Discovery of lirafugratinib (RLY-4008), a highly selective irreversible small-molecule inhibitor of FGFR2.

Fibroblast growth factor receptor (FGFR) kinase inhibitors have been shown to be effective in the treatment of intrahepatic cholangiocarcinoma and other advanced solid tumors harboring FGFR2 alterations, but the toxicity of these drugs frequently leads to dose reduction or interruption of treatment such that maximum efficacy cannot be achieved. The most common adverse effects are hyperphosphatemia caused by FGFR1 inhibition and diarrhea due to FGFR4 inhibition, as current therapies are not selective among the FGFRs. Designing selective inhibitors has proved difficult with conventional approaches because the orthosteric sites of FGFR family members are observed to be highly similar in X-ray structures. In this study, aided by analysis of protein dynamics, we designed a selective, covalent FGFR2 inhibitor. In a key initial step, analysis of long-timescale molecular dynamics simulations of the FGFR1 and FGFR2 kinase domains allowed us to identify differential motion in their P-loops, which are located adjacent to the orthosteric site. Using this insight, we were able to design orthosteric binders that selectively and covalently engage the P-loop of FGFR2. Our drug discovery efforts culminated in the development of lirafugratinib (RLY-4008), a covalent inhibitor of FGFR2 that shows substantial selectivity over FGFR1 (~250-fold) and FGFR4 (~5,000-fold) in vitro, causes tumor regression in multiple FGFR2-altered human xenograft models, and was recently demonstrated to be efficacious in the clinic at doses that do not induce clinically significant hyperphosphatemia or diarrhea.

Dual Antiplatelet Treatment up to 72 Hours after Ischemic Stroke.

BACKGROUND: Dual antiplatelet treatment has been shown to lower the risk of recurrent stroke as compared with aspirin alone when treatment is initiated early (≤24 hours) after an acute mild stroke. The effect of clopidogrel plus aspirin as compared with aspirin alone administered within 72 hours after the onset of acute cerebral ischemia from atherosclerosis has not been well studied. METHODS: In 222 hospitals in China, we conducted a double-blind, randomized, placebo-controlled, two-by-two factorial trial involving patients with mild ischemic stroke or high-risk transient ischemic attack (TIA) of presumed atherosclerotic cause who had not undergone thrombolysis or thrombectomy. Patients were randomly assigned, in a 1:1 ratio, within 72 hours after symptom onset to receive clopidogrel (300 mg on day 1 and 75 mg daily on days 2 to 90) plus aspirin (100 to 300 mg on day 1 and 100 mg daily on days 2 to 21) or matching clopidogrel placebo plus aspirin (100 to 300 mg on day 1 and 100 mg daily on days 2 to 90). There was no interaction between this component of the factorial trial design and a second part that compared immediate with delayed statin treatment (not reported here). The primary efficacy outcome was new stroke, and the primary safety outcome was moderate-to-severe bleeding - both assessed within 90 days. RESULTS: A total of 6100 patients were enrolled, with 3050 assigned to each trial group. TIA was the qualifying event for enrollment in 13.1% of the patients. A total of 12.8% of the patients were assigned to a treatment group no more than 24 hours after stroke onset, and 87.2% were assigned after 24 hours and no more than 72 hours after stroke onset. A new stroke occurred in 222 patients (7.3%) in the clopidogrel-aspirin group and in 279 (9.2%) in the aspirin group (hazard ratio, 0.79; 95% confidence interval [CI], 0.66 to 0.94; P = 0.008). Moderate-to-severe bleeding occurred in 27 patients (0.9%) in the clopidogrel-aspirin group and in 13 (0.4%) in the aspirin group (hazard ratio, 2.08; 95% CI, 1.07 to 4.04; P = 0.03). CONCLUSIONS: Among patients with mild ischemic stroke or high-risk TIA of presumed atherosclerotic cause, combined clopidogrel-aspirin therapy initiated within 72 hours after stroke onset led to a lower risk of new stroke at 90 days than aspirin therapy alone but was associated with a low but higher risk of moderate-to-severe bleeding. (Funded by the National Natural Science Foundation of China and others; INSPIRES ClinicalTrials.gov number, NCT03635749.).

