Metabolism/Immunity Dual-Regulation Thermogels Potentiating Immunotherapy of Glioblastoma Through Lactate-Excretion Inhibition and PD-1/PD-L1 Blockade.

Intrinsic immunosuppressive tumor microenvironment (ITM) and insufficient tumor infiltration of T cells severely impede the progress of glioblastoma (GBM) immunotherapy. In this study, it is identify that inhibiting the expression of glucose transporter 1 (GLUT1) can facilitate the prevention of lactate excretion from tumor glycolysis, which significantly alleviates the lactate-driven ITM by reducing immunosuppressive tumor-associated macrophages (TAMs) and regulatory T cells (Tregs). Simultaneously, the findings show that the generated inflammatory cytokine IFN-γ during immune activation aggravates the immune escape by upregulating immune checkpoint programmed death-ligand 1 (PD-L1) in tumor cells and TAMs. Therefore, an injectable thermogel loaded with a GLUT1 inhibitor BAY-876 and a PD-1/PD-L1 blocker BMS-1 (Gel@B-B) for dual-regulation of metabolism and immunity of GBM is developed. Consequently, in situ injection of Gel@B-B significantly delays tumor growth and prolongs the survival of the orthotopic GBM mouse model. By actively exposing tumor antigens to antigen-presenting cells, the GBM vaccine combined with Gel@B-B is found to significantly increase the fraction of effector T cells (Th1/CTLs) in the tumor microenvironment, thereby remarkably mitigating tumor recurrence long-term. This study may provide a promising strategy for GBM immunotherapy.

Allosteric inhibitor of SHP2 enhances macrophage endocytosis and bacteria elimination by increasing caveolae activation and protects against bacterial sepsis.

The uncontrolled bacterial infection-induced cytokine storm and sequential immunosuppression are commonly observed in septic patients, which indicates that the activation of phagocytic cells and the efficient and timely elimination of bacteria are crucial for combating bacterial infections. However, the role of dysregulated immune cells and their disrupted function in sepsis remains unclear. Here, we found that macrophages exhibited the impaired endocytosis capabilities in sepsis by Single-cell RNA sequencing and bulk RNA sequencing. Caveolae protein Caveolin-1 (Cav-1) of macrophages was inactivated by SHP2 rapidly during Escherichia coli (E.coli) infection. Allosteric inhibitor of SHP2 effectively maintains Cav-1 phosphorylation to enhance macrophage to endocytose and eliminate bacteria. Additionally, TLR4 endocytosis of macrophage was also enhanced upon E.coli infection by SHP099, inducing an increased and rapidly resolved inflammatory response. In vivo, pretreatment or posttreatment with inhibitor of SHP2 significantly reduced the bacterial burden in organs and mortality of mice subjected E.coli infection or CLP-induced sepsis. The cotreatment of inhibitor of SHP2 with an antibiotic conferred complete protection against mortality in mice. Our findings suggest that Cav-1-mediated endocytosis and bacterial elimination may play a critical role in the pathogenesis of sepsis, highlighting inhibitor of SHP2 as a potential therapeutic agent for sepsis.

Plant volatiles mediated the orientation preference of slugs to different plant species.

BACKGROUND: Slugs mechanically damage plant leaves, resulting in significant economic losses. However, there are limited cost-efficient strategies available in slug management. By studying how slugs utilize plant volatiles to locate host plants, we can gain insights into the design of attractants and repellents. RESULTS: Bioassay results suggest slugs (Agriolimax agrestis) prefer to orientate to lettuce (Lactuca sativa), cabbage (Brassica oleracea L.), and young tobacco seedlings, compared with old tobacco seedlings. We analyzed the volatomics of lettuce, cabbage, young and old tobacco seedlings. 2-(2-butoxyethoxy)-ethanol acetate (2EA) had high abundance while nonanal, decanal, and ß-cylocitral had relatively low content in volatiles. Old tobacco seedlings released significantly more hexanal but fewer 1,4-dihydro-4-oxopyridazine (DO). In olfactory tests, hexanal, nonanal, decanal, and ß-cylocitral showed strong repellency to slugs, while DO at a dose of 500 ng/µL and 2EA at a dose of 1% were attractive to slugs. The two alkanes, hexadecane and heptadecane, had no effect on slug orientating to host plants. DO and 2EA can thus alleviate the repellency of hexanal, nonanal, decanal and ß-cylocitral. CONCLUSION: The high emission of hexanal in old tobacco seedlings helps repel slugs, while 2EA and DO attract slugs to lettuce and cabbage. These findings suggest that these chemicals can be utilized in the design of repellents and attractants, and contribute to constructing a push-pull system for slug control. © 2023 Society of Chemical Industry.

