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1.
Bioorg Chem ; 101: 103901, 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32590225

RESUMO

TNF Receptor Associated Protein 1 (TRAP1) is a mitochondrial paralog of Hsp90 related to the promotion of tumorigenesis in various cancers via maintaining mitochondrial integrity, reducing the production of reactive oxygen species, and reprogramming cellular metabolism. Consequently, Hsp90 and TRAP1 have been targeted to develop cancer therapeutics. Herein, we report a series of pyrazolo[3,4-d]pyrimidine derivatives that are mitochondria-permeable TRAP1 inhibitors. Structure-based drug design guided the optimization of potency, leading to the identification of compounds 47 and 48 as potent TRAP1 and Hsp90 inhibitors with good metabolic and plasma stability as well as acceptable CYP and hERG inhibition. X-ray co-crystallization studies confirmed both 47 and 48 interact with the ATP binding pocket in the TRAP1 protein. Compounds 47 and 48 demonstrated excellent anticancer efficiency in various cancer cells, with limited toxicity over normal hepatocyte and prostate cells. Mouse PC3 xenograft studies showed 47 and 48 significantly reduced tumor growth.

2.
Cell Rep ; 31(12): 107803, 2020 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-32579929

RESUMO

The function of enhancer RNAs (eRNAs) in transcriptional regulation remains obscure. By analyzing the genome-wide nascent transcript profiles in breast cancer cells, we identify a special group of eRNAs that are essential for estrogen-induced transcriptional repression. Using eRNAs of TM4SF1 and EFEMP1 as the paradigms, we find that these RNA molecules not only stabilize promoter-enhancer interactions but also recruit liganded estrogen receptor α (ERα) to particular enhancer regions, facilitate the formation of a functional transcriptional complex, and cause gene silencing. Interestingly, ERα is shown to directly bind with eRNAs by its DNA-binding domain. These eRNAs help with the formation of a specific ERα-centered transcriptional complex and promote the association of the histone demethylase KDM2A, which dismisses RNA polymerase II from designated enhancers and suppresses the transcription of target genes. Our work demonstrates a complete mechanism underlying the action of eRNAs in modulating and refining the locus-specific transcriptional program.

3.
Nat Commun ; 11(1): 2178, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32358548

RESUMO

Electrochemical synthesis of H2O2 through a selective two-electron (2e-) oxygen reduction reaction (ORR) is an attractive alternative to the industrial anthraquinone oxidation method, as it allows decentralized H2O2 production. Herein, we report that the synergistic interaction between partially oxidized palladium (Pdδ+) and oxygen-functionalized carbon can promote 2e- ORR in acidic electrolytes. An electrocatalyst synthesized by solution deposition of amorphous Pdδ+ clusters (Pd3δ+ and Pd4δ+) onto mildly oxidized carbon nanotubes (Pdδ+-OCNT) shows nearly 100% selectivity toward H2O2 and a positive shift of ORR onset potential by ~320 mV compared with the OCNT substrate. A high mass activity (1.946 A mg-1 at 0.45 V) of Pdδ+-OCNT is achieved. Extended X-ray absorption fine structure characterization and density functional theory calculations suggest that the interaction between Pd clusters and the nearby oxygen-containing functional groups is key for the high selectivity and activity for 2e- ORR.

