Identification and validation of tumor-specific T cell receptors from tumor infiltrating lymphocytes using tumor organoid co-cultures.

T cell receptor-engineered T cells (TCR-Ts) therapy is promising for cancer immunotherapy. Most studies have focused on identifying tumor-specific T cell receptors (TCRs) through predicted tumor neoantigens. However, current algorithms for predicting tumor neoantigens are unreliable and many neoantigens are derived from non-coding regions. Thus, the technological platform for identifying tumor-specific TCRs using natural antigens expressed on tumor cells is urgently needed. In this study, tumor organoids-enriched tumor infiltrating lymphocytes (oeT) were obtained by repeatedly stimulation of autologous patient-derived organoids (PDO) in vitro. The oeT cells specifically responded to autologous tumor PDO by detecting CD137 expression and the secretion of IFN-γ using enzyme-linked immunospot assay. The measurement of oeT cell-mediated killing of three-dimensional organoids was conducted using a caspase3/7 flow cytometry assay kit. Subsequently, tumor-specific T cells were isolated based on CD137 expression and their TCRs were identified through single-cell RT-PCR analysis. The specificity cytotoxicity of TCRs were confirmed by transferring to primary peripheral blood T cells. The co-culture system proved highly effective in generating CD8+ tumor-specific oeT cells. These oeT cells effectively induced IFN-γ secretion and exhibited specificity in killing autologous tumor organoids, while not eliciting a cytotoxic response against normal organoids. The analysis conducted by TCRs revealed a significant expansion of T cells within a specific subset of TCRs. Subsequently, the TCRs were cloned and transferred to peripheral blood T cells generation engineered TCR-Ts, which adequately recognized and killed tumor cell in a patient-specific manner. The co-culture system provided an approach to generate tumor-specific TCRs from tumor-infiltrating lymphocytes of patients with colorectal cancer, and tumor-specific TCRs can potentially be used for personalized TCR-T therapy.

Cellular spermine targets JAK signaling to restrain cytokine-mediated autoimmunity.

Prolonged activation of the type I interferon (IFN-I) pathway leads to autoimmune diseases such as systemic lupus erythematosus (SLE). Metabolic regulation of cytokine signaling is critical for cellular homeostasis. Through metabolomics analyses of IFN-ß-activated macrophages and an IFN-stimulated-response-element reporter screening, we identified spermine as a metabolite brake for Janus kinase (JAK) signaling. Spermine directly bound to the FERM and SH2 domains of JAK1 to impair JAK1-cytokine receptor interaction, thus broadly suppressing JAK1 phosphorylation triggered by cytokines IFN-I, IFN-II, interleukin (IL)-2, and IL-6. Peripheral blood mononuclear cells (PBMCs) from individuals with SLE showing decreased spermine concentrations exhibited enhanced IFN-I and lupus gene signatures. Spermine treatment attenuated autoimmune pathogenesis in SLE and psoriasis mice and reduced IFN-I signaling in monocytes from individuals with SLE. We synthesized a spermine derivative (spermine derivative 1 [SD1]) and showed that it had a potent immunosuppressive function. Our findings reveal spermine as a metabolic checkpoint for cellular homeostasis and a potential immunosuppressive molecule for controlling autoimmune disease.

Design and synthesis of 6-C-alkyl-DMDP type nanomolar inhibitors of ß-galactosidase and ß-glucosidase based on broussonetine S and related derivatives.

