Life Sciences Research for Lifelong Health


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Title / Authors / Details Open Access Download

A novel phosphate-starvation response in fission yeast requires the endocytic function of Myosin I.
Petrini E, Baillet V, Cridge J, Hogan CJ, Guillaume C, Ke H, Brandetti E, Walker S, Koohy H, Spivakov M, Varga-Weisz P

Endocytosis is essential for uptake of many substances into the cell, but how it links to nutritional signalling is poorly understood. Here we show a novel role for endocytosis in regulating the response to low phosphate in Schizosaccharomyces pombe. Loss of function of Myo1, Sla2/End4 or Arp2, proteins involved in the early steps of endocytosis, led to increased proliferation in low phosphate media compared to controls. We show that once cells are deprived of phosphate they undergo a quiescence response that is dependent on the endocytic function of Myo1. Transcriptomic analysis revealed a wide perturbation of gene expression with induction of stress-regulated genes upon phosphate starvation in wildtype but not Δmyo1 cells. Thus, endocytosis plays a pivotal role in mediating the cellular response to nutrients, bridging the external environment and internal molecular functions of the cell.

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Journal of cell science, , 1477-9137, , 2015

PMID: 26345368

Open Access

Cell cycle progression is an essential regulatory component of phospholipid metabolism and membrane homeostasis.
Sanchez-Alvarez M, Zhang Q, Finger F, Wakelam MJ, Bakal C

We show that phospholipid anabolism does not occur uniformly during the metazoan cell cycle. Transition to S-phase is required for optimal mobilization of lipid precursors, synthesis of specific phospholipid species and endoplasmic reticulum (ER) homeostasis. Average changes observed in whole-cell phospholipid composition, and total ER lipid content, upon stimulation of cell growth can be explained by the cell cycle distribution of the population. TORC1 promotes phospholipid anabolism by slowing S/G2 progression. The cell cycle stage-specific nature of lipid biogenesis is dependent on p53. We propose that coupling lipid metabolism to cell cycle progression is a means by which cells have evolved to coordinate proliferation with cell and organelle growth.

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Open biology, 5, 2046-2441, , 2015

PMID: 26333836

Open Access

Polycomb repressive complex PRC1 spatially constrains the mouse embryonic stem cell genome.
Schoenfelder S, Sugar R, Dimond A, Javierre BM, Armstrong H, Mifsud B, Dimitrova E, Matheson L, Tavares-Cadete F, Furlan-Magaril M, Segonds-Pichon A, Jurkowski W, Wingett SW, Tabbada K, Andrews S, Herman B, LeProust E, Osborne CS, Koseki H, Fraser P, Luscombe NM, Elderkin S

The Polycomb repressive complexes PRC1 and PRC2 maintain embryonic stem cell (ESC) pluripotency by silencing lineage-specifying developmental regulator genes. Emerging evidence suggests that Polycomb complexes act through controlling spatial genome organization. We show that PRC1 functions as a master regulator of mouse ESC genome architecture by organizing genes in three-dimensional interaction networks. The strongest spatial network is composed of the four Hox gene clusters and early developmental transcription factor genes, the majority of which contact poised enhancers. Removal of Polycomb repression leads to disruption of promoter-promoter contacts in the Hox gene network. In contrast, promoter-enhancer contacts are maintained in the absence of Polycomb repression, with accompanying widespread acquisition of active chromatin signatures at network enhancers and pronounced transcriptional upregulation of network genes. Thus, PRC1 physically constrains developmental transcription factor genes and their enhancers in a silenced but poised spatial network. We propose that the selective release of genes from this spatial network underlies cell fate specification during early embryonic development.

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Nature genetics, , 1546-1718, , 2015

PMID: 26323060

Open Access

Editorial: Lipid Signaling in T Cell Development and Function.
Sauer K, Okkenhaug K

Frontiers in immunology, 6, 1664-3224, 410, 2015

PMID: 26322043

Open Access

Three Dimensional Organization of the Nucleus: adding DNA sequences to the big picture.
Gilbert DM, Fraser P

Genome biology, 16, 1474-760X, 181, 2015

PMID: 26319739

Open Access

Phosphoinositide 3-kinase-related overgrowth: cellular phenotype and future therapeutic options.
Parker VE, Knox RG, Zhang Q, Wakelam MJ, Semple RK

Somatic activating mutations in PIK3CA, which encodes the p110α catalytic subunit of phosphoinositide-3-kinase (PI3K) are frequently found in cancers and have been identified in a spectrum of mosaic overgrowth disorders ranging from isolated digit enlargement to more extensive overgrowth of the body, brain, or vasculature. We aimed to study affected dermal fibroblasts with a view to inform therapeutic studies, and to observe cancer-associated mutations in isolation.

