The H/F substitution strategy can achieve large spontaneous polarization in 1D hybrid perovskite ferroelectrics.

Hybrid organic-inorganic perovskite (HOIP) ferroelectrics exhibit polarization reversibility and have a wide range of applications in the fields of smart switches, memorizers, sensors, etc. However, the inherent limitations of small spontaneous polarization (P s) and large coercive field (E c) in ferroelectrics have impeded their broader utilization in electronics and data storage. Molecular ferroelectrics, as a powerful supplement to inorganic ferroelectrics, have shown great potential in the new generation of flexible wearable electronic devices. The important research responsibility is to greatly improve progressiveness and overcome the above limitations. Here, a novel one-dimensional (1D) HOIP ferroelectric, (3-F-BTAB)PbBr3 (3-F-BTAB = 3-fluorobenzyltrimethylammonium), was successfully synthesized by employing the H/F substitution strategy to modify parent compound (BTAB)PbBr3 (BTAB = benzyltrimethylammonium), which undergoes a ferroelectric phase transition with Aizu notation 2/mF2 at 420 K. Notably, (3-F-BTAB)PbBr3 demonstrates exceptional ferroelectric properties with a large P s of 7.18 µC cm-2 and a low E c of 1.78 kV cm-1. As far as we know, (3-F-BTAB)PbBr3 features the largest P s among those reported for 1D lead-based HOIP ferroelectrics. This work enriches the 1D lead-based ferroelectric family and provides guidance for applying ferroelectrics in low-voltage polar memories.

The phosphatase inhibitor BVT-948 can be used to efficiently screen functional sexual development proteins in the malaria parasite Plasmodium berghei.

BACKGROUND: Studying and discovering the molecular mechanism of Plasmodium sexual development is crucial for the development of transmission blocking drugs and malaria eradication. The aim of this study was to investigate the feasibility of using phosphatase inhibitors as a tool for screening proteins essential for Plasmodium sexual development and to discover proteins affecting the sexual development of malaria parasites. METHODS: Differences in protein phosphorylation among Plasmodium gametocytes incubated with BVT-948 under in vitro ookinete culture conditions were evaluated using phosphoproteomic methods. Gene Ontology (GO) analysis was performed to predict the mechanism by which BVT-948 affected gametocyte-ookinete conversion. The functions of 8 putative proteins involved in Plasmodium berghei sexual development were evaluated. Bioinformatic analysis was used to evaluate the possible mechanism of PBANKA_0100800 in gametogenesis and subsequent sexual development. RESULTS: The phosphorylation levels of 265 proteins decreased while those of 67 increased after treatment with BVT-948. Seven of the 8 genes selected for phenotype screening play roles in P. berghei sexual development, and 4 of these were associated with gametocytogenesis. PBANKA_0100800 plays essential roles in gametocyte-ookinete conversion and transmission to mosquitoes. CONCLUSIONS: Seven proteins identified by screening affect P. berghei sexual development, suggesting that phosphatase inhibitors can be used for functional protein screening.

Boosting Cancer Immunotherapy via Reversing PD-L1-Mediated Immunosuppression with a Molecularly Imprinted Lysosomal Nanodegrader.

Immune checkpoint blockade therapy has achieved important clinical advances in several types of tumors, particularly via targeting the PD-1/PD-L1 axis. However, existing therapeutic strategies that suppress the PD-1/PD-L1 signal pathway usually experience low treatment efficacy and the risk of causing autoimmune diseases. Herein, we report a cancer cell-targeted molecularly imprinted lysosomal nanodegrader (MILND) for boosting immune checkpoint blockade therapy against tumors. The MILND, imprinted with the N-terminal epitope of PD-L1 as an imprinting template, could specifically target the PD-L1 on tumor cells to promote cellular uptake. This process further induces the transport of PD-L1 into lysosomes for degradation, ultimately resulting in the downregulation of PD-L1 expression levels on tumor cells. As a result, a T cell-mediated immune response in the body was activated via the blockade of the PD-1/PD-L1 signaling pathway, which triggered a durable antitumor efficacy. In vivo experiments demonstrated that the MILND could effectively accumulate in tumor sites and exhibit strong tumor growth suppression efficacy in a xenograft tumor model without obvious side effects. Therefore, the MILND provides not only a promising strategy for boosting cancer immunotherapy but also insights for developing molecular imprinting-empowered nanomedicines.

