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Most adults have access to two different number systems to represent numerical information an exact number system, which relies on different forms of number symbols to represent exact numerical information, and an approximate number system, which allows for approximate estimates of numerical quantities. Here we investigate the integration between the symbolic and non-symbolic numerical information (i.e., "numerical integration"), and how numerical integration relates to adults' formal math abilities. We administered two tasks to measure numerical integration. For a number comparison task with non-symbolic dot arrays and Arabic numerals, participants indicated the larger of two sequentially presented stimuli that were same-format (dot-dot or numeral-numeral), or mixed-format (dot-numeral or numeral-dot). For a number-letter discrimination task, participants identified Arabic numerals or letter pairs that co-occurred with dot arrays (matching or mismatching the quantity represented by the numeral). In the number comparison task, participants were significantly slower when comparing mixed-format stimuli, especially when Arabic numerals were presented first and dot arrays second, suggesting estrangement between symbolic and non-symbolic numerical information and an asymmetry depending on the order in which the numerical information is presented. In contrast, in the number-letter discrimination task, participants were significantly faster in number-letter discrimination for matching dot arrays and numerals, suggesting integration between symbolic and non-symbolic numerical information. Surprisingly, some measures of numerical estrangement derived from the number comparison task significantly correlated with adults' performance on a standardized math assessment. Thus, we conclude that numerical integration or estrangement is task-dependent, and adults with greater levels of symbolic estrangement tend to have higher math skills.Salmonella enterica serovars cause millions of infections each year that result either in typhoid fever or salmonellosis. Among those serovars that cause typhoid fever, Salmonella enterica subspecies Typhi can form biofilms on gallstones in the gallbladders of acutely-infected patients, leading to chronic carriage of the bacterium. These biofilms are recalcitrant to antibiotic-mediated eradication, leading to chronic fecal shedding of the bacteria, which results in further disease transmission. Herein, we report the synthesis and anti-biofilm activity of a 55-member library of small molecules based upon a previously identified hit that both inhibits and disrupts S. Typhi and S. Typhimurium (a nontyphoidal model serovar for S. Typhi) biofilms. Lead compounds inhibit S. Typhimurium biofilm formation in vitro at sub-micromolar concentrations, and disperse biofilms with five-fold greater potentency than the parent compound. Three of the most promising compounds demonstrated synergy with ciprofloxacin in a murine model of chronic Salmonella carriage. This work furthers the development of effective anti-biofilm agents as a promising therapeutic avenue for the eradication of typhoidal Salmonella.The therapeutic potential of 3H-pyrrolo[2,3-c]quinolines-the main core of Marinoquinoline natural products-has been explored for the development of new anti-TB agents. The chemical modification of various positions in this scaffold has led to the discovery of two pyrroloquinolines (compounds 50 and 54) with good in vitro activity against virulent strains of Mycobacterium tuberculosis (H37Rv, MIC = 4.1 μM and 4.2 μM, respectively). Enzymatic assays showed that both derivatives are inhibitors of glutamate-5-kinase (G5K, encoded by proB gene), an essential enzyme for this pathogen involved in the first step of the proline biosynthesis pathway. G5K catalyzes the phosphoryl-transference of the γ-phosphate group of ATP to L-glutamate to provide L-glutamyl-5-phosphate and ADP, and also regulates the synthesis of L-proline. The results of various molecular dynamics simulation studies revealed that the inhibition of G5K would be caused by allosteric interaction of these compounds with the interface between enzyme domains, against different pockets and with distinct recognition patterns. The binding of compound 54 promotes long-distance conformational changes at the L-glutamate binding site that would prevent it from anchoring for catalysis, while compound 50 alters the ATP binding site architecture for recognition. Enzyme assays revealed that compound 50 caused a substancial increase in the Kmapp for ATP, while no significant effect was observed for derivative 54. This work also demonstrates the potential of the G5K enzyme as a biological target for the development of new anti-TB drugs.The emergence of multidrug resistance (MDR) in tumors leads to reduced chemotherapeutic efficacy, and P-glycoprotein (P-gp) overexpression is one of the main causes of MDR. In previous reports, we demonstrated that a variety of hederagenin (HD) derivatives could reverse MDR in tumors in vivo and in vitro. To further enrich the structure types, enhance the activity, and improve the structure-activity relationships (SARs), three series of HD derivatives were designed and synthesized in this study via A-ring fusion and innovative utilization of the structural advantages of nitrogen-containing heterocycles and benzyl group substitution. We evaluated the MDR reversal activity of 21 HD derivatives in KBV (multidrug-resistant oral epidermoid carcinoma) cells and refined their SARs. The results of cell experiments illustrated that more than half of the compounds had MDR reversal activity. Among them, compound 16 displayed relatively stronger MDR reversal ability, as it improved the sensitivity of KBV cells to paclitaxel, vincristine, mitoxantrone and cisplatin with IC50 values of 3.19, 0.65, 125.30, and 4.54 nM, respectively. The results of mechanistic analysis demonstrated that compound 16 inhibited the efflux function of P-gp by activating P-gp ATPase and increased the accumulation of rhodamine 123 in KBV cells. Importantly, the efficacy of paclitaxel against KBV cancer cell-derived