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1.
PLoS Pathog ; 16(3): e1008459, 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-32226051

RESUMO

Hepatitis B virus (HBV) delivers a partially double-stranded, relaxed circular (RC) DNA genome in complete virions to the host cell nucleus for conversion to the covalently closed circular (CCC) DNA, which establishes and sustains viral infection. An overlength pregenomic RNA (pgRNA) is then transcribed from CCC DNA and packaged into immature nucleocapsids (NCs) by the viral core (HBc) protein. pgRNA is reverse transcribed to produce RC DNA in mature NCs, which are then enveloped and secreted as complete virions, or delivered to the nucleus to replenish the nuclear CCC DNA pool. RC DNA, whether originating from extracellular virions or intracellular mature NCs, must be released upon NC disassembly (uncoating) for CCC DNA formation. HBc is known to undergo dynamic phosphorylation and dephosphorylation at its C-terminal domain (CTD) to facilitate pgRNA packaging and reverse transcription. Here, two putative phosphorylation sites in the HBc N-terminal domain (NTD), S44 and S49, were targeted for genetic and biochemical analysis to assess their potential roles in viral replication. The NTD mutant that mimics the non-phosphorylated state (N2A) was competent in all steps of viral replication tested from capsid assembly, pgRNA packaging, reverse transcription, to virion secretion, except for a decrease in CCC DNA formation. On the other hand, the phosphor-mimetic mutant N2E showed a defect in the early step of pgRNA packaging but enhanced the late step of mature NC uncoating and consequently, increased CCC DNA formation. N2E also enhanced phosphorylation in CTD and possibly elsewhere in HBc. Furthermore, inhibition of the cyclin-dependent kinase 2 (CDK2), which is packaged into viral capsids, could block CCC DNA formation. These results prompted us to propose a model whereby rephosphorylation of HBc at both NTD and CTD by the packaged CDK2, following CTD dephosphorylation during NC maturation, facilitates uncoating and CCC DNA formation by destabilizing mature NCs.

2.
Artigo em Inglês | MEDLINE | ID: mdl-32139878

RESUMO

BACKGROUND: The androgen receptor (AR) is a key prostate cancer drug target. Suppression of AR signaling mediated by the full-length AR (AR-FL) is the therapeutic goal of all existing AR-directed therapies. AR-targeting agents impart therapeutic benefit, but lead to AR aberrations that underlie disease progression and therapeutic resistance. Among the AR aberrations specific to castration-resistant prostate cancer (CRPC), AR variants (AR-Vs) have emerged as important indicators of disease progression and therapeutic resistance. METHODS: We conducted a systemic review of the literature focusing on recent laboratory studies on AR-Vs following our last review article published in 2016. Topics ranged from measurement and detection, molecular origin, regulation, genomic function, and preclinical therapeutic targeting of AR-Vs. We provide expert opinions and perspectives on these topics. RESULTS: Transcript sequences for 22 AR-Vs have been reported in the literature. Different AR-Vs may arise through different mechanisms, and can be regulated by splicing factors and dictated by genomic rearrangements, but a low-androgen environment is a prerequisite for generation of AR-Vs. The unique transcript structures allowed development of in situ and in-solution measurement and detection methods, including mRNA and protein detection, in both tissue and blood specimens. AR-V7 remains the main measurement target and the most extensively characterized AR-V. Although AR-V7 coexists with AR-FL, genomic functions mediated by AR-V7 do not require the presence of AR-FL. The distinct cistromes and transcriptional programs directed by AR-V7 and their coregulators are consistent with genomic features of progressive disease in a low-androgen environment. Preclinical development of AR-V-directed agents currently focuses on suppression of mRNA expression and protein degradation as well as targeting of the amino-terminal domain. CONCLUSIONS: Current literature continues to support AR-Vs as biomarkers and therapeutic targets in prostate cancer. Laboratory investigations reveal both challenges and opportunities in targeting AR-Vs to overcome resistance to current AR-directed therapies.

