UTF1 is a chromatin-associated protein involved in ES cell differentiation

Embryonic stem (ES) cells are able to grow indefinitely (self-renewal) and have the potential to differentiate into all adult cell types (pluripotency). The regulatory network that controls pluripotency is well characterized, whereas the molecular basis for the transition from self-renewal to the differentiation of ES cells is much less understood, although dynamic epigenetic gene silencing and chromatin compaction are clearly implicated. In this study, we report that UTF1 (undifferentiated embryonic cell transcription factor 1) is involved in ES cell differentiation. Knockdown of UTF1 in ES and carcinoma cells resulted in a substantial delay or block in differentiation. Further analysis using fluorescence recovery after photobleaching assays, subnuclear fractionations, and reporter assays revealed that UTF1 is a stably chromatin-associated transcriptional repressor protein with a dynamic behavior similar to core histones. An N-terminal Myb/SANT domain and a C-terminal domain containing a putative leucine zipper are required for these properties of UTF1. These data demonstrate that UTF1 is a strongly chromatin-associated protein involved in the initiation of ES cell differentiation

<i>ATP5PO </i>levels regulate enteric nervous system development in zebrafish, linking Hirschsprung disease to Down Syndrome

Hirschsprung disease (HSCR) is a complex genetic disorder characterized by the absence of enteric nervous system (ENS) in the distal region of the intestine. Down Syndrome (DS) patients have a &gt;50-fold higher risk of developing HSCR than the general population, suggesting that overexpression of human chromosome 21 (Hsa21) genes contribute to HSCR etiology. However, identification of responsible genes remains challenging. Here, we describe a genetic screening of potential candidate genes located on Hsa21, using the zebrafish. Candidate genes were located in the DS-HSCR susceptibility region, expressed in the human intestine, were known potential biomarkers for DS prenatal diagnosis, and were present in the zebrafish genome. With this approach, four genes were selected: RCAN1, ITSN1, ATP5PO and SUMO3. However, only overexpression of ATP5PO, coding for a component of the mitochondrial ATPase, led to significant reduction of ENS cells. Paradoxically, in vitro studies showed that overexpression of ATP5PO led to a reduction of ATP5PO protein levels. Impaired neuronal differentiation and reduced mitochondrial ATP production, were also detected in vitro, after overexpression of ATP5PO in a neuroblastoma cell line. Finally, epistasis was observed between ATP5PO and ret, the most important HSCR gene. Taken together, our results identify ATP5PO as the gene responsible for the increased risk of HSCR in DS patients in particular if RET variants are also present, and show that a balanced expression of ATP5PO is required for normal ENS development.</p

Erratum: Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017

Interpretation: By quantifying levels and trends in exposures to risk factors and the resulting disease burden, this assessment offers insight into where past policy and programme efforts might have been successful and highlights current priorities for public health action. Decreases in behavioural, environmental, and occupational risks have largely offset the effects of population growth and ageing, in relation to trends in absolute burden. Conversely, the combination of increasing metabolic risks and population ageing will probably continue to drive the increasing trends in non-communicable diseases at the global level, which presents both a public health challenge and opportunity. We see considerable spatiotemporal heterogeneity in levels of risk exposure and risk-attributable burden. Although levels of development underlie some of this heterogeneity, O/E ratios show risks for which countries are overperforming or underperforming relative to their level of development. As such, these ratios provide a benchmarking tool to help to focus local decision making. Our findings reinforce the importance of both risk exposure monitoring and epidemiological research to assess causal connections between risks and health outcomes, and they highlight the usefulness of the GBD study in synthesising data to draw comprehensive and robust conclusions that help to inform good policy and strategic health planning

Lipids, beta-secretase 1, and Alzheimer disease

An imbalance in lipid metabolism in Alzheimer disease (AD) is still poorly understood. Phospholipids (PLs) have multifactorial participation in AD, including the hyperactivation of phospholipases, mitochondrial stress, peroxisomal dysfunction, and irregular fatty acid composition. The reestablishment of physiological conditions of cholesterol, sphingolipids, phospholipids, and others is an interesting therapeutic target to reduce the progression of AD. In this chapter we propose the positive effect of BACE1 silencing produces a balance of phospholipid profile in desaturase enzymes-depending mode to reduce the inflammation response, and recover the cognitive function in an Alzheimer animal model. Pointing out there is a great need for new well-designed research focused on preventing phospholipid imbalance, and their consequent energy metabolism impairment, proinflammation and enzymatic overprocessing, which would help to prevent unhealthy aging and AD progression.</p

