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// Xiao Luo 1, * , Yerfan Jiaerken 1, * , Xinfeng Yu 1 , Peiyu Huang 1 , Tiantian Qiu 1 , Yunlu Jia 3 , Kaicheng Li 1 , Xiaojun Xu 1 , Zhujing Shen 1 , Xiaojun Guan 1 , Jiong Zhou 2 and Minming Zhang 1 , for The Alzheimer’s Disease Neuroimaging Initiative (ADNI) 1 Department of Radiology, The Second Affiliated Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China 2 Department of Neurology, The Second Affiliated Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China 3 Department of Surgical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China * These authors have contributed equally to this work Correspondence to: Minming Zhang, email: zhangminming@zju.edu.cn Keywords: apolipoprotein E (APOE), cerebral small-vascular disease (CSVD), white matter hyperintensities (WMH), dilated perivascular space (dPVS), cognition Abbreviations: APOE: apolipoprotein E; CSVD: cerebral small-vascular disease; WMH: white matter hyperintensities; dPVS: dilated perivascular space; MBs: microbleeds Received: December 29, 2016 Accepted: April 07, 2017 Published: May 09, 2017 ABSTRACT Objective: It remains unclear if and how the interactions between APOE genotypes and cerebral small-vessel diseases (CSVD) lead to cognitive decline in the long term. Based on ADNI cohort, this longitudinal study aimed to clarify the potential relationship among APOE genotype, CSVD and cognition by integrating multi-level data. Method: There were 135 healthy elderly (including e2, e4 allele carriers and e3 homozygotes) who had completed two years’ follow-up. MRI markers of CSVD, including white matter hyperintensities (WMH), dilated perivascular space (dPVS), microbleeds and lacune, were assessed. Besides, neuropathological factors including Alzheimer’s disease-related pathology measured by CSF and PiB-PET were assessed. Repeated measurements ANOVAs were performed to test impact of different APOE genotypes on CSVD. Results: We found that APOE e4 carriers had significantly more frontal WMH burden and basal ganglia dPVS at baseline and faster progression of frontal WMH burden during follow-up. Furthermore, our results showed that APOE e4 carriers had significantly decreased Aβ 1-42 level, and its level was negatively related with baseline and progressive total WMH burden. Then, general linear modals indicated interaction between basal frontal WMH burden and e4 allele was related with declining trend of cognition. Conclusion: Our findings suggested APOE e4 allele was associated with increased Aβ deposition, which may lead to the formation and progression of WMH, especially in frontal lobe. Besides, interaction between the increased frontal WMH burden and e4 allele can exert long-term detrimental effects on individual’s trajectory of cognition.

Background: At present, the infection and prevalence rates of tuberculosis (TB) are still high in worldwide. The Xpert MTB/RIF technology has improved the diagnosis speed of Mycobacterium tuberculosis (MTB) and facilitated the rapid treatment of TB patients. Methods: We searched experimental data derived from Xpert MTB/RIF for detecting MTB in gastric aspirates in PubMed, Embase, Web Of Science, and the Cochrane Library databases between January 2012 to April 2019. A summary receiver operating characteristic curve (SROC curve) was used to analyze the pooled sensitivity, pooled specificity, PLR, NLR, and DOR for determining the accuracy of the test. Results: Our database search resulted in 10 relevant articles. The pooled sensitivity of Xpert MTB/RIF for detecting TB in GA was 86% (95% CI, 83–89%), and I2 = 93.4%. The pooled specificity was 92% (95% CI, 90–93%) and I2 = 97.8%. In addition, the positive LR was 12.12 (95% CI, 5.60–26.21), negative LR was 0.20 (95% CI, 0.11–0.36), and the diagnostic odds ratio (DOR) was 147.04 (95% CI, 37.20–581.19). Using the SROC curve, the AUC was 0.9730 and Q* was 0.9248 (SE = 0.0261). The publication bias was P=0.517 (P>0.05). Conclusions: The Xpert MTB/RIF for detecting MTB in gastric aspirates was highly accurate. In addition, we observed that the publication bias in the present study was low. Hence, the Xpert MTB/RIF technology is highly accurate and has the advantage of rapid testing for MTB in clinical samples.

Background Along with Alzheimer’s disease (AD) continuum, AD neuropathologies propagate trans-neuronally, causing the memory circuit disorganization and memory deficit. However, no evidence supports the hypothesis in vivo to date. Methods Based on biological diagnosis criteria, we divided subjects into 5 groups by setting the CSF cutoff point at 192 pg/ml for Aβ 1-42 (A) and 23 pg/ml for P-tau 181 (T): Group 0, cognitively normal (CN) with normal Aβ 1-42 and P-tau 181 (A−T−); Group 1, CN with A+T−; Group 2, CN with A+T+; Group 3, mild cognitive impairments (MCI) with A+T+; Group 4, AD with A+T+. We defined the memory circuit as the hippocampus (HP), cingulum-angular bundles (CAB), and precuneus cortex, respectively representing the starting point, core connecting fiber, and connected downstream cortex. Then we assessed the HP subfields volume, CAB diffusion metric (whole tract-level and waypoint-wise), and precuneus volume. Finally, we correlated neuroimaging measures with cognitive and neuropathological data. Results Along AD continuum, HP subfields volume initially increased and then decreased, starting from the early stage (CN with A+T-). CAB integrity loss on both whole tract-level and waypoint-wise in MCI and AD with A+T+ and progressed along AD continuum. Regarding precuneus, we only found the decreased volume in MCI and AD with A+T+, with CN stage spared. Further, memory circuit structure impairment correlated with more AD neuropathology and worse memory profile. Conclusion Our results support the tau propagation theory in the memory circuit, suggested that the memory circuit impairments starting from the HP, then propagating to the downstream projection tract and cortex.

The separation of benzene and cyclohexane is one of the most challenging tasks in the petrochemical field. However, conventional separation methods suffer from cumbersome operation, huge energy expenditure, or use of entrainers. Herein, we develop an environmentally friendly and energy saving adsorptive separation strategy using nonporous adaptive crystals of a hybrid[3]arene (1). Adaptive 1 crystals separate benzene from an equimolar benzene/cyclohexane mixture with a purity of 97.5%. The selectivity comes from the stability and variability of the new crystal structure upon capture of the preferred guest, benzene. Moreover, reversible transformations between the nonporous guest-free structure and the guest-containing structure make 1 highly recyclable.

