Nanovaccines Mediated Subcutis-to-Intestine Cascade for Improved Protection against Intestinal Infections.

Parenteral vaccines typically can prime systemic humoral immune response, but with limited effects on cellular and mucosal immunity. Here, a subcutis-to-intestine cascade for navigating nanovaccines to address this limitation is proposed. This five-step cascade includes lymph nodes targeting, uptaken by dendritic cells (DCs), cross-presentation of antigens, increasing CCR9 expression on DCs, and driving CD103+ DCs to mesenteric lymph nodes, in short, the LUCID cascade. Specifically, mesoporous silica nanoparticles are encapsulated with antigen and adjuvant toll-like receptor 9 agonist cytosine-phosphate-guanine oligodeoxynucleotides, and further coated by a lipid bilayer containing all-trans retinoic acid. The fabricated nanovaccines efficiently process the LUCID cascade to dramatically augment cellular and mucosal immune responses. Importantly, after being vaccinated with Salmonella enterica serovar Typhimurium antigen-loaded nanovaccine, the mice generate protective immunity against challenge of S. Typhimurium. These findings reveal the efficacy of nanovaccines mediated subcutis-to-intestine cascade in simultaneously activating cellular and mucosal immune responses against mucosal infections.

The Liexi fauna: a new Lagerstätte from the Lower Ordovician of South China.

The Ordovician Lagerstätten record substantial amounts of excellent preservation and soft-bodied fossils during the Great Ordovician Biodiversification Event (GOBE). However, few Lagerstätten are known from the Lower Ordovician, most of which are preserved in restricted environments and high-latitude regions. Here, we report on a new tropical Lagerstätte, Liexi fauna, which has been recently discovered from a carbonate succession within the Lower Ordovician Madaoyu Formation in western Hunan, South China. It contains a variety of soft tissues, as well as rich shelly fossils, including palaeoscolecidan worms, possible Ottoia, trilobites, echinoderms, sponges, graptolites, polychaetes, bryozoans, conodonts and other fossils. The fauna includes taxa that are not only Cambrian relics, but also taxa originated during the Ordovician, constituting a complex and complete marine ecosystem. The coexistence of the Cambrian relics and Ordovician taxa reveals the critical transition between the Cambrian and Palaeozoic Evolutionary faunas. The unusual Liexi fauna provides new evidence for understanding Ordovician macroevolution and the onset of the GOBE.

[Applying Chitosan-Modified Nanoemulsion in Nasal Vaccine Delivery].

OBJECTIVE: To prepare a chitosan-modified cationic nanoemulsion that could be used to prolong the residence time of nasal vaccines in the nasal cavity and improve the cellular uptake efficiency so as to enhance the immune efficacy of nasal vaccines. METHODS: A nanoemulsion-based vaccine coated with chitosan was prepared, and the particle size, potential, antigen encapsulation efficiency, stability as well as cytotoxicity were examined. The uptake efficiency of vaccine on different cells and the residence time of vaccine in the nasal cavity were measured. Finally, nasal vaccine was administered on mice and the antibody levels in the serum and in the nasal lavage fluids of the immunized mice were examined. RESULTS: The nanoemulsion-based vaccine had an average particle size of (167.2±0.75) nm, a polydispersity index (PDI) of 0.21±0.01, and an average potential of (13.7±0.85) mV. The encapsulation efficiency of antigen was 92.7%. The nanoemulsion-based vaccine had good stability and did not show obvious cytotoxicity in Madin-Darby canine kidney (MDCK) epithelial cells. The vaccine demonstrated relatively high cellular uptake of antigens on DC2.4 and MDCK cells at (49.7±3.45)% and (59.7±2.19)%, respectively. Besides, the cationic nanoemulsion also significantly increased the residence time of the antigen, and a considerable amount of nanoemulsion-based vaccine was found remaining in the nasal cavity 60 minutes after administration. Compared with free antigen and the nanoemulsion without chitosan modification, the chitosan-modified nanoemulsion vaccine induced higher systemic and mucosal antibody levels in mice after nasal immunization ( P<0.01). CONCLUSION: The chitosan-modified nanoemulsion vaccine prepared in the study can enhance the immune efficacy of nasal vaccines, showing great potential to be used as a delivery carrier for nasal vaccines.

