Epidemiological studies indicate that smoking is negatively correlated with the incidence and development of Alzheimer's disease (AD). Nicotine was reported to be the active factor. However, the detailed mechanisms still remain to be fully elucidated. Early growth response gene 1 (EGR-1) plays important roles in several important biological processes such as promoting cell growth, differentiation, anti oxidative stress, and apoptosis, but few in the pathogenesis of AD. In the present study, we show that nicotine can activate the MAPK/ERK/EGR-1 signaling pathway partially through α7 nAChR. In addition, the up-regulation of EGR-1 by nicotine can also increase the phosphorylation of CyclinD1 which contributes to the attenuation of amyloid-β (Aβ(25-35)) -induced neurotoxicity. Although nicotine and Aβ(25-35) can activate EGR-1, the expression of EGR-1 is down-regulated following treatment with nicotine and Aβ(25-35). This study demonstrates that low dose nicotine attenuates Aβ(25-35)-induced neurotoxicity in vitro and in vivo through activating EGR-1 pathway.

Arsenic (As) exposure is a significant worldwide environmental health concern. Low dose, chronic arsenic exposure has been associated with a higher than normal risk of skin, lung, and bladder cancer, as well as cardiovascular disease and diabetes. While arsenic-induced biological changes play a role in disease pathology, little is known about the dynamic cellular changes resulting from arsenic exposure and withdrawal.

Four popular somatic single nucleotide variant (SNV) calling methods (Varscan, SomaticSniper, Strelka and MuTect2) were carefully evaluated on the real whole exome sequencing (WES, depth of ~50X) and ultra-deep targeted sequencing (UDT-Seq, depth of ~370X) data. The four tools returned poor consensus on candidates (only 20% of calls were with multiple hits by the callers). For both WES and UDT-Seq, MuTect2 and Strelka obtained the largest proportion of COSMIC entries as well as the lowest rate of dbSNP presence and high-alternative-alleles-in-control calls, demonstrating their superior sensitivity and accuracy. Combining different callers does increase reliability of candidates, but narrows the list down to very limited range of tumor read depth and variant allele frequency. Calling SNV on UDT-Seq data, which were of much higher read-depth, discovered additional true-positive variations, despite an even more tremendous growth in false positive predictions. Our findings not only provide valuable benchmark for state-of-the-art SNV calling methods, but also shed light on the access to more accurate SNV identification in the future.

Brain tumor remains the leading cause of disease-related death in children. Many studies have focused on the complex biological process involved in pediatric brain tumors but little is know about the possible role of microRNAs in the genesis of these tumors.

Iron imbalance is a feature of liver damage. However, the biological correlation of serum hepcidin, a key regulator of iron homeostasis, with liver malfunction is undefined. To this end, we piloted the Chinese population studies to address whether hepcidin is linked to liver functionality. The serum hepcidin, ferritin, alanine transaminase, aspartate transaminase, gamma-glutamyltransferase and bilirubin were examined in two independent Chinese cohorts consisted of 3455 individuals. After adjustment for sex, age, body mass index, smoking habits, drinking categories and diabetic status, a positive association between hepcidin and alanine transaminase (ALT) (beta = 0.18 ± 0.01, P < 0.0001) was discovered using linear regression in a cohort consisting of 1813 individuals. This association was then validated in the second independent cohort of 1642 individuals (beta = 0.08 ± 0.02, P < 0.0001). Furthermore, consistent with cohort study, by applying both CCl4 and lipopolysaccharide induced mouse liver injury models, at least 2-fold elevations in hepcidin expression, serum ALT and inflammatory cytokine IL-6 were discovered during the initiation stage of liver injury. Our findings suggest that increased serum hepcidin may reflect a protective response to the iron status and elevated serum cytokines during liver injury. Additional studies are warranted to validate these findings and test their potential clinical relevance in patients.

