Association of lipid-lowering drugs with risk of sarcopenia: a drug target mendelian randomization study and meta-analysis.

BACKGROUND: Lipid-lowering drugs are widely used among the elderly, with some studies suggesting links to muscle-related symptoms. However, the causality remains uncertain. METHODS: Using the Mendelian randomization (MR) approach, we assessed the causal effects of genetically proxied reduced low-density lipoprotein cholesterol (LDL-C) through inhibitions of hydroxy-methyl-glutaryl-CoA reductase (HMGCR), proprotein convertase subtilisin/kexin type 9 (PCSK9), and Niemann-Pick C1-like 1 (NPC1L1) on sarcopenia-related traits, including low hand grip strength, appendicular lean mass, and usual walking pace. A meta-analysis was conducted to combine the causal estimates from different consortiums. RESULTS: Using LDL-C pooled data predominantly from UK Biobank, genetically proxied inhibition of HMGCR was associated with higher appendicular lean mass (beta = 0.087, P = 7.56 × 10- 5) and slower walking pace (OR = 0.918, P = 6.06 × 10- 9). In contrast, inhibition of PCSK9 may reduce appendicular lean mass (beta = -0.050, P = 1.40 × 10- 3), while inhibition of NPC1L1 showed no causal impact on sarcopenia-related traits. These results were validated using LDL-C data from Global Lipids Genetics Consortium, indicating that HMGCR inhibition may increase appendicular lean mass (beta = 0.066, P = 2.17 × 10- 3) and decelerate walking pace (OR = 0.932, P = 1.43 × 10- 6), whereas PCSK9 inhibition could decrease appendicular lean mass (beta = -0.048, P = 1.69 × 10- 6). Meta-analysis further supported the robustness of these causal associations. CONCLUSIONS: Genetically proxied HMGCR inhibition may increase muscle mass but compromise muscle function, PCSK9 inhibition could result in reduced muscle mass, while NPC1L1 inhibition is not associated with sarcopenia-related traits and this class of drugs may serve as viable alternatives to sarcopenia individuals or those at an elevated risk.

Multiarmed Aromatic Ammonium Salts Boost the Efficiency and Stability of Inverted Organic Solar Cells.

Inverted organic solar cells (OSCs) have attracted much attention because of their outstanding stability, with zinc oxide (ZnO) being commonly used as the electron transport layer (ETL). However, both surface defects and the photocatalytic effect of ZnO could lead to serious photodegradation of acceptor materials. This, in turn, hampers the improvement of the efficiency and stability in OSCs. Herein, we developed a multiarmed aromatic ammonium salt, namely, benzene-1,3,5-triyltrimethanaminium bromide (PhTMABr), for modifying ZnO. This compound possesses mild weak acidity aimed at removing the residual amines present within ZnO film. In addition, the PhTMABr could also passivate surface defects of ZnO through multiple hydrogen-bonding interactions between its terminal amino groups and the oxygen anion of ZnO, leading to a better interface contact, which effectively enhances charge transport. As a result, an efficiency of 18.75% was achieved based on the modified ETL compared to the bare ZnO (PCE = 17.34%). The devices utilizing the modified ZnO retained 87% and 90% of their initial PCE after thermal stress aging at 65 °C for 1500 h and continuous 1-sun illumination with maximum power point (MPP) tracking for 1780 h, respectively. Importantly, the extrapolated T80 lifetime with MPP tracking exceeds 10 000 h. The new class of materials employed in this work to modify the ZnO ETL should pave the way for enhancing the efficiency and stability of OSCs, potentially advancing their commercialization process.

USP38 exacerbates pressure overload-induced left ventricular electrical remodeling.