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Lancet (London, England), 385 Suppl 1, 1474-547X, S77, 2015

PMID: 26312899

PI3Kδ Regulates the Magnitude of CD8+ T Cell Responses after Challenge with Listeria monocytogenes.
Pearce VQ, Bouabe H, MacQueen AR, Carbonaro V, Okkenhaug K

PI3Ks regulate diverse immune cell functions by transmitting intracellular signals from Ag, costimulatory receptors, and cytokine receptors to control cell division, differentiation, survival, and migration. In this study, we report the effect of inhibiting the p110δ subunit of PI3Kδ on CD8(+) T cell responses to infection with the intracellular bacteria Listeria monocytogenes. A strong dependency on PI3Kδ for IFN-γ production by CD8(+) T cells in vitro was not recapitulated after Listeria infection in vivo. Inactivation of PI3Kδ resulted in enhanced bacterial elimination by the innate immune system. However, the magnitudes of the primary and secondary CD8 +: T cell responses were reduced. Moreover, PI3Kδ activity was required for CD8(+) T cells to provide help to other responding CD8(+) cells. These findings identify PI3Kδ as a key regulator of CD8(+) T cell responses that integrates extrinsic cues, including those from other responding cells, to determine the collective behavior of CD8(+) T cell populations responding to infection.

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Journal of immunology (Baltimore, Md. : 1950), , 1550-6606, , 2015

PMID: 26311905

Open Access

Comparison of Hi-C results using in-solution versus in-nucleus ligation.
Nagano T, Várnai C, Schoenfelder S, Javierre BM, Wingett SW, Fraser P

Chromosome conformation capture and various derivative methods such as 4C, 5C and Hi-C have emerged as standard tools to analyze the three-dimensional organization of the genome in the nucleus. These methods employ ligation of diluted cross-linked chromatin complexes, intended to favor proximity-dependent, intra-complex ligation. During development of single-cell Hi-C, we devised an alternative Hi-C protocol with ligation in preserved nuclei rather than in solution. Here we directly compare Hi-C methods employing in-nucleus ligation with the standard in-solution ligation.

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Genome biology, 16, 1474-760X, 175, 2015

PMID: 26306623

Open Access

Phosphatidylinositolphosphate Phosphatase Activities and Cancer.
Rudge SA, Wakelam MJ

Signalling through the PI3kinases pathways mediates the actions of a plethora of hormones, growth factors, cytokines and neurotransmitters upon their target cells following receptor occupation. Over-activation of these pathways has been implicated in a number of pathologies in particular a range of malignancies. The tight regulation of signalling pathways necessitates the involvement of both stimulatory a terminating enzymes, inappropriate activation of a pathway can thus result from activation or inhibition of the two signalling arms. A range of enzymes have been identified that catalyse the hydrolysis of phosphoinositides, this review outlines these and highlights those that have been implicated in promoting malignancy.

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Journal of lipid research, , 0022-2275, , 2015

PMID: 26302980

Cowden's syndrome with immunodeficiency.
Browning MJ, Chandra A, Carbonaro V, Okkenhaug K, Barwell J

Cowden's syndrome is a rare, autosomal dominant disease caused by mutations in the phosphoinositide 3-kinase and phosphatase and tensin homolog (PTEN) gene. It is associated with hamartomatous polyposis of the gastrointestinal tract, mucocutaneous lesions and increased risk of developing certain types of cancer. In addition to increased risk of tumour development, mutations in PTEN have also been associated with autoimmunity in both mice and humans. Until now, however, an association between Cowden's syndrome and immune deficiency has been reported in a single patient only.

