Aberrant activation of hippocampal astrocytes causes neuroinflammation and cognitive decline in mice.

Reactive astrocytes are associated with neuroinflammation and cognitive decline in diverse neuropathologies; however, the underlying mechanisms are unclear. We used optogenetic and chemogenetic tools to identify the crucial roles of the hippocampal CA1 astrocytes in cognitive decline. Our results showed that repeated optogenetic stimulation of the hippocampal CA1 astrocytes induced cognitive impairment in mice and decreased synaptic long-term potentiation (LTP), which was accompanied by the appearance of inflammatory astrocytes. Mechanistic studies conducted using knockout animal models and hippocampal neuronal cultures showed that lipocalin-2 (LCN2), derived from reactive astrocytes, mediated neuroinflammation and induced cognitive impairment by decreasing the LTP through the reduction of neuronal NMDA receptors. Sustained chemogenetic stimulation of hippocampal astrocytes provided similar results. Conversely, these phenomena were attenuated by a metabolic inhibitor of astrocytes. Fiber photometry using GCaMP revealed a high level of hippocampal astrocyte activation in the neuroinflammation model. Our findings suggest that reactive astrocytes in the hippocampus are sufficient and required to induce cognitive decline through LCN2 release and synaptic modulation. This abnormal glial-neuron interaction may contribute to the pathogenesis of cognitive disturbances in neuroinflammation-associated brain conditions.

Enhancing the activity of Pd ensembles on graphene by manipulating coordination environment.

Atomic dispersion of metal catalysts on a substrate accounts for the increased atomic efficiency of single-atom catalysts (SACs) in various catalytic schemes compared to the nanoparticle counterparts. However, lacking neighboring metal sites has been shown to deteriorate the catalytic performance of SACs in a few industrially important reactions, such as dehalogenation, CO oxidation, and hydrogenation. Metal ensemble catalysts (Mn), an extended concept to SACs, have emerged as a promising alternative to overcome such limitation. Inspired by the fact that the performance of fully isolated SACs can be enhanced by tailoring their coordination environment (CE), we here evaluate whether the CE of Mn can also be manipulated in order to enhance their catalytic activity. We synthesized a set of Pd ensembles (Pdn) on doped graphene supports (Pdn/X-graphene where X = O, S, B, and N). We found that introducing S and N onto oxidized graphene modifies the first shell of Pdn converting Pd-O to Pd-S and Pd-N, respectively. We further found that the B dopant significantly affected the electronic structure of Pdn by serving as an electron donor in the second shell. We examined the performance of Pdn/X-graphene toward selective reductive catalysis, such as bromate reduction, brominated organic hydrogenation, and aqueous-phase CO2 reduction. We observed that Pdn/N-graphene exhibited superior performance by lowering the activation energy of the rate-limiting step, i.e., H2 dissociation into atomic hydrogen. The results collectively suggest controlling the CE of SACs in an ensemble configuration is a viable strategy to optimize and enhance their catalytic performance.

Free-standing membrane incorporating single-atom catalysts for ultrafast electroreduction of low-concentration nitrate.

The release of wastewaters containing relatively low levels of nitrate (NO3-) results in sufficient contamination to induce harmful algal blooms and to elevate drinking water NO3- concentrations to potentially hazardous levels. In particular, the facile triggering of algal blooms by ultra-low concentrations of NO3- necessitates the development of efficient methods for NO3- destruction. However, promising electrochemical methods suffer from weak mass transport under low reactant concentrations, resulting in long treatment times (on the order of hours) for complete NO3- destruction. In this study, we present flow-through electrofiltration via an electrified membrane incorporating nonprecious metal single-atom catalysts for NO3- reduction activity enhancement and selectivity modification, achieving near-complete removal of ultra-low concentration NO3- (10 mg-N L-1) with a residence time of only a few seconds (10 s). By anchoring Cu single atoms supported on N-doped carbon in a carbon nanotube interwoven framework, we fabricate a free-standing carbonaceous membrane featuring high conductivity, permeability, and flexibility. The membrane achieves over 97% NO3- removal with high N2 selectivity of 86% in a single-pass electrofiltration, which is a significant improvement over flow-by operation (30% NO3- removal with 7% N2 selectivity). This high NO3- reduction performance is attributed to the greater adsorption and transport of nitric oxide under high molecular collision frequency coupled with a balanced supply of atomic hydrogen through H2 dissociation during electrofiltration. Overall, our findings provide a paradigm of applying a flow-through electrified membrane incorporating single-atom catalysts to improve the rate and selectivity of NO3- reduction for efficient water purification.

