The BTB-BACK-TAZ domain protein MdBT2 reduces drought resistance by weakening the positive regulatory effect of MdHDZ27 on apple drought tolerance via ubiquitination.

Drought stress is one of the dominating challenges to the growth and productivity in crop plants. Elucidating the molecular mechanisms of plants responses to drought stress is fundamental to improve fruit quality. However, such molecular mechanisms are poorly understood in apple (Malus domestica Borkh.). In this study, we explored that the BTB-BACK-TAZ protein, MdBT2, negatively modulates the drought tolerance of apple plantlets. Moreover, we identified a novel Homeodomain-leucine zipper (HD-Zip) transcription factor, MdHDZ27, using a yeast two-hybrid (Y2H) screen with MdBT2 as the bait. Overexpression of MdHDZ27 in apple plantlets, calli, and tomato plantlets enhanced their drought tolerance by promoting the expression of drought tolerance-related genes [responsive to dehydration 29A (MdRD29A) and MdRD29B]. Biochemical analyses demonstrated that MdHDZ27 directly binds to and activates the promoters of MdRD29A and MdRD29B. Furthermore, in vitro and in vivo assays indicate that MdBT2 interacts with and ubiquitinates MdHDZ27, via the ubiquitin/26S proteasome pathway. This ubiquitination results in the degradation of MdHDZ27 and weakens the transcriptional activation of MdHDZ27 on MdRD29A and MdRD29B. Finally, a series of transgenic analyses in apple plantlets further clarified the role of the relationship between MdBT2 and MdHDZ27, as well as the effect of their interaction on drought resistance in apple plantlets. Collectively, our findings reveal a novel mechanism by which the MdBT2-MdHDZ27 regulatory module controls drought tolerance, which is of great significance for enhancing the drought resistance of apple and other plants.

Discovery of (quinazolin-6-yl)benzamide derivatives containing a 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline moiety as potent reversal agents against P-glycoprotein-mediated multidrug resistance.

P-glycoprotein (P-gp) is an important factor leading to multidrug resistance (MDR) in cancer treatment. The co-administration of anticancer drugs and P-gp inhibitors has been a treatment strategy to overcome MDR. In recent years, tyrosine kinase inhibitor Lapatinib has been reported to reverse MDR through directly interacting with ABC transporters. In this work, a series of P-gp inhibitors (1-26) was designed and synthesized by integrating the quinazoline core of Lapatinib into the molecule framework of the third-generation P-gp inhibitor Tariquidar. Among them, compound 14 exhibited better MDR reversal activity than Tariquidar. The docking results showed compound 14 displayed the L-shaped molecular conformation. Importantly, compound 14 increased the accumulation of Adriamycin (ADM) and rhodamine 123 (Rh123) in MCF7/ADM cells. Besides, compound 14 significantly increased ADM-induced apoptosis and inhibited the proliferation, migration and invasion of MCF7/ADM cells. It was also demonstrated that compound 14 significantly inhibited the growth of MCF7/ADM xenograft tumors by increasing the sensitivity of ADM. In summary, compound 14 has the potential to overcome MDR caused by P-gp.

Regulation of a vacuolar proton-pumping P-ATPase MdPH5 by MdMYB73 and its role in malate accumulation and vacuolar acidification.

As the main organic acid in fruits, malate is produced in the cytoplasm and is then transported into the vacuole. It accumulates by vacuolar proton pumps, transporters, and channels, affecting the taste and flavor of fruits. Among the three types of proton pumps (V-ATPases, V-PPases, and P-ATPases), the P-ATPases play an important role in the transport of malate into vacuoles. In this study, the transcriptome data, collected at different stages after blooming and during storage, were analyzed and the results demonstrated that the expression of MdPH5, a vacuolar proton-pumping P-ATPase, was associated with both pre- and post-harvest malate contents. Moreover, MdPH5 is localized at the tonoplast and regulates malate accumulation and vacuolar pH. In addition, MdMYB73, an upstream MYB transcription factor of MdPH5, directly binds to its promoter, thereby transcriptionally activating its expression and enhancing its activity. In this way, MdMYB73 can also affect malate accumulation and vacuolar pH. Overall, this study clarifies how MdMYB73 and MdPH5 act to regulate vacuolar malate transport systems, thereby affecting malate accumulation and vacuolar pH. Supplementary Information: The online version contains supplementary material available at 10.1007/s42994-023-00115-7.

