Association between autonomic dysfunction with motor and non-motor symptoms in patients with Parkinson's disease.

To investigate the association between autonomic dysfunction (AutD) and motor as well as non-motor symptoms (NMS) in patients with Parkinson's disease (PD). Fifty-three PD patients were divided into two groups based on the number of domains affected by AutD: a multi-domain AutD group (AutD-M) and a single-domain AutD group (AutD-S), as evaluated using the Scale for Outcomes in Parkinson's disease-Autonomic (SCOPA-AUT), which assesses autonomic symptoms, one of the NMS. A comprehensive comparison was conducted between the two groups, including clinical measures such as clinical scales, quantitative evaluations of motor function and exercise capacity. Spearman correlation analysis was employed to investigate the relationship between AutD severity and PD symptoms. Additionally, we performed multiple linear regression model analysis to determine whether associations between SCOPA-AUT scores and clinical assessments remained significant after adjusting for Hoehn and Yahr stage, sex, and age. PD patients in the AutD-M group exhibited significantly more severe NMS and motor symptoms compared to those in the AutD-S group. In correlation analysis, SCOPA-AUT scores showed significant correlations with multiple clinical symptoms, such as most of the NMS, 10-MWT and CPET parameters. Furthermore, regression analysis also revealed that more pronounced fatigue, anxiety, depressive symptoms, worse walking speed and impaired exercise capacity were associated with higher SCOPA-AUT scores. The presence of AutD is correlated with emotional disturbances, decreased exercise endurance, and impaired gait function in patients with PD. Early management of AutD may prove beneficial in alleviating some NMS and motor symptoms in PD.

Interferon-Gamma-Inducible Protein 16 Inhibits Hepatocellular Carcinoma via Interferon Regulatory Factor 3 on Chemosensitivity.

BACKGROUND AND AIM: Previous reports have suggested IFI16 as a tumor suppressor in hepatocellular carcinoma (HC). Nonetheless, the biological significance of IFI16 and its mechanism concerning resistance to cisplatin (DDP) in HC requires further exploration. METHODS: Samples of tumor and corresponding para-carcinoma tissues were acquired from patients with HC. Furthermore, DDP-resistant cell lines of HC, specifically HCC, Huh7 and Hepatoblastoma, HepG3, were generated by gradually increasing the concentration of DDP. Cell apoptosis and DNA damage were evaluated by utilizing flow cytometry assay and TUNEL staining. The interaction between IFI16 and interferon regulatory factor 3 (IRF3) proteins were analyzed using Co-Immunoprecipitation (Co-IP) assay. In vivo assays were conducted by establishing HC subcutaneous xenograft tumor models. RESULTS: The study found a reduction in IFI16 expression in both HC tissues and DDP-resistant HC cell lines. The binding of IFI16 to IRF3 regulated DNA damage-associated markers in vitro. Overexpression of IFI16 heightened the susceptibility of DDP-induced apoptosis and DNA damage, which was counteracted by IRF3 knockdown, while strengthened by IRF3 overexpression. Moreover, overexpression of IFI16 diminished in vivo DDP-resistant HC tumorigenicity. CONCLUSION: In summary, our findings suggest that IFI16 serves as a tumor suppressor in HC by promoting DNA damage via its interaction with IRF3, thereby reversing DDP resistance.

Sorbitol Destroyed Intestinal Microfold Cells (M Cells) Development through Inhibition of PDE4-Mediated RANKL Expression.

