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Passive radiative cooling material of cellulose by coupling inorganic nanoparticles, have demonstrated competitive advantages in sustainably cooling buildings and constructions due to their voluminous availability, biodegradability, renewability, and natural origin. However, the weak stability of cellulose-inorganic nanoparticle materials when exposed to water or external forces remains a significant challenge that impedes their practical application. In this study, we proposed an easy-to-prepare, scalable, and robust cooling cellulose composite by coupling nano-SiO 2 and cellulose acetate (CA) within cellulose fibers, using the mature pulping and paper process (filling of inorganic particles of nano-SiO 2 and subsequent sizing of polymer of CA). More importantly, the CA molecules form the strong bonding with the cellulose molecules due to the high similarity of their molecular structure, which makes CA function as a "glue" to effectively fasten nano-SiO 2 on the cellulose fibers. Correspondingly, our cellulose composite features desirable robustness and structural stability even undergoing mechanical beating and water-soaking treatments, demonstrating its excellent robustness and desirable adaptability to natural environments, such as wind and rain. As a result, despite undergoing water-soaking (for 40 days) or environmental exposure (for 90 days), the cooling cellulose composite still exhibits excellent solar reflectance (>95 %) and infrared thermal emissivity (>0.95 at 8-13 μm), enabling sub-ambient temperature (∼6.5 °C during daytime and ∼8 °C at nighttime) throughout the day. Our cooling cellulose composite demonstrates promising potential as an environmentally friendly, low-cost, and stable cooling material in our low-carbon society., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Two series of 2,4-diarylaminopyrimidine derivatives containing sulfonamide moiety were designed and synthesized for screening as inhibitors of focal adhesion kinase (FAK). Most compounds significantly inhibited the enzymatic activities of FAK, and the best compound was 7b (IC 50  = 0.27 nM). A majority of aminoethyl sulfonamide derivatives could effectively inhibit the proliferation of human cancer cell lines (HCT116, A549, MDA-MB-231 and Hela) expressing high levels of FAK. Particularly, compounds 7b, 7c, and 7o exhibited more significant efficacy against all of four cancer cell lines within concentrations of 1.5 μM. Furthermore, these three compounds displayed higher selectivity of cancer cells over normal cells (SI value > 14), compared to the positive control TAE226 (SI value = 1.63). Interestingly, introduction of dithiocarbamate moiety to the aminoethyl sulfonamide derivatives can indeed improve the antiproliferative activities against A549 cells. Especially, compound 8d demonstrated most significant cytotoxicity activity against A549 cells with an IC 50 value of 0.08 μM, which is 20-fold superior to parent compound 7k. Additionally, compound 7b, which display the best anti-FAK potency, can inhibit the clone formation and migration of HCT-116 cells, and cause cell cycle arrest at G2/M phase, inducing apoptosis by promoting ROS production. Overall, these results suggest that 7b is a valuable FAK inhibitor that deserves further optimization to improve its druggability., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The Eph (erythropoietin-producing human hepatocellular) receptor family, the largest subclass of receptor tyrosine kinases (RTKs), plays essential roles in embryonic development and neurogenesis. The intracellular Sterile Alpha Motif (SAM) domain presents a critical structural feature that distinguishes Eph receptors from other RTKs and participates in recruiting and binding downstream molecules. This study identified SASH1 (SAM and SH3 domain containing 1) as a novel Eph receptor-binding partner through SAM-SAM domain interactions. Our comprehensive biochemical analyses revealed that SASH1 selectively interacts with Eph receptors via its SAM1 domain, displaying the highest affinity for EphA8. The high-resolution crystal structure of the EphA8-SASH1 complex provided insights into the specific intermolecular interactions between these proteins. Cellular assays confirmed that EphA8 and SASH1 co-localize and co-precipitate in mammalian cells, with cancer mutations (EphA8 R942H