The present study aims to evaluate the potential of transcriptomic profiles in evaluating the impacts of complex mixtures of pollutants at environmentally relevant concentrations on aquatic vertebrates. The changes in gene expression were determined using microarray in the liver of male zebrafish (Danio rerio) exposed to surface water collected from selected locations on the Hun River, China. The numbers of differentially expressed genes (DEGs) in each treatment ranged from 728 to 3292, which were positively correlated with chemical oxygen demand (COD). Predominant transcriptomic responses included peroxisome proliferator-activated receptors (PPAR) signaling and steroid biosynthesis. Key pathways in immune system were also affected. Notably, two human diseases related pathways, insulin resistance and Salmonella infection were enriched. Clustering analysis and principle component analysis with DEGs differentiated the upstream and downstream site of Shenyang City, and the mainstream and the tributary sites near the junction. Comparison the gene expression profiles of zebrafish exposed to river surface water with those to individual chemicals found higher similarity of the river water with estradiol than several other organic pollutants and metals. Results suggested that the transcriptomic profiles of zebrafish is promising in differentiating surface water with pollution gradient and different discharges and in providing valuable information to support discharge management.

DNA methylation in repetitive elements (RE) suppresses their mobility and maintains genomic stability, and decreases in it are frequently observed in tumor and/or surrogate tissues. Averaging methylation across RE in genome is widely used to quantify global methylation. However, methylation may vary in specific RE and play diverse roles in disease development, thus averaging methylation across RE may lose significant biological information. The ambiguous mapping of short reads by and high cost of current bisulfite sequencing platforms make them impractical for quantifying locus-specific RE methylation. Although microarray-based approaches (particularly Illumina's Infinium methylation arrays) provide cost-effective and robust genome-wide methylation quantification, the number of interrogated CpGs in RE remains limited. We report a random forest-based algorithm (and corresponding R package, REMP) that can accurately predict genome-wide locus-specific RE methylation based on Infinium array profiling data. We validated its prediction performance using alternative sequencing and microarray data. Testing its clinical utility with The Cancer Genome Atlas data demonstrated that our algorithm offers more comprehensively extended locus-specific RE methylation information that can be readily applied to large human studies in a cost-effective manner. Our work has the potential to improve our understanding of the role of global methylation in human diseases, especially cancer.

Severe myopic anisometropia has been identified to have heritability, but the pathogenesis of anisometropia still remains obscure.

California's almond growers face challenges with nitrogen management as new legislatively mandated nitrogen management strategies for almond have been implemented. These regulations require that growers apply nitrogen to meet, but not exceed, the annual N demand for crop and tree growth and nut production. To accurately predict seasonal nitrogen demand, therefore, growers need to estimate block-level almond yield early in the growing season so that timely N management decisions can be made. However, methods to predict almond yield are not currently available. To fill this gap, we have developed statistical models using the Stochastic Gradient Boosting, a machine learning approach, for early season yield projection and mid-season yield update over individual orchard blocks. We collected yield records of 185 orchards, dating back to 2005, from the major almond growers in the Central Valley of California. A large set of variables were extracted as predictors, including weather and orchard characteristics from remote sensing imagery. Our results showed that the predicted orchard-level yield agreed well with the independent yield records. For both the early season (March) and mid-season (June) predictions, a coefficient of determination (R 2) of 0.71, and a ratio of performance to interquartile distance (RPIQ) of 2.6 were found on average. We also identified several key determinants of yield based on the modeling results. Almond yield increased dramatically with the orchard age until about 7 years old in general, and the higher long-term mean maximum temperature during April-June enhanced the yield in the southern orchards, while a larger amount of precipitation in March reduced the yield, especially in northern orchards. Remote sensing metrics such as annual maximum vegetation indices were also dominant variables for predicting the yield potential. While these results are promising, further refinement is needed; the availability of larger data sets and incorporation of additional variables and methodologies will be required for the model to be used as a fertilization decision support tool for growers. Our study has demonstrated the potential of automatic almond yield prediction to assist growers to manage N adaptively, comply with mandated requirements, and ensure industry sustainability.