Red fluorescent pyrazoline-BODIPY nanoparticles for ultrafast and long-term bioimaging.

Fluorescence bioimaging is very significant in studying biological processes. Fluorescent nanoparticles (NPs) manufactured from aggregation-induced emission (AIE) materials, as promising candidates, have attracted more attention. However, it is still a challenge to explore suitable AIE NPs for bioimaging. Herein, we synthesized pyrazoline-BODIPY (PZL-BDP) with a donor and acceptor (D-A) structure by a condensation reaction, cultured its single crystal, and studied its twisted intramolecular charge transfer (TICT) and AIE effects. PZL-BDP could self-assemble to form red fluorescent nanoparticles (PZL-BDP NPs) which showed a good fluorescence quantum yield of 15.8% in water. PZL-BDP NPs with excellent stability and biocompatibility exhibited a large Stokes shift (Δλ = 111 nm) which resulted in the reduction of external interference and enhancement of the fluorescence contrast. Furthermore, these nanoparticles could be readily internalized by HeLa cells and they stain the cells in just five seconds, indicating an ultrafast bioimaging protocol. Moreover, long-term tracking fluorescence signals in vivo for about 12 days were obtained. The bright red fluorescence, ultrafast cell staining ability, and long-term in vivo tracking competence outline the great potential of rational design nanomaterials with AIE characteristics for monitoring biological processes.

Osthole inhibited the activity of CYP2C9 in human liver microsomes and influenced indomethacin pharmacokinetics in rats.

Osthol, a pharmacologically active ingredient in various traditional Chinese medicines, is predominantly metabolized by CYP2C9. It may be co-administered with other drugs which are metabolized by CYP2C9 in clinical medicine. However, CYP2C9*1/*2/*3 genotype on the pharmacokinetics of osthole and its metabolic diversity between rat and human are unclear.In this study, we investigated the effects of osthole on enzyme activity of CYP2C11/CYP2C9 in rat liver microsomes (RLMs) and human liver microsomes (HLMs), to distinguish metabolic manner of osthole in different species. Interestingly, we found that osthole inhibits the activity of CYP2C11 in a non-competitive manner in RLMs, while inhibits CYP2C9 activity in a competitive manner in pooled HLMs. Then, the effects of CYP2C9*1/*2/*3 allele on the pharmacokinetics of osthole were identified. In human CYP2C9 isoform, the Ki value of 21.93 µM (CYP2C9*1), 18.10 µM (CYP2C9*2), 13.12 µM (CYP2C9*3) indicate that there are individual differences in the inhibition of osthole on CYP2C9 activity.We investigated how the indomethacin pharmacokinetics was affected by osthole in SD rat. To estimate the area under the curve (AUC), maximum plasma concentration (Cmax) and apparent clearance (CL/F), indomethacin (10 mg/kg) was given orally combined with osthole (20 mg/kg) in adult SD rat. We found the value of PK on indomethacin, such as the AUC0-∞, was from 176.40 ± 17.29 to 173.74 ± 27.69 µg/ml h-1, Cmax from 9.02 ± 1.24 to 9.89 ± 0.82 µg/ml and CL/F from 0.11 ± 0.01 to 0.12 ± 0.04 mg/kg/h which were unsignificantly changed compared with the control groups. However, the Tmax was prolonged from 2.00 ± 0.00 h to 7.33 ± 1.15 h, and T1/2 increased from 8.38 ± 2.30 h to 11.37 ± 2.11 h. These results indicate that osthole could potentially affect the metabolism of indomethacin in vivo.

An aptamer based fluorometric assay for amyloid-ß oligomers using a metal-organic framework of type Ru@MIL-101(Al) and enzyme-assisted recycling.

