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Abstract The tunable properties of halide perovskite/two dimensional (2D) semiconductor mixed-dimensional van der Waals heterostructures offer high flexibility for innovating optoelectronic and photonic devices. However, the general and robust growth of high-quality monocrystalline halide perovskite/2D semiconductor heterostructures with attractive optical properties has remained challenging. Here, we demonstrate a universal van der Waals heteroepitaxy strategy to synthesize a library of facet-specific single-crystalline halide perovskite/2D semiconductor (multi)heterostructures. The obtained heterostructures can be broadly tailored by selecting the coupling layer of interest, and can include perovskites varying from all-inorganic to organic-inorganic hybrid counterparts, individual transition metal dichalcogenides or 2D heterojunctions. The CsPbI2Br/WSe2 heterostructures demonstrate ultrahigh optical gain coefficient, reduced gain threshold and prolonged gain lifetime, which are attributed to the reduced energetic disorder. Accordingly, the self-organized halide perovskite/2D semiconductor heterostructure lasers show highly reproducible single-mode lasing with largely reduced lasing threshold and improved stability. Our findings provide a high-quality and versatile material platform for probing unique optoelectronic and photonic physics and developing further electrically driven on-chip lasers, nanophotonic devices and electronic-photonic integrated systems.

Aims: Myocardial ischemia can affect traditional right ventricular (RV) pacing parameters, but it is unclear whether coronary artery disease (CAD) impact the pacing parameters and electrophysiological characteristics of left bundle branch area pacing (LBBaP) as a physiological pacing representative. Methods: Patients who underwent coronary angiography (CAG) after/before the LBBaP procedure and underwent percutaneous coronary intervention after LBBaP procedure were divided into CAD group and Non-CAD group according to visual CAG. Pacing parameters and electrophysiological characteristics were recorded at LBBaP implantation. Multivariate logistic regression analysis was implemented to evaluate the association between CAD and higher capture threshold. Sensitivity analyses were conducted to verify result stability. Results: A total of 176 patients met inclusion criteria (115 Non-CAD patients and 61 CAD patients) with a mean age of 71.1 ± 9.0 years. Compared with the Non-CAD patients, CAD patients had the higher capture threshold (0.67 ± 0.22 V vs. 0.82 ± 0.28 V, P

Pervasive transcription of the mammalian genome produces hundreds of thousands of noncoding RNAs (ncRNAs). Numerous studies have suggested that some of these ncRNAs regulate multiple cellular processes and play important roles in physiological and pathological processes. Notably, a large subset of ncRNAs is enriched on chromatin and participates in regulating gene expression and the dynamics of chromatin structure and status. In this review, we summarize recent advances in the functional study of chromatin-associated ncRNAs and mechanistic insights into how these ncRNAs associate with chromatin. We also discuss the potential future challenges which still need to be overcome in this field.

BackgroundLowering lipid variability may be a potential strategy for improving the inflammatory state in patients with coronary heart disease (CHD). This study investigated the association between the variability of non-high-density lipoprotein cholesterol (non-HDL-C) and the neutrophil-to-lymphocyte ratio (NLR).MethodsThis study enrolled 2,711 CHD patients subjected to percutaneous coronary intervention (PCI). During the 1-year follow-up period after PCI, the variability of non-HDL-C was assessed using standard deviation (SD), coefficient of variation (CV), and variability independent of mean (VIM). NLR was calculated as the ratio of absolute neutrophil count to absolute lymphocyte count. The relationship between the non-HDL-C variability and the average NLR level during follow-ups was examined using a linear regression analysis.ResultsThe mean age of the patients was 64.4 ± 10.8 years, with 72.4% being male. The average NLR level was 2.98 (2.26–4.14) during the follow-up (1 year after PCI). The variability of non-HDL-C was 0.42 (0.26–0.67) for SD, 0.17 (0.11–0.25) for CV, and 0.02 (0.01–0.03) for VIM. A locally weighted scatterplot smoothing curve indicates that the average levels of NLR increased with increasing variability of non-HDL-C. Regardless of the variability assessment method used, non-HDL-C variability was significantly positively associated with the average NLR level during follow-ups: SD [β (95% CI) = 0.681 (0.366–0.996)], CV [β (95% CI) = 2.328 (1.458–3.197)], and VIM [β (95% CI) = 17.124 (10.532–23.715)]. This association remained consistent across subgroups stratified by age, gender, diabetes, and hypertension.ConclusionThe variability of non-HDL-C was positively associated with NLR in patients with CHD, suggesting that reducing non-HDL-C variability may improve the low-grade inflammatory state in CHD patients.

