Interface design for all-solid-state lithium batteries.

The operation of high-energy all-solid-state lithium-metal batteries at low stack pressure is challenging owing to the Li dendrite growth at the Li anodes and the high interfacial resistance at the cathodes1-4. Here we design a Mg16Bi84 interlayer at the Li/Li6PS5Cl interface to suppress the Li dendrite growth, and a F-rich interlayer on LiNi0.8Mn0.1Co0.1O2 (NMC811) cathodes to reduce the interfacial resistance. During Li plating-stripping cycles, Mg migrates from the Mg16Bi84 interlayer to the Li anode converting Mg16Bi84 into a multifunctional LiMgSx-Li3Bi-LiMg structure with the layers functioning as a solid electrolyte interphase, a porous Li3Bi sublayer and a solid binder (welding porous Li3Bi onto the Li anode), respectively. The Li3Bi sublayer with its high ionic/electronic conductivity ratio allows Li to deposit only on the Li anode surface and grow into the porous Li3Bi sublayer, which ameliorates pressure (stress) changes. The NMC811 with the F-rich interlayer converts into F-doped NMC811 cathodes owing to the electrochemical migration of the F anion into the NMC811 at a high potential of 4.3 V stabilizing the cathodes. The anode and cathode interlayer designs enable the NMC811/Li6PS5Cl/Li cell to achieve a capacity of 7.2 mAh cm-2 at 2.55 mA cm-2, and the LiNiO2/Li6PS5Cl/Li cell to achieve a capacity of 11.1 mAh cm-2 with a cell-level energy density of 310 Wh kg-1 at a low stack pressure of 2.5 MPa. The Mg16Bi84 anode interlayer and F-rich cathode interlayer provide a general solution for all-solid-state lithium-metal batteries to achieve high energy and fast charging capability at low stack pressure.

Sexual stage-specific A-to-I mRNA editing is mediated by tRNA-editing enzymes in fungi.

A-to-I RNA editing catalyzed by adenosine-deaminase-acting-on-RNA (ADARs) was assumed to be unique to metazoans because fungi and plants lack ADAR homologs. However, genome-wide messenger RNA (mRNA) editing was found to occur specifically during sexual reproduction in filamentous ascomycetes. Because systematic characterization of adenosine/cytosine deaminase genes has implicated the involvement of TAD2 and TAD3 orthologs in A-to-I editing, in this study, we used genetic and biochemical approaches to characterize the role of FgTAD2, an essential adenosine-deaminase-acting-on-tRNA (ADAT) gene, in mRNA editing in Fusarium graminearum. FgTAD2 had a sexual-stage-specific isoform and formed heterodimers with enzymatically inactive FgTAD3. Using a repeat-induced point (RIP) mutation approach, we identified 17 mutations in FgTAD2 that affected mRNA editing during sexual reproduction but had no effect on transfer RNA (tRNA) editing and vegetative growth. The functional importance of the H352Y and Q375*(nonsense) mutations in sexual reproduction and mRNA editing were confirmed by introducing specific point mutations into the endogenous FgTAD2 allele in the wild type. An in vitro assay was developed to show that FgTad2-His proteins purified from perithecia, but not from vegetative hyphae, had mRNA editing activities. Moreover, the H352Y mutation affected the enzymatic activity of FgTad2 to edit mRNA but had no effect on its ADAT activity. We also identified proteins co-purified with FgTad2-His by mass spectrometry analysis and found that two of them have the RNA recognition motif. Taken together, genetic and biochemical data from this study demonstrated that FgTad2, an ADAT, catalyzes A-to-I mRNA editing with the stage-specific isoform and cofactors during sexual reproduction in fungi.

Functions and mechanisms of A-to-I RNA editing in filamentous ascomycetes.

