Activity-dependent p25 generation regulates synaptic plasticity and Aß-induced cognitive impairment.

Cyclin-dependent kinase 5 regulates numerous neuronal functions with its activator, p35. Under neurotoxic conditions, p35 undergoes proteolytic cleavage to liberate p25, which has been implicated in various neurodegenerative diseases. Here, we show that p25 is generated following neuronal activity under physiological conditions in a GluN2B- and CaMKIIα-dependent manner. Moreover, we developed a knockin mouse model in which endogenous p35 is replaced with a calpain-resistant mutant p35 (Δp35KI) to prevent p25 generation. The Δp35KI mice exhibit impaired long-term depression and defective memory extinction, likely mediated through persistent GluA1 phosphorylation at Ser845. Finally, crossing the Δp35KI mice with the 5XFAD mouse model of Alzheimer's disease (AD) resulted in an amelioration of ß-amyloid (Aß)-induced synaptic depression and cognitive impairment. Together, these results reveal a physiological role of p25 production in synaptic plasticity and memory and provide new insights into the function of p25 in Aß-associated neurotoxicity and AD-like pathology.

Cholesterol suppresses AMFR-mediated PDL1 ubiquitination and degradation in HCC.

The degradation of proteasomes or lysosomes is emerging as a principal determinant of programmed death ligand 1 (PDL1) expression, which affects the efficacy of immunotherapy in various malignancies. Intracellular cholesterol plays a central role in maintaining the expression of membrane receptors; however, the specific effect of cholesterol on PDL1 expression in cancer cells remains poorly understood. Cholesterol starvation and stimulation were used to modulate the cellular cholesterol levels. Immunohistochemistry and western blotting were used to analyze the protein levels in the samples and cells. Quantitative real-time PCR, co-immunoprecipitation, and confocal co-localization assays were used for mechanistic investigation. A xenograft tumor model was constructed to verify these results in vivo. Our results showed that cholesterol suppressed the ubiquitination and degradation of PDL1 in hepatocellular carcinoma (HCC) cells. Further mechanistic studies revealed that the autocrine motility factor receptor (AMFR) is an E3 ligase that mediated the ubiquitination and degradation of PDL1, which was regulated by the cholesterol/p38 mitogenic activated protein kinase axis. Moreover, lowering cholesterol levels using statins improved the efficacy of programmed death 1 (PD1) inhibition in vivo. Our findings indicate that cholesterol serves as a signal to inhibit AMFR-mediated ubiquitination and degradation of PDL1 and suggest that lowering cholesterol by statins may be a promising combination strategy to improve the efficiency of PD1 inhibition in HCC.

State-dependent memory retrieval: insights from neural dynamics and behavioral perspectives.

Memory retrieval is strikingly susceptible to external states (environment) and internal states (mood states and alcohol), yet we know little about the underlying mechanisms. We examined how internally generated states influence successful memory retrieval using the functional magnetic resonance imaging (fMRI) of laboratory mice during memory retrieval. Mice exhibited a strong tendency to perform memory retrieval correctly only in the reinstated mammillary body-inhibited state, in which mice were trained to discriminate auditory stimuli in go/no-go tasks. fMRI revealed that distinct auditory cues engaged differential brain regions, which were primed by internal state. Specifically, a cue associated with a reward activated the lateral amygdala, while a cue signaling no reward predominantly activated the postsubiculum. Modifying these internal states significantly altered the neural activity balance between these regions. Optogenetic inhibition of those regions in the precue period blocked the retrieval of type-specific memories. Our findings suggest that memory retrieval is under the control of two interrelated neural circuits underlying the neural basis of state-dependent memory retrieval.

Signal Photon Extraction Method for ICESat-2 Data Using Slope and Elevation Information Provided by Stereo Images.

