E2F4 actively promotes the initiation and maintenance of nerve growth factor-induced cell differentiation

E2F transcription factors play a critical role in cell cycle progression through the regulation of genes required for G(1)/S transition. They are also thought to be important for growth arrest; however, their potential role in the cell differentiation process has not been previously examined. Here, we demonstrate that E2F4 is highly upregulated following the neuronal differentiation of PC12 cells with nerve growth factor (NGF), while E2F1, E2F3, and E2F5 are downregulated. Immunoprecipitation and subcellular fractionation studies demonstrated that both the nuclear localization of E2F4 and its association with the Rb family member p130 increased following neuronal differentiation. The forced expression of E2F4 markedly enhanced the rate of PC12 cell differentiation induced by NGF and also greatly lowered the rate at which cells lost their neuronal phenotype following NGF removal. Importantly, this effect occurred in the absence of any significant change in the growth regulation of PC12 cells by NGF. Further, the downregulation of E2F4 expression with antisense oligodeoxynucleotides inhibited NGF-induced neurite outgrowth, indicating an important role for this factor during PC12 cell differentiation. Finally, E2F4 expression was found to increase dramatically in the developing rat cerebral cortex and cerebellum, as neuroblasts became postmitotic and initiated terminal differentiation. These findings demonstrate that, in addition to its effects on cell proliferation, E2F4 actively promotes the neuronal differentiation of PC12 cells as well as the retention of this state. Further, this effect is independent of alterations in cell growth and may involve interactions between E2F4 and the neuronal differentiation program itself. E2F4 may be an important participant in the terminal differentiation of neuroblasts

The Impact of MicroRNAs on Brain Aging and Neurodegeneration

The molecular instructions that govern gene expression regulation are encoded in the genome and ultimately determine the morphology and functional specifications of the human brain. As a consequence, changes in gene expression levels might be directly related to the functional decline associated with brain aging. Small noncoding RNAs, including miRNAs, comprise a group of regulatory molecules that modulate the expression of hundred of genes which play important roles in brain metabolism. Recent comparative studies in humans and nonhuman primates revealed that miRNAs regulate multiple pathways and interconnected signaling cascades that are the basis for the cognitive decline and neurodegenerative disorders during aging. Identifying the roles of miRNAs and their target genes in model organisms combined with system-level studies of the brain would provide more comprehensive understanding of the molecular basis of brain deterioration during the aging process

A High Density of Human Communication-Associated Genes in Chromosome 7q31-q36: Differential Expression in Human and Non-Human Primate Cortices

The human brain is distinguished by its remarkable size, high energy consumption, and cognitive abilities compared to all other mammals and non-human primates. However, little is known about what has accelerated brain evolution in the human lineage. One possible explanation is that the appearance of advanced communication skills and language has been a driving force of human brain development. The phenotypic adaptations in brain structure and function which occurred on the way to modern humans may be associated with specific molecular signatures in today’s human genome and/or transcriptome. Genes that have been linked to language, reading, and/or autism spectrum disorders are prime candidates when searching for genes for human-specific communication abilities. The database and genome-wide expression analyses we present here revealed a clustering of such communication-associated genes (COAG) on human chromosomes X and 7, in particular chromosome 7q31-q36. Compared to the rest of the genome, we found a high number of COAG to be differentially expressed in the cortices of humans and non-human primates (chimpanzee, baboon, and/or marmoset). The role of X-linked genes for the development of human-specific cognitive abilities is well known. We now propose that chromosome 7q31-q36 also represents a hot spot for the evolution of human-specific communication abilities. Selective pressure on the T cell receptor beta locus on chromosome 7q34, which plays a pivotal role in the immune system, could have led to rapid dissemination of positive gene variants in hitchhiking COAG

Methylation and Expression Analyses of the 7q Autism Susceptibility Locus Genes MEST, COPG2, and TSGA14 in Human and Anthropoid Primate Cortices

