The N-terminal domain of Lhcb proteins is critical for recognition of the LHCII kinase

AbstractThe light-harvesting chlorophyll (Chl) a/b complex of photosystem (PS) II (LHCII) plays important roles in the distribution of the excitation energy between the two PSs in the thylakoid membrane during state transitions. In this process, LHCII, homo- or heterotrimers composed of Lhcb1–3, migrate between PSII and PSI depending on the phosphorylation status of Lhcb1 and Lhcb2. We have studied the mechanisms of the substrate recognition of a thylakoid threonine kinase using reconstituted site-directed trimeric Lhcb protein–pigment complex mutants. Mutants lacking the positively charged residues R/K upstream of phosphorylation site (Thr) in the N-terminal domain of Lhcb1 were no longer phosphorylated. Besides, the length of the peptide upstream of the phosphorylated site (Thr) is also crucial for Lhcb phosphorylation in vitro. Furthermore, the two N-terminal residues of Lhcb appear to play a key role in the phosphorylation kinetics because Lhcb with N-terminal RR was phosphorylated much faster than with RK. Therefore, we conclude that the substrate recognition of the LHCII kinase is determined to a large extent by the N-terminal sequence of the Lhcb proteins. The study provides new insights into the interactions of the Lhcb proteins with the LHCII kinase

Dual blockage of STAT3 and ERK1/2 eliminates radioresistant GBM cells.

Radiotherapy (RT) is the major modality for control of glioblastoma multiforme (GBM), the most aggressive brain tumor in adults with poor prognosis and low patient survival rate. To improve the RT efficacy on GBM, the mechanism causing tumor adaptive radioresistance which leads to the failure of tumor control and lethal progression needs to be further elucidated. Here, we conducted a comparative analysis of RT-treated recurrent tumors versus primary counterparts in GBM patients, RT-treated orthotopic GBM tumors xenografts versus untreated tumors and radioresistant GBM cells versus wild type cells. The results reveal that activation of STAT3, a well-defined redox-sensitive transcriptional factor, is causally linked with GBM adaptive radioresistance. Database analysis also agrees with the worse prognosis in GBM patients due to the STAT3 expression-associated low RT responsiveness. However, although the radioresistant GBM cells can be resensitized by inhibition of STAT3, a fraction of radioresistant cells can still survive the RT combined with STAT3 inhibition or CRISPR/Cas9-mediated STAT3 knockout. A complementally enhanced activation of ERK1/2 by STAT3 inhibition is identified responsible for the survival of the remaining resistant tumor cells. Dual inhibition of ERK1/2 and STAT3 remarkably eliminates resistant GBM cells and inhibits tumor regrowth. These findings demonstrate a previously unknown feature ofSTAT3-mediated ERK1/2 regulation and an effective combination of two targets in resensitizing GBM to RT

Modelling of plasma response to 3D external magnetic field perturbations in EAST

Sustained mitigation and/or suppression of type-I edge localized modes (ELMs) has been achieved in EAST high-confinement plasmas, utilizing the resonant magnetic perturbation (RMP) fields produced by two rows of magnetic coils located just inside the vacuum vessel. Systematic toroidal modelling of the plasma response to these RMP fields with various coil configurations (with dominant toroidal mode number n = 1, 2, 3, 4) in EAST is, for the first time, carried out by using the MARS-F code (Liu et al 2000 Phys. Plasmas 7 3681), with results reported here. In particular, the plasma response is computed with varying coil phasing (the toroidal phase difference of the coil currents) between the upper and lower rows of coils, from 0 to 360°. Four figures of merit, constructed based on the MARS-F computations, are used to determine the optimal coil phasing. The modelled results, taking into account the plasma response, agree well with the experimental observations in terms of the coil phasing for both the mitigated and the suppressed ELM cases in EAST experiments. This study provides a crucial confirmation of the role of the plasma edge peeling response in ELM control, complementing similar studies carried out for other tokamak devices

Remodeling the Epigenetic Landscape of Cancer—Application Potential of Flavonoids in the Prevention and Treatment of Cancer