G-site residue S67 is involved in the fungicide-degrading activity of a tau class glutathione S-transferase from Carica papaya.

Thiram is a toxic fungicide extensively used for the management of pathogens in fruits. Although it is known that thiram degrades in plant tissues, the key enzymes involved in this process remain unexplored. In this study, we report that a tau class glutathione S-transferase (GST) from Carica papaya can degrade thiram. This enzyme was easily obtained by heterologous expression in Escherichia coli, showed low promiscuity toward other thiuram disulfides, and catalyzed thiram degradation under physiological reaction conditions. Site-directed mutagenesis indicated that G-site residue S67 shows a key influence for the enzymatic activity toward thiram, while mutation of residue S13, which reduced the GSH oxidase activity, did not significantly affect the thiram-degrading activity. The formation of dimethyl dithiocarbamate, which was subsequently converted into carbon disulfide, and dimethyl dithiocarbamoylsulfenic acid as the thiram degradation products suggested that thiram undergoes an alkaline hydrolysis that involves the rupture of the disulfide bond. Application of the GST selective inhibitor 4-chloro-7-nitro-2,1,3-benzoxadiazole reduced papaya peel thiram-degrading activity by 95%, indicating that this is the main degradation route of thiram in papaya. GST from Carica papaya also catalyzed the degradation of the fungicides chlorothalonil and thiabendazole, with residue S67 showing again a key influence for the enzymatic activity. These results fill an important knowledge gap in understanding the catalytic promiscuity of plant GSTs and reveal new insights into the fate and degradation products of thiram in fruits.

FANCD2 deficiency sensitizes SHH medulloblastoma to radiotherapy via ferroptosis.

Radiotherapy is one of the standard therapeutic regimens for medulloblastoma (MB). Tumor cells utilize DNA damage repair (DDR) mechanisms to survive and develop resistance during radiotherapy. It has been found that targeting DDR sensitizes tumor cells to radiotherapy in several types of cancer, but whether and how DDR pathways are involved in the MB radiotherapy response remain to be determined. Single-cell RNA sequencing was carried out on 38 MB tissues, followed by expression enrichment assays. Fanconi anemia group D2 gene (FANCD2) expression was evaluated in MB samples and public MB databases. The function of FANCD2 in MB cells was examined using cell counting assays (CCK-8), clone formation, lactate dehydrogenase activity, and in mouse orthotopic models. The FANCD2-related signaling pathway was investigated using assays of peroxidation, a malondialdehyde assay, a reduced glutathione assay, and using FerroOrange to assess intracellular iron ions (Fe2+ ). Here, we report that FANCD2 was highly expressed in the malignant sonic hedgehog (SHH) MB subtype (SHH-MB). FANCD2 played an oncogenic role and predicted worse prognosis in SHH-MB patients. Moreover, FANCD2 knockdown markedly suppressed viability, mobility, and growth of SHH-MB cells and sensitized SHH-MB cells to irradiation. Mechanistically, FANCD2 deficiency led to an accumulation of Fe2+ due to increased divalent metal transporter 1 expression and impaired glutathione peroxidase 4 activity, which further activated ferroptosis and reduced proliferation of SHH-MB cells. Using an orthotopic mouse model, we observed that radiotherapy combined with silencing FANCD2 significantly inhibited the growth of SHH-MB cell-derived tumors in vivo. Our study revealed FANCD2 as a potential therapeutic target in SHH-MB and silencing FANCD2 could sensitize SHH-MB cells to radiotherapy via inducing ferroptosis. © 2024 The Pathological Society of Great Britain and Ireland.

TH1L involvement in colorectal cancer pathogenesis by regulation of CCL20 through the NF-κB signalling pathway.

TH1L (also known as NELF-C/D) is a member of the Negative Elongation Factor (NELF) complex, which is a metazoan-specific factor that regulates RNA Polymerase II (RNAPII) pausing and transcription elongation. However, the function and molecular mechanisms of TH1L in cancer progression are still largely unknown. In this study, we found that TH1L was highly expressed in colorectal cancer (CRC) tissues and the faeces of CRC patients. Overexpression of TH1L significantly enhanced the proliferation and migration of CRC cells, while its knockdown markedly suppressed these processes. In mechanism, RNA sequencing revealed that CCL20 was upregulated in TH1L-overexpressed CRC cells, leading to activation of the NF-κB signalling pathway. Rescue assays showed that knockdown of CCL20 could impair the tumour-promoting effects of THIL in CRC cells. Taken together, these results suggest that TH1L may play a vital role via the CCL20/NF-κB signalling pathway in CRC proliferation and migration and may serve as a potential target for diagnosis and therapy of CRC.

