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Bertoletti A.,National University of Singapore | Bertoletti A.,Singapore Institute for Clinical science | Bertoletti A.,University of Birmingham | Rivino L.,National University of Singapore
Current Opinion in Infectious Diseases | Year: 2014

Purpose of review Hepatitis B virus (HBV) causes a large proportion of chronic liver disease worldwide, The limited efficiency of current treatments based on the use of nucleotide/nucleoside analogues or interferon-alpha requires the development of new therapeutic tools for the treatment of chronic HBV, We summarize the most recent therapeutic strategies designed to directly target HBV-infected hepatocytes or to restore antiviral immunity during chronic HBV infection, Recent findings Novel therapies directly target HBV-infected hepatocytes by inducing covalently closed circular DNA degradation or by inhibiting HBV entry or the expression of viral proteins, In addition, immunotherapeutic approaches may boost HBV-specific T-cell responses or stimulate the intrahepatic innate response, Summary These new therapeutic approaches have mainly been tested in animal models, In humans, therapeutic strategies could be tailored to different chronic HBV patients in relation to their clinical and virological disease profile. Copyright © 2014 Lippincott Williams & Wilkins.


Rehermann B.,U.S. National Institutes of Health | Bertoletti A.,National University of Singapore | Bertoletti A.,Singapore Institute for Clinical science
Hepatology | Year: 2015

Hepatitis B virus (HBV) and hepatitis C virus (HCV) cause a large proportion of acute and chronic liver disease worldwide. Over the past decades many immunological studies defined host immune responses that mediate spontaneous clearance of acute HBV and HCV infection. However, host immune responses are also relevant in the context of treatment-induced clearance of chronic HBV and HCV infection. First, the pretreatment level of interferon-stimulated genes as well as genetic determinants of innate immune responses, such as single nucleotide polymorphisms near the IFNL3 gene, are strong predictors of the response to interferon-alpha (IFN-α)-based therapy. Second, IFN-α, which has been a mainstay of HBV and HCV therapy over decades, and ribavirin, which has also been included in interferon-free direct antiviral therapy for HCV, modulate host immune responses. Third, both IFN-α-based and IFN-α-free treatment regimens of HBV and HCV infection alter the short-term and long-term adaptive immune response against these viruses. Finally, treatment studies have not just improved the clinical outcomes, but also provided opportunities to study virus-host interaction. This review summarizes our current knowledge on how a patient's immune response affects the treatment outcome of HBV and HCV infection and how innate and adaptive immune responses themselves are altered by the different treatment regimens. © 2014 by the American Association for the Study of Liver Diseases.


Rifkin-Graboi A.,Singapore Institute for Clinical science
Biological psychiatry | Year: 2013

Antenatal maternal cortisol levels associate with alterations in the amygdala, a structure associated with emotion regulation, in the offspring. However, because offspring brain and behavior are commonly assessed years after birth, the timing of such maternal influences is unclear. This study aimed to examine the association between antenatal maternal depressive symptomatology and neonatal amygdala volume and microstructure and thus establish evidence for the transgenerational transmission of vulnerability for affective disorders during prenatal development. Our study recruited Asian mothers at 10 to 13 weeks pregnancy and assessed maternal depression at 26 weeks gestation using the Edinburgh Postnatal Depression Scale. Structural magnetic resonance imaging and diffusion tensor imaging were performed with 157 nonsedated, 6- to 14-day-old newborns and then analyzed to extract the volume, fractional anisotropy, and axial diffusivity values of the amygdala. Adjusting for household income, maternal age, and smoking exposure, postconceptual age at magnetic resonance imaging, and birth weight, we found significantly lower fractional anisotropy (p = .009) and axial diffusivity (p = .028), but not volume (p = .993), in the right amygdala in the infants of mothers with high compared with those with low-normal Edinburgh Postnatal Depression Scale scores. The results reveal a significant relation between antenatal maternal depression and the neonatal microstructure of the right amygdala, a brain region closely associated with stress reactivity and vulnerability for mood anxiety disorders. These findings suggest the prenatal transmission of vulnerability for depression from mother to child and that interventions targeting maternal depression should begin early in pregnancy. © 2013 Society of Biological Psychiatry.