Abstracts: Background: Glasgow prognostic score (GPS) is a reliable scoring system reflecting both nutritional and inflammatory factors. The association of inflammation and nutrition with contrast-associated acute kidney injury (CA-AKI) has been validated. This study set out to determine the impact of GPS and its derived scores on CA-AKI incidence. Methods: Populations treated with coronary angiography with/without percutaneous coronary intervention were screened retrospectively. According to C-reactive protein and albumin, three kinds of GPSs were involved: GPS, modified GPS (mGPS), and the cutoff-based GPS (cGPS) which was derived by calculating the optimal cutoff values of two parameters. Primary endpoint was CA-AKI. Pearson’ r correlation, linear/logistic regression, receiver operating characteristic curve as well as subgroup analyses were conducted. Results: Totally, 3150 patients were valid for analysis, and the mean age was 67.5 years old, with 66.4 % male. Of these, 610 patients suffered CA-AKI. All three kinds of GPSs were independently associated with the SCr elevation proportion (GPS: β = 4.850, 95%CI [3.700 to 8.722], P

BackgroundCaffeine is widely consumed not only in coffee but also in soft drinks and tea. However, the long-term health effects of caffeine are still controversial, especially in people with high cardiovascular risk such as elderly patients with hypertension.MethodsThis study analyzed data from the National Health and Nutrition Examination Survey 2003–2018. Caffeine intake was calculated by two 24-h dietary recall interviews. Complex sampling-weighted multivariable Cox proportional hazards models were used to compare the hazard ratios (HRs) of all-cause and cardiovascular mortality in elderly hypertensive patients with different caffeine intake (

Abstract Congestive heart failure (HF) is a known risk factor of contrast-induced acute kidney injury (CI-AKI). However, the relationship of the classification and severity of HF with CI-AKI remains under-explored. From January 2009 to April 2019, we recruited patients undergoing elective PCI who had complete pre- and post-operative creatinine data. According to the levels of ejection fraction (EF), HF was classified as HF with reduced EF (HFrEF) [EF

Abstract Background Obstruction of coronary microcirculation can lead to myocardial ischemia and poor prognosis. Salvianolate exerts cardiovascular protection at cellular levels. However, no studies have confirmed the effect of salvianolate on stable coronary heart disease (CHD) with high fractional flow reserve (FFR) and myocardial microcirculatory disturbances. Methods/design This study will enroll 78 patients who have stable coronary disease with 50 to 70% stenosis in major coronary arteries and whose FFR > 0.80 and index of microcirculatory resistance (IMR) > 25. Patients will be randomly divided into the salvianolate group or the placebo group. After above evaluations, salvianolate 200 mg will be intravenously dripped immediately for the next 30 min and subsequent 7 days in the salvianolate group, and matching 0.9% normal saline will be arranged in the placebo group. IMR will be reevaluated in immediate phase after first 30 min of salvianolate or placebo treatment. The primary end point will be the IMR change in this phase, and the secondary end points will be the total ischemic burden assessed by the Seattle angina scale, quality of life scale, Holter electrocardiography, and 6-min walk test after 7 days before discharge. Discussion This study will firstly clarify the improvement effect of salvianolate on coronary microcirculation and provide an effective treatment method for stable CHD patients with high FFR and myocardial microcirculatory disturbance. Trial registration Chinese Clinical Trial Registry ChiCTR1800018772 . Registered on 9 October 2018 and updated on 2 March 2020

