Assessment of the APCC Coupled MME Suite in Predicting the Distinctive Climate Impacts of Two Flavors of ENSO during Boreal Winter

Forecast skill of the APEC Climate Center (APCC) Multi-Model Ensemble (MME) seasonal forecast system in predicting two main types of El Nino-Southern Oscillation (ENSO), namely canonical (or cold tongue) and Modoki ENSO, and their regional climate impacts is assessed for boreal winter. The APCC MME is constructed by simple composite of ensemble forecasts from five independent coupled ocean-atmosphere climate models. Based on a hindcast set targeting boreal winter prediction for the period 19822004, we show that the MME can predict and discern the important differences in the patterns of tropical Pacific sea surface temperature anomaly between the canonical and Modoki ENSO one and four month ahead. Importantly, the four month lead MME beats the persistent forecast. The MME reasonably predicts the distinct impacts of the canonical ENSO, including the strong winter monsoon rainfall over East Asia, the below normal rainfall and above normal temperature over Australia, the anomalously wet conditions across the south and cold conditions over the whole area of USA, and the anomalously dry conditions over South America. However, there are some limitations in capturing its regional impacts, especially, over Australasia and tropical South America at a lead time of one and four months. Nonetheless, forecast skills for rainfall and temperature over East Asia and North America during ENSO Modoki are comparable to or slightly higher than those during canonical ENSO events

Pyruvate Dehydrogenase Kinase Is a Metabolic Checkpoint for Polarization of Macrophages to the M1 Phenotype

Metabolic reprogramming during macrophage polarization supports the effector functions of these cells in health and disease. Here, we demonstrate that pyruvate dehydrogenase kinase (PDK), which inhibits the pyruvate dehydrogenase-mediated conversion of cytosolic pyruvate to mitochondrial acetyl-CoA, functions as a metabolic checkpoint in M1 macrophages. Polarization was not prevented by PDK2 or PDK4 deletion but was fully prevented by the combined deletion of PDK2 and PDK4; this lack of polarization was correlated with improved mitochondrial respiration and rewiring of metabolic breaks that are characterized by increased glycolytic intermediates and reduced metabolites in the TCA cycle. Genetic deletion or pharmacological inhibition of PDK2/4 prevents polarization of macrophages to the M1 phenotype in response to inflammatory stimuli (lipopolysaccharide plus IFN-γ). Transplantation of PDK2/4-deficient bone marrow into irradiated wild-type mice to produce mice with PDK2/4-deficient myeloid cells prevented M1 polarization, reduced obesity-associated insulin resistance, and ameliorated adipose tissue inflammation. A novel, pharmacological PDK inhibitor, KPLH1130, improved high-fat diet-induced insulin resistance; this was correlated with a reduction in the levels of pro-inflammatory markers and improved mitochondrial function. These studies identify PDK2/4 as a metabolic checkpoint for M1 phenotype polarization of macrophages, which could potentially be exploited as a novel therapeutic target for obesity-associated metabolic disorders and other inflammatory conditions

Cancer-Associated Fibroblast-Induced Resistance to Chemotherapy and Radiotherapy in Gastrointestinal Cancers

In the past few decades, the role of cancer-associated fibroblasts (CAFs) in resistance to therapies for gastrointestinal (GI) cancers has emerged. Clinical studies focusing on GI cancers have revealed that the high expression of CAF-related molecules within tumors is significantly correlated with unfavorable therapeutic outcomes; however, the exact mechanisms whereby CAFs enhance resistance to chemotherapy and radiotherapy in GI cancers remain unclear. The cells of origin of CAFs in GI cancers include normal resident fibroblasts, mesenchymal stem cells, endothelial cells, pericytes, and even epithelial cells. CAFs accumulated within GI cancers produce cytokines, chemokines, and growth factors involved in resistance to therapies. CAF-derived exosomes can be engaged in stroma-related resistance to treatments, and several non-coding RNAs, such as miR-92a, miR-106b, CCAL, and H19, are present in CAF-derived exosomes and transferred to GI cancer cells. The CAF-induced desmoplastic reaction interferes with drug delivery to GI cancer cells, evoking resistance to chemotherapy. However, due to the heterogeneity of CAFs in GI cancers, identifying the exact mechanism underlying CAF-induced resistance may be difficult. Recent advancements in single-cell “omics” technologies could offer clues for revealing the specific subtypes and biomarkers related to resistance