Hanson M.A.,University of Southampton | Gluckman P.D.,University of Auckland | Gluckman P.D.,Singapore Institute for Clinical science
Best Practice and Research: Clinical Obstetrics and Gynaecology | Year: 2015

The rapidly rising prevalence of non-communicable diseases (NCDs) represents a major challenge to public health and clinical medicine globally. NCDs are increasing rapidly in high-income countries, but even more rapidly in some low-middle-income countries with insufficient resources to meet the challenge. Whilst not identified in the Millennium Development Goals, there is much attention paid to NCDs in the discussions at many levels on the Sustainable Development Goals, as they underpin economic, social and environmental development in the post-2015 era. In this article, we discuss how a life-course approach to health, commencing of necessity in early development, can provide new opportunities for addressing this challenge. The approach can leverage human health capital throughout life and across generations. New insights into mechanisms, especially those processes by which the developmental environment affects epigenetic processes in the developing offspring, offer the prospect of identifying biomarkers of future risks. New interventions to promote health literacy, lifestyle and physical fitness in adolescents, young adults and their children hold great promise. In this respect, health-care professionals concerned with preconceptional, pregnancy and newborn care will have a vital role to play. © 2014 Elsevier Ltd. All rights reserved.


Kaur B.,Singapore Institute for Clinical science | Henry J.,Singapore Institute for Clinical science
Advances in Food and Nutrition Research | Year: 2014

Type 2 diabetes is characterized by significant losses of important micronutrients due to metabolic basis of the disease and its complications. Evidence of changes in trace mineral and vitamin metabolism as a consequence of type 2 diabetes is reviewed in this chapter. This review is not a meta-analysis but an overview of the micronutrient status, metabolic needs, and potential micronutrient requirements in type 2 diabetics. This chapter will not concentrate on vitamin D and type 2 diabetes as this is a topic that has been extensively reviewed before. The less well-known micronutrients notably zinc, magnesium, chromium, copper, manganese, iron, selenium, vanadium, B-group vitamins, and certain antioxidants are assessed. While some evidence is available to demonstrate the positive influence of micronutrient supplementation on glycemic control, much remains to be investigated. Additional research is necessary to characterize better biomarkers of micronutrient status and requirements in type 2 diabetics. The optimal level of micronutrient supplementation to achieve glucose homeostasis in type 2 diabetics remains a challenge. © 2014 Elsevier Inc.


Hellstrom I.C.,McGill University | Dhir S.K.,McGill University | Diorio J.C.,McGill University | Meaney M.J.,McGill University | Meaney M.J.,Singapore Institute for Clinical Science
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2012

Variations in parental care direct phenotypic development across many species. Variations in maternal pup licking/grooming (LG) in the rat regulate the development of individual differences in hypothalamic-pituitary-adrenal responses to stress. The adult offspring of mothers that show an increased frequency of pup LG have increased hippocampal glucocorticoid receptor (GR) expression and more modest pituitary-adrenal responses to stress. This parental effect is mediated by the epigenetic programming of a GR exon 1 promoter (exon 17) through the binding of the transcription factor nerve growth factor-inducible factor A (NGFI-A). In this paper, we report that: (i) the association of NGFI-A with the exon 17 GR promoter is dynamically regulated by mother-pup interactions; (ii) this effect is mimicked by artificial tactile stimulation comparable to that provided by pup LG; (iii) that serotonin (5-HT) induces an NGFI-A-dependent increase in GR transcription in hippocampal neurons and NGFI-A overexpression is sufficient for this effect; and (iv) that thyroid hormones and 5-HT are key mediators of the effects of pup LG and tactile stimulation on NGFI-A binding to the exon 17 GR promoter in hippocampus. These findings suggest that pup LG directly activates 5-HT systems to initiate intracellular signalling pathways in the hippocampus that regulate GR transcription. © 2012 The Royal Society.