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Journal of medical genetics, 52, 1468-6244, 856-9, 2015

PMID: 26246517

Open Access

Fgf and Esrrb integrate epigenetic and transcriptional networks that regulate self-renewal of trophoblast stem cells.
Latos PA, Goncalves A, Oxley D, Mohammed H, Turro E, Hemberger M

Esrrb (oestrogen-related receptor beta) is a transcription factor implicated in embryonic stem (ES) cell self-renewal, yet its knockout causes intrauterine lethality due to defects in trophoblast development. Here we show that in trophoblast stem (TS) cells, Esrrb is a downstream target of fibroblast growth factor (Fgf) signalling and is critical to drive TS cell self-renewal. In contrast to its occupancy of pluripotency-associated loci in ES cells, Esrrb sustains the stemness of TS cells by direct binding and regulation of TS cell-specific transcription factors including Elf5 and Eomes. To elucidate the mechanisms whereby Esrrb controls the expression of its targets, we characterized its TS cell-specific interactome using mass spectrometry. Unlike in ES cells, Esrrb interacts in TS cells with the histone demethylase Lsd1 and with the RNA Polymerase II-associated Integrator complex. Our findings provide new insights into both the general and context-dependent wiring of transcription factor networks in stem cells by master transcription factors.

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Nature communications, 6, 2041-1723, 7776, 2015

PMID: 26206133

Open Access

Chromatin organization in pluripotent cells: emerging approaches to study and disrupt function.
Lopes Novo C, Rugg-Gunn PJ

Translating the vast amounts of genomic and epigenomic information accumulated on the linear genome into three-dimensional models of nuclear organization is a current major challenge. In response to this challenge, recent technological innovations based on chromosome conformation capture methods in combination with increasingly powerful functional approaches have revealed exciting insights into key aspects of genome regulation. These findings have led to an emerging model where the genome is folded and compartmentalized into highly conserved topological domains that are further divided into functional subdomains containing physical loops that bring cis-regulatory elements to close proximity. Targeted functional experiments, largely based on designable DNA-binding proteins, have begun to define the major architectural proteins required to establish and maintain appropriate genome regulation. Here, we focus on the accessible and well-characterized system of pluripotent cells to review the functional role of chromatin organization in regulating pluripotency, differentiation and reprogramming.

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Briefings in functional genomics, , 2041-2657, , 2015

PMID: 26206085

Open Access

Regulation of ribosomal DNA amplification by the TOR pathway.
Jack CV, Cruz C, Hull RM, Keller MA, Ralser M, Houseley J

Repeated regions are widespread in eukaryotic genomes, and key functional elements such as the ribosomal DNA tend to be formed of high copy repeated sequences organized in tandem arrays. In general, high copy repeats are remarkably stable, but a number of organisms display rapid ribosomal DNA amplification at specific times or under specific conditions. Here we demonstrate that target of rapamycin (TOR) signaling stimulates ribosomal DNA amplification in budding yeast, linking external nutrient availability to ribosomal DNA copy number. We show that ribosomal DNA amplification is regulated by three histone deacetylases: Sir2, Hst3, and Hst4. These enzymes control homologous recombination-dependent and nonhomologous recombination-dependent amplification pathways that act in concert to mediate rapid, directional ribosomal DNA copy number change. Amplification is completely repressed by rapamycin, an inhibitor of the nutrient-responsive TOR pathway; this effect is separable from growth rate and is mediated directly through Sir2, Hst3, and Hst4. Caloric restriction is known to up-regulate expression of nicotinamidase Pnc1, an enzyme that enhances Sir2, Hst3, and Hst4 activity. In contrast, normal glucose concentrations stretch the ribosome synthesis capacity of cells with low ribosomal DNA copy number, and we find that these cells show a previously unrecognized transcriptional response to caloric excess by reducing PNC1 expression. PNC1 down-regulation forms a key element in the control of ribosomal DNA amplification as overexpression of PNC1 substantially reduces ribosomal DNA amplification rate. Our results reveal how a signaling pathway can orchestrate specific genome changes and demonstrate that the copy number of repetitive DNA can be altered to suit environmental conditions.

