O-GlcNAcylation in cancer development and immunotherapy.

O-linked ß-D-N-acetylglucosamine (O-GlcNAc), as a posttranslational modification (PTM), is a reversible reaction that attaches ß-N-GlcNAc to Ser/Thr residues on specific proteins by O-GlcNAc transferase (OGT). O-GlcNAcase (OGA) removes the O-GlcNAc from O-GlcNAcylated proteins. O-GlcNAcylation regulates numerous cellular processes, including signal transduction, the cell cycle, metabolism, and energy homeostasis. Dysregulation of O-GlcNAcylation contributes to the development of various diseases, including cancers. Accumulating evidence has revealed that higher expression levels of OGT and hyper-O-GlcNAcylation are detected in many cancer types and governs glucose metabolism, proliferation, metastasis, invasion, angiogenesis, migration and drug resistance. In this review, we describe the biological functions and molecular mechanisms of OGT- or O-GlcNAcylation-mediated tumorigenesis. Moreover, we discuss the potential role of O-GlcNAcylation in tumor immunotherapy. Furthermore, we highlight that compounds can target O-GlcNAcylation by regulating OGT to suppress oncogenesis. Taken together, targeting protein O-GlcNAcylation might be a promising strategy for the treatment of human malignancies.

Comparison of three cell-based drug screening platforms for HSV-1 infection.

Acyclovir (ACV) and its derivatives have been highly effective for treating recurrent, lytic infections with Herpes Simplex Virus, type 1 (HSV-1), but searches for additional antiviral drugs are motivated by recent reports of resistance to ACV, particularly among immunocompromised patients. In addition, the relative neurotoxicity of ACV and its inability to prevent neurological sequelae among HSV-1 encephalitis survivors compel searches for new drugs to treat HSV-1 infections of the central nervous system (CNS). Primary drug screens for neurotropic viruses like HSV-1 typically utilize non-neuronal cell lines, but they may miss drugs that have neuron specific antiviral effects. Therefore, we compared the effects of a panel of conventional and novel anti-herpetic compounds in monkey epithelial (Vero) cells, human induced pluripotent stem cells (hiPSCs)-derived neural progenitor cells (NPCs) and hiPSC-derived neurons (N = 73 drugs). While the profiles of activity for the majority of the drugs were similar in all three tissues, Vero cells were less likely than NPCs to identify drugs with substantial inhibitory activity in hiPSC-derived neurons. We discuss the relative merits of each cell type for antiviral drug screens against neuronal infections with HSV-1.

Ventromedial prefrontal cortex, adding value to autobiographical memories.

The medial prefrontal cortex (mPFC) has been consistently implicated in autobiographical memory recall and decision making. Its function in decision making tasks is believed to relate to value representation, but its function in autobiographical memory recall is not yet clear. We hypothesised that the mPFC represents the subjective value of elements during autobiographical memory retrieval. Using functional magnetic resonance imaging during an autobiographical memory recall task, we found that the blood oxygen level dependent (BOLD) signal in ventromedial prefrontal cortex (vmPFC) was parametrically modulated by the affective values of items in participants' memories when they were recalling and evaluating these items. An unrelated modulation by the participant's familiarity with the items was also observed. During retrieval of the event, the BOLD signal in the same region was modulated by the personal significance and emotional intensity of the memory, which was correlated with the values of the items within them. These results support the idea that vmPFC processes self-relevant information, and suggest that it is involved in representing the personal emotional values of the elements comprising autobiographical memories.

Evidence for holistic episodic recollection via hippocampal pattern completion.

Recollection is thought to be the hallmark of episodic memory. Here we provide evidence that the hippocampus binds together the diverse elements forming an event, allowing holistic recollection via pattern completion of all elements. Participants learn complex 'events' from multiple overlapping pairs of elements, and are tested on all pairwise associations. At encoding, element 'types' (locations, people and objects/animals) produce activation in distinct neocortical regions, while hippocampal activity predicts memory performance for all within-event pairs. When retrieving a pairwise association, neocortical activity corresponding to all event elements is reinstated, including those incidental to the task. Participant's degree of incidental reinstatement correlates with their hippocampal activity. Our results suggest that event elements, represented in distinct neocortical regions, are bound into coherent 'event engrams' in the hippocampus that enable episodic recollection--the re-experiencing or holistic retrieval of all aspects of an event--via a process of hippocampal pattern completion and neocortical reinstatement.

Medial Prefrontal Cortex: Adding Value to Imagined Scenarios.