Although lack of ADAR (adenosine deaminase acting on RNA) orthologs, genome-wide A-to-I editing occurs specifically during sexual reproduction in a number of filamentous ascomycetes, including Fusarium graminearum and Neurospora crassa. Unlike ADAR-mediated editing in animals, fungal A-to-I editing has a strong preference for hairpin loops and U at -1 position, which leads to frequent editing of UAG and UAA stop codons. Majority of RNA editing events in fungi are in the coding region and cause amino acid changes. Some of these editing events have been experimentally characterized for providing heterozygote and adaptive advantages in F. graminearum. Recent studies showed that FgTad2 and FgTad3, 2 ADAT (adenosine deaminase acting on tRNA) enzymes that normally catalyze the editing of A34 in the anticodon of tRNA during vegetative growth mediate A-to-I mRNA editing during sexual reproduction. Stage specificity of RNA editing is conferred by stage-specific expression of short transcript isoforms of FgTAD2 and FgTAD3 as well as cofactors such as AME1 and FIP5 that facilitate the editing of mRNA in perithecia. Taken together, fungal A-to-I RNA editing during sexual reproduction is catalyzed by ADATs and it has the same sequence and structural preferences with editing of A34 in tRNA.

A non-pheromone GPCR is essential for meiosis and ascosporogenesis in the wheat scab fungus.

Meiosis is essential for generating genetic diversity and sexual spores, but the regulation of meiosis and ascosporogenesis is not clear in filamentous fungi, in which dikaryotic and diploid cells formed inside fruiting bodies are not free living and independent of pheromones or pheromone receptors. In this study, Gia1, a non-pheromone GPCR (G protein-coupled receptor) with sexual-specific expression in Fusarium graminearum, is found to be essential for ascosporogenesis. The gia1 mutant was normal in perithecium development, crozier formation, and karyogamy but failed to undergo meiosis, which could be partially rescued by a dominant active mutation in GPA1 and activation of the Gpmk1 pathway. GIA1 orthologs have conserved functions in regulating meiosis and ascosporogenesis in Sordariomycetes. GIA1 has a paralog, GIP1, in F. graminearum and other Hypocreales species which is essential for perithecium formation. GIP1 differed from GIA1 in expression profiles and downstream signaling during sexual reproduction. Whereas the C-terminal tail and IR3 were important for intracellular signaling, the N-terminal region and EL3 of Gia1 were responsible for recognizing its ligand, which is likely a protein enriched in developing perithecia, particularly in the gia1 mutant. Taken together, these results showed that GIA1 encodes a non-pheromone GPCR that regulates the entry into meiosis and ascosporogenesis via the downstream Gpmk1 MAP kinase pathway in F. graminearum and other filamentous ascomycetes.

Paraventricular Thalamus Dynamically Modulates Aversive Memory via Tuning Prefrontal Inhibitory Circuitry.

The impact of stress on the formation and expression of memory is well studied, especially on the contributions of stress hormones. But how stress affects brain circuitry dynamically to modulate memory is far less understood. Here, we used male C57BL6/J mice in an auditory fear conditioning as a model system to examine this question and focused on the impact of stress on dorsomedial prefrontal cortex (dmPFC) neurons which play an important role in probabilistic fear memory. We found that paraventricular thalamus (PVT) neurons are robustly activated by acute restraining stress. Elevated PVT activity during probabilistic fear memory expression increases spiking in the dmPFC somatostatin neurons which in turn suppresses spiking of dmPFC parvalbumin (PV) neurons, and reverts the usual low fear responses associated with probabilistic fear memory to high fear. This dynamic and reversible modulation allows the original memory to be preserved and modulated during memory expression. In contrast, elevated PVT activity during fear conditioning impairs synaptic modifications in the dmPFC PV-neurons and abolishes the formation of probabilistic fear memory. Thus, PVT functions as a stress sensor to modulate the formation and expression of aversive memory by tuning inhibitory functions in the prefrontal circuitry.SIGNIFICANCE STATEMENT The impact of stress on cognitive functions, such as memory and executive functions, are well documented especially on the impact by stress hormone. However, the contributions of brain circuitry are far less understood. Here, we show that a circuitry-based mechanism can dynamically modulate memory formation and expression, namely, higher stress-induced activity in paraventricular thalamus (PVT) impairs the formation and expression of probabilistic fear memory by elevating the activity of somatostatin-neurons to suppress spiking in dorsomedial prefrontal parvalbumin (PV) neurons. This stress impact on memory via dynamic tuning of prefrontal inhibition preserves the formed memory but enables a dynamic expression of memory. These findings have implications for better stress coping strategies as well as treatment options including better drug targets/mechanisms.