Broussonetine S (9), its C-1' and C-10' stereoisomers, and their corresponding enantiomers have been synthesized from enantiomeric arabinose-derived cyclic nitrones, with cross metathesis (CM), epoxidation and Keck asymmetric allylation as key steps. Glycosidase inhibition assays showed that broussonetine S (9) and its C-10' epimer (10'-epi-9) were nanomolar inhibitors of bovine liver ß-galactosidase and ß-glucosidase; while their C-1' stereoisomers were 10-fold less potent towards these enzymes. The glycosidase inhibition results and molecular docking calculations revealed the importance of the configurations of pyrrolidine core and C-1' hydroxyl for inhibition potency and spectra. Together with the docking calculations we previously reported for α-1-C-alkyl-DAB derivatives, we designed and synthesized a series of 6-C-alkyl-DMDP derivatives with very simple alkyl chains. The inhibition potency of these derivatives was enhanced by increasing the length of the side chain, and maintained at nanomolar scale inhibitions of bovine liver ß-glucosidase and ß-galactosidase after the alkyl groups are longer than eight or ten carbons for the (6R)-C-alkyl-DMDP derivatives and their 6S epimers, respectively. Molecular docking calculations indicated that each series of 6-C-alkyl-DMDP derivatives resides in the same active site of ß-glucosidase or ß-galactosidase with basically similar binding conformations, and their C-6 long alkyl chains extend outwards along the hydrophobic groove with similar orientations. The increasing inhibitions of ß-glucosidase and ß-galactosidase with the number of carbon atoms in the side chains may be explained by improved adaptability of longer alkyl chains in the hydrophobic grooves. In addition, the lower ß-glucosidase and ß-galactosidase inhibitions of (6S)-C-alkyl-DMDP derivatives than their C-6 R stereoisomers can be attributed to the misfolding of their alkyl chains and resulted decreased adaptability in the hydrophobic groove. The work reported herein is valuable for design and development of more potent and selective inhibitors of ß-galactosidase and ß-glucosidase, which have potential in treatment of lysosomal storage diseases. Furthermore, part of the 6-C-alkyl-DMDP derivatives and their enantiomers were also tested as potential anti-cancer agents; all the compounds tested were found with moderate cytotoxic effects on MKN45 cells, which would indicate potential applications of these iminosugars in development of novel anticancer agents.

A Highly Sensitive Dual-Drive Microfluidic Device for Multiplexed Detection of Respiratory Virus Antigens.

Conventional microfluidic systems that rely on capillary force have a fixed structure and limited sensitivity, which cannot meet the demands of clinical applications. Herein, we propose a dual-drive microfluidic device for sensitive and flexible detection of multiple pathogenic microorganisms antigens/antibodies. The device comprises a portable microfluidic analyzer and a dual-drive microfluidic chip. Along with capillary force, a second active driving force is provided by a removable self-driving valve in the waste chamber. The interval between these two driving forces can be adjusted to control the reaction time in the microchannel, optimizing the formation of antigen-antibody complexes and enhancing sensitivity. Moreover, the material used in the self-driving valve can be changed to adjust the active force strength needed for different tests. The device offers quantitative analysis for respiratory syncytial virus antigen and SARS-CoV-2 antigen using a 35 µL sample, delivering results within 5 min. The detection limits of the system were 1.121 ng/mL and 0.447 ng/mL for respiratory syncytial virus recombinant fusion protein and SARS-CoV-2 recombinant nucleoprotein, respectively. Although the dual-drive microfluidic device has been used for immunoassay for respiratory syncytial virus and SARS-CoV-2 in this study, it can be easily adapted to other immunoassay applications by changing the critical reagents.

Slow-Release Effect Assisted Crystallization for Sequential Deposition Realizes Efficient Inverted Perovskite Solar Cells.

The two-step sequential deposition strategy has been widely recognized in promoting the research and application of perovskite solar cells, but the rapid reaction of organic salts with lead iodide inevitably affects the growth of perovskite crystals, accompanied by the generation of more defects. In this study, the regulation of crystal growth was achieved in a two-step deposition method by mixing 1-naphthylmethylammonium bromide (NMABr) with organic salts. The results show that the addition of NMABr effectively delays the aggregation and crystallization behavior of organic salts; thereby, the growth of the optimal crystal (001) orientation of perovskite is promoted. Based on this phenomenon of delaying the crystallization process of perovskite, the "slow-release effect assisted crystallization" is defined. Moreover, the incorporation of the Br element expands the band gap of perovskite and mitigates material defects as nonradiative recombination centers. Consequently, the power conversion efficiency (PCE) of the enhanced perovskite solar cells (PSCs) reaches 20.20%. It is noteworthy that the hydrophobic nature of the naphthalene moiety in NMABr can enhance the humidity resistance of PSCs, and the perovskite phase does not decompose for more than 3000 h (30-40% RH), enabling it to retain 90% of its initial efficiency even after exposure to a nitrogen environment for 1200 h.

Precise Modulation of Pericyte Dysfunction by a Multifunctional Nanoprodrug to Ameliorate Alzheimer's Disease.

