Gaussian representation of coarse-grained interactions of liquids: Theory, parametrization, and transferability.

Coarse-grained (CG) interactions determined via bottom-up methodologies can faithfully reproduce the structural correlations observed in fine-grained (atomistic resolution) systems, yet they can suffer from limited extensibility due to complex many-body correlations. As part of an ongoing effort to understand and improve the applicability of bottom-up CG models, we propose an alternative approach to address both accuracy and transferability. Our main idea draws from classical perturbation theory to partition the hard sphere repulsive term from effective CG interactions. We then introduce Gaussian basis functions corresponding to the system's characteristic length by linking these Gaussian sub-interactions to the local particle densities at each coordination shell. The remaining perturbative long-range interaction can be treated as a collective solvation interaction, which we show exhibits a Gaussian form derived from integral equation theories. By applying this numerical parametrization protocol to CG liquid systems, our microscopic theory elucidates the emergence of Gaussian interactions in common phenomenological CG models. To facilitate transferability for these reduced descriptions, we further infer equations of state to determine the sub-interaction parameter as a function of the system variables. The reduced models exhibit excellent transferability across the thermodynamic state points. Furthermore, we propose a new strategy to design the cross-interactions between distinct CG sites in liquid mixtures. This involves combining each Gaussian in the proper radial domain, yielding accurate CG potentials of mean force and structural correlations for multi-component systems. Overall, our findings establish a solid foundation for constructing transferable bottom-up CG models of liquids with enhanced extensibility.

Pixel-Grouping G(E) Functions for Estimating Dose Rates from Unknown Source Distributions with a Position-Sensitive Detector.

Estimating accurate radiation doses when a radioactive source's location is unknown can protect workers from radiation exposure. Unfortunately, depending on a detector's shape and directional response variations, conventional G(E) function can be prone to inaccurate dose estimations. Therefore, this study estimated accurate radiation doses regardless of source distributions, using the multiple G(E) function groups (i.e., pixel-grouping G(E) functions) within a position-sensitive detector (PSD), which records the response position and energy inside the detector. Investigations revealed that, compared with the conventional G(E) function when source distributions are unknown, this study's proposed pixel-grouping G(E) functions improved dose estimation accuracy by more than 1.5 times. Furthermore, although the conventional G(E) function produced substantially larger errors in certain directions or energy ranges, the proposed pixel-grouping G(E) functions estimate doses with more uniform errors at all directions and energies. Therefore, the proposed method estimates the dose with high accuracy and provides reliable results regardless of the location and energy of the source.

Phyotochemical candidates repurposing for cancer therapy and their molecular mechanisms.

Though limited success through chemotherapy, radiotherapy and surgery has been obtained for efficient cancer therapy for modern decades, cancers are still considered high burden to human health worldwide to date. Recently repurposing drugs are attractive with lower cost and shorter time compared to classical drug discovery, just as Metformin from Galega officinalis, originally approved for treating Type 2 diabetes by FDA, is globally valued at millions of US dollars for cancer therapy. As most previous reviews focused on FDA approved drugs and synthetic agents, current review discussed the anticancer potential of phytochemicals originally approved for treatment of cardiovascular diseases, diabetes, infectious diarrhea, depression and malaria with their molecular mechanisms and efficacies and suggested future research perspectives.

Ghost imaging with Bayesian denoising method.

We propose a Bayesian denoising method to improve the quality of ghost imaging. The proposed method achieved the highest PSNR and SSIM in both binary and gray-scale targets with fewer measurements. Experimentally, it obtained a reconstructed image of a USAF target where the PSNR and SSIM of the image were up to 12.80 dB and 0.77, respectively, whereas those of traditional ghost images were 7.24 dB and 0.28 with 3000 measurements. Furthermore, it was robust against additive Gaussian noise. Thus, this method could make the ghost imaging technique more feasible as a practical application.

Discrete Convolution-Based Energy Spectrum Configuring Method for the Analysis of the Intrinsic Radiation of 176Lu.

