Mannan-Decorated Lipid Calcium Phosphate Nanoparticle Vaccine Increased the Antitumor Immune Response by Modulating the Tumor Microenvironment.

With the rapid development of tumor immunotherapy, nanoparticle vaccines have attracted much attention as potential therapeutic strategies. A systematic review and analysis must be carried out to investigate the effect of mannose modification on the immune response to nanoparticles in regulating the tumor microenvironment, as well as to explore its potential clinical application in tumor therapy. Despite the potential advantages of nanoparticle vaccines in immunotherapy, achieving an effective immune response in the tumor microenvironment remains a challenge. Tumor immune escape and the overexpression of immunosuppressive factors limit its clinical application. Therefore, our review explored how to intervene in the immunosuppressive mechanism in the tumor microenvironment through the use of mannan-decorated lipid calcium phosphate nanoparticle vaccines to improve the efficacy of immunotherapy in patients with tumors and to provide new ideas and strategies for the field of tumor therapy.

Repair Engineering of Crystal Structure in van der Waals Materials by Probe Electron Beam.

The advancement of electronic technology has led to increasing research on performance and stability. Continuous electrical pulse stimulation can cause crystal structure changes, affecting performance and accelerating aging. Controlled repair of these defects is crucial. In this study, we investigated crystal structure changes in van der Waals (vdW) InSe crystals under continuous electric pulses by using electron beam lithography (EBL) and spherical aberration corrected transmission electron microscopy (Cs-TEM). Results show that electrical pulses induce amorphous regions in the InSe lattice, increasing the device resistance. We used Cs-STEM probe scanning for precise repair, abbreviated SPRT, to optimize device performance. SPRT is related to electric fields induced by the electron beam and can be applied to other 2D materials like α-In2Se3 and CrSe2, offering a potential approach to extend device lifespan.

Insulin enhances acid-sensing ion channel currents in rat primary sensory neurons.

Insulin has been shown to modulate neuronal processes through insulin receptors. The ion channels located on neurons may be important targets for insulin/insulin receptor signaling. Both insulin receptors and acid-sensing ion channels (ASICs) are expressed in dorsal root ganglia (DRG) neurons. However, it is still unclear whether there is an interaction between them. Therefore, the purpose of this investigation was to determine the effects of insulin on the functional activity of ASICs. A 5 min application of insulin rapidly enhanced acid-evoked ASIC currents in rat DRG neurons in a concentration-dependent manner. Insulin shifted the concentration-response plot for ASIC currents upward, with an increase of 46.2 ± 7.6% in the maximal current response. The insulin-induced increase in ASIC currents was eliminated by the insulin receptor antagonist GSK1838705, the tyrosine kinase inhibitor lavendustin A, and the phosphatidylinositol-3 kinase antagonist wortmannin. Moreover, insulin increased the number of acid-triggered action potentials by activating insulin receptors. Finally, local administration of insulin exacerbated the spontaneous nociceptive behaviors induced by intraplantar acid injection and the mechanical hyperalgesia induced by intramuscular acid injections through peripheral insulin receptors. These results suggested that insulin/insulin receptor signaling enhanced the functional activity of ASICs via tyrosine kinase and phosphatidylinositol-3 kinase pathways. Our findings revealed that ASICs were targets in primary sensory neurons for insulin receptor signaling, which may underlie insulin modulation of pain.

CXCL10 Enhances Acid-Sensing Ion Channel Currents in Rat Dorsal Root.

