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1.
ACS Omega ; 9(18): 20086-20100, 2024 May 07.
Article in English | MEDLINE | ID: mdl-38737092

ABSTRACT

In this study, gas contents, geochemical features, and origins of coalbed methane (CBM) and their influence factors were investigated on nos. 7 and 8 CBM reservoirs from the Suzhou mining area of the Huaibei coalfield. Results have shown that the selected CBM reservoirs are characterized by various thickness (0.50-9.19 m) and buried depth (619-1226 m), but have relatively better lithology of surrounding rocks. Coal samples have similar maturity (Ro,max = 0.71-1.05%), but show differences in chemical composition and macerals. Gas content of nos. 7 and 8 CBM reservoirs ranges from 6.13-12.25 m3/t, but the value of former is lower than that of later one overall. In addition, CH4 is a predominantly component with a value of 88.23-99.00% (avg. 96.69%), and the heavy hydrocarbon gas (C2+) is 0.00-1.93% (avg. 0.41%). The δ13CCH4 value ranges from -64.54 to -46.36‰ (avg. -53.92‰), and the δ13DCH4 value is -224.36 to -211.75‰ (avg. -219.09‰). Based on the analysis of components and isotopic values, the CBM samples are thermogenic (20.92-71.30%; avg 50.09%) and secondary biogenic gases (28.70-74.49%; avg. 49.91%). Gas content shows changeable characteristics at a buried depth of 300-1300 m, which is affected by buried depth, reservoir temperature and pressure, Mad and vitrinite. However, the CH4 concentration shows no correlation with buried depth. Moreover, the buried depth is significantly positively correlated to δ13CCH4 and δ13DCH4. Based on the relationship between gas content and isotope values, it suggests that δ13CCH4 or δ13DCH4 may have a relationship with the main controlling factors of gas content.

2.
Nano Lett ; 24(18): 5420-5428, 2024 May 08.
Article in English | MEDLINE | ID: mdl-38666707

ABSTRACT

Artificial intelligence has surged forward with the advent of generative models, which rely heavily on stochastic computing architectures enhanced by true random number generators with adjustable sampling probabilities. In this study, we develop spin-orbit torque magnetic tunnel junctions (SOT-MTJs), investigating their sigmoid-style switching probability as a function of the driving voltage. This feature proves to be ideally suited for stochastic computing algorithms such as the restricted Boltzmann machines (RBM) prevalent in pretraining processes. We exploit SOT-MTJs as both stochastic samplers and network nodes for RBMs, enabling the implementation of RBM-based neural networks to achieve recognition tasks for both handwritten and spoken digits. Moreover, we further harness the weights derived from the preceding image and speech training processes to facilitate cross-modal learning from speech to image generation. Our results clearly demonstrate that these SOT-MTJs are promising candidates for the development of hardware accelerators tailored for Boltzmann neural networks and other stochastic computing architectures.

3.
Adv Sci (Weinh) ; : e2402182, 2024 Apr 15.
Article in English | MEDLINE | ID: mdl-38622896

ABSTRACT

The incorporation of randomness into stochastic computing can provide ample opportunities for applications such as simulated annealing, non-polynomial hard problem solving, and Bayesian neuron networks. In these cases, a considerable number of random numbers with an accurate and configurable probability distribution function (PDF) are indispensable. Preferably, these random numbers are provided at the hardware level to improve speed, efficiency, and parallelism. In this paper, how spin-orbit torque magnetic tunnel junctions (SOT-MTJs) with high barriers are suitable candidates for the desired true random number generators is demonstrated. Not only do these SOT-MTJs perform excellently in speed and endurance, but their randomness can also be conveniently and precisely controlled by a writing voltage, which makes them a well-performed Bernoulli bit. By utilizing these SOT-MTJ-based Bernoulli bits, any PDF, including Gaussian, uniform, exponential, Chi-square, and even arbitrarily defined distributions can be realized. These PDF-configurable true random number generators can then promise to advance the development of stochastic computing and broaden the applications of the SOT-MTJs.

