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Compact and adaptable CRISPR-Cas systems enable genome engineering applications in various contexts via high-efficiency delivery. The adeno-associated virus (AAV) is a widely used delivery system. One of the most compact type II-C Cas9 orthologs—CjCas9, derived from Campylobacter jejuni, is particularly appealing for AAV delivery. However, the editing efficiency of CjCas9 limits its applications. In this study, we used structure-guided protein engineering to improve the editing efficiency of CjCas9. Subsequently, we developed a miniature transcriptional activator (LDE-CjCas9-VPR) and base editors engineered from CjCas9 (LDE-CjABE and LDE-CjCBE). LDE-CjABE effectively induced genome editing in human and mouse cells. Through AAV delivery, LDE-CjABE enhanced the on-target editing efficiency, and off-target editing was not detected in the mouse retina. Therefore, the compact size and high editing efficiency of LDE-CjCas9 broadens the target scope of transcription activation and base editing toolsets for therapeutic applications.

Abstract Wet age‐related macular degeneration (AMD) is a common cause of vision loss in the elderly. It is characterised by choroidal neovascularisation (CNV), caused by overexpression of vascular endothelial growth factor (VEGF), resulting in abnormal vessel proliferation. Current clinical management predominantly relies on anti‐VEGF agents, which require frequent and costly injections. Clustered regularly interspaced short palindromic repeats (CRISPR) technology has emerged as a promising strategy for permanently suppressing angiogenesis by targeting the VEGF‐related pathway. Increased research suggests that disrupting this pathway holds potential for preventing CNV progression. This review provides an overview of the aetiology, classification and pathophysiology of wet AMD, followed by a concise summary of current gene editing research using the CRISPR/Cas system via viral vector delivery strategies to target ocular pro‐angiogenic factors, including Hif‐1α, VEGF and VEGFR. The importance of timely targeting of VEGFA is emphasised and the challenges associated with gene editing therapies are also highlighted.

Abstract Background Age‐related macular degeneration (AMD), particularly wet AMD characterised by choroidal neovascularization (CNV), is a leading cause of vision loss in the elderly. The hypoxia‐inducible factor‐1α (HIF‐1α)/vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR2) pathway contributes to CNV pathogenesis. Previous gene editing research indicated that disrupting these genes in retinal pigment epithelial cells could have a preventive effect on CNV progression. However, no studies have yet been conducted using gene editing to disrupt VEGF signalling after CNV induction for therapeutic validation, which is critical to the clinical application of wet AMD gene editing therapies. Method Here, we employed the single‐adeno‐associated virus‐mediated Nme2Cas9 to disrupt key molecules in VEGF signalling, Hif1α, Vegfa and Vegfr2 after inducing CNV and estimated their therapeutic effects. Results We found that Nme2Cas9 made efficient editing in target genes up to 71.8% post 11 days in vivo. And only Nme2Cas9‐Vegfa treatment during the early stage of CNV development reduced the CNV lesion area by 49.5%, compared to the negative control, while Nme2Cas9‐Hif1α or Nme2Cas9‐Vegfr2 treatment did not show therapeutic effect. Besides, no off‐target effects were observed in Nme2Cas9‐mediated gene editing in vivo. Conclusions This study provides proof‐of‐concept possibility of employing Nme2Cas9 for potential anti‐angiogenesis therapy in wet AMD.

BeiDou Medium Earth Orbit moderate-energy electron detection data play an important role in space environment effect analysis including satellite anomaly diagnosis, satellite risk estimation, etc. However, the data contain outliers which cause obstacle for the subsequent usage significantly. To solve this problem, we propose an outlier detection method based on convolutional neural networks (CNNs) which can learn a rule from labeled historical data and detect outliers from the detection data. With this method, we can identify outliers and do some follow-up operations to improve the data quality. In comparison with general methods, this CNN method provides a more reliable and rapid way to build dataset for the follow-up work.