Both CXCL10/CXCR3 and acid-sensing ion channels (ASICs) are expressed in nociceptive sensory neurons and participate in various pain processes, but it is still unclear whether there is a link between them. Herein, we report that CXCL10 enhances the electrophysiological activity of ASICs in rat dorsal root ganglia (DRG) neurons. A brief (10 min) application of CXCL10 increased acid-evoked ASIC currents in a concentration-dependent manner. CXCL10 increased the maximum response of ASICs to acidic stimuli without changing their sensitivity. CXCL10 enhanced ASIC currents in DRG cells through CXCR3, as this enhancement was completely blocked by AMG487, a selective CXCR3 antagonist. CXCL10 also increased ASIC3 currents in CHO cells coexpressing ASIC3 and CXCR3 but not in cells expressing ASIC3 alone. The CXCL10-mediated increase in ASIC currents was prevented by the application of either the G protein inhibitor GDP-ß-S or the p38 mitogen-activated protein kinase (MAPK) inhibitor SB202190 but not by the ERK inhibitor U0126 or the JNK inhibitor SP600125. Moreover, CXCL10 increased the number of action potentials triggered by acidic stimuli via CXCR3. CXCL10 dose-dependently exacerbated acid-induced nociceptive behavior in rats through peripheral CXCR3. These results indicated that CXCL10/CXCR3 signaling enhanced ASIC-mediated electrophysiological activity in DRG neurons and nociception in rats via a p38 MAPK-dependent pathway, revealing a novel mechanism underlying pain. CXCL10/CXCR3 signaling may be an effective target in the treatment of pain associated with tissue acidification.

Combining single-cell and bulk RNA sequencing, NK cell marker genes reveal a prognostic and immune status in pancreatic ductal adenocarcinoma.

The NK cell is an important component of the tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC), also plays a significant role in PDAC development. This study aimed to explore the relationship between NK cell marker genes and prognosis, immune response of PDAC patients. By scRNA-seq data, we found the proportion of NK cells were significantly downregulated in PDAC and 373 NK cell marker genes were screened out. By TCGA database, we enrolled 7 NK cell marker genes to construct the signature for predicting prognosis in PDAC patients. Cox analysis identified the signature as an independent factor for pancreatic cancer. Subsequently, the predictive power of signature was validated by 6 GEO datasets and had an excellent evaluation. Our analysis of relationship between the signature and patients' immune status revealed that the signature has a strong correlation with immunocyte infiltration, inflammatory reaction, immune checkpoint inhibitors (ICIs) response. The NK cell marker genes are closely related to the prognosis and immune capacity of PDAC patients, and they have potential value as a therapeutic target.

Peer learning is both preferable and less expensive than score-based peer review: Initial experience at a tertiary academic center.

PURPOSE: To examine radiologist experiences and perceptions during a transition from score-based peer review to a peer learning program, and to assess differences in time-cost efficiency between the two models of quality improvement. METHODS: Differences in Likert scale survey responses from radiologists (N = 27) in a multispecialty group at a single tertiary academic center before and following intervention were evaluated by Mann-Whitney U test. Multiple variable linear regression analysis assessed independent variables and program preference. RESULTS: All positive impacts rated significantly higher for the peer learning program. Workflow disruption for the peer learning program rated significantly lower. 70.4 % (19 of 27) preferred the new program, and 25.9 % (7 of 27) preferred the old program. Only the "worth investment" questionnaire score demonstrated a significant correlation to program preference and with an effect that was greatest among all variables (Beta = 1.11, p = 0.02). There was a significantly decreased amount of time per month used to complete peer learning exercises (0.76 ± 0.45 h, N = 27) versus peer review exercises (1.71 ± 1.84 h, N = 34, p = 0.011). The result was a difference of 0.95 ± 1.89 h/month (11.4 ± 22.7 h/year), translating to an estimated direct salary time-cost saving of $1653.68/year/radiologists and a direct productivity time-cost saving of $3469.39/year/radiologist when utilizing the peer learning program. CONCLUSIONS: There was a strongly positive perception of the new peer learning program. There was a substantial implied direct time-cost saving from the transition to the peer learning program. PRECIS: The peer learning model emphasizes learning from errors via feedback in a non-punitive environment. This model was positively perceived and demonstrated substantial implied direct time-cost saving.

Pulmonary Alveolar Proteinosis-associated Pulmonary Fibrosis: Evolutional Changes and Radiologic-Pathologic Correlation.

Pulmonary alveolar proteinosis (PAP) is a rare disease with frequently favorable outcomes. In a minority of patients with primary or secondary PAP, the disease course may be complicated by pulmonary fibrosis (PF) despite appropriate management. Imaging and histopathologic manifestations of uncomplicated PAP are well-known. In contrast, radiologic-pathologic descriptions of PAP-associated PF (PAP-PF) are limited. The current manuscript presents three cases of PAP-PF, each with serial high-resolution CT imaging demonstrating the longitudinal progression of this unusual complication, with concordant pathologic findings in two patients. Much remains to be known regarding adverse prognostic factors contributing to PAP-PF. Early recognition of radiologic-pathologic manifestations would allow timely diagnosis and management optimization. Keywords: CT, Lung, Inflammation, Pathology © RSNA, 2023.