Laser altimetry data from the Ice, Cloud, and land Elevation Satellite-2 (ICESat-2) contain a lot of noise, which necessitates the requirement for a signal photon extraction method. In this study, we propose a density clustering method, which combines slope and elevation information from optical stereo images and adaptively adjusts the neighborhood search direction in the along-track direction. The local classification density threshold was calculated adaptively according to the uneven spatial distribution of noise and signal density, and reliable surface signal points were extracted. The performance of the algorithm was validated for strong and weak beam laser altimetry data using optical stereo images with different resolutions and positioning accuracies. The results were compared qualitatively and quantitatively with those obtained using the ATL08 algorithm. The signal extraction quality was better than that of the ATL08 algorithm for steep slope and low signal-to-noise ratio (SNR) regions. The proposed method can better balance the relationship between recall and precision, and its F1-score was higher than that of the ATL08 algorithm. The method can accurately extract continuous and reliable surface signals for both strong and weak beams among different terrains and land cover types.

Interactions between Plasmonic Nanoantennas and Vortex Beams.

The orbital angular momentum (OAM) of light offers a new degree of freedom for light-matter interactions, yet how to control such interactions with this physical dimension remains open. Here, by developing a numerical method enabling optical OAM simulations, we provide insights into complex plasmon behaviors with the physical dimension of OAM, and we prove in theory that plasmonic nanostructures can function as efficient antennas to intercept and directionally reradiate the power of OAM beams. The interplay between optical OAM and spin angular momentum (SAM) generates novel particle polarizations and radiations, which were inaccessible before. For arrayed nanoparticles, coherent surface plasmons with specific phase retardations determined by OAM of the beams enable directional power radiations, making a phased array antenna. These findings expand our knowledge of nanoplasmonics in the OAM area and are promising for quantum information processing and dynamic sensing of ultraweak biosignals.

Suv39h1 regulates memory stability by inhibiting the expression of Shank1 in hippocampal newborn neurons.

Adult newborn neurons are involved in memory encoding and extinction, but the neural mechanism is unclear. We found the adult newborn neurons at 4 weeks are recruited by learning and subjected to epigenetic regulations, consequently reducing their ability to be re-recruited later. After removal of the epigenetic blockage, Suv39h1 KO mice showed an increased recruiting number of aged newborn neurons and enhanced flexibility in learning tasks. Besides NRXN1, we found SHANK1, the synaptic scaffold protein, is one of the major targets of Suv39h1, regulating memory stability. Expression of Shank1 is transiently engaged to enhance synaptogenesis during learning and is strongly suppressed by Suv39h1 from 5 h after learning. Exogenously overexpression of Shank1 in dentate gyrus increased the density of mushroom spines and decreased the persistency of old memories. Our study indicated the activity-regulated epigenetic modification in newly matured newborn neurons in hippocampus insulates temporally distinct experiences and stabilizes old memories.

Modulation of Metal Halide Structural Units for Light Emission.

ConspectusWith the development of solid-state lighting technology, efficient light sources that combine high brightness, wide range, and good stability are in high demand for next-generation lighting and displays. Metal halides are emerging as promising luminescent materials due to their versatility for desirable light emission manipulations. This is because the optical activity of the metal halide material depends on the metal halide structural unit and the organic ions or coordinated organic ligands. The different assembly of metal halide units and organic parts can enable versatile light emissions, such as lead halide perovskites (LHPs) and copper halide-organic hybrids. Impressively, the external quantum efficiency of the LHP based light-emitting diodes (LEDs) has improved significantly from 0.1% to over 20% in just five years. With this great progress, the structural lability and toxicity of the LHPs are now the critical issues that need to be addressed for practical applications. These issues are mainly rooted in the intrinsic lead composition and low formation energy crystal structure of the widely adopted LHPs. Thus, the modulation of the structure and composition of the basic metal halide structural units is considered a rational strategy to address these issues.In this Account, we will present a general material design using metal halide structural units as basic building blocks to build up metal halide luminescent materials for solid-state lighting devices. Following this route, we will emphasize the modulation of metal halide structural units to tackle the existing challenges in lead halides, including the instability of crystalline structure, ion migration, and the presence of toxic lead. Considering basic components in structural units, we will highlight ionic engineering in LHPs via ion doping, substitution, and modification to enhance the crystal structural stability and suppress ion migration. To replace toxic lead, we will introduce recent advances in the modulation of lead-free halide structural units by active ion doping and organic ligand coordination to fabricate highly luminescent materials. Finally, we will present future strategies of metal halide structural unit modulation for solid-state light emissions. We hope this Account will provide new insights for designing metal halide materials from the viewpoint of the modulation of the basic building blocks and inspire future studies of advanced metal halide materials for solid-state light emitting applications.