3.
Biochem Pharmacol ; 175: 113898, 2020 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-32145262

RESUMO

Porcine milk exosomes play an important role in mother-infant communication. Deoxynivalenol (DON) is a toxin which causes serious damage to the animal intestinal mucosa. Our previous study showed porcine milk exosomes facilitate mice intestine development, but the effects of these exosomes to antagonize DON toxicity is unclear. Our in vivo results showed that milk exosomes attenuated DON-induced damage on the mouse body weight and intestinal epithelium growth. In addition, these exosomes could reverse DON-induced inhibition on cell proliferation and tight junction proteins (TJs) formation and reduce DON-induced cell apoptosis. In vitro, exosomes up-regulated the expression of miR-181a, miR-30c, miR-365-5p and miR-769-3p in IPEC-J2 cells and then down-regulated the expression of their targeting genes in p53 pathway, ultimately attenuating DON-induced damage by promoting cell proliferation and TJs and by inhibiting cell apoptosis. In conclusion, porcine milk exosomes could protect the intestine against DON damage, and these protections may take place through the miRNAs in exosomes. These results indicated that the addition of miRNA-enriched exosomes to feed or food could be used as a novel preventative measure for necrotizing enterocolitis.

4.
Fitoterapia ; 143: 104546, 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32173423

RESUMO

Eight new compounds (Entanutilins O-V; 1-8), including four limonoids, two steroids, one triterpenoid and one lignan were isolated from the stem barks of Entandrophragma utile. Their structures were determined by detailed spectroscopic analyses (HRESIMS and 1D/2D-NMR). Bioactivity screening indicated that compounds 1, 6 and 7 exhibited effective in reversing resistance in MCF-7/DOX cells at a nontoxic concentration of 30 µM with 18.18-, 7.43- and 7.94-fold enhancing effect, respectively, meanwhile, compounds 5 and 6 showed moderate NO inhibitory activities in LPS-activated RAW 264.7 macrophages.

5.
Nature ; 579(7799): 368-374, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32188941

RESUMO

Two-dimensional van der Waals heterostructures (vdWHs) have attracted considerable interest1-4. However, most vdWHs reported so far  are created by an arduous micromechanical exfoliation and manual restacking process5, which-although versatile for proof-of-concept demonstrations6-16 and fundamental studies17-30-is clearly not scalable for practical technologies. Here we report a general synthetic strategy for two-dimensional vdWH arrays between metallic transition-metal dichalcogenides (m-TMDs) and semiconducting TMDs (s-TMDs). By selectively patterning nucleation sites on monolayer or bilayer s-TMDs, we precisely control the nucleation and growth of diverse m-TMDs with designable periodic arrangements and tunable lateral dimensions at the predesignated spatial locations, producing a series of vdWH arrays, including VSe2/WSe2, NiTe2/WSe2, CoTe2/WSe2, NbTe2/WSe2, VS2/WSe2, VSe2/MoS2 and VSe2/WS2. Systematic scanning transmission electron microscopy studies reveal nearly ideal vdW interfaces with widely tunable moiré superlattices. With the atomically clean vdW interface, we further show that the m-TMDs function as highly reliable synthetic vdW contacts for the underlying WSe2 with excellent device performance and yield, delivering a high ON-current density of up to 900 microamperes per micrometre in bilayer WSe2 transistors. This general synthesis of diverse two-dimensional vdWH arrays provides a versatile material platform for exploring exotic physics and promises a scalable pathway to high-performance devices.

6.
Artigo em Inglês | MEDLINE | ID: mdl-32203015

RESUMO

OBJECTIVE: For heart transplantation, donor heart status needs to be evaluated during normothermic ex situ perfusion (ESHP). Left ventricular end-systolic elastance (Ees) measures the left ventricular contractile function, but its estimation requires the occlusion of the left atrium line in the ESHP, which may cause unnecessary damage to the donor heart. We present a novel method to quantify Ees based on hemodynamic parameters obtained from only one steady-state PV loop in ESHP. METHODS: Ees was obtained by the end-systolic point (Pes, Ves) and the volume axis intercept point of Ees (V0). V0 was estimated through the support vector machine regression (SVR) method using parameters derived from the measured steady-state PV loop. To achieve high V0 estimation accuracy, a filter-based support vector machine recursive feature elimination method (SVM-RFE) algorithm selected the parameters for V0 estimation. Hemodynamic parameter samples (n = 101) obtained from ESHP experiments with pig s hearts were used to train the Ees calculation model. Early post-transplantation outcomes in six heart transplantation experiments were then estimated from the trained Ees calculation model. RESULTS: Ees calculated by the proposed method agreed well with conventional multi-beat estimates obtained by the occlusion process (r = 0.88, p < 0.001, n = 101) and was capable of predicting the early post-transplant cardiac index (r = 0.84, p < 0.05, n = 6). CONCLUSION: This method effectively assesses left ventricular contractility during ESHP and predicts early post-transplant outcomes in the porcine model. SIGNIFICANCE: Our approach is the first to quantify Ees by estimating V0 from steady-state beats in ESHP for accurately predicting early post-transplantation outcomes.

