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Human immunodeficiency virus (HIV) continues to be a significant global health challenge despite decades of research and advances in treatment. Substantial gaps in our understanding of the mechanisms of HIV pathogenesis and the host immune responses still exist. The interaction between HIV and these immune responses is pivotal in the disease progression to acquired immunodeficiency syndrome (AIDS). Recently, the caspase recruitment domain-containing protein 8 (CARD8) inflammasome has emerged as a crucial factor in orchestrating innate immune responses to HIV infection and exerting a substantial impact on viral pathogenesis. CARD8 restricts viral replication by detecting the activity of HIV protease. Conversely, it also contributes to the depletion of CD4+ T cells, a key feature of disease progression towards AIDS. The purpose of this review is to summarize the role of the CARD8 inflammasome in HIV pathogenesis, delving into its mechanisms of action and potential implications for the development of therapeutic strategies.

Permanent magnet synchronous motor (PMSM) speed control systems with conventional linear active disturbance rejection control (CLADRC) strategy encounter issues regarding the coupling between dynamic response and disturbance suppression and have poor performance in suppressing complex nonlinear disturbances. In order to address these issues, this paper proposes an improved two-degree-of-freedom LADRC (TDOF-LADRC) strategy, which can enhance the disturbance rejection performance of the system while decoupling entirely the system's dynamic and anti-disturbance performance to boost the system robustness and simplify controller parameter tuning. PMSM models that consider total disturbances are developed to design the TDOF-LADRC speed controller accurately. Moreover, to evaluate the control performance of the TDOF-LADRC strategy, its stability is proven, and the influence of each controller parameter on the system control performance is analyzed. Based on it, a comparison is made between the disturbance observation ability and anti-disturbance performance of TDOF-LADRC and CLADRC to prove the superiority of TDOF-LADRC in rejecting disturbances. Finally, experiments are performed on a 750 W PMSM experimental platform, and the results demonstrate that the proposed TDOF-LADRC exhibits the properties of two degrees of freedom and improves the disturbance rejection performance of the PMSM system.

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ABSTRACTA critical determinant for early post-entry events, the HIV-1 capsid (CA) protein forms the conical core when it rearranges around the dimeric RNA genome and associated viral proteins. Although mutations in CA have been reported to alter innate immune sensing of HIV-1, a direct link between core stability and sensing of HIV-1 nucleic acids has not been established. Herein, we assessed how manipulating the stability of the CA lattice through chemical and genetic approaches affects innate immune recognition of HIV-1. We found that destabilization of the CA lattice resulted in potent sensing of reverse transcription products when destabilization per se does not completely block reverse transcription. Surprisingly, due to the combined effects of enhanced reverse transcription and defects in nuclear entry, two separate CA mutants that form hyperstable cores induced innate immune sensing more potently than destabilizing CA mutations. At low concentrations that allowed the accumulation of reverse transcription products, CA-targeting compounds GS-CA1 and lenacapavir measurably impacted CA lattice stability in cells and modestly enhanced innate immune sensing of HIV. Interestingly, innate immune activation observed with viruses containing unstable cores was abolished by low doses of lenacapavir. Innate immune activation observed with both hyperstable and unstable CA mutants was dependent on the cGAS-STING DNA-sensing pathway and reverse transcription. Overall, our findings demonstrate that CA lattice stability and reverse transcription are finely balanced to support reverse transcription and minimize cGAS-STING-mediated sensing of the resulting viral DNA.IMPORTANCEIn HIV-1 particles, the dimeric RNA genome and associated viral proteins and enzymes are encased in a proteinaceous lattice composed of the viral capsid protein. Herein, we assessed how altering the stability of this capsid lattice through orthogonal genetic and chemical approaches impacts the induction of innate immune responses. Specifically, we found that decreasing capsid lattice stability results in more potent sensing of viral reverse transcription products, but not the genomic RNA, in a cGAS-STING-dependent manner. The recently developed capsid inhibitors lenacapavir and GS-CA1 enhanced the innate immune sensing of HIV-1. Unexpectedly, due to increased levels of reverse transcription and cytosolic accumulation of the resulting viral cDNA, capsid mutants with hyperstable cores also resulted in the potent induction of type I interferon-mediated innate immunity. Our findings suggest that HIV-1 capsid lattice stability and reverse transcription are finely balanced to minimize exposure of reverse transcription products in the cytosol of host cells.

Abstract Detecting exosomal markers using laser desorption/ionization time‐of‐flight mass spectrometry (LDI‐TOF MS) is a novel approach for examining liquid biopsies of non‐small cell lung cancer (NSCLC) samples. However, LDI‐TOF MS is limited by low sensitivity and poor reproducibility when analyzing intact proteins directly. In this report, gold nanoparticles/cellulose nanocrystals (AuNPs/CNC) is introduced as the matrix for direct analysis of intact proteins in NSCLC serum exosomes. AuNPs/CNC with “dual dispersion” effects dispersed and stabilized AuNPs and improved ion inhibition effects caused by protein aggregation. These features increased the signal‐to‐noise ratio of [M+H]+ peaks by two orders of magnitude and lowered the detection limit of intact proteins to 0.01 mg mL–1. The coefficient of variation with or without AuNPs/CNC is measured as 10.2% and 32.5%, respectively. The excellent reproducibility yielded a linear relationship (y = 15.41x – 7.983, R2 = 0.989) over the protein concentration range of 0.01 to 20 mg mL–1. Finally, AuNPs/CNC‐assisted LDI‐TOF MS provides clinically relevant fingerprint information of exosomal proteins in NSCLC serum, and characteristic proteins S100 calcium‐binding protein A10, Urokinase plasminogen activator surface receptor, Plasma protease C1 inhibitor, Tyrosine‐protein kinase Fgr and Mannose‐binding lectin associated serine protease 2 represented excellent predictive biomarkers of NSCLC risk.

