A Redox-Activatable DNA Nanodevice for Spatially-Selective, AND-Gated Imaging of ATP and Glutathione in Mitochondria.

Design of biosensors capable of imaging ATP and glutathione (GSH) in mitochondria remains a challenge, despite their importance in elucidating their correlated pathophysiological events. Here, we report a new strategy that uses redox-activatable aptamer sensor design combined with nanoparticle-based targeting capability to achieve spatially controlled, AND-gated imaging of ATP and GSH in mitochondria. The DNA nanodevice was designed by the controlled assembly of the redox-responsive ATP aptamer probe on the nanoparticles and further decorated with mitochondria-targeting signals. We demonstrate that the system allows for mitochondria-specific, correlated imaging of ATP and GSH in living cells and in vivo. Furthermore, because the system can be lighted up only when meeting the "dual keys" (overexpressed ATP and GSH in mitochondria) simultaneously, the DNA nanodevice enables specific imaging of tumors in vivo with improved tumor-to-normal tissue ratio. This work illustrates the potential of the DNA nanodevices in the imaging of mitochondrial multivariate targets.

[Study of IR Property of Glow Discharge Polymer (GDP)].

To achieve the object of NIF ignition , it is required to prepare high density fuel targets . For DD layer, IR-layering can be used to improve its surface roughness. In this paper, glow discharge polymer (GDP) flat films and capsules were synthesized. The IR absorptive properties of GDP were thoroughly studied by using infrared spectrometer and microscopy while the extinction coefficients of GDP flat film at specific wavelengths were obtained. By comparing absorption properties of flat films and capsules, it is found that thermal treatments can lower the OH content of GDP and thus improve IR layering of DD ice. Finally, the needed IR power of integration sphere were estimated by using data obtained for future DD layering experiments in this paper. The results have laid a solid foundation for the implementation of DD IR layering.

Preclinical pharmacokinetics of TPN729MA, a novel PDE5 inhibitor, and prediction of its human pharmacokinetics using a PBPK model.

AIM: TPN729MA is a novel selective PDE5 inhibitor currently under clinical development in China for the treatment of erectile dysfunction. In this study we characterized its preclinical pharmacokinetics (PK) and predict its human PK using a physiologically based pharmacokinetic (PBPK) model. METHODS: The preclinical PK of TPN729MA was studied in rats and dogs. Human clearance (CL) values for TPN729MA were predicted from various allometric methods and from intrinsic CL determined in human liver microsomes. Human PK and plasma concentration versus time profiles of TPN729MA were predicted by using a PBPK model in GastroPlus. Considering the uncertainties in the prediction, a preliminary human study was conducted in 3 healthy male volunteers with an oral dose of 25 mg. RESULTS: After a single intravenous administration of TPN729MA at a dose of 1 mg/kg in rats and 3 mg/kg in dogs, the plasma CL was 69.7 mL·min(-1)·kg(-1) in rats and 26.3 mL·min(-1)·kg(-1) in dogs, and the steady-state volumes of distribution (V(ss)) were 7.35 L/kg in rats and 6.48 L/kg in dogs. The oral bioavailability of TPN729MA was 10% in rats and above 34% in dogs. Profiles of predicted plasma concentration versus time were similar to those observed in humans at 25 mg, and the predicted T(max), C(max) and AUC values were within 2-fold of the observed values. CONCLUSION: TPN729MA demonstrates good preclinical PK. This compound is a valuable candidate for further clinical development. This study shows the benefits of using a PBPK model to predict PK in humans.

[Predicting pharmacokinetics of anti-cancer drug, famitinib in human using physiologically based pharmacokinetic model].

This study is to establish physiologically based pharmacokinetic (PBPK) models of famitinib in rat and monkey, and then to predict the pharmacokinetics and tissue distribution of famitinib in human based on the PBPK models. According to published paper, previous studies and the chemical properties of famitinib predicted by ACD/ADME suite and SimCYP, the PBPK models of rat and monkey were established and optimized using GastroPlus. And then, the PBPK models were applied to predict the pharmacokinetic and tissue distribution of famitinib in human. The results showed that the PBPK models of rat and monkey can fit the observed data well, and the AUC0-∞, ratios of observed and calculated data in rat and monkey were 1.00 and 0.97, respectively. The AUC0-∞, ratios of observed and predicted data in human were 1.63 (rat to human) and 1.57 (monkey to human), respectively. The rat and monkey PBPK models of famitinib were well established, and the PBPK models were applied in predicting pharmacokinetic of famitinib in human successfully. Hence, the PBPK model of famitinib in human could be applied in future drug-drug interaction study.