Objective: Microfold cells (M cells) are specific intestinal epithelial cells for monitoring and transcytosis of antigens, microorganisms, and pathogens in the intestine. However, the mechanism for M-cell development remained elusive. Materials and Methods: Real-time polymerase chain reaction, immunofluorescence, and western blotting were performed to analyze the effect of sorbitol-regulated M-cell differentiation in vivo and in vitro, and luciferase and chromatin Immunoprecipitation were used to reveal the mechanism through which sorbitol-modulated M-cell differentiation. Results: Herein, in comparison to the mannitol group (control group), we found that intestinal M-cell development was inhibited in response to sorbitol treatment as evidenced by impaired enteroids accompanying with decreased early differentiation marker Annexin 5, Marcksl1, Spib, sox8, and mature M-cell marker glycoprotein 2 expression, which was attributed to downregulation of receptor activator of nuclear factor kappa-В ligand (RANKL) expression in vivo and in vitro. Mechanically, in the M-cell model, sorbitol stimulation caused a significant upregulation of phosphodiesterase 4 (PDE4) phosphorylation, leading to decreased protein kinase A (PKA)/cAMP-response element binding protein (CREB) activation, which further resulted in CREB retention in cytosolic and attenuated CREB binds to RANKL promoter to inhibit RANKL expression. Interestingly, endogenous PKA interacted with CREB, and this interaction was destroyed by sorbitol stimulation. Most importantly, inhibition of PDE4 by dipyridamole could rescue the inhibitory effect of sorbitol on intestinal enteroids and M-cell differentiation and mature in vivo and in vitro. Conclusion: These findings suggested that sorbitol suppressed intestinal enteroids and M-cell differentiation and matured through PDE4-mediated RANKL expression; targeting to inhibit PDE4 was sufficient to induce M-cell development.

Helicobacter pylori promotes gastric intestinal metaplasia through activation of IRF3-mediated kynurenine pathway.

BACKGROUND: Metabolic reprogramming is a critical event for cell fate and function, making it an attractive target for clinical therapy. The function of metabolic reprogramming in Helicobacter pylori (H. pylori)-infected gastric intestinal metaplasia remained to be identified. METHODS: Xanthurenic acid (XA) was measured in gastric cancer cells treated with H. pylori or H. pylori virulence factor, respectively, and qPCR and WB were performed to detect CDX2 and key metabolic enzymes expression. A subcellular fractionation approach, luciferase and ChIP combined with immunofluorescence were applied to reveal the mechanism underlying H. pylori mediated kynurenine pathway in intestinal metaplasia in vivo and in vitro. RESULTS: Herein, we, for the first time, demonstrated that H. pylori contributed to gastric intestinal metaplasia characterized by enhanced Caudal-related homeobox transcription factor-2 (CDX2) and mucin2 (MUC2) expression, which was attributed to activation of kynurenine pathway. H. pylori promoted kynurenine aminotransferase II (KAT2)-mediated kynurenine pathway of tryptophan metabolism, leading to XA production, which further induced CDX2 expression in gastric epithelial cells. Mechanically, H. pylori activated cyclic guanylate adenylate synthase (cGAS)-interferon regulatory factor 3 (IRF3) pathway in gastric epithelial cells, leading to enhance IRF3 nuclear translocation and the binding of IRF3 to KAT2 promoter. Inhibition of KAT2 could significantly reverse the effect of H. pylori on CDX2 expression. Also, the rescue phenomenon was observed in gastric epithelial cells treated with H. pylori after IRF3 inhibition in vitro and in vivo. Most importantly, phospho-IRF3 was confirmed to be a clinical positive relationship with CDX2. CONCLUSION: These finding suggested H. pylori contributed to gastric intestinal metaplasia through KAT2-mediated kynurenine pathway of tryptophan metabolism via cGAS-IRF3 signaling, targeting the kynurenine pathway could be a promising strategy to prevent gastric intestinal metaplasia caused by H. pylori infection. Video Abstract.

Vitronectin Destroyed Intestinal Epithelial Cell Differentiation through Activation of PDE4-Mediated Ferroptosis in Inflammatory Bowel Disease.