Strategic combination of bacteriophages with highly susceptible cells for enhanced intestinal settlement and resistant cell killing.

Avian pathogenic Escherichia coli (APEC) causes enormous economic losses and is a primary contributor to the emergence of multidrug resistance (MDR)-related problems in the poultry industry. Bacteriophage (phage) therapy has been successful in controlling MDR, but phage-resistant variants have rapidly emerged through the horizontal transmission of diverse phage defense systems carried on mobile genetic elements. Consequently, while multiple phage cocktails are recommended for phage therapy, there is a growing need to explore simpler and more cost-effective phage treatment alternatives. In this study, we characterized two novel O78-specific APEC phages, φWAO78-1 and φHAO78-1, in terms of their morphology, genome, physicochemical stability and growth kinetics. Additionally, we assessed the susceptibility of thirty-two O78 APEC strains to these phages. We analyzed the roles of highly susceptible cells in intestinal settlement and fecal shedding (susceptible cell-assisted intestinal settlement and shedding, SAIS) of phages in chickens via coinoculation with phages. Furthermore, we evaluated a new strategy, susceptible cell-assisted resistant cell killing (SARK), by comparing phage susceptibility between resistant cells alone and a mixture of resistant and highly susceptible cells in vitro. As expected, high proportions of O78 APEC strains had already acquired multiple phage defense systems, exhibiting considerable resistance to φWAO78-1 and φHAO78-1. Coinoculation of highly susceptible cells with phages prolonged phage shedding in feces, and the coexistence of susceptible cells markedly increased the phage susceptibility of resistant cells. Therefore, the SAIS and SARK strategies were demonstrated to be promising both in vivo and in vitro.

Tuning Local Atomic Structures in MoS2 Based Catalysts for Electrochemical Nitrate Reduction.

In recent years, there has been a substantial surge in the investigation of transition-metal dichalcogenides such as MoS2 as a promising electrochemical catalyst. Inspired by denitrification enzymes such as nitrate reductase and nitrite reductase, the electrochemical nitrate reduction catalyzed by MoS2 with varying local atomic structures is reported. It is demonstrated that the hydrothermally synthesized MoS2 containing sulfur vacancies behaves as promising catalysts for electrochemical denitrification. With copper doping at less than 9% atomic ratio, the selectivity of denitrification to dinitrogen in the products can be effectively improved. X-ray absorption characterizations suggest that two sulfur vacancies are associated with one copper dopant in the MoS2 skeleton. DFT calculation confirms that copper dopants replace three adjacent Mo atoms to form a trigonal defect-enriched region, introducing an exposed Mo reaction center that coordinates with Cu atom to increase N2 selectivity. Apart from the higher activity and selectivity, the Cu-doped MoS2 also demonstrates remarkably improved tolerance toward oxygen poisoning at high oxygen concentration. Finally, Cu-doped MoS2 based catalysts exhibit very low specific energy consumption during the electrochemical denitrification process, paving the way for potential scale-up operations.

Tackling Challenges of Long-Term Electrode Stability in Electrochemical Treatment of 1,4-Dioxane in Groundwater.