[Chemical constituents of Euphorbia dracunculoides].

Sixteen compounds including daphnoretin (1), isofraxidin (2), scopoletin (3), kaempferol (4), quercetin (5), guaijaverin (6), astragalin (7), quercetin-3-O-ß-D-glucopyranoside (8), naringenin-7-O-ß-D-glucopyranoside (9), 5-O-methylapi- genin-7-O-ß-D-glucopyranoside (10), methyl gallate (11), prionitiside A (12), (2S)-2,3-dihydroxypropyl-1,6,8-trihydroxy-3- methyl-9,10- dioxoanthracene-2-carboxylate (13), 3,3'-di-O-methyl ellagic acid (14), 3'-O-methyl-3,4-O,O-metheneellagic acid-4'-O-ß-D- glucopyranoside (15) and 3,4-methylenedioxy-3'-O-methylellagic acid (16), were isolated from the 70% acetone extract of Euphorbia dracunculoides Lam. Among them, compounds 1-3, 6-9, 11, and 14 were isolated from E. dracunculoides for the first time, and compounds 10, 12, 13, 15, and 16 were firstly obtained from the genus Euphorbia. Their structures were elucidated by spectroscopic analysis, including 1H-NMR, 13C-NMR, and ESI-MS.

SLC4A4 is a novel driver of enzalutamide resistance in prostate cancer.

The androgen receptor signaling inhibitor (ARSI) enzalutamide (Enz) has shown critical efficacy in the treatment of advanced prostate cancer (PCa). However, the development of drug resistance is a significant factor contributing to mortality in PCa patients. We aimed to explore the key mechanisms of Enz-resistance. Through analysis of GEO databases, we identified SLC4A4 as a novel driver in Enz resistance. Long-term Enz treatment leads to the up-regulation of SLC4A4, which in turn mediates P53 lactylation via the NF-κB/STAT3/SLC4A4 axis, ultimately leading to the development of Enz resistance and progression of PCa. SLC4A4 knockdown overcomes Enz resistance both in vitro and in vivo. Hence, our results suggest that targeting SLC4A4 could be a promising therapeutic strategy for Enz resistance. STATEMENT OF SIGNIFICANCE: SLC4A4 is a novel driver of enzalutamide resistance.

KRAS mutation status between left- and right-sided colorectal cancer: are there any differences in computed tomography?

PURPOSE: To investigate the differences in clinicopathological and imaging features according to KRAS mutation status in left- and right-sided colorectal cancer. METHOD: A total of 157 patients with pathologically proven colorectal cancer and preoperative contrast-enhanced multidetector CT examinations were enrolled. According to the tumor location and KRAS status, they were divided into two groups: the left-sided colorectal cancer (LCC) group (wild type, mutant type) and the right-sided colorectal cancer (RCC) group (wild type, mutant type). Clinicopathological and imaging features were recorded in each group. The imaging observation indicators included short axis diameter (SAD), longitudinal tumor length (LTL), tumor shape, pericolic fat stranding, bowel stenosis, intratumoral low-density range, enhancement pattern, and bowel obstruction. Univariate and multivariate logistic regression analyses were performed to compare the difference in KRAS mutation status between groups. RESULTS: In the LCC group, SAD, tumor shape, degree of pericolic fat stranding, and bowel obstruction were significant indicators for predicting KRAS status (P < 0.05). In the RCC group, CA19-9, SAD, and intratumoral low-density range were significant indicators for predicting KRAS status (P < 0.05.). The area under the curve (AUC) of the combination image indicators in the LCC group was 0.802 [cutoff point 0.372, 95% confidence interval (CI) 0.718-0.888, sensitivity 85.4%, specificity 72.0%]. The AUC in the RCC group was 0.828 (cutoff point 0.647, 95% CI 0.726-0.931, sensitivity 79.5%, specificity 75.0%). CONCLUSION: The CT imaging features associated with KRAS mutation status in the LCC and RCC groups were different. The combination of tumor location and imaging features can help to further improve the predictive value of KRAS status.

