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Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are both derived from epidermal keratinocytes but are phenotypically diverse. To improve the understanding of keratinocyte carcinogenesis, it is critical to understand epigenetic alterations, especially those that govern gene expression. We examined changes to the enhancer-associated histone acetylation mark H3K27ac by mapping matched tumor-normal pairs from 11 patients (five with BCC and six with SCC) undergoing Mohs surgery. Our analysis uncovered cancer-specific enhancers on the basis of differential H3K27ac peaks between matched tumor-normal pairs. We also uncovered biological pathways potentially altered in keratinocyte carcinoma, including enriched epidermal development and Wnt signaling pathways enriched in BCCs and enriched immune response and cell activation pathways in SCCs. We also observed enrichment of transcription factors that implicated SMAD and JDP2 in BCC pathogenesis and FOXP1 in SCC pathogenesis. On the basis of these findings, we prioritized three loci with putative regulation events (FGFR2 enhancer in BCC, intragenic regulation of FOXP1 in SCC, and WNT5A promoter in both subtypes) and validated our findings with published gene expression data. Our findings highlight unique and shared epigenetic alterations in histone modifications and potential regulators for BCCs and SCCs that likely impact the divergent oncogenic pathways, paving the way for targeted drug discoveries.

Tropical ecosystems are an important sink for atmospheric CO2; however, plant growth is restricted by phosphorus (P) availability. Although soil microbiota facilitate organic P turnover and inorganic P mobilization, their role in carbon-phosphorus coupled processes remains poorly understood. To advance this topic, soils collected from four sites representing highly weathered tropical soils in the El Yunque National Forest, Puerto Rico were incubated with exogenous PO43− under controlled laboratory conditions. P amendment increased CO2 respiration by 14–23% relative to control incubations for soils sampled from all but the site with the greatest total and bioavailable soil P. Metatranscriptomics revealed an increase in the relative transcription of genes involved in cell growth and uptake of other nutrients in response to P amendment. A new methodology to normalize gene expression by population-level relative (DNA) abundance revealed that the pattern of increased transcription of cell growth and division genes with P amendment was community-wide. Soil communities responsive to P amendment possessed a greater relative abundance of α-glucosyl polysaccharide biosynthesis genes, suggestive of enhanced C storage under P-limiting conditions. Phosphorylase genes governing the degradation of α-glucosyl polysaccharides were also more abundant and increased in relative transcription with P amendment, indicating a shift from energy storage towards growth. Conversely, microbial communities in soils nonresponsive to P amendment were found to have metabolisms tuned for the phosphorolysis of labile plant-derived substrates, such as β-glucosyl polysaccharides. Collectively, our results provided quantitative estimates of increased soil respiration upon alleviation of P constraints and elucidated several underlying ecological and molecular mechanisms involved in this response.

Immunometabolism is an emerging field that focuses on the role of cellular metabolism in the regulation of immune cells. Recent studies have revealed an intensive link between the metabolic state and the functions of immune cells. MicroRNAs (miRNAs) are small non-coding, single-stranded RNAs generally consisting of 18-25 nucleotides that exert crucial roles in regulating gene expression at the posttranscriptional level. Although the role of miRNAs in immune regulation has long been recognized, their roles in immunometabolism have not yet been well established. Over the past decade, increasing studies have proven that miRNAs are intensively involved in the metabolic control of immune cells including macrophages, T cells, B cells and dendritic cells. In this review, we highlight recent emerging findings in the miRNA-mediated metabolic control of immune cells.

Graves' disease (GD) is a common autoimmune thyroid disease characterized by positive thyroid stimulating hormone receptor antibody. To better understand its molecular pathogenesis, we adopted the weighted gene co-expression network analysis to reveal co-expression modules of key genes involved in the pathogenesis of GD, protein-protein interaction network analysis to identify the hub genes related to GD development and functional analyses to explore their possible functions. Our results showed that 1) a total of 2667 differentially expressed genes in our microarray study and 16 different gene co-expression modules were associated with GD, and 2) the most significant module was associated with the percentage of macrophages, T follicular helper cells and CD4+ memory T cells and mainly enriched in immune regulation and immune response. Overall, our study reveals several key gene co-expression modules and functional pathways involved in GD, which provides some novel insights into the pathogenesis of GD.