Electrochemical advanced oxidation is an appealing point-of-use groundwater treatment option for removing pollutants such as 1,4-dioxane, which is difficult to remove by using conventional separation-based techniques. This study addresses a critical challenge in employing electrochemical cells in practical groundwater treatment─electrode stability over long-term operation. This study aims to simulate realistic environmental scenarios by significantly extending the experimental time scale, testing a flow-through cell in addition to a batch reactor, and employing an electrolyte with a conductivity equivalent to that of groundwater. We first constructed a robust titanium suboxide nanotube mesh electrode that is utilized as both anode and cathode. We then implemented a pulsed electrolysis strategy in which reactive oxygen species are generated during the anodic cycle, and the electrode is regenerated during the cathodic cycle. Under optimized conditions, single-pass treatment through the cell (effective area: 2 cm2) achieved a remarkable 65-70% removal efficiency for 1,4-dioxane in the synthetic groundwater for over 100 h continuous operation at a low current density of 5 mA cm-2 and a water flux of 6 L m-2 h-1. The electrochemical cell and pulse treatment scheme developed in this study presents a critical advancement toward practical groundwater treatment technology.

Selective O2-to-H2O2 Electrosynthesis by a High-Performance, Single-Pass Electrofiltration System Using Ibuprofen-Laden CNT Membranes.

Producing H2O2 through a selective, two-electron (2e) oxygen reduction reaction (ORR) is challenging, especially when it serves as an advanced oxidation process (AOP) for cost-effective water decontamination. Herein, we attain a 2e-selectivity H2O2 production using a carbon nanotube electrified membrane with ibuprofen (IBU) molecules laden (IBU@CNT-EM) in an ultrafast, single-pass electrofiltration process. The IBU@CNT-EM can generate H2O2 at a rate of 25.62 mol gCNT-1 h-1 L-1 in the permeate with a residence time of 1.81 s. We demonstrated that an interwoven, hydrophilic-hydrophobic membrane nanostructure offers an excellent air-to-water transport platform for ORR acceleration. The electron transfer number of the ORR for IBU@CNT at neutral pH was confirmed as 2.71, elucidating a near-2e selectivity to H2O2. Density functional theory (DFT) studies validated an exceptional charge distribution of the IBU@CNT for the O2 adsorption. The adsorption energies of the O2 and *OOH intermediates are proportional to the H2O2 selectivity (64.39%), higher than that of the CNT (37.81%). With the simple and durable production of H2O2 by IBU@CNT-EM electrofiltration, the permeate can actuate Fenton oxidation to efficiently decompose emerging pollutants and inactivate bacteria. Our study introduces a new paradigm for developing high-performance H2O2-production membranes for water treatment by reusing environmental functional materials.

Effects of Ionic Interferents on Electrocatalytic Nitrate Reduction: Mechanistic Insight.

Nitrate, a prevalent water pollutant, poses substantial public health concerns and environmental risks. Electrochemical reduction of nitrate (eNO3RR) has emerged as an effective alternative to conventional biological treatments. While extensive lab work has focused on designing efficient electrocatalysts, implementation of eNO3RR in practical wastewater settings requires careful consideration of the effects of various constituents in real wastewater. In this critical review, we examine the interference of ionic species commonly encountered in electrocatalytic systems and universally present in wastewater, such as halogen ions, alkali metal cations, and other divalent/trivalent ions (Ca2+, Mg2+, HCO3-/CO32-, SO42-, and PO43-). Notably, we categorize and discuss the interfering mechanisms into four groups: (1) loss of active catalytic sites caused by competitive adsorption and precipitation, (2) electrostatic interactions in the electric double layer (EDL), including ion pairs and the shielding effect, (3) effects on the selectivity of N intermediates and final products (N2 or NH3), and (4) complications by the hydrogen evolution reaction (HER) and localized pH on the cathode surface. Finally, we summarize the competition among different mechanisms and propose future directions for a deeper mechanistic understanding of ionic impacts on eNO3RR.

Effect of Solitary Osteochondroma on Alignment and Length in the Lower Extremities.