A novel role of the splenic volume in Crohn's disease: evaluating the efficacy of infliximab.

Background: A number of patients with Crohn's disease (CD) suffer from loss of response to infliximab (IFX) therapy. Splenic volume is reported to be enlarged in patients with CD compared to normal individuals. The association between splenic volume and IFX efficacy in CD remains unclear. Methods: We performed a retrospective study of patients with CD who received regular IFX treatment at Zhongshan Hospital, Fudan University, between August 2015 and December 2021. We collected baseline characteristics and clinical features from medical records in the CD database of Zhongshan Hospital. We accurately measured the splenic volume using semi-auto spleen segmentation software, followed by the analysis of splenic volume and IFX efficacy. Results: We included 49 patients with CD receiving IFX treatment, of whom 41 responded to IFX and 8 failed to respond to IFX. Splenic volume, as well as volume adjusted for body mass index (SV/BMI) and body weight (SV/W), was significantly decreased after IFX treatment in responders but increased in non-responders compared to the volume before the treatment. Accordingly, the levels of leukocyte count, platelet count, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) were decreased after IFX treatment in responders. Contrarily, the levels of hemoglobin, albumin, and tumor necrosis factor (TNF)-α were elevated in responders. Moreover, both CRP and TNF-α levels were significantly positively correlated with SV/BMI in all patients. Conclusion: Splenic volume, especially SV/BMI and SV/W, was reduced after IFX treatment in CD patients responsive to IFX. SV/BMI was positively correlated with disease activity. Splenic volume is a promising indicator to evaluate IFX efficacy in CD.

Diagnostic performance of gadoxetic acid-enhanced abbreviated magnetic resonance imaging protocol in small hepatocellular carcinoma (≤2 cm) in high-risk patients.

BACKGROUND: Biannual Ultrasound showed insufficient sensitivity in detecting small or early-stage hepatocellular carcinoma (HCC). Abbreviated magnetic resonance imaging (A-MRI) protocols with fewer sequences demonstrated higher HCC detection sensitivity than ultrasound with acceptable cost and examination time. PURPOSE: To compare the diagnostic performance of gadoxetic acid-enhanced A-MRI with a full sequence MRI (F-MRI) protocol for small HCC (≤2 cm) in cirrhotic or hepatitis B virus-infected high-risk patients. MATERIAL AND METHODS: Two hundred and four consecutive patients with 166 pathologically confirmed small HCC who underwent preoperative gadoxetic acid-enhanced MRI were retrospectively included. A-MRI set comprised T1-weighted hepatobiliary phase imaging, T2-weighted imaging, diffusion-weighted imaging and apparent diffusion coefficient mapping. Two independent radiologists blinded to clinical data assessed the A-MRI set and F-MRI set. Per-patient HCC and per-lesion HCC diagnostic performance were compared. RESULTS: Per-patient HCC detection sensitivity of A-MRI set was 93.8% and 91.2% for observer 1 and observer 2, and, for the F-MRI set, the per-patient HCC detection sensitivity was 96.6% and 95.2%, respectively. There was no significant difference in per-patient sensitivity, specificity and per-lesion HCC detection sensitivity between the two imaging sets for both readers. (P = 0.06-0.25) The A-MRI set showed higher sensitivity on HCC without arterial phase hyperenhancement, and the F-MRI set demonstrated with higher sensitivity on HCC with arterial phase hyperenhancement (P < 0.05). CONCLUSION: A-MRI using diagnostic criteria including hypointensity on hepatobiliary phase plus mild to moderate hyperintensity on T2-weighted imaging or restricted diffusion demonstrated comparable sensitivity and specificity for small HCC compared to the F-MRI protocol in high-risk patients.