4.
Artigo em Inglês | MEDLINE | ID: mdl-32367707

RESUMO

Prussian blue analogues (PBAs) have been highlighted as electrode materials for aqueous rechargeable batteries (ARBs) because of their favorable crystal structure and electrochemical activity. However, dissolution of the transition-metal ions during cycling degrades the materials and hinders the development of long-life-span batteries. To overcome this limitation, a strategy to revive the capacity degradation of PBA-based cathodes was developed herein based on designing all-PBA-based core@shell materials, while specific reduction upon introducing the shell layers was minimized. The core@shell materials were constructed using a V/Fe PBA (high capacity) core and a Cu/Fe PBA (high cycling stability) shell via a two-step co-precipitation method. The electrochemical performances including specific capacity, cycling stability, and rate capability as a function of the Cu/Fe PBA shell thickness were explored. At the optimal Cu/Fe PBA thickness, improved capacity retention after 200 cycles of >90% (72% for the core only) was attained with negligible capacity reductions from 94 (core only) to 90 (core@shell) mA h g-1, arising from the high electrochemical activity and stability of the Cu/Fe PBA shell and stabilized interfaces due to the crystallographic coherence between the core and shell materials. In addition, the power performance of the core@shell materials was significantly improved, e.g., C38.4C/C0.6C for a core@shell of 80% and core only of 62%, arising from the unique chemical coordination and facile ion diffusion kinetics of the Cu/Fe PBA shell. The newly developed V/Fe@Cu/Fe PBA-based cathodes offer an effective strategy for fabricating sustainable and low-cost ARBs.

5.
J Ultrasound Med ; 2020 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-32420654

RESUMO

OBJECTIVES: To compare the prognostic factors of fetuses with microcystic and macrocystic congenital pulmonary airway malformations (CPAMs). METHODS: We retrospectively evaluated fetuses with CPAMs at Asan Medical Center. The CPAM size, mass effect, and maximum cyst size in macrocystic CPAMs were evaluated prenatally. The adverse postnatal outcomes, including respiratory symptoms, mechanical ventilation, and surgery, were evaluated. RESULTS: In 118 cases, 2 fetal deaths and 1 neonatal death occurred. All cases of fetal hydrops and complete regression after birth were in the macrocystic and microcystic CPAM groups, respectively. Twenty-four neonates (20.7%) had respiratory symptoms, and 18 (15.5%) required mechanical ventilation. Sixty-three neonates (54.3%) underwent surgery, of whom 21 (33.3%) required surgery in the neonatal period. The maximum congenital pulmonary airway malformation volume ratio was significantly associated with all postnatal outcomes (P < .05), and the optimal cutoff values were lower for respiratory symptoms, mechanical ventilation, and neonatal surgery in the macrocystic CPAMs. The maximum cyst size was also associated with all postnatal outcomes in macrocystic CPAMs (P < .05). CONCLUSIONS: Different cutoff values for the maximum congenital pulmonary airway malformation volume ratio should be applied according to the CPAM type for the prediction of postnatal outcomes. The maximum cyst size can also be a useful prognostic factor in macrocystic CPAMs.

6.
Korean J Fam Med ; 2020 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-32434302

RESUMO

Background: Previous studies have shown that body composition is associated with chronic kidney disease (CKD), and perimenopause is associated with increased fat mass and decreased lean body mass. Muscle wasting is common among patients with CKD. Sarcopenic obesity (SO) refers to excess adiposity with decreased muscle mass. However, little is known about the relationship between SO and renal function decline. Here, we identified the relationship between SO and decreased estimated glomerular filtration rate (eGFR) in postmenopausal women. Methods: We conducted a cross-sectional study based on the data from the Korea National Health and Nutrition Examination Survey (2008-2011). We analyzed 4,560 postmenopausal women who underwent dual energy X-ray absorptiometry. Sarcopenia was defined based on weight-adjusted appendicular skeletal muscle mass. Obesity was defined based on body mass index. The eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. Subjects were classified into four groups: normal, obese, sarcopenic, and sarcopenic obese. Logistic regression analysis was performed to examine the association between SO and decreased eGFR. The results were adjusted for variable confounders. Results: In the unadjusted model, the odds ratio (OR) of decreased eGFR for SO was 1.67 (95% confidence interval [CI], 1.23-2.26). The obese and sarcopenic groups had ORs of 0.67 (95% CI, 0.44-1.03) and 0.70 (95% CI, 0.44-1.10), respectively. After controlling for confounding variables, there was also a significant association between SO and decreased eGFR (adjusted OR, 1.48; 95% Cl, 1.05-2.07). Conclusion: SO was independently associated with decreased eGFR in postmenopausal Korean women.

