Spontaneous generation and active manipulation of real-space optical vortices.

Optical vortices are beams of light that carry orbital angular momentum1, which represents an extra degree of freedom that can be generated and manipulated for photonic applications2-8. Unlike vortices in other physical entities, the generation of optical vortices requires structural singularities9-12, but this affects their quasiparticle nature and hampers the possibility of altering their dynamics or making them interacting13-17. Here we report a platform that allows the spontaneous generation and active manipulation of an optical vortex-antivortex pair using an external field. An aluminium/silicon dioxide/nickel/silicon dioxide multilayer structure realizes a gradient-thickness optical cavity, where the magneto-optic effects of the nickel layer affect the transition between a trivial and a non-trivial topological phase. Rather than a structural singularity, the vortex-antivortex pairs present in the light reflected by our device are generated through mathematical singularities in the generalized parameter space of the top and bottom silicon dioxide layers, which can be mapped onto real space and exhibit polarization-dependent and topology-dependent dynamics driven by external magnetic fields. We expect that the field-induced engineering of optical vortices that we report will facilitate the study of topological photonic interactions and inspire further efforts to bestow quasiparticle-like properties to various topological photonic textures such as toroidal vortices, polarization and vortex knots, and optical skyrmions.

Prorocentin-5: A Cytotoxic Polyketide from the Benthic Marine Dinoflagellate Prorocentrum lima.

Prorocentrin-5 (1) was isolated from the benthic marine dinoflagellate Prorocentrum lima. A combination of NMR spectroscopy, quantum chemical calculations, and chemical reactions was then employed to elucidate its molecular structure, including the configurations of all stereogenic centers. In cytotoxicity assays, prorocentin-5 exhibited potent activity against the HCT-116 and Neuro2a cell lines, with IC50 values of 4.4 and 2.8 µM, respectively. Furthermore, 1 increased the apoptotic cell population and induced cell cycle arrest, leading to the accumulation of cells in the S or G2/M phase and an accompanying decrease in the G0/G1 phase in HCT-116, Neuro2a, and HepG2 cells.

Customizing Radiative Decay Dynamics of Two-Dimensional Excitons via Position- and Polarization-Dependent Vacuum-Field Interference.

Embodying bosonic and interactive characteristics in two-dimensional space, excitons in transition metal dichalcogenides (TMDCs) have garnered considerable attention. The utilization of the strong-correlation effects, long-range transport, and valley-dependent properties requires customizing exciton decay dynamics. Vacuum-field manipulation allows radiative decay engineering without disturbing intrinsic material properties. However, conventional flat mirrors cannot customize the radiative decay landscape in TMDC's plane or support vacuum-field interference with desired spectrum and polarization properties. Here, we present a meta-mirror platform resolving the issues with more optical degrees of freedom. For neutral excitons of the monolayer MoSe2, the optical layout formed by meta-mirrors manipulated the radiative decay rate in space by 2 orders of magnitude and revealed the statistical correlation between emission intensity and spectral line width. Moreover, the anisotropic meta-mirror demonstrated polarization-dependent radiative decay control. Our platform would be promising to tailor two-dimensional distributions of lifetime, density, diffusion, and polarization of TMDC excitons in advanced opto-excitonic applications.

Manipulative-based Activity Using Pop Beads for Demonstration of Sanger Sequencing.

Sanger sequencing, also known as dideoxy sequencing, is a widely used method for DNA sequencing, particularly for cloned plasmids and clinical samples. This technique requires a combination of essential biochemistry skills, such as a chain-termination reaction, gel electrophoresis, and fluorescence detection. Unfortunately, there is a lack of activities that replicate the Sanger sequencing process for students to learn and practice these skills. To address this issue, a manipulative-based Sanger sequencing activity was developed that incorporates colorful pop beads to demonstrate a chain-termination reaction, separation of products, and fluorescence detection. The beads represent deoxynucleotides and dideoxynucleotides, allowing for a visual representation of DNA fragment generation. This kinesthetic learning activity offers a high visual impact for students, aiding in their understanding of the Sanger sequencing process, and can also be used to illustrate polymerase chain reaction (PCR)-based techniques.

High-affinity free ubiquitin sensors for quantifying ubiquitin homeostasis and deubiquitination.