Comparative transcriptome and coexpression network analysis reveals key pathways and hub candidate genes associated with sunflower (Helianthus annuus L.) drought tolerance.

BACKGROUND: Drought severely limits sunflower production especially at the seedling stage. To investigate the response mechanism of sunflowers to drought stress, we utilized two genotypes of sunflower materials with different drought resistances as test materials. The physiological responses were investigated under well-watered (0 h) and drought-stressed conditions (24 h, 48 h, and 72 h). RESULTS: ANOVA revealed the greatest differences in physiological indices between 72 h of drought stress and 0 h of drought stress. Transcriptome analysis was performed after 72 h of drought stress. At 0 h, there were 7482 and 5627 differentially expressed genes (DEGs) in the leaves of K55 and K58, respectively, and 2150 and 2527 DEGs in the roots of K55 and K58, respectively. A total of 870 transcription factors (TFs) were identified among theDEGs, among which the high-abundance TF families included AP2/ERF, MYB, bHLH,and WRKY. Five modules were screened using weighted gene coexpressionnetwork analysis (WGCNA), three and two of which were positively and negatively, respectively, related to physiological traits. KEGG analysis revealedthat under drought stress, "photosynthesis", "carotenoid biosynthesis", "starch and sucrose metabolism", "ribosome", "carotenoid biosynthesis", "starch and sucrose metabolism", "protein phosphorylation" and "phytohormone signaling" are six important metabolic pathways involved in the response of sunflower to drought stress. Cytoscape software was used to visualize the three key modules, and the hub genes were screened. Finally, a total of 99 important candidate genes that may be associated with the drought response in sunflower plants were obtained, and the homology of these genes was compared with that in Arabidopsis thaliana. CONCLUSIONS: Taken together, our findings could lead to a better understanding of drought tolerance in sunflowers and facilitate the selection of drought-tolerant sunflower varieties.

Ni─Co─O─S Derived Catalysts on Hierarchical N-doped Carbon Supports with Strong Interfacial Interactions for Improved Hybrid Water Splitting Performance.

Simultaneously improving electrochemical activity and stability is a long-term goal for water splitting. Herein, hierarchical N-doped carbon nanotubes on carbon nanowires derived from PPy are grown on carbon cloth, serving as a support for NiCo oxides/sulfides. The hierarchical electrodes annealed in N2 or H2/N2 display improved intrinsic activity and stability for hydrogen evolution reaction (HER) and glucose oxidation reaction. Compared with Pt/C||Ir/C in alkaline media, the glucose electrolysis assembled with electrodes exhibits a cell voltage of 1.38 V at 10 mA cm-2, durability for >12 h at 50 mA cm-2, and resistance to glucose/gluconic acid poisoning. In addition, electrocatalysts can also be applied in ethanol oxidation reactions. Systematic characterizations reveal the strong interactions between NiCo and N-doped carbon support-induced partial charge transfer at the interface and regulate the local electronic structure of active sites. Density functional theory calculations demonstrate that the synergistic effect between N-doped carbon supports, metallic NiCo, and NiCo oxides/sulfides optimize the adsorption energy of H2O and the H* free energy for HER. The energy barrier of the dehydrogenation of glucose effectively decreased. This work will attract attention to the role of metal-support interactions in enhancing the intrinsic activity and stability of electrocatalysts.

Hydrogen sulfide donors across time: From origins to cutting-edge applications.