There has been considerable interest in inorganic scintillators based on lutetium due to their favorable physical properties. Despite their advantages, lutetium-based scintillators could face issues because of the natural occurring radioisotope of 176Lu that is contained in natural lutetium. In order to mitigate its potential shortcomings, previous works have studied to understand the energy spectrum of the intrinsic radiation of 176Lu (IRL). However, few studies have focused on the various principal types of photon interactions with matter; in other words, only the full-energy peak according to the photoelectric effect or internal conversion have been considered for understanding the energy spectrum of IRL. Thus, the approach we have used in this study considers other principal types of photon interactions by convoluting each energy spectrum with combinations for generating the spectrum of the intrinsic radiation of 176Lu. From the results, we confirm that the method provides good agreement with the experiment. A significant contribution of this study is the provision of a new approach to process energy spectra induced by mutually independent radiation interactions as a single spectrum.

p53 dependent LGR5 inhibition and caspase 3 activation are critically involved in apoptotic effect of compound K and its combination therapy potential in HCT116 cells.

Though ginsenoside metabolite compound K was known to have antitumor effect in several cancers, its underlying apoptotic mechanism still remains unclear so far. Thus, in the present study, the apoptotic mechanism of compound K was explored in colorectal cancer cells (CRCs) in association with leucine rich repeat containing G protein-coupled receptor 5 (LGR5) that was overexpressed in colorectal cancers with poor survival rate. Here compound K significantly reduced viability of HCT116p53+/+ cells better than that of HCT116p53-/- cells. Consistently, compound K increased sub G1 population and attenuated the expression of LGR5, c-Myc, procaspase3, Pin1 in HCT116p53+/+ cells more than in HCT116p53-/- cells. Conversely, caspase 3 inhibitor Z-DEVD-FMK reversed inhibitory effect of compound K on LGR5, c-Myc and procaspase3 in HCT116 cells. Consistently, inhibition of LGR5 using transfection method enhanced suppression of pro-PARP, Bcl-xL c-Myc, Snail and Pin1 in compound K treated HCT116p53+/+ cells. Furthermore, compound K synergistically potentiated antitumor effect of 5-fluorouracil (5-FU) or Doxorubicin to reduce the survival genes and cytotoxicity in HCT116p53+/+ cells. Overall, our findings provide scientific insight that compound K induces apoptosis in colon cancer cells via caspase and p53 dependent LGR5 inhibition with combination therapy potential with 5-FU or doxorubicin.

Molecular networks of FOXP family: dual biologic functions, interplay with other molecules and clinical implications in cancer progression.

Though Forkhead box P (FOXP) transcription factors comprising of FOXP1, FOXP2, FOXP3 and FOXP4 are involved in the embryonic development, immune disorders and cancer progression, the underlying function of FOXP3 targeting CD4 + CD25+ regulatory T (Treg) cells and the dual roles of FOXP proteins as an oncogene or a tumor suppressor are unclear and controversial in cancers to date. Thus, the present review highlighted research history, dual roles of FOXP proteins as a tumor suppressor or an oncogene, their molecular networks with other proteins and noncoding RNAs, cellular immunotherapy targeting FOXP3, and clinical implications in cancer progression.

Single dose of dexamethasone is not associated with postoperative recurrence and mortality in breast cancer patients: a propensity-matched cohort study.

BACKGROUND: Dexamethasone is widely used in cancer patients despite the concern that perioperative glucocorticoids may potentially cause immunosuppression. However, studies on the influence of dexamethasone on cancer recurrence after curative surgery have produced conflicting results. The goal of our study was to compare postoperative recurrence-free survival and overall survival between patients with breast cancer who received perioperative dexamethasone and those who did not. METHODS: The medical records of 2729 patients who underwent breast cancer surgery between November 2005 and December 2010 were reviewed. These patients were followed up until December 2015. The patients were categorised according whether they received a single dose of intravenous dexamethasone perioperatively or not. Cox regression analyses were conducted to evaluate any associations between dexamethasone usage with postoperative recurrence and mortality. Additionally, we performed a sensitivity test with propensity score matching to adjust for selection bias. RESULTS: Among the 2628 patients, 236 (8.5%) received perioperative dexamethasone. No increasing risk for recurrence (hazard ratio [HR], 1.442; 95% confidence interval [CI], 0.969-2.145; P = 0.071) or mortality (HR, 1.256; 95% CI, 0.770-2.047; P = 0.361) after breast cancer surgery were identified in patients who received dexamethasone. Similarly, propensity score matching did not show significant associations in postoperative recurrence (HR, 1.389; 95% CI, 0.904-2.132; P = 0.133) or mortality (HR, 1.506; 95% CI, 0.886-2.561; P = 0.130) in patients who received dexamethasone. CONCLUSIONS: We found that a perioperative single dose of dexamethasone is not associated with increased recurrence or mortality after curative surgery in breast cancer patients.