Ipsilateral and contralateral patent processus vaginalis in pediatric patients with a unilateral nonpalpable testis.

This study aimed to investigate the incidence of patent processus vaginalis (PPV) in pediatric patients with a unilateral nonpalpable testis and explore the associated factors. From May 2014 to April 2017, 152 boys who were diagnosed with a unilateral nonpalpable testis and underwent laparoscopy in Shanghai Children's Hospital (Shanghai, China) were included in this study. The data were collected and reviewed, and the results were analyzed regarding the age at operation, side, development, and position of the nonpalpable testis. The mean age of the patients was 2.6 (standard deviation: 2.3) years. The testis was absent in 14 cases, nonviable in 81 cases, and viable in 57 cases. The incidence of PPV was 37.5% (57 of 152) on the ipsilateral side and 16.4% (25 of 152) on the contralateral side. The ipsilateral PPV was more prevalent when the nonpalpable testis occurred on the right side ( P < 0.01). Besides, patients with a viable testis had a greater incidence of ipsilateral PPV than those with a nonviable or absent testis ( P < 0.01). Moreover, this rate was the highest when the testis was in the abdominal cavity and the lowest when the testis was in the scrotum (both P < 0.01). However, the incidence of contralateral PPV was independent of all the factors. In conclusion, in children with a nonpalpable testis, the incidence of an ipsilateral PPV was significantly related to the side, development, and position of the testis, while it was independent of these factors on the contralateral side.

Use of Radioiodinated Peptide Arg-Arg-Leu Targeted to Neovasculari- zation as well as Tumor Cells in Molecular Tumor Imaging.

OBJECTIVE: To explore a tumor peptide imaging agent Arginine-Arginine-Leucine (Tyr-Cys-Gly-Gly-Arg-Arg- Leu-Gly-Gly-Cys, tripeptide RRL [tRRL]) that targeted to tumor cells and tumor-derived endothelial cells (TDECs) and primarily investigate the possible relationship between tRRL and vascular endothelial growth factor receptor 2 (VEGFR-2). METHODS: The tRRL sequence motif was identified as a tumor molecular marker specifically binding to TDECs. Tyrosine was conjugated to the amino terminal of RRL (Cys-Gly-Gly-Arg-Arg-Leu-Gly-Gly-Cys) for labeling with radionuclide iodine-131 ((131)I-tRRL). The uptake ability and molecular binding of tRRL to tumor cells and angiogenic endothelium were studied using flow cytometry and radioactivity counter in vitro. Whether VEGFR-2 is the binging site of tRRL was investigated. Biodistribution and single-photon emission computed tomography (SPECT) imaging of (131)I-tRRL were used to evaluate the effectiveness of this new imaging agent to visualize varied tumor xenografts in nude mice. RESULTS: In vitro cellular uptake experiments revealed that tRRL could not only adhere to tumor angiogenic endothelial cells but also largely accumulate in malignant tumor cells. VEGFR-2, which is highly expressed on TDECs, was probably not the solely binding ligand for tRRL targeted to tumor angiogenic endothelium. (131)I-tRRL mainly accumulated in tumors in vivo, not other organs at 24 h after injection. SPECT imaging with (131)I-tRRL clearly visualized tumors in nude mice, especially at 24 h. CONCLUSION: Radioiodinated tRRL offers a noninvasive nuclear imaging method for functional molecular imaging of tumors targeted to neovascularization, and may be a promising candidate for tumor radioimmunotherapeutic carrier.

Vacancy engineering of two-dimensional W2N3 nanosheets for efficient CO2 hydrogenation.

Peaking carbon emissions and achieving carbon neutrality have become the consensus goal of the international community to solve the environmental problems threatening mankind caused by accumulative greenhouse gases like CO2. Herein we proposed vacancy engineering of two-dimensional (2D) topological W2N3 for efficient CO2 hydrogenation into high value-added chemicals and fuels. Spherical aberration corrected scanning transmission electron microscopy (Cs-corrected STEM) confirmed a large amount of N vacancies on the catalyst surface, which significantly reduced the energy barrier for the formation of the essential intermediates of *CO and *CHO as revealed by density functional theory (DFT) calculations. Consequently, the highly stable catalyst exhibited efficient CO2 hydrogenation superior to many previous reports with a maximum CO2 conversion rate of 24% and a high selectivity of 23% for C2+ hydrocarbons. This work provided not only insight into the vacancy-controlled CO2 hydrogenation mechanism, but also fresh ammunition to bring the remaining potential of 2D topological transition metal nitrides in the field of catalysis.