This review aims to analyze the developmental trajectory of hydrogen sulfide (H2S) donors over the past three decades and explore the historical background, research hotspots, and emerging trends in related fields from a temporal perspective. A total of 5092 literature articles on H2S donors were retrieved from the Web of Science Core Collection (WoSCC), encompassing 1303 journals, 20638 authors, 10992 institutions, and 459 countries and regions. Utilizing CiteSpace as a bibliometric tool, historical features, evolving active topics, and emerging trends in the field of H2S donors were identified. Over the past 30 years, the field of H2S donors has remained in a prominent stage. This article discusses both inorganic and organic types of H2S donors, including NaHS and Na2S, GYY4137, AP39, and AP123, as well as briefly outlines research and applications of H2S donors in nanotechnology, advanced materials, composite materials, nanostructures, and optical properties. Mechanistically, the review outlines how H2S donors regulate cellular signal transduction, anti-inflammatory responses, neuroprotection, and other pathways within the organism by modulating protein S-sulfhydration, antioxidant effects, and interactions with metal proteins. In terms of applications, the review summarizes the extensive use of H2S donors in biomedical research, encompassing cardiovascular, neurological, anti-inflammatory, and anti-cancer characteristics, as well as their potential applications in the treatment of metabolic diseases. Finally, challenges and limitations faced by H2S donor research are discussed, and potential future research directions are proposed.

Ang-1 and VEGF: central regulators of angiogenesis.

Angiopoietin-1 (Ang-1) and Vascular Endothelial Growth Factor (VEGF) are central regulators of angiogenesis and are often inactivated in various cardiovascular diseases. VEGF forms complexes with ETS transcription factor family and exerts its action by downregulating multiple genes. Among the target genes of the VEGF-ETS complex, there are a significant number encoding key angiogenic regulators. Phosphorylation of the VEGF-ETS complex releases transcriptional repression on these angiogenic regulators, thereby promoting their expression. Ang-1 interacts with TEK, and this phosphorylation release can be modulated by the Ang-1-TEK signaling pathway. The Ang-1-TEK pathway participates in the transcriptional activation of VEGF genes. In summary, these elements constitute the Ang-1-TEK-VEGF signaling pathway. Additionally, Ang-1 is activated under hypoxic and inflammatory conditions, leading to an upregulation in the expression of TEK. Elevated TEK levels result in the formation of the VEGF-ETS complex, which, in turn, downregulates the expression of numerous angiogenic genes. Hence, the Ang-1-dependent transcriptional repression is indirect. Reduced expression of many target genes can lead to aberrant angiogenesis. A significant overlap exists between the target genes regulated by Ang-1-TEK-VEGF and those under the control of the Ang-1-TEK-TSP-1 signaling pathway. Mechanistically, this can be explained by the replacement of the VEGF-ETS complex with the TSP-1 transcriptional repression complex at the ETS sites on target gene promoters. Furthermore, VEGF possesses non-classical functions unrelated to ETS and DNA binding. Its supportive role in TSP-1 formation may be exerted through the VEGF-CRL5-VHL-HIF-1α-VH032-TGF-ß-TSP-1 axis. This review assesses the regulatory mechanisms of the Ang-1-TEK-VEGF signaling pathway and explores its significant overlap with the Ang-1-TEK-TSP-1 signaling pathway.

Development of in vitro microfluidic models to study endothelial responses to pulsatility with different mechanical circulatory support devices.

Continuous-flow ventricular assist devices (CFVAD) and counterpulsation devices (CPD) are used to treat heart failure (HF). CFVAD can diminish pulsatility, but pulsatile modes have been implemented to increase vascular pulsatility. The effects of CFVAD in a pulsatile mode and CPD support on the function of endothelial cells (ECs) are yet to be investigated. In this study, two in vitro microfluidic models for culturing ECs are proposed to reproduce blood pressure (BP) and wall shear stress (WSS) on the arterial endothelium while using these medical devices. The layout and parameters of the two microfluidic systems were optimized based on the principle of hemodynamic similarity to efficiently simulate physiological conditions. Moreover, the unique design of the double-pump and double afterload systems could successfully reproduce the working mode of CPDs in an in vitro microfluidic system. The performance of the two systems was verified by numerical simulations and in vitro experiments. BP and WSS under HF, CFVAD in pulsatile modes, and CPD were reproduced accurately in the systems, and these induced signals improved the expression of Ca2+, NO, and reactive oxygen species in ECs, proving that CPD may be effective in normalizing endothelial function and replacing CFVAD to a certain extent to treat non-severe HF. This method offers an important tool for the study of cell mechanobiology and a key experimental basis for exploring the potential value of mechanical circulatory support devices in reducing adverse events and improving outcomes in the treatment of HF in the future.

