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Endotoxicity originating from a dangerous debris (i.e., lipopolysaccharide, LPS) of Gram-negative bacteria is a challenging clinical problem, but no drugs or therapeutic strategies that can successfully address this issue have been identified yet. In this study, we report a subnanometer gold cluster that can efficiently block endotoxin activity to protect against sepsis. The endotoxin blocker consists of a gold nanocluster that serves as a flakelike substrate and a coating of short alkyl motifs that act as an adhesive to dock with LPS by compacting the intramolecular hydrocarbon chain-chain distance ( d-spacing) of lipid A, an endotoxicity active site that can cause overwhelming cytokine induction resulting in sepsis progression. Direct evidence showed the d-spacing values of lipid A to be decreased from 4.19 Å to either 3.85 or 3.54 Å, indicating more dense packing densities in the presence of subnanometer gold clusters. In terms of biological relevance, the concentrations of key pro-inflammatory NF-κB-dependent cytokines, including plasma TNF-α, IL-6, and IL-1β, and CXC chemokines, in LPS-challenged mice showed a noticeable decrease. More importantly, we demonstrated that the treatment of antiendotoxin gold nanoclusters significantly prolonged the survival time in LPS-induced septic mice. The ultrasmall gold nanoclusters could target lipid A of LPS to deactivate endotoxicity by compacting its packing density, which might constitute a potential therapeutic strategy for the early prevention of sepsis caused by Gram-negative bacterial infection.

Full-bridge phase-shifted converters sometimes add external resonant inductors to achieve zero-voltage switching during light load conditions. The magnetic components in the circuit include a resonant inductor, transformer, and output inductor. These magnetic components occupy a sizable portion of the circuit volume, which results in low power density. To achieve higher power density, this paper analyzes the magnetic integration of these three magnetic components into one core. This analysis derives the flux density and output ripple current by calculating the dc-ac flux and equivalent output inductance during operation intervals. The resonant inductor in the traditional full-bridge phase-shifted converter is replaced by adjusting the distance between primary-side winding and secondary-side winding. Finally, the prototype of a 500-W full-bridge phase-shifted converter which operates with 380-V input voltage and 12-V output voltage is implemented using integrated magnetic technology.

Objective Osteoporosis is a multifactorial disease associated with inflammation and hormone imbalance. It is noteworthy that dry eye syndrome shares a similar pathophysiology with osteoporosis. Both diseases are more prevalent among the elderly and females. Dry eye syndrome can result in impaired vision, which increases the risk of fall and fracture when osteoporosis exists. In this study, we investigated whether osteoporosis is associated with an increased risk of developing dry eye syndrome. Methods Claims data from the National Health Insurance Research Database (NHIRD) of Taiwan were used to conduct a retrospective population-based cohort study covering the period from January 1, 2000, to December 31, 2011. Multiple logistic regression was used to determine whether osteoporosis is an independent factor in the risk of developing dry eye syndrome, with risk estimates presented in the form of odds ratios (ORs). Results The exclusion of patients with specific autoimmune diseases and those younger than 50 years old resulted in 42,365 patients in the osteoporosis group and 147,460 patients in the comparison group during the study period. The number of patients newly diagnosed with dry eye syndrome was 6,478 (15.29%) in the osteoporosis group and 15,396 (10.44%) in the comparison group. The crude OR of patients with osteoporosis developing dry eye syndrome was 1.55 and the 95% confidence interval (95% CI) was 1.50–1.60. After adjusting for patients’ age, sex, and underlying comorbidities, the adjusted OR was 1.26 and the 95% CI was 1.22–1.30. Subgroup analysis revealed this association in each age group and among females but not among males. Conclusions Our results demonstrate that osteoporosis is a risk factor for the subsequent development of dry eye syndrome. Clinicians should be aware of the early symptoms of dry eye syndrome in osteoporotic patients in order to prevent further complications.

A structure-based virtual screening strategy, comprising homology modeling, ligand-support binding site optimization, virtual screening, and structure clustering analysis, was developed and used to identify novel tryptophan 2,3-dioxygenase (TDO) inhibitors. Compound 1 (IC50 = 711 nM), selected by virtual screening, showed inhibitory activity toward TDO and was subjected to structural modifications and molecular docking studies. This resulted in the identification of a potent TDO selective inhibitor (11e, IC50 = 30 nM), making it a potential compound for further investigation as a cancer therapeutic and other TDO-related targeted therapy.