The medial prefrontal cortex (mPFC) is consistently implicated in the network supporting autobiographical memory. Whereas more posterior regions in this network have been related to specific processes, such as the generation of visuospatial imagery or the association of items and contexts, the functional contribution of the mPFC remains unclear. However, the involvement of mPFC in estimation of value during decision-making suggests that it might play a similar role in memory. We investigated whether mPFC activity reflects the subjective value of elements in imagined scenarios. Participants in an MRI scanner imagined scenarios comprising a spatial context, a physiological state of need (e.g., thirst), and two items that could be congruent (e.g., drink) or incongruent (e.g., food) with the state of need. Memory for the scenarios was tested outside the scanner. Our manipulation of subjective value by imagined need was verified by increased subjective ratings of value for congruent items and improved subsequent memory for them. Consistent with our hypothesis, fMRI signal in mPFC reflected the modulation of an item's subjective value by the imagined physiological state, suggesting the mPFC selectively tracked subjective value within our imagination paradigm. Further analyses showed uncorrected effects in non-mPFC regions, including increased activity in the insula when imagining states of need, the caudate nucleus when imagining congruent items, and the anterior hippocampus/amygdala when imagining subsequently remembered items. We therefore provide evidence that the mPFC plays a role in constructing the subjective value of the components of imagined scenarios and thus potentially in reconstructing the value of components of autobiographical recollection.

Self-assembled micelles based on pH-sensitive PAE-g-MPEG-cholesterol block copolymer for anticancer drug delivery.

A novel amphiphilic triblock pH-sensitive poly(ß-amino ester)-g-poly(ethylene glycol) methyl ether-cholesterol (PAE-g-MPEG-Chol) was designed and synthesized via the Michael-type step polymerization and esterification condensation method. The synthesized copolymer was determined with proton nuclear magnetic resonance and gel permeation chromatography. The grafting percentages of MPEG and cholesterol were determined as 10.93% and 62.02%, calculated from the area of the characteristic peaks, respectively. The amphiphilic copolymer was confirmed to self-assemble into core/shell micelles in aqueous solution at low concentrations. The critical micelle concentrations were 6.92 and 15.14 mg/L at pH of 7.4 and 6.0, respectively, obviously influenced by the changes of pH values. The solubility of pH-responsive PAE segment could be transformed depending on the different values of pH because of protonation-deprotonation of the amino groups, resulting in pH sensitivity of the copolymer. The average particle size of micelles increased from 125 nm to 165 nm with the pH decreasing, and the zeta potential was also significantly changed. Doxorubicin (DOX) was entrapped into the polymeric micelles with a high drug loading level. The in vitro DOX release from the micelles was distinctly enhanced with the pH decreasing from 7.4 to 6.0. Toxicity testing proved that the DOX-loaded micelles exhibited high cytotoxicity in HepG2 cells, whereas the copolymer showed low toxicity. The results demonstrated how pH-sensitive PAE-g-MPEG-Chol micelles were proved to be a potential vector in hydrophobic drug delivery for tumor therapy.

Drug release from pH-sensitive polymeric micelles with different drug distributions: insight from coarse-grained simulations.

How to control the release of drugs from pH-sensitive polymeric micelles is an issue of common concern, which is important to the effectiveness of the micelles. The components and properties of polymers can notably influence the drug distributions inside micelles which is a key factor that affects the drug release from the micelles. In this work, the dissipative particle dynamics simulation method is first used to study the structural transformation of micelles during the protonation process and the drug release process from micelles with different drug distributions. And then the effects of polymer structures, including different lengths of hydrophilic blocks, pH-sensitive blocks and hydrophobic blocks, on drug release are also studied. In the end, several corresponding design principles of pH-sensitive polymers for drug delivery are proposed according to the simulation results. This work is in favor of establishing qualitative rules for the design and optimization of congener polymers for desired drug delivery, which is of great significance to provide a potential approach for the development of new multiblock pH-sensitive polymeric micelles.

Dissipative particle dynamics studies of doxorubicin-loaded micelles assembled from four-arm star triblock polymers 4AS-PCL-b-PDEAEMA-b-PPEGMA and their pH-release mechanism.

Dissipative particle dynamics (DPD) simulation was applied to investigate the microstructures of the micelles self-assembled from pH-sensitive four-arm star triblock poly(ε-caprolactone)-b-poly(2-(diethylamino)ethyl methacrylate)-b-poly(poly(ethylene glycol) methyl ether methacrylate) (4AS-PCL-b-PDEAEMA-b-PPEGMA). In the optimized system, the micelles have a core-mesosphere-shell three-layer structure. The drug-loading process and its distribution at different formulations in the micelles were studied. The results show that DOX molecules distributed in the core and the interface between the core and the mesosphere, suggesting the potential encapsulation capacity of DOX molecules. More drugs were loaded in the micelles with the increase in DOX, and the size of micelles became larger. However, some openings start to generate on the PEG shell when the DOX reaches a certain concentration. By changing the pH values of the system, different morphologies of the micelles were acquired after the pH-sensitive blocks PDEAEMA were protonated, the mechanism of which was also analyzed through correlating functions. The results indicated that the sudden increase in solubility parameter of the pH-sensitive blocks and the swelling of the micelles were the key factors on the change of morphologies. Furthermore, with the decrease in pH value, the number and size of the cracks on the surface of the micelles were larger, which may have a direct effect on the drug release. In conclusion, 4AS-PCL-b-PDEAEMA-b-PPEGMA has great promising applications in delivering hydrophobic anticancer drugs for improved cancer therapy.

Intentional forgetting reduces the semantic processing of to-be-forgotten items: an ERP study of item-method directed forgetting.