[Insect odorant receptors and their olfactory signal transduction pathway].

Protection against insect bites is one of the main strategies in prevention and control of the vector-borne diseases. However, due to the obvious shortcomings of traditional control methods, it is necessary to develop new control measures. Most insects rely on their olfactory systems for host and mate location. Interfering with insect olfactory systems is becoming a hot research area in the control of vector-borne diseases. As odorant receptors play a major role in perception of odorant molecules by insect olfactory system, this paper summarizes the recent progress on insect odorant receptors and their olfactory signal transduction.

Inhibition of MDA-MB-231 cell proliferation by pHLIP(Var7)-P1AP and SPECT imaging of MDA-MB-231 breast cancer-bearing nude mice using 125I-pHLIP(Var7)-P1AP.

AIM: To observe the effect of pHLIP(Var7)-P1AP on the proliferation of MDA-MB-231 triple-negative breast cancer cells and the small-animal single-photon-emission computed tomography (SPECT) imaging of breast cancer-bearing mice carrying MDA-MB-231 cells. METHODS: Peptide pHLIP(Var7)-P1AP was synthesized by solid-phase peptide synthesis. The binding of fluorescently labeled pHLIP(Var7)-P1AP to MDA-MB-231 cells under various pH conditions and its effect on MDA-MB-231 cell proliferation were analyzed. pHLIP(Var7)-P1AP was labeled with 125I, and the biological distribution of 125I-pHLIP(Var7)-P1AP in the breast cancer mouse model carrying MDA-MB-231 cells as well as the outcome of small-animal SPECT imaging were evaluated. RESULTS: pHLIP(Var7)-P1AP was successfully synthesized. Under pH 6.0, fluorescently labeled pHLIP(Var7)-P1AP had a higher binding ability to MDA-MB-231 cells and significantly inhibited the proliferation of MDA-MB-231 cells. The labeling efficiency of pHLIP(Var7)-P1AP with 125I was 33.1 ±â€Š2.7 %, and the radiochemical purity was 98.5 ±â€Š1.8 %. 125I-pHLIP(Var7)-P1AP showed a high concentration in tumors. Small-animal SPECT imaging showed clearly visible tumors at 4 h after injection. CONCLUSIONS: In the acidic environment, pHLIP(Var7)-P1AP can efficiently target MDA-MB-231 cells and inhibit their growth. Small-animal SPECT of 125I-pHLIP(Var7)-P1AP can clearly image tumors.

Health-Related Quality of Life in Predominantly Young Parental Living Liver Donors: A Cross-Sectional Study in China.

Objective: The health-related quality of life (HRQoL) of donors deserves attention and must be considered for a long time. Many of the published studies had small sample sizes, and research from mainland China, in particular, is scant. Thus, this study aimed to investigate the HRQoL of living liver donors and identify the influencing factors of the HRQoL in mainland China. Methods: This is a cross-sectional study. The data were collected from the liver transplantation center, the Tianjin First Center Hospital, China. Living liver donors older than 18 years and at a minimum of 1-month, post-donation was included. The HRQoL was evaluated using the Medical Outcome Study Short form 36 (SF-36). Sociodemographic and clinical-related variables, HRQoL status, and its potential impact factors were analyzed. Results: A total of 382 living liver donors completed the survey. The median number of months post-donation was 25, and parental donors (99.2%) were the most frequent relationship. The majority of the participants (372, 97.4%) donated their left lateral lobes. Thirty-two (8.4%) donors suffered complications, and of them, 7 suffered from biliary leakage (1.8%), which was the most common one in this study. The physical functioning (PF), role-physical (RP), bodily pain (BP), general health (GH), social functioning (SF), role-emotional (RE), and mental health (MH) scores among the living liver donors were significantly better than those of the Chinese norms. Short-time post-donation [odds ratio (OR): 0.008; p < 0.001] and male recipients (OR:0.195; p = 0.024) were associated with the likelihood of a poor physical related quality of life. Conclusions: Despite, in general, good HRQoL outcomes, we also believed that liver donation has an obvious influence on the physical functions of liver donors. More attention and long-term follow-ups are necessary for donors at higher risk based on identified influencing factors and correlates.