Pericyte dysfunction severely undermines cerebrovascular integrity and exacerbates neurodegeneration in Alzheimer's disease (AD). However, pericyte-targeted therapy is a yet-untapped frontier for AD. Inspired by the elevation of vascular cell adhesion molecule-1 (VCAM-1) and reactive oxygen species (ROS) levels in pericyte lesions, we fabricated a multifunctional nanoprodrug by conjugating the hybrid peptide VLC, a fusion of the VCAM-1 high-affinity peptide VHS and the neuroprotective apolipoprotein mimetic peptide COG1410, to curcumin (Cur) through phenylboronic ester bond (VLC@Cur-NPs) to alleviate complex pericyte-related pathological changes. Importantly, VLC@Cur-NPs effectively homed to pericyte lesions via VLC and released their contents upon ROS stimulation to maximize their regulatory effects. Consequently, VLC@Cur-NPs markedly increased pericyte regeneration to form a positive feedback loop and thus improved neurovascular function and ultimately alleviated memory defects in APP/PS1 transgenic mice. We present a promising therapeutic strategy for AD that can precisely modulate pericytes and has the potential to treat other cerebrovascular diseases.

Self-Assembled PLGA-Pluronic F127 Microsphere for Sustained Drug Release for Osteoarthritis.

For many years, sustained-release drug delivery systems (SRDDS) have emerged as a featured topic in the pharmaceutical field. Particularly for chronic diseases, such as osteoarthritis, there is a lot of demand for SRDDS because of the long treatment period and repetitive medication administration. Thus, we developed an injectable PLGA-F127 microsphere (MS) that is capable of the in situ conversion to an implant. The microprecipitation method for PLGA-F127 MS was established, and the physicochemical stability of the products was confirmed. The microspheres were assembled into a single mass in 37 °C aqueous conditions and showed a remarkably delayed drug release profile. First, the release started with no significant initial burst and lagged for 60 days. After that, in the next 40 days, the remaining 75% of the drugs were constantly released until day 105. We expect that our PLGA-F127 MS could be employed to extend the release period of 2 months of medication to 4 months. This could be a valuable solution for developing novel SRDDS for local injections.

Multidimensional autophagy nano-regulator boosts Alzheimer's disease treatment by improving both extra/intraneuronal homeostasis.

Intraneuronal dysproteostasis and extraneuronal microenvironmental abnormalities in Alzheimer's disease (AD) collectively culminate in neuronal deterioration. In the context of AD, autophagy dysfunction, a multi-link obstacle involving autophagy downregulation and lysosome defects in neurons/microglia is highly implicated in intra/extraneuronal pathological processes. Therefore, multidimensional autophagy regulation strategies co-manipulating "autophagy induction" and "lysosome degradation" in dual targets (neuron and microglia) are more reliable for AD treatment. Accordingly, we designed an RP-1 peptide-modified reactive oxygen species (ROS)-responsive micelles (RT-NM) loading rapamycin or gypenoside XVII. Guided by RP-1 peptide, the ligand of receptor for advanced glycation end products (RAGE), RT-NM efficiently targeted neurons and microglia in AD-affected region. This nano-combination therapy activated the whole autophagy-lysosome pathway by autophagy induction (rapamycin) and lysosome improvement (gypenoside XVII), thus enhancing autophagic degradation of neurotoxic aggregates and inflammasomes, and promoting Aß phagocytosis. Resultantly, it decreased aberrant protein burden, alleviated neuroinflammation, and eventually ameliorated memory defects in 3 × Tg-AD transgenic mice. Our research developed a multidimensional autophagy nano-regulator to boost the efficacy of autophagy-centered AD therapy.

Selecting autochthonous lactic acid bacteria for co-inoculation in Chinese bayberry wine production: Stress response, starter cultures application and volatilomic study.