BACKGROUND Ustekinumab, a human-derived monoclonal antibody that targets the p40 subunit of interleukin (IL)-12 and IL-23, has excellent clinical efficacy and safety in treating psoriasis, with a long half-life. However, no reports have described the use of human skin/serum samples to elucidate its molecular mechanisms. MATERIAL AND METHODS Twenty-four psoriasis patients were enrolled in our double-blind study and randomly divided into placebo and ustekinumab-administered groups. Dynamic changes in psoriasis area-severity index scores, and mRNA and protein levels of p35 and p40 were analyzed at 3 time points (before treatment and during the 12th and 24th weeks of treatment). RESULTS Ustekinumab initially increased and then decreased p35 mRNA expression, but increased p40 mRNA levels throughout the study. The p35 protein levels were not significantly altered, while p40 protein levels were increased after the first 2 injections but decreased after the third injection. CONCLUSIONS We concluded that 2 equilibria influence the efficacy of ustekinumab against psoriasis. First, because of the dual roles of p35 in psoriasis pathogenesis, homeostasis occurs between p35 and p40 expression levels. The second balance lies between the upregulation of p40 mRNA levels and the ability of ustekinumab to neutralize the function of the elevated p40 protein.

Based on the data of the listed companies in strategic emerging industries in China, this paper uses GMM panel estimation method to measure the impact of government intervention on the performance of independent innovation and analyzes the impact of financial support on the effect of government intervention. The conclusions are as follows: Firstly, there is a lag effect in the performance of independent innovation, and there is also a lag effect in the patent application and main business income. In addition, there is an inverted U-shaped relationship between the patent application of one period lag and the current patent application, while there is no inverted U-shaped relationship between the main business income of one period lag and the current main business income. Secondly, government subsidies, additional deduction of R&D expenses, and value-added tax incentives have a significant effect on the number of patent applications, and the reduction of income tax burden can improve the main business income. Thirdly, after adding the financial support adjustment variables, we find that the influence direction of government intervention on the independent innovation performance has not changed, but the influence degree is weaker. Fourthly, the capital investment and labor input can significantly improve the performance of enterprise independent innovation.

Separation of monochlorotoluene isomers is a vital process to obtain highly pure p-chlorotoluene, which is irreplaceable in the production of medicines and pesticides. However, traditional separation methods suffer from great energy consumption, cumbersome operation or use of organic desorbents. Herein, an energy-efficient and environmentally friendly method is developed through an absorptive separation strategy based on nonporous adaptive crystals of perethylated pillar[5]arene (EtP5) and pillar[6]arene (EtP6). EtP5 and EtP6 crystals separate p-chlorotoluene from a p-chlorotoluene/o-chlorotoluene equimolar mixture with purities of 99.1% and 96.1%, respectively and show no decrease in selectivity upon cycling. The selectivity is attributed to both the stability of the final crystal structure upon guest capture and suitable host cavity size/shape. Besides, we discovered the gate-opening behavior changes of EtP5 crystals at different temperatures after absorption of p-chlorotoluene/o-chlorotoluene mixtures with various p-chlorotoluene fractions, which is helpful to understand the thermodynamics of the absorption process.

Cyanide is extremely hazardous to living organisms and the environment. Owing to its wide range of applications and high toxicity, the development of functional materials for cyanide detection and sensing is highly desirable. Host-guest complexation between bis(p-phenylene)-34-crown-10 H and N-methylacridinium salt G remarkably decreases the detection limit for cyanide anions compared with that of the guest itself. The [2]pseudorotaxane selectively recognizes the cyanide anion with high optical sensitivity as a result of the nucleophilic addition of the cyanide anion at the 9-position of G. The host-guest complexation is further incorporated into supramolecular materials for the visual detection of cyanide anions, especially the detection of cellular cyanide excretion with a detection limit of 0.6 μm. This supramolecular method provides an extremely distinct strategy for the visual detection of cyanide anions.

Molecular recognition based on cationic water-soluble pillar[n]arenes shows considerable advantages in their application in biological and environmental systems, such as excellent anion-binding ability and antimicrobial properties. Unique complex models are discovered in this work where a cationic water-soluble pillar[6]arene binds with disodium 1,5-naphthalenedisulfonate and disodium 2,6-naphthalenedisulfonate at the ratio of 1 : 2, which is proven by results from nuclear magnetic resonance spectroscopy, isothermal titration calorimetry, fluorescence spectroscopy experiments and transmission electron microscopy.

Objective.This phase I study aimed to systematically assess the safety, local tolerability, pharmacokinetics, and preliminary efficacy of topical icotinib hydrochloride cream in patients with mild to moderate plaque psoriasis.Materials and Methods.Eligible Chinese adult patients with mild to moderate psoriasis were assigned to the icotinib cream or vehicle group. Icotinib cream with increasing concentrations (0.5%, 1.0%, 2.0%, and 4.0%) or vehicle were administered by the fingertip unit method to the skin lesions twice a day for 4 weeks. Safety assessments included the incidence and severity of adverse events (AEs), local tolerability at the treatment area, vital signs, and laboratory examinations. Plasma levels of icotinib were also measured for the pharmacokinetics calculation. The efficacy was preliminarily explored by assessing the improvement in the severity level using Target Plaque Severity Score (TPSS) and overall improvement using the Psoriasis Area Severity Index (PASI) and Dermatological Quality Life Index.Results.Forty-one patients were enrolled and qualified for safety analysis. 27 (65.9%) patients experienced at least one AE, of which application-site adverse drug reactions (ADRs) were reported in 6 (14.6%) patients. All ADRs were of grade 1 or 2, most common irritation (4.5%), itching (3.1%), and erythema (2.4%), and resolved during follow-up. The systemic exposure to icotinib was very low; the highest plasma concentration was 0.214 ng/mL, while the area under the curve from 0 to 12 hours was 1.626 h·ng/mL. The TPSS improved for all icotinib groups after treatment in a dose- and time-dependent manner.Conclusion.This phase 1 study demonstrated favorable safety, tolerable toxicity, and preliminary efficacy of icotinib cream in patients with mild to moderate psoriasis. The dose concentration of 2.0% (twice daily based on the fingertip unit method) is recommended for further study.Study Design.This is a single-center, randomized, double-blind, and vehicle-controlled study.