or G978D) impairing this interaction. We demonstrated that SAM-SAM interaction is critical for SASH1-mediated regulation of EphA8 kinase activity, shedding new light on the Eph signaling pathway and expanding our understanding of the molecular basis of the tumor suppressor gene SASH1., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The accuracy and timeliness of the pathologic diagnosis of soft tissue tumors (STTs) critically affect treatment decision and patient prognosis. Thus, it is crucial to make a preliminary judgement on whether the tumor is benign or malignant with hematoxylin and eosin-stained images. A deep learning-based system, Soft Tissue Tumor Box (STT-BOX), is presented herein, with only hematoxylin and eosin images for malignant STT identification from benign STTs with histopathologic similarity. STT-BOX assumed gastrointestinal stromal tumor as a baseline for malignant STT evaluation, and distinguished gastrointestinal stromal tumor from leiomyoma and schwannoma with 100% area under the curve in patients from three hospitals, which achieved higher accuracy than the interpretation of experienced pathologists. Particularly, this system performed well on six common types of malignant STTs from The Cancer Genome Atlas data set, accurately highlighting the malignant mass lesion. STT-BOX was able to distinguish ovarian malignant sex-cord stromal tumors without any fine-tuning. This study included mesenchymal tumors that originated from the digestive system, bone and soft tissues, and reproductive system, where the high accuracy of migration verification may reveal the morphologic similarity of the nine types of malignant tumors. Further evaluation in a pan-STT setting would be potential and prospective, obviating the overuse of immunohistochemistry and molecular tests, and providing a practical basis for clinical treatment selection in a timely manner., (Copyright © 2023 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Pyruvate kinase M2 isoform (PKM2) plays a key role in cancer progression through both metabolic and non-metabolic functions, thus it is recognized as a potential target for cancer diagnosis and treatment. In this study, we discovered a sulfonamide-dithiocarbamate compound 8a as a novel PKM2 activator from a random screening of an in-house compound library. Then, a series of lead compound 8a analogs were designed and synthesized for screening as potent PKM2 activators. Among them, compound 8b (AC 50  = 0.136 µM) and 8k (AC 50  = 0.056 µM) showed higher PKM2 activation activities than positive control NZT (AC 50  = 0.228 µM), and they (IC 50  < 1 µM) exhibited more significant anti-proliferative activities against human tumor cell lines than NZT (IC 50  > 10 µM). Especially, compound 8k inhibited the proliferation of multiple cancer cells, but showed little toxicity on normal cells. In addition, we found that compound 8k inhibit the colony formation of MCF7 cells. Western blot analysis demonstrated that 8k could reduce PKM2 nuclear localization and block the downstream signaling pathway of PKM2, resulting in suppression of tumor cell proliferation. Overall, compound 8k may be a promising candidate for further mechanistic investigation of PKM2 and cancer therapy., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Neutrophils are a major component of immune defense and are recruited through neutrophil chemotaxis in response to invading pathogens. However, the molecular mechanism that controls neutrophil chemotaxis remains unclear. Here, we report that PTENα, the first isoform identified in the PTEN family, regulates neutrophil deformability and promotes chemotaxis of neutrophils. A high level of PTENα is detected in neutrophils and lymphoreticular tissues. Homozygous deletion of PTENα impairs chemoattractant-induced migration of neutrophils. We show that PTENα physically interacts with cell membrane cross-linker moesin through its FERM domain and dephosphorylates moesin at Thr558, which disrupts the association of filamentous actin with the plasma membrane and subsequently induces morphologic changes in neutrophil pseudopodia. These results demonstrate that PTENα acts as a phosphatase of moesin and modulates neutrophil-mediated host immune defense. We propose that PTENα signaling is a potential target for the treatment of infections and immune diseases., (© 2019 by The American Society of Hematology.)

The UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferases (GalNAc-Ts) catalyze mucin-type O-glycosylation by transferring α-N-acetylgalactosamine (GalNAc) from UDP- GalNAc to Ser or Thr residues of target proteins. We resolved the crystal structures of GalNAc-T7, a GalNAc-T capable of glycosylating consecutive sites, and of its complex with the donor substrate UDP-GalNAc. The N-terminal catalytic domain and C-terminal lectin domain are connected by a flexible linker, forming a narrow cleft for the acceptor substrate. Only the α subdomain of the lectin domain binds to the glycosyl group, indicating that key residues determine substrate binding. Compared to the Apo structure, the loop covering the catalytic center of the complex show significant conformational changes, indicating the mechanism of the catalytic reaction., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Myelin protein zero-like protein 1 (MPZL1) is a member of the immunoglobulin superfamily, and is also a receptor of concanavalin A (ConA). MPZL1 is upregulated in hepatocellular carcinoma (HCC) and accelerates migration of HCC cells. However, function of MPZL1 as a receptor of ConA and its role in HCC development are largely unknown. To elucidate the functional basis, we have determined the crystal structure of the extracellular domain of MPZL1 at 2.7 Å resolution. Overall, it folds like a typical immunoglobulin variable-like domain that is much like MPZ. Unexpectedly, we found Asn50 is a unique glycosylation site and the glycosylation mediates its interaction with ConA. Furthermore, we also found that MPZL1 exists as a homodimer in the crystal, in which hydrogen bonds between Ser86 and Val145 play an important role. Our results demonstrate that glycosylation of Asn50 is essential for its function as a receptor of ConA. We propose that dimerization of MPZL1 participates in control of its signal transmission in cell adhesion., (Copyright © 2018 Elsevier Inc. All rights reserved.)

In our recent study, the design and performance of type-I counter-current chromatography (CCC) were changed and improved by multilayer coil. In the present study, the performance of protein separation using the multilayer coil configuration in type-I CCC was investigated under various flow rates. In order to overcome the noise signal interrupting the target peaks, a hollow fiber membrane dialyzer was inserted between CCC column outlet and inlet of the monitor. The separation was performed with a two-phase solvent system composed of polyethylene glycol 1000/dibasic potassium phosphate each at 12.5% (w/w) in deionized water and lysozyme and myoglobin were used as the test samples. The retention of stationary phase in the head to tail elution mode was lower than that in the tail to head elution mode, but Rs (peak resolution) was opposite. The intermittently pressed tubing can efficiently improve the performance of protein separation by type-I CCC with the multilayer coil. The best Rs was 1.54 and obtained at the flow rate of 0.10 ml/min under a revolution speed of 200 rpm. The present result indicated that type-I CCC can be as a potential powerful tool of protein separation for the first time., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Mitochondrial disease (MD) is a rare mitochondrial respiratory chain disorder with a high mortality and extremely challenging to treat. Although genomic, transcriptomic, and proteomic analyses have been performed to investigate the pathogenesis of MD, the role of metabolomics in MD, particularly of lipidomics remains unclear. This study was undertaken to identify potential lipid biomarkers of MD. An untargeted lipidomic approach was used to compare the plasma lipid metabolites in 20 MD patients and 20 controls through Liquid Chromatography coupled to Mass Spectrometry. Volcano plot analysis was performed to identify the different metabolites. Receiver operating characteristic (ROC) curves were constructed and the area under the ROC curves (AUC) was calculated to determine the potentially sensitive and specific biomarkers. A total of 41 lipids were significantly different in MD patients and controls. ROC curve analysis showed the top 5 AUC values of lipids (phosphatidylinositols 38:6, lysoPC 20:0, 19:0, 18:0, 17:0) are more than 0.99. Multivariate ROC curve based exploratory analysis showed the AUC of combination of top 5 lipids is 1, indicating they may be potentially sensitive and specific biomarkers for MD. We propose combination of these lipid species may be more valuable in predicting the development and progression of MD, and this will have important implications for the diagnosis and treatment of MD., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Acute gouty arthritis (AGA) is one of the most common forms of auto-inflammatory arthritis. IL-17 is a key proinflammatory cytokine which has been implicated in several autoimmune diseases. However, to date little is known about the role of IL-17 in AGA. In the present study, we show that serum IL-17 levels are significantly elevated in AGA patients early in the onset of symptoms of gout, and decrease