Exploring Aqueous Solution-Processed Pseudohalide Rare-Earth Double Perovskite Ferroelectrics toward X-ray Detection with High Sensitivity.

Three-dimensional (3D) pseudohalide rare-earth double perovskites (PREDPs) have garnered significant attention for their versatile physical properties, including ferroelectricity, ferroelasticity, large piezoelectric responses, and circularly polarized luminescence. However, their potential for X-ray detection remains unexplored, and the low Curie temperature (TC) limits the performance window for PREDP ferroelectrics. Here, by applying the chemical regulation strategies involving halogen substitution on the organic cation and Rb/Cs substitution to the PREDP [(R)-M3HQ]2RbEu(NO3)6 [(R)-M3HQ = (R)-N-methyl-3-hydroxylquinuclidinium] with a low TC of 285 K, a novel 3D PREDP ferroelectric [(R)-CM3HQ]2CsEu(NO3)6 [(R)-CM3HQ = (R)-N-chloromethyl-3-hydroxylquinuclidinium] are successfully synthesized, for which the TC reaches 344 K. More importantly, such a strategy endowed [(R)-CM3HQ]2CsEu(NO3)6 with notable X-ray detection capabilities. Centimeter-sized [(R)-CM3HQ]2CsEu(NO3)6 single crystals fabricated from aqueous solutions demonstrated a sensitivity of 1307 µC Gyair-1 cm-2 and a low detectable dose rate of 152 nGyair s-1, the highest sensitivity reported for hybrid double perovskite ferroelectric detectors. This work positions PREDPs as promising candidates for the next generation of eco-friendly optoelectronic materials and also offers substantial insights into the interaction between structure, composition, and functionality in ferroelectric materials.

Stereo-Active Lone Pairs Induced Second Harmonic Generation Responses and Electrocatalytic Activity in Hybrid Material.

The lone pair electrons in the electronic structure of molecules have been a prominent research focus in chemistry for more than a century. Stable s2 lone pair electrons significantly influence material properties, including thermoelectric properties, nonlinear optical properties, ferroelectricity, and electro(photo)catalysis. While major advances have been achieved in understanding the influence of lone pair electrons on material characteristics, research on this effect in organic-inorganic hybrid materials is in its initial stage. In this work, we successfully obtained a novel organic-inorganic hybrid multifunctional material incorporating Ge with 4s2 lone pair electrons, (MeHDabco)2[GeBr3]4-H2O (MeHDabco=N-methyl-1,4-diazabicyclo[2.2.2]octane) (1). Driven by the stereochemically active lone pair electrons on the Ge2+, 1 crystallizes in the noncentrosymmetric space group P21 at room temperature and exhibits good second harmonic generation (SHG) responses. Interestingly, 1 also shows electrocatalytic activity for the hydrogen evolution reaction (HER) due to the existence of lone pair electrons on Ge2+ cations. The electrochemical experiment combined with the density functional theory (DFT) calculations revealed that the lone pair electrons act as both an active site for proton adsorption and facilitate the ionization of water. This work not only emphasizes the important role of lone pair electrons in material properties and functions but also provides new insight for designing novel Ge-based multifunctional hybrid materials.

Microbiota-gut-liver-brain axis and hepatic encephalopathy.

Hepatic encephalopathy (HE) is a clinical manifestation of neurological and psychiatric abnormalities that are caused by complications of liver dysfunction including hyperammonemia, hyperuricemia, and portal hypertension. Accumulating evidence suggests that HE could be reversed through therapeutic modifications of gut microbiota. Multiple preclinical and clinical studies have indicated that gut microbiome affects the physiological function of the liver, such as the regulation of metabolism, secretion, and immunity, through the gut-liver crosstalk. In addition, gut microbiota also influences the brain through the gut-brain crosstalk, altering its physiological functions including the regulation of the immune, neuroendocrine, and vagal pathways. Thus, key molecules that are involved in the microbiota-gut-liver-brain axis might be able to serve as clinical biomarkers for early diagnosis of HE, and could be effective therapeutic targets for clinical interventions. In this review, we summarize the pathophysiology of HE and further propose approaches modulating the microbiota-gut-liver-brain axis in order to provide a comprehensive understanding of the prevention and potential clinical treatment for HE with a microbiota-targeted therapy.