In this study, we sought to control the assembly of an endotoxin known as the biologically supramolecular lipopolysaccharide (LPS, which consists of three portions: an O antigen, a core carbohydrate, and a lipid A molecule) in order to modulate immunological responses in a manner that has the potential for utilization in vaccine development. Changing the structures of LPS aggregates from lamellas to specific nonlamellas (i.e., cubosomes and hexosomes) can dramatically enhance the strength of LPS in causing inflammatory responses, leading to highly active responses. In order to control the formation of cubosome-free and hexosome-free nonlamellas, we designed a simple strategy based on the use of hydrophilic gold nanodots (AuNDs) to control LPS assembly to facilitate the formation of stable endotoxin nanovesicles, which are stable precursors of cubosomes and hexosomes with specific immunological effects. Structurally, the wall thicknesses of these nanovesicles are exactly twice the lengths of a single LPS molecule, indicating that the LPS molecules adopt a tail-to-tail arrangement (with the lipid A portions acting as the tail domain). The involvement of the hydrophilic AuNDs to laterally link polar domains of LPS can result in the progressive extension of an endotoxically active zone of lipid A assembly, leading to the eventual formation of large-size nanovesicles. Our results showed that endotoxin nanovesicles with such dense lipid A units can elicit the stronger inflammatory gene expressions, including interleukin 6 (IL-6), IL-1A, TNF-α, C-X-C chemokine ligand (CXCL) 1, 2, and 11, which have characteristics of T-helper 1 adjuvants. These findings provide evidence that the concept of manipulating the surface hydrophilicity of AuNDs to control LPS assembly in order to avoid the formation of highly active cubosomes and hexosomes, and thereby modulate immunological responses appropriately, could prove useful in vaccine development.

When gold nanoparticles (AuNPs) become extremely small (

Infectious bronchitis virus (IBV) variants constantly emerge and pose economic threats to poultry farms worldwide. Numerous studies on the molecular and pathogenic characterization of IBV variants have been performed between 2007 and 2017, which we have reviewed herein. We noted that viral genetic mutations and recombination events commonly gave rise to distinct IBV genotypes, serotypes and pathotypes. In addition to characterizing the S1 genes, full viral genomic sequencing, comprehensive antigenicity, and pathogenicity studies on emerging variants have advanced our understanding of IBV infections, which is valuable for developing countermeasures against IBV field outbreaks. This review of IBV variants provides practical value for understanding their phylogenetic relationships and epidemiology from both regional and worldwide viewpoints.

Photodynamic therapy (PDT) typically involves oxygen (O

Fondaparinux, a synthetic pentasaccharide based on the heparin antithrombin-binding domain, is an approved clinical anticoagulant. Although it is a better and safer alternative to pharmaceutical heparins in many cases, its high cost, which results from the difficult and tedious synthesis, is a deterrent for its widespread use. The chemical synthesis of fondaparinux was achieved in an efficient and concise manner from commercially available D-glucosamine, diacetone α-D-glucose, and penta-O-acetyl-D-glucose. The method involves suitably functionalized building blocks that are readily accessible and employs shared intermediates and a series of one-pot reactions that considerably reduce the synthetic effort and improve the yield.

Purpose– This paper aims to examine the determinants of socioeconomic factors on housing prices and their differential effects among regions.Design/methodology/approach– This study employs a hierarchical linear model to analyze the housing and socioeconomic data of 363 metropolitan statistical areas (MSAs) in the USA.Findings– This study generates four findings. First, the population, the percentage of the elderly in population, violent crime rates, and foreclosure rates produce greater effects on housing prices in the Northeast than those in the West. Second, the population produces a greater effect on housing prices in the Northeast than those in the Midwest. Third, mortgage rates produce less significant effects on housing prices in the Northeast than those in the Midwest. Fourth, the population, the percentage of the elderly in population, and rent-income ratio produce greater effects on housing prices in the Northeast than those in the South.Research limitations/implications– Based on data collected for 2010, this study analyzes socioeconomic factors on the demand side under the implicit assumption that supply side remains constant. Future research can lift the restriction on fixed supply assumption.Practical implications– The results can provide information to buyers and sellers about how socioeconomic factors affect housing prices. Moreover, this study also provides useful information for the government to design and implement relevant housing policies.Originality/value– This is the pioneering study to examine the differential effect of socioeconomic factors on metropolitan housing prices among regions by employing dummy regional variables to detect changes in slope coefficients. These detailed conclusions would enhance the efficiency of transaction in housing markets.

A data streams is a sequence of dynamic, continuous, unbounded and real time data items with a very high data rate that can only be read once. In data mining, clustering is one of useful techniques for discovering interesting data in the underlying data objects. The problem of clustering can be defined formally as follows: given n data points in the d-dimensional metric space, partition the data points into k clusters such that the data points within a cluster are more similar to each other than data points in different clusters. In the data streams environment, the difficulties of data streams clustering contain storage overhead, low clustering quality and a low updating efficiency. Therefore, in this paper, we present a new clustering algorithm with high quality, GDense, for data streams. The GDense algorithm has high quality due to two kinds of partition: cells and quadcells, and two kinds of threshold: δ and (1/4)δ. From our simulation results, no matter what condition (including the number of data points, the number of cells, the size of the sliding window, and the threshold of dense cell) is, the clustering purity of our GDense algorithm is always higher than that of the CDS-Tree algorithm.