FGL2 as a predictive biomarker for prognosis and immunotherapy in bladder cancer.

Background: Metastasis and immunosuppression result in unfavorable prognosis in bladder cancer (BLCA). FGL1 and FGL2 are two members of the fibrinogen-related proteins family, but their potential effects on BLCA remain elusive. Methods: The expression profile of FGL1 and FGL2 in BLCA was analyzed in multiple databases. Furthermore, the expression of FGL2 was validated in BLCA tissues. The predictive capability of FGL2 was evaluated by Kaplan-Meier analysis, univariate analysis, and multivariate Cox regression. A nomogram model was constructed based on FGL2 expression and clinicopathological parameters for clinical practice. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analyses (GSEA) were performed to investigate enrichment in the biological processes. In addition, the correlation between FGL2 and immunological characteristics in the BLCA tumor microenvironment (TME), including tumor-infiltrating immune cells (TICs), cancer-immunity cycles, immune checkpoint molecules (ICPs), immunophenoscores (IPS), and response to anti-PD-L1 immunotherapy was further analyzed. Results: FGL2 was found to be downregulated in BLCA due to hypermethylation of the FGL2 promoter region, which was associated with an unfavorable prognosis. Moreover, BLCA patients with high FGL2 expression exhibited better response to immunotherapy. Conclusions: Our research revealed that FGL2 was downregulated in BLCA and was negatively correlated with DNA methylation. High FGL2 expression was confirmed as an independent risk for prognosis. Moreover, FGL2 is a promising indicator for the response to immunotherapy in patients with BLCA.

PANI/GO and Sm co-modified Ti/PbO2 dimensionally stable anode for highly efficient amoxicillin degradation: Performance assessment, impact parameters and degradation mechanism.

The abuse and uncontrolled discharge of antibiotics present a severe threat to environment and human health, necessitating the development of efficient and sustainable treatment technology. In this work, we employ a facile one-step electrodeposition method to prepare polyaniline/graphite oxide (PANI/GO) and samarium (Sm) co-modified Ti/PbO2 (Ti/PbO2-PANI/GO-Sm) electrode for the degradation of amoxicillin (AMX). Compared with traditional Ti/PbO2 electrode, Ti/PbO2-PANI/GO-Sm electrode exhibits more excellent oxygen evolution potential (2.63 V) and longer service life (56 h). In degradation experiment, under optimized conditions (50 mg L-1 AMX, 20 mA cm-2, pH 3, 0.050 M Na2SO4, 25 °C), Ti/PbO2-PANI/GO-Sm electrode achieves remarkable removal efficiencies of 88.76% for AMX and 79.92% for chemical oxygen demand at 90 min. In addition, trapping experiment confirms that ·OH plays a major role in the degradation process. Based on theoretical calculation and liquid chromatography-mass spectrometer results, the heterocyclic portion of AMX molecule is more susceptible to ·OH attacks. Thus, this novel electrode offers a sustainable and efficient solution to address environmental challenges posed by antibiotic-contaminated wastewater.

Room-temperature epitaxial welding of 3D and 2D perovskites.