Amyloid-beta (Aß) oligomers causing neuron damage are regarded as potential therapeutic targets and diagnostic markers for Alzheimer's disease (AD). A homogeneous turn-on fluorometric aptasensor is described for Aß oligomers. It is highly selective and non-invasive and based on (a) the use of a luminescent metal-organic framework carrying aptamer-modified AuNPs (L-MOF/Apt-Au) as tracking agent, and (b) enzyme-assisted target recycling signal amplification. The tracking agent does not emit fluoresce by fluorescence resonance energy transfer (FRET) between the luminescent MOF as donor and Apt-Au as the acceptor under the excitation wavelength of 466 nm. When Aß oligomers are added to the tracking agent solution, the Apt-Au on tracking agent can preferentially bind with Aß oligomers and then be released. This turns the "off" signal of the luminescent MOF tracer to the "on" state. The enzyme (Rec Jf exonuclease) added into the supernatant further improves sensitivity due to enzyme-assisted target-recycling signal amplification. The assay has an excellent linear response to Aß oligomers from 1.0 pM to 10 nM, with a detection limit of 0.3 pM. This homogeneous turn-on fluorometric method is expected to have potential and applications in clinical diagnosis. Graphical abstractSchematic representation of fluorometric assay for amyloid-ß oligomers based on luminescence metal-organic framework nanocomposites as tracking agent with exonuclease-assisted target recycling.

Visualization and colorimetric determination of clenbuterol in pork by using magnetic beads modified with aptamer and complementary DNA as capture probes, and G-quadruplex/hemin and DNA antibody on the metal-organic framework MIL-101(Fe) acting as a peroxidase mimic.

A visualization strategy is described for the detection of clenbuterol (CLB). It is using of antibody against dsDNA and G-quadruplex/hemin labeled on a metal organic framework of type MIL-101(Fe) (G-quadruplex/hemin-anti-DNA/MIL-101) acting as a peroxidase mimetic, and magnetic beads modified with aptamer and complementary DNA (MB/Apt-cDNA) as capture probes. The detection reagent was prepared via the reactions between the double stranded DNA (Apt-cDNA) in capture probes and anti-DNA in peroxidase mimetic. In the presence of CLB, the aptamer on the magnetic beads preferentially binds CLB, and the peroxidase mimetic is released to the supernatant after magnetic separation. The released peroxidase mimetic can catalyze the TMB/H2O2 chromogenic system under mild conditions. This leads to the development of a blue-green coloration whose absorbance is measured at 650 nm. The detection limit is as low as 34 fM of CLB. The method was applied to the determination of CLB in pork samples and gave results that were consistent with data obtained with an ELISA kit. Graphical abstract A visualization strategy is described for the detection of clenbuterol. The selectivity of detection system for clenbuterol is excellent compared with other interferents. The method was applied to the determination of CLB in pork samples.

[Effect of silencing the VDR gene on the migration and invasion of prostate cancer cells].

OBJECTIVE: To investigate the effect of small interfering RNA silencing the vitamin D receptor (VDR) on the biological behavior of prostate cancer PC-3 cells. METHODS: We constructed the VDR-shRNA lentiviral vector and determined the mRNA and protein expressions of VDR by RT-PCR and Western blot. Using scratch wound healing and Transwell chamber assays, we detected the changes in the migration and invasiveness of the PC-3 cells after silencing VDR. RESULTS: The VDR-shRNA plasmid significantly interfered the VDR expression and successfully screened the cell lines with stable VDR-shRNA interference. The rate of scratch wound healing was markedly lower in the VDR interference group than in the blank control and LV3 negative control groups (59% vs 73.6% and 77.8%, P <0.05), but with no statistically significant difference between the latter two (P >0.05), and so was the count of permeable cells (P <0.05), but with no significant difference between the latter two groups, either (P >0.05). The migration ability and invasiveness of the VDR-treated cells were remarkably decreased as compared with those of the control cells. CONCLUSIONS: Down-regulated expression of the VDR gene may reduce the migration and invasiveness of prostate cancer cells.

Trilobatin, a Novel Naturally Occurring Food Additive, Ameliorates Alcoholic Liver Disease in Mice: Involvement of Microbiota-Gut-Liver Axis and Yap/Nrf2 Signaling Pathway.

