Clinical features of patients with mutations in genes for nanophthalmos.

BACKGROUND/AIMS: To distinguish the clinical feature of nanophthalmos (NNO) caused by mutations in protease serine 56 (PRSS56), membrane-type frizzled-related protein (MFRP), myelin regulatory factor (MYRF) and transmembrane protein 98 (TMEM98) and to evaluate the association between angle-closure glaucoma (ACG) and NNO. METHODS: Variants in those four genes were identified through exome sequencing/whole genome sequencing data, and bioinformatic analysis was conducted to identify pathogenic/likely pathogenic (P/LP) variants. This observational study comprehensively summarised ophthalmological data of 67 patients with NNO from 63 families. Ocular parameters from 68 eyes without surgical treatment were subjected to further analysis. RESULTS: Totally, 67 patients from 63 families harboured 57 P/LP variants in the four genes, including 30 in PRSS56 (47.6%), 23 in MFRP (36.5%), 5 in TMEM98 (7.9%) and 5 in MYRF (7.9%). ACG was present in 79.1% of patients. An analysis of ocular parameters from 68 eyes revealed that shorter axial length (AL), lower vitreous-to-AL ratios and severe foveal hypoplasia were associated with variants in PRSS56 and MFRP. Uveal effusion was more common in patients with PRSS56 variants, while retinitis pigmentosa was frequently observed in patients with MFRP variants. Patients with MYRF variants exhibited the thinnest retinal nerve fibre layer thickness. Patients with TMEM98 variants had an earlier average onset age of glaucoma. CONCLUSION: Variants in PRSS56 and MFRP are the most common genetic cause of NNO. ACG is a severe complication frequently observed in these patients. Earlier onset of ACG is observed in patients with dominant NNO, while foveal hypoplasia is more common in patients with recessive disease. Recognising these features is helpful in clinical care and genetic counselling.

Points of interest linear attention network for real-time non-rigid liver volume to surface registration.

BACKGROUND: In laparoscopic liver surgery, accurately predicting the displacement of key intrahepatic anatomical structures is crucial for informing the doctor's intraoperative decision-making. However, due to the constrained surgical perspective, only a partial surface of the liver is typically visible. Consequently, the utilization of non-rigid volume to surface registration methods becomes essential. But traditional registration methods lack the necessary accuracy and cannot meet real-time requirements. PURPOSE: To achieve high-precision liver registration with only partial surface information and estimate the displacement of internal liver tissues in real-time. METHODS: We propose a novel neural network architecture tailored for real-time non-rigid liver volume to surface registration. The network utilizes a voxel-based method, integrating sparse convolution with the newly proposed points of interest (POI) linear attention module. POI linear attention module specifically calculates attention on the previously extracted POI. Additionally, we identified the most suitable normalization method RMSINorm. RESULTS: We evaluated our proposed network and other networks on a dataset generated from real liver models and two real datasets. Our method achieves an average error of 4.23 mm and a mean frame rate of 65.4 fps in the generation dataset. It also achieves an average error of 8.29 mm in the human breathing motion dataset. CONCLUSIONS: Our network outperforms CNN-based networks and other attention networks in terms of accuracy and inference speed.

JinLiDa granules alleviates cardiac hypertrophy and inflammation in diabetic cardiomyopathy by regulating TP53.