Heparanase degrades heparan sulfate in glomerular basement membrane (GBM) and plays an important role in diabetic nephropathy (DN). However, its regulating mechanisms remain to be deciphered. Our present study showed that the major advanced glycation endproducts (AGEs), CML-BSA, significantly increased heparanase expression in cultured podocytes and the effect was blocked by the receptor for advanced glycation endproducts (RAGE) knockdown, antibody and antagonist. In addition, NF-κB p65 phosphorylation was elevated and the increased heparanase expression and secretion upon CML-BSA could be attenuated by NF-κB inhibitor PDTC. Mechanistically, CML-BSA activated heparanase promoter through p65 directly binding to its promoter. Furthermore, the in vivo study showed that serum and renal cortex AGEs levels, glomerular p65 phosphorylation and heparanase expression were significantly increased in DN mice. Taken together, our data suggest that AGEs and RAGE interaction increases podocyte heparanase expression by activating NF-κB signal pathway, which is involved in GBM damages of DN.

Non-thyroidal illness syndrome (NTIS) is characterized by decreased serum triiodothyronine level without increased thyroid-stimulating hormone level during critical illness. The summary data on the prevalence of NTIS in cardiovascular patients are lacking, and its prognostic role in cardiovascular patients is also unclear.We performed a systematic review and meta-analysis to comprehensively determine the prevalence and the prognostic role of NTIS in cardiovascular patients. The prevalence of NTIS was pooled using random-effect meta-analysis and the hazard ratios (HRs) for all-cause mortality, cardiac mortality and major adverse cardiovascular events (MACE) were also pooled.Forty-one studies were finally included. The pooled prevalence of NTIS in cardiovascular patients was 21.7% (95% CI 18.4%-25.3%). Subgroup by the types of cardiovascular diseases showed the prevalence of NTIS was highest in patients with heart failure (24.5%), followed by acute myocardial infarction (18.9%) and acute coronary syndrome (17.1%). Meta-analysis of studies using strict diagnostic criteria of NITS showed that the pooled prevalence of NTIS in cardiovascular patients was 17.6% (95% CI 14.5%-21.2%). NTIS was independently associated with increased risks of all-cause mortality (HR=2.52, 95% CI 1.87-3.40, P0.001) and cardiac mortality (HR=2.06, 95% CI 1.58-2.69, P0.001) in cardiovascular patients. NTIS was also an independent predictor of MACE in cardiovascular patients (HR=1.73, 95% CI 1.32-2.26, P0.001).NTIS is very common in patients with cardiovascular diseases. NTIS is an independent prognostic factor in cardiovascular patients and is associated with increased risks of all-cause mortality, cardiac mortality and MACE.

Over four hundred different microRNAs (miRNAs) have been identified in the genome of the model organism the nematode Caenorhabditis elegans. As the germline is dedicated to the preservation of each species, and almost half of all the cells in an adult nematode are germline, it is likely that regulatory miRNAs are important for germline development and maintenance. In C. elegans the miR35 family has strong maternal effects, contributing to normal embryogenesis and to adult fecundity. To determine whether any particular miRNAs are greatly enriched in the C. elegans germline we used RNA-seq to compare the miRNA populations in several germline-defective strains of adult C. elegans worms, including glp-4(germline proliferation-4), glh-1(germline helicase-1) and dcr-1(dicer-1). Statistical analyses of RNA-seq comparisons identified 13 miRNAs that are germline-enriched, including seven members of the well-studied miR35 family that were reduced as much as 1000-fold in TaqMan qRT PCR miRNA assays. Along with the miR35s, six others: miR-56 (a member of the miR51 family),-70, -244, -260 , -788 and -4813, none of which previously considered as such, were also identified by RNA-seq as germline-enriched candidates. We went on to develop a successful miRNA in situ hybridization protocol for C. elegans, revealing miR35s specifically concentrate during oogenesis in the pachytene region of the gonad, and persist throughout early embryogenesis, while in adult animals neither let-7 nor miR-228 has a germline-bias.

