Learning within a sensory-motor circuit links action to expected outcome.

The cortex integrates sound- and movement-related signals to predict the acoustic consequences of behavior and detect violations from expectations. Although expectation- and prediction-related activity has been observed in the auditory cortex of humans, monkeys, and mice during vocal and non-vocal acoustic behaviors, the specific cortical circuitry required for forming memories, recalling expectations, and making predictions remains unknown. By combining closed-loop behavior, electrophysiological recordings, longitudinal pharmacology, and targeted optogenetic circuit activation, we identify a cortical locus for the emergence of expectation and error signals. Movement-related expectation signals and sound-related error signals emerge in parallel in the auditory cortex and are concentrated in largely distinct neurons, consistent with a compartmentalization of different prediction-related computations. On a trial-by-trial basis, expectation and error signals are correlated in auditory cortex, consistent with a local circuit implementation of an internal model. Silencing the auditory cortex during motor-sensory learning prevents the emergence of expectation signals and error signals, revealing the auditory cortex as a necessary node for learning to make predictions. Prediction-like signals can be experimentally induced in the auditory cortex, even in the absence of behavioral experience, by pairing optogenetic motor cortical activation with sound playback, indicating that cortical circuits are sufficient for movement-like predictive processing. Finally, motor-sensory experience realigns the manifold dimensions in which auditory cortical populations encode movement and sound, consistent with predictive processing. These findings show that prediction-related signals reshape auditory cortex dynamics during behavior and reveal a cortical locus for the emergence of expectation and error.

The synergistic effect of metal ions and amino acids on the fermentation of ß-CGTase-producing statin DF257.

To meet the growing demand of ß-cyclodextrin (CD), innovative approaches are being developed to improve the production of ß-CD by ß-cyclodextrin glucose-transferase (CGTase). Considering the low production and efficacy of wild-type ß-CGTase-producing strains, to obtain the strains suitable for industrial production of ß-CGTase, the recombinant engineered bacteria strain DF257 is constructed by transfecting with the plasmid expressing His tagged ß-CGTase. The fermentation of ß-CGTase-expressing DF257 was optimized in the presence of different metal ions, amino acids, and incubated at a certain temperature and pH condition. The results showed that when Mg2+ and isoleucine were added into the culture medium at 0.5 mM and 0.5 g/L, respectively, the enzyme activity of ß-CGTase increased significantly after incubation at 37 °C with the initial pH of 7.5. In addition, the optimal temperature for ß-CGTase with the addition of Mg2+ and isoleucine was also determined. The T half of ß-CGTase under 50, 55, 60 and 65 °C was 9.5, 8.8, 6.2 and 1.2 h, respectively. Further investigation showed that ß-CGTase kept stable under the pH 6.0-10.0, and pH 7.5 was identified as the optimal pH condition of ß-CGTase. With the addition of Mg2+ and isoleucine, the kinetic properties of ß-CGTase in the cyclization reaction had a similar form with Michaelis equation under 50 °C and pH 7.5, and Vmax, Km, and Kcat was 3.74 mg/mL/min, 3.28 mg/mL, and 31.17/s, respectively. The possible underlying mechanism by which Mg2+ and isoleucine synergistically improved the thermostability of ß-CGTase was investigated by the surface hydrophobicity index analysis, Fourier transform infrared spectroscopy and differential scanning calorimetry (DSC) analysis. The results indicated that addition of Mg2+ and isoleucine maintained the spatial structure and enhanced the thermostability of ß-CGTase. These findings provided a theoretical basis for realizing the industrialization application of ß-CGTase in promoting the generation of ß-CD.

Fish who act on impulse must learn the consequences.

Animals learn internal models that link specific behaviors to their anticipated sensory outcomes. In this issue of Neuron, Wallach and Sawtell1 discover that freely moving fish learn how the sensory outcome of a single behavior changes with local context.

Activation Enhancement and Grain Size Improvement for Poly-Si Channel Vertical Transistor by Laser Thermal Annealing in 3D NAND Flash.

