GERMLINE GAIN-OF-FUNCTION MUTATIONS of ALK DISRUPT CENTRAL NERVOUS SYSTEM DEVELOPMENT

International audienceNeuroblastoma (NB) is a frequent embryonal tumour of sympathetic ganglia and adrenals with extremely variable outcome. Recently, somatic amplification and gain-of-function mutations of the anaplastic lymphoma receptor tyrosine kinase (ALK, MIM 105590) gene, either somatic or germline, were identified in a significant proportion of NB cases. Here we report a novel syndromic presentation associating congenital NB with severe encephalopathy and abnormal shape of the brainstem on brain MRI in two unrelated sporadic cases harbouring de novo, germline, heterozygous ALK gene mutations. Both mutations are gain-of-function mutations that have been reported in NB and NB cell lines. These observations further illustrate the role of oncogenes in both tumour predisposition and normal development, and shed light on the pleiotropic and activity-dependent role of ALK in humans. More generally, missing germline mutations relative to the spectrum of somatic mutations reported for a given oncogene may be a reflection of severe effects during embryonic development, and may prompt mutation screening in patients with extreme phenotypes

Integrated stratigraphy of the Priabonian (upper Eocene) Urtsadzor section, Armenia

The transition from the Bartonian to the Priabonian, as traditionally understood, has long been associated with a series of extinctions and originations in several microfossil groups. The planktonic foraminifer genus Morozovelloides and large species of Acarinina suffered a rapid global extinction, as did many radiolarians. Calcareous nannofossils show several assemblage changes including the acme beginning of Cribrocentrum erbae and the lowest and highest occurrences of Chiasmolithus oamaruensis and C. grandis respectively. In shallow water environments, larger foraminifera also show an extinction among large species of Nummulites, as well as the first occurrences of the stratigraphically important genus Spiroclypeus. However, the correlation between shallow and deep water records remains uncertain, as do the mechanisms driving these biotic events. Here we present the results of a new integrated stratigraphical study (calcareous nannofossils, planktonic foraminifera, larger benthic foraminifera, and low-resolution magnetostratigraphy) of the Urtsadzor section in south-western Armenia which appears to be continuous through this interval. The Urtsadzor section consists of calcareous siltstones rich in micro- and nannofossils, with interbedded limestones containing abundant larger benthic foraminifera. Our new data enable us to correlate larger foraminiferal events with global plankton biostratigraphy, in a section outside of southwest Europe where most previous correlations have been based. At Urtsadzor, the large Nummulites species of N. millecaput-group are present throughout the whole section but decrease in abundance toward the top. The first occurrence of Spiroclypeus, also occurs in the upper part of the section, marking the SBZ 18/19 boundary. These events are associated with the phylogenetic development of the Nummulites fabianii and Heterostegina reticulata lineages. However, the calcareous plankton biostratigraphy indicates the section is well within the Priabonian; within planktonic foraminiferal Zones E14 and E15 and calcareous nannoplankton Zones CNE 18 and CNE 19. These results indicate larger foraminiferal events occur well above the planktonic foraminiferal extinction level and nannofossil assemblage changes indicating the events are not synchronous across groups, with implications for biostratigraphy and recognition of the basal Priabonian in different depositional settings and regions

Programmable disorder in random DNA tilings

Scaling up the complexity and diversity of synthetic molecular structures will require strategies that exploit the inherent stochasticity of molecular systems in a controlled fashion. Here we demonstrate a framework for programming random DNA tilings and show how to control the properties of global patterns through simple, local rules. We constructed three general forms of planar network—random loops, mazes and trees—on the surface of self-assembled DNA origami arrays on the micrometre scale with nanometre resolution. Using simple molecular building blocks and robust experimental conditions, we demonstrate control of a wide range of properties of the random networks, including the branching rules, the growth directions, the proximity between adjacent networks and the size distribution. Much as combinatorial approaches for generating random one-dimensional chains of polymers have been used to revolutionize chemical synthesis and the selection of functional nucleic acids, our strategy extends these principles to random two-dimensional networks of molecules and creates new opportunities for fabricating more complex molecular devices that are organized by DNA nanostructures

Quantifying the Potential Health Impacts of Unvented Combustion in Homes – A Meta- Analysis

While a growing body of scientific literature describes the population health impacts of fossil fuel production and burning via climate and air pollution pathways, less is known about the health impacts of indoor combustion. This paper summarizes the results of studies from the last two decades that investigated the association between exposure to sources of unvented combustion pollutants in homes and a range of health outcomes. We found gas combustion to be associated with 6-28% (95% confidence intervals) increased odds of asthma symptoms, 4-51% increased odds of systemic symptoms, 7-81% increased odds of asthma medication use, and 3-12% increased risk of mortality. These findings can be used to improve public health, for example, by informing requirements for improved ventilation and source control, justifying switching to vented appliances, better regulation of device emissions and quantifying the benefits of electrification of end-uses. Dose-response relationships between human health, NO2 exposure, and other byproducts of combustion are not characterized with a high degree of precision. However, there is clear evidence of a wide range of health effects, even at low levels of exposure. Despite the various designs, geographic sites, length of follow-up, and study dates, we noted a level of consistency between the studies within the current meta-analysis, and with previous ones, which strengthens the level of confidence in our findings

Comparison of Land Cover/Land Use and Habitat Classification Systems for Habitat Mapping from Space: Strengths and Weaknesses Evidenced in Mediterranean Sites of Natura 2000 Network

