Inverted perovskite solar cells using dimethylacridine-based dopants.

Doping of perovskite semiconductors1 and passivation of their grain boundaries2 remain challenging but essential for advancing high-efficiency perovskite solar cells. Particularly, it is crucial to build perovskite/indium tin oxide (ITO) Schottky contact based inverted devices without predepositing a layer of hole-transport material3-5. Here we report a dimethylacridine-based molecular doping process used to construct a well-matched p-perovskite/ITO contact, along with all-round passivation of grain boundaries, achieving a certified power conversion efficiency (PCE) of 25.39%. The molecules are shown to be extruded from the precursor solution to the grain boundaries and the bottom of the film surface in the chlorobenzene-quenched crystallization process, which we call a molecule-extrusion process. The core coordination complex between the deprotonated phosphonic acid group of the molecule and lead polyiodide of perovskite is responsible for both mechanical absorption and electronic charge transfer, and leads to p-type doping of the perovskite film. We created an efficient device with a PCE of 25.86% (reverse scan) and that maintained 96.6% of initial PCE after 1,000 h of light soaking.

UBQLN2 and HSP70 participate in Parkin-mediated mitophagy by facilitating outer mitochondrial membrane rupture.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two aging-related neurodegenerative diseases that share common key features, including aggregation of pathogenic proteins, dysfunction of mitochondria, and impairment of autophagy. Mutations in ubiquilin 2 (UBQLN2), a shuttle protein in the ubiquitin-proteasome system (UPS), can cause ALS/FTD, but the mechanism underlying UBQLN2-mediated pathogenesis is still uncertain. Recent studies indicate that mitophagy, a selective form of autophagy which is crucial for mitochondrial quality control, is tightly associated with neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and ALS. In this study, we show that after Parkin-dependent ubiquitination of damaged mitochondria, UBQLN2 is recruited to poly-ubiquitinated mitochondria through the UBA domain. UBQLN2 cooperates with the chaperone HSP70 to promote UPS-driven degradation of outer mitochondrial membrane (OMM) proteins. The resulting rupture of the OMM triggers the autophagosomal recognition of the inner mitochondrial membrane receptor PHB2. UBQLN2 is required for Parkin-mediated mitophagy and neuronal survival upon mitochondrial damage, and the ALS/FTD pathogenic mutations in UBQLN2 impair mitophagy in primary cultured neurons. Taken together, our findings link dysfunctional mitophagy to UBQLN2-mediated neurodegeneration.

The interaction between E3 ubiquitin ligase Parkin and mitophagy receptor PHB2 links inner mitochondrial membrane ubiquitination to efficient mitophagy.

The autophagic clearance of mitochondria has been defined as mitophagy, which is triggered by mitochondrial damage and serves as a major pathway for mitochondrial homeostasis and cellular quality control. PINK1 and Parkin-mediated mitophagy is the most extensively studied form of mitophagy, which has been linked to the pathogenesis of neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. The current paradigm of this particular mitophagy pathway is that the ubiquitination of the outer mitochondrial membrane is the key step to enable the recognition of damaged mitochondria by the core autophagic component autophagosome. However, whether the inner mitochondrial membrane (IMM) is ubiquitinated by Parkin and its contribution to sufficient mitophagy remain unclear. Here, using molecular, cellular, and biochemical approaches, we report that prohibitin 2 (PHB2), an essential IMM receptor for mitophagy, is ubiquitinated by Parkin and thereby gains higher affinity to the autophagosome during mitophagy. Our findings suggest that Parkin directly binds to PHB2 through its RING1 domain and promotes K11- and K33-linked ubiquitination on K142/K200 sites of PHB2, thereby enhancing the interaction between PHB2 and MAP1LC3B/LC3B. Interestingly and importantly, our study allows us to propose a novel model in which IMM protein PHB2 serves as both a receptor and a ubiquitin-mediated base for autophagosome recruitment to ensure efficient mitophagy.

Realizing Textured Zinc Metal Anodes through Regulating Electrodeposition Current for Aqueous Zinc Batteries.