Efficacy of Adherence-Enhancing Interventions for Immunosuppressive Therapy in Solid Organ Transplant Recipients: A Systematic Review and Meta-Analysis Based on Randomized Controlled Trials.

BACKGROUND: Immunosuppressant non-adherence is a widespread problem among solid organ recipients. With the newly published clinical trials, the randomized controlled trials (RCTs) based systematic review of adherence-enhancing interventions on immunosuppressant adherence in solid organ recipients has not been completed. In this systematic review and meta-analysis, we compared the efficacy of adherence-enhancing interventions versus routine intervention, as performed with RCTs, on immunosuppressant adherence in solid organ transplantation recipients. METHODS: PubMed, Embase, Cochrane Library, CINAHL full text, and PsycINFO were searched from database inception to December 2019. This review was conducted following the PRISMA's reporting guidelines and according to the principles recommended by Cochrane Handbook for Systematic Review. RESULTS: The search yielded 10,479 articles. A total of 27 articles (26 studies) with 715 participants were included in our analysis. Results from the meta-analysis revealed that as compared with that of the routine intervention group, the rates of overall adherence, dosing adherence, and timing adherence were significantly increased within the adherence-enhancing intervention group, with the pooled risk ratio (RR) of overall adherence = 1.17, [95% confidence interval (CI): 1.07 to 1.28; p = 0.0006]; RR of dosing adherence = 1.21 (95% CI: 1.08 to 1.36, p = 0.001); RR of timing adherence = 1.16 (95% CI: 1.03 to 1.29, p = 0.01). There was a significantly increased adherence score in the adherence-enhancing intervention group; however, no statistical significance on the immunosuppressant blood concentration was found between the two study groups. Results obtained from a subgroup analysis shown interventions led by a multidisciplinary team, both the assessment time at 6 months and 12 months demonstrated a significantly increased adherence rate in the intervention group compared with the control group. CONCLUSIONS: The findings of this report indicate that clinicians (doctors and nurses) should maintain a long-term intervention protocol to ensure immunosuppressant adherence within solid organ transplant recipients. To accomplish this goal, we recommend a multidisciplinary team-led, comprehensive intervention approach combined with mobile health monitoring for the administration of an effective immunosuppressive therapy regimen.

[Uptake kinetics of hTERT antisense molecular probe by cells and its biological properities].

OBJECTIVE: To observe the cell uptake kinetics and specific gene expression effect of hTERT antisense molecular probe in vitro. METHODS: Antisense molecular probes targeting hTERT mRNA were radiolabeled with technetium-99m by the method of bifunctional chelator. HepG2 cells expressing hTERT were cultured. The uptake kinetics of molecular probes mediated by liposome or not in cells were examined in vitro. RT-PCR (reverse transcriptase polymerase chain reaction) method was performed to assay the specific gene expression effect of the molecular probes. All data were analyzed by the statistic software of SPSS 12.0. RESULTS: The labeling efficiencies of molecular probe reached (76 +/- 5) % (n = 5), the specific activity was up to 1.850 x 10(6) Bq/microg, and the radiochemical purity was above 96% after purification. The absolute accumulation of (99m)Tc, whether on antisense or sense molecular probe, was clearly higher with liposome-mediated than without liposome-mediated (P < 0.05). Furthermore, liposome advanced the peak time of cellular uptake of antisense molecular probe, with the highest accumulation occurring at the end of 2 h, and remaining at the same level till 3 h later. In comparison with sense molecular probe, antisense molecular probe preserved the capacity to bind living hTERT-expressing cells specifically and inhibited the expression of hTERT mRNA significantly as well as ASON. CONCLUSION: Liposome-mediated method could increase cell uptake of molecular probes in vitro. Antisense molecular probe preserved the capacity to inhibit the expression of targeting mRNA specifically. All results provided the basis for further in vivo study.

Diaqua-{6,6'-dimeth-oxy-2,2'-[ethane-1,2-diylbis(nitrilo-methyl-idyne)]diphenolato-κO,N,N',O'}manganese(III) perchlorate 18-crown-6 hemisolvate monohydrate.