Suppression of STAT3 Phosphorylation and RelA/p65 Acetylation Mediated by MicroRNA134 Plays a Pivotal Role in the Apoptotic Effect of Lambertianic Acid.

As p300-mediated RelA/p65 hyperacetylation by signal transducers and activators of transcription 3 (STAT3) is critical for NF-κB activation, in the current study, the apoptotic mechanism of lambertianic acid (LA) was explored in relation to STAT3 phosphorylation and RelA/p65 acetylation in MCF-7, DU145, PC-3, and MDA-MB-453 cells. LA significantly increased the cytotoxicity, sub G 1 population, and the cleavage of poly (ADP-ribose) polymerase (PARP) in MDA-MB-453 or PC-3 cells (STAT3 mutant), more than in the MCF-7 or DU145 cells (STAT3 wild). Consistently, LA inhibited the phosphorylation of STAT3 and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and disrupted the interaction between p-STAT3, p300, NF-κB, and RelA/p65 acetylation (Ac-RelA/p65) in the MCF-7 and DU145 cells. Also, LA reduced the nuclear translocation of STAT3 and NF-κB via their colocalization, and also suppressed the protein expression of XIAP, survivin, Bcl-2, Bcl-xL, vascular endothelial growth factor (VEGF), Cox-2, c-Myc and mRNA expression of interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α) in MCF-7 cells. Conversely, IL-6 blocked the ability of LA to suppress the cytotoxicity and PARP cleavage, while the depletion of STAT3 or p300 enhanced the PARP cleavage of LA in the MCF-7 cells. Notably, LA upregulated the level of miRNA134 and so miRNA134 mimic attenuated the expression of pro-PARP, p-STAT3, and Ac-RelA, while the miRNA134 inhibitor reversed the ability of LA to reduce the expression of Ac-RelA and pro-PARP in MCF-7 cells. Overall, these findings suggest that LA induced apoptosis via the miRNA-134 mediated inhibition of STAT3 and RelA/p65 acetylation.

Lambertianic Acid Sensitizes Non-Small Cell Lung Cancers to TRAIL-Induced Apoptosis via Inhibition of XIAP/NF-κB and Activation of Caspases and Death Receptor 4.

Lambertianic acid (LA) is a biologically active compound from the leaves of Pinus koraiensis. In the present study, apoptotic mechanisms of LA plus TNF-related apoptosis-inducing ligand (TRAIL) were elucidated in non-small cell lung cancer cells (NSCLCs). Cytotoxicity assay, flow cytometry, immunoprecipitation, and Western blotting were performed. Here, combined treatment of LA and TRAIL increased cytotoxicity, sub-G1 population, cleaved poly (ADP-ribose) polymerase (PARP), and caspase3/8/9 in A549 and H1299 cells compared to LA or TRAIL alone. Furthermore, combined treatment of LA and TRAIL significantly decreased antiapoptotic proteins such as B-cell lymphoma 2 (Bcl-2), Fas-like inhibitor protein (FLIP), and X-linked inhibitor of apoptosis protein (XIAP), and enhanced the activation of proapoptotic proteins Bid compared to LA or TRAIL alone. In addition, combined treatment of LA and TRAIL upregulated the expression of Death receptor 4 (DR4) and downregulated phosphorylation of nuclear factor κ-light-chain-enhancer of activated B cells (p-NF-κB), inhibitory protein of kB family (p-IκB), and FLIP in A549 and H1299 cells along with disrupted binding of XIAP with caspase3 or NF-κB. Overall, these findings suggest that lambertianic acid enhances TRAIL-induced apoptosis via inhibition of XIAP/NF-κB in TRAIL resistant NSCLCs.

The Anti-Wrinkle Mechanism of Melatonin in UVB Treated HaCaT Keratinocytes and Hairless Mice via Inhibition of ROS and Sonic Hedgehog Mediated Inflammatory Proteins.