Ubiquitin (Ub) conjugation is an essential post-translational modification that affects nearly all proteins in eukaryotes. The functions and mechanisms of ubiquitination are areas of extensive study, and yet the dynamics and regulation of even free (that is, unconjugated) Ub are poorly understood. A major impediment has been the lack of simple and robust techniques to quantify Ub levels in cells and to monitor Ub release from conjugates. Here, we describe avidity-based fluorescent sensors that address this need. The sensors bind specifically to free Ub, have dissociation constant Kd values down to 60 pM and, together with a newly developed workflow, allow us to distinguish and quantify the pools of free, protein-conjugated and thioesterified forms of Ub from cell lysates. Alternatively, free Ub in fixed cells can be visualized microscopically by staining with a sensor. Real-time assays using the sensors afford unprecedented flexibility and precision to measure deubiquitination of virtually any (poly)Ub conjugate.

Arthroscopic gel-type autologous chondrocyte implantation presents histologic evidence of regenerating hyaline-like cartilage in the knee with articular cartilage defect.

PURPOSE: To investigate the clinical, radiological, and histological results of arthroscopic gel-type autologous chondrocyte implantation (GACI) in treating chondral defects of the knee. METHODS: This study prospectively examined five males and five females with a mean age of 40.3 ± 10.3 years who underwent arthroscopic GACI between March 2012 and February 2013. The gel comprised a mixture of 1 ml of fibrinogen plus 0.1-0.2 ml of thrombin. The mean size of chondral defect was 2.9 ± 1.2 cm2 (range 1.2-5.4 cm2). International knee documentation committee (IKDC) subjective score, knee injury and osteoarthritis outcome score (KOOS), knee society score, and visual analog scale (VAS) for pain were assessed preoperatively and during regular follow-up examinations performed for up to 5 years postoperatively. Serial magnetic resonance imaging was performed for up to 2 years after the surgery to observe healing, using the modified magnetic resonance observation of cartilage repair tissue (MOCART) score. In eight patients, second-look arthroscopy was performed at 1 year after the implantation to assess the status of treated cartilage, and a portion of regenerated cartilage was harvested for histologic evaluation. RESULTS: The mean VAS score (p = 0.045), IKDC subjective score (p = 0.041), KOOS pain (p = 0.025), KOOS activities of daily living (p = 0.048), and KOOS quality of life (p = 0.029) showed significant improvement at 5 years after the surgery. The modified MOCART evaluation showed that the scores were 59.5 ± 29.4 and 85.0 ± 8.0 at 12 weeks and 2 years after the operation, respectively. Histologic examination demonstrated a mean regenerated cartilage thickness of 3.5 ± 0.8 mm and a mean Oswestry score of 8.2 ± 1.8. Immunohistochemistry analysis showed that the expression of collagen type II was more evident and more evenly distributed than collagen type I in regenerated cartilage. There was a significant correlation between Oswestry score and change in VAS scale from postoperative 2-5 years. CONCLUSIONS: Arthroscopic GACI produces satisfactory clinical and radiologic outcomes, and histologic evaluation confirms sufficient regeneration of hyaline-like cartilage that correlates with improved symptoms. Therefore, it is an acceptable, minimally invasive, and technically simple option for the restoration of cartilage defects of the knee. LEVEL OF EVIDENCE: IV.

LPA Gene, Ethnicity, and Cardiovascular Events.

