[Scale Effects of Landscape Pattern on Impacts of River Water Quality： A Meta-analysis].

The landscape pattern determines water pollution source and sink processes and plays an important role in regulating river water quality. Due to scale effects, studies on the relationship between landscape pattern and river water quality showed variance at different scales. However, there is still a lack of integrated study on the scale effect of landscape pattern and river water quality dynamics. This study collected 4 041 data from results of previous publications to address the characteristics of landscape pattern and river water quality dynamics at different scales and to identify the key temporal and spatial scales as well as landscape pattern indices for regulating river water quality. The results indicated that, compared to precipitation events, base flow periods, and interannual scales, the high-flow period was the key temporal scale for linking landscape pattern on river water quality. Compared to the watershed scale, the landscape pattern of buffer zones had a greater impact on river water quality. The high-flow period-buffer zone scale was the key spatiotemporal coupling scale for linking landscape pattern and river water quality. Compared to croplands, water bodies, grasslands, and the overall landscape of the watershed, the landscape pattern of forests and urban areas had a greater impact on river water quality. Fragmentation degree was the most important landscape pattern factor regulating river water quality. In river water quality management, it is important to focus on the landscape configuration of buffer zones, increase forest area, reduce patch density of forests and water bodies, and decrease the aggregation degree of urban areas.

Future Trends in Obolodiplosis robiniae Distribution across Eurasian Continent under Global Climate Change.

Obolodiplosis robiniae was discovered in Eurasia at the beginning of the 21st century. In this study, we explore the present and future (in the years 2050 and 2070) trends in the potential distribution of O. robiniae in Eurasia under diverse climate change scenarios based on a maximum entropy model. Our findings indicated that the current potential distribution area of O. robiniae is within the range of 21°34' and 65°39' N in the Eurasian continent. The primary factor controlling the distribution of O. robiniae is temperature. The highly and moderately suitable areas are mainly distributed in the semi-humid and semi-arid regions, which also happen to be the locations where the host black locust (Robinia pseudoacacia L.) grows at its fastest rate. The forecast of the potential distribution area of O. robiniae revealed that the species would benefit from global warming. The region suitable for the habitat of O. robiniae is characterized by a large-scale northward expansion trend and an increase in temperature. This information would help the forestry quarantine departments of Asian and European countries provide early warnings on the probable distribution areas of O. robiniae and provide a scientific basis for the prevention and control of O. robiniae spread and outbreaks.

Simultaneous phosphorus and nitrogen removal with different C/N ratios in a low oxygen aeration system: Microorganisms and mechanisms.

In this study, a combined system with simultaneous nitrification, denitrification, and phosphorus removal was operated in continuous low oxygen aeration mode, and the effect of lower oxygen aeration (dissolved oxygen [DO] 0.5-1.5 mg/L) on its performance was examined. The combined system consisted of sludge and high-efficiency biological packing and was operated using four carbon/nitrogen ratios (C/N) with being 10:1, 8:1, 6:1, 10:1. Experimental results showed that the combined system could perform an efficient nitrogen and phosphorus removal under low DO and C/N ratio of 8:1 condition, and removal efficiencies of chemical oxygen demand (COD), NH4 + -N, and PO4 3- -P were 80.01%, 99.03%, and 89.51%, respectively. High-throughput analysis indicated that the functional species of denitrifying bacteria, including Ferruginibacter Azospira, Comamonas, Bacilli, Hyphomicrobium, Thauera, and Comamonadaceae, were important participants in biological nutrient removal. Meanwhile, Acinetobacter was enriched in the combined system, which contributed to phosphorus removal. PRACTITIONER POINTS: A combined system was operated firstly under continuous low oxygen condition. The lower dissolved oxygen (DO) of the combined system was maintained at 0.50-1.5 mg/L level. The combined system could realize simultaneous phosphorus and nitrogen removal under C/N ratio of 8:1. Several functional bacteria were enriched in the coupled systems.

Synthesis of Melatonin Derivatives and the Neuroprotective Effects on Parkinson's Disease Models of Caenorhabditis elegans.