Machine-Learning-Driven G-Quartet-Based Circularly Polarized Luminescence Materials.

Circularly polarized luminescence (CPL) materials have garnered significant interest due to their potential applications in chiral functional devices. Synthesizing CPL materials with a high dissymmetry factor (glum ) remains a significant challenge. Inspired by efficient machine learning (ML) applications in scientific research, this work demonstrates ML-based techniques for the first time to guide the synthesis of G-quartet-based CPL gels with high glum values and multiple chiral regulation strategies. Employing an "experiment-prediction-verification" approach, this work devises a ML classification and regression model for the solvothermal synthesis of G-quartet gels in deep eutectic solvents. This process illustrates the relationship between various synthesis parameters and the glum value. The decision tree algorithm demonstrates superior performance across six ML models, with model accuracy and determination coefficients amounting to 0.97 and 0.96, respectively. The screened CPL gels exhibiting a glum value up to 0.15 are obtained through combined ML guidance and experimental verification, among the highest ones reported till now for biomolecule-based CPL systems. These findings indicate that ML can streamline the rational design of chiral nanomaterials, thereby expediting their further development.

Targeted protein degradation in drug development: Recent advances and future challenges.

Targeted protein degradation (TPD) has emerged as a promising therapeutic approach with potential advantages over traditional occupancy-based inhibitors in terms of dosing, side effects and targeting "undruggable" proteins. Targeted degraders can theoretically bind any nook or cranny of targeted proteins to drive degradation. This offers convenience versus the small-molecule inhibitors that must function in a well-defined pocket. The degradation process depends mainly on two cell self-destruction mechanisms, namely the ubiquitin-proteasome system and the lysosomal degradation pathway. Various TPD strategies (e.g., proteolytic-targeting chimeras, molecular glues, lysosome-targeting chimeras, and autophagy-targeting chimeras) have been developed. These approaches hold great potential for targeting dysregulated proteins, potentially offering therapeutic benefits. In this article, we systematically review the mechanisms of various TPD strategies, potential applications to drug discovery, and recent advances. We also discuss the benefits and challenges associated with these TPD strategies, aiming to provide insight into the targeting of dysregulated proteins and facilitate their clinical applications.

AI-Assisted Disease Monitoring Using Stretchable Polymer-Based Sensors.

Flexible sensors have attracted significant attention for medical applications. Herein, an AI-assisted stretchable polymer-based (AISP) sensor has been developed based on the Beer-Lambert law for disease monitoring and telenursing. Benefiting from the use of superior polymer materials, the AISP sensor features a high tensile strain of up to 100%, durability of >10,000 tests, excellent waterproofness, and no effect of temperature (1.6-60.9 °C). Such advantages support the capability that the AISP can be flexibly pasted on the skin surface as a wearable device for real-time monitoring of multiple physiological parameters. An AISP sensor-based swallowing recognition technique has been proposed with a high accuracy of up to 88.89%. Likewise, it has been expanded to a remote nursing assistance system to meet critical patients' physiological requirements and daily care. The hands-free communication experiment and robot control applications have also been successfully conducted based on the constructed system. Such merits demonstrate its potential as a medical toolkit and indicate promise for intelligent healthcare.

The Bacillus cereus toxin alveolysin disrupts the intestinal epithelial barrier by inducing microtubule disorganization through CFAP100.

Bacillus cereus is a Gram-positive bacterium that mainly causes self-limiting emetic or diarrheal illness but can also cause skin infections and bacteremia. Symptoms of B. cereus ingestion depend on the production of various toxins that target the gastric and intestinal epithelia. From a screen of bacterial isolates from human stool samples that compromised intestinal barrier function in mice, we identified a strain of B. cereus that disrupted tight and adherens junctions in the intestinal epithelium. This activity was mediated by the pore-forming exotoxin alveolysin, which increased the production of the membrane-anchored protein CD59 and of cilia- and flagella-associated protein 100 (CFAP100) in intestinal epithelial cells. In vitro, CFAP100 interacted with microtubules and promoted microtubule polymerization. CFAP100 overexpression stabilized microtubules in intestinal epithelial cells, leading to disorganization of the microtubule network and perturbation of tight and adherens junctions. The disruption of cell junctions by alveolysin depended on the increase in CFAP100, which in turn depended on CD59 and the activation of PI3K-AKT signaling. These findings demonstrate that, in addition to forming membrane pores, B. cereus alveolysin can permeabilize the intestinal epithelium by disrupting epithelial cell junctions in a manner that is consistent with intestinal symptoms and may allow the bacteria to escape the intestine and cause systemic infections. Our results suggest the potential value of targeting alveolysin or CFAP100 to prevent B. cereus-associated intestinal diseases and systemic infections.