7.
Medicine (Baltimore) ; 99(12): e19276, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32195932

RESUMO

This study aimed to investigate the efficacy and safety of drug-eluting beads (DEB) transarterial chemoembolization (TACE) treatment in Chinese intrahepatic cholangiocarcinoma (ICC) patients.37 ICC patients underwent DEB-TACE treatment in CTILC study (registered on clinicaltrials.gov with registry No. NCT03317483) were included in this present study. Treatment response was assessed according to modified Response Evaluation Criteria in Solid Tumors (mRECIST). Overall survival (OS) was calculated from the time of DEB-TACE operation until the date of death from any causes. Liver function change and adverse events (AEs) were recorded during and after DEB-TACE operation.3 (8.1%) patients achieved complete response (CR) and 22 (59.5%) patients achieved partial response (PR), with objective response rate (ORR) of 67.6%. After DEB-TACE treatment, mean OS was 376 days (95%CI: 341-412 days). Multivariate logistic regression analysis revealed that Bilobar disease (P = .040, OR: 0.105, 95% CI: 0.012-0.898) and portal vein invasion (P = .038, OR: 0.104, 95% CI: 0.012-0.881) could independently predict less possibility of ORR. Patients with ALB abnormal, TP abnormal, ALT abnormal and AST abnormal were increased at 1-week post DEB-TACE treatment (P = .034, P = .001, P < .001, P = .006, respectively), while returned to the levels at baseline after 1 to 3 months (all P > .050). Besides, most of the AEs were mild including pain, fever, vomiting, and nausea in this study.DEB-TACE was effective and well tolerated in treating ICC patients, and bilobar disease as well as portal vein invasion were independently correlated with less probability of ORR achievement.

8.
Chem Commun (Camb) ; 2020 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-32125332

RESUMO

Transition metal oxides are widely regarded as one of the most promising candidates for lithium-ion battery (LIB) anodes. However, the mechanisms of irreversible reactions occurring during the charging/discharging process are still controversial. In this study, the atomic structural transitions of the MnO@C anode upon lithiation/delithiation at the first cycle of charging and discharging are elucidated. Based on the quantities of Li embedded and released in different states, the anisotropy of the crystal plane of lithiation/delithiation in MnO is directly observed. We determine that lithium ions can be completely inserted into/extracted from MnO(220), while this cannot be achieved in MnO(200), which is the main reason for capacity degradation. This study reveals the reaction mechanisms and structural evolution in the electrochemical reactions of MnO@C anode materials during lithiation and delithiation. Additionally, it also provides guidance for the fabrication and optimization of MnO-based materials for LIBs in the future.

9.
Mol Cell Probes ; : 101540, 2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-32084582

RESUMO

AIM: LncRNA MALAT1 is involved in regulation of angiogenesis, however, its expression and mechanism in infantile hemangioma (IH) are less reported. The study aimed to investigate MALAT1 in IH and to reveal the potential mechanism of MALAT1 acting on IH. METHODS: Isolated form IH tissue, human CD31+ hemangioma endothelial cells (HemECs) were cultured and sorted by magnetic-activated cell sorting (MACS). Quantitative real-time (qRT)-PCR was performed to detect the expressions of MALAT1, miR-206 and VEGFA. The correlations among MALAT1, miR-206 and VEGFA were confirmed by bioinformatics analysis and dual-luciferase reporter assay. The effects of MALAT1, miR-206 and VEGFA on cell proliferation were detected by cell counting kit-8 (CCK-8) and cell colony formation assay. Flow cytometry, wound scratch, Transwell and Tube formation assay were performed to determine cell apoptosis, migration, invasion and vasoformation, respectively. Apoptosis-related proteins were determined by Western blot. RESULTS: The results showed that MALAT1 and VEGFA were high-expressed and miR-206 was low-expressed in IH tissues. SiMALAT1 negatively affected the cell proliferation, migration, invasion and vasoformation of HemECs and promoted apoptosis of HemECs. Moreover, Bcl-2 expression was significantly inhibited and the expressions of Bax and c cleaved-3 were greatly promoted. MALAT1 directly targeted and inhibited the expression of miR-206, and VEGFA was predicted to be the target gene for miR-206. SiMALAT1 suppressed the cell proliferation, migration, invasion and vasoformation of HemECs through modulating miR-206/VEGFA axis. CONCLUSION: Knock-down of MALAT1 inhibits the growth of HemECs through regulating miR-206/VEGFA axis, indicating that MALAT1 is a potential therapeutic mechanism for the treatment of IH.