Catalytic NIR chemiluminescence sensor with enhanced persistence and intensity for in vivo imaging.

Chemiluminescence (CL) is a self-illumination phenomenon that involves the emission of light from chemical reactions, and it provides favorable spatial and temporal information on biological processes. However, it is still a great challenge to construct effective CL sensors that equip strong CL intensity, long emission wavelength, and persistent luminescence for deep tissue imaging. Here, we report a liposome encapsulated polymer dots (Pdots)-based system using catalytic CL substrates (L-012) as energy donor and fluorescent polymers and dyes (NIR 695) as energy acceptors for efficient Near-infrared (NIR) CL in vivo imaging. Thanks to the modulation of paired donor and acceptor distance and the slow diffusion of biomarker by liposome, the Pdots show a NIR emission wavelength (λ em, max = 720 nm), long CL duration (>24 h), and a high chemiluminescence resonance energy transfer efficiency (46.5 %). Furthermore, the liposome encapsulated Pdots possess excellent biocompatibility, sensitive response to H2O2, and persistent whole-body NIR CL imaging in the drug-induced inflammation and the peritoneal metastatic tumor mouse model. In a word, this NIR-II CL nanoplatform with long-lasting emission and high spatial-temporal resolution will be a concise strategy in deep tissue imaging and clinical diagnostics.

[Characteristics and Source Apportionment of VOCs Initial Mixing Ratio in Beijing During Summer].

To clarify the characteristics and source apportionment of the VOCs initial mixing ratio in Beijing in summer, continuous monitoring of VOCs was conducted in the Beijing urban area from May to August 2022, and the initial mixing ratio was calculated using the photochemical ratio method. The results showed that:① during the study period, initial φ(TVOCs) in the Beijing urban area were (30.0 ±11.5)×10-9, in which the proportion of VOCs and alkanes containing oxygen reached 34.2% and 33.2%, respectively. The species with high volume fractions were low carbon substances such as acetone, ethane, acetaldehyde, and propane. ② The initial TVOCs mixing ratio in Beijing showed a slightly unimodal trend, reaching the peak at 11:00 and slightly decreasing in the afternoon. ③ Isoprene, acetaldehyde, n-butanal, and ethylene were the major contributors to the generation of O3, whereas toluene, isoprene, m-paraxylene, and ethylbenzene were the major contributors to the generation of secondary organic aerosols. ④ Based on the initial mixing ratio of PMF analysis, it was found that aging background and secondary sources (30%) contributed the most to VOCs in Beijing, and motor vehicle sources (25%) were the main primary human sources. In addition, solvent and fuel volatile sources contributed 16%, combustion sources contributed 11%, industrial process sources contributed 9%, and natural sources contributed 9%. ⑤ The anthropogenic sources of Beijing were mainly from the eastern and southern regions, whereas the natural sources were from the western and northwestern regions. This research showed that vehicle emissions should be further reduced, and regional joint prevention and control to reduce VOCs in the whole region is an effective means to control VOCs in Beijing.

Organic-Inorganic Rare-Earth Double Perovskite Ferroelectric with Large Piezoelectric Response and Ferroelasticity for Flexible Composite Energy Harvesters.

Hybrid organic-inorganic perovskite (HOIP) ferroelectric materials have great potential for developing self-powered electronic transducers owing to their impressive piezoelectric performance, structural tunability and low processing temperatures. Nevertheless, their inherent brittle and low elastic moduli limit their application in electromechanical conversion. Integration of HOIP ferroelectrics and soft polymers is a promising solution. In this work, a hybrid organic-inorganic rare-earth double perovskite ferroelectric, [RM3HQ]2RbPr(NO3)6 (RM3HQ = (R)-N-methyl-3-hydroxylquinuclidinium) is presented, which possesses multiaxial nature, ferroelasticity and satisfactory piezoelectric properties, including piezoelectric charge coefficient (d33) of 102.3 pC N-1 and piezoelectric voltage coefficient (g33) of 680 × 10-3 V m N-1. The piezoelectric generators (PEG) based on composite films of [RM3HQ]2RbPr(NO3)6@polyurethane (PU) can generate an open-circuit voltage (Voc) of 30 V and short-circuit current (Isc) of 18 µA, representing one of the state-of-the-art PEGs to date. This work has promoted the exploration of new HOIP ferroelectrics and their development of applications in electromechanical conversion devices.