[Research progress of the regulation of orphan nuclear receptors on chronic liver diseases].

The development of chronic liver disease can be promoted by excessive fat accumulation, dysbiosis, viral infections and persistent inflammatory responses, which can lead to liver inflammation, fibrosis and carcinogenesis. An in-depth understanding of the etiology leading to chronic liver disease and the underlying mechanisms influencing its development can help identify potential therapeutic targets for targeted treatment. Orphan nuclear receptors (ONRs) are receptors that have no corresponding endogenous ligands to bind to them. The study of these ONRs and their biological properties has facilitated the development of synthetic ligands, which are important for investigating the effective targets for the treatment of a wide range of diseases. In recent years, it has been found that ONRs are essential for maintaining normal liver function and their dysfunction can affect a variety of liver diseases. ONRs can influence pathophysiological activities such as liver lipid metabolism, inflammatory response and cancer cell proliferation by regulating hormones/transcription factors and affecting the biological clock, oxidative stress, etc. This review focuses on the regulation of ONRs, mainly including retinoid related orphan nuclear receptors (RORs), pregnane X receptor (PXR), leukocyte cell derived chemotaxin 2 (LECT2), Nur77, and hepatocyte nuclear factor 4α (HNF4α), on the development of different types of chronic liver diseases in different ways, in order to provide useful references for the therapeutic strategies of chronic liver diseases based on the regulation of ONRs.

Novel target and treatment agents for natural killer/T-cell lymphoma.

The rapidly increasing use of high-throughput screening had produced a plethora of expanding knowledge on the molecular basis of natural killer/T-cell lymphoma (NKTCL), which in turn has revolutionized the treatment. Specifically, the use of asparaginase-containing regimens has led to substantial improvement in survival outcomes in NKTCL patients. Novel treatment strategies that are currently under development include cell-surface-targeted antibodies, immune checkpoint inhibitors, Epstein-Barr virus targeted cytotoxic T lymphocyte, immunomodulatory agents, chimeric antigen receptor T cells, signaling pathway inhibitors and epigenetic targeted agents. In almost all cases, initial clinical studies of newly developed treatment are conducted in patients relapsed, and refractory NKTCL due to very limited treatment options. This review summarizes the results of these novel treatments for NKTCL and discusses their potential for likely use in NKTCL in a wider setting in the future.

Global trends and frontiers in research on exercise training for heart failure: a bibliometric analysis from 2002 to 2022.

Background: Heart failure is a common cardiovascular disease that imposes a heavy clinical and economic burden worldwide. Previous research and guidelines have supported exercise training as a safe, effective, and cost-efficient treatment to intervene in heart failure. The aim of this study was to analyze the global published literature in the field of exercise training for heart failure from 2002 to 2022, and to identify hot spots and frontiers within this research field. Methods: Bibliometric information on literature on the topic of exercise training for heart failure published between 2002 and 2022 was searched and collected in the Web of Science Core Collection. CiteSpace 6.1.R6 (Basic) and VOSviewer (1.6.18) were applied to perform bibliometric and knowledge mapping visualization analyses. Results: A total of 2017 documents were retrieved, with an upward-stable trend in the field of exercise training for heart failure. The US authors were in the first place with 667 documents (33.07%), followed by Brazilian authors (248, 12.30%) and Italian authors (182, 9.02%). The Universidade de São Paulo in Brazil was the institution with the highest number of publications (130, 6.45%). The top 5 active authors were all from the USA, with Christopher Michael O'Connor and William Erle Kraus publishing the most documents (51, 2.53%). The International Journal of Cardiology (83, 4.12%) and the Journal of Applied Physiology (78, 3.87%) were the two most popular journals, while Cardiac Cardiovascular Systems (983, 48.74%) and Physiology (299, 14.82%) were the two most popular categories. Based on the results of keyword co-occurrence network and co-cited reference network, the hot spots and frontiers of research in the field of exercise training for heart failure were high-intensity interval training, behaviour therapy, heart failure with preserved ejection fraction, and systematic reviews. Conclusion: The field of exercise training for heart failure has experienced two decades of steady and rapid development, and the findings of this bibliometric analysis provide ideas and references for relevant stakeholders such as subsequent researchers for further exploration.

