Mapping the Chemical Space of Active-Site Targeted Covalent Ligands for Protein Tyrosine Phosphatases.

Protein tyrosine phosphatases (PTPs) are an important class of enzymes that modulate essential cellular processes through protein dephosphorylation and are dysregulated in various disease states. There is demand for new compounds that target the active sites of these enzymes, for use as chemical tools to dissect their biological roles or as leads for the development of new therapeutics. In this study, we explore an array of electrophiles and fragment scaffolds to investigate the required chemical parameters for covalent inhibition of tyrosine phosphatases. Our analysis juxtaposes the intrinsic electrophilicity of these compounds with their potency against several classical PTPs, revealing chemotypes that inhibit tyrosine phosphatases while minimizing excessive, potentially non-specific reactivity. We also assess sequence divergence at key residues in PTPs to explain their differential susceptibility to covalent inhibition. We anticipate that our study will inspire new strategies to develop covalent probes and inhibitors for tyrosine phosphatases.

Preliminary assessment of the safety factors in K-DEMO for fusion compatible regulatory framework.

We open an avenue for discussing how we can pave the way for compliance with existing regulations is a far-reaching factor for settling nuclear fusion technology. Based on a model of the Korean Fusion Demonstration Reactor (K-DEMO) with a target fusion power of 2.2 GW, we assess the intrinsic safety determinants of internal energy sources, the expected radioactive waste, and the tritium management. Regarding these safety factors, we scrutinize the compatibility of the current legislative environment in Korea with K-DEMO and envisage foreseeable obstacles, such as licensing of the nuclear facilities and acceptability of the radioactive waste. Based on precedent licenses for the Korean Superconducting Tokamak Advanced Research (KSTAR) and lessons learned from the International Thermonuclear Experimental Reactor (ITER), we examine hazardous factors that would threaten regulatory compliance of K-DEMO. This approach can help shape a fusion-compatible framework for consolidating the necessary technical provisions and regulatory baselines reflecting social acceptance with a sense of safety. Fusion-compatible aspects in the regulatory environment are discussed, from fusion philosophy to subordinate administrative and technical guidelines, facility classification, and detailed methods guaranteeing integrity and safety. This paper will contribute to the timely settlement of fusion demonstration facilities and subsequent commercial plants.

Learning from ancestors.

Predicting ancestral sequences of protein kinases reveals the molecular details that underlie different modes of activation.

Mesoporous silica-based nanoplatforms for the delivery of photodynamic therapy agents.

Photodynamic therapy (PDT) is an established method for the treatment of cancer which utilizes light, a photosensitizer (PS), and oxygen. Unfavourable characteristics of most PSs, such as low solubility and tumour specificity have led many researchers to adopt nanoscale drug delivery platforms for use in PDT. Mesoporous silica nanoparticles (MSNs) form a significant part of that effort, due to their ease and controllability of synthesis, ease of loading, availability of diverse surface functionalization, and biocompatibility. Therefore, in this review, we discuss the properties of MSNs as they pertain to their use in PDT and review the latest advances in the field, comparing the different approaches currently being used.

Forward projection matrix derivation through Monte-Carlo ray-tracing of KSTAR infra-red imaging video bolometer (IRVB).

The infrared imaging video bolometer (IRVB) as a foil bolometry technique can be an alternative solution to the conventional resistive bolometer due to its electro-magnetic immunity and 2D plasma profiles. The plasma profile of the IRVB cannot be directly derived from the foil images due to the difference between the foil pixel number and the plasma pixel number and the line integrated nature of the incident rays on the foil. So, it needs tomography such as the Phillips-Thikhonov algorithm. The projection matrix constructing the foil image from the plasma very directly influences the tomography. So, the projection matrix needs to be constructed precisely. For the technique calculating the precise projection matrix, a forward Monte-Carlo ray-tracing method is proposed here, and this technique can provide the detailed descriptions of the foil image. And it can give enhanced performance in the reconstructions of the plasmas with spatially localized power.

Reconstruction of radiation profiles near the plasma boundary using an infrared imaging video bolometer in KSTAR.