Lipid mediator resolvin D2 inhibits ATP currents in rat primary sensory neurons.

Resolvin D2 (RvD2), an endogenous lipid mediator derived from docosahexaenoic acid, has been demonstrated to have analgesic effects. However, little is known about the mechanism underlying RvD2 in pain relief. Herein, we demonstrate that RvD2 targeted the P2X3 receptor as an analgesic. The electrophysiological activity of P2X3 receptors was suppressed by RvD2 in rat dorsal root ganglia (DRG) neurons. RvD2 pre-application dose-dependently decreased α,ß-methylene-ATP (α,ß-meATP)-induced inward currents. RvD2 remarkably decreased the maximum response to α,ß-meATP, without influencing the affinity of P2X3 receptors. RvD2 also voltage-independently suppressed ATP currents. An antagonist of the G protein receptor 18 (GPR18), O-1918, prevented the RvD2-induced suppression of ATP currents. Additionally, intracellular dialysis of the Gαi/o -protein antagonist pertussis toxin (PTX), the PKA antagonist H89, or the cAMP analog 8-Br-cAMP also blocked the RvD2-induced suppression. Furthermore, α,ß-meATP-triggered depolarization of membrane potential along with the action potential bursts in DRG neurons were inhibited by RvD2. Lastly, RvD2 attenuated spontaneous nociceptive behaviors as well as mechanical allodynia produced by α,ß-meATP in rats via the activation of the peripheral GPR18. These findings indicated that RvD2 inhibited P2X3 receptors in rat primary sensory neurons through GPR18, PTX-sensitive Gαi/o -proteins, and intracellular cAMP/PKA signaling, revealing a novel mechanism that underlies its analgesic effects by targeting P2X3 receptors.

CCK-8 enhances acid-sensing ion channel currents in rat primary sensory neurons.

Cholecystokinin (CCK) is a peptide that has been implicated in pain modulation. Acid sensitive ion channels (ASICs) also play an important role in pain associated with tissue acidification. However, it is still unclear whether there is an interaction between CCK signaling and ASICs during pain process. Herein, we report that a functional link between them in rat dorsal root ganglion (DRG) neurons. Pretreatment with CCK-8 concentration-dependently increased acid-evoked ASIC currents. CCK-8 increased the maximum response of ASICs to acid, but did not changed their acid sensitivity. Enhancement of ASIC currents by CCK-8 was mediated by the stimulation of CCK2 receptor (CCK2R), rather than CCK1R. The enhancement of ASIC currents by CCK-8 was prevented by application of either G-protein inhibitor GDP-ß-S or protein kinase C (PKC) inhibitor GF109203×, but not by protein kinase A (PKA) inhibitor H-89 or JNK inhibitor SP600125. Moreover, CCK-8 increased the number of action potentials triggered by acid stimuli by activating CCK2R. Finally, CCK-8 dose-dependently exacerbated acid-induced nociceptive behavior in rats through local CCK2R. Together, these results indicated that CCK-8/CCK2R activation enhanced ASIC-mediated electrophysiological activity in DRG neurons and nociception in rats. The enhancement effect depended on G-proteins and intracellular PKC signaling rather than PKA and JNK signaling pathway. These findings provided that CCK-8/CCK2R is an important therapeutic target for ASIC-mediated pain.

Heat- and Pressure-driven Room-temperature Polymorphic Transition Accompanied with Switchable SHG Signal in a New Chiral Hexagonal Perovskite.