Trilobatin, a novel natural food additive, exerts a protective effect on acute liver injury. However, whether Trilobatin can protect against alcoholic liver disease (ALD) has not been elucidated. This research is intended to ascertain the impact of Trilobatin on ALD in mice and decipher the potential underlying mechanisms. Lieber-DeCarli liquid alcohol diet was used to induce ALD in mice, followed by administration of Trilobatin (10, 20, 40 mg·kg-1·d-1) for 15 days. The results suggested that Trilobatin significantly alleviated ethanol-induced hepatic injury in mice. Furthermore, RNA-Seq analysis revealed that yes-associated protein (YAP) downregulation occurred in the liver after Trilobatin treatment. Mechanistically, Trilobatin directly bound to YAP and hindered its nuclear translocation, which activated the Nrf2 pathway to reduce pro-inflammatory cytokines and oxidative stress. Intriguingly, 16S rDNA analysis results revealed that Trilobatin reshaped the gut microbiota, reducing harmful bacteria and increasing beneficial bacteria. It also enhanced tight junction proteins, defending against damage to the intestinal barrier. These findings not only highlight the microbiota-gut-liver axis and YAP/Nrf2 pathway as crucial potential targets to treat ALD but also reveal that Trilobatin effectively protects against ALD, at least partly, through modulating the microbiota-gut-liver axis and YAP/Nrf2 pathway.

Trilobatin attenuates cerebral ischaemia/reperfusion-induced blood-brain barrier dysfunction by targeting matrix metalloproteinase 9: The legend of a food additive.

BACKGROUND AND PURPOSE: Blood-brain barrier (BBB) breakdown is one of the crucial pathological changes of cerebral ischaemia-reperfusion (I/R) injury. Trilobatin (TLB), a naturally occurring food additive, exerts neuroprotective effects against cerebral I/R injury as demonstrated in our previous study. This study was designed to investigate the effect of TLB on BBB disruption after cerebral I/R injury. EXPERIMENTAL APPROACH: Rats with focal cerebral ischaemia caused by transient middle cerebral artery occlusion were studied along with brain microvascular endothelial cells and human astrocytes to mimic BBB injury caused by oxygen and glucose deprivation/reoxygenation (OGD/R). KEY RESULTS: The results showed that TLB effectively maintained BBB integrity and inhibited neuronal loss following cerebral I/R challenge. Furthermore, TLB increased tight junction proteins including ZO-1, Occludin and Claudin 5, and decreased the levels of apolipoprotein E (APOE) 4, cyclophilin A (CypA) and phosphorylated nuclear factor kappa B (NF-κB), thereby reducing proinflammatory cytokines. TLB also decreased the Bax/Bcl-2 ratio and cleaved-caspase 3 levels along with a reduced number of apoptotic neurons. Molecular docking and transcriptomics predicted MMP9 as a prominent gene evoked by TLB treatment. The protective effects of TLB on cerebral I/R-induced BBB breakdown was largely abolished by overexpression of MMP9, and the beneficial effects of TLB on OGD/R-induced loss of BBB integrity in human brain microvascular endothelial cells and astrocyte co-cultures was markedly reinforced by knockdown of MMP9. CONCLUSIONS AND IMPLICATIONS: Our findings reveal a novel property of TLB: preventing BBB disruption following cerebral I/R via targeting MMP9 and inhibiting APOE4/CypA/NF-κB axis.

Intelligent classification of major depressive disorder using rs-fMRI of the posterior cingulate cortex.

Major Depressive Disorder (MDD) is a widespread psychiatric condition that affects a significant portion of the global population. The classification and diagnosis of MDD is crucial for effective treatment. Traditional methods, based on clinical assessment, are subjective and rely on healthcare professionals' expertise. Recently, there's growing interest in using Resting-State Functional Magnetic Resonance Imaging (rs-fMRI) to objectively understand MDD's neurobiology, complementing traditional diagnostics. The posterior cingulate cortex (PCC) is a pivotal brain region implicated in MDD which could be used to identify MDD from healthy controls. Thus, this study presents an intelligent approach based on rs-fMRI data to enhance the classification of MDD. Original rs-fMRI data were collected from a cohort of 430 participants, comprising 197 patients and 233 healthy controls. Subsequently, the data underwent preprocessing using DPARSF, and the amplitudes of low-frequency fluctuation values were computed to reduce data dimensionality and feature count. Then data associated with the PCC were extracted. After eliminating redundant features, various types of Support Vector Machines (SVMs) were employed as classifiers for intelligent categorization. Ultimately, we compared the performance of each algorithm, along with its respective optimal classifier, based on classification accuracy, true positive rate, and the area under the receiver operating characteristic curve (AUC-ROC). Upon analyzing the comparison results, we determined that the Random Forest (RF) algorithm, in conjunction with a sophisticated Gaussian SVM classifier, demonstrated the highest performance. Remarkably, this combination achieved a classification accuracy of 81.9 % and a true positive rate of 92.9 %. In conclusion, our study improves the classification of MDD by supplementing traditional methods with rs-fMRI and machine learning techniques, offering deeper neurobiological insights and aiding accuracy, while emphasizing its role as an adjunct to clinical assessment.