Molecularly Imprinted Nanomedicine for Anti-angiogenic Cancer Therapy via Blocking Vascular Endothelial Growth Factor Signaling.

The VEGF-VEGFR2 (VEGF = vascular endothelial growth factor) signaling has been a promising target in cancer therapy. However, because conventional anti-angiogenic therapeutics suffer from drawbacks, particularly severe side effects, novel anti-angiogenic strategies are much needed. Herein, we report the rational engineering of VEGF-targeted molecularly imprinted polymer nanoparticles (nanoMIP) for anti-angiogenic cancer therapy. The anti-VEGF nanomedicine was prepared via a state-of-the-art molecular imprinting approach using the N-terminal epitope of VEGF as the template. The nanoMIP could target the two major pro-angiogenic isoforms (VEGF165 and VEGF121) with high affinity and thereby effectively block the VEGF-VEGFR2 signaling, yielding a potent anti-angiogenic effect of "killing two birds with one stone". In vivo experiments demonstrated that the anti-VEGF nanoMIP effectively suppressed tumor growth via anti-angiogenesis in a xenograft model of human colon carcinoma without apparent side effects. Thus, this study not only proposes an unprecedented anti-angiogenic strategy for cancer therapy but also provides a new paradigm for the rational development of MIPs-based "drug-free" nanomedicines.

Introducing Ferroelasticity into 1D Hybrid Lead Halide Semiconductor by Halogen Substitution Strategy.

Organic-inorganic hybrid lead halide perovskites (OLHPs), represented by (CH3 NH3 )PbI3 , are one of the research focus due to their exceptional performance in optoelectronic applications, and ferroelastic domain walls are benign to their charge carrier transport that is confirmed recently. Among them, the 1D OLHPs feature better stability against desorption and moisture, but related 1D ones possessing ferroelasticity are rarely investigated and reported so far. In this work, the 1D ferroelastic semiconductor (N-iodomethyl-N-methyl-morpholinium)PbI3 ((IDMML)PbI3 ) is prepared successfully by introducing successively halogenate atoms from Cl, Br to I into the organic cation of the prototype (N,N-dimethylmorpholinium)PbI3 ((DMML)PbI3 ). Notably, (IDMML)PbI3 shows the narrow bandgap energy (≈2.34 eV) according to the ultraviolet-visible absorption spectrum and the theoretical calculation, and possesses the evident photoconductive characteristic with the on/off ratio of current of ≈50 under the 405 nm light irradiation. This work provides a new case for the ferroelastic OLHPs and will inspire intriguing research in the field of optoelectronic.

ROS-Responsive Fluorescent Sensor Array for Precise Diagnosis of Cancer via pH-Controlled Multicolor Gold Nanoclusters.

Intracellular reactive oxygen species (ROS) are closely associated with cancer cell types. Therefore, ROS-based pattern recognition is a promising strategy for precise diagnosis of cancer, but such a possibility has never been reported yet. Herein, we proposed an ROS-responsive fluorescent sensor array based on pH-controlled histidine-templated gold nanoclusters (AuNCs@His) to distinguish cancer cell types and their proliferation states. In this strategy, three types of AuNCs@His with diverse fluorescence profiles were first synthesized by only adjusting the pH value. Upon the addition of various ROS, fluorescence quenching of three types of AuNCs@His occurred with different degrees, thereby forming unique optical "fingerprints", which were well-clustered into several separated groups without overlap by principal component analysis (PCA). The sensing mechanism was attributable to the oxidation of AuNCs@His by ROS, as revealed by X-ray photoemission spectroscopy, Fourier transform infrared spectroscopy, 1H nuclear magnetic resonance spectroscopy, and electrospray ionization mass spectrometry. Based on the ROS-responsive sensing pattern, cancer cell types were successfully differentiated via PCA with 100% accuracy. Additionally, the proposed sensor array exhibited excellent performance in distinguishing the proliferation states of cancer cells, which was supported by the results of the Ki-67 immunohistochemistry assay. Overall, the ROS-responsive fluorescent sensor array can serve as a promising tool for precise diagnosis of cancer, indicating great potential for clinical application.