Objective: Vitronectin (VTN) has been reported to trigger cell pyroptosis to aggravate inflammation in our previous study. However, the function of VTN in inflammatory bowel disease (IBD) remains to be addressed. Methods: Real-time PCR and western blotting were performed to analyze VTN-regulated intestinal epithelial cell (IEC) differentiation through ferroptosis, and immunofluorescence (IF), luciferase, and chromatin immunoprecipitation were used to identify whether VTN-modulated ferroptosis is dependent on phosphodiesterase 4 (PDE4)/protein kinase A (PKA)/cyclic adenosine monophosphate-response element-binding protein (CREB) cascade pathway. In vivo experiment in mice and a pilot study in patients with IBD were used to confirm inhibition of PDE4-alleviated IECs ferroptosis, leading to cell differentiation during mucosal healing. Results: Herein, we found that caudal-related homeobox transcription factor 2-mediated IECs differentiation was impaired in response to VTN, which was attributed to enhanced ferroptosis characterized by decreased glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 expression. Inhibition of ferroptosis in IECs rescued the inhibitory effect of VTN on cell differentiation. Further analysis showed that VTN triggered phosphorylation of PDE4, leading to inhibit PKA/CREB activation and CREB nuclear translocation, which further reduced GPX4 transactivation. Endogenous PKA interacted with CREB, and this interaction was destroyed in response to VTN stimulation. What is more, overexpression of CREB in CaCO2 cells overcame the promotion of VTN on ferroptosis. Most importantly, inhibition of PDE4 by roflumilast or dipyridamole could alleviate dextran sulfate sodium-induced colitis in mice and in a pilot clinical study confirmed by IF. Conclusions: These findings demonstrated that highly expressed VTN disrupted IECs differentiation through PDE4-mediated ferroptosis in IBD, suggesting targeting PDE4 could be a promising therapeutic strategy for patients with IBD.

Exploiting the Fracture in Metal-Organic Frameworks: A General Strategy for Bifunctional Atom-Precise Nanocluster/ZIF-8(300 °C) Composites.

Atom-precise nanoclusters-metal-organic framework (APNC/MOF) composites, as bifunctional material with well-defined structures, have attracted considerable attention in recent years. Despite the progress made to date, there is an urgent need to develop a generic and scalable approach for all APNCs. Herein, the authors present the Exploiting Fracture Strategy (EFS) and successfully construct a super-stable bifunctional APNC/ZIF-8(300 °C) composite overcoming the limitations of previous strategies in selecting APNCs. The EFS utilizes the fracture of ZnN in ZIF-8 after annealing at 300 °C. This method is suitable for all kinds of S/P protected APNCs with different sizes, including uncharged clusters Au1 Ag39 , Ag40 , negatively charged Au12 Ag32 , positively charged Ag46 Au24 , Au4 Cu4 and P-ligand-protected Pd3 Cl. Importantly, the generated APNC/MOF show significantly improved performances, for example, the activities of Au12 Ag32 /ZIF-8(300°C), Au4 Cu4 /ZIF-8(300°C), and Au1 Ag39 /ZIF-8(300°C) in the corresponding reactions are higher than those of Au12 Ag32 , Au4 Cu4 , and Au1 Ag39 , respectively. In particular, Au12 Ag32 /ZIF-8(300 °C) shows higher activity than Au12 Ag32 @ZIF-8. Therefore, this work offers guidance for the design of bifunctional APNC/MOF composites with excellent optimization of properties and opens up new horizons for future related nanomaterial studies and nanocatalyst designs.

Versatile Superatom Complex Nanocluster for the Construction of Framework Materials.

Accurately controlling the assembly of nanometer-sized building blocks presents an important but significant challenge for the construction of functional framework materials, which requires the development of highly stable versatile nanosized assembly modules with multiple coordination sites. In this study, [Ag23(SAdm)12]3+ (Ag23, in which SAdm = 1-adamantanethiol, i.e., C10H15S), a chiral superatom complex nanocluster, was synthesized and assembled into various topologies. We constructed two kinds of framework materials, i.e., superatom complex inorganic framework (SCIF) and superatom complex organic framework (SCOF) materials, including [Ag23(SAdm)12](SbF6)2X (Ag23-1; X = Cl-/SbF6-, a SCIF), [Ag23(SAdm)12](SbF6)3 (Ag23-2, a SCIF), [Ag23(SAdm)12](SbF6)3(bpy)3 (Ag23-bpy, a SCOF, in which bpy = 4,4'-bipyridine, i.e., C10H8N2), and [Ag23(SAdm)12](SbF6)3(dpbz)3 (Ag23-dpbz, a SCOF, in which dpbz = 1,4-bis(4-pyridyl)benzene, i.e., C16H12N2), owing to strong interactions between the versatile Ag23 and the inorganic and organic linkers. Ag23-1, Ag23-2, and Ag23-bpy exhibit two superstructures with interpenetrating frameworks and adamantane-like, hexagonal, and cubic topologies, while Ag23-dpbz displays three superstructures with interpenetrating frameworks and cubic topologies. Ag23-dpbz exhibits the largest specific surface area as well as the strongest photoluminescence and electrochemiluminescence signals owing to its dense network arrangement. This work contributes to the construction of nanocluster-based framework materials and helps to elucidate the effect of the assembly mode on the material properties and functionalities.