BackgroundIncreased plaque vulnerability and higher lipid variability are causes of adverse cardiovascular events. Despite a close association between glucose and lipid metabolisms, the influence of elevated glycated hemoglobin A1c (HbA1c) on plaque vulnerability and lipid variability remains unclear.MethodsAmong subjects undergoing percutaneous coronary intervention (PCI) from 2009 through 2019, 366 patients received intravascular optical coherence tomography (OCT) assessment and 4,445 patients underwent the scheduled follow-ups within 1 year after PCI. Vulnerability features of culprit vessels were analyzed by OCT examination, including the assessment of lipid, macrophage, calcium, and minimal fibrous cap thickness (FCT). Visit-to-visit lipid variability was determined by different definitions including standard deviation (SD), coefficient of variation (CV), and variability independent of the mean (VIM). Multivariable linear regression analysis was used to verify the influence of HbA1c on plaque vulnerability features and lipid variability. Exploratory analyses were also performed in non-diabetic patients.ResultsAmong enrolled subjects, the pre-procedure HbA1c was 5.90 ± 1.31%, and the average follow-up HbA1c was 5.98 ± 1.16%. By OCT assessment, multivariable linear regression analyses demonstrated that patients with elevated HbA1c had a thinner minimal FCT (β = −6.985, P = 0.048), greater lipid index (LI) (β = 226.299, P = 0.005), and higher macrophage index (β = 54.526, P = 0.045). Even in non-diabetic patients, elevated HbA1c also linearly decreased minimal FCT (β = −14.011, P = 0.036), increased LI (β = 290.048, P = 0.041) and macrophage index (β = 120.029, P = 0.048). Subsequently, scheduled follow-ups were performed during 1-year following PCI. Multivariable linear regression analyses proved that elevated average follow-up HbA1c levels increased the VIM of lipid profiles, including low-density lipoprotein cholesterol (β = 2.594, P < 0.001), high-density lipoprotein cholesterol (β = 0.461, P = 0.044), non-high-density lipoprotein cholesterol (β = 1.473, P < 0.001), total cholesterol (β = 0.947, P < 0.001), and triglyceride (β = 4.217, P < 0.001). The result was consistent in non-diabetic patients and was verified when SD and CV were used to estimate variability.ConclusionIn patients undergoing elective PCI, elevated HbA1c increases the atherosclerotic plaque vulnerability and the visit-to-visit variability of lipid profiles, which is consistent in non-diabetic patients.

The COVID-19 pandemic has required health services worldwide to adapt to dramatically changing healthcare needs and risks across all medical specialties. In the dermatology department at Princess Alexandra Hospital, Brisbane, Australia, we developed and implemented a teledermatology system with 1 week's notice to help reduce infection risk bidirectionally, while saving patients many hours of travel and waiting time with acceptable technological substitutes for the clinical encounters. In this study, we report the efficacy and tolerability of our telephone consultation and store and forward imaging system, including patient experience from validated survey data. Our design, implementation and usage of a remote-default system provides experience and lessons to draw upon in developing future telemedicine systems to address dermatology service maldistribution – an issue affecting large areas of Australia – as well as preparedness for future infection mitigation requirements.

Summary: Repetitive elements are abundantly distributed in mammalian genomes. Here, we reveal a striking association between repeat subtypes and gene function. SINE, L1, and low-complexity repeats demarcate distinct functional categories of genes and may dictate the time and level of gene expression by providing binding sites for different regulatory proteins. Importantly, imaging and sequencing analysis show that L1 repeats sequester a large set of genes with specialized functions in nucleolus- and lamina-associated inactive domains that are depleted of SINE repeats. In addition, L1 transcripts bind extensively to its DNA in embryonic stem cells (ESCs). Depletion of L1 RNA in ESCs leads to relocation of L1-enriched chromosomal segments from inactive domains to the nuclear interior and de-repression of L1-associated genes. These results demonstrate a role of L1 DNA and RNA in gene silencing and suggest a general theme of genomic repeats in orchestrating the function, regulation, and expression of their host genes. : Lu et al. report a striking association between genomic repeats and gene regulation and demonstrate a key role of L1 repeat RNA in sequestering L1-rich sequences and associated genes in inactive domains for silencing, revealing a general theme of repeat sequences in shaping gene regulatory networks within their host genome. Keywords: repetitive elements, L1, B1 or Alu, SINE, low-complexity repeats, gene function, regulation and expression, nucleolus and lamina-associated domains, L1 RNA, gene silencing