Background: Autoimmune thyroid diseases (AITDs) are chronic autoimmune diseases specific to thyroid and mainly include Graves' diseases (GD) and Hashimoto' thyroiditis (HT). The adaptive immunoreactivity of CD4+ T cells plays a crucial role in the pathogenesis of AITDs, but very little has been known about its changes in disease status. Methods: We collected peripheral CD4+ T cells from 12 GD patients, including 6 newly diagnosed GD (NGD) and 6 refractory GD (RGD) patients, 6 HT patients and 6 healthy controls, and examined the gene expression profiles of T cells receptor (TCR) β chain complementarity determining region 3 (CDR3) using high-throughput sequencing. Results: Some TCR genes were expressed more preferentially in AITDs group than in the healthy control group, including TRBV15 (P=0.001), TRBV4-2 (P=0.003), TRBV9 (P=0.007), TRBV3-2 (P=0.012), TRBV7-8 (P=0.015), TRBV25-1 (P=0.019), TRBV12-4 (P=0.019) and TRBV27 (P=0.02) in GD patients as well as TRBV29-1 (P=0.004), TRBV12-4 (P=0.004), TRBV6-5 (P=0.011), TRBV7-2 (P=0.012), TRBV27 (P=0.012), TRBV9 (P=0.031) and TRBV4-2 (P=0.032) in HT patients. Moreover, subgroup analysis of GD showed that the difference in the TCR spectrum between the normal group and NGD was not obvious, but a large number of differential genes appeared in the RGD group. Conclusion: TCR spectrum has changed in patients with AITDs with many genes being upregulated. Moreover, this difference is not apparent in GD patients at the initial stage, but as the disease progresses, the differences in TCR profiles became more pronounced. Funding: The present work was supported by grants from the Science and Technology Development Fund of Pudong New District Minsheng Scientific Research (Medical and Health) Project (No. PKJ2018-Y39) and the National Natural Science Foundation of China (Nos. 81873636 and 81670722). Declaration of Interest: The authors declare that they have no conflict of interest. Ethical Approval: The study was approved by the Ethics Committee of Zhoupu Hospital. All subjects were informed of the present research project and signed written informed consent.

Background Studies of the prevalence of latent autoimmune diabetes in adults in China have reported inconsistent findings. We did a systematic review and meta-analysis to estimate the prevalence of latent autoimmune diabetes in adults in China. Methods For the systematic review, we searched PubMed, Embase, China Knowledge Resource Integrated Database, and Wanfang Medicine Database to identify studies investigating the prevalence of latent autoimmune diabetes in adults in China. In our meta-analysis we included hospital-based studies that recruited patients with newly diagnosed (less than 1 year from diagnosis) type 2 diabetes or population-based studies, which assessed the prevalence of latent autoimmune diabetes in adults in China and used a radioimmunoassay to test for glutamic acid decarboxylase autoantibodies. Subgroup analyses were done by study design, sex, and types of autoantibodies. Random-effects meta-analysis was used to pool the prevalence rate with 95% CIs. Ethical approval was granted by the ethical committee of our hospital This study was registered at PROSPERO, number CRD42016040163. Findings 12 studies with a total of 21 576 individuals were included. There were three population-based studies and nine hospital-based studies recruiting patients with newly diagnosed types 2 diabetes. The meta-analysis of 12 studies showed that the prevalence of latent autoimmune diabetes in adults in Chinese patients with type 2 diabetes was 7·4% (95% CI 6·5–8·5; 21 576 participants from 12 studies), which was similar to that in white populations (6·8%, 5·6–8·3; 28 415 participants from 15 studies). The prevalence of latent autoimmune diabetes in adults from the population-based studies was 6·7% (95% CI 5·4–8·3; 12 144 participants from three studies) and the prevalence of latent autoimmune diabetes in adults from hospital-based studies was 7·8% (6·9–8·8; 9432 participants from nine studies). The prevalence of latent autoimmune diabetes in adults in men was 7·9% (95% CI 6·2–10·0; 10 947 participants from ten studies) and in women was 7·0% (5·7–8·5; 9440 participants from ten studies). Subgroup analysis by types of autoantibodies suggested that glutamic acid decarboxylase autoantibodies was the highest prevalence (5·9%, 95% CI 5·2–6·8; 24 068 participants from 12 studies), followed by islet cell antibodies (2·4%, 1·5–3·8; 678 participants from two studies), insulin autoantibodies (2·1%, 1·4–3·2; 6559 participants from six studies), zinc transporter type 8 antibodies (1·7%, 1·5–2·1; 7059 participants from two studies), and protein tyrosine phosphatase-like IA-2 autoantibodies (1·7%, 1·2–2·4; 16 748 participants from 5 studies). The prevalence of latent autoimmune diabetes in adults diagnosed by non-glutamic acid decarboxylase autoantibodies in China was 1·7% (95% CI 1·0–2·8; 18 671 participants from eight studies). Interpretation Our finding provides evidence for a high prevalence of latent autoimmune diabetes in adults in China. Additionally, screening of latent autoimmune diabetes in adults with multiple diabetes-associated autoantibodies is necessary in China. Funding None.

