High-mobility InSnZnO Thin Film Transistors via Introducing Water Vapor Sputtering Gas.

There is always a doubt that introducing water during oxide growing has a positive or negative effect on the properties of oxide films and devices. Herein, a comparison experiment on the condition of keeping the same oxygen atom flux in the sputtering chamber is designed to examine the influences of H2O on In-Sn-Zn-O (ITZO) films and their transistors. In comparison to no-water films, numerous unstable hydrogen-related defects are induced on with-water films at the as-deposited state. Paradoxically, this induction triggers an ordered enhancement in the microstructure of the films during conventional annealing, characterized by a reduction in H-related and vacancy (Vo) defects as well as an increase in film packing density and the M-O network ordering. Ultimately, the no-water thin-film transistors (TFTs) exhibit nonswitching behavior, whereas 5 sccm-water TFT demonstrates excellent electrical performance with a remarkable saturation field-effect mobility (µFE) of 122.10 ± 5.00 cm2·V-1·s-1, a low threshold (Vth) of -2.30 ± 0.40 V, a steep sub-threshold swing (SS) of 0.18 V·dec-1, a high output current (Ion) of 1420 µA, and a small threshold voltage shift ΔVth of -0.77 V in the negative bias stability test (3600 s).

Cell-free fat extract regulates oxidative stress and alleviates Th2-mediated inflammation in atopic dermatitis.

Atopic dermatitis (AD) is a common inflammatory skin disease that significantly affects patients' quality of life. This study aimed to evaluate the therapeutic potential of cell-free fat extract (FE) in AD. In this study, the therapeutic effect of DNCB-induced AD mouse models was investigated. Dermatitis scores and transepidermal water loss (TEWL) were recorded to evaluate the severity of dermatitis. Histological analysis and cytokines measurement were conducted to assess the therapeutic effect. Additionally, the ability of FE to protect cells from ROS-induced damage and its ROS scavenging capacity both in vitro and in vivo were investigated. Furthermore, we performed Th1/2 cell differentiation with and without FE to elucidate the underlying therapeutic mechanism. FE reduced apoptosis and cell death of HaCat cells exposed to oxidative stress. Moreover, FE exhibited concentration-dependent antioxidant activity and scavenged ROS both in vitro and vivo. Treatment with FE alleviated AD symptoms in mice, as evidenced by improved TEWL, restored epidermis thickness, reduced mast cell infiltration, decreased DNA oxidative damage and lower inflammatory cytokines like IFN-γ, IL-4, and IL-13. FE also inhibited the differentiation of Th2 cells in vitro. Our findings indicate that FE regulates oxidative stress and mitigates Th2-mediated inflammation in atopic dermatitis by inhibiting Th2 cell differentiation, suggesting that FE has the potential as a future treatment option for AD.

[Postoperative effect analysis of different surgical techniques used in facial nerve reconstruction].

Objective:To investigate the factors and efficacy of different surgical techniques used in facial nerve（FN） reconstruction. Methods:A retrospective analysis was conducted on 24 patients who underwent facial nerve reconstruction surgery in our department from January 2016 to January 2021. The duration of total facial nerve paralysis was less than 18 months. The study included 5 surgical techniques, including 6 cases of FN anastomosis（Group A）, 5 cases of FN grafting（sural nerve or great auricular nerve）（Group B）, 5 cases of side-to-end facial-hypoglossal nerve anastomosis（Group C）, 4 cases of side-to-end FN grafting（sural nerve or great auricular nerve） hypoglossal nerve anastomosis（Group D）, and 4 cases of dual nerve reanimation（Group E）. The postoperative follow-up period was ≥1 year. Results:The HB-Ⅲ level of FN function at 1 year after surgery was 83.3%（5/6） in group A, 60.0%（3/5） in group B, 40.0%（2/5） in group C, 25.0%（1/4） in group D, and 50.0%（2/4） in group E. In patients without multiple FN repair, the incidence of synkinesis was 15.0%（3/20）, while no cases of synkinesis were observed in patients with dual nerve reanimation. The patients who underwent hypoglossal-facial side-to-end anastomosis showed no hypoglossal nerve dysfunction. Conclusion:Different FN repair techniques result in varying postoperative FN function recovery, as personalized repair should be managed. Among the various techniques, FN end-to-end anastomosis after FN transposition is recommended as to reduce the number of anastomotic stoma, while hypoglossal-facial side-to-end anastomosis is advocated as to prevent postoperative hypoglossal nerve dysfunction. Additionally, dual nerve repair can effectively improve smile symmetry and reduce synkinesis, which enhances patients' quality.