The association between the dietary pattern in abdominal obesity based on visceral fat index and dyslipidaemia in the Henan Rural Cohort Study.

The present study aimed to explore the association between dietary patterns in abdominal obesity obtained by reduced-rank regression (RRR) with visceral fat index (VFI) as a dependent variable and dyslipidemia in rural adults in Henan, China. A total of 29538 people aged 18-79 were selected from the Henan Rural Cohort Study. RRR analysis was used to identify dietary patterns; logistic regression analysis and restricted cubic spline regression models were applied to analyze the association between dietary patterns in abdominal obesity and dyslipidemia. VFI was used as a mediator to estimate the mediation effect. The dietary pattern in abdominal obesity was characterized by high carbohydrate and red meat intake and low consumption of fresh fruits, vegetables, milk, etc. After full adjustment, the highest quartile of dietary pattern scores was significantly associated with an increased risk of dyslipidemia (OR: 1·33, 95 % CI 1·23-1·44, Ptrend < 0·001), there was a non-linear dose-response relationship between them (Poverall-association < 0·001, Pnon-lin-association = 0·022). The result was similar in dose-response between the dietary pattern scores and VFI. The indirect effect partially mediated by VFI was significant (OR: 1·07, 95 % CI 1·06-1·08). VIF explained approximately 53·3 % of odds of dyslipidemia related to the dietary pattern. Abdominal obesity dietary pattern scores positively affected VFI and dyslipidemia; there was a dose-response in both relationships. Dyslipidemia progression increased with higher abdominal obesity dietary pattern scores. In addition, VFI played a partial mediating role in relationship between abdominal obesity dietary pattern and dyslipidemia.

All-optical frequency-dependent magnetic switching in metal-insulator-metal stub structures.

Many attempts to switch magnetization with optical pulses were based on free-space coupling schemes of circularly polarized light pulses, so-called all-optical helicity-dependent magnetic switching; however, waveguide coupling schemes are promising for on-chip all-optical magnetic switching. Metal-insulator-metal (MIM) stub structures provide a promising platform for highly integrated photonic circuits, thanks to their compact size, on-chip compatibility, and ease of fabrication. We found clockwise and counterclockwise ring-like modes in the MIM stub structure, which can act as effective magnetic fields with two opposite directions due to the inverse Faraday effect. Effective magnetic field spectra inside the MIM stub have dual resonant peaks at which the effective magnetic field intensity reaches its extreme values with opposite signs, corresponding to binary magnetic states. Switching between the binary magnetic states can be achieved by altering the optical pump frequency. The all-optical frequency-dependent magnetic switching in the MIM stub may provide a chip-compatible and ultracompact tool for ultrafast switching of magnetic order.

Analysis of the therapeutic effect of artificial leather embedding combined with fascial sleeve flap transplantation on chronic wounds of lower limbs with bone and plate exposure.

BACKGROUND: After severe trauma of lower limbs, bone, tendon or plate graft exposure is common. The traditional repair method is to use a variety of skin flap transplantation to cover the exposed part, but the wound often can not heal after operation, or the wound is cracked, ulcer, sinus, bone and steel plate are exposed again after wound healing. The reason for this result is that when the flap is covered, the space around the bone plate is not well closed, forming a dead cavity, blood and exudate accumulation, hematoma formation or infection, and finally the wound ruptures again. In addition, due to the swelling and contracture of the flap after operation, the suture tension between the flap and the receiving area becomes larger, the skin becomes thinner and broken, and then the wound is formed. In order to solve the above problems, we carried out the study of artificial true skin embedding combined with fascial sleeve flap transplantation in the treatment of chronic bone plate exposed wounds of lower limbs. METHODS: In this paper, 11 cases of chronic wounds with bone exposure and skin necrosis after steel plate implantation were selected. First stage is the wound bed preparation including primary wound expansion, removal of necrotic tissue and incision of sinus wall, removal of deep necrotic bone and fibrotic scarred skin on the outer wall of steel plate to normal tissue on the outer edge of the wound, removal of precipitated peptone and purulent fur in the hole, periphery and bone space of the steel plate, and removal of tendon tissue with basal necrosis and disintegration of the wound. After vacuum sealing drainage (VSD) 1-2 weeks, the peritraumatic basal granulation tissue grew well and there was no necrotic tissue in the wound. In the second stage, the exposed bone was covered with artificial dermis, the steel plate hole or the periphery and the basal space were filled, and the exposed steel plate was completely embedded, and then the fascia sleeve flap was transplanted to cover the wound. The sural neurovascular flap was performed in nine cases and the lateral superior malleolar artery perforator flap in two case. RESULTS: The flap survived well in all 11 cases. During the follow-up of 6 months to the removal of the plate, there was no case of rupture, exposure and sinus formation. CONCLUSIONS: Artificial dermal covering combined with fascial sleeve flap transplantation can effectively avoid wound dehiscence or sinus formation caused by foreign body retention, infection and flap contracture. It has good effect in repairing chronic wounds with bone plate exposure after severe trauma of lower limbs.

