Design of a novel multiepitope vaccine with CTLA-4 extracellular domain against Mycoplasma pneumoniae: A vaccine-immunoinformatics approach.

BACKGROUND: Community-acquired pneumonia often stems from the macrolide-resistant strain of Mycoplasma pneumoniae, yet no effective vaccine exists against it. METHODS: This study proposes a vaccine-immunoinformatics strategy for Mycoplasma pneumoniae and other pathogenic microbes. Specifically, dominant B and T cell epitopes of the Mycoplasma pneumoniae P30 adhesion protein were identified through immunoinformatics method. The vaccine sequence was then constructed by coupling with CTLA-4 extracellular region, a novel molecular adjuvant for antigen-presenting cells. Subsequently, the vaccine's physicochemical properties, antigenicity, and allergenicity were verified. Molecular dynamics modeling was employed to confirm interaction with TLR-2, TLR-4, B7-1, and B7-2. Finally, the vaccine underwent in silico cloning for expression. RESULTS: The vaccine exhibited both antigenicity and non-allergenicity. Molecular dynamics simulation, post-docking with TLR-2, TLR-4, B7-1, and B7-2, demonstrated stable interaction between the vaccine and these molecules. In silico cloning confirmed effective expression of the vaccine gene in insect baculovirus vectors. CONCLUSION: This vaccine-immunoinformatics approach holds promise for the development of vaccines against Mycoplasma pneumoniae and other pathogenic non-viral and non-bacterial microbes.

Cold plasma for enhancing covalent conjugation of ovalbumin-gallic acid and its functional properties.

The utilization of cold plasma (CP) treatment to promote covalent conjugation of ovalbumin (OVA) and gallic acid (GA), as well as its functionality, were investigated. Results demonstrated that CP significantly enhanced the covalent grafting of OVA and GA. The maximum conjugation of GA, 24.33 ± 2.24 mg/g, was achieved following 45 s of CP treatment. Covalent conjugation between GA and OVA were confirmed through analyses of total sulfhydryl (-SH) group, Fourier transform infrared (FTIR) spectroscopy, and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Unfolding of the OVA molecule occurred upon conjugation with GA, as evidenced by multiple spectroscopy analyses. Additionally, conjugation with GA resulted in significant improvements in the antioxidant activity and emulsifying properties of OVA. This study demonstrated that CP is a robust and sustainable technique for promoting the covalent conjugate of polyphenols and proteins, offering a novel approach to enhance the functional properties of proteins.

Protopanaxadiol Targeting Membrane Induces HepG2 Cell Apoptosis Via Raft-like Formation and Tubulation Disruption.

Protopanaxadiol (PPD), which has a molecular structure similar to cholesterol, is a potent anticancer agent that has been proposed to target the lipid membrane for the pharmacological effects. However, the underlying mechanism by which PPD modulates the cell membrane leading to cancer cell death is not be fully understood. In this work, we used single cell infrared spectroscopy, scanning electron microscopy and confocal microscopy to investigate the effects of PPD on human hepatocellular carcinoma (HepG2) cells, focusing on the change in membrane structure. We found that PPD significantly reduced the number of membrane tubules over the course of treatment. Interestingly, the addition of PPD could promote the formation of lipid raft-like domains (PPD rafts) and even restore the domain disruption caused by methyl-beta-cyclodextrin depletion of membrane cholesterol. In addition, PPD pre-treatment may increase the induction effect of FasL, which impairs cell viability, although it does not appear to be beneficial for Fas clustering in the PPD rafts. Collectively, these results highlight a non-classical mechanism by which PPD induces HepG2 apoptosis by directly affecting the physical properties of the cell membrane, providing a novel insight into understanding membrane-targeted therapy.

Characteristics of men who have casual sex with men among Chinese university students: A cross-sectional study.