BACKGROUND: Ubiquitin-specific protease 38 (USP38), belonging to the USP family, is recognized for its role in controlling protein degradation and diverse biological processes. Ventricular arrhythmias (VAs) following heart failure (HF) are closely linked to ventricular electrical remodeling, yet the specific mechanisms underlying VAs in HF remain inadequately explored. In this study, we examined the impact of USP38 on VAs in pressure overload-induced HF. METHODS: Cardiac-specific USP38 knockout mice, cardiac-specific USP38 transgenic mice and their matched control littermates developed HF induced by aortic banding (AB) surgery. After subjecting the mice to AB surgery for a duration of four weeks, comprehensive investigations were conducted, including pathological analysis and electrophysiological assessments, along with molecular analyses. RESULTS: We observed increased USP38 expression in the left ventricle of mice with HF. Electrocardiogram showed that the USP38 knockout shortened the QRS interval and QTc, while USP38 overexpression prolonged these parameters. USP38 knockout decreased the susceptibility of VAs by shortening action potential duration (APD) and prolonging effective refractory period (ERP). In addition, USP38 knockout increased ion channel and Cx43 expression in ventricle. On the contrary, the increased susceptibility of VAs and the decreased expression of ventricular ion channels and Cx43 were observed with USP38 overexpression. In both in vivo and in vitro experiments, USP38 knockout inhibited TBK1/AKT/CAMKII signaling, whereas USP38 overexpression activated this pathway. CONCLUSION: Our data indicates that USP38 increases susceptibility to VAs after HF through TBK1/AKT/CAMKII signaling pathway, Consequently, USP38 may emerge as a promising therapeutic target for managing VAs following HF.

Assessment of early anthracycline-induced cardiotoxicity and liver injury with T2 and T2* mapping in rabbit models.

OBJECTIVES: To evaluate the early prevalence of anthracycline-induced cardiotoxicity (AIC) and anthracycline-induced liver injury (AILI) using T2 and T2* mapping and to explore their correlations. MATERIALS AND METHODS: The study included 17 cardiotoxic rabbits that received weekly injections of doxorubicin and magnetic resonance imaging (MRI) every 2 weeks for 10 weeks. Cardiac function and T2 and T2* values were measured on each period. Histopathological examinations for two to five rabbits were performed after each MRI scan. The earliest sensitive time and the threshold of MRI parameters for detecting AIC and AILI based on these MRI parameters were obtained. Moreover, the relationship between myocardial and liver damage was assessed. RESULTS: Early AIC could be detected by T2 mapping as early as the second week and focused on the 7th, 11th, and 12th segments of left ventricle. The cutoff value of 46.64 for the 7th segment had the best diagnostic value, with an area under the curve (of 0.767, sensitivity of 100%, and specificity of 52%. T2* mapping could detect the change in iron content for early AIC at the middle interventricular septum and AILI as early as the sixth week (p = 0.014, p = 0.027). The T2* values of the middle interventricular septum showed a significant positive association with the T2* values of the liver (r = 0.39, p = 0.002). CONCLUSION: T2 and T2* mapping showed value one-stop assessment of AIC and AILI and could obtain the earliest MRI diagnosis point and optimal parameter thresholds for these conditions. CLINICAL RELEVANCE STATEMENT: Anthracycline-induced cardiotoxicity could be detected by T2 mapping as earlier as the second week, mainly focusing on the 7th, 11th, and 12th segments of left ventricle. Combined with T2* mapping, hepatoxicity and supplementary cardiotoxicity were assessed by one-stop scan. KEY POINTS: • MRI screening time of cardiotoxicity was as early as the second week with focusing on T2 values of the 7th, 11th, and 12th segments of left ventricle. • T2* mapping could be used as a complement to T2 mapping to evaluate cardiotoxicity and as an effective index to detect iron change in the early stages of chemotherapy. • The T2* values of the middle interventricular septum showed a significant positive association with the T2* values of the liver, indicating that iron content in the liver and heart increased with an increase in the chemotherapeutic drugs.

Relationships among anxiety, depression, and health-related quality of life in adult epilepsy: A network analysis.

OBJECTIVE: Comorbid depression and anxiety in patients with epilepsy (PWE) are common and frequently under-treated, thus, causing poor health-related quality of life (HRQoL). However, little is known regarding the interconnections between anxious/depressive symptoms and the dimensions of HRQoL. Therefore, we conducted a network analysis to explore these relationships in detail among Chinese adult PWE. METHODS: A cohort of adult PWE was consecutively recruited from the First Affiliated Hospital of Chongqing Medical University. HRQoL, depression, and anxiety were measured with Quality of Life in Epilepsy Inventory-31, Neurological Disorders Depression Inventory for Epilepsy, and Generalized Anxiety Disorder 7-Item Scale, respectively. A regularized partial correlation network was constructed to investigate the interconnections between symptoms of anxiety/depression and the dimensions of HRQoL. We calculated expected influence (EI) and bridge expected influence (BEI) values to identify the most influential nodes. RESULTS: A total of 396 PWE were enrolled in this study, 78.1% of whom had focal onset epilepsy. The prevalence of anxiety and depression was 30.3% and 28.8%, respectively. The symptoms "frustrated" and "uncontrollable worry" had the highest EI values, whereas "emotional well-being", "seizure worry", "difficulty finding pleasure", and "nervousness or anxiety" had the highest BEI values. CONCLUSION: This study provides new insights into the relationships among anxiety, depression, and HRQoL. Critical central symptoms and bridge symptoms identified in the network might help to quickly identify PWE comorbid anxiety and depression in busy outpatient settings, thereby enabling early intervention and enhancing quality of life.