Psoriasis is a T-cell mediated disease that involves IL-23/Th17 and IL-12/Th1 axes. Ustekinumab, a fully human monoclonal antibody targeting the p40 subunit of both IL-12 and IL-23, has proven to be efficient and safe for treating patients with psoriasis. Yet, there have been no reports with human skin/blood samples that would elucidate the molecular mechanisms by which ustekinumab calms psoriasis skin lesions. To investigate the efficacy and molecular pathway (RORC, t-BOX and GATA) of ustekinumab in treating patients with psoriasis skin lesions. A total of 30 patients with psoriasis were randomized into placebo group and treatment group. PASI of each patient was calculated at 0, 12 and 24 weeks post-treatment. The mRNA levels of RORC, t-BOX and GATA in peripheral blood mononuclear cells separated from patients’ whole blood were analyzed using qPCR. Decreased mRNA of RORC, t-BOX and GATA were observed after continuous injections, indicating that ustekinumab exerts its effect by interacting with these molecules; while no significant difference in foxp3 mRNA levels were found between placebo group and treatment group.

Background The biological diagnosis criteria of the Alzheimer’s disease (AD) suggests that previous work may misclassify the cognitive impairment caused by other factors into AD. Consequently, re-assessing the imaging profile of AD continuum is needed. Considering the high vulnerability of cortical association fibers, we aimed to elucidate the cortical demyelination process in the AD continuum biologically defined.Methods According to the biological diagnosis criteria, we determined the positive amyloid status (A+) as cerebrospinal fluid (CSF) amyloid1–42 < 192 pg/ml, Florbetapir Positron emission tomography (PET) composite standardized uptake value ratio (SUVR) >1.11. Also, the positive Tau status (T+) was determined as p-Tau181 > 23 pg/ml. Based on the cognitive characterization, we further categorized 252 subjects into 27 cognitively unimpaired with normal AD biomarkers (A−T−, controls), 49 preclinical AD (A+T+), 113 AD with mild cognitive impairment (MCI) (A+T+), and 63 AD dementia (A+T+). We estimated the intracortical myelin content used the T1- and T2-weighted (T1W/T2W) ratio mapping. To investigate the sensitivity of the ratio mapping, we also utilized well-validated AD imaging biomarkers as the reference, including gray matter volume and Fludeoxyglucose PET (FDG-PET). Based on the general linear model, we conducted the voxel-wise two-sample T-tests between the controls and each group in the AD continuum.Results Compared to the controls, the results showed that the preclinical AD patients exhibited decreased T1W/T2W ratio value in the right inferior parietal lobule (IPL); as the disease progresses, the prodromal AD patients demonstrated lower ratio value in bilateral IPL, with hippocampus (HP) atrophy. Lastly, the AD dementia patients exhibited decreased ratio value in bilateral IPL and hippocampus; also, we observed the bilateral temporal cortices atrophy and widespread decreased metabolism in the AD dementia patients. After corrected with gray volume, the results remained mostly unchanged.Conclusion Our study implied the decreased right IPL T1W/T2W ratio might represent early AD-related demyelination in disease continuum. Additionally, we demonstrated that the T1W/T2W ratio mapping is an easy-to-implement and sensitive metric to assess the intracortical myelin content in AD, particularly in the early stage.

Under the application of intensive nanosecond pulsed electric fields (nsPEFs), the electric shielding of the cellular membrane can be broken down and the permeability of the cellular membrane would augment dramatically, which is known as electroporation. This effect has been successfully used in drugs transmembrane transport and non-thermal tumor ablation. In this study, we propose that nsPEFs induce the anisotropic conductivity for electroporation with the evidence that conductivity of the cellular membrane increases mostly in the normal direction, with full consideration of the tangential dielectric relaxation effect of the cellular membrane. The corresponding simulation models are built to verify and analyze the impact of the normal electroporation and tangential dispersion on the electroporation process. The typical influential factors and indicators for normal electroporation and tangential dispersion, transmembrane potential, polarization vectors, conductivity tensor components, etc., are probed in the spherical cell model. Results show that normal electroporation would reduce the local pore density in dispersive models that results in a relative higher transmembrane voltage, and tangential dispersion would increase the pore density, in the meantime, expedite the electroporation process. Taking the normal electroporation and tangential dispersion into account can extend the electroporated area, increase the pore amount, and attenuate the bipolar cancelation effect in terms of the spatial distribution of nanopores. The model in this study can reflect the more accurate spatiotemporal evolution of the anisotropic parameters in the nsPEFs induced electroporation than proposed models, which is instructive to parameter selection of the nsPEF in applications.

Mild cognitive impairment (MCI) is a heterogeneous condition associated with a high risk of progressing to Alzheimer's disease (AD). Although functional brain network alterations have been observed in progressive MCI (pMCI), the underlying pathological mechanisms of network alterations remain unclear. In the present study, we evaluated neuropsychological, imaging, and cerebrospinal fluid (CSF) data at baseline across a cohort of: 21 pMCI patients, 33 stable MCI (sMCI) patients, and 29 normal controls. Fast eigenvector centrality mapping (fECM) based on resting-state functional MRI (rsfMRI) was used to investigate brain network organization differences among these groups, and we further assessed its relation to cognition and AD-related pathology. Our results demonstrated that pMCI had decreased eigenvector centrality (EC) in left temporal pole and parahippocampal gyrus, and increased EC in left middle frontal gyrus compared to sMCI. In addition, compared to normal controls, patients with pMCI showed decreased EC in right hippocampus and bilateral parahippocampal gyrus, and sMCI had decreased EC in right middle frontal gyrus and superior parietal lobule. Correlation analysis showed that EC in the left temporal pole was related to Wechsler Memory Scale-Revised Logical Memory (WMS-LM) delay score (r = 0.467, p = 0.044) and total tau (t-tau) level in CSF (r = -0.509, p = 0.026) in pMCI. Our findings implicate EC changes of different brain network nodes in the prognosis of pMCI and sMCI. Importantly, the association between decreased EC of brain network node and pathological changes may provide a deeper understanding of the underlying pathophysiology of pMCI.