4.
Materials (Basel) ; 17(5)2024 Mar 05.
Article in English | MEDLINE | ID: mdl-38473670

ABSTRACT

A new heat source combination, consisting of a uniform body heat source and a tilted double ellipsoidal heat source, has been developed for cold metal transfer (CMT) wire-arc additive manufacturing of Mg-Gd-Y-Zn-Zr alloy. Simulations were conducted to analyze the temperature field and stress distribution during the process. The optimal combination of feeding speed and welding speed was found to be 8 m/min and 8 mm/s, respectively, resulting in the lowest thermal accumulation and residual stress. Z-axis residual stress was identified as the main component of residual stress. Electron Backscatter Diffraction (EBSD) testing showed weak texture strength, and Kernel Average Misorientation (KAM) analysis revealed that the 1st layer had the highest residual stress, while the 11th layer had higher residual stress than the 6th layer. Microhardness in the 1st, 11th, and 6th layers varies due to residual stress impacts on dislocation density. Higher residual stress increases dislocation density, raising microhardness in components. The experimental results were highly consistent with the simulated results.

5.
Sci Adv ; 9(44): eadg9819, 2023 Nov 03.
Article in English | MEDLINE | ID: mdl-37910619

ABSTRACT

Spin-orbit torque (SOT) is a promising strategy to deterministically switch the perpendicular magnetization, but usually requires an in-plane magnetic field for breaking the mirror symmetry, which is not suitable for most advanced industrial applications. Van der Waals (vdW) materials with low crystalline symmetry and topological band structures, e.g., Weyl semimetals (WSMs), potentially serve as an outstanding system that may simultaneously realize field-free switching and high energy efficiency. Yet, the demonstration of these superiorities at room temperature has not been realized. Here, we achieve a field-free switching of perpendicular magnetization by using a layered type II WSM, TaIrTe4, in a TaIrTe4/Ti/CoFeB system at room temperature with the critical switching current density ~2.4 × 106 A cm-2. The field-free switching is ascribed to the out-of-plane SOT allowed by the low crystal symmetry. Our work suggests that using low-symmetry materials to generate SOT is a promising route for the manipulation of perpendicular magnetization at room temperature.

6.
BMC Infect Dis ; 23(1): 459, 2023 Jul 10.
Article in English | MEDLINE | ID: mdl-37430187

ABSTRACT

BACKGROUND: This study aimed to establish an effective ultrasound diagnostic nomogram for benign or malignant lymph nodes in HIV-infected patients. METHODS: The nomogram is based on a retrospective study of 131 HIV-infected patients who underwent ultrasound assess at the Shanghai Public Health Clinical Center from December 2017 to July 2022. The nomogram's predictive accuracy and discriminative ability were determined by concordance index (C-index) and calibration curve analysis. A nomogram combining the lymph node US characteristics were generated based on the multivariate logistic regression results. RESULTS: Predictors contained in the ultrasound diagnostic nomogram included age (OR 1.044 95%CI: 1.014-1.074 P = 0.004), number of enlarged lymph node regions (OR 5.445 95%CI: 1.139-26.029 P = 0.034), and color Doppler flow imaging (CDFI) grades (OR 9.614 95%CI: 1.889-48.930 P = 0.006). The model displayed good discrimination with a C (ROC) of 0.775 and good calibration. CONCLUSIONS: The proposed nomogram may result in more-accurate diagnostic predictions for benign or malignant lymph nodes in patients with HIV infection.


Subject(s)
HIV Infections , Humans , Nomograms , Retrospective Studies , China , Ultrasonography , Lymph Nodes/diagnostic imaging
7.
World J Surg Oncol ; 20(1): 404, 2022 Dec 20.
Article in English | MEDLINE | ID: mdl-36539825