Acid-Ionizable Iron Nanoadjuvant Augments STING Activation for Personalized Vaccination Immunotherapy of Cancer.

The critical challenge for cancer vaccine-induced T-cell immunity is the sustained activation of antigen cross-presentation in antigen-presenting cells (APCs) with innate immune stimulation. In this study, it is first discovered that the clinically used magnetic contrast agents, iron oxide nanoparticles (IONPs), markedly augment the type-I interferon (IFN-I) production profile of the stimulator of interferon genes (STING) agonist MSA-2 and achieve a 16-fold dosage-sparing effect in the human STING haplotype. Acid-ionizable copolymers are coassembled with IONPs and MSA-2 into iron nanoadjuvants to concentrate STING activation in the draining lymph nodes. The top candidate iron nanoadjuvant (PEIM) efficiently delivers the model antigen ovalbumin (OVA) to CD169+ APCs and facilitates antigen cross-presentation to elicit a 55-fold greater frequency of antigen-specific CD8+ cytotoxic T-lymphocyte response than soluble antigen. PEIM@OVA nanovaccine immunization induces potent and durable antitumor immunity to prevent tumor lung metastasis and eliminate established tumors. Moreover, PEIM nanoadjuvant is applicable to deliver autologous tumor antigen and synergizes with immune checkpoint blockade therapy for prevention of postoperative tumor recurrence and distant metastasis in B16-OVA melanoma and MC38 colorectal tumor models. The acid-ionizable iron nanoadjuvant offers a generalizable and readily translatable strategy to augment STING cascade activation and antigen cross-presentation for personalized cancer vaccination immunotherapy.

CRISPR/Cas9-Mediated Mutagenesis of Antennapedia in Spodoptera frugiperda.

The homeotic gene Antennapedia (Antp) has been identified as playing a pivotal role in the morphogenesis of the thorax and wings across various insect species. Leveraging insights from previous studies, the functional characterization of Antp in S. frugiperda was undertaken using RT-qPCR and the CRISPR/Cas9 genome-editing system. Phylogenetic analyses indicate that Antp shares a high degree of sequence homology among Lepidoptera species. The expression profile of SfAntp was detected by RT-qPCR. The results showed that SfAntp was expressed in the whole growth cycle of S. frugiperda, the expression level was the highest in the egg stage, and the expression level was higher from 12 h to 48 h. Tissue-specific expression profiling demonstrated that SfAntp was most abundantly expressed in the thoracic segments and legs. To functionally disrupt SfAntp, two sgRNA sites were designed at the first exon of SfAntp and the gene was knocked out by CRISPR/Cas9 via microinjection. The results showed that the deletion of SfAntp produced a mutant phenotype of thoracic fusion, thoracic leg defect, leg-like protrusions between the head and thoracic segments and pupation deformity. In addition, deletion of SfAntp resulted in high embryo mortality. Through DNA sequencing, it was found that the target site of the SfAntp mutant had different degrees of frameshift mutations, indicating that the mutant phenotype was indeed caused by the knockout of SfAntp.

Inhibition of O-GlcNAc transferase activates type I interferon-dependent antitumor immunity by bridging cGAS-STING pathway.