Abstract The innate immune stimulator of interferon genes (STING) pathway is known to activate type I interferons (IFN-I) and participate in generating antitumor immunity. We previously produced hDT806, a recombinant diphtheria immunotoxin, and demonstrated its efficacy against head and neck squamous cell carcinoma (HNSCC). However, it’s unknown whether the tumor-intrinsic STING plays a role in the anti-HNSCC effects of hDT806. In this study, we investigated the innate immune modulation of hDT806 on HNSCC. hDT806 significantly upregulated the level of STING and the ratio of p-TBK1/TBK1 in the HNSCC cells. Moreover, intratumoral hDT806 treatment increased the expression of STING-IFN-I signaling proteins including IFNA1, IFNB, CXCL10 and MX1, a marker of IFN-I receptor activity, in the HNSCC xenografts. Overexpression of STING mimicked the hDT806-induced upregulation of the STING-IFN-I signaling and induced apoptosis in the HNSCC cells. In the mouse xenograft models of HNSCC with STING overexpression, we observed a significant suppression of tumor growth and reduced tumor weight with increased apoptosis compared to their control xenograft counterparts without STING overexpression. Collectively, our data revealed that hDT806 may act as a stimulator of tumor-intrinsic STING-IFN-I signaling to inhibit tumor growth in HNSCC.

Hepatocellular carcinoma (HCC) mostly occurs in the background of liver fibrosis, and activated hepatic stellate cells (HSCs) exist in HCC tissues and adjacent tissues. HSC activation is involved throughout the development of HCC precancerous lesions, which has gradually attracted the attention of related researchers. In addition, HCC can promote the activation of HSCs, which in turn accelerates the occurrence and development of HCC by promoting tumor angiogenesis. In this review, we reviewed 264 studies from PubMed and ScienceDirect to summarize and analyze current significant fibrotic signaling in HCC. As a result, we found 10 fibrotic signaling pathways that are closely related to the activation, proliferation, invasion, migration, and promotion of apoptosis of HCC cells. In addition, we found that crosstalk between various fibrotic signaling pathways of HCC, hypoxia-induced energy metabolic reprogramming of HCC cells, matrix stiffness and stemness of HCC cells, and ferroptosis of HCC cells and HSCs are the latest research hotspots. Furthermore, related drugs that have been found to target these 10 fibrotic signaling pathways of HCC are listed. Our study provides a new reference for developing anti-HCC drugs.

Abstract. Innate immune responses are the host's first line of defense against human immunodeficiency virus type 1 (HIV-1) infection, with pattern recognition receptors detecting viral specific pathogen-associated molecular patterns and initiating antiviral responses. In response to HIV-1 nucleic acids or proteins, some pattern recognition receptors have the ability to assemble a large multiprotein complex called the inflammasome, which triggers pro-inflammatory cytokine release and a form of lytic programmed cell death called pyroptosis. Here, we review our current understanding of the mechanism of the inflammasome in sensing HIV-1 infection. Furthermore, we discuss the contribution of inflammasome activation in HIV-1 pathogenesis as well as potential strategies of targeting inflammasome activation for the treatment of HIV-1 infection.

Background Interactions between immune and tumor cells are critical to determining cancer progression and response. In addition, preclinical prediction of immune-related drug efficacy is limited by interspecies differences between human and mouse, as well as inter-person germline and somatic variation. To address these gaps, we developed an autologous system that models the tumor microenvironment (TME) from individual patients with solid tumors.Method With patient-derived bone marrow hematopoietic stem and progenitor cells (HSPCs), we engrafted a patient’s hematopoietic system in MISTRG6 mice, followed by transfer of patient-derived xenograft (PDX) tissue, providing a fully genetically matched model to recapitulate the individual’s TME. We used this system to prospectively study tumor-immune interactions in patients with solid tumor.Results Autologous PDX mice generated innate and adaptive immune populations; these cells populated the TME; and tumors from autologously engrafted mice grew larger than tumors from non-engrafted littermate controls. Single-cell transcriptomics revealed a prominent vascular endothelial growth factor A (VEGFA) signature in TME myeloid cells, and inhibition of human VEGF-A abrogated enhanced growth.Conclusions Humanization of the interleukin 6 locus in MISTRG6 mice enhances HSPC engraftment, making it feasible to model tumor-immune interactions in an autologous manner from a bedside bone marrow aspirate. The TME from these autologous tumors display hallmarks of the human TME including innate and adaptive immune activation and provide a platform for preclinical drug testing.

Introduction African American women (AA), particularly those living in the Southeastern USA, experience disproportionately high rates of HIV infection. Pre-exposure prophylaxis (PrEP) is a highly effective HIV prevention tool that may circumvent barriers to traditional HIV prevention tools, such as condom use; however, very little is known about how to improve PrEP access and uptake among AA women who may benefit from PrEP use. This project aims to understand how to increase PrEP access among AA women in the rural Southern USA, which may ultimately affect HIV incidence in this population.Methods and analysis The goal of the current study is to systematically adapt a patient–provider communication tool to increase PrEP uptake among AA women receiving care at a federally qualified health centre in Alabama. We will use an iterative implementation process, by assessing the feasibility, acceptability and preliminary impact of the tool on PrEP uptake, using a pilot preintervention/postintervention design (N=125). We will evaluate women’s reasons for declining a referral to a PrEP provider, reasons for incomplete referrals, reasons for not initiating PrEP after a successful referral and ongoing PrEP use at 3 and 12 months after PrEP initiation among our sample. The proposed work will significantly contribute to our understanding of factors impacting PrEP uptake and use among AA women, particularly in underserved areas in the Deep South that are heavily impacted by the HIV epidemic and experience worse HIV-related health outcomes relative to other areas in the USA.Ethics and dissemination This protocol has been approved by the Institutional Review Board (IRB) at University of Alabama at Birmingham (Birmingham, AL; protocol 300004276). All participants will review a detailed informed consent form approved by the IRB and will provide written or verbal informed consent prior to enrolment. Results will be disseminated through peer-reviewed manuscripts, reports, and local, national and international presentations.Trial registration number NCT04373551.

