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1.
Nikhil K. Tulsian Valerie Jia-En Sin Hwee-Ling Koh Ganesh S. Anand 《International journal of molecular sciences》2021,22(10)
Phosphodiesterases (PDEs) hydrolyze cyclic nucleotides to modulate multiple signaling events in cells. PDEs are recognized to actively associate with cyclic nucleotide receptors (protein kinases, PKs) in larger macromolecular assemblies referred to as signalosomes. Complexation of PDEs with PKs generates an expanded active site that enhances PDE activity. This facilitates signalosome-associated PDEs to preferentially catalyze active hydrolysis of cyclic nucleotides bound to PKs and aid in signal termination. PDEs are important drug targets, and current strategies for inhibitor discovery are based entirely on targeting conserved PDE catalytic domains. This often results in inhibitors with cross-reactivity amongst closely related PDEs and attendant unwanted side effects. Here, our approach targeted PDE–PK complexes as they would occur in signalosomes, thereby offering greater specificity. Our developed fluorescence polarization assay was adapted to identify inhibitors that block cyclic nucleotide pockets in PDE–PK complexes in one mode and disrupt protein-protein interactions between PDEs and PKs in a second mode. We tested this approach with three different systems—cAMP-specific PDE8–PKAR, cGMP-specific PDE5–PKG, and dual-specificity RegA–RD complexes—and ranked inhibitors according to their inhibition potency. Targeting PDE–PK complexes offers biochemical tools for describing the exquisite specificity of cyclic nucleotide signaling networks in cells. 相似文献
2.
Nabil Yassine Steve Barker Khaled Hayatleh Bhaskar Choubey Rajasekhar Nagulapalli 《Analog Integrated Circuits and Signal Processing》2018,95(3):409-414
This paper proposes a system to detect and measure blink rate to determine fatigue levels. The method involved analysing specific frames to determine that a blink occurred, and then monitoring the time between successive blinks. The program was simulated in python using a Raspberry Pi Zero and a standard USB camera. For the blink rate detection block, a gate level schematic was implemented in Cadence software using 65 nm CMOS technology. The design was based around an asynchronous 6-bit based edge counter which was designed using D-flip-flops. The simulation calculated the average blink rate and compared this to the most recent blink rate. The outcome would determine if an alarm signal should be sent to the alarm. The system consumed 130 μA from a 1.2 V power supply. 相似文献
3.
Shana Wagner Megan Waldman Simran Arora Sinan Wang Valerie Scott Dr. Kabirul Islam 《Chembiochem : a European journal of chemical biology》2019,20(9):1133-1138
Histone demethylases play a critical role in mammalian gene expression by removing methyl groups from lysine residues in degree- and site-specific manner. To specifically interrogate members and isoforms of this class of enzymes, we have developed demethylase variants with an expanded active site. The mutant enzymes are capable of performing lysine demethylation with wild-type proficiency, but are sensitive to inhibition by cofactor-competitive molecules embellished with a complementary steric “bump”. The selected inhibitors show more than 20-fold selectivity over the wild-type demethylase, thus overcoming issues typical to pharmacological and genetic approaches. The mutant–inhibitor pairs are shown to act on a physiologically relevant full-length substrate. By engineering a conserved amino acid to achieve member-specific perturbation, this study provides a general approach for studying histone demethylases in diverse cellular processes. 相似文献
4.
Erwan Diler Vanessa Leblanc Hervé Gueuné Nicolas Larché Valerie Deydier Yannick Linard Didier Crusset Dominique Thierry 《工业材料与腐蚀》2021,72(1-2):218-234
In the context of the high-level radioactive waste disposal CIGEO, the corrosion rate due to microbially influenced corrosion (MIC) has to be evaluated. In France, it is envisaged to dispose of high- and intermediate-level long-lived radioactive waste at a depth of 500 m in a deep geological disposal, drilled in the Callovo-Oxfordian claystone (Cox) formation. To do so, a carbon steel casing will be inserted inside disposal cells, which are horizontal tunnels drilled in the Cox. A specific cement grout will be injected between the carbon steel casing and the claystone. A study was conducted to evaluate the possibility of MIC on carbon steel in the foreseeable high radioactive waste disposal. The corrosiveness of various environments was investigated at 50°C and 80°C with or without microorganisms enriched from samples of Andra's underground research laboratory. The monitoring of corrosion during the experiments was ensured using gravimetric method and real-time corrosion monitoring using sensors based on the measurements of the electrical resistance. The corrosion data were completed with microbiological analyses including cultural and molecular characterizations. 相似文献
5.
Discretization of continuous time autoregressive (AR) processes driven by a Brownian motion and embedding of discrete time AR sequences driven by a Gaussian white noise are classical issues. The article aims at establishing and using such discretization and embedding formulae between extended AR continuous time processes and discrete time sequences. The continuous-time processes are driven by either Brownian or jump processes, and may have random coefficients depending on time; Lévy-driven processes are also considered. The innovation of the discrete time processes may be of many types – including Gaussian. In one way, observing the continuous time AR process at discrete times leads the AR dynamics of the discretized process to be characterized. The other way round, AR sequences can be embedded, in the almost sure sense, into continuous time AR processes with the same dynamics. Illustration is provided through many examples and simulation. 相似文献
6.