BACKGROUND: JinLiDa granules (JLD) is a traditional Chinese medicine (TCM) used to treat type 2 diabetes mellitus with Qi and Yin deficiency. Clinical evidence has shown that JLD can alleviate diabetic cardiomyopathy, but the exact mechanism is not yet clear. PURPOSE: The purpose of this study was to examine the potential role and mechanism of JLD in the treatment of diabetic cardiomyopathy through network pharmacological analysis and basic experiments. METHODS: The targets of JLD associated with diabetic cardiomyopathy were examined by network pharmacology. Protein interaction analysis was performed on the targets, and the associated pathways were searched by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Diabetic mice were treated with low or high doses of JLD by gavage, and AC16 and H9C2 cardiomyocytes exposed to high-glucose conditions were treated with JLD. The analysis results were verified by various experimental techniques to examine molecular mechanisms. RESULTS: Network pharmacological analysis revealed that JLD acted on the tumor suppressor p53 (TP53) during inflammation and fibrosis associated with diabetic cardiomyopathy. The results of basic experiments showed that after JLD treatment, ventricular wall thickening in diabetic mouse hearts was attenuated, cardiac hypertrophy and myocardial inflammation were alleviated, and the expression of cardiac hypertrophy- and inflammation-related factors in cardiomyocytes exposed to a high-glucose environment was decreased. Cardiomyocyte morphology also improved after JLD treatment. TP53 expression and the tumor necrosis factor (TNF) and transforming growth factor beta-1 (TGFß1) signaling pathways were significantly altered, and inhibiting TP53 expression effectively alleviated the activation of the TNF and TGFß1 signaling pathways under high glucose conditions. Overexpression of TP53 activated these signaling pathways. CONCLUSIONS: JLD acted on TP53 to regulate the TNF and TGFß1 signaling pathways, effectively alleviating cardiomyocyte hypertrophy and inflammation in high glucose and diabetic conditions. Our study provides a solid foundation for the future treatment of diabetic cardiomyopathy with JLD.

The effect of acupuncture on gastrointestinal recovery after abdominal surgery: a narrative review from clinical trials.

Abdominal surgery is a critical surgery, with more and more attention being paid to postoperative life quality and associated complications in recent years. Among these complications, postoperative gastrointestinal dysfunction is the most common complication of abdominal surgery. Acupuncture therapy is a treatment approach based on the Traditional Chinese Medicine (TCM) theory, and its feasibility in aiding the gastrointestinal recovery after abdominal surgery is supported by both TCM theory and animal experiments. A lot of clinical research has been conducted to evaluate its efficacy, albeit with limitations and at preliminary stages. Moreover, intervention timing, acupoint selection, and patient benefits should also be considered in clinical practices. This article summarizes the progress of clinical research on acupuncture therapy in the gastrointestinal recovery after abdominal surgery, and discusses related issues and operations, with the aim to provide new insights and prospect for the incorporation of acupuncture into the Enhanced Recovery After Surgery (ERAS) protocol.

Aberrant expression of NEDD4L disrupts mitochondrial homeostasis by downregulating CaMKKß in diabetic kidney disease.

Disturbance in mitochondrial homeostasis within proximal tubules is a critical characteristic associated with diabetic kidney disease (DKD). CaMKKß/AMPK signaling plays an important role in regulating mitochondrial homeostasis. Despite the downregulation of CaMKKß in DKD pathology, the underlying mechanism remains elusive. The expression of NEDD4L, which is primarily localized to renal proximal tubules, is significantly upregulated in the renal tubules of mice with DKD. Coimmunoprecipitation (Co-IP) assays revealed a physical interaction between NEDD4L and CaMKKß. Moreover, deletion of NEDD4L under high glucose conditions prevented rapid CaMKKß protein degradation. In vitro studies revealed that the aberrant expression of NEDD4L negatively influences the protein stability of CaMKKß. This study also explored the role of NEDD4L in DKD by using AAV-shNedd4L in db/db mice. These findings confirmed that NEDD4L inhibition leads to a decrease in urine protein excretion, tubulointerstitial fibrosis, and oxidative stress, and mitochondrial dysfunction. Further in vitro studies demonstrated that si-Nedd4L suppressed mitochondrial fission and reactive oxygen species (ROS) production, effects antagonized by si-CaMKKß. In summary, the findings provided herein provide strong evidence that dysregulated NEDD4L disturbs mitochondrial homeostasis by negatively modulating CaMKKß in the context of DKD. This evidence underscores the potential of therapeutic interventions targeting NEDD4L and CaMKKß to safeguard renal tubular function in the management of DKD.