Combined brain topological metrics with machine learning to distinguish essential tremor and tremor-dominant Parkinson's disease.

BACKGROUND: Essential tremor (ET) and Parkinson's disease (PD) are the two most prevalent movement disorders, sharing several overlapping tremor clinical features. Although growing evidence pointed out that changes in similar brain network nodes are associated with these two diseases, the brain network topological properties are still not very clear. OBJECTIVE: The combination of graph theory analysis with machine learning (ML) algorithms provides a promising way to reveal the topological pathogenesis in ET and tremor-dominant PD (tPD). METHODS: Topological metrics were extracted from Resting-state functional images of 86 ET patients, 86 tPD patients, and 86 age- and sex-matched healthy controls (HCs). Three steps were conducted to feature dimensionality reduction and four frequently used classifiers were adopted to discriminate ET, tPD, and HCs. RESULTS: A support vector machine classifier achieved the best classification performance of four classifiers for discriminating ET, tPD, and HCs with 89.0% mean accuracy (mACC) and was used for binary classification. Particularly, the binary classification performances among ET vs. tPD, ET vs. HCs, and tPD vs. HCs were with 94.2% mACC, 86.0% mACC, and 86.3% mACC, respectively. The most power discriminative features were mainly located in the default, frontal-parietal, cingulo-opercular, sensorimotor, and cerebellum networks. Correlation analysis results showed that 2 topological features negatively and 1 positively correlated with clinical characteristics. CONCLUSIONS: These results demonstrated that combining topological metrics with ML algorithms could not only achieve high classification accuracy for discrimination ET, tPD, and HCs but also help to reveal the potential brain topological network pathogenesis in ET and tPD.

Designing a sparse sensor array for sound field reconstruction using compressive-equivalent source method.

The compressive-equivalent source method (C-ESM) can reconstruct the sound field radiated by sparsely distributed sound sources with a reduced number of sensors. To ensure the performance of the C-ESM, the transfer matrix between the sensors and equivalent point sources should exhibit sufficient incoherence. Given that the configuration of the sensor array affects this incoherence condition, concern regarding the sensor array design would arise. To address such concern, this paper proposes a sensor array design approach. The primary objective of this approach is to minimize the mean coherence of the transfer matrix within the developed iterative framework, providing the incoherence condition required by the C-ESM. Subsequently, the designed sensor array is utilized by the C-ESM for the reconstructions. The effectiveness and practicality of the proposed approach are validated through numerical simulations and experiments.

Real-time nearfield acoustic holography using particle velocity.

In this paper, a series of impulse response functions between acoustic quantities on the source plane and particle velocity on the hologram plane are derived. In virtue of these functions, real-time nearfield acoustic holography (RT-NAH) is extended from pressure-based to particle velocity. Pressure, normal velocity, acceleration, and displacement radiated from planar sources can be reconstructed by measuring time-dependent particle velocity signals on the hologram plane. A simulation of an excited aluminum plate is performed to evaluate the difference in accuracy between RT-NAHs based on pressure and based on particle velocity. This study also examines the impact of impulse response functions on the reconstruction results, allowing for detailed analysis of the reconstruction accuracy based on these functions. The simulation results demonstrate that using RT-NAH based on particle velocity obtains significantly higher-accuracy reconstruction results when reconstructing normal velocity and displacement and slightly more accurate reconstructed pressure and normal acceleration.

Repairing distorted hologram data for sound field reconstruction.