The O-GlcNAc transferase (OGT) is an essential enzyme that mediates protein O-GlcNAcylation, a unique form of posttranslational modification of many nuclear and cytosolic proteins. Recent studies observed increased OGT and O-GlcNAcylation levels in a broad range of human cancer tissues compared to adjacent normal tissues, indicating a universal effect of OGT in promoting tumorigenesis. Here, we show that OGT is essential for tumor growth in immunocompetent hosts by repressing the cyclic GMP-AMP synthase (cGAS)-dependent DNA sensing pathway. We found that deletion of OGT (Ogt-/-) caused a marked reduction in tumor growth in both syngeneic tumor models and a genetic colorectal cancer (CRC) model induced by mutation of the Apc gene (Apcmin). Pharmacological inhibition or genetic deletion of OGT induced a robust genomic instability (GIN), leading to cGAS-dependent production of the type I interferon (IFN-I) and IFN-stimulated genes (ISGs). As a result, deletion of Cgas or Sting from Ogt-/- cancer cells restored tumor growth, and this correlated with impaired CD8+ T cell-mediated antitumor immunity. Mechanistically, we found that OGT-dependent cleavage of host cell factor C1 (HCF-1) is required for the avoidance of GIN and IFN-I production in tumors. In summary, our results identify OGT-mediated genomic stability and activate cGAS-STING pathway as an important tumor cell-intrinsic mechanism to repress antitumor immunity.

Relationship between left ventricular mechanical synchrony and left ventricular systolic function: a CZT-SPECT analysis.

BACKGROUND: CZT-SPECT has good agreement in the evaluation of mechanical synchronization compared with conventional SPECT. The aim of this study was to evaluate the correlation between left ventricular mechanical contraction synchrony and left ventricular systolic function by gated myocardial perfusion imaging (GMPI) using cadmium-zine-telluride (CZT) single photon emission computed tomography (SPECT). METHODS: This retrospective study involved 371 patients (239 males and 132 females, mean age 61.06 ± 11.78 years old) who underwent GMPI at the Nuclear Medicine Department of Shanxi Cardiovascular Hospital from January 2020 to August 2020. Systolic synchrony parameters and left ventricular systolic function parameters were calculated via Emory Cardiac Toolbox, including PP, PSD, PHB, HS, HK, EDV, ESV, and LVEF. Based on LVEF value, patients were divided into the severe reduction group (group 1, 127 cases, EF < 35%), moderate reduction group (group 2, 47 cases, 35% ≤ EF < 45%), mild reduction group (group 3, 50 cases, 45% ≤ EF < 50%) and normal group (group 4, 147 cases, EF ≥ 50%). Differences in PP, PSD, PHB, HS and HK among the four groups were compared using one-way ANOVA. Differences between two groups were compared using LSD-t test. The correlation among functional and mechanical contraction synchrony factors were analyzed using Pearson test. RESULTS: PP, PSD, PHB, HS and HK were significantly different among the four groups (F = 5.20, 188.72, 202.88, 171.05, 101.36, P < 0.001). Pairwise comparison tests showed significant differences in PSD and PHB in each two groups, and HS and HK in each two groups except for group 2 and 3 (t = 0.28 and 0.39, both P > 0.001). PP was significantly higher in group 1, relative to group 3 (t = 2.43, P < 0.001) and group 4 (t = 3.67, P < 0.001). Pearson correlation analysis revealed that LVEF negatively correlates with PP, PSD, PHB (r = 0.194, - 0.790, - 0.799, all P < 0.001). HS and HK showed positive correlation for LVEF (r = 0.778 and 0.795, P < 0.001), PSD, PHB and ESV were had good positive correlation (r = 0.778, 0.795, P < 0.001), PSD, PHB and EDV had good positive correlation (r = 0.722, 0.732, P < 0.001). However, PP had poor correlation with EDV (r = 0.095, P > 0.001). HS and HK were negatively correlated with EDV and ESV (r = - 0.700 to - 0.594, P < 0.001). CONCLUSION: CZT SPECT GMPI provided left ventricular mechanical contraction synchrony parameters that correlated well with left ventricular systolic function. Worse left ventricular mechanical contraction synchrony lead to decreased LVEF, making the systolic synchrony parameters valuable in the prediction of left ventricular systolic function.

Enzyme-like copper-encapsulating magnetic nanoassemblies for switchable T1-weighted MRI and potentiating chemo-/photo-dynamic therapy.