Intrauterine adhesion (IUA) is a common endometrial disease and one of the main causes of infertility in women of childbearing age. Current treatment strategies, such as hysteroscopic adhesion resection, hysteroscopic transcervical resection of adhesion (TCRA), the use of local hormone drugs, and anti-adhesion scaffold implantation, do not provide a satisfactory pregnancy outcome for moderate-severe IUA, which presents a great challenge in reproductive medicine. With the development of material engineering, various bioactive and functional hydrogels have been developed using natural and synthetic biomaterials. These hydrogels are not only used as barely physical barriers but are also designed as vectors of hormone drugs, growth factors, and stem cells. These characteristics give bioactive hydrogels potentially important roles in the prevention and treatment of IUA. However, there is still no systematic review or consensus on the current advances and future research direction in this field. Herein, we review recent advances in bioactive hydrogels as physical anti-adhesion barriers, in situ drug delivery systems, and 3D cell delivery and culture systems for seeded cells in IUA treatment. In addition, current limitations and future perspectives are presented for further research guidance, which may provide a comprehensive understanding of the application of bioactive hydrogels in intrauterine adhesion treatment.

Temporomandibular joint disorders (TMD) are a common health condition caused by the structural or functional disorders of masticatory muscles and the temporomandibular joint (TMJ). Abnormal mandibular movement in TMD patients may cause pain, chronic inflammation, and other discomfort, which could be relieved by a variety of drugs through various delivery systems. In this study, we summarized commonly used therapeutic agents in the management of TMD as well as novel bioactive molecules in preclinical stage and clinical trials. The emerging therapy strategies such as novel intra-TMJ delivery systems and implants based on tissue engineering are also discussed. This comprehensive review will strengthen our understanding of pharmacological approaches for TMD therapy.

Cognitive dysfunction is one of the serious complications induced by status epilepticus (SE), which has a significant negative impact on patients’ quality of life. Previous studies demonstrated that the pathophysiological changes after SE such as oxidative stress, inflammatory reaction contribute to neuronal damage. A recent study indicated that preventive astaxanthin (AST) alleviated epilepsy-induced oxidative stress and neuronal apoptosis in the brain. In the present study, rats were treated with vehicle or AST 1 h after SE onset and were injected once every other day for 2 weeks (total of seven times). The results showed that the cognitive function in SE rats was significantly impaired, and AST treatment improved cognitive function in the Morris water maze (MWM). Magnetic resonance imaging (MRI), hematoxylin-eosin (HE) staining and TdT-mediated dUTP Nick-End Labeling (TUNEL) staining showed obvious damage in the hippocampus of SE rats, and AST alleviated the damage. Subsequently, we evaluated the effect of AST on relative pathophysiology to elucidate the possible mechanisms. To evaluate the oxidative stress, the expression of malondialdehyde (MDA) and superoxide dismutase (SOD) in plasma were detected using commercially available kits. NADPH oxidase-4 (Nox-4), p22phox, NF-E2-related factor 2 (Nrf-2), heme oxygenase 1 (Ho-1) and sod1 in the parahippocampal cortex and hippocampus were detected using western blot and real-time polymerase chain reaction (RT-PCR). The levels of MDA in plasma and Nox-4 and p22phox in the brain increased in SE rats, and the levels of SOD in plasma and Nrf-2, Ho-1 and sod1 in the brain decreased. Treatment with AST alleviated these changes. We also detected the levels of inflammatory mediators like cyclooxygenase-2 (cox-2), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and NF-κB phosphorylation p65 (p-p65)/p65 in the brain. The inflammatory reaction was significantly activated in the brain of SE rats, and AST alleviated neuroinflammation. We detected the levels of p-Akt, Akt, B-cell lymphoma-2 (Bcl-2), Bax, cleaved caspase-3, and caspase-3 in the parahippocampal cortex and hippocampus using western blot. The levels of p-Akt/Akt and Bcl-2 decreased in SE rats, Bax and cleaved caspase-3/caspase-3 increased, while AST alleviated these changes. The present study indicated that AST exerted an reobvious neuroprotective effect in pilocarpine-induced SE rats.