This paper proposes a distorted hologram data repair approach for sound field reconstruction. In this approach, an equivalent source model is established by placing a set of equivalent sources near the hologram surface to represent the measured hologram pressures. Each hologram pressure is simultaneously assigned an indicator to describe whether its measurement is corrupted by errors or not. This model is then formulated within a modal framework by utilizing the modes generated through the singular value decomposition of the transfer matrix between the hologram and nearby equivalent source surfaces. Subsequently, the indicators and modal coefficients are assigned the 0-1 and Gaussian prior distributions, respectively, and their posterior distributions are derived using the Bayesian method. The means of the posterior distributions are calculated to discriminate corrupted measurements and repair distorted hologram pressures. Repaired hologram pressures are finally utilized for reconstructions using the equivalent source method. Results from both numerical simulations conducted under various parameter settings and two experiments demonstrate the effectiveness of the proposed approach in automatically discriminating all the corrupted measurements and accurately repairing the distorted hologram pressures. Furthermore, the accuracy of the reconstructions using the repaired hologram pressures is comparable to that achieved with the correctly measured pressures.

Analytical method for studying acoustic fields radiated by general spherical sound sources in thermoviscous fluids.

The study of acoustic radiation from spherical sound sources plays a crucial role in understanding the thermoviscous effects in practical acoustic problems. However, finding a general solution of acoustic radiation from spherical sound sources in thermoviscous fluids remains a formidable challenge. To advance this issue, an analytical method is developed in this paper to calculate the acoustic field radiated by spherical sound sources with the isothermal boundary condition and arbitrary velocity boundary condition. The developed method is utilized to present the solutions of the acoustic field generated by an oscillating sphere and a general spherical sound source, and the accuracy and validity of these solutions are verified through analytical and numerical methods.

Low-Molecular-Weight Peptides Prepared from Hypsizygus marmoreus Exhibit Strong Antioxidant and Antibacterial Activities.

Hypsizygus marmoreus has abundant proteins and is a potential source for the development of bioactive peptides. However, currently, the research on the bioactive components of H. marmoreus mainly focuses on polysaccharides, and there is no relevant research on the preparation of bioactive peptides. In this article, an ultrasound-assisted extraction method was used to extract proteins from H. marmoreus, and then, four peptides with different molecular weight ranges were prepared through protease hydrolysis and molecular classification. The antioxidant and antibacterial activities were also studied. Under the optimal conditions, the extraction rate of H. marmoreus proteins was 53.6%. Trypsin exhibited the highest hydrolysis rate of H. marmoreus proteins. The optimal parameters for enzymatic hydrolysis were a substrate concentration of 3.7%, enzyme addition of 5700 U/g, pH value of 7, extraction temperature of 55 °C, and time of 3.3 h. Under these conditions, the peptide yield was 59.7%. The four types of H. marmoreus peptides were prepared by molecular weight grading. Among them, peptides with low molecular weight (<1 kDa) had stronger antioxidant and antibacterial activities. This study provides a theoretical basis for the efficient preparation of H. marmoreus peptides and the development of antioxidant and antibacterial peptide products.

Abnormalities in spontaneous brain activity and functional connectivity are associated with cognitive impairments in children with type 1 diabetes mellitus.

BACKGROUND: It remains unclear whether alterations in brain function occur in the early stage of pediatric type 1 diabetes mellitus(T1DM). We aimed to examine changes in spontaneous brain activity and functional connectivity (FC) in children with T1DM using resting-state functional magnetic resonance imaging (rs-fMRI), and to pinpoint potential links between neural changes and cognitive performance. METHODS: In this study, 22 T1DM children and 21 age-, sex-matched healthy controls underwent rs-fMRI. The amplitude of low frequency fluctuations (ALFF) and seed-based FC analysis were performed to examine changes in intrinsic brain activity and functional networks in T1DM children. Partial correlation analyses were utilized to explore the correlations between ALFF values and clinical parameters. RESULTS: The ALFF values were significantly lower in the lingual gyrus (LG) and higher in the left medial superior frontal gyrus (MSFG) in T1DM children compared to controls. Subsequent FC analysis indicated that the LG had decreased FC with bilateral inferior occipital gyrus, and the left MSFG had decreased FC with right precentral gyrus, right inferior parietal gyrus and right postcentral gyrus in children with T1DM. The ALFF values of LG were positively correlated with full-scale intelligence quotient and age at disease onset in T1DM children, while the ALFF values of left MSFG were positively correlated with working memory scores. CONCLUSION: Our findings revealed abnormal spontaneous activity and FC in brain regions related to visual, memory, default mode network, and sensorimotor network in the early stage of T1DM children, which may aid in further understanding the mechanisms underlying T1DM-associated cognitive dysfunction.