Indoor surfaces may be adsorptive sinks with the potential to change Indoor Air Quality. To estimate this effect, the sorption parameters of formaldehyde and toluene were assessed on five floorings by an experimental method using solid-phase microextraction in an airtight emission cell. Adsorption rate constants ranged from 0.003 to 0.075 m·h−1, desorption rate constants from 0.019 to 0.51 h−1, and the partition coefficient from 0.005 to 3.9 m, and these parameters vary greatly from one volatile organic compound/material couple to another indicating contrasted sorption behaviors. A rubber was identified as a sink of formaldehyde characterized by a very low desorption constant close to 0. For these sorbent floorings identified, the adsorption rates of formaldehyde are from 2 to 4 times higher than those of toluene. Two models were used to evaluate the sink effects of floorings on indoor pollutant concentrations in one room from different realistic conditions. The scenarios tested came to the conclusion that the formaldehyde sorption on one rubber (identified as a sink) has a maximum contribution from 15% to 21% for the conditions of low air exchange rate. For other floorings, the sorption has a minor contribution less than or equal to 5%, regardless of the air exchange rate. 相似文献
7.
Cornish AS Ng WC Ho VC Wong HL Lam JC Lam PK Leung KM 《The Science of the total environment》2007,376(1-3):335-345
The bamboo shark Chiloscyllium plagiosum is an abundant benthic species along the shallow continental shelf of Southeast Asia. It is commonly taken by fishermen in China, India, Taiwan and Thailand for human consumption. This study measured trace metal and organochlorine concentrations in C. plagiosum collected from the southern waters of Hong Kong, China. Metals (Ag, Cd, Cr, Cu, Mn, Ni, Pb and Zn) were measured in three different tissues: dorsal muscle, spleen and liver. Polychlorinated biphenyls (PCBs) and chlorinated pesticides in the dorsal muscle were identified and quantified using gas chromatography. Metal concentrations varied among the three different tissues, with liver having higher levels of Ag and Cd, and spleen possessing higher levels of Cu and Mn. Both Ni and Pb in all tissues were below the detection limit. Tissue concentrations of Cr, Cu, Mn and Zn generally decreased with increasing body weight whilst no significant concentration-size relationship was found for other metals. In muscle tissues, total PCBs ranged from 1.056-4.771 ng/g (wet wt.) with a median of 1.801 ng/g, while total DDTs ranged from 0.602-23.55 ng/g with a median of 1.109 ng/g, in which p,p'-DDE was the predominant metabolite. Levels of total hexachlorohexanes and cyclodienes were low. The pesticide p,p'-DDT was the only compound found to be positively correlated with body weight, indicating temporal bioaccumulation of this compound. Zn concentrations in the muscle of C. plagiosum were comparatively higher than recorded in other shark species, however, concentrations of other metals and organochlorines were relatively low. C. plagiosum feeds primarily on polychaetes, shrimps and small fishes, and thus is unlikely to contain levels of contaminants of human health concern. 相似文献
8.
A key challenge for research and practice is to understand how the ecosystem approach can be rolled out in spatial planning, management and decision-making. Any framework used to apply the ecosystem approach needs to not only be environmentally coherent but also socially meaningful. Drawing on semi-structured interviews and case studies, this paper examines the potential role of one place-based approach, landscape character assessment, as a medium to ensure socio-ecological relevance in operationalising the ecosystem approach. Our findings show that although place-based approaches have value as frameworks for distilling the ecosystem approach into a manageable form, their ecological relevance is a subject of debate. However, the potential relationship between landscape character, function and ecosystem services presented a powerful pathway for operationalising the ecosystem approach. The ecosystem approach may, in turn, complement landscape character assessment by providing a framework for exploring the functional dimension of landscape condition. 相似文献
9.
The practice of architecture is very similar in different national settings despite what may be very different sociological and cultural origins of the profession, the attendant variances in how work is organized and distinctions in equality and gender roles. The aim of this paper is to examine the quest for equality in architecture for women in the UK and Spain reporting the findings of a comparative study into women architects’ careers in the two countries. Within the qualitative paradigm, semi-structured in-depth interviews were carried out with a total of 55 women architects in the UK and Spain. Findings indicate surprising differences in levels and terms of equality for women in the two countries and marked differences in women’s experiences of working as an architect. Women have come to the profession in Spain much later than their British counterparts and, somewhat surprisingly, are present in greater numbers. However, despite there being more of a ‘critical mass’ this has not served to improve their situation; they report much higher levels of discrimination and find it difficult to progress in their careers. Conclusions argue for a stronger approach by the professional bodies to help improve the position of women. 相似文献
10.
Comparative Cytotoxicity of Artemisinin and Cisplatin and Their Interactions with Chlorogenic Acids in MCF7 Breast Cancer Cells 下载免费PDF全文
Dr. John O. Suberu Dr. Isolda Romero‐Canelón Dr. Neil Sullivan Prof. Alexei A. Lapkin Dr. Guy C. Barker 《ChemMedChem》2014,9(12):2791-2797
In parts of Africa and Asia, self‐medication with a hot water infusion of Artemisia annua (Artemisia tea) is a common practice for a number of ailments including malaria and cancer. In our earlier work, such an extract showed better potency than artemisinin alone against both chloroquine‐sensitive and ‐resistant parasites. In this study, in vitro tests of the infusion in MCF7 cells showed high IC50 values (>200 μM ). The combination of artemisinin and 3‐caffeoylquinic acid (3CA), two major components in the extract, was strongly antagonistic and gave a near total loss of cytotoxicity for artemisinin. We observed that the interaction of 3CAs with another cytotoxic compound, cisplatin, showed potentiation of activity by 2.5‐fold. The chelation of cellular iron by 3CA is hypothesized as a possible explanation for the loss of artemisinin activity. 相似文献