An infrared imaging video bolometer using tomographic inversion can provide the total radiated power and 2-D radiation profiles, which are crucial information for impurity seeding experiments. Because large amounts of impurities exist at the plasma edge, accurate reconstruction of the radiation profiles near the material boundary is an important issue. In this study, two methods of boundary condition treatment are compared. One involves the exclusion of plasma pixels outside the boundary before reconstruction, whereas the other excludes these pixels after reconstruction. Phantom reconstruction tests are performed with D-shaped and divertor radiation profiles, and the second method shows an improvement in the boundary-reconstruction results compared with the first method. Using the second method, the radiation profiles of krypton (Kr) seeded H-mode plasmas in KSTAR are reconstructed. A significant amount of input power is dissipated through the Kr radiation. The 2-D reconstructed radiation profiles show that Kr mostly accumulates at the plasma core rather than at the edge.

Responsive alginate-cisplatin nanogels for selective imaging and combined chemo/radio therapy of proliferating macrophages.

BACKGROUND: Atherosclerosis is a major global health concern. Targeting macrophages is hypothesized as an alternative treatment for atherosclerosis. METHODS: We synthesized alginate-based cisplatin-loaded nanogels (TANgel) as a pH-responsive drug-releasing theranostic nanoplatform for macrophage cells. Carboxylic acid groups of alginic acid were modified with iminodiacetic acid (IDA) to enhance chelation of platinum ions. The near infrared (NIR) fluorophore ATTO655 was conjugated to the modified alginic acid. Cisplatin was used as an antiproliferation drug and as a crosslinking agent between alginate molecules to form TANgel. Release behavior of cisplatin from TANgel was analyzed under different pH conditions. Cellular uptake and therapeutic efficacy of TANgel were tested in the macrophage cell line J774A.1 and normal human cell lines such as HDMVECn. RESULTS: The nanogel had a narrow size distribution of approximately 100 nm. The nanogel showed highly pH-responsive drug release behavior. All incorporated cisplatin was released at pH 5 within 48 h, while less than 15% was released at pH 7.4. The nanogel was preferentially taken up by J774A.1 cells compared to normal human cells, enabling selective NIR fluorescence imaging and chemotherapy of macrophage cells. In addition, the nanogel formulation lowered the therapeutic concentration of the drug with and without low dose radiation therapy (RT) compared to the free drug form. CONCLUSIONS: This nanogel system may have potential utility for selective NIR fluorescence imaging and combined chemo/radio therapy of proliferating macrophage cells in atherosclerotic regions, allowing for reduction of systemic toxicity.

Recent advances in nanoparticle carriers for photodynamic therapy.

This review summarizes recent advances in the development of nanoparticles (NPs) for efficient photodynamic therapy (PDT), particularly the development and application of various NPs based on organic and inorganic materials. PubMed database was used for literature search with the terms including NP, nanomedicine, PDT, photosensitizer (PSs), and drug delivery. For successful PDT, it is essential to deliver PSs to target disease sites. A number of NPs have been developed and tested as the carriers for both imaging and therapy, an approach termed "nanomedicine". Many studies of NP carriers showed increased water solubility and stability of PSs for in vivo injection, and these NP carriers provided benefits including longer circulation in blood and higher accumulation of PSs at disease sites. This review describes new techniques in PDT such as aggregation-induced emission (AIE) and luminescence-based PDT, and provides insights on NPs and PDT for biomedical researchers working to develop or apply NPs in efficient PDT.

Theranostic Nanosystems for Targeted Cancer Therapy.

Nanomaterials have revolutionized cancer imaging, diagnosis, and treatment. Multifunctional nanoparticles in particular have been designed for targeted cancer therapy by modulating their physicochemical properties to be delivered to the target and activated by internal and/or external stimuli. This review will focus on the fundamental "chemical" design considerations of stimuli-responsive nanosystems to achieve favorable tumor targeting beyond biological barriers and, furthermore, enhance targeted cancer therapy. In addition, we will summarize innovative smart nanosystems responsive to external stimuli (e.g., light, magnetic field, ultrasound, and electric field) and internal stimuli in the tumor microenvironment (e.g., pH, enzyme, redox potential, and oxidative stress).