The bit density is generally increased by stacking more layers in 3D NAND Flash. Lowering dopant activation of select transistors results from complex integrated processes. To improve channel dopant activation, the test structure of vertical channel transistors was used to investigate the influence of laser thermal annealing on dopant activation. The activation of channel doping by different thermal annealing methods was compared. The laser thermal annealing enhanced the channel activation rate by at least 23% more than limited temperature rapid thermal annealing. We then comprehensively explore the laser thermal annealing energy density on the influence of Poly-Si grain size and device performance. A clear correlation between grain size mean and grain size sigma, large grain size mean and sigma with large laser thermal annealing energy density. Large laser thermal annealing energy density leads to tightening threshold voltage and subthreshold swing distribution since Poly-Si grain size regrows for better grain size distribution with local grains optimization. As an enabler for next-generation technologies, laser thermal annealing will be highly applied in 3D NAND Flash for better device performance with stacking more layers, and opening new opportunities of novel 3D architectures in the semiconductor industry.

A Novel Capacitorless 1T DRAM with Embedded Oxide Layer.

A novel vertical dual surrounding gate transistor with embedded oxide layer is proposed for capacitorless single transistor DRAM (1T DRAM). The embedded oxide layer is innovatively used to improve the retention time by reducing the recombination rate of stored holes and sensing electrons. Based on TCAD simulations, the new structure is predicted to not only have the characteristics of fast access, random read and integration of 4F2 cell, but also to realize good retention and deep scaling. At the same time, the new structure has the potential of scaling compared with the conventional capacitorless 1T DRAM.

Precise movement-based predictions in the mouse auditory cortex.

Many of the sensations experienced by an organism are caused by their own actions, and accurately anticipating both the sensory features and timing of self-generated stimuli is crucial to a variety of behaviors. In the auditory cortex, neural responses to self-generated sounds exhibit frequency-specific suppression, suggesting that movement-based predictions may be implemented early in sensory processing. However, it remains unknown whether this modulation results from a behaviorally specific and temporally precise prediction, nor is it known whether corresponding expectation signals are present locally in the auditory cortex. To address these questions, we trained mice to expect the precise acoustic outcome of a forelimb movement using a closed-loop sound-generating lever. Dense neuronal recordings in the auditory cortex revealed suppression of responses to self-generated sounds that was specific to the expected acoustic features, to a precise position within the movement, and to the movement that was coupled to sound during training. Prediction-based suppression was concentrated in L2/3 and L5, where deviations from expectation also recruited a population of prediction-error neurons that was otherwise unresponsive. Recording in the absence of sound revealed abundant movement signals in deep layers that were biased toward neurons tuned to the expected sound, as well as expectation signals that were present throughout the cortex and peaked at the time of expected auditory feedback. Together, these findings identify distinct populations of auditory cortical neurons with movement, expectation, and error signals consistent with a learned internal model linking an action to its specific acoustic outcome.

Exosomes derived from immunogenically dying tumor cells as a versatile tool for vaccination against pancreatic cancer.

Despite tremendous progress achieved in immunotherapy, many critical challenges in treating pancreatic ductal adenocarcinoma (PDAC) persist. Considering the poor vascularization of PDAC, after intramuscular administration exosomes can targeted deliver "cargos" to pancreatic tumors and bypass obstructions of the intrinsic overexpressed stroma through lymphatics. Herein, we propose a strategy to derive exosomes from immunogenically dying tumor cells and exploit their properties for several purposes, including antigen presentation, adjuvant supply, and "cargo" delivery of vaccines against pancreatic cancer via intramuscular injection. To enhance the immunostimulatory effects, the MART-1 peptide is modified to the exosomes to expand T-cell-related responses. Furthermore, CCL22 siRNA is electroporated into the exosomes (referred to as spMEXO) to hinder the CCR4/CCL22 axis between DCs and Tregs, thereby suppressing Treg expansion. Both in vitro and in vivo studies demonstrate that spMEXO can serve as an effective prophylactic vaccine to delay tumor growth, whereas combining spMEXO with PDAC first-line chemotherapeutics (co-administration of gemcitabine with albumin-paclitaxel) demonstrated significantly enhanced therapeutic effects in established PANC-02 tumors. Therefore, the present work provides an effective strategy to employ cancer vaccines through intramuscular injection in PDAC and highlights the potential of exosomes derived from immunogenically dying tumor cells as a versatile tool to develop nanovaccines for immunotherapy.

