Distinct chromatin signatures in the Arabidopsis male gametophyte.

Epigenetic reprogramming in the germline contributes to the erasure of epigenetic inheritance across generations in mammals but remains poorly characterized in plants. Here we profiled histone modifications throughout Arabidopsis male germline development. We find that the sperm cell has widespread apparent chromatin bivalency, which is established by the acquisition of H3K27me3 or H3K4me3 at pre-existing H3K4me3 or H3K27me3 regions, respectively. These bivalent domains are associated with a distinct transcriptional status. Somatic H3K27me3 is generally reduced in sperm, while dramatic loss of H3K27me3 is observed at only ~700 developmental genes. The incorporation of the histone variant H3.10 facilitates the establishment of sperm chromatin identity without a strong impact on resetting of somatic H3K27me3. Vegetative nuclei harbor thousands of specific H3K27me3 domains at repressed genes, while pollination-related genes are highly expressed and marked by gene body H3K4me3. Our work highlights putative chromatin bivalency and restricted resetting of H3K27me3 at developmental regulators as key features in plant pluripotent sperm.

Selenium in selenium-rich rice sold in China and risk assessment.

Selenium-rich rice samples of 52 brands were bought from supermarkets on line in China and analysed for Se with ICP-MS. The Se concentration of Se-rich rice in China ranged from 0.012 ± 0.001 to 0.558 ± 0.057 mg/kg with an average of 0.090 ± 0.092 mg/kg. Rice samples with Se concentrations below 0.04 mg/kg accounted for 36.5% of the total samples. Se concentrations between 0.04 and 0.3 mg/kg accounted for 61.6%. Taking the upper tolerable limit of 400 µg/d as the risk standard, the risk of selenium intake by selenium-rich rice was low and the risk index was far less than 100%. With the upper intake limit of 100 µg/d and the adequate intake of 70 µg/d as the risk standard, the maximum intake risk index was higher than 100%, indicating a certain risk in the consumption of selenium-rich rice.

A Bayesian decision-theoretic approach to incorporate preclinical information into phase I oncology trials.

Leveraging preclinical animal data for a phase I oncology trial is appealing yet challenging. In this paper, we use animal data to improve decision-making in a model-based dose-escalation procedure. We make a proposal for how to measure and address a prior-data conflict in a sequential study with a small sample size. Animal data are incorporated via a robust two-component mixture prior for the parameters of the human dose-toxicity relationship. The weights placed on each component of the prior are chosen empirically and updated dynamically as the trial progresses and more data accrue. After completion of each cohort, we use a Bayesian decision-theoretic approach to evaluate the predictive utility of the animal data for the observed human toxicity outcomes, reflecting the degree of agreement between dose-toxicity relationships in animals and humans. The proposed methodology is illustrated through several data examples and an extensive simulation study.

Synergistic neuroprotection by coffee components eicosanoyl-5-hydroxytryptamide and caffeine in models of Parkinson's disease and DLB.

Hyperphosphorylated α-synuclein in Lewy bodies and Lewy neurites is a characteristic neuropathological feature of Parkinson's disease (PD) and Dementia with Lewy bodies (DLB). The catalytic subunit of the specific phosphatase, protein phosphatase 2A (PP2A) that dephosphorylates α-synuclein, is hypomethylated in these brains, thereby impeding the assembly of the active trimeric holoenzyme and reducing phosphatase activity. This phosphatase deficiency contributes to the accumulation of hyperphosphorylated α-synuclein, which tends to fibrillize more than unmodified α-synuclein. Eicosanoyl-5-hydroxytryptamide (EHT), a fatty acid derivative of serotonin found in coffee, inhibits the PP2A methylesterase so as to maintain PP2A in a highly active methylated state and mitigates the phenotype of α-synuclein transgenic (SynTg) mice. Considering epidemiologic and experimental evidence suggesting protective effects of caffeine in PD, we sought, in the present study, to test whether there is synergy between EHT and caffeine in models of α-synucleinopathy. Coadministration of these two compounds orally for 6 mo at doses that were individually ineffective in SynTg mice and in a striatal α-synuclein preformed fibril inoculation model resulted in reduced accumulation of phosphorylated α-synuclein, preserved neuronal integrity and function, diminished neuroinflammation, and improved behavioral performance. These indices were associated with increased levels of methylated PP2A in brain tissue. A similar profile of greater PP2A methylation and cytoprotection was found in SH-SY5Y cells cotreated with EHT and caffeine, but not with each compound alone. These findings suggest that these two components of coffee have synergistic effects in protecting the brain against α-synuclein-mediated toxicity through maintenance of PP2A in an active state.

Autophagy maintains tumour growth through circulating arginine.

