Perfect Talbot self-imaging effect of aperiodic gratings.

We propose and investigate a class of aperiodic grating structure which can achieve perfect Talbot effect under certain conditions. The aperiodic grating structure is obtained by the superposition of two or more sine terms. In the case of two sine terms, the Talbot effect can be realized when the period ratio of two terms is arbitrary. While in the case of more than two sine terms, the period ratios of each term must meet certain extra conditions. The theory has been further verified by numerical simulations. It expands the field of Talbot effect and is of potential significance for subsequent research applications such as optical imaging and measurement.

Enhanced Oxygen Evolution of a Magnetic Catalyst by Regulating Intrinsic Magnetism.

The promotion of magnetic field on catalytic performance has attracted extensive attention. However, little research has been reported on the performance of the oxygen evolution reaction (OER) for the modulating intrinsic magnetism of the catalyst under a magnetic field. Herein, we adjusted the intrinsic magnetism of the CoxNi1-xFe2O4-nanosheet by adjusting the ratio of Co and Ni, and researched the relationship between the OER activity and the intrinsic magnetism. The results indicate that the CoFe2O4-nanosheet has the most OER activity increases in the magnetic field due to the optimal intrinsic magnetism. The required overpotential of CoFe2O4-nanosheet@NF to reach a current density of 10 mA cm-2 was reduced by 21 mV under about 100 mT magnetic field compared with no magnetic field, and the degree of improvement of OER activity of different magnetic catalysts in the same magnetic field is positively correlated with the intrinsic magnetism of the catalyst. Therefore, magnetic field assistance provides a new, effective, and general strategy to improve the activity of electrodes for water splitting.

AAV for Gene Therapy in Ocular Diseases: Progress and Prospects.

Owing to the promising therapeutic effect and one-time treatment advantage, gene therapy may completely change the management of eye diseases, especially retinal diseases. Adeno-associated virus (AAV) is considered one of the most promising viral gene delivery tools because it can infect various types of tissues and is considered as a relatively safe gene delivery vector. The eye is one of the most popular organs for gene therapy, since its limited volume is suitable for small doses of AAV stably transduction. Recently, an increasing number of clinical trials of AAV-mediated gene therapy are underway. This review summarizes the biological functions of AAV and its application in the treatment of various ocular diseases, as well as the characteristics of different AAV delivery routes in clinical applications. Here, the latest research progresses in AAV-mediated gene editing and silencing strategies to modify that the genetic ocular diseases are systematically outlined, especially by base editing and prime editing. We discuss the progress of AAV in ocular optogenetic therapy. We also summarize the application of AAV-mediated gene therapy in animal models and the difficulties in its clinical transformation.

Variants of the adeno-associated virus serotype 9 with enhanced penetration of the blood-brain barrier in rodents and primates.

The development of gene therapies for the treatment of diseases of the central nervous system has been hindered by the limited availability of adeno-associated viruses (AAVs) that efficiently traverse the blood-brain barrier (BBB). Here, we report the rational design of AAV9 variants displaying cell-penetrating peptides on the viral capsid and the identification of two variants, AAV.CPP.16 and AAV.CPP.21, with improved transduction efficiencies of cells of the central nervous system on systemic delivery (6- to 249-fold across 4 mouse strains and 5-fold in cynomolgus macaques, with respect to the AAV9 parent vector). We also show that the neurotropism of AAV.CPP.16 is retained in young and adult macaques, that this variant displays enhanced transcytosis at the BBB as well as increased efficiency of cellular transduction relative to AAV9, and that it can be used to deliver antitumour payloads in a mouse model of glioblastoma. AAV capsids that can efficiently penetrate the BBB will facilitate the clinical translation of gene therapies aimed at the central nervous system.

BBB-crossing adeno-associated virus vector: An excellent gene delivery tool for CNS disease treatment.