Icariside II mitigates myocardial infarction by balancing mitochondrial dynamics and reducing oxidative stress through the activation of Nrf2/SIRT3 signaling pathway.

Nuclear factor erythroid 2-related factor 2 (Nrf2)/silent mating type information regulation 2 homolog 3 (SIRT3) signaling pathway plays a pivotal role in regulating mitochondrial dynamics and oxidative stress, which are considered to be the principal pathogenesis of myocardial infarction (MI). Our previous study proved that pretreatment with icariside II (ICS II), a major active ingredient of Herbal Epimedii, exerts cardioprotective effect on MI, however, whether post-treatment with ICS II can alleviate MI and its underlying mechanism are still uncertain. Therefore, the present study was designed to investigate the therapeutic effect and the possible mechanism of ICS II on MI both in vivo and in vitro. The results revealed that post-treatment with ICS II markedly ameliorated myocardial injury in MI-induced mice and mitigated oxygen and glucose deprivation (OGD)-elicited cardiomyocyte injury. Further researches showed that ICS II promoted mitochondrial fusion, and suppressed mitochondrial fission and oxidative stress, which were achieved by facilitating the nuclear translocation of Nrf2 and activation of SIRT3. In summary, our findings indicate that ICS II mitigates MI-induced mitochondrial dynamics disorder and oxidative stress via activating the Nrf2/SIRT3 signaling pathway.

A Middle Ordovician Burgess Shale-type fauna from Castle Bank, Wales (UK).

Burgess Shale-type faunas are critical to our understanding of animal evolution during the Cambrian, giving an unrivalled view of the morphology of ancient organisms and the ecology of the earliest animal-dominated communities. Rare examples in Lower Ordovician strata such as the Fezouata Biota illustrate the subsequent evolution of ecosystems but only from before the main phase of the Great Ordovician Biodiversification Event. Later Ordovician Konservat-Lagerstätten are not directly comparable with the Burgess Shale-type faunas as they do not represent diverse, open-shelf communities, limiting our ability to track ecological development through the critical Ordovician biodiversification interval. Here we present the Castle Bank fauna: a highly diverse Middle Ordovician Burgess Shale-type fauna from Wales (UK) that is directly comparable with the Burgess Shale and Chengjiang biotas in palaeoenvironment and preservational style. The deposit includes animals with morphologies similar to the iconic Cambrian taxa Opabinia, Yohoia and Wiwaxia, combined with early examples of more derived groups such as barnacles. Many taxa such as kinorhynchs show the small sizes typical of modern faunas, illustrating post-Cambrian miniaturization. Castle Bank provides a new perspective on early animal evolution, revealing the next chapter in ecosystem development following the Chengjiang, Burgess Shale and Fezouata biotas.

A MnAl double adjuvant nanovaccine to induce strong humoral and cellular immune responses.

At present, the most widely used aluminum adjuvants have poor ability to induce effective Th1 type immune responses. Existing evidence suggests that manganese is a potential metal adjuvant by activating cyclic guanosine phospho-adenosine synthase (cGAS)-interferon gene stimulator protein (STING) signaling pathway to enhance humoral and cellular immune response. Hence, the effective modulation of metal components is expected to be a new strategy to improve the efficiency of vaccine immunization. Here, we constructed a manganese and aluminum dual-adjuvant antigen co-delivery system (MnO2-Al-OVA) to enhance the immune responses of subunit vaccines. Namely, the aluminum hydroxide was first fused on the surface of the pre-prepared MnO2 nanoparticles, which were synthesized by a simple redox reaction with potassium permanganate (KMnO4) and oleic acid (OA). The engineered MnO2-Al-OVA could remarkably promote cellular internalization and maturation of dendritic cells. After subcutaneous vaccination, MnO2-Al-OVA rapidly migrated into the lymph nodes (LNs) and efficiently activate the cGAS-STING pathway, greatly induced humoral and cellular immune responses. Of note, our findings underscore the importance of coordination manganese adjuvants in vaccine design by promoting the activation of the cGAS-STING-IFN-I pathway. With a good safety profile and facile preparation process, this dual-adjuvant antigen co-delivery nanovaccine has great potential for clinical translation prospects.