Bright and Near-Unity Polarized Light Emission Enabled by Highly Luminescent Cu2I2-Dimer Cluster-Based Hybrid Materials.

As one fundamental property of light, polarization has a huge impact in quantum optics and optoelectronics through light-matter interactions. However, the bright and near-unity polarized light emissions in the visible range by solid crystalline materials are scantly realized. Here, we report well-defined quasi two-dimensional (2D) hybrid crystals based on the linear alignment of Cu2I2-dimer/bidentate ligand hybrid clusters for achieving bright and near-unity linearly polarized light emissions. Using first-principle calculations, we demonstrate that the superaligned transition dipole moments are the key for the observed excellent polarized light emissions. To further enhance the photoluminescence (PL) polarization degree, we fabricate Cu2I2-dimer-based hybrid nanobelts, which display high PL quantum yield (up to 64%) and ultrahigh PL polarization degree (∼0.99). Our reported copper iodine cluster-based luminescent hybrid materials for bright and highly polarized light emissions will have great potential for future quantum optics applications.

Spectrally Stable and Efficient Pure Red CsPbI3 Quantum Dot Light-Emitting Diodes Enabled by Sequential Ligand Post-Treatment Strategy.

Metal halide perovskites are promising semiconductors for next-generation light-emitting diodes (LEDs) due to their high luminance, excellent color purity, and handily tunable band gap. However, it remains a great challenge to develop perovskite LEDs (PeLEDs) with pure red emission at the wavelength of 630 nm. Herein, we report a spectrally stable and efficient pure red PeLED by employing sequential ligand post-treated CsPbI3 quantum dots (QDs). The synthesized CsPbI3 QDs with a size of ∼5 nm are treated in sequential steps using the ligands of 1-hydroxy-3-phenylpropan-2-aminium iodide (HPAI) and tributylsulfonium iodide (TBSI), respectively. The CsPbI3 QD films exhibit improved optoelectronic properties, which enables the fabrication of a pure red PeLED with a peak external quantum efficiency (EQE) of 6.4% and a stable EL emission centered at the wavelength of 630 nm. Our reported sequential ligand post-treatment strategy opens a new route to improve the stability and efficiency of PeLEDs based on QDs.

Advancements in MAFLD Modeling with Human Cell and Organoid Models.

Metabolic (dysfunction) associated fatty liver disease (MAFLD) is one of the most prevalent liver diseases and has no approved therapeutics. The high failure rates witnessed in late-phase MAFLD drug trials reflect the complexity of the disease, and how the disease develops and progresses remains to be fully understood. In vitro, human disease models play a pivotal role in mechanistic studies to unravel novel disease drivers and in drug testing studies to evaluate human-specific responses. This review focuses on MAFLD disease modeling using human cell and organoid models. The spectrum of patient-derived primary cells and immortalized cell lines employed to model various liver parenchymal and non-parenchymal cell types essential for MAFLD development and progression is discussed. Diverse forms of cell culture platforms utilized to recapitulate tissue-level pathophysiology in different stages of the disease are also reviewed.

Chiral Phosphine-Copper Iodide Hybrid Cluster Assemblies for Circularly Polarized Luminescence.