The presence of the blood-brain barrier (BBB) remains a challenge in the treatment of central nervous system (CNS) diseases, as it hinders the infiltration of many therapeutic drugs into the brain parenchyma. Therefore, developing efficacious pharmacological agents that can traverse the BBB is crucial for optimal treatment of diseases of the CNS such as neurodegenerative conditions and brain tumors. Adeno-associated virus (AAV), one of the most promising gene therapy vectors, has been shown to cross the BBB safely and is non-pathogenic in nature and therefore has been utilized for numerous diseases of the CNS. Along with the development of protein engineering techniques such as directed evolution including DNA shuffling, a great number of BBB-crossing AAVs have been developed, that could be systemically injected for therapeutic benefit. In this review, we discuss several feasible approaches to improve transportation of therapeutic agents to the CNS. We also discuss the advantages of using BBB-crossing AAVs, their role as a gene delivery agent and highlight the different types of BBB-AAV vectors that have been developed in order to provide a greater insight into how they can be used in diseases of the CNS.

Challenges in adeno-associated virus-based treatment of central nervous system diseases through systemic injection.

Adeno-associated virus (AAV) vector, an excellent gene therapy vector, has been widely used in the treatment of various central nervous system (CNS) diseases. Due to the presence of the blood-brain barrier (BBB), early attempts at AAV-based CNS diseases treatment were mainly performed through intracranial injections. Subsequently, systemic injections of AAV9, the first AAV that was shown to have BBB-crossing ability in newborn and adult mice, were assessed in clinical trials for multiple CNS diseases. However, the development of systemic AAV injections to treat CNS diseases is still associated with many challenges, such as the efficiency of AAV in crossing the BBB, the peripheral toxicity caused by the expression of AAV-delivered genes, and the immune barrier against AAV in the blood. In this review, we will introduce the biology of the AAV vector and the advantages of systemic AAV injections to treat CNS diseases. Most importantly, we will introduce the challenges associated with systemic injection of therapeutic AAV in treating CNS diseases and suggest feasible solutions.

Different T-cell subsets in glioblastoma multiforme and targeted immunotherapy.

Glioblastoma multiforme (GBM) is a brain tumor with a high mortality rate. Surgical resection combined with radiotherapy and chemotherapy is the standard treatment for GBM patients, but the 5-year survival rate of patients despite this treatment is low. Immunotherapy has attracted increasing attention in recent years. As the pioneer and the main effector cells of immunotherapy, T cells play a key role in tumor immunotherapy. However, the T cells in GBM microenvironment are inhibited by the highly immunosuppressive environment of GBM, posing huge challenges to T cell-based GBM immunotherapy. This review summarizes the effects of the GBM microenvironment on the infiltration and function of different T-cell subsets and the possible strategies to overcome immunosuppression, and thus enhance the effectiveness of GBM immunotherapy.

Glioblastoma-Derived Extracellular Vesicles Facilitate Transformation of Astrocytes via Reprogramming Oncogenic Metabolism.

Glioblastoma (GBM) may arise from astrocytes through a multistep process involving a progressive accumulation of mutations. We explored whether GBM-derived extracellular vesicles (EVs) may facilitate neoplastic transformation and malignant growth of astrocytes. We utilized conditioned media (CM) of cultured glioma cells, its sequential filtration, diverse cell-based assays, RNA sequencing, and metabolic assays to compare the effects of EV-containing and EV-depleted CM. GBM EVs facilitated the neoplastic growth of pre-transformed astrocytes but not normal human or mouse astrocytes. They induced proliferation, self-renewal, and colony formation of pre-transformed astrocytes and enhanced astrocytoma growth in a mouse allograft model. GBM EVs appear to reprogram astrocyte metabolism by inducing a shift in gene expression that may be partly associated with EV-mediated transfer of full-length mRNAs encoding ribosomal proteins, oxidative phosphorylation, and glycolytic factors. Our study suggests an EV/extracellular RNA (exRNA)-mediated mechanism that contributes to astrocyte transformation via metabolic reprograming and implicates horizontal mRNA transfer.

Simultaneous downregulation of miR-21 and upregulation of miR-7 has anti-tumor efficacy.