BACKGROUND: The relationship of LPA single nucleotide polymorphisms (SNPs), apolipoprotein(a) isoforms, and lipoprotein(a) [Lp(a)] levels with major adverse cardiovascular events (MACE) in different ethnic groups is not well known. METHODS: LPA SNPs, apolipoprotein(a) isoforms, Lp(a), and oxidized phospholipids on apolipoprotein B-100 (OxPL-apoB) levels were measured in 1792 black, 1030 white, and 597 Hispanic subjects enrolled in the Dallas Heart Study. Their interdependent relationships and prospective association with MACE after median 9.5-year follow-up were determined. RESULTS: LPA SNP rs3798220 was most prevalent in Hispanics (42.38%), rs10455872 in whites (14.27%), and rs9457951 in blacks (32.92%). The correlation of each of these SNPs with the major apolipoprotein(a) isoform size was highly variable and in different directions among ethnic groups. In the entire cohort, Cox regression analysis with multivariable adjustment revealed that quartiles 4 of Lp(a) and OxPL-apoB were associated with hazard ratios (95% confidence interval) for time to MACE of 2.35 (1.50-3.69, P<0.001) and 1.89 (1.26-2.84, P=0.003), respectively, versus quartile 1. Addition of the major apolipoprotein(a) isoform and the 3 LPA SNPs to these models attenuated the risk, but significance was maintained for both Lp(a) and OxPL-apoB. Evaluating time to MACE in specific ethnic groups, Lp(a) was a positive predictor and the size of the major apolipoprotein(a) isoform was an inverse predictor in blacks, the size of the major apolipoprotein(a) isoform was an inverse predictor in whites, and OxPL-apoB was a positive predictor in Hispanics. CONCLUSIONS: The prevalence and association of LPA SNPs with size of apolipoprotein(a) isoforms, Lp(a), and OxPL-apoB levels are highly variable and ethnicity-specific. The relationship to MACE is best explained by elevated plasma Lp(a) or OxPL-apoB levels, despite significant ethnic differences in LPA genetic markers.

Coronary artery calcium score plays an important role for cardiovascular risk stratification in the statin benefit groups of asymptomatic individuals.

BACKGROUND: The purpose of this study was to describe and analyze the relationship between statin benefit groups based on statin-intensity class of drugs and coronary artery calcium score (CACS) using multidetector computed tomography (MDCT) in an asymptomatic Korean population. METHODS: A total of 3914 asymptomatic individuals (mean age: 55 ± 10 years; male: female = 2649: 1265) who underwent MDCT for health examination between January 2009 and December 2012 were retrospectively enrolled. They were categorized into three groups based on statin-intensity class of drugs (high-intensity (n = 1284, 32.8%); moderate-intensity (n = 1602, 40.9%) and low-intensity (n = 931, 23.8%) statin therapy groups) according to the American College of Cardiology (ACC)/American heart Association (AHA) 2013 guideline and the relationship between CACS and statin benefit group was analyzed. The statin benefit group was defined as individuals who should be considered moderate- and high-intensity statin therapy. RESULTS: Ten-year atherosclerotic cardiovascular disease (ASCVD; 12.6 ± 5.3% vs. 2.9 ± 1.9%, p < 0.001) and CACS (98 ± 270 vs. 3 ± 2, p < 0.001) were significantly higher in the high-intensity group compared to the moderate-intensity statin therapy group. In the high-intensity statin therapy group, age [odds ratio: 1.299 (1.137-1.483), p < 0.001], male gender [odds ratio: 44.252 (1.959-999.784), p = 0.001], and fasting blood glucose [odds ratio: 1.046 (1.007-1.087), p = 0.021] were independent risk factors associated with CACS ≥300 on multivariate logistic regression analysis. CONCLUSIONS: CACS on MDCT might be an important complementary tool for cardiovascular disease risk stratification. This study indicates that individualization of statin therapy as well as lifestyle modification will be useful in asymptomatic individuals, especially those in whom high-intensity statin therapy is required.

Reduction in lipoprotein-associated apoC-III levels following volanesorsen therapy: phase 2 randomized trial results.

Elevated apoC-III levels predict increased cardiovascular risk when present on LDL and HDL particles. We developed novel high-throughput chemiluminescent ELISAs that capture apoB, lipoprotein (a) [Lp(a)], and apoA-I in plasma and then detect apoC-III on these individual lipoproteins as apoCIII-apoB, apoCIII-Lp(a), and apoCIII-apoAI complexes, respectively. We assessed the effects on these complexes of placebo or 100-300 mg volanesorsen, a generation 2.0+ antisense drug that targets apoC3 mRNA in patients with hypertriglyceridemia, including familial chylomicronemia syndrome (n = 3), volanesorsen monotherapy (n = 51), and as add-on to fibrate (n = 26), treated for 85 days and followed for 176 days. Compared with placebo, volanesorsen was associated with an 82.3 ± 11.7%, 81.3 ± 15.7%, and 80.8 ± 13.6% reduction in apoCIII-apoB, apoCIII-Lp(a), and apoCIII-apoA-I, respectively (300 mg dose;P< 0.001 for all), at day 92. Strong correlations in all assay measures were noted with total plasma apoC-III, chylomicron-apoC-III, and VLDL-apoC-III. In conclusion, novel high-throughput ELISAs were developed to detect lipoprotein-associated apoC-III, including for the first time on Lp(a). Volanesorsen uniformly lowers apoC-III on apoB-100, Lp(a), and apoA-I lipoproteins, and may be a potent agent to reduce triglycerides and cardiovascular risk mediated by apoC-III.