Crystallography modulation of zinc (Zn) metal anode is promising to promote Zn reversibility in aqueous electrolytes, but efficiently constructing Zn with specific crystallographic texture remains challenging. Herein, we report a current-controlled electrodeposition strategy to texture the Zn electrodeposits in conventional aqueous electrolytes. Using the electrolytic cell with low-cost Zn(CH3 COO)2 electrolyte and Cu substrate as a model system, the texture of as-deposited Zn gradually transforms from (101) to (002) crystal plane as increasing the current density from 20 to 80 mA cm-2 . Moreover, the high current accelerates the Zn nucleation rate with abundant nuclei, enabling uniform deposition. The (002) texture permits stronger resistance to dendrite growth and interfacial side reactions than the (101) texture. The resultant (002)-textured Zn electrode achieves deep cycling stability and supports the stable operation of full batteries with conventional V/Mn-based oxide cathodes.

In-Situ Integration of a Hydrophobic and Fast-Zn2+ -Conductive Inorganic Interphase to Stabilize Zn Metal Anodes.

The irreversible issues of Zn anode stemming from dendrite growth and water-induced erosion have severely hindered the commercialization of rechargeable aqueous Zn batteries. Herein, a hydrophobic and fast-Zn2+ -conductive zinc hexacyanoferrate (HB-ZnHCF) interphase layer is in situ integrated on Zn by a rapid room-temperature wet-chemistry method to address these dilemmas. Different from currently proposed hydrophilic inorganic cases, the hydrophobic and compact HB-ZnHCF interphase effectively prevents the access of water molecules to Zn surface, thus avoiding H2 evolution and Zn corrosion. Moreover, the HB-ZnHCF with large internal ion channels, strong zincophilicity, and high Zn2+ transference number (0.86) permits fast Zn2+ transport and enables smooth Zn deposition. Remarkably, the resultant HB-ZnHCF@Zn electrode delivers unprecedented reversibility with 99.88 % Coulombic efficiency over 3000 cycles, realizes long-term cycling over 5800 h (>8 months, 1 mA cm-2 ) and 1000 h (10 mA cm-2 ), and assures the stable operation of full Zn battery with both coin- and pouch-type configurations.

Study on pickling technology to control fouling of ceramic membrane treating secondary treated effluent.

The application of membrane technology in the field of water treatment was increasingly widespread, but membrane fouling still restricted its development, and the membrane needed to be chemically cleaned. This research focused on the high-efficiency pickling technology of ceramic membrane, and developed the cleaning technology of ceramic membrane in cooperation with surfactant. In the experiment, the municipal secondary effluent was used as the raw water, and the single-step, mixed and step-by-step cleaning effects of three strong acids, three weak acids and surfactants on ceramic membranes and polyvinylidene difluoride (PVDF) membranes were investigated. For ceramic membrane, the optimal cleaning combination was H2SO4 first and then DTAC, and the flux recovery rate could reach 96.94%; for PVDF membrane, the optimal cleaning combination was HNO3 first and then H2SO4, and the flux recovery rate could reach 93.72%. In addition, the surface of initial, polluted, and cleaned membranes were analyzed by scanning electron microscope and contact angle, and the fouling mechanism of the ceramic membrane was analyzed. The results showed that through physical cleaning and chemical cleaning, most of the pollutants on the membrane surface and pores were removed. The cleaning method can effectively control the membrane pollution.

Comparative transcriptomic and metabolomic analyses of carotenoid biosynthesis reveal the basis of white petal color in Brassica napus.

MAIN CONCLUSION: The molecular mechanism underlying white petal color in Brassica napus was revealed by transcriptomic and metabolomic analyses. Rapeseed (Brassica napus L.) is one of the most important oilseed crops worldwide, but the mechanisms underlying flower color in this crop are known less. Here, we performed metabolomic and transcriptomic analyses of the yellow-flowered rapeseed cultivar 'Zhongshuang 11' (ZS11) and the white-flowered inbred line 'White Petal' (WP). The total carotenoid contents were 1.778-fold and 1.969-fold higher in ZS11 vs. WP petals at stages S2 and S4, respectively. Our findings suggest that white petal color in WP flowers is primarily due to decreased lutein and zeaxanthin contents. Transcriptome analysis revealed 10,116 differentially expressed genes with a fourfold or greater change in expression (P-value less than 0.001) in WP vs. ZS11 petals, including 1,209 genes that were differentially expressed at four different stages and 20 genes in the carotenoid metabolism pathway. BnNCED4b, encoding a protein involved in carotenoid degradation, was expressed at abnormally high levels in WP petals, suggesting it might play a key role in white petal formation. The results of qRT-PCR were consistent with the transcriptome data. The results of this study provide important insights into the molecular mechanisms of the carotenoid metabolic pathway in rapeseed petals, and the candidate genes identified in this study provide a resource for the creation of new B. napus germplasms with different petal colors.