In this study, partial nitrification-anammox process was established in two-stage sequencing batch constructed wetlands (SBCWs) to achieve autotrophic nitrogen removal for low-strength ammonium wastewater treatment. The operational parameters of the partial nitrification process were investigated and optimized, for the subsequent anammox process. The results indicated idle time and reaction time had significant influences to partial nitrification SBCW (WPN). In the WPN with optimal condition (idle time = 7.5 h, reaction time = 16 h), the effluent nitrite to ammonium ratio (NO2−-N/NH4+-N) remained stable at 1.24 ± 0.09, which favored the anammox process. The anammox SBCW (WAmx) was established rapidly within 61 d. The two-stage SBCWs showed high-efficient nitrogen removal capacity, with effluent total nitrogen (TN) concentration of 3.89 ± 0.62 mg/L and TN removal rate of 81.11 ± 2.92 %. Moreover, high-throughput sequencing revealed that Nitrosomonas (37.5 %) was dominant under optimal condition in WPN and responsible for partial nitrification process. Candidatus Brocadia (26.5 %) was enriched in WAmx, undertaking anammox process with synergism of flanking bacteria. This study provides a sustainable alternative for low-strength wastewater treatment.

To achieve advanced nutrient removal in wastewater treatment plants (WWTPs) with limited land and reuse wastewater in a low-cost way, a pilot-scale pipeline biofilm system integrating advanced simultaneous nitrogen and phosphorus removal with tailwater pressure transportation from WWTPs was proposed in this research. Results indicated that with the wall-attached polyurethane foams, the system was established after 7 days of starting operation and the enriched biomass reached 12.79 kg/m3. Simultaneous high-efficiency purification and high velocity (0.7 m/s) delivery of tailwater were realized. Furthermore, the removal efficiency was significantly affected by COD/TN and flow velocity. Under the optimal condition, the removal efficiencies of COD, NH4+-N, NO3−-N, TN and PO43--P were 85.97 ± 4.53 %, 78.63 ± 4.00 %, 98.17 ± 1.19 %, 94.99 ± 0.90 % and 82.52 ± 5.45 %, respectively. TN removal rate per unit area biocarrier was 32.17 × 10-3 mg/(L h m2) and PO43--P removal rate was 1.24 × 10-3 mg/(L h m2). High-throughput sequencing validated that heterotrophic nitrification - aerobic denitrification bacteria (Acinetobacter), denitrifying polyphosphate - accumulating organisms (Dechloromonas) and denitrifying bacteria (Hydrogenophaga, Cloacibacterium and Clostridium) synergistically contributed to pollutants removal. This study provided a new strategy for advanced nutrient removal and sewage reuse.

To reveal nitrogen removal mechanisms under environmental stresses, biofilm reactors were operated at different temperatures (10 °C–35 °C) treating saline wastewater (salinity 3%). The results showed nitrogen removal efficiency was 98.46% at 30 °C and 60.85% at 10 °C, respectively. Both ammonia oxidizing archaea (AOA) and ammonia oxidizing bacteria (AOB) participated in nitrification. 94.9% of the overall ammonia oxidation was attributed to AOA at 10 °C, but only 48.2% of that was undertaken by AOA at 35 °C. AOA had a greater contribution at low temperature, which demonstrated that nitrogen removal pathway varied with temperature. Aerobic denitrification was more stable than anoxic denitrification. High-throughput sequencing showed Crenarchaeota was the dominant AOA (97.02–34.47%), cooperating with various heterotrophic AOB. Real-time PCR indicated that AOA was three orders of magnitude more abundant than AOB. AOA was more resistant to low temperature and high-saline stresses. Ammonia oxidizers had distinct responses to temperature change and showed diverse relationships at different temperatures.

Essential oils (EOs) are naturally occurring substances that have shown great prospect in the field of antimicrobial, antioxidant and pest control by nontoxic mechanisms. In this regard, EOs are considered the promising and eco-friendly approach for controlling harmful algae. In this study, the anti-cyanobacterial activity of EOs eugenol against Microcystis aeruginosa are evaluated from the perspective of photosynthetic efficiency, the behavior of extracellular organic matter (EOM), endogenous plant hormone synthesis, and nitric oxide signaling pathway. Results showed that the photosynthetic activity of M. aeruginosa decreased significantly after eugenol treatments. Eugenol treatment resulted in cells rupture and the release of EOM. Levels of endogenous plant hormones salicylic acid (SA) and jasmonic acid (JA) were enhanced separately by 2.32 and 2.01 times after 4 d of exposure to eugenol. And the inhibition of SA and JA biosynthesis further promotes the inhibitory effects of eugenol on algae. Additionally, the signaling molecule nitric oxide (NO) increased significantly by 3.78-fold. Furthermore, the influence of NO on microalgae exposed to eugenol was also determined, suggesting that the inhibitory effect of eugenol stress might be associated with NO generation in M. aeruginosa. These findings will be helpful for the understanding of the fate and potential of eugenol in harmful algae control.

High salinity and high organic concentration impose negative impacts on autotrophic nitrification, which hinders efficient nitrogen removal. To achieve efficient nitrogen removal, high saline wastewater nitrogen removal systems with different COD/TN ratios based on heterotrophic nitrification-aerobic denitrification (HN-AD) process were established in this study. Results demonstrated that the COD/TN ratio had significant effects on nitrogen removal efficiency, microbial community structures and metabolic pathways. The optimal COD/TN ratio was 25 for nitrogen removal, with NH4+-N and TN removal rates of 11.86 mg·L−1·h−1 and 11.50 mg·L−1·h−1, respectively (3.65 and 3.31 times higher than those COD/TN ratio of 10). 16S rRNA high-throughput sequencing revealed that HN-AD functional bacteria (Pseudomonas, Bacillus, Paracoccus) with highest abundance (7.61%) played a key role in high saline wastewater treatment. And Halomonas, Nitrincola and Oceanimonas participated in the denitrification process. Moreover, the abundance of genes related to nitrogen removal was the highest (1.90%) revealed by functional genes prediction.