RASSF4 Attenuates Metabolic Dysfunction-Associated Steatotic Liver Disease Progression via Hippo Signaling and Suppresses Hepatocarcinogenesis.

BACKGROUND & AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a dynamic chronic liver disease closely related to metabolic abnormalities such as diabetes and obesity. MASLD can further progress to metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis, and even hepatocellular carcinoma (HCC). However, the mechanisms underlying the progression of MASLD and further progression to liver fibrosis and liver cancer are unknown. METHODS: In this study, we performed transcriptome analysis in livers from mice with MASLD and found suppression of a potential anti-oncogene, RAS association domain protein 4 (RASSF4). RASSF4 expression levels were measured in liver or tumor tissues of patients with MASH or HCC, respectively. We established RASSF4 overexpression and knockout mouse models. The effects of RASSF4 were evaluated by quantitative polymerase chain reaction, Western blotting, histopathological analysis, wound healing assays, Transwell assays, EdU incorporation assays, colony formation assays, sorafenib sensitivity assays, and tumorigenesis assays. RESULTS: RASSF4 was significantly down-regulated in MASH and HCC samples. Using liver-specific RASSF4 knockout mice, we demonstrated that loss of hepatic RASSF4 exacerbated hepatic steatosis and fibrosis. In contrast, RASSF4 overexpression prevented steatosis in MASLD mice. In addition, RASSF4 in hepatocytes suppressed the activation of hepatic stellate cells (HSCs) by reducing transforming growth factor beta secretion. Moreover, we found that RASSF4 is an independent prognostic factor for HCC. Mechanistically, we found that RASSF4 in the liver interacts with MST1 to inhibit YAP nuclear translocation through the Hippo pathway. CONCLUSIONS: These findings establish RASSF4 as a therapeutic target for MASLD and HCC.

Interpretation of Frequency Effect for High-Strength Steels with Three Different Strength Levels via Crystal Plasticity Finite Element Method.

The fatigue behavior of a high-strength bearing steel tempered under three different temperatures was investigated with ultrasonic frequency and conventional frequency loading. Three kinds of specimens with various yield strengths exhibited obvious higher fatigue strengths under ultrasonic frequency loading. Then, a 2D crystal plasticity finite element method was adopted to simulate the local stress distribution under different applied loads and loading frequencies. Simulations showed that the maximum residual local stress was much smaller under ultrasonic frequency loading in contrast to that under conventional frequency at the same applied load. It was also revealed that the maximum local stress increases with the applied load under both loading frequencies. The accumulated plastic strain was adopted as a fatigue indicator parameter to characterize the frequency effect, which was several orders smaller than that obtained under conventional loading frequencies when the applied load was fixed. The increment of accumulated plastic strain and the load stress amplitude exhibited a linear relationship in the double logarithmic coordinate system, and an improved fatigue life prediction model was established.

Determinants of Parental Intention to Vaccinate Young Adolescent Girls against the Human Papillomavirus in Taiwan: An Online Survey Study.

