Dorsal CA1 NECTIN3 Reduction Mediates Early-Life Stress-Induced Object Recognition Memory Deficits in Adolescent Female Mice.

Early-life stress (ES) leads to cognitive dysfunction in female adolescents, but the underlying neural mechanisms remain elusive. Recent evidence suggests that the cell adhesion molecules NECTIN1 and NECTIN3 play a role in cognition and ES-related cognitive deficits in male rodents. In this study, we aimed to investigate whether and how nectins contribute to ES-induced cognitive dysfunction in female adolescents. Applying the well-established limited bedding and nesting material paradigm, we found that ES impairs recognition memory, suppresses prefrontal NECTIN1 and hippocampal NECTIN3 expression, and upregulates corticotropin-releasing hormone (Crh) and its receptor 1 (Crhr1) mRNA levels in the hippocampus of adolescent female mice. Genetic experiments revealed that the reduction of dorsal CA1 (dCA1) NECTIN3 mediates ES-induced object recognition memory deficits, as knocking down dCA1 NECTIN3 impaired animals' performance in the novel object recognition task, while overexpression of dCA1 NECTIN3 successfully reversed the ES-induced deficits. Notably, prefrontal NECTIN1 knockdown did not result in significant cognitive impairments. Furthermore, acute systemic administration of antalarmin, a CRHR1 antagonist, upregulated hippocampal NECTIN3 levels and rescued object and spatial memory deficits in stressed mice. Our findings underscore the critical role of dCA1 NECTIN3 in mediating ES-induced object recognition memory deficits in adolescent female mice, highlighting it as a potential therapeutic target for stress-related psychiatric disorders in women.

Graph neural pre-training based drug-target affinity prediction.

Computational drug-target affinity prediction has the potential to accelerate drug discovery. Currently, pre-training models have achieved significant success in various fields due to their ability to train the model using vast amounts of unlabeled data. However, given the scarcity of drug-target interaction data, pre-training models can only be trained separately on drug and target data, resulting in features that are insufficient for drug-target affinity prediction. To address this issue, in this paper, we design a graph neural pre-training-based drug-target affinity prediction method (GNPDTA). This approach comprises three stages. In the first stage, two pre-training models are utilized to extract low-level features from drug atom graphs and target residue graphs, leveraging a large number of unlabeled training samples. In the second stage, two 2D convolutional neural networks are employed to combine the extracted drug atom features and target residue features into high-level representations of drugs and targets. Finally, in the third stage, a predictor is used to predict the drug-target affinity. This approach fully utilizes both unlabeled and labeled training samples, enhancing the effectiveness of pre-training models for drug-target affinity prediction. In our experiments, GNPDTA outperforms other deep learning methods, validating the efficacy of our approach.

NLRP3 Inflammasome Activation Mediates Hepatitis E Virus-Induced Neuroinflammation.

Hepatitis E virus (HEV) is a foodborne zoonotic pathogen that is supposed to be one of the most common causes of acute viral hepatitis. However, HEV infection has been recently associated with a wide spectrum of extrahepatic manifestations, particularly neurological disorders. Previous studies have shown that HEV is able to cross the blood-brain barrier (BBB) and induce inflammatory response of the central nervous system. However, the pathogenesis of HEV-induced neuroinflammation and tissue injury of the central nervous system have yet to be fully elucidated. In this study, activation of NLRP3 inflammasome following HEV infection were investigated. In a gerbil model infected by HEV, brain histopathological changes including gliosis, neuronophagia and neuron injury were observed and expression of NLRP3, caspase-1, IL-1ß and IL-18 were elevated. Brain microvascular endothelial cells (BMECs) are key components of the BBB that protects the brain from various challenges. Following HEV infection, virus-like particles range from 30 to 40 nm in diameter were observed in human BMECs (hBMECs). Enhanced expression levels of NLRP3 and subsequent ASC, caspase-1, IL-1ß and IL-18 were detected in infected cells. Treatment with MCC950 alleviated HEV infection induced activation of NLRP3 inflammasome, mitochondrial damage and VE-cadherin degradation. The findings provide new insights into HEV-associated neuroinflammation. Moreover, targeting NLRP3 inflammasome signalling is a promising therapeutic in HEV-induced neurological disorder.

