High expression of LncRNA HOTAIR is a risk factor for temozolomide resistance in glioblastoma via activation of the miR-214/ß-catenin/MGMT pathway.

HOX transcript antisense RNA (HOTAIR) is upregulated in glioblastoma (GBM) and associated with temozolomide (TMZ) resistance. However, the mechanisms underlying HOTAIR-mediated TMZ resistance remains poorly understood. HOTAIR expression in glioma-related public datasets and drug response estimation were analyzed using bioinformatics. These findings were verified by overexpressing HOTAIR in TMZ-sensitive U251 cells and/or silencing HOTAIR in resistant U251 cells (U251R). The cytotoxic effects were evaluated using cell viability assay and flow cytometry analysis of cell cycle and apoptosis. In this study, we found that HOTAIR was upregulated in TMZ-resistant GBM cell lines and patients with high HOTAIR expression responded poorly to TMZ therapy. HOTAIR knockdown restored TMZ sensitivity in U251R cells, while HOTAIR overexpression conferred TMZ resistance in U251 cells. Wnt/ß-catenin signaling was enriched in patients with high HOTAIR expression; consistently, HOTAIR positively regulated ß-catenin expression in U251 cells. Moreover, HOTAIR-mediated TMZ resistance was associated with increased MGMT protein level, which resulted from the HOTAIR/miR-214-3p/ß-catenin network. Besides, GBM with high HOTAIR expression exhibited sensitivity to methotrexate. Methotrexate enhanced TMZ sensitivity in U251R cells, accompanied by reduced expression of HOTAIR and ß-catenin. Thus, we conlcude that HOTAIR is a risk factor for TMZ resistance and methotrexate may represent a potential therapeutic drug for patients with high HOTAIR expression level.

Foot-and-mouth disease virus antigenic landscape and reduced immunogenicity elucidated in atomic detail.

Unlike most other picornaviruses, foot-and-mouth disease (FMD) intact virions (146S) dissociate easily into small pentameric subunits (12S). This causes a dramatically decreased immunogenicity by a mechanism that remains elusive. Here, we present the high-resolution structures of 12S (3.2 Å) and its immune complex of a single-domain antibody (VHH) targeting the particle interior (3.2 Å), as well as two 146S-specific VHHs complexed to distinct sites on the 146S capsid surface (3.6 Å and 2.9 Å). The antigenic landscape of 146S is depicted using 13 known FMD virus-antibody complexes. Comparison of the immunogenicity of 146S and 12S in pigs, focusing on the resulting antigenic sites and incorporating structural analysis, reveals that dissociation of 146S leads to structural alteration and destruction of multiple epitopes, resulting in significant differences in antibody profiles/lineages induced by 12S and 146S. Furthermore, 146S generates higher synergistic neutralizing antibody titers compared to 12S, whereas both particles induce similar total FMD virus specific antibody titers. This study can guide the structure-based rational design of novel multivalent and broad-spectrum recombinant vaccines for protection against FMD.

FGFR1-mediated enhancement of foot-and-mouth disease virus entry.

Foot-and-mouth disease virus (FMDV), a member of picornavirus, can enter into host cell via macropinocytosis. Although it is known that receptor tyrosine kinases (RTKs) play a crucial role in FMDV macropinocytic entry, the specific RTK responsible for regulating this process and the intricacies of RTK-mediated downstream signaling remain to be elucidated. Here, we conducted a screening of RTK inhibitors to assess their efficacy against FMDV. Our findings revealed that two compounds specifically targeting fibroblast growth factor receptor 1 (FGFR1) and FMS-like tyrosine kinase 3 (FLT3) significantly disrupted FMDV entry. Furthermore, additional evaluation through gene knockdown and overexpression confirmed the promotion effect of FGFR1 and FLT3 on FMDV entry. Interestingly, we discovered that the increasement of FMDV entry facilitated by FGFR1 and FLT3 can be ascribed to increased macropinocytic uptake. Additionally, in-depth mechanistic study demonstrated that FGFR1 interacts with FMDV VP3 and undergoes phosphorylation during FMDV entry. Furthermore, the FGFR1 inhibitor inhibited FMDV-induced activation of p21-activated kinase 1 (PAK1) on Thr212 and Thr423 sites. Consistent with these findings, the ectopic expression of FGFR1 resulted in a concomitant increase in phosphorylation level of PAK1 on Thr212 and Thr423 sites. Taken together, our findings represent the initial exploration of FGFR1's involvement in FMDV macropinocytic entry, providing novel insights with potential implications for the development of antiviral strategies.