Strategies for the biological synthesis of D-glucuronic acid and its derivatives.

D-glucuronic acid is a kind of glucose derivative, which has excellent properties such as anti-oxidation, treatment of liver disease and hyperlipidemia, and has been widely used in medicine, cosmetics, food and other fields. The traditional production methods of D-glucuronic acid mainly include natural extraction and chemical synthesis, which can no longer meet the growing market demand. The production of D-glucuronic acid by biocatalysis has become a promising alternative method because of its high efficiency and environmental friendliness. This review describes different production methods of D-glucuronic acid, including single enzyme catalysis, multi-enzyme cascade, whole cell catalysis and co-culture, as well as the intervention of some special catalysts. In addition, some feasible enzyme engineering strategies are provided, including the application of enzyme immobilized scaffold, enzyme mutation and high-throughput screening, which provide good ideas for the research of D-glucuronic acid biocatalysis.

Tom70-regulated mitochondrial biogenesis via TFAM improves hypoxia-induced dysfunction of pulmonary vascular endothelial cells and alleviates hypoxic pulmonary hypertension.

BACKGROUND: Hypoxic pulmonary hypertension (HPH) is a common type of pulmonary hypertension and characterized by pulmonary vascular remodeling and constriction. A large number of studies have shown that pulmonary vascular endothelial cells (PVECs) dysfunction plays an important role in the initiation and development stages of HPH, but the mechanism of PVECs dysfunction after hypoxia remains unclear. In this study, we explored the exact mechanism of PVECs dysfunction after hypoxia. METHODS: In vitro, we used primary cultured PVECs hypoxia model to mimic HPH injury. We detected the expressions of mitochondrial biogenesis markers, mitochondrial transcription factor A (TFAM) level inside mitochondria, mitochondrial quantity and function, and the components expressions of translocase of outer mitochondrial membrane (TOM) at 24 h after hypoxia. To explore the effects of Tom70 on mitochondrial biogenesis and functions of PVECs after hypoxia, Tom70 overexpression adenovirus was constructed, and the expressions of mitochondrial biogenesis markers, TFAM level inside mitochondria, mitochondrial quantity and function, and the functions of PVECs were detected. And in vivo, we used cre-dependent overexpression adenovirus of Tom70 in the Cdh5-CreERT2 mouse model of HPH to verify the role of upregulating PVECs Tom70 in improving HPH. RESULTS: Hypoxia obviously increased the expressions of mitochondrial biogenesis markers for PGC-1α, NRF-1 and TFAM, but reduced the content of TFAM in mitochondria and the quantity and functions of mitochondria. In addition, only Tom70 expression among the TOM components was significantly decreased after hypoxia, and up-regulation of Tom70 significantly increased the content of TFAM in mitochondria of PVECs by transporting TFAM into mitochondria after hypoxia, enhanced the quantity and functions of mitochondria, improved the functions of PVECs, and ultimately alleviated HPH. CONCLUSION: The findings of present study demonstrated that hypoxia induced the decreased expression of Tom70 in PVECs, reduced the mitochondrial biogenesis-associated TFAM protein transporting into mitochondria, inhibited mitochondrial biogenesis, caused PVECs injury, and prompted the formation of HPH. However, up-regulation of Tom70 abolished the hypoxia-induced injurious effects on PVECs and alleviated HPH.

The lysosome-phagosome pathway mediates immune regulatory mechanisms in Mesocentrotus nudus against Vibrio coralliilyticus infection.