Zhang T.Y.,McGill University | Labonte B.,McGill University | Wen X.L.,McGill University | Turecki G.,McGill University | And 2 more authors.
Neuropsychopharmacology | Year: 2013

Parental care influences development across mammals. In humans such influences include effects on phenotypes, such as stress reactivity, which determine individual differences in the vulnerability for affective disorders. Thus, the adult offspring of rat mothers that show an increased frequency of pup licking/grooming (ie, high LG mothers) show increased hippocampal glucocorticoid receptor (GR) expression and more modest hypothalamicpituitaryadrenal responses to stress compared with the offspring of low LG mothers. In humans, childhood maltreatment associates decreased hippocampal GR expression and increased stress responses in adulthood. We review the evidence suggesting that such effects are mediated by epigenetic mechanisms, including DNA methylation and hydroxymethylation across GR promoter regions. We also present new findings revealing associated histone post-translational modifications of a critical GR promoter in rat hippocampus. Taken together these existing evidences are consistent with the idea that parental influences establish stable phenotypic variation in the offspring through effects on intracellular signaling pathways that regulate the epigenetic state and function of specific regions of the genome. © 2013 American College of Neuropsychopharmacology. All rights reserved.


Lim A.L.,Singapore Institute for Clinical science | Ferguson-Smith A.C.,Singapore Institute for Clinical science | Ferguson-Smith A.C.,University of Cambridge
Seminars in Cell and Developmental Biology | Year: 2010

Genomic imprinting in gametogenesis marks a subset of mammalian genes for parent-of-origin-dependent monoallelic expression in the offspring. In mice, the identification and manipulation of individual imprinted genes has shown that the diverse products of these genes are largely devoted to controlling pre- and postnatal growth. Human syndromes with parental origin effects have been characterized both at the phenotypic and genotypic levels, allowing further elucidation of the function and regulation of imprinted genes. Evidence suggests that a compromised in utero environment influences fetal growth through the modulation of epigenetic states. However it is not known whether imprinted genes, by their nature, might be more or less susceptible to such environmental influences. Here we review the progress made in addressing the influence of a compromised in utero environment on the behavior of imprinted genes. We also examine whether these environmental influences may have an impact on the later development of human disease. © 2009 Elsevier Ltd. All rights reserved.


Ferguson-Smith A.C.,University of Cambridge | Ferguson-Smith A.C.,Singapore Institute for Clinical science | Patti M.-E.,Harvard University
Cell Metabolism | Year: 2011

Maternal nutrition and metabolism are critical determinants of adult offspring health. Recent reports describe adverse offspring outcomes associated with the father's diet, indicating nongenetic inheritance of paternal experience. Determining underlying mechanisms may require reconsideration of our understanding of the heritability of epigenetic states. © 2011 Elsevier Inc.


Bagot R.C.,McGill University | Meaney M.J.,McGill University | Meaney M.J.,Singapore Institute for Clinical science
Journal of the American Academy of Child and Adolescent Psychiatry | Year: 2010

Objective: Child and adolescent psychiatry is rife with examples of the sustained effects of early experience on brain function. The study of behavioral genetics provides evidence for a relation between genomic variation and personality and with the risk for psychopathology. A pressing challenge is that of conceptually integrating findings from genetics into the study of personality without regressing to arguments concerning the relative importance of genomic variation versus nongenomic or environmental influences. Method: Epigenetics refers to functionally relevant modifications to the genome that do not involve a change in nucleotide sequence. This review examines epigenetics as a candidate biological mechanism for gene × environment interactions, with a focus on environmental influences that occur during early life and that yield sustained effects on neural development and function. Results: The studies reviewed suggest that epigenetic remodeling occurs in response to the environmental activation of cellular signalling pathways associated with synaptic plasticity, epigenetic marks are actively remodeled during early development in response to environmental events that regulate neural development and function, and epigenetic marks are subject to remodeling by environmental influences even at later stages in development. Conclusion: Epigenetic remodeling might serve as an ideal mechanism for phenotypic plasticitythe process whereby the environment interacts with the genome to produce individual differences in the expression of specific traits. © 2010 American Academy of Child and Adolescent Psychiatry.

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