The Venus ionosphere in the northern polar region

PLASLIFE is a computer simulation which assists in the interpretation of high latitude ionospheric observations and, in this study, is applied to the polar regions of Venus. The Venus Express spacecraft samples the high latitude ionosphere in the northern hemisphere of the planet. On 4 August 2008 it was inserted into a new orbit with pericentre located below 200 km close to 86° N. The ASPERA-4 instrument on the spacecraft records the first extended in situ data set of the plasma environment in this sector. The observed ionospheric ion and electron populations exhibit significant variation between orbits and, by compensating for the effects of solar zenith angle and altitude, the relative contributions of photoionisation and plasma transport can be investigated. These variations are discussed with respect to parameters including local time and solar flux. Comparisons are drawn with the terrestrial ionosphere

The contribution and therapeutic potential of epigenetic modifications in Alzheimer’s disease

Alzheimer’s disease is a progressive neurodegenerative disorder, affecting 50 million people worldwide, for which there is no cure or effective treatment. Individuals suffering from Alzheimer’s show a decline in cognition over time beginning with memory loss and ultimately leading to severe dementia and inability to care for themselves. The cause of Alzheimer’s is not known but likely involves a combination of genetic, biochemical and environmental factors. Some genes have been identified as risk factors but monozygotic twins discordant for Alzheimer’s disease suggest other factors must contribute to development of the disease. Investigation on epigenetic marks including DNA methylation and post-translational modifications of histones have shown that the patterns of these modifications change with age in the human population. Though individuals show specific differences in epigenetic marks at the individual gene level, there is a consistent pattern of epigenetic changes at the genome scale across the population. Similar changes have been identified in patients with Alzheimer’s disease, though these occur at an earlier age compared to healthy individuals. The early cognitive impairment in Alzheimer’s disease can be mistaken for premature ageing correlating with the timing of epigenetic changes occurring at a younger age in individuals with Alzheimer’s. Such observations suggest that the epigenetic changes may contribute to disease pathology. Exactly how epigenetic modifications contribute to specific aspects of Alzheimer’s disease is the focus of many researcher groups across the world. A number of drugs are available that inhibit the enzymes that modify chromatin and change the epigenetic landscape of the genome. Therefore, an understanding of the role of chromatin modifications in Alzheimer’s could offer an opportunity for novel therapeutic strategies. Research using animal models of Alzheimer’s suggests that the epigenetic changes in Alzheimer’s disease may have a profound impact on cognition and underlie cognitive impairment while there is no clear evidence that they might contribute directly to neuronal loss

Two Types of K⁺ Channel Subunit, Erg1 and KCNQ2/3, Contribute to the M-Like Current in a Mammalian Neuronal Cell

The potassium M current was originally identified in sympathetic ganglion cells, and analogous currents have been reported in some central neurons and also in some neural cell lines. It has recently been suggested that the M channel in sympathetic neurons comprises a heteromultimer of KCNQ2 and KCNQ3 (Wang et al., 1998) but it is unclear whether all other M-like currents are generated by these channels. Here we report that the M-like current previously described in NG108–15 mouse neuroblastoma x rat glioma cells has two components, “fast” and “slow”, that may be differentiated kinetically and pharmacologically. We provide evidence from PCR analysis and expression studies to indicate that these two components are mediated by two distinct molecular species of K+ channel: the fast component resembles that in sympathetic ganglia and is probably carried byKCNQ2/3 channels, whereas the slow component appears to be carried by merg1a channels. Thus, the channels generating M-like currents in different cells may be heterogeneous in molecular composition

Histone deacetylase inhibitors induce medulloblastoma cell death independent of HDACs recruited in REST repression complexes

Background Repressor element 1‐silencing transcription factor (REST) acts as a transcriptional repressor by recruiting several chromatin modifiers, including histone deacetylase (HDAC). Elevated REST expression in medulloblastoma has been associated with tumor progression nevertheless, the tumor shows high sensitivity to HDAC inhibitors (HDACi). However, the functional implications of REST and its requirement for HDACi‐induced anti‐cancer effects are not well understood. Methods In this study, the expression of REST was evaluated across the medulloblastoma subgroups and subtypes using published gene expression data. Further, the expression of REST was modulated using the CRISPR/Cas9 knockout and shRNA knockdown in the Daoy medulloblastoma cell line. Results The results of this study showed that the expression of REST is elevated in most medulloblastoma subgroups compared to the non‐cancerous cerebellum. Blocking of REST expression resulted in increasing the expression of REST‐regulated genes, a moderate decrease in the fraction of the cells in the S‐phase, and reducing the cells' migration ability. However, REST deficiency did not lead to a marked decrease in the Daoy cell viability and sensitivity to HDACi. Conclusion The findings of this study indicate that REST is not essential for sustaining the proliferation/viability of the Daoy cells. It also revealed that the anti‐proliferative effect of HDACi is independent of REST expression