Under the trend in climate change, global warming, and the increasingly serious urban heat island effect, promoting urban wind corridor planning to reduce urban temperature and mitigate the effect of urban heat islands has received widespread attention in many cities. With emerging awareness of the need to explicitly incorporate climate considerations into urban planning and design, integrating current spatial analysis and simulation tools to enhance urban wind corridor planning to obtain the best urban ventilation effect has become an increasingly important research topic in green city development. However, how to systematically carry out urban wind corridor planning by employing related technology and simulation tools is a topic that needs to be explored urgently in both theory and practice. Taking Zhumadian City in China as an example, this study proposes a method and planning approach that uses remote sensing (RS), geographic information system (GIS), and computational fluid dynamics (CFD) in an integrated way to understand urban landscape and to conduct urban wind corridor planning. The research results reveal that the urban form of Zhumadian City favors the development of urban wind corridors, and that the railway lines and some major roads in the city have the potential to be developed as the city’s main wind corridors. However, there are still ventilation barriers resulting from the existing land use model and building layout patterns that need to be adjusted. In terms of local-level analysis, the CFD simulation analysis also reveals that some common building layout patterns may result in environments with poor ventilation. Finally, based on the results of our empirical analysis and local planning environment, specific suggestions are provided on how to develop appropriate strategies for urban wind corridor planning and adjustments related to land use planning and building layout patterns in order to mitigate the impact of the urban heat island effect.

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Liver fibrosis is the common consequence of various chronic liver injuries and is mainly characterized by the imbalance between the production and degradation of extracellular matrix, which leads to the accumulation of interstitial collagen and other matrix components. Matrix metalloproteinases (MMPs) and their specific inhibitors, that is, tissue inhibitors of metalloproteinases (TIMPs), play a crucial role in collagen synthesis and lysis. Previous in vivo and in vitro studies of our laboratory found repressing extracellular matrix (ECM) accumulation by restoring the balance between MMPs and TIMPs can alleviate liver fibrosis. We conducted a review of articles published in PubMed and Science Direct in the last decade until February 1, 2023, which were searched for using these words “MMPs/TIMPs” and “Hepatic Fibrosis.” Through a literature review, this article reviews the experimental studies of liver fibrosis based on MMPs/TIMPs, summarizes the components that may exert an anti-liver fibrosis effect by affecting the expression or activity of MMPs/TIMPs, and attempts to clarify the mechanism of MMPs/TIMPs in regulating collagen homeostasis, so as to provide support for the development of anti-liver fibrosis drugs. We found the MMP-TIMP-ECM interaction can result in better understanding of the pathogenesis and progression of hepatic fibrosis from a different angle, and targeting this interaction may be a promising therapeutic strategy for hepatic fibrosis. Additionally, we summarized and analyzed the drugs that have been found to reduce liver fibrosis by changing the ratio of MMPs/TIMPs, including medicine natural products.

HIV-1 usually utilizes CCR5 as its coreceptor and rarely switches to a CXCR4-tropic virus until the late stage of infection. CCR5+CD4+ T cells are the major virus-producing cells in viremic individuals as well as SIV-infected nonhuman primates. The differentiation of CCR5+CD4+ T cells is associated with the availability of IL-15, which increases during acute HIV-1 infection. Here, we report that CCR5 was expressed by CD4+ T cells exhibiting effector or effector memory phenotypes with high expression levels of the IL-2/IL-15 receptor common β and γ chains. IL-15, but not IL-7, improved the survival of CCR5+CD4+ T cells, drove their expansion, and facilitated HIV-1 infection in vitro and in humanized mice. Our study suggests that IL-15 plays confounding roles in HIV-1 infection, and future studies on the IL-15–based boosting of anti–HIV-1 immunity should carefully examine the potential effects on the expansion of HIV-1 reservoirs in CCR5+CD4+ T cells.

When multiple Virtual Synchronous Generators (VSGs) operate in parallel in an islanded grid, power and frequency oscillations will occur when one VSG goes offline. However, the existing literature does not cover the related analysis and transient suppression schemes for this scenario. To analyze these complex high-order system dynamics, this paper first establishes an intuitive equivalent circuit model for multiple VSGs, and the frequency domain expressions of the multi-machine VSG system during the VSG offline transient simulation are then derived. Based on the multi-VSG model and its transient oscillations analysis, this paper further proposes a configuration scheme for the equivalent circuit parameters. Equivalently, the virtual inertia, damping coefficient and virtual impedance of the VSGs can be configured. With the proposed parameter configuration scheme, the power oscillation during the VSG offline transient can be eliminated, as verified by experiments with a microgrid lab platform using three VSGs. Compared with the existing multi-VSG studies, the proposed scheme is not only the first attempt to study the transient suppression when a VSG goes offline, but also is more intuitive in analysis and less complicated in the controller parameter tuning.

Marine industrial structure is an important indicator of the quality of marine economic development. This paper used the shift-share analysis method and introduced the growth rate index, regional structure effect index and regional competitiveness effect index to compare and analyze the marine industrial structure and competitiveness of six cities in the Liaoning coastal economic belt from 2009 to 2018. The research showed that the marine economy of Liaoning coastal economic belt developed rapidly. The overall structure of the marine industry was good, but within the marine industry, the development of the marine primary industry was slow and the comprehensive competitiveness was low. The proportion of emerging marine industries in the secondary marine industry was relatively small. The marine tertiary industry had become the leading industry of Liaoning coastal economic belt with obvious development advantages. Liaoning Coastal Economic Belt should pay more attention to the rational allocation of industrial development and try hard to form a coordinated and complementary sustainable development structure among industries.

In this study, we explore the precise trajectory tracking control problem of autonomous underwater vehicle (AUV) under the disturbance of the underwater environment. First, a model-free adaptive control (MFAC) is designed based on data-driven ideology and a full-form dynamic linearization (FFDL) method is utilized to online estimate time-varying parameter pseudo gradient (PG) to establish an equivalent data model of AUV motion. Second, the iterative extended state observer (IESO) scheme is designed to combine with FFDL-MFAC. Because the proposed novel controller is able to learn from repeated iterations, the proposed novel controller can estimate and compensate the model approximation error produced by external environmental unknown disturbance. Third, three-dimensional motion is decoupled into horizontal and vertical and a multi closed-loop control structure is designed that exhibits faster convergence rate and reduces sensitivity to parameter jumps than single closed-loop system. Finally, two simulation scenarios are designed featuring non external disturbance and Gaussian noise of signal-to-noise ratio of 90 dB. The simulation results reveal the superiority of FFDL. Furthermore, we adpot the technical parameters data of T-SEA I AUV to conduct numerical simulation, aunderwater trajectory as the tracking scenario and set waves to 0.5 m and current to 0.2 m/s to simulate Lv.2 ocean conditions of "International Ocean State Standard". The simulation results demonstrate the effectiveness and robustness of the proposed tracking control algorithm.