Chiral chromophores and their ordered assemblies are intriguing for yielding circularly polarized luminescence (CPL) and exploring intrinsic structure-light emission relationships. With the extensively studied chiral organic molecules and inorganic nanoparticle assemblies for the amplified CPL, the assemblies of copper halide hybrid clusters have attracted intensive attention due to their potential efficient CPL. Here, we report robust chiral phosphine-copper iodide hybrid clusters and their layered assemblies in crystalline states for amplified CPL. We reveal that the intermolecular interactions endow the clusters with the capability of assembling into chiral crystalline CPL materials, including hexagonal platelet-shaped microcrystals (glum ≈ 9.5 × 10-3) and highly oriented crystalline films (glum ≈ 5 × 10-3). Owing to the high crystalline feature of the thin film, we demonstrate an electroluminescent device with bright electroluminescence (1200 cd m-2).

Mutations in ASH1L confer susceptibility to Tourette syndrome.

Tourette syndrome (TS) is a childhood-onset neuropsychiatric disorder characterized by repetitive motor movements and vocal tics. The clinical manifestations of TS are complex and often overlap with other neuropsychiatric disorders. TS is highly heritable; however, the underlying genetic basis and molecular and neuronal mechanisms of TS remain largely unknown. We performed whole-exome sequencing of a hundred trios (probands and their parents) with detailed records of their clinical presentations and identified a risk gene, ASH1L, that was both de novo mutated and associated with TS based on a transmission disequilibrium test. As a replication, we performed follow-up targeted sequencing of ASH1L in additional 524 unrelated TS samples and replicated the association (P value = 0.001). The point mutations in ASH1L cause defects in its enzymatic activity. Therefore, we established a transgenic mouse line and performed an array of anatomical, behavioral, and functional assays to investigate ASH1L function. The Ash1l+/- mice manifested tic-like behaviors and compulsive behaviors that could be rescued by the tic-relieving drug haloperidol. We also found that Ash1l disruption leads to hyper-activation and elevated dopamine-releasing events in the dorsal striatum, all of which could explain the neural mechanisms for the behavioral abnormalities in mice. Taken together, our results provide compelling evidence that ASH1L is a TS risk gene.

Increasement of O-acetylhomoserine production in Escherichia coli by modification of glycerol-oxidative pathway coupled with optimization of fermentation.

OBJECTIVE: O-acetylhomoserine (OAH) is an important platform chemical to produce high-valuable chemicals. To improve the production of O-acetylhomoserine from glycerol, the glycerol-oxidative pathway was investigated and the optimization of fermentation with crude glycerol was carried out. RESULTS: The glycerol-uptake system and glycerol-oxidative pathway were modified and O-acetyltransferase from Corynebacterium glutamicum was introduced into the engineered strain to produce O-acetylhomoserine. It was found that overexpression of glycerol 3-phosphate dehydrogenase improved the OAH production to 6.79 and 4.21 g/L from pure and crude glycerol, respectively. And the higher OAH production depending on higher level of transcription of glpD. Two-step statistical approach was employed to optimize the fermentation conditions. The significant effects of glycerol, ammonium chloride and yeast extract were screened applying Plackett-Burman design and were optimized further by employing the Response Surface Methodology. Under optimized conditions, the OAH production was up to 9.42 and 7.01 g/L when pure and crude glycerol were used in shake flask cultivations, respectively. CONCLUSIONS: The enzymatic step catalyzing the oxidation of glycerol through GlpD was the key step for OAH production, which served the foundation for realization of a consistent OAH production from crude glycerol in the future.

Potassium Bromide Surface Passivation on CsPbI3-xBrx Nanocrystals for Efficient and Stable Pure Red Perovskite Light-Emitting Diodes.

All-inorganic lead halide perovskite nanocrystals (NCs) are potential candidates for fabricating high-performance light-emitting diodes (LEDs) owing to their precisely tunable bandgaps, high photoluminescence (PL) efficiency, and excellent color purities. However, the performance of pure red (630-640 nm) all-inorganic perovskite LEDs is still limited by the halide segregation-induced instability of the electroluminescence (EL) of mixed halide CsPbI3-xBrx NCs. Herein, we report an effective approach to improving the EL stability of pure red all-inorganic CsPbI3-xBrx NC-based LEDs via the passivation of potassium bromide on NCs. By adding potassium oleate to the reaction system, we obtained potassium bromide surface-passivated (KBr-passivated) CsPbI3-xBrx NCs with pure red PL emission and a photoluminescence quantum yield (PLQY) exceeding 90%. We determine that most potassium ions present on the surface of NCs bind with bromide ions and thus demonstrate that potassium bromide surface passivation of NCs can both improve the PL stability and inhibit the halide segregation of NCs. Using KBr-passivated CsPbI3-xBrx NCs as an emitting layer, we fabricated stable and pure red perovskite LEDs with emission at 637 nm, showing a maximum brightness of 2671 cd m-2, maximum external quantum efficiency of 3.55%, and good EL stability. The proposed KBr-passivated NC strategy will open a new avenue for fabricating efficient, stable, and tunable pure color perovskite NC LEDs.