Background Lung cancer has the highest rate of morbidity and mortality among various cancer types, being responsible for over 1.69 million deaths per year. Approximately 80–85% of the lung cancer patients diagnosed present non-small cell lung cancer (NSCLC), while 10–15% present small cell lung cancer (SCLC). Mutations in the epidermal growth factor receptor (EGFR) have been observed in ∼50% of patients, in particular, in East Asian NSCLC patients. The single-point mutation L858R (exon 21) and amino acids deletions in the tyrosine kinase (TK) domain (exon 19) constitute 90% of all EGFR-activating mutations. Methods We introduced an acrylamide group as a Michael acceptor, resulting in compound 2, which showed potent in vitroactivity in both wild and mutant EGFR kinases and potent anti-proliferative activity in HCC827 lung cancer cell line. In this work, we apply SBDD to guide the optimization of lead compound 2and perform a detailed structure-activity relationship (SAR) study to bring this drug candidate into the next development stage. Results We optimized the compound 2by scaffold hopping and by exploiting the potent inhibitory activity of various warhead groups. The results of the multi-objective optimization obtained the clinical candidate, compound 78 (DBPR112), which not only displayed a potent inhibitory activity against EGFR L858R/T790M double mutations, but also exhibited 10-fold potency better than 3rd generation inhibitor, osimertinib, against three EGFR and one HER2 exon 20 insertion mutations, since there are currently no EGFR-directed therapies approved specifically for the treatment of this mutation. Conclusions X-ray co-crystal study of EGFRWTKinase and compound 78 revealed the potential of future design for mutant-selective inhibitors. Finally, furanopyrimidine 78 was selected as a clinical candidate to conduct all preclinical experiments and is currently undergoing phase 1 clinical trial in Taiwan. Clinical trial identification NCT03246854. Legal entity responsible for the study The authors. Funding National Health Research Institutes, Taiwan. Disclosure All authors have declared no conflicts of interest.

Heparin and heparan sulfate bind a host of basic proteins that take advantage of the sugar's dense structural information. The significance of these interactions in various aspects of development, physiology, and disease stimulated keen interest in evaluating structure-activity relationships. The well-defined heparin and heparan sulfate oligosaccharides needed for these studies can be mainly accessed by chemical synthesis and, more recently by chemoenzymatic means. The various synthetic strategies available to chemical synthesis have recently enabled the acquisition of several regular and irregular sequences, including a number of dodecasaccharides, through improved coupling methods and judicial protecting group manipulations. Controlled chain elongation and critical application of modification enzymes allowed the generation of well-defined constructs via chemoenzymatic synthesis. Investigations of various protein interactions with the synthetic constructs delivered valuable information that could aid future drug development endeavors.

Potassium carbonate (K 2 CO 3 ) has demonstrated to be an efficient n-type dopant in improving the performance of the Alq 3 -based organic light-emitting diodes (OLEDs). K 2 CO 3 -doped tris(8-hydroxyquinolinato)aluminum (Alq 3 ) layers with various concentrations were prepared by the co-evaporating method and the role of K 2 CO 3 was investigated. When 10% K 2 CO 3 was doped into an Alq 3 electron-transporting layer, device properties such as the turn-on voltage, the maximum luminance, and the device efficiency were improved. K 2 CO 3 -doped Alq 3 layers possess an enhanced electron injection and transporting ability. The higher mobility of the K 2 CO 3 -doped samples has been derived using space–charge–limited current (SCLC) measurements. X-ray and ultraviolet photoelectron spectroscopy results show that some electrons transfer from K 2 CO 3 into Alq 3 , which increases the electron concentration in Alq 3 films and moves the Fermi level close to the lowest unoccupied molecular orbital (LUMO) of Alq 3 . Therefore, the electron injection and transport efficiency are both enhanced due to a lower electron injection barrier and a higher electron mobility, which improve the charge carrier balance in OLEDs and lead to better device efficiency.

We report on caged Pt nanoclusters that are able to exert tumor-inside activation for anticancer chemotherapeutics and to minimize systemic toxicity. By shrinking the Pt size to 1 nm, it possesses corrodibility for dissolution in weakly acidic organelles to release toxic Pt ions. The therapeutic effect in exerting tumor-inside activation is confirmed in vivo by post-modifying a pH-cleavable PEG corona and mixing it with a tumor-homing peptide for tumour suppression.

Gold nanoparticles (AuNPs) have been established to sufficiently eradicate tumors by means of heat production for photothermal therapy. However, the translation of the AuNPs from bench to the clinic still remains to be solved until realizing high bioclearance after treatment. Herein, we developed a simple strategy for simultaneous formation and assembly of small-size gold nanoparticles (Au-SNPs) to form a novel nanocomposite in the presence of gum arabic (GA) by synchrotron X-ray irradiation in an aqueous solution within 5 min. GA, a porous polysaccharide, can not only provide a confined space in which to produce uniform Au-SNPs (1.6 ± 0.7 nm in diameter), but can also facilitate the formation of Au-SNPs@GA (diameter ≈ 40 nm) after irradiating synchrotron X-rays. Specifically, the Au-SNPs@GA possesses high thermal stability and a strong photothermal effect for killing cancer cells. Importantly, a bioclearance study demonstrated that the Au-SNPs@GA can be gradually excreted by the renal and hepatobiliary system, which might be due to the breakdown and oxidation of GA under irradiating synchrotron X-rays. Thus, the novel gold nanocomposite can be promising photothermal agents for cancer treatment at the therapeutic level, minimizing toxicity concerns regarding long-term accumulation in vivo.

