Molecular Analysis of Precursor Lesions in Familial Pancreatic Cancer

PMCID: PMC3553106This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Making Friends in the Rainforest: Negrito Adaptation to Risk and Uncertainty

The so-called negritos adapt not just to a tropical forest environment but also to an environment characterized by perturbations and fluctuations. As with other hunter-gatherers in the region and, indeed, throughout the world, they use both social and ecological methods to enhance their chances of survival in this changing environment: socially, they have developed networks of trading and marriage partners; ecologically, they maintain patches of key resources that are available for future harvesting. As evidenced in the case of the Batek (Orang Asli), patterns of forest structure and composition are sometimes direct outcomes of intentional resource concentration and enrichment strategies. While little of the above is controversial anthropologically, what has drawn some debate is the nature of the relationship with partner societies. Conventional wisdom posits relations of inequality between foragers and others : foragers and farmers are often construed as hierarchical dyads where foragers supply products or labor to farmers in exchange for agricultural harvests and other trade goods. This kind of adaptation appears to be one of divergent specialization. However, there are cases, such as in the relationship between Batek and Semaq Beri, where both societies follow a roughly similar mode of adaptation, and specialization has not materialized. In sum, while not denying that hierarchy and inequality exist, I suggest that they have to be contextualized within a larger strand of relationships that includes both hierarchy and egality. Further, such relationships are part of the general portfolio of risk reduction strategies, following which access to widely scattered environmental resources, and passage from one location to another, is enhanced not by competing with and displacing neighbors but by maintaining a flexible regime of friendly exchange partners

Craniodental Affinities of Southeast Asia\u27s Negritos and the Concordance with Their Genetic Affinities

Genetic research into Southeast Asia\u27s negritos has revealed their deep-rooted ancestry, with time depth comparable to that of Southwest Pacific populations. This finding is often interpreted as evidence that negritos, in contrast to other Southeast Asians, can trace much of their ancestry directly back to the early dispersal of Homo sapiens in the order of 70 kya from Africa to Pleistocene New Guinea and Australia. One view on negritos is to lump them and Southwest Pacific peoples into an Australoid race whose geographic distribution had included Southeast Asia prior to the Neolithic incursion of Mongoloid farmers. Studies into Semang osteology have revealed some hints of Southwest Pacific affinities in cranial shape, dental morphology, and dental metrical shape. On the other hand, the Andamanese have been shown to resemble Africans in their craniometrics and South Asians in their dental morphology, while Philippine negritos resemble Mongoloid Southeast Asians in these respects and also in their dental metrics. This study expands the scope of negrito cranial comparisons by including Melayu Malays and additional coverage of South Asians. It highlights the distinction between the Mongoloid-like Philippine negritos and the Andamanese and Semang (and Senoi of Malaya) with their non-Mongoloid associations. It proposes that the early/mid-Holocene dispersal of the B4a1a mitochondrial DNA clade across Borneo, the Philippines, and Taiwan may be important for understanding the distinction between Philippine and other negritos

The protein tyrosine kinase Tec regulates a CD44highCD62L- Th17 subset

The generation of Th17 cells has to be tightly controlled during an immune response. In this study, we report an increase in a CD44 2 effector/memory Th17 populations

HDAC7 Is a Repressor of Myeloid Genes Whose Downregulation Is Required for Transdifferentiation of Pre-B Cells into Macrophages