Anti-tumor effects of telmisartan in glioma-astrocyte non-contact co-cultures: A critical role of astrocytic IL-6-mediated paracrine growth promotion.

Telmisartan, an angiotensin II type 1 receptor (AT1R) blocker, exhibits broad anti-tumor activity. However, in vitro, anti-proliferative effects are shown at doses far beyond the therapeutic plasma concentration. Considering the role of tumor microenvironment in glioma progression, glioma-astrocyte co-cultures were employed to test the anti-tumor potential of low-dose telmisartan. When a high dose was required for a direct anti-proliferative effect on glioma cell lines, a low dose significantly inhibited glioma cell proliferation and migration in the co-culture system. Under co-culture conditions, upregulated IL-6 expression in astrocytes played a critical role in glioma progression. Silencing IL-6 in astrocytes or IL-6R in glioma cells reduced proliferation and migration. Telmisartan (5 µM) inhibited astrocytic IL-6 expression, and its anti-tumor effects were reversed by silencing IL-6 or IL-6R and inhibiting signal transducer and activator of transcription 3 (STAT3) activity in glioma cells. Moreover, the telmisartan-driven IL-6 downregulation was not imitated by losartan, an AT1R blocker with little capacity of peroxisome proliferator-activated receptor-gamma (PPARγ) activation, but was eliminated by a PPARγ antagonist, indicating that the anti-glioma effects of telmisartan rely on its PPARγ agonistic activity rather than AT1R blockade. This study highlights the importance of astrocytic IL-6-mediated paracrine signaling in glioma growth and the potential of telmisartan as an adjuvant therapy for patients with glioma, especially those with hypertension.

Effect of Basalt/Steel Individual and Hybrid Fiber on Mechanical Properties and Microstructure of UHPC.

Ultra High-Performance Concrete (UHPC) is a cement-based composite material with great strength and durability. Fibers can effectively increase the ductility, strength, and fracture energy of UHPC. This work describes the impacts of individual or hybrid doping of basalt fiber (BF) and steel fiber (SF) on the mechanical properties and microstructure of UHPC. We found that under individual doping, the effect of BF on fluidity was stronger than that of SF. Moreover, the compressive, flexural, and splitting tensile strength of UHPC first increased and then decreased with increasing BF dosage. The optimal dosage of BF was 1%. At a low content of fiber, UHPC reinforced by BF demonstrated greater flexural strength than that reinforced by SF. SF significantly improved the toughness of UHPC. However, a high SF dosage did not increase the strength of UHPC and reduced the splitting tensile strength. Secondly, under hybrid doping, BF was partially substituted for SF to improve the mechanical properties of hybrid fiber UHPC. Consequently, when the BF replacement rate increased, the compressive strength of UHPC gradually decreased; on the other hand, there was an initial increase in the fracture energy, splitting tensile strength, and flexural strength. The ideal mixture was 0.5% BF + 1.5% SF. The fluidity of UHPC with 1.5% BF + 0.5% SF became the lowest with a constant total volume of 2%. The microstructure of hydration products in the hybrid fiber UHPC became denser, whereas the interface of the fiber matrix improved.

Peceleganan Spray for the Treatment of Skin Wound Infections: A Randomized Clinical Trial.