[Identification of horn-derived animal medicines based on detection of keratin-derived characteristic peptides].

Due to the highly stable structure of keratin, the extraction and dissolution steps of animal medicines rich in keratin are complex, which seriously restricts the detection efficiency and flux. Therefore, this study simplified the pre-treatment steps of horn samples and optimized the detection methods of characteristic peptides to improve the efficiency of identifying the specificity of horn-derived animal medicines. For detection of the characteristic peptides in horn-derived animal medicines treated with/without iodoace-tamide(IAA), the ion pair conditions of the characteristic peptides were optimized, and the retention time, intensity and other data of the specific peptides were compared between the samples treated with/without IAA. Two pre-treatment methods, direct enzymatic hydrolysis and total protein extraction followed by enzymatic hydrolysis, were used to prepare horn-derived animal medicine samples. The effects of different methods on the detection of specific peptides in the samples of Saiga antelope horn, water buffalo horn, goat horn, and yak horn were compared regarding the retention time of specific peptides and ion intensity. The results indicated that after direct enzymatic hydrolysis, the specific peptides in the samples without IAA treatment can be detected. Compared with the characteristic peptides in the samples treated with IAA, their retention time shifted back and the mass spectrometry response slightly decreased. The specific peptides of the samples without IAA treatment had good specificity and did not affect the specificity identification of horn-derived animal medicines. Overall, the process of direct enzymatic hydrolysis can be used to treat horn samples, omitting the steps of protein extraction and dithiothreitol and IAA treatment, significantly improving the pre-treatment efficiency without affecting the specificity identification of horn-derived animal medicines. This study provides ideas for quality research and standard improvement of horn-derived animal medicines.

Discovery of Natural Potent HMG-CoA Reductase Degraders for Lowering Cholesterol.

Exploitation of key protected wild plant resources makes great sense, but their limited populations become the major barrier. A particular strategy for breaking this barrier was inspired by the exploration of a resource-saving fungal endophyte Penicillium sp. DG23, which inhabits the key protected wild plant Schisandra macrocarpa. Chemical studies on the cultures of this strain afforded eight novel indole diterpenoids, schipenindolenes A-H (1-8), belonging to six diverse skeleton types. Importantly, semisyntheses suggested some key nonenzymatic reactions constructing these molecules and provided targeted compounds, in particular schipenindolene A (Spid A, 1) with low natural abundance. Remarkably, Spid A was the most potent HMG-CoA reductase (HMGCR) degrader among the indole diterpenoid family. It degraded statin-induced accumulation of HMGCR protein, decreased cholesterol levels and acted synergistically with statin to further lower cholesterol. Mechanistically, transcriptomic and proteomic profiling suggested that Spid A potentially activated the endoplasmic reticulum-associated degradation (ERAD) pathway to enhance the degradation of HMGCR, while simultaneously inhibiting the statin-activated expression of many key enzymes in the cholesterol and fatty acid synthesis pathways, thereby strengthening the efficacy of statins and potentially reducing the side effects of statins. Collectively, this study suggests the potential of Spid A for treating cardiovascular disease.

[Cystic fibrosis primarily presenting with pseudo-Bartter syndrome: a report of three cases and literature review]. / 以假性Bartter综合征为主要表现的囊性纤维化患儿3ä¾‹å¹¶æ–‡çŒ®å¤ä¹ .

OBJECTIVES: To summarize the clinical characteristics and genetic variations in children with cystic fibrosis (CF) primarily presenting with pseudo-Bartter syndrome (CF-PBS), with the aim to enhance understanding of this disorder. METHODS: A retrospective analysis was performed on the clinical data of three children who were diagnosed with CF-PBS in Hunan Children's Hospital from January 2018 to August 2023, and a literature review was performed. RESULTS: All three children had the onset of the disease in infancy. Tests after admission showed hyponatremia, hypokalemia, hypochloremia, and metabolic alkalosis, and genetic testing showed the presence of compound heterozygous mutation in the CFTR gene. All three children were diagnosed with CF. Literature review obtained 33 Chinese children with CF-PBS, with an age of onset of 1-36 months and an age of diagnosis of 3-144 months. Among these children, there were 29 children with recurrent respiratory infection or persistent pneumonia (88%), 26 with malnutrition (79%), 23 with developmental retardation (70%), and 18 with pancreatitis or extrapancreatic insufficiency (55%). Genetic testing showed that c.2909G>A was the most common mutation site of the CFTR gene, with a frequency of allelic variation of 23% (15/66). CONCLUSIONS: CF may have no typical respiratory symptoms in the early stage. The possibility of CF-PBS should be considered for infants with recurrent hyponatremia, hypokalemia, hypochloremia, and metabolic alkalosis, especially those with malnutrition and developmental retardation. CFTR genetic testing should be performed as soon as possible to help with the diagnosis of CF.