Methyl regulation triggers high-temperature ferroelastic phase transition.

The multifunctional tuning of solid-state dielectric switches constructed from organic-inorganic hybrid materials (OIHMs) has received great attention. In particular, molecular ferroelastics with dielectric phase transitions have considerable potential in the optical and electrical fields owing to their adjustable structures and physical features. However, it remains a challenge to effectively design ferroelastics with high phase transition temperature (Tc). We used [TTMA]2CdI4 (TTMA = tetramethylammonium, 1) as a template to continuously increase the molecular weight and change the structure of the hybrid material by modifying and extending the alkane chain in the cation. Therefore, a series of OIHMs were eventually developed: [TMEA]2CdI4 (TMEA = trimethylethylammonium, 2), [TMPA]2CdI4 (TMPA = trimethylpropylammonium, 3), and [TMIPA]2CdI4 (TMIPA = trimethyliso-propylammonium, 4). Among them, the Tc of ferroelastic 3 increased up to 387 K. DSC and temperature-related dielectric constant tests prove the occurrence of the phase transition for 1, 2, and 3. The structures further indicate that the phase transition is caused by the order-disorder cation motion. The extension of the alkyl chain greatly increases Tc and endows 3 with ferroelasticity at room temperature.

Leveraging Macrophage-Mediated Cancer Immunotherapy via a Cascading Effect Induced by a Molecularly Imprinted Nanocoordinator.

Reprogramming tumor-associated macrophages (TAMs) has emerged as a promising strategy in cancer immunotherapy. Targeted therapeutics integrating multiple functions to fully leverage the antitumor immune functions of macrophages without affecting systemic or tissue-resident macrophages are crucial for TAM reprogramming. Herein, by integrating molecular imprinting and nanotechnology, we rationally designed and engineered an unprecedented nanocoordinator for targeted remolding of TAMs to fully leverage the antitumor efficacy of macrophages by inducing a cascade effect. The nanocoordinator features a magnetic iron oxide nanoinner core and sialic acid-imprinted shell. Intravenously administered into systemic circulation, the nanocoordinator can rapidly accumulate at the tumor site in response to an external magnet. Then, by specifically binding to sialic acid overexpressed on tumor cells, the nanocoordinator anchors at the tumor site with prolonged retention time. Via binding with the nanocoordinator, tumor cells are tagged with a foreign substance, which promotes the intrinsic phagocytosis of macrophages. Subsequently, the nanocoordinator taken up by macrophages effectively promotes the polarization of macrophages toward the M1 phenotype, thus activating the immunotherapeutic efficacy of macrophages. Synergized by the cascade effect, this nanocoordinator effectively harnesses TAMs for macrophage-mediated immunotherapy. This study offers new TAM-targeted therapeutics that allows us to fully leverage the antitumor immune functions of macrophages without affecting the normal tissue.

Alterations in the intestinal microbiome and metabolic profile of patients with cirrhosis supplemented with lactulose, Clostridium butyricum, and Bifidobacterium longum infantis: a randomized placebo-controlled trial.