Importance: Peceleganan spray is a novel topical antimicrobial agent targeted for the treatment of skin wound infections. However, its efficacy and safety remain unclear. Objective: To assess the safety and efficacy of peceleganan spray for the treatment of wound infections. Design, Setting, and Participants: This multicenter, open-label, phase 3 randomized clinical trial recruited and followed up 570 adult patients diagnosed with secondary open wound infections from 37 hospitals in China from August 23, 2021, to July 16, 2022. Interventions: Patients were randomized to 2 groups with a 2:1 allocation. One group received treatment with 2% peceleganan spray (n = 381) and the other with 1% silver sulfadiazine (SSD) cream (n = 189). Main Outcomes and Measures: The primary efficacy outcome was the clinical efficacy rate (the number of patients fulfilling the criteria for efficacy of the number of patients receiving the treatment) on the first day following the end of treatment (day 8). The secondary outcomes included the clinical efficacy rate on day 5 and the bacterial clearance rate (cases achieving negative bacteria cultures after treatment of all cases with positive bacteria cultures before treatment) on days 5 and 8. The safety outcomes included patients' vital signs, physical examination results, electrocardiographic findings, blood test results, and adverse reactions. Results: Among the 570 patients randomized to 1 of the 2 groups, 375 (98.4%) in the 2% peceleganan treatment group and 183 (96.8%) in the 1% SSD control group completed the trial (n = 558). Of these, 361 (64.7%) were men, and the mean (SD) age was 48.6 (15.3) years. The demographic characteristics were similar between groups. On day 8, clinical efficacy was achieved by 339 patients (90.4%) in the treatment group and 144 (78.7%) in the control group (P < .001). On day 5, clinical efficacy was achieved by 222 patients (59.2%) in the treatment group and 90 (49.2%) in the control group (P = .03). On day 8, bacterial clearance was achieved by 80 of 334 patients (24.0%) in the treatment group and in 75 of 163 (46.0%) in the control group (P < .001). On day 5, bacterial clearance was achieved by 55 of 334 patients (16.5%) in the treatment group and 50 of 163 (30.7%) in the control group (P < .001). The adverse events related to the application of peceleganan spray and SSD cream were similar. Conclusions and Relevance: This randomized clinical trial found that peceleganan spray is a safe topical antimicrobial agent with a satisfactory clinical efficacy rate for the treatment of skin wound infections, while the effectiveness of bacterial clearance remains uncertain. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR2100047202.

Virus-like particle-based multipathogen vaccine of FMD and SVA elicits balanced and broad protective efficacy in mice and pigs.

Inactivated vaccines lack the capability to serologically differentiate between infected and vaccinated animals, thereby impeding the effective eradication of pathogen. Conversely, vaccines based on virus-like particles (VLPs) emulate natural viruses in both size and antigenic structure, presenting a promising alternative to overcome these limitations. As the complexity of swine infectious diseases increases, the increase of vaccine types and doses may intensify the stress response. This exacerbation can lead to diminished productivity, failure of immunization, and elevated costs. Given the critical dynamics of co-infection and the clinically indistinguishable symptoms associated with foot-and-mouth disease virus (FMDV) and senecavirus A (SVA), there is a dire need for an efficacious intervention. To address these challenges, we developed a combined vaccine composed of three distinct VLPs, specifically designed to target SVA and FMDV serotypes O and A. Our research demonstrates that this trivalent VLP vaccine induces antigen-specific and robust serum antibody responses, comparable to those produced by the respective monovalent vaccines. Moreover, the immune sera from the combined VLP vaccine strongly neutralized FMDV type A and O, and SVA, with neutralization titers comparable to those of the individual vaccines, indicating a high level of immunogenic compatibility among the three VLP components. Importantly, the combined VLPs vaccines-immunized sera conferred efficient protection against single or mixed infections with FMDV type A and O, and SVA viruses in pigs. In contrast, individual vaccines could only protect pigs against homologous virus infections and not against heterologous challenges. This study presents a novel combined vaccines candidate against FMD and SVA, and provides new insights for the development of combination vaccines for other viral swine diseases.

Association between BMI and osteoporotic fractures at different sites in Chinese women: a case-control retrospective study in Changsha.