Epigenetics, including DNA methylation, histone modification, and noncoding RNA regulation, are physiological regulatory changes that affect gene expression without modifying the DNA sequence. Although epigenetic disorders are considered a sign of cell carcinogenesis and malignant events that affect tumor progression and drug resistance, in view of the reversible nature of epigenetic modifications, clinicians believe that associated mechanisms can be a key target for cancer prevention and treatment. In contrast, epidemiological and preclinical studies indicated that the epigenome is constantly reprogrammed by intake of natural organic compounds and the environment, suggesting the possibility of utilizing natural compounds to influence epigenetics in cancer therapy. Flavonoids, although not synthesized in the human body, can be consumed daily and are common in medicinal plants, vegetables, fruits, and tea. Recently, numerous reports provided evidence for the regulation of cancer epigenetics by flavonoids. Considering their origin in natural and food sources, few side effects, and remarkable biological activity, the epigenetic antitumor effects of flavonoids warrant further investigation. In this article, we summarized and analyzed the multi-dimensional epigenetic effects of all 6 subtypes of flavonoids (including flavonols, flavones, isoflavones, flavanones, flavanols, and anthocyanidin) in different cancer types. Additionally, our report also provides new insights and a promising direction for future research and development of flavonoids in tumor prevention and treatment via epigenetic modification, in order to realize their potential as cancer therapeutic agents

Genetic variants, pathophysiological pathways, and oral anticoagulation in patients with hypertrophic cardiomyopathy and atrial fibrillation

Atrial fibrillation (AF) is commonly prevalent in patients with hypertrophic cardiomyopathy (HCM). However, whether the prevalence and incidence of AF are different between genotype-positive vs. genotype-negative patients with HCM remains controversial. Recent evidence has indicated that AF is often the first presentation of genetic HCM patients in the absence of a cardiomyopathy phenotype, implying the importance of genetic testing in this population with early-onset AF. However, the association of the identified sarcomere gene variants with HCM occurrence in the future remains unclear. How the identification of these cardiomyopathy gene variants should influence the use of anticoagulation therapy for a patient with early-onset AF is still undefined. In this review, we sought to assess the genetic variants, pathophysiological pathways, and oral anticoagulation in patients with HCM and AF

Terahertz Probing Irreversible Phase Transitions Related to Polar Clusters in Bi0.5Na0.5TiO3-based Ferroelectric

Electric-field-induced phase transitions in Bi0.5Na0.5TiO3 (BNT)-based relaxor ferroelectrics are essential to the controlling of their electrical properties and consequently in revolutionizing their dielectric and piezoelectric applications. However, the fundamental understanding of these transitions is a long-standing challenge due to their complex crystal structures. Given the structural inhomogeneity at the nanoscale or sub-nanoscale in these materials, dielectric response characterization based on terahertz (THz) electromagnetic-probe beam-fields, is intrinsically coordinated to lattice dynamics during DC-biased poling cycles. The complex permittivity reveals the field-induced phase transitions to be irreversible. This profoundly counters the claim of reversibility, the conventional support for which, is based upon the peak that is manifest in each of four quadrants of the current-field curves. The mechanism of this irreversibility is solely attributed to polar clusters in the transformed lattices. These represent an extrinsic factor which is quiescent in the THz spectral domain

Intensity of Caring About an Action’s Side-Effect Mediates Attributions of Actor’s Intentions

The side-effect effect (SEE) is the observation that people’s intuition about whether an action was intentional depends on whether the outcome is good or bad. The asymmetric response, however, does not represent all subjects’ judgments (Nichols and Ulatowski, 2007). It remains unexplored on subjective factors that can mediate the size of SEE. Thus, the current study investigated whether an individual related factor, specifically, whether adults’ intensity of caring about an outcome of someone’s actions influences their judgments about whether that person intended the outcome. We hypothesized that participants’ judgments about fictional agents’ responsibility for their action’s side-effects would depend on how much they care about the domain of the side-effect. In two experiments, the intensity of caring affected participants’ ascription of intention to an agent’s negative unintended side-effect. The stronger ascription of intentionality to negative than positive side-effects (i.e., the SEE; Knobe, 2003) was found only in domains in which participants reported higher levels of caring. Also, the intensity of caring increased intentionality attributions reliably for negative side-effects but not for positive side-effects. These results suggest that caring about a domain mediates an asymmetrical ascription of intentionality to negative more than positive side-effects

Discovery and Validation of Nitroxoline as a Novel STAT3 Inhibitor in Drug-resistant Urothelial Bladder Cancer