Effects of Klebsiella michiganensis LDS17 on Codonopsis pilosula growth, rhizosphere soil enzyme activities, and microflora, and genome-wide analysis of plant growth-promoting genes.

Codonopsis pilosula is a perennial herbaceous liana with medicinal value. It is critical to promote Codonopsis pilosula growth through effective and sustainable methods, and the use of plant growth-promoting bacteria (PGPB) is a promising candidate. In this study, we isolated a PGPB, Klebsiella michiganensis LDS17, that produced a highly active 1-aminocyclopropane-1-carboxylate deaminase from the Codonopsis pilosula rhizosphere. The strain exhibited multiple plant growth-promoting properties. The antagonistic activity of strain LDS17 against eight phytopathogenic fungi was investigated, and the results showed that strain LDS17 had obvious antagonistic effects on Rhizoctonia solani, Colletotrichum camelliae, Cytospora chrysosperma, and Phomopsis macrospore with growth inhibition rates of 54.22%, 49.41%, 48.89%, and 41.11%, respectively. Inoculation of strain LDS17 not only significantly increased the growth of Codonopsis pilosula seedlings but also increased the invertase and urease activities, the number of culturable bacteria, actinomycetes, and fungi, as well as the functional diversity of microbial communities in the rhizosphere soil of the seedlings. Heavy metal (HM) resistance tests showed that LDS17 is resistant to copper, zinc, and nickel. Whole-genome analysis of strain LDS17 revealed the genes involved in IAA production, siderophore synthesis, nitrogen fixation, P solubilization, and HM resistance. We further identified a gene (koyR) encoding a plant-responsive LuxR solo in the LDS17 genome. Klebsiella michiganensis LDS17 may therefore be useful in microbial fertilizers for Codonopsis pilosula. The identification of genes related to plant growth and HM resistance provides an important foundation for future analyses of the molecular mechanisms underlying the plant growth promotion and HM resistance of LDS17. IMPORTANCE: We comprehensively evaluated the plant growth-promoting characteristics and heavy metal (HM) resistance ability of the LDS17 strain, as well as the effects of strain LDS17 inoculation on the Codonopsis pilosula seedling growth and the soil qualities in the Codonopsis pilosula rhizosphere. We conducted whole-genome analysis and identified lots of genes and gene clusters contributing to plant-beneficial functions and HM resistance, which is critical for further elucidating the plant growth-promoting mechanism of strain LDS17 and expanding its application in the development of plant growth-promoting agents used in the environment under HM stress.

Inhibition of calcium-sensing receptor by its antagonist promotes gastrointestinal motility in a Parkinson's disease mouse model.