Resilience, coping style, and COVID-19 stress: effects on the quality of life in frontline health care workers.

The aims of the study were to assess the contribution of resilience, coping style, and COVID-19 stress on the quality of life (QOL) in frontline health care workers (HCWs). The study was a cross-sectional surveyperformed among 309 HCWs in a tertiaryhospital during the outbreak of COVID-19 in China. Data were collected through an anonymous, self-rated questionnaire, including demographic data, a 10-item COVID-19 stress questionnaire, Generic QOL Inventory-74, Connor-Davidson Resilience Scale, and the Simplified Coping Style Questionnaire. Hierarchical regression was used to analyse the relationship between the study variables and the QOL. Among the 309 participants, resilience and active coping were positively correlated with the QOL (P<0.001), whereas, working in confirmed case wards, COVID-19 stress, and passive coping were negatively correlated with the QOL (P<0.001). Resilience and the active coping were negatively correlated with COVID-19 stress (P<0.001). Resilience, coping style,and COVID-19 stressaccounted for 32%, 13%, and 8% of the variance in predicting the Global QOL, respectively. In conclusion, working in confirmed COVID-19 case wards and COVID-19 stress impaired the QOL in HCWs. Psychological intervention to improve the resilience and coping style, and reduce COVID-19 stress are important in improving the QOL and mental health of HCWs.

Algicidal activity of a novel indigenous bacterial strain of Paracoccus homiensis against the harmful algal bloom species, Karenia mikimotoi.

Harmful algal blooms have deleterious effects on aquatic ecosystems and human health. The application of algicidal bacteria is a promising and environmentally friendly method of preventing and eradicating harmful algal blooms. In this study, a screen for algicidal agents against harmful algal blooms was used to identify an algicidal bacterial strain (strain O-4) isolated from a Karenia mikimotoi culture. Strain O-4 exhibited a strong inhibitory effect on harmful K. mikimotoi and was identified as Paracoccus homiensis via 16S rRNA gene sequence analysis. This strain killed K. mikimotoi by secreting active algicidal compounds, which were stable at temperatures of -80-121 °C but were sensitive to strongly acidic conditions (pH = 2). The algicidal properties of strain O-4 against K. mikimotoi were cell density- and time-dependent. No significant changes or negative effects were noted for two other Chlorophyta species, which highlighted the specificity of the studied algicidal substance. Finally, single-factor experiments revealed the optimum growth conditions of strain O-4 under different pH and temperature conditions. Therefore, strain O-4 has the potential to be used as a bio-agent for reducing the biomass of harmful K. mikimotoi blooms.

Investigating native capillary zone electrophoresis-mass spectrometry on a high-end quadrupole-time-of-flight mass spectrometer for the characterization of monoclonal antibodies.

Native capillary zone electrophoresis-mass spectrometry (CZE-MS) has attracted attentions for the characterization of monoclonal antibodies (mAbs) due to the potential of CZE for highly efficient separations of mAbs under native conditions as well as its compatibility with native electrospray ionization (ESI)-MS. However, the low sample loading capacity and limited separation resolution of native CZE for large proteins and protein complexes (e.g. mAbs) impede the widespread adoption of native CZE-MS. Here, we present a novel native capillary isoelectric focusing (cIEF)-assisted CZE-MS method for the characterization of mAbs with much larger sample loading capacity and significantly better separation resolution than native CZE-MS alone. The native cIEF-assisted CZE-MS employed separation capillaries with a new carbohydrate-based neutral coating, a commercilized electrokinetically pumped sheathflow CE-MS interface, and a high-end quadrupole-time-of-flight (Q-TOF) mass spectrometer. Using the method, we documented the separations of different proteoforms of the SigmaMAb and the detection of its various glyco-proteoforms and homodimer. The native cIEF-assisted CZE-MS separated the NIST mAb into three peaks with a submicroliter sample loading volume, corresponding to its different proteoforms. We observed that both the NIST mAb and its homodimer had eight glyco-proteoforms, four of which had low abundance. The results demonstrate the potential of our native cIEF-assisted CZE-MS method for advancing the characterization of large proteins and protein complexes under native conditions.

