Transcriptional activation of rice CINNAMOYL-CoA REDUCTASE 10 by OsNAC5, contributes to drought tolerance by modulating lignin accumulation in roots.

Drought is a common abiotic stress for terrestrial plants and often affects crop development and yield. Recent studies have suggested that lignin plays a crucial role in plant drought tolerance; however, the underlying molecular mechanisms are still largely unknown. Here, we report that the rice (Oryza sativa) gene CINNAMOYL-CoA REDUCTASE 10 (OsCCR10) is directly activated by the OsNAC5 transcription factor, which mediates drought tolerance through regulating lignin accumulation. CCR is the first committed enzyme in the monolignol synthesis pathway, and the expression of 26 CCR genes was observed to be induced in rice roots under drought. Subcellular localisation assays revealed that OsCCR10 is a catalytically active enzyme that is localised in the cytoplasm. The OsCCR10 transcript levels were found to increase in response to abiotic stresses, such as drought, high salinity, and abscisic acid (ABA), and transcripts were detected in roots at all developmental stages. In vitro enzyme activity and in vivo lignin composition assay suggested that OsCCR10 is involved in H- and G-lignin biosynthesis. Transgenic rice plants overexpressing OsCCR10 showed improved drought tolerance at the vegetative stages of growth, as well as higher photosynthetic efficiency, lower water loss rates, and higher lignin content in roots compared to non-transgenic (NT) controls. In contrast, CRISPR/Cas9-mediated OsCCR10 knock-out mutants exhibited reduced lignin accumulation in roots and less drought tolerance. Notably, transgenic rice plants with root-preferential overexpression of OsCCR10 exhibited higher grain yield than NT controls plants under field drought conditions, indicating that lignin biosynthesis mediated by OsCCR10 contributes to drought tolerance.

Locus coeruleus in memory formation and Alzheimer's disease.

Catecholamine neurons of the locus coeruleus (LC) in the dorsal pontine tegmentum innervate the entire neuroaxis, with signaling actions implicated in the regulation of attention, arousal, sleep-wake cycle, learning, memory, anxiety, pain, mood, and brain metabolism. The co-release of norepinephrine (NE) and dopamine (DA) from LC terminals in the hippocampus plays a role in all stages of hippocampal-memory processing. This catecholaminergic regulation modulates the encoding, consolidation, retrieval, and reversal of hippocampus-based memory. LC neurons in awake animals have two distinct firing modes: tonic firing (explorative) and phasic firing (exploitative). These two firing modes exert different modulatory effects on post-synaptic dendritic spines. In the hippocampus, the firing modes regulate long-term potentiation (LTP) and long-term depression, which differentially regulate the mRNA expression and transcription of plasticity-related proteins (PRPs). These proteins aid in structural alterations of dendritic spines, that is, structural long-term potentiation (sLTP), via expansion and structural long-term depression (sLTD) via contraction of post-synaptic dendritic spines. Given the LC's role in all phases of memory processing, the degeneration of 50% of the LC neuron population occurring in Alzheimer's disease (AD) is a clinically relevant aspect of disease pathology. The loss of catecholaminergic regulation contributes to dysfunction in memory processes along with impaired functions associated with attention and task completion. The multifaceted role of the LC in memory and general task performance and the close correlation of LC degeneration with neurodegenerative disease progression together implicate it as a target for new clinical assessment tools.

The small peptide world in long noncoding RNAs.

Long noncoding RNAs (lncRNAs) are a group of transcripts that are longer than 200 nucleotides (nt) without coding potential. Over the past decade, tens of thousands of novel lncRNAs have been annotated in animal and plant genomes because of advanced high-throughput RNA sequencing technologies and with the aid of coding transcript classifiers. Further, a considerable number of reports have revealed the existence of stable, functional small peptides (also known as micropeptides), translated from lncRNAs. In this review, we discuss the methods of lncRNA classification, the investigations regarding their coding potential and the functional significance of the peptides they encode.

En bloc and segmental deletions of human XIST reveal X chromosome inactivation-involving RNA elements.