A Micro-Environment Regulator for Filling the Clinical Treatment Gap after a Glioblastoma Operation.

The rapid postoperative recurrence and short survival time of glioblastoma (GBM) patients necessitate immediate and effective postoperative treatment. Herein, an immediate and mild postoperative local treatment strategy is developed that regulates the postoperative microenvironment and delays GBM recurrence. Briefly, an injectable hydrogel system (imGEL) loaded with Zn(II)2 -AMD3100 (AMD-Zn) and CpG oligonucleotide nanoparticles (CpG NPs) is injected into the operation cavity, with long-term function to block the recruitment of microglia/ macrophages and activate cytotoxic T cells. The finding indicated that the imGEL can regulate the immune microenvironment, inhibit GBM recurrence, and gain valuable time for subsequent adjuvant clinical chemotherapy.

The effect of encoding task on the forgetting of object gist and details.

One important feature of episodic memory is that it contains fine-grained and vividly recollected details. How to improve and maintain detailed information over time has been one of the central issues in memory research. Previous studies have inconsistent findings on whether detailed memory is forgotten more rapidly than gist memory. In this study, we investigated to what extent different encoding tasks modulated forgetting of gist and detailed information. In three experiments, participants were presented pictures of common objects and were asked to name them (Experiment 1), describe the details about them (Experiment 2) or imagine scenes associated with them (Experiment 3). After intervals of 10 minutes, one day, one week and one month, gist and detailed memories of the pictures were tested and assessed using a remember/know/guess judgement. The results showed that after the naming task, gist and detailed memories were forgotten at a similar rate, but after the description and the imagination tasks, detailed memory was forgotten at a slower rate than gist memory. The forgetting rate of gist memory was the slowest after the naming task, while that of detailed memory was the slowest after the description task. In addition, when three experiments were compared, the naming task enhanced the contributions of recollection and familiarity for gist memory, while the description task enhanced the contribution of familiarity for detailed memory. These results reveal the importance of the encoding task in the forgetting of gist and detailed information, and suggest a possible way to maintain perceptual details of objects at longer intervals.

Sequentially Triggered Bacterial Outer Membrane Vesicles for Macrophage Metabolism Modulation and Tumor Metastasis Suppression.

Metabolic interactions between different cell types in the tumor microenvironment (TME) often result in reprogramming of the metabolism to be totally different from their normal physiological processes in order to support tumor growth. Many studies have attempted to inhibit tumor growth and activate tumor immunity by regulating the metabolism of tumors and other cells in TME. However, metabolic inhibitors often suffer from the heterogeneity of tumors, since the favorable metabolic regulation of malignant cells and other cells in TME is often inconsistent with each other. Therefore, we reported the design of a pH-sensitive drug delivery system that targets different cells in TME successively. Outer membrane vesicles (OMVs) derived from Gram-negative bacteria were applied to coload paclitaxel (PTX) and regulated in development and DNA damage response 1 (Redd1)-siRNA and regulate tumor metabolism microenvironment and suppress tumor growth. Our siRNA@M-/PTX-CA-OMVs could first release PTX triggered by the tumor pH (pH 6.8). Then the rest of it would be taken in by M2 macrophages to increase their level of glycolysis. Great potential was observed in TAM repolarization, tumor suppression, tumor immune activation, and TME remolding in the triple-negative breast cancer model. The application of the OMV provided an insight for establishing a codelivery platform for chemical drugs and genetic medicines.

Macrophage-Disguised Manganese Dioxide Nanoparticles for Neuroprotection by Reducing Oxidative Stress and Modulating Inflammatory Microenvironment in Acute Ischemic Stroke.