Melatonin (MT) is a hormone with antioxidant activity secreted by the pineal gland in the human brain, which is highly efficient in scavenging free radicals and plays an important role in the neuro-immuno-endocrine system. Emerging evidence showed that MT supplementation was a potential therapeutic strategy for Parkinson's disease (PD), which inhibits pathways associated with oxidative stress in PD. In this study, we reported a C7-selective olefination of melatonin under rhodium catalysis with the aid of PIII-directing groups and synthesized 10 new melatonin-C7-cinnamic acid derivatives (6a-6j). The antioxidant potential of the compounds was evaluated both by ABTS and ORAC methods. Among these newly synthesized melatonin derivatives, 6a showed significantly higher activity than MT at 10-5 M. In the transgenic Caenorhabditis elegans model of PD, 6a significantly reduces alpha-synuclein aggregation and dopaminergic neuronal damage in nematodes while reducing intracellular ROS levels and recovers behavioral dysfunction induced by dopaminergic neurodegeneration. Further study of the mechanism of action of this compound can provide new therapeutic ideas and treatment strategies for PD.

Alum Adjuvant and Built-in TLR7 Agonist Synergistically Enhance Anti-MUC1 Immune Responses for Cancer Vaccine.

The tumor-associated antigen mucin 1 (MUC1) is an attractive target of antitumor vaccine, but its weak immunogenicity is a big challenge for the development of vaccine. In order to enhance immune responses against MUC1, herein, we conjugated small molecular toll-like receptor 7 agonist (TLR7a) to carrier protein BSA via MUC1 glycopeptide to form a three-component conjugate (BSA-MUC1-TLR7a). Furthermore, we combined the three-component conjugate with Alum adjuvant to explore their synergistic effects. The immunological studies indicated that Alum adjuvant and built-in TLR7a synergistically enhanced anti-MUC1 antibody responses and showed Th1-biased immune responses. Meanwhile, antibodies elicited by the vaccine candidate effectively recognized tumor cells and induced complement-dependent cytotoxicity. In addition, Alum adjuvant and built-in TLR7a synergistically enhanced MUC1 glycopeptide-specific memory CD8+ T-cell immune responses. More importantly, the vaccine with the binary adjuvant can significantly inhibit tumor growth and prolong the survival time of mice in the tumor challenge experiment. This novel vaccine construct provides an effective strategy to develop antitumor vaccines.

MUC1 Specific Immune Responses Enhanced by Coadministration of Liposomal DDA/MPLA and Lipoglycopeptide.

Mucin 1 (MUC1), a well-known tumor-associated antigen and attractive target for tumor immunotherapy, is overexpressed in most human epithelial adenomas with aberrant glycosylation. However, its low immunogenicity impedes the development of MUC1-targeted antitumor vaccines. In this study, we investigated three liposomal adjuvant systems containing toll-like receptor 4 (TLR4) agonist monophosphoryl lipid A (MPLA) and auxiliary lipids of different charges: cationic lipid dimethyldioctadecylammonium (DDA), neutral lipid distearoylglycerophosphocholine (DSPC) or anionic lipid dioleoylphosphatidylglycerol (DOPG), respectively. ELISA assay evidenced that the positively charged DDA/MPLA liposomes are potent immune activators, which induced remarkable levels of anti-MUC1 antibodies and exhibited robust Th1-biased immune responses. Importantly, the antibodies induced by DDA/MPLA liposomes efficiently recognized and killed MUC1-positive tumor cells through complement-mediated cytotoxicity. In addition, antibody titers in mice immunized with P2-MUC1 vaccine were significantly higher than those from mice immunized with P1-MUC1 or MUC1 vaccine, which indicated that the lipid conjugated on MUC1 antigen also played important role for immunomodulation. This study suggested that the liposomal DDA/MPLA with lipid-MUC1 is a promising antitumor vaccine, which can be used for the immunotherapy of various epithelial carcinomas represented by breast cancer.

From design to clinic: Engineered peptide nanomaterials for cancer immunotherapy.