This study focused on isolating and characterising autochthonous lactic acid bacteria (LAB) from spontaneously fermented Chinese bayberry (CB) and their potential application in CB wine fermentation in co-inoculation with yeast starter cultures. Numerous LAB, including Lactiplantibacillus (Lp.) plantarum (9), Limosilactobacillus (Lb.) fermentum (6), Lactococcus (Lc.) lactis (3), Enterococcus (Ec.) hirae (1), Leuconostoc (Le.) mesenteroides (1), and Weissella (Ws.) cibaria (1), were isolated and identified. The isolated strains Lp. plantarum ZFM710 and ZFM715, together with Lb. fermentum ZFM720 and ZFM722, adapted well to unfavourable fermentation environment, including ethanol, osmolality, and acidity stresses, were selected for producing CB wine by co-inoculation with Saccharomyces cerevisiae. During fermentation, the presence of LAB promoted the development of S. cerevisiae, while the population dynamics of LAB in different groups at different stages showed strain-specific differences. Fermentation trials involving LAB yielded a lower ethanol concentration except for Lp. plantarum ZFM715. Compared to the pure S. cerevisiae fermented sample, the addition of LAB led to a clear modulation in organic acid composition. Lb. fermentum strains in co-fermentation led to significant decreases in each classified group of aroma compounds, while Lp. plantarum ZFM715 significantly increased the complexity and intensity of aroma compounds, as well as the intensities of fruity and floral notes. The study selects interesting strains for the design of starter cultures for use in CB wine production, underlining the interest in the selection of autochthonous LAB in fruit wines, with the aim of improving the adaptation of bacteria to specific environmental conditions and shaping the unique traits of the finished products.

Establishment of fluorescence multi-flow cytometric immunoassay for the simultaneous quantitative detection of six allergen-sIgE antibodies.

BACKGROUND: The in vitro specific IgE (sIgE) assays now commonly used in clinical laboratories are not only time-consuming and expensive but also require many serum samples. To address these limitations, a novel fluorescent microsphere-based multiplex flow cytometric immunoassay was developed. This innovative assay enables rapid and simultaneous quantitative detection of multiple allergen-sIgE antibodies. OBJECTIVE: To establish a new method for the simultaneous quantitative detection of 6 allergen-sIgE antibodies based on fluorescence multiplex flow cytometry. METHODS: Six different encoded fluorescent microspheres were selected to covalently couple 6 allergens, and their antigen-coupling activities were verified. After optimizing the multiplexing procedure and reaction conditions, including the concentration of microspheres encapsulated by allergens, reaction temperature, and reaction time, standard curves were established to quantify the 6 allergen-sIgE, and their performance was evaluated according to clinical guidelines. RESULTS: The chosen analytical mode was optimized for the detection of the 6 allergens-sIgE for 70 minutes. The established coefficients of variation for multiplex flow cytometry reproducibility and intermediate precision were less than 10%. Linear regression analysis showed a highly significant quantitative correlation between the results of the multiple analyses of Dermatophagoides pteronyssinus, Dermatophagoides farinae, Artemisia, and cat hair allergens and ImmunoCAP (Thermo Fisher Scientific): the r2 values ranged from 0.85 to 0.97 (P < .0001). In addition, there was a high correlation between the results of the multiplex analysis of dog hair allergens and the capture enzyme-linked immunosorbent assay (r2 = 0.92, P < .0001). CONCLUSION: A high-throughput system called multiplex flow cytometry has been developed for the simultaneous detection of 6 inhalant allergens. The method has the advantage of being rapid and using less serum. Furthermore, it has the potential to be expanded to include other allergens and biologic agents.

Extending dual-targeting upper-limit in liposomal delivery of lithospermic acid B for Alzheimer's mitochondrial revitalization.

Mitochondrial dysfunction is a pivotal event in Alzheimer's disease (AD) pathogenesis. Lithospermic acid B (LA) has shown promise in safeguarding mitochondria, yet the underlying mechanism remains elusive. Here, we present evidence that LA rejuvenated AD-related mitochondrial pool by co-activating mitophagy and mitochondria biogenesis via PINK1/LC3B/P62 and PGC-1α/Nrf2. To advance in vivo application, hydrophilic LA was encapsulated in liposome (MT-LIP@LA) composed of D-mannosamine-cholesterol/DSPE-PEG2000-Tet1/lecithin (molar ratio, 3:0.3:10) for cascaded brain-neuron targeting. MT-LIP demonstrated 4.3-fold enhanced brain accumulation (2.57%dose/g-brain) than LIP (0.60%dose/g-brain) and precisely targeted neurons at AD lesion sites. Mechanism studies unraveled factors contributing to the preeminent brain targeting ability of MT-LIP: (1) high-density modified mannose efficiently binds to glucose transporter 1 (GLUT1) on blood-brain barrier (BBB); (2) prone to trafficking towards caveolin-Golgi pathway during transcytosis. This augmented therapeutic platform efficiently restored mitochondrial health, prevented neurodegeneration, and ameliorated memory deficits in 3 × Tg-AD transgenic mice. Our studies revealed the underlying pharmacological mechanism of LA and provided a concise but efficient platform for neuronal mitochondria quality control in vivo.