ABSTRACT

OBJECTIVE: This investigation aimed to explore the relationship between sarcopenia and severe postoperative complications, relapse-free survival (RFS), and overall survival (OS) in patients with retroperitoneal liposarcoma (RLPS). MATERIAL AND METHODS: This retrospective study included 72 RLPS patients (47 men, 25 women; mean age, 57.49 years, SD 10.92) who had abdominal CT exams. Clinical information was recorded, including RLPS characteristics (histologic subtypes, grade, size), laboratory assessment (ALB, PALB, A/G, Hb, SCr), relapse-free survival, overall survival, and postoperative complications. The relationships between those variables and RFS and OS were analyzed using Cox proportional hazard models. RESULTS: There were 8 severe postoperative complications (Clavien-Dindo grade > 2). The chi-square test showed sarcopenia was associated with severe postoperative complications (P = 0.011). In multivariate analysis, sarcopenia was not associated with relapse-free survival (P = 0.574) and overall survival (P = 0.578). CONCLUSIONS: Sarcopenia predicts worse surgical complications but does not affect relapse-free survival and overall survival.


Subject(s)
Liposarcoma , Retroperitoneal Neoplasms , Sarcopenia , Male , Humans , Female , Middle Aged , Prognosis , Retrospective Studies , Retroperitoneal Neoplasms/complications , Retroperitoneal Neoplasms/surgery , Liposarcoma/complications , Liposarcoma/surgery , Sarcopenia/complications , Chronic Disease , Postoperative Complications
8.
J Clin Transl Res ; 8(5): 339-343, 2022 Oct 31.
Article in English | MEDLINE | ID: mdl-36090013

ABSTRACT

Background: There are lacking standard treatment guidelines for aggressive fibromatosis (AF) because of its rarity. Aim: This study aimed to investigate the risk factors for recurrence and survival of abdominal AF after radical surgical resection. Methods: From August 2012 to December 2020, a retrospective analysis was conducted on the clinical data of 69 AF in Shanghai Public Health Clinical Center Affiliated to Fudan University, with the tumor locating either in the abdominal wall or in the abdominal cavity. The main observation end point was progression-free survival time (PFS) and overall survival time (OS). Results: All 69 patients achieved microscopic R0 resection, 10 (14.5%) had local recurrence, and 3 (4.3%) died. The PFS rate after 1, 3, 5, and 10 years was 96.8%, 87.7%, 78.8%, and 78.8%, respectively. The OS rate after 1, 3, 5, and 10 years was 100%, 100%, 92.9%, and 81.3%, respectively. In 10 patients with recurrence, the median recurrence time was 17.6 months. Concomitant familial adenomatous polyposis (FAP) and history of previous recurrence were independent risk factors of post-operative recurrence. Conclusion: After radical surgery of abdominal AF, the local recurrence rate was 15%. Concomitant FAP and a previous history of recurrence were independent risk factors of post-operative recurrence. R0 and a combined organ resection should be performed especially in FAP patients to minimize the recurrence and improve the prognosis. Relevance for Patients: The present study identifies the risk factors of recurrence in AF and suggests R0 resection especially in concomitant FAP patients. A wait-and-see strategy should not be generally implemented and radical surgery will bring clinical benefits to patients with such kind of rare disease.

9.
Front Surg ; 9: 935048, 2022.
Article in English | MEDLINE | ID: mdl-35903259

ABSTRACT

Introduction: Cowden syndrome is a rare autosomal dominant genetic disease associated with PTEN mutation and is mainly shown as systemic multisystem lesions. The incidence of adenocarcinoma of the duodenum with Cowden syndrome in Asian males is rare. We hereby describe the diagnosis, treatment, and prognosis of a patient with duodenal carcinoma and Cowden syndrome. Case Description: A 40-year-old Chinese man was hospitalized because of gastrointestinal hemorrhage and anemia due to infiltrating adenocarcinoma of the descending part of the duodenum. He also had typical signs of Cowden syndrome, such as multiple polyps of the gastrointestinal tract, macrocephaly, papilloma of the tongue, soles hyperkeratosis, and melanosis spots. After the pancreaticoduodenectomy (classic Whipple), the lesions revealed the presence of hamartomatoid polyps, and some of them mutated into non-mucinous adenocarcinoma (80%) and mucinous adenocarcinoma (20%). Further investigation showed a lack of PTEN protein expression in the duodenal neoplasm, and genetic analysis showed the mutation of p.E242fs in PTEN. The patient was followed up for 1 year. There was no appearance of recurrence or distant metastasis. Conclusion: It is suggested that we should pay more attention to the differential diagnosis of duodenal carcinoma combined with gastrointestinal polyps. If multiple gastrointestinal polyps with gastrointestinal bleeding are encountered, Cowden syndrome should be considered, and timely diagnosis and treatment should be implemented.

