Assimiliating an Associative Trait: from Eco-Physiology to Epigenetics

The possible evolutionary significance of epigenetic memory and codes is a key problem for extended evolutionary synthesis and biosemiotics. In this paper, some less known original works are reviewed which highlight theoretical parallels between current evolutionary epigenetics, on the one hand, and its predecessors in the eco-physiology of higher nervous activity, on the other. Recently, these areas have begun to converge, with first evidence now indicating the possibility of transgenerational epigenetic inheritance of conditional associations in the mammalian nervous system, and related findings in other taxa. This can serve as an interesting example of evolutionary code-making, where the molecular mechanisms underlying arbitrary associations between stimuli involve lasting changes in gene expression that may be transmitted epigenetically across generations, and which in some cases could be further assimilated into the genome over subsequent evolution. Although preliminary, such epigenetic scenarios would also offer an interesting, if so far overlooked parallel to earlier research carried out by one of I.P. Pavlov’s leading students, acad. P.K. Anokhin, and his colleagues, but also by eminent eco-physiologists of the time, several of whom offered arguments for the possibility of unconditional reflexes representing evolutionarily later, specialized, and reduced forms of associative reflexes, from which they may be derived. Although discarded under the growing dominance of modern synthesis, these early epigenetic investigations may deserve renewed attention in the modern context, and if further confirmed, could open essentially new perspectives on the morphofunctional evolution of the nervous system.     

来自禽流感病毒与表观遗传学的挑战

近年来,高致病性禽流感病毒及表观遗传学是广受关注的生物医学领域。《 中国科学C辑：生命科学》 (Science in China Series C-Life Sciences)在2009年连续发表了两个专题,对两个研究领域的现状及发展态势,特别是当前一些具有挑战性的问题,进行了综合评述。表观遗传学专题包括三个论题：a. 迄今对组蛋白和非组蛋白甲基化的认识和了解,重点论述了组蛋白的甲基标记及去甲基化酶对组蛋白甲基化的动力学调控;b. miRNA的生物发生及其在转录后基因沉默的功能作用;c. 植物中RNA指导的DNA甲基化和去甲基化。禽流感病毒专题重点综合评述了高致病性人H5N1禽流感病毒研究领域的现状及其挑战,包括流行病学,疾病控制及病毒作用机理。有5篇评述全面总结了高致病性禽流感A(H5N1)感染,特别是人患禽流感,在中国大陆和香港特别行政区的发现及处置全过程,包括疫情沿起和传播,临床诊断,病毒特性,以及政府和公共卫生机构的政策和措施,为有效预防今后可能再度发生类似的疫情提供了可贵的实际经验。该专题还包括了4篇述评和研究论文,对病毒种间传播的宿主原因及感染人的分子病理学,流感病毒核蛋白(NP)的三维结构及其与RNA的相互作用,以及流感病毒RNA聚合酶PA亚基的三维结构与功能,进行了深度解析,并讨论了基于结构的抗流感药物研发前景．     

雄激素受体对真核基因转录的调控

雄激素受体是典型的核受体,它对真核基因转录的调控作用受到日益广泛的重视。本文主要阐述了雄激素受体的分子结构,重点总结了雄激素受体介导真核基因转录起始的过程,概述了激素受体辅助使用因子及受体的核转运等受体功能的调控,这些是进一步研究真核基因表达调控机制及治疗雄激素相关疾病的理论基础。     

鸟类羽毛色素的合成机理与调控机制

鸟类作为色彩最丰富的陆生脊椎动物,其体表覆盖着颜色多样的羽毛,在伪装、择偶、信号识别等多方面具有重要功能,因此羽毛颜色引起了研究者的极大兴趣。羽毛颜色总体分为由化学物质产生的色素色和由物理结构产生的结构色,其中常见色素有两大类。根据近年来对羽毛色素的研究进展,本文总结了黑色素和类胡萝卜素的类型、合成途径、获取途径以及相关基因,为深入研究羽毛色素合成、代谢的分子调控机制提供科学依据。     