10.
Phytochemistry ; 172: 112282, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32036186

RESUMO

Seventeen highly oxygenated and rearranged limonoids, including nine previously undescribed phragmalin-type limonoids with 1,8,9- and 8,9,30-orthesters (entanutilins C-K, 1-9), three undescribed limonoids with rare rearranged-6/6/7/5 skeleton (entanutilins L-N, 10-12), and 5 known limonoids, were isolated from the stem barks of Entandrophragma utile from Ghana (Africa). Their structures including absolute configurations were elucidated based on comprehensive spectroscopic analyses, such as HRESIMS, 1D/2D-NMR, CD exciton chirality method, time-dependent density functional theory (TDDFT)/ECD calculations, and single-crystal X-ray diffraction. Bioactivity screenings suggested that some of these compounds effectively reversed resistance in MCF-7/DOX cells at a nontoxic concentration of 30 µM with 6- to 19-fold enhancing effects.


Assuntos
Limoninas , Meliaceae , Cristalografia por Raios X , Humanos , Espectroscopia de Ressonância Magnética , Estrutura Molecular
11.
Chemosphere ; 249: 126097, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32078851

RESUMO

Benz(a)anthracene (BaA) is a polycyclic aromatic hydrocarbons (PAHs), that belongs to a group of carcinogenic and mutagenic persistent organic pollutants found in a variety of ecological habitats. In this study, the efficient biodegradation of BaA by a green alga Chlamydomonas reinhardtii (C. reinhardtii) CC-503 was investigated. The results showed that the growth of C. reinhardtii was hardly affected with an initial concentration of 10 mg/L, but was inhibited significantly under higher concentrations of BaA (>30 mg/L) (p < 0.05). We demonstrated that the relatively high concentration of 10 mg/L BaA was degraded completely in 11 days, which indicated that C. reinhardtii had an efficient degradation system. During the degradation, the intermediate metabolites were determined to be isomeric phenanthrene or anthracene, 2,6-diisopropylnaphthalene, 1,3-diisopropylnaphthalene, 1,7-diisopropylnaphthalene, and cyclohexanol. The enzymes involved in the degradation included the homogentisate 1,2-dioxygenase (HGD), the carboxymethylenebutenolidase, the ribulose 1,5-bisphosphate carboxylase/oxygenase (Rubisco) and the ubiquinol oxidase. The respective genes encoding these proteins were significantly up-regulated ranging from 3.17 fold to 13.03 fold and the activity of enzymes, such as HGD and Rubisco, was significantly induced up to 4.53 and 1.46 fold (p < 0.05), during the BaA metabolism. This efficient degradation ability suggests that the green alga C. reinhardtii CC-503 may be a sustainable candidate for PAHs remediation.

12.
J Anim Sci ; 98(3)2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32067038

RESUMO

A key member of the nuclear receptor superfamily is the peroxisome proliferator-activated receptor alpha (PPARA) isoform, which in nonruminants is closely associated with fatty acid oxidation. Whether PPARA plays a role in milk fatty acid synthesis in ruminants is unknown. The main objective of the present study was to use primary goat mammary epithelial cells (GMEC) to activate PPARA via the agonist WY-14643 (WY) or to silence it via transfection of small-interfering RNA (siRNA). Three copies of the peroxisome proliferator-activated receptor response element (PPRE) contained in a luciferase reporter vector were transfected into GMEC followed by incubation with WY at 0, 10, 20, 30, 50, or 100 µM. A dose of 50 µM WY was most effective at activating PPRE without influencing PPARA mRNA abundance. Transfecting siRNA targeting PPARA decreased its mRNA abundance to 20% and protein level to 50% of basal levels. Use of WY upregulated FASN, SCD1, ACSL1, DGAT1, FABP4, and CD36 (1.1-, 1.5-, 2-, 1.4-, 1.5-, and 5-fold, respectively), but downregulated DGAT2 and PGC1A (-20% and -40%, respectively) abundance. In contrast, triacylglycerol concentration decreased and the content and desaturation index of C16:1 and C18:1 increased. Thus, activation of PPARA via WY appeared to channel fatty acids away from esterification. Knockdown of PPARA via siRNA downregulated ACACA, SCD1, AGPAT6, CD36, HSL, and SREBF1 (-43%, -67%, -16%, -56%, -26%, and -29%, respectively), but upregulated ACSL1, DGAT2, FABP3, and PGC1A (2-, 1.4-, 1.3-, and 2.5-fold, respectively) mRNA abundance. A decrease in the content and desaturation index of C16:1 and C18:1 coupled with an increase in triacylglycerol content accompanied those effects at the mRNA level. Overall, data suggest that PPARA could promote the synthesis of MUFA in GMEC through its effects on mRNA abundance of genes related to fatty acid synthesis, oxidation, transport, and triacylglycerol synthesis.

