Altered translation of GATA1 in Diamond-Blackfan anemia

Ribosomal protein haploinsufficiency occurs in diverse human diseases including Diamond-Blackfan anemia (DBA)[superscript 1, 2], congenital asplenia[superscript 3] and T cell leukemia[superscript 4]. Yet, how mutations in genes encoding ubiquitously expressed proteins such as these result in cell-type– and tissue-specific defects remains unknown[superscript 5]. Here, we identify mutations in GATA1, encoding the critical hematopoietic transcription factor GATA-binding protein-1, that reduce levels of full-length GATA1 protein and cause DBA in rare instances. We show that ribosomal protein haploinsufficiency, the more common cause of DBA, can lead to decreased GATA1 mRNA translation, possibly resulting from a higher threshold for initiation of translation of this mRNA in comparison with other mRNAs. In primary hematopoietic cells from patients with mutations in RPS19, encoding ribosomal protein S19, the amplitude of a transcriptional signature of GATA1 target genes was globally and specifically reduced, indicating that the activity, but not the mRNA level, of GATA1 is decreased in patients with DBA associated with mutations affecting ribosomal proteins. Moreover, the defective hematopoiesis observed in patients with DBA associated with ribosomal protein haploinsufficiency could be partially overcome by increasing GATA1 protein levels. Our results provide a paradigm by which selective defects in translation due to mutations affecting ubiquitous ribosomal proteins can result in human disease.National Institutes of Health (U.S.) (Grant P01 HL32262)National Institutes of Health (U.S.) (Grant U54 HG003067-09

Blood n-3 fatty acid levels and total and cause-specific mortality from 17 prospective studies.

The health effects of omega-3 fatty acids have been controversial. Here we report the results of a de novo pooled analysis conducted with data from 17 prospective cohort studies examining the associations between blood omega-3 fatty acid levels and risk for all-cause mortality. Over a median of 16 years of follow-up, 15,720 deaths occurred among 42,466 individuals. We found that, after multivariable adjustment for relevant risk factors, risk for death from all causes was significantly lower (by 15-18%, at least p < 0.003) in the highest vs the lowest quintile for circulating long chain (20-22 carbon) omega-3 fatty acids (eicosapentaenoic, docosapentaenoic, and docosahexaenoic acids). Similar relationships were seen for death from cardiovascular disease, cancer and other causes. No associations were seen with the 18-carbon omega-3, alpha-linolenic acid. These findings suggest that higher circulating levels of marine n-3 PUFA are associated with a lower risk of premature death.The EPIC Norfolk study (DOI 10.22025/2019.10.105.00004) has received funding from the Medical Research Council (MR/N003284/1 and MC-UU_12015/1) and Cancer Research UK (C864/A14136). NJW, NGF, and FI were supported by the Medical Research Council Epidemiology Unit core funding [MC_UU_12015/1 and MC_UU_12015/5]. NJW and NGF acknowledge support from the National Institute for Health Research Cambridge Biomedical Research Centre [IS-BRC-1215-20014] and NJW is an NIHR Senior Investigator

Izloženost štakora niskim razinama olova tijekom fetalnog i ranoga postnatalnog razvoja šteti učenju pasivnim izbjegavanjem kazne kasnije u odrasloj dobi

This follow-up study investigated the effects of low-level lead exposure during prenatal and early postnatal period on learning and memory in rats immediately after exposure has ceased at weaning and later in their adulthood. Male Wistar-derived rats were exposed to lead (as 0.2 % lead acetate solution) through their mothers during pregnancy and lactation until they were weaned. Mothers of control rats were given tap water during pregnancy and lactation. All pups were weaned on tap water at 21 days of age and were followed up until 120 days old. Low-level lead exposure did not affect their body weight at any time during the experiment. Blood lead in the exposed rats was significantly higher on postnatal day 22 and dropped to control values by day 120. Passive avoidance test showed impaired memory retention in the exposed rats on postnatal days 25 and 120. This suggests that exposure to low-lead levels during foetal and early postnatal development of brain tissue can cause memory impairment that lasts into adulthood.Cilj je ovoga prospektivnog istraživanja bio utvrditi kako izloženost niskim razinama olova tijekom gestacije i ranoga postnatalnog razvoja utječe na učenje i pamćenje u štakora odmah nakon prestanka izloženosti (odbijanjem od sise) te kasnije u odrasloj dobi. Mužjaci štakora izloženi su olovu u obliku 0,2 %-tne otopine olovova acetata preko majke tijekom gestacije te za cijeloga trajanja laktacije sve do odbijanja od sise. Sve to vrijeme majke kontrolnih štakora dobivale su vodu iz pipe. Svi su štakorčići odbijeni od sise 21 dan nakon okota i otada piju vodu iz pipe. Praćeni su do 120. dana života. Izloženost niskim razinama olova nije dovela do razlika u tjelesnoj težini između izloženih i kontrolnih štakorčića. Razine olova u krvi bile su značajno više u izloženih štakora 22 dana od okota, da bi do 120. dana pale na razinu u kontrolnih štakora. Test pasivnoga izbjegavanja pokazao je oštećenje pamćenja u izloženih štakora 25. i 120. dana nakon okota. To potvrđuje da izloženost niskim razinama olova tijekom fetalnoga i ranoga postnatalnog razvoja moždanog tkiva može dovesti to oštećenja u pamćenju koje traje sve do odrasle dobi

Gender differences in marital status moderation of genetic and environmental influences on subjective health

From the IGEMS Consortium, data were available from 26,579 individuals aged 23 to 102 years on 3 subjective health items: self-rated health (SRH), health compared to others (COMP), and impact of health on activities (ACT). Marital status was a marker of environmental resources that may moderate genetic and environmental influences on subjective health. Results differed for the 3 subjective health items, indicating that they do not tap the same construct. Although there was little impact of marital status on variance components for women, marital status was a significant modifier of variance in all 3 subjective health measures for men. For both SRH and ACT, single men demonstrated greater shared and nonshared environmental variance than married men. For the COMP variable, genetic variance was greater for single men vs. married men. Results suggest gender differences in the role of marriage as a source of resources that are associated with subjective health

Similarities and differences in aneurysmal subarachnoid haemorrhage between eastern Finland and northern Sydney

A significant body of literature on aneurysmal subarachnoid haemorrhage has emerged from Finland. The Finnish source from a small founding population, rather than from a wide heterogeneous source such as used for other populations, suggests the need for caution when attempting to generalise using Finnish data. This study aims to identify the differences and similarities between the aneurysmal subarachnoid haemorrhage populations of eastern Finland and northern Sydney to ascertain whether information that is derived from Finland has applicability to an Australian context. Existing aneurysmal subarachnoid haemorrhage databases of Kuopio University Hospital in eastern Finland and the Royal North Shore and Dalcross Private Hospitals in northern Sydney from 2000 to 2005 were combined and analysed. A total of 879 patients were identified. Comparisons fell into three categories: features that were similar between the two populations; those with apparent differences that may be explained by methods of data collection or referral patterns; and differences that probably represent a true difference between these populations. The differences suggest that genetic predispositions for aneurysm development may not affect the likelihood for aneurysmal rupture.5 page(s