Age-related macular degeneration (AMD) is a complex disease with multiple initiators and pathways that converge on death for retinal pigment epithelial (RPE) cells. In this study, effects of taurine on calpains, autophagy, endoplasmic reticulum (ER) stress, and apoptosis in ARPE-19 cells (a human RPE cell line) were investigated. We first confirmed that autophagy, ER stress and apoptosis in ARPE-19 cells were induced by Earle's balanced salt solution (EBSS) through starvation to induce RPE metabolic stress. Secondly, inhibition of ER stress by 4-phenyl butyric acid (4-PBA) alleviated autophagy and apoptosis, and suppression of autophagy by 3-methyl adenine (3-MA) reduced the cell apoptosis, but the ER stress was minimally affected. Thirdly, the apoptosis, ER stress and autophagy were inhibited by gene silencing of calpain-2 and overexpression of calpain-1, respectively. Finally, taurine suppressed both the changes of the important upstream regulators (calpain-1 and calpain-2) and the activation of ER stress, autophagy and apoptosis, and taurine had protective effects on the survival of ARPE-19 cells. Collectively, this data indicate that taurine inhibits starvation-triggered endoplasmic reticulum stress, autophagy, and apoptosis in ARPE-19 cells by modulating the expression of calpain-1 and calpain-2.

The molecular mechanisms involved in human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND) remain poorly understood. It has been recently reported that HIV-1 Tat transactivation requires menin, suggesting that menin may be involved in HAND pathogenesis. But the role of menin is not clear. Here, we found that protein level of menin was increased in simian-human immunodeficiency chimeric virus (SHIV)-SF162.P4 and simian immunodeficiency virus (SIV) sm543-3-infected rhesus macaques compared with the controls by immunohistochemistry (IHC) and western blot. Menin mainly expressed in the frontal cortex neurons of the brain, more importantly, the number of menin-staining cells was positively correlated with cleaved-caspase-3-positive cells while it was negatively correlated with a neuron-specific nuclear protein NeuN-positive cells, suggesting that expression of menin may induce neuronal apoptosis. Further studies showed that menin level was significantly increased during Tat-induced apoptosis, while downregulation of menin by pll3.7-MEN1-shRNA attenuated the Tat-induced cleavage of caspase-3 and caspase-8 in SY5Y cells and primary neuron cultures. Together, our findings reveal a pro-apoptotic role of menin in the brains of the SIV-infected macaques and the cultured neurons, indicating that targeting menin may be potential to block the HIV-1 Tat induced neuronal damage in HAND.

The identification of HER2 overexpression in a subset of gastric adenocarcinoma (GA) patients represents a significant step forward in unveiling the molecular complexity of this disease. The predictive and prognostic value of HER2 amplification in advanced HER2 inhibitor-treated GA patients has been investigated. However, its predictive value in resectable patients remains elusive.

Mutations in POLE /POLD1 proofreading domain can cause deficiencies in DNA repair, conferring ultramutated cancer phenotypes. Preliminary clinical studies have revealed an association between POLE/POLD1 mutations and beneficial clinical outcomes to immune checkpoint inhibitor (ICI) therapy This study aims to investigate the genomic characteristics of POLE/POLD-mutant tumors and the prognostic value of POLE/POLD mutation for ICI treatment.

Diabetic retinopathy (DR) is a common microvascular complication that may cause severe visual impairment and blindness in patients with type 2 diabetes mellitus (T2DM). Early detection of DR will expand the range of potential treatment options and enable better control of disease progression. Epigenetic dysregulation has been implicated in the pathogenesis of microvascular complications in patients with T2DM. We sought to explore the diagnostic value of 5-hydroxymethylcytosines (5hmC) in circulating cell-free DNA (cfDNA) for DR, taking advantage of a highly sensitive technique, the 5hmC-Seal. The genome-wide 5hmC profiles in cfDNA samples from 35 patients diagnosed with DR and 35 age-, gender-, diabetic duration-matched T2DM controls were obtained using the 5hmC-Seal, followed by a case-control analysis and external validation. The genomic distribution of 5hmC in cfDNA from patients with DR reflected potential gene regulatory relevance, showing co-localization with histone modification marks for active expression (e.g., H3K4me1). A three-gene signature (MESP1, LY6G6D, LINC01556) associated with DR was detected using the elastic net regularization on the multivariable logistic regression model, showing high accuracy to distinguish patients with DR from T2DM controls (AUC [area under curve] = 91.4%; 95% CI [confidence interval], 84.3- 98.5%), achieving a sensitivity of 88.6% and a specificity of 91.4%. In an external testing set, the 5hmC model detected 5 out of 6 DR patients and predicted 7 out of 8 non-DR patients with other microvascular complications. Circulating cfDNA from patients with DR contained 5hmC information that could be exploited for DR detection. As a novel non-invasive approach, the 5hmC-Seal holds the promise to be an integrated part of patient care and surveillance tool for T2DM patients.