Immunotherapy has revolutionized the field of cancer therapy. Nanomaterials can further improve the efficacy and safety of immunotherapy because of their tunability and multifunctionality. Owing to their natural biocompatibility, diverse designs, and dynamic self-assembly, peptide-based nanomaterials hold great potential as immunotherapeutic agents for many malignant cancers, with good immune response and safety. Over the past several decades, peptides have been developed as tumor antigens, effective antigen delivery carriers, and self-assembling adjuvants for cancer immunotherapy. In this review, we give a brief introduction to the use of peptide-based nanomaterials for cancer immunotherapy as antigens, carriers, and adjuvants, and to their current clinical applications. Overall, this review can facilitate further understanding of peptide-based nanomaterials for cancer immunotherapy and may pave the way for designing safe and efficient methods for future vaccines or immunotherapies.

Autophagy inhibitors increase the susceptibility of KRAS-mutant human colorectal cancer cells to a combined treatment of 2-deoxy-D-glucose and lovastatin.

RAS-driven colorectal cancer relies on glucose metabolism to support uncontrolled growth. However, monotherapy with glycolysis inhibitors like 2-deoxy-D-glucose causes limited effectiveness. Recent studies suggest that anti-tumor effects of glycolysis inhibition could be improved by combination treatment with inhibitors of oxidative phosphorylation. In this study we investigated the effect of a combination of 2-deoxy-D-glucose with lovastatin (a known inhibitor of mevalonate pathway and oxidative phosphorylation) on growth of KRAS-mutant human colorectal cancer cell lines HCT116 and LoVo. A combination of lovastatin (>3.75 µM) and 2-deoxy-D-glucose (>1.25 mM) synergistically reduced cell viability, arrested cells in the G2/M phase, and induced apoptosis. The combined treatment also reduced cellular oxygen consumption and extracellular acidification rate, resulting in decreased production of ATP and lower steady-state ATP levels. Energy depletion markedly activated AMPK, inhibited mTOR and RAS signaling pathways, eventually inducing autophagy, the cellular pro-survival process under metabolic stress, whereas inhibition of autophagy by chloroquine (6.25 µM) enhanced the cytotoxic effect of the combination of lovastatin and 2-deoxy-D-glucose. These in vitro experiment results were reproduced in a nude mouse xenograft model of HCT116 cells. Our findings suggest that concurrently targeting glycolysis, oxidative phosphorylation, and autophagy may be a promising regimen for the management of RAS-driven colorectal cancers.

Effects of co-pyrolysis of rice husk and sewage sludge on the bioavailability and environmental risks of Pb and Cd.

In this study, biochars were produced by co-pyrolysis of rice husk and sewage sludge, the environmental risk of heavy metal (Pd and Cd) in the biochars was assessed. Co-pyrolysis resulted in a lower yield but a higher C content compared with sewage sludge pyrolysis alone, the relative contents of Pb and Cd in biochars were declined. Co-pyrolysis process transformed the bioavailable heavy metals into stable speciation. The environmental risk assessment codes of Pb and Cd were reduced by 1-2 grades. The co-pyrolysis technology provides a feasible method for the safe disposal of heavy metal-contaminated sewage sludge.

Clathrin-independent but dynamin-dependent mechanisms mediate Ca2+-triggered endocytosis of the glutamate GluK2 receptor upon excitotoxicity.

We first explore the features of GluK2 endocytosis during kainate excitotoxicity and then explore the role of Ca2+ in the regulation of GluK2 endocytosis. The roles of Ca2+ were examined by treating cells with Ca2+ inhibitors or chelators. Surface biotinylation was used to examine the surface localization of GluK2. Immunoprecipitation followed by immunoblotting was used to identify the interaction of GluK2 with the endocytosis regulator protein-interacting with C kinase 1 and dynamin. Dynamin phosphorylation was examined by immunoblotting with the corresponding antibodies. Our results show that GluK2 internalization is blocked by inhibitors of clathrin-independent endocytosis and relies on intracellular Ca2+/calcineurin signaling. Protein-interacting with C kinase 1-GluK2 interaction is regulated by Ca2+/calcineurin signaling. Dynamin participates in the regulation of GluK2 surface localization. Also, calcineurin activation is related to dynamin function during kainate excitotoxicity. In conclusion, GluK2 receptor endocytosis is probably a clathrin-independent and dynamin-dependent process regulated by the peak Ca2+ transient. This work indicates the roles of the Ca2+ network in the regulation of GluK2 endocytosis during kainate excitotoxicity.