BACKGROUND: There is a lack of information about the effects of untreated solitary osteochondroma (SO) on longitudinal growth of the lower extremities in children and adolescents. This study aimed to assess the coronal alignment and length of the lower extremity in patients with SO around the knee and to identify the factors related to the development of deformities. METHODS: We retrospectively reviewed 111 patients diagnosed with SO around the knee. The patients were classified into 2 groups depending on the location of the SO: 51 in the distal femur and 60 in the proximal tibia. Characteristics of the lesions, such as type, location, size, and distance from the joint line, were determined. Radiographic analysis of the lower limbs included mechanical lateral distal femoral angle, mechanical medial proximal tibial angle, whole-leg length, femoral length, and tibial length. RESULTS: The mean age at the time of diagnosis was 12.3±3.4 years. No statistically significant differences were found between the affected and contralateral sides for mechanical lateral distal femoral angle and mechanical medial proximal tibial angle in either the distal femur or the proximal tibia groups. In patients with femoral lesions, the femoral and whole-leg lengths were significantly shorter on the affected side than on the unaffected side ( P <0.001 and 0.002, respectively), and the mean differences were 2.1±3.6 and 2.1±4.4 mm, respectively. Univariate logistic regression analysis did not reveal any factors associated with limb length discrepancy (LLD). In patients with tibial lesions, no statistically significant differences were found in LLD. CONCLUSIONS: SOs around the knee did not cause clinically significant deformity of the lower extremity. However, in contrast to proximal tibia lesions, SO in the distal femur was associated with the shortening of the affected limb. Consideration should be given to the development of LLD in skeletally immature children with SO in the distal femur. LEVEL OF EVIDENCE: Level III-retrospective comparative study.

Exploration of Point-of-Care Ultrasonography for Silicone Breast Implant Rupture Detection and Classification.

Background and Objectives: The surge in breast-related surgeries in Korea underscores the critical need for an accurate early diagnosis of silicone breast implant-related issues. Complications such as BIA-ALCL and BIA-SCC add complexity to breast health concerns, necessitating vigilant monitoring. Despite advancements, discrepancies persist between ultrasonographic and pathologic classifications of silicone implant ruptures, highlighting a need for enhanced diagnostic tools. This study explores the reliability of ultrasonography in diagnosing silicone breast implant ruptures and determining the extent of silicone migration, specifically with a focus on guiding potential capsulectomy based on pathology. Materials and Methods: A comprehensive review of medical records encompassing 5557 breast implants across 2790 patients who underwent ultrasound-assisted examinations was conducted. Among the screened implants, 8.9% (249 cases) were diagnosed with silicone breast implant rupture through ultrasonography. Subsequently, 89 women underwent revisional surgery, involving capsulectomy. The pathological analysis of 111 periprosthetic capsules from these cases aimed to assess the extent of silicone migration, and the findings were juxtaposed with the existing ultrasonographic rupture classification. Results: The diagnostic agreement between preoperative sonography and postoperative findings reached 100% for silicone breast implant ruptures. All eighty prosthetic capsules exhibiting a snowstorm sign in ultrasonography demonstrated silicone migration to capsules upon pathologic findings. Conclusions: High-resolution ultrasonography emerged as a valuable and reliable imaging modality for diagnosing silicone breast implant ruptures, with a notable ability to ascertain the extent of free silicone migration to capsules. This diagnostic precision is pivotal in informing decisions about potential capsulectomy during revisional surgery. The study advocates for an update to the current binary ultrasonographic classification, suggesting a more nuanced categorization into three types (subcapsular, intracapsular, and extracapsular) based on pathology.

ATP-competitive partial antagonists of the IRE1α RNase segregate outputs of the UPR.

The unfolded protein response (UPR) homeostatically matches endoplasmic reticulum (ER) protein-folding capacity to cellular secretory needs. However, under high or chronic ER stress, the UPR triggers apoptosis. This cell fate dichotomy is promoted by differential activation of the ER transmembrane kinase/endoribonuclease (RNase) IRE1α. We previously found that the RNase of IRE1α can be either fully activated or inactivated by ATP-competitive kinase inhibitors. Here we developed kinase inhibitors, partial antagonists of IRE1α RNase (PAIRs), that partially antagonize the IRE1α RNase at full occupancy. Biochemical and structural studies show that PAIRs promote partial RNase antagonism by intermediately displacing the helix αC in the IRE1α kinase domain. In insulin-producing ß-cells, PAIRs permit adaptive splicing of Xbp1 mRNA while quelling destructive ER mRNA endonucleolytic decay and apoptosis. By preserving Xbp1 mRNA splicing, PAIRs allow B cells to differentiate into immunoglobulin-producing plasma cells. Thus, an intermediate RNase-inhibitory 'sweet spot', achieved by PAIR-bound IRE1α, captures a desirable conformation for drugging this master UPR sensor/effector.