B lymphopoiesis is the result of several cell-commitment, lineage-choice, and differentiation processes. Every differentiation step is characterized by the activation of a new, lineage-specific, genetic program and the extinction of the previous one. To date, the central role of specific transcription factors in positively regulating these distinct differentiation processes to acquire a B cell-specific genetic program is well established. However, the existence of specific transcriptional repressors responsible for the silencing of lineage inappropriate genes remains elusive. Here we addressed the molecular mechanism behind repression of non-lymphoid genes in B cells. We report that the histone deacetylase HDAC7 was highly expressed in pre-B cells but dramatically down-regulated during cellular lineage conversion to macrophages. Microarray analysis demonstrated that HDAC7 re-expression interfered with the acquisition of the gene transcriptional program characteristic of macrophages during cell transdifferentiation; the presence of HDAC7 blocked the induction of key genes for macrophage function, such as immune, inflammatory, and defense response, cellular response to infections, positive regulation of cytokines production, and phagocytosis. Moreover, re-introduction of HDAC7 suppressed crucial functions of macrophages, such as the ability to phagocytose bacteria and to respond to endotoxin by expressing major pro-inflammatory cytokines. To gain insight into the molecular mechanisms mediating HDAC7 repression in pre-B cells, we undertook co-immunoprecipitation and chromatin immunoprecipitation experimental approaches. We found that HDAC7 specifically interacted with the transcription factor MEF2C in pre-B cells and was recruited to MEF2 binding sites located at the promoters of genes critical for macrophage function. Thus, in B cells HDAC7 is a transcriptional repressor of undesirable genes. Our findings uncover a novel role for HDAC7 in maintaining the identity of a particular cell type by silencing lineage-inappropriate genes

Terror from the Sky: Unconventional Linguistic Clues to the Negrito Past

Within recorded history. most Southeast Asian peoples have been of southern Mongoloid physical type, whether they speak Austroasiatic, Tibeto-Burman, Austronesian, Tai-Kadai, or Hmong-Mien languages. However, population distributions suggest that this is a post-Pleistocene phenomenon and that for tens of millennia before the last glaciation ended Greater Mainland Southeast Asia, which included the currently insular world that rests on the Sunda Shelf, was peopled by short, dark-skinned, frizzy-haired foragers whose descendants in the Philippines came to be labeled by the sixteenth-century Spanish colonizers as negritos, a term that has since been extended to similar groups throughout the region. There are three areas in which these populations survived into the present so as to become part of written history: the Philippines, the Malay Peninsula, and the Andaman Islands. All Philippine negritos speak Austronesian languages, and all Malayan negritos speak languages in the nuclear Mon-Khmer branch of Austroasiatic, but the linguistic situation in the Andamans is a world apart. Given prehistoric language shifts among both Philippine and Malayan negritos, the prospects of determining whether disparate negrito populations were once a linguistically or culturally unified community would appear hopeless. Surprisingly, however, some clues to a common negrito past do survive in a most unexpected way

Identification of the molecular signatures integral to regenerating photoreceptors in the retina of the zebra fish

Investigating neuronal and photoreceptor regeneration in the retina of zebra fish has begun to yield insights into both the cellular and molecular means by which this lower vertebrate is able to repair its central nervous system. However, knowledge about the signaling molecules in the local microenvironment of a retinal injury and the transcriptional events they activate during neuronal death and regeneration is still lacking. To identify genes involved in photoreceptor regeneration, we combined light-induced photoreceptor lesions, laser-capture microdissection of the outer nuclear layer (ONL) and analysis of gene expression to characterize transcriptional changes for cells in the ONL as photoreceptors die and are regenerated. Using this approach, we were able to characterize aspects of the molecular signature of injured and dying photoreceptors, cone photoreceptor progenitors, and microglia within the ONL. We validated changes in gene expression and characterized the cellular expression for three novel, extracellular signaling molecules that we hypothesize are involved in regulating regenerative events in the retina