Near-infrared fluorescent probe based on the regulatory dye pKa for imaging of H2S in rice roots and living cells.

Hydrogen sulfide (H2S) is a key factor in various biological processes such as plant grow and its response to environmental stress. Here, we develop a novel near-infrared (NIR) fluorescent probe for detecting hydrogen sulfide based on the regulatory NIR dye pKa values. After triggering the H2S substitution response, probe A with introducing the cyano moiety not only exhibits a significant near-infrared emission (Emax: 724 nm) response in physiological environments, but also shows a fast response, high selectivity, and sensitivity (LOD as 0.52 µM). In addition, probe A with low biological cytotoxicity is successfully used for imaging detection of cellular exogenous and endogenous hydrogen sulfide. More importantly, in situ imaging of probe A tracks the H2S fluctuations in the rice root system and its response to environmental stress. Hence, this work offers a new NIR fluorescence imaging monitoring tool for hydrogen sulfide in biological systems.

Glucose deprivation triggers DCAF1-mediated inactivation of Rheb-mTORC1 and promotes cancer cell survival.

Low glucose is a common microenvironment for rapidly growing solid tumors, which has developed multiple approaches to survive under glucose deprivation. However, the specific regulatory mechanism remains largely elusive. In this study, we demonstrate that glucose deprivation, while not amino acid or serum starvation, transactivates the expression of DCAF1. This enhances the K48-linked polyubiquitination and proteasome-dependent degradation of Rheb, inhibits mTORC1 activity, induces autophagy, and facilitates cancer cell survival under glucose deprivation conditions. This study identified DCAF1 as a new cellular glucose sensor and uncovered new insights into mechanism of DCAF1-mediated inactivation of Rheb-mTORC1 pathway for promoting cancer cell survival in response to glucose deprivation.

Spatiotemporal changes in fine particulate matter and ozone in the oasis city of Korla, northeastern Tarim Basin of China.

Air pollution is a serious environmental health concern for humans and other living organisms. This study analyzes the spatial and temporal characteristics of air pollutant concentrations, changes in the degree of pollution, and the wavelet coherence of the air quality index (AQI) with pollutants in various monitoring stations. The analysis is based on long-term time series data (January 2016 to December 2023) of air pollutants (PM2.5, PM10, and O3) from Korla, an oasis city in the northeastern part of the Tarim Basin, China. The concentrations of PM2.5, PM10, and O3 in Korla showed a cyclical trend from 2016 to 2023; PM10 concentrations exhibited all-season exceedance and PM2.5 exhibited exceedance only in spring. PM2.5 and PM10 showed a seasonal distribution of spring > winter > fall > summer; O3 concentrations showed a seasonal distribution of summer > spring > fall > winter. Strong positive wavelet coherence between PM and Air Quality Index (AQI) data series suggests that the AQI data series can effectively characterize fluctuating trends in PM concentrations. Moreover, PM10 levels IV and VI were maintained at approximately 10%, indicating that sand and dust have a substantial influence on air quality and pose potential threats to the health of urban inhabitants. Based on the results of this study, future efforts must strengthen relative countermeasures for sand prevention and control, select urban greening species with anti-pollution capabilities, rationally expand urban green spaces, and restrict regulations for reducing particulate matter emissions within city areas.

An activated near-infrared mitochondrion-targetable fluorescent probe for rapid detection of NADH.

A novel NIR fluorescent probe based on quinoline-conjugated benzo[cd]indol dual-salt for NADH was developed. This probe swiftly detects and responds sensitively to both endogenous and exogenous NADH alterations, enabling imaging of NADH fluctuations in type II diabetic and AD model cells.

Reed-root-based solar-driven evaporator with a faster capillary water transfer rate for effective steam generation.

