Highlights d Discovery of prognosis-associated proteins and pathways at early stage of LUAD d Proteomics revealed three subtypes related to clinical and molecular features d Identification of subtype-specific kinases and cancerassociated phosphoproteins d Identification of potential prognostic biomarkers and drug targets in LUAD

Elabela (ELA) or Toddler is a recently discovered hormone which is required for normal development of heart and vasculature through activation of apelin receptor (APJ), a G protein-coupled receptor (GPCR), in zebrafish. The present study explores whether the ELA-APJ signaling pathway is functional in the mammalian system. Using reverse-transcription PCR, we found that ELA is restrictedly expressed in human pluripotent stem cells and adult kidney whereas APJ is more widely expressed. We next studied ELA-APJ signaling pathway in reconstituted mammalian cell systems. Addition of ELA to HEK293 cells over-expressing GFP-AJP fusion protein resulted in rapid internalization of the fusion receptor. In Chinese hamster ovarian (CHO) cells over-expressing human APJ, ELA suppresses cAMP production with EC50 of 11.1 nM, stimulates ERK1/2 phosphorylation with EC50 of 14.3 nM and weakly induces intracellular calcium mobilization. Finally, we tested ELA biological function in human umbilical vascular endothelial cells and showed that ELA induces angiogenesis and relaxes mouse aortic blood vessel in a dose-dependent manner through a mechanism different from apelin. Collectively, we demonstrate that the ELA-AJP signaling pathways are functional in mammalian systems, indicating that ELA likely serves as a hormone regulating the circulation system in adulthood as well as in embryonic development.

Genome-wide association studies have revealed numerous risk loci associated with diverse diseases. However, identification of disease-causing variants within association loci remains a major challenge. Divergence in gene expression due to cis-regulatory variants in noncoding regions is central to disease susceptibility. We show that integrative computational analysis of phylogenetic conservation with a complexity assessment of co-occurring transcription factor binding sites (TFBS) can identify cis-regulatory variants and elucidate their mechanistic role in disease. Analysis of established type 2 diabetes risk loci revealed a striking clustering of distinct homeobox TFBS. We identified the PRRX1 homeobox factor as a repressor of PPARG2 expression in adipose cells and demonstrate its adverse effect on lipid metabolism and systemic insulin sensitivity, dependent on the rs4684847 risk allele that triggers PRRX1 binding. Thus, cross-species conservation analysis at the level of co-occurring TFBS provides a valuable contribution to the translation of genetic association signals to disease-related molecular mechanisms.

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The elevation of serum alanine aminotransferase (ALT) is regarded as an indicator of liver damage based on the presumption that ALT protein is specifically and abundantly expressed in the liver. However, ALT elevation is also observed in non-liver injury conditions (for example, muscle injury) and in apparently healthy people. Conversely, serum ALT activity is normal in many patients with confirmed liver diseases (for example, cirrhosis and hepatitis C infection). To improve the diagnostic value of the ALT assay and to understand the molecular basis for serum ALT changes in various pathophysiological conditions, we have cloned rat ALT isoenzyme ALT1 and ALT2 complementary DNAs (cDNAs), examined their tissue expressions at the messenger RNA and protein levels, and determined ALT1 and ALT 2 serum levels in response to liver damage in rodents. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis shows that ALT1 messenger RNA is widely distributed and mainly expressed in intestine, liver, fat tissues, colon, muscle, and heart, in the order of high to low expression level, whereas ALT2 gene expression is more restricted, mainly in liver, muscle, brain, and white adipose tissue. The tissue distribution pattern of ALT1 and ALT2 proteins largely agrees with their messenger RNA expression. Interestingly, hepatic ALT2 protein is approximately four times higher in male rats than in female rats. In addition, ALT isoenzymes distribute differentially at the subcellular level in that ALT1 is a cytoplasmic protein and ALT2 a mitochondrial protein, supporting bioinformatic prediction of mitochondrial localization of ALT2. Conclusion: Using animal models of hepatoxicity induced by carbon tetrachloride and acetaminophen, we found that both serum ALT1 and ALT2 protein levels were significantly elevated and correlated with ALT activity, providing, for the first time, the molecular basis for the elevated total serum ALT activity. (HEPATOLOGY 2009;49:598-607.)

The oomycete Phytophthora infestans was the causal agent of the Irish Great Famine and is a recurring threat to global food security. The pathogen can reproduce both sexually and asexually, with high potential to adapt to various environments and great risk to break disease resistance genes in potato. As are other oomycetes, P. infestans is regarded to be diploid during the vegetative phase of its life cycle, although some studies reported trisomy and polyploidy. Using microsatellite fingerprinting, genome-wide assessment of single nucleotide polymorphisms, nuclear DNA quantification, and microscopic counting of chromosome numbers, we assessed the ploidy level of a comprehensive selection of isolates. All progenies from sexual populations of P. infestans in nature were found to be diploid, in contrast nearly all dominant asexual lineages, including the most important pandemic clonal lineages US-1 and 13_A2 were triploid. Such triploids possess significantly more allelic variation than diploids. We observed that triploid genotype can change to a diploid genome constitution when exposed to artificial stress conditions. This study reveals that fluctuations in the ploidy level may be a key factor in the adaptation process of this notorious plant destroyer and imposes an extra challenge to control this disease.

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Surface‐enhanced Raman spectroscopy (SERS) is a surface‐sensitive technique that enhances Raman scattering by molecules adsorbed on nanostructures. The advantages of using SERS include high detection sensibility and fast analysis, thus it is a potentially promising tool for sensing metabolic cancer molecules in trace amounts. To explore this new method of lung cancer detection, we analyzed saliva samples from 61 lung cancer patients and 66 healthy controls. An SERS system and a nano‐modified chip were used in this study. Statistics were analyzed using support vector machine (SVM) and random forest algorithms. The leave‐one‐out algorithm was used based on SVM results to analyze differences in saliva between lung cancer patients and controls. There was a significant difference between the saliva of patients with lung cancer and healthy controls using the Raman spectrum; the intensity of the spectral line in lung cancer patients was weaker than in controls and 12 characteristic peaks were detected. Saliva SERS peaks have been characterized to refer to tissues, body fluids, and biological standard Raman peaks, but it is difficult to identify molecules with current information. The sensitivity and specificity of Raman spectroscopy data and SVM classification results of lung cancer patients and normal saliva samples were both 100%. Using the leave‐one‐out algorithm, the sensitivity was 95.08% and the specificity was 100%. The sensitivity of the random forest method was 96.72% and specificity was 100%. Our results show that SERS has the potential to detect lung cancer.