Genome-Wide Characterization and Analysis of Metallothionein Family Genes That Function in Metal Stress Tolerance in Brassica napus L.

Brassica plants exhibit both high biomass productivity and high rates of heavy metal absorption. Metallothionein (MT) proteins are low molecular weight, cysteine-rich, metal-binding proteins that play crucial roles in protecting plants from heavy metal toxicity. However, to date, MT proteins have not been systematically characterized in Brassica. In this study, we identified 60 MTs from Arabidopsis thaliana and five Brassica species. All the MT family genes from Brassica are closely related to Arabidopsis MTs, encoding putative proteins that share similar functions within the same clades. Genome mapping analysis revealed high levels of synteny throughout the genome due to whole genome duplication and segmental duplication events. We analyzed the expression levels of 16 Brassica napus MTs (BnaMTs) by RNA-sequencing and real-time RT-PCR (RT-qPCR) analysis in plants under As3+ stress. These genes exhibited different expression patterns in various tissues. Our results suggest that BnaMT3C plays a key role in the response to As3+ stress in B. napus. This study provides insight into the phylogeny, origin, and evolution of MT family members in Brassica, laying the foundation for further studies of the roles of MT proteins in these important crops.

Self-Forming Interlocking Interfaces on the Immiscible Polymer Bilayers via Gelation-Mediated Phase Separation.

Gelation-mediated phase separation is applied to prepare immiscible polymer bilayer films with an interlocking interface structure. Polymer systems consisting of copolymer of urea and polydimethylsiloxane and epoxy are selected to demonstrate the feasibility. When the epoxy fraction exceeds 25 wt%, well-defined bilayer structures self-form by a one-pot casting method in which the phase separation state is fixed by an evaporation-induced gelation. Microscopy studies of the resulting bilayers clearly reveal that interlocking structures form during the bilayer films construct. The interlocking structures lead to an enhanced interfacial adhesion and higher fracture energy. The current strategy might offer a facile way to in situ create an interlocking interface between immiscible polymer systems.

Free-Standing Conducting Polymer Films for High-Performance Energy Devices.

Thick, uniform, easily processed, highly conductive polymer films are desirable as electrodes for solar cells as well as polymer capacitors. Here, a novel scalable strategy is developed to prepare highly conductive thick poly(3,4-ethylenedioxythiophene):polystyrene sulfonate (HCT-PEDOT:PSS) films with layered structure that display a conductivity of 1400 S cm(-1) and a low sheet resistance of 0.59 ohm sq(-1). Organic solar cells with laminated HCT-PEDOT:PSS exhibit a performance comparable to the reference devices with vacuum-deposited Ag top electrodes. More importantly, the HCT-PEDOT:PSS film delivers a specific capacitance of 120 F g(-1) at a current density of 0.4 A g(-1). All-solid-state flexible symmetric supercapacitors with the HCT-PEDOT:PSS films display a high volumetric energy density of 6.80 mWh cm(-3) at a power density of 100 mW cm(-3) and 3.15 mWh cm(-3) at a very high power density of 16160 mW cm(-3) that outperforms previous reported solid-state supercapacitors based on PEDOT materials.

Sonic Hedgehog dependent phosphorylation by CK1α and GRK2 is required for ciliary accumulation and activation of smoothened.

Hedgehog (Hh) signaling regulates embryonic development and adult tissue homeostasis through the GPCR-like protein Smoothened (Smo), but how vertebrate Smo is activated remains poorly understood. In Drosophila, Hh dependent phosphorylation activates Smo. Whether this is also the case in vertebrates is unclear, owing to the marked sequence divergence between vertebrate and Drosophila Smo (dSmo) and the involvement of primary cilia in vertebrate Hh signaling. Here we demonstrate that mammalian Smo (mSmo) is activated through multi-site phosphorylation of its carboxyl-terminal tail by CK1α and GRK2. Phosphorylation of mSmo induces its active conformation and simultaneously promotes its ciliary accumulation. We demonstrate that graded Hh signals induce increasing levels of mSmo phosphorylation that fine-tune its ciliary localization, conformation, and activity. We show that mSmo phosphorylation is induced by its agonists and oncogenic mutations but is blocked by its antagonist cyclopamine, and efficient mSmo phosphorylation depends on the kinesin-II ciliary motor. Furthermore, we provide evidence that Hh signaling recruits CK1α to initiate mSmo phosphorylation, and phosphorylation further increases the binding of CK1α and GRK2 to mSmo, forming a positive feedback loop that amplifies and/or sustains mSmo phosphorylation. Hence, despite divergence in their primary sequences and their subcellular trafficking, mSmo and dSmo employ analogous mechanisms for their activation.