The XIST RNA is a non-coding RNA that induces X chromosome inactivation (XCI). Unlike the mouse Xist RNA, how the human XIST RNA controls XCI in female cells is less well characterized, and its functional motifs remain unclear. To systematically decipher the XCI-involving elements of XIST RNA, 11 smaller XIST segments, including repeats A, D and E; human-specific repeat elements; the promoter; and non-repetitive exons, as well as the entire XIST gene, were homozygously deleted in K562 cells using the Cas9 nuclease and paired guide RNAs at high efficiencies, followed by high-throughput RNA sequencing and RNA fluorescence in situ hybridization experiments. Clones containing en bloc and promoter deletions that consistently displayed no XIST RNAs and a global up-regulation of X-linked genes confirmed that the deletion of XIST reactivates the inactive X chromosome. Systematic analyses of segmental deletions delineated that exon 5 harboring the non-repeat element is important for X-inactivation maintenance, whereas exons 2, 3 and 4 as well as the other repeats in exon 1 are less important, a different situation from that of mouse Xist. This Cas9-assisted dissection of XIST allowed us to understand the unique functional domains within the human XIST RNA.

TERIUS: accurate prediction of lncRNA via high-throughput sequencing data representing RNA-binding protein association.

BACKGROUND: LncRNAs are long regulatory non-coding RNAs, some of which are arguably predicted to have coding potential. Despite coding potential classifiers that utilize ribosome profiling data successfully detected actively translated regions, they are less sensitive to lncRNAs. Furthermore, lncRNA annotation can be susceptible to false positives obtained from 3' untranslated region (UTR) fragments of mRNAs. RESULTS: To lower these limitations in lncRNA annotation, we present a novel tool TERIUS that provides a two-step filtration process to distinguish between bona fide and false lncRNAs. The first step successfully separates lncRNAs from protein-coding genes showing enhanced sensitivity compared to other methods. To eliminate 3'UTR fragments, the second step takes advantage of the 3'UTR-specific association with regulator of nonsense transcripts 1 (UPF1), leading to refined lncRNA annotation. Importantly, TERIUS enabled the detection of misclassified transcripts in published lncRNA annotations. CONCLUSIONS: TERIUS is a robust method for lncRNA annotation, which provides an additional filtration step for 3'UTR fragments. TERIUS was able to successfully re-classify GENCODE and miTranscriptome lncRNA annotations. We believe that TERIUS can benefit construction of extensive and accurate non-coding transcriptome maps in many genomes.

Role of human epididymis protein 4 in chemoresistance and prognosis of epithelial ovarian cancer.

AIM: Human epididymis protein 4 (HE4) is a novel biomarker for epithelial ovarian cancer. This study was designed to evaluate the role of HE4 in chemo-response against anti-cancer drugs and prognosis of epithelial ovarian cancer. METHODS: HE4-depleted cells and HE4-overexpressing cells were generated. The effect of HE4 gene silencing and overexpression was examined using a cell viability assay after exposure to chemotherapeutic agents and the signaling pathway. We studied the expression of HE4 in ovarian cancer tissue and the prognostic significance. Cytoplasmic staining was graded for intensity and percentage of positive cells. The grades were multiplied to determine an H-score. RESULTS: Knockdown of HE4 in OVCAR-3 cells resulted in reduction in cell growth and increased sensitivity to paclitaxel and cisplatin compared to control cells. This effect originated from the decreased activation of cell-growth-related signaling, such as AKT and Erk mediated by epidermal growth factor (EGF), while overexpression of HE4 resulted in enhanced cell growth and suppressed the anti-tumorigenic activity of paclitaxel. Activation of AKT and Erk pathways was enhanced in HE4-overexpressing cells compared to control cells. Based on the results of multivariate analysis, the risk of death was significantly higher in patients with an H-score > 4. CONCLUSION: HE4 induces chemoresistance against anti-cancer drugs and activates the AKT and Erk pathways to enhance tumor survival. HE4 expression in ovarian cancer tissue is associated with a worse prognosis for epithelial ovarian cancer patients.