7.
Redox Biol ; 32: 101511, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32244177

RESUMO

The Ataxia-telangiectasia mutated (ATM) kinase responds to DNA double-strand breaks and other forms of cellular stress, including reactive oxygen species (ROS). Recent work in the field has uncovered links between mitochondrial ROS and ATM activation, suggesting that ATM acts as a sensor for mitochondrial derived ROS and regulates ROS accumulation in cells through this pathway. In addition, characterization of cells from Ataxia-telangiectasia patients as well as ATM-deficient mice and cell models suggest a role for ATM in modulating mitochondrial gene expression and function. Here we review ROS responses related to ATM function, recent evidence for ATM roles in mitochondrial maintenance and turnover, and the relationship between ATM and regulation of protein homeostasis.

8.
Artigo em Inglês | MEDLINE | ID: mdl-32286728

RESUMO

The electrochemical carbon dioxide reduction reaction (CO2 RR) to produce synthesis gas (syngas) with tunable CO/H2 ratios has been studied by supporting Pd catalysts on transition metal nitride (TMN) substrates. Combining experimental measurements and density functional theory (DFT) calculations, Pd-modified niobium nitride (Pd/NbN) is found to generate much higher CO and H2 partial current densities and greater CO Faradaic efficiency than Pd-modified vanadium nitride (Pd/VN) and commercial Pd/C catalysts. In-situ X-ray diffraction identifies the formation of PdH in Pd/NbN and Pd/C under CO2 RR conditions, whereas the Pd in Pd/VN is not fully transformed into the active PdH phase. DFT calculations show that the stabilized *HOCO and weakened *CO intermediates on PdH/NbN are critical to achieving higher CO2 RR activity. This work suggests that NbN is a promising substrate to modify Pd, resulting in an enhanced electrochemical conversion of CO2 to syngas with a potential reduction in precious metal loading.

9.
Fish Shellfish Immunol ; 102: 20-27, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32272258

RESUMO

The aquaculture industry in Korea has grown rapidly since the 1960s, and it is a major food source. However, the expansion of aquaculture systems has increased the chances of infectious disease outbreaks, and vaccination plays an important role in commercial fish farming. This is the first comprehensive review of commercial fish vaccines in Korea. It not only provides an overview of commercially available fish vaccines and their associated approval processes and laws, but also some perspectives on research advances regarding fish vaccines in Korea. In Korea, fish vaccines are approved only after their safety and effectiveness have been verified according to the Pharmaceutical Affairs Act, and after approval, each vaccine lot must pass the national evaluation criteria. As of the end of 2019, 29 vaccines were approved for 10 fish pathogens, including both single and combination vaccines containing more than two inactivated pathogens. The approved fish vaccines consist of 2 immersion vaccines, as well as 1 intramuscular and 26 intraperitoneal vaccines, which require syringe injection. All the 29 vaccines are manufactured as formalin-inactivated vaccines; 1 is an adjuvant vaccine and 28 are non-adjuvant vaccines; 25 are bacterial vaccines, 2 are viral vaccines, 1 is a parasite vaccine, and 1 is a parasite and bacterial vaccine. In terms of the target fish species, 27 vaccines are used in the olive flounder (Paralichthys olivaceus), 1 in the starry flounder (Platichthys stellatus), and 1 in the red seabream (Pagrus major), striped beakfish (Oplegnathus fasciatus), and amberjack (Seriola quinqueradiata). This imbalance exists mostly because the olive flounder is the main farmed fish species in Korea. In 2018, 67.71 million vaccine doses were distributed following satisfactory performance in the national evaluation. They were used to vaccinate approximately 80.6% of farmed olive flounders.