BACKGROUND: Osteoporotic fractures are a growing problem in an aging society. The association between body mass index (BMI) and osteoporotic fractures varies by fracture site and ethnicity. Limited knowledge exists regarding this association in native Chinese, particularly utilizing local databases as reference sources. OBJECTIVE: To investigate the association between BMI and osteoporotic fractures at different sites in Chinese women. METHODS: Three thousand ninety-eight female patients with radiographic fractures and 3098 age- and sex-matched healthy controls without fractures were included in the study. Both of them underwent assessment using dual-energy X-ray absorptiometry (DXA), with BMD measurements calculated using our own BMD reference database. Participants were classified into underweight (BMI < 18.5 kg/m2), normal weight (18.5 ≤ BMI < 24.0 kg/m2), overweight (24 ≤ BMI < 28 kg/m2) and obese (BMI ≥ 28 kg/m2) according to the Chinese BMI classification standard. RESULTS: There were 2296 (74.1%) vertebral fractures, 374 (12.1%) femoral neck fractures, and 428 (13.8%) other types of fractures in the case group. Bone mineral density (BMD) was almost lower in the fracture groups compared to the control groups (p = 0.048 to < 0.001). Compared with normal weight, underweight had a protective effect on total [odds ratio (OR) = 0.61; 95% confidence interval (CI), 0.49 -0.75; P< 0.001], and lumbar fractures (OR = 0.52; 95% CI, 0.41 - 0.67; P < 0.001), while obesity was associated with an increased risk for total (OR = 2.26; 95% CI, 1.85 - 2.76; P < 0.001), lumbar (OR = 2.17; 95% CI, 1.72 - 2.73; P < 0.001), and femoral neck fractures (OR = 4.08; 95% CI, 2.18 - 7.63; P < 0.001). Non-linear associations were observed between BMI and fractures: A J-curve for total, lumbar, and femoral neck fractures, and no statistical change for other types of fractures. Underweight was found to be a risk factor for other types of fracturess after adjusting for BMD (OR = 2.29; 95% CI, 1.09 - 4.80; P < 0.001). Osteoporosis and osteopenia were identified as risk factors for almost all sites of fracture when compared to normal bone mass. CONCLUSIONS: Underweight has a protective effect on total and lumbar spine fractures in Chinese women, while obesity poses a risk factor for total, lumbar, and femoral neck fractures. The effect of BMI on fractures may be mainly mediated by BMD.

Enhanced antigen-specific CD8 T cells contribute to early protection against FMDV through swine DC vaccination.

Foot-and-mouth disease virus (FMDV) remains a challenge for cloven-hooved animals. The currently licensed FMDV vaccines induce neutralizing antibody (NAb)-mediated protection but show defects in the early protection. Dendritic cell (DC) vaccines have shown great potency in inducing rapid T-cell immunity in humans and mice. Whether DC vaccination could enhance early protection against FMDV has not been elaborately explored in domestic pigs. In this study, we employed DC vaccination as an experimental approach to study the roles of cellular immunity in the early protection against FMDV in pigs. Autologous DCs were differentiated from the periphery blood mononuclear cells of each pig, pulsed with inactivated FMDV (iFMDV-DC) and treated with LPS, and then injected into the original pigs. The cellular immune responses and protective efficacy elicited by the iFMDV-DC were examined by multicolor flow cytometry and tested by FMDV challenge. The results showed that autologous iFMDV-DC immunization induced predominantly FMDV-specific IFN-γ-producing CD4+ T cells and cytotoxic CD8+ T cells (CTLs), high NAb titers, compared to the inactivated FMDV vaccine, and accelerated the development of memory CD4 and CD8 T cells, which was concomitantly associated with early protection against FMDV virulent strain in pigs. Such early protection was associated with the rapid proliferation of secondary T-cell response after challenge and significantly contributed by secondary CD8 effector memory T cells. These results demonstrated that rapid induction of cellular immunity through DC immunization is important for improving early protection against FMDV. Enhancing cytotoxic CD8+ T cells may facilitate the development of more effective FMDV vaccines.IMPORTANCEAlthough the currently licensed FMDV vaccines provide NAb-mediated protection, they have defects in early immune protection, especially in pigs. In this study, we demonstrated that autologous swine DC immunization augmented the cellular immune response and induced an early protective response against FMDV in pigs. This approach induced predominantly FMDV-specific IFN-γ-producing CD4+ T cells and cytotoxic CD8+ T cells, high NAb titers, and rapid development of memory CD4 and CD8 T cells. Importantly, the early protection conferred by this DC immunization is more associated with secondary CD8+ T response rather than NAbs. Our findings highlighted the importance of enhancing cytotoxic CD8+ T cells in early protection to FMDV in addition to Th1 response and identifying a strategy or adjuvant comparable to the DC vaccine might be a future direction for improving the current FMDV vaccines.

[Evaluation of the humoral immunity in mice induced by foot-and-mouth disease virus-like particles-ZIF-8 complexes with different sizes].

To further enhance the immune effect of the foot-and-mouth disease (FMD) virus-like particles (VLPs) vaccine, this study prepared FMDV VLPs-zeolitic imidazolate (framework-8, ZIF-8) complexes with different particle sizes. We used a biomimetic mineralization method with Zn2+ and 2-methylimidazole in different concentration ratios to investigate the effect of size on the immunization effect. The results showed that FMDV VLPs-ZIF-8 with three different sizes were successfully prepared, with an approximate size of 70 nm, 100 nm, and 1 000 nm, respectively. Cytotoxicity and animal toxicity tests showed that all three complexes exhibited excellent biological safety. Immunization tests in mice showed that all three complexes enhanced the titers of neutralizing and specific antibodies, and their immune effects improved as the size of the complexes decreased. This study showed that ZIF-8 encapsulation of FMDV VLPs significantly enhanced their immunogenic effect in a size-dependent manner.