Autophagy captures intracellular components and delivers them to lysosomes, where they are degraded and recycled to sustain metabolism and to enable survival during starvation1-5. Acute, whole-body deletion of the essential autophagy gene Atg7 in adult mice causes a systemic metabolic defect that manifests as starvation intolerance and gradual loss of white adipose tissue, liver glycogen and muscle mass1. Cancer cells also benefit from autophagy. Deletion of essential autophagy genes impairs the metabolism, proliferation, survival and malignancy of spontaneous tumours in models of autochthonous cancer6,7. Acute, systemic deletion of Atg7 or acute, systemic expression of a dominant-negative ATG4b in mice induces greater regression of KRAS-driven cancers than does tumour-specific autophagy deletion, which suggests that host autophagy promotes tumour growth1,8. Here we show that host-specific deletion of Atg7 impairs the growth of multiple allografted tumours, although not all tumour lines were sensitive to host autophagy status. Loss of autophagy in the host was associated with a reduction in circulating arginine, and the sensitive tumour cell lines were arginine auxotrophs owing to the lack of expression of the enzyme argininosuccinate synthase 1. Serum proteomic analysis identified the arginine-degrading enzyme arginase I (ARG1) in the circulation of Atg7-deficient hosts, and in vivo arginine metabolic tracing demonstrated that serum arginine was degraded to ornithine. ARG1 is predominantly expressed in the liver and can be released from hepatocytes into the circulation. Liver-specific deletion of Atg7 produced circulating ARG1, and reduced both serum arginine and tumour growth. Deletion of Atg5 in the host similarly regulated [corrected] circulating arginine and suppressed tumorigenesis, which demonstrates that this phenotype is specific to autophagy function rather than to deletion of Atg7. Dietary supplementation of Atg7-deficient hosts with arginine partially restored levels of circulating arginine and tumour growth. Thus, defective autophagy in the host leads to the release of ARG1 from the liver and the degradation of circulating arginine, which is essential for tumour growth; this identifies a metabolic vulnerability of cancer.

The impact of fertilization on the chicken egg yolk plasma and granule proteome 24 hours post-lay at room temperature: capitalizing on high-pH/low-pH reverse phase chromatography in conjunction with tandem mass tag (TMT) technology.

Chicken egg yolk is a rich source of nutrients providing high quality proteins, vitamins, minerals, carotenoids and antioxidants. Chicken egg yolk, recovered from whole egg within 24 hours post-lay has been utilized as a starting material in the preparation of a dietary supplement that has been demonstrated to lead to gains in muscle mass in a human clinical study. Further, an oil derived from chicken egg yolk has been utilized as a topical agent to treat third degree burn injury. The molecular changes that take place in fertilized, chicken egg yolk during the first 24 hours post-lay are not well understood. By studying how the protein composition of egg yolk varies with fertility status, one can utilize this knowledge to develop egg yolk-based products that have been optimized for specific applications. In this study, a direct quantitative comparison was made between the proteome of fertilized chicken egg yolk and the proteome of unfertilized chicken egg yolk, both maintained at 20 °C and analyzed within 24 hours post-lay. Egg yolk proteins from each fertility state were digested with trypsin, labeled with distinct chemical labels (tandem mass tag reagents) and then combined in a 1 : 1 ratio. A TMT-labeled tryptic digest derived from chicken egg yolk proteins (fertilized and unfertilized) was separated using high-pH/low-pH reverse-phase chromatography and analyzed using mass spectrometry. 225 protein identifications were made from this TMT-labeled tryptic digest based on a minimum of 2 unique peptides observed per protein. 9 proteins increased in abundance in fertilized egg yolk relative to unfertilized egg yolk and 9 proteins decreased in abundance in fertilized egg yolk relative to unfertilized egg yolk. Some proteins that increased in abundance in fertilized egg yolk play an important role in angiogenesis (pleiotrophin, histidine rich glycoprotein) and defense against pathogens (mannose-binding lectin, ß-defensin 11, serum amyloid P-component, ovostatin). Based on this study, fertilized chicken egg yolk may be more useful as a starting material relative to unfertilized chicken egg yolk for the purpose of enriching or isolating proteins with pro-angiogenic and anti-microbial properties.

[Observation and multifactor analysis of refractory medium-severe heart failure by micro-inflammation modification in uremic patients].

OBJECTIVE: To investigate the therapeutic strategies and prognostic factors of refractory medium-severe heart failure in uremic patients. METHODS: A single center, self control clinical research was conducted, and the data consisted of 30 uremic patients with refractory medium-severe heart failure undergoing maintenance hemodialysis (MHD), who received routine combined modality therapy and Xuebijing injection (to modify micro-inflammation). The systolic function of the left ventricle was compared before and after therapy. Multiple linear regression models were established to predict the improvements of systolic function of ventricle. Relationship between the accumulated dose of Xuebijing injection and changes of C-reactive protein (ΔCRP) was observed. RESULTS: The values of left ventricle ejection fraction (LVEF), fractional shortening (FS), and stroke volume (SV) after therapy were improved compared with those before therapy [LVEF: 0.42±0.07 vs. 0.34±0.04, FS: (21.07±3.83)% vs. (16.33±2.43)%, SV: 66.83±7.00 ml vs. 52.20±7.62 ml, all P<0.01]. In terms of cardiac output (CO), there was no statistical difference before and after therapy (4.77±0.65 L/min vs. 4.49±0.68 L/min, P>0.05). In the multiple linear regression models of ΔLVEF, ΔFS and ΔSV, the independent variables that affect dependent variables included age, ΔCRP, changes of hemoglobin (ΔHb), accumulated dose of Xuebijing injection, changes of HCO(3)(-) (Δ HCO(3)(-)), changes of serum creatinine (ΔSCr), Hb and CRP after therapy, the factors and weights of which had slight variation on accordance with different dependent variables. There was significant positive correlation between accumulated dose of Xuebijing injection and ΔCRP (r=0.561, P=0.001). CONCLUSIONS: Xuebijing injection can improve heart function in uremic patients by modifying micro-inflammation, whose accumulated dose and therapeutic effect show positive correlation. In addition the improvement of heart failure has something to do with age, ΔHb, Hb after therapy, the correction of acidosis and dialysis sufficiency.