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Proceedings of the National Academy of Sciences of the United States of America, 112, 1091-6490, 9674-9, 2015

PMID: 26195783

Open Access

Inflammation-induced formation of fat-associated lymphoid clusters.
Bénézech C, Luu NT, Walker JA, Kruglov AA, Loo Y, Nakamura K, Zhang Y, Nayar S, Jones LH, Flores-Langarica A, McIntosh A, Marshall J, Barone F, Besra G, Miles K, Allen JE, Gray M, Kollias G, Cunningham AF, Withers DR, Toellner KM, Jones ND, Veldhoen M, Nedospasov SA, McKenzie AN, Caamaño JH

Fat-associated lymphoid clusters (FALCs) are a type of lymphoid tissue associated with visceral fat. Here we found that the distribution of FALCs was heterogeneous, with the pericardium containing large numbers of these clusters. FALCs contributed to the retention of B-1 cells in the peritoneal cavity through high expression of the chemokine CXCL13, and they supported B cell proliferation and germinal center differentiation during peritoneal immunological challenges. FALC formation was induced by inflammation, which triggered the recruitment of myeloid cells that expressed tumor-necrosis factor (TNF) necessary for signaling via the TNF receptors in stromal cells. Natural killer T cells (NKT cells) restricted by the antigen-presenting molecule CD1d were likewise required for the inducible formation of FALCs. Thus, FALCs supported and coordinated the activation of innate B cells and T cells during serosal immune responses.

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Nature immunology, , 1529-2916, , 2015

PMID: 26147686

DYRK1A-mediated Cyclin D1 Degradation in Neural Stem Cells Contributes to the Neurogenic Cortical Defects in Down Syndrome.
Najas S, Arranz J, Lochhead PA, Ashford AL, Oxley D, Delabar JM, Cook SJ, Barallobre MJ, Arbonés ML

Alterations in cerebral cortex connectivity lead to intellectual disability and in Down syndrome, this is associated with a deficit in cortical neurons that arises during prenatal development. However, the pathogenic mechanisms that cause this deficit have not yet been defined. Here we show that the human DYRK1A kinase on chromosome 21 tightly regulates the nuclear levels of Cyclin D1 in embryonic cortical stem (radial glia) cells, and that a modest increase in DYRK1A protein in transgenic embryos lengthens the G1 phase in these progenitors. These alterations promote asymmetric proliferative divisions at the expense of neurogenic divisions, producing a deficit in cortical projection neurons that persists in postnatal stages. Moreover, radial glial progenitors in the Ts65Dn mouse model of Down syndrome have less Cyclin D1, and Dyrk1a is the triplicated gene that causes both early cortical neurogenic defects and decreased nuclear Cyclin D1 levels in this model. These data provide insights into the mechanisms that couple cell cycle regulation and neuron production in cortical neural stem cells, emphasizing that the deleterious effect of DYRK1A triplication in the formation of the cerebral cortex begins at the onset of neurogenesis, which is relevant to the search for early therapeutic interventions in Down syndrome.

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EBioMedicine, 2, 2352-3964, 120-34, 2015

PMID: 26137553

Open Access

Influence of nutrient-derived metabolites on lymphocyte immunity.
Veldhoen M, Ferreira C

Organisms need to protect themselves against potential dangers from their surroundings, yet they require constant and intimate interactions with the same environment for their survival. The immune system is instrumental for protection against invading organisms and their toxins. The immune system consists of many cell types and is highly integrated within other tissues. Immune activity is particularly enriched at surfaces that separate the host from its environment, such as the skin and the gastrointestinal tract. This enables protection at sites directly at risk but also enables environmental factors to influence the maturation and function of immune structures and cells. Recent work has indicated that the diet in particular is able to influence the immune system and thus affect the development of inflammatory disease. This review aims to highlight recent work on how external factors, with a focus on those derived from the diet such as vitamin A, can have a direct or indirect deterministic influence on the activity and function of immunity.

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Nature medicine, , 1546-170X, , 2015

PMID: 26121194

The dynamics of Rho GTPase signaling and implications for targeting cancer and the tumor microenvironment.
Pajic M, Herrmann D, Vennin C, Conway JR, Chin VT, Johnsson AE, Welch HC, Timpson P

Numerous large scale genomics studies have demonstrated that cancer is a molecularly heterogeneous disease, characterized by acquired changes in the structure and DNA sequence of tumor genomes. More recently, the role of the equally complex tumor microenvironment in driving the aggressiveness of this disease is increasingly being realized. Tumor cells are surrounded by activated stroma, creating a dynamic environment that promotes cancer development, metastasis and chemoresistance. The Rho family of small GTPases plays an essential role in the regulation of cell shape, cytokinesis, cell adhesion, and cell motility. Importantly, these processes need to be considered in the context of a complex 3-dimensional (3D) environment, with reciprocal feedback and cross-talk taking place between the tumor cells and host environment. Here we discuss the role of molecular networks involving Rho GTPases in cancer, and the therapeutic implications of inhibiting Rho signaling in both cancer cells and the emerging concept of targeting the surrounding stroma.