Peptidyl ω-Asp Selenoesters Enable Efficient Synthesis of N-Linked Glycopeptides.

Chemical synthesis is an attractive approach allows for the assembly of homogeneous complex N-linked glycopeptides and glycoproteins, but the limited coupling efficiency between glycans and peptides hampered the synthesis and research in the related field. Herein we developed an alternative glycosylation to construct N-linked glycopeptide via efficient selenoester-assisted aminolysis, which employs the peptidyl ω-asparagine selenoester and unprotected glycosylamine to perform rapid amide-bond ligation. This glycosylation strategy is highly compatible with the free carboxylic acids and hydroxyl groups of peptides and carbohydrates, and readily available for the assembly of structure-defined homogeneous N-linked glycopeptides, such as segments derived from glycoprotein EPO and IL-5.

Multifunctional Protein Conjugates with Built-in Adjuvant (Adjuvant-Protein-Antigen) as Cancer Vaccines Boost Potent Immune Responses.

Many cancer vaccines are not successful in clinical trials, mainly due to the challenges associated with breaking immune tolerance. Herein, we report a new strategy using an adjuvant-protein-antigen (three-in-one protein conjugates with built-in adjuvant) as an anticancer vaccine, in which both the adjuvant (small-molecule TLR7 agonist) and tumor-associated antigen (mucin 1, MUC1) are covalently conjugated to the same carrier protein (BSA). It is shown that the protein conjugates with built-in adjuvant can increase adjuvant's stimulation, prevent adjuvant's systemic toxicities, facilitate the codelivery of adjuvants and antigens, and enhance humoral and cellular immune responses. The IgG antibody titers elicited by the self-adjuvanting three-in-one protein conjugates were significantly higher than those elicited by the vaccine mixed with TLR7 agonist (more than 15-fold) or other traditional adjuvants. Importantly, the potent immune responses against cancer cells suggest that this new vaccine construct is an effective strategy for the personalized antitumor immunotherapy.

MicroRNA-144 represses gliomas progression and elevates susceptibility to Temozolomide by targeting CAV2 and FGF7.

Malignant gliomas are the most common tumor in central nervous system with poor prognosis. Due to the limitation of histological classification in earlier diagnosis and individualized medicine, it is necessary to combine the molecular signatures and the pathological characteristics of gliomas. Lots of microRNAs presented abnormal expression in gliomas and modulated gliomas development. Exploration the miRNAs profile is helpful for the diagnosis, therapy and prognosis of gliomas. It has been demonstrated that miR-144 plays important roles in solid tumors. However, the detail mechanisms remained unrevealed. In this study, we have demonstrated the level of miR-144 decreased in glioma tissues from patients, especially in gliomas with higher grades. MiR-144 was also validated have lower expression in glioma cell lines compared with cortical neuron cell by using qRT-PCR. The in vitro functional experiment indicated miR-144 improved gliomas progression through repressing proliferation, sensitizing to chemotherapeutics and inhibiting metastasis. We further identified fibroblast growth factor 7 (FGF7) and Caveolin 2 (CAV2) were target genes of miR-144 by luciferase reporter assay and western blotting. The mechanisms study suggested forced FGF7 expression elevated Akt activation and decreased reactive oxygen species (ROS) generation. The MTT and cell cycle assay indicated miR-144 suppressed glioma cells proliferation through modulating FGF mediated Akt signaling pathway. Meanwhile, miR-144 promoted Temozolomide (TMZ) induced apoptosis in glioma cells via increasing ROS production by using FACS. On the other hand, CAV2, as another target of miR-144, accelerated glioma cells migration and invasion via promoting glioma cells EMT progress. Retrieved expression of FGF7 or CAV2 rescued the proliferation and migration function mediated by miR-144. Furthermore, the in vivo experiments in PDX models displayed the anti-tumor function of miR-144, which could be retrieved by overexpression of FGF7 and CAV2. Taken together, these findings indicated miR-144 acted as a potential target against gliomas progression and uncovered a novel regulatory mechanism, which may provide a new therapeutic strategy and prognostic indicator for gliomas.

The Cannabinoid WIN 55,212-2 Reduces Delayed Neurologic Sequelae After Carbon Monoxide Poisoning by Promoting Microglial M2 Polarization Through ST2 Signaling.