A shuttle effect free lithium sulfur battery based on a hybrid electrolyte.

A room temperature hybrid electrolyte based lithium-sulfur cell was successfully cycled with an excellent coulombic efficiency of 100%. The initial discharge specific capacities of up to 1528 mA h g(-1), 1386 mA h g(-1) and 1341 mA h g(-1), respectively, at C/20, C/5 and C/2 rates were realized and remained at 720 mA h g(-1) after 40 cycles at the C/5 rate.

Organic Cations Texture Zinc Metal Anodes for Deep Cycling Aqueous Zinc Batteries.

Manipulating the crystallographic orientation of zinc (Zn) metal to expose more (002) planes is promising to stabilize Zn anodes in aqueous electrolytes. However, there remain challenges involving the non-epitaxial electrodeposition of highly (002) textured Zn metal and the maintenance of (002) texture under deep cycling conditions. Herein, a novel organic imidazolium cations-assisted non-epitaxial electrodeposition strategy to texture electrodeposited Zn metals is developed. Taking the 1-butyl-3-methylimidazolium cation (Bmim+) as a paradigm additive, the as-prepared Zn film ((002)-Zn) manifests a compact structure and a highly (002) texture without containing (100) signal. Mechanistic studies reveal that Bmim+ featuring oriented adsorption on the Zn-(002) plane can reduce the growth rate of (002) plane to render the final exposure of (002) texture, and homogenize Zn nucleation and suppress H2 evolution to enable the compact electrodeposition. In addition, the formulated Bmim+-containing ZnSO4 electrolyte effectively sustains the (002) texture even under deep cycling conditions. Consequently, the combination of (002) texture and Bmim+-containing electrolyte endows the (002)-Zn electrode with superior cycling stability over 350 h under 20 mAh cm-2 with 72.6% depth-of-discharge, and assures the stable operation of full Zn batteries with both coin-type and pouch-type configurations, significantly outperforming the (002)-Zn and commercial Zn-based batteries in Bmim+-free electrolytes.

Cost-effectiveness of palbociclib plus fulvestrant as second-line therapy of women with HR+/HER2- advanced breast cancer - A Chinese healthcare system perspective.

Aim: To evaluate the cost-effectiveness of palbociclib plus fulvestrant in the second-line treatment of women with hormone receptor-positive and human epidermal growth factor receptor 2-negative advanced breast cancer based on the latest published follow-up data from the perspective of the Chinese healthcare system. Methods: In view of the PALOMA-3 trial, a Markov model was built for this purpose, which included three health states: progression-free survival (PFS), progressed disease (PD), and death. The cost and health utilities were mainly derived from the published literature. One-way sensitivity analysis and probabilistic sensitivity analysis were carried out to verify the robustness of the model. Results: In the base case analysis, compared with the placebo plus fulvestrant arm, the palbociclib plus fulvestrant arm yielded an additional 0.65 quality-adjusted life years (QALYs) (2.56 QALYs vs. 1.90 QALYs) with an incremental cost of $36,139.94 ($55,482.06 vs. $19,342.12), resulting an incremental cost-effectiveness ratio (ICER) of $55,224.90/QALY, which was deeply higher than a willingness-to-pay (WTP) threshold of $34,138.28 per QALY in China. The results of one-way sensitivity analysis indicated that the utility of PFS, cost of palbociclib, and cost of neutropenia had a great influence on the ICER. Conclusions: Palbociclib plus fulvestrant is unlikely to be cost-effective in comparison with placebo plus fulvestrant as second-line therapy of women with HR+/HER2- advanced breast cancer.

Study on Corrosion Behavior and Mechanism of Ultrahigh-Strength Hot-Stamping Steel Based on Traditional and Compact Strip-Production Processes.

Hot-stamping steel is a type of high-strength steel that is mainly used in key safety components such as the front and rear bumpers, A-pillars, and B-pillars of vehicles. There are two methods of producing hot-stamping steel, i.e., the traditional process and the near net shape of compact strip production (CSP) process. To assess the potential risks of producing hot-stamping steel using CSP, the microstructure and mechanical properties, and especially the corrosion behavior were focused on between the traditional and CSP processes. The original microstructure of hot-stamping steel produced by the traditional process and the CSP process is different. After quenching, the microstructures transform into full martensite, and their mechanical properties meet the 1500 MPa grade. Corrosion tests showed that the faster the quenching speeds, the smaller the corrosion rate of the steel. The corrosion current density changes from 15 to 8.6 µA·cm-2. The corrosion resistance of hot-stamping steel produced by the CSP process is slightly better than that of traditional processes, mainly since the inclusion size and distribution density of CSP-produced steel were both smaller than those of the traditional process. The reduction of inclusions reduces the number of corrosion sites and improves the corrosion resistance of steel.