Differential ubiquitin binding by the acidic loops of Ube2g1 and Ube2r1 enzymes distinguishes their Lys-48-ubiquitylation activities.

The ubiquitin E2 enzymes, Ube2g1 and Ube2r1, are able to synthesize Lys-48-linked polyubiquitins without an E3 ligase but how that is accomplished has been unclear. Although both E2s contain essential acidic loops, only Ube2r1 requires an additional C-terminal extension (184-196) for efficient Lys-48-ubiquitylation activity. The presence of Tyr-102 and Tyr-104 in the Ube2g1 acidic loop enhanced both ubiquitin binding and Lys-48-ubiquitylation and distinguished Ube2g1 from the otherwise similar truncated Ube2r1(1-183) (Ube2r1C). Replacement of Gln-105-Ser-106-Gly-107 in the acidic loop of Ube2r1C (Ube2r1C(YGY)) by the corresponding residues from Ube2g1 (Tyr-102-Gly-103-Tyr-104) increased Lys-48-ubiquitylation activity and ubiquitin binding. Two E2∼UB thioester mimics (oxyester and disulfide) were prepared to characterize the ubiquitin binding activity of the acidic loop. The oxyester but not the disulfide derivative was found to be a functional equivalent of the E2∼UB thioester. The ubiquitin moiety of the Ube2r1C(C93S)-[(15)N]UB(K48R) oxyester displayed two-state conformational exchange, whereas the Ube2r1C(C93S/YGY)-[(15)N]UB(K48R) oxyester showed predominantly one state. Together with NMR studies that compared UB(K48R) oxyesters of the wild-type and the acidic loop mutant (Y102G/Y104G) forms of Ube2g1, in vitro ubiquitylation assays with various mutation forms of the E2s revealed how the intramolecular interaction between the acidic loop and the attached donor ubiquitin regulates Lys-48-ubiquitylation activity.

Evaluation of the incremental prognostic value of the combination of CYP2C19 poor metabolizer status and ABCB1 3435 TT polymorphism over conventional risk factors for cardiovascular events after drug-eluting stent implantation in East Asians.

PURPOSE: We evaluated the incremental prognostic value of combining the CYP2C19 poor metabolizer (PM) and ABCB1 3435 TT for adverse clinical outcomes over conventional risk factors in a percutaneous coronary intervention (PCI) cohort. METHODS: We enrolled 2,188 patients. The primary end point was a composite of death from any cause, nonfatal myocardial infarction (MI), and stroke during 1-year follow-up. The population was stratified into the following four groups: CYP2C19 EM/IM+ABCB1 3435 CC/CT, CYP2C19 EM/IM+ABCB1 3435 TT, CYP2C19 PM+ABCB1 3435 CC/CT, and CYP2C19 PM+ABCB1 3435 TT. RESULTS: A total of 87 (3.97%) primary end-point events occurred (64 deaths, 8 non-fatal MIs and 15 strokes). Multivariate Cox analysis indicated that CYP2C19 PM+ABCB1 3435 TT status was a significant predictor of the primary end point (hazard ratio = 4.51, 95% confidence interval (CI) = 1.92-10.58). However, addition of combined genetic status to the clinical risk model did not improve the model discrimination (C-statistic = 0.786 (95% CI = 0.734-0.837) to 0.785 (95% CI = 0.733-0.838)) or risk reclassification (categorical net reclassification improvement (0.040, P = 0.32), integrated discrimination improvement (0.021, P = 0.026)). CONCLUSIONS: In a real-world East Asian PCI population taking clopidogrel, although the concurrent presence of CYP2C19 PM and ABCB1 TT is a strong independent predictor of adverse outcomes, the combined status of two at-risk variants does not have an incremental prognostic value beyond that of the conventional clinical risk factors.Genet Med 18 8, 833-841.

Confidence limits for patient-specific IMRT dose QA: a multi-institutional study in Korea.