Clinical characteristics of COVID-19 in children compared with adults in Shandong Province, China.

AIMS AND BACKGROUND: The COVID-19 outbreak spread in China and is a threat to the world. We reported on the epidemiological, clinical, laboratory, and radiological characteristics of children cases to help health workers better understand and provide timely diagnosis and treatment. METHODS: Retrospectively, two research centers' case series of 67 consecutive hospitalized cases including 53 adult and 14 children cases with COVID-19 between 23 Jan 2020 and 15 Feb 2020 from Jinan and Rizhao were enrolled in this study. Epidemiological, clinical, laboratory, and radiological characteristics of children and adults were analyzed and compared. RESULTS: Most cases in children were mild (21.4%) and conventional cases (78.6%), with mild clinical signs and symptoms, and all cases were of family clusters. Fever (35.7%) and dry cough (21.4%) were described as clinical manifestations in children cases. Dry cough and phlegm were not the most common symptoms in children compared with adults (p = 0.03). In the early stages of the disease, lymphocyte counts did not significantly decline but neutrophils count did in children compared with adults (p = 0.02). There was a lower level of CRP (p = 0.00) in children compared with adults. There were 8 (57.1%) asymptomatic cases and 6 (42.9%) symptomatic cases among the 14 children cases. The age of asymptomatic patients was younger than that of symptomatic patients (p = 0.03). Even among asymptomatic patients, 5 (62.5%) cases had lung injuries including 3 (60%) cases with bilateral involvement, which was not different compared with that of symptomatic cases (p = 0.58, p = 0.74). CONCLUSIONS: The clinical symptoms of children are mild, there is substantial lung injury even among children, but that there is less clinical disease, perhaps because of a less pronounced inflammatory response, and that the occurrence of this pattern appears to inversely correlate with age.

Different Types of Ligand Exchange Induced by Au Substitution in a Maintained Nanocluster Template.

Precisely regulating the ligand exchange on the nanocluster (NC) surface is challenging but important for fully understanding metal-ligand interactions and transformations. In this work, the homosilver nanocluster Ag40(TBBM)22(CH3COO)10 (Ag40) and its Au-substitution derivative AuAg39(TBBM)20(CH3COO)12 (AuAg39) have been synthesized and characterized by single-crystal X-ray crystallography (SC-XRD), nuclear magnetic resonance (NMR), X-ray photoelectron spectroscopy (XPS), and thermogravimetric analysis (TGA). By precisely controlling the template metal exchange progress, the intermediate product, namely, AuAg39(TBBM)21(CH3COO)11 (AuAg39-inter), was also obtained and then characterized by SC-XRD. These three nanoclusters possess a similar metallic framework, albeit some of the thiol ligands of Ag40 have been replaced by the introduced acetate ligands in both AuAg39-inter and AuAg39. Furthermore, Ag40 and AuAg39 NCs can serve as chiral amplifiers for testing the ee values of 2-chloropropionic acid, ibuprofen, naproxen, and isoleucine with high sensitivity.

Low preoperative serum ALB level is independently associated with poor overall survival in endometrial cancer patients.

Aim: To reveal the prognostic significance of serum albumin (ALB) concentration in endometrial cancer (EC) patients in China. Patients & methods: 345 EC patients were enrolled in a single center, and the preoperative serum ALB concentration were measured. Kaplan-Meier curve analysis and Cox proportional hazards regression model were performed to evaluate the associations between ALB concentration and overall survival (OS) of EC patients. Results: The EC patients with lower preoperative serum ALB concentration exhibited a significantly poorer OS (p < 0.05). Univariate analysis and multivariate analysis indicated that serum ALB concentration was an independent prognostic factor of unfavorable OS for EC patients. Conclusion: Our results showing that ALB concentration may serve as an independent prognostic factor for EC patients.