Delayed neurologic sequelae (DNS) are among the most serious complications of carbon monoxide (CO) poisoning caused partly by elevated neuroinflammation. WIN 55,212-2, a non-selective agonist of cannabinoid receptors, has been demonstrated to have anti-inflammatory properties in various brain disorders. The anti-inflammatory action of WIN 55,212-2 is potentially associated with driving microglial M2 polarization. ST2 signaling is important in regulating inflammatory responses and microglial polarization. Therefore, we aimed to investigate the neuroprotective effect of WIN 55,212-2 on DNS after CO poisoning and elucidate its relationship with ST2-mediated microglial M2 polarization. The behavioral tests showed that treatment with WIN 55,212-2 significantly ameliorates the cognitive impairment induced by CO poisoning. This behavioral improvement was accompanied by reduced neuron loss, decreased production of pro-inflammatory cytokines, and a limited number of microglia in the hippocampus. Moreover, WIN 55,212-2 elevated the protein expression of IL-33 (the ligand of ST2) and ST2, increased the ratio of CD206-positive (M2 phenotype) and ST2-positive microglia, and augmented production of M2 microglia-associated cytokines in the hippocampus of CO-exposed rats. Furthermore, we observed that the WIN 55,212-2-mediated increases in ST2 protein expression, CD206-positive and ST2-positive microglia, and microglia-associated cytokines were blocked by the cannabinoid receptor 2 (CB2R) antagonist AM630 but not by the cannabinoid receptor 1 (CB1R) antagonist AM251. In contrast, the WIN 55,212-2-induced upregulation of the IL-33 protein expression was inhibited by AM251 but not by AM630. Altogether, these findings reveal cannabinoid receptors as promising therapeutic agents for CO poisoning and identify ST2 signaling-related microglial M2 polarization as a new mechanism of cannabinoid-induced neuroprotection.

Liposomal Antitumor Vaccines Targeting Mucin 1 Elicit a Lipid-Dependent Immunodominant Response.

The tumor-associated antigen mucin 1 (MUC1) has been pursued as an attractive target for cancer immunotherapy, but the poor immunogenicity of the endogenous antigen hinders the development of vaccines capable of inducing effective anti-MUC1 immunodominant responses. Herein, we prepared synthetic anti-MUC1 vaccines in which the hydrophilic MUC1 antigen was N-terminally conjugated to one or two palmitoyl lipid chains (to form amphiphilic Pam-MUC1 or Pam2 -MUC1). These amphiphilic lipid-tailed MUC1 antigens were self-assembled into liposomes containing the NKT cell agonist αGalCer as an adjuvant. The lipid-conjugated antigens reshaped the physical and morphological properties of liposomal vaccines. Promising results showed that the anti-MUC1 IgG antibody titers induced by the Pam2 -MUC1 vaccine were more than 30- and 190-fold higher than those induced by the Pam-MUC1 vaccine and the MUC1 vaccine without lipid tails, respectively. Similarly, vaccines with the TLR1/2 agonist Pam3 CSK4 as an adjuvant also induced conjugated lipid-dependent immunological responses. Moreover, vaccines with the αGalCer adjuvant induced significantly higher titers of IgG antibodies than vaccines with the Pam3 CSK4 adjuvant. Therefore, the non-covalent assembly of the amphiphilic lipo-MUC1 antigen and the NKT cell agonist αGalCer as a glycolipid adjuvant represent a synthetically simple but immunologically effective approach for the development of anti-MUC1 cancer vaccines.

Peptide-free Synthetic Nicotine Vaccine Candidates with α-Galactosylceramide as Adjuvant.