BACKGROUND: The Calcium-sensing receptor (CaSR) participates in the regulation of gastrointestinal (GI) motility under normal conditions and might be involved in the regulation of GI dysmotility in patients with Parkinson's disease (PD). METHODS: CaSR antagonist-NPS-2143 was applied in in vivo and ex vivo experiments to study the effect and underlying mechanisms of CaSR inhibition on GI dysmotility in the MPTP-induced PD mouse model. FINDINGS: Oral intake of NPS-2143 promoted GI motility in PD mice as shown by the increased gastric emptying rate and shortened whole gut transit time together with improved weight and water content in the feces of PD mice, and the lack of influence on normal mice. Meanwhile, the number of cholinergic neurons, the proportion of serotonergic neurons, as well as the levels of acetylcholine and serotonin increased, but the numbers of nitrergic and tyrosine hydroxylase immunoreactive neurons, and the levels of nitric oxide synthase and dopamine decreased in the myenteric plexus in the gastric antrum and colon of PD mice in response to NPS-2143 treatment. Furthermore, the numbers of c-fos positive neurons in the nucleus tractus solitarius (NTS) and cholinergic neurons in the dorsal motor nucleus of the vagus (DMV) increased in NPS-2143 treated PD mice, suggesting the involvement of both the enteric (ENS) and central (CNS) nervous systems. However, ex vivo results showed that NPS-2143 directly inhibited the contractility of antral and colonic strips in PD mice via a non-ENS mediated mechanism. Further studies revealed that NPS-2143 directly inhibited the voltage gated Ca2+ channels, which might, at least in part, explain its direct inhibitory effects on the GI muscle strips. INTERPRETATION: CaSR inhibition by its antagonist ameliorated GI dysmotility in PD mice via coordinated neuronal regulation by both ENS and CNS in vivo, although the direct effects of CaSR inhibition on GI muscle strips were suppressive.

Correlation between S100A7 and immune characteristics, methylation, tumor stemness and tumor heterogeneity in pan-cancer and its role in chemotherapy resistance in breast cancer.

OBJECTIVE: To explore the relationships between S100A7 and the immune characteristics, tumor heterogeneity, and tumor stemness pan-cancer as well as the effect of S100A7 on chemotherapy sensitivity in breast cancer. METHODS: TCGA-BRCA and TCGA-PANCANCER RNA-seq data and clinical follow-up survival data were collected from the University of California Santa Cruz database. Survival analyses were performed to explore the relationship between S100A7 expression and pan-cancer prognosis. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, and Gene Set Enrichment Analysis (GSEA) were used to identify the potential pathways related to the differentially expressed genes in breast cancer. Spearman's and Wilcoxon's tests were used to investigate the relationships between S100A7 expression and immune characteristics, methylation, tumor heterogeneity, and tumor stemness. The potential functions of S100A7 and its influence on chemotherapy sensitivity in breast cancer were elucidated using reverse transcription-quantitative PCR, Cell Counting Kit-8 (CCK-8) assay, Transwell assay, and wound healing assay. RESULTS: S100A7 was highly expressed in most types of tumors and was associated with poor prognosis. S100A7 was closely associated with immunomodulators, immune checkpoint and immune cell infiltration. Further, S100A7 was related to tumor mutational burden, tumor heterogeneity, methylation and tumor stemness in breast cancer. High S100A7 expression was associated with the invasiveness, migration, proliferation and chemotherapy resistance of breast cancer cells in vitro experiments. CONCLUSION: High S100A7 expression was related with poor prognosis and chemotherapy resistance in breast cancer, making it a potential immune and chemotherapy resistance biomarker.

Scoping review of obesity interventions: Research frontiers and publication status.

Obesity and overweight are significant global health issues, and numerous obesity intervention studies have been conducted. Summarizing current knowledge of interventions aims to inform researchers and policymakers to keep up-to-date with the latest scientific advancements and trends. In this review, we comprehensively retrieved and screened 4,541 studies on obesity intervention published between 2018 and 2022 in the Web of Science Core Collection, and objectively presented research frontiers using bibliometric analysis. The research frontiers of intervention are mainly focused on dietary, exercise, pharmacological interventions, bariatric surgery, environmental, and cognitive interventions. Time-restricted eating is the hottest research topic, followed by probiotics and Roux-en-Y gastric bypass. Gut microbiota is located in the "Basic and transversal themes" quadrant with a high centrality and low density, which has great development potentiality. Obesity intervention is becoming increasingly common,and we advocate for researchers to undertake more focused research endeavors that consider the specific characteristics of diverse populations or patients.