Dietary Polysaccharide-Rich Extract from Noni (Morinda citrifolia L.) Fruit Modified Ruminal Fermentation, Ruminal Bacterial Community and Nutrient Digestion in Cashmere Goats.

In two consecutive studies, we evaluated the effects of polysaccharide-rich noni (Morinda citrifolia L.) fruit extract (NFP) on ruminal fermentation, ruminal microbes and nutrient digestion in cashmere goats. In Exp. 1, the effects of a diet containing NFP of 0, 0.1%, 0.2%, 0.4% and 0.55% on in vitro ruminal fermentation at 3, 6, 9, 12 and 24 h were determined, whereas in Exp. 2, fourteen cashmere goats (46.65 ± 3.36 kg of BW ± SD) were randomly assigned to two treatments: the basal diet with or without (CON) supplementation of NFP at 4 g per kg DM (0.4%). The in vitro results showed that NFP linearly increased concentrations of volatile fatty acids (VFA), quadratically decreased ammonia-N concentration, and changed pH, protozoa number, gas production and the microbial protein (MCP) concentration, and was more effective at 0.4% addition, which yielded similar results in ruminal fermentation in Exp. 2. In addition, NFP increased the apparent digestibility of dry matter and crude protein and the abundance of Firmicutes, and reduced the abundance of Bacteroides and Actinobacteria. Ruminococcus_1 was positively associated with VFA concentration. The Rikenellaceae_RC9_gut_group was positively correlated with protozoa and negatively correlated with MCP concentration. Thus, NFP has potential as a ruminal fermentation enhancer for cashmere goats.

Orientational Electrodeposition of Highly (002)-Textured Zinc Metal Anodes Enabled by Iodide Ions for Stable Aqueous Zinc Batteries.

Regulating the crystallographic texture of the zinc (Zn) metal anode is promising to promote Zn reversibility in aqueous electrolytes, but the direct fabrication of specific textured Zn still remains challenging. Herein, we report a facile iodide ion (I-)-assisted electrodeposition strategy that can scalably fabricate highly (002) crystal plane-textured Zn metal anode (H-(002)-Zn). Theoretical and experimental characterizations demonstrate that the presence of I- additives can significantly elevate the growth rate of the Zn (100) plane, homogenize the Zn nucleation, and promote the plating kinetics, thus enabling the uniform H-(002)-Zn electrodeposition. Taking the electrolytic cell with the conventional ZnSO4-based electrolyte and commercial Cu substrate as a model system, the Zn texture gradually transforms from (101) to (002) as the increase of NaI additive concentration. In the optimized 1 M ZnSO4 + 0.8 M NaI electrolyte, the as-prepared H-(002)-Zn features a compact structure and an ultrahigh intensity ratio of (002) to (101) signal without containing the (100) signal. The free-standing H-(002)-Zn electrode manifests stronger resistance to interfacial side reactions than the conventional (101)-textured Zn electrode, thus delivering a high efficiency of 99.88% over 400 cycles and ultralong cycling lifespan over 6700 h (>9 months at 1 mA cm-2) and assuring the stable operation of full Zn batteries. This work will enlighten the efficient electrosynthesis of high-performance Zn anodes for practical aqueous Zn batteries.

Effects of Artemisia ordosica Crude Polysaccharide on Antioxidant and Immunity Response, Nutrient Digestibility, Rumen Fermentation, and Microbiota in Cashmere Goats.