Since 2018, Taiwan has included the human papillomavirus (HPV) vaccination into its national immunization program for junior high school girls. However, the reports of side effects following vaccination have increased parental concerns. This study investigated parental intentions regarding the HPV vaccination for their daughters and related factors in Taiwan. A total of 213 parents of girls aged between 12 and 15 years participated in an online survey. The survey collected data on various factors, including the parental intention to vaccinate their daughters against HPV; the motivation behind the vaccinations, as measured using the Motors of Human Papillomavirus Vaccination Acceptance Scale; an understanding of the reasons behind the government's promotion of HPV vaccinations; concerns regarding the side effects of vaccinations for their daughters; an awareness of the reported side effects of HPV vaccines experienced by some individuals; the exposure to information on HPV vaccines from social media; and mental health status, measured using the Brief Symptom Rating Scale. The associations between these variables and the parental intention to vaccinate their daughters against HPV were examined using a multivariable linear regression analysis model. The findings revealed a moderate to high level of intention among participants to vaccinate their daughters against HPV. Parents who perceived a greater value in HPV vaccination for their daughters' health (B = 0.524, standard error [se] = 0.039, p < 0.001) and had greater autonomy in decision-making regarding vaccination (B = 0.086, se = 0.038, p = 0.026) exhibited a higher intention to vaccinate their daughters against HPV. Conversely, parents who expressed greater concern regarding the side effects of HPV vaccines for their daughters had a lower intention to vaccinate (B = -0.762, se = 0.203, p < 0.001). Based on these findings, this study recommends integrating these factors into the design of intervention programs aimed at enhancing parental intentions to vaccinate their daughters against HPV.

Millijoule Terahertz Radiation from Laser Wakefields in Nonuniform Plasmas.

We report the experimental measurement of millijoule terahertz (THz) radiation emitted in the backward direction from laser wakefields driven by a femtosecond laser pulse of few joules interacting with a gas target. By utilizing frequency-resolved energy measurement, it is found that the THz spectrum exhibits two peaks located at about 4.5 and 9.0 THz, respectively. In particular, the high frequency component emerges when the drive laser energy exceeds 1.26 J, at which electron acceleration in the forward direction is detected simultaneously. Theoretical analysis and particle-in-cell simulations indicate that the THz radiation is generated via mode conversion from the laser wakefields excited in plasma with an up-ramp profile, where radiations both at the local electron plasma frequency and its harmonics are produced. Such intense THz sources may find many applications in ultrafast science, e.g., manipulating the transient states of matter.

Mechanical-enhanced and Durable Zwitterionic Hydrogel Coating for Inhibiting Coagulation and Reducing Bacterial Infection.

Blood-contact medical devices are indispensable for clinical interventions, yet their susceptibility to thrombosis and bacterial infections poses substantial risks to treatment efficacy and patient well-being. In this study, we introduce a polysulfobetaine/alginate-CuII (SAC) zwitterionic hydrogel coating on polyurethane (PU) surfaces. This approach retained the superhydrophilic and antifouling nature of pSBMA while conferring the antibacterial effects of copper ions. Meanwhile, the copper alginate network intertwines with the polysulfobetaine (pSBMA) network, enhancing its mechanical properties and overcoming inherent weaknesses, thereby improving coating durability. Compared to the substrate, the SAC hydrogel coating significantly reduces thrombus adhesion mass by approximately 81.5% during extracorporeal blood circulation and effectively prevents bacterial biofilm formation even in a high-concentration bacterial milieu over 30 days. Moreover, the results from an isolated blood circulation model in New Zealand white rabbits affirm the impressive anticoagulant efficacy of the SAC hydrogel coating. Our findings suggest that this hydrogel coating and its application method hold promise as a solution for blood-contact material surface modification to address thrombosis and bacterial biofilm formation simultaneously. This article is protected by copyright. All rights reserved.

A dynamic regulatory switch for phase separation of FUS protein: Zinc ions and zinc finger domain.

Zinc is an important trace element in the human body, and its homeostasis is closely related to amyotrophic lateral sclerosis (ALS). Cytoplasmic FUS proteins from patients with ALS aggregate their important pathologic markers. Liquid-liquid phase separation (LLPS) of FUS can lead to its aggregation. However, whether and how zinc homeostasis affects the aggregation of disease-associated FUS proteins in the cytoplasm remains unclear. Here, we found that zinc ion enhances LLPS and promotes the aggregation in the cytoplasm for FUS protein. In the FUS, the cysteine of the zinc finger (ZnF), recognizes and binds to zinc ions, reducing droplet mobility and enhancing protein aggregation in the cytoplasm. The mutation of FUS cysteine disrupts the dynamic regulatory switch of zinc ions and ZnF, resulting in insensitivity to zinc ions. These results suggest that the dynamic regulation of LLPS by binding with zinc ions may be a widespread mechanism and provide a new understanding of neurological diseases such as ALS and other ZnF protein-related diseases.