The autism susceptibility locus on human chromosome 7q32 contains the maternally imprinted MEST and the non-imprinted COPG2 and TSGA14 genes. Autism is a disorder of the ‘social brain’ that has been proposed to be due to an overbalance of paternally expressed genes. To study regulation of the 7q32 locus during anthropoid primate evolution, we analyzed the methylation and expression patterns of MEST, COPG2, and TSGA14 in human, chimpanzee, Old World monkey (baboon and rhesus macaque), and New World monkey (marmoset) cortices. In all human and anthropoid primate cortices, the MEST promoter was hemimethylated, as expected for a differentially methylated imprinting control region, whereas the COPG2 and TSGA14 promoters were completely demethylated, typical for transcriptionally active non-imprinted genes. The MEST gene also showed comparable mRNA expression levels in all analyzed species. In contrast, COPG2 expression was downregulated in the human cortex compared to chimpanzee, Old and New World monkeys. TSGA14 either showed no differential regulation in the human brain compared to chimpanzee and marmoset or a slight upregulation compared to baboon. The human-specific downregulation supports a role for COPG2 in the development of a ‘social brain’. Promoter methylation patterns appear to be more stable during evolution than gene expression patterns, suggesting that other mechanisms may be more important for inter-primate differences in gene expression

East Midlands Research into Ageing Network (EMRAN) Discussion Paper Series

Academic geriatric medicine in Leicester . There has never been a better time to consider joining us. We have recently appointed a Professor in Geriatric Medicine, alongside Tom Robinson in stroke and Victoria Haunton, who has just joined as a Senior Lecturer in Geriatric Medicine. We have fantastic opportunities to support students in their academic pursuits through a well-established intercalated BSc programme, and routes on through such as ACF posts, and a successful track-record in delivering higher degrees leading to ACL post. We collaborate strongly with Health Sciences, including academic primary care. See below for more detail on our existing academic set-up. Leicester Academy for the Study of Ageing We are also collaborating on a grander scale, through a joint academic venture focusing on ageing, the ‘Leicester Academy for the Study of Ageing’ (LASA), which involves the local health service providers (acute and community), De Montfort University; University of Leicester; Leicester City Council; Leicestershire County Council and Leicester Age UK. Professors Jayne Brown and Simon Conroy jointly Chair LASA and have recently been joined by two further Chairs, Professors Kay de Vries and Bertha Ochieng. Karen Harrison Dening has also recently been appointed an Honorary Chair. LASA aims to improve outcomes for older people and those that care for them that takes a person-centred, whole system perspective. Our research will take a global perspective, but will seek to maximise benefits for the people of Leicester, Leicestershire and Rutland, including building capacity. We are undertaking applied, translational, interdisciplinary research, focused on older people, which will deliver research outcomes that address domains from: physical/medical; functional ability, cognitive/psychological; social or environmental factors. LASA also seeks to support commissioners and providers alike for advice on how to improve care for older people, whether by research, education or service delivery. Examples of recent research projects include: ‘Local History Café’ project specifically undertaking an evaluation on loneliness and social isolation; ‘Better Visits’ project focused on improving visiting for family members of people with dementia resident in care homes; and a study on health issues for older LGBT people in Leicester. Clinical Geriatric Medicine in Leicester We have developed a service which recognises the complexity of managing frail older people at the interface (acute care, emergency care and links with community services). There are presently 17 consultant geriatricians supported by existing multidisciplinary teams, including the largest complement of Advance Nurse Practitioners in the country. Together we deliver Comprehensive Geriatric Assessment to frail older people with urgent care needs in acute and community settings. The acute and emergency frailty units – Leicester Royal Infirmary This development aims at delivering Comprehensive Geriatric Assessment to frail older people in the acute setting. Patients are screened for frailty in the Emergency Department and then undergo a multidisciplinary assessment including a consultant geriatrician, before being triaged to the most appropriate setting. This might include admission to in-patient care in the acute or community setting, intermediate care (residential or home based), or occasionally other specialist care (e.g. cardiorespiratory). Our new emergency department is the county’s first frail friendly build and includes fantastic facilities aimed at promoting early recovering and reducing the risk of hospital associated harms. There is also a daily liaison service jointly run with the psychogeriatricians (FOPAL); we have been examining geriatric outreach to oncology and surgery as part of an NIHR funded study. We are home to the Acute Frailty Network, and those interested in service developments at the national scale would be welcome to get involved. Orthogeriatrics There are now dedicated hip fracture wards and joint care with anaesthetists, orthopaedic surgeons and geriatricians. There are also consultants in metabolic bone disease that run clinics. Community work Community work will consist of reviewing patients in clinic who have been triaged to return to the community setting following an acute assessment described above. Additionally, primary care colleagues refer to outpatients for sub-acute reviews. You will work closely with local GPs with support from consultants to deliver post-acute, subacute, intermediate and rehabilitation care services. Stroke Medicine 24/7 thrombolysis and TIA services. The latter is considered one of the best in the UK and along with the high standard of vascular surgery locally means one of the best performances regarding carotid intervention