A prediction model for new-onset atrial fibrillation following coronary artery bypass graft surgery: A multicenter retrospective study.

Objective: Developing and assessing a risk prediction model of postoperative atrial fibrillation (POAF) after coronary artery bypass grafting (CABG), and aims to provide a reference for the prediction and prevention. Design: A retrospective case-control study. Setting: Three major urban teaching and university hospitals and tertiary referral centers. Participants: consecutive patients undergoing CABG. Interventions: The study was retrospective and no interventions were administered to patients. Measurements and main results: In the study, the overall new-onset POAF prevalence was approximately 28%. A prediction model for POAF with nine significant indicators was developed, and identified new predictors of POAF: left ventricular end diastolic diameter (LVEDD), intraoperative defibrillation, and intraoperative temporary pacing lead implantation. The model had good discrimination in both the derivation and validation cohorts, with the area under the receiver operating characteristic curves (AUCs) of 0.621 (95% CI = 0.602-0.640) and 0.616 (95% CI = 0.579-0.651), respectively, and showed good calibration. Compared with CHA2DS2-VASc, HATCH score, and the prediction model of POAF after CABG developed based on a small sample of clinical data from a single center in China, the model in this study had better discrimination. Conclusion: We have developed and validated a new prediction model of POAF after CABG using multicenter data that can be used in the clinic for early identification of high-risk patients of POAF, and to help effectively prevent POAF in postoperative patients.

Targeted delivery of pexidartinib to tumor-associated macrophages via legumain-sensitive dual-coating nanoparticles for cancer immunotherapy.

Tumor-associated macrophage (TAM) is regarded as an appealing cell target for cancer immunotherapy. However, it remains challenging to selectively eliminate M2-like TAM in tumor microenvironment. In this work, we employed a legumain-sensitive dual-coating nanosystem (s-Tpep-NPs) to deliver CSF-1R inhibitor pexidartinib (PLX3397) for targeting TAM therapy. The PLX3397-loaded NPs exhibited uniform size of ∼240 nm in diameter, good drug loading capacity and efficiency, as well as sustained drug release profile. Compared to non-sensitive counterpart ns-Tpep-NPs, s-Tpep-NPs showed distinguished selectivity upon M1 and M2 macrophage uptake with relation to incubation time and dose. Besides, the selectivity of anti-proliferation effect was also identified for s-Tpep-NPs against M1 and M2 macrophage. In vivo imaging demonstrated that s-Tpep-NPs exhibited much higher tumoral accumulation and TAM recognition specificity as compared to non-sensitive ns-Tpep-NPs. In vivo efficacy verified that s-Tpep-NPs formulation was much more effective than ns-Tpep-NPs and other PLX3397 formulations to treat B16F10 melanoma via targeting TAM depletion and modulating tumor immune microenvironment. Overall, this study provides a robust and promising nanomedicine strategy for TAM-targeted cancer immunotherapy.

Cannabinoid Receptor Agonist WIN55, 212-2 Attenuates Injury in the Hippocampus of Rats after Deep Hypothermic Circulatory Arrest.