Photodynamic therapy (PDT) has become a promising cancer treatment due to in situ generation of cytotoxic reactive oxygen (ROS); however, it remains limited by the hypoxia of tumor microenvironment (TME) and penetration depth of laser. Herein, we developed a kind of GSH-/H2O2-responsive copper-encapsulating magnetic nanoassemblies (MNSs) for switchable T1-weighted magnetic resonance imaging (MRI) and enzyme-like activity potentiating PDT of cancer. MNSs were rationally constructed using the chelation effect of copper ions (Cu2+) with polyacrylic acid-coated ultrasmall iron oxide nanoparticles (UIONPs). After uptake by tumor cells, the incorporated Cu2+ of MNSs was reduced to Cu+ through the intracellular GSH, which resulted in the disassembly of MNSs accompanied by the "silenced" MR signal shifting to a positive state. Sequentially, the generated Cu+ manifested peroxidase-like activity, catalyzing local H2O2 in TME to cytotoxic ·OH for chemodynamic therapy. Furthermore, Cu2+ and UIONPs could decompose H2O2 to O2, thus providing extra oxygen necessary for enhancing the PDT effect of photosensitizer IR-780. Finally, IR-780-loading MNSs (MNSs@IR-780) under laser irradiation significantly inhibited tumor growth and prolonged the survival of gastric MGC-803 tumor-bearing mice. Therefore, this study provides a versatile nanoplatform as a tumor-responsive theragnostic agent. STATEMENT OF SIGNIFICANCE: Tumor hypoxia and penetration depth of laser severely hindered the PDT of cancer. Valence-convertible metal ions (VCMI, e.g., Cu2+/Cu+, Fe3+/Fe2+) have been reported as Fenton-like agents disintegrating H2O2 to O2 to enhance PDT. Tumor-delivery of VCMI is of essential importance for in situ triggering of a Fenton-like reaction. We thereby developed magnetic nanoassemblies (MNSs) to encapsulate Cu2+ and load photosensitizer (IR-780). Stimulated by GSH and H2O2, MNSs performed catalase/peroxidase-like activity that provided extra O2 for PDT and catalyzed H2O2 to ·OH for CDT. Consequently, IR-780-loading MNSs under laser irradiation significantly inhibit the tumor growth due to effective tumor delivery of Cu2+ and IR-780. This study might offer a feasible nanoplatform for tumor-delivery of metal ions and drugs.

Performances of whole-brain dynamic and static functional connectivity fingerprinting in machine learning-based classification of major depressive disorder.

Background: Alterations in static and dynamic functional connectivity during resting state have been widely reported in major depressive disorder (MDD). The objective of this study was to compare the performances of whole-brain dynamic and static functional connectivity combined with machine learning approach in differentiating MDD patients from healthy controls at the individual subject level. Given the dynamic nature of brain activity, we hypothesized that dynamic connectivity would outperform static connectivity in the classification. Methods: Seventy-one MDD patients and seventy-one well-matched healthy controls underwent resting-state functional magnetic resonance imaging scans. Whole-brain dynamic and static functional connectivity patterns were calculated and utilized as classification features. Linear kernel support vector machine was employed to design the classifier and a leave-one-out cross-validation strategy was used to assess classifier performance. Results: Experimental results of dynamic functional connectivity-based classification showed that MDD patients could be discriminated from healthy controls with an excellent accuracy of 100% irrespective of whether or not global signal regression (GSR) was performed (permutation test with P < 0.0002). Brain regions with the most discriminating dynamic connectivity were mainly and reliably located within the default mode network, cerebellum, and subcortical network. In contrast, the static functional connectivity-based classifiers exhibited unstable classification performances, i.e., a low accuracy of 38.0% without GSR (P = 0.9926) while a high accuracy of 96.5% with GSR (P < 0.0002); moreover, there was a considerable variability in the distribution of brain regions with static connectivity most informative for classification. Conclusion: These findings suggest the superiority of dynamic functional connectivity in machine learning-based classification of depression, which may be helpful for a better understanding of the neural basis of MDD as well as for the development of effective computer-aided diagnosis tools in clinical settings.

Superlarge living hyaline cartilage graft contributed by the scale-changed porous 3D culture system for joint defect repair.

It is known that an excellent hyaline cartilage phenotype, an internal microstructure with safe crosslinking and available size flexibility are the key factors of cartilage grafts that allow for clinical application. Living hyaline cartilage grafts (LhCGs) constructed by phase-transfer hydrogel (PTCC) systems were reported to have a hyaline phenotype and bionic microstructure. By employing chondrocytes to secrete matrix in the hydrogel and then removing the material to obtain material-free tissuein vitro, LhCG technology exhibited superior performance in cartilage repair. However, PTCC systems could only produce small-sized LhCGs because of medium delivery limitations, which hinders the clinical application of LhCGs. In this study, we prepared three different noncrosslinked gelatin microspheres with diameters from 200 µm to 500 µm, which replaced the original pore-forming agent. The new PTCC system with the mixed and gradient porous structure was used for the preparation of superlarge LhCGs with a continuous structure and hyaline phenotype. Compared to the original technique, the porous gradient structure promoted nutrient delivery and cartilage matrix secretion. The small size of the microporous structure promoted the rapid formation of matrix junctions. The experimental group with a mixed gradient increased cartilage matrix secretion significantly by more than 50% compared to the that of the control. The LhCG final area reached 7 cm2without obvious matrix stratification in the mixed gradient group. The design of the scale-changed porous PTCC system will make LhCGs more promising for clinical application.