BCL6 is critical for the development of a diverse primary B cell repertoire

BCL6 protects germinal center (GC) B cells against DNA damage–induced apoptosis during somatic hypermutation and class-switch recombination. Although expression of BCL6 was not found in early IL-7–dependent B cell precursors, we report that IL-7Rα–Stat5 signaling negatively regulates BCL6. Upon productive VH-DJH gene rearrangement and expression of a μ heavy chain, however, activation of pre–B cell receptor signaling strongly induces BCL6 expression, whereas IL-7Rα–Stat5 signaling is attenuated. At the transition from IL-7–dependent to –independent stages of B cell development, BCL6 is activated, reaches expression levels resembling those in GC B cells, and protects pre–B cells from DNA damage–induced apoptosis during immunoglobulin (Ig) light chain gene recombination. In the absence of BCL6, DNA breaks during Ig light chain gene rearrangement lead to excessive up-regulation of Arf and p53. As a consequence, the pool of new bone marrow immature B cells is markedly reduced in size and clonal diversity. We conclude that negative regulation of Arf by BCL6 is required for pre–B cell self-renewal and the formation of a diverse polyclonal B cell repertoire

Distinct roles for E12 and E47 in B cell specification and the sequential rearrangement of immunoglobulin light chain loci

The E2A gene products, E12 and E47, are critical regulators of B cell development. However, it remains elusive whether E12 and E47 have overlapping and/or distinct functions during B lymphopoiesis. We have generated mice deficient for either E12 or E47 and examined their roles in B cell maturation. We show that E47 is essential for developmental progression at the prepro–B cell stage, whereas E12 is dispensable for early B cell development, commitment, and maintenance. In contrast, both E12 and E47 play critical roles in pre–B and immature B cells to promote immunoglobulin λ (Igλ) germline transcription as well as Igλ VJ gene rearrangement. Furthermore, we show that E12 as well as E47 is required to promote receptor editing upon exposure to self-antigen. We demonstrate that increasing levels of E12 and E47 act to induce Igλ germline transcription, promote trimethylated lysine 4 on histone 3 (H3) as well as H3 acetylation across the Jλ region, and activate Igλ VJ gene rearrangement. We propose that in the pre–B and immature B cell compartments, gradients of E12 and E47 activities are established to mechanistically regulate the sequential rearrangement of the Ig light chain genes

Identification of Pax6-Dependent Gene Regulatory Networks in the Mouse Lens

Lineage-specific DNA-binding transcription factors regulate development by activating and repressing particular set of genes required for the acquisition of a specific cell type. Pax6 is a paired domain and homeodomain-containing transcription factor essential for development of central nervous, olfactory and visual systems, as well as endocrine pancreas. Haploinsufficiency of Pax6 results in perturbed lens development and homeostasis. Loss-of-function of Pax6 is incompatible with lens lineage formation and results in abnormal telencephalic development. Using DNA microarrays, we have identified 559 genes expressed differentially between 1-day old mouse Pax6 heterozygous and wild type lenses. Of these, 178 (31.8%) were similarly increased and decreased in Pax6 homozygous embryonic telencephalon [Holm PC, Mader MT, Haubst N, Wizenmann A, Sigvardsson M, Götz M (2007) Loss- and gain-of-function analyses reveals targets of Pax6 in the developing mouse telencephalon. Mol Cell Neurosci 34: 99–119]. In contrast, 381 (68.2%) genes were differently regulated between the lens and embryonic telencephalon. Differential expression of nine genes implicated in lens development and homeostasis: Cspg2, Igfbp5, Mab21l2, Nrf2f, Olfm3, Spag5, Spock1, Spon1 and Tgfb2, was confirmed by quantitative RT-PCR, with five of these genes: Cspg2, Mab21l2, Olfm3, Spag5 and Tgfb2, identified as candidate direct Pax6 target genes by quantitative chromatin immunoprecipitation (qChIP). In Mab21l2 and Tgfb2 promoter regions, twelve putative individual Pax6-binding sites were tested by electrophoretic mobility shift assays (EMSAs) with recombinant Pax6 proteins. This led to the identification of two and three sites in the respective Mab21l2 and Tgfb2 promoter regions identified by qChIPs. Collectively, the present studies represent an integrative genome-wide approach to identify downstream networks controlled by Pax6 that control mouse lens and forebrain development