OBJECTIVES: Postoperative neurological deficits remain a challenge in cardiac surgery employing deep hypothermic circulatory arrest (DHCA). This study aimed to investigate the effect of WIN55, 212-2, a cannabinoid agonist, on brain injury in a rat model of DHCA. METHODS: Twenty-four male Sprague Dawley rats were randomly divided into three groups: a control group (which underwent cardiopulmonary bypass (CPB) only), a DHCA group (CPB with DHCA), and a WIN group (WIN55, 212-2 pretreatment before CPB with DHCA). Histopathological changes in the brain were evaluated by hematoxylin-eosin staining. Plasma levels of superoxide dismutase (SOD) and proinflammatory cytokines including interleukin (IL)-1ß, IL-6, and tumor necrosis factor-alpha (TNF-a) were determined using an enzyme-linked immunosorbent assay (ELISA). The expression of SOD in the hippocampus was detected by Western blot and immunofluorescence staining. Levels of apoptotic-related protein caspase-3 and type 1 cannabinoid receptor (CB1R) in the hippocampus were evaluated by Western blot. RESULTS: WIN55, 212-2 administration attenuated histopathological injury of the hippocampus in rats undergoing DHCA, associated with lowered levels of IL-1ß, IL-6, and TNF-α (p < 0.05, p < 0.001, and p < 0.01, vs. DHCA, respectively) and an increased level of SOD (p < 0.05 vs. DHCA). WIN55, 212-2 treatment also increased the content of SOD in the hippocampus. The protein expression of caspase-3 was downregulated and the expression of CB1R was upregulated in the hippocampus by WIN55, 212-2. CONCLUSIONS: the administration of WIN55, 212-2 alleviates hippocampal injury induced by DHCA in rats by regulating intrinsic inflammatory and oxidative stress responses through a CB1R-dependent mechanism.

Late Split-Application with Reduced Nitrogen Fertilizer Increases Yield by Mediating Source-Sink Relations during the Grain Filling Stage in Summer Maize.

In the North China Plain, the excessive application of nitrogen (N) fertilizer for ensuring high yield and a single application at sowing for simplifying management in farmer practice lead to low N use efficiency and environmental risk in maize (Zea mays L.) production. However, it is unclear whether and how late split application with a lower level of N fertilizer influences maize yield. To address this question, a two-year field experiment was conducted with two commercial maize cultivars (Zhengdan 958 and Denghai 605) using a lower level of N input (180 kg ha-1) by setting up single application at sowing and split application at sowing and later stages (V12, R1, and R2) with four different ratios, respectively. The maize yield with split-applied 180 kg ha-1 N did not decrease compared to the average yield with 240 kg ha-1 N input in farmer practice, while it increased by 6.7% to 11.5% in the four N split-application treatments compared with that of the single-application control. Morphological and physiological analyses demonstrated that late split application of N (i) increased the net photosynthetic rate and chlorophyll content and thus promoted the photosynthetic efficiency during the reproductive stages; (ii) promoted the sink capacity via improved kernel number, endosperm cells division, and grain-filling rate; and (iii) increased the final N content and N efficiency in the plant. Therefore, we propose that late split application of N could reduce N fertilizer input and coordinately improve N efficiency and grain yield in summer maize production, which are likely achieved by optimizing the source-sink relations during the grain-filling stage.

Ethylene inhibits malate accumulation in apple by transcriptional repression of aluminum-activated malate transporter 9 via the WRKY31-ERF72 network.

Malic acid accumulation in the vacuole largely determines acidity and perception of sweetness of apple. It has long been observed that reduction in malate level is associated with increase in ethylene production during the ripening process of climacteric fruits, but the molecular mechanism linking ethylene to malate reduction is unclear. Here, we show that ethylene-modulated WRKY transcription factor 31 (WRKY31)-Ethylene Response Factor 72 (ERF72)-ALUMINUM ACTIVATED MALATE TRANSPORTER 9 (Ma1) network regulates malate accumulation in apple fruit. ERF72 binds to the promoter of ALMT9, a key tonoplast transporter for malate accumulation of apple, transcriptionally repressing ALMT9 expression in response to ethylene. WRKY31 interacts with ERF72, suppressing its transcriptional inhibition activity on ALMT9. In addition, WRKY31 directly binds to the promoters of ERF72 and ALMT9, transcriptionally repressing and activating ERF72 and ALMT9, respectively. The expression of WRKY31 decreases in response to ethylene, lowering the transcription of ALMT9 directly and via its interactions with ERF72. These findings reveal that the regulatory complex WRKY31 forms with ERF72 responds to ethylene, linking the ethylene signal to ALMT9 expression in reducing malate transport into the vacuole during fruit ripening.

Diagnostic Performance of Contrast Enhanced CT Alone or in Combination with (Non-)Enhanced MRI for Colorectal Liver Metastasis.