OBJECTIVES: The characteristics of men who have sex with men (either exclusively or with both men and women; MSM) who engaged in casual sex among Chinese male university students have not been compared with the characteristics of men who have sex with only women (MSW). This information is important for tailoring targeted behavioral interventions to prevent human immunodeficiency virus (HIV)/sexually transmitted infection (STI) transmission in this subgroup of MSM. METHODS: Data were derived from a large cross-sectional electronic questionnaire survey conducted at 13 universities in Zhejiang Province, China, in 2018. Bivariate analyses were used to compare demographic, HIV-related psychosocial, and behavioral characteristics between MSM and MSW students who engaged in casual sex during the previous year. Proportion differences between the two groups and their 95% confidence intervals were analyzed. RESULTS: Among the 583 sexually active male students who engaged in casual sex during the previous year, 128 and 455 were MSM and MSW, respectively. Compared with MSW students, larger proportions of MSM students reported knowing that male-to-male sexual behavior was the main mode of HIV transmission among Chinese students (62.5% vs. 45.5%), consenting to commercial sex (67.2% vs. 53.4%), wanting to know the HIV serostatus of partners before casual sex (65.8% vs. 51.3%), feeling at risk of HIV infection (40.5% vs. 11.8%), high condom-decision scale scores (55.3% vs. 42.6%), engaging in sex with ≥ 5 casual sex partners (44.6% vs. 25.9%), searching for casual partners online (89.2% vs. 51.3%), consuming alcohol before casual sex (64.8% vs. 45.0%), engaging in sex with regular partners (83.1% vs. 67.0%), engaging in commercial sex (54.2% vs. 26.4%), and visiting a clinic for voluntary counselling and testing (VCT) (16.4% vs. 8.4%). However, compared with MSW students, smaller proportions of MSM students reported knowing that consistent condom use could prevent HIV transmission (80.5% vs. 95.2%) and that VCT should be actively sought after risky sexual behavior (78.9% vs. 93.8%), using condoms sometimes/often (26.4% vs. 44.3%), and consistently using condoms (28.9% vs. 40.1%) while engaging in sex with casual partners. CONCLUSIONS: MSM students who engaged in casual sex were at a greater risk of HIV/STI transmission, compared with MSW students. Comprehensive interventions to address the risks of unprotected male-to-male sex, searching for casual sex partners online, and non-use of HIV testing services are needed to reduce the burden of HIV/STI transmission among this subgroup of MSM.

Development of a Safe and Effective Bacillus thuringiensis-Based Nanobiopesticide for Controlling Tea Pests.

Mg(OH)2 was used as the nanocarrier of the Bacillus thuringiensis (Bt) Cry1Ac protein, and the synthesized Cry1Ac-Mg(OH)2 composites were regular and uniform nanosheets. Nano-Mg(OH)2 could effectively improve the insecticidal effect of the Cry1Ac protein toward Ectropis obliqua. It could enhance the damage degree of the Cry1Ac protein to intestinal epithelial cells and microvilli, induce and enrich the production of reactive oxygen species (ROS) in the midgut, and enhance the degradation of the Cry1Ac protein into active fragments. Furthermore, an anti-rinsing assay showed that the Cry1Ac-Mg(OH)2 composites were bound to the notch structure of the tea leaf surface. The retention of the Cry1Ac protein increased by 11.45%, and sprayed nano-Mg(OH)2 was rapidly absorbed by different tissues of tea plants. Moreover, nano-Mg(OH)2 and composites did not significantly affect non-target organisms. These results show that nano-Mg(OH)2 can serve as a safe and effective biopesticide carrier, which provides a new approach for stable and efficient Bt preparation.

N-Terminal α-Helices in Domain I of Bacillus thuringiensis Vip3Aa Play Crucial Roles in Disruption of Liposomal Membrane.

Bacillus thuringiensis Vip3 toxins form a tetrameric structure crucial for their insecticidal activity. Each Vip3Aa monomer comprises five domains. Interaction of the first four α-helices in domain I with the target cellular membrane was proposed to be a key step before pore formation. In this study, four N-terminal α-helix-deleted truncations of Vip3Aa were produced and, it was found that they lost both liposome permeability and insecticidal activity against Spodoptera litura. To further probe the role of domain I in membrane permeation, the full-length domain I and the fragments of N-terminal α-helix-truncated domain I were fused to green fluorescent protein (GFP), respectively. Only the fusion carrying the full-length domain I exhibited permeability against artificial liposomes. In addition, seven Vip3Aa-Cry1Ac fusions were also constructed by combination of α-helices from Vip3Aa domains I and II with the domains II and III of Cry1Ac. Five of the seven combinations were determined to show membrane permeability in artificial liposomes. However, none of the Vip3Aa-Cry1Ac combinations exhibited insecticidal activity due to the significant reduction in proteolytic stability. These results indicated that the N-terminal helix α1 in the Vip3Aa domain I is essential for both insecticidal activity and liposome permeability and that domain I of Vip3Aa preserved a high liposome permeability independently from domains II-V.

