Microbial and biochemical changes during the moulding of hay

RESP-498

Transcriptional activation of pericentromeric satellite repeats and disruption of centromeric clustering upon proteasome inhibition

Heterochromatinisation of pericentromeres, which in mice consist of arrays of major satellite repeats, are important for centromere formation and maintenance of genome stability. The dysregulation of this process has been linked to genomic stress and various cancers. Here we show in mice that the proteasome binds to major satellite repeats and proteasome inhibition by MG132 results in their transcriptional de-repression; this de-repression is independent of cell-cycle perturbation. The transcriptional activation of major satellite repeats upon proteasome inhibition is accompanied by delocalisation of heterochromatin protein 1 alpha (HP1α) from chromocentres, without detectable change in the levels of histone H3K9me3, H3K4me3, H3K36me3 and H3 acetylation on the major satellite repeats. Moreover, inhibition of the proteasome was found to increase the number of chromocentres per cell, reflecting destabilisation of the chromocentre structures. Our findings suggest that the proteasome plays a role in maintaining heterochromatin integrity of pericentromeres

Self-heating of Hay and Grain in Dewar Flasks and the Development of Farmer's Lung Antigens

In moist hay allowed to self-heat aerobically in Dewax flasks, the pattern of temperature change with time was affected considerably by the type of hay and duration of storage, but there was a relationship between water content and maximum temperature reached, Below 29 yo water con-tent there was little heating or antigen production; in the critical range of 29-34 yo water content, different lots of hay self-heated to different tem-peratures between 33 and 55 " and varied widely in their content of farmer's lung hay antigen complex (FLH), the wetter hays usually producing the more antigen; all samples with 40 % water heated to c. 6.5 ' and produced FLH antigen, associated with the presence of Thermopolysporu polyspora. Pro-gressively less antigen, especially in the lower regions of the flasks, was produced as water content increased from 47 to 68 yo. Moist barley and oat grain also self-heated and produced FLH antigen, usually only in the middle of the grain mass, where T. polysporu was most abundant; the drier upper layers and the lower regions where excess water accumulated were free from the antigen

Farmer's lung disease: the development of antigens in moulding hay

RESP-512

Sex differences in gene expression and proliferation are dependent on the epigenetic modifier HP1γ

Summary Sex differences in growth rate in very early embryos have been recognized in a variety of mammals and attributed to sex-chromosome complement effects as they occur before overt sexual differentiation. We previously found that sex-chromosome complement, rather than sex hormones regulates heterochromatin-mediated silencing of a transgene and autosomal gene expression in mice. Here, sex dimorphism in proliferation was investigated. We confirm that male embryonic fibroblasts proliferate faster than female fibroblasts and show that this proliferation advantage is completely dependent upon heterochromatin protein 1 gamma (HP1γ). To determine whether this sex-regulatory effect of HP1γ was a more general phenomenon, we performed RNA sequencing on MEFs derived from males and females, with or without HP1γ. Strikingly, HP1γ was found to be crucial for regulating nearly all sexually dimorphic autosomal gene expression because deletion of the HP1γ gene in males abolished sex differences in autosomal gene expression. The identification of a key epigenetic modifier as central in defining gene expression differences between males and females has important implications for understanding physiological sex differences and sex bias in disease

Genetic nomenclature for the H-2 complex of the mouse

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46730/1/251_2005_Article_BF01564058.pd

Tissue graft rejection in mice

A liver-slice to kidney-bed grafting system was used to study the course of rejection of a specific tissue across various genetic barriers in inbred strains of mice. Rejection or survival, scored histologically at various times after grafting, demonstrated that multiple non H-2 differences cause rejection at least as rapidly as H-2 differences. Differences at the K end of the mouse major histocompatibility complex cause tissue rejection more rapidly than do differences at the D end of the complex. The latter differences cause chronic rejection similar to that found across several minor H locus barriers. The H-2 haplotype carried by the recipient or the strength of the H-2 antigens of the donor affect the survival time in liver tissue grafts. Studies employing this model system will contribute to the definition of different immunogenetic parameters affecting survival of various tissues in a genetically well-defined animal model.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46746/1/251_2005_Article_BF01576941.pd

Use of whole genome sequencing to determine genetic basis of suspected mitochondrial disorders: cohort study.

OBJECTIVE: To determine whether whole genome sequencing can be used to define the molecular basis of suspected mitochondrial disease. DESIGN: Cohort study. SETTING: National Health Service, England, including secondary and tertiary care. PARTICIPANTS: 345 patients with suspected mitochondrial disorders recruited to the 100 000 Genomes Project in England between 2015 and 2018. INTERVENTION: Short read whole genome sequencing was performed. Nuclear variants were prioritised on the basis of gene panels chosen according to phenotypes, ClinVar pathogenic/likely pathogenic variants, and the top 10 prioritised variants from Exomiser. Mitochondrial DNA variants were called using an in-house pipeline and compared with a list of pathogenic variants. Copy number variants and short tandem repeats for 13 neurological disorders were also analysed. American College of Medical Genetics guidelines were followed for classification of variants. MAIN OUTCOME MEASURE: Definite or probable genetic diagnosis. RESULTS: A definite or probable genetic diagnosis was identified in 98/319 (31%) families, with an additional 6 (2%) possible diagnoses. Fourteen of the diagnoses (4% of the 319 families) explained only part of the clinical features. A total of 95 different genes were implicated. Of 104 families given a diagnosis, 39 (38%) had a mitochondrial diagnosis and 65 (63%) had a non-mitochondrial diagnosis. CONCLUSION: Whole genome sequencing is a useful diagnostic test in patients with suspected mitochondrial disorders, yielding a diagnosis in a further 31% after exclusion of common causes. Most diagnoses were non-mitochondrial disorders and included developmental disorders with intellectual disability, epileptic encephalopathies, other metabolic disorders, cardiomyopathies, and leukodystrophies. These would have been missed if a targeted approach was taken, and some have specific treatments