Logistic analysis of delayed reporting of emergency blood potassium and comparison of improved outcomes.

Potassium testing is an essential test in emergency medicine. Turnaround time (TAT) is the time between specimen receipt by the laboratory and the release of the test report. A brief in-laboratory TAT increases emergency department effectiveness. Optimizing processes to shorten TAT using other tools requires extensive time, resources, training, and support. Therefore, we aimed to find a convenient way to shorten TAT, identify risk factors affecting the timeliness of emergency potassium test reporting, and verify the intervention's effects. The dependent variable was emergency potassium reporting time > 30 or < 30 min. Logistic analysis was performed on monitorable factors, such as sex, age, potassium results, number of items, specimen processing time (including centrifugation and time before specimen loading), critical value ratio, instrument status, shift where the report was issued, specimen status, and work experience, as independent variables. In the multivariate analysis, work experience, instrument failure rate, and specimen processing time were risk factors for emergency blood potassium reporting exceeding 30 min. Improvement measures were implemented, significantly decreasing the timeout rate for acute potassium reporting. Our study confirms the usefulness of logistics in reducing the time required to report potassium levels in the emergency department, providing a new perspective on quality management.

Alterations of serum neuropeptide levels and their relationship to cognitive impairment and psychopathology in male patients with chronic schizophrenia.

Serum neuropeptide levels may be linked to schizophrenia (SCZ) pathogenesis. This study aims to examine the relation between five serum neuropeptide levels and the cognition of patients with treatment-resistant schizophrenia (TRS), chronic stable schizophrenia (CSS), and in healthy controls (HC). Three groups were assessed: 29 TRS and 48 CSS patients who were hospitalized in regional psychiatric hospitals, and 53 HC. After the above participants were enrolled, we examined the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the blood serum levels of α-melanocyte stimulating hormone (α-MSH), ß-endorphin (BE), neurotensin (NT), oxytocin (OT) and substance.P (S.P). Psychiatric symptoms in patients with SCZ were assessed with the Positive and Negative Syndrome Scale. SCZ patients performed worse than HC in total score and all subscales of the RBANS. The levels of the above five serum neuropeptides were significantly higher in SCZ than in HC. The levels of OT and S.P were significantly higher in CSS than in TRS patients. The α-MSH levels in TRS patients were significantly and negatively correlated with the language scores of RBANS. However, the BE and NT levels in CSS patients were significantly and positively correlated with the visuospatial/constructional scores of RBANS. Moreover, the interaction effect of NT and BE levels was positively associated with the visuospatial/constructional scores of RBANS. Therefore, abnormally increased serum neuropeptide levels may be associated with the physiology of SCZ, and may cause cognitive impairment and psychiatric symptoms, especially in patients with TRS.

Discovery of potential WEE1 inhibitors via hybrid virtual screening.

G2/M cell cycle checkpoint protein WEE1 kinase is a promising target for inhibiting tumor growth. Although various WEE1 inhibitors have entered clinical investigations, their therapeutic efficacy and safety profile remain unsatisfactory. In this study, we employed a comprehensive virtual screening workflow, which included Schrödinger-Glide molecular docking at different precision levels, as well as the utilization of tools such as MM/GBSA and Deepdock to predict the binding affinity between targets and ligands, in order to identify potential WEE1 inhibitors. Out of ten molecules screened, 50% of these molecules exhibited strong inhibitory activity against WEE1. Among them, compounds 4 and 5 showed excellent inhibitory activity with IC50 values of 1.069 and 3.77 nM respectively, which was comparable to AZD1775. Further investigations revealed that compound 4 displayed significant anti-proliferative effects in A549, PC9, and HuH-7 cells and could also induce apoptosis and G1 phase arrest in PC9 cells. Additionally, molecular dynamics simulations unveiled the binding details of compound 4 with WEE1, notably the crucial hydrogen bond interactions formed with Cys379. In summary, this comprehensive virtual screening workflow, combined with in vitro testing and computational modeling, holds significant importance in the development of promising WEE1 inhibitors.