RATIONALE AND OBJECTIVES: To compare the diagnostic performance of contrast enhanced CT (CE-CT), CE-CT combined with non-enhanced MRI (NE-MRI) or contrast enhanced MRI (CE-MRI) for colorectal liver metastasis (CRLM). MATERIALS AND METHODS: Sixty-six colorectal cancer patients with 198 focal liver lesions who underwent preoperative abdominal CE-CT and MRI examinations were included respectively. The images were assessed independently by two readers in three protocols (1: CE-CT, 2: CE-CT+NE-MRI, 3: CE-CT+CE-MRI). The diagnostic performance of each protocol was analyzed by receiver operating characteristic (ROC) curve and the areas under ROC (AUCs) were calculated and compared. RESULTS: The detection rates of protocol 2 were 90.9%-92.9% for liver lesions and 86.4%-89.6% for CRLM, and both significantly higher than protocol 1 of 82.8%-85.4% and 76.8%-80.8% (p<0.001-0.001), whereas similar to protocol 3 of 91.9%-94.4% and 87.2%-91.2% (p 0.250-1.000). The AUCs of protocol 2 were greater than protocol 1 for all lesions (0.914-0.934 vs. 0.779-0.799, p<0.001) and lesions < 10mm (0.726-0.776 vs. 0.528-0.561, p<0.001), and were not inferior to that of protocol 3 (0.929-0.949 in all lesions and 0.754-0.821 in lesion < 10mm, p 0.053-0.162). CONCLUSION: CE-CT combined with NE-MRI offered superior diagnostic performance for CRLM compared to CE-CT alone and showed comparable performance to CE-CT combined with CE-MRI.

Osteosarcopenic obesity and its components-osteoporosis, sarcopenia, and obesity-are associated with blood cell count-derived inflammation indices in older Chinese people.

BACKGROUND: The aim of this study was to investigate the associations of osteosarcopenic obesity (OSO) and its components with complete blood cell count-derived inflammation indices. METHODS: In this cross-sectional study, data of 648 participants aged ≥60 years (men/women: 232/416, mean age: 67.21 ± 6.40 years) were collected from January 2018 to December 2020. Areal bone mineral density and body fat percentage were used to define osteopenia/osteoporosis and obesity, respectively. The criteria of the 2019 Asian Working Group for Sarcopenia were used to diagnose sarcopenia. Based on the number of these conditions, participants were divided into four groups: OSO/0, OSO/1, OSO/2, and OSO/3. Logistic regression analysis was conducted to identify associations between blood cell count-derived inflammation indices and the number of disorders with abnormal body composition. RESULTS: Systemic inflammation response index (SIRI), white blood cells, neutrophil-to-lymphocyte ratio (NLR), aggregate inflammation systemic index (AISI), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) showed statistically significant differences among the four groups (P < 0.05). Unlike in the OSO/0 group, in all other groups, AISI, SIRI, PLR, and NLR were significantly associated with increased likelihood of having multiple disorders with abnormal body composition after adjustment for confounders (P < 0.0001 for all). However, LMR showed an inverse correlation with the number of these conditions (P < 0.05). CONCLUSION: Higher SIRI, AISI, NLR, and PLR values and lower LMR values are closely associated with OSO and its individual components-osteoporosis, sarcopenia, and obesity-in older adults, suggesting that the value of these indices in the evaluation of OSO warrants further investigation.

Application of Neurotoxin-Induced Animal Models in the Study of Parkinson's Disease-Related Depression: Profile and Proposal.