Prediction of Infarct Transmurality From C-Reactive Protein Level and Mean Platelet Volume in Patients With ST-Elevation Myocardial Infarction: Comparison of the Predictive Values of Cardiac Enzymes.

BACKGROUND: High C-reactive protein (CRP) and mean platelet volume (MPV) levels are associated with poor prognosis in patients with ST-segment elevation myocardial infarction (STEMI). The aim of this study was to evaluate the relationship between CRP level or MPV and infarct transmurality in patients with STEMI. METHODS: We retrospectively reviewed CRP level, MPV, and infarct transmurality in 112 STEMI patients who were assessed with contrast-enhanced cardiac magnetic resonance imaging. RESULTS: When the cut-off peak CRP level and MPV were set at 2.35 mg/dl and 7.3 fl using receiver operating characteristic curves analysis, the sensitivity was 67.3/69.2% and specificity was 76.7/76.7% for differentiating between the groups with and those without transmural involvement. Peak CRP level, MPV, peak creatine kinase-MB (CK-MB) level, and peak high-sensitivity cardiac troponin T (hs-cTnT) level had comparable predictive values for transmural involvement (area under the curve, 0.749, 0.761, 0.680, and 0.696, respectively). High peak CRP level and MPV were independent predictors of transmural involvement after adjusting for the peak CK-MB level, peak hs-cTnT level, baseline thrombolysis in myocardial infarction flow grade, and left ventricular ejection fraction (odds ratio: 5.16/5.42, 95% confidence interval: 1.84-14.50/2.03-14.47, P = 0.002/0.001, respectively) in the logistic regression analysis. CONCLUSION: The results of this study show that peak CRP level and MPV are predictive markers for transmural involvement. Their predictive power for transmural involvement is independent of and comparable to that of peak CK-MB and hs-cTnT levels.

Clinical outcome prediction from mean platelet volume in patients undergoing percutaneous coronary intervention in Korean cohort: Implications of more simple and useful test than platelet function testing.

The aim of this study was to determine the associations of the mean platelet volume (MPV) with the development of adverse outcomes after percutaneous coronary intervention (PCI) and platelet reactivity. MPV and platelet function testing were analysed in 208 patients who underwent PCI. The primary endpoint was cardiac death. The secondary endpoint analysed was cardiovascular events (CVE): the composite of myocardial infarction (MI), target vessel revascularization (TVR), and stent thrombosis (ST). The median MPV level, aspirin reaction unit (ARU), P2Y12 reaction units (PRU) and P2Y12% inhibition (PI%) of clopidogrel were 8.55 (IQR 8.00-9.18) fl, 401.0 (IQR 389.3-442.0) ARU, 222.0 (IQR 169.0-272.3) PRU and 22 (IQR 9-38) %, respectively. We observed that high values of MPV were associated with elevated ARU (r = 0.165, p = 0.017) and decreased PI% (r = -0.167, p = 0.016). There were 10 events of cardiac death, 3 MI (including 1 event of ST), and 8 TVR during a mean of 7.6 months of follow-up. The Kaplan-Meier analysis revealed that the higher MPV group (≥8.55 fl, median) had a significantly higher cardiac death rate compared to the lower MPV group (<8.55 fl) (7.7% vs. 1.9%, log-rank: p = 0.035). However, aspirin or clopidogrel resistance (>550 ARU, <40 PI%, respectively) did not predict cardiac death. When the MPV cut-off level was set to 8.55 fl using the receiver operating characteristic curve, the sensitivity was 80% and the specificity was 51.5% for differentiating between the group with cardiac death and the group without cardiac death. This value was more useful in patients with clinical diagnosis of acute coronary syndrome (ACS). Furthermore, ACS patients with an MPV over 8.55 fl had high cardiac death and CVE risk without atorvastatin loading before PCI (Log-Rank = 0.0031, 0.0023, respectively). The results of this study show that MPV was a predictive marker for cardiac death after PCI; its predictive power for cardiac death was more useful in patients with ACS.

Optimal design of synthetic circular RNAs.