Background Studies of the prevalence of depression in patients with type 2 diabetes in China have reported inconsistent findings. The purpose of this study was to assess the prevalence and independent risk factors of depression in patients with type 2 diabetes in China. Methods We did a systematic review and meta-analysis of papers published in PubMed (1980–2016), Embase (1980–2016), China National Knowledge Infrastructure (1999–2016), and Wanfang Medical database (1998–2016). We selected population-based, cross-sectional studies investigating the prevalence of depression in patients with type 2 diabetes in China. We used a random-effects meta-analysis to pool the prevalence and relative risks (RR) with 95% CIs. This study was registered at PROSPERO, number CRD42016039795. Findings 26 studies published between May, 2003, and February, 2016, were included. The studies included 66 475 patients with type 2 diabetes in China. A meta-analysis of six studies comparing the depression prevalence in diabetes patients and healthy controls suggested that type 2 diabetes was associated with a doubled risk of depression in Chinese people (RR 2·06; 95% CI 1·46–2·92; p 1c (RR 1·44, 95% CI 1·11–1·88; p=0·0068), and use of insulin (RR 2·08, 95% CI 1·28–3·37; p=0·0030). Interpretation We found a high prevalence of depression in Chinese patients with type 2 diabetes. Patients with diabetes and depression should receive more attention than at present in the medical settings of China and effective interventions to decrease depression risk in patients with diabetes are needed. Funding National Natural Science Foundation of China (number 81471004).

Background Studies of type 1 diabetes incidence in China have conflicting findings, and the epidemiology of type 1 diabetes in China is unclear. We aimed to assess the incidence and epidemiology of type 1 diabetes in relation to age, sex, and geographical area in mainland China. Methods In this systematic review and meta-analysis, we searched Pubmed (Jan 1, 1980, to May 18, 2016), Embase (Jan 1, 1980 to May 18, 2016), China National Knowledge Infrastructure (Jan 1, 1999, to May 20, 2016), and Wanfang Medical Database (Jan 1, 1998, to May 19, 2016) to identify population-based studies of type 1 diabetes incidence in mainland China. Only population-based studies with data on the incidence of type 1 diabetes in mainland China were included, and studies with overlapping data from included studies were excluded. We extracted data from the published reports and used random-effects meta-analysis to pool the incidence and incidence rate ratios (IRRs) with 95% CIs. We used the Q statistic and I 2 method to assess heterogeneity, and also did subgroup analyses by sex, age, and geographical area. Additionally, we used time trends to explore the difference in incidence over time. This study is registered with PROSPERO, number CRD42016039284. Findings We identified 816 reports from the search and included 19 reports of population-based studies published between 1994 and 2015 in the analysis. Overall incidence of type 1 diabetes in mainland China was 0·74 (95% CI 0·55–1·00) per 100 000 person-years between 1980 and 2013. Incidence (per 100 000 person-years) increased rapidly from 0·57 (0·43–0·75) in 1990 to 1·04 (0·64–1·68) in 2000 and 3·36 (1·66–6·82) in 2010 (p Interpretation To our knowledge, this is the first systematic review and meta-analysis to confirm the increasing incidence of type 1 diabetes over time in mainland China. Obvious disparities in incidence by sex, age, and geographical areas exist. Funding National Natural Science Foundation of China (81471004).