Depression can be a non-motor symptom, a risk factor, and even a co-morbidity of Parkinson's disease (PD). In either case, depression seriously affects the quality of life of PD patients. Unfortunately, at present, a large number of clinical and basic studies focused on the pathophysiological mechanism of PD and the prevention and treatment of motor symptoms. Although there has been increasing attention to PD-related depression, it is difficult to achieve early detection and early intervention, because the clinical guidelines mostly refer to depression developed after or accompanied by motor impairments. Why is there such a dilemma? This is because there has been no suitable preclinical animal model for studying the relationship between depression and PD, and the assessment of depressive behavior in PD preclinical models is as well a very challenging task since it is not free from the confounding from the motor impairment. As a common method to simulate PD symptoms, neurotoxin-induced PD models have been widely used. Studies have found that neurotoxin-induced PD model animals could exhibit depression-like behaviors, which sometimes manifested earlier than motor impairments. Therefore, there have been attempts to establish the PD-related depression model by neurotoxin induction. However, due to a lack of unified protocol, the reported results were diverse. For the purpose of further promoting the improvement and optimization of the animal models and the study of PD-related depression, we reviewed the establishment and evaluation strategies of the current animal models of PD-related depression based on both the existing literature and our own research experience, and discussed the possible mechanism and interventions, in order to provide a reference for future research in this area.

Alternative Splicing Regulation of Glycine-Rich Proteins via Target of Rapamycin-Reactive Oxygen Species Pathway in Arabidopsis Seedlings Upon Glucose Stress.

Glucose can serve as both the source of energy and regulatory signaling molecule in plant. Due to the environmental and metabolic change, sugar levels could affect various developmental processes. High glucose environment is hardly conductive to the plant growth but cause development arrest. Increasing evidence indicate that alternative splicing (AS) plays a pivotal role in sugar signaling. However, the regulatory mechanism upon glucose stress remains unclear. The full-length transcriptomes were obtained from the samples of Arabidopsis seedlings with 3% glucose and mock treatment, using Oxford Nanopore sequencing technologies. Further analysis indicated that many genes involved in photosynthesis were significantly repressed and many genes involved in glycolysis, mitochondrial function, and the response to oxidative stress were activated. In total, 1,220 significantly differential alternative splicing (DAS) events related to 619 genes were identified, among which 75.74% belong to intron retention (IR). Notably, more than 20% of DAS events come from a large set of glycine-rich protein (GRP) family genes, such as GRP7, whose AS types mostly belong to IR. Besides the known productive GRP transcript isoforms, we identified a lot of splicing variants with diverse introns spliced in messenger RNA (mRNA) region coding the glycine-rich (GR) domain. The AS pattern of GRPs changed and particularly, the productive GRPs increased upon glucose stress. These ASs of GRP pre-mRNAs triggered by glucose stress could be abolished by AZD-8055, which is an ATP competitive inhibitor for the target of rapamycin (TOR) kinase but could be mimicked by H2O2. Additionally, AS pattern change of arginine/serine-rich splicing factor 31(RS31) via TOR pathway, which was previously described in response to light and sucrose signaling, was also induced in a similar manner by both glucose stress and reactive oxygen species (ROS). Here we conclude that (i) glucose stress suppresses photosynthesis and activates the glycolysis-mitochondria energy relay and ROS scavenging system; (ii) glucose stress triggers transcriptome-wide AS pattern changes including a large set of splicing factors, such as GRPs and RS31; (iii) high sugars regulate AS pattern change of both GRPs and RS31 via TOR-ROS pathway. The results from this study will deepen our understanding of the AS regulation mechanism in sugar signaling.

[Research progress on role of traditional Chinese medicine in hepatic fibrosis based on miRNA-mediated activation of NLRP3 inflammasome].