10.
J Oncol ; 2022: 9514697, 2022.
Article in English | MEDLINE | ID: mdl-35813857

ABSTRACT

Our previous study has indicated that cancer-associated fibroblasts (CAFs) play a crucial role in regulating gemcitabine resistance through transferring exosomal miRNA-106b to cancer cells. Tumor-associated macrophages (TAMs) are recently verified to facilitate gemcitabine resistance. However, the effect of CAFs in regulating TAMs function in pancreatic cancer (PCa) remains unclear. Here, primary CAFs were extracted from tumor tissues of PCa patients, and CAFs-derived exosomes (CAFs-Exo) were acquired and authenticated by transmission electron microscopy, qNano, and western blot analysis. The role of exosomal miRNA-320a in facilitating macrophage M2 polarization was investigated in vitro. We found that CAFs-derived conditioned medium (CM) possessed a higher potential to promote macrophage M2 polarization compared with normal fibroblasts (NFs) or PCa cell-derived CM. Furthermore, CAFs-Exo treatment polarized macrophage to M2 phenotype. miRNA-320a levels were remarkably increased in CAFs-Exo versus NFs-Exo. More important, miRNA-320a could be transferred from CAFs to macrophages through exosomes, and miRNA-320a overexpression in macrophages facilitated its M2 polarization. Functionally, miRNA-320a-overexpressed macrophages facilitated PCa cell proliferation and invasion. CAFs pretreated with miRNA-320a inhibitor reduced miRNA-320a expression in CAFs-Exo and led to decreased M2 macrophage polarization. Finally, we verified that miRNA-320a polarized macrophage to M2 phenotype by regulating PTEN/PI3Kγ signaling. Taken together, the current data demonstrated that CAFs-derived exosomal miRNA-320a facilitated macrophage M2 polarization to accelerate malignant behavior of PCa cells.

11.
Nat Commun ; 13(1): 3723, 2022 Jun 28.
Article in English | MEDLINE | ID: mdl-35764620

ABSTRACT

In conventional ferromagnet/spacer/ferromagnet sandwiches, noncollinear couplings are commonly absent because of the low coupling energy and strong magnetization. For antiferromagnets (AFM), the small net moment can embody a low coupling energy as a sizable coupling field, however, such AFM sandwich structures have been scarcely explored. Here we demonstrate orthogonal interlayer coupling at room temperature in an all-antiferromagnetic junction Fe2O3/Cr2O3/Fe2O3, where the Néel vectors in the top and bottom Fe2O3 layers are strongly orthogonally coupled and the coupling strength is significantly affected by the thickness of the antiferromagnetic Cr2O3 spacer. From the energy and symmetry analysis, the direct coupling via uniform magnetic ordering in Cr2O3 spacer in our junction is excluded. The coupling is proposed to be mediated by the non-uniform domain wall state in the spacer. The strong long-range coupling in an antiferromagnetic junction provides an unexplored approach for designing antiferromagnetic structures and makes it a promising building block for antiferromagnetic devices.