Reperfusion injury is still a major challenge that impedes neuronal survival in ischemic stroke. However, the current clinical treatments are remained on single pathological process, which are due to lack of comprehensive neuroprotective effects. Herein, a macrophage-disguised honeycomb manganese dioxide (MnO2 ) nanosphere loaded with fingolimod (FTY) is developed to salvage the ischemic penumbra. In particular, the biomimetic nanoparticles can accumulate actively in the damaged brain via macrophage-membrane protein-mediated recognition with cell adhesion molecules that are overexpressed on the damaged vascular endothelium. MnO2 nanosphere can consume excess hydrogen peroxide (H2 O2 ) and convert it into desiderated oxygen (O2 ), and can be decomposed in acidic lysosome for cargo release, so as to reduce oxidative stress and promote the transition of M1 microglia to M2 type, eventually reversing the proinflammatory microenvironment and reinforcing the survival of damaged neuron. This biomimetic nanomedicine raises new strategy for multitargeted combined treatment of ischemic stroke.

Biomimetic Dendrimer-Peptide Conjugates for Early Multi-Target Therapy of Alzheimer's Disease by Inflammatory Microenvironment Modulation.

Current therapeutic strategies for Alzheimer's disease (AD) treatments mainly focus on ß-amyloid (Aß) targeting. However, such therapeutic strategies have limited clinical outcomes due to the chronic and irreversible impairment of the nervous system in the late stage of AD. Recently, inflammatory responses, manifested in oxidative stress and glial cell activation, have been reported as hallmarks in the early stages of AD. Based on the crosstalk between inflammatory response and brain cells, a reactive oxygen species (ROS)-responsive dendrimer-peptide conjugate (APBP) is devised to target the AD microenvironment and inhibit inflammatory responses at an early stage. With the modification of the targeting peptide, this nanoconjugate can efficiently deliver peptides to the infected regions and restore the antioxidant ability of neurons by activating the nuclear factor (erythroid-derived 2)-like 2 signaling pathway. Moreover, this multi-target strategy exhibits a synergistic function of ROS scavenging, promoting Aß phagocytosis, and normalizing the glial cell phenotype. As a result, the nanoconjugate can reduce ROS level, decrease Aß burden, alleviate glial cell activation, and eventually enhance cognitive functions in APPswe/PSEN1dE9 model mice. These results indicate that APBP can be a promising candidate for the multi-target treatment of AD.

Pancreatic cancer-targeting exosomes for enhancing immunotherapy and reprogramming tumor microenvironment.

Immunotherapy has gained increasing focus in treating pancreatic ductal adenocarcinoma (PDAC), since conventional therapies like chemotherapy could not provide satisfactory improvement in overall survival outcome of PDAC patients. However, it is still not the game changing solution due to the unique tumor microenvironment and low cancer immunogenicity of PDAC. Thus, inducing more intratumoral effector immune cells as well as reversing immunosuppression is the core of PDAC treatment. Herein, we demonstrate an exosome-based dual delivery biosystem for enhancing PDAC immunotherapy as well as reversing tumor immunosuppression of M2-like tumor associated macrophages (M2-TAMs) upon disruption of galectin-9/dectin 1 axis. The deliver system is constructed from bone marrow mesenchymal stem cell (BM-MSC) exosomes, electroporation-loaded galectin-9 siRNA, and surficially modified with oxaliplatin (OXA) prodrug as an immunogenic cell death (ICD)-trigger. The use of biomaterials, BM-MSC exosomes, can significantly improve tumor targeting efficacy, thus increasing drug accumulation in the tumor site. The combined therapy (iEXO-OXA) elicits anti-tumor immunity through tumor-suppressive macrophage polarization, cytotoxic T lymphocytes recruitment and Tregs downregulation, and achieves significant therapeutic efficacy in cancer treatment.

Click-Nucleic-Acid-Containing Codelivery System Inducing Collapse of Cellular Homeostasis for Tumor Therapy through Bidirectional Regulation of Autophagy and Glycolysis.