Endowing room-temperature polymorphs with both long-term stability and easy interconvertibility is a big challenge due to the complexity of intermolecular interactions. Herein, we present a chiral hexagonal perovskite (R-3-hydroxy-1-methylpiperidinium)[CdCl3 ] having two room-temperature crystalline forms featuring obviously distinct second-harmonic-generation (SHG) signals with a high switching contrast of ~18 times. The two room-temperature forms could be long-term stable yet easily interconvertible through an irreversible thermal-induced phase transition and a pressure-driven backward transition, by switching hydrogen bonds via collective reorientation of ordered homochiral cations. Based on the essential role of homochiral organic cations in inducing switchable hydrogen bond linkages, this present instance provides good evidence that relatively irregular organic cations could induce more obvious inorganic chain deformations, thus endowing polymorphs with significantly different SHG signals at room temperature.

Simultaneous manipulation of spatial fundamental and harmonic electromagnetic waves by microwave nonlinear metasurfaces.

In the area of manipulating the spatial electromagnetic (EM) waves fields, the metasurfaces have become much more attractive and powerful in recent years. Here, we propose a design to realize the simultaneous control of spatial fundamental and harmonic EM waves applying nonlinear metasurfaces in microwave band. The proposed meta-atom composed of three topological layers which are transmitting antenna, nonlinear wave guiding and receiving antenna respectively. And the critical factor of generating the harmonic is the nonlinear chip which is integrated into the middle layer. The microstrip power divider and phase shifter in each meta-atom are preciously tailored to actualize the spatial control of the fundamental and harmonic transmission beams in the far field. One prototype of the nonlinear metasurfaces is fabricated and corresponding radiation patterns of fundamental and harmonic modes are observed very well in the experience that can verify the validity of our proposed method.

CDC23 knockdown suppresses the proliferation, migration and invasion of liver cancer via the EMT process.

Liver cancer (LC) is a malignant tumour that is associated with high mortality rates worldwide. Cell division cycle 23 (CDC23) acts as an oncogene in papillary thyroid cancer. In addition, epithelial-mesenchymal transition (EMT) is frequently involved in the malignant metastasis of various cancer types. Therefore, we hypothesized that CDC23 may regulate the malignant biological behaviours of LC cells through EMT. Proliferation, colony formation and Transwell assays, western blotting and xenograft experiments were performed. The results of the present study showed that CDC23 was highly expressed in LC cell lines. In addition, it was found via multiple in vitro assays that CDC23 knockdown reduced the proliferation, migration and invasion of LC cell lines. Finally, an in vivo study confirmed that CDC23 knockdown inhibited the growth of xenograft LC in nude mice. More importantly, the changes in the levels of EMT-related marker proteins were analysed in the sh-CDC23 group compared with the sh-NC group of cells and xenografts. E-cadherin was upregulated, and N-cadherin and vimentin were significantly downregulated after CDC23 silencing. Taken together, these results revealed that the knockdown of CDC23 inhibits the progression of LC by regulating EMT and that CDC23 may be a novel therapeutic target for LC.

Metformin inhibits spontaneous excitatory postsynaptic currents in spinal dorsal cord neurons from paclitaxel-treated rats.

Introduction: Cancer patients treated with paclitaxel often develop chemotherapy-induced peripheral neuropathy, which has not been effectively treated with drugs. The anti-diabetic drug metformin is effective in the treatment of neuropathic pain. The aim of this study was to elucidate effect of metformin on paclitaxel-induced neuropathic pain and spinal synaptic transmission. Methods: Electrophysiological experiments on rat spinal slices were performed in vitro and mechanical allodynia quantified in vitro. Results: The present data demonstrated that intraperitoneal injection of paclitaxel produced mechanical allodynia and potentiated spinal synaptic transmission. Intrathecal injection of metformin significantly reversed the established mechanical allodynia induced by paclitaxel in rats. Either spinal or systemic administration of metformin significantly inhibited the increased frequency of spontaneous excitatory postsynaptic currents (sEPSCs) in spinal dorsal horn neurons from paclitaxel-treated rats. We found that 1 h incubation of metformin also reduced the frequency rather than the amplitude of sEPSCs in the spinal slices from paclitaxel-treated rats. Discussion: These results suggested that metformin was able to depress the potentiated spinal synaptic transmission, which may contribute to alleviating the paclitaxel-induced neuropathic pain.

Group II metabotropic glutamate receptor activation attenuates acid-sensing ion channel currents in rat primary sensory neurons.