Spatiotemporal Pattern and Its Determinants for Newly Reported HIV/AIDS Among Older Adults in Eastern China From 2004 to 2021: Retrospective Analysis Study.

BACKGROUND: In recent years, the number and proportion of newly reported HIV/AIDS cases among older adults have increased dramatically. However, research on the pattern of temporal and spatial changes in newly reported HIV/AIDS among older adults remains limited. OBJECTIVE: This study analyzed the spatial and temporal distribution of HIV/AIDS cases and its influencing factors among older adults in Eastern China from 2004 to 2021, with the goal of improving HIV/AIDS prevention and intervention. METHODS: We extracted data on newly reported HIV/AIDS cases between 2004 and 2021 from a case-reporting system and used a Joinpoint regression model and an age-period-cohort model to analyze the temporal trends in HIV/AIDS prevalence. Spatial autocorrelation and geographically weighted regression models were used for spatial aggregation and influence factor analysis. RESULTS: A total of 12,376 participants with HIV/AIDS were included in the study. The newly reported HIV infections among older adults increased from 0.13 cases per 100,000 people in 2004 to 7.00 cases per 100,000 people in 2021. The average annual percent change in newly reported HIV infections was 28.0% (95% CI -21.6% to 34.8%). The results of the age-period-cohort model showed that age, period, and cohort factors affected the newly reported HIV infections among older adults. The newly reported HIV/AIDS cases among men who have sex with men (MSM) had spatial clustering, and the hotspots were mainly concentrated in Hangzhou. The disposable income of urban residents, illiteracy rate among people aged 15 years or older, and number of hospital beds per 1000 residents showed a positive association with the newly reported HIV infections among older MSM in the Zhejiang province. CONCLUSIONS: HIV/AIDS among older adults showed an increasing trend and was influenced by age, period, and cohort effects. Older MSM with HIV/AIDS showed regional clustering and was associated with factors such as the disposable income of urban residents, the illiteracy rate among people aged 15 years or older, and the number of hospital beds per 1000 people. Targeted prevention and control measures are needed to reduce HIV infection among those at higher risk.

Visible-light-driven water-soluble zinc oxide quantum dots for efficient control of citrus canker.

BACKGROUND: Citrus canker caused by Xanthomonas citri subsp. citri (Xcc) is a devastating bacterial disease that reduces citrus yield and quality, posing a serious threat to the citrus industry. Several conventional chemicals have been used to control citrus canker. However, this approach often leads to the excessive use of chemical agents, can exacerbate environmental pollution and promotes the development of resistant Xcc. Therefore, there is significant interest in the development of efficient and environmentally friendly technologies to control citrus canker. RESULTS: In this study, water-soluble ZnO quantum dots (ZnO QDs) were synthesised as an efficient nanopesticide against Xcc. The results showed that the antibacterial activity of ZnO QDs irradiated with visible light [half-maximal effective concentration (EC50) = 33.18 µg mL-1] was ~3.5 times higher than that of the dark-treated group (EC50 = 114.80 µg mL-1). ZnO QDs induced the generation of reactive oxygen species (•OH, •O- 2 and 1O2) under light irradiation, resulting in DNA damage, cytoplasmic destruction, and decreased catalase and superoxide dismutase activities. Transcription analysis showed downregulation of Xcc genes related to 'biofilms, virulence, adhesion' and 'DNA transfer' exposure to ZnO QDs. More importantly, ZnO QDs also promoted the growth of citrus. CONCLUSION: This research provides new insights into the photocatalytic antibacterial mechanisms of ZnO QDs and supports the development of more efficient and safer ZnO QDs-based nanopesticides to control citrus canker. © 2024 Society of Chemical Industry.