Comparative transcriptomics reveals new insights into melatonin-enhanced drought tolerance in naked oat seedlings.

The growth and development of naked oat (Avena nuda L.) seedlings, a grain recognized as nutritious and healthy, is limited by drought. Melatonin plays a positive role in plants under drought stress. However, its function is unclear in naked oats. This study demonstrated that melatonin enhances drought stress tolerance in oat seedlings. Melatonin application alleviated the declining growth parameters of two naked oat varieties, Huazao No.2 (H2) and Jizhangyou No.15 (J15), under drought stress by increasing the chlorophyll content and photosynthetic rate of leaves. Melatonin pretreatment induced differential gene expression in H2 and J15 under drought stress. Subsequently, the differential gene expression responses to melatonin in the two varieties were further analyzed. The key drought response transcription factors and the regulatory effect of melatonin on drought-related transcription factors were assessed, focusing on genes encoding proteins in the ABA signal transduction pathway, including PYL, PP2C, ABF, SNRK2, and IAA. Taken together, this study provides new insights into the effect and underlying mechanism of melatonin in alleviating drought stress in naked oat seedlings.

Effects of drought stress during critical periods on the photosynthetic characteristics and production performance of Naked oat (Avena nuda L.).

Revealing the effects of drought stress on the photosynthetic characteristics and yield of naked oats (Avena nuda L.) is significant for enhancing the productivity of oats. In this study, a potted experiment consisting of four water levels was conducted in the Bashang area of Hebei Province, China. The drought stress period was established as the continual 8 days during the jointing-heading stage. The aims were to reveal the impacts of drought stress on the photosynthetic characteristics and yield of naked oats during the critical stage. The results showed that the photosynthetic rate (Pn), transpiration rate (Tr), and stomatal conductance (Gs) decreased under all conditions of drought stress. The intercellular CO2 concentration (Ci) decreased under light drought stress, while it increased under moderate and severe drought stress. The initial chlorophyll fluorescence rate (Fo) increased by 9.03-50.92% under drought stress, and the maximum fluorescence rate (Fm) decreased by 8.49-19.73% under drought stress. The photochemical efficiency (Fv/Fm) increased by 10.37-24.12% under drought stress. The yields decreased by 9.5-12.7%, 16.8-27.0% and 44.1-47.7% under light, moderate and severe drought stress during the critical stage, respectively. The grains per panicle decreased by 1.7-12.5%, 8.3-24.3% and 32.7-34.2% under light, moderate and severe drought stress conditions, respectively. The 1000-grain weight decreased by 5.7-8.6%, 12.7-14.5% and 16.8-19.1% under light, moderate and severe drought stress conditions, respectively. The panicle numbers did not vary significantly among the different drought stress treatments. The photosynthetic rate, stomatal conductance and transpiration all had significant positive relationships with the yield of naked oat (P < 0.01). Parameters of PS II except for Fo all had significant positive relationships with the yield of naked oats (P < 0.05). This study is significant for enhancing the production efficiency of naked oat under drought stress.

Bispecific prodrug nanoparticles circumventing multiple immune resistance mechanisms for promoting cancer immunotherapy.