[Construction of foot-and-mouth disease virus like particles-induced expression vectors and screening of BHK-21 cell pools].

Transient expression is the major method to express foot-and-mouth disease virus (FMDV) capsid proteins in mammalian cells. To achieve stable expression of FMDV capsid proteins and efficient assembly of virus like particles (VLPs) in cells, the plasmids of piggyBac (PB) transposon-constitutive expression and PB transposon-tetracycline (Tet) inducible expression vectors were constructed. The function of the plasmids was tested by fluorescent proteins. By adding antibiotics, the constitutive cell pools (C-WT, C-L127P) expressing P12A3C (WT/L127P) genes and the inducible cell pools (I-WT, I-L127P) expressing P12A3C (WT/L127P) genes were generated. The genes of green fluorescent protein, 3C protease and reverse tetracycline transactivator (rtTA) were integrated into chromosome, which was confirmed by fluorescence observation and PCR testing. The cell pool I-L127P has a stronger production capacity of capsid proteins and VLPs, which was confirmed by Western blotting and enzyme linked immunosorbent assay (ELISA), respectively. In conclusion, inducing the chromosomal expression of FMDV capsid proteins was firstly reported, which may facilitate the technical process of mammalian production of FMDV VLPs vaccine and the construction of mammalian inducible expression systems for other proteins.

Self-Assembling Nanovaccine Fused with Flagellin Enhances Protective Effect against Foot-and-Mouth Disease Virus.

Nanovaccines based on self-assembling nanoparticles (NPs) can show conformational epitopes of antigens and they have high immunogenicity. In addition, flagellin, as a biological immune enhancer, can be fused with an antigen to considerably enhance the immune effect of antigens. In improving the immunogenicity and stability of a foot-and-mouth disease virus (FMDV) antigen, novel FMDV NP antigens were prepared by covalently coupling the VP1 protein and truncated flagellin containing only N-terminus D0 and D1 (N-terminal aa 1-99, nFLiC) with self-assembling NPs (i301). The results showed that the fusion proteins VP1-i301 and VP1-i301-nFLiC can assemble into NPs with high thermal tolerance and stability, obtain high cell uptake efficiency, and upregulate marker molecules and immune-stimulating cytokines in vitro. In addition, compared with monomeric VP1 antigen, high-level cytokines were stimulated with VP1-i301 and VP1-i301-nFLiC nanovaccines in guinea pigs, to provide clinical protection against viral infection comparable to an inactivated vaccine. This study provides new insight for the development of a novel FMD vaccine.

Telmisartan inhibits microglia-induced neurotoxic A1 astrocyte conversion via PPARγ-mediated NF-κB/p65 degradation.

Astrocytes are crucially involved in neuroinflammation. Activated astrocytes exhibit at least two phenotypes, A1 (neurotoxic) and A2 (neuroprotective). The A1 phenotype is the major reactive astrocyte phenotype involved in aging and neurodegenerative diseases. Telmisartan, which is an antihypertensive agent, is a promising neuroprotective agent. This study aimed to investigate the effects of telmisartan on the phenotype of reactive astrocytes. Astrocytes were activated by culturing with the conditioned medium derived from lipopolysaccharide-stimulated microglia. This conditioned medium induced early, transient A2 astrocyte conversion (within 24 h) and late, sustained A1 conversion (beginning at 24 h and lasting up to 7 days), with a concomitant increase in the production of pro-inflammatory cytokines (interleukin [IL]-1ß, tumor necrosis factor [TNF]α, and IL-6) and phosphorylation of nuclear factor-κB (NF-κB)/p65. Telmisartan treatment promoted and inhibited A2 and A1 conversion, respectively. Telmisartan reduced total and phosphorylated p65 protein levels. Losartan, a specific angiotensin II type-1 receptor (AT1R) blocker, did not influence the reactive state of astrocytes. Additionally, AT1R activation by angiotensin II did not induce the expression of pro-inflammatory cytokines and A1/A2 markers, indicating that the AT1R signaling pathway is not involved in the astrocyte-mediated inflammatory response. A peroxisome proliferator-activated receptor γ (PPARγ) antagonist reversed the effects of telmisartan. Moreover, telmisartan-induced p65 downregulation was reversed by the proteasome inhibitor MG132. These results indicate that telmisartan suppresses activated microglia-induced neurotoxic A1 astrocyte conversion through p65 degradation. Our findings contribute towards the elucidation of the anti-inflammatory activity of telmisartan in brain disorders.