Avian coronavirus infectious bronchitis virus (IBV) poses economic threat to the poultry industry worldwide. Pathogenic IBV 3575/08 was isolated from broilers vaccinated with the attenuated viral vaccine derived from a Taiwan strain 2575/98. In this study, extensive investigations were conducted on the genome sequences, antigenicity, pathogenicity, and host immune responses of several IBV strains in specific-pathogen-free chickens. Sequence analyses revealed that 3575/08 and 2575/98 shared high homology in their structural genes, but not in non-structural accessory proteins such as 3a, 3b and 5b. Despite a high degree of homology in their spike protein genes, cross neutralization test showed low cross protection between 3575/08 and 2575/98, suggesting distinct antigenicity for the two strains. Animal challenge experiments exhibited strong respiratory and renal pathogenicity for 3575/08. In addition, early and prolonged viral shedding and rapid viral dissemination were observed. Immune gene expression profiling by PCR array showed chickens infected with 3575/08 had delayed expression of a subset of early innate immune genes, whereas chickens infected with the wild-type or attenuated-type 2575/08 revealed quick gene induction and efficient virus control. In summary, this study reveals a new IBV strain, which harbors a known local genotype but displays remarkably altered antigenicity, pathogenicity and host defenses.

Numerous biomolecules possess α-D-glucosamine as structural component. However, chemical glycosylations aimed at this backbone are usually not easily attained without generating the unwanted β-isomer. We report herein a versatile approach in affording full α-stereoselectivity built upon a carefully selected set of orthogonal protecting groups on a D-glucosaminyl donor. The excellent stereoselectivity provided by the protecting group combination was found independent of leaving groups and activators. With the trichloroacetimidate as the optimum donor leaving group, core skeletons of glycosylphosphatidyl inositol anchors, heparosan, heparan sulfate, and heparin were efficiently assembled. The orthogonal protecting groups were successfully manipulated to further carry out the total syntheses of heparosan tri- and pentasaccharides and heparin di-, tetra-, hexa-, and octasaccharide analogues. Using the heparin analogues, heparin-binding hemagglutinin, a virulence factor of Mycobacterium tuberculosis, was found to bind at least six sugar units with the interaction notably being entropically driven.

Maternal infection during pregnancy may affect fetal brain development and lead to neurological and mental disorders. Previously, we used lipopolysaccharide [LPS, 33 μg/kg, intraperitoneal injection] exposure on gestation day 10.5 to mimic maternal bacterial infection in rats and found reduced dopaminergic and serotoninergic neurons in the offspring. In the present study, we examined the anxiety and stress responses of the affected offspring and the neurophysiological changes in their brains. Our results show that LPS rats displayed more anxiety-like behaviors and heightened stress responses. Dopamine (DA) in the nucleus accumbens and serotonin (5-HT) in the medial prefrontal cortex and the hippocampus were significantly reduced in LPS rats. Their glucocorticoid receptors in the dorsal hippocampus and the 5-HT(1A) receptors in the dorsal and ventral hippocampus were also reduced. In addition, chronic but not acute fluoxetine treatment reversed the behavioral changes and increased hippocampal 5-HT(1A) receptor expression. This study demonstrates that LPS exposure during a critical time of embryonic development could produce long-term reduction of DA and 5-HT and other neurophysiological changes; such alterations may be associated with the increases in stress response and anxiety-like behaviors in the offspring.

Microdrilling is an essential process in the electronics, aviation, and semiconductor industries. Since microdrills have low rigidness and a high aspect ratio, precise drilling parameters are required to prevent tool breakage from excessive thrust force or torque. This study implements thousand-micron grade microdrilling experiments in alumina ceramic to investigate the effects of drilling parameters on hole characteristics. Because ceramic has poor machinability, the holes must be fabricated by peck-drilling at shallow depths and continuous cooling. The drilling parameters analyzed included the spindle revolution speed, drill feed rate, peck-drilling return distance, and centering drill depth. Characteristics of the hole diameter and roundness were measured by a computer numerical control (CNC) image measurement device. The optimal parameters combination was derived by a two-stage Taguchi's experiment. This study also observes tool wear on chisel edge and generalizes manufacturing tolerance to obtain sta...