ASK1 Enhances Angiotensin II-Induced Liver Fibrosis In Vitro by Mediating Endoplasmic Reticulum Stress-Dependent Exosomes.

BACKGROUND: Apoptosis signal-regulating kinase 1 (ASK1) has been reported to induce fibrotic signaling in the setting of oxidative stress. However, the role of ASK1 and its mechanism of action in angiotensin II- (Ang II-) induced liver fibrosis remain largely unknown. METHODS: Human hepatic LX-2 stellate cells were treated with Ang II alone or cotreated with Ang II plus an ASK1 inhibitor (GS-4997) or siRNA-targeting ASK1. Immunofluorescent staining, real-time PCR, and western blotting were used to determine the expressionof α-SMA, Col I, and Col III expression. Cell viability was assessed by the CCK-8 assay. The concentrations of IL-1ß, IL-18, and TNF-α in conditioned medium were determined by ELISA. The levels of intracellular ROS in LX-2 cells were analyzed using a ROS assay kit. Exosome size was determined by electron microscopy. RESULTS: Ang II markedly increased the expression of extracellular matrix (ECM) proteins (α-SMA, Col I, and Col III) and proinflammatory cytokines (IL-1ß, IL-18, and TNF-α). Ang II also increased the expression of endoplasmic reticulum stress (ERS) markers (GRP78, p-PERK, and CHOP) and p-ASK1. Results also showed that pretreatment with GS-4997 or siRNA could abolish all the abovementioned effects on LX-2 cells. Furthermore, we found that exosome release caused by ASK1-mediated ERS was involved in the activation of LX-2 cells by Ang II. The activation of LX-2 cells could be blocked by treating the exosomes with annexin. CONCLUSIONS: In summary, we found that ASK1 mediates Ang II-activated ERS in HSCs and the subsequent activation of HSCs, suggesting a promising strategy for treating liver fibrosis.

Assembly of the Thiolated [Au1 Ag22 (S-Adm)12 ]3+ Superatom Complex into a Framework Material through Direct Linkage by SbF6 - Anions.

Building framework materials with desirable properties and enhanced functionalities with nanocluster/superatom complexes as building blocks remains a challenge in the field of nanomaterials. In this study, the chiral [Au1 Ag22 (S-Adm)12 ]3+ nanocluster/superatom complex (SC, in which S-Adm=1-adamantanethiol) was employed as a building block to construct the three-dimensional (3D) superatom complex inorganic framework (SCIF) materials SCIF-1 and SCIF-2 through inorganic SbF6 - linkers. SCIF-1 is racemic due to the assembly of two SC enantiomers in a single crystal. In SCIF-2, the SC enantiomers are packed in separate crystals, thus producing larger channels and a circularly polarized luminescence (CPL) response. These two 3D SCIF materials exhibit unique sensitive photoluminescence (PL) in protic solvents. Our study provides a new pathway for creating novel open-framework materials with superatom complexes and a foundation for the further development of 3D framework materials for sensing and other applications.

Three-dimensional Octameric Assembly of Icosahedral M13 Units in [Au8 Ag57 (Dppp)4 (C6 H11 S)32 Cl2 ]Cl and its [Au8 Ag55 (Dppp)4 (C6 H11 S)34 ][BPh4 ]2 Derivative.

The high-dimensional (that is, three-dimensional (3D)) assembly of nanomaterials is an effective means of improving their properties; however, achieving this assembly at the atomic level remains challenging. Herein, we obtained a novel nanocluster, [Au8 Ag57 (Dppp)4 (C6 H11 S)32 Cl2 ]Cl (Dppp=1,3-bis(diphenylphosphino)propane) showing a 3D octameric assembly mode involving the kernel penetration of eight complete icosahedral Au@Ag10 Au2 units for the first time. The atomically precise structure was determined by single-crystal X-ray diffraction, and further confirmed by thermogravimetric analysis, X-ray photoelectron spectroscopy, and electrospray ionization mass spectrometry measurements. Furthermore, ligand-induced transformation prompted the conversion of [Au8 Ag57 (Dppp)4 (C6 H11 S)32 Cl2 ]Cl, with complete octameric fusion into [Au8 Ag55 (Dppp)4 (C6 H11 S)34 ][BPh4 ]2 , with incomplete octameric fusion. These observations will hopefully facilitate further research on the assembly of M13 nanobuilding blocks.