Maternal Rest/Nrsf Regulates Zebrafish Behavior through snap25a/b

During embryonic development, regulation of gene expression is key to creating the many subtypes of cells that an organism needs throughout its lifetime. Recent work has shown that maternal genetics and environmental factors have lifelong consequences on diverse processes ranging from immune function to stress responses. The RE1-silencing transcription factor (Rest) is a transcriptional repressor that interacts with chromatin-modifying complexes to repress transcription of neural specific genes during early development. Here we show that in zebrafish, maternally supplied rest regulates expression of target genes during larval development and has lifelong impacts on behavior. Larvae deprived of maternal rest are hyperactive and show atypical spatial preferences. Adult male fish deprived of maternal rest present with atypical spatial preferences in a novel environment assay. Transcriptome sequencing revealed 158 genes that are repressed by maternal rest in blastula stage embryos. Furthermore, we found that maternal rest is required for target gene repression until at least 6 dpf. Importantly, disruption of the RE1 sites in either snap25a or snap25b resulted in behaviors that recapitulate the hyperactivity phenotype caused by absence of maternal rest. Both maternal rest mutants and snap25a RE1 site mutants have altered primary motor neuron architecture that may account for the enhanced locomotor activity. These results demonstrate that maternal rest represses snap25a/b to modulate larval behavior and that early Rest activity has lifelong behavioral impacts

Alzheimer’s disease: the potential of epigenetic treatments and current clinical candidates

Alzheimer’s disease is a progressive and fatal neurodegenerative disease affecting 50 million people worldwide, characterized by memory loss and neuronal degeneration. Current treatments have limited efficacy and there is no cure. Alzheimer's is likely caused by a combination of factors, providing several potential therapeutic targets. One area of interest is the epigenetic regulation of gene expression within the brain. Epigenetic marks, including DNA methylation and histone modifications, show consistent changes with age and in those with Alzheimer’s. Some epigenetic regulation has been linked to disease pathology and progression and are the focus of current research. Epigenetic regulators might make promising therapeutic targets yet challenges need to be overcome to generate an efficacious drug lacking deleterious side effects

The functions of repressor element 1-silencing transcription factor in models of epileptogenesis and post-ischemia

Epilepsy is a debilitating neurological disorder characterised by recurrent seizures for which 30% of patients are refractory to current treatments. The genetic and molecular aetiologies behind epilepsy are under investigation with the goal of developing new epilepsy medications. The transcriptional repressor REST (Repressor Element 1-Silencing Transcription factor) is a focus of interest as it is consistently upregulated in epilepsy patients and following brain insult in animal models of epilepsy and ischemia. This review analyses data from different epilepsy models and discusses the contribution of REST to epileptogenesis. We propose that in healthy brains REST acts in a protective manner to homeostatically downregulate increases in excitability, to protect against seizure through downregulation of BDNF (Brain-Derived Neurotrophic Factor) and its receptor, TrkB (Tropomyosin receptor kinase B). However, in epilepsy patients and post-seizure, REST may increase to a larger degree, which allows downregulation of the glutamate receptor subunit GluR2. This leads to AMPA glutamate receptors lacking GluR2 subunits, which have increased permeability to Ca2+, causing excitotoxicity, cell death and seizure. This concept highlights therapeutic potential of REST modulation through gene therapy in epilepsy patients

Mapping the methylation status of the miR-145 promoter in saphenous vein smooth muscle cells from individuals with type 2 diabetes