Doxorubicin (DOX)-mediated cardiotoxicity can exacerbate mortality in oncology patients, but related pharmacotherapeutic measures are relatively limited. Ferroptosis was recently identified as a major mechanism of DOX-induced cardiotoxicity. Idebenone, a novel ferroptosis inhibitor, is a well-described clinical drug widely used. However, its role and pathological mechanism in DOX-induced cardiotoxicity are still unclear. In this study, we demonstrated the effects of idebenone on DOX-induced cardiotoxicity and elucidated its underlying mechanism. A single intraperitoneal injection of DOX (15 mg/kg) was administrated to establish DOX-induced cardiotoxicity. The results showed that idebenone significantly attenuated DOX-induced cardiac dysfunction due to its ability to regulate acute DOX-induced Fe2+ and ROS overload, which resulted in ferroptosis. CESTA and BLI further revealed that idebenone's anti-ferroptosis effect was mediated by FSP1. Interestingly, idebenone increased FSP1 protein levels but did not affect Fsp1 mRNA levels in the presence of DOX. Idebenone could form stable hydrogen bonds with FSP1 protein at K355, which may influence its association with ubiquitin. The results confirmed that idebenone stabilized FSP1 protein levels by inhibiting its ubiquitination degradation. In conclusion, this study demonstrates idebenone attenuated DOX-induced cardiotoxicity by inhibiting ferroptosis via regulation of FSP1, making it a potential clinical drug for patients receiving DOX treatment.

This study proposes a multi-energy complementary heating system that uses solar energy combined with biomass energy as the main heat source, with electricity as an auxiliary heat source. The system aims to tackle the low efficiency, high energy consumption, and pollution associated with traditional heating methods in rural southern Xinjiang, enhancing performance and productivity. It is designed to operate in five modes based on the region’s climate and building heat load requirements. An experimental platform was set up in eight rural households in Tumushuk City, Xinjiang, where winter heating tests were conducted. The goal of this study was to analyze the economic and environmental benefits of the system. The results showed that the energy utilization efficiencies of the five modes were 56.84%, 74.34%, 70.1%, 63.13%, and 59.68%. The corresponding CO2 emissions were 3.56 kg/d, 45.09 kg/d, 105.75 kg/d, 30.97 kg/d, and 76.79 kg/d. The environmental and economic costs for each mode were 0.0493 USD/d, 0.6398 USD/d, 1.5029 USD/d, 0.4384 USD/d, and 1.0905 USD/d. It is clear that as an auxiliary heat source, biomass energy is more beneficial than electricity. All five modes maintained indoor temperatures of 18 °C or higher, meeting winter heating needs in cold regions. The results of this study provide important data support for the promotion and application of solar and biomass heating systems in the rural areas of southern Xinjiang and also provide valuable references for solving the problem of decentralized heating in rural areas.

Genome-wide association study (GWAS) have identified over 1,000 loci associated with blood pressure. However, these loci only explain 6% of heritability. Transcriptome-wide association studies (TWAS) combine GWAS summary data with expression quantitative trait loci (eQTL) to provide a better approach to finding genes associated with complex traits. GWAS summary data (N = 450,584) for essential hypertension originating from European samples were subjected to Post-GWAS analysis using FUMA software and then combined with eQTL data from Genotype-Tissues Expression Project (GTEx) v8 for TWAS analysis using UTMOST, FUSION software, and then validated the results with SMR. FUMA identified 346 significant genes associated with hypertension, FUSION identified 461, and UTMOST cross-tissue analysis identified 34, of which 5 were common. SMR validation identified 3 key genes: ENPEP, USP38, and KCNK3. In previous GWAS studies on blood pressure regulation, the association of ENPEP and KCNK3 with hypertension has been established, and the association between USP38 and blood pressure regulation still needs further validation.

Multi-energy complementary heating (MECH) is the most promising and potential heating technology of the future. However, owing to the increase in energy types, the system is complex, and the operation procedure cumbersome. In addition, due to the uncertainty of climate conditions, it is difficult to develop a general control strategy suitable for all heating systems. In order to study the optimal control strategy of MECH systems with solar, biomass, and electric energy as three heat sources in cold regions, the system heating was tested over different periods during the entire heating season for rural residential buildings in cold regions, and the operating performance of the system was evaluated. The MECH experiment, based on the optimal control strategy, was compared with other different heating systems, and the economic and environmental benefits of the system were further evaluated. The results showed that, compared with room temperature control strategy (RS-CON), the control strategy of the heat storage tank (HST-CON) with sufficient solar energy (SE) can afford a higher solar fraction by 10%, more HST heating hours, and lower operating costs and CO2 emissions. During heating operation, Mode 3 [biomass boiler (BB) + heat storage tank (HST) heating] was the best heating mode. At the end of the heating period, Mode 5 (HST heating) met the indoor heat demand and had a significant energy-saving effect. From the perspective of the whole heating season, HST-CON heating operation can generate lower energy consumption costs and achieve almost zero CO2 emissions. This study is of great significance because it provides an engineering reference for the rational the utilization of MECH systems in cold regions.