Acid-sensing ion channels (ASICs) play an important role in pain associated with tissue acidification. Peripheral inhibitory group II metabotropic glutamate receptors (mGluRs) have analgesic effects in a variety of pain conditions. Whether there is a link between ASICs and mGluRs in pain processes is still unclear. Herein, we show that the group II mGluR agonist LY354740 inhibited acid-evoked ASIC currents and action potentials in rat dorsal root ganglia neurons. LY354740 reduced the maximum current response to protons, but it did not change the sensitivity of ASICs to protons. LY354740 inhibited ASIC currents by activating group II mGluRs. We found that the inhibitory effect of LY354740 was blocked by intracellular application of the Gi/o protein inhibitor pertussis toxin and the cAMP analogue 8-Br-cAMP and mimicked by the protein kinase A (PKA) inhibitor H-89. LY354740 also inhibited ASIC3 currents in CHO cells coexpressing mGluR2 and ASIC3 but not in cells expressing ASIC3 alone. In addition, intraplantar injection of LY354740 dose-dependently alleviated acid-induced nociceptive behavior in rats through local group II mGluRs. Together, these results suggested that activation of peripheral group II mGluRs inhibited the functional activity of ASICs through a mechanism that depended on Gi/o proteins and the intracellular cAMP/PKA signaling pathway in rat dorsal root ganglia neurons. We propose that peripheral group II mGluRs are an important therapeutic target for ASIC-mediated pain.

Group II metabotropic glutamate receptor activation suppresses ATP currents in rat dorsal root ganglion neurons.

P2X3 receptors and group II metabotropic glutamate receptors (mGluRs) have been found to be expressed in primary sensory neurons. P2X3 receptors participate in a variety of pain processes, while the activation of mGluRs has an analgesic effect. However, it's still unclear whether there is a link between them in pain. Herein, we reported that the group II mGluR activation inhibited the electrophysiological activity of P2X3 receptors in rat dorsal root ganglia (DRG) neurons. Group II mGluR agonist LY354740 concentration-dependently decreased P2X3 receptor-mediated and α,ß-methylene-ATP (α,ß-meATP)-evoked inward currents in DRG neurons. LY354740 significantly suppressed the maximum response of P2X3 receptor to α,ß-meATP, but did not change their affinity. Inhibition of ATP currents by LY354740 was blocked by the group II mGluR antagonist LY341495, also prevented by the intracellular dialysis of either the Gi/o protein inhibitor pertussis toxin, the cAMP analog 8-Br-cAMP, or the protein kinase A (PKA) inhibitor H-89. Moreover, LY354740 decreased α,ß-meATP-induced membrane potential depolarization and action potential bursts in DRG neurons. Finally, intraplantar injection of LY354740 also relieved α,ß-meATP-induced spontaneous nociceptive behaviors and mechanical allodynia in rats by activating peripheral group Ⅱ mGluRs. These results indicated that peripheral group II mGluR activation inhibited the functional activity of P2X3 receptors via a Gi/o protein and cAMP/PKA signaling pathway in rat DRG neurons, which revealed a novel mechanism underlying analgesic effects of peripheral group II mGluRs. This article is part of the Special Issue on "Purinergic Signaling: 50 years".

Comparison of Survival Outcomes of Chemotherapy Plus Surgery vs Chemotherapy Alone for Patients With Isolated Liver Metastases From Gallbladder Carcinoma.

BACKGROUND: Chemotherapy is the standard of treatment for metastatic gallbladder carcinoma (GBC). It is unclear whether chemotherapy plus surgery improves the survival outcomes of patients with isolated liver metastases from GBC. We aimed to investigate the survival benefits of chemotherapy plus surgery in GBC with isolated liver metastases compared to those of chemotherapy alone. METHODS: We identified 406 patients with isolated liver metastases from GBC who underwent chemotherapy alone or chemotherapy plus surgery between 2010 and 2015 from Surveillance, Epidemiology, and End Results. Patients were divided into 3 subgroups: group I, chemotherapy alone (n = 263); group II, chemotherapy combined with cholecystectomy (n = 116); and group III, chemotherapy combined with cholecystectomy plus hepatectomy (n = 27). The cancer-specific survival and overall survival were evaluated. RESULTS: Compared with group I, group II revealed a longer survival time (P < .001). In addition, the survival time of the group III was also prolonged (P < .001). Multivariate cox analysis showed that treatment strategy was an independent prognostic factor. CONCLUSION: Chemotherapy combined with resection of the primary tumor plus or not plus resection of the metastatic lesions may be beneficial in GBC with isolated liver metastases.