Chiral Topological Superconductivity in Superconductor-Obstructed Atomic Insulator-Ferromagnetic Insulator Heterostructures.

Implementing topological superconductivity (TSC) and Majorana states (MSs) is one of the most significant and challenging tasks in both fundamental physics and topological quantum computations. In this work, taking the obstructed atomic insulator (OAI) Nb_{3}Br_{8}, s-wave superconductor (SC) NbSe_{2}, and ferromagnetic insulator (FMI) CrI_{3} as an example, we propose a new setup to realize the 2D chiral TSC and MSs in the SC/OAI/FMI heterostructure, which could avoid the subband problem effectively and has the advantage of huge Rashba spin-orbit coupling. As a result, the TSC phase can be stabilized in a wide region of chemical potential and Zeeman splitting, and four distinct TSC phases with superconducting Chern number N=-1,-2,-3, 3 can be achieved. Moreover, a 2D Bogoliubov-de Gennes Hamiltonian based on the triangular lattice of obstructed Wannier charge centers, combined with the s-wave superconductivity paring and Zeeman splitting, is constructed to understand the whole topological phase diagram analytically. These results expand the application of OAIs and pave a new way to realize the TSC and MSs with unique advantages.

Majorana Zero Modes Induced by the Meissner Effect at Small Magnetic Field.

One key difficulty in realizing Majorana zero modes (MZMs) is the required high magnetic field, which causes serious issues, e.g., shrinks the superconducting gap, reduces topological region, and weakens their robustness against disorders. In this Letter, we propose that the Meissner effect can bring the topological superconducting phase to a superconductor/topological-insulator/superconductor (SC/TI/SC) hybrid system. Remarkably, the required magnetic field strength (<10 mT) to support MZMs has been reduced by several orders of magnitude compared to that (>0.5 T) in the previous schemes. Tuning the phase difference between the top and bottom superconductors can control the number and position of the MZMs. In addition, we account for the electrostatic potential in the superconductor/topological-insulator (SC/TI) interface through the self-consistent Schrödinger-Poisson calculation, which shows the experimental accessibility of our proposal. Our proposal only needs a small magnetic field of less than 10 mT and is robust against the chemical potential fluctuation, which makes the SC/TI/SC hybrid an ideal Majorana platform.

Bavachin ameliorates neuroinflammation and depressive-like behaviors in streptozotocin-induced diabetic mice through the inhibition of PKCδ.

Depression and diabetes are closely linked; however, the pathogenesis of depression associated with diabetes is unclear, and there are no clinically effective antidepressant drugs for diabetic patients with depression. Bavachin is an important active ingredient in Fructus Psoraleae. In this study, we evaluated the anti-neuroinflammatory and antidepressant effects associated with diabetes and the molecular mechanisms of bavachin in a streptozotocin-induced diabetes mouse model. We found that bavachin clearly decreased streptozotocin (STZ)-induced depressive-like behaviors in mice. It was further found that bavachin significantly inhibited microglia activation and the phosphorylation level of PKCδ and inhibited the activation of the NF-κB pathway in vivo and in vitro. Knockdown of PKCδ with siRNA-PKCδ partially reversed the inhibitory effect of bavachin on the NF-κB pathway and the level of pro-inflammatory factors. We further found that PKCδ directly bound to bavachin based on molecular docking and pull-down assays. We also found that bavachin improved neuroinflammation-induced neuronal survival and functional impairment and that this effect may be related to activation of the ERK and Akt pathways mediated by the BDNF pathway. Taken together, these data suggested that bavachin, by targeting inhibition PKCδ to inhibit the NF-κB pathway, further reduced the inflammatory response and oxidative stress and subsequently improved diabetic neuronal survival and function and finally ameliorated diabetes-induced depressive-like behaviors in mice. For the first time, we found that bavachin is a potential agent for the treatment of diabetes-associated neuroinflammation and depression and that PKCδ is a potential target for the treatment of diabetes-associated neuroinflammation, including depression.

Design, Synthesis and Antifungal Activities of Novel Pyrazole Analogues Containing the Aryl Trifluoromethoxy Group.