From Glucose to Polymers: A Continuous Chemoenzymatic Process.

Efforts to synthesize degradable polymers from renewable resources are deterred by technical and economic challenges; especially, the conversion of natural building blocks into polymerizable monomers is inefficient, requiring multistep synthesis and chromatographic purification. Herein we report a chemoenzymatic process to address these challenges. An enzymatic reaction system was designed that allows for regioselective functional group transformation, efficiently converting glucose into a polymerizable monomer in quantitative yield, thus removing the need for chromatographic purification. With this key success, we further designed a continuous, three-step process, which enabled the synthesis of a sugar polymer, sugar poly(orthoester), directly from glucose in high yield (73 % from glucose). This work may provide a proof-of-concept in developing technically and economically viable approaches to address the many issues associated with current petroleum-based polymers.

Mitigation of Hydrophobicity-Induced Immunotoxicity by Sugar Poly(orthoesters).

Polymeric nanoparticles (NPs) derived from self-assemblies of amphiphilic polymers have demonstrated great potential in clinical applications. However, there are challenges ahead. Notably, immunotoxicity remains a major roadblock that deters the NPs from further applications. Studies suggested that the hydrophobic component is a primary cause, yet biocompatible hydrophobic carbohydrate-based polymers may help mitigate this issue. Herein we design and synthesize novel NP systems having glucose poly(orthoesters) hydrophobic scaffold and polyethylene glycol (PEG) hydrophilic shell. The new NPs exhibited low immunotoxicity both in vitro and in vivo, as measured by the induced cytokine levels. In contrast, when other polymers, such as polylactide (PLA) or polycaprolactone (PCL), were used as the hydrophobic scaffold, the cytokine levels were orders of magnitude higher. Results from our multiple immunological studies indicate that carbohydrate-based polymers can largely mitigate the hydrophobicity-induced immunotoxicity, and thereby they may be good candidate polymers to engineer low immunotoxic biomaterials for various biomedical studies.

Discovery of aminopyridine-containing spiro derivatives as EGFR mutations inhibitors.

Neratinib is an oral pan HER inhibitor, that irreversibly inhibits EGFR and HER2 and was proven to be effective against multiple EGFR mutations. In previous study, we reported spiro [indoline-3, 4'-piperidine]-2-ones as anticancer agents. In this study, we designed aminopyridine-containing spiro [indoline-3,4'-piperidine] derivatives A1-A4 using Neratinib and spiro [indoline-3, 4'-piperidine]-2-one compound patented as lead structure, then replaced piperidine with cyclopropane to obtain B1-B7 and replaced indoline with benzmorpholine to get C1-C4 and D1-D2. We synthesized these compounds and evaluated their residual activities under 0.5 M drug concentration on EGFR and ERBB2. Most of compounds showed stronger inhibition on EGFR-wt and ERBB2, in which A1-A4 showed excellent inhibitory activity with inhibition percentage on EGFR-wt kinase of 7%, 6%, 19%, 27%, respectively and 9%, 5%, 12%, 34% on ERBB2 kinase compared with 2% and 6% of Neratinib.

Aggregation-Induced Emission (AIE) in Ag-Au Bimetallic Nanocluster.

Herein we report the synthesis and structure determination of a non-fluorescent Au4 Ag5 (dppm)2 (SAdm)6 (BPh4 ) (dppm=bis(diphenylphosphino)methane and HSAdm=1-adamantane mercaptan) nanocluster in methanol with extremely strong AIE when aggregating to the solid state (i.e., film or crystal). This phenomenon was rarely reported in structural determined noble metal nanoclusters. The extended X-ray absorption fine structure (EXAFS) measurement ruled out the hypothesis that the luminescence originated from the structure change in different states. Besides, the crystal structure (determined by X-ray diffraction) revealed that the tightly combined left- and right-handed enantiomers induced the strong restriction of intramolecular motions (RIM), which may have an impact on aggregation-induced emission.