There has been a growing interest in augmented reality (AR) methods for gait guidance and rehabilitation. These methods have been effective in guiding spatial gait parameters, such as stride length, and temporal cycle times when paired with rhythmic stimuli. However, few studies have explored the simultaneous spatial and temporal guidance of gaits and have primarily focused on one of several aspects. Gait parameters are related, and changing one might have unintended effects on others; thus, simultaneous guidance is required. In this study, we designed and evaluated a system that provides simultaneous spatial and temporal guidance using a synchronized walking avatar in AR. The system requires a head-mounted display (HMD) and presents a walking avatar involving auditory cues synchronized with the foot-contact timing of the participant via a mutual entrainment model. Spatial feedback is provided by distance changes between the participant and avatar, and the effects on stride length are observed. Phase difference changes between the avatar and participant serve as temporal cues that are used to guide the cycle time. The stride length and cycle-time of eight participants walking along a straight corridor wearing the HMD were recorded and analyzed. Four experimental conditions were applied comprising combinations of increases and decreases in the spatial and temporal cues. Furthermore, the results demonstrated that spatial and temporal feedback had almost independent effects on respective gait parameters. These findings reveal that this combination of spatiotemporal cueing can be extremely effective in gait guidance without loss of effectiveness from single modality cues.

Background Currently, the most predominant type of liver cancer is hepatocellular carcinoma (HCC), which is also the fourth leading cause of cancer-related death in the global population. Pyroptosis is an emerging form of cell death that affects the prognosis of cancer patients by modulating tumor cell migration, proliferation and invasion. However, the evaluation of pyroptosis in the prognosis of HCC is still insufficient. Methods A total of 365 HCC patients from the TCGA-LIHC cohort were classified into two distinct subtypes using consensus clustering of pyroptosis-related genes (PRGs). Following univariate Cox analysis of differentially expressed genes between subtypes, we established a prognostic model (PRGs-score, PRGS) by LASSO Cox analysis. We further tested the predictive power of the prognostic model in the ICGC (LIRI-JP) and GEO (GSE14520) cohorts. The tumor microenvironment (TME) was studied using the CIBERSORT. The enrichment scores for immune cells and immune functions in low- and high-PRGS groups were assessed using ssGSEA. The IMvigor210 cohort was used to investigate the immunotherapy efficacy. Furthermore, we validated the expression of prognostic genes in PRGS by RT-qPCR in vitro. Results The subtyping of HCC based on PRGs exhibited distinct clinical characteristics. We developed a prognostic model PRGS by differentially expressed genes between different subtypes. The results showed that PRGS could well forecast the survival of HCC patients in different cohorts and was associated with the immune microenvironment. Moreover, PRGS was considered to be an independent prognostic risk factor and superior to other pyroptosis-related signatures. Low-PRGS implied greater immune cell infiltration and better overall survival with immunotherapy. The results of RT-qPCR also showed that prognostic genes were significantly dysregulated in HCC. Conclusions PRGS has promising application in forecasting the prognosis of HCC patients, and its relationship with the immune microenvironment provides a basis for the subsequent treatment and research of HCC.

Maintaining body temperature within a narrow range is vital for warm-blooded animals. In rodents, the preoptic area (POA) of the hypothalamus detects and regulates core body temperature. However, knowledge about the thermal regulation center in primates remains limited. Here, we show that activating a subpopulation of POA neurons by a chemogenetic strategy reliably induces hypothermia in anesthetized and freely moving macaques. Comprehensive monitoring of physiological parameters reveals that such hypothermia is accompanied by autonomic changes including a rise in heart rate, skeletal muscle activity, and correlated biomarkers in blood. Consistent with enhanced ambulatory movement during hypothermia, the animals show a full range of cold-defense behaviors. Resting-state fMRI confirms the chemogenetic activation of POA and charts a brain-wide network of thermoregulation. Altogether, our findings demonstrate the central regulation of body temperature in primates and pave the way for future application in clinical practice.

The role of NK cells against HIV-1 infections remains to be elucidated in vivo. While humanized mouse models potentially could be used to directly evaluate human NK cell responses during HIV-1 infection, improved functional development of human NK cells in these hosts is needed. Here, we report the humanized MISTRG-6-15 mouse model, in which NK cells were quick to expand and exhibit degranulation, cytotoxicity, and proinflammatory cytokine production in nonlymphoid organs upon HIV-1 infection but had reduced functionality in lymphoid organs. Although HIV-1 infection induced functional impairment of NK cells, antiretroviral therapy reinvigorated NK cells in response to HIV-1 rebound after analytic treatment interruption. Moreover, a broadly neutralizing antibody, PGT121, enhanced NK cell function in vivo, consistent with antibody-dependent cellular cytotoxicity. Monoclonal antibody depletion of NK cells resulted in higher viral loads in multiple nonlymphoid organs. Overall, our results in humanized MISTRG-6-15 mice demonstrated that NK cells provided direct anti–HIV-1 responses in vivo but were limited in their responses in lymphoid organs.

Abstract Background Neovasculogenesis is characteristic of herniated lumbar discs, in which extruded nucleus pulposus is prone to heme iron-induced cytotoxicity (increased oxidative stress causing ferroptosis). However, recent analyses of neovascularization are very complicated, and the mechanism of action is rarely reported. Methods Matrix-assisted laser desorption/ionization–time-of-flight mass spectrometry (MALDI-TOF MS) was performed to analyze human herniated and nonherniated nucleus pulposus. Then, the clinical relevance of the MALDI-TOF MS results and Pfirrmann classification of the degenerative nucleus pulposus were analyzed. To explore the mechanism, the heme-induced ferroptosis effect was evaluated at both the tissue and cell levels using high-resolution MALDI-TOF MS and molecular biology methods. Results The spectra revealed that hemoglobin (Hb) and heme signals were greatly increased, thus serving as predictors of vasculogenesis in herniated nucleus pulposus. The clinical relevance analysis demonstrated that the intensity of Hb and heme peaks was closely related to the Pfirrmann classification of degenerative nucleus pulposus. Mechanistically, increased heme catabolism and downregulation of glutathione peroxidase 4 (GPX4) levels were detected in herniated nucleus pulposus, reflecting iron-dependent cell death or ferroptosis. Iron levels was also increased in herniated nucleus pulposus compared with that in nonherniated nucleus pulposus. Furthermore, accuracy mass measurements confirmed that the levels of ferroptosis-related metabolites, such as glutathione, arachidonic acid (AA), sphinganine, polyunsaturated fatty acid (PUFA), and tricarboxylic acid (TCA) cycle metabolites, were significantly different between herniated and nonherniated tissues, indicating that the interior of the herniated tissues is a pro-oxidant environment. Moreover, heme-induced ferroptosis was verified in human nucleus pulposus cells (HNPCs), and the underlying mechanism might be associated with the Notch pathway. Conclusions Neovascularization in herniated nucleus pulposus may expose tissues to high levels of heme, which can induce cytotoxicity and ferroptosis within tissues and accelerate the progressive degeneration of herniated nucleus pulposus. This study is beneficial for understanding the pathological mechanism of herniated nucleus pulposus and facilitating the development of nonoperative interventions for treating lumbar disc herniation (LDH).

