IDENTIFICATION OF FACTORS INVOLVED IN DNA METHYLATION OF CPG-ISLAND-PROMOTERS

Repression of many tumor suppressor genes (TSGs) in cancer is mediated by aberrantly increased DNA methylation levels at promoter CpG islands (CGI). About one-fourth of empirically defined human promoters are surrounded by or contain clustered repetitive elements. It was previously observed that a sharp transition of methylation occurs between highly methylated repetitive elements (SINE or LINE) and unmethylated CGI-promoters (e.g. P16, VHL, CDH and RIL) in normal tissues. The functions that lead to increased CGI methylation in cancer remain poorly understood. We propose that CGI-promoters contain cis-elements for triggering de novo DNA methylation. In the first part of our project, we established a site-specific integration system with enforced local transcriptional repression in colorectal cancer cells and monitored the occurrence of de novo DNA methylation in exogenous fragments containing a CGI-promoter and repetitive elements. Initial de novo methylation was seeded at specific CG sites in a repetitive element, and accelerated by persistent binding of a KRAB-containing transcriptional repressor. Furthermore, additional repetitive elements (LINE and SINE) located adjacent to the promoter could confer DNA methylation spreading into the CGI particularly in the setting of KRAB-factor binding. However, a repressive chromatin alone was not sufficient to initiate DNA methylation, which required specific DNA sequences and was integration-site (and/or cell-line) specific. In addition, all the methylation observed showed slow and gradual accumulation over several months of culture. Overall, these results demonstrate a requirement for specific DNA sequences to trigger de novo DNA methylation, and repetitive elements as cis-regulatory factors to cooperate with strengthened transcriptional repression in promoting methylation spreading. In the second part, we re-introduced disrupted DNMT3B or DNMT1 into HCT116 DKO cells and mapped the remethylation pattern through a profiling method (DREAM). Moderate remethylation occurred when DNMT3B was re-expressed with a preference toward non-CGI and non-promoter regions. Hence, there exists a set of genomic regions with priority to be targets for DNMT3B in somatic cells.

Mid- to late Holocene Indian Ocean Monsoon variability recorded in four speleothems from Socotra Island, Yemen

Four stalagmites covering the last 7.0 ka were sampled on Socotra, an island in the northern Indian Ocean to investigate the evolution of the northeast Indian Ocean Monsoon (IOM) since the mid Holocene. On Socotra, rain is delivered at the start of the southwest IOM in May–June and at the start of the northeast IOM from September to December. The Haggeher Mountains act as a barrier forcing precipitation brought by the northeast winds to fall preferentially on the eastern side of the island, where the studied caves are located. δ18O and δ13C and Mg/Ca and Sr/Ca signals in the stalagmites reflect precipitation amounts brought by the northeast winds. For stalagmite STM6, this amount effect is amplified by kinetic effects during calcite deposition. Combined interpretation of the stalagmites' signals suggest a weakening of the northeast precipitation between 6.0 and 3.8 ka. After 3.8 ka precipitation intensities remain constant with two superimposed drier periods, between 0 and 0.6 ka and from 2.2 to 3.8 ka. No link can be established with Greenland ice cores and with the summer IOM variability. In contrast to the stable northeast rainy season suggested by the records in this study, speleothem records from western Socotra indicate a wettening of the southwest rainy season on Socotra after 4.4 ka. The local wettening of western Socotra could relate to a more southerly path (more over the Indian Ocean) taken by the southwest winds. Stalagmite STM5, sampled at the fringe between both rain areas displays intermediate δ18O values. After 6.2 ka, similar precipitation changes are seen between eastern Socotra and northern Oman indicating that both regions are affected similarly by the monsoon. Different palaeoclimatologic records from the Arabian Peninsula currently located outside the ITCZ migration pathway display an abrupt drying around 6 ka due to their disconnection from the southwest rain influence. Records that are nowadays still receiving rain by the southwest winds, suggest a more gradual drying reflecting the weakening of the southwest monsoon.

Ecosystem impacts of feral rabbits on World Heritage sub-Antarctic Macquarie Island: A palaeoecological perspective

The introduction and establishment of non-indigenous species through human activities often poses a major threat to natural biodiversity. In many parts of the world management efforts are therefore focused on their eradication. The environment of World Heritage sub-Antarctic Macquarie Island has been severely damaged by non-indigenous species including rabbits, rats and mice, introduced from the late AD 1800s. An extensive eradication programme is now underway which aims to remove all rabbits and rodents. To provide a long-term context for assessing the Island's pre-invasion state, invasion impacts, and to provide a baseline for monitoring its recovery, we undertook a palaeoecological study using proxies in a lake sediment core. Sedimentological and diatom analyses revealed an unproductive catchment and lake environment persisted for ca. 7100 years prior to the introduction of the invasive species. After ca. AD 1898, unprecedented and statistically significant environmental changes occurred. Lake sediment accumulation rates increased >100 times due to enhanced catchment inputs and within-lake production. Total carbon and total nitrogen contents of the sediments increased by a factor of four. The diatom flora became dominated by two previously rare species. The results strongly suggest a causal link between the anthropogenic introduction of rabbits and the changes identified in the lake sediments. This study provides an example of how palaeoecology may be used to determine baseline conditions prior to the introduction of non-indigenous species, quantify the timing and extent of changes, and help monitor the recovery of the ecosystem and natural biodiversity following successful non-indigenous species eradication programmes.