13.
mBio ; 11(1)2020 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-32071277

RESUMO

The covalently closed circular (CCC) DNA of hepatitis B virus (HBV) functions as the only viral transcriptional template capable of producing all viral RNA species and is essential to initiate and sustain viral replication. CCC DNA is converted from a relaxed circular (RC) DNA, in which neither of the two DNA strands is covalently closed. As RC DNA mimics damaged cellular DNA, the host cell DNA damage repair (DDR) system is thought to be responsible for HBV CCC DNA formation. The potential role of two major cellular DDR pathways, the ataxia telangiectasia mutated (ATM) pathway and the ATM and Rad3-related (ATR) pathway, in HBV CCC DNA formation was thus investigated. Inhibition, or expression knockdown, of ATR and its downstream signaling factor CHK1, but not of ATM, decreased CCC DNA formation during de novo HBV infection, as well as intracellular CCC DNA amplification, when RC DNA from extracellular virions and intracellular nucleocapsids, respectively, is converted to CCC DNA. Furthermore, a novel RC DNA processing product with 5' truncated minus strands was detected when the ATR-CHK1 pathway was inhibited, further indicating that this pathway controls RC DNA processing during its conversion to CCC DNA. These results provide new insights into how host cells recognize and process HBV RC DNA in order to produce CCC DNA and have implications for potential means to block CCC DNA production.IMPORTANCE Hepatitis B virus (HBV) chronically infects hundreds of millions of people and remains a major cause of viral hepatitis, cirrhosis, and liver cancer. HBV persistence is sustained by a viral nuclear episome that directs all viral gene expression needed to support viral replication. The episome is converted from an incomplete DNA precursor in viral particles in an ill-understood process. We report here that the incomplete DNA precursor is recognized by the host cell in a way similar to the sensing of damaged cellular DNA for subsequent repair to form the nuclear episome. Intense efforts are ongoing to develop novel antiviral strategies to eliminate CCC DNA so as to cure chronic HBV infection. Our results here provide novel insights into, and suggest novel ways of perturbing, the process of episome formation. Furthermore, our results inform mechanisms of cellular DNA damage recognition and repair, processes essential for normal cell growth.

14.
J Agric Food Chem ; 68(10): 3277-3285, 2020 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-32054265

RESUMO

5-Hydroxy-l-tryptophan (5-HTP) is the primary product that converts l-tryptophan into 5-hydroxytryptamine by a rate-limiting enzyme. Our previous study found that 5-HTP could promote the intracellular calcium level in goat mammary epithelial cells (GMECs). Herein, first, dairy goats were injected with 5-HTP or saline daily from 7 days before delivery, and the calcium level in colostrum of 5-HTP-injected goats was significantly higher than that of saline-injected goats. Moreover, miR-99a-3p expression was significantly increased after 5-HTP treatment from transcriptome sequencing analysis and quantitative real-time polymerase chain reaction. In addition, it was found that ATP2B1 is one of the target genes of miR-99a-3p predicted by bioinformatic methods, which plays a crucial role in the maintenance of intracellular calcium homeostasis of mammary epithelial cells. Next, we confirmed that miR-99a-3p could increase the intracellular calcium level via decreasing ATP2B1 in GMECs. Taken together, we draw the conclusion that 5-HTP promotes the calcium level in colostrum possibly by increasing intracellular calcium of mammary epithelial cells induced by the miR-99a-3p/ATP2B1 axis.