Nanomedicines have achieved several breakthroughs in cancer treatment over the past decades; however, their potential immunotoxicities are ignored, which results in serious adverse effects and greatly reduces the potential in clinical translation. Herein, we innovatively develop a theranostic supramolecular polymer using β-cyclodextrin as the host and camptothecin (CPT) as the guest linked by a glutathione-cleavable disulfide bond. The supramolecular polymerization remarkably increases the solubility of CPT by a factor of 232 and effectively inhibits its lactone ring opening in physiological environment, which is favorable for intravenous formulation and maintenance of the therapeutic efficacy. Supramolecular nanoparticles can be prepared through orthogonal self-assembly driven by π-π stacking interaction, host-guest complexation, and hydrogen bonds. The sophisticated nanomedicine constructed from the obtained supramolecular polymer can be specifically delivered to tumor sites and rapidly excreted from body after drug release, thus effectively avoiding systemic toxicity, especially long-term immunotoxicity. In vivo investigations demonstrate this supramolecular nanomedicine possesses superior antitumor performance and antimetastasis capability. This pioneering example integrating the advantages of the dynamic nature of supramolecular chemistry and nanotechnology provides a promising platform for cancer theranostics.

Light-emitting supramolecular coordination complexes (SCCs) have been widely studied for applications in the chemical and biological sciences. Herein, we report the coordination-driven self-assembly of two highly emissive platinum(II) supramolecular triangles (1 and 2) containing BODIPY-based bridging ligands. The metallacycles exhibit favorable anticancer activities against HeLa cells (IC50 of 6.41 and 2.11 μM). The characteristic ∼570 nm fluorescence of the boron dipyrromethene (BODIPY) moieties in the metallacycles permits their intracellular visualization using confocal microscopy. Additionally, the BODIPY fluorophore is an excellent photodynamic agent, making the metallacycles as ideal therapeutics for photodynamic therapy (PDT) and chemotherapy. In vitro studies demonstrate that the combination indexes against HeLa cells are 0.56 and 0.48 for 1 and 2, respectively, confirming their synergistic anticancer effect. More importantly, these SCCs also exhibit superior anticancer efficacy toward cisplatin-...

Vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF) have been shown to keep angiogenesis activation and inhibition in balance in normal and pathological conditions. In this study, we examined the expression of VEGF and PEDF in keratinocytes and fibroblasts from normal and psoriatic skin to evaluate their potential roles and interactions in the development of psoriasis. The expression of VEGF and PEDF was detected in normal and psoriatic skin ex vivo and in co-cultured keratinocytes and fibroblasts in vitro, and increased in keratinocytes and fibroblasts from psoriatic skin compared with those cells from normal skin. Our results suggest that PEDF act as a multipotent factor in the skin and the imbalance of PEDF and VEGF may be responsible for the transformation from normal skin to psoriasis.

In this paper, MCI diagnostic model based on neuropsychological scales was researched, and the performance of which was improved by combination of multiple neuropsychological scales. The data of 41 subjects includes 15 AD patients, 12 aMCI patients and 14 normal subjects as control group. Each subject was tested on the neuropsychology scales, which include MMSE, ADAS-cog and CCWS. The feature selection was based on Support Vector Machines-Recursive Feature Elimination (SVM-RFE), then use the PCA algorithm for feature compression. Support Vector Machines was utilized to build the classification model, and the classifier performance were evaluated based on accuracy, and using 10-fold cross validation. Finally, three neuropsychology scales were combined, and the result showed that classification accuracy for AD vs NC, AD vs aMCI and aMCI vs NC respectively was 1.0, 1.0 and 0.9, and classification of the three categories is up to 0.93. The results show that combination of multiple neuropsychological scales can improve the diagnostic performance and classifier performance of aMCI.

The first cationic water-soluble biphen[3]arene was synthesized and its host–guest complexation with sodium 1-hexanesulfonate was investigated, which was further used to change the aggregation of the amphiphilic guest in water.

Due to the differences in the cavity size of the hosts and the charge and length of the guests, a cationic water-soluble pillar[6]arene (WP6) selectively complexes with ATP to form a stable 1 : 1 inclusion complex WP6⊃ATP. This host–guest complexation was utilized to efficiently inhibit the hydrolysis of ATP, arising from the existence of the hydrophobic cavity of WP6. A folic acid functionalized diblock copolymer (FA-PEG-b-PAA) was employed to PEGylate WP6 to endow the polyion complex (PIC) micelles with specific targeting ability, preferentially delivering WP6 to folate receptor over-expressing KB cell. This host–guest complexation was further used to block the efflux pump to transport anticancer drugs out of cells by cutting off the energy source, which enhanced the efficacy of the cancer chemotherapy of DOX·HCl towards drug resistant MCF-7/ADR cell. This supramolecular method provides an extremely distinct strategy to potentially overcome multidrug resistance (MDR).