Cigarette smoke aggravates asthma by inducing memory-like type 3 innate lymphoid cells

Cigarette smoking may exacerbate asthma, but the underlying mechanisms have not been studied extensively in human patients. Here authors show that type 3 innate lymphoid cells with activated phenotypes are found in the sputum and blood of smokers in higher frequencies, which might result in the aggravation of asthma. Although cigarette smoking is known to exacerbate asthma, only a few clinical asthma studies have been conducted involving smokers. Here we show, by comparing paired sputum and blood samples from smoking and non-smoking patients with asthma, that smoking associates with significantly higher frequencies of pro-inflammatory, natural-cytotoxicity-receptor-non-expressing type 3 innate lymphoid cells (ILC3) in the sputum and memory-like, CD45RO-expressing ILC3s in the blood. These ILC3 frequencies positively correlate with circulating neutrophil counts and M1 alveolar macrophage frequencies, which are known to increase in uncontrolled severe asthma, yet do not correlate with circulating eosinophil frequencies that characterize allergic asthma. In vitro exposure of ILCs to cigarette smoke extract induces expression of the memory marker CD45RO in ILC3s. Cigarette smoke extract also impairs the barrier function of airway epithelial cells and increases their production of IL-1 beta, which is a known activating factor for ILC3s. Thus, our study suggests that cigarette smoking increases local and circulating frequencies of activated ILC3 cells, plays a role in their activation, thereby aggravating non-allergic inflammation and the severity of asthma.N

Tubulointerstitial nephritis antigen-like 1 from cancer-associated fibroblasts contribute to the progression of diffuse-type gastric cancers through the interaction with integrin β1

Abstract Background Tumor cells of diffuse-type gastric cancer (DGC) are discohesive and infiltrate into the stroma as single cells or small subgroups, so the stroma significantly impacts DGC progression. Cancer-associated fibroblasts (CAFs) are major components of the tumor stroma. Here, we identified CAF-specific secreted molecules and investigated the mechanism underlying CAF-induced DGC progression. Methods We conducted transcriptome analysis for paired normal fibroblast (NF)-CAF isolated from DGC patient tissues and proteomics for conditioned media (CM) of fibroblasts. The effects of fibroblasts on cancer cells were examined by transwell migration and soft agar assays, western blotting, and in vivo. We confirmed the effect of blocking tubulointerstitial nephritis antigen-like 1 (TINAGL1) in CAFs using siRNA or shRNA. We evaluated the expression of TINAGL1 protein in frozen tissues of DGC and paired normal stomach and mRNA in formalin-fixed, paraffin-embedded (FFPE) tissue using RNA in-situ hybridization (RNA-ISH). Results CAFs more highly expressed TINAGL1 than NFs. The co-culture of CAFs increased migration and tumorigenesis of DGC. Moreover, CAFs enhanced the phosphorylation of focal adhesion kinase (FAK) and mesenchymal marker expression in DGC cells. In an animal study, DGC tumors co-injected with CAFs showed aggressive phenotypes, including lymph node metastasis. However, increased phosphorylation of FAK and migration were reduced by blocking TINAGL1 in CAFs. In the tissues of DGC patients, TINAGL1 was higher in cancer than paired normal tissues and detected with collagen type I alpha 1 chain (COL1A1) in the same spot. Furthermore, high TINAGL1 expression was significantly correlated with poor prognosis in several public databases and our patient cohort diagnosed with DGC. Conclusions These results indicate that TINAGL1 secreted by CAFs induces phosphorylation of FAK in DGC cells and promotes tumor progression. Thus, targeting TINAGL1 in CAFs can be a novel therapeutic strategy for DGC

Targeting interleukin-6 as a strategy to overcome stroma-induced resistance to chemotherapy in gastric cancer