Though melatonin is known to improve ultraviolet B (UVB)-induced oxidative damage and inflammatory conditions via the blockade of the nuclear factor (NF)-κB, interleukin (IL)-6, there is no report on the anti-wrinkle effect of melatonin to date. Hence in the present study, the anti-wrinkle mechanism of melatonin was elucidated in UVB treated HaCaT keratinocytes and hairless mice. Herein melatonin protected against a radical initiator tert-Butyl hydroperoxide (t-BOOH) induced reactive oxygen species (ROS) production, matrix metalloprotease 1 (MMP-1), pro-collagen and cytotoxicity in HaCaT keratinocytes. Additionally, melatonin suppressed the expression of sonic hedgehog (SHH) and GLI1 for hedgehog signaling and p-NF-κB, cyclooxygenase (COX-2), phospho-extracellular signal-regulated kinase-1 (p-ERK) for inflammatory responses in UVB treated HaCaT keratinocytes. Furthermore, melatonin protected skin from wrinkle formation, transdermal water loss in hairless mice irradiated by UVB for 8 weeks. Notably, melatonin prevented against epidermal thickness and dermal collagen degradation in UVB irradiated hairless mice by Hematoxylin and Eosin and Masson’s trichrome staining. Taken together, these findings suggest that melatonin reduces wrinkle formation via inhibition of ROS/SHH and inflammatory proteins such as NF-κB/COX-2/ERK/MMP1.

Inhibition of Wnt3a/FOXM1/ß-Catenin Axis and Activation of GSK3ß and Caspases are Critically Involved in Apoptotic Effect of Moracin D in Breast Cancers.

Although Moracin D derived from Morus alba was known to have anti-inflammatory and antioxidant activities, the underlying antitumor mechanism of Moracin D has not been unveiled thus far. Thus, in the recent study, the apoptotic mechanism of Moracin D was elucidated in breast cancer cells. Herein, Moracin D exerted significant cytotoxicity in MDA-MB-231 and MCF-7 cells. Furthermore, Moracin D increased sub G1 population; cleaved poly (Adenosine diphosphate (ADP-ribose)) polymerase (PARP); activated cysteine aspartyl-specific protease 3 (caspase 3); and attenuated the expression of c-Myc, cyclin D1, B-cell lymphoma 2 (Bcl-2), and X-linked inhibitor of apoptosis protein (XIAP) in MDA-MB231 cells. Of note, Moracin D reduced expression of Forkhead box M1 (FOXM1), ß-catenin, Wnt3a, and upregulated glycogen synthase kinase 3 beta (GSK3ß) on Tyr216 along with disturbed binding of FOXM1 with ß-catenin in MDA-MB-231 cells. Conversely, GSK3ß inhibitor SB216763 reversed the apoptotic ability of Moracin D to reduce expression of FOXM1, ß-catenin, pro-caspase3, and pro-PARP in MDA-MB-231 cells. Overall, these findings provide novel insight that Moracin D inhibits proliferation and induces apoptosis via suppression of Wnt3a/FOXM1/ß-catenin signaling and activation of caspases and GSK3ß.

Estimation of ambient dose equivalent rate with a plastic scintillation detector using the least-square and first-order methods-based G(E) function.

Dose-rate monitoring instruments measure the ambient dose equivalent and hence are crucial for protecting workers from radiation exposure. Although plastic scintillation detectors (PSDs) are ideal equipment for dosimetry, they are rarely used owing to the lower detection efficiency than other scintillation detectors. In this study, we acquired ten types of G(E) functions to utilize a PSD in spectroscopic dosimetry using the least-square and first-order methods. The energy response of PSD was much improved in terms of dose evaluation.

Pulse height estimation and pulse shape discrimination in pile-up neutron and gamma ray signals from an organic scintillation detector using multi-task learning.

We developed a multi-tasking deep learning model for simultaneous pulse height estimation and pulse shape discrimination for pile-up n/γ signals. Compared with single-tasking models, our model showed better spectral correction performance with higher recall for neutrons. Further, it achieved more stable neutron counting with less signal loss and a lower error rate in the predicted gamma ray spectra. Our model can be applied to a dual radiation scintillation detector to discriminatively reconstruct each radiation spectrum for radioisotope identification and quantitative analysis.

The Effect of Additional Stepwise Venous Inflow on Differential Hypoxia of Veno-Arterial Extracorporeal Membrane Oxygenation.