The objective of this experiment was to investigate the effect of dietary supplementation with Artemisia ordosica crude polysaccharide (AOCP) on growth performance, nutrient digestibility, antioxidant and immunity capacity, rumen fermentation parameters, and the microbiota of cashmere goats. A total of 12 cashmere goats (2 years old) with similar weight (38.03 ± 2.42 kg of BW ± SD) were randomly divided into two dietary treatments with six replicates. The treatments were as follows: (1) control (CON, basal diet); and (2) AOCP treatment (AOCP, basal diet with 0.3% AOCP). Pre-feeding was conducted for 7 days, followed by an experimental period of 21 days. The results showed that the ADG; feed/gain (F/G); and the digestibility of DM, CP, and ADF of cashmere goats in the AOCP group were greater than in the CON group (p < 0.05). Still, there was no significant effect on the digestibility of EE, NDF, Ca, and P (p > 0.05). Compared to the CON group, AOCP increased BCP, propionate, butyrate, isobutyrate, valerate, isovalerate, and TVFA concentrations (p < 0.05), but it reduced the protozoa numbers of acetate and A/P (p < 0.05). The serum CAT, GSH-Px, T-SOD, 1L-6, and NO levels were higher in AOCP than in the CON group (p < 0.05). The addition of AOCP increased the Sobs and Ace estimators (p < 0.05) and reduced the Simpson estimator in the ruminal fluid compared to the CON group (p < 0.05). Additionally, the AOCP group increased the colonization of beneficial bacteria by positively influencing GSH-Px and IL-6 (norank_f__F082, unclassified_p__Firmicutes), as well as bacteria negatively associated with F/G (norank_f__norank_o__Bacteroidales, unclassified_p__Firmicutes, and norank_f__F082). It decreased the colonization of potential pathogenic bacteria (Aeromonas and Escherichia-Shigella) (p < 0.05) compared to the CON group. In conclusion, 0.3% AOCP improves the growth performance, nutrient digestibility, antioxidant status, immune function, rumen fermentation, and microflora of cashmere goats.

Tailored engineering of Fe3O4 and reduced graphene oxide coupled architecture to realize the full potential as electrode materials for lithium-ion batteries.

Developing advanced electrode materials with appropriate compositions and exquisite configurations is crucial in fabricating lithium-ion batteries (LIBs) with high energy density and fast charging capability plateau. Herein, a Fe3O4@reduced graphene oxide (Fe3O4@rGO) coupled architecture was rationally designed and in-situ synthesized. Monodispersed mesoporous Fe3O4 nanospheres were homogeneously formed and strongly bound on interconnected macroporous rGO frameworks to form well-defined three-dimensional (3D) hierarchical porous morphologies. This tailored Fe3O4@rGO coupled architecture fully exploited the advantages of Fe3O4 and rGO to overcome their inherent challenges, including spontaneous aggregating/excessive restacking tendency, sluggish ions diffusion/electrons transportation, and severe volume expansion/structural collapse. Benefitting from their synergistic effects, the optimized Fe3O4@rGO composite electrode exhibited an improved electrochemical reactivity, electrical conductivity, electrolyte accessibility, and structural stability. The optimized composite electrode displayed a high specific capacity of 1296.8 mA h g-1 at 0.1 A g-1 after 100 cycles, even retaining 555.1 mA h g-1 at 2 A g-1 after 2000 cycles. The electrochemical kinetics analysis revealed the predominantly pseudocapacitive behaviors of the Fe3O4@rGO heterogeneous interfaces, accounting for the excellent electrode performance. This study proposes a viable strategy for use in engineering hybrid composites with coupled architectures to optimize their potential as high-performance electrode materials for use in LIBs.

Chlorpromazine affects autophagy in association with altered Rag GTPase-mTORC1-TFEB signaling.

Autophagy is a critical protein and organelle quality control system, which regulates cellular homeostasis and survival. Growing pieces of evidence suggest that autophagic dysfunction is strongly associated with many human diseases, including neurological diseases and cancer. Among various autophagic regulators, microphthalmia (MiT)/TFE transcription factors, including transcription factor EB (TFEB), have been shown to act as the master regulators of autophagosome and lysosome biogenesis in both physiological and pathological conditions. According to the previous studies, chlorpromazine (CPZ), an FDA-approved antipsychotic drug, affects autophagy in diverse cell lines, but the underlying mechanism remains elusive. In our present study, we find that CPZ treatment induces TFEB nuclear translocation through Rag GTPases, the upstream regulators of mechanistic target of rapamycin complex 1 (mTORC1) signaling. Meanwhile, CPZ treatment also blocks autophagosome-lysosome fusion. Notably, we find a significant accumulation of immature autophagosome vesicles in CPZ-treated cells, which may impede cellular homeostasis due to the dysfunction of the autophagy-lysosome pathway. Interestingly and importantly, our data suggest that the expression of the active form of Rag GTPase heterodimers helps in reducing the accumulation of autophagosomes in CPZ-treated cells, further suggesting a major contribution of the Rag GTPase-mTORC1-TFEB signaling axis in CPZ-induced autophagic impairment.