MYLK and CALD1 as molecular targets in bladder cancer.

Bladder cancer (BC) is a malignant tumor that occurs in bladder mucosa. However, relationship between myosin light chain kinase (MYLK) and CALD1 and BC remains unclear. The BC datasets GSE65635 and GSE100926 were downloaded from gene expression omnibus by GPL14951 and GPL14550. Multiple datasets were merged and batched. Differentially expressed genes (DEGs) were screened and weighted gene co-expression network analysis was performed. gene ontology (GO) and Kyoto Encyclopedia of Gene and Genome analysis, gene set enrichment analysis, immune infiltration analysis, survival analysis and Comparative Toxicogenomics Database were performed. TargetScan screened miRNAs that regulated central DEGs. 1026 DEGs were identified. According to GO analysis, DEGs were mainly enriched in cancer pathway, cGMP-PKG signaling pathway, Apelin signaling pathway and proteoglycans in cancer. The enrichment items are similar to GO and Kyoto Encyclopedia of Gene and Genome enrichment projects for DEGs, which were mainly enriched in cancer pathways and leukocyte trans-endothelial cell migration. Among enrichment projects of metascape, GO has regulation of the enzyme-linked receptor protein signaling pathway and silk-based process, as well as an enrichment network stained by enrichment terms and P values. Nine core genes (ACTA2, MYLK, MYH11, MYL9, ACTG2, TPM1, TPM2, TAGLN and CALD1) were obtained, which were highly expressed in tumor tissue samples and lowly expressed in normal tissue samples. Nine genes were associated with necrosis, inflammation, tumor, edema, and ureteral obstruction. MYLK and CALD1 are highly expressed in the BC. The higher expression of MYLK and CALD1, the worse prognosis.

Abnormal activation of the Wnt3a/ß-catenin signaling pathway promotes the expression of T-box transcription factor 3(TBX3) and the epithelial-mesenchymal transition pathway to mediate the occurrence of adenomyosis.

BACKGROUND: T-box transcription factor 3(TBX3) is a transcription factor that can regulate cell proliferation, apoptosis, invasion, and migration in different tumor cells; however, its role in adenomyosis (ADM) has not been previously studied. Some of ADM's pathophysiological characteristics are similar to those of malignant tumors (e.g., abnormal proliferation, migration, and invasion). METHODS AND RESULTS: We hypothesized that TBX3 might have a role in ADM. We used tamoxifen-induced Institute of Cancer research (ICR) mice to establish ADM disease model. The study procedure included western blotting and immunohistochemistry to analyze protein levels; additionally, we used intraperitoneal injection of Wnt/ß-catenin pathway inhibitor XAV-939 to study the relationship between TBX3 and Wnt/ß-catenin pathway as well as Anti-proliferation cell nuclear antigen( PCNA) and TUNEL to detect cell proliferation and apoptosis, respectively. TBX3 overexpression and epithelial-to-mesenchymal transition (EMT) in ADM mice was found to be associated with activation of the Wnt3a/ß-catenin pathway. Treatment with XAV-939 in ADM mice led to the inhibition of both TBX3 and EMT; moreover, abnormal cell proliferation was suppressed, the depth of invasion of endometrium cells was limited. Thus, the use of XAV-939 effectively inhibited further invasion of endometrial cells. CONCLUSION: These findings suggest that TBX3 may play an important role in the development of ADM. The expression of TBX3 in ADM was regulated by the Wnt3a/ß-catenin pathway. The activation of the Wnt3a/ß-catenin pathway in ADM promoted TBX3 expression and induced the occurrence of EMT, thus promoting cell proliferation and inhibiting apoptosis, ultimately accelerating the development of ADM. The study provides a reference for the diagnosis of ADM.