Circular RNAs are an unusual class of single-stranded RNAs whose ends are covalently linked via back-splicing. Due to their versatility, the need to express circular RNAs in vivo and in vitro has increased. Efforts have been made to efficiently and precisely synthesize circular RNAs. However, a review on the optimization of the processes of circular RNA design, synthesis, and delivery is lacking. Our review highlights the multifaceted aspects considered when producing optimal circular RNAs and summarizes the available options for each step of exogenous circular RNA design and synthesis, including circularization strategies. Additionally, this review describes several potential applications of circular RNAs.

Stroke or coronary artery disease prediction from mean platelet volume in patients with type 2 diabetes mellitus.

The aim of this study was to determine the association of mean platelet volume (MPV) with the development of stroke or coronary artery disease (CAD) in diabetes mellitus (DM). MPV was analyzed in 200 Korean patients with DM. The primary endpoint was composite of ischemic stroke/CAD events. The mean MPV was 7.6 ± 0.8 fl. There were 14 ischemic stroke events and 8 CAD events during a mean of 28.4 months of follow-up. The Kaplan-Meier analysis revealed that the higher tertile MPV group (≥7.9 fl) had a significantly higher stroke/CAD rate compared to the lower tertile MPV group (≤7.3 fl) (29.9% vs. 2.8%, log-rank: p < 0.001). Higher MPV was an independent predictor of stroke/CAD risk after adjusting for 10-year risk ≥10%, hypertension, dyslipidemia, and previous stroke or transient ischemic attack history (hazard ratio: 11.92, 95% confidence interval 2.68-52.92, p = 0.001) in the Cox proportional hazard analysis. When the MPV cut-off level was set to 7.95 fl using the receiver operating characteristic curve, the sensitivity was 91% and the specificity was 80% for differentiating between the group with stroke/CAD and the group without stroke/CAD. This value was more useful in patients with hypertension. The results of this study show that MPV is a predictive marker for stroke/CAD; its predictive power for stroke/CAD is independent of age, gender, hypertension, and hemoglobin A1C.

Preoperative immune landscape predisposes adverse outcomes in hepatocellular carcinoma patients with liver transplantation.

Immune class in hepatocellular carcinoma (HCC) has been shown to possess immunogenic power; however, how preestablished immune landscapes in premalignant and early HCC stages impact the clinical outcomes of HCC patients remains unexplored. We sequenced bulk transcriptomes for 62 malignant tumor samples from a Korean HCC cohort in which 38 patients underwent total hepatectomy, as well as for 15 normal and 47 adjacent nontumor samples. Using in silico deconvolution of expression mixtures, 22 immune cell fractions for each sample were inferred, and validated with immune cell counting by immunohistochemistry. Cell type-specific immune signatures dynamically shifted from premalignant stages to the late HCC stage. Total hepatectomy patients displayed elevated immune infiltration and prolonged disease-free survival compared to the partial hepatectomy patients. However, patients who exhibited an infiltration of regulatory T cells (Tregs) during the pretransplantation period displayed a high risk of tumor relapse with suppressed immune responses, and pretreatment was a potential driver of Treg infiltration in the total hepatectomy group. Treg infiltration appeared to be independent of molecular classifications based on transcriptomic data. Our study provides not only comprehensive immune signatures in adjacent nontumor lesions and early malignant HCC stages but also clinical guidance for HCC patients who will undergo liver transplantation.

Scrub Typhus and Abnormal Electrocardiography.

This study compared the frequency of abnormal electrocardiogram (ECG) types between scrub typhus patient group and age- and gender-matched health checkup group and their associations with disease severity in scrub typhus patient. Demographic characteristics and ECG and laboratory findings of patients with scrub typhus admitted to Chosun University Hospital, and normal subjects visiting the hospital for health checkup from January 2008 to December 2012 were retrospectively studied. Electrocardiogram abnormalities at admission were observed in 72 of 165 (43.6%) scrub typhus confirmed patients. The following ECG abnormalities were observed: arrhythmic group (31 cases, 18.8%), ischemic change group (25 cases, 15.1%), prolonged QT group (32 cases, 19.4%).Compared with the age and gender-matched health checkup group, ECG abnormalities were more commonly observed in scrub typhus patient group (13.9% versus 43.6%, P < 0.001). In addition, when compared with the normal ECG group, scrub typhus in the abnormal ECG group showed greater disease severity and this phenomenon was particularly prominent in the prolonged QT group. Based on our study prolonged QT observed in approximately 20% of patients with scrub typhus, clinicians should pay additional attention to drugs that affect QT interval.