Abstract Background Although the tumor stroma in solid tumors like gastric cancer (GC) plays a crucial role in chemo-resistance, specific targets to inhibit the interaction between the stromal and cancer cells have not yet been utilized in clinical practice. The present study aims to determine whether cancer-associated fibroblasts (CAFs), a major component of the tumor stroma, confer chemotherapeutic resistance to GC cells, and to discover potential targets to improve chemo-response in GC. Methods To identify CAF-specific proteins and signal transduction pathways affecting chemo-resistance in GC cells, secretome and transcriptome analyses were performed. We evaluated the inhibiting effect of CAF-specific protein in in vivo and in vitro models and investigated the expression of CAF-specific protein in human GC tissues. Results Secretome and transcriptome data revealed that interleukin-6 (IL-6) is a CAF-specific secretory protein that protects GC cells via paracrine signaling. Furthermore, CAF-induced activation of the Janus kinase 1-signal transducer and activator of transcription 3 signal transduction pathway confers chemo-resistance in GC cells. CAF-mediated inhibition of chemotherapy-induced apoptosis was abrogated by the anti-IL-6 receptor monoclonal antibody tocilizumab in various experimental models. Clinical data revealed that IL-6 was prominently expressed in the stromal portion of GC tissues, and IL-6 upregulation in GC tissues was correlated with poor responsiveness to chemotherapy. Conclusions Our data provide plausible evidence for crosstalk between GC cells and CAFs, wherein IL-6 is a key contributor to chemoresistance. These findings suggest the potential therapeutic application of IL-6 inhibitors to enhance the responsiveness to chemotherapy in GC

HVC1 ameliorates hyperlipidemia and inflammation in LDLR−/− mice

Abstract Background HVC1 consists of Coptidis Rhizoma (dried rhizome of Coptischinensis), Scutellariae Radix (root of Scutellariabaicalensis), Rhei Rhizoma (rhizome of Rheum officinale), and Pruni Cortex (cortex of Prunusyedoensis Matsum). Although the components are known to be effective in various conditions such as inflammation, hypertension, and hypercholesterolemia, there are no reports of the molecular mechanism of its hypolipidemic effects. Methods We investigated the hypolipidemic effect of HVC1 in low-density lipoprotein receptor-deficient (LDLR−/−) mice fed a high-cholesterol diet for 13 weeks. Mice were randomized in to 6 groups: ND (normal diet) group, HCD (high-cholesterol diet) group, and treatment groups fed HCD and treated with simvastatin (10 mg/kg, p.o.) or HVC1 (10, 50, or 250 mg/kg, p.o.). Results HVC1 regulated the levels of total cholesterol, triglyceride (TG), low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol in mouse serum. In addition, it regulated the transcription level of the peroxisome proliferator-activated receptors (PPARs), sterol regulatory element-binding proteins (SREBP)-2, 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase, lipoprotein lipase (LPL), apolipoprotein B (apo B), liver X receptor (LXR), and inflammatory cytokines (IL-1β, IL-6, and TNF-α). Furthermore, HVC1 activated 5′ adenosine monophosphate-activated protein kinase (AMPK). Conclusion Our results suggest that HVC1 might be effective in preventing high-cholesterol diet-induced hyperlipidemia by regulating the genes involved in cholesterol and lipid metabolism, and inflammatory responses

Additional file 1 of Tubulointerstitial nephritis antigen-like 1 from cancer-associated fibroblasts contribute to the progression of diffuse-type gastric cancers through the interaction with integrin β1

Additional file 1: Fig. S1. Schematic diagram for proteomic and transcriptome analysis. Fig. S2. (A) Western blotting for FAK phosphorylation in fibroblast co-cultured MKN45 and KATO-III cells. Representative images and graph of the transwell migration assay of MKN45 (B) and KATO-III (C) with or without fibroblasts (magnification, × 100). Fig. S3. Normalized protein expression by housekeeping genes from Fig. 1A (A), 1E (B), 1F (C), 1G (D), 4B (E), and 4E (F). Fig. S4. (A) Cell proliferation assay for NF- or CAF-CM treated SNU601 cells. (B) qRT-PCR for TINAGL1 gene expression in NF-CAF133 pair. Tumor volume (C) and weight (D) for Fig. 3E. (E) Representative images for H&E and immunohistochemistry staining at the tumor margin (scale bars, 50 μm). Fig. S5. (A) RT-PCR for hTERT and TINAGL1 expression in wild-type and immortalized NF-CAF47 pairs. (C) Representative images and graph of the transwell migration assay of immortalized fibroblast co-cultured SNU601 cells (magnification, × 100). Data were analyzed using the Kruskal–Wallis test with Dunn’s test. *P < 0.05. Fig. S6. (A) Western blotting for Twist expression in siRNA transfected CAF47 co-cultured SNU601 cells. (B) Western blotting for EMT marker expression in PF-573,228-treated SNU601 cells. Tumor weight (C) and volume graph (D) for Fig. 4I. (E) Representative images for H&E and immunohistochemistry staining at the tumor margin (scale bars, 50 μm). Fig. S7. Gene expression correlation between TINAGL1 and ITGB1, ITGA5, and ITGAV from the GSE15459 (A, n = 200) and TCGA-STAD datasets (B, n = 375). Fig. S8. (A) Kaplan–Meier plots for TINAGL1 and COL1A1, ACTA2, or FAP expression in intestinal-type gastric cancer patients from the GSE15459 dataset (n = 99). (B) Kaplan–Meier plots for TINAGL1 and COL1A1, ACTA2, or FAP expression in gastric cancer patients from the TCGA-STAD dataset (n = 54 for diffuse, 155 for intestinal)

