Tropical cyclones (TCs) are a hazard to life and property and a prominent element of the global climate system; therefore, understanding and predicting TC location, intensity, and frequency is of ...both societal and scientific significance. Methodologies exist to predict basinwide, seasonally aggregated TC activity months, seasons, and even years in advance. It is shown that a newly developed high-resolution global climate model can produce skillful forecasts of seasonal TC activity on spatial scales finer than basinwide, from months and seasons in advance of the TC season. The climate model used here is targeted at predicting regional climate and the statistics of weather extremes on seasonal to decadal time scales, and comprises high-resolution (50 km × 50 km) atmosphere and land components as well as more moderate-resolution (∼100 km) sea ice and ocean components. The simulation of TC climatology and interannual variations in this climate model is substantially improved by correcting systematic ocean biases through “flux adjustment.” A suite of 12-month duration retrospective forecasts is performed over the 1981–2012 period, after initializing the climate model to observationally constrained conditions at the start of each forecast period, using both the standard and flux-adjusted versions of the model. The standard and flux-adjusted forecasts exhibit equivalent skill at predicting Northern Hemisphere TC season sea surface temperature, but the flux-adjusted model exhibits substantially improved basinwide and regional TC activity forecasts, highlighting the role of systematic biases in limiting the quality of TC forecasts. These results suggest that dynamical forecasts of seasonally aggregated regional TC activity months in advance are feasible.
Background
Several previous researches had found artery stiffness associated skeletal muscle mass, but not considering muscle strength and physical performance, which also were compositions of ...sarcopenia. This study aims to reveal the relationship of artery stiffness and sarcopenia using the Asian Working Group for Sarcopenia criteria.
Methods
Study was performed on 1002 Chinese community dwelling participants aged ≥65 years from November 2016 to March 2017. Body composition, muscle strength, physical performance, and brachial-ankle pulse wave velocity (baPWV) considering as artery stiffness index were measured.
Results
In multiple regression analysis, baPWV was associated with handgrip (β=−0.13, P=0.04) and Relative skeletal muscle mass index (ASM/Ht
2
) (β=−0.02, P<0.01), but not with 4-meter velocity (P=0.21). Multiple logistic regression analysis showed that 1-SD (3.50m/s) increased in baPWV was still associated with a 11% (CI, 4%–20%; P<0.01) higher odds of being sarcopenia. In the gender subgroup analysis, the relationship of baPWV and sarcopenia remain significant in men (OR, 1.23; 95% CI, 1.07–1.42, P<0.01), but not in women (P=0.07).
Conclusions
High brachial-ankle pulse wave velocity is associated with sarcopenia in Chinese community-dwelling elderly, with gender differences.
Mitochondrial abnormalities have been noted in lupus, but the causes and consequences remain obscure. Autophagy-related genes ATG5, ATG7 and IRGM have been previously implicated in autoimmune ...disease. We reasoned that failure to clear defective mitochondria via mitophagy might be a foundational driver in autoimmunity by licensing mitochondrial DNA-dependent induction of type I interferon. Here, we show that mice lacking the GTPase IRGM1 (IRGM homolog) exhibited a type I interferonopathy with autoimmune features. Irgm1 deletion impaired the execution of mitophagy with cell-specific consequences. In fibroblasts, mitochondrial DNA soiling of the cytosol induced cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)-dependent type I interferon, whereas in macrophages, lysosomal Toll-like receptor 7 was activated. In vivo, Irgm1
tissues exhibited mosaic dependency upon nucleic acid receptors. Whereas salivary and lacrimal gland autoimmune pathology was abolished and lung pathology was attenuated by cGAS and STING deletion, pancreatic pathology remained unchanged. These findings reveal fundamental connections between mitochondrial quality control and tissue-selective autoimmune disease.