As a rapid proliferating tissue, tumor cells have to optimize nutrient utilization to withstand harsh conditions. Several approaches have been explored to inhibit the growth and metastasis of tumor by disrupting the reprogrammed tumor metabolism. However, nutrient limitations within solid tumors may induce the metabolic flexibility of malignant cells to sustain growth and survival using one nutrient to fill metabolite pools normally supplied by the other. To overcome this predicament, a promising click-nucleic-acid-containing platform for codelivery of rapamycin, anti-PFKFB4 siRNA, and targeting ligand aptamer AS1411 was applied. PFKFB4 could act as a promising target for tumor therapy for being a molecular fulcrum that could couple glycolysis to autophagy by promoting aggressive metastatic tumors. The downregulation of PFKFB4 can help inhibit the SRC3/Akt/mTOR pathway, leading autophagy to the direction of promoting apoptosis of tumor cells, which is induced by the collapse of tumor cellular homeostasis, while low dosages of rapamycin could decrease surgery-induced immune dysfunction. Enhanced tumor autophagy, favorable in vivo antitumor efficacy, and effective systematic immune activation are observed after treatment, suggesting that autophagy and glycolysis can serve as an integrated target for tumor treatment.

Schematic memories develop quickly, but are not expressed unless necessary.

Episodic memory retrieval is increasingly influenced by schematic information as memories mature, but it is unclear whether this is due to the slow formation of schemas over time, or the slow forgetting of the episodes. To address this, we separately probed memory for newly learned schemas as well as their influence on episodic memory decisions. In this experiment, participants encoded images from two categories, with the location of images in each category drawn from a different spatial distribution. They could thus learn schemas of category locations by encoding specific episodes. We found that images that were more consistent with these distributions were more precisely retrieved, and this schematic influence increased over time. However, memory for the schema distribution, measured using generalization to novel images, also became less precise over time. This incongruity suggests that schemas form rapidly, but their influence on episodic retrieval is dictated by the need to bolster fading memory representations.

Penetrable Nanoplatform for "Cold" Tumor Immune Microenvironment Reeducation.

Lack of tumor-infiltration lymphocytes (TILs) and resistances by overexpressed immunosuppressive cells (principally, myeloid-derived suppressor cells (MDSCs)) in tumor milieu are two major challenges hindering the effectiveness of immunotherapy for "immune-cold" tumors. In addition, the natural physical barrier existing in solid cancer also limits deeper delivery of drugs. Here, a tumor-targeting and light-responsive-penetrable nanoplatform (Apt/PDGs/@pMOF) is developed to elicit intratumoral infiltration of cytotoxic T cells (CTLs) and reeducate immunosuppressive microenvironment simultaneously. In particular, porphyrinic metal-organic framework (pMOF)-based photodynamic therapy (PDT) induces tumor immunogenic cell death (ICD) to promote CTLs intratumoral infiltration and hot "immune-cold" tumor. Upon being triggered by PDT, the nearly 10 nm adsorbed drug-loaded dendrimer de-shields from the nanoplatform and spreads into the deeper tumor, eliminating MDSCs and reversing immunosuppression, eventually reinforcing immune response. Meanwhile, the designed nanoplatform also has a systemic MDSC inhibition effect and moderate improvement of overall antitumor immune responses, resulting in effective suppression of distal tumors within less significant immune-related adverse effects (irAEs) induced.