Human Oocyte-derived Methylation Differences Persist In The Placenta Revealing Widespread Transient Imprinting

Thousands of regions in gametes have opposing methylation profiles that are largely resolved during the post-fertilization epigenetic reprogramming. However some specific sequences associated with imprinted loci survive this demethylation process. Here we present the data describing the fate of germline-derived methylation in humans. With the exception of a few known paternally methylated germline differentially methylated regions (DMRs) associated with known imprinted domains, we demonstrate that sperm-derived methylation is reprogrammed by the blastocyst stage of development. In contrast a large number of oocyte-derived methylation differences survive to the blastocyst stage and uniquely persist as transiently methylated DMRs only in the placenta. Furthermore, we demonstrate that this phenomenon is exclusive to primates, since no placenta-specific maternal methylation was observed in mouse. Utilizing single cell RNA-seq datasets from human preimplantation embryos we show that following embryonic genome activation the maternally methylated transient DMRs can orchestrate imprinted expression. However despite showing widespread imprinted expression of genes in placenta, allele-specific transcriptional profiling revealed that not all placenta-specific DMRs coordinate imprinted expression and that this maternal methylation may be absent in a minority of samples, suggestive of polymorphic imprinted methylation

Hominin-specific regulatory elements selectively emerged in oligodendrocytes and are disrupted in autism patients

Speciation is associated with substantial rewiring of the regulatory circuitry underlying the expression of genes. Determining which changes are relevant and underlie the emergence of the human brain or its unique susceptibility to neural disease has been challenging. Here we annotate changes to gene regulatory elements (GREs) at cell type resolution in the brains of multiple primate species spanning most of primate evolution. We identify a unique set of regulatory elements that emerged in hominins prior to the separation of humans and chimpanzees. We demonstrate that these hominin gains perferentially affect oligodendrocyte function postnatally and are preferentially affected in the brains of autism patients. This preference is also observed for human-specific GREs suggesting this system is under continued selective pressure. Our data provide a roadmap of regulatory rewiring across primate evolution providing insight into the genomic changes that underlie the emergence of the brain and its susceptibility to neural disease

Variable BCG efficacy in rhesus populations: Pulmonary BCG provides protection where standard intra-dermal vaccination fails

Pathogenesis and treatment of chronic pulmonary disease

Simian Immunodeficiency Virus Infection of Chimpanzees (Pan troglodytes) Shares Features of Both Pathogenic and Non-pathogenic Lentiviral Infections.

The virus-host relationship in simian immunodeficiency virus (SIV) infected chimpanzees is thought to be different from that found in other SIV infected African primates. However, studies of captive SIVcpz infected chimpanzees are limited. Previously, the natural SIVcpz infection of one chimpanzee, and the experimental infection of six chimpanzees was reported, with limited follow-up. Here, we present a long-term study of these seven animals, with a retrospective re-examination of the early stages of infection. The only clinical signs consistent with AIDS or AIDS associated disease was thrombocytopenia in two cases, associated with the development of anti-platelet antibodies. However, compared to uninfected and HIV-1 infected animals, SIVcpz infected animals had significantly lower levels of peripheral blood CD4+ T-cells. Despite this, levels of T-cell activation in chronic infection were not significantly elevated. In addition, while plasma levels of β2 microglobulin, neopterin and soluble TNF-related apoptosis inducing ligand (sTRAIL) were elevated in acute infection, these markers returned to near-normal levels in chronic infection, reminiscent of immune activation patterns in 'natural host' species. Furthermore, plasma soluble CD14 was not elevated in chronic infection. However, examination of the secondary lymphoid environment revealed persistent changes to the lymphoid structure, including follicular hyperplasia in SIVcpz infected animals. In addition, both SIV and HIV-1 infected chimpanzees showed increased levels of deposition of collagen and increased levels of Mx1 expression in the T-cell zones of the lymph node. The outcome of SIVcpz infection of captive chimpanzees therefore shares features of both non-pathogenic and pathogenic lentivirus infections.This work was supported by the Biotechnology and Biological Sciences Research Council and by the Wellcome Trust.This is the final version of the article. It first appeared from PLOS via http://dx.doi.org/10.1371/journal.ppat.100514