Foot-and-mouth disease virus downregulates vacuolar protein sorting 28 to promote viral replication.

Vacuolar protein sorting 28 (Vps28), a component of the ESCRT-I (endosomal sorting complex required for transport I), plays an important role in the pathogen life cycle. Here, we investigated the reciprocal regulation between Vps28 and the foot-and-mouth disease virus (FMDV). Overexpression of Vps28 decreased FMDV replication. On the contrary, the knockdown of Vps28 increased viral replication. Subsequently, the mechanistic study showed that Vps28 destabilized the replication complex (RC) by associating with 3A rather than 2C protein. In addition, Vps28 targeted FMDV VP0, VP1, and VP3 for degradation to inhibit viral replication. To counteract this, FMDV utilized tactics to restrict Vps28 to promote viral replication. FMDV degraded Vps28 mainly through the ubiquitin-proteasome pathway. Additional data demonstrated that 2B and 3A proteins recruited E3 ubiquitin ligase tripartite motif-containing protein 21 to degrade Vps28 at Lys58 and Lys25, respectively, and FMDV 3Cpro degraded Vps28 through autophagy and its protease activity. Meantime, the 3Cpro-mediated Vps28 degradation principally alleviated the ability to inhibit viral propagation. Intriguingly, we also demonstrated that the N-terminal and C-terminal domains of Vps28 were responsible for the suppression of FMDV replication, which suggested the elaborated counteraction between FMDV and Vps28. Collectively, our results first investigate the role of ESCRTs in host defense against picornavirus and unveil underlying strategies utilized by FMDV to evade degradation machinery for triumphant propagation. IMPORTANCE ESCRT machinery plays positive roles in virus entry, replication, and budding. However, little has been reported on its negative regulation effects during viral infection. Here, we uncovered the novel roles of ESCRT-I subunit Vps28 on FMDV replication. The data indicated that Vps28 destabilized the RC and impaired viral structural proteins VP0, VP1, and VP3 to inhibit viral replication. To counteract this, FMDV hijacked intracellular protein degradation pathways to downregulate Vps28 expression and thus promoted viral replication. Our findings provide insights into how ESCRT regulates pathogen life cycles and elucidate additional information regarding FMDV counteraction of host antiviral activity.

A novel Gd3+ DTPA-bisamide complex with high relaxivity as an MRI contrast agent.

A novel Gd(III) complex-based magnetic resonance imaging (MRI) contrast agent GdL has been designed and synthesized, which exhibited a much higher relaxivity (7.8 mM-1 s-1) than the commercially used Magnevist® (3.5 mM-1 s-1), good water solubility (>100 mg mL-1), excellent thermodynamic stability (log KGdL = 17.21 ± 0.27), high biosafety and biocompatibility. In particular, the relaxivity of GdL increased to 26.7 mM-1 s-1 in a 4.5% bovine serum albumin (BSA) solution at 1.5 T, which was not significant in other commercial MRI contrast agents. The interaction sites and interaction types of GdL and BSA were further demonstrated by molecular docking simulations. Furthermore, the in vivo MRI behaviour was evaluated by using a 4T1 tumour-bearing mouse model. These results suggested that GdL is an excellent T1-weighted MRI contrast agent and has the potential to be applied in clinical diagnosis.

Self-healable polymer complex with a giant ionic thermoelectric effect.