Dysregulation of miRNA expression has been implicated in cancer. Numerous strategies have been explored to modulate miR but sub-optimal delivery and inability to concurrently target multiple pathways involved in tumor progression have limited their efficacy. In this study, we explored the potential co-modulation of upregulated miR-21 and downregulated miR-7 to enhance therapeutic outcomes in heterogenic tumor types. We first engineered lentiviral (LV) and adeno-associated viral (AAV) vectors that preferentially express anti-sense miR against miR-21(miRzip-21) and show that modulating miR-21 via miRzip extensively targets tumor cell proliferation, migration and invasion in vitro in a broad spectrum of cancer types and has therapeutic efficacy in vivo. Next, we show a significantly increased expression of caspase-mediated apoptosis by simultaneously downregulating miR-21 and upregulating miR-7 in different tumor cells. In vivo co-treatment with AAV-miRzip-21 and AAV-miR-7 in mice bearing malignant brain tumors resulted in significantly decreased tumor burden with a corresponding increase in survival. To our knowledge, this is the first study that demonstrates the therapeutic efficacy of simultaneously upregulating miR-7 and downregulating miR-21 and establishes a roadmap towards clinical translation of modulating miRs for various cancer types.

Engineering, delivery, and biological validation of artificial microRNA clusters for gene therapy applications.

The cellular machinery regulating microRNA biogenesis and maturation relies on a small number of simple steps and minimal biological requirements and is broadly conserved in all eukaryotic cells. The same holds true in disease. This allows for a substantial degree of freedom in the engineering of transgenes capable of simultaneously expressing multiple microRNAs of choice, allowing a more comprehensive modulation of microRNA landscapes, the study of their functional interaction, and the possibility of using such synergism for gene therapy applications. We have previously engineered a transgenic cluster of functionally associated microRNAs to express a module of suppressed microRNAs in brain cancer for therapeutic purposes. Here, we provide a detailed protocol for the design, cloning, delivery, and utilization of such artificial microRNA clusters for gene therapy purposes. In comparison with other protocols, our strategy effectively decreases the requirements for molecular cloning, because the nucleic acid sequence encoding the combination of the desired microRNAs is designed and validated in silico and then directly synthesized as DNA that is ready for subcloning into appropriate delivery vectors, for both in vitro and in vivo use. Sequence design and engineering require 4-5 h. Synthesis of the resulting DNA sequence requires 4-6 h. This protocol is quick and flexible and does not require special laboratory equipment or techniques, or multiple cloning steps. It can be easily executed by any graduate student or technician with basic molecular biology knowledge.

IL1RN mediates the suppressive effect of methionine deprivation on glioma proliferation.

Metabolic abnormality is one of the hallmarks of cancer cells, and limiting material supply is a potential breakthrough approach for cancer treatment. Increasing researchers have been involved in the study of glioma cell metabolism reprogramming since the significance of IDH1 was confirmed in glioma. However, the molecular mechanisms underlying metabolic reprogramming induced by methionine deprivation regulates glioma cell proliferation remain unclear. Here we demonstrated that methionine deprivation inhibited glioma cell proliferation via downregulating interleukin 1 receptor antagonist (IL1RN) both in vitro and in vivo, methionine deprivation or knocking down IL1RN induced glioma cell cycle arrest. Moreover, we confirmed that IL1RN is a tumor associated gene and its expression is negatively correlated with the survival time of glioma patients. Altogether these results demonstrate a strong rationale insight that targeting amino acid metabolism such as methionine deprivation/IL1RN related gene therapy may offer novel direction for glioma treatment.

Preliminary study and bioinformatics analysis on the potential role of CagQ in type IV secretion system of H.pylori.

Helicobacter pylori (H.pylori), is a major causative agent of chronic gastritis, gastric carcinoma and duodenal ulcer. Remarkably, H.pylori carries cytotoxin-associated gene pathogenicity island (CagPAI) which encodes a type IV secretion system (T4SS). T4SS is capable of forming a syringe-like structure to deliver oncoprotein cytotoxin-associated Antigen (CagA) into gastric epithelial cells and resulting in a cascade of events in host cells, such as induction of pro-inflammatory cytokines, alteration of cellular gene expression and cytoskeletal rearrangements. Among of those proteins in T4SS, CagQ still remains unknown functions. In this study, we performed analysis of protein-protein interaction and revealed that CagQ correlated with the most virulence factor CagA in T4SS. Interestingly, our data demonstrated that CagQ-deficient mutant strain had significantly lower expression in both mRNA and protein levels of CagA compared with H.pylori wild-type strain 26695. Moreover, we demonstrated that CagQ deletion also played a vital role in suppressing CagA-induced apoptosis of host gastric epithelial cells. To further investigate the role of CagQ in T4SS, we used bioinformatics analysis to provide a preliminary insight into CagQ. These results showed that CagQ possessed a transmembrane region from amino acid 50-68 which is also consistent with the prediction of hydrophobic scale and structure modeling. Thus, we conclude that CagQ is a membrane protein in T4SS and is crucial for maintaining CagA expression and CagA-induced apoptotic effects. This provides a novel specific therapeutic target for H.pylori CagA-induced gastroduodenal diseases.