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Small GTPases, , 2154-1256, 1-11, 2015

PMID: 26103062

Open Access

5-Formylcytosine can be a stable DNA modification in mammals.
Bachman M, Uribe-Lewis S, Yang X, Burgess HE, Iurlaro M, Reik W, Murrell A, Balasubramanian S

5-Formylcytosine (5fC) is a rare base found in mammalian DNA and thought to be involved in active DNA demethylation. Here, we show that developmental dynamics of 5fC levels in mouse DNA differ from those of 5-hydroxymethylcytosine (5hmC), and using stable isotope labeling in vivo, we show that 5fC can be a stable DNA modification. These results suggest that 5fC has functional roles in DNA that go beyond being a demethylation intermediate.

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Nature chemical biology, 11, 1552-4469, 555-7, 2015

PMID: 26098680

PI3K inhibitors in inflammation, autoimmunity and cancer.
Stark AK, Sriskantharajah S, Hessel EM, Okkenhaug K

The healthy immune system protects against infection and malignant transformation without causing significant damage to host tissues. Immune dysregulation results in diverse pathologies including autoimmune disease, chronic inflammatory disorders, allergies as well as immune deficiencies and cancer. Phosphoinositide 3-kinase (PI3K) signalling has been shown to be a key pathway in the regulation of the immune response and continues to be the focus of intense research. In recent years we have gained detailed understanding of PI3K signalling, and saw the development of potent and highly selective small molecule inhibitors, of which several are currently in clinical trials for the treatment of immune-related disorders and cancer. The role of PI3K signalling in the immune response has been the subject of detailed reviews; here we focus on relevant recent progress in pre-clinical and clinical development of PI3K inhibitors.

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Current opinion in pharmacology, 23, 1471-4973, 82-91, 2015

PMID: 26093105

Open Access

JSBML 1.0: providing a smorgasbord of options to encode systems biology models.
Rodriguez N, Thomas A, Watanabe L, Vazirabad IY, Kofia V, Gómez HF, Mittag F, Matthes J, Rudolph J, Wrzodek F, Netz E, Diamantikos A, Eichner J, Keller R, Wrzodek C, Fröhlich S, Lewis NE, Myers CJ, Le Novère N, Palsson BØ, Hucka M, Dräger A

JSBML, the official pure Java programming library for the Systems Biology Markup Language (SBML) format, has evolved with the advent of different modeling formalisms in systems biology and their ability to be exchanged and represented via extensions of SBML. JSBML has matured into a major, active open-source project with contributions from a growing, international team of developers who not only maintain compatibility with SBML, but also drive steady improvements to the Java interface and promote ease-of-use with end users.

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Bioinformatics (Oxford, England), , 1367-4811, , 2015

PMID: 26079347

Open Access

Forget the Parents: Epigenetic Reprogramming in Human Germ Cells.
von Meyenn F, Reik W

Epigenetic reprogramming in the germline resets genomic potential and erases epigenetic memory. Three studies by Gkountela et al., Guo et al., and Tang et al. analyze the transcriptional and epigenetic landscape of human primordial germ cells, revealing a unique transcriptional network and progressive and conserved global erasure of DNA methylation.

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Cell, 161, 1097-4172, 1248-51, 2015

PMID: 26046435

Short-term diabetic hyperglycemia suppresses celiac ganglia neurotransmission, thereby impairing sympathetically mediated glucagon responses.
Mundinger TO, Cooper E, Coleman MP, Taborsky GJ