Naive T cells respond to antigen stimulation by exiting from quiescence and initiating clonal expansion and functional differentiation, but the control mechanism is elusive. Here we describe that ...Raptor-mTORC1-dependent metabolic reprogramming is a central determinant of this transitional process. Loss of Raptor abrogated T cell priming and T helper 2 (Th2) cell differentiation, although Raptor function is less important for continuous proliferation of actively cycling cells. mTORC1 coordinated multiple metabolic programs in T cells including glycolysis, lipid synthesis, and oxidative phosphorylation to mediate antigen-triggered exit from quiescence. mTORC1 further linked glucose metabolism to the initiation of Th2 cell differentiation by orchestrating cytokine receptor expression and cytokine responsiveness. Activation of Raptor-mTORC1 integrated T cell receptor and CD28 costimulatory signals in antigen-stimulated T cells. Our studies identify a Raptor-mTORC1-dependent pathway linking signal-dependent metabolic reprogramming to quiescence exit, and this in turn coordinates lymphocyte activation and fate decisions in adaptive immunity.
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•mTORC1-dependent metabolic reprogramming drives exit of T cells from quiescence•mTORC1 coordinates T cell glycolysis, lipogenesis, and oxidative phosphorylation•Raptor links glucose metabolism to cytokine responsiveness and Th2 cell generation•Raptor integrates TCR and CD28 costimulation signals
We have recently identified and characterized a novel oncogene, maelstrom (MAEL) from 1q24, in the pathogenesis of hepatocellular carcinoma. In this study, MAEL was investigated for its oncogenic ...role in urothelial carcinoma of the bladder (UCB) tumorigenesis/aggressiveness and underlying molecular mechanisms. Here, we report that overexpression of MAEL in UCB is important in the acquisition of an aggressive and/or poor prognostic phenotype. In UCB cell lines, knockdown of MAEL by short hairpin RNA is sufficient to inhibit cell growth, invasiveness/metastasis and suppressed epithelial-mesenchymal transition (EMT), whereas ectopic overexpression of MAEL promoted cell growth, invasive and/or metastatic capacity and enhanced EMT both in vitro and in vivo. We further demonstrate that MAEL could induce UCB cell EMT by downregulating a critical downstream target, the metastasis suppressor 1 (MTSS1) gene, ultimately leading to an increased invasiveness of cancer cells. Notably, overexpression of MAEL in UCB cells substantially enhanced the enrichment of DNA methyltrans-ferase (DNMT)3B and histone deacetylase (HDAC)1/2 on the promoter of the MTSS1, and thereby epigenetically suppressing the MTSS1 transcription. Downregulation of MTSS1 by MAEL in UCB cells is partially dependent on DNMT3B. Furthermore, we identify that beside the gene amplification of MAEL, miR-186 is a key negative regulator of MAEL and downregulation of miR-186 is another important mechanism for MAEL overexpression in UCBs. These data suggest that overexpression of MAEL, caused by gene amplification and/or decreased miR-186, has a critical oncogenic role in UCB pathogenesis by downregulation of MTSS1, and MAEL could be used as a novel prognostic marker and/or effective therapeutic target for human UCB.
Distant metastasis is the major cause of cancer-related death, and epithelial-to-mesenchymal transition (EMT) has a critical role in this process. Accumulating evidence indicates that EMT can be ...regulated by microRNAs (miRNAs). miR-29c has been implicated as a tumor suppressor in several human cancers. However, the role of miR-29c in the progression of colorectal cancer (CRC) metastasis remains largely unknown.
The expression of miR-29c was examined by qRT-PCR in a cohort of primary CRC (PC) and distant liver metastasis (LM) tissues. A series of in vivo and in vitro assays were carried out in order to elucidate the functions of miR-29c and the molecular mechanisms underlying the pathogenesis of metastatic CRC.
miR-29c was markedly downregulated in PCs with distant metastasis and determined to be an independent predictor of shortened patient survival. But LM tissues showed higher levels of miR-29c than that in PC tissues. In CRC cells, miR-29c dramatically suppressed cell migration and invasion abilities in vitro and cancer metastasis in vivo. In addition, miR-29c inhibited EMT and negatively regulated Wnt/β-catenin signaling pathway. Guanine nucleotide binding protein alpha13 (GNA13) and protein tyrosine phosphatase type IVA (PTP4A) were identified as direct targets of miR-29c, which acted through ERK/GSK3β/β-catenin and AKT/GSK3β/β-catenin pathways, respectively, to regulate EMT. Furthermore, significant associations between miR-29c, its target genes (GNA13 and PTP4A) and EMT markers were validated in both PC and LM tissues.