Background: Patients with Alzheimer's disease (AD) manifest progressive decline in writing abilities. Most studies on agraphia in AD have been performed in the alphabetic system, such as English. However, these findings may not be applicable to other written language systems. The unique features of the Chinese written script could affect the patterns of agraphia in Chinese AD patients. The aim of this study was to explore the features of writing errors in Chinese patients with AD and amnestic mild cognitive impairment (a-MCI), as well as to study the relationship between their writing errors and neuropsychological functions. Methods: In this study, we performed an observational study in a group of subjects including 17 AD patients, 14 patients with a-MCI, and 16 elderly healthy controls. We analyzed the writing errors in these subjects and also studied the relationship between their writing errors and neuropsychological functions. Results: Our study showed that in patients whose mother tongue is Chinese, writing ability was comparatively well preserved in the MCI phase but significantly impaired when the disease progressed to the stage of AD. The writing errors showed corresponding increase with the severity of cognition decline, both in the types of errors and rate of occurrence. Analysis of the writing errors showed that word substitution and unintelligible words were the most frequent error types that occurred in all the three study groups. The occurrence rate of unintelligible words was significantly higher in the AD group compared with the a-MCI group ( P = 0.024) and control group ( P = 0.018). In addition, the occurrence rates of word substitution were also significantly higher in AD ( P = 0.013) and a-MCI groups ( P = 0.037) than that of control group. However, errors such as totally no response, visuospatial impairment, paragraph agraphia, ideograph, and perseverative writing errors were only seen in AD group. Besides, we also found a high occurrence rate of visuoconstructional errors (13.3%) in our AD group. Conclusions: Our study confirmed that agraphia is an important feature in patients with AD. The writing error profile in patients whose native language is Chinese was unique compared to patients using the alphabetic language system.

A water-soluble hybrid[4]arene was synthesized for the first time and its pH-responsive host–guest complexation with paraquat in water was investigated. This new host–guest recognition motif was further applied in the construction of a supra-amphiphile.

With the rapid development of image processing for scene recognition and visual communication, there is an intense demand to provide the observer with a high-resolution image not only for offering better visualization but also for extracting additional details. In recent years, the invention of super-resolution imaging techniques has overcome the diffraction barrier and has provided clear insights into biological processes at the cellular and molecular scale. In general, the commonly used probes for super-resolution imaging are focused on fluorescent proteins, quantum dots and organic small-molecule fluorophores. Their photostability, biocompatibility and specificity, however, leave much to be desired. Aggregation-induced emission (AIE), a fascinating photoluminescence phenomenon, has found a wide range of applications in fluorescent sensors, biological probes and smart nanomaterials. Herein, we introduce a new class of AIE-based bioprobes for super-resolution imaging, which has recently been reported by Tang and co-workers. The results will inspire the design of AIE luminogens for specific super-resolution imaging in more fields.

A triple-component supra-amphiphile WSP5⊃G1@A is constructed based on phenylboronic acid/diols dynamic covalent chemistry and water-soluble pillararenes/trimethylamine host–guest recognition. Diols-responsive self-assembly of this ternary supra-amphiphile is fully investigated in aqueous solution.

Supramolecular brush copolymers have attracted continuing interest due to their unusual architectures, fascinating properties, and potential applications in many fields involving smart stimuli-responsive drug delivery systems. Herein, the first pillararene-based amphiphilic supramolecular brush copolymer (P5-PEG-Biotin⊃PTPE) was constructed on the basis of the host–guest molecular recognition between a water-soluble pillar[5]arene (P5) and a viologen salt (M). P5-PEG-Biotin⊃PTPE self-assembled into supramolecular nanoparticles (SNPs), which were utilized as a self-imaging drug delivery vehicle by taking advantage of the aggregation-induced emission (AIE) effect. Encapsulation of anticancer drug doxorubicin (DOX) caused deactivation of the fluorescences of both the tetraphenylethene (TPE) and DOX chromophores due to the energy transfer relay (ETR) effect, mediated by Förster resonance energy transfer (FRET) and aggregation-caused quenching (ACQ). The release of loaded DOX molecules can be triggered by low pH and reductase, recovering the “silenced” fluorescence caused by the interruption of the ETR effect, achieving in situ visualization of the drug release process by observing the location and magnitude of the energy transfer-dependent fluorescence variation. The biotin ligands on the surfaces of the DOX-loaded SNPs act as targeting agents to deliver DOX preferentially to cancer cells over-expressing biotin receptor. In vitro studies demonstrated that the loading of DOX by this supramolecular nanomaterial exhibited selective cytotoxicity towards cancer cells over normal cells. The potency of this sophisticated supramolecular drug delivery system in cancer therapy was further evaluated in HeLa tumor-bearing mice. In vivo experiments confirmed that the DOX-loaded SNPs possess excellent antitumor efficacy with negligible systemic toxicity.

Here we report the unprecedented preparation of nanoparticles with near-infrared (NIR) emission enhanced by host-guest complexation between a water-soluble pillar[5]arene (WP5) and a cyanostilbene derivative (1) in water. Amphiphilic 1 self-assembles in water to form nanoribbons with relatively weak NIR emission at low concentrations. However, after addition of equimolar WP5, these nanoribbons transform into nanoparticles with stronger NIR emission due to the formation of a supramolecular amphiphile and host-guest complexation-enhanced aggregation. These nanoparticles show pH responsiveness, and collapse after treatment with acid. More importantly, these nanoparticles can be used in living cell imaging.

Background: Amnestic mild cognitive impairment (aMCI) is a heterogeneous condition. Based on clinical symptoms, aMCI could be categorized into single-domain aMCI (SD-aMCI, only memory deficit) and multi-domain aMCI (MD-aMCI, one or more cognitive domain deficit). As core intrinsic functional architecture, inter-hemispheric connectivity maintains many cognitive abilities. However, few studies investigated whether SD-aMCI and MD-aMCI have different inter-hemispheric connectivity pattern.Methods: We evaluated inter-hemispheric connection pattern using fluorine-18 positron emission tomography – fluorodeoxyglucose (18F PET-FDG), resting-state functional MRI and structural T1 in 49 controls, 32 SD-aMCI, and 32 MD-aMCI patients. Specifically, we analyzed the 18F PET-FDG (intensity normalized by cerebellar vermis) in a voxel-wise manner. Then, we estimated inter-hemispheric functional and structural connectivity by calculating the voxel-mirrored homotopic connectivity (VMHC) and corpus callosum (CC) subregions volume. Further, we correlated inter-hemispheric indices with the behavioral score and pathological biomarkers.Results: We found that MD-aMCI exhibited more several inter-hemispheric connectivity damages than SD-aMCI. Specifically, MD-aMCI displayed hypometabolism in the bilateral middle temporal gyrus (MTG), inferior parietal lobe, and left precuneus (PCu) (p < 0.001, corrected). Correspondingly, MD-aMCI showed decreased VMHC in MTG, PCu, calcarine gyrus, and postcentral gyrus, as well as smaller mid-posterior CC than the SD-aMCI and controls (p < 0.05, corrected). Contrary to MD-aMCI, there were no neuroimaging indices with significant differences between SD-aMCI and controls, except reduced hypometabolism in bilateral MTG. Within aMCI patients, hypometabolism and reduced inter-hemispheric connectivity correlated with worse executive ability. Moreover, hypometabolism indices correlated to increased amyloid deposition.Conclusion: In conclusion, patients with MD-aMCI exhibited the more severe deficit in inter-hemispheric communication than SD-aMCI. This long-range connectivity deficit may contribute to cognitive profiles and potentially serve as a biomarker to estimate disease progression of aMCI patients.