We have previously shown that adenosine A1AR antagonists, adenosine A2aAR antagonists, and caffeine have significant inhibitory effects on the activation and proliferation of hepatic stellate cells in alcoholic liver fibrosis. Many recent studies have found that moderate coffee consumption is beneficial for various liver diseases. The main active ingredient of coffee is caffeine, which is a natural non-selective adenosine receptor antagonist. Moreover, numerous preclinical epidemiological studies and clinical trials have examined the association between frequent coffee consumption and the risk of developing different liver diseases. In this review, we summarize and analyze the prophylactic and therapeutic effects of caffeine on various liver diseases, with an emphasis on cellular assays, animal experiments, and clinical trials. To review the prevention and treatment effects of caffeine on different liver diseases, we searched all literature before 19 July 2022, using “caffeine” and “liver disease” as keywords from the PubMed and ScienceDirect databases. We found that moderate coffee consumption has beneficial effects on various liver diseases, possibly by inhibiting adenosine binding to its receptors. Caffeine is a potential drug for the prevention and treatment of various liver diseases.

The morbidity and mortality of hepatic fibrosis caused by various etiologies are high worldwide, and the trend is increasing annually. At present, there is no effective method to cure hepatic fibrosis except liver transplantation, and its serious complications threaten the health of patients and cause serious medical burdens. Additionally, there is no specific drug for the treatment of hepatic fibrosis, and many drugs with anti-hepatic fibrosis effects are in the research and development stage. Recently, remarkable progress has been made in the research and development of anti-hepatic fibrosis drugs targeting different targets. We searched websites such as PubMed, ScienceDirect, and Home-ClinicalTrials.gov and found approximately 120 drugs with anti-fibrosis properties, some of which are in phase Ⅱ or Ⅲ clinical trials. Additionally, although these drugs are effective against hepatic fibrosis in animal models, most clinical trials have shown poor results, mainly because animal models do not capture the complexity of human hepatic fibrosis. Besides, the effect of natural products on hepatic fibrosis has not been widely recognized at home and abroad. Furthermore, drugs targeting a single anti-hepatic fibrosis target are prone to adverse reactions. Therefore, currently, the treatment of hepatic fibrosis requires a combination of drugs that target multiple targets. Ten new drugs with potential for development against hepatic fibrosis were selected and highlighted in this mini-review, which provides a reference for clinical drug use.

Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) have emerged as important mediators of intercellular communication in response to cartilage damage. In this study, we sought to characterize the inhibitory role of microRNA (miR)-31 encapsulated in synovial MSC (SMSC)-derived EVs in knee osteoarthritis (OA). The expression of miR-31, lysine demethylase 2A (KDM2A), E2F transcription factor 1 (E2F1), and pituitary tumor transforming gene 1 (PTTG1) was validated in cartilage tissues of knee OA patients. Following SMSC-EV extraction and identification, chondrocytes with the miR-31 inhibitor were added with SMSC-EVs, whereupon the effects of miR-31 on proliferation and migration of chondrocytes were assessed. The interaction among miR-31, KDM2A, E2F1, and PTTG1 in chondrocyte activities was probed in vitro, along with an in vivo mouse knee OA model. We identified downregulated miR-31, E2F1, and PTTG1 and upregulated KDM2A in cartilage tissues of knee OA patients. SMSC-EV-packaged miR-31 potentiated chondrocyte proliferation and migration as well as cartilage formation by targeting KDM2A. Mechanistically, KDM2A bound to the transcription factor E2F1 and inhibited its transcriptional activity. Enrichment of E2F1 in the PTTG1 promoter region activated PTTG1 transcription, accelerating chondrocyte proliferation and migration. SMSC-EVs and EVs from miR-31-overexpressed SMSCs alleviated cartilage damage and inflammation in knee joints in vivo. SMSC-EV-encapsulated miR-31 ameliorates knee OA via the KDM2A/E2F1/PTTG1 axis.

The DC current flow controller (CFC) has capability of enhancing the control freedom of current/power flow in multi-terminal DC (MTDC) grids and solving the barrier of uncontrollability of DC branch currents. The control margins of the DC branch currents can be further improved if the power flow reversal is achieved with the DC CFC. An improved DC CFC (I-DCCFC) utilized in the meshed MTDC (M2TDC) grid is investigated with three contributions: (1) Regarding a traditional DC CFC (T-DCCFC), its operational mode and operating principle are analysed. The fact that T-DCCFC only has singular quadrant operation capability, which constrains the power flow reversal, is explained. (2) The I-DCCFC with double quadrants operation capability is presented. Its operating principle with power flow reversal capability is analysed. (3) Based on the control strategy of the T-DCCFC, the control strategy of the I-DCCFC is developed and the ability to isolate the DC fault is analysed. The simulation model of a three-terminal M2TDC grid with the I-DCCFC is established in PSCAD/EMTDC. The effectiveness of the I-DCCFC in controlling the DC branch currents with power flow reversal capability and fault isolation under the fault condition is verified by the simulation results. As the I-DCCFC inherits the modular design concept with strong scalability, it can be expanded into an improved multi-line DC CFC according to the actual demands.