Quantitative Proteomics Characterization of the Effect and Mechanism of Trichostatin A on the Hippocampus of Type II Diabetic Mice.

Diabetic encephalopathy (DE) is one of the complications of diabetes mellitus with mild-to-moderate cognitive impairment. Trichostatin A (TSA) has been revealed to show protective effect on central nervous systems in Alzheimer's disease (AD) and hypoxic-ischemic brain injury. However, the effect and molecular mechanism of TSA on cognitive function of DE are unknown. Here, we demonstrated that cognitive function was damaged in diabetic mice versus normal mice and treatment with TSA improved cognitive function in diabetic mice. Proteomic analysis of the hippocampus revealed 174 differentially expressed proteins in diabetic mice compared with normal mice. TSA treatment reversed the expression levels of 111 differentially expressed proteins grouped into functional clusters, including the longevity regulating pathway, the insulin signaling pathway, peroxisomes, protein processing in the endoplasmic reticulum, and ribosomes. Furthermore, protein-protein interaction network analysis of TSA-reversed proteins revealed that UBA52, CAT, RPL29, RPL35A, CANX, RPL37, and PRKAA2 were the main hub proteins. Multiple KEGG pathway-enriched CAT and PRKAA2 levels were significantly decreased in the hippocampus of diabetic mice versus normal mice, which was reversed by TSA administration. Finally, screening for potential similar or ancillary drugs for TSA treatment indicated that HDAC inhibitors ISOX, apicidin, and panobinostat were the most promising similar drugs, and the PI3K inhibitor GSK-1059615, the Aurora kinase inhibitor alisertib, and the nucleophosmin inhibitor avrainvillamide-analog-6 were the most promising ancillary drugs. In conclusion, our study revealed that CAT and PRKAA2 were the key proteins involved in the improvement of DE after TSA treatment. ISOX, apicidin, and panobinostat were promising similar drugs and that GSK-1059615, alisertib, and avrainvillamide-analog-6 were promising ancillary drugs to TSA in the treatment of DE.

Job stressors and burnout among clinical nurses: a moderated mediation model of need for recovery and career calling.

BACKGROUND: Burnout is a major concern in healthcare professions. Although theory and empirical evidence support the relationship between job stressors and burnout, the question remains how and when the job stressors are related to burnout. Based on conservation of resources theory and effort recovery model, the current study aimed to provide a deeper understanding of the effect of job stressors on burnout by investigating the mediating role of need for recovery and the moderating role of career calling. METHODS: A cross-sectional online survey was conducted among 709 nurses enrolled from eight public hospitals in China. The Work Stressors Scale, Psychological Detachment Scale, Brief Calling Scale, and Maslach Burnout Inventory were used to collect data. Hierarchical regression analysis with bootstrapping procedure was performed to test the proposed model. RESULTS: The results showed that need for recovery mediated the job stressors-burnout relationship, and that high career calling buffered against the relationships between job stressors and need for recovery and burnout. Furthermore, the result revealed a moderated mediation model that career calling buffered the indirect effect of job stressors on burnout through need for recovery. CONCLUSIONS: Our findings suggest that environmental demands and personal resource are important antecedents of nurses' burnout. Career calling as personal resources can serve as a protective factor that guards against burnout. Thus, nursing managers can reduce nurse burnout by focusing on effective strategies related to recovery experiences, as well as investing in training career calling.

An interpretable ensemble learning model facilitates early risk stratification of ischemic stroke in intensive care unit: Development and external validation of ICU-ISPM.