The host–guest complexations between a water-soluble pillar[5]arenes ( WP5 ) and choline derivatives with different alkyl chain lengths were investigated. The hydrophobic interactions played a significant role in these pillar[5]arene-based host–guest complexations. By taking advantage of hydrophobic interactions, the cavity of WP5 could be further employed to inhibit the hydrolysis of acetylcholine in the presence of acetylcholinesterase.

The first water-soluble biphen[3]arene was synthesized. Its pH-responsive host–guest complexation with secondary ammonium salts in water was investigated. This novel recognition motif was further used in controllable self-assembly and controlled release.

A dual-responsive supra-amphiphile was firstly constructed based on a water-soluble pillar[7]arene and a naphthalene diimide-containing guest with a long alkyl chain and a trimethylammonium group. The morphology of the self-assembly formed from this supra-amphiphile could be adjusted by changing the solution pH or adding α-cyclodextrin.

Chemotherapy is currently one of the most effective ways to treat cancer. However, traditional chemotherapy faces several obstacles to clinical trials, such as poor solubility/stability, non-targeting capability and uncontrollable release of the drugs, greatly limiting their anticancer efficacy and causing severe side effects towards normal tissues. Supramolecular chemotherapy integrating non-covalent interactions and traditional chemotherapy is a highly promising candidate in this regard and can be appropriately used for targeted drug delivery. By taking advantage of supramolecular chemistry, some limitations impeding traditional chemotherapy for clinical applications can be solved effectively. Therefore, we present here a review summarizing the progress of supramolecular chemotherapy in cancer treatment based on host–guest recognition and provide guidance on the design of new targeting supramolecular chemotherapy combining diagnostic and therapeutic functions. Based on a large number of state-of-the-art studies, our review will advance supramolecular chemotherapy on the basis of host–guest recognition and promote translational clinical applications.

Host–guest complexations of a twisted cucurbit[15]uril with some paraquat derivatives and bispyridinium salts in aqueous solution are investigated by nuclear magnetic resonance, UV–vis spectrometry and isothermal titration calorimetry. These complexations are mainly enthalpy-driven.

Familial Alzheimer's disease (FAD) is characterized by a positive family history of dementia and typically occurs at an early age with an autosomal dominant pattern of inheritance. Amyloid precursor protein (APP), presenilin1 (PSEN1), and presenilin2 (PSEN2) are the major causative genes of FAD. The spectrum of mutations in patients with FAD has been investigated extensively in the Caucasian population but rarely in the Chinese population. Here, we performed whole-exome sequencing in a total of 15 unrelated Chinese patients with FAD. Among them, 12 were found to carry missense variants in APP, PSEN1, and PSEN2. Two novel variants (APP: p.D244G, p.K687Q), 3 variants not previously associated with FAD (APP: p.T297M, p.D332G; PSEN1: p.R157S), and 7 previously reported pathogenic variants (APP: p.V717I; PSEN1: p.M139I, p.T147I, p.L173W, p.F177S, p.R269H; PSEN2: p.V139M) were identified. The novel variant APP p.K687Q was classified as likely pathogenic, and the other 4 variants (APP: p.D244G, p.T297M, p.D332G; PSEN1: p.R157S) were classified as uncertain significance. Therefore, APP, PSEN1, and PSEN2 mutations account for 2 (25.0%), 5 (62.5%), and 1 (12.5%) of the genotyped cases positive for mutations, respectively. Furthermore, the genotype–phenotype correlations were described. Our findings broaden the genetic spectrum of FAD with APP, PSEN1, and PSEN2 variants.

We describe an outbreak of carbapenemase-producing Klebsiella pneumoniae in a neonatal intensive care unit and assess the effect of infection control measures. Our assessment indicates that active surveillance culture is very useful in identifying multidrug-resistant organisms and its prevention from transmission. Besides contact precaution, environment disinfection, good compliance of hand hygiene, and single-room isolation is very important for preventing transmission of carbapenemase-producing K pneumoniae isolates.

Recent years, laser spike annealing (LSA) is considered to be mainstream technology for ultra-shallow junction (USJ), silicide formation and extended to insulated gate bipolar transistor (IGBT) annealing. Now, Shanghai Micro Electronics Equipment (SMEE) has achieved to find the solution for field stop IGBT (FS-IGBT) annealing. Comparing to traditional rapid thermal process (RTP), the advantages of LSA can be shown from several aspects. Firstly, I will introduce our laser annealing tool for FS-IGBT with its key specification overall and explain the consideration why FS-IGBT need LSA. Secondly, some experiment datum and predictable results have been analyzed and summarized in this article. Our work will continue to improve the tool performance by stability, repeatability and uniformity. Last but not least, we believed that laser spike annealing will become one of the key processes for FS-IGBT in the near future.

In clinical settings, it is difficult to distinguish Alzheimer’s disease (AD) from vascular dementia (VD). The present study summarizes a clinical method to distinguish VD and AD at the early stage of the diseases. This study evaluated the possibility of differentiating 25 VD, 25 AD, and 25 healthy individuals (control, CN) by means of power spectral analysis and standardized low-resolution brain electromagnetic tomography (sLORETA) within alpha 1, alpha 2, beta 1, beta 2, delta, and theta frequency bands. Electroencephalogram (EEG) spectral analysis and sLORETA indicated that higher diffuse delta/theta and lower central/posterior fast frequency bands were present in AD compared with CN. VD showed diffuse increased theta power compared with CN and lower delta than AD. AD also presented diffuse higher theta on spectral analysis and decreased alpha 2 and beta 1 values in central/temporal regions by sLORETA. Mini Mental State Examination (MMSE) scores were significantly associated with frontal alpha 1 sLORETA solutions ( r = 0.91616, P < .001) and relative power ( r = 0.87322, P < .01) in AD, but no correlations were found in VD. In conclusion, EEG spectral and sLORETA together could be a tool to distinguish the different EEG rhythmic activities in AD and VD.