Tailoring Thermoresponsive Polymer Architecture to Enhance Antifouling and Fouling Reversibility of Membranes.

Cleaning a fouled membrane using warm water, instead of commonly used fouling control chemicals, is an approach advocated in resource-limited settings, where small-scale membrane filtration is used to provide clean water. Thermoresponsive polymers coated onto membranes undergo a conformational change across their lower critical solution temperature (LCST), enabling foulant removal during such temperature-swing cleaning. However, their intrinsic hydrophobicity above the LCST poses a fundamental material challenge. In this study, we examine how thermoresponsive polymers can be optimally copolymerized with hydrophilic polymers by precisely manipulating monomer arrangement of thermoresponsive N-isopropylacrylamide and hydrophilic 2-[2-(2-methoxyethoxy)ethoxy]ethyl acrylate. We successfully grafted these copolymers with different monomer arrangements onto poly(ether sulfone) ultrafiltration membranes while maintaining other polymer characteristics, such as the degree of polymerization and grafting density, constant. We found that placing hydrophilic polymer blocks at the outermost surface above the thermoresponsive polymer blocks is critical to achieving high surface hydrophilicity while preserving the thermoresponsive functionality. We demonstrate enhanced fouling resistance and efficient temperature-swing cleaning with optimized copolymer design based on their interaction with bovine serum albumin during static adsorption, filtration, and cleaning processes. These findings emphasize the importance of accurately tailoring the polymer architecture to enable more efficient filtration with reduced fouling and the capability to effectively clean the fouled membrane by simply using warm water.

Peroxymonosulfate-Based Electrochemical Advanced Oxidation: Complication by Oxygen Reduction Reaction.

Peroxymonosulfate (PMS)-based electrochemical advanced oxidation processes (EAOPs) have received widespread attention in recent years, but the precise nature of PMS activation and its impact on the overall process performance remain poorly understood. This study presents the first demonstration of the critical role played by the oxygen reduction reaction in the effective utilization of PMS and the subsequent enhancement of overall pollutant remediation. We observed the concurrent generation of H2O2 via oxygen reduction during the cathodic PMS activation by a model nitrogen-doped carbon nanotube catalyst. A complex interplay between H2O2 generation and PMS activation, as well as a locally increased pH near the electrode due to the oxygen reduction reaction, resulted in a SO4•-/•OH-mixed oxidation environment that facilitated pollutant degradation. The findings of this study highlight a unique dependency between PMS-driven and H2O2-driven EAOPs and a new perspective on a previously unexplored route for further enhancing PMS-based treatment processes.

Pulsed Electrolysis of Boron-Doped Carbon Dramatically Improves Impurity Tolerance and Longevity of H2O2 Production.

Electrocatalytic water treatment has emerged in the limelight of scientific interest, yet its long-term viability remains largely in the dark. Herein, we present for the first time a comprehensive framework on how to optimize pulsed electrolysis to bolster catalyst impurity tolerance and overall longevity. By examining real wastewater constituents and assessing different catalyst designs, we deconvolute the complexities associated with key pulsing parameters to formulate optimal sequences that maximize operational lifetime. We showcase our approach for cathodic H2O2 electrosynthesis, selected for its widespread importance to wastewater treatment. Our results unveil superior performance for a boron-doped carbon catalyst over state-of-the-art oxidized carbon, with high selectivity (>75%) and near complete recoveries in overpotentials even in the presence of highly detrimental Ni2+ and Zn2+ impurities. We then adapt these fine-tuned settings, obtained under a three-electrode arrangement, for practical two-electrode operation using a novel strategy that conserves the desired electrochemical potentials at the catalytic interface. Even under various impurity concentrations, our pulses substantially improve long-term H2O2 production to 287 h and 35 times that attainable via conventional electrolysis. Our findings underscore the versatility of pulsed electrolysis necessary for developing more practical water treatment technologies.