A Nitrogen Molecular Sensing System, Comprised of the ALLANTOINASE and UREIDE PERMEASE 1 Genes, Can Be Used to Monitor N Status in Rice.

Nitrogen (N) is an essential nutrient for plant growth and development, but its concentration in the soil is often insufficient for optimal crop production. Consequently, improving N utilization in crops is considered as a major target in agricultural biotechnology. However, much remains to be learnt about crop N metabolism for application. In this study, we have developed a molecular sensor system to monitor the N status in rice (Oryza sativa). We first examined the role of the ureide, allantoin, which is catabolized into allantoin-derived metabolites and used as an N source under low N conditions. The expression levels of two genes involved in ureide metabolism, ALLANTOINASE (OsALN) and UREIDE PERMEASE 1 (OsUPS1), were highly responsive to the N status. OsALN was rapidly up-regulated under low N conditions, whereas OsUPS1 was up-regulated under high N conditions. Taking advantage of the responses of these two genes to N status, we generated transgenic rice plants harboring the molecular N sensors, proALN::ALN-LUC2 and proUPS1::UPS1-LUC2, comprising the gene promoters driving expression of the luciferase reporter. We observed that expression of the transgenes mimicked transcriptional regulation of the endogenous OsALN and OsUPS1 genes in response to exogenous N status. Importantly, the molecular N sensors showed similar levels of specificity to nitrate and ammonium, from which we infer their sensing abilities. Transgenic rice plants expressing the proUPS1::UPS1-LUC2 sensor showed strong luminescence under high exogenous N conditions (>1 mM), whereas transgenic plants expressing the proALN::ALN-LUC2 sensor showed strong luminescence under low exogenous N conditions (<0.1 mM). High exogenous N (>1 mM) substantially increased internal ammonium and nitrate levels, whereas low exogenous N (<0.1 mM) had no effect on internal ammonium and nitrate levels, indicating the luminescence signals of molecular sensors reflect internal N status in rice. Thus, proALN::ALN-LUC2 and proUPS1::UPS1-LUC2 represent N molecular sensors that operate over a physiological and developmental range in rice.

Stroke or left atrial thrombus prediction using antithrombin III and mean platelet volume in patients with nonvalvular atrial fibrillation.

BACKGROUND: CHADS2 (congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, stroke) and CHA2 DS2 -VASc (congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, stroke, vascular disease, age 65 to 74 years, sex category) scores showed just moderate discrimination ability in predicting thromboembolic complications in patients with nonvalvular atrial fibrillation (AF). HYPOTHESIS: To determine the association of antithrombin III (AT-III) deficiency and mean platelet volume (MPV) with the development of stroke or left atrial (LA) thrombus in patients with AF. METHODS: AT-III and MPV were analyzed in 352 patients with AF. The primary endpoint was a composite of ischemic stroke event and incidental LA thrombus. RESULTS: There were 50 events (14.2%) during a mean 35.4 months of follow-up. A significantly higher stroke or LA thrombus rate was observed in the low-AT-III group (<70%) than that in the high-AT-III group (≥70%). A significantly higher stroke or LA thrombus rate was observed in the high-MPV group (≥7.0 fL) than that in the low-MPV group (<7.0 fL). AF patients with an MPV ≥7.0 fL and AT-III deficiency had higher stroke or LA thrombus risk than those without an MPV ≥7.0 fL and AT-III deficiency. In the Cox proportional hazard analysis, high MPV was found to be an independent predictor of stroke or LA thrombus risk (hazard ratio: 6.408; 95% confidence interval: 2.874-14.286). Although AT-III deficiency was not an independent predictor of stroke or LA thrombus risk, a trend was observed. CONCLUSIONS: High MPV and AT-III deficiency were predictive markers for stroke or LA thrombus. Their predictive power for stroke was independent of antiplatelet treatment, anticoagulation therapy, and a high CHA2 DS2 -VASc score in patients with AF.