This study aims to investigate tolerance levels for patient-specific IMRT dose QA (DQA) using the confidence limits (CL) determined by a multi-institutional study. Eleven institutions participated in the multi-institutional study in Korea. A total of 155 DQA measurements, consisting of point-dose differences (high- and low-dose regions) and gamma passing rates (composite and per-field) for IMRT patients with brain, head and neck (H&N), abdomen, and prostate cancers were examined. The Shapiro-Wilk test was used to evaluate the normality of data grouped by the treatment sites and the DQA methods. The confidence limit coefficients in cases of the normal distribution, and the two-sided Student's t-distribution were applied to determine the confidence limits for the grouped data. The Spearman's test was applied to assess the sensitivity of DQA results within the limited groups. The differences in CLs between the two confidence coefficients based on the normal and t-distributions were negligible for the point-dose data and the gamma passing rates with 3%/3 mm criteria. However, with 2%/2 mm criteria, the difference in CLs were 1.6% and 2.2% for composite and per-field measurements, respectively. This resulted from the large standard deviation and the more sensitive criteria of 2%/2 mm. There was no noticeable correlation among the different QA methods. Our multi-institutional study suggested that the CL was not a suitable metric for defining the tolerance level when the statistics of the sample group did not follow the normality and had a large standard deviation.

Optimal duration of dual antiplatelet therapy after drug-eluting stent implantation: a randomized, controlled trial.

BACKGROUND: The risks and benefits of long-term dual antiplatelet therapy remain unclear. METHODS AND RESULTS: This prospective, multicenter, open-label, randomized comparison trial was conducted in 24 clinical centers in Korea. In total, 5045 patients who received drug-eluting stents and were free of major adverse cardiovascular events and major bleeding for at least 12 months after stent placement were enrolled between July 2007 and July 2011. Patients were randomized to receive aspirin alone (n=2514) or clopidogrel plus aspirin (n=2531). The primary end point was a composite of death resulting from cardiac causes, myocardial infarction, or stroke 24 months after randomization. At 24 months, the primary end point occurred in 57 aspirin-alone group patients (2.4%) and 61 dual-therapy group patients (2.6%; hazard ratio, 0.94; 95% confidence interval, 0.66-1.35; P=0.75). The 2 groups did not differ significantly in terms of the individual risks of death resulting from any cause, myocardial infarction, stent thrombosis, or stroke. Major bleeding occurred in 24 (1.1%) and 34 (1.4%) of the aspirin-alone group and dual-therapy group patients, respectively (hazard ratio, 0.71; 95% confidence interval, 0.42-1.20; P=0.20). CONCLUSIONS: Among patients who were on 12-month dual antiplatelet therapy without complications, an additional 24 months of dual antiplatelet therapy versus aspirin alone did not reduce the risk of the composite end point of death from cardiac causes, myocardial infarction, or stroke. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01186146.

Ultra-specific zeptomole microRNA detection by plasmonic nanowire interstice sensor with Bi-temperature hybridization.

MicroRNAs (miRNAs) are emerging new biomarkers for many human diseases. To fully employ miRNAs as biomarkers for clinical diagnosis, it is most desirable to accurately determine the expression patterns of miRNAs. The optimum miRNA profiling method would feature 1) highest sensitivity with a wide dynamic range for accurate expression patterns, 2) supreme specificity to discriminate single nucleotide polymorphisms (SNPs), and 3) simple sensing processes to minimize measurement variation. Here, an ultra-specific detection method of miRNAs with zeptomole sensitivity is reported by applying bi-temperature hybridizations on single-crystalline plasmonic nanowire interstice (PNI) sensors. This method shows near-perfect accuracy of SNPs and a very low detection limit of 100 am (50 zeptomole) without any amplification or labeling steps. Furthermore, multiplex sensing capability and wide dynamic ranges (100 am-100 pm) of this method allows reliable observation of the expression patterns of miRNAs extracted from human tissues. The PNI sensor offers combination of ultra-specificity and zeptomole sensitivity while requiring two steps of hybridization between short oligonucleotides, which could present the best set of features for optimum miRNA sensing method.

Clinical significance of chronic kidney disease and atrial fibrillation on morbidity and mortality in patients with acute myocardial infarction.