In two ERP experiments, we examined whether active inhibition is involved in intentional forgetting. Both experiments consisted of a nondirected-forgetting (nDF) and a directed-forgetting (DF) block. Participants were sequentially presented with a prime, an R/F (remember/forget) cue, and a target. Participants made lexical decisions to both the primes and targets (Experiment 1) or only to the targets (Experiment 2). They were also instructed to remember or to forget the primes in response to the R/F cues in the DF block but to ignore these cues in the nDF block. The N400 semantic priming effect was observed when comparing the ERPs elicited by semantically unrelated and related targets in the DF block. In comparison to the nDF block, the N400 effect was greatly reduced for targets preceded by F cues in the DF block. These findings suggest that semantic processing is reduced by the instruction to forget and active inhibition is involved in intentional forgetting.

pH-sensitive micelles self-assembled from multi-arm star triblock co-polymers poly(ε-caprolactone)-b-poly(2-(diethylamino)ethyl methacrylate)-b-poly(poly(ethylene glycol) methyl ether methacrylate) for controlled anticancer drug delivery.

A series of amphiphilic 4- and 6-armed star triblock co-polymers poly(ε-caprolactone)-b-poly(2-(diethylamino)ethyl methacrylate)-b-poly(poly(ethylene glycol) methyl ether methacrylate) (4/6AS-PCL-b-PDEAEMA-b-PPEGMA) were developed by a combination of ring opening polymerization and continuous activators regenerated by electron transfer atom transfer radical polymerization. The critical micelle concentration values of the star co-polymers in aqueous solution were extremely low (2.2-4.0mgl(-1)), depending on the architecture of the co-polymers. The self-assembled blank and doxorubicin (DOX)-loaded three layer micelles were spherical in shape with an average size of 60-220nm determined by scanning electron microscopy and dynamic light scattering. The in vitro release behavior of DOX from the three layer micelles exhibited pH-dependent properties. The DOX release rate was significantly accelerated by decreasing the pH from 7.4 to 5.0, due to swelling of the micelles at lower pH values caused by the protonation of tertiary amine groups in DEAEMA in the middle layer of the micelles. The in vitro cytotoxicity of DOX-loaded micelles to HepG2 cells suggested that the 4/6AS-PCL-b-PDEAEMA-b-PPEGMA micelles could provide equivalent or even enhanced anticancer activity and bioavailability of DOX and thus a lower dosage is sufficient for the same therapeutic efficacy. The results demonstrate that the pH-sensitive multilayer micelles could have great potential application in delivering hydrophobic anticancer drugs for improved cancer therapy.

[Preparation and characterization of upconversion phosphor based on AlF3-YbF3 : Er3+].

In the present paper, AlF3-YbF3 : Er3+ was prepared by high temperature solid phase reaction, and the concentration effect of Er3+ on luminous intensity of phosphors was studied. The crystal structures of the phosphors were characterized by means of X-ray diffraction (XRD), and the upconversion luminescence properties of phosphor were studied by fluorescence emission spectra. Upon 980 nm excitation, when the Er3+ concentration was fixed to be 0.7 mol%, the maximum red emission intensities can be obtained in the sample. Furthermore, the research results showed that the fitted slope for red transition emission was 2.24, indicating that red emission is due to a two-photon excitation process.

Synthesis and physicochemical characterization of amphiphilic triblock copolymer brush containing pH-sensitive linkage for oral drug delivery.

A novel and well-defined pH-sensitive amphiphilic triblock copolymer brush poly(lactide)-b-poly(methacrylic acid)-b-poly(poly(ethylene glycol) methyl ether monomethacrylate) (PLA-b-PMAA-b-PPEGMA) and its self-assembled micelles were developed for oral administration of hydrophobic drugs. The copolymer and its precursors were synthesized by the combination of activators regenerated by electron transfer atom transfer radical polymerization (ARGET ATRP) and ring-opening polymerization (ROP) techniques. The molecular structures and characteristics were confirmed by GPC, (1)H NMR, and FT-IR. The critical micelle concentration (CMC) values of PLA-b-PMAA-b-PPEGMA in aqueous medium varied from 1.4 to 2.6 mg/L, and the partition equilibrium constant (K(v)) of pyrene in micellar solutions ranged from 2.873 × 10(5) to 3.312 × 10(5). The average sizes of the self-assembled blank and drug-loaded micelles were 140-250 nm determined by DLS in aqueous solution. The morphology of the micelles was found to be spherical by SEM. Nifedipine (NFD), a poorly water-soluble drug, was selected as the model drug and wrapped into the core of micelles via dialysis method. The in vitro release behavior of NFD from the micelles was pH-dependent. In simulated gastric fluid (SGF, pH 1.2), the cumulative release percent of NFD was relative low, while in simulated intestinal fluid (SIF, pH 7.4), more than 96% was released within 24 h. All the results showed that the pH-sensitive PLA-b-PMAA-b-PPEGMA micelle may be a prospective candidate as oral drug delivery carrier for hydrophobic drugs with controlled release behavior.