The MYB transcription factor MYB103 acts upstream of TRICHOME BIREFRINGENCE-LIKE27 in regulating aluminum sensitivity by modulating the O-acetylation level of cell wall xyloglucan in Arabidopsis thaliana.

Modification of the O-acetylation level of xyloglucan (XyG) appears to affect aluminum (Al) sensitivity in Arabidopsis by modulating its binding capacity to Al. However, the transcriptional regulation of this process remains largely unknown. In our previous studies, we found that the expression of TRICHOME BIREFRINGENCE-LIKE27 (TBL27), which is responsible for the O-acetylation of XyG, was downregulated under Al stress. In the present study, we showed that the expression of an R2R3-type transcription factor-encoding gene, MYB103, was also inhibited by Al exposure and exhibited a co-expression pattern with TBL27 in roots and siliques, suggesting a potential link between MYB103 and TBL27. The loss of function of MYB103 resulted in increased Al sensitivity, as indicated by more inhibited root growth and elevated root Al content compared with the wild type. Moreover, we also detected increased Al accumulation in the root cell wall and the hemicellulose fraction, which was attributed to the changes in the O-acetylation level of XyG rather than the XyG content itself. In addition, further analysis revealed that MYB103 positively activated TBL27 expression by directly binding to the TBL27 promoter region, and TBL27 overexpression in the myb103 mutant rescued the Al-sensitive phenotype of the mutant to the wild-type level. Taken together, we conclude that MYB103 acts upstream of TBL27 to positively regulate Al resistance by modulating the O-acetylation of the cell wall XyG.

Identification of essential tremor based on resting-state functional connectivity.

Currently, machine-learning algorithms have been considered the most promising approach to reach a clinical diagnosis at the individual level. This study aimed to investigate whether the whole-brain resting-state functional connectivity (RSFC) metrics combined with machine-learning algorithms could be used to identify essential tremor (ET) patients from healthy controls (HCs) and further revealed ET-related brain network pathogenesis to establish the potential diagnostic biomarkers. The RSFC metrics obtained from 127 ET patients and 120 HCs were used as input features, then the Mann-Whitney U test and the least absolute shrinkage and selection operator (LASSO) methods were applied to reduce feature dimensionality. Four machine-learning algorithms were adopted to identify ET from HCs. The accuracy, sensitivity, specificity and the area under the curve (AUC) were used to evaluate the classification performances. The support vector machine, gradient boosting decision tree, random forest and Gaussian naïve Bayes algorithms could achieve good classification performances with accuracy at 82.8%, 79.4%, 78.9% and 72.4%, respectively. The most discriminative features were primarily located in the cerebello-thalamo-motor and non-motor circuits. Correlation analysis showed that two RSFC features were positively correlated with tremor frequency and four RSFC features were negatively correlated with tremor severity. The present study demonstrated that combining the RSFC matrices with multiple machine-learning algorithms could not only achieve high classification accuracy for discriminating ET patients from HCs but also help us to reveal the potential brain network pathogenesis in ET.

The NAC transcription factor ANAC017 regulates aluminum tolerance by regulating the cell wall-modifying genes.