At a global level, protected sites have been established for the primary purpose of conserving biodiversity, with survey and monitoring of habitats undertaken largely within their boundaries. However, because of increasing human populations with greater access to resources, there is a need to now consider monitoring anthropic activities in the surrounding landscapes as pressures and disturbances are impacting on the functioning and biodiversity values of many protected sites. Earth Observation (EO) data acquired across a range of spatial and temporal scales offer new opportunities for monitoring biodiversity over varying time-scales, either through direct or indirect mapping of species or habitats. However, Land Cover (LC) and/or Land Use (LU), rather than habitat maps are generated in many national and international programs and, whilst the translation from one classification to the other is desirable, differences in definitions and criteria have so far limited the establishment of a unified approach. Focusing on both natural and non-natural environments associated with Natura 2000 sites in the Mediterranean, this paper considers the extent to which three common LC/LU taxonomies (CORINE, the Food and Agricultural Organisation (FAO) Land Cover Classification System (FAO-LCCS) and the IGBP) can be translated to habitat taxonomies with minimum use of additional environmental attributes and/or in situ data. A qualitative and quantitative analysis based on the Jaccard's index established the FAO-LCCS as being the most useful taxonomy for harmonizing LC/LU maps with different legends and dealing with the complexity of habitat description and as a framework for translating EO-derived LC/LU to habitat categories. As demonstration, a habitat map of a wetland site is obtained through translation of the LCCS taxonomy

Typology of Environment-Related Provisions in Regional Trade Agreements

The last 25 years have witnessed a rapid increase in regional trade agreements (RTAs). Although RTAs generally aim at lowering tariff and non-tariff trade barriers, an increasing number of trade agreements extend their scope to cover specific policy areas such as environmental protection and sustainable development. This paper establishes a comprehensive typology and quantitative analysis of environment-related provisions included in RTAs. The analysis covers all the RTAs currently into force that have been notified to the WTO between 1957 and May 2016, namely 270 trade agreements. While environmental exceptions, along with environmental cooperation continue to be the most common types of environment-related provisions, many other different types of provisions are incorporated in an increasing number of RTAs. The common feature of all environment-related provisions, including environmental exceptions, is their heterogeneity in terms of structure, language and scope

Tumor Invasion of Salmonella enterica Serovar Typhimurium Is Accompanied by Strong Hemorrhage Promoted by TNF-α

BACKGROUND:Several facultative anaerobic bacteria with potential therapeutic abilities are known to preferentially colonize solid tumors after systemic administration. How they efficiently find and invade the tumors is still unclear. However, this is an important issue to be clarified when bacteria should be tailored for application in cancer therapy. METHODOLOGY/PRINCIPAL FINDINGS:We describe the initial events of colonization of an ectopic transplantable tumor by Salmonella enterica serovar Typhimurium. Initially, after intravenous administration, bacteria were found in blood, spleen, and liver. Low numbers were also detected in tumors associated with blood vessels as could be observed by immunohistochemistry. A rapid increase of TNF-alpha in blood was observed at that time, in addition to other pro-inflammatory cytokines. This induced a tremendous influx of blood into the tumors by vascular disruption that could be visualized in H&E stainings and quantified by hemoglobin measurements of tumor homogenate. Most likely, together with the blood, bacteria were flushed into the tumor. In addition, blood influx was followed by necrosis formation, bacterial growth, and infiltration of neutrophilic granulocytes. Depletion of TNF-alpha retarded blood influx and delayed bacterial tumor-colonization. CONCLUSION:Our findings emphasize similarities between Gram-negative tumor-colonizing bacteria and tumor vascular disrupting agents and show the involvement of TNF-alpha in the initial phase of tumor-colonization by bacteria

Spin density studies on p-O2NC6F4CNSSN: A heavy p-block organic ferromagnet

A complete picture of the spin density distribution in the organic radical p-O2NC6F4CNSSN has been obtained by a combination of polarized neutron diffraction, electron paramagnetic resonance (EPR), and electron-nuclear double resonance (ENDOR) spectroscopies, and ab initio density-functional theory (DFT) calculations. Polarized neutron diffraction revealed that the spin distribution is predominantly localized on the N and S atoms (+0.25μB and +0.28μB, respectively) of the heterocyclic ring with a small negative spin density on the heterocyclic C atom (−0.06μB). These spin populations are in excellent agreement with both ab initio DFT calculations (spin populations on the C, N, and S sites of −0.07, 0.22 and 0.31, respectively) and cw-EPR studies which estimated the spin population on the N site as 0.24. The DFT calculated spin density revealed less than 1% spin delocalization onto the perfluoroaryl ring, several orders of magnitude lower than the density on the heterocyclic ring. cw-ENDOR studies at both X-band (9 GHz) and Q-band (34 GHz) frequencies probed the spin populations on the two chemically distinct F atoms. These spin populations on the F atoms ortho and meta to the dithiadiazolyl ring are of magnitude 10−3 and 10−4, respectively

Application of prolonged microdialysis sampling in carboplatin-treated cancer patients

Purpose: To better understand the mechanisms underlying (in)sensitivity of tumors to anticancer drugs, assessing intra-tumor drug pharmacokinetics (PKs) could be important. We explored the feasibility of microdialysis in tumor tissue for multiple days in a clinical setting, using carboplatin as model drug. Methods: Plasma and microdialysate samples from tumor and adipose normal tissues were collected up to 47 h after dosing in eight carboplatin-treated patients with an accessible (sub)cutaneous tumor. Results: Pharmacokinetics were evaluable in tumor tissue in 6/8 patients and in adipose normal tissue in 3/8 patients. Concentration-time curves of unbound platinum in both the tissues followed the pattern of the curves in plasma, with exposure ratios of tissue versus plasma ranging from 0.64 to 1.46. Conclusions: Microdialysis can be successfully employed in ambulant patients for multiple days, which enables one to study tissue PK of anticancer drugs in normal and malignant tissues in more detail