Low expression of LncRNA AFAP1-AS1 inhibits proliferation and promotes apoptosis of non-small cell lung cancer cells through inhibiting wnt signaling pathway.

To detect the effects of long non-coding ribonucleic acid (lncRNA) actin filament-associated protein 1-antisense RNA1 (AFAP1-AS1) on the proliferation and apoptosis of non-small cell lung cancer (NSCLC) A549 cells and its mechanism. 1) The expression of lncRNA AFAP1-AS1 in NSCLC A549 cells was detected via quantitative reverse transcription-polymerase chain reaction (qRT-PCR). 2) The changes in proliferation and apoptosis of A549 cells after low expression of lncRNA AFAP1-AS1 were detected using cell counting kit-8 (CCK-8) and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assays. 3) The changes in Wnt signaling pathway proteins in A549 cells after low expression of lncRNA AFAP1-AS1 were detected using Western blotting. 1) The expression of lncRNA AFAP1-AS1 rose in A549 cells (P<0.01). 2) After low expression of lncRNA AFAP1-AS1, the growth of A549 cells was inhibited, and apoptosis was promoted. 3) After low expression of lncRNA AFAP1-AS1, the mRNA and protein expressions of glycogen synthase kinase (GSK) and ß-catenin declined (P<0.05). Lowly-expressed AFAP1-AS1 inhibits the proliferation and promotes the apoptosis of NSCLC A549 cells via inhibiting the Wnt signaling pathway.

A new species of shrew moles, genus Uropsilus Milne-Edwards, 1871 (Mammalia, Eulipotyphla, Talpidae), from the Wuyi Mountains, Jiangxi Province, eastern China.

Asian shrew moles, genus Uropsilus, are the most primitive members of family Talpidae. They are distributed mainly in southwestern China and adjacent Bhutan, Myanmar, and Vietnam. In June 2022, we collected five specimens of Uropsilus from Mount Huanggang, Jiangxi Province, eastern China, which is the highest peak of the Wuyi Mountains. We sequenced two mitochondrial (CYT B and 12S rRNA) and three nuclear (PLCB4, RAG1, and RAG2) genes to estimate the phylogenetic relationship of the five shrew moles. We also compared their morphology with recognized species within the genus. Our results show that these specimens collected from Mount Huanggang differ from all named species in Uropsilus. We formally describe the species here as Uropsilushuanggangensissp. nov. Morphologically, the new species is distinguishable from the other Uropsilus species by the combination of dark chocolate-brown pelage, long snout, enlarged first upper incisor, similarly sized lacrimal and infraorbital foramens, and the curved and sickle-like coronoid process. The genetic distances of the cytochrome b (CYT B) gene between U.huanggangensis and other recognized Uropsilus species ranged between 9.3% and 16.4%. The new species is geographically distant from other species in the genus and is the easternmost record of the Uropsilus. The divergence time of U.huanggangensis was estimated to be the late Pliocene (1.92 Ma, 95% CI = 0.88-2.99).

The mechanism of action of myricetin against lung adenocarcinoma based on bioinformatics, in silico and in vitro experiments.

Myricetin is a natural flavonoid with anti-cancer and anti-inflammatory effects, but its mechanism for treating lung adenocarcinoma (LUAD) remains unclearly. Therefore, bioinformatics, in silico and in vitro experiments were employed to elucidate this issue in this study. The core targets of myricetin against LUAD were screened by PharmaMapper (v2017), Assistant for Clinical Bioinformatics, STRING (v11.5) and Cytoscape (v3.8.1). Using Kaplan-Meier Plotter (v2022.04.20), UALCAN (v2021.12.13) and GEPIA (v2.0) databases, the correlation between core genes and the prognosis of LUAD patients were analyzed, and the expression levels of core genes were verified. In silico studies were used to analyze the binding energies and sites of myricetin with core genes. The effects of myricetin on H1975 cells were explored through thiazolyl blue (MTT), cell migration, colony formation and western blot assays. A total of 72 potential targets of myricetin against LUAD were identified through bioinformatics. Among the four core targets obtained by multiple networks and in silico assays, the up-regulated MMP9 (HR = 1.14 (1-1.29), logrank P = 0.046) and down-regulated PIK3R1 (HR = 0.58 (0.51-0.66), logrank P < 1E-16) were positively correlated with poor survival outcomes in LUAD patients. In vitro experiments demonstrated that myricetin inhibited the proliferation and migration of H1975 cells, promoting their apoptosis. Myricetin inhibits the proliferation of H1975 cells and induces cell apoptosis through its influence on the expression levels of MMP1, MMP3, MMP9, and PIK3R1 and regulating the multiple pathways these genes participate in. Both MMP9 and PIK3R1 are potential biomarkers for LUAD.