Formation of epitaxial heterostructures via post-growth self-assembly is important in the design and preparation of functional hybrid systems combining unique properties of the constituents. This is particularly attractive for the construction of metal halide perovskite heterostructures, since their conventional solution synthesis usually leads to non-uniformity in composition, crystal phase and dimensionality. Herein, we demonstrate that a series of two-dimensional and three-dimensional perovskites of different composition and crystal phase can form epitaxial heterostructures through a ligand-assisted welding process at room temperature. Using the CsPbBr3/PEA2PbBr4 heterostructure as a demonstration, in addition to the effective charge and energy transfer across the epitaxial interface, localized lattice strain was observed at the interface, which was extended to the top layer of the two-dimensional perovskite, leading to multiple new sub-bandgap emissions at low temperature. Given the versatility of our strategy, unlimited hybrid systems are anticipated, yielding composition-, interface- and/or orientation-dependent properties.

A comparative study of H2 sensing performance of stoichiometric polymorphs of titanium carbide MXenes loaded with Pd nanodots.

Although titanium-based MXenes have been widely reported for gas sensing, the effect of crystal stoichiometric variations on the sensing properties has been rarely reported. Herein, stoichiometric polymorphs of titanium carbide MXenes (i.e., Ti3C2Tx and Ti2CTx) loaded with Pd nanodots (NDs) prepared by photochemical reduction were investigated for room-temperature H2 sensing. Interestingly, we found that Pd/Ti2CTx exhibited greatly enhanced sensitivity to H2, along with faster response and recovery rates compared to Pd/Ti3C2Tx. The H2 adsorption induced resistance change in Pd/Ti2CTx was higher than that of Pd/Ti3C2Tx due to the more effective charge transfer at the heterointerface of Pd/Ti2CTx, which was confirmed by shifts of binding energies and theoretical calculation results. We hope this work could be helpful to design more high-performance MXene-based gas sensors.

A prognostic model based on necroptosis-related genes for prognosis and therapy in bladder cancer.

Bladder cancer, one of the most prevalent malignant cancers, has high rate of recurrence and metastasis. Owing to genomic instability and high-level heterogeneity of bladder cancer, chemotherapy and immunotherapy drugs sensitivity and lack of prognostic markers, the prognosis of bladder cancer is unclear. Necroptosis is a programmed modality of necrotic cell death in a caspase-independent form. Despite the fact that necroptosis plays a critical role in tumor growth, cancer metastasis, and cancer patient prognosis, necroptosis-related gene sets have rarely been studied in bladder cancer. As a result, the development of new necroptosis-related prognostic indicators for bladder cancer patients is critical. Herein, we assessed the necroptosis landscape of bladder cancer patients from The Cancer Genome Atlas database and classified them into two unique necroptosis-related patterns, using the consensus clustering. Then, using five prognosis-related genes, we constructed a prognostic model (risk score), which contained 5 genes (ANXA1, DOK7, FKBP10, MAP1B and SPOCD1). And a nomogram model was also developed to offer the clinic with a more useful prognostic indicator. We found that risk score was significantly associated with clinicopathological characteristics, TIME, and tumor mutation burden in patients with bladder cancer. Moreover, risk score was a valid guide for immunotherapy, chemotherapy, and targeted drugs. In our study, DOK7 was chosen to further verify our prognosis model, and functional assays indicated that knockdown the expression of DOK7 could prompt bladder cancer proliferation and migration. Our work demonstrated the potential role of prognostic model based on necroptosis genes in the prognosis, immune landscape and response efficacy of immunotherapy of bladder cancer.

Specificity in Generalization Effects of Transcranial Direct Current Stimulation Over the Left Inferior Frontal Gyrus in Primary Progressive Aphasia.