10.
Bioorg Med Chem Lett ; 30(2): 126809, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31839539

RESUMO

As the most abundant heat shock protein (HSP), Hsp90 is actively involved in tumor cell growth and various responses to anti-carcinogenic stress. Hsp90 has thus emerged as a potential drug target. A structure-based drug design approach was applied to develop novel resorcinolyltriazole derivatives as Hsp90 inhibitors. Structure-activity relationships (SARs) and molecular docking were investigated to provide a rationale for binding affinity and paralog selectivity. Click chemistry between iodoethynylresorcinol and an azido derivative was used to synthesize a new family of 2-((4-resorcinolyl)-5-aryl-1,2,3-triazol-1-yl) acetates that exhibited Hsp90 binding affinities of 40-100 nM (IC50). Among the synthesized molecules, the triazole alkyl acetates displayed the highest Hsp90 binding affinities. Their potency against Hsp90 was over 100-fold stronger than against TRAP1 and 1-3-fold stronger than against Grp94. In particular, compounds 18, 19, and 30 had Hsp90 inhibitory activities of ~45 nM (IC50) and they displayed over 350-fold selectivity for Hsp90 over TRAP1.

11.
Angew Chem Int Ed Engl ; 59(8): 3033-3037, 2020 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-31826317

RESUMO

The electrochemical CO2 reduction reaction (CO2 RR) to yield synthesis gas (syngas, CO and H2 ) has been considered as a promising method to realize the net reduction in CO2 emission. However, it is challenging to balance the CO2 RR activity and the CO/H2 ratio. To address this issue, nitrogen-doped carbon supported single-atom catalysts are designed as electrocatalysts to produce syngas from CO2 RR. While Co and Ni single-atom catalysts are selective in producing H2 and CO, respectively, electrocatalysts containing both Co and Ni show a high syngas evolution (total current >74 mA cm-2 ) with CO/H2 ratios (0.23-2.26) that are suitable for typical downstream thermochemical reactions. Density functional theory calculations provide insights into the key intermediates on Co and Ni single-atom configurations for the H2 and CO evolution. The results present a useful case on how non-precious transition metal species can maintain high CO2 RR activity with tunable CO/H2 ratios.

12.
Chem Commun (Camb) ; 56(1): 106-108, 2019 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-31793562

RESUMO

The isotopic effect on the electrochemical CO2 reduction reaction (CO2RR) is investigated in this study. A higher CO2RR selectivity over its competing hydrogen evolution reaction was observed in D2O-based electrolytes compared with the H2O-based counterparts, which can be attributed to the lower [D+] concentration than [H+].

13.
Sci Rep ; 9(1): 19539, 2019 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-31862953

RESUMO

Both high activity and mass production potential are important for bifunctional electrocatalysts for overall water splitting. Catalytic activity enhancement was demonstrated through the formation of CoS2 nanoparticles with mono-phase and extremely porous structures. To fabricate porous structures at the nanometer scale, Co-based metal-organic frameworks (MOFs), namely a cobalt Prussian blue analogue (Co-PBA, Co3[Co(CN)6]2), was used as a porous template for the CoS2. Then, controlled sulfurization annealing converted the Co-PBA to mono-phase CoS2 nanoparticles with ~ 4 nm pores, resulting in a large surface area of 915.6 m2 g-1. The electrocatalysts had high activity for overall water splitting, and the overpotentials of the oxygen evolution reaction and hydrogen evolution reaction under the operating conditions were 298 mV and -196 mV, respectively, at 10 mA cm-2.

14.
Chem Commun (Camb) ; 55(88): 13311-13314, 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31631199

RESUMO

Herein, we report a strategy for generating conformationally restricted α-helix mimetic small molecules by introducing covalent bridges that limit rotation about the central axis of α-helix mimetics. We demonstrate that the bridged α-helix mimetics have enhanced binding affinity and specificity to the target protein due to the restricted conformation as well as extra interaction of the bridge with the protein surface.


Assuntos
Compostos Heterocíclicos de Anel em Ponte/química , Proteína de Sequência 1 de Leucemia de Células Mieloides/química , Bibliotecas de Moléculas Pequenas/química , Compostos Heterocíclicos de Anel em Ponte/farmacologia , Humanos , Células Jurkat , Modelos Moleculares , Conformação Molecular , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia
15.
J Am Chem Soc ; 141(44): 17771-17782, 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31615202