Lipids, beta-secretase 1, and Alzheimer disease

An imbalance in lipid metabolism in Alzheimer disease (AD) is still poorly understood. Phospholipids (PLs) have multifactorial participation in AD, including the hyperactivation of phospholipases, mitochondrial stress, peroxisomal dysfunction, and irregular fatty acid composition. The reestablishment of physiological conditions of cholesterol, sphingolipids, phospholipids, and others is an interesting therapeutic target to reduce the progression of AD. In this chapter we propose the positive effect of BACE1 silencing produces a balance of phospholipid profile in desaturase enzymes-depending mode to reduce the inflammation response, and recover the cognitive function in an Alzheimer animal model. Pointing out there is a great need for new well-designed research focused on preventing phospholipid imbalance, and their consequent energy metabolism impairment, proinflammation and enzymatic overprocessing, which would help to prevent unhealthy aging and AD progression

Prevention of microgliosis halts early memory loss in a mouse model of Alzheimer's disease

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline, the neuropathological formation of amyloid-beta (Aβ) plaques and neurofibrillary tangles. The best cellular correlates of the early cognitive deficits in AD patients are synapse loss and gliosis. In particular, it is unclear whether the activation of microglia (microgliosis) has a neuroprotective or pathological role early in AD. Here we report that microgliosis is an early mediator of synaptic dysfunction and cognitive impairment in APP/PS1 mice, a mouse model of increased amyloidosis. We found that the appearance of microgliosis, synaptic dysfunction and behavioral impairment coincided with increased soluble Aβ42 levels, and occurred well before the presence of Aβ plaques. Inhibition of microglial activity by treatment with minocycline (MC) reduced gliosis, synaptic deficits and cognitive impairments at early pathological stages and was most effective when provided preventive, i.e., before the onset of microgliosis. Interestingly, soluble Aβ levels or Aβ plaques deposition were not affected by preventive MC treatment at an early pathological stage (4 months) whereas these were reduced upon treatment at a later stage (6 months). In conclusion, this study demonstrates the importance of early-stage prevention of microgliosis on the development of cognitive impairment in APP/PS1 mice, which might be clinically relevant in preventing memory loss and delaying AD pathogenesis

Prevention of microgliosis halts early memory loss in a mouse model of Alzheimer's disease

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline, the neuropathological formation of amyloid-beta (Aβ) plaques and neurofibrillary tangles. The best cellular correlates of the early cognitive deficits in AD patients are synapse loss and gliosis. In particular, it is unclear whether the activation of microglia (microgliosis) has a neuroprotective or pathological role early in AD. Here we report that microgliosis is an early mediator of synaptic dysfunction and cognitive impairment in APP/PS1 mice, a mouse model of increased amyloidosis. We found that the appearance of microgliosis, synaptic dysfunction and behavioral impairment coincided with increased soluble Aβ42 levels, and occurred well before the presence of Aβ plaques. Inhibition of microglial activity by treatment with minocycline (MC) reduced gliosis, synaptic deficits and cognitive impairments at early pathological stages and was most effective when provided preventive, i.e., before the onset of microgliosis. Interestingly, soluble Aβ levels or Aβ plaques deposition were not affected by preventive MC treatment at an early pathological stage (4 months) whereas these were reduced upon treatment at a later stage (6 months). In conclusion, this study demonstrates the importance of early-stage prevention of microgliosis on the development of cognitive impairment in APP/PS1 mice, which might be clinically relevant in preventing memory loss and delaying AD pathogenesis

Report of the first workshop on the genetic map of bovine chromosome 1

A report of the first workshop on the genetic map of bovine chromosome 1 (BTA1) is presented. Five laboratories contributed 31 962 informative meioses from 70 loci. Thirty-two loci which had been typed by at least two laboratories were used to construct a framework genetic map with a likelihood ratio support of at least 1000:1 for locus order. The resulting sex-averaged framework map contained 26 loci and spanned 163.6 CM. The lengths of the female and male maps were 159.5 CM and 165.3 CM, respectively, and there was evidence for an expansion in the telomeric one-third of the male map. Of the four cases where order for closely linked loci differed among the maps produced for each of the contributing laboratories, a consensus order was obtained for three in the framework map. The average genetic distance between framework loci on the sex-averaged map was 6.3 CM