OBJECTIVES: Generalization (or near-transfer) effects of an intervention to tasks not explicitly trained are the most desirable intervention outcomes. However, they are rarely reported and even more rarely explained. One hypothesis for generalization effects is that the tasks improved share the same brain function/computation with the intervention task. We tested this hypothesis in this study of transcranial direct current stimulation (tDCS) over the left inferior frontal gyrus (IFG) that is claimed to be involved in selective semantic retrieval of information from the temporal lobes. MATERIALS AND METHODS: In this study, we examined whether tDCS over the left IFG in a group of patients with primary progressive aphasia (PPA), paired with a lexical/semantic retrieval intervention (oral and written naming), may specifically improve semantic fluency, a nontrained near-transfer task that relies on selective semantic retrieval, in patients with PPA. RESULTS: Semantic fluency improved significantly more in the active tDCS than in the sham tDCS condition immediately after and two weeks after treatment. This improvement was marginally significant two months after treatment. We also found that the active tDCS effect was specific to tasks that require this IFG computation (selective semantic retrieval) but not to other tasks that may require different computations of the frontal lobes. CONCLUSIONS: We provided interventional evidence that the left IFG is critical for selective semantic retrieval, and tDCS over the left IFG may have a near-transfer effect on tasks that depend on the same computation, even if they are not specifically trained. CLINICAL TRIAL REGISTRATION: The Clinicaltrials.gov registration number for the study is NCT02606422.

High-Performance Lithium Metal Batteries Enabled by a Fluorinated Cyclic Ether with a Low Reduction Potential.

Electrolyte engineering is crucial for developing high-performance lithium metal batteries (LMB). Here, we synthesized two cosolvents methyl bis(fluorosulfonyl)imide (MFSI) and 3,3,4,4-tetrafluorotetrahydrofuran (TFF) with significantly different reduction potentials and add them into LiFSI-DME electrolytes. The LiFSI/TFF-DME electrolyte gave an average Li Coulombic efficiency (CE) of 99.41 % over 200 cycles, while the average Li CEs for MFSI-based electrolyte is only 98.62 %. Additionally, the TFF-based electrolytes exhibited a more reversible performance than the state-of-the-art fluorinated 1,4-dimethoxylbutane electrolyte in both Li||Cu half-cell and anode-free Cu||LiNi0.8 Mn0.1 Co0.1 O2 full cell. More importantly, the decomposition product from bis(fluorosulfonyl)imide anion could react with ether solvent, which destroyed the SEI, thus decreasing cell performance. These key discoveries provide new insights into the rational design of electrolyte solvents and cosolvents for LMB.

Nitrogen repression of deoxynivalenol biosynthesis is mediated by Mep2 ammonium permease in Fusarium graminearum.

Fusarium graminearum is an important wheat pathogen and a producer of deoxynivalenol (DON). Biosynthesis of DON is suppressed by ammonium and induced by arginine and polyamines. To better understand ammonium repression of DON biosynthesis, in this study, we functionally characterized three ammonium permease (MEP) genes in F. graminearum. All the mep deletion mutants were normal in growth on V8 agar. Whereas deletion of MEP1 had no detectable phenotypes, the mep2 and mep3 mutants had defects in hyphal growth under ammonium limiting conditions and infection of wheat heads, with the latter having less severe defects. Deletion of MEP2 but not MEP3 affected nitrogen repression of DON biosynthesis and genes involved in nitrate metabolism. The mep2 mep3 double mutant had more severe defects in nitrogen repression than the mep2 mutant and was defective in ascospore releasing. Mutant alleles of MEP2 with truncated C-terminal cytoplasmic tail (CT) failed to complement the mep2 mutant. Expression of a dominant active allele of RAS2 partially rescued the defects of mep2 in nitrogen repression. Taken together, these results suggest that Mep2 acts as the major sensor of ammonium availability in F. graminearum and its CT region functions in nitrogen repression via RAS2 and downstream signalling pathways.

Identification of ENO1 as a prognostic biomarker and molecular target among ENOs in bladder cancer.