Our findings highlight the important role of miR-29c in regulating CRC EMT via GSK-3β/β-catenin signaling by targeting GNA13 and PTP4A and provide new insights into the metastatic basis of CRC.
Neoadjuvant therapy is recommended for locally advanced esophageal cancer, but the optimal strategy remains unclear. We aimed to evaluate the safety and efficacy of neoadjuvant chemoradiotherapy ...(nCRT) versus neoadjuvant chemotherapy (nCT) followed by minimally invasive esophagectomy (MIE) for locally advanced esophageal squamous cell carcinoma (ESCC).
Eligible patients staged as cT3-4aN0-1M0 ESCC were randomly assigned (1 : 1) to the nCRT or nCT group stratified by age, cN stage, and centers. The chemotherapy, based on paclitaxel and cisplatin, was administered to both groups, while concurrent radiotherapy was added for the nCRT group; then MIE was carried out. The primary endpoint was 3-year overall survival. This study is registered with ClinicalTrials.gov (NCT03001596).
A total of 264 patients were eligible for the intention-to-treat analysis. By 30 November 2021, 121 deaths had occurred. The median follow-up was 43.9 months (interquartile range 36.6-49.3 months). The overall survival in the intention-to-treat population was comparable between the nCRT and nCT strategies hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.58-1.18; P = 0.28, with a 3-year survival rate of 64.1% (95% CI 56.4% to 72.9%) versus 54.9% (95% CI 47.0% to 64.2%), respectively. There were also no differences in progression-free survival (HR 0.83, 95% CI 0.59-1.16; P = 0.27) and recurrence-free survival (HR 1.07, 95% CI 0.71-1.60; P = 0.75), although the pathological complete response in the nCRT group (31/112, 27.7%) was significantly higher than that in the nCT group (3/104, 2.9%; P < 0.001). Besides, a trend of lower risk of recurrence was observed in the nCRT group (P = 0.063), while the recurrence pattern was similar (P = 0.802).
NCRT followed by MIE was not associated with significantly better overall survival than nCT among patients with cT3-4aN0-1M0 ESCC. The results underscore the pending issue of the best strategy of neoadjuvant therapy for locally advanced bulky ESCC.
•The CMISG1701 trial assessed the safety and efficacy of nCRT versus nCT followed by MIE for locally advanced bulky ESCC.•The nCRT followed by MIE strategy could not improve survival significantly compared with the nCT strategy.•The best strategy of neoadjuvant therapy for locally advanced bulky ESCC remains a pending issue.
Cumulative evidence from histology-based studies demonstrate that the currently available intravascular imaging techniques have fundamental limitations that do not allow complete and detailed ...evaluation of plaque morphology and pathobiology, limiting the ability to accurately identify high-risk plaques. To overcome these drawbacks, new efforts are developing for data fusion methodologies and the design of hybrid, dual-probe catheters to enable accurate assessment of plaque characteristics, and reliable identification of high-risk lesions. Today several dual-probe catheters have been introduced including combined near infrared spectroscopy-intravascular ultrasound (NIRS-IVUS), that is already commercially available, IVUS-optical coherence tomography (OCT), the OCT-NIRS, the OCT-near infrared fluorescence (NIRF) molecular imaging, IVUS-NIRF, IVUS intravascular photoacoustic imaging and combined fluorescence lifetime-IVUS imaging. These multimodal approaches appear able to overcome limitations of standalone imaging and provide comprehensive visualization of plaque composition and plaque biology. The aim of this review article is to summarize the advances in hybrid intravascular imaging, discuss the technical challenges that should be addressed in order to have a use in the clinical arena, and present the evidence from their first applications aiming to highlight their potential value in the study of atherosclerosis.