Summary: Embryonic stem cells (ESCs) exhibit high levels of ribosomal RNA (rRNA) transcription and ribosome biogenesis. Here, we reveal an unexpected role for an essential DEAD-box helicase, DDX18, in antagonizing the polycomb repressive complex 2 (PRC2) to prevent deposition of the repressive H3K27me3 mark onto rDNA in pluripotent cells. DDX18 binds and sequesters PRC2 in the outer layer of the nucleolus and counteracts PRC2 complex formation in vivo and in vitro. DDX18 knockdown leads to increased occupancy of PRC2 and H3K27me3 at rDNA loci, accompanied by drastically decreased rRNA transcription and reduced ribosomal protein expression and translation. Auxin-induced rapid degradation of DDX18 enhances PRC2 binding at rDNA. The inhibition of PRC2 partially rescues the effects of DDX18 depletion on rRNA transcription and ESC self-renewal. These results demonstrate a critical role for DDX18 in safeguarding the chromatin and transcriptional integrity of rDNA by counteracting the epigenetic silencing machinery to promote pluripotency. : Zhang et al. report an interplay between the DEAD-box helicase DDX18 and the polycomb repressive complex 2 (PRC2) in governing the hyperactive state of ribosomal DNA in pluripotency regulation. DDX18 counteracts PRC2 complex formation and prevents PRC2 binding and aberrant histone methylation at rDNA loci. Keywords: stem cell pluripotency, DDX18, RNA-binding protein, PRC2, rRNA transcription, rDNA loci, nucleolus

Background/Aims: Myocardial ischemia/reperfusion (I/R) injury (MI/RI) is a critical cause of death in patients with heart disease. However, the pharmaco-therapeutical outcome for MI/RI remains unsatisfactory. Innovative approaches for enhancing drug sensitivity and recovering myocardial function in MI/RI treatment are urgently needed. The purpose of this study was to evaluate the protective effects of exenatide-loaded poly(L-lysine)-poly(ethylene glycol)-poly(L-lysine) (PLL-PEG-PLL) nanoparticles (NPs) against MI/RI. Methods: The size of PLL-PEG-PLL NPs and the loading and release rates of exenatide were determined. The in vitro NP cytotoxicity was evaluated using newborn rat cardiomyocytes. Rats pretreated with free exenatide or exenatide/PLL-PEG-PLL polyplexes were subjected to 0.5-h ischemia and 2-h reperfusion in the left anterior descending coronary artery. The histopathologic lesions were assessed using hematoxylin-eosin staining. The general physiological indices, including blood pressure (BP), heart rate (HR), the left ventricular ejection fraction (LVEF) and end-diastolic pressure (LEVDP), and the left ventricular pressure maximal rate of rising (dp/dtmax), were monitored using a non-invasive blood pressure analyzer and color Doppler echocardiography. The antioxidative activity in the myocardial tissue was measured. The myocardial enzymatic activity was further estimated by determining the serum levels of creatine kinase (CK), lactate dehydrogenase (LDH), cardiac troponin T (cTnT), and glucagon-like peptide-1 (GLP-1), as well as the expression of GLP-1R in the myocardial tissue. Results: Exenatide preconditioning attenuated the oxidative stress injury and promoted the myocardial function in I/R-induced myocardial injury, while the application of block copolymer PLL-PEG-PLL as a potential exenatide nanocarrier with sustained release significantly enhanced the bioavailability of exenatide. Conclusion: The block copolymer PLL-PEG-PLL may function as a potent exenatide nanocarrier for augmenting pharmacotherapy against MI/RI with unprecedented clinical benefits. Further study is needed to better clarify the underlying mechanisms.