Consciousness lies at the heart of our existence and experience. To probe how perceptual consciousness emerges in the brain, we recorded brain-wide intracranial electroencephalography signals from human patients while their perceptual consciousness was effectively manipulated using the continuous flash suppression paradigm. We observed substantial differences in brain activities when visual information gradually enters consciousness. Specifically, the functional connectivity first increases and then decreases, oscillations in the low-frequency band reduce in power, and those in the high-frequency band remain unchanged. We employed random forest-based classification to characterize the transitions from no perception to subconsciousness and then to consciousness, which showed an increase in signal variance at the second transition rather than the first. Further, the frontal-parietal junction dominates the first transition, whereas the temporal-frontal lobes dominate the second transition. Finally, we identified the most relevant neuronal features associated with consciousness. Altogether, these findings shed fresh light on the emergence of visual consciousness.

Proton Exchange Membrane Fuel Cell (PEMFC) is difficult for application because of its high current and wide voltage output. A fractional order PID controller is introduced to a Four-Switch Buck-Boost DC/DC converter to stabilize the power output in this paper. To reduce the inductor current ripple, a kind of dual-triggered switch strategy is employed in detail, and an accurate dynamic model of DC/DC converter is proposed for fuel cell measurement and control system. Then a fractional order PID controller is designed for voltage module compensation, in which a stochastic inertia weight PSO algorithm is employed to optimize the parameters of this controller. The results of simulation and experiment indicate that the compensation effect of fractional order PID controller has better performance than the integer order controller, which is robust to the variation of fuel cell system dynamics and power request.

Yttrium-doped barium zirconate (BZY) has emerged as an attractive candidate for application as a proton (H+)-conducting solid electrolyte due to its high ionic conductivity and excellent chemical stability. In this study, the conductivities of BaZr(1−x)YxO3−δ (BZY, x = 0, 0.037, 0.074, 0.148, and 0.22) with different carriers were studied based on density functional theory (DFT) and experiments. The results revealed that yttrium doping can effectively reduce the energy barrier for the migration of protons and oxygen ions (O2−). When comparing the energy barriers for protons and oxygen ions, the energy barriers for proton migration were found to be lower than those for oxygen ion migration, which indicates that a proton conductor can offer the advantages of lower activation energy and, possibly, higher conductivity. An analysis of the electronic structure of the BZYs found that the top of the valence band exceeded the Fermi energy level following yttrium doping. As a result, the electron conductivity increased as the yttrium content increased. Furthermore, this study also tested the total conductivity of BaZr(1−x)YxO3−δ (BZY, x = 0.1, 0.2, 0.3, and 0.4) and found the trend of the total conductivity to be consistent with the results of the DFT calculations.

This paper focuses on developing a data-driven trajectory tracking control approach for autonomous underwater vehicles (AUV) under uncertain external disturbance and time-delay. A novel model-free adaptive predictive control (MFAPC) approach based on a fuzzy state observer (FSO) was designed to achieve high precision. Concretely, the mathematical model of AUV motion was analyzed, and simplified via model decoupling, thus providing the model basis with an explicit physical explanation for the controller. Second, the MFAPC scheme for a multiple-inputs and multiple-outputs (MIMO) discrete time system was derived, that estimates system external disturbance. The controller can online estimate and predictive time-varying parameter pseudo-Jacobian matrix (PJM) to establish equivalent state space data-model for AUV motion system. Third, the Takagi–Sugeno (T–S) fuzzy model based state observer was designed to combine with the MFAPC scheme for the first time, which was used to online decline the state error generated by system uncertain time-delay. In addition, the stability of the proposed control scheme was analyzed. Finally, two trajectory tracking scenarios were designed to verify the effectiveness and robustness of the proposed FMFAPC scheme, and the simulations are implemented using the realistic parameters of T-SEA AUV.

Three marketed anti-PD-L1 antibodies almost have severe immune-mediated side effects. The therapeutic effects of anti-PD-L1 chemical inhibitors are not satisfied in the clinical trials. Here we constructed human-derived protein scaffolds library and screened scaffolds with a shape complementary to the PD-1 binding domain of PD-L1. The RNA binding domain of U1 snRNPA was selected as one of potential binders because it had the most favorable binding energies with PD-L1 and conformed to pre-established biological criteria for the screening of candidates. The recombinant U1 snRNPA (rU1 snRNPA) in Escherichia coli exhibits anti-cancer activity in melanoma and breast cancer by reactivating tumor-suppressed T cells in vitro and anti-melanoma activity in vivo. Considering hydrophobic and electrostatic interactions, three residues were mutated on the interface of U1 snRNPA and PD-L1 complex, and the ranked variants by PatchDock and A32D showed an increased active phenotype. The screening of human-derived protein scaffolds may become the potential development of therapeutic agents.

Newly diagnosed pancreatic cancer increases year by year, while the prognosis of pancreatic cancer has not been very good. Statin drugs were found to have protective effects against a variety of cancers, but their association with pancreatic cancer remains to be clarified. This study used different pancreatic cancer cell lines and in different animal models to confirm the relationship between simvastatin and pancreatic cancer. Flow cytometry and luciferase-based bioluminescent images were used to investigate the cell cycle and tumor growth changes under simvastatin treatment. Simvastatin decreased the MIA PaCa-2 cells, PANC-1 cells, and BxPC-3 cell viability significantly and may arrest the cell cycle in the G0 phase. During in vivo study, subcutaneously implanted simvastatin pre-treated pancreatic cancer cells and intraperitoneally treated simvastatin continuously demonstrated a slower tumor growth rate and decreased the tumor/body weight ratio significantly. In intravenous implant models, implanted simvastatin-pre-treated BxPC-3 cells and cells treated along with simvastatin significantly decreased the tumor growth curve. Implanting the simvastatin-pre-treated pancreatic cells in the subcutaneous model showed better growth inhibition than the intravenous model. These results suggest simvastatin treatment may relate to different signaling pathways in local growth and metastasis. Pancreatic cancer cells presented different growth patterns in different animal-induced models, which could be important for clinical reference when it comes to the relationship of long-term statin use and pancreatic cancer.