Type 2 diabetes mellitus prevalence is growing globally, and the leading cause of mortality in these patients is cardiovascular disease. Epigenetic mechanisms such as microRNAs (miRs) and DNA methylation may contribute to complications of type 2 diabetes mellitus. We discovered an aberrant type 2 diabetes mellitus–smooth muscle cell phenotype driven by persistent up-regulation of miR-145. This study aimed to determine whether elevated expression was due to changes in methylation at the miR-145 promoter. Smooth muscle cells were cultured from saphenous veins of 22 non-diabetic and 22 type 2 diabetes mellitus donors. DNA was extracted, bisulphite treated and pyrosequencing used to interrogate methylation at 11 CpG sites within the miR-145 promoter. Inter-patient variation was high irrespective of type 2 diabetes mellitus. Differential methylation trends were apparent between non-diabetic and type 2 diabetes mellitus–smooth muscle cells at most sites but were not statistically significant. Methylation at CpGs −112 and −106 was consistently lower than all other sites explored in non-diabetic and type 2 diabetes mellitus–smooth muscle cells. Finally, miR-145 expression per se was not correlated with methylation levels observed at any site. The persistent up-regulation of miR-145 observed in type 2 diabetes mellitus–smooth muscle cells is not related to methylation at the miR-145 promoter. Crucially, miR-145 methylation is highly variable between patients, serving as a cautionary note for future studies of this region in primary human cell types

Inhibition of ionotropic GluR signaling preserves oligodendrocyte lineage and myelination in an ex vivo rat model of white matter ischemic injury

Preterm infants have a high risk of neonatal white matter injury (WMI). WMI leads to reduced myelination, inflammation, and clinical neurodevelopmental deficits for which there are no effective treatments. Ionotropic glutamate receptor (iGluR) induced excitotoxicity contributes to oligodendrocyte (OL) lineage cell loss and demyelination in brain models of neonatal and adult WMI. Here, we hypothesized that simulated ischemia (oxygen–glucose deprivation) damages white matter via activation of iGluR signaling, and that iGluR inhibition shortly after WMI could mitigate OL loss, enhance myelination, and suppress inflammation in an ex vivo cerebellar slice model of developing WMI. Inhibition of iGluR signaling by a combined block of AMPA and NMDA receptors, shortly after simulated ischemia, restored myelination, reduced apoptotic OLs, and enhanced OL precursor cell proliferation and maturation as well as upregulated expression of transcription factors regulating OL development and remyelination. Our findings demonstrate that iGluR inhibition post–injury alleviates OL lineage cell loss and inflammation and promotes myelination upon developing WMI. The findings may help to develop therapeutic interventions for the WMI treatment

Assessment at UK medical schools varies substantially in volume, type and intensity and correlates with postgraduate attainment

BACKGROUND: In the United Kingdom (UK), medical schools are free to develop local systems and policies that govern student assessment and progression. Successful completion of an undergraduate medical degree results in the automatic award of a provisional licence to practice medicine by the General Medical Council (GMC). Such a licensing process relies heavily on the assumption that individual schools develop similarly rigorous assessment policies. Little work has evaluated variability of undergraduate medical assessment between medical schools. That absence is important in the light of the GMC's recent announcement of the introduction of the UKMLA (UK Medical Licensing Assessment) for all doctors who wish to practise in the UK. The present study aimed to quantify and compare the volume, type and intensity of summative assessment across medicine (A100) courses in the United Kingdom, and to assess whether intensity of assessment correlates with the postgraduate attainment of doctors from these schools. METHODS: Locally knowledgeable students in each school were approached to take part in guided-questionnaire interviews via telephone or Skype(TM). Their understanding of assessment at their medical school was probed, and later validated with the assessment department of the respective medical school. We gathered data for 25 of 27 A100 programmes in the UK and compared volume, type and intensity of assessment between schools. We then correlated these data with the mean first-attempt score of graduates sitting MRCGP and MRCP(UK), as well as with UKFPO selection measures. RESULTS: The median written assessment volume across all schools was 2000 min (mean = 2027, SD = 586, LQ = 1500, UQ = 2500, range = 1000-3200) and 1400 marks (mean = 1555, SD = 463, LQ = 1200, UQ = 1800, range = 1100-2800). The median practical assessment volume was 400 min (mean = 472, SD = 207, LQ = 400, UQ = 600, range = 200-1000). The median intensity (minutes per mark ratio) of summative written assessment was 1.24 min per mark (mean = 1.28, SD = 0.30, LQ = 1.11, UQ = 1.37, range = 0.85-2.08). An exploratory analysis suggested a significant correlation of total assessment time with mean first-attempt score on both the knowledge and the clinical assessments of MRCGP and of MRCP(UK). CONCLUSIONS: There are substantial differences in the volume, format and intensity of undergraduate assessment between UK medical schools. These findings suggest a potential for differences in the reliability of detecting poorly performing students, or differences in identifying and stratifying academically equivalent students for ranking in the Foundation Programme Application System (FPAS). Furthermore, these differences appear to directly correlate with performance in postgraduate examinations. Taken together, our findings highlight highly variable local assessment procedures that warrant further investigation to establish their potential impact on students