Background Carbamazepine, an anticonvulsant and a mood-stabilizing drug, is the main cause of the Stevens–Johnson syndrome (SJS) and its related disease, toxic epidermal necrolysis (TEN), in Southeast Asian countries. Carbamazepine-induced SJS–TEN is strongly associated with the HLA-B*1502 allele. We sought to prevent carbamazepine-induced SJS–TEN by using HLA-B*1502 screening to prospectively identify subjects at genetic risk for the condition. Methods From 23 hospitals in Taiwan, we recruited 4877 candidate subjects who had not taken carbamazepine. We genotyped DNA purified from the subjects' peripheral blood to determine whether they carried the HLA-B*1502 allele. Those testing positive for HLA-B*1502 (7.7% of the total) were advised not to take carbamazepine and were given an alternative medication or advised to continue taking their prestudy medication; those testing negative (92.3%) were advised to take carbamazepine. We interviewed the subjects by telephone once a week for 2 months to monitor them ...

Carbamazepine (CBZ) has been reported as the most common culprit drug for Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in several Asian countries including Thailand. A strong association between HLA-B*1502 and CBZ-induced SJS/TEN has been reported in Han Chinese but not in Caucasian and Japanese populations. A case-control study was conducted to determine whether HLA-B*1502 is a valid pharmacogenetic test for SJS/TEN caused by CBZ in a Thai population. Among 42 CBZ-induced patients with SJS/TEN, 37 (88.10%) patients carried the HLA-B*1502 while only 5 (11.90%) of the CBZ-tolerant controls had this allele. The risk of CBZ-induced SJS/TEN was significantly higher in the patients with HLA-B*1502, with an odds ratio (OR) of 54.76 [95% confidence interval (CI) 14.62-205.13, p = 2.89 x 10(-12)]. The sensitivity and specificity of HLA-B*1502 for prediction of CBZ-induced SJS/TEN were 88.10%. By assuming a 0.27% as a prevalence rate of CBZ-induced SJS/TEN in a Thai population, the positive predictive value (PPV) and negative predictive value (NPV) of the HLA-B*1502 were 1.92% and 99.96%. Results from this study suggest that HLA-B*1502 may be a useful pharmacogenetic test for screening Thai individuals who may be at risk for CBZ-induced SJS and TEN.

A 1988 survey, funded by the US Environmental Protection Agency (EPA) and conducted by the American Fisheries Society, identified the need to standardize the approaches for evaluating risks and developing fish consumption advisories that are comparable across different jurisdictions. A major tool for evaluating the progress in developing such nationally consistent information is EPA's web-based National Listing of Fish Advisories (NLFA) database, which has archived fish advisory information since 1993. The NLFA comprises both a database and Geographic Information System mapping components that are implemented using the National Hydrography Dataset (NHD). EPA and the US Geological Survey have developed an enhanced NHD product (NHDPlus) that is applied to define an interstate waters framework for the conterminous USA. This NHDPlus-based framework provides an efficient watershed-oriented approach for identifying interstate advisories from NLFA. We provide summaries of (1) the degree of consistency documented for inland waters where states have issued advisories for shared interstate NHD reaches and (2) the patterns for interstate advisories organized according to the ecoregions developed for EPA's Wadeable Streams Assessment. Approaches are also discussed for addressing interstate consistency issues for fish advisories in coastal waters making use of the NHDPlus combined with other nationally consistent frameworks, such as the 12-digit hydrologic unit code subwatersheds in the Watershed Boundary Dataset. Probability survey methods are recommended as a way to promote increased interjurisdictional consistency in the development of the monitoring and risk assessment conclusions reflected in NLFA, as well as in other EPA water quality-based programs.

A low-cost PC-based control X–Y table is constructed with AC servo motors and ball screw mechanisms to achieve long-range micro-positioning. This X–Y mechatronics system is integrated with a machine vision system to construct a visual based motion control system for industrial positioning applications, especially for the optical inspection purpose. Although the visual based servo system has the vision information to guide the servomechanism motion, it cannot obtain accurate positioning objective, especially, for the micro–nano positioning. It still needs a good servo controller to monitor the object step change after receiving the motion command from the machine vision system. Here, a new intelligent model-free controller was proposed to achieve quick transient response and precise steady state accuracy. The integration of this intelligent servo system and a machine vision system is implemented on the LCD color filter cross mark alignment application. The dynamic positioning performance and robustness of this control system are evaluated based on experimental results.

The first helical double-stranded polymer by ring-opening metathesis polymerization (ROMP) of a bisnorbornene derivative and the replication of a single-stranded polynorbornene leading to its complementary polynorbornene derivative are described. Base-promoted hydrolysis of this polymer affords the corresponding single-stranded polymer and the linker, ferrocene-1,1'-dicarboxylic acid, in excellent yield. Three forms (helical, supercoil, and ladder) of the polymer have been observed by scanning tunneling microscopy (STM) and simulated by molecular mechanical and dynamical calculations. The polymer thus obtained has a structural resemblance to DNA by having similar width, number of monomeric units per pitch, five-membered rings in the polymeric frame, perpendicular linkers to the backbones, and similar spacing between neighboring monomeric units. In the replication study, the single-stranded polynorbornene acts as a template for norbornene monomer adhesion via ester linkage. This polymer is treated with Grubbs-I catalyst to proceed the ROMP to afford the corresponding unsymmetric double-stranded polymer. After hydrolysis, a complementary polynorbornenecarboxylic acid is produced. This approach may provide a versatile entry for the design, synthesis, and physicochemical investigations of new types of polymers for simulation of biological systems as well as materials applications.