Palladium Single-Atom (In)Stability Under Aqueous Reductive Conditions.

Here, we investigate the stability and performance of single-atom Pd on TiO2 for the selective dechlorination of 4-chlorophenol. A challenge inherent to single atoms is their high surface free energy, which results in a tendency for the surface migration and aggregation of metal atoms. This work evaluates various factors affecting the stability of Pd single-atoms, including atomic dispersion, coordination environment, and substrate properties, under reductive aqueous conditions. The transition from single atoms to clusters vastly enhanced dechlorination kinetics without diminishing carbon-chlorine bond selectivity. X-ray absorption spectroscopy analysis using both in situ and ex situ conditions followed the dynamic transformation of single atoms into amorphous clusters, which consist of a unique unsaturated coordination environment and few nanometer diameter. The intricate relationship between stability and performance underscores the vital role of detailed characterization to properly determine the true active species for dehalogenation reactions.

Plasmon-enabled degradation of organic micropollutants in water by visible-light illumination of Janus gold nanorods.

The development of sustainable methods for the degradation of pollutants in water is an ongoing critical challenge. Anthropogenic organic micropollutants such as pharmaceuticals, present in our water supplies in trace quantities, are currently not remediated by conventional treatment processes. Here, we report an initial demonstration of the oxidative degradation of organic micropollutants using specially designed nanoparticles and visible-wavelength sunlight. Gold "Janus" nanorods (Au JNRs), partially coated with silica to enhance their colloidal stability in aqueous solutions while also maintaining a partially uncoated Au surface to facilitate photocatalysis, were synthesized. Au JNRs were dispersed in an aqueous solution containing peroxydisulfate (PDS), where oxidative degradation of both simulant and actual organic micropollutants was observed. Photothermal heating, light-induced hot electron-driven charge transfer, and direct electron shuttling under dark conditions all contribute to the observed oxidation chemistry. This work not only provides an ideal platform for studying plasmonic photochemistry in aqueous medium but also opens the door for nanoengineered, solar-based methods to remediate recalcitrant micropollutants in water supplies.

Spatially separating redox centers on 2D carbon nitride with cobalt single atom for photocatalytic H2O2 production.

Redox cocatalysts play crucial roles in photosynthetic reactions, yet simultaneous loading of oxidative and reductive cocatalysts often leads to enhanced charge recombination that is detrimental to photosynthesis. This study introduces an approach to simultaneously load two redox cocatalysts, atomically dispersed cobalt for improving oxidation activity and anthraquinone for improving reduction selectivity, onto graphitic carbon nitride (C3N4) nanosheets for photocatalytic H2O2 production. Spatial separation of oxidative and reductive cocatalysts was achieved on a two-dimensional (2D) photocatalyst, by coordinating cobalt single atom above the void center of C3N4 and anchoring anthraquinone at the edges of C3N4 nanosheets. Such spatial separation, experimentally confirmed and computationally simulated, was found to be critical for enhancing surface charge separation and achieving efficient H2O2 production. This center/edge strategy for spatial separation of cocatalysts may be applied on other 2D photocatalysts that are increasingly studied in photosynthetic reactions.

Use of High-Resolution Ultrasound in Characterizing the Surface Topography of a Breast Implant.

Background and Objectives: With the emergence of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL), it has become necessary to identify the implant shell type patients have received. Therefore, an immediate, reliable method for identifying a breast implant shell type is essential. Evidence-based research and applying a real-world technique that identifies the surface topographic information of the inserted breast implants, without surgery, has become of paramount importance for breast implant physicians. Methods and Materials: A review of the medical records of 1901 patients who received 3802 breast implants and subsequently received an ultrasound-assisted examination was performed. All patients received not only a breast cancer examination but also a high-resolution ultrasonography (HRUS) assisted examination of the device at a single center between 31 August 2017 and 31 December 2022. Results: Most patients had breast implants within 10 years (77.7%) of the examination. Of the 3802 implants screened, 2034 (53.5%) were identified with macro-textured shell topography in ultrasonography. A macrotextured shell type implant was used in 53.5% of cases and a smooth type in 42.7% of cases. Seventy-three (1.9%) breast implant shell types could not be identified due to ruptures. However, 250 breast implant shell types could be identified despite rupture cases (6.5%). Conclusions: HRUS was found to be a useful and reliable image modality for identifying various surface shell types of breast implants. The shell type information would be helpful to patients who lack information about their breast implants and are concerned about BIA-ALCL.