gradually as symptoms diminish. Correlation analysis indicated that IL-17 expression is not only positively correlated with disease activity, but is also correlated with serum levels of IL-1β which plays a critical role in the differentiation of IL-17 - γδT cells into IL-17 + γδT cells. Flow cytometry analysis indicated that γδ T cells are a major source of IL-17 production during the early onset of AGA. We therefore identify IL-17 as a potential novel biomarker for AGA and suggest that targeting the γδ T cell/IL-17 immune axis is a potential strategy for treatment of acute flares of AGA., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Migraine is a highly disabling primary headache associated with a high socioeconomic burden and a generally high prevalence. The clinical management of migraine remains a challenge. This study was undertaken to identify potential serum biomarkers of migraine. Using Liquid Chromatography coupled to Mass Spectrometry (LC-MS), the metabolomic profile of migraine was compared with healthy individuals. Principal component analysis (PCA) and Orthogonal partial least squares-discriminant analysis (orthoPLS-DA) showed the metabolomic profile of migraine is distinguishable from controls. Volcano plot analysis identified 10 serum metabolites significantly decreased during migraine. One of these was serotonin, and the other 9 were amino acids. Pathway analysis and enrichment analysis showed tryptophan metabolism (serotonin metabolism), arginine and proline metabolism, and aminoacyl-tRNA biosynthesis are the three most prominently altered pathways in migraine. ROC curve analysis indicated Glycyl-l-proline, N-Methyl-dl-Alanine and l-Methionine are potential sensitive and specific biomarkers for migraine. Our results show Glycyl-l-proline, N-Methyl-dl-Alanine and l-Methionine may be as specific or more specific for migraine than serotonin which is the traditional biomarker of migraine. We propose that therapeutic manipulation of these metabolites or metabolic pathways may be helpful in the prevention and treatment of migraine., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Advances in high-resolution mass spectrometers with faster scanning capabilities and higher sensitivities have expanded these instruments' functionality beyond traditional data-dependent acquisition in targeted metabolomics. Apart from the traditional multiple reaction monitoring strategy, the parallel reaction monitoring (PRM) strategy is also used for targeted metabolomics quantification. The high resolution and mass accuracy of full-scan (MS1) and tandem mass spectrometry (MS/MS) scan result in sufficient selectivity by monitoring all MS/MS fragment ions for each target precursor and simultaneously providing flexibility in assay method construction and post-acquisition data analysis. In this study, using an orthogonal quadrupole-time of flight liquid chromatography-mass spectrometry system (QTOF LC-MS), we investigated the applicability of a large-scale targeted lipidomic assay using scheduled PRM. This method monitored 222 lipids belonging to 15 lipid species in serum. Robustness, reproducibility, and quantitative performance were assessed using chemical standards and serum samples. Finally, we demonstrated the application of this PRM-based targeted metabolomic workflow to systemic lupus erythematosus, a severe autoimmunological disease. Results showed that 63 lipids belonging to 11 lipid species were significantly changed. In summary, at the first time, a robust targeted lipidomic workflow was established using PRM acquisition strategy on a Q-TOF platform, providing another powerful tool for targeted metabolomic analysis., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Untargeted metabolomic profiling has been widely used in recent years. However, the low reproducibility of the data-dependent acquisition (DDA) strategy presents a major bottleneck that considerably limits the reliability of metabolomic studies in biological and clinical research. The data-independent acquisition (DIA) strategy is proposed to solve the above-mentioned problem, and it is gaining popularity. This paper presents a novel approach for performing metabolomic analysis using an untargeted, liquid chromatography-data independent-mass spectrometry (LC-DIA-MS) strategy on a quadrupole-Orbitrap platform. Using chemical standards and metabolites extracted from serum samples, we optimized the LC-DIA-MS parameters to analyze hydrophilic metabolites and lipids. The quantitative performance and analytical reliability were evaluated, and the performances of DIA, DDA, and all-ion fragmentation mode were compared. Finally, as a proof of concept, we applied the constructed DIA workflow to a comparative metabolomic study of papillary thyroid carcinoma (TC) serum samples. Several metabolites, including carnitine, trimethylamine N-oxide, and some amino acids, significantly changed between patients and healthy controls. This study demonstrated the feasibility and advantage of the DIA strategy on untargeted metabolomic analysis for biological study and clinical biomarker