On the basis of the three-component synthetic methodology developed by us, a total of twenty-six pyrazole compounds bearing aryl OCF3 were designed and synthesized. Their chemical structures were characterized by 1H and 13C nuclear magnetic resonance and high-resolution mass spectrometry. These compounds were evaluated systematically for antifungal activities in vitro against six plant pathogenic fungi by the mycelium growth rate method. Most of the compounds showed some activity against each of the fungi at 100 µg/mL. Compounds 1t and 1v exhibited higher activity against all the tested fungi, and 1v displayed the highest activity against F. graminearum with an EC50 value of 0.0530 µM, which was comparable with commercial pyraclostrobin. Structure-activity relationship analysis showed that, with respect to the R1 substituent, the straight chain or cycloalkyl ring moiety was a key structural moiety for the activity, and the R2 substituent on the pyrazole ring could have significant effects on the activity. Simple and readily available pyrazoles with potent antifungal activity were obtained, which are ready for further elaboration to serve as a pharmacophore in new potential antifungal agents.

Design of a novel multiepitope vaccine against Chlamydia pneumoniae using the extracellular protein as a target.

Chlamydia pneumoniae (C. pneumoniae) infection in humans is universal and causes various respiratory infectious diseases, making a safe and effective preventive vaccine essential. In this study, a multi-epitope vaccine with CTLA-4 extracellular structure was constructed by an immunoinformatics approach. Since MOMP protein is the major extracellular protein in C. pneumoniae and has good immunogenicity and high conservation, we selected the MOMP protein of C. pneumoniae as the antigen target, predicted the T and B cell epitopes of the MOMP protein and then connected the CTLA-4 extracellular structure with the predicted dominant epitopes by various linkers to construct a multi-epitope vaccine. The biochemical characterization of the multi-epitope vaccine showed its immunogenicity and anti-allergic properties. The tertiary structure of this vaccine, along with molecular docking, molecular dynamics simulation, and principal component analysis, showed that the multi-epitope vaccine structure interacted with B7 (B7-1, B7-2) and toll-like receptors (TLR-2, TLR-4). Ultimately, the vaccine was cloned and effectively expressed in silico on an insect baculovirus expression vector (pFastBac1). These analyses showed that the designed vaccine could potentially target antigen-presenting cells and was immune to C. pneumoniae, which provided novel strategies for developing the vaccine.

circFAM134B is a key factor regulating reticulophagy-mediated ferroptosis in hepatocellular carcinoma.

Ferroptosis is an important mode of regulated cell death (RCD). Its inhibition is closely related to therapeutic resistance and poor prognosis in hepatocellular carcinoma (HCC). Previous reports have demonstrated ferroptosis as a biological process highly dependent on selective autophagy, such as ferritinophagy, lipophagy, and clockophagy. Our study also revealed a role for ER-phagy-mediated ferroptosis in HCC cells treated with multi-targeted tyrosine kinase inhibitors (TKIs). In the current study, we found that the homologous circular RNA (circRNA) of the family with sequence similarity 134, member B (FAM134B), hsa_circ_0128505 (was abbreviated as circFAM134B in the present study), was identified to specifically target ER-phagy to promote lenvatinib (LV)-induced ferroptosis using reactive oxygen species (ROS), Fe2+, malondialdehyde (MDA), and western blot (WB) assays in HCC cells. RNA pull-down and mass spectrometry analyses suggested that circFAM134B and FAM134B mRNA were enriched with several common interacting proteins. Among them, poly (A) binding protein cytoplasmic 4 (PABPC4) was identified as the most enriched binding partner. It was proven to be a novel antagonist against the nonsense-mediated mRNA decay (NMD) mechanism. We then applied RNA immunoprecipitation (RIP), RNA pull-down, luciferase reporter, and NMD reporter gene assays to further explore the exact role and underlying mechanism of circFAM134B-PABPC4-FAM134B axis in HCC cells. circFAM134B was confirmed as a sponge that competitively interacted with PABPC4, thereby influencing FAM134B mRNA nonsense decay. Our results provide novel evidences and strategies for the comprehensive treatment of HCC.

Intracardiac biopsy of cardiac tumors with echocardiographic guidance: Case report.