Enhanced Fluorescence Imaging and Photodynamic Cancer Therapy Using Hollow Mesoporous Nanocontainers.

Here we show that "off-on" type of photodynamic therapy agents could be developed using hollow mesoporous silica nanoparticles (HMSNPs), which can be used not only for enhancing delivery of photosensitizers to cancer cells but also for enabling switchable optical properties of the photosensitizers. Fluorescence and singlet oxygen generation of the photosensitizer-loaded HMSNP are turned off in its native state. In vitro cell studies showed that this HMSNP-based "off-on" agent may have potential utility in selective fluorescence detection and photodynamic therapy of cancers.

Indocyanine green-loaded hollow mesoporous silica nanoparticles as an activatable theranostic agent.

Here we report indocyanine green (ICG)-loaded hollow mesoporous silica nanoparticles (ICG@HMSNP) as an activatable theranostic platform. Near-infrared fluorescence and singlet oxygen generation of ICG@HMSNP was effectively quenched (i.e. turned off) in its native state because of the fluorescence resonance energy transfer between ICG molecules. Therefore, ICG@HMSNP was nonfluorescent and nonphototoxic in the extracellular region. After the nanoparticles entered the cancer cells via endocytosis, they became highly fluorescent and phototoxic. In addition, intracellular uptake of ICG@HMSNP was 2.75 times higher than that of free ICG, resulting in an enhanced phototherapy of cancer.

Coordinated underground measurements of gamma-ray emitting radionuclides for plasma physics research.

Forty-eight samples made of CaF2, LiF and YVO4 were placed inside the KSTAR Tokamak and irradiated by neutrons and charged particles from eight plasma pulses. The aim was to provide information for plasma diagnostics. Due to the short pulse durations, the activities induced in the samples were low and therefore measurements were performed in five low-background underground laboratories. Details of the underground measurements, together with data on the quality control amongst the radiometric laboratories, are presented.

Probe diagnostics in the far scrape-off layer plasma of Korea Superconducting Tokamak Advanced Research tokamak using a sideband harmonic method.

Plasma characteristics in the far scrape-off layer region of tokamak play a crucial role in the stable plasma operation and its sustainability. Due to the huge facility, electrical diagnostic systems to measure plasma properties have extremely long cable length resulting in large stray current. To overcome this problem, a sideband harmonic method was applied to the Korea Superconducting Tokamak Advanced Research tokamak plasma. The sideband method allows the measurement of the electron temperature and the plasma density without the effect of the stray current. The measured plasma densities are compared with those from the interferometer, and the results show reliability of the method.

Development of a particle injection system for impurity transport study in KSTAR.

A solid particle injection system is developed for KSTAR. The system has a compact size, compatibility with a strong magnetic field and high vacuum environment, and the capability to inject a small amount of solid particles with a narrow injection angle. The target flight-distance of 10 cm has been achieved with a particle loss rate of less than 10%. Solid impurity particles such as tungsten and carbon will be injected by this system at the midplane in KSTAR. The impurity transport feature will be studied with a soft X-ray array, a vacuum ultra-violet diagnostic, and Stand Alone Non-Corona code.

Protuberant fibro-osseous lesions of the temporal bone: two additional case reports.

The most commonly encountered fibro-osseous lesions of the skull bone are fibrous dysplasia and ossifying fibroma. Two cases of a unique "protuberant fibro-osseous lesion of the temporal bone" were first described by Selesnick and colleagues in 1999, and 2 further cases were reported in 2010 under the name "Bullough lesion". We recently found 2 new cases of this rare entity. Two Korean female patients aged 70 and 54 years presented with slow growing postauricular masses without pain or tenderness for 6 and 7 years, respectively. Computed tomography revealed a 2.9 cm calcified mass in the temporal bone of the first patient, and a 5.5 cm enhancing mass with internal cartilaginous matrix in the temporal bone of the second patient. Intramedullary or intracranial extension was not found in either case, and en bloc removals were performed. Microscopically, multiple round to oval osseous islands were scattered throughout the bland fibrous stroma in both cases. The osseous islands varied in size and were lamellar or woven, without osteoblastic rimming, and surrounded by fibroblastic bands. Neither patient has shown evidence of postoperative recurrence for 18 months. The location, histology, and clinical course of these 2 cases were identical to the 4 cases previously reported, although age and sex varied. The lesions were tested for the R201H mutation in the GNAS gene, which is present in fibrous dysplasia. No mutations were found, suggesting a different genetic background for these lesions.