The neural substrates of affective face recognition in patients with Hwa-Byung and healthy individuals in Korea

Hwa-Byung (HB) is a Korean culture-bound psychiatric syndrome caused by the suppression of anger. HB patients have various psychological and somatic symptoms, such as chest discomfort, a sensation of heat, and the sensation of having an epigastric mass. In this study, we measured brain activity in HB patients and healthy individuals in response to affective facial stimuli. Using functional magnetic resonance imaging (fMRI), the current study measured neural responses to neutral, sad, and angry facial stimuli in 12 healthy individuals and 12 patients with HB. In response to all types of facial stimuli, HB patients showed increased activations in the lingual gyrus and fusiform gyrus compared with healthy persons, but they showed relatively lower activation in the thalamus. We also found that patients with HB showed lower activity in response to the neutral condition in the right ACC than healthy controls. The current study indicates that the suppression of affect results in aberrant function of the brain regions of the visual pathway, and functional impairment in the ACC may contribute to the pathophysiology of HB.Lee BT, 2007, PROG NEURO-PSYCHOPH, V31, P1487, DOI 10.1016/j.pnpbp.2007.06.030Pfleiderer B, 2007, WORLD J BIOL PSYCHIA, V8, P269, DOI 10.1080/15622970701216673FRODL T, 2007, WORLD J BIO IN PRESSKIM MJ, 2007, J PSYCHIATR RES, V42, P268Wang W, 2006, NAT NEUROSCI, V9, P1330, DOI 10.1038/nn1768Strauss MM, 2005, NEUROIMAGE, V26, P389, DOI 10.1016/j.neuroimage.2005.01.053Seminowicz DA, 2004, NEUROIMAGE, V22, P409, DOI 10.1016/j.neuroimage.2004.01.015LEE WH, 2004, J KOREAN NEUROPSYCHI, V43, P552Yucel M, 2003, J PSYCHIATR NEUROSCI, V28, P350Adams RB, 2003, SCIENCE, V300, P1536MURPHY FC, 2003, COGN AFFECT BEHAV NE, V3, P207Rauch SL, 2003, ANN NY ACAD SCI, V985, P389Yang TT, 2002, NEUROREPORT, V13, P1737Sanders GS, 2002, TRENDS COGN SCI, V6, P190BRETT M, 2002, 8 INT C FUNCT MAPP H, V16WHALEN PJ, 2002, SEMIN CLIN NEUROPSYC, V7, P234PARK YJ, 2002, HEALTH CARE WOMEN IN, V23, P389Whalen PJ, 2001, EMOTION, V1, P70, DOI 10.1037/1528-3542.1.1.70PARK YJ, 2001, J TRANSCULT NURS, V12, P115Damasio AR, 2000, NAT NEUROSCI, V3, P1049Haxby JV, 2000, TRENDS COGN SCI, V4, P223*AM PSYCH ASS, 2000, DIAGN STAT MAN MENTHAN OS, 2000, STRUCTURED CLIN INTEPhillips ML, 1999, PSYCHIAT RES-NEUROIM, V92, P11Blair RJR, 1999, BRAIN, V122, P883Sprengelmeyer R, 1998, P ROY SOC LOND B BIO, V265, P1927Kanwisher N, 1997, J NEUROSCI, V17, P4302SERGENT J, 1992, BRAIN, V115, P15Felleman DJ, 1991, CEREB CORTEX, V1, P1, DOI 10.1093/cercor/1.1.1MIN SK, 1989, J KOREAN NEUROPSYCHI, V28, P604LIN KM, 1983, AM J PSYCHIAT, V140, P105EKMAN P, 1980, J PERS SOC PSYCHOL, V39, P1125OLDFIELD RC, 1971, NEUROPSYCHOLOGIA, V9, P97HAMILTON M, 1967, BRIT J SOC CLIN PSYC, V6, P278