Flexible Aerogel Materials: A Review on Revolutionary Flexibility Strategies and the Multifunctional Applications.

The design and preparation of flexible aerogel materials with high deformability and versatility have become an emerging research topic in the aerogel fields, as the brittle nature of traditional aerogels severely affects their safety and reliability in use. Herein, we review the preparation methods and properties of flexible aerogels and summarize the various controlling and design methods of aerogels to overcome the fragility caused by high porosity and nanoporous network structure. The mechanical flexibility of aerogels can be revolutionarily improved by monomer regulation, nanofiber assembly, structural design and controlling, and constructing of aerogel composites, which can greatly broaden the multifunctionality and practical application prospects. The design and construction criterion of aerogel flexibility is summarized: constructing a flexible and deformable microstructure in an aerogel matrix. Besides, the derived multifunctional applications in the fields of flexible thermal insulation (flexible thermal protection at extreme temperatures), flexible wearable electronics (flexible sensors, flexible electrodes, electromagnetic shielding, and wave absorption), and environmental protection (oil/water separation and air filtration) are summarized. Furthermore, the future development prospects and challenges of flexible aerogel materials are also summarized. This review will provide a comprehensive research basis and guidance for the structural design, fabrication methods, and potential applications of flexible aerogels.

B(C6F5)3/Chiral Phosphoric Acid Catalyzed Asymmetric Aza-Diels-Alder Reaction of Imines and Unactivated Dienes.

Herein, we report an asymmetric aza-Diels-Alder reaction of quinoxalinones or benzoxazinones with unactivated dienes by utilizing a B(C6F5)3/chiral phosphoric acid catalyst to construct chiral six-membered N-heterocycles. Various quinoxalinones or benzoxazinones with electron-withdrawing and electron-donating groups and unactivated dienes were tolerated (up to 99% yield and 99% ee) in the methodology with only 2 mol % catalyst loading. Moreover, the luminescence mechanism and photophysical properties of the product were tested and used for anticounterfeiting of QR codes.

A Phase I Clinical Study Comparing the Pharmacokinetics, Safety, and Immunogenicity of GB221 Injection and Trastuzumab (Herceptin®) in Healthy Chinese Adults.

BACKGROUND AND OBJECTIVE: GB221 is a recombinant humanized anti-HER2 monoclonal antibody. The purpose of this study was to evaluate the pharmacokinetic, safety, and immunogenicity of GB221 in healthy Chinese adults in comparison to trastuzumab (Herceptin®). METHODS: In this randomized, double-blind, parallel-group phase I clinical trial, 88 subjects were randomized 1:1 to receive a single intravenous infusion (90-100 min) of GB221 or trastuzumab (6 mg/kg). The primary pharmacokinetic parameters-maximum observed serum concentration (Cmax), area under the serum concentration-time curve from zero to the last quantifiable concentration at time t (AUC0-t), and area under the serum concentration-time curve from time zero to infinity (AUC0-∞)-of GB221 and trastuzumab were compared to establish whether the 90% confidence interval (CI) attained the 80-125% bioequivalence standard. Safety and immunogenicity were also evaluated. RESULTS: The GB221 group (n = 43) and the trastuzumab group (n = 44) showed similar pharmacokinetic characteristics. The geometric mean ratios (90% CI) of Cmax, AUC0-t, and AUC0-∞ between the two groups were 107.53% (102.25-113.07%), 108.31% (103.57-113.26%), and 108.34% (103.57-113.33%), respectively. The incidence of treatment-emergent adverse events (TEAEs) was 83.7% (36/43) of the subjects in the GB221 group and 95.5% (42/44) of the subjects in the trastuzumab group. No subjects withdrew from the trial due to TEAEs, and there were no occurrences of serious adverse events. All subjects tested negative for antidrug antibodies (ADA). CONCLUSION: GB221 demonstrated similar pharmacokinetics to trastuzumab and comparable safety and immunogenicity in healthy Chinese adults.