Short-term hyperglycemia suppresses superior cervical ganglia neurotransmission. If this ganglionic dysfunction also occurs in the islet sympathetic pathway, sympathetically mediated glucagon responses could be impaired. Our objectives were 1) to test for a suppressive effect of 7 days of streptozotocin (STZ) diabetes on celiac ganglia (CG) activation and on neurotransmitter and glucagon responses to preganglionic nerve stimulation, 2) to isolate the defect in the islet sympathetic pathway to the CG itself, and 3) to test for a protective effect of the WLD(S) mutation. We injected saline or nicotine in nondiabetic and STZ-diabetic rats and measured fos mRNA levels in whole CG. We electrically stimulated the preganglionic or postganglionic nerve trunk of the CG in nondiabetic and STZ-diabetic rats and measured portal venous norepinephrine and glucagon responses. We repeated the nicotine and preganglionic nerve stimulation studies in nondiabetic and STZ-diabetic WLD(S) rats. In STZ-diabetic rats, the CG fos response to nicotine was suppressed, and the norepinephrine and glucagon responses to preganglionic nerve stimulation were impaired. In contrast, the norepinephrine and glucagon responses to postganglionic nerve stimulation were normal. The CG fos response to nicotine, and the norepinephrine and glucagon responses to preganglionic nerve stimulation, were normal in STZ-diabetic WLD(S) rats. In conclusion, short-term hyperglycemia's suppressive effect on nicotinic acetylcholine receptors of the CG impairs sympathetically mediated glucagon responses. WLD(S) rats are protected from this dysfunction. The implication is that this CG dysfunction may contribute to the impaired glucagon response to insulin-induced hypoglycemia seen early in type 1 diabetes.

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American journal of physiology. Endocrinology and metabolism, 309, 1522-1555, E246-55, 2015

PMID: 26037249

Allele-specific binding of ZFP57 in the epigenetic regulation of imprinted and non-imprinted monoallelic expression.
Strogantsev R, Krueger F, Yamazawa K, Shi H, Gould P, Goldman-Roberts M, McEwen K, Sun B, Pedersen R, Ferguson-Smith AC

Selective maintenance of genomic epigenetic imprints during pre-implantation development is required for parental origin-specific expression of imprinted genes. The Kruppel-like zinc finger protein ZFP57 acts as a factor necessary for maintaining the DNA methylation memory at multiple imprinting control regions in early mouse embryos and embryonic stem (ES) cells. Maternal-zygotic deletion of ZFP57 in mice presents a highly penetrant phenotype with no animals surviving to birth. Additionally, several cases of human transient neonatal diabetes are associated with somatic mutations in the ZFP57 coding sequence.

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Genome biology, 16, 1474-760X, 112, 2015

PMID: 26025256

Open Access

The kinase DYRK1A reciprocally regulates the differentiation of Th17 and regulatory T cells.
Khor B, Gagnon JD, Goel G, Roche MI, Conway KL, Tran K, Aldrich LN, Sundberg TB, Paterson AM, Mordecai S, Dombkowski D, Schirmer M, Tan PH, Bhan AK, Roychoudhuri R, Restifo NP, O'Shea JJ, Medoff BD, Shamji AF, Schreiber SL, Sharpe AH, Shaw SY, Xavier RJ

The balance between Th17 and T regulatory (Treg) cells critically modulates immune homeostasis, with an inadequate Treg response contributing to inflammatory disease. Using an unbiased chemical biology approach, we identified a novel role for the dual specificity tyrosine-phosphorylation-regulated kinase DYRK1A in regulating this balance. Inhibition of DYRK1A enhances Treg differentiation and impairs Th17 differentiation without affecting known pathways of Treg/Th17 differentiation. Thus, DYRK1A represents a novel mechanistic node at the branch point between commitment to either Treg or Th17 lineages. Importantly, both Treg cells generated using the DYRK1A inhibitor harmine and direct administration of harmine itself potently attenuate inflammation in multiple experimental models of systemic autoimmunity and mucosal inflammation. Our results identify DYRK1A as a physiologically relevant regulator of Treg cell differentiation and suggest a broader role for other DYRK family members in immune homeostasis. These results are discussed in the context of human diseases associated with dysregulated DYRK activity.

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eLife, 4, 2050-084X, , 2015

PMID: 25998054

Open Access

Data Resource Profile: Accessible Resource for Integrated Epigenomic Studies (ARIES).
Relton CL, Gaunt T, McArdle W, Ho K, Duggirala A, Shihab H, Woodward G, Lyttleton O, Evans DM, Reik W, Paul YL, Ficz G, Ozanne SE, Wipat A, Flanagan K, Lister A, Heijmans BT, Ring SM, Davey Smith G

International journal of epidemiology, 44, 1464-3685, 1181-90, 2015

PMID: 25991711

Open Access