12.
World J Surg Oncol ; 20(1): 158, 2022 May 18.
Article in English | MEDLINE | ID: mdl-35585636

ABSTRACT

BACKGROUND: Most retroperitoneal sarcoma (RPS) operations require combined multi-organ resection, and the proportion of unplanned reoperation is high. However, there are no relevant studies on reoperation for RPS. METHODS: Patients who underwent at least once unplanned reoperation at Shanghai Public Health Clinical Center, Fudan University, China, from August 2009 to December 2021 were retrospectively analyzed. The baseline characteristics, primary surgery, and reoperation information, postoperative complications, and survival were analyzed. RESULTS: A total of 51 patients were included. Among them, 21 (41.2%) were male and 30 (58.8%) were female. The median age was 51 (interquartile range [IQR], 49-63) years. Most (88.3%) had a history of abdominal surgery. Dedifferentiated liposarcoma, well-differentiated liposarcoma, leiomyosarcoma, and others accounted for 50.9%, 21.6%, 15.7%, and 11.8%, respectively. The conditions of the primary operation were as follows: 35 (68.6%) patients achieved complete surgical resection, 48 patients had combined organ resection, and a median of 3 (IQR, 2-4) organs was removed, of which 5 (9.9%) were combined with pancreaticoduodenectomy. The median operative time was 330 (IQR, 245-440) min, and the median estimated blood loss was 1500 (IQR, 500-2600) ml. The median postoperative hospital stay was 42 (IQR, 23-82) days. For reoperation, the most common reasons were bleeding (31.3%), complications related to intestinal anastomosis (27.4%), and intestinal perforation (19.9%). The mortality rate after reoperation was 39.2% (20/51). Twelve (23.5%) patients underwent reoperation at least twice. CONCLUSIONS: Unplanned reoperation among retroperitoneal sarcoma correlates with established measures of surgical quality.


Subject(s)
Retroperitoneal Neoplasms , Sarcoma , Soft Tissue Neoplasms , China , Female , Humans , Male , Middle Aged , Neoplasm Recurrence, Local/surgery , Reoperation , Retroperitoneal Neoplasms/surgery , Retrospective Studies , Sarcoma/surgery , Soft Tissue Neoplasms/surgery , Survival Rate
13.
Nano Lett ; 22(12): 4646-4653, 2022 Jun 22.
Article in English | MEDLINE | ID: mdl-35583209

ABSTRACT

As the core of spintronics, the transport of spin aims at a low-dissipation data process. The pure spin current transmission carried by magnons in antiferromagnetic insulators is natively endowed with superiority such as long-distance propagation and ultrafast speed. However, the traditional control of magnon transport in an antiferromagnet via a magnetic field or temperature variation adds critical inconvenience to practical applications. Controlling magnon transport by electric methods is a promising way to overcome such embarrassment and to promote the development of energy-efficient antiferromagnetic logic. Here, the experimental realization of an electric field-induced piezoelectric strain-controlled magnon spin current transmission through the antiferromagnetic insulator in the Y3Fe5O12/Cr2O3/Pt trilayer is reported. An efficient and nonvolatile manipulation of magnon propagation/blocking is achieved by changing the relative direction between the Néel vector and spin polarization, which is tuned by ferroelastic strain from the piezoelectric substrate. The piezoelectric strain-controlled antiferromagnetic magnon transport opens an avenue for the exploitation of antiferromagnet-based spin/magnon transistors with ultrahigh energy efficiency.

14.
ACS Appl Mater Interfaces ; 13(35): 42258-42265, 2021 Sep 08.
Article in English | MEDLINE | ID: mdl-34427434

ABSTRACT

An experimental study of the phenomenon of electric current influence on the value and orientation of the exchange bias field (HEB) in the Pt/Co/NiO structure is carried out. Depending on the direction of the magnetization in a ferromagnet (FM) layer and the current pulse amplitude, the value of the HEB field can be changed repeatedly in the range of ±7.5 mT. A few experiments are performed to separate the contributions from two current-induced effects: (i) an injection of the spin current into an antiferromagnet layer (AFM) and (ii) Joule heating. As a result, we conclude that the modification in the HEB field during current pulse transmission in the Pt/Co/NiO structure is due to heating and the low value of Néel temperature (TN = 162 °C). This fact explains the absence of the exchange bias effect on the spin-orbit torque (SOT)-assisted magnetization switching. The most striking observation to emerge from the experimental data analysis is that depending on the initial spin configuration of the domain structure in the FM layer and the current pulse amplitude, the exchange bias can be changed locally. This opens up prospects for creating exchange-coupled FM/AFM structures with dynamically tuned parameters of the exchange bias, which can be used for the development of magnetic memory, neuromorphic, and logic devices based on magnetic nanosystems.