Background/Aims: Paeoniflorin (PF) is known to have anti-inflammatory and paregoric effects, but the mechanism underlying its analgesic effect remains unclear. The aim of this study was to clarify the effect of PF on Freund’s complete adjuvant (CFA)-induced inflammatory pain and explore the underlying molecular mechanism. Methods: An inflammatory pain model was established by intraplantar injection of CFA in C57BL/6J mice. After intrathecal injection of PF daily for 8 consecutive days, thermal and mechanical withdrawal thresholds, the levels of inflammatory factors TNF-α, IL-1β and IL-6, microglial activity, and the expression of Akt-NF-κB signaling pathway in the spinal cord tissue were detected by animal ethological test, cell culture, enzyme-linked immunosorbent assay, immunofluorescence histochemistry, and western blot. Results: PF inhibited the spinal microglial activation in the CFA-induced pain model. The production of proinflammatory cytokines was decreased in the central nervous system after PF treatment both in vivo and in vitro. PF further displayed a remarkable effect on inhibiting the activation of Akt-NF-κB signaling pathway in vivo and in vitro. Conclusion: These results suggest that PF is a potential therapeutic agent for inflammatory pain and merits further investigation.

Background/Aims: Diabetes mellitus can exacerbate renal ischemia-reperfusion (I/R) injury (RI/RI). The aim of the present study was to evaluate the protective effect of GSK-3β inhibition (TDZD-8) on I/R-induced renal injury through the Nrf2/HO-1 pathway in a streptozocin (STZ)-induced diabetic rat model. Methods: STZ-induced diabetic rats preconditioned with TDZD-8 and ZnPP were subjected to renal I/R. The extent of renal morphologic lesions. Renal function was assessed from blood urea nitrogen (BUN) and serum creatinine (Scr), as determined utlizing commercial kits. Oxidative stress and inflammatory activity in the kidney tissue was estimated from levels of malondialdehyde (MDA), interleukin-10 (IL-10), tumor necrosis factor-α (TNF-α), and nitric oxide (NO), as well as the activities of superoxide dismutase (SOD) and glutathione (GSH) using qRT-PCR and ELISA. The expressions of Nrf2, HO-1, Bcl-2 and NF-κB in the renal tissue were measured by qRT-PCR and western blotting. Results: I/R-induced renal inflammation was reduced significantly by TDZD-8 pretreatment. Preconditioning with TDZD-8 suppressed NF-κB expression and enhanced Bcl-2 expression in the renal tissue. The upregulated level of malondialdehyde (MDA), and reduced activities of superoxide dismutase (SOD) and glutathione (GSH) in I/R-shocked rats were markedly restored by TDZD-8 pretreatment. Furthermore, pretreatment with TDZD-8 enhanced activation of the Nrf2/HO-1 pathway in the renal tissue of diabetic RI/RI rats. Conclusion: These findings suggest that preconditioning with TDZD-8 may protect the kidney from I/R-induced damage via the activation of the Nrf2/HO-1 pathway in STZ-induced diabetic rats. Further detailed studies are needed to further clarify the underlying mechanisms.

Background/Aims: Diabetes mellitus (DM) can lead to renal damage and dysfunction, and exacerbate renal ischemia/reperfusion injury (RI/RI). The aim of this study was to investigate the protective effect of GSK-3β inhibitor TDZD-8 against RI/RI through Nrf2/TrxR2 signaling pathway in a rat DM model. Methods: A DM rat model was established by a single injection of streptozocin. Diabetic rats were pretreated with TDZD-8 (1 mg/kg bw) or TDZD-8+auranofin (10 nmol/L, 5ml/kg bw), and then subjected to 45-min ischemia and 24-h reperfusion. Rats were equally randomized into four groups: a Sham-operated group, a RI/RI group, a TDZD-8 group, and a TDZD-8+auranofin group. Serum levels of BUN and Scr were measured. SOD activity, MDA content, and Nrf2, TrxR2 and caspase-3 expressions in rat kidney tissues were determined. Results: Renal function was improved, oxidative stress and cell apoptosis were reduced, and the expression of Nrf2 and TrxR2 was up-regulated in TDZD-8 treated rats as compared with those in auranofin treated rats. Conclusion: TDZD-8 may exert its protective effect against RI/RI by regulating the Nrf2/TrxR2 signaling pathway in the kidney tissue in DM.