Astrocyte-derived adenosine excites sleep-promoting neurons in the ventrolateral preoptic nucleus: Astrocyte-neuron interactions in the regulation of sleep.

Although ATP and/or adenosine derived from astrocytes are known to regulate sleep, the precise mechanisms underlying the somnogenic effects of ATP and adenosine remain unclear. We selectively expressed channelrhodopsin-2 (ChR2), a light-sensitive ion channel, in astrocytes within the ventrolateral preoptic nucleus (VLPO), which is an essential brain nucleus involved in sleep promotion. We then examined the effects of photostimulation of astrocytic ChR2 on neuronal excitability using whole-cell patch-clamp recordings in two functionally distinct types of VLPO neurons: sleep-promoting GABAergic projection neurons and non-sleep-promoting local GABAergic neurons. Optogenetic stimulation of VLPO astrocytes demonstrated opposite outcomes in the two types of VLPO neurons. It led to the inhibition of non-sleep-promoting neurons and excitation of sleep-promoting neurons. These responses were attenuated by blocking of either adenosine A1 receptors or tissue-nonspecific alkaline phosphatase (TNAP). In contrast, exogenous adenosine decreased the excitability of both VLPO neuron populations. Moreover, TNAP was expressed in galanin-negative VLPO neurons, but not in galanin-positive sleep-promoting projection neurons. Taken together, these results suggest that astrocyte-derived ATP is converted into adenosine by TNAP in non-sleep-promoting neurons. In turn, adenosine decreases the excitability of local GABAergic neurons, thereby increasing the excitability of sleep-promoting GABAergic projection neurons. We propose a novel mechanism involving astrocyte-neuron interactions in sleep regulation, wherein endogenous adenosine derived from astrocytes excites sleep-promoting VLPO neurons, and thus decreases neuronal excitability in arousal-related areas of the brain.

In vivo detection of hydrogen sulfide in the brain of live mouse: application in neuroinflammation models.

PURPOSE: Hydrogen sulfide (H2S) plays important roles in brain pathophysiology. However, nuclear imaging probes for the in vivo detection of brain H2S in living animals have not been developed. Here, we report the first nuclear imaging probe that enables in vivo imaging of endogenous H2S in the brain of live mice. METHODS: Utilizing a bis(thiosemicarbazone) backbone, a fluorescent ATSM-FITC conjugate was synthesized. Its copper complex, Cu(ATSM-FITC) was thoroughly tested as a biosensor for H2S. The same ATSM-FITC ligand was quantitatively labeled with [64Cu]CuCl2 to obtain a radioactive [64Cu][Cu(ATSM-FITC)] imaging probe. Biodistribution and positron emission tomography (PET) imaging studies were performed in healthy mice and neuroinflammation models. RESULTS: The Cu(ATSM-FITC) complex reacts instantly with H2S to release CuS and becomes fluorescent. It showed excellent reactivity, sensitivity, and selectivity to H2S. Endogenous H2S levels in living cells were successfully detected by fluorescence microscopy. Exceptionally high brain uptake of [64Cu][Cu(ATSM-FITC)] (> 9% ID/g) was observed in biodistribution and PET imaging studies. Subtle changes in brain H2S concentrations in live mice were accurately detected by quantitative PET imaging. Due to its dual modality feature, increased H2S levels in neuroinflammation models were characterized at the subcellular level by fluorescence imaging and at the whole-body scale by PET imaging. CONCLUSION: Our biosensor can be readily utilized to study brain H2S function in live animal models and shows great potential as a novel imaging agent for diagnosing brain diseases.