BACKGROUND: Enolase is an essential enzyme in the process of glycolysis and has been implicated in cancer progression. Though dysregulation of ENOs has been reported in multiple cancers, their prognostic value and specific role in bladder cancer (BLCA) remain unclear. METHODS: Multiple databases were employed to examine the expression of ENOs in BLCA. The expression of ENO1 was also validated in BLCA cell lines and tissue samples by western blotting and immunohistochemistry. Kaplan-Meier analysis, ROC curve, univariate and multivariate Cox regression were performed to evaluate the predictive capability of the ENO1. Gene ontology (GO) and Gene Set Enrichment Analyses (GSEA) analysis were employed to perform the biological processes enrichment. Function experiments were performed to explore the biological role of ENO1 in BLCA. The correlation of ENO1 with immune cell infiltration was explored by CIBERSORT. RESULTS: By analyzing three ENO isoforms in multiple databases, we identified that ENO1 was the only significantly upregulated gene in BLCA. High expression level of ENO1 was further confirmed in BLCA tissue samples. Aberrant ENO1 overexpression was associated with clinicopathological characteristics and unfavorable prognosis. Functional studies demonstrated that ENO1 depletion inhibited cancer cell aggressiveness. Furthermore, the expression level of ENO1 was correlated with the infiltration levels of immune cells and immune-related functions. CONCLUSIONS: Taken together, our results indicated that ENO1 might serve as a promising prognostic biomarker for prognosticating prognosis associated with the tumor immune microenvironment, suggesting that ENO1 could be a potential immune-related target against BLCA.

Deposition of Vertically Aligned Ag/Ag2 S Nanoflakes on EGaIn Particles for Humidity Sensing.

Liquid metals, which possess both good electrical conductivity and liquid-like processability, have drawn much attention recently. They are also capable of acting as synthesis templates to guide the deposition of other functional materials. Herein, through an in-situ galvanic replacement reaction assisted by ultrasonication, core-shell EGaIn/Ag particles composed of EGaIn cores and vertically aligned Ag nanoflakes as shells were prepared; they were further sulfurized to yield ternary EGaIn/Ag/Ag2 S core-shell composite particles. A humidity sensor based on EGaIn/Ag/Ag2 S particles showed much higher sensing response than EGaIn and EGaIn/Ag. Such superior performance could be attributed to the n-type semiconducting character of Ag2 S allowing it to receive electrons from water molecules at low humidity, and its highly hydrophilic surface allowing it to absorb more water molecules at higher humidity so as to enable the formation of ion-conductive paths.

Eliminating accidental deviations to minimize generalization error and maximize replicability: Applications in connectomics and genomics.

Replicability, the ability to replicate scientific findings, is a prerequisite for scientific discovery and clinical utility. Troublingly, we are in the midst of a replicability crisis. A key to replicability is that multiple measurements of the same item (e.g., experimental sample or clinical participant) under fixed experimental constraints are relatively similar to one another. Thus, statistics that quantify the relative contributions of accidental deviations-such as measurement error-as compared to systematic deviations-such as individual differences-are critical. We demonstrate that existing replicability statistics, such as intra-class correlation coefficient and fingerprinting, fail to adequately differentiate between accidental and systematic deviations in very simple settings. We therefore propose a novel statistic, discriminability, which quantifies the degree to which an individual's samples are relatively similar to one another, without restricting the data to be univariate, Gaussian, or even Euclidean. Using this statistic, we introduce the possibility of optimizing experimental design via increasing discriminability and prove that optimizing discriminability improves performance bounds in subsequent inference tasks. In extensive simulated and real datasets (focusing on brain imaging and demonstrating on genomics), only optimizing data discriminability improves performance on all subsequent inference tasks for each dataset. We therefore suggest that designing experiments and analyses to optimize discriminability may be a crucial step in solving the replicability crisis, and more generally, mitigating accidental measurement error.

Establishment of an optimized orthotopic bladder cancer model in mice.

BACKGROUND: Bladder cancer (BC) is one of the most common malignancies of the genitourinary system. Animal models offer an important tool to explore tumour initiation, progression, and therapeutic mechanisms. Our aim is to construct an optimized orthotopic BC model which is predictable, reproducible, and convenient. METHODS: The optimized orthotopic BC model was constructed in male C57BL/6 mice utilizing microsyringes to inoculate them with a murine BC cell line (MB49). Anesthetised mice were inoculated with an MB49 cell suspension (10 µL) at approximately 5 × 106/mL. The whole process of modelling was observed and monitored every 3 days for 21 days utilizing HE staining and transabdominal ultrasonography (TUS). RESULTS: In this study, the model showed excellent success rates for tumour formation (96.67%) and metastatic rate (89.66%). Compared to the control group (sham operation), mice in the modelling group had serous cachexia, visible haematuresis and weight loss (all P < 0.05). The lungs, liver, ureter and kidneys were found to have tumour metastasis. Moreover, the average survival time (19.73 ± 1.69 d) of modelling mice was significantly shorter than that of the control mice (P < 0.05), which remained alive. CONCLUSION: Our study established a method using microsyringes to inject murine BC cells into the bladder wall, creating a stable transplantable BC model in mice.