Enhancement of Declarative Memory: From Genetic Regulation to Non-invasive Stimulation

The problem of memory enhancement is extremely important in intellectual activity areas and therapy of different types of dementia, including Alzheimer’s disease (AD). The attempts to solve this problem have come from different research fields. In the first part of our review, we describe the results of targeting certain genes involved in memory-associated molecular pathways. The second part of the review is focused on the deep stimulation of brain structures that can slow down memory loss in AD. The third part describes the results of the use of non-invasive brain stimulation techniques for memory modulation, consolidation, and retrieval in healthy people and animal models. Integration of data from different research fields is essential for the development of efficient strategies for memory enhancement.     

Regulation of processing bodies: From viruses to cancer epigenetic machinery

Processing bodies (PBs) are 100–300 nm cytoplasmic messenger ribonucleoprotein particle (mRNP) granules that regulate eukaryotic gene expression. These cytoplasmic compartments harbor messenger RNAs (mRNAs) and several proteins involved in mRNA decay, microRNA silencing, nonsense-mediated mRNA decay, and splicing. Though membrane-less, PB structures are maintained by RNA-protein and protein-protein interactions. PB proteins have intrinsically disordered regions and low complexity domains, which account for its liquid to liquid phase separation. In addition to being dynamic and actively involved in the exchange of materials with other mRNPs and organelles, they undergo changes on various cellular cues and environmental stresses, including viral infections. Interestingly, several PB proteins are individually implicated in cancer development, and no study has addressed the effects on PB dynamics after epigenetic modifications of cancer-associated PB genes. In the current review, we summarize modulations undergone by P bodies or P body components upon viral infections. Furthermore, we discuss the selective and widely investigated PB proteins that undergo methylation changes in cancer and their potential as biomarkers.     

Androgen receptor phosphorylation. Regulation and identification of the phosphorylation sites

Activation of signal transduction kinase cascades has been shown to alter androgen receptor (AR) activity. Although it has been suggested that changes in AR phosphorylation might be directly responsible, the basal and regulated phosphorylations of the AR have not been fully determined. We have identified the major sites of AR phosphorylation on ARs expressed in COS-1 cells using a combination of peptide mapping, Edman degradation, and mass spectrometry. We describe the identification of seven AR phosphorylation sites, show that the phosphopeptides seen with exogenously expressed ARs are highly similar to those seen with endogenous ARs in LNCaP cells and show that specific agonists differentially regulate the phosphorylation state of endogenous ARs in LNCaP prostate cancer cells. Treatment of LNCaP cells with the synthetic androgen, R1881, elevates phosphorylation of serines 16, 81, 256, 308, 424, and 650. Ser-94 appears constitutively phosphorylated. Forskolin, epidermal growth factor, and phorbol 12-myristate 13-acetate increase the phosphorylation of Ser-650. The kinetics of phosphorylation of most sites in response to hormone or forskolin is temporally delayed, reaching a maximum at 2 h post-stimulation. The exception is Ser-81, which continues to display increasing phosphorylation at 6 h. These data provide a basis for analyzing mechanisms of cross-talk between growth factor signaling and androgen in prostate development, physiology, and cancer.     

Androgen Regulation of Murine β-Glucuronidase Expression: Identification and Characterization of a Nonresponse Variant

One of the major features of beta-glucuronidase (GUS) expression in inbred strains of the house mouse, Mus musculus, is the responsiveness of this enzyme to androgen stimulation in tubule cells of the kidney. Both GUS-specific and nonspecific mutations have been described which define genes that serve to control this response. During examination of the expression of GUS in the interbreeding subspecies, Mus hortulanus, a new GUS haplotype was uncovered that is characterized, in part, by a lack of GUS response to androgen stimulation in an apparently responsive kidney. Blot hybridization analyses of kidney RNA with a radiolabeled murine GUS cDNA shows this lack of response to be reflected in GUS mRNA levels. The difference in heat stability of GUS activity between M. hortulanus and a responsive inbred strain, ICR/Ha, was utilized to assess the contribution of each parent to kidney levels of GUS in androgen-treated and -untreated F1 progeny of these strains. The results, together with preliminary genetic studies, suggest that the element controlling this responsiveness (or the lack thereof) is cis-active and tightly linked to the GUS structural gene on chromosome 5. It is not known whether this element is identical to another GUS-specific, cis-active element, Gus-r, which also controls the androgen response of GUS in mouse kidney.     