Satellite Image Time Series (SITS) is a data set that includes satellite images across several years with a high acquisition rate. Radiometric normalization is a fundamental and important preprocessing method for remote sensing applications using SITS due to the radiometric distortion caused by noise between images. Normalizing the subject image based on the reference image is a general strategy when using traditional radiometric normalization methods to normalize multi-temporal imagery (usually two or three scenes in different time phases). However, these methods are unsuitable for calibrating SITS because they cannot minimize the radiometric distortion between any pair of images in SITS. The existing relative radiometric normalization methods for SITS are based on linear assumptions, which cannot effectively reduce nonlinear radiometric distortion caused by continuously changing noise in SITS. To overcome this problem and obtain a more accurate SITS, we propose a nonlinear radiometric normalization model (NMAG) for SITS based on Artificial Neural Networks (ANN) and Greedy Algorithm (GA). In this method, GA is used to determine the correction order of SITS and calculate the error between the image to be corrected and normalized images, which avoids the selection of a single reference image. ANN is used to obtain the optimal solution of error function, which minimizes the radiometric distortion between different images in SITS. The SITS composed of 21 Landsat-8 images in Tianjin, China, from October 2017 to January 2019 was selected to test the method. We compared NMAG with other two contrast methods (Contrast Method 1 (CM1) and Contrast Method 2 (CM2)), and found that the average root mean square error (μRMSE) of NMAG (497.22) is significantly smaller than those of CM1 (641.39) and CM2 (543.47), and the accuracy of normalized SITS obtained using NMAG increases by 22.4% and 8.5% compared with CM1 and CM2, respectively. These experimental results confirm the effectiveness of NMAG in reducing radiometric distortion caused by continuously changing noise between images in SITS.

Polycomb Repressive Complex 2 (PRC2) function and DNA methylation (DNAme) are typically correlated with gene repression. Here, we show that PRC2 is required to maintain expression of maternal microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) from the Gtl2-Rian-Mirg locus, which is essential for full pluripotency of iPSCs. In the absence of PRC2, the entire locus becomes transcriptionally repressed due to gain of DNAme at the intergenic differentially methylated regions (IG-DMRs). Furthermore, we demonstrate that the IG-DMR serves as an enhancer of the maternal Gtl2-Rian-Mirg locus. Further analysis reveals that PRC2 interacts physically with Dnmt3 methyltransferases and reduces recruitment to and subsequent DNAme at the IG-DMR, thereby allowing for proper expression of the maternal Gtl2-Rian-Mirg locus. Our observations are consistent with a mechanism through which PRC2 counteracts the action of Dnmt3 methyltransferases at an imprinted locus required for full pluripotency.

Abstract.: The discovery of endothelial progenitor cells (EPCs) provides us with a novel treatment strategy for complications requiring therapeutic revascularization and vascular repair. However, the feasibility of this strategy may be limited due to reduced number and impaired function of EPCs under stimulation of TNF-α. The present study was designed to investigate the effect of rosiglitazone on EPC apoptosis induced by TNF-α and the molecular mechanisms involved. Rosiglitazone attenuated apoptosis of TNF-α–stimulated EPCs in a dose-dependent manner. Rosiglitazone decreased caspase-3 activity and cleavages of caspase-3, caspase-7, and parp. Rosiglitazone also moderated the dissipation of mitochondrial membrane potential caused by TNF-α treatment and reduced the expression of bax and the release of cytochrome c. Furthermore, rosiglitazone inhibited phosphorylations of ERK/MAPK and NF-κB signal molecules. Both ERK and NF-κB inhibitors decreased TNF-α–induced apoptosis of EPCs, as well as the expression of cleaved caspase-3 and parp. These results suggest that rosiglitazone may mediate the inhibitory effect on EPCs apoptosis under TNF-α stimulation through suppression of ERK/MAPK and NF-κB signal pathways. Keywords:: endothelial progenitor cell, TNF-α, rosiglitazone, apoptosis, molecular mechanism