Highly Luminescent Copper Iodide Cluster Based Inks with Photoluminescence Quantum Efficiency Exceeding 98.

Highly luminescent inks are desirable for various applications such as decorative coating, art painting, and anticounterfeiting, to name a few. However, present inks display low photoluminescent efficiency requiring a strong excitation light to make them glow. Here, we report a highly luminescent ink based on the copper-iodide/1-Propyl-1,4-diazabicyclo[2.2.2]octan-1-ium (Cu4I6(pr-ted)2) hybrid cluster with a quantum efficiency exceeding 98%. Under the interaction between the Cu4I6(pr-ted)2 hybrid cluster and polyvinylpyrrolidone (PVP), the highly luminescent Cu4I6(pr-ted)2/PVP ink can be facilely prepared via the one-pot solution synthesis. The obtained ink exhibits strong green light emission that originates from the efficient phosphorescence of Cu4I6(pr-ted)2 nanocrystals. Attractively, the ink displays high conversion efficiency for the ultraviolet light to bright green light emission due to its wide Stokes shift, implying great potential for anticounterfeiting and luminescent solar concentrator coating.

Switching From Fear to No Fear by Different Neural Ensembles in Mouse Retrosplenial Cortex.

Fear extinction is generally considered a form of new learning that inhibits previously acquired fear memories. Here, by tracking immediate early gene expression in vivo, we found that contextual fear extinction training evoked distinct neural ensembles in mouse retrosplenial cortex (RSC). The optogenetic reactivation of these extinction-activated neurons in the RSC was sufficient to suppress a fear response, while the reactivation of conditioning-activated neurons in the same area promoted a fear response. The generation of such an extinction-memory-related neural ensemble was associated with adult neurogenesis, as abolishing newborn neurons in the adult hippocampus via X-ray irradiation eliminated both the extinction-activated neurons in the RSC and the optogenetic-reactivation-induced suppression of contextual fear memory. Therefore, switching from fear to no fear in response to the same context is modulated by the RSC through an extinction-activated neural ensemble, the generation of which might require adult neurogenesis in the hippocampus.

Few-Nanometer-Sized α-CsPbI3 Quantum Dots Enabled by Strontium Substitution and Iodide Passivation for Efficient Red-Light Emitting Diodes.

Cubic phase CsPbI3 quantum dots (α-CsPbI3 QDs) as a newly emerging type of semiconducting QDs hold tremendous promise for fundamental research and optoelectronic device applications. However, stable and sub-5 nm-sized α-CsPbI3 QDs have rarely been demonstrated so far due to their highly labile ionic structure and low phase stability. Here, we report a novel strontium-substitution along with iodide passivation strategy to stabilize the cubic phase of CsPbI3, achieving the facile synthesis of α-CsPbI3 QDs with a series of controllable sizes down to sub-5 nm. We demonstrate that the incorporation of strontium ions can significantly increase the formation energies of α-CsPbI3 QDs and hence reduce the structure distortion to stabilize the cubic phase at the few-nanometer size. The size ranging from 15 down to sub-5 nm of as-prepared stable α-CsPbI3 QDs allowed us to investigate their unique size-dependent optical properties. Strikingly, the few-nanometer-sized α-CsPbI3 QDs turned out to retain high photoluminescence and highly close packing in solid state thin films, and the fabricated red light emitting diodes exhibited high brightness (1250 cd m-2 at 9.2 V) and good operational stability (L50 > 2 h driven by 6 V). The developed cation-substitution strategy will provide an alternative method to prepare uniform and finely size-controlled colloidal lead halide perovskite QDs for various optoelectronic applications.