Expert consensus on irrigation and intracanal medication in root canal therapy.

Chemical cleaning and disinfection are crucial steps for eliminating infection in root canal treatment. However, irrigant selection or irrigation procedures are far from clear. The vapor lock effect in the apical region has yet to be solved, impeding irrigation efficacy and resulting in residual infections and compromised treatment outcomes. Additionally, ambiguous clinical indications for root canal medication and non-standardized dressing protocols must be clarified. Inappropriate intracanal medication may present side effects and jeopardize the therapeutic outcomes. Indeed, clinicians have been aware of these concerns for years. Based on the current evidence of studies, this article reviews the properties of various irrigants and intracanal medicaments and elucidates their effectiveness and interactions. The evolution of different kinetic irrigation methods, their effects, limitations, the paradigm shift, current indications, and effective operational procedures regarding intracanal medication are also discussed. This expert consensus aims to establish the clinical operation guidelines for root canal irrigation and a position statement on intracanal medication, thus facilitating a better understanding of infection control, standardizing clinical practice, and ultimately improving the success of endodontic therapy.

The impact of intellectual property rights protection on green innovation: A quasi-natural experiment based on the pilot policy of the Chinese intellectual property court.

In the context of high-quality economic development in China, it is important to promote green innovation development by protecting intellectual property rights (IPR). Taking the pilot policy of the intellectual property courts in Beijing, Shanghai, and Guangzhou for example in a quasi-natural experiment, this article examines the effect of IPR protection on the development of corporate green innovation and its mechanisms by using a difference-in-differences model and a mediating effect model based on Chinese enterprise data from 2011 to 2019. The study found that first, IPR protection promotes enterprise green technological innovation; second, IPR protection affects green innovation through enterprise financing constraints and R&D investment; that is, increasing enterprise R&D investment and alleviating enterprise financing constraints are two important channels through which IPR protection promotes enterprise green technological innovation.

A multi-scale attention residual-based U-Net network for stroke electrical impedance tomography.

Electrical impedance tomography (EIT), a non-invasive, radiation-free, and convenient imaging technique, has been widely used in the diagnosis of stroke. However, due to soft-field nonlinearity and the ill-posed inverse problem, EIT images always suffer from low spatial resolution. Therefore, a multi-scale convolutional attention residual-based U-Net (MARU-Net) network is proposed for stroke reconstruction. Based on the U-Net network, a residual module and a multi-scale convolutional attention module are added to the concatenation layer. The multi-scale module extracts feature information of different sizes, the attention module strengthens the useful information, and the residual module improves the performance of the network. Based on the above advantages, the network is used in the EIT system for stroke imaging. Compared with convolutional neural networks and one-dimensional convolutional neural networks, the MARU-Net network has fewer artifacts, and the reconstructed image is clear. At the same time, the reduction of noisy artifacts in the MARU-Net network is verified. The results show that the image correlation coefficient of the reconstructed image with noise is greater than 0.87. Finally, the practicability of the network is verified by a model physics experiment.

Differential intestinal effects of water and foodborne exposures of nano-TiO2 in the mussel Mytilus coruscus under elevated temperature.