Amino Pyridine Iodine as an Additive for Defect-Passivated Perovskite Solar Cells.

Defect passivation of the perovskite surface and grain boundary (GBs) has become a widely adopted approach to reduce charge recombination. Research has demonstrated that functional groups with Lewis acid or base properties can successfully neutralize trap states and limit nonradiative recombination. Unlike traditional Lewis acid-base organic molecules that only bind to a single anionic or cationic defect, zwitterions can passivate both anionic and cationic defects simultaneously. In this work, zwitterions organic halide salt 1-amino pyridine iodine (AmPyI) is used as a perovskite for defect passivation. It is found that a pair of amino lone electrons in AmPyI can passivate defects surface and GBs through hydrogen bonding with perovskite, and the introduced I- can bind to uncoordinated Pb2+ while also controlling the surface morphology of the film and improving the crystallinity. In the presence of the AmPyI additive, we obtained about 1.24 µm of amplified perovskite grains and achieved an efficiency of 23.80% with minimal hysteresis.

Dual Enzyme Cascade-Activated Popcorn-Like Nanoparticles Efficiently Remodeled Stellate Cells to Alleviate Pancreatic Desmoplasia.

In pancreatic cancer, excessive desmoplastic stroma severely impedes drug access to tumor cells. By reverting activated pancreatic stellate cells (PSCs) to quiescence, all-trans retinoic acid (ATRA) can attenuate their stromal synthesis and remodel the tumor-promoting microenvironment. However, its modulatory effects have been greatly weakened due to its limited delivery to PSCs. Therefore, we constructed a tripeptide RFC-modified gelatin/oleic acid nanoparticle (RNP@ATRA), which delivered ATRA in an enzyme-triggered popcorn-like manner and effectively resolved the delivery challenges. Specifically, surface RFC was cleaved by aminopeptidase N (APN) on the tumor endothelium to liberate l-arginine, generating nitric oxide (NO) for tumor-specific vasodilation. Then, massive nanoparticles were pushed from the vessels into tumors, showing 5.1- and 4.0-fold higher intratumoral accumulation than free ATRA and APN-inert nanoparticles, respectively. Subsequently, in the interstitium, matrix metalloproteinase-2-induced gelatin degradation caused RNP@ATRA to rapidly release ATRA, promoting its interstitial penetration and PSC delivery. Thus, activated PSCs were efficiently reverted to quiescence, and stroma secretion and vascular compression were reduced, thereby enhancing intratumoral delivery of small-molecule or nanosized chemotherapeutics. Ultimately, RNP@ATRA combined with chemotherapeutics markedly suppressed tumor growth and metastasis without causing additional toxicities. Overall, this work provides a potential nanoplatform for the efficient delivery of PSC-modifying agents in pancreatic cancer and other stroma-rich tumors.

Water temperature and chlorophyll a density drive the genetic and epigenetic variation of Vallisneria natans across a subtropical freshwater lake.

Plant genetic diversity differs in habitat's oscillations, especially species distributed under heterogeneous environmental conditions. Freshwater ecosystems are vulnerable to biotic and abiotic impacts, which affect the genetic and epigenetic variations in aquatic plants. The extent of environmental heterogeneous attributes can be examined based on genetic and epigenetic variations. Such variations under environmental gradient can provide evidence for understanding the correlations between rapid environmental changes and species evolution. In this study, we performed amplified fragment polymorphism length and methylated-sensitive amplified polymorphism analysis to depict the genetic and epigenetic variations of Vallisneria natans in a subtropical lake. Results showed that this species maintained a relatively high genetic diversity (mean H E = 0.320, I = 0.474, PPL = 85.93%) and epigenetic variation (mean eH E = 0.282, eI = 0.428, ePPL = 83.91%). Water body temperature and chlorophyll a density were positively correlated to the genetic and epigenetic variations. The clonal generates of V. natans depicted a relative high methylation level and shew ancestral scenario between the genet and the second clonal generation. These findings revealed that species diversity is unevenly distributed under environmental heterogeneity, even at a fine geographic scale. Environmental characteristics in relation to temperature and chlorophyll a should be considered in the analysis of the genetic and epigenetic variations. Additionally, epigenetic variations between genets and ramets should be considered with caution when applied to analysis of other aquatic species.