Background: Primary cardiac tumors are very rare, and about 20-30% of them are malignant tumors. Since early signs of cardiac tumors are non-specific, diagnosis can be challenging. There is a lack of the recommended guidelines or standardized strategies for diagnosis and optimal treatment for this disease. As the definite diagnoses of most tumors are made by pathologic confirmation, biopsied tissue is essential in determining the treatment for patients with cardiac tumors. Recently, intracardiac echocardiography (ICE) has been introduced to assist biopsy procedures of cardiac tumors and it provides high-quality imaging. Case Description: Due to its low prevalence and variable presentation, cardiac malignant tumors usually are easily missed. Hereby, we report three cases of patients who presented with non-specific signs of cardiac disorder and was initially suspended diagnosis as lung infection or cancer. Under the guidance of ICE, cardiac biopsies were successfully on cardiac masses, giving critical data for diagnosis and treatment planning. No procedural complications were obtained in our cases. These cases are intended to highlight the clinical value and importance of ICE-guided biopsy of intracardiac mass. Conclusions: The diagnosis of primary cardiac tumors relies on the histopathological results. In our experience, using ICE for biopsy of an intracardiac mass is an attractive tool to increase diagnostic results and reduce the risk of cardiac complications associated with inadequate targeting of the biopsy catheters.

A case of subclinical immune checkpoint inhibitor-associated myocarditis in non-small cell lung cancer.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have been widely used in the treatment of cancer. Moreover, immune-related adverse events (irAEs) have become a new clinical challenge. ICI-associated myocarditis is a rare but fatal condition among diverse organ injuries, and early recognition and effective interventions are critical for patients. CASE PRESENTATION: In this report, we present the case of a healthy 60-year-old male who was diagnosed with lung squamous cell carcinomas following chemotherapy and received ICIs. The patient presented with asymptomatic cardiac biomarker elevation followed by immune-related myocarditis. Fortunately, the patient achieved a good clinical result after receiving high-dose steroids. The treatment with ICIs was discontinued because of recurrent increases in troponin T. CONCLUSION: ICI-mediated associated myocarditis is an uncommon but potentially life-threatening adverse event. The current data suggest that clinicians need to be cautious about reinitiation in low-grade patients; however, further study of the diagnosis and treatment is necessary.

Molecular engineering to red-shift the absorption band of AIE photosensitizers and improve their ROS generation ability.

Photodynamic therapy (PDT) with aggregation-induced emission photosensitizers (AIE-PSs) has attracted increasing attention for their enhanced fluorescence and reactive oxygen species (ROS) generation abilities upon aggregation. However, it is difficult for AIE-PSs to simultaneously achieve long-wavelength excitation (>600 nm) and high singlet oxygen quantum yield, which restricts their application in deep-tissue PDT. In this study, four novel AIE-PSs were developed by appropriate molecular engineering, and their absorption peaks shifted from 478 to 540 nm with a tail extending to 700 nm. Meanwhile, their emission peaks were also moved from 697 nm to 779 nm with a tail extending over 950 nm. Importantly, their singlet oxygen quantum yields successfully increased from 0.61 to 0.89. Moreover, TBQ, the best photosensitizer developed by us, has been successfully applied to image-guided PDT in BALB/C mice bearing 4T1 breast cancer under red light (605 ± 5 nm) irradiation, with IC50 less than 2.5 µM at a low light dose (10.8 J cm-2). The success of this molecular engineering indicates that increasing the number of acceptors is more effective at red-shifting the absorption band of AIE-PSs than increasing the number of donors, and extending the π-conjugation of acceptors will red-shift the absorption-emission band, increase the maximum molar extinction coefficient, and improve the ROS generation ability of AIE-PSs, thus providing a new strategy for the design of advanced AIE-PSs for deep-tissue PDT.

Protopanaxadiol manipulates gut microbiota to promote bone marrow hematopoiesis and enhance immunity in cyclophosphamide-induced immunosuppression mice.