Background: Liver cirrhosis is commonly accompanied by intestinal dysbiosis and metabolic defects. Many clinical trials have shown microbiota-targeting strategies represent promising interventions for managing cirrhosis and its complications. However, the influences of the intestinal metagenomes and metabolic profiles of patients have not been fully elucidated. Methods: We administered lactulose, Clostridium butyricum, and Bifidobacterium longum infantis as a synbiotic and used shotgun metagenomics and non-targeted metabolomics to characterize the results. Results: Patients treated with the synbiotic for 12 weeks had lower dysbiosis index (DI) scores than placebo-treated patients and patients at baseline (NIP group). We identified 48 bacterial taxa enriched in the various groups, 66 differentially expressed genes, 18 differentially expressed virulence factor genes, 10 differentially expressed carbohydrate-active enzyme genes, and 173 metabolites present at differing concentrations in the Synbiotic versus Placebo group, and the Synbiotic versus NIP group. And Bifidobacteria species, especially B. longum, showed positive associations with many differentially expressed genes in synbiotic-treated patients. Metabolites pathway enrichment analysis showed that synbiotic significantly affected purine metabolism and aminoacyl-tRNA biosynthesis. And the purine metabolism and aminoacyl-tRNA biosynthesis were no longer significant differences in the Synbiotic group versus the healthy controls group. In conclusion, although littles influence on clinical parameters in the early intervention, the synbiotic showed a potential benefit to patients by ameliorating intestinal dysbiosis and metabolic defects; and the DI of intestinal microbiota is useful for the evaluation of the effect of clinical microbiota-targeting strategies on cirrhotic patients. Clinical Trial Registration: https://www.clinicaltrials.gov, identifiers NCT05687409.

Oral Fungal Alterations in Patients with COVID-19 and Recovered Patients.

The oral bacteriome, gut bacteriome, and gut mycobiome are associated with coronavirus disease 2019 (COVID-19). However, the oral fungal microbiota in COVID-19 remains unclear. This article aims to characterize the oral mycobiome in COVID-19 and recovered patients. Tongue coating specimens of 71 COVID-19 patients, 36 suspected cases (SCs), 22 recovered COVID-19 patients, 36 SCs who recovered, and 132 controls from Henan are collected and analyzed using internal transcribed spacer sequencing. The richness of oral fungi is increased in COVID-19 versus controls, and beta diversity analysis reveals separate fungal communities for COVID-19 and control. The ratio of Ascomycota and Basidiomycota is higher in COVID-19, and the opportunistic pathogens, including the genera Candida, Saccharomyces, and Simplicillium, are increased in COVID-19. The classifier based on two fungal biomarkers is constructed and can distinguish COVID-19 patients from controls in the training, testing, and independent cohorts. Importantly, the classifier successfully diagnoses SCs with positive specific severe acute respiratory syndrome coronavirus 2 immunoglobulin G antibodies as COVID-19 patients. The correlation between distinct fungi and bacteria in COVID-19 and control groups is depicted. These data suggest that the oral mycobiome may play a role in COVID-19.

EPIC: Emotion Perception by Spatio-Temporal Interaction Context of Gait.

Recently, psychophysiological computing has received considerable attention. Due to easy acquisition at a distance and less conscious initiation, gait-based emotion recognition is considered as a valuable research branch in the field of psychophysiological computing. However, most existing methods rarely explore the spatio-temporal context of gait, which limits the ability to capture the higher-order relationship between emotion and gait. In this paper, we utilize a range of research, including psychophysiological computing and artificial intelligence, to propose an integrated emotion perception framework called EPIC, which can find novel joint topology and generate thousands of synthetic gaits by spatio-temporal interaction context. First, we analyze the joint coupling among non-adjacent joints by calculating Phase Lag Index (PLI), which can discover the latent connection among body joints. Second, to synthesize more sophisticated and accurate gait sequences, we explore the effect of spatio-temporal constraints, and propose a new loss function that utilizes the Dynamic Time Warping (DTW) algorithm and pseudo-velocity curve to constrain the output of Gated Recurrent Units (GRU). Finally, Spatial Temporal Graph Convolution Networks (ST-GCN) is used to classify emotions using the generation and the real data. Experimental results demonstrate our approach achieves the accuracy of 89.66%, and outperforms the state-of-the-art methods on Emotion-Gait dataset.

Synaptotagmin-3 interactions with GluA2 mediate brain damage and impair functional recovery in stroke.