Abstract Many different encoding algorithms for systematic polar codes (SPC) have been introduced since SPC was proposed in 2011. However, the number of the computing units of exclusive OR (XOR) has not been optimized yet. According to an iterative property of the generator matrix and particular lower triangular structure of the matrix, we propose an optimized encoding algorithm (OEA) of SPC that can reduce the number of XOR computing units compared with existing non-recursive algorithms. We also prove that this property of the generator matrix could extend to different code lengths and rates of the polar codes. Through the matrix segmentation and transformation, we obtain a submatrix with all zero elements to save computation resources. The proportion of zero elements in the matrix can reach up to 58.5% from the OEA for SPC when the code length and code rate are 2048 and 0.5, respectively. Furthermore, the proposed OEA is beneficial to hardware implementation compared with the existing recursive algorithms in which signals are transmitted bidirectionally.

Evaluation of light field image (LFI), especially micro-lens camera light field (LF), is a new and challenging work. The development of image quality assessment (IQA) metric of LFIs relies on the subjective quality assessment database. In this paper, we establish a perceptual quality assessment dataset consisting of 240 distorted images from 8 source images with five distortion types. Furthermore, a no-reference IQA metric is proposed by combining 2D and 3D characteristics of LFI with the Support Vector Regression (SVR) model. The performance of the proposed metric is demonstrated by comparing with some classical full reference IQA metrics both on the presented dataset and a third-party dataset. The experiment results show that our method has a better performance than others.

Urbanization has been proven to be a critical factor in modifying local or regional climate characteristics. This research aims to examine the impact of urbanization on extreme climate indices in the Yangtze River Economic Belt (YREB), China, by using meteorological observation data from 2000 to 2019. Three main steps are involved. First, a clustered threshold method based on remote-sensing nighttime light data is used to extract urban built-up areas, and urban and rural meteorological stations can be identified based on the boundary of urban built-up areas. Nonparametric statistical tests, namely, the Mann–Kendall test and Sen’s slope, are then applied to measure the trend characteristics of extreme climate indices. Finally, the urbanization contribution rate is employed to quantify the impact of urbanization on extreme climate indices. The results indicate that urbanization has a more serious impact on extreme temperature indices than on extreme precipitation indices in the YREB. For extreme temperature indices, urbanization generally causes more (less) frequent occurrence of warm (cold) events. The impact of urbanization on different extreme temperature indices has heterogeneous characteristics, including the difference in contamination levels and spatial variation of the impacted cities. For extreme precipitation indices, only a few cities impacted by urbanization are detected, but among these cities, urbanization contributes to increasing the trend of all indices.

HIV-1 protease (PR) is a viral enzyme that cleaves the Gag and Gag-Pol polyprotein precursors to convert them into their functional forms, a process which is essential to generate infectious viral particles. Due to its broad substrate specificity, HIV-1 PR can also cleave certain host cell proteins. Several studies have identified host cell substrates of HIV-1 PR and described the potential impact of their cleavage on HIV-1-infected cells. Of particular interest is the interaction between PR and the caspase recruitment domain-containing protein 8 (CARD8) inflammasome. A recent study demonstrated that CARD8 can sense HIV-1 PR activity and induce cell death. While PR typically has low levels of intracellular activity prior to viral budding, premature PR activation can be achieved using certain non-nucleoside reverse transcriptase inhibitors (NNRTIs), resulting in CARD8 cleavage and downstream pyroptosis. Used together with latency reversal agents, the induction of premature PR activation to trigger CARD8-mediated cell killing may help eliminate latent reservoirs in people living with HIV. This represents a novel strategy of utilizing PR as an antiviral target through premature activation rather than inhibition. In this review, we discuss the viral and host substrates of HIV-1 protease and highlight potential applications and advantages of targeting CARD8 sensing of HIV-1 PR.

In the past decades, the taxonomic status of the cyanobacterial family Phormidiaceae has always been chaotic and problematic. In this study, filamentous cyanobacteria were investigated in the east of China, and twenty strains isolated from different locations of Zhejiang Province were characterized. Using the polyphasic approach combining morphological, molecular and phylogenetic features, these strains were grouped within the members of the genera Ancylothrix and Potamolinea, the newly recorded genera of cyanobacteria in China. Based on the collected taxonomic information of the family Phormidiaceae, cyanobacterial systematics at family level were further discussed. This study provided a simple and efficient example to perform the phylogenetic evaluation for the monophyly and rationality of currently used families of cyanobacteria by using the regional strains based on the polyphasic approach.

Over 90% of head and neck squamous cell carcinoma (HNSCC) overexpresses the epidermal growth factor receptor (EGFR). However, the EGFR-targeted monotherapy response rate only achieves 10–30% in HNSCC. Recombinant immunotoxin (RIT) often consists of an antibody targeting a tumor antigen and a toxin (e.g., diphtheria toxin [DT]) that kills cancer cells. We produced a humanized RIT, designated as hDT806, targeting overexpressed EGFR and investigated its effects in HNSCC. Distinct from the EGFR-targeted tyrosine kinase inhibitor erlotinib or antibody cetuximab, hDT806 effectively suppressed cell proliferation in the four HNSCC lines tested (JHU-011, -013, -022, and -029). In JHU-029 mouse xenograft models, hDT806 substantially reduced tumor growth. hDT806 decreased EGFR protein levels and disrupted the EGFR signaling downstream effectors, including MAPK/ERK1/2 and AKT, while increased proapoptotic proteins, such as p53, caspase-9, caspase-3, and the cleaved PAPR. The hDT806-induced apoptosis of HNSCC cells was corroborated by flow cytometric analysis. Furthermore, hDT806 resulted in a drastic inhibition in RNA polymerase II carboxy-terminal domain phosphorylation critical for transcription and a significant increase in the γH2A.X level, a DNA damage marker. Thus, the direct disruption of EGFR signaling, transcription inhibition, DNA damage, as well as apoptosis induced by hDT806 may contribute to its antitumor efficacy in HNSCC.