Cancer immunotherapy is impaired by the intrinsic and adaptive immune resistance. Herein, a bispecific prodrug nanoparticle was engineered for circumventing immune evasion of the tumor cells by targeting multiple immune resistance mechanisms. A disulfide bond-linked bispecific prodrug of NLG919 and JQ1 (namely NJ) was synthesized and self-assembled into a prodrug nanoparticle, which was subsequently coated with a photosensitizer-modified and tumor acidity-activatable diblock copolymer PHP for tumor-specific delivery of NJ. Upon tumor accumulation via passive tumor targeting, the polymeric shell was detached for facilitating intracellular uptake of the bispecific prodrug. NJ was then activated inside the tumor cells for releasing JQ1 and NLG919 via glutathione-mediated cleavage of the disulfide bond. JQ1 is a bromodomain-containing protein 4 inhibitor for abolishing interferon gamma-triggered expression of programmed death ligand 1. In contrast, NLG919 suppresses indoleamine-2,3-dioxygenase 1-mediated tryptophan consumption in the tumor microenvironment, which thus restores robust antitumor immune responses. Photodynamic therapy (PDT) was performed to elicit antitumor immunogenicity by triggering immunogenic cell death of the tumor cells. The combination of PDT and the bispecific prodrug nanoparticle might represent a novel strategy for blockading multiple immune evasion pathways and improving cancer immunotherapy.

Regulation of the HBV Entry Receptor NTCP and its Potential in Hepatitis B Treatment.

Hepatitis B virus (HBV) is a globally prevalent human DNA virus responsible for more than 250 million cases of chronic liver infection, a condition that can lead to liver inflammation, cirrhosis, and hepatocellular carcinoma. Sodium taurocholate co-transporting polypeptide (NTCP), a transmembrane protein highly expressed in human hepatocytes and a mediator of bile acid transport, has been identified as the receptor responsible for the cellular entry of both HBV and its satellite, hepatitis delta virus (HDV). This has led to significant advances in our understanding of the HBV life cycle, especially the early steps of infection. HepG2-NTCP cells and human NTCP-expressing transgenic mice have been employed as the primary cell culture and animal models, respectively, for the study of HBV, and represent valuable approaches for investigating its basic biology and developing treatments for infection. However, the mechanisms involved in the regulation of NTCP transcription, translation, post-translational modification, and transport are still largely elusive. Improvements in our understanding of NTCP biology would likely facilitate the design of new therapeutic drugs for the prevention of the de novo infection of naïve hepatocytes. In this review, we provide critical findings regarding NTCP biology and discuss important questions that remain unanswered.

Bioinspired Stretchable Fiber-Based Sensor toward Intelligent Human-Machine Interactions.

Wearable integrated sensing devices with flexible electronic elements exhibit enormous potential in human-machine interfaces (HMI), but they have limitations such as complex structures, poor waterproofness, and electromagnetic interference. Herein, inspired by the profile of Lindernia nummularifolia (LN), a bionic stretchable optical strain (BSOS) sensor composed of an LN-shaped optical fiber incorporated with a stretchable substrate is developed for intelligent HMI. Such a sensor enables large strain and bending angle measurements with temperature self-compensation by the intensity difference of two fiber Bragg gratings' (FBGs') center wavelength. Such configurations enable an excellent tensile strain range of up to 80%, moreover, leading to ultrasensitivity, durability (≥20,000 cycles), and waterproofness. The sensor is also capable of measuring different human activities and achieving HMI control, including immersive virtual reality, robot remote interactive control, and personal hands-free communication. Combined with the machine learning technique, gesture classification can be achieved using muscle activity signals captured from the BSOS sensor, which can be employed to obtain the motion intention of the prosthetic. These merits effectively indicate its potential as a solution for medical care HMI and show promise in smart medical and rehabilitation medicine.

INPP5E and Coordination of Signaling Networks in Cilia.

Primary cilia are ubiquitous mechanosensory organelles that specifically coordinate a series of cellular signal transduction pathways to control cellular physiological processes during development and in tissue homeostasis. Defects in the function or structure of primary cilia have been shown to be associated with a large range of diseases called ciliopathies. Inositol polyphosphate-5-phosphatase E (INPP5E) is an inositol polyphosphate 5-phosphatase that is localized on the ciliary membrane by anchorage via its C-terminal prenyl moiety and hydrolyzes both phosphatidylinositol-4, 5-bisphosphate (PtdIns(4,5)P2) and PtdIns(3,4,5)P3, leading to changes in the phosphoinositide metabolism, thereby resulting in a specific phosphoinositide distribution and ensuring proper localization and trafficking of proteins in primary cilia. In addition, INPP5E also works synergistically with cilia membrane-related proteins by playing key roles in the development and maintenance homeostasis of cilia. The mutation of INPP5E will cause deficiency of primary cilia signaling transduction, ciliary instability and ciliopathies. Here, we present an overview of the role of INPP5E and its coordination of signaling networks in primary cilia.