15.
ACS Nano ; 15(5): 9076-9083, 2021 May 25.
Article in English | MEDLINE | ID: mdl-33977721

ABSTRACT

Spin-current and spin-wave-based devices have been considered as promising candidates for next-generation information transport and processing and wave-based computing technologies with low-power consumption. Spin pumping has attracted tremendous attention and has led to interesting phenomena, including the line width broadening, which indicates damping enhancement due to energy dissipation. Recently, chiral spin pumping of spin waves has been experimentally realized and theoretically studied in magnetic nanostructures. Here, we experimentally observe by Brillouin light scattering (BLS) microscopy the line width broadening sensitive to magnetization configuration in a hybrid metal-insulator nanostructure consisting of a Co nanowire grating dipolarly coupled to a planar continuous YIG film, consistent with the results of the measured hysteresis loop. Tunable line width broadening has been confirmed independently by propagating spin-wave spectroscopy, where unidirectional spin waves are detected. Position-dependent BLS measurement unravels an oscillating-like behavior of magnon populations in Co nanowire grating, which might result from the magnon trap effect. These results are thus attractive for reconfigurable nanomagnonics devices.

16.
Eur J Pharm Sci ; 153: 105488, 2020 Oct 01.
Article in English | MEDLINE | ID: mdl-32712217

ABSTRACT

Atomoxetine (ATX), a selective and potent inhibitor of the presynaptic norepinephrine transporter, is used mainly to treat attention-deficit hyperactivity disorder. Although multiple adverse effects associated with ATX have been reported including severe liver injuries, the mechanisms of ATX-related toxicity remain largely unknown. Metabolism frequently contributes to adverse effects of a drug through reactive metabolites, and the bioactivation status of ATX is still not investigated yet. Here, we systematically investigated ATX metabolism, bioactivation, species difference in human, mouse, and rat liver microsomes (HLM, MLM, and RLM) and in mice using metabolomic approaches as mice and rats are commonly used animal models for the studies of drug toxicity. We identified thirty one ATX metabolites and adducts in LMs and mice, 16 of which are novel. In LMs, we uncovered two methoxyamine-trapped aldehydes, two cyclization metabolites, detoluene-ATX, and ATX-N-hydroxylation for the first time. Detoluene-ATX and one cyclization metabolite were also observed in mice. Using chemical inhibitors and recombinant CYP enzymes, we demonstrated that CYP2C8 and CYP2B6 mainly contribute to the formation of aldehyde; CYP2D6 is the dominant enzyme for the formation of ATX cyclization and detoluene-ATX; CYP3A4 is major enzyme responsible for the hydroxylamine formation. The findings concerning aldehydes should be very useful to further elucidate the mechanistic aspects of adverse effects associated with ATX from metabolic angles. Additionally, the species differences for each metabolite should be helpful to investigate the contribution of specific metabolites to ATX toxicity and possible drug-drug interactions in suitable models.


Subject(s)
Attention Deficit Disorder with Hyperactivity , Microsomes, Liver , Animals , Atomoxetine Hydrochloride , Metabolomics , Mice , Norepinephrine , Rats
18.
Antioxid Redox Signal ; 30(16): 1900-1910, 2019 06 01.
Article in English | MEDLINE | ID: mdl-30358421

ABSTRACT

AIMS: Quantitative imaging of glutathione (GSH) with high spatial and temporal resolution is essential for studying the roles of GSH in redox biology. To study the long-standing question of compartmentalization of GSH, especially its distribution between the nucleus and cytosol, an organelle-targeted quantitative probe is needed. RESULTS: We developed a reversible reaction-based ratiometric fluorescent probe-HaloRT-that can quantitatively measure GSH dynamics with subcellular resolution in real time. Using HaloRT, we quantitatively measured the GSH concentrations in the nucleus and cytosol of HeLa cells and primary hepatocytes under different treatment conditions and found no appreciable concentration gradients between these two organelles. Innovation and Conclusion: We developed the first reversible ratiometric GSH probe that can be universally targeted to any organelle of interest. Taking advantage of this new tool, we provided definitive evidence showing that GSH concentrations are not significantly different between the nucleus and cytosol, challenging the view of nuclear compartmentalization of GSH.