Reported here is a cooperative effect that the sensing efficiency of the active group on gold nanoparticles (GNPs) can be significantly influenced by another proximal functional group. We previously developed a visual sensing scheme for K+ by 15-crown-5-CH2O(CH2)12SH functionalized GNPs in aqueous matrix. Upon adding K+, the GNP solution changes from red to blue. Such a transform is triggered by a 2-to-1 sandwich complexation of crown to K+, resulting in the red shift of surface plasmon absorption due to GNP aggregation. Herein, we discover that introducing a second functionality, thioctic acid (TA), onto GNPs significantly affects the sensing efficiency of crown moieties (15-crown-5-CH2O(CH2)n)SH and 12-crown-4-CH2O(CH2)nSH, where n = 4, 8, and 12). The rate constant of K+ recognition by TA- and 15-crown-5-CH2O(CH2)4S-bifunctionalized GNPs is more than 4 orders of magnitude faster than the others containing longer methylene chains. The same chain-length dependence is also found in the case of Na+ sensing by 12-crown-4 functionalized GNPs. The discrepancy in sensing performance is attributed to a cooperative effect that the negatively charged carboxylate of TA may preorganize the crown moiety for K+ recognition. This method is applied to measure K+ and Na+ in human urine by UV-visible spectrometry. By adjusting the concentrations of GNPs, the dynamic ranges tuned for K+ and Na+ are, respectively, 6.25 microM-1.12 mM and 0.156-4.00 mM, suitable for real samples pretreated simply by 10-fold dilution. The results ([K+] = 20.3 mM, [Na+] = 45.1 mM) agree with those obtained from ICP-AES ([K+] = 19.8 mM, [Na+] = 43.8 mM).

Improvement in stability of self-assembled monolayers (SAMs) has been demonstrated by using an underpotentially deposited (upd) interlayer between the SAMs and gold substrate. In this study, we show that the upd adlayers can be applied to improve the packing density of thiophenol SAMs due to controlling the binding scheme of the sulfur headgroup from an sp3 to an sp hybridization configuration. Examined here are the structures of SAMs on gold substrate pre-modified by four types of upd adatoms that are electrodeposited at several coverages representing the finish of distinct upd processes. The SAM structures of a homologous series of n-alkanethiols (CH3(CH2)nSH, n = 4−11 and 13−15) are characterized by contact angle measurements and infrared reflectance absorption spectroscopy. The results show the odd−even effect that the orientation of the terminal methyl group is alternatively associated with the number of methylene units, indicating that sulfur headgroup adopts an sp3 hybridization on Au/Bi(upd) and a...

We propose a two-step approach to functionalize gold nanoparticles prepared by reducing tetrachloroauric acid by trisodium citrate in water. The chloride and citrate physisorbed on the gold nanoparticles are first displaced by thioctic acid (TA), which is then exchanged by thiols containing the desired functionality during the second step. TA bears a carboxylate group and disulfide; at high pH, the negative charge of the former stabilizes gold nanoparticles and the disulfide develops two S−Au bonds, retarding the desorption kinetics upon further functionalization. The slow kinetics of TA desorption is crucial to establishing sufficient steric stabilization for the gold core while losing electrostatic stabilization. Successful attachment of carboxylate, crown ether, cyclodextrin, pyridine, and amino functionalities is verified by surface sensitive techniques. In most cases, ca. 80% of the TA molecules are displaced. The nanoparticles are stable under solution pH where the surface group is ionized. Although...

Linear metal string complexes of [MnL4(NCS)2] (Scheme 1, M = NiII, CoII, or CrII; n = 3 or 5; L = dpa- or tpda2- where dpa- is dipyridylamido anion and tpda2- is tripyridyldiamido dianion) are studied for the fundamental understanding of the effect of inter-nuclei interactions on electron transfer (ET). The metal strings are isolated within n-alkanethiol monolayers and the properties of ET through various metal strings are differentiated by scanning tunneling microscopy. Although very similar in physical dimension, their apparent heights against the same alkanethiol background are significantly different. The discrepancy is ascribed to electron localization−delocalization among the metal centers.

The structures of n-alkanoic acid monolayers (CH3(CH2)mCO2H, m = 5, 6, 11, 13−22) self-assembled on gold premodified by electrodeposition of a silver or copper adlayer are studied by contact angle measurements, IRAS (infrared reflectance−absorption spectroscopy), and XPS (X-ray photoelectron spectroscopy). Prior to immersion into the fatty acid-containing solutions, the substrates are prepared by underpotential deposition (upd), resulting in a sub-monolayer or full monolayer of silver or copper on gold. The adlayer promotes anchoring of carboxylate headgroup and assembly of n-alkanoic acids, which would otherwise exhibit no chemisorption on bare gold. The results show that the monolayers exhibit low wettability, all-trans methylene conformation, and a bidentate binding scheme of the carboxylate headgroups onto the upd-modified substrate. The odd−even effect of alternating peak intensity of the methyl-stretching modes is significant for monolayers on silver upd surface and, to a less extent, yet notably, f...