High exchangeable calcium concentrations in soils on Barro Colorado Island, Panama

The soils on four lithologies (basaltic conglomerates, Bohio; Andesite; volcanoclastic sediments with basaltic agglomerates, Caimito volcanic; foraminiferal limestone, Caimito marine) on Barro Colorado Island (BCI) have high exchangeable Ca concentrations and cation-exchange capacities (CEC) compared to other tropical soils on similar parent material. In the 0–10 cm layer of 24 mineral soils, pH values ranged from 5.7 (Caimito volcanic and Andesite) to 6.5 (Caimito marine), concentrations of exchangeable Ca from 134 mmolc kg− 1 (Caimito volcanic) to 585 mmolc kg− 1 (Caimito marine), and cation exchange capacities from 317 mmolc kg− 1 (Caimito volcanic) to 933 mmolc kg− 1 (Caimito marine). X-ray diffractometry of the fraction < 2 μm revealed that smectites dominated the clay mineral assemblage in soil except on Caimito volcanic, where kaolinite was the dominant clay mineral. Exchangeable Ca concentrations decreased with increasing soil depth except on Caimito marine. The weathering indices Chemical Index of Alteration (CIA), Plagioclase Index of Alteration (PIA) and Weathering Index of Parker (WIP) determined for five soils on all geological formations, suggested that in contrast to expectation the topsoil (0–10 cm) appeared to be the least and the subsoil (50–70 cm) and saprolite (isomorphically weathered rock in the soil matrix) the most weathered. Additionally, the weathering indices indicated depletion of base cations and enrichment of Al-(hydr)oxides throughout the soil profile. Tree species did not have an effect on soil properties. Impeded leaching and the related occurrence of overland flow seem to be important in determining clay mineralogy. Our results suggest that (i) edaphic conditions favor the formation of smectites on most lithologies resulting in high CEC and thus high retention capacity for Ca and (ii) that there is an external source such as dust or sea spray deposition supplying Ca to the soils.

The Effects of Flowline Length Evolution on Chemistry-Delta O-18 Profiles from Penny Ice Cap, Baffin Island, Canada

The isotopic and chemical signatures for ice-age and Holocene ice from Summit, Greenland and Penny Ice Cap, Baffin Island, Canada, arc compared. The usual pattern of low delta(18)O, high Ca2+ and high Cl- is presented in the Summit records, but Penny Ice Cap has lower than present Cl- in its ice-age ice. A simple extension of the Hansson model (Hansson, 1994) is developed and used to simulate these signatures. The low ice-age Cl- from Penny Ice Cap is explained by having the ice-age ice originating many thousands of km inland near the centre of the Laurentide ice sheet and much further from the marine sources. Summit's flowlines all start close to the present site. The Penny Ice Cap early-Holocene delta(18)O's had to be corrected to offset the Laurentide meltwater distortion. The analysis suggests that presently the Summit and Penny Ice Cap marine impurity originates about,500 km away, and that presently Penny Ice Cap receives a significant amount of local continental impurity.

Acute muscular sarcocystosis: an international investigation among ill travelers returning from tioman island, malaysia, 2011-2012.

BACKGROUND Through 2 international traveler-focused surveillance networks (GeoSentinel and TropNet), we identified and investigated a large outbreak of acute muscular sarcocystosis (AMS), a rarely reported zoonosis caused by a protozoan parasite of the genus Sarcocystis, associated with travel to Tioman Island, Malaysia, during 2011-2012. METHODS Clinicians reporting patients with suspected AMS to GeoSentinel submitted demographic, clinical, itinerary, and exposure data. We defined a probable case as travel to Tioman Island after 1 March 2011, eosinophilia (>5%), clinical or laboratory-supported myositis, and negative trichinellosis serology. Case confirmation required histologic observation of sarcocysts or isolation of Sarcocystis species DNA from muscle biopsy. RESULTS Sixty-eight patients met the case definition (62 probable and 6 confirmed). All but 2 resided in Europe; all were tourists and traveled mostly during the summer months. The most frequent symptoms reported were myalgia (100%), fatigue (91%), fever (82%), headache (59%), and arthralgia (29%); onset clustered during 2 distinct periods: "early" during the second and "late" during the sixth week after departure from the island. Blood eosinophilia and elevated serum creatinine phosphokinase (CPK) levels were observed beginning during the fifth week after departure. Sarcocystis nesbitti DNA was recovered from 1 muscle biopsy. CONCLUSIONS Clinicians evaluating travelers returning ill from Malaysia with myalgia, with or without fever, should consider AMS, noting the apparent biphasic aspect of the disease, the later onset of elevated CPK and eosinophilia, and the possibility for relapses. The exact source of infection among travelers to Tioman Island remains unclear but needs to be determined to prevent future illnesses.

Bounded Seas: Island Parsing Without Shipwrecks

Imprecise manipulation of source code (semi-parsing) is useful for tasks such as robust parsing, error recovery, lexical analysis, and rapid development of parsers for data extraction. An island grammar precisely defines only a subset of a language syntax (islands), while the rest of the syntax (water) is defined imprecisely. Usually, water is defined as the negation of islands. Albeit simple, such a definition of water is naive and impedes composition of islands. When developing an island grammar, sooner or later a programmer has to create water tailored to each individual island. Such an approach is fragile, however, because water can change with any change of a grammar. It is time-consuming, because water is defined manually by a programmer and not automatically. Finally, an island surrounded by water cannot be reused because water has to be defined for every grammar individually. In this paper we propose a new technique of island parsing - bounded seas. Bounded seas are composable, robust, reusable and easy to use because island-specific water is created automatically. We integrated bounded seas into a parser combinator framework as a demonstration of their composability and reusability.