Solar-driven steam evaporation technology, known for its low energy consumption and environmental friendliness, has emerged as a promising approach for seawater desalination, wastewater purification, etc. However, creating a low-cost solar evaporation system that simultaneously achieves rapid water transport, efficient light absorption, and salt tolerance remains challenging. Here, a dual-layer evaporator based on reed roots has been developed after a simple H2O2 delignification treatment and flame treatment, which exhibited enhanced water transport performance and photothermal properties. As excepted, delignification treatment enhanced the capillary water transport ability of reed roots, which is conducive to promoting the dilution of salt in the evaporator and preventing salt deposition. The evaporator demonstrates an impressive steam generation efficiency of 83.5 % and a remarkable water evaporation rate of 1.407 kg m-2 h-1 under 1 sun, thanks to its well-designed structure and optimized performance. Moreover, the evaporator exhibited excellent practical performance for outdoor applications and demonstrates a remarkable capacity for sewage purification, effectively treating heavy metal ion wastewater as well as dye wastewater. As a result, the objective of our research is to explore opportunities for the implementation of deployable, cost-effective, low-carbon-footprint solar water purification systems, particularly for some impoverished regions, to ensure the provision of high-quality water.

Dorsal CA3 overactivation mediates witnessing stress-induced recognition memory deficits in adolescent male mice.

Witnessing violent or traumatic events is common during childhood and adolescence and could cause detrimental effects such as increased risks of psychiatric disorders. This stressor could be modeled in adolescent laboratory animals using the chronic witnessing social defeat (CWSD) paradigm, but the behavioral consequences of CWSD in adolescent animals remain to be validated for cognitive, anxiety-like, and depression-like behaviors and, more importantly, the underlying neural mechanisms remain to be uncovered. In this study, we first established the CWSD model in adolescent male mice and found that CWSD impaired cognitive function and increased anxiety levels and that these behavioral deficits persisted into adulthood. Based on the dorsal-ventral functional division in hippocampus, we employed immediate early gene c-fos immunostaining after behavioral tasks and found that CWSD-induced cognition deficits were associated with dorsal CA3 overactivation and anxiety-like behaviors were associated with ventral CA3 activity reduction. Indeed, chemogenetic activation and inhibition of dorsal CA3 neurons mimicked and reversed CWSD-induced recognition memory deficits (not anxiety-like behaviors), respectively, whereas both inhibition and activation of ventral CA3 neurons increased anxiety-like behaviors in adolescent mice. Finally, chronic administration of vortioxetine (a novel multimodal antidepressant) successfully restored the overactivation of dorsal CA3 neurons and the cognitive deficits in CWSD mice. Together, our findings suggest that dorsal CA3 overactivation mediates CWSD-induced recognition memory deficits in adolescent male mice, shedding light on the pathophysiology of adolescent CWSD-induced adverse effects and providing preclinical evidence for early treatment of stress-induced cognitive deficits.

Fluoxetine reverses early-life stress-induced depressive-like behaviors and region-specific alterations of monoamine transporters in female mice.

The sex difference that females are more vulnerable to depression than males has been recently replicated in an animal model of early-life stress (ES) called the limited bedding and nesting material (LBN) paradigm. Adopting this animal model, we have previously examined the effects of ES on monoamine transporter (MATs) expression in stress-related regions in adult female mice, and the reversal effects of a novel multimodal antidepressant, vortioxetine. In this study, replacing vortioxetine with a classical antidepressant, fluoxetine, we aimed to replicate the ES effects in adult female mice and to elucidate the commonality and differences between fluoxetine and vortioxetine. We found that systemic 30-day treatment with fluoxetine successfully reversed ES-induced depression-like behaviors (especially sucrose preference) in adult female mice. At the molecular level, we largely replicated the ES effects, such as reduced serotonin transporter (SERT) expression in the amygdala and increased norepinephrine transporter (NET) expression in the medial prefrontal cortex (mPFC) and hippocampus. Similar reversal effects of fluoxetine and vortioxetine were observed, including SERT in the amygdala and NET in the mPFC, whereas different reversal effects were observed for NET in the hippocampus and vesicular monoamine transporters expression in the nucleus accumbens. Overall, these results demonstrate the validity of the LBN paradigm to induce depression-like behaviors in female mice, highlight the involvement of region-specific MATs in ES-induced depression-like behaviors, and provide insights for further investigation of neurobiological mechanisms, treatment, and prevention associated with depression in women.

Effect of ATG8 or SAC1 deficiency on the cell proliferation and lifespan of the long-lived PMT1 deficiency yeast cells.

Autophagy is pivotal in maintaining intracellular homeostasis, which involves various biological processes, including cellular senescence and lifespan modulation. Being an important member of the protein O-mannosyltransferase (PMT) family of enzymes, Pmt1p deficiency can significantly extend the replicative lifespan (RLS) of yeast cells through an endoplasmic reticulum (ER) unfolded protein response (UPR) pathway, which is participated in protein homeostasis. Nevertheless, the mechanisms that Pmt1p regulates the lifespan of yeast cells still need to be explored. In this study, we found that the long-lived PMT1 deficiency strain (pmt1Δ) elevated the expression levels of most autophagy-related genes, the expression levels of total GFP-Atg8 fusion protein and free GFP protein compared with wild-type yeast strain (BY4742). Moreover, the long-lived pmt1Δ strain showed the greater dot-signal accumulation from GFP-Atg8 fusion protein in the vacuole lumen through a confocal microscope. However, deficiency of SAC1 or ATG8, two essential components of the autophagy process, decreased the cell proliferation ability of the long-lived pmt1Δ yeast cells, and prevented the lifespan extension. In addition, our findings demonstrated that overexpression of ATG8 had no potential effect on the RLS of the pmt1Δ yeast cells, and the maintained incubation of minimal synthetic medium lacking nitrogen (SD-N medium as starvation-induced autophagy) inhibited the cell proliferation ability of the pmt1Δ yeast cells with the culture time, and blocked the lifespan extension, especially in the SD-N medium cultured for 15 days. Our results suggest that the long-lived pmt1Δ strain enhances the basal autophagy activity, while deficiency of SAC1 or ATG8 decreases the cell proliferation ability and shortens the RLS of the long-lived pmt1Δ yeast cells. Moreover, the maintained starvation-induced autophagy impairs extension of the long-lived pmt1Δ yeast cells, and even leads to the cell death.

Small-molecule probes from bench to bedside: advancing molecular analysis of drug-target interactions toward precision medicine.

Over the past decade, remarkable advances have been witnessed in the development of small-molecule probes. These molecular tools have been widely applied for interrogating proteins, pathways and drug-target interactions in preclinical research. While novel structures and designs are commonly explored in probe development, the clinical translation of small-molecule probes remains limited, primarily due to safety and regulatory considerations. Recent synergistic developments - interfacing novel chemical probes with complementary analytical technologies - have introduced and expedited diverse biomedical opportunities to molecularly characterize targeted drug interactions directly in the human body or through accessible clinical specimens (e.g., blood and ascites fluid). These integrated developments thus offer unprecedented opportunities for drug development, disease diagnostics and treatment monitoring. In this review, we discuss recent advances in the structure and design of small-molecule probes with novel functionalities and the integrated development with imaging, proteomics and other emerging technologies. We further highlight recent applications of integrated small-molecule technologies for the molecular analysis of drug-target interactions, including translational applications and emerging opportunities for whole-body imaging, tissue-based measurement and blood-based analysis.

Effects of Dietary Chlorogenic Acid Supplementation on Growth Performance, Meat Quality, and Muscle Flavor Substances in Finishing Pigs.

With the prohibition of antibiotics in feed, certain phytocompounds have been widely studied as feed additives. Chlorogenic acid (CGA), a natural polyphenol found in plants, possesses anti-inflammatory, antioxidant, and metabolic regulatory features. The objective of this study was to investigate the effects of dietary chlorogenic acid supplementation on growth performance and carcass traits, as well as meat quality, nutrient value and flavor substances of Duroc × Landrace × Yorkshire (DLY) pigs. Forty healthy DLY pigs (initial body weight (BW): 26.69 ± 0.37) were allotted to four treatment groups and were fed with the control diet, which was supplemented with 25 mg kg-1, 50 mg kg-1, and 100 mg kg-1 CGA, respectively. The trial lasted 100 days. The results suggested that dietary CGA supplementation had no effect (p < 0.05) on the average daily gain (ADG) and feed conversion ratio (FC). Herein, it was found that 50 mg kg-1 CGA-containing diet not only increased the dressing percentage and perirenal fat, but also reduced the rate of muscular pH decline (p < 0.05). In the longissimus thoracis (LT) muscle, the myofiber-type-related genes such as the MyHC IIa and MyHC IIX mRNA levels were increased by 100 mg kg-1 CGA. The results also indicated that the 100 mg kg-1 CGA-containing diet increased the content of crude fat, glycogen, total amino acids, and flavor amino acids, but decreased the inosine and hypoxanthine concentration in LT (p < 0.05). Meanwhile, the lipogenic gene ACC1 mRNA level was elevated by 50 mg kg-1 CGA. Instead, 100 mg kg-1 CGA downregulated the expression level of NT5C2, an enzyme responsible for inosine-5'-monophosphate (IMP) degradation. Additionally, 100 mg kg-1 CGA decreased the malondialdehyde (MDA) content, but increased the glutathione peroxidase (GSH-Px) content as well as antioxidant gene (HO-1, NQO-1, NRF2) mRNA levels in LT muscle. These findings showed that dietary CGA could partly improve carcass traits and muscle flavor without negatively affecting growth performance, and the underlying mechanism may be due to the antioxidant properties induced by CGA.

Enhanced oxygen reduction upon Ag-Fe-doped polyacrylonitrile@UiO-66-NH2 nanofibers to improve power-generation performance of microbial fuel cells.

Microbial fuel cells (MFCs) have great potential as a new energy technology that utilizes microorganisms to produce electrical energy by decomposing organic matter. A cathode catalyst is key to achieving an accelerated cathodic oxygen reduction reaction (ORR) in MFCs. We prepared a Zr-based metal organic-framework-derived silver-iron co-doped bimetallic material based on electrospun nanofibers by promoting the in situ growth of UiO-66-NH2 on polyacrylonitrile (PAN) nanofibers and named it as CNFs-Ag/Fe-m:n doped catalyst (m:n were 0, 1:1, 1:2, 1:3, and 2:1, respectively). Experimental results combined with density functional theory (DFT) calculations reveal that a moderate amount of Fe doped in CNFs-Ag-1:1 reduces the Gibbs free energy in the last step of the ORR. This indicates that Fe doping improves the performance of the catalytic ORR, and MFCs equipped with CNFs-Ag/Fe-1:1 exhibit a maximum power density of 737. 45 mW m-2, significantly higher than that obtained for MFCs using commercial Pt/C (457.99 mW m-2).

The causal involvement of the BDNF-TrkB pathway in dentate gyrus in early-life stress-induced cognitive deficits in male mice.

Cognitive dysfunction is a significant, untreated clinical need in patients with psychiatric disorders, for which preclinical studies are needed to understand the underlying mechanisms and to identify potential therapeutic targets. Early-life stress (ELS) leads to long-lasting deficits of hippocampus-dependent learning and memory in adult mice, which may be associated with the hypofunction of the brain-derived neurotrophic factor (BDNF) and its high-affinity receptor, tropomyosin receptor kinase B (TrkB). In this study, we carried out eight experiments using male mice to examine the causal involvement of the BDNF-TrkB pathway in dentate gyrus (DG) and the therapeutic effects of the TrkB agonist (7,8-DHF) in ELS-induced cognitive deficits. Adopting the limited nesting and bedding material paradigm, we first demonstrated that ELS impaired spatial memory, suppressed BDNF expression and neurogenesis in the DG in adult mice. Downregulating BDNF expression (conditional BDNF knockdown) or inhibition of the TrkB receptor (using its antagonist ANA-12) in the DG mimicked the cognitive deficits of ELS. Acute upregulation of BDNF (exogenous human recombinant BDNF microinjection) levels or activation of TrkB receptor (using its agonist, 7,8-DHF) in the DG restored ELS-induced spatial memory loss. Finally, acute and subchronic systemic administration of 7,8-DHF successfully restored spatial memory loss in stressed mice. Subchronic 7,8-DHF treatment also reversed ELS-induced neurogenesis reduction. Our findings highlight BDNF-TrkB system as the molecular target of ELS-induced spatial memory deficits and provide translational evidence for the intervention at this system in the treatment of cognitive deficits in stress-related psychiatric disorders, such as major depressive disorder.

Dephasing Dynamics in a Non-Equilibrium Fluctuating Environment.

We performed a theoretical study of the dephasing dynamics of a quantum two-state system under the influences of a non-equilibrium fluctuating environment. The effect of the environmental non-equilibrium fluctuations on the quantum system is described by a generalized random telegraph noise (RTN) process, of which the statistical properties are both non-stationary and non-Markovian. Due to the time-homogeneous property in the master equations for the multi-time probability distribution, the decoherence factor induced by the generalized RTN with a modulatable-type memory kernel can be exactly derived by means of a closed fourth-order differential equation with respect to time. In some special limit cases, the decoherence factor recovers to the expression of the previous ones. We analyzed in detail the environmental effect of memory modulation in the dynamical dephasing in four types of dynamics regimes. The results showed that the dynamical dephasing of the quantum system and the conversion between the Markovian and non-Markovian characters in the dephasing dynamics under the influence of the generalized RTN can be effectively modulated via the environmental memory kernel.

Integration of solid-phase microextraction and surface-enhanced Raman spectroscopy for in-vivo screening of polybrominated diphenyl ether.

The monitoring of polybrominated diphenyl ethers (PBDEs) is of great significance owing to their high persistence, bioaccumulation, and toxicity to humans and animals. In this study, a sensitive and reproducible probe that integrates solid-phase microextraction and surface-enhanced Raman spectroscopy (SPME-SERS) was developed for screening PBDEs in multiphase specimens, including live fish, water, and electrical products. A roughed Cu fiber with an Ag layer was fabricated with dual functions. BDE-15 was readily extracted and detected on the SPME-SERS probe consisting of propanethiol-modified Ag nanoplates on a Cu wire. A clear linear relationship (R2 = 0.988) was established between the SERS intensity at 782 cm-1 and the logarithmic concentrations (from 100 ppb to 100 ppm), with a detection limit of 15 ppb. This proposed method enables continuous in vivo monitoring in fish without complicated pretreatments. The results obtained by this SPME-SERS approach were validated by high-performance liquid chromatography and showed good agreement. This "extracting and detecting" SPME-SERS method provides a potential tool to monitor the occurrence, formation, and migration of PBDEs.

Heterostructure-induced enhanced oxygen catalysis behavior based on metal cobalt coupled with compound anchored on N-doped carbon nanofiber for microbial fuel cell.

High-efficiency oxygen reduction reaction (ORR) electrocatalyst in microbial fuel cells (MFCs) is important to boost the power production efficiency and reduce overall cost. Herein, we demonstrate a novel nitrogen (N)-doped carbon nanofiber (N-CNF) supported metal and metal compound heterostructure derived from metal-organic frameworks (MOFs), which endows superior electrocatalytic activity by optimizing the coupling modulation effect. The resulting cobalt/cobalt phosphide and cobalt/cobalt sulfide nanoparticles embedded in N-doped carbon nanofiber (Co/CoP/Co2P@N-CNF, Co/CoS2@N-CNF) present superior ORR activity and methanol tolerance. Moreover, the assembled MFCs modified with Co/CoP/Co2P@N-CNF and Co/CoS2@N-CNF composite also achieve higher power density (375.16 and 400.06 mW m-2) as well as coulombic efficiency (11.2 %, 12.4 %), superior than that of Pt/C electrode (333.70 mW m-2, 10.4 %). Impressively, the Co/CoS2@N-CNF electrode exhibits long-term stability and durability in dual-chamber MFCs. A high-performance heterostructure cathode with an effective strategy for bridging nanocatalysis and practical MFCs is reported and presented.

Assessment of air quality before and during the COVID-19 and its potential health impacts in an arid oasis city: Urumqi, China.

As a key node city of the "Silk Road Economic Belt" Urumqi has been listed as one of the ten most polluted cities in the world, posing a serious threat to the urban environment and residents' health. This study analyzed the air quality before and during the COVID-19 (Coronavirus disease 2019) pandemic and its potential health effects based on the data of PM2.5, PM10, SO2, NO2, CO, and O3_8h levels from 10 air quality monitoring stations in Urumqi from January 1, 2017, to December 31, 2021. As per the results, the concentrations of the air pollutants PM2.5, PM10, SO2, NO2, CO, and O3_8h in Urumqi from 2017 to 2021 showed a cyclical trend, and the implementation of COVID-19 prevention and control measures could effectively reduce the concentration(ρ) of air pollutants. The mean value of ρ(PM2.5) decreased from 2017 to 2021, whereas ρ(O3_8h) showed a waveform change trend (increased in 2017-2018, decreased in 2018-2020, and increased after 2020). Meanwhile, the maximum annual average values of ρ(PM2.5) and ρ(O3_8h) for the six monitoring stations during 2017-2021 occurred at sites S2 (74.37 µg m-3) and S6 (91.80 µg m-3), respectively; rapid industrialization had a greater impact on PM2.5 and O3_8h concentrations compared to commercial and residential areas. In addition, the air quality index data series can characterize the fluctuation trend of PM2.5. The high pollution levels (Class IV and V) of the air pollutants PM2.5 and O3_8h in Urumqi have been decreasing annually, and good days can account for 80-95% of the total number of days in the year, indicating that the number of days with a potential threat to residents' health is gradually decreasing. Therefore, more attention should be paid in controlling and managing air pollution in Urumqi.

USP8 inhibitor-induced DNA damage activates cell cycle arrest, apoptosis, and autophagy in esophageal squamous cell carcinoma.

Increasing evidence suggests that targeting ubiquitin-specific peptidase 8 (USP8) serves as an attractive anti-cancer strategy. However, the role of USP8 inhibitor, DUB-IN-1, in esophageal squamous cell carcinoma (ESCC) cells still needs to be explored. Here, immunohistochemistry was employed to examine the expression of USP8 in ESCC tissues. Cell Counting Kit-8 (CCK-8) was used to evaluate cell proliferation ability, and propidium iodide (PI) was selected to test the effect of DUB-IN-1 on cell cycle. AnnexinV-FITC/PI staining and the activity of caspase 3 were detedcted to evaluate apoptosis. Transmission electron microscope, microtubule-associated protein 1 light-chain 3 (LC3) expression, and acridine orange (AO) staining were selected to check if there was autophagy. Comet assay and γ-H2AX immunofluorescence was used to monitor DNA damage. Rescue experiment was used to determine the key role of of p53 in cell cycle, apoptosis, and autophagy. Results revealed that the leve of USP8 was higher in ESCC tissues than that in tissues adjacent to carcinoma. DUB-IN-1, an USP8 inhibitor, caused DNA damage, led to G2/M phase block by p53-p21 axis, and triggered apoptosis by regulating the p53 target proteins including Bax, Noxa, and Puma. Besides, DUB-IN-1 could stimulate autophagy through p53-dependent adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) activation. Taken together, this study revealed the cytotoxic effects and the mechanism of DUB-IN-1, which indicated that DUB-IN-1 may be a novel inhibitor targeting USP8 that can kill ESCC cells. USP8 inhibitor, DUB-IN-1, treatment could inhibit esophageal squamous cell carcinoma cell growth and induce G2/M cell cycle arrest, apoptosis, and autophagy by DNA damage-induced p53 activation. DUB-IN-1 treatment led to G2/M cell cycle arrest by upregulating the protein level of p21 and triggered apoptosis by modulating the p53 target proteins including Bax, Noxa, and Puma. Meanwhile, DUB-IN-1 treatment stimulated protective autophagy through p53-dependent AMPK activation. Collectively, these findings suggested that DNA damage-triggered p53 activation, p53-Puma/Noxa/Bax, p53-p21, and p53-AMPK pathways were all involved in the effect of DUB-IN-1.