Studies on formation of carborane film prepared by using a deuterium glow discharge method.

Carborane powders (C2B10H12) were deposited on silicon substrates and the physical properties of the films were investigated as functions of the distance of the sample from the electrode, the carborane mass, and the plasma-pulse. To obtain the optimum thickness of the films, three silicon substrates were positioned at 6.5, 16.5, and 36.5 cm from the electrode, and the thickness of the samples was analyzed by using XRD, TEM, and SEM. For the deposition, the carborane powder was warmed to 80 degrees C in 10 minutes and was applied a DC-power pulse of 900 W (150 volts, 6 amps) for 2 hours. The mass of carborane and the on-time sequence were varied during the deposition. The combined results of XRD and TEM studies revealed that the structure of the deposited film is an amorphous phase. A careful analysis of the SEM images show that the thickness of the carborane films increased as increasing the mass of the flown carborane while it remained constant when a plasma-pulse time was varied. The thickest film of 353 A was achieved from the samples placed closest to the carborane inlet and the thickness became thinner as farther from the source suggesting that the density of the evaporated carborane powder in a chamber decreased as increasing the distance of the sample from the carborane inlet.

Preparation of an aqueous suspension of stabilized TiO2 nanoparticles in primary particle form.

To prepare stabilized TiO2 nanoparticles (TiO2 NPs) in aqueous media as a suspension of the primary particles, we attempted to optimize the conditions for dispersing stable, aggregated TiO2 NPs (A-TiO2 NPs) in aqueous HCl/NaOH solutions or 5 mM pH buffered aqueous solutions. The A-TiO2 NPs with a hydrodynamic diameter (or DLS size) of 150 +/- 20 nm could be dispersed at high concentration (63.5 +/- 0.5 mg/ml) in a 5 mM phosphate buffer (PB) solution of pH 8, and a primary TiO2 (P-TiO2) NP suspension (1.2 +/- 0.3 mg/ml) with DLS size of 30 +/- 5 nm could be separated from the highly concentrated A-TiO2 NP suspension by sonication and subsequent centrifugation. It was observed by comparing the UV-Vis absorption spectra of the A-TiO2 and P-TiO2 NP suspensions that the extinction coefficient of the TiO2 NPs in the aqueous suspension depended on the degree of aggregation. The stabilized P-TiO2 NP suspension in aqueous solution can be used to study nanotoxicity as well as to characterize the physicochemical properties of TiO2 NPs.

First results on disruption mitigation by massive gas injection in Korea Superconducting Tokamak Advanced Research.

Massive gas injection (MGI) system was developed on Korea Superconducting Tokamak Advanced Research (KSTAR) in 2011 campaign for disruption studies. The MGI valve has a volume of 80 ml and maximum injection pressure of 50 bar, the diameter of valve orifice to vacuum vessel is 18.4 mm, the distance between MGI valve and plasma edge is ~3.4 m. The MGI power supply employs a large capacitor of 1 mF with the maximum voltage of 3 kV, the valve can be opened in less than 0.1 ms, and the amount of MGI can be controlled by the imposed voltage. During KSTAR 2011 campaign, MGI disruptions are carried out by triggering MGI during the flat top of circular and limiter discharges with plasma current 400 kA and magnetic field 2-3.5 T, deuterium injection pressure 39.7 bar, and imposed voltage 1.1-1.4 kV. The results show that MGI could mitigate the heat load and prevent runaway electrons with proper MGI amount, and MGI penetration is deeper under higher amount of MGI or lower magnetic field. However, plasma start-up is difficult after some of D(2) MGI disruptions due to the high deuterium retention and consequently strong outgassing of deuterium in next shot, special effort should be made to get successful plasma start-up after deuterium MGI under the graphite first wall.