Synaptotagmin III (Syt3) is a Ca2+-dependent membrane-traffic protein that is highly concentrated in synaptic plasma membranes and affects synaptic plasticity by regulating post-synaptic receptor endocytosis. Here, we show that Syt3 is upregulated in the penumbra after ischemia/reperfusion (I/R) injury. Knockdown of Syt3 protects against I/R injury, promotes recovery of motor function, and inhibits cognitive decline. Overexpression of Syt3 exerts the opposite effects. Mechanistically, I/R injury augments Syt3-GluA2 interactions, decreases GluA2 surface expression, and promotes the formation of Ca2+-permeable AMPA receptors (CP-AMPARs). Using a CP-AMPAR antagonist or dissociating the Syt3-GluA2 complex via TAT-GluA2-3Y peptide promotes recovery from neurological impairments and improves cognitive function. Furthermore, Syt3 knockout mice are resistant to cerebral ischemia because they show high-level expression of surface GluA2 and low-level expression of CP-AMPARs after I/R. Our results indicate that Syt3-GluA2 interactions, which regulate the formation of CP-AMPARs, may be a therapeutic target for ischemic insults.

Daridorexant for the treatment of insomnia disorder: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Daridorexant is a novel dual orexin receptor antagonist that has shown efficacy as a treatment for insomnia in multiple randomized clinical trials. However, the efficacy and safety of daridorexant for treatment of insomnia disorder has not been characterized comprehensively in the literature. Therefore, we performed a meta-analysis of available studies. We performed a meta-analysis to systematically evaluate the efficacy and safety of daridorexant for treatment of insomnia disorder. METHODS: MEDLINE, Embase, Cochrane Library, and Clinicaltrials.gov for randomized controlled trials were systematically searched up to February 2022. Relative risk and standard mean difference were used to evaluate clinical outcomes. RESULTS: We pooled 2271 patients from 4 randomized clinical trials, and evaluated efficacy endpoints. We found that 50 mg of daridorexant was superior to placebo for 4 efficacy outcomes including wake time after sleep onset, latency to persistent sleep, subjective total sleep time, and Insomnia Daytime Symptoms and Impacts Questionnaire domain score (P < .05). In addition, there were no significant differences (P > .05) in adverse events between daridorexant and placebo. CONCLUSIONS: Different dosages of daridorexant were tested for treatment of insomnia; however, 5 and 10 mg are not available because of issues of suboptimal effectiveness. Daridorexant showed better efficacy and safety for treatment of insomnia disorder at doses of 25 and 50 mg.

GluA1 Degradation by Autophagy Contributes to Circadian Rhythm Effects on Cerebral Ischemia Injury.

The mechanisms of many diseases, including central nervous system disorders, are regulated by circadian rhythms. The development of brain disorders such as depression, autism, and stroke is strongly associated with circadian cycles. Previous studies have shown that cerebral infarct volume is smaller at night (active phase) than during the day (inactive phase) in ischemic stroke rodent models. However, the underlying mechanisms remain unclear. Increasing evidence suggests that glutamate systems and autophagy play important roles in the pathogenesis of stroke. Here, we report that GluA1 expression was decreased and autophagic activity was increased in active-phase male mouse models of stroke compared with the inactive-phase models. In the active-phase model, induction of autophagy decreased the infarct volume, whereas inhibition of autophagy increased the infarct volume. Meanwhile, GluA1 expression was decreased following activation of autophagy and increased following inhibition of autophagy. We used Tat-GluA1 to uncouple p62, an autophagic adapter, from GluA1 and found that this blocked the degradation of GluA1, an effect similar to that of inhibition of autophagy in the active-phase model. We also demonstrated that knock-out of the circadian rhythm gene Per1 abolished the circadian rhythmicity of the volume of infarction and also abolished GluA1 expression and autophagic activity in wild-type (WT) mice. Our results suggest an underlying mechanism by which the circadian rhythm participates in the autophagy-dependent regulation of GluA1 expression, which influences the volume of infarction in stroke.SIGNIFICANCE STATEMENT Circadian rhythms affect the pathophysiological mechanisms of disease. Previous studies suggested that circadian rhythms affect the infarct volume in stroke, but the underlying mechanisms remain largely unknown. Here, we demonstrate that the smaller infarct volume after middle cerebral artery occlusion/reperfusion (MCAO/R) during the active phase is related to lower GluA1 expression and activation of autophagy. The decrease in GluA1 expression during the active phase is mediated by the p62-GluA1 interaction, followed by direct autophagic degradation. In short, GluA1 is the substrate of autophagic degradation, which mainly occurs after MCAO/R during the active phase but not the inactive phase.