EHMT1/GLP; biochemical function and association with brain disorders

The gene EHMT1 that encodes the Euchromatic Histone Methyltransferase-1, also known as GLP (G9a-like protein), has been associated with a number of neurodevelopmental and neurodegenerative disorders. GLP is a member of the euchromatic lysine histone methyltransferase family, along with EHMT2 or G9A. As its name implies, Ehmt1/GLP is involved in the addition of methyl groups to histone H3 lysine 9, a generally repressive mark linked to classical epigenetic process such as genomic imprinting, X-inactivation, and heterochromatin formation. However, GLP also plays both a direct and indirect role in regulating DNA-methylation. Here, we discuss what is currently known about the biochemical function of Ehmt1/GLP and its association, via various genetic studies, with brain disorders

The challenges of renal replacement therapy and renal palliative care in the elderly

Much of the increase in take on rate for dialysis in recent years is accounted for by older patients in whom a treatment as demanding as dialysis was previously thought to be contraindicated. The decision to dialyse the elderly often remains difficult, as recent data suggest that those with significant comorbidities are unlikely to survive more than 4-6 months longer on dialysis than they would have done if treated conservatively. It is also important to recognise that conservative treatment is not simply defined by the decision not to dialyse. Good conservative care comprises active disease management eg treatment of anaemia with erythropoietin stimulating agents and intravenous iron, and supportive care which may become increasingly complex eg pain relief with fentanyl and alfentanyl, towards the end of life. Those older patients who do decide to dialyse must contend with all the usual end of life issues facing older people, in addition to the option, denied to the rest of us, of dialysis withdrawal which effectively allows them to die at a time of their choosing

Extreme internal charging currents in medium Earth orbit: Analysis of SURF plate currents on Giove-A

Relativistic electrons can penetrate spacecraft shielding and can damage satellite components. Spacecraft in medium Earth orbit pass through the heart of the outer radiation belt and may be exposed to large fluxes of relativistic electrons, particularly during extreme space weather events. In this study we perform an extreme value analysis of the daily average internal charging currents at three different shielding depths in medium Earth orbit as a function of L∗ and along the orbit path. We use data from the SURF instrument on board the European Space Agency's Giove-A spacecraft from December 2005 to January 2016. The top, middle, and bottom plates of this instrument respond to electrons with energies >500 keV, >700 keV, and >1.1 MeV, respectively. The 1 in 10 year daily average top plate current decreases with increasing L∗ ranging from 1.0 pA cm−2 at L∗=4.75 to 0.03 pA cm−2 at L∗=7.0. The 1 in 100 year daily average top plate current is a factor of 1.2 to 1.8 larger than the corresponding 1 in 10 year current. The 1 in 10 year daily average middle and bottom plate currents also decrease with increasing L∗ ranging from 0.4 pA cm−2 at L∗=4.75 to 0.01 pA cm−2 at L∗=7.0. The 1 in 100 year daily average middle and bottom plate currents are a factor of 1.2 to 2.7 larger than the corresponding 1 in 10 year currents. Averaged along the orbit path the 1 in 10 year daily average top, middle, and bottom plate currents are 0.22, 0.094, and 0.094 pA cm−2, respectively

Risk taking and impulsive behaviour: fundamental discoveries, theoretical perspectives and clinical implications

Our willingness to take risks, our ability to wait or the speed with which to make decisions are central features of our personality. However, it is now recognized that impulsive and risk-taking behaviours are not a unitary construct, and different aspects can be both psychologically and neurally dissociated. The range of neurochemicals and brain systems that govern these behaviours is extensive, and this may be a contributing factor to the phenotypic range seen in the human population. However, this variety can also be pathological as extremes in risk-taking and impulsive behaviours are characteristics of many neuropsychiatric and indeed neurodegenerative disorders. This spans obsessive–compulsive disorder, where behaviour becomes ridged and non-spontaneous, to the nonsensical risk-taking seen in gambling and drug taking

Relation between coronary risk and coronary mortality in women of the Renfrew and Paisley survey: comparison with men

Most epidemiological and intervention studies in patients with coronary artery disease have focused on men, the assumption being that such data can be extrapolated to women. However, there is little evidence to support this belief. We have completed a fifteen-year follow-up of 15 399 adults, including 8262 women, who lived in Renfrew and Paisley and were aged 45-64 years when screened between 1972 and 1976. We identified 490 deaths from coronary heart disease (CHD) in women and 878 in men. Women were more likely to have high cholesterol, to be obese, and to come from lower social classes than men, but they smoked less and had similar blood pressures. The relative risk--top to bottom quintile (95% Cl)--of cholesterol for coronary death after adjustment for all other risk markers was slightly greater in women (1[middle dot]77 [1[middle dot]45, 2[middle dot]16]) than in men (1[middle dot]56 [1[middle dot]32, 1[middle dot]85]), but absolute and attributable risk were lower. Thus, women in the top quintile for cholesterol had lower coronary mortality (6[middle dot]1 deaths per thousand patient years) than men in the bottom quintile (6[middle dot]8 deaths per thousand patient years). Moreover, it was estimated that there would have been only 103 (21 %) fewer CH D deaths in women, yet 211 (24%) fewer in men, if mortality had been the same for women and men in the lowest quintiles of cholesterol. Trends showing similar relative risks in these women, but lower absolute and attributable risks than in men, were present for smoking, diastolic blood pressure, and social class. There was no relation between obesity and coronary death after adjustment for other risks. Our results suggest that some other factors protect women against CHD. The potential for women to reduce their risk of CH D by changes in lifestyle may be less than for men.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30146/1/0000523.pd

