Mutations of the ret protooncogene in German multiple endocrine neoplasia families: Relation between genotype and phenotype.

It has been suggested that not only the position but also the nature of the mutations of the ret protooncogene strongly correlate with the clinical manifestation of the multiple endocrine neoplasm type 2 (MEN 2) syndrome. In particular, individuals with a Cys634-Arg substitution should have a greater risk of developing parathyroid disease. We, therefore, analyzed 94 unrelated families from Germany with inherited medullary thyroid carcinoma (MTC) for mutation of the ret protooncogene. In all but 1 of 59 families with MEN 2A, germline mutations in the extracellular domain of the ret protein were found. Some 81% of the MEN 2A mutations affected codon 634. Phenotype-genotype correlations suggested that the prevalence of pheochromocytoma and hyperparathyroidism is significantly higher in families with codon 634 mutations, but there was no correlation with the nature of the mutation. In all but 1 of 27 familial MTC (FMTC) families, mutations were detected in 1 of 4 cysteines in the extracellular domain of the ret protooncogene. Half of the FMTC mutations affected codon 634. Mutations outside of codon 634 occurred more often in FMTC families than in MEN 2A families. In all but 1 of 8 MEN 2B patients, de novo mutations in codon 918 were found. These data confirm the preferential localization of MEN 2-associated mutations and the correlation between disease phenotype and the position of the ret mutation, but there was no correlation between the occurrence of hyperparathyroidism or pheochromocytoma and the nature of the mutation

Total VOC reactivity in the planetary boundary layer: 2. A new indicator for determining the sensitivity of the ozone production to VOC and NO

A new indicator is proposed for determining if tropospheric ozone production in a specifiacr eai s limitedb yV OC or NOx.T he indicato1r 9= r•ø•C/•oød•Xes cribeths e ratio of the lifetimes of OH against the losses by reacting with VOC and NOx. Whereas •oøx• c anb e obtainebdy c onventionmale asurementthse, n ewp umpa ndp robeO H approach which is described in part one of this publication makes it now possible to obtain also ß_ov •o c ßI ndicator values above a thresholdv alue of 0.2 __+50 % are representativeo f NOx-saturatedc onditionsw here an increaseo f NOx emissionsc auses lower ozone production.F or valuesb elow 0.01 the ozone productioni s very insensitivet o changeso f VOC emissionsT. he robustnesso f this indicator againsts everalp arameters sucha s temperature,h umidity,p hotolysisa, nd initial ozone concentrationsis tested in a box model and comparedt o the robustnesso f other earlier proposedi ndicators.I n contrast to earlier proposed indicators, this new one is not based on photochemically producedl ong-liveds peciesb ut describest he instantaneousr egime of an air parcel. Three-dimensionasl imulations howst hat this indicator is quite successfuiln estimatingt he impact of increasedo r reducede missionso n the ozone concentrationsfo r each location in the modeling area. This will make it a very helpful tool for developing ozone abatement strategies

Total VOC reactivity in the planetary boundary layer: 1. Estimation by a pump and probe OH experiment

The reactivityo f hydroxyrl adical (OH) with total volatile organicc ompounds (VOC), Z kvoc[VOC ], is directly obtained in the planetary boundary layer (PBL). The method is basedo n a perturbationt echniquew here high initial OH concentrationsa re createdb yf lashp hotolysoisf ozonea nds ubsequerneta ctiono f O(•D) withH 20. Laserinduced fluorescence is used to measure the residual OH concentration at different time delays after the perturbation (<100 ms) and obtain a direct estimate of the OH lifetime rOH for different atmospheric conditions. For specific experimental conditions the transportb y the wind may be neglected,a nd the chemicalp rocessesg overningt he OH decaym ay be expressedb y a detailed box model. With a simple chemicale quation derived in this paper using roll and complementarym easurementso f CO, 03, and NOx, an in situ estimate of Z kvoc[VOC ] in the PBL is retrieved with an uncertainty of less than 20% in comparisont o the detailed box model calculationsT. his analysisi s applied to laboratory measurementsw ith three syntheticN Ox/VOC/O 3 gas mixtures,a nd the retrieved OH lifetimes and total VOC reactivitya re discusseda gainstm odel predictions