Palaeoecology of Cambrian-Ordovician acritarchs from China: evidence for a progressive invasion of the marine habitats.

Palaeozoic acritarchs mostly represent organic-walled cysts of marine phytoplankton, and therefore, as primary producers, played an important role in the evolution of marine ecosystems. In this study, we use a selection of the most abundant acritarch taxa from the Cambrian and Ordovician of China to understand the evolution of the palaeoecological patterns of the phytoplankton over the period. The taxa are attributed to 40 easily distinguishable morphotypes, of which the precise palaeoenvironmental distribution from 60 localities is available. By placing the 40 morphotypes on inshore-offshore transects it can be concluded that acritarch microfloras were limited to inshore environments during the early Cambrian, and progressively extended from inshore environments to offshore marine habitats during the later parts of the Cambrian and towards the Early Ordovician, with a prominent shift near the Cambrian-Ordovician boundary, confirming the onset of the 'Ordovician plankton revolution'. In addition, the acritarch morphotypes evolved from low-diversity assemblages in the early Cambrian, dominated by simple spherical forms with limited ornamentation and simple process structures, to highly diverse assemblages with very complex morphologies in the Early and Middle Ordovician. During the Ordovician, the complex acritarch assemblages occupied most marine habitats, with palaeoecological distribution patterns similar to modern dinoflagellates. This article is part of the theme issue 'The impact of Chinese palaeontology on evolutionary research'.

Decreased degree centrality values as a potential neuroimaging biomarker for migraine: A resting-state functional magnetic resonance imaging study and support vector machine analysis.

Objective: Misdiagnosis and missed diagnosis of migraine are common in clinical practice. Currently, the pathophysiological mechanism of migraine is not completely known, and its imaging pathological mechanism has rarely been reported. In this study, functional magnetic resonance imaging (fMRI) technology combined with a support vector machine (SVM) was employed to study the imaging pathological mechanism of migraine to improve the diagnostic accuracy of migraine. Methods: We randomly recruited 28 migraine patients from Taihe Hospital. In addition, 27 healthy controls were randomly recruited through advertisements. All patients had undergone the Migraine Disability Assessment (MIDAS), Headache Impact Test - 6 (HIT-6), and 15 min magnetic resonance scanning. We ran DPABI (RRID: SCR_010501) on MATLAB (RRID: SCR_001622) to preprocess the data and used REST (RRID: SCR_009641) to calculate the degree centrality (DC) value of the brain region and SVM (RRID: SCR_010243) to classify the data. Results: Compared with the healthy controls (HCs), the DC value of bilateral inferior temporal gyrus (ITG) in patients with migraine was significantly lower and that of left ITG showed a positive linear correlation with MIDAS scores. The SVM results showed that the DC value of left ITG has the potential to be a diagnostic biomarker for imaging, with the highest diagnostic accuracy, sensitivity, and specificity for patients with migraine of 81.82, 85.71, and 77.78%, respectively. Conclusion: Our findings demonstrate abnormal DC values in the bilateral ITG among patients with migraine, and the present results provide insights into the neural mechanism of migraines. The abnormal DC values can be used as a potential neuroimaging biomarker for the diagnosis of migraine.

Nanoparticles with rough surface improve the therapeutic effect of photothermal immunotherapy against melanoma.

