaved), accompanied by fluorescence "Turn-On". With this NIRF "Turn-On" property, 1-NPs were successfully applied for tumor-targeted imaging. We envision that our nanoparticles could be applied for fluorescence-guided tumor surgery in the near future.