A case of a resected benign myxoma-like hemorrhagic cyst, which later recurred as undifferentiated pleomorphic sarcoma in the left atrium.

RATIONALE: An intracardiac cystic mass is a rare type of mass found in the left atrium. The differential diagnosis of an intracardiac cystic mass includes hydatid cysts, bronchogenic cysts, intracardiac varices, and hemorrhages in some tumor types, including myxoma. PATIENT CONCERNS: We present the case of a 68-year-old woman who presented with episodic dyspnea. DIAGNOSES-INTERVENTIONS-OUTCOMES: Transthoracic echocardiography (TTE) revealed the presence of a left atrial mass mimicking myxoma. However, in postoperative findings, it was determined that the mass was actually a hemorrhagic cyst. Eighteen months later, the patient presented with recurrent exertional dyspnea and TTE revealed the recurrence of a left atrial mass. Computed tomography showed that the mass extended into the right atrium, inferior vena cava, and coronary sinus. After re-operation, the final histological diagnosis was determined to be an undifferentiated pleomorphic sarcoma in the left atrium. LESSONS: An intracardiac hemorrhagic cyst was suspected during the operation of a benign-looking LA mass. As such, we recommend that other rare etiologies be considered and more biopsies be performed when possible.

Incredible RNA: Dual Functions of Coding and Noncoding.

Since the RNA world hypothesis was proposed, a large number of regulatory noncoding RNAs (ncRNAs) have been identified in many species, ranging from microorganisms to mammals. During the characterization of these newly discovered RNAs, RNAs having both coding and noncoding functions were discovered, and these were considered bifunctional RNAs. The recent use of computational and high-throughput experimental approaches has revealed increasing evidence of various sources of bifunctional RNAs, such as protein-coding mRNAs with a noncoding isoform and long ncRNAs bearing a small open reading frame. Therefore, the genomic diversity of Janus-faced RNA molecules that have dual characteristics of coding and noncoding indicates that the functional roles of RNAs have to be revisited in cells on a genome-wide scale. Such studies would allow us to further understand the complex gene-regulatory network in cells. In this review, we discuss three major genomic sources of bifunctional RNAs and present a handful of examples of bifunctional RNA along with their functional roles.

Protein Tyrosine Phosphatase N2 Is a Positive Regulator of Lipopolysaccharide Signaling in Raw264.7 Cell through Derepression of Src Tyrosine Kinase.

T cell protein tyrosine phosphatase N2 (PTPN2) is a phosphotyrosine-specific nonreceptor phosphatase and is ubiquitously expressed in tissues. Although PTPN2 functions as an important regulator in different signaling pathways, it is still unclear what is specific target protein of PTPN2 and how is regulated in lipopolysaccharide (LPS)-induced inflammatory signaling pathway. Here, we found that PTPN2 deficiency downregulated the expression of LPS-mediated pro-inflammtory cytokine genes. Conversely, overexpression of PTPN2 in Raw264.7 cells enhanced the expression and secretion of those cytokines. The activation of MAPK and NF-κB signaling pathways by LPS was reduced in PTPN2-knockdowned cells and ectopic expression of PTPN2 reversed these effects. Furthermore, we found that PTNP2 directly interacted with Src and removed the inhibitory Tyr527 phosphorylation of Src to enhance the activatory phosphorylation of Tyr416 residue. These results suggested that PTPN2 is a positive regulator of LPS-induced inflammatory response by enhancing the activity of Src through targeting the inhibitory phosphor-tyrosine527 of Src.

Prediction of Long-Term Mortality Based on Neutrophil-Lymphocyte Ratio After Percutaneous Coronary Intervention.