Repeated cycles of first-line chemotherapy drugs such as doxorubicin (DOX) and cisplatin (CIS) trigger frequent chemoresistance in recurrent urothelial bladder cancer (UBC). Nitroxoline (NTX), an antibiotic to treat urinary tract infections, has been recently repurposed for cancer treatment. Here we aimed to investigate whether NTX suppresses drug-resistant UBC and its molecular mechanism. The drug-resistant cell lines T24/DOX and T24/CIS were established by continual exposure of parental cell line T24 to DOX and CIS, respectively. T24/DOX and T24/CIS cells were resistant to DOX and CIS, respectively, but they were sensitive to NTX time-and dose-dependently. Overexpressions of STAT3 and P-glycoprotein (P-gp) were identified in T24/DOX and T24/CIS, which could be reversed by NTX. Western blot revealed that NTX downregulated p-STAT3, c-Myc, Cyclin D1, CDK4, CDK6, Bcl-xL, Mcl-1, and Survivin, which were further confirmed by Stattic, a selective STAT3 inhibitor. In vivo, NTX exhibited the significant anti-tumor effect in T24/DOX and T24/CIS tumor-bearing mice. These results suggested that NTX-induced P-gp reversal, G0/G1 arrest, and apoptosis in drug-resistant UBC were mediated by inhibition of STAT3 signaling. Our findings repurpose NTX as a novel STAT3 inhibitor to induce P-gp reversal, G0/G1 arrest, and apoptosis in drug-resistant UBC

The Cell Cycle Checkpoint Gene, RAD17 rs1045051, Is Associated with Prostate Cancer Risk

Human RAD17, as an agonist of checkpoint signaling, plays an essential role in mediating DNA damage. This hospital-based case-control study aimed to explore the association between RAD17 rs1045051, a missense sin-gle nucleotide polymorphism (SNP), and prostate cancer risk. Subjects were 358 prostate cancer patients and 314 cancer-free urology patients undergoing treatment at the Zhujiang Hospital of Southern Medical University in China. RAD17 gene polymorphism rs1045051 was evaluated by the SNaPshot method. Compared with the RAD17 gene polymorphism rs1045051 AA genotype, there was a higher risk of prostate cancer for the CC gen-otype (adjusted odds ratio [AOR] = 1.731, 95% confidence interval [95%CI] = 1.031−2.908, p = 0.038). Compared with the A allele, the C allele was significantly associated with the disease status (AOR = 1.302, 95%CI = 1.037−1.634, p = 0.023). All these findings indicate that in the SNP rs1045051, both the CC genotype and C allele may have a substantial influence on the prostate cancer risk

Dual-Functional PLGA Nanoparticles Co-Loaded with Indocyanine Green and Resiquimod for Prostate Cancer Treatment

Purpose: With the advance of screening techniques, there is a growing number of low-risk or intermediate-risk prostate cancer (PCa) cases, remaining a serious threat to men's health. To obtain better efficacy, a growing interest has been attracted to develop such emerging treatments as immunotherapy and focal therapy. However, few studies offer guidance on whether and how to combine these modalities against PCa. This study was designed to develop dual-functional nanoparticles (NPs) which combined photothermal therapy (PTT) with immunotherapy and determine the anti-tumor efficacy for PCa treatment. Methods: By a double emulsion technique, the drug nanocarrier, poly(lactic-co-glycolic acid) or PLGA, was applied for co-loading of a fluorescent dye, indocyanine green (ICG) and a toll-like receptor 7/8 (TLR7/8) agonist resiquimod (R848) to synthesize PLGA-ICG-R848 NPs. Next, we determined their characteristic features and evaluated whether they inhibited the cell viability in multiple PCa cell lines. After treatment with PLGA-ICG-R848, the maturation markers of bone marrow-derived dendritic cells (BMDCs) were detected by flow cytometry. By establishing a subcutaneous xenograft model of mouse PCa, we explored both the anti-tumor effect and immune response following the NPs-based laser ablation. Results: With a mean diameter of 157.7 nm, PLGA-ICG-R848 exhibited no cytotoxic effect in PCa cells, but they significantly decreased RM9 cell viability to (3.9 +/- 1.0)% after laser irradiation. Moreover, PLGA-ICG-R848 promoted BMDCs maturation with the significantly elevated proportions of CD11c+CD86+ and CD11c+CD80+ cells. Following PLGA-ICG-R848-based laser ablation in vivo, the decreased bioluminescent signals indicated a significant inhibition of PCa growth, while the ratio of splenic natural killer (NK) cells in PLGA-ICG-R848 was (3.96 +/- 1.88)% compared with (0.99 +/- 0.10)% in PBS group, revealing the enhanced immune response against PCa. Conclusion: The dual-functional PLGA-ICG-R848 NPs under laser irradiation exhibit the anti-tumor efficacy for PCa treatment by combining PTT with immunotherapy