Photothermal therapy has been intensively investigated for treating cancer in recent years. However, the long-term therapeutic outcome remains unsatisfying due to the frequently occurred metastasis and recurrence. To address this challenge, immunotherapy has been combined with photothermal therapy to activate anti-tumor immunity and relieve the immunosuppressive microenvironment within tumor sites. Here, we engineered silica-based core‒shell nanoparticles (JQ-1@PSNs-R), in which silica cores were coated with the photothermal agent polydopamine, and a bromodomain-containing protein 4 (BRD4) inhibitor JQ-1 was loaded in the polydopamine layer to combine photothermal and immune therapy for tumor elimination. Importantly, to improve the therapeutic effect, we increased the surface roughness of the nanoparticles by hydrofluoric acid (HF) etching during the fabrication process, and found that the internalization of JQ-1@PSNs-R was significantly improved, leading to a strengthened photothermal killing effect as well as the increased intracellular delivery of JQ-1. In the animal studies, the multifunctional nanoparticles with rough surfaces effectively eradicated melanoma via photothermal therapy, successfully activated tumor-specific immune responses against residual tumor cells, and further prevented tumor metastasis and recurrence. Our results indicated that JQ-1@PSNs-R could serve as an innovative and effective strategy for combined cancer therapy.

Abnormal hubs in global network as potential neuroimaging marker in generalized anxiety disorder at rest.

Background: Mounting studies have reported altered neuroimaging features in generalized anxiety disorder (GAD). However, little is known about changes in degree centrality (DC) as an effective diagnostic method for GAD. Therefore, we aimed to explore the abnormality of DCs and whether these features can be used in the diagnosis of GAD. Methods: Forty-one GAD patients and 45 healthy controls participated in the study. Imaging data were analyzed using DC and receiver operating characteristic (ROC) methods. Results: Compared with the control group, increased DC values in bilateral cerebellum and left middle temporal gyrus (MTG), and decreased DC values in the left medial frontal orbital gyrus (MFOG), fusiform gyrus (FG), and bilateral posterior cingulate cortex (PCC). The ROC results showed that the DC value of the left MTG could serve as a potential neuroimaging marker with high sensitivity and specificity for distinguishing patients from healthy controls. Conclusion: Our findings demonstrate that abnormal DCs in the left MTG can be observed in GAD, highlighting the importance of GAD pathophysiology.

Smart combination of aluminum hydroxide and MF59 to induce strong cellular immune responses.

As two of the most widely used adjuvants, aluminum hydroxide and the oil-in-water emulsion MF59 have their intrinsic limitations: classical aluminum gel induces only weak cellular immune responses while MF59 cannot be used as an antigen delivery system due to its poor physical interaction with antigen molecules. Herein, we combined these two adjuvants and constructed a novel nano-vaccine delivery system by inserting aluminum hydroxide into the surface of a modified MF59 nano-emulsion (AlNEs). A model antigen ovalbumin (OVA) and an immune potentiator CpG were adsorbed on the surface of AlNEs (hereinafter AlNEs-OVA-CpG) through a facile mixing step. After subcutaneous injection, AlNEs-OVA-CpG effectively drained to lymph nodes, delivered both cargos into lymph node-resident antigen presenting cells (APCs), and escaped from lysosomes into the cytoplasm, resulting in enhanced antigen cross-presentation. Finally, AlNEs-OVA-CpG induced potent antigen-specific humoral and cellular immune responses, which significantly inhibited tumor growth and prolonged mice survival in a EG7-OVA tumor model. In sum, our results suggested that AlNEs have a great prospect to induce CD8+ T cell responses for subunit antigens.

Advancedoral vaccine delivery strategies for improving the immunity.

Infectious diseases continue to inflict a high global disease burden. The consensus is that vaccination is the most effective option against infectious diseases. Oral vaccines have unique advantages in the prevention of global pandemics due to their ease of use, high compliance, low cost, and the ability to induce both systemic and mucosal immune responses. However, challenges of adapting vaccines for oral administration remain significant. Foremost among these are enzymatic and pH-dependent degradation of antigens in the stomach and intestines, the low permeability of mucus barrier, the nonspecific uptake of antigens at the intestinal mucosal site, and the immune suppression result from the elusive immune tolerance mechanisms. Innovative delivery techniques promise great potential for improving the flexibility and efficiency of oral vaccines. A better understanding of the delivery approaches and the immunological mechanisms of oral vaccine delivery systems may provide new scientific insight and tools for developing the next-generation oral vaccine. Here, an overview of the advanced technologies in the field of oral vaccination is proposed, including mucus-penetrating nanoparticle (NP), mucoadhesive delivery vehicles, targeting antigen-presenting cell (APC) nanocarriers and enhanced paracellular delivery strategies and so on. Meanwhile, the mechanisms of delivery vectors interact with mucosal barriers are discussed.