In the cation of the title compound, [Mn(C(18)H(18)N(2)O(4))(H(2)O)(2)]ClO(4)·0.5C(12)H(24)O(6)·H(2)O, the Mn(III) ion is coordinated by two water O atoms, and two O atoms and two N atoms from the tetradentate 6,6'-dimeth-oxy-2,2'-[ethane-1,2-diylbis(nitrilo-methyl-idyne)]di-phenolate ligand, completing a distorted octa-hedral geometry. One O atom of the 18-crown-6-ether is disordered over two positions with occupancies of 0.70 (2) and 0.30 (2).

{6,6'-Dimeth-oxy-2,2'-[4-bromo-o-phenyl-enebis(nitrilo-methyl-idyne)]diphenolato}nickel(II) methanol solvate.

In the title compound, [Ni(C(22)H(17)BrN(2)O(4))]·CH(3)OH, the Ni(II) ion is in a slightly distorted square-planar geometry involving an N(2)O(2) atom set of the tetra-dentate Schiff base ligand. The asymmetric unit contains one nickel complex and one methanol solvent mol-ecule. The dihedral angle between the aromatic ring planes of the central aromatic ring and other two aromatic rings are 10.8 (3) and 6.0 (2)°. The crystal structure is stabilized by inter-molecular C-H⋯O and C-H⋯Br and by intra-molecular O-H⋯O hydrogen bonds.

(E)-2-[(2-Amino-4,5-dibromo-phen-yl)imino-meth-yl]-6-methoxy-phenol.

The title compound, C(14)H(12)Br(2)N(2)O(2), was prepared from the condensation of 4,5-dibromo-1,2-phenyl-enediamine and 2-hydr-oxy-3-methoxy-benzaldehyde in methanol. The N=C double bond shows a trans conformation and the dihedral angle between the aromatic ring planes is 5.9 (4)°. In the crystal structure, there are intra-molecular O-H⋯N and N-H⋯N and inter-molecular N-H⋯O hydrogen bonds, the latter resulting in inversion dimers.

Di-µ-chlorido-bis-[chlorido(N,N-di-methyl-ethylenediamine-κN,N')zinc(II)].

The centrosymmetric dinuclear title compound, [Zn(2)Cl(4)(C(4)H(12)N(2))(2)], is isostructural with its previously reported Cu(II) analogue [Phelps, Goodman & Hodgson (1976 ▶). Inorg. Chem.15, 2266-2270]. In the title compound, each of the Zn(II) ions is coordinated by two N atoms from a chelating N,N-dimethyl-ethylenediamine ligand, two bridging Cl atoms and one terminal Cl atom. The coordination environment is distorted square-pyramidal. The Zn-Cl bond distances of the two bridging Cl atoms are distinctly different: the equatorial Cl atom exbibits a Zn-Cl distance of 2.318 (1) Šand the axial Cl atom exbibits a Zn-Cl distance of 2.747 (2) Å, which is significantly longer. The mol-ecule can thus be seen as a dimer of two nearly square-planar monomeric units which are related to each other by an inversion center located in the middle of the dimer. Within one monomeric unit, the Zn atom, the two N atoms and the two Cl atoms are almost coplanar, with a mean deviation of only 0.05 (1) Šfrom the associated least-squares plane. The Zn⋯Zn distance within the dimer is 3.472 (3) Å. N-H⋯Cl and C-H⋯Cl hydrogen-bond inter-actions connect neighboring mol-ecules with each other.

Tris(1,10-phenanthroline-κN,N')iron(II) µ-oxido-bis[trichloridoferrate(III)] ethanol hemisolvate.

The title compound, [Fe(C(12)H(8)N(2))(3)][Fe(2)Cl(6)O]·0.5CH(3)CH(2)OH, consists of one [Fe(phen)(3)](2+) cation (phen = 1,10-phen-anthroline), one [Fe(2)Cl(6)O](2-) anion and one half-mol-ecule of ethanol. In the cation, the Fe(II) atom is coordinated by six N atoms from three phen ligands in a distorted octa-hedral geometry. In the bent anion, two Fe(III) atoms are connected by a bridging oxide O atom [bridging angle = 160.6 (4)°], and each Fe(III) atom is also coordinated by three Cl atoms, completing a distorted tetra-hedral geometry.