RESUMO

Aromatization of light alkanes is of great interest because this can expand the raw materials used to produce aromatics to include fractions of natural gas that are readily available and inexpensive. Combining CO2 reduction with ethane dehydrogenation and aromatization can also mitigate CO2 emissions. A one-step process that can produce liquid aromatics from the reactions of CO2 and ethane using phosphorus (P)- and gallium (Ga)-modified ZSM-5 has been evaluated at 873 K and atmospheric pressure. The addition of P improves the hydrothermal stability of Ga/ZSM-5, reduces coke formation on the catalyst surface, and allows the formation of more liquid aromatics through the tandem reactions of CO2-assisted oxidative dehydrogenation of ethane and subsequent aromatization. Density functional theory calculations provide insights into the effect of Ga- and P- modification on ethane dehydrogenation to ethylene as well as the role of CO2 on the production of aromatics.

16.
Micromachines (Basel) ; 10(10)2019 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-31590301

RESUMO

In this paper, we present a numerical study of a metamaterial absorber that provides polarization-insensitive absorption over a broad bandwidth of operation over the mid-infrared region. The absorber consists of a periodically patterned metal-dielectric-metal structure integrated with an epsilon-near-zero (ENZ) nanolayer into the insulating dielectric gap region. Such an anomalous broadband absorber is achieved thanks to a couple of resonant modes including plasmon and ENZ modes that are excited under mid-IR light illumination. By adding a 0.06-µm-thick ENZ layer between the patterned gold rectangular grating and the SiO2 dielectric layer, the absorber captures >95% light over a 1.5 µm bandwidth centered at a near-8-µm wavelength over a wide range of oblique incidence under transverse-magnetic and -electric polarizations. The designed ENZ-based wideband absorber has potential for many practical applications, including sensing, imaging and solar energy harvesting over a wide frequency regime.

17.
Nat Commun ; 10(1): 4454, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31575854

RESUMO

While cracks are usually considered detrimental, crack generation can be harnessed for various applications, for example in ceramic materials, via directing crack propagation and crack opening. Here, we find that electron beam irradiation prompts a crack suppression phenomenon in a copper (Cu) thin film on a polyimide substrate, allowing for the control of crack formation in terms of both location and shape. Under tensile strain, cracks form on the unirradiated region of the Cu film whereas cracks are prevented on the irradiated region. We attribute this to the enhancement of the adhesion at the Cu-polyimide interface by electrons transmitted through the Cu film. Finally, we selectively form conductive regions in a Cu film on a polyimide substrate under tension and fabricate a strain-responsive organic light-emitting device.

19.
Cell Host Microbe ; 26(3): 301-303, 2019 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-31513766

RESUMO

Because Drosophila larvae do not possess intestinal stem cells, it is unknown how damaged gut cells are replenished. In this issue of Cell Host & Microbe, Houtz et al. (2019) show that larvae have a unique gut repair mechanism that involves borrowing stem cells originally reserved for adult gut formation.


Assuntos
Drosophila , Roubo , Animais , Intestinos , Larva , Células-Tronco
20.
Appl Opt ; 58(22): 6105-6111, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31503933

RESUMO

The theoretical prediction of a display viewing angle control using a guest-host (GH) liquid crystal (LC) cell has been reported by Chen et al. [Jpn. J. Appl. Phys.48, 062401 (2009)JJAPA50021-492210.1143/JJAP.48.062401]. We experimentally confirmed the viewing angle control property of the GH cell and also investigated its dependence on the extinction coefficient of the GH mixture. The GH cell with a negative dielectric anisotropy and a vertical orientation was attached on front of the display panel, resulting in narrow viewing (NV) property at the field-off state. The GH molecules were switched to a planar orientation, which is also orthogonal to the polarization direction of light at the field-on state, showing wide viewing (WV) property. We varied the concentration of a guest dichroic dye in a host LC and measured the extinction coefficients of the mixtures. We simulated the viewing control property using the measured extinction coefficients and found that the horizontal viewing angle can be controlled using the GH cell, but the vertical viewing angle cannot be controlled. Then, we experimentally confirmed the horizontal viewing angle control using the GH cell. The extinction between the NV and the WV states was increased with a greater extinction coefficient of the GH molecules, but the transmittance was decreased.

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