In this study, we develop a stretchable/self-healable polymer, PEDOT:PAAMPSA:PA, with remarkably high ionic thermoelectric (iTE) properties: an ionic figure-of-merit of 12.3 at 70% relative humidity (RH). The iTE properties of PEDOT:PAAMPSA:PA are optimized by controlling the ion carrier concentration, ion diffusion coefficient, and Eastman entropy, and high stretchability and self-healing ability are achieved based on the dynamic interactions between the components. Moreover, the iTE properties are retained under repeated mechanical stress (30 cycles of self-healing and 50 cycles of stretching). An ionic thermoelectric capacitor (ITEC) device using PEDOT:PAAMPSA:PA achieves a maximum power output and energy density of 4.59 µW‧m-2 and 1.95 mJ‧m-2, respectively, at a load resistance of 10 KΩ, and a 9-pair ITEC module produces a voltage output of 0.37 V‧K-1 with a maximum power output of 0.21 µW‧m-2 and energy density of 0.35 mJ‧m-2 at 80% RH, demonstrating the potential for a self-powering source.

Local and systemic effects of IDH mutations on primary glioma patients.

Adult gliomas are divided into isocitrate dehydrogenase (IDH) wild-type and IDH mutant subtypes according to the new 2021 World Health Organization classification system. However, the local and systemic effects of IDH mutations on primary glioma patients are not well illustrated. Retrospective analysis, immune-cell infiltration analysis, meta-analysis, and immunohistochemistry assay were applied in the present study. The results from our cohort showed that IDH mutant gliomas own a lower proliferating rate compared to that in wild-type gliomas. Patients with mutant IDH exhibited a higher frequency of seizures in both our cohort and the cohort from the meta-analysis. Mutations in IDH result in lower levels of intra-tumour but higher levels of circulating CD4+ and CD8+ T lymphocytes. Levels of neutrophils in both intra-tumour and circulating blood were lower in IDH mutant gliomas. Moreover, IDH mutant glioma patients receiving radiotherapy in combination with chemotherapy exhibited better overall survival with respect to radiotherapy alone. Mutations in IDH alters the local and circulating immune microenvironment, and increases the sensitivity of tumour cell to chemotherapy.

Local and systemic immune responses induced by intranasal immunization with biomineralized foot-and-mouth disease virus-like particles.

Introduction: Foot-and-mouth disease virus (FMDV) infects the host by invading mucosal epithelial cells of the respiratory or digestive tract. Therefore, establishing a specific antiviral mucosal immune barrier can effectively block viral invasion. Methods: We evaluated local mucosal and systemic immune responses elicited by intranasal immunization of mice with foot-and-mouth disease (FMD) calcium phosphate mineralized virus-like particles (CaP-VLPs) and tested whether three commercial mucosal adjuvants enhanced the immunogenicity of the antigen. The biosafety of the vaccine was verified through gross observation and pathological analysis of the lungs. Results: CaP-VLPs effectively induced secretion of IgA (sIgA) from multiple sites in mouse mucosa and produced anti-FMD-specific IgG in the serum. Splenic lymphocytes specifically proliferated and secreted IFN-γ following antigen stimulation, indicating the vaccine can induce a certain level of cellular immune response. Finally, the pathological examination confirmed that CaP-VLPs did not cause substantial damage to the lungs of animals after immunization via mucosal administration. Notably, the vaccine mixed with S adjuvant increased the content of sIgA and serum IgG, and the high level of IgG in serum was maintained at least 7 weeks. Discussion: Overall, this study reveals that FMD CaP-VLPs can induce good local mucosal immune and systemic immune response through intranasal immunization, and the immune response was specifically enhanced by S adjuvant. These data support that CaP-VLPs-S as a candidate mucosal vaccine for the prevention of FMD vaccine infection.

Poly(I:C) and CpG improve the assembly of foot-and-mouth disease virus-like particles and immune response in mice.

Virus-like particles (VLPs) are extremely potent, safe, and serviceable vaccine platforms. Good assembly efficiency of VLPs is the key to reducing vaccine production costs and eliciting a robust immune response. This study adopted CpG and Poly (I:C) as scaffolds to facilitate the assembly of foot-and-mouth disease virus (FMDV) VLPs in vitro. The VLPs and the co-assembly products were characterized by particle size, zeta potential, gel retardation measurement, nuclease digestion experiments, size-exclusion chromatography, transmission electron microscopy and circular dichroism analysis. Our results indicated the successful encapsulation of CpG and Poly (I:C) inside VLPs without any effect on shape or size. Vaccination in mice also elicited a robust immune response. This study demonstrated that CpG and Poly (I:C) improved the efficiency of FMDV VLPs assembly and enhanced immune response, further proposing a new idea for improving the efficiency of VLPs assembly and enriching the in vitro VLPs assembly strategies.