Sea urchins are a popular model species for studying invertebrate diseases. The immune regulatory mechanisms of the sea urchin Mesocentrotus nudus during pathogenic infection are currently unknown. This study aimed to reveal the potential molecular mechanisms of M. nudus during resistance to Vibrio coralliilyticus infection by integrative transcriptomic and proteomic analyses. Here, we identified a total of 135,868 unigenes and 4,351 proteins in the four infection periods of 0 h, 20 h, 60 h and 100 h in M. nudus. In the I20, I60 and I100 infection comparison groups, 10,861, 15,201 and 8,809 differentially expressed genes (DEGs) and 2,188, 2,386 and 2,516 differentially expressed proteins (DEPs) were identified, respectively. We performed an integrated comparative analysis of the transcriptome and proteome throughout the infection phase and found very a low correlation between transcriptome and proteome changes. KEGG pathway analysis revealed that most upregulated DEGs and DEPs were involved in immune strategies. Notably, "lysosome" and "phagosome" activated throughout the infection process, could be considered the two most important enrichment pathways at the mRNA and protein levels. The significant increase in phagocytosis of infected M. nudus coelomocytes further demonstrated that the lysosome-phagosome pathway played an important immunological role in M. nudus resistance to pathogenic infection. Key gene expression profiles and protein‒protein interaction analysis revealed that cathepsin family and V-ATPase family genes might be key bridges in the lysosome-phagosome pathway. In addition, the expression patterns of key immune genes were verified using qRT‒PCR, and the different expression trends of candidate genes reflected, to some extent, the regulatory mechanism of immune homeostasis mediated by the lysosome-phagosome pathway in M. nudus against pathogenic infection. This work will provide new insights into the immune regulatory mechanisms of sea urchins under pathogenic stress and help identify key potential genes/proteins for sea urchin immune responses.

Highly activated oxygen redox enabling large-capacity Li-rich layered manganese-based oxide cathodes.

Li-rich Mn-based layered materials are considered the most promising next-generation high-energy-density cathode materials due to their high capacity, but their large irreversible capacity loss and severe voltage attenuation hinder their practical application. The limited operating voltage also makes it difficult to satisfy the increasing demand of high energy density in future applications. Inspired by the high voltage platform of Ni-rich LiNi0.8Co0.1Mn0.1O2, we design and prepare a Li1.2Ni0.32Co0.04Mn0.44O2 (LLMO811) cathode material with increased Ni content via the acrylic acid polymerization method and regulate the amounts of excess lithium of LLMO. It is found that LLMO-L3 with 3% excess lithium has the highest initial discharge capacity of 250 mA h g-1 with a coulombic efficiency of 83.8%. Taking advantage of a high operating voltage of about 3.75 V, the material achieves an impressive high energy density of 947 W h kg-1. Moreover, the capacity at 1C reaches 193.2 mA h g-1, which is higher than that of ordinary LLMO811. This large capacity is attributed to the highly reversible O redox reaction, and the strategy used to achieve this would throw some light on the exploration of high-energy-density cathodes.

Astragaloside IV Alleviates Atorvastatin-Induced Hepatotoxicity via AMPK/SIRT1 Pathway.

INTRODUCTION: Atorvastatin (ATO) is often used to reduce blood lipids and prevent atherosclerosis, but excessive use of ATO will lead to hepatotoxicity. This paper investigated the effects of astragaloside IV (AS IV), which has multiple biological functions, on ATO-induced hepatotoxicity and the underlying mechanism. METHODS: ATO treatment induced a rat model of hepatotoxicity, followed by AS IV treatment. Colorimetric kits were used to detect rat liver function indexes including aspartate aminotransferase (AST), alanine transaminase (ALT), malondialdehyde (MDA), and reduced glutathione (GSH). Reactive oxygen species (ROS) level was determined by 2', 7'-Dichlorodihydrofluorescein diacetate kit. The liver fibrosis and F4/80 expression were detected by Sirius red staining and immunochemistry. Mitochondrial electron transport chain complex I and complex IV activities were examined. The level of mitochondrial membrane potential (MMP) was detected by JC-1 staining. The inflammatory factor levels were detected by quantitative real-time polymerase chain reaction. Western blot detected apoptosis-related proteins and AMPK/SIRT1-related proteins. RESULTS: ATO increased ALT, AST, MDA, and ROS levels and decreased GSH content but was subsequently reversed by AS IV. AS IV alleviated liver tissue damage caused by ATO. AS IV elevated complex I and complex IV activity and promoted MMP levels in ATO rats. ATO promoted inflammatory factor release in SD rats but was then suppressed by AS IV. AS IV inhibited Bax, cleaved caspase-3 but up-regulated Bcl-2 in ATO-induced rats. ATO inhibited SIRT1 expression and AMPK phosphorylation, which was subsequently promoted by AS IV. CONCLUSION: AS IV inhibits ATO-induced hepatotoxicity by activating the AMPK/SIRT1 pathway.