The role of Notch signaling in gastric carcinoma: molecular pathogenesis and novel therapeutic targets.

Notch signaling, an evolutionarily conserved signaling cascade system, is involved in promoting the progression of different types of cancers. Within the past decades, the Notch signaling pathway has increasingly been shown to have a primary role in deciding the fate of cancer cells and cancer stem cells in the stomach. Most components of Notch signaling are strongly expressed at different levels in gastric carcinoma tissue samples and are associated with a considerable number of clinical parameters. Moreover, crosstalk signaling between the Notch pathway and the Wnt, Ras, and NF-κB pathways promotes the process of gastric carcinogenesis. Consequently, this increases proliferation and prevents apoptosis in gastric cancer cells, and it contributes to the induction of angiogenesis and accelerates the progression of the epithelial-to-mesenchymal transition. Although the Notch signaling pathway presents novel therapeutic targets for cancer therapeutic intervention, there is still a dearth of in-depth understanding of the molecular mechanisms of Notch signaling in gastric carcinoma. In this review, we summarize the landscape of the Notch signaling pathway and recent findings on Notch signaling in gastric cancer. Furthermore, advanced studies and clinical treatments targeting the Notch signaling pathway arediscussed.

Helicobacter pylori CagI is associated with the stability of CagA.

The type Ⅳ secretion system (T4SS) of H. pylori encoded by cag pathogenicity island mediates the injection of the toxin CagA, which is considered as a paradigm for bacterial carcinogenesis. T4SS is generally composed of a set of proteins, the majority of which still remain unclear. In this study, we have identified CagI, one of the T4SS proteins, which interacted with CagA and played an important role for CagA stability.

Microarray analysis of Long non-coding RNA expression profiles in human gastric cells and tissues with Helicobacter pylori Infection.

BACKGROUND: Although Helicobacter pylori (H.pylori) is the dominant gastrointestinal pathogen, the genetic and molecular mechanisms underlying H.pylori-related diseases have not been fully elucidated. Long non-coding RNAs (lncRNAs) have been identified in eukaryotic cells, many of which play important roles in regulating biological processes and pathogenesis. However, the expression changes of lncRNAs in human infected by H.pylori have been rarely reported. This study aimed to identify the dysregulated lncRNAs in human gastric epithelial cells and tissues infected with H.pylori. METHODS: The aberrant expression profiles of lncRNAs and mRNAs in GES-1 cells with or without H.pylori infection were explored by microarray analysis. LncRNA-mRNA co-expression network was constructed based on Pearson correlation analysis. Gene Ontology (GO) and KEGG Pathway analyses of aberrantly expressed mRNAs were performed to identify the related biological functions and pathologic pathways. The expression changes of target lncRNAs were validated by qRT-PCR to confirm the microarray data in both cells and clinical specimens. RESULTS: Three hundred three lncRNAs and 565 mRNAs were identified as aberrantly expressed transcripts (≥2 or ≤0.5-fold change, P < 0.05) in cells with H.pylori infection compared to controls. LncRNA-mRNA co-expression network showed the core lncRNAs/mRNAs which might play important roles in H.pylori-related pathogenesis. GO and KEGG analyses have indicated that the functions of aberrantly expressed mRNAs in H.pylori infection were related closely with inflammation and carcinogenesis. QRT-PCR data confirmed the expression pattern of 8 (n345630, XLOC_004787, n378726, LINC00473, XLOC_005517, LINC00152, XLOC_13370, and n408024) lncRNAs in infected cells. Additionally, four down-regulated (n345630, XLOC_004787, n378726, and LINC00473) lncRNAs were verified in H.pylori-positive gastric samples. CONCLUSION: Our study provided a preliminary exploration of lncRNAs expression profiles in H.pylori-infected cells by microarray. These dysregulated lncRNAs might contribute to the pathological processes during H.pylori infection.