xenograft tumors in nude mice was enhanced by compound 16 based on the growth suppression rate of 56.24%. These results indicated that introducing nitrogen-containing heterocycles could effectively improve the MDR reversal activity of HD derivatives, which appear to be promising lead compounds for tumor MDR reversal agent development.Recent advances in micro-electromechanical systems (MEMS) has allowed unprecedent perspectives for label-free detection (LFD) of biological and chemical analytes. Additionally, these LFD technologies offer the potential to design high resolution and high throughput sensing platforms, with the promise of further miniaturization. However, the immobilization of biomolecules onto inorganic surfaces without impacting their sensing abilities is crucial for designing these LFD technologies. Currently, covalent functionalization of self-assembled monolayers (SAMs) present promising pathways for improving assay sensitivity, reproducibility, surface stability and proximity of binding sites to the sensor surface. Herein, we investigate the use of chemical vapor deposition of 3-(glycidyloxypropyl)-trimethoxysilane (GOPTS) as a versatile SAM for the covalent functionalization of a SiO2 microcantilever array (MCA) for carbohydrate-lectin interactions with picogram sensitivity. Additionally, we demonstrate glycan immobilization to MCA is feasible using traditional piezoelectric microarray printer technology. Given the complexity of the glycome, the ability to spot samples in a high-throughput manner establishes our MCA as robust, label-free, and scalable means to analyze carbohydrate-protein interactions These findings demonstrate that GOPTS SAMs provide a suitable biofunctionalization route for MEMS and provides the proof of principle that can be extended to various LFD technologies toward a truly high-throughput and high-resolution platform.Circulating tumour DNAs (ctDNAs) have been reported to be associated with real-time information of progression; however, an accurate and sensitive method has not been established. Herein, a novel dual-signal amplification strategy based on a pump-free surface-enhanced Raman scattering (SERS) microfluidic chip and a catalytic hairpin assembly (CHA) technique was developed for the dynamic monitoring of BRAF V600E and KRAS G12V, which are two non-small cell lung cancer (NSCLC)-related ctDNAs. In the presence of targets, CHA reactions can be triggered between two hairpin DNAs, fixing Pd-Au core-shell nanorods (Pd-AuNRs) onto the magnetic beads (MBs) surface. Thereafter, the composite structures can assemble under the action of magnet, enabling dual-amplification of SERS signal. Using this strategy, the limit of detection (LOD) was low (i.e. at the aM level) in serum. Furthermore, the entire chip-based analysis process could be completed within 5 min, eliminating manual incubation and heavy-duty injection pumps. The selectivity, reproducibility and uniformity of the proposed pump-free SERS microfluidic chip were satisfactory. This superior analysis strategy was finally applied to quantify BRAF V600E and KRAS G12V in tumour-bearing nude mice serum, the results of which corresponded with those of real-time polymerase chain reaction. Overall, this study provides a promising alternative tool for the dynamic monitoring of ctDNA expression level which can benefit the clinical diagnosis of NSCLC.Development of a specific "light-up" sensor for detection of psychoactive drug has been a great challenge in forensic analysis. To achieve this goal, an aggregation induced emission (AIE) functional monomer containing both phenylboronic group and double bond was synthesized for construction of molecularly imprinted polymers (MIPs) based fluorescent sensor. In this AIE-MIP sensor, the AIE fluorophore could vibrate freely in the absence of the target analyte (cathinone, CAT), while this vibration was restricted after the specific molecular recognition, leading to "light-up" character of the corresponding sensor. FT-IR and LC-MS characterizations proved the AIE monomer was successfully introduced onto AIE-MIPs. SEM analysis indicated the AIE-MIPs was ∼140 nm in diameter. click here Binding experiments indicated the AIE-MIPs owned high specificity towards CAT. Fluorescent studies confirmed that the "light-up" capability of the AIE-MIPs was highly selective. On this basis, the AIE-MIP sensor was applied in detecting CAT in forensic samples. The sensor reached a detection limit of 0.32 μmol L-1 and exhibited a linear range of 2-12 μmol L-1. Compared to previously reported MIPs based electrochemical sensors and fluorescent sensors for measurement of CAT drug and its analogue, the present AIE-MIP sensor showed much higher sensitivity. To the best of our knowledge, this is the first time that an AIE functional monomer was synthesized for molecular imprinting, and also the first "light-up" AIE-MIP sensor to be reported. We believe that this versatile design of the specific "light-up" sensor can be used as a general protocol for construction of advanced sensor in various fields.Visualization of cell apoptosis can effectively assist early disease diagnosis, precisely reveal pathogenic mechanisms and continuously evaluate curative effect. However, monitoring partial stage of the apoptosis can not accurately or even mistakenly illustrate the apoptotic pathways. Herein, a novel tetrahedral DNA probe (TDNA-WCP) consists of a multi-armed tetrahedral DNA and three special sensing arms for simultaneously fluorescence imaging cytochrome c (Cyt c) and telomerase is proposed to visualize the early and late stages (i.e. whole-course) of cell apoptosis with highly temporal and spatial consistency. The TDNA-WCPs possessing good sensitivity, selectivity, stability and biocompatibility, show attractive performance on real-time, sensitive and specific visualization of intracellular Cyt c and telomerase, and have strong abilities to monitor the oxidative stress of cells and evaluate the drug efficacy, which can be a potential and interesting tool for studying molecular mechanisms of apoptosis regulation or screening the apoptosis-based drugs.
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