Guillain-Barre syndrome (GBS) is an autoimmune disease of the nervous system and is the most common acute polyneuropathy. Both cellular and humoral immunity are believed to be involved in the ...pathogenesis of GBS, and various types of activated CD4+ T cells are thought to orchestrate the onset and progression of GBS. Lymphoplasma exchange (LPE) filtering out activated lymphocytes while exchanging plasma has been used for GBS treatment for years. However the treatment is still not yet optimal. In order to assess the efficacy of this treatment, we evaluate the effect of LPE and determine the appropriate frequency of LPE treatments for GBS patients through comparing the neurological deficit scores and the changes in related immunology indicators of GBS patients before and after LPE treatment. Twenty-four patients with GBS who received LPE were evaluated for immunologic indicants before treatment, on the second day, and the fourth day after the treatment. The immunoglobulin complement and CD4+ T lymphocyte subsets were tested by flow cytometry. The patients' Medical Research Council sum scores were increased from 25.7±10.4 up to. 36.7±10.4 (P=0.019) and their Hughes scores decreased from 3.7±0.76 to 3.1±0.73 (P=0.027) at 7 days after LPE. In the peripheral blood from patients received LPE treatment, the levels of immunoglobulin, complement, monocytes and fibrinogen were significantly reduced. The percentages of Th1 and Th17 cells in the CD4+ T lymphocyte subsets were significantly decreased, whereas the Th2 and Treg cells were increased in patients after treatment. The changes in CD4+T lymphocyte subsets were correlated with patient MRC score changes. Our data indicate that LPE is effective in treating GBS patients by directly removing immunoglobulin, complement, monocytes, and fibrinogen as well as regulating lymphocyte subsets in the peripheral blood.
The formulation and simulation characteristics of two new global coupled climate models developed at NOAA’s Geophysical Fluid Dynamics Laboratory (GFDL) are described. The models were designed to ...simulate atmospheric and oceanic climate and variability from the diurnal time scale through multicentury climate change, given our computational constraints. In particular, an important goal was to use the same model for both experimental seasonal to interannual forecasting and the study of multicentury global climate change, and this goal has been achieved.
Two versions of the coupled model are described, called CM2.0 and CM2.1. The versions differ primarily in the dynamical core used in the atmospheric component, along with the cloud tuning and some details of the land and ocean components. For both coupled models, the resolution of the land and atmospheric components is 2° latitude × 2.5° longitude; the atmospheric model has 24 vertical levels. The ocean resolution is 1° in latitude and longitude, with meridional resolution equatorward of 30° becoming progressively finer, such that the meridional resolution is 1/3° at the equator. There are 50 vertical levels in the ocean, with 22 evenly spaced levels within the top 220 m. The ocean component has poles over North America and Eurasia to avoid polar filtering. Neither coupled model employs flux adjustments.
The control simulations have stable, realistic climates when integrated over multiple centuries. Both models have simulations of ENSO that are substantially improved relative to previous GFDL coupled models. The CM2.0 model has been further evaluated as an ENSO forecast model and has good skill (CM2.1 has not been evaluated as an ENSO forecast model). Generally reduced temperature and salinity biases exist in CM2.1 relative to CM2.0. These reductions are associated with 1) improved simulations of surface wind stress in CM2.1 and associated changes in oceanic gyre circulations; 2) changes in cloud tuning and the land model, both of which act to increase the net surface shortwave radiation in CM2.1, thereby reducing an overall cold bias present in CM2.0; and 3) a reduction of ocean lateral viscosity in the extratropics in CM2.1, which reduces sea ice biases in the North Atlantic.
Both models have been used to conduct a suite of climate change simulations for the 2007 Intergovernmental Panel on Climate Change (IPCC) assessment report and are able to simulate the main features of the observed warming of the twentieth century. The climate sensitivities of the CM2.0 and CM2.1 models are 2.9 and 3.4 K, respectively. These sensitivities are defined by coupling the atmospheric components of CM2.0 and CM2.1 to a slab ocean model and allowing the model to come into equilibrium with a doubling of atmospheric CO₂. The output from a suite of integrations conducted with these models is freely available online (seehttp://nomads.gfdl.noaa.gov/).
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