Acceleration of urbanization has brought about a series of problems, which include irreversible changes to urban surfaces and continuous increases in land surface temperatures (LSTs). In this context, analysis of the driving factors and spatial heterogeneity of urban LST is of considerable importance for mitigating urban heat island effects and promoting healthy and comfortable urban living environments. This study explored the relationship between the spatial characteristics and driving factors of the LST by using a geographically weighted regression (GWR) model to analyze multisource data from the Xigang District of Dalian City. The results showed that the urban heat island effect in Xigang District is significant, with LSTs generally above 28°C at the end of August, mostly concentrated in the range of 38–40°C. The highest LST values were detected in northern port and harbor areas; the lowest LST values occurred in mountainous forest areas. The global Moran’s I value was 0.994, which was indicative of a very high positive correlation, and local Moran’s I values formed H-H and L-L type clusters concentrated in the northern harbor area and southern mountainous area, respectively. Finally, the GWR model could reflect the spatial heterogeneity of the relationships between LST and its driving factors well. Among these, in terms of natural physical factors, digital elevation model, normalized difference vegetation index, and modified normalized difference water index data were found to be negatively correlated with LSTs in most cases; in the social dimension, the point-of-interest number and building-coverage ratio were generally positively correlated with LSTs.

Glioblastomas, accounting for approximately 50% of gliomas, comprise the most aggressive, highly heterogeneous, and malignant brain tumors. The objective of this study was to develop and evaluate a new targeted therapy, i.e., highly potent natural compound verrucarin A (Ver-A), delivered with monoclonal antibody-directed extracellular vesicle (mAb-EV). First, the high surface expression of epidermal growth factor receptor (EGFR) in glioblastoma patient tissue and cell lines was confirmed using immunohistochemistry staining, flow cytometry, and Western blotting. mAb-EV-Ver-A was constructed by packing Ver-A and tagging anti-EGFR mAb to EV generated from HEK293F culture. Confocal microscopy and the In Vivo Imaging System demonstrated that mAb-EV could penetrate the blood–brain barrier, target intracranial glioblastoma xenografts, and deliver drug intracellularly. The in vitro cytotoxicity study showed IC50 values of 2–12 nM of Ver-A. The hematoxylin and eosin staining of major organs in the tolerated dose study indicated minimal systemic toxicity of mAb-EV-Ver-A. Finally, the in vivo anti-tumor efficacy study in intracranial xenograft models demonstrated that EGFR mAb-EV-Ver-A effectively inhibited glioblastoma growth, but the combination with VEGF mAb did not improve the therapeutic efficacy. This study suggested that mAb-EV is an effective drug delivery vehicle and natural Ver-A has great potential to treat glioblastoma.

For many physical systems, the fractional-order system can describe the dynamics more accurately comparing with the integer-order system. However, its parameters, which include not only the identification of model coefficients but also the estimation of fractional orders, are more difficult to be identified. This paper proposes a modified quantum bacterial foraging algorithm (MQBFA) for parameters identification of the fractional-order system, and the MQBFA algorithm is a relatively new issue in recent years with strong engineering backgrounds. Not only does the proposed MQBFA algorithm apply the real number encoding of the single gene to effectively perform encoding, but it also utilizes a continuously varying rotation angle to update the rotation gate. First, a real number encoding of the single gene is designed to improve the searching efficiency of the algorithm. Second, an improved quantum rotation angle is applied to update the rotation angle continuously and adaptively. Third, the modificatory factor of probability amplitude is introduced to enrich the population diversity. In addition, to prevent the generation of invariant solutions in the early stage of quantum evolution, probability of optimal rotation angle is presented. Furthermore, the convergence of the proposed algorithm is analyzed. Based on several benchmark functions and parameters identification of the fractional-order system, simulation results and comparisons demonstrate the effectiveness of the proposed MQBFA algorithm.

Particle size distribution (PSD) measurement based on the static light scattering method has been widely used in the environmental field and combustion diagnostics, such as PM2.5 measurement and combustion process monitoring. The PSD inversion is mathematically related to the Fredholm integral equation of the first kind. Although the Tikhonov regularization algorithm is one of the effective inversion methods to solve the ill-posed linear equation, it still has the disadvantages of excessive smoothness and low accuracy. Thus, a preconditioned Landweber algorithm combined with the Tikhonov regularization theory (the improved algorithm) is proposed in this paper. The Tikhonov regularization theory is used to pretreat the preconditioner B contained in the preconditioned Landweber algorithm. Simulations are conducted to compare the inversion results of the conventional Landweber algorithm, the preconditioned Landweber algorithm, the Tikhonov Chahine algorithm, and the improved algorithm at different signal-to-noise ratios. A CCD-based small-angle forward scattering measurement system is built. A standardized polystyrene microsphere with a diameter of 35.05 μm is used to evaluate the above algorithms. Both numerical and experimental results show that the improved algorithm improves the accuracy of the inversion results and is insensitive to the ring parameter of the detector. The experimental results of the standardized polystyrene microsphere reveal that the relative errors for the median diameter 50 μm are better than 3%. The improved algorithm can provide a highly reliable and stable inversion result.

This paper investigates the containment control problem of discrete-time first-order multi-agent system composed of multiple leaders and followers, and we propose a proportional-integral (PI) coordination control protocol. Assume that each follower has a directed path to one leader, and we consider several cases according to different topologies composed of the followers. Under the general directed topology that has a spanning tree, the frequency-domain analysis method is used to obtain the sufficient convergence condition for the followers achieving the containment-rendezvous that all the followers reach an agreement value in the convex hull formed by the leaders. Specially, a less conservative sufficient condition is obtained for the followers under symmetric and connected topology. Furthermore, it is proved that our proposed protocol drives the followers with unconnected topology to converge to the convex hull of the leaders. Numerical examples show the correctness of the theoretical results.

Pedestrian evacuation and modification of traffic facilities were previously studied to increase the traffic efficiency and the safety of pedestrians. In this article, we first design a new robot-assisted pedestrian control scheme. We consider a different scenario that the inflow of all the entrances to the corridor can be controlled by mobile robots. Based on the collected image data of the experimental corridor, we obtain the regulated pedestrian velocity and build the relationship function between the adjustable motion frequency of the robot and the regulated pedestrian velocity. To achieve the optimal traffic flow in the designed scenario, we set up the macroscopic pedestrian model for the modified unidirectional pedestrian corridor with several controlled entrances. The pedestrian inflow of each entrance is controlled by adjusting the motion frequency of the robot moving in a transverse direction. Then the state feedback controller is designed and the stability of the controller is analyzed based on the Lyapunov stability theory. The theoretical analysis guides the movement of robots. Finally, the simulation results demonstrate the efficiency of the controlled pedestrian system. Our study can flexibly manage the pedestrian flow by applying advanced robotics technology on macro level, which can provide ideal global control effect.