Photodynamic therapy (PDT) typically involves oxygen (O2 ) consumption and therefore suffers from greatly limited anticancer therapeutic efficacy in tumor hypoxia. Here, it is reported for the first time that amine-terminated, PAMAM dendrimer-encapsulated gold nanoclusters (AuNCs-NH2 ) can produce O2 for PDT via their intrinsic catalase-like activity. The AuNCs-NH2 not only show optimum H2 O2 consumption via the catalase-like activity over the physiological pH range (i.e., pH 4.8-7.4), but also extend such activity to acidic conditions. The possible mechanism is deduced from that the enriched tertiary amines of dendrimers are easily protonated in acidic solutions to facilitate the preadsorption of OH on the metal surface, thereby favorably triggering the catalase-like reaction. By taking advantage of the exciting feature on AuNCs-NH2 , the possibility to supply O2 via the catalase-like activity of AuNCs-NH2 for PDT against hypoxia of cancer cells was further studied. This proof-of-concept study provides a simple way to combine current O2 -dependent cancer therapy of PDT to overcome cancer cell hypoxia, thus achieving more effective anticancer treatments.

Importance There are few reports evaluating awake, office-based carbon dioxide (CO 2 ) laser surgery for laryngeal lesions. To date, this study was the largest reported case series of office-based laryngeal surgery by fiber delivery CO 2 laser. Office-based laryngeal surgical procedures have become increasingly popular. Technical problems and treatment outcomes associated with the use of a CO 2 laser for office-based laryngeal surgery have yet to be fully addressed. Objectives To discuss a single institution’s clinical experience with office-based CO 2 laser laryngeal surgery and the feasibility and limitations associated with this procedure. Design, Setting, and Participants This retrospective study evaluated 49 laryngeal surgical procedures performed using a CO 2 laser in 40 consecutive adult patients at a single institution in Taiwan from July 1, 2014, through September 30, 2015. Laryngeal lesions treated included vocal fold leukoplakia (n = 13), benign vocal fold lesions (n = 10), Reinke edema (n = 4), recurrent respiratory papillomatosis (n = 6), and lesions outside the vocal folds (n = 7). Interventions Office-based laryngeal surgery performed using a CO 2 laser under topical anesthesia. Main Outcomes and Measures Videolaryngoscopy was performed on all patients at each follow-up point. Among patients with benign vocal lesions and Reinke edema, videolaryngostroboscopy, voice laboratory measurements, perceptual measurements of vocal quality, and subjective evaluations were conducted before and after surgery. Results Among the 40 patients included in this study (28 men [70%] and 12 women [30%]; median [range] age, 56 [29-83] years), median follow-up time was 6.5 months (range, 1-21 months). Among the 49 procedures, 2 (4%) could not be tolerated by patients owing to severe gag reflex and laryngeal hypersensitivity, 6 (12%) could not completely evaporate lesions owing to an inadequate surgical field or laryngeal instability, and 1 (2%) led to a complication (ie, mild vocal fold wound stiffness). In addition, 2 patients with premalignant vocal fold leukoplakia showed lesion recurrence in the subglottic area. Among patients with benign vocal lesions and Reinke edema, postoperative phonatory function showed large improvements in jitter (effect size, 0.61; median difference, −0.98%; 95% CI, −1.57% to −0.11%), noise to harmonic ratio (effect size, 0.63; median difference, −0.02; 95% CI, −0.07 to −0.01), maximal phonation time (effect size, 0.61; median difference, 3.6 seconds; 95% CI, 1.9 to 8.8 seconds), and Voice Handicap Index–10 score (effect size, 0.60; median difference, −7; 95% CI, −12 to −2). Conclusions and Relevance Office-based laryngeal surgery performed using a CO 2 laser was shown to be a feasible treatment option for various types of vocal lesions. However, patients should not undergo this procedure if they have multiple bulky lesions or lesions involving the subglottic area, the laryngeal ventricle, or (in cases of inadequate laryngeal stability) the free edge of a vocal fold.