Ischemic stroke (IS) is a common and severe condition that requires intensive care unit (ICU) admission, with high mortality and variable prognosis. Accurate and reliable predictive tools that enable early risk stratification can facilitate interventions to improve patient outcomes; however, such tools are currently lacking. In this study, we developed and validated novel ensemble learning models based on soft voting and stacking methods to predict in-hospital mortality from IS in the ICU using two public databases: MIMIC-IV and eICU-CRD. Additionally, we identified the key predictors of mortality and developed a user-friendly online prediction tool for clinical use. The soft voting ensemble model, named ICU-ISPM, achieved an AUROC of 0.861 (95% CI: 0.829-0.892) and 0.844 (95% CI: 0.819-0.869) in the internal and external test cohorts, respectively. It significantly outperformed the APACHE scoring system and was more robust than individual models. ICU-ISPM obtained the highest performance compared to other models in similar studies. Using the SHAP method, the model was interpretable, revealing that GCS score, age, and intubation were the most important predictors of mortality. This model also provided a risk stratification system that can effectively distinguish between low-, medium-, and high-risk patients. Therefore, the ICU-ISPM is an accurate, reliable, interpretable, and clinically applicable tool, which is expected to assist clinicians in stratifying IS patients by the risk of mortality and rationally allocating medical resources. Based on ICU-ISPM, an online risk prediction tool was further developed, which was freely available at: http://ispm.idrblab.cn/.

Correlations between Multiple SNPs and HbF Levels in ß-Thalassemia Carriers.

BACKGROUND: Increased hemoglobin F (HbF) expression in individuals with ß-thalassemia contributes to the alleviation of pathological phenomena and the reduction of mortality. We have investigated the correlation between six single nucleotide polymorphisms (SNPs) in BCL11A, XmnI-HBG2, HBS1L-MYB, and ANTXR1 and the levels of HbF in ß-thalassemia carriers. METHODS: Samples were collected from 330 cases of ß-thalassemia carriers. The genotypes of the rs4671393, rs-7482144, rs28384513, rs4895441, rs9399137, and rs4527238 were determined using Sanger sequencing. RESULTS: The results both of quantitative and qualitative analysis showed that rs4671393 (BCL11A), rs7482144 (Xmn1-HBG2), and rs9399137 (HBS1L-MYB) in ß-thalassemia carriers correlated with the levels of HbF (p < 0.05), only rs28384513 (HBS1L-MYB) and rs4527238 (ANTXR1) were associated with HbF expression in ß-thalassemia minor (p < 0.05). CONCLUSIONS: These results indicate that the SNP rs4527238 in the ANTXR1 gene was found likely to play a role as a modulator of HbF levels in ß-thalassemia carriers for the first time.

Discovery of 2-Aminopyrimidine Derivatives as Potent Dual FLT3/CHK1 Inhibitors with Significantly Reduced hERG Inhibitory Activities.

FLT3 inhibitors as single agents have limited effects because of acquired and adaptive resistance and the cardiotoxicity related to human ether-a-go-go-related gene (hERG) channel blockade further impedes safe drugs to the market. Inhibitors having potential to overcome resistance and reduce hERG affinity are highly demanded. Here, we reported a dual FLT3/CHK1 inhibitor 18, which displayed potencies to overcome varying acquired resistance in BaF3 cells with FLT3-TKD and FLT3-ITD-TKD mutations. Moreover, 18 displayed high selectivity over c-KIT more than 1700-fold and greatly reduced hERG affinity, with an IC50 value of 58.4 µM. Further mechanistic studies demonstrated 18 can upregulate p53 and abolish the outgrowth of adaptive resistant cells. In the in vivo studies, 18 demonstrated favorable PK profiles and good safety, suppressed the tumor growth in the MV-4-11 cell inoculated mouse xenograft model, and prolonged the survival in the Molm-13 transplantation model, supporting its further development.

AIEE-Active Flavones as a Promising Tool for the Real-Time Tracking of Uptake and Distribution in Live Zebrafish.