BACKGROUND/AIMS: Atrial fibrillation (AF) often coexists with acute myocardial infarction (AMI), and chronic kidney disease (CKD) is a major risk for AMI. However, the combined impact of CKD and AF on the mortality and morbidity in AMI population has not been determined. METHODS: Between January 2004 and December 2009, a total of 4,738 AMI patients were enrolled prospectively. Patients were divided into four groups according to the combined status of CKD and AF. The primary endpoint was a combination of 5-year major adverse cardiac and cerebrovascular events (MACCE). RESULTS: The prevalence of AF was significantly higher in CKD patients than in non-CKD patients (6.76 vs. 3.31%, p < 0.001). The highest cumulative event rate of MACCE and death was observed in patients with both CKD and AF (68.5 and 64.0%), respectively. In multivariable analyses, compared with patients with neither AF nor CKD, hazard ratios (HR) for composite of MACCE were 1.66 (95% CI, 1.14-2.41), 1.24 (95% CI, 1.06-1.46), and 2.10 (95% CI, 1.42-3.13) for patients with AF only, those with CKD only, and those with both CKD and AF, respectively (p for interaction = 0.935). Patients with both CKD and AF had a greatest risk for all-cause mortality (HR 2.54; 95% CI, 1.60-4.53), and the significant synergistic interaction was observed between CKD and AF (p for interaction = 0.015). CONCLUSION: The combined effect of AF and CKD on the risk of MACCE after an AMI is stronger than any separate condition, and it confers a synergistic effect on the all-cause mortality risk.

Negative association between plasma aldosterone concentration/plasma renin activity and morning blood pressure surge in never-treated hypertensive patients.

Morning blood pressure (BP) surge (MS) has been known to be a predictor of cardiovascular events. Currently, few studies have evaluated the underlying mechanism underlying MS, which may include neurohormonal factors and the renin-angiotensin-aldosterone system (RAAS). This study aimed to examine plasma aldosterone concentration (PAC) and plasma renin activity (PRA) and BP parameters with or without MS in never-treated subjects with essential hypertension. This cross-sectional study included a total of 261 patients (mean age: 48.8 years; 60.5% male) with never-treated essential hypertension who were registered in a working group at The Catholic University of Korea. The patients were divided into the MS group, which was defined as having the highest quartile of morning BP increase from sleep (>31 mmHg; n = 66) and the non-MS group (≤31 mmHg; n = 195). We collected 24-h ambulatory BP, pulse wave velocity, ankle brachial index, PAC and PRA from all patients. The measured PAC and PRA were lower in the MS group than in the non-MS group (PAC: 9.0 ± 5.4 ng/dl versus 12.2 ± 8.7 ng/dl, p < 0.001; PRA: 1.7 ± 1.3 ng/ml/h versus 2.6 ± 3.6 ng/ml/h, p = 0.002). The MS group had greater variations in daytime, nighttime and 24-h systolic blood pressure (SBPs) than the non-MS group (24-h SBP: 15.6 ± 4.4 mm Hg for the non-MS group and 18.9 ± 4.9 mmHg for the MS group; p < 0.001 for each). It is generally accepted that the sympathetic nervous system plays a major role in the regulation of BP variability. Therefore, further studies on sympathetic nervous system activation in hypertensives with extreme MS are needed. MS in enrolled patients who were at relatively low risk in this study may be less affected by the RAAS.

Diagnosis of high-Ni NCA/Gr-Si cells before rapid capacity drop by monitoring the heterogeneous degradation.

Understanding the degradation of lithium-ion batteries is of utmost significance for preventing unexpected capacity drops and addressing safety concerns. The manner in which batteries degrade during operation has a notable influence on their subsequent cycle performance. In particular, the rapid capacity drop related to the spatial heterogeneity of the anode degradation highlights the necessity of a health indicator for an accurate battery diagnosis. A novel health indicator established in this study, the Dominant degradation factors among Negative and Positive electrodes (DNP) scores, enables clear identification of degraded states despite comparable capacity levels. Specifically, batteries with heterogeneous anode degradation exhibited negative scores and the aggravation of the cycle performance. It is anticipated that this health indicator can provide a distinct evaluation of batteries based on their degraded states, supporting onboard battery management and the efficient allocation of resources for the battery reuse industry.