Assuntos
5-Hidroxitriptofano/administração & dosagem , Cálcio/metabolismo , Células Epiteliais/metabolismo , Cabras/metabolismo , Glândulas Mamárias Animais/metabolismo , MicroRNAs/genética , Leite/química , Animais , Cálcio/análise , Células Epiteliais/efeitos dos fármacos , Feminino , Cabras/genética , Lactação , Glândulas Mamárias Animais/citologia , Glândulas Mamárias Animais/efeitos dos fármacos , MicroRNAs/metabolismo , Leite/metabolismo
15.
Biomed Pharmacother ; 125: 109918, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32036213

RESUMO

OBJECTIVES: Drug abuse is one of the most severe global social and public health problems, especially in China. However, objective blood biomarkers that are easy to detect are still in great need. This study was aim to explore the expression pattern of circulating microRNAs (miRNAs) in subjects with drug addiction and test the potential of altered serum miRNAs as noninvasive diagnostic tools for drug abuse. METHODS: Serum samples were obtained from 42 heroin abusers, 42 methamphetamine (MA) abusers and 42 controls. Microarray-based miRNA analysis was first applied to screen unique serum miRNA profiles in drug abusers on a training set of serum samples from 12 heroin abusers, 12 MA abusers and 12 control subjects. The expression levels of selected candidate miRNAs were subsequently verified in individual samples of the training set and further confirmed independently in a validation set of samples from 30 heroin abusers, 30 MA abusers and 30 controls using real-time quantitative polymerase chain reaction (RT-qPCR). RESULTS: Microarray analysis identified 116 and 109 significantly altered miRNAs in heroin abusers and MA abusers, respectively. Three miRNAs, including let-7b-5p, miR-206 and miR-486-5p, were verified to be significantly and steadily increased in heroin abusers, and miR-9-3p was significantly increased in MA abusers compared with normal controls. The areas under the curve (AUCs) of the ROC curve of these miRNAs ranged from 0.718 to 0.867. CONCLUSIONS: Our study raises the possibility that the altered serum miRNAs could potentially be used as an auxiliary tool to identify individuals in drug abuse and addiction.

16.
Fitoterapia ; 142: 104518, 2020 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-32092532

RESUMO

Aphanamoxene A-D (1-4), three new acyclic diterpene derivatives and one new acyclic norsesquiterpene were isolated from the seed of Aphanamixis polystachya. Their structures were elucidated on the basis of extensive spectroscopic methods, including 1D and 2D NMR and HRESIMS. And the absolute configuration of 1 was achieved by Mosher method. These acyclic terpenoids (1-4) showed obvious nitric oxide production inhibitory activity on lipopolysaccharide-Induced RAW264.7 macrophages with IC50 values of 17.6 ± 1.4, 9.8 ± 0.7, 16.6 ± 1.2, and 14.2 ± 0.9 µM, respectively.

17.
Phys Rev Lett ; 124(5): 051301, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32083933

RESUMO

We improve the test of the gravitational inverse-square law at the submillimeter range by suppressing the vibration of the electrostatic shielding membrane to reduce the disturbance coupled from the residual surface potential. The result shows that, at a 95% confidence level, the gravitational inverse-square law holds (|α|≤1) down to a length scale λ=48 µm. This work establishes the strongest bound on the magnitude α of the Yukawa violation in the range of 40-350 µm, and improves the previous bounds by up to a factor of 3 at the length scale λ≈70 µm. Furthermore, the constraints on the power-law potentials are improved by about a factor of 2 for k=4 and 5.