Use of femoral-femoral veno-arterial (VA) extracorporeal membrane oxygenation (ECMO) for cardiopulmonary support during lung transplantation can be inadequate for efficient distribution of oxygenated blood into the coronary circulation. We hypothesized that creating a left-to-right shunt flow using veno-arterio-venous (VAV) ECMO would alleviate the differential hypoxia. Total 10 patients undergoing lung transplantation were enrolled in this study. An additional inflow cannula was inserted into the right internal jugular (RIJ) vein for VAV ECMO. During left one-lung ventilation using a 1.0 inspired oxygen fraction (FiO2), the left-to-right shunt flow was incrementally increased from 0 to 500, 1,000, and 1,500 ml/min. The arterial oxygen partial pressure (PaO2) and oxygen saturation (SaO2) were measured at the proximal ascending aorta and right radial artery. The ascending aorta gas analysis revealed that six patients had a PaO2/FiO2 ratio less than 200 mm Hg at a 0 ml/min shunt flow. The PaO2 (SaO2) values were 48.5 ± 14.8 mm Hg (80.9 ± 11.6%) at the ascending aorta and 77.8 ± 69.7 mm Hg (83.3 ± 13.2%) at the right radial artery. As the left-to-right shunt flow rate increased over 1,000 ml/min, the PaO2 and SaO2 values for the ascending aorta and right radial artery significantly increased. In conclusion, femoral-femoral VA ECMO can produce suboptimal coronary oxygenation in patients unable to tolerate one-lung ventilation. A left-to-right shunt using VAV ECMO can alleviate the differential hypoxia.

The Pivotal Role of Long Noncoding RNA RAB5IF in the Proliferation of Hepatocellular Carcinoma Via LGR5 Mediated ß-Catenin and c-Myc Signaling.

In the current study, the function of long noncoding RNA (LncRNA) RAB5IF was elucidated in hepatocellular carcinoma (HCCs) in association with LGR5 related signaling. Here TCGA analysis revealed that LncRNA RAB5IF was overexpressed in HCC, and its overexpression level was significantly (p < 0.05) correlated with poor prognosis in patients with HCC. Furthermore, LncRNA RAB5IF depletion suppressed cell proliferation and colony formation, increased sub G1 population, cleavage of poly ADP-ribose polymerase (PARP) and cysteine aspartyl-specific protease (caspase 3) and attenuated the expression of procaspase 3, pro-PARP and B-cell lymphoma 2 (Bcl-2) in HepG2 and Hep3B cells. Furthermore, LncRNA RAB5IF depletion reduced the expression of LGR5 and its downstreams such as ß-catenin and c-Myc in HepG2 and Hep3B cells. Notably, LGR5 depletion also attenuated the expression of pro-PARP, pro-caspase3, ß-catenin and c-Myc in HepG2 and Hep3B cells. Conversely, LGR5 overexpression upregulated ß-catenin and c-Myc in Alpha Mouse Liver 12 (AML-12) normal hepatocytes. Overall, these findings provide novel evidence that LncRNA RAB5IF promotes the growth of hepatocellular carcinoma cells via LGR5 mediated ß-catenin and c-Myc signaling as a potent oncogenic target.

CNOT2 Is Critically Involved in Atorvastatin Induced Apoptotic and Autophagic Cell Death in Non-Small Cell Lung Cancers.

Though Atorvastatin has been used as a hypolipidemic agent, its anticancer mechanisms for repurposing are not fully understood so far. Thus, in the current study, its apoptotic and autophagic mechanisms were investigated in non-small cell lung cancers (NSCLCs). Atorvastatin increased cytotoxicity, sub G1 population, the number of apoptotic bodies, cleaved poly (ADP-ribose) polymerase (PARP) and caspase 3 and activated p53 in H1299, H596, and H460 cells. Notably, Atorvastatin inhibited the expression of c-Myc and induced ribosomal protein L5 and L11, but depletion of L5 reduced PARP cleavages induced by Atorvastatin rather than L11 in H1299 cells. Also, Atorvastatin increased autophagy microtubule-associated protein 1A/1B-light chain 3II (LC3 II) conversion, p62/sequestosome 1 (SQSTM1) accumulation with increased number of LC3II puncta in H1299 cells. However, late stage autophagy inhibitor chloroquine (CQ) increased cytotoxicity in Atorvastatin treated H1299 cells compared to early stage autophagy inhibitor 3-methyladenine (3-MA). Furthermore, autophagic flux assay using RFP-GFP-LC3 constructs and Lysotracker Red or acridine orange-staining demonstrated that autophagosome-lysosome fusion is blocked by Atorvastatin treatment in H1299 cells. Conversely, overexpression of CCR4-NOT transcription complex subunit 2(CNOT2) weakly reversed the ability of Atorvastatin to increase cytotoxicity, sub G1 population, cleavages of PARP and caspase 3, LC3II conversion and p62/SQSTM1 accumulation in H1299 cells. In contrast, CNOT2 depletion enhanced cleavages of PARP and caspase 3, LC3 conversion and p62/SQSTM1 accumulation in Atorvastatin treated H1299 cells. Overall, these findings suggest that CNOT2 signaling is critically involved in Atorvastatin induced apoptotic and autophagic cell death in NSCLCs.