Rumen and Serum Metabolomes in Response to Endophyte-Infected Tall Fescue Seed and Isoflavone Supplementation in Beef Steers

Fescue toxicosis impacts beef cattle production via reductions in weight gain and muscle development. Isoflavone supplementation has displayed potential for mitigating these effects. The objective of the current study was to evaluate isoflavone supplementation with fescue seed consumption on rumen and serum metabolomes. Angus steers (n = 36) were allocated randomly in a 2 × 2 factorial arrangement of treatments including endophyte-infected (E+) or endophyte-free (E−) tall fescue seed, with (P+) or without (P−) isoflavones. Steers were provided a basal diet with fescue seed for 21 days, while isoflavones were orally administered daily. Following the trial, blood and rumen fluid were collected for metabolite analysis. Metabolites were extracted and then analyzed by UPLC-MS. The MAVEN program was implemented to identify metabolites for MetaboAnalyst 4.0 and SAS 9.4 statistical analysis. Seven differentially abundant metabolites were identified in serum by isoflavone treatment, and eleven metabolites in the rumen due to seed type (p \u3c 0.05). Pathways affected by treatments were related to amino acid and nucleic acid metabolism in both rumen fluid and serum (p \u3c 0.05). Therefore, metabolism was altered by fescue seed in the rumen; however, isoflavones altered metabolism systemically to potentially mitigate detrimental effects of seed and improve animal performance

TLR7 gain-of-function genetic variation causes human lupus

Although circumstantial evidence supports enhanced Toll-like receptor 7 (TLR7) signalling as a mechanism of human systemic autoimmune disease evidence of lupus-causing TLR7 gene variants is lacking. Here we describe human systemic lupus erythematosus caused by a TLR7 gain-of-function variant. TLR7 is a sensor of viral RNA and binds to guanosine. We identified a de novo, previously undescribed missense TLR7Y264H variant in a child with severe lupus and additional variants in other patients with lupus. The TLR7Y264H variant selectively increased sensing of guanosine and 2',3'-cGMP1 and was sufficient to cause lupus when introduced into mice. We show that enhanced TLR7 signalling drives aberrant survival of B cell receptor (BCR)-activated B cells, and in a cell-intrinsic manner, accumulation of CD11c+ age-associated B cells and germinal centre B cells. Follicular and extrafollicular helper T cells were also increased but these phenotypes were cell-extrinsic. Deficiency of MyD88 (an adaptor protein downstream of TLR7) rescued autoimmunity, aberrant B cell survival, and all cellular and serological phenotypes. Despite prominent spontaneous germinal-centre formation in Tlr7Y264H mice, autoimmunity was not ameliorated by germinal-centre deficiency, suggesting an extrafollicular origin of pathogenic B cells. We establish the importance of TLR7 and guanosine-containing self-ligands for human lupus pathogenesis, which paves the way for therapeutic TLR7 or MyD88 inhibition

Characterization of Novel and Uncharacterized p53 SNPs in the Chinese Population – Intron 2 SNP Co-Segregates with the Common Codon 72 Polymorphism

Multiple single nucleotide polymorphisms (SNPs) have been identified in the tumor suppressor gene p53, though the relevance of many of them is unclear. Some of them are also differentially distributed in various ethnic populations, suggesting selective functionality. We have therefore sequenced all exons and flanking regions of p53 from the Singaporean Chinese population and report here the characterization of some novel and uncharacterized SNPs - four in intron 1 (nucleotide positions 8759/10361/10506/11130), three in intron 3 (11968/11969/11974) and two in the 3′UTR (19168/19514). Allelic frequencies were determined for all these and some known SNPs, and were compared in a limited scale to leukemia and lung cancer patient samples. Intron 2 (11827) and 7 (14181/14201) SNPs were found to have a high minor allele frequency of between 26–47%, in contrast to the lower frequencies found in the US population, but similar in trend to the codon 72 polymorphism (SNP12139) that shows a distribution pattern correlative with latitude. Several of the SNPs were linked, such as those in introns 1, 3 and 7. Most interestingly, we noticed the co-segregation of the intron 2 and the codon 72 SNPs, the latter which has been shown to be expressed in an allele-specific manner, suggesting possible regulatory cross-talk. Association analysis indicated that the T/G alleles in both the co-segregating intron 7 SNPs and a 4tagSNP haplotype was strongly associated increased susceptibility to lung cancer in non-smoker females [OR: 1.97 (1.32, 3.394)]. These data together demonstrate high SNP diversity in p53 gene between different populations, highlighting ethnicity-based differences, and their association with cancer risk

Shiming Strategy for the Phase Shifters Used in the European XFEL

The undulator systems of the European XFEL need a total of 91 Phase Shifters. The 1st field integral of these devices must not exceed 0.004Tmm for working gaps > 16mm. For smaller gaps it is slightly released. In spiteof the highly magnetically symmetric design and considerable effort such as the selection and sorting of the magnets small 1st field integral errors cannot be excluded. In this paper a strategy is studied to correct small gap dependent kicking errors as expected for the phase shifters of the XFEL.EU.by using shims of different geometries and sizes. It is found, thatsmall gap dependent kicking errors can well be corrected for using thismethod. This is a systematic effort to provide effective fast tuning methods,which can be applied for the mass production. The meaning of shimsignature will be explained in this paper. The method is demonstrated bysimulations and measurements

Contribution of Nicotine and Nornicotine toward the Production of <i>N</i>′‑Nitrosonornicotine in Air-Cured Tobacco (<i>Nicotiana tabacum</i>)

<i>N</i>′-Nitrosonornicotine (<b>6</b>) is a potent and organ-specific carcinogen found in tobacco and tobacco smoke in substantial amounts. Nicotine (<b>1</b>) and nornicotine (<b>2</b>) are proposed to be the precursors of <b>6</b> in tobacco. Since <b>1</b> can be rapidly demethylated to <b>2</b> in tobacco, to distinguish between the direct formation of <b>6</b> from these potential precursors is difficult. A gas chromatography/thermal energy analyzer method using two columns in series was developed to separate the enantiomers of <b>6</b>, <i>N</i>′-nitrosoanabasine (<b>7</b>), and <i>N</i>′-nitrosoanatabine (<b>8</b>). Tobacco lines with different combinations of three nicotine demethylases inhibited were grown in the field. Air-cured leaves were analyzed for the enantiomeric composition of four main alkaloids and their corresponding tobacco-specific nitrosamines. The percentage of (<i>R</i>)-<b>6</b> of total <b>6</b> varied from 7% to 69% in mutant lines. The measured <b>6</b> had the same enantiomeric composition as <b>2</b>, rather than <b>1</b>, even when the level of <b>2</b> was reduced to 0.6% of <b>1</b> in a triple mutant line. The pattern of the enantiomeric composition of <b>1</b>, <b>2</b>, and <b>6</b> demonstrated that the direct formation of <b>6</b> from <b>1</b>, if it occurs, is negligible in air-cured tobacco. Since (<i>S</i>)-<b>6</b> is more highly carcinogenic than its <i>R</i> form, the reduction of (<i>S</i>)-<b>2</b> should be a priority for the reduction of <b>6</b>