In recent years, liver fibrosis has become a hotspot in the field of liver diseases. MicroRNA(miRNA)-mediated Nod-like receptor pyrin domain containing 3(NLRP3) inflammasome activation is pivotal in the pathogenesis of liver fibrosis. The present study mainly discussed the role of miRNA-mediated NLRP3 inflammasome activation in the pathogenesis of liver fibrosis. Different miRNA molecules regulated liver fibrosis by mediating NLRP3 inflammasome activation, including miRNA-350-3 p(miR-350-3 p)/interleukin-6(IL-6)-mediated signal transducer and activator of transcription 3(STAT3)/c-myc signaling pathway, miR-148 a-induced autophagy and apoptosis of hepatic stellate cells via hedgehog signaling pathway, miR-155-mediated NLRP3 inflammasome by the negative feedback of the suppressor of cytokine signaling-1(SOCS-1), miR-181 a-mediated downstream NLRP3 inflammatory pathway activation through mitogen-activated protein kinase kinase(MEK)/extracellular signal-regulated kinase(ERK)/nuclear transcription factor κB(NF-κB) inflammatory pathway, miR-21-promoted expression of NF-κB and NLRP3 of RAW264.7 cells in mice by inhibiting tumor necrosis factor-α inducible protein 3(A20), and miR-20 b-promoted expression of IL-1ß and IL-18 by activating NLRP3 signaling pathway. Additionally, the anti-liver fibrosis mechanism of different active components in Chinese medicines(such as Curcumae Rhizoma, Glycyrrhizae Radix et Rhizoma, Aurantii Fructus, Polygoni Cuspidati Rhizoma et Radix, Moutan Cortex, Paeoniae Radix Alba, Epimedii Folium, and Cinnamomi Cortex) was also explored based on the anti-liver fibrosis effect of miRNA-mediated NLRP3 inflammasome activation.

Assessment of XC functionals for the study of organic molecules with superhalogen substitution. A systematic comparison between DFT and CCSD(T).

A systematic density functional theory study, including 17 exchange-correlation functionals, was performed on 22 composite structures consisting of organic molecules, e.g., ethylene, ethane, and benzene, and superhalogen substitutions arising from [MgX3]- and [Mg2X5]- (X = F, Cl). Range-separated hybrid functionals ωB97M-V, ωB97X-D3(BJ), ωB97XD, ωB97X, and CAM-B3LYP, as well as double-hybrid functionals B2PLYP and DSD-PBEP86-D3(BJ), are verified to provide reliable results with accuracy approaching that at the coupled-cluster single double triple [CCSD(T)] level. The basis set effect of density functional theory calculation is usually moderate, and triple-ξ quality, e.g., Def2-TZVP, is enough in most cases. In addition, the average values from HF and MP2 method, indicated as (MP2 + HF)/2, are also quite close to those of CCSD(T).

Nomogram to predict 3-month unfavorable outcome after thrombectomy for stroke.

BACKGROUND: Mechanical thrombectomy (MT) is an effective treatment for large-vessel occlusion in acute ischemic stroke, however, only some revascularized patients have a good prognosis. For stroke patients undergoing MT, predicting the risk of unfavorable outcomes and adjusting the treatment strategies accordingly can greatly improve prognosis. Therefore, we aimed to develop and validate a nomogram that can predict 3-month unfavorable outcomes for individual stroke patient treated with MT. METHODS: We analyzed 258 patients with acute ischemic stroke who underwent MT from January 2018 to February 2021. The primary outcome was a 3-month unfavorable outcome, assessed using the modified Rankin Scale (mRS), 3-6. A nomogram was generated based on a multivariable logistic model. We used the area under the receiver-operating characteristic curve to evaluate the discriminative performance and used the calibration curve and Spiegelhalter's Z-test to assess the calibration performance of the risk prediction model. RESULTS: In our visual nomogram, gender (odds ratio [OR], 3.40; 95%CI, 1.54-7.54), collateral circulation (OR, 0.46; 95%CI, 0.28-0.76), postoperative mTICI (OR, 0.06; 95%CI, 0.01-0.50), stroke-associated pneumonia (OR, 5.76; 95%CI, 2.79-11.87), preoperative Na (OR, 0.82; 95%CI, 0.72-0.92) and creatinine (OR, 1.02; 95%CI, 1.01-1.03) remained independent predictors of 3-month unfavorable outcomes in stroke patients treated with MT. The area under the nomogram curve was 0.8791 with good calibration performance (P = 0.873 for the Spiegelhalter's Z-test). CONCLUSIONS: A novel nomogram consisting of gender, collateral circulation, postoperative mTICI, stroke-associated pneumonia, preoperative Na and creatinine can predict the 3-month unfavorable outcomes in stroke patients treated with MT.