Online violent video games and online aggressive behavior among Chinese college students: The role of anger rumination and self-control.

Online aggressive behavior (OAB) has received increasing attention in recent years, and that playing online violent video games (OVVG) is an important predictor of OAB. However, little is known of the mediating and moderating mechanisms underlying this relationship. This study aims to investigate (a) the mediating role of anger rumination in the association between OVVG and OAB and (b) the moderating role of self-control in the relationship between anger rumination and OAB. A total of 595 Chinese college students (M age = 19.59 years, SD age = 1.40) completed measurements regarding OVVG, anger rumination, self-control, and OAB. The correlation analyses showed that OVVG was significantly positively associated with anger rumination and OAB. Mediation analyses revealed anger rumination partially mediated the link between OVVG and OAB. Moderated mediation further indicated that anger rumination was not associated with OAB for individuals with high levels of self-control. However, for those with low levels of self-control, anger rumination was significantly associated with OAB. These findings suggest that the improvement of self-control and the decline of anger rumination could be a practicable way to address the issue of OAB effectively.

Biodegradable Zwitterion/PLGA Scaffold Enables Robust Healing of Rat Calvarial Defects with Ultralow Dose of rhBMP-2.

Designing smart scaffolds to reduce administration dosage under the premise of functional healing of bone defects to avoid the severe side effects associated with BMP-2 treatments is one of the essential goals in bone tissue engineering. Here, we report a novel biodegradable PLGA/PSBMA composite as the scaffold for bone tissue engineering. The introduction of zwitterionic PSBMA components can alter the intrinsic burst degradation behavior of PLGA and enable a sustained degradation of the scaffold over the time. The PLGA/PSBMA scaffold can sequester rhBMP-2 and enable a sustained release of the sequestered rhBMP-2 with preserved bioactivity. Furthermore, PLGA/PSBMA scaffolds were able to guide robust healing of critical-sized nonunion calvarial defects (5 mm) at an ultralow dose of 400 ng/scaffold, at which level successful healing of critical-sized bone defects has never been reported. These findings indicate the PLGA/PSBMA scaffolds as novel high-efficiency rhBMP-2 delivery vehicles for bone tissue engineering, and the concept of utilizing the material, which is capable of maintaining the bioactivity of the proteins in the preparation of scaffolds, may open a new avenue for the design of smart scaffolds/vehicles for high-efficiency protein/bioactive drug therapies.

Modulation of learning safety signals by acute stress: paraventricular thalamus and prefrontal inhibition.

Distinguishing between cues predicting safety and danger is crucial for survival. Impaired learning of safety cues is a central characteristic of anxiety-related disorders. Despite recent advances in dissecting the neural circuitry underlying the formation and extinction of conditioned fear, the neuronal basis mediating safety learning remains elusive. Here, we showed that safety learning reduces the responses of paraventricular thalamus (PVT) neurons to safety cues, while activation of these neurons controls both the formation and expression of safety memory. Additionally, the PVT preferentially activates prefrontal cortex somatostatin interneurons (SOM-INs), which subsequently inhibit parvalbumin interneurons (PV-INs) to modulate safety memory. Importantly, we demonstrate that acute stress impairs the expression of safety learning, and this impairment can be mitigated when the PVT is inhibited, indicating PVT mediates the stress effect. Altogether, our findings provide insights into the mechanism by which acute stress modulates safety learning.