BACKGROUND: The preprocedural neutrophil-lymphocyte ratio (NLR) is related to adverse outcomes in patients with coronary artery disease. We hypothesized that high NLR is a predictor of cardiac death after percutaneous coronary intervention (PCI). The objective of this investigation was to assess the associations of NLR, high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-B type natriuretic peptide (NT-proBNP) with the occurrence of cardiac death after PCI. MATERIALS AND METHODS: The NLR, hs-cTnT and NT-proBNP were analyzed in 372 patients who underwent PCI. The primary end point was cardiac death. RESULTS: The median NLR was 2.3 (interquartile range: 1.5-4.1). There were 21 cardiac death events during a mean follow-up duration of 25.8 months. With the NLR cutoff level set to 3.3 using the receiver-operating characteristic curve, the sensitivity and specificity for differentiating between the group with cardiac death and the group without cardiac death were 85.7% and 59.3%, respectively. Kaplan-Meier analysis revealed that the higher NLR group (≥3.3) had a significantly higher cardiac death rate than the lower NLR group (<3.3) (11.1% versus 1.4%, log-rank: P < 0.0001). This value was more useful in patients with heart failure (NT-proBNP ≥ 300ng/L) or myocardial injury (hs-cTnT ≥ 100ng/L). CONCLUSIONS: The outcomes of the current study demonstrate that high NLR is a predictor of cardiac death after PCI, especially in patients with heart failure or myocardial injury.

Smad7 Modulates Epidermal Growth Factor Receptor Turnover through Sequestration of c-Cbl.

Epidermal growth factor (EGF) regulates various cellular events, including proliferation, differentiation, migration, and tumorigenesis. For the maintenance of homeostasis, EGF signaling should be tightly regulated to prevent the aberrant activation. Smad7 has been known as inhibitory Smad that blocks the signal transduction of transforming growth factor ß. In the process of cell proliferation or transformation, Smad7 has been shown the opposite activities as a promoter or suppressor depending on cell types or microenvironments. We found that the overexpression of Smad7 in human HaCaT keratinocyte cells and mouse skin tissues elevated EGF receptor (EGFR) activity by impairing ligand-induced ubiquitination and degradation of activated receptor, which is induced by the E3 ubiquitin ligase c-Cbl. The C-terminal MH2 region but not MH1 region of Smad7 is critical for interaction with c-Cbl to inhibit the ubiquitination of EGFR. Interestingly, wild-type Smad7, but not Smad6 or mutant Smad7, destabilized the EGF-induced complex formation of c-Cbl and EGFR. These data suggest a novel role for Smad7 as a promoter for prolonging the EGFR signal in keratinocyte and skin tissue by reducing its ligand-induced ubiquitination and degradation.

Prediction of infarct severity from triiodothyronine levels in patients with ST-elevation myocardial infarction.

BACKGROUND/AIMS: The aim of the present study was to evaluate the relationship between thyroid hormone levels and infarct severity in patients with ST-elevation myocardial infarction (STEMI). METHODS: We retrospectively reviewed thyroid hormone levels, infarct severity, and the extent of transmurality in 40 STEMI patients evaluated via contrast-enhanced cardiac magnetic resonance imaging. RESULTS: The high triiodothyronine (T3) group (≥ 68.3 ng/dL) exhibited a significantly higher extent of transmural involvement (late transmural enhancement > 75% after administration of gadolinium contrast agent) than did the low T3 group (60% vs. 15%; p = 0.003). However, no significant difference was evident between the high- and low-thyroid-stimulating hormone/free thyroxine (FT4) groups. When the T3 cutoff level was set to 68.3 ng/dL using a receiver operating characteristic curve, the sensitivity was 80% and the specificity 68% in terms of differentiating between those with and without transmural involvement. Upon logistic regression analysis, high T3 level was an independent predictor of transmural involvement after adjustment for the presence of diabetes mellitus (DM) and the use of glycoprotein IIb/IIIa inhibitors (odds ratio, 40.62; 95% confidence interval, 3.29 to 502; p = 0.004). CONCLUSIONS: The T3 level predicted transmural involvement that was independent of glycoprotein IIb/IIIa inhibitor use and DM positivity.