Primary progressive aphasia (PPA) is a progressive neurodegenerative disorder characterized by the deterioration of language functions. The Han language bears some unique features from the Latin languages; however, the features of PPA in the Han language-speaking population are not well understood. In this study, we performed a 3-year follow-up on a Han language-speaking PPA patient with corresponding changes in magnetic resonance imaging (MRI). During the early stage, linguistic analysis revealed several symptoms including difficulty with auditory comprehension, right-left disorientation, reading disorders, and agraphia, specifically the execution of serial oral instructions. This Chinese PPA patient presented with a reading disorder, but his word comprehension ability remained intact. There are two different possible modalities of incorrect writing in this case. The patient also presented with noun-verb double dissociation. The early-stage MRI showed atrophy of the left frontal lobe, which was most severe in the inferior frontal gyrus. Three years later, the patient was found to have progressive atrophy in the parietal, frontal, and temporal lobes, among which the frontal lobe remained the most severely affected region. The brain imaging of the Chinese-speaking PPA patient showed changes similar to those of a Latin language-speaking PPA patient. The prominent change was asymmetrical atrophy in the frontal and temporal lobes. This is the first report of noun-verb double dissociation existing in a Chinese-language speaking PPA patient. The dissociation may be related to an impaired function of the inferior frontal gyrus, which is likely associated with verb-naming in Chinese-speaking people. Several unique features were observed in this case, including impairment in writing ability.

In pushing of the projects of "the Guanzhong-Tianshui Economic Zone" and "Xian-Xianyang Integration",financial development in Shaanxi has also become one of the important topics of current research.On the basis of the theory of financial sustainable development,this paper builds evaluation index system of the financial sustainable development and using empirical analysis in this paper.At the same time,its doing comparative research of financial sustainable development level of the eight major cities in Shaanxi.This papers aim is to provide some recommendations about financial policies and development strategies for the relevant departments.

Amnestic mild cognitive impairment can be further classified as single-domain aMCI (SD-aMCI) with isolated memory deficit, or multi-domain aMCI (MD-aMCI) if memory deficit is combined with impairment in other cognitive domains. Prior studies reported these clinical subtypes presumably differ in etiology. Thus, we aimed to explore the possible mechanisms between different aMCI subtypes by assessing alteration in brain activity and brain vasculature, and their relations with CSF AD biomarkers. 49 healthy controls, 32 SD-aMCI, and 32 MD-aMCI, who had undergone structural scans, resting-state functional MRI (rsfMRI) scans and neuropsychological evaluations, were identified. Regional homogeneity (ReHo) was employed to analyze regional synchronization. Periventricular white matter hyperintensities (PWMH) and deep WMH (DWMH) volume of each participant was quantitatively assessed. AD biomarkers from CSF were also measured. SD-aMCI showed decreased ReHo in medial temporal gyrus (MTG), and increased ReHo in lingual gyrus (LG) and superior temporal gyrus (STG) relative to controls. MD-aMCI showed decreased ReHo, mostly located in precuneus (PCu), LG and postcentral gyrus (PCG), relative to SD-aMCI and controls. As for microvascular disease, MD-aMCI patients had more PWMH burden than SD-aMCI and controls. Correlation analyses indicated mean ReHo in differenced regions were related with memory, language, and executive function in aMCI patients. However, no significant associations between PWMH and behavioral data were found. The Aβ level was related with the ReHo value of STG in SD-aMCI. MD-aMCI displayed different patterns of abnormal regional synchronization and more severe PWMH burden compared with SD-aMCI. Therefore aMCI is not a uniform disease entity, and MD-aMCI group may show more complicated pathologies than SD-aMCI group.

The ecoenvironment of regional finance's evaluation methodology is the hot issue in recent years. This paper systematic sorted these evaluation methodologies and its research and application situation. It illustrates the contents of the single evaluation method and the comprehensive evaluation method, then comparative analysis from perspective, data dependence and operation complexity. And it make the difference and characteristics between using single and comprehensive evaluation method clear. Finally, put forward some thoughts for the regional financial ecoenvironment's evaluation.

Psoriasis, a common inflammatory skin disease, is characterized by epidermal hyperplasia, abnormal differentiation, angiogenesis, immune activation, and inflammation. Involucrin is an early terminal differentiation marker of epidermal keratinocytes. In this study, we determined the immunolocalization of involucrin in psoriatic lesions and normal skin of individuals without psoriasis by means of immunofluorescence (IF) assay. Furthermore, the regulation of involucrin by interleukin (IL)-13, IL-17A, endothelin (ET)-1, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ was investigated by Western blot. Extracellular regulate protein kinases 1/2 (ERK1/2) and glycogen syntheses kinase-3β (GSK-3β) inhibitors were also included to define the roles of these signals in the production of involucrin in both psoriatic and normal keratinocytes. In psoriatic lesional skin, involucrin was detected in the stratum spinosum, but not in the basal or the cornified layer. In normal skin, involucrin was restricted to the granular layer and the upper stratum spinosum. IL-13, IL-17A, ET-1, TNF-α, and IFN-γ up-regulate expression of involucrin in both psoriatic and normal keratinocytes. However, this effect was abolished by ERK1/2 and GSK-3β inhibitors. In conclusion, involucrin is up-regulated in psoriatic keratinocytes. IL-13, IL-17A, ET-1, TNF-α, and IFN-γ could increase involucrin protein levels in psoriatic and normal keratinocytes. The ERK1/2 and GSK-3β signaling pathways may play positive roles in regulating epidermal differentiation as observed in psoriasis.