Protopanaxadiol (PPD) has potential immunomodulatory effects, but the underlying mechanism remains unclear. Here, we explored the potential roles of gut microbiota in the immunity regulation mechanisms of PPD using a cyclophosphamide (CTX)-induced immunosuppression mouse model. Our results showed that a medium dose of PPD (PPD-M, 50 mg/kg) effectively ameliorated the immunosuppression induced by CTX treatment by promoting bone marrow hematopoiesis, increasing the number of splenic T lymphocytes and regulating the secretion of serum immunoglobulins and cytokines. Meanwhile, PPD-M protected against CTX-induced gut microbiota dysbiosis by increasing the relative abundance of Lactobacillus, Oscillospirales, Turicibacter, Coldextribacter, Lachnospiraceae, Dubosiella, and Alloprevotella and reducing the relative abundance of Escherichia-Shigella. Importantly, PPD-M lost the ability to promote bone marrow hematopoiesis and enhance immunity when the gut microbiota was depleted by broad-spectrum antibiotics. Moreover, PPD-M promoted the production of microbiota-derived immune-enhancing metabolites including cucurbitacin C, l-gulonolactone, ceramide, DG, prostaglandin E2 ethanolamide, palmitoyl glucuronide, 9R,10S-epoxy-stearic acid, and 9'-carboxy-gamma-chromanol. KEGG topology analysis showed that the PPD-M treatment significantly enriched the sphingolipid metabolic pathway with ceramide as a main metabolite. Our findings reveal that PPD enhances immunity by manipulating gut microbiota and has the potential to be used as an immunomodulator in cancer chemotherapy.

Identification of a novel transthyretin mutation D39Y in a cardiac amyloidosis patient and its biochemical characterizations.

Hereditary transthyretin cardiac amyloidosis (hATTR-CA) is a rare autosomal dominantly inherited disease caused by mutations in the transthyretin (TTR) gene. TTR mutations often cause the instability of transthyretin, production of misfolded proteins, and ultimately excessive deposition of insoluble amyloid fibrils in the myocardium, thereby leading to cardiac dysfunction. Herein, we report a novel transthyretin D39Y mutation in a Chinese family. We characterized the kinetic and thermodynamic stabilities of D39Y mutant TTR, revealing that TTR D39Y mutant was less stable than WT TTR and more stable than amyloidogenic mutation TTR L55P. Meanwhile, the only FDA approved drug Tafamidis showed satisfactory inhibitory effect toward ATTR amyloid formation and strong binding affinity in test tube revealed by isothermal titration calorimetry. Finally, we measured the well-folded tetrameric TTR concentration in patient's and his descents' blood serum using a previously reported UPLC-based assay. Notably, the tetramer concentrations gradually increased from symptomatic D39Y gene carrier father, to asymptomatic D39Y gene carrier daughter, and further to wild type daughter, suggesting the decrease in functional tetrameric TTR concentration may serve as an indicator for disease age of onset in D39Y gene carriers. The study described a Chinese family with hATTR-CA due to the TTR variant D39Y with its destabilizing effect in both kinetic and thermodynamic stabilities.

Mesoporous Silica Nanoparticles Induce Intracellular Peroxidation Damage of Phytophthora infestans: A New Type of Green Fungicide for Late Blight Control.

Nanopesticides are considered to be a promising alternative strategy for enhancing bioactivity and delaying the development of pathogen resistance to pesticides. Here, a new type of nanosilica fungicide was proposed and demonstrated to control late blight by inducing intracellular peroxidation damage to Phytophthora infestans, the pathogen associated with potato late blight. Results indicated that the structural features of different silica nanoparticles were largely responsible for their antimicrobial activities. Mesoporous silica nanoparticles (MSNs) exhibited the highest antimicrobial activity with a 98.02% inhibition rate of P. infestans, causing oxidative stress responses and cell structure damage in P. infestans. For the first time, MSNs were found to selectively induce spontaneous excess production of intracellular reactive oxygen species in pathogenic cells, including hydroxyl radicals (•OH), superoxide radicals (•O2-), and singlet oxygen (1O2), leading to peroxidation damage in P. infestans. The effectiveness of MSNs was further tested in the pot experiments as well as leaf and tuber infection, and successful control of potato late blight was achieved with high plant compatibility and safety. This work provides new insights into the antimicrobial mechanism of nanosilica and highlights the use of nanoparticles for controlling late blight with green and highly efficient nanofungicides.