Aluminum (Al) toxicity is one of the key factors limiting crop production in acid soils; however, little is known about its transcriptional regulation in plants. In this study, we characterized the role of a NAM, ATAF1/2, and cup-shaped cotyledon 2 (NAC) transcription factors (TFs), ANAC017, in the regulation of Al tolerance in Arabidopsis (Arabidopsis thaliana). ANAC017 was localized in the nucleus and exhibited constitutive expression in the root, stem, leaf, flower, and silique, although its expression and protein accumulation were repressed by Al stress. Loss of function of ANAC017 enhanced Al tolerance when compared with wild-type Col-0 and was accompanied by lower root and root cell wall Al content. Furthermore, both hemicellulose and xyloglucan content decreased in the anac017 mutants, indicating the possible interaction between ANAC017 and xyloglucan endotransglucosylase/hydrolase (XTH). Interestingly, the expression of XTH31, which is responsible for xyloglucan modification, was downregulated in the anac017 mutants regardless of Al supply, supporting the possible interaction between ANAC017 and XTH31. Yeast one-hybrid, dual-luciferase reporter assay, and chromatin immunoprecipitation-quantitative PCR analysis revealed that ANAC017 positively regulated the expression of XTH31 through directly binding to the XTH31 promoter region, and overexpression of XTH31 in the anac017 mutant background rescued its Al-tolerance phenotype. In conclusion, we identified that the tTF ANAC017 acts upstream of XTH31 to regulate Al tolerance in Arabidopsis.

Ubiquitin-specific protease 38 promotes inflammatory atrial fibrillation induced by pressure overload.

AIMS: Atrial structural and electrical remodelling is a major reason for the initiation and perpetuation of atrial fibrillation (AF). Ubiquitin-specific protease 38 (USP38) is a deubiquitinating enzyme, but its function in the heart remains unknown. The aim of this study was to investigate the effect of USP38 in pressure overload-induced AF. METHODS AND RESULTS: Cardiac-specific knockout USP38 and cardiac-specific transgenic USP38 mice and their corresponding control mice were used in this study. After 4 weeks with or without aortic banding (AB) surgery, atrial echocardiography, atrial histology, electrophysiological study, and molecular analysis were assessed. Ubiquitin-specific protease 38 knockout mice showed a remarkable improvement in vulnerability to AF, atrial weight and diameter, atrial fibrosis, and calcium-handling protein expression after AB surgery. Conversely, USP38 overexpression further increased susceptibility to AF by exacerbating atrial structural and electrical remodelling. Mechanistically, USP38 interacted with and deubiquitinated nuclear factor-kappa B (NF-κB), and USP38 overexpression increased the level of p-NF-κB in vivo and in vitro, accompanied by the upregulation of NOD-like receptor protein 3 (NLRP3) and inflammatory cytokines, suggesting that USP38 contributes to adverse effects by driving NF-κB/NLRP3-mediated inflammatory responses. CONCLUSION: Overall, our study indicates that USP38 promotes pressure overload-induced AF through targeting NF-κB/NLRP3-mediated inflammatory responses.

mTORC2 acts as a gatekeeper for mTORC1 deficiency-mediated impairments in ILC3 development.

Group 3 innate lymphoid cells (ILC3s) are mediators of intestinal immunity and barrier function. Recent studies have investigated the role of the mammalian target of rapamycin complex (mTOR) in ILC3s, whereas the mTORC1-related mechanisms and crosstalk between mTORC1 and mTORC2 involved in regulating ILC3 homeostasis remain unknown. In this study, we found that mTORC1 but not mTORC2 was critical in ILC3 development, IL-22 production, and ILC3-mediated intestinal homeostasis. Single-cell RNA sequencing revealed that mTORC1 deficiency led to disruption of ILC3 heterogeneity, showing an increase in differentiation into ILC1-like phenotypes. Mechanistically, mTORC1 deficiency decreased the expression of NFIL3, which is a critical transcription factor responsible for ILC3 development. The activities of both mTORC1 and mTORC2 were increased in wild-type ILC3s after activation by IL-23, whereas inhibition of mTORC1 by Raptor deletion or rapamycin treatment resulted in increased mTORC2 activity. Previous studies have demonstrated that S6K, the main downstream target of mTORC1, can directly phosphorylate Rictor to dampen mTORC2 activity. Our data found that inhibition of mTORC1 activity by rapamycin reduced Rictor phosphorylation in ILC3s. Reversing the increased mTORC2 activity via heterozygous or homozygous knockout of Rictor in Raptor-deleted ILC3s resulted in severe ILC3 loss and complete susceptibility to intestinal infection in mice with mTORC1 deficiency (100% mortality). Thus, mTORC1 acts as a rheostat of ILC3 heterogeneity, and mTORC2 protects ILC3s from severe loss of cells and immune activity against intestinal infection when mTORC1 activity is diminished.