With the wide use of nanomaterials in daily life, nano-titanium dioxide (nano-TiO2) presents potential ecological risks to marine ecosystems, which can be exacerbated by ocean warming (OW). However, most previous studies have only centered around waterborne exposure, while there is a scarcity of studies concentrating on the impact of trophic transfer exposure on organisms. We investigated the differences in toxic effects of 100 µg/L nano-TiO2 on mussels via two pathways (waterborne and foodborne) under normal (24 °C) and warming (28 °C) conditions. Single nano-TiO2 exposure (waterborne and foodborne) elevated the superoxide dismutase (SOD) and catalase (CAT) activities as well as the content of glutathione (GSH), indicating activated antioxidatant response in the intestine. However, depressed antioxidant enzymes and accumulated peroxide products (LPO and protein carbonyl content, PCC) demonstrated that warming in combination with nano-TiO2 broke the prooxidant-antioxidant homeostasis of mussels. Our findings also indicated that nano-TiO2 and high temperature exhibited adverse impacts on amylase (AMS), trypsin (PS), and trehalase (THL). Additionally, activated immune function (lysozyme) comes at the cost of energy expenditure of protein (decreased protein concentration). The hydrodynamic diameter of nano-TiO2 at 24 °C (1693-2261 nm) was lower than that at 28 °C (2666-3086 nm). Bioaccumulation results (range from 0.022 to 0.432 µg/g) suggested that foodborne induced higher Ti contents in intestine than waterborne. In general, the combined effects of nano-TiO2 and warming demonstrated a more pronounced extent of interactive effects and severe damage to antioxidant, digestive, and immune parameters in mussel intestine. The toxicological impact of nano-TiO2 was intensified through trophic transfer. The toxic effects of nano-TiO2 are non-negligible and can be exerted together through both water- and foodborne exposure routes, which deserves further investigation.

CKR-1 orchestrates two motor states from a single motoneuron in C. elegans.

Neuromodulation is pivotal in modifying neuronal properties and motor states. CKR-1, a homolog of the cholecystokinin receptor, modulates robust escape steering and undulation body bending in C. elegans. Nevertheless, the mechanisms through which CKR-1 governs these motor states remain elusive. We elucidate the head motoneuron SMD as the orchestrator of both motor states. This regulation involves two neuropeptides: NLP-12 from DVA enhances undulation body curvature, while NLP-18 from ASI amplifies Ω-turn head curvature. Moreover, synthetic NLP-12 and NLP-18 peptides elicit CKR-1-dependent currents in Xenopus oocytes and Ca2+ transients in SMD neurons. Notably, CKR-1 shows higher sensitivity to NLP-18 compared to NLP-12. In situ patch-clamp recordings reveal CKR-1, NLP-12, and NLP-18 are not essential for neurotransmission at C. elegans neuromuscular junction, suggesting that SMD independently regulates head and body bending. Our studies illustrate that a single motoneuron SMD utilizes a cholecystokinin receptor CKR-1 to integrate two motor states.

p53 accelerates endothelial cell senescence in diabetic retinopathy by enhancing FoxO3a ubiquitylation and degradation via UBE2L6.

Diabetic retinopathy (DR) is the most common ocular fundus disease in diabetic patients. Chronic hyperglycemia not only promotes the development of diabetes and its complications, but also aggravates the occurrence of senescence. Previous studies have shown that DR is associated with senescence, but the specific mechanism has not been fully elucidated. Here, we first detected the differentially expressed genes (DEGs) and cellular senescence level of db/db mouse retinas by bulk RNA sequencing. Then, we used single-cell sequencing (scRNA-seq) to identify the main cell types in the retina and analyzed the DEGs in each cluster. We demonstrated that p53 expression was significantly increased in retinal endothelial cell cluster of db/db mice. Inhibition of p53 can reduce the expression of SA-ß-Gal and the senescence-associated secretory phenotype (SASP) in HRMECs. Finally, we found that p53 can promote FoxO3a ubiquitination and degradation by increasing the expression of the ubiquitin-conjugating enzyme UBE2L6. Overall, our results demonstrate that p53 can accelerate the senescence process of endothelial cells and aggravate the development of DR. These data reveal new targets and insights that may be used to treat DR.