Biothiols have been reported to involve in intracellular redox-homeostasis against oxidative stress. In this study, a highly selective and sensitive fluorescent probe for sensing biothiols is explored by using an ultrasmall gold nanodot (AuND), the dendrimer-entrapped Au 8 -cluster. This strategy relies upon a thiol/disulfide exchange to trigger the fluorescence change through a photoinduced electron transfer (PET) process between the Au 8 -cluster (as an electron donor) and 2-pyridinethiol (2-PyT) (as an electron acceptor) for sensing biothiols. When 2-PyT is released via the cleavage of disulfide bonds by biothiols, the PET process from the Au 8 -cluster to 2-PyT is initiated, resulting in fluorescence quenching. The fluorescence intensity was found to decrease linearly with glutathione (GSH) concentration (0–1500 μM) at physiological relevant levels and the limit of detection for GSH was 15.4 μM. Compared to most nanoparticle-based fluorescent probes that are limited to detect low molecular weight thiols (LMWTs; i.e., GSH and cysteine), the ultrasmall Au 8 -cluster-based probe exhibited less steric hindrance and can be directly applied in selectively and sensitively detecting both LMWTs and high molecular weight thiols (HMWTs; i.e., protein thiols). Based on such sensing platform, the surface-functionalized Au 8 -cluster has significant promise for use as an efficient nanoprobe for intracellular fluorescence imaging of biothiols including protein thiols in living cells whereas other nanoparticle-based fluorescent probes cannot.

The objective of this study was to characterize the infectious bursal disease viruses (IBDVs) circulating in broiler chicken farms in China between 2012 and 2013. The VP2 gene sequences of nine newly isolated IBDVs, obtained using reverse transcriptase polymerase chain reaction, were determined and compared with worldwide reference isolates, which have been previously well characterized. Phylogenetic analysis revealed that the nine broiler IBDV isolates are closely related to very virulent IBDV (vvIBDV) strains. Analysis of the predicted amino acid sequences of VP2 from the nine vvIBDVs isolated from the broilers revealed that they share 99.2 to 100% sequence similarity. Additionally, amino acids A222, I242, I256, I294 and S299 of VP2 that are conserved among previously characterized vvIBDV strains are also encoded by the nine isolates. This study confirms the circulation of vvIBDVs in Chinese broiler chicken farms experienced slow evolution and was relatively stable in China.

We present an alternative to self-assembled monolayers (SAMs) of ω-functionalized alkanethiols on gold. Substrates utilized here are gold modified by electrochemical deposition of silver or copper monolayers. The metal adlayers promote anchoring of carboxylate headgroups and assembly of ω-alkanoic acids, which would otherwise exhibit no chemisorption on bare gold. Infrared reflectance absorption spectroscopy shows that the films exhibit general characteristics of SAMs. The binding scheme is different from SAMs of alkanethiols on gold and alkanoic acids on silver or copper surfaces. Wetability results obtained from contact angle measurements indicate that such films are more reproducible than SAMs of alkanoic acids on bulk silver and copper.

Quantum dots (QDs) are one of most utilized nanomaterials in nanocrystalline semiconductors. QDs emit near-infrared fluorescence and can be applied as probes for detecting vasculature and imaging in biological systems. Since QDs have potential in clinical application, the toxicity of QDs needs to be carefully evaluated. In our present study, we elucidate the cytotoxic mechanisms of QDs using a mouse renal adenocarcinoma (RAG) cell line. QDs in RAG cells increased intracellular reactive oxygen species (ROS) levels and induced autophagy at 6 h, leading to subsequent apoptosis at 24 h. QDs entered the cells and were located within the endoplasmic reticulum (ER), endosome, and lysosome at 6 h and endosome, lysosome, and mitochondria at 24 h. However, QDs only affected mitochondrial function and did not induce ER stress. N-Acetylcysteine, an antioxidant agent, reduced intracellular ROS levels and decreased QD-induced autophagy but enhanced QD-induced cell death. Moreover, 3-methylamphetamine (an autophagy inhibitor) also reduced the cell viability in QD-treated cells. These findings suggest that ROS plays an essential role in the regulation of QD-induced autophagy, which subsequently enhances cell survival. Taken together, these results suggest that oxidative stress-induced autophagy is a defense/survival mechanism against the cytotoxicity of QD.

Gold nanoparticles (AuNPs) have been established to sufficiently eradicate tumors by means of heat production for photothermal therapy. However, the translation of the AuNPs from bench to the clinic still remains to be solved until realizing high bioclearance after treatment. Herein, we developed a simple strategy for simultaneous formation and assembly of small-size gold nanoparticles (Au-SNPs) to form a novel nanocomposite in the presence of gum arabic (GA) by synchrotron X-ray irradiation in an aqueous solution within 5 min. GA, a porous polysaccharide, can not only provide a confined space in which to produce uniform Au-SNPs (1.6 ± 0.7 nm in diameter), but can also facilitate the formation of Au-SNPs@GA (diameter ≈ 40 nm) after irradiating synchrotron X-rays. Specifically, the Au-SNPs@GA possesses high thermal stability and a strong photothermal effect for killing cancer cells. Importantly, a bioclearance study demonstrated that the Au-SNPs@GA can be gradually excreted by the renal and hepatobiliary system, which might be due to the breakdown and oxidation of GA under irradiating synchrotron X-rays. Thus, the novel gold nanocomposite can be promising photothermal agents for cancer treatment at the therapeutic level, minimizing toxicity concerns regarding long-term accumulation in vivo.