In recent years, aggregation-induced emission enhancement (AIEE) molecules have shown great potential for applications in the fields of bio-detection, imaging, optoelectronic devices, and chemical sensing. Based on our previous studies, we investigated the fluorescence properties of six flavonoids and confirmed that compounds 1-3 have good aggregation-induced emission enhancement (AIEE) properties through a series of spectroscopic experiments. Compounds with AIEE properties have addressed the limitation imposed by the aggregation-caused quenching (ACQ) of classic organic dyes owing to their strong fluorescence emission and high quantum yield. Based on their excellent fluorescence properties, we evaluated their performance in the cell and we found that they could label mitochondria specifically by comparing their Pearson correlation coefficients (R) with Mito Tracker Red and Lyso-Tracker Red. This suggests their future application in mitochondrial imaging. Furthermore, studies of uptake and distribution characterization in 48 hpf zebrafish larvae revealed their potential for monitoring real-time drug behavior. The uptake of compounds by larvae varies significantly across different time cycles (between uptake and utilization in the tissue). This observation has important implications for the development of visualization techniques for pharmacokinetic processes and can enable real-time feedback. More interestingly, according to the data presented, tested compounds aggregated in the liver and intestine of 168 hpf larvae. This finding suggests that they could potentially be used for monitoring and diagnosing liver and intestinal diseases.

Nobiletin with AIEE Characteristics for Targeting Mitochondria and Real-Time Dynamic Tracking in Zebrafish.

Nobiletin is a natural product with multiple physiological activities and is the main ingredient of Pericarpium Citri Reticulatae. We successfully discovered that nobiletin exhibits aggregation induced emission enhancement (AIEE) properties and it has significant advantages such as a large Stokes shift, good stability and excellent biocompatibility. The increase in methoxy groups endows nobiletin a greater fat-solubility, bioavailability and transport rate than the corresponding unmethoxylated flavones. Ulteriorly, cells and zebrafish were used to explore the application of nobiletin in biological imaging. It emits fluorescence in cells and is specifically targeted at mitochondria. Moreover, it has a noteworthy affinity for the digestive system and liver of zebrafish. Due to the unique AIEE phenomenon and stable optical properties of nobiletin, it paves the way for discovering, modifying and synthesizing more molecules with AIEE characteristics. Furthermore, it has a great prospect with regard to imaging cells and cellular substructures, such as mitochondria, which play crucial roles in cell metabolism and death. Indeed, three-dimensional real-time imaging in zebrafish provides a dynamic and visual tool for studying the absorption, distribution, metabolism and excretion of drugs. In this article, more directions and inspiration can be presented for the exploration of non-invasive pharmacokinetic research and intuitive drug pathways or mechanisms.

Novel compound heterozygous mutations in the AFG3L2 gene in a Chinese child with microcephaly, early-onset seizures, and cerebral atrophy.

Background: The most common disease caused by biallelic AFG3L2 mutations is spastic ataxia type 5 (SPAX5). Identification of complex phenotypes resulting from biallelic AFG3L2 mutations has been increasing in recent years. Methods: A retrospective analysis was performed on a child with microcephaly and recurrent seizures. The child underwent physical and neurological examinations, laboratory tests, electroencephalography (EEG), and brain magnetic resonance imaging (MRI). Trio-whole-exome sequencing (trio-WES) was performed to identify possible causative mutations. Results: We described a child who exhibited early-onset and intractable epilepsy, developmental regression, microcephaly, and premature death. Neuroimaging revealed global cerebral atrophy (GCA) involving the cerebrum, cerebellum, corpus callosum, brainstem, cerebellar vermis, and basal ganglia. On trio-WES, two novel compound heterozygous mutations, c.1834G > T (p.E612*) and c.2176-6T > A in the AFG3L2 gene, were identified in this patient. Conclusions: Our findings have expanded the mutation spectrum of the AFG3L2 gene and identified a severe neurodegenerative phenotype of global cerebral atrophy caused by biallelic AFG3L2 mutations.