Imprinted genes influencing the quality of maternal care

In mammals successful rearing imposes a cost on later reproductive fitness specifically on the mother creating the potential for parental conflict. Loss of function of three imprinted genes in the dam result in deficits in maternal care suggesting that, like maternal nutrients, maternal care is a resource over which the parental genomes are in conflict. However, the induction of maternal care is a complex and highly regulated process. Unsurprisingly many gene disruptions, as well as adverse environmental exposures in pregnancy, result in maternal care deficits. Recent compelling evidence for a more purposeful imprinting phenomenon comes from studying the impact of two imprinted genes, Phlda2 and Peg3, expressed in the placenta on the mother’s behaviour. The explicit demonstration that imprinted genes expressed in the offspring influence maternal behaviour lends significant weight to the hypothesis that maternal care is a resource that has been manipulated by the paternal genome

Observations of red-giant variable stars by Aboriginal Australians

Aboriginal Australians carefully observe the properties and positions of stars, including both overt and subtle changes in their brightness, for subsistence and social application. These observations are encoded in oral tradition. I examine two Aboriginal oral traditions from South Australia that describe the periodic changing brightness in three pulsating, red-giant variable stars: Betelgeuse (Alpha Orionis), Aldebaran (Alpha Tauri), and Antares (Alpha Scorpii). The Australian Aboriginal accounts stand as the only known descriptions of pulsating variable stars in any Indigenous oral tradition in the world. Researchers examining these oral traditions over the last century, including anthropologists and astronomers, missed the description of these stars as being variable in nature as the ethnographic record contained several misidentifications of stars and celestial objects. Arguably, ethnographers working on Indigenous Knowledge Systems should have academic training in both the natural and social sciences.Comment: The Australian Journal of Anthropology (2018

Distinct physiological and behavioural functions for parental alleles of imprinted Grb10

Imprinted genes, defined by their preferential expression of a single parental allele, represent a subset of the mammalian genome and often have key roles in embryonic development1, but also postnatal functions including energy homeostasis2 and behaviour3, 4. When the two parental alleles are unequally represented within a social group (when there is sex bias in dispersal and/or variance in reproductive success)5, 6, imprinted genes may evolve to modulate social behaviour, although so far no such instance is known. Predominantly expressed from the maternal allele during embryogenesis, Grb10 encodes an intracellular adaptor protein that can interact with several receptor tyrosine kinases and downstream signalling molecules7. Here we demonstrate that within the brain Grb10 is expressed from the paternal allele from fetal life into adulthood and that ablation of this expression engenders increased social dominance specifically among other aspects of social behaviour, a finding supported by the observed increase in allogrooming by paternal Grb10-deficient animals. Grb10 is, therefore, the first example of an imprinted gene that regulates social behaviour. It is also currently alone in exhibiting imprinted expression from each of the parental alleles in a tissue-specific manner, as loss of the peripherally expressed maternal allele leads to significant fetal and placental overgrowth. Thus Grb10 is, so far, a unique imprinted gene, able to influence distinct physiological processes, fetal growth and adult behaviour, owing to actions of the two parental alleles in different tissues

Intracellular trafficking and replication of Burkholderia cenocepacia in human cystic fibrosis airway epithelial cells

We investigated the trafficking of Burkholderia cenocepacia , an opportunistic respiratory pathogen of persons with cystic fibrosis (CF), in immortalized CF airway epithelial cells in vitro . Our results indicate that bacteria enter cells in a process involving actin rearrangement. Whereas both live and heat-killed bacteria reside transiently in early endosomes, only live bacteria escape from late endosomes to colocalize in vesicles positive for lysosomal membrane marker LAMP1, endoplasmic reticulum (ER) membrane marker calnexin, and autophagosome marker monodansylcadavarine (MDC). Twenty-four hours after infection, microcolonies of live bacteria were observed in the perinuclear area colocalizing with calnexin. In contrast, after ingestion, dead bacteria colocalized with late endosome marker Rab7, and lysosome markers LAMP1 and cathepsin D, but not with calnexin or MDC. Six to eight hours after ingestion of dead bacteria, degraded bacterial particles were observed in the cytoplasm and in vesicles positive for cathepsin D. These results indicate that live B. cenocepacia gain entry into human CF airway cells by endocytosis, escape from late endosomes to enter autophagosomes that fail to fuse with mature lysosomes, and undergo replication in the ER. This survival and replication strategy may contribute to the capacity of B. cenocepacia to persist in the lungs of infected CF patients.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75744/1/j.1462-5822.2006.00724.x.pd