To testify that endothelial cells (ECs) induce astrocyte maturation by leukaemia inhibitory factor (LIF) secretion.

The forkhead-box transcription factors of O subfamily (FOXO) play important roles in regulation of various biological functions. We cloned foxo1, foxo3, foxo4, and foxo6 from Xenopus tropicalis (hereafter X. tropicalis), and examined their expression in embryos and adult tissues. Maternal transcripts of foxo1 and foxo3 genes are detected within the animal half of the early embryo, their zygotic transcripts show distinct patterns. At late tailbud stages, foxo1 expression is observed mainly in eye, brain, branchial arches, and pronephros. In addition to eye, brain, branchial arches and pronephros, foxo3 expression is also evident in heart and somites. Foxo4 expression was not detected in oocytes. At late tailbud stages, foxo4 is mainly expressed in eye, brain, branchial arches and otic vesicle. Foxo6 expression was not detectable until stage 36, with a specific expression in nasal pits. Obvious expression of foxo1, foxo3 and foxo4, but not foxo6, is detected by RT-PCR both in oocytes and in embryos at examined stages. The expression of foxo1, foxo3 and foxo4 is observed in all tested adult tissues including heart, muscle, liver, lung, stomach and small intestine, while foxo6 is only detectable in stomach and small intestine. The differential expression pattern of foxo genes suggests that they exert distinct functions during embryonic development and in various organs of X. tropicalis.

The 5-methylcytosines (5mC) have been implicated in the pathogenesis of diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). However, the role of 5-hydroxymethylcytosines (5hmC) that are generated from 5mC through active demethylation, in lymphomagenesis is unknown. We profiled genome-wide 5hmC in circulating cell-free DNA (cfDNA) from 73 newly diagnosed patients with DLBCL and FL. We identified 294 differentially modified genes between DLBCL and FL. The differential 5hmC in the DLBCL/FL-differentiating genes co-localized with enhancer marks H3K4me1 and H3K27ac. A four-gene panel (CNN2, HMG20B, ACRBP, IZUMO1) robustly represented the overall 5hmC modification pattern that distinguished FL from DLBCL with an area under curve of 88.5% in the testing set. The median 5hmC modification levels in signature genes showed potential for separating patients for risk of all-cause mortality. This study provides evidence that genome-wide 5hmC profiles in cfDNA differ between DLBCL and FL and could be exploited as a non-invasive approach.

To investigate the comprehensive genomic profiling and programmed cell death ligand-1 (PD-L1) expression of primary lymphoepithelioma-like carcinoma (LELC) of different anatomical sites in the Chinese population and explore potential therapeutic strategies.

We performed proteogenomic characterization of intrahepatic cholangiocarcinoma (iCCA) using paired tumor and adjacent liver tissues from 262 patients. Integrated proteogenomic analyses prioritized genetic aberrations and revealed hallmarks of iCCA pathogenesis. Aflatoxin signature was associated with tumor initiation, proliferation, and immune suppression. Mutation-associated signaling profiles revealed that TP53 and KRAS co-mutations may contribute to iCCA metastasis via the integrin-FAK-SRC pathway. FGFR2 fusions activated the Rho GTPase pathway and could be a potential source of neoantigens. Proteomic profiling identified four patient subgroups (S1-S4) with subgroup-specific biomarkers. These proteomic subgroups had distinct features in prognosis, genetic alterations, microenvironment dysregulation, tumor microbiota composition, and potential therapeutics. SLC16A3 and HKDC1 were further identified as potential prognostic biomarkers associated with metabolic reprogramming of iCCA cells. This study provides a valuable resource for researchers and clinicians to further identify molecular pathogenesis and therapeutic opportunities in iCCA.

The matricellular protein periostin plays a critical role in liver inflammation, fibrosis, and even carcinoma. Here, the biological function of periostin in alcohol-related liver disease (ALD) was investigated.