18.
Artigo em Inglês | MEDLINE | ID: mdl-32094489

RESUMO

BACKGROUND: Approximately 10-30% of men with mCRPC will test positive for AR-V7 using one of two analytically and clinically validated circulating tumor cell (CTC)-based assays. These men have poor outcomes with approved AR-targeting therapies but may retain sensitivity to chemotherapy. Here, we discuss the clinical implications of testing and strategies that may benefit AR splice variant (AR-V)-positive men and discuss whether such variants are passengers or drivers of aggressive clinical behavior. METHODS: We conducted a systemic review of the literature, covering updates since our 2016 review on androgen receptor variants in mCRPC, outcomes, and existing and novel approaches to therapy. We provide an expert opinion about management strategies for AR-V7-positive men and key unanswered research questions. RESULTS: AR-V7-positive men, defined by Epic nuclear protein detection or the modified AdnaTest mRNA detection in CTCs, identify a subset of men with mCRPC that have a low probability of response to AR-targeting therapy with short progression-free and overall survival in multivariable analyses. AR-variants do not exist in isolation, but rather in the context of a complex, heterogeneous, and evolving mCRPC genome and phenotype as well as patient-specific clinical heterogeneity, and multiple mechanisms of resistance likely exist in patients regardless of AR-V7 detection. Efforts to develop broader resistance assays are needed, and effective treatment strategies beyond taxanes are needed to address the causal driver role of AR-variants and to benefit patients with AR-V-expressing prostate cancer. CONCLUSIONS: CTC AR-V7 detection using the AdnaTest mRNA or Epic nuclear protein assays represents the first analytically and prospective clinically validated liquid biopsy assays that may inform treatment decisions in men with mCRPC, particularly after failure of first-line AR-therapy. The importance of AR-variants is likely to increase with the earlier use of AR-targeting strategies in other settings, and novel interventions for these men are needed.

19.
Oxid Med Cell Longev ; 2020: 9894037, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32089787

RESUMO

Alzheimer's disease (AD) is the most common cause of dementia among senior citizen. Ganoderma lucidum triterpenoids (GLTs) have nutritional health benefits and has been shown to promote health and longevity, but a protective effect of GLTs on AD damage has not yet been reported. The objective of this research was to elucidate the phylactic effect of GLTs on AD model mice and cells and to explore its underlying mechanisms. Morris water maze (MWM) test was conducted to detect changes in the cognitive function of mice. Hematoxylin-eosin (HE) staining was applied to observe pathological changes in the hippocampus. Silver nitrate staining was applied to observe the hippocampal neuronal tangles (NFTs). Apoptosis of the hippocampal neurons in mouse brain tissue was determined by TUNEL staining. The expression levels of apoptosis-related protein Bcl2, Bax, and caspase 3/cleaved caspase 3; antioxidative protein Nrf2, NQO1, and HO1; and ROCK signaling pathway-associated proteins ROCK2 and ROCK1 were measured by western blot. In vivo experiments show that 5-month-old APP/PS1 mice appeared to have impaired acquisition of spatial learning and GLTs could reduce cognitive impairment in AD mice. Compared to normal mice, the hippocampus of APP/PS1 mouse's brains was severely damaged, while GLTs could alleviate this symptom by inhibiting apoptosis, relieving oxidative damage, and inactivating the ROCK signaling pathway. In in vitro cell experiments, Aß 25-35 was applied to induce hippocampal neurons into AD model cells. GLTs promoted cell proliferation, facilitated superoxide dismutase (SOD) expression, and inhibited malondialdehyde (MDA) and lactic dehydrogenase (LDH) expression of neurons. Our study highlights that GLTs improve cognitive impairment, alleviate neuronal damage, and inhibit apoptosis in the hippocampus tissues and cells in AD through inhibiting the ROCK signaling pathway.

20.
Sci Rep ; 10(1): 140, 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31924846

RESUMO

Macrophage migration inhibitory factor (MIF) has been recognized as a major player in the pathogenesis of atherosclerosis. This study determined the association between polymorphisms of MIF gene and acute coronary syndrome (ACS). The polymorphism of MIF gene (rs755622, rs1007888 and rs2096525) was analyzed in 1153 healthy controls and 699 ACS cases in Chinese Han population. Plasma MIF level was also measured in part of ACS patients (139/19.9%) and healthy controls (129/11.2%) randomly. Most participants including healthy controls and ACS patients carried rs755622 GG (63.1% vs. 56.7%) and CG genotypes (33.1% vs. 38.9%) and G allele of rs755622 (79.6% vs. 76.1%, respectively), while CC genotype (3.8% vs. 4.4%) and C allele (20.4% vs. 23.9%) carriers were the lowest. Multivariate logistic regression analysis showed that carriers with rs755622 C allele had a higher risk of ACS compared to other genotypes (AOR = 1.278, 95% CI: 1.042-1.567). In addition, CC genotype carriers had the highest plasma levels of MIF than other genotype carriers. The MIF level in ACS patients with CC genotype was significantly higher than ACS patients carrying GG genotype and healthy controls carrying 3 different genotypes of MIF gene rs755622. Our findings indicate that MIF gene rs755622 variant C allele is associated with increased risk of ACS. Identification of this MIF gene polymorphism may help for predicting the risk of ACS.

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