Bone marrow mesenchymal stem cells-derived exosomes for penetrating and targeted chemotherapy of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most intractable malignancy, with an only 6% 5-year relative survival rate. The dismal therapeutic effect is attributed to the chemotherapy resistance and unique pathophysiology with abundant inflammatory cytokines and abnormal hyperplasia of extracellular matrix (ECM). Based on the theory that bone marrow mesenchymal stem cells (BM-MSCs) can influence the tumorous microenvironment and malignant growth of PDAC, we employed exosomes (Exos) derived from BM-MSCs as PDAC-homing vehicles to surpass the restrictions of pathological ECM and increase the accumulation of therapeutics in tumor site. To overcome chemoresistance of PDAC, paclitaxel (PTX) and gemcitabine monophosphate (GEMP)-an intermediate product of gemcitabine metabolism-were loaded in/on the purified Exos. In this work, the Exo delivery platform showed superiorities in homing and penetrating abilities, which were performed on tumor spheroids and PDAC orthotopic models. Meanwhile, the favorable anti-tumor efficacy in vivo and in vitro, plus relatively mild systemic toxicity, was found. Loading GEMP and PTX, benefitting from the naturally PDAC selectivity, the Exo platform we constructed performs combined functions on excellent penetrating, anti-matrix and overcoming chemoresistance (Scheme 1). Worth expectantly, the Exo platform may provide a prospective approach for targeted therapies of PDAC.

Supramolecular Hunter Stationed on Red Blood Cells for Detoxification Based on Specific Molecular Recognition.

Efficient removal of deadly toxicants by blood purification remains predominant in poisoning treatment. Current strategies mainly rely on absorptive scavengers that normally have no selectivity to the adsorbates, which could result poor clinical outcomes to certain toxic species due to the passivity and inaccuracy of the detoxification procedure. Herein, a positive, accurate, and customized detoxification strategy was proposed. Based on the sophisticated molecule design and thoughtful structure analysis of the aimed toxicant paraquat, a supramolecular hunter stationed on red blood cells (RBC) is developed to continuously track paraquat in the blood. In this construct, a Janus dendrimer amphiphile (JDA) molecule was synthesized with the aim of facilely anchoring onto RBC membranes while bridging to load the antidote WP6 that could precisely recognize paraquat. In vitro and in vivo results demonstrate the effective toxicant-hunting and harm-neutralizing capability of the system through a guest-exchange reaction. This strategy provides a different insight in designing scavengers that can actively, precisely, and continuously hunt toxicants through a supramolecular approach.

Co-delivery of Cu(I) chelator and chemotherapeutics as a new strategy for tumor theranostic.

Chelating Cu from tumors has been verified as an effective and promising strategy for cancer therapy through antiangiogenesis. However, systematic removal Cu by injecting with Cu chelators will result unavoidable side effects, since Cu is indispensable to the body. In this work, a micelle targeting to tumors' newborn vessels based on a polypeptide was developed to co-load DOX and Probe X, which can go through an "OFF-to-ON" procedure to report the Cu+-capture events in vivo in a real-time way by giving near infrared (NIR) fluorescence and photoacoustic signal. By co-delivering antiangiogenesis and chemotherapeutic reagents, the tumor can be significantly suppressed, meanwhile with a low systematic toxicity. Hopefully, this work can offer new insights in designing sophisticated antitumor strategy.

GLUT1-mediated effective anti-miRNA21 pompon for cancer therapy.

Oncogenic microRNAs are essential components in regulating the gene expression of cancer cells. Especially miR21, which is a major player involved of tumor initiation, progression, invasion and metastasis in several cancers. The delivery of anti-miR21 sequences has significant potential for cancer treatment. Nevertheless, since anti-miR21 sequences are extremely unstable and they need to obtain certain concentration to function, it is intensely difficult to build an effective delivery system for them. The purpose of this work is to construct a self-assembled glutathione (GSH)-responsive system with tumor accumulation capacity for effective anti-miR21 delivery and cancer therapy. A novel drug delivery nanosphere carrying millions of anti-miR21 sequences was developed through the rolling circle transcription (RCT) method. GSH-responsive cationic polymer polyethyleneimine (pOEI) was synthesized to protect the nanosphere from degradation by Dicer or other RNase in normal cells and optimize the pompon-like nanoparticle to suitable size. Dehydroascorbic acid (DHA), a targeting molecule, which is a substrate of glucose transporter 1 (GLUT 1) and highly expressed on malignant tumor cells, was connected to pOEI through PEG, and then the polymer was used for contracting a RNA nanospheres into nanopompons. The anti-miR21 nanopompons showed its potential for effective cancer therapy.