It is well established that atrial fibrillation (AF) is far more common in elderly humans. Autonomic activation is thought to be an operative mechanism for AF propensity. The aim of the study was to investigate the impact of age on atrial tachyarrhythmia induction in a rabbit model. Six old (aged 4–6 years) and 9 young (aged 3-4 months) New Zealand white rabbits were subjected to a catheter-based electrophysiological study. Atrial tachyarrhythmia susceptibility was tested by burst pacing before and after infusion of increasing concentrations of acetylcholine. Both young and old rabbits were in normal sinus rhythm at the beginning of the infusion/burst pacing protocol. The old rabbits had faster heart rates and a marked increase in atrial tachyarrhythmias compared to the young rabbits. Nonsustained and sustained AF events were more frequent in the old rabbits. No significant fibrosis was observed in the atria of either young or old rabbits. In conclusion, the old rabbits have a greater propensity for induction of AF. The significantly faster heart rates in the old rabbits suggest that dominant sympathetic activity may play an important role in the propensity for AF in this group.

The unfolded protein response (UPR) is an adaptive signaling pathway utilized to sense and alleviate the stress of protein folding in the endoplasmic reticulum (ER). In mammals, the UPR is mediated through three proximal sensors PERK/PEK, IRE1, and ATF6. PERK/PEK is a protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 to inhibit protein synthesis. Activation of IRE1 induces splicing of XBP1 mRNA to produce a potent transcription factor. ATF6 is a transmembrane transcription factor that is activated by cleavage upon ER stress. We show that in Caenorhabditis elegans, deletion of either ire-1 or xbp-1 is synthetically lethal with deletion of either atf-6 or pek-1, both producing a developmental arrest at larval stage 2. Therefore, in C. elegans, atf-6 acts synergistically with pek-1 to complement the developmental requirement for ire-1 and xbp-1. Microarray analysis identified inducible UPR (i-UPR) genes, as well as numerous constitutive UPR (c-UPR) genes that require the ER stress transducers during normal development. Although ire-1 and xbp-1 together regulate transcription of most i-UPR genes, they are each required for expression of nonoverlapping sets of c-UPR genes, suggesting that they have distinct functions. Intriguingly, C. elegans atf-6 regulates few i-UPR genes following ER stress, but is required for the expression of many c-UPR genes, indicating its importance during development and homeostasis. In contrast, pek-1 is required for induction of approximately 23% of i-UPR genes but is dispensable for the c-UPR. As pek-1 and atf-6 mainly act through sets of nonoverlapping targets that are different from ire-1 and xbp-1 targets, at least two coordinated responses are required to alleviate ER stress by distinct mechanisms. Finally, our array study identified the liver-specific transcription factor CREBh as a novel UPR gene conserved during metazoan evolution.

Enzyme-linked i2mmunosorbent assays (ELISAs) that measure circulating phylloquinone have become commercially available, but their validity is uncertain. The objective of this study was to compare plasma phylloquinone concentrations measured using two commercially available ELISAs with concentrations measured using a validated high-performance liquid chromatography (HPLC) assay in 108 samples obtained from participants in a depletion (~10 mcg phylloquinone/d)-supplementation (~500 mcg phylloquinone/d) study. The geometric mean of plasma phylloquinone measured with ELISA A was 0.70 nmol/L, 37% lower than that measured with HPLC. The mean of the ELISA B measures was 12.4 nmol/L, >700% higher than the HPLC measures. Plasma phylloquinone measured using HPLC was significantly lower during phylloquinone depletion than supplementation (0.4 ± 0.1 compared with 1.2 ± 0.2 nmol/L; P < 0.001). Neither of the two ELISAs detected any significant difference in plasma phylloquinone concentrations between depletion and supplementation (ELISA A, P = 0.76; ELISA B, P = 0.29). These findings reinforce the need to validate plasma phylloquinone assays as they become available. [ABSTRACT FROM AUTHOR]