A Maximum Divergence Approach to Optimal Policy in Deep Reinforcement Learning.

Model-free reinforcement learning algorithms based on entropy regularized have achieved good performance in control tasks. Those algorithms consider using the entropy-regularized term for the policy to learn a stochastic policy. This work provides a new perspective that aims to explicitly learn a representation of intrinsic information in state transition to obtain a multimodal stochastic policy, for dealing with the tradeoff between exploration and exploitation. We study a class of Markov decision processes (MDPs) with divergence maximization, called divergence MDPs. The goal of the divergence MDPs is to find an optimal stochastic policy that maximizes the sum of both the expected discounted total rewards and a divergence term, where the divergence function learns the implicit information of state transition. Thus, it can provide better-off stochastic policies to improve both in robustness and performance in a high-dimension continuous setting. Under this framework, the optimality equations can be obtained, and then a divergence actor-critic algorithm is developed based on the divergence policy iteration method to address large-scale continuous problems. The experimental results, compared to other methods, show that our approach achieved better performance and robustness in the complex environment particularly. The code of DivAC can be found in https://github.com/yzyvl/DivAC.

The northern corn leaf blight resistance gene Ht1 encodes an nucleotide-binding, leucine-rich repeat immune receptor.

Northern corn leaf blight, caused by the fungal pathogen Exserohilum turcicum, is a major disease of maize. The first major locus conferring resistance to E. turcicum race 0, Ht1, was identified over 50 years ago, but the underlying gene has remained unknown. We employed a map-based cloning strategy to identify the Ht1 causal gene, which was found to be a coiled-coil nucleotide-binding, leucine-rich repeat (NLR) gene, which we named PH4GP-Ht1. Transgenic testing confirmed that introducing the native PH4GP-Ht1 sequence to a susceptible maize variety resulted in resistance to E. turcicum race 0. A survey of the maize nested association mapping genomes revealed that susceptible Ht1 alleles had very low to no expression of the gene. Overexpression of the susceptible B73 allele, however, did not result in resistant plants, indicating that sequence variations may underlie the difference between resistant and susceptible phenotypes. Modelling of the PH4GP-Ht1 protein indicated that it has structural homology to the Arabidopsis NLR resistance gene ZAR1, and probably forms a similar homopentamer structure following activation. RNA sequencing data from an infection time course revealed that 1 week after inoculation there was a threefold reduction in fungal biomass in the PH4GP-Ht1 transgenic plants compared to wild-type plants. Furthermore, PH4GP-Ht1 transgenics had significantly more inoculation-responsive differentially expressed genes than wild-type plants, with enrichment seen in genes associated with both defence and photosynthesis. These results demonstrate that the NLR PH4GP-Ht1 is the causal gene underlying Ht1, which represents a different mode of action compared to the previously reported wall-associated kinase northern corn leaf blight resistance gene Htn1/Ht2/Ht3.

Community succession of microbial populations related to CNPS biological transformations regulates product maturity during cow-manure-driven composting.

The main objective of present study was to understand the community succession of microbial populations related to carbon-nitrogen-phosphorus-sulfur (CNPS) biogeochemical cycles during cow-manure-driven composting and their correlation with product maturity. The abundance of microbial populations associated with C degradation, nitrification, cellular-P transport, inorganic-P dissolution, and organic-P mineralization decreased gradually with composting but increased at the maturation phase. The abundance of populations related to N-fixation, nitrate-reduction, and ammonification increased during the mesophilic stage and decreased during the thermophilic and maturation stages. The abundance of populations related to C fixation and denitrification increased with composting; however, the latter tended to decrease at the maturation stage. Populations related to organic-P mineralization were the key manipulators regulating compost maturity, followed by those related to denitrification and nitrification; those populations were mediated by inorganic N and available P content. This study highlighted the consequence of microbe-driven P mineralization in improving composting efficiency and product quality.