Bariatric surgery reduces sleep apnea in obese patients with obstructive sleep apnea by increasing pharyngeal cross-sectional area during the early postoperative period.

OBJECTIVE: Bariatric surgery (BS) is considered one of the most effective treatments for obese individuals with Obstructive Sleep Apnea (OSA). However, otolaryngologists have raised concerns about the structural alterations caused by BS on the upper respiratory tract, especially, on the pharyngeal cavity. METHODS: In this study, we recruited 42 individuals who underwent BS at our hospital. They were divided into two groups based on apnea-hypopnea index (AHI): mild group (5 ≤ AHI < 15) and moderate-severe group (AHI ≥ 15). The participants were followed up for 12 months and several indicators, including body mass index (BMI), polysomnography (PSG), and acoustic pharyngometry (APh), were assessed repeatedly before surgery and at 3, 6, and 12 months (m) after surgery. RESULTS: Participants exhibited significant decreases in BMI (F = 128.1, P = 0.001) and total weight loss (F = 176.7, P < 0.001) after BS. The AHI value among obese patients with mild OSA decreased significantly within three months after surgery (0 day vs. 3 months, P < 0.01), and decreased significantly more than 12 months with moderate-to-severe patients (0 day vs. 3 months, 3 months vs. 6 months, 6 months vs. 12 months, P < 0.01). The therapeutic effect of OSA of the mild group was significantly better compared with that of the moderate-severe group at 6 months (mean rank = 28.13 vs. 14.21, P < 0.001) and 12 m (mean rank = 26.75 vs. 15.52, P = 0.001). The APh results revealed that the pharyngeal volume of the two groups increased significantly between 0 day and 6 months after surgery (P < 0.01). The oropharyngeal junction (OPJ) area and the glottal area were increased significantly between 0 day and 6 m after surgery (P < 0.01). CONCLUSION: BS can relieve apnea and OSA symptoms among obese patients with OSA, especially in the early postoperative period. Moreover, OSA severity was closely associated with OPJ and glottal areas, rather than pharyngeal cavity volume.

The genetic adaptations of Toxoptera aurantii facilitated its rapid multiple plant hosts dispersal and invasion.

Toxoptera aurantii Boyer de Fonscolombe (Hemiptera: Aphididae) can attack many plant hosts, including tea (Camellia sinensis L.), citrus (Citrus spp.), lychee (Litchi chinensis Sonn.), banana (Musa spp.), and pineapple (Ananas comasus L.) among others. It is a widely distributed hexapod and one of the most destructive pests in tea plantations, causing enormous economic losses in tea production each year. A high-quality reference genome is important to study the phylogenetics and evolution of T. aurantii because its genome is highly heterozygous and repetitive. We obtained a de novo genome assembly of T. aurantii at the chromosome level using a combination of long Nanopore reads from sequencing with high-throughput chromosome conformation capture technology. When finally assembled, the genome was 318.95 Mb on four chromosomes with a 15.19 Mb scaffold N50. A total of 12,162 genes encoded proteins, while there were 22.01% repetitive sequences that totaled 67.73 Mb. Phylogenetic analyses revealed that T. aurantii and Aphis gossypii parted ways approximately 7.6 million years ago (Mya). We used a combination of long-read single-molecule sequencing with Hi-C-based chromatin interaction maps that resulted in a reference chromosomal level reference genome of T. aurantii that was high quality. Our results will enable the exploration of the genetics behind the special biological features of T. aurantii and also provide a source of data that should be useful to compare the compare genome among the Hemiptera.

Effects of Parent-Child Sandplay Therapy for preschool children with autism spectrum disorder and their mothers: A randomized controlled trial.