Peptides are generally needed as T-helper epitopes in nicotine vaccines to induce effective antibody responses, but the highly polymorphic property of major histocompatibility complex (MHC) molecules may limit opportunities of B cell to receive CD4+ T-cell help. Invariant natural killer T (iNKT) cells recognize lipid antigens presented by the nonpolymorphic CD1d molecule that is conserved in mammals to a great extent. iNKT cells also display some similar functions to conventional CD4+ T-helper cells, especially they license dendritic cells stimulate antibody isotype switching by B cells. Herein, α-galactosylceramide (αGalCer), a classical iNKT cell agonist, serves as an adjuvant in synthetic nicotine vaccine candidates absent of peptide or protein. Our study reveals that αGalCer displays better adjuvant activity than Pam3CSK4 (a commonly used lipopeptide TLR agonist). Remarkably, the covalent linker between the nicotine hapten and αGalCer is not critical. Self-assembly of the lipid-tailed nicotine and αGalCer into the liposome represents a structurally simple but immunologically effective way to develop nicotine vaccines. This is the first time to introduce the iNKT cell agonist as an adjuvant to an antidrug vaccine. This discovery may contribute to improving the efficacy of clinical candidate nicotine vaccines in the future.

Comparison between minimally invasive plate osteosynthesis and open plating for proximal humeral fractures: a meta-analysis.

AIM: We conducted this meta-analysis for comparing the efficacy and safety in proximal humeral fractures by treatment minimally invasive plate osteosynthesis and open plating. METHODS: The potential academic literature were identified from the Cochrane Library, Springer, PubMed, Embase and ScienceDirect. Pooled data were analyzed by RevMan 5.1. RESULTS: Seven studies marched with the inclusion criteria. Meta-analysis showed the significant differences in terms of blood loss, operative time, length of hospital stays and constant score between two groups. No significant differences were found in time to union, the union rate and complications. CONCLUSION: Minimally invasive plate osteosynthesis in proximal humeral fractures provided significantly shorter operative times, length of hospital stays, less blood loss and better clinical outcomes without increasing complications.

miR-183-96-182 clusters alleviated ox-LDL-induced vascular endothelial cell apoptosis in vitro by targeting FOXO1.

OBJECTIVE: To investigate the role of FOXO1 and miR-183-96-182 clusters in ox-LDL induced endothelial cell apoptosis. METHODS: FOXO1 overexpression (OE) and knockdown (KD) as well as AKT1 OE in human umbilical vein endothelial cells (HUVECs) and human aortic endothelial cells (HAECs) were achieved by lentiviral transduction. Upregulation of miR-183-5p, miR-182-5p or miR-96-5p was mimicked by agomir treatment. FOXO1 gene transcription was monitored by FOXO1 promotor reporter assay. Cell apoptosis in culture was monitored by TiterTACS in situ detection. Regulation of FOXO1 gene expression by an miRNA targeting mechanism was monitored by AGO2-RNA immunoprecipitation assay. RESULTS: FOXO1 mRNA and protein expression levels in ox-LDL treated HUVECs or HAECs were significantly upregulated due to transcriptional and miRNA targeting mechanisms. MiR-183-5p, miR-182-5p and miR-96-5p expression levels in HUVECs or HAECs were significantly reduced by ox-LDL treatment, the overexpression of which by agomir treatment partially reduced the FOXO1 mRNA/protein expression levels and cell apoptosis which was upregulated by ox-LDL treatment. FOXO1 overexpression antagonized the effect of the agomir treatment indicated above. MiR-183-5p, miR-182-5p and miR-96-5p agomir treatment partially rescued the FOXO1 pSer256/total FOXO1 protein ratio and the AKT1 pSer473 level that were reduced by ox-LDL treatment in the HUVECs or HAECs. AKT1 overexpression significantly reduced FOXO1 protein expression, increased miR-182-5p and miR-183-5p expression, and partially alleviated ox-LDL induced HUVEC or HAEC apoptosis in an miR-183-5p and miR-182-5p-dependent manner. CONCLUSION: miR-183-96-182 clusters could partially alleviate ox-LDL-induced apoptosis in HUVECs or HAECs by targeting FOXO1.

Preparation of Protein Conjugates via Homobifunctional Diselenoester Cross-Linker.

Adipic acid diselenoester was developed as an efficient cross-linker for covalent protein conjugation with a variety of small molecular haptens, including mono- and disaccharides, peptide, fluorescence dye, and nicotine. Compared to the counterparts of N-hydroxysuccinimide (NHS) and p-nitrophenyl (PNP) linkers, the diselenoester linker demonstrates improved balance between reactivity and stability and coupling of haptens to proteins under mild conditions with high incorporation efficiency.