On the impact of urban surface exchange parameterisations on air quality simulations: the Athens case

Most of the standard mesoscale models represent the dynamic and thermodynamic surface exchanges in urban areas with the same technique used for ruralareas (based on Monin–Obukhov similarity theory and a surface energy budget). However it has been shown that this technique is not able to fully capture the structure of the turbulent layer above a city. Aim of this study is to evaluate the importance for meteorological and air quality simulations, of properly capture the dynamic and thermodynamic surface exchanges in urban areas. Two sets of simulations were performed over the city of Athens (Greece): a first using a mesoscale model with a detailed urban surface exchange parameterisation (able to reproduce the surface exchanges better than the traditionalmethod), and a second with the traditionalapproach. Meteorological outputs are passed to a Eulerian photochemical model (the photochemical model is run offline). Comparison with measurements shows better agreement for the simulation with the detailed parameterisation. The differences between the simulations concern, mainly, wind speed (maximum difference of 0.5–1ms-1), night-time temperatures (2–3°C), turbulence intensity (2m2 s-2) and heat fluxes (0.15Kms-1) over the urban area, urban nocturnal land breeze intensity, timing and extension of sea breeze. These differences modify the pollutant distribution (e.g. for ozone maximum differences are of the order of 30 ppb). Differences between the simulations are also found in AOT60 values (inside and outside the city) and in O3 chemicalregimes

Quantum Criticality in Heavy Fermion Metals

Quantum criticality describes the collective fluctuations of matter undergoing a second-order phase transition at zero temperature. Heavy fermion metals have in recent years emerged as prototypical systems to study quantum critical points. There have been considerable efforts, both experimental and theoretical, which use these magnetic systems to address problems that are central to the broad understanding of strongly correlated quantum matter. Here, we summarize some of the basic issues, including i) the extent to which the quantum criticality in heavy fermion metals goes beyond the standard theory of order-parameter fluctuations, ii) the nature of the Kondo effect in the quantum critical regime, iii) the non-Fermi liquid phenomena that accompany quantum criticality, and iv) the interplay between quantum criticality and unconventional superconductivity.Comment: (v2) 39 pages, 8 figures; shortened per the editorial mandate; to appear in Nature Physics. (v1) 43 pages, 8 figures; Non-technical review article, intended for general readers; the discussion part contains more specialized topic

Cooperation of cancer drivers with regulatory germline variants shapes clinical outcomes

Pediatric malignancies including Ewing sarcoma (EwS) feature a paucity of somatic alterations except for pathognomonic driver-mutations that cannot explain overt variations in clinical outcome. Here, we demonstrate in EwS how cooperation of dominant oncogenes and regulatory germline variants determine tumor growth, patient survival and drug response. Binding of the oncogenic EWSR1-FLI1 fusion transcription factor to a polymorphic enhancerlike DNA element controls expression of the transcription factor MYBL2 mediating these phenotypes. Whole-genome and RNA sequencing reveals that variability at this locus is inherited via the germline and is associated with variable inter-tumoral MYBL2 expression. High MYBL2 levels sensitize EwS cells for inhibition of its upstream activating kinase CDK2 in vitro and in vivo, suggesting MYBL2 as a putative biomarker for anti-CDK2-therapy. Collectively, we establish cooperation of somatic mutations and regulatory germline variants as a major determinant of tumor progression and highlight the importance of integrating the regulatory genome in precision medicine

Find the weakest link. A comparison between demographic, genetic and demo-genetic metapopulation extinction times

<p>Abstract</p> <p>Background</p> <p>While the ultimate causes of most species extinctions are environmental, environmental constraints have various secondary consequences on evolutionary and ecological processes. The roles of demographic, genetic mechanