Estimating neighborhood-based mortality risk associated with air pollution: A prospective study.

Effect modification of integrated neighborhood environment on associations of air pollution with mortality remained unclear. We analyzed data from UK biobank prospective study (n = 421,650, median 12.5 years follow-up) to examine disparities of mortality risk associated with air pollution among varied neighborhood settings. Fine particulate matter (PM2.5), PM10 and nitrogen dioxide (NO2) were measured and assigned to each participants' address. Diverse ecological and societal settings of neighborhoods were integrated with principal component analysis and categorized into disadvantaged, intermediate and advantaged levels. We estimated mortality risk associated with air pollution across diverse neighborhoods using Cox regression. We calculated community-level proportions of mortality attributable to air pollutants. There was evidence of higher all-cause and respiratory disease mortality risk associated with PM2.5 and NO2 among those in disadvantaged neighborhoods. In disadvantaged communities, air pollutants explained larger proportions of deaths and such disparities persisted over past decades. Across 2010-2021, reducing PM2.5 and NO2 to 10 µg/m3 (World Health Organization limits) would save 87,000 (52,000-120,000) and 91,000 (37,000-145,000) deaths of populations aged ≥ 40 years, with 150 000 deaths occurred in disadvantaged neighborhood settings. These findings suggested that disadvantaged neighborhoods can exacerbate mortality risk associated with air pollution.

Srcap haploinsufficiency induced autistic-like behaviors in mice through disruption of Satb2 expression.

Mutations in the SRCAP gene are among the genetic alterations identified in autism spectrum disorders (ASD). However, the pathogenic mechanisms remain unclear. In this study, we demonstrate that Srcap+/- mice manifest deficits in social novelty response, as well as increased repetitive behaviors, anxiety, and impairments in learning and memory. Notably, a reduction in parvalbumin-positive neurons is observed in the retrosplenial cortex (RSC) and dentate gyrus (DG) of these mice. Through RNA sequencing, we identify dysregulation in 27 ASD-related genes in Srcap+/- mice. Specifically, we find that Srcap regulates expression of Satb2 via H2A.z in the promoter. Therapeutic intervention via retro-orbital injection of adeno-associated virus (AAV)-Satb2 in neonatal Srcap+/- mice leads to amelioration of the neurodevelopmental and ASD-like abnormalities. Furthermore, the expression of Satb2 only in the RSC of adolescent mice rectifies social novelty impairments. These results underscore the pivotal role of Srcap in neurodevelopment, by regulating Satb2, providing valuable insights for the pathophysiology of ASD.

Whole-brain in vivo base editing reverses behavioral changes in Mef2c-mutant mice.

Whole-brain genome editing to correct single-base mutations and reduce or reverse behavioral changes in animal models of autism spectrum disorder (ASD) has not yet been achieved. We developed an apolipoprotein B messenger RNA-editing enzyme, catalytic polypeptide-embedded cytosine base editor (AeCBE) system for converting C·G to T·A base pairs. We demonstrate its effectiveness by targeting AeCBE to an ASD-associated mutation of the MEF2C gene (c.104T>C, p.L35P) in vivo in mice. We first constructed Mef2cL35P heterozygous mice. Male heterozygous mice exhibited hyperactivity, repetitive behavior and social abnormalities. We then programmed AeCBE to edit the mutated C·G base pairs of Mef2c in the mouse brain through the intravenous injection of blood-brain barrier-crossing adeno-associated virus. This treatment successfully restored Mef2c protein levels in several brain regions and reversed the behavioral abnormalities in Mef2c-mutant mice. Our work presents an in vivo base-editing paradigm that could potentially correct single-base genetic mutations in the brain.

Silver-Catalyzed Cascade Radical Bicyclization Reaction: An Atom- and Step-Economical Strategy Accessing γ-Lactam Containing Isoquinolinediones.

An efficient and convenient method for the cascade radical bicyclization of N-phenyl-4-pentenamides with N-methyl-N-methacryloylbenzamides under silver-catalyzed conditions is described. Based on this newly developed strategy, a variety of valuable γ-lactam containing isoquinolinediones can be effectively synthesized in one step within 0.5 h, during which two C-C bonds, one C-N bond, and two new N-heterocycles were formed concurrently. With N-aryl allyl carbamates, similar 2-oxazolidinone substituted isoquinolinedione compounds can likewise be produced. The approach demonstrates wide functional group compatibility, high step- and atom-economy, and the ability to be scaled up to gram quantities in a satisfactory yield. It marks the first instance of introducing γ-lactams into isoquinoline-1,3(2H,4H)-diones to construct linked hybrid drug-like molecules, thereby making this strategy highly attractive to drug discovery.

Taok1 haploinsufficiency leads to autistic-like behaviors in mice via the dorsal raphe nucleus.

Strong evidence from human genetic studies associates the thousand and one amino acid kinase 1 (TAOK1) gene with autism spectrum disorder (ASD). In this work, we discovered a de novo frameshifting mutation in TAOK1 within a Chinese ASD cohort. We found that Taok1 haploinsufficiency induces autistic-like behaviors in mice. Importantly, we observed a significant enrichment of Taok1 in the dorsal raphe nucleus (DRN). The haploinsufficiency of Taok1 considerably restrained the activation of DRN neurons during social interactions, leading to the aberrant phosphorylation of numerous proteins. Intriguingly, the genetic deletion of Taok1 in VGlut3-positive neurons of DRN resulted in mice exhibiting autistic-like behaviors. Ultimately, reintroducing wild-type Taok1, but not its kinase-dead variant, into the DRN of adult mice effectively mitigated the autistic-like behaviors associated with Taok1 haploinsufficiency. This work suggests that Taok1, through its influence in the DRN, regulates social interaction behaviors, providing critical insights into the etiology of ASD.

Chromatin Remodeling Induced by ARID1A Loss in Lung Cancer Promotes Glycolysis and Confers JQ1 Vulnerability.

ARID1A is a key mammalian SWI/SNF complex subunit that is mutated in 5% to 11% of lung cancers. Although recent studies have elucidated the mechanism underlying dysregulation of the switch/sucrose non-fermentable (SWI/SNF) complexes in cancers, the significance of ARID1A loss and its implications in lung cancers remain poorly defined. This study investigates how ARID1A loss affects initiation and progression of lung cancer. In genetically engineered mouse models bearing mutant Kras and a deficient Trp53 allele (KP), ARID1A loss (KPA) promoted lung tumorigenesis. Analysis of the transcriptome profiles of KP and KPA tumors suggested enhanced glycolysis following ARID1A loss, and expression of the glycolytic regulators Pgam1, pyruvate kinase M (Pkm), and Pgk1 was significantly increased in ARID1A-deficient lung tumors. Furthermore, ARID1A loss increased chromatin accessibility and enhanced hypoxia-inducible factor-1α (HIF1α) binding to the promoter regions of Pgam1, Pkm, and Pgk1. Loss of ARID1A in lung adenocarcinoma also resulted in loss of histone deacetylase 1 (HDAC1) recruitment, increasing acetylation of histone-4 lysine at the promoters of Pgam1, Pkm, and Pgk1, and subsequently enhancing BRD4-driven transcription of these genes. Metabolic analyses confirmed that glycolysis is enhanced in ARID1A-deficient tumors, and genetic or pharmacologic inhibition of glycolysis inhibited lung tumorigenesis in KPA mice. Treatment with the small molecule bromodomain and extraterminal protein (BET) inhibitor JQ1 compromised both initiation and progression of ARID1A-deficient lung adenocarcinoma. ARID1A negatively correlated with glycolysis-related genes in human lung adenocarcinoma. Overall, ARID1A loss leads to metabolic reprogramming that supports tumorigenesis but also confers a therapeutic vulnerability that could be harnessed to improve the treatment of ARID1A-deficient lung cancer. SIGNIFICANCE: This study links ARID1A loss with enhanced glycolysis in lung cancer and demonstrates the preclinical efficacy of BET inhibitor therapy as a strategy to combat tumor growth.

SENP1 in the retrosplenial agranular cortex regulates core autistic-like symptoms in mice.

Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder, causing defects of social interaction and repetitive behaviors. Here, we identify a de novo heterozygous gene-truncating mutation of the Sentrin-specific peptidase1 (SENP1) gene in people with ASD without neurodevelopmental delay. We find that Senp1+/- mice exhibit core autistic-like symptoms such as social deficits and repetitive behaviors but normal learning and memory ability. Moreover, we find that inhibitory and excitatory synaptic functions are severely affected in the retrosplenial agranular (RSA) cortex of Senp1+/- mice. Lack of Senp1 leads to increased SUMOylation and degradation of fragile X mental retardation protein (FMRP), also implicated in syndromic ASD. Importantly, re-introducing SENP1 or FMRP specifically in RSA fully rescues the defects of synaptic function and autistic-like symptoms of Senp1+/- mice. Together, these results demonstrate that disruption of the SENP1-FMRP regulatory axis in the RSA causes autistic symptoms, providing a candidate region for ASD pathophysiology.

Impact of 4th of July Fireworks on Spatiotemporal PM2.5 Concentrations in California Based on the PurpleAir Sensor Network: Implications for Policy and Environmental Justice.

Fireworks are often used in celebration, causing short term, extremely high particulate matter air pollution. In recent years, the rapid development and expansion of low-cost air quality sensors by companies such as PurpleAir has enabled an understanding of air pollution at a much higher spatiotemporal resolution compared to traditional monitoring networks. In this study, real-time PM2.5 measurements from 751 PurpleAir sensors operating from June to July in 2019 and 2020 were used to examine the impact of 4th of July fireworks on hourly and daily PM2.5 concentrations at the census tract and county levels in California. American Community Survey (ACS) and CalEnviroScreen 3.0 data were used to identify correlations between PM2.5 measurements and socioeconomic status (SES). A two-step method was implemented to assure the quality of raw PM2.5 sensor data and sensor calibration against co-located reference instruments. The results showed that over 67% and 81% of counties experienced immediate impacts related to fireworks in 2019 and 2020, respectively. Relative to 2019, the peak PM2.5 concentrations on July 4th and 5th 2020 were, on average, over 50% higher in California, likely due to the COVID-19-related increase in the use of household-level fireworks. This increase was most pronounced in southern counties, which tend to have less strict firework-related regulations and a greater use of illegal fireworks. Los Angeles County experienced the highest July 4th daily PM2.5 levels both in 2019 (29.9 µg·m-3) and 2020 (42.6 µg·m-3). Spatial hot spot analyses generally showed these southern counties (e.g., Los Angeles County) to be regional air pollution hotspots, whereas the opposite pattern was seen in the north (e.g., San Francisco). The results also showed PM2.5 peaks that were over two-times higher among communities with lower SES, higher minority group populations, and higher asthma rates. Our findings highlight the important role that policy and enforcement can play in reducing firework-related air pollution and protecting public health, as exemplified by southern California, where policy was more relaxed and air pollution was higher (especially in 2020 when the 4th of July coincided with the COVID-19-lockdown period), and in disadvantaged communities where disparities were greatest.

Multilevel Edge Features Guided Network for Image Denoising.

Image denoising is a challenging inverse problem due to complex scenes and information loss. Recently, various methods have been considered to solve this problem by building a well-designed convolutional neural network (CNN) or introducing some hand-designed image priors. Different from previous works, we investigate a new framework for image denoising, which integrates edge detection, edge guidance, and image denoising into an end-to-end CNN model. To achieve this goal, we propose a multilevel edge features guided network (MLEFGN). First, we build an edge reconstruction network (Edge-Net) to directly predict clear edges from the noisy image. Then, the Edge-Net is embedded as part of the model to provide edge priors, and a dual-path network is applied to extract the image and edge features, respectively. Finally, we introduce a multilevel edge features guidance mechanism for image denoising. To the best of our knowledge, the Edge-Net is the first CNN model specially designed to reconstruct image edges from the noisy image, which shows good accuracy and robustness on natural images. Extensive experiments clearly illustrate that our MLEFGN achieves favorable performance against other methods and plenty of ablation studies demonstrate the effectiveness of our proposed Edge-Net and MLEFGN. The code is available at https://github.com/MIVRC/MLEFGN-PyTorch.

The electrochemical storage mechanism of an In2S3/C nanofiber anode for high-performance Li-ion and Na-ion batteries.

There are only a handful of reports on indium sulfide (In2S3) in the electrochemical energy storage field without a clear electrochemical reaction mechanism. In this work, a simple electrospinning method has been used to synthesize In2S3/C nanofibers for the first time. In lithium-ion batteries (LIBs), the In2S3/C nanofiber electrode can not only deliver a high initial reversible specific capacity of 696.4 mA h g-1 at 50 mA g-1, but also shows ultra-long cycle life with a capacity retention of 80.5% after 600 cycles at 1000 mA g-1. In sodium-ion batteries (SIBs), the In2S3/C nanofibers electrode can exhibit a high initial reversible specific capacity (393.7 mA h g-1 at 50 mA g-1) and excellent cycling performance with a high capacity retention of 97.3% after 300 cycles at 1000 mA g-1. The excellent electrochemical properties mainly benefited from In2S3 being encapsulated by a carbon matrix, which buffers the volume expansion and significantly improves the conductivity of the composite. Furthermore, the structural evolution of In2S3 during the first lithiation/delithiation and sodiation/desodiation processes has been illustrated by ex situ XRD. The results confirm that the reaction mechanism of In2S3 in both LIBs and SIBs can be summarized as conversion reactions and alloying reactions, which provide theoretical support for the development of In2S3 in the field of electrochemistry.

Reversal of Social Recognition Deficit in Adult Mice with MECP2 Duplication via Normalization of MeCP2 in the Medial Prefrontal Cortex.

Methyl-CpG binding protein 2 (MeCP2) is a basic nuclear protein involved in the regulation of gene expression and microRNA processing. Duplication of MECP2-containing genomic segments causes MECP2 duplication syndrome, a severe neurodevelopmental disorder characterized by intellectual disability, motor dysfunction, heightened anxiety, epilepsy, autistic phenotypes, and early death. Reversal of the abnormal phenotypes in adult mice with MECP2 duplication (MECP2-TG) by normalizing the MeCP2 levels across the whole brain has been demonstrated. However, whether different brain areas or neural circuits contribute to different aspects of the behavioral deficits is still unknown. Here, we found that MECP2-TG mice showed a significant social recognition deficit, and were prone to display aversive-like behaviors, including heightened anxiety-like behaviors and a fear generalization phenotype. In addition, reduced locomotor activity was observed in MECP2-TG mice. However, appetitive behaviors and learning and memory were comparable in MECP2-TG and wild-type mice. Functional magnetic resonance imaging illustrated that the differences between MECP2-TG and wild-type mice were mainly concentrated in brain areas regulating emotion and social behaviors. We used the CRISPR-Cas9 method to restore normal MeCP2 levels in the medial prefrontal cortex (mPFC) and bed nuclei of the stria terminalis (BST) of adult MECP2-TG mice, and found that normalization of MeCP2 levels in the mPFC but not in the BST reversed the social recognition deficit. These data indicate that the mPFC is responsible for the social recognition deficit in the transgenic mice, and provide new insight into potential therapies for MECP2 duplication syndrome.

Solubilization of phloretin via steviol glycoside-based solid dispersion and micelles.

In this study, the solubility of phloretin (PT) was enhanced via steviol glycoside (STE)-based micelle (MC) and solid dispersion (SD). Computer simulation, characterization, interaction with serum albumin (SA) and in vitro release were carried out to investigate the solubilization mechanisms and the difference in their solubilization capacities. For PT-loaded MC (STE-PT MC), PT was encapsulated into the hydrophobic core of a spherical micelle with a droplet diameter of 5 nm. For PT-loaded SD (STE-PT SD), PT was completely dispersed with the amorphous state in STE. Most of those PTs were directly dissolved in water, and few were encapsulated by STE micelles. The amorphous state combined with relatively large micelles contributed to the high solubilization capacity of STE-PT SD. In addition, PT of STE-PT SD exhibited a higher dissolution rate and more effective interaction with SA than that of STE-PT MC. No undesirable chemical interaction between PT and STE occurred.

Antibacterial Activity and Mode of Action of Dihydromyricetin from Ampelopsis grossedentata Leaves against Food-Borne Bacteria.

Dihydromyricetin (DMY) has recently attracted increased interest due to its considerable health-promoting activities but there are few reports on its antibacterial activity and mechanism. In this paper, the activity and mechanisms of DMY from Ampelopsis grossedentata leaves against food-borne bacteria are investigated. Moreover, the effects of pH, thermal-processing, and metal ions on the antibacterial activity of DMY are also evaluated. The results show that DMY exhibits ideal antibacterial activity on five types of food-borne bacteria (Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Salmonella paratyphi, and Pseudomonas aeruginosa). The activities of DMY against bacteria are extremely sensitive to pH, thermal-processing, and metal ions. The morphology of the tested bacteria is changed and damaged more seriously with the exposure time of DMY. Furthermore, the results of the oxidative respiratory metabolism assay and the integrity of the cell membrane and wall tests revealed that the death of bacteria caused by DMY might be due to lysis of the cell wall, leakage of intracellular ingredients, and inhibition of the tricarboxylic acid cycle (TCA) pathway.

Enhanced plasma miR-142-5p promotes the progression of intrahepatic cholangiocarcinoma via targeting PTEN.

The aim of the present study was to evaluate the expression and specific role of microRNA (miR)-142-5p in the progression of intrahepatic cholangiocarcinoma (ICC). Reverse transcription-quantitative polymerase chain reaction was performed to evaluate miR-142-5p expression in patients with ICC and healthy control subjects. The results revealed that plasma miR-142-5p was significantly increased in patients with ICC compared with the control group. Furthermore, miR-142-5p was also increased in ICC tissues compared with adjacent non-neoplastic tissues. Compared with patients with Ta-T1 stage ICC, miR-142-5p was significantly elevated in patients with ICC ≥T2 stage. Patients with ICC at G3 stage had much higher plasma miR-142-5p levels compared with those at G1/2 stage. Receiver operating characteristic analysis indicated that miR-142-5p could be used as a biomarker to differentiate patients with ICC from healthy controls. Kaplan-Meier analysis demonstrated that plasma miR-142-5p was negatively correlated with survival in patients with ICC. A dual luciferase reporter assay indicated that miR-142-5p significantly suppressed the relative luciferase activity of pmirGLO-PTEN-3' untranslated region compared with the control group. In summary, the results of the present study provide novel data indicating that plasma miR-142-5p is significantly upregulated in patients with ICC. miR-142-5p may therefore have potential as a biomarker for screening patients with ICC from healthy controls.

Nitrogen-Doped TiO2-C Composite Nanofibers with High-Capacity and Long-Cycle Life as Anode Materials for Sodium-Ion Batteries.

Nitrogen-doped TiO2-C composite nanofibers (TiO2/N-C NFs) were manufactured by a convenient and green electrospinning technique in which urea acted as both the nitrogen source and a pore-forming agent. The TiO2/N-C NFs exhibit a large specific surface area (213.04 m2 g-1) and a suitable nitrogen content (5.37 wt%). The large specific surface area can increase the contribution of the extrinsic pseudocapacitance, which greatly enhances the rate capability. Further, the diffusion coefficient of sodium ions (D Na+) could be greatly improved by the incorporation of nitrogen atoms. Thus, the TiO2/N-C NFs display excellent electrochemical properties in Na-ion batteries. A TiO2/N-C NF anode delivers a high reversible discharge capacity of 265.8 mAh g-1 at 0.05 A g-1 and an outstanding long cycling performance even at a high current density (118.1 mAh g-1) with almost no capacity decay at 5 A g-1 over 2000 cycles. Therefore, this work sheds light on the application of TiO2-based materials in sodium-ion batteries.

Occurrence, distribution, and potential affecting factors of organophosphate flame retardants in sewage sludge of wastewater treatment plants in Henan Province, Central China.

Organophosphate esters (OPEs) are widely used as flame retardants. In this study, the occurrence and distribution of six OPEs were investigated in sewage sludge from 24 wastewater treatment plants (WWTPs) in 18 cities of Henan province, Central China. The results indicated that all target OPEs were detected in the sludge samples with the detection rate of 95.8%, except tris(dichloropropyl)phosphate (TDCP). The total concentration of the six OPEs ranged from 38.6 to 508 µg kg(-1). Tris(2-chloroethyl)phosphate (TCEP), tris(2-butoxyethyl)phosphate (TBEP), and tris(2-chloroiso-propyl)phosphate (TCPP) were found to be predominant, with concentrations ranging from 2.50 to 203, 1.60 to 383, and 6.70-161 µg kg(-1), respectively. The potential factors affecting OPE levels in sewage sludge, such as wastewater source, sludge characteristics, operational conditions, treatment techniques, and total organic carbon (TOC) of sludge in WWTPs were investigated. The results indicated that the total concentration of OPEs in sewage sludge has no significant relationship with the individual parameters (p > 0.05). However, significant correlations were found between triphenyl phosphate (TPhP) level and treatment capacity (R = 0.484, p < 0.05), processing volume (R = 0.495, p < 0.05), and serving population (R = 0.591, p < 0.05). Furthermore, the relationship between treatment techniques and the total concentration of OPEs in sewage sludge was also investigated in this study, and the results illustrated that the levels of OPEs in sludge were independent of the solid retention time (SRT).