PURPOSE: To evaluate the effects of the Parent-Child Sandplay Therapy (PCST) Program on autism behaviors, social responsiveness and sleep quality among preschool children with autism spectrum disorder (ASD), and their mothers' parenting stress. DESIGN AND METHODS: A prospective, randomized controlled, parallel-group trial was employed. Fifty-two child-mother dyads were randomly assigned to an intervention group (n = 26) or a control group (n = 26) from February 2017 to February 2019. The intervention group was treated with a 20-week PCST Program plus an Applied Behavior Analysis-based program (ABA-based program), whereas the control group received only the ABA-based program. Outcome measures included the Autism Behavior Checklist total scores, Social Responsiveness Scale scores, Children's Sleep Habits Questionnaire scores, and Parenting Stress Index-Short Form scores, measured at baseline, post-intervention (20 weeks after baseline) and follow-up assessments (32 weeks after baseline). RESULTS: Finally, 43 dyads completed the study. The linear mixed model analysis resulted in a significant group*time interaction effect of ABC score (Est = 2.027, t = 3.277; p < 0.01), SRS score (Est = 3.377, t = 6.095; p < 0.01), PSI-SF score (Est = 3.873, t = 4.253, p < 0.01), and CSHQ score (Est = 3.158, t = 6.485; p < 0.05). CONCLUSION: Our findings suggested that the PCST Program could potentially improve social interaction and sleep quality of preschool children with ASD while decreasing parenting stress. PRACTICE IMPLICATIONS: The PCST Program was found to be a feasible and a promising treatment for children with mild-to-moderate ASD as well as for their parents. It was a nurse-led program, which could be integrated into the usual nursing care of children with autism spectrum disorder in special education schools. TRIAL REGISTRATION: Chinese Clinical Trials Registry, ChiCTR2100047699.

Pharmacological Inhibition of the Asparaginyl Endopeptidase (AEP) in an Alzheimer's Disease Model Improves the Survival and Efficacy of Transplanted Neural Stem Cells.

Stem-cell-based therapy is very promising for Alzheimer's disease (AD), yet has not become a reality. A critical challenge is the transplantation microenvironment, which impacts the therapeutic effect of stem cells. In AD brains, amyloid-beta (Aß) peptides and inflammatory cytokines continuously poison the tissue microenvironment, leading to low survival of grafted cells and restricted efficacy. It is necessary to create a growth-supporting microenvironment for transplanted cells. Recent advances in AD studies suggest that the asparaginyl endopeptidase (AEP) is a potential intervention target for modifying pathological changes. We here chose APP/PS1 mice as an AD model and employed pharmacological inhibition of the AEP for one month to improve the brain microenvironment. Thereafter, we transplanted neural stem cells (NSCs) into the hippocampus and maintained therapy for one more month. We found that inhibition of AEPs resulted in a significant decrease of Aß, TNF-α, IL-6 and IL-1ß in their brains. In AD mice receiving NSC transplantation alone, the survival of NSCs was at a low level, while in combination with AEP inhibition pre-treatment the survival rate of engrafted cells was doubled. Within the 2-month treatment period, implantation of NSCs plus pre-inhibition of the AEP significantly enhanced neural plasticity of the hippocampus and rescued cognitive impairment. Neither NSC transplantation alone nor AEP inhibition alone achieved significant efficacy. In conclusion, pharmacological inhibition of the AEP ameliorated brain microenvironment of AD mice, and thus improved the survival and therapeutic efficacy of transplanted stem cells.

Study on the Flame Retardancy of Rigid Polyurethane Foam with Phytic Acid-Functionalized Graphene Oxide.

A rigid polyurethane foam (RPUF) composite was prepared by compounding phytic acid (PA)-functionalized Graphite oxide (PA-GO) with flame-retardant poly (Ammonium phosphate) (APP) and expandable graphite (EG). The effects of PA-GO on the thermal, flame-retardant, and mechanical properties of RPUF were studied using a thermogravimetric analyzer, a limiting oxygen index (LOI) tester, a UL-94 vertical combustion tester, a cone calorimeter, scanning electron microscopy, and a universal tensile testing machine. The results indicated that there was a significant synergistic flame-retardant effect between PA-GO and the intumescent flame retardants (IFR) in the RPUF matrix. Compared with RPUF-1, the addition of 0.3 wt% PA-GO could increase LOI from 25.7% to 26.5%, increase UL-94 rating from V-2 to V-0, and reduce the peak heat release rate (PHRR) and total heat release rate (THR) by 28.5% and 22.2%, respectively. Moreover, the amount of residual char increased from 22.2 wt% to 24.6 wt%, and the char layer was continuous and dense, with almost no holes. Meanwhile, the loss of mechanical properties was apparently lightened.