Development of NADPH-Diaphorase in the Avian Retina: Regulation by Calcium Ions and Relation to Nitric Oxide Synthase

Abstract: Nitric oxide plays an important role as an intercellular messenger in the CNS. In the present work we measured NADPH-diaphorase activity, which is considered to be a marker of cells producing nitric oxide, in homogenates of the developing chick retina. The enzyme activity can be detected beginning in 8-day-old embryonic retinas with no further quantitative variations throughout development. Arginine analogues inhibit ∼65% of the activity in embryonic retinas and 50% in posthatched retinas. The enzyme is stimulated 50% by 2 m M calcium chloride in retinas from 8 to 14 embryonic days, but this effect decreases to 20% in 17-day embryonic retinas and practically disappears in posthatched animals. The stimulation by calcium is completely blocked by arginine analogues. The decrease in enzyme activity at posthatched retinas is not due to stimulation by endogenous calcium or the presence of insufficient amounts of calmodulin, because addition of EGTA or calmodulin, respectively, did not restore the stimulation to levels observed at embryonic stages. Inhibition of NADPH-diaphorase activity by N ^G-nitro- l -arginine or l - N ^G-(iminoethyl)ornithine is concentration dependent with IC₅₀ values of ∼1 m M at all stages studied. However, in the presence of calcium, the inhibition by both analogues is shifted to the left and is apparently biphasic at all developmental stages, including in posthatched animals, with IC₅₀ values in the low micromolar range. NADPH-diaphorase was also detected by histochemistry in specific groups of cells in the early embryonic retina and in subsets of amacrine and ganglion cells, as well as in photoreceptors, in more developed retinas. The results indicate that different isoforms of nitric oxide synthase are present in the chick retina and that a calcium-dependent isoform is predominant in early periods of development.     

Gene Targeting Approaches to Neuroendocrinology: Oxytocin, Maternal Behavior, and Affiliation

Transgenic technology affords exciting new opportunities in the field of behavioral neuroendocrinology. We have extended our research into the behavioral function of oxytocin in maternal and social behavior using two transgenic approaches: (i) targeted deletion of the oxytocin gene in mice and (ii) augmented oxytocin receptor expression in the brain. Mice genetically deficient in oxytocin can mate, give birth, and display normal maternal behavior; however, milk ejection and certain aspects of social behavior are affected. Comparative studies of oxytocin receptors have led to the observation that species differences in social organization are associated with differences in receptor distribution. Specifically, monogamous prairie voles and nonmonogamous, asocial montane voles exhibit different patterns of OT receptor expression in the brain. Transgenic mice have been created with a reporter gene driven by the prairie vole oxytocin receptor gene promoter. Analysis of the expression pattern suggests that it should be possible to manipulate receptor expression in the vole brain in order to examine the effects of receptor distribution on behavior.     

Regulation of Survival Networks in Senescent Cells: From Mechanisms to Interventions

Cellular senescence is a state of stable cell cycle arrest arising in response to DNA and mitochondrial damages. Senescent cells undergo morphological, structural and functional changes that are influenced by a number of variables, including time, stress, tissue, and cell type. The heterogeneity of the senescent phenotype is exemplified by the many biological properties that senescent cells can cover. The advent of innovative model organisms has demonstrated a functional role of senescent cells during embryogenesis, tissue remodeling, tumorigenesis and aging. Importantly, prolonged and aberrant persistence of senescent cells is often associated with tissue dysfunction and pathology, and is partially the consequence of mechanisms that enhance survival and resistance to cell death. Here, we describe the main molecular players involved in promoting survival of senescent cells, with particular emphasis on the regulation of senescence-associated anti-apoptotic pathways. We discuss the consequences these pathways have in providing resistance to intrinsic and extrinsic pro-apoptotic signals. Finally, we highlight the importance of these pathways in the development of targets for senolytic interventions.     