Subject(s)
Biomarkers , Glutathione/metabolism , Molecular Imaging , Fluorescent Dyes/chemistry , Fluorescent Dyes/metabolism , HeLa Cells , Humans , Intracellular Space/metabolism , Microscopy, Confocal , Molecular Structure , Oxidation-Reduction
19.
Appl Radiat Isot ; 137: 91-101, 2018 Jul.
Article in English | MEDLINE | ID: mdl-29597105

ABSTRACT

Massive efforts have been made to investigate the characteristics of the CdZnTe detector under different extreme conditions. In this paper, we experimented with different radiation sources to investigate the imaging screening effect of the pixelated CdZnTe detector under ultrahigh irradiance. A donut-shaped irradiation image was obtained due to the increase in the X-ray tube current or the tube voltage. Moreover, statistical data revealed that the total count of all pixels was not significantly different, while the event-count of irradiated area pixels decreased significantly. A consequence of the screening effect was that the event counts redistributed among pixels that are located in the irradiated area, while the inner electric field was distorted. This leads to the catastrophic performance degradation of the central pixels. According to the Poisson equation, we developed a theoretical model of the CdZnTe detector using the finite element software COMSOL to enable an in-depth investigation of carrier collection in the CdZnTe crystal. A comparison between the simulations and the test results showed that pixels in the central irradiated area are completely screened under the ultrahigh irradiance because of the emergence of the relatively higher potential region, which can distort the electron drift path. Furthermore, the photon-generated signal can be collected only partly at the edge of the irradiated area, which was relatively stable because the collection area in the CdZnTe volume was relatively limited. The imaging results deduced from the simulations are well consistent with the experimental data.

20.
Proc Natl Acad Sci U S A ; 113(18): 4970-5, 2016 May 03.
Article in English | MEDLINE | ID: mdl-27084884

ABSTRACT

Protein-protein interactions (PPIs) play a central role in most biological processes, and therefore represent an important class of targets for therapeutic development. However, disrupting PPIs using small-molecule inhibitors (SMIs) is challenging and often deemed as "undruggable." We developed a cell-based functional assay for high-throughput screening to identify SMIs for steroid receptor coactivator-3 (SRC-3 or AIB1), a large and mostly unstructured nuclear protein. Without any SRC-3 structural information, we identified SI-2 as a highly promising SMI for SRC-3. SI-2 meets all of the criteria of Lipinski's rule [Lipinski et al. (2001) Adv Drug Deliv Rev 46(1-3):3-26] for a drug-like molecule and has a half-life of 1 h in a pharmacokinetics study and a reasonable oral availability in mice. As a SRC-3 SMI, SI-2 can selectively reduce the transcriptional activities and the protein concentrations of SRC-3 in cells through direct physical interactions with SRC-3, and selectively induce breast cancer cell death with IC50 values in the low nanomolar range (3-20 nM), but not affect normal cell viability. Furthermore, SI-2 can significantly inhibit primary tumor growth and reduce SRC-3 protein levels in a breast cancer mouse model. In a toxicology study, SI-2 caused minimal acute cardiotoxicity based on a hERG channel blocking assay and an unappreciable chronic toxicity to major organs based on histological analyses. We believe that this work could significantly improve breast cancer treatment through the development of "first-in-class" drugs that target oncogenic coactivators.


Subject(s)
Benzimidazoles/pharmacology , Hydrazones/pharmacology , Nuclear Receptor Coactivator 3/antagonists & inhibitors , Animals , Benzimidazoles/pharmacokinetics , Breast Neoplasms/pathology , Cell Line, Tumor , Female , Humans , Hydrazones/pharmacokinetics , Mice , Nuclear Receptor Coactivator 3/metabolism , Protein Processing, Post-Translational/drug effects , Transcription, Genetic/drug effects
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