screening., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Trimethylamine-N-oxide (TMAO) is a metabolite generated from choline, betaine and carnitine in a gut microbiota-dependent way. This molecule is associated with development of atherosclerosis and cardiovascular events. A sensitive liquid chromatographic electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) has been developed and validated for the simultaneous determination of TMAO related molecules including TMAO, betaine, choline, and carnitine in mouse plasma. Analytes are extracted after protein precipitation by methanol and subjected to LC-ESI-MS/MS without preliminary derivatization. Separation of analytes was achieved on an amide column with acetonitrile-water as the mobile phase. This method has been fully validated in this study in terms of selectivity, linearity, sensitivity, precision, accuracy, and carryover effect, and the stability of the analyte under various conditions has been confirmed. This developed method has successfully been applied to plasma samples of our mouse model., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Platelet-derived growth factor receptor α (PDGFRA) is a Type III receptor tyrosine kinase, and this kinase is a target for treatment of gastrointestinal stromal tumors (GIST) as it is frequently mutated in these cancers. Most of the mutations that cause constitutive activation of PDGFRA occur in either the activation loop (A-loop) or in the juxtamembrane (JM) domain, such as the mutations D842V or V561D respectively. Treatment of PDGFRA-mutated GIST with imatinib is successful in some cases, but the D842V mutation is imatinib-resistant. To better understand the mechanism of PDGFRA drug-resistance, we have determined the crystal structure of the PDGFRA kinase domain in the auto-inhibited form, and studied the kinetics of the D842V mutation. Auto-inhibited PDGFRA is stabilized by the JM domain, which inserts into the active site of the kinase. The conserved residue Asp842 makes extensive contacts with several A-loop residues to maintain PDGFRA in the "DFG out" conformation, which stabilizes the kinase in the inactive state and facilitates the binding of imatinib. The D842V mutation would therefore be expected to activate the kinase and hinder the binding of drug through destabilizing the "DFG out" conformation. Furthermore, our kinetic data show that drug resistance in the D842V mutation may also in part result from its increased affinity for ATP. The PDGFRA kinase domain structure we report in this study has potential to facilitate development of new agents which can inhibit this kinase, including both its activating and drug-resistant mutations., (Copyright © 2016. Published by Elsevier Inc.)

N-methylpurine DNA glycosylase (MPG), a DNA repair enzyme, functions in the DNA base excision repair (BER) pathway. Aberrant over-expression of MPG in various cancers suggests an important role of MPG in carcinogenesis. Identification of MPG-interacting proteins will help to dissect the molecular link between MPG and cancer development. In the present study, using immunoprecipitation coupled with mass spectrometry (IP/MS), we screened ubiquitin-like, containing PHD and RING finger domains 1 (UHRF1), an essential protein required for the maintenance of DNA methylation, as a MPG-interacting protein. Endogenous co-immunoprecipitation assay in cancer cells confirmed that UHRF1 interacted with MPG in a p53 status-independent manner. Confocal microscopy showed that endogenous MPG and UHRF1 were co-localized in the nucleoplasm. Furthermore, co-immunoprecipitation assay indicated that UHRF2, the homolog of UHRF1, could also interact with MPG. These results show that MPG and the UHRF family of proteins interact, thus providing a functional linkage between MPG and UHRF1/2., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Accumulation of excess lipids is associated with heart failure. The effects of transgenic expression of diacylglycerol acyl transferase 1 (DGAT1) in cardiomyocytes is controversial. We explored whether mice expressing DGAT1 via the myosin heavy chain (MHC) promoter develop heart dysfunction with aging or after crossing with mice over expressing peroxisome proliferator-activated receptor γ (PPARγ) in the heart. MHC-DGAT1 transgenic mice had increased heart triglyceride but no evidence of heart dysfunction, even up to age 12 months. The MHC-DGAT1 transgene improved heart dysfunction and survival of MHC-PPARγ-expressing transgenic mice. Both diacylglycerol and ceramide levels in the heart were reduced by this cross, as were the levels of several mRNAs of genes involved in lipid metabolism. There were fewer large lipid droplets in MHC-DGAT1×MHC-PPARγ mice compared with MHC-PPARγ, but total lipid content was not changed. Therefore, overexpression of DGAT1 is not toxic to the heart but reduces levels of toxic lipids and improves lipotoxic cardiomyopathy. Moreover, the beneficial effects of DGAT1 illustrate the interrelationship of several lipid metabolic pathways and the difficulty of assigning benefit to an isolated change in one potentially toxic lipid species.