Neuroendocrinology and its Quantitative Development: A Bioengineering View

Honor thy father and thy mother, say the Holy Scriptures [1], for they at least gave thee this biological life, but honor thy teachers, too, for they gave thee knowledge and example.     

Plasma Cells: From Cytokine Production to Regulation in Experimental Autoimmune Encephalomyelitis

B cells are a critical arm of the adaptive immune system. After encounter with antigen, B cells are activated and differentiate into plasmablasts (PBs) and plasma cells (PCs). Although their frequency is low, PB/PCs can be found in all lymphoid organs including peripheral lymph nodes and spleen. Upon immunization, depending on the location of where B cells encounter their antigen, PB/PCs subsequently home to and accumuate in the bone marrow and the intestine where they can survive as long-lived plasma cells for years, continually producing antibody. Recent evidence has shown that, in addition to producing antibodies, PB/PCs can also produce cytokines such as IL-17, IL-10, and IL-35. In addition, PB/PCs that produce IL-10 have been shown to play a regulatory role during experimental autoimmune encephalomyelitis, an animal model of neuroinflammation. The purpose of this review is to describe the phenotype and function of regulatory PB/PCs in the context of experimental autoimmune encephalomyelitis and in patients with multiple sclerosis.     

Neuroendocrinology and neurobiology of sebaceous glands

The nervous system communicates with peripheral tissues through nerve fibres and the systemic release of hypothalamic and pituitary neurohormones. Communication between the nervous system and the largest human organ, skin, has traditionally received little attention. In particular, the neuro‐regulation of sebaceous glands (SGs), a major skin appendage, is rarely considered. Yet, it is clear that the SG is under stringent pituitary control, and forms a fascinating, clinically relevant peripheral target organ in which to study the neuroendocrine and neural regulation of epithelia. Sebum, the major secretory product of the SG, is composed of a complex mixture of lipids resulting from the holocrine secretion of specialised epithelial cells (sebocytes). It is indicative of a role of the neuroendocrine system in SG function that excess circulating levels of growth hormone, thyroxine or prolactin result in increased sebum production (seborrhoea). Conversely, growth hormone deficiency, hypothyroidism, and adrenal insufficiency result in reduced sebum production and dry skin. Furthermore, the androgen sensitivity of SGs appears to be under neuroendocrine control, as hypophysectomy (removal of the pituitary) renders SGs largely insensitive to stimulation by testosterone, which is crucial for maintaining SG homeostasis. However, several neurohormones, such as adrenocorticotropic hormone and α‐melanocyte‐stimulating hormone, can stimulate sebum production independently of either the testes or the adrenal glands, further underscoring the importance of neuroendocrine control in SG biology. Moreover, sebocytes synthesise several neurohormones and express their receptors, suggestive of the presence of neuro‐autocrine mechanisms of sebocyte modulation. Aside from the neuroendocrine system, it is conceivable that secretion of neuropeptides and neurotransmitters from cutaneous nerve endings may also act on sebocytes or their progenitors, given that the skin is richly innervated. However, to date, the neural controls of SG development and function remain poorly investigated and incompletely understood. Botulinum toxin‐mediated or facial paresis‐associated reduction of human sebum secretion suggests that cutaneous nerve‐derived substances modulate lipid and inflammatory cytokine synthesis by sebocytes, possibly implicating the nervous system in acne pathogenesis. Additionally, evidence suggests that cutaneous denervation in mice alters the expression of key regulators of SG homeostasis. In this review, we examine the current evidence regarding neuroendocrine and neurobiological regulation of human SG function in physiology and pathology. We further call attention to this line of research as an instructive model for probing and therapeutically manipulating the mechanistic links between the nervous system and mammalian skin.