A Modular Biosensor Design for Quantitative Measurement of Free Nedd8.

The objective of our study was to develop a genetically encoded biosensor for quantification of Nedd8, a post-translational modifier that regulates cellular signals through conjugation to other proteins. Perturbations in the balance of free (i.e., unconjugated) and conjugated Nedd8 caused by defects in Nedd8 enzymes or cellular stress are implicated in various diseases. Despite the biological and biomedical importance of Nedd8 dynamics, no method exists for direct quantification of free Nedd8, hindering the study of Nedd8 and activities of its associated enzymes. Genetically encoded biosensors are established as tools to study other dynamic systems, but limitations of current biosensor design methods make them poorly suited for free Nedd8 quantification. We have developed a modular method to design genetically encoded biosensors that employs a target binding domain and two reporter domains positioned on opposite sides of the target binding site. Target quantification is based on competition between target binding and the interaction of the reporter domains. We applied our design strategy to free Nedd8 quantification by developing a selective binder for free Nedd8 and combining it with fluorescent or split nanoluciferase reporters. Our sensors produced quantifiable and specific signals for free Nedd8 and enabled real-time monitoring of deneddylation by DEN1 with a physiological substrate. Our sensor design will be useful for high-throughput screening for deneddylation inhibitors, which have potential in treatment of cancers such as acute lymphoblastic leukemia. The modular design strategy can be extended to develop genetically encoded quantitative biosensors for other proteins of interest.

Socioeconomic status and cardiovascular mortality in over 170,000 cancer survivors.

AIMS: Cardiovascular health is acknowledged as a crucial concern among cancer survivors. Socioeconomic status (SES) is an essential but often neglected risk factor for cardiovascular disease (CVD). We conducted this study to identify the relationship between SES and CVD mortality in cancer survivors. METHODS AND RESULTS: Using the National Health Insurance Service-National Health Examinee database, we identified cancer survivors diagnosed and surviving beyond 5 years post-diagnosis. SES was assessed based on insurance premiums and classified into 5 groups. The primary outcome was overall CVD mortality. This study analyzed 170 555 individuals (mean age 60.7 ± 11.9 years, 57.8% female). A gradual increase in risk was observed across SES groups: adjusted hazard ratios (95% confidence intervals) for overall CVD mortality were 1.15 (1.04-1.26), 1.28 (1.15-1.44), 1.31 (1.18-1.46), and 2.13 (1.30-3.49) for the second, third, and fourth quartile, and medical aid group (the lowest SES group) compared to the highest SES group, respectively (p for trend < 0.001). The lowest SES group with hypertension exhibited a 3.4-fold higher risk of CVD mortality compared to the highest SES group without hypertension. Interaction analyses revealed that low SES synergistically interacts with hypertension, heightening the risk of CVD mortality (synergy index 1.62). CONCLUSION: This study demonstrates a significant correlation between low SES and increased CVD mortality among cancer survivors. Particularly, the lowest SES group, when combined with hypertension, significantly escalates CVD mortality. Our findings underscore the critical importance of recognizing SES as a significant risk factor for CVD mortality in this population of cancer survivors.

Our population-based cohort study, involving over 170 000 cancer survivors, demonstrates a significant association between socioeconomic status (SES) and cardiovascular disease (CVD) mortality.

Perovskite nanocomposites: synthesis, properties, and applications from renewable energy to optoelectronics.

The oxide and halide perovskite materials with a ABX3 structure exhibit a number of excellent properties, including a high dielectric constant, electrochemical properties, a wide band gap, and a large absorption coefficient. These properties have led to a range of applications, including renewable energy and optoelectronics, where high-performance catalysts are needed. However, it is difficult for a single structure of perovskite alone to simultaneously fulfill the diverse needs of multiple applications, such as high performance and good stability at the same time. Consequently, perovskite nanocomposites have been developed to address the current limitations and enhance their functionality by combining perovskite with two or more materials to create complementary materials. This review paper categorizes perovskite nanocomposites according to their structural composition and outlines their synthesis methodologies, as well as their applications in various fields. These include fuel cells, electrochemical water splitting, CO2 mitigation, supercapacitors, and optoelectronic devices. Additionally, the review presents a summary of their research status, practical challenges, and future prospects in the fields of renewable energy and electronics.