Krüppel-like factor 2 (KLF2) has been demonstrated to be essential for normal lung development, erythroid differentiation, T-cell differentiation, migration and homing. However, the mechanisms underlying the regulation of KLF2, in particular its responsible E3 ligase is still unclear. Here we show that the homologous to E6AP carboxyl terminus (HECT)-type ubiquitin ligase Smad ubiquitination regulatory factor 1 (Smurf1) interacts with and targets KLF2 for poly-ubiquitination and proteasomal degradation specifically in lung cancer H1299 cells. The catalytic ligase activity of Smurf1 is required for it to regulate KLF2. Consequently, Smurf1 represses the transcriptional factor activity of KLF2 and regulates the expression its downstream genes such as CD62L and Wee1. This study provided the first evidence that Smurf1 functions as an E3 ligase to promote the ubiquitination and proteasomal degradation of KLF2., (Copyright © 2011 Elsevier Inc. All rights reserved.)

NuSAP is a microtubule-associated protein that plays an important role in spindle assembly. NuSAP deficiency in mice leads to early embryonic lethality. Spindle assembly in NuSAP-deficient cells is highly inefficient and chromosomes remain dispersed in the mitotic cytoplasm. ATM is a key kinase that phosphorylates a series of substrates to mediate G1/S control. However, the role of ATM at the G2/M phase is not well understood. Here we demonstrate that ectopic expression of NuSAP lead to mitotic arrest observably dependent on the kinase activity of ATM. When endogenous ATM was depleted or its kinase activity was inhibited, NuSAP could not cause mitotic arrest. We further show ATM interacts with NuSAP and phosphorylates NuSAP on Ser124. The phosphorylation and interaction occur specifically at G2/M-phase. Collectively, our work has uncovered an ATM-dependent checkpoint pathway that prevents mitotic progression by targeting a microtubule-associated protein, NuSAP., (Copyright © 2010 Elsevier Inc. All rights reserved.)

There is a delicate relationship between nutrition and reproduction of mitten crab (Eriocheir sinensis). The crabs store significant amounts of energy in hepatopancreas, which is prepared for significant energy output and expenditure during reproduction, but the internal molecular mechanism has never been known. Here we present the first relationship between hepatopancreas and testis of E. sinensis. We acquired 6287 high quality expressed sequence tags (EST), representing 3829 unigenes totally, from healthy male mitten crabs of first grade. We investigated the Gene Ontology and the main metabolism processes of hepatopancreas and testis from E. sinensis. Genes most likely expressed more frequently and localized in hepatopancreas, and abundant genes from testis for multiple functions. Many genes important for the nutrition regulation are in the EST resource, including arginine kinase, leptin receptor-like protein, seminal plasma glycoprotein 120, and many kinds of zinc finger proteins. The EST data also revealed genes such as heat shock protein 70, testis enhanced gene transcript (TEGT), Cyclin K, etc. predicted to play important roles in regulation of reproduction mechanisms. Among these genes, alignment of leptin receptor-like protein and vasa-like protein from E. sinensis and other species showed even more genomic information on E. sinensis. We identified seventeen genes relevant to control of nutrition mechanisms and eleven genes involved in regulation of reproduction. And this study provides insights into the genetic and molecular mechanisms of nutrition and reproduction in the crab. Such information would facilitate the optimization of breeding in the aquaculture of mitten crabs.