Enhancement of Microglia Functions by Developed Nano-Immuno-Synergist to Ameliorate Immunodeficiency for Malignant Glioma Treatment.

Resident microglia are key factors in mediating immunity against brain tumors, but the microglia in malignant glioma are functionally impaired. Little immunotherapy is explored to restore microglial function against glioma. Herein, oleanolic acid (OA) (microglia "restorer") and D PPA-1 peptide (immune checkpoint blockade) are integrated on a nano-immuno-synergist (D PAM@OA) to work coordinately. The self-assembled OA core is coated with macrophage membrane for efficient blood-brain barrier penetration and microglia targeting, on which D PPA-1 peptide is attached via acid-sensitive bonds for specific release in tumor microenvironment. With the enhanced accumulation of the dual drugs in their respective action sites, D PAM@OA effectively promotes the recruitment and activation of effector T cells by inhibiting aberrant activation of Signal transducer and activator of transcription (STAT-3) pathway in microglia, and assists activated effector T cells in killing tumor cells by blocking elevated immune checkpoint proteins in malignant glioma. Eventually, as adjuvant therapy, the rationally designed nano-immuno-synergist hinders malignant glioma progression and recurrence with or without temozolomide. The work demonstrates the feasibility of a nano-formulation for microglia-based immunotherapy, which may provide a new direction for the treatment of brain tumors.

Dyclonine relieves the Parkinson's disease progression in rotenone-induced Drosophila model.

It has been estimated that there will be 930 million Parkinson's disease (PD) patients in 2030 in the whole world. However, no therapy has been effective for PD until now. Only levodopa is the available primary drug for the treatment of motor symptoms. Therefore, it is an urgent task to develop new drugs to inhibit the progression of PD and improve the quality of the patient's life. Dyclonine which was found to have antioxidant activity and would benefit patients with Friedreich's ataxia, is a commonly used local anesthetic. Here, we reported that dyclonine improved the motor ability and loss of dopaminergic neurons in the rotenone-induced Drosophila PD model for the first time. Furthermore, dyclonine upregulated the Nrf2/HO pathway, decreased the ROS and MDA levels, and inhibited the apoptosis of neurons in the brain of PD model flies. Hence, dyclonine might be an attractive FDA-approved drug for the exploration of effective PD therapy.

Association between high galectin expression and poor prognosis in hematologic cancers: a systematic review and meta-analysis.

BACKGROUND: Galectin (Gal) is considered a promising immune checkpoint molecule. More and more studies have shown that high expression levels of galectins in hematologic cancer are positively correlated with poor clinical prognosis. However, the exact prognostic significance of galectins remains unclear. METHODS: PubMed, Embase, Web of Science, and Cochrane Library were searched for studies addressing the correlation of galectin expression levels with prognosis of hematologic cancers. Stata software was used to estimate hazard ratios (HR) and 95% confidence intervals (CI). RESULT: Hematologic cancer patients with high galectin expression levels showed poor overall survival (OS, HR = 2.43, 95% CI: 1.95, 3.04), disease-free survival (DFS, HR = 3.29, 95% CI: 1.61, 6.71), and event-free survival (EFS, HR = 2.20, 95% CI: 1.47, 3.29) outcomes. Subgroup analysis revealed that high expression levels of galectins pointed to relatively poor OS in MDS (HR = 5.44, 95% CI: 2.09, 14.18), as compared to AML, CHL and CLL. No correlation was found between galectins and OS in NHL and MM. Among the three galectins, Gal-9 (HR = 3.60, 95% CI: 2.03, 6.38) showed higher correlation with poor prognosis than Gal-1 and Gal-3. In addition, use of peripheral blood (HR = 2.96, 95% CI: 2.07, 4.22) samples and qRT-PCR (HR = 2.80, 95% CI: 1.96, 4.01) method for galectin detection were shown to improve its prognostic correlation in hematologic cancers. CONCLUSION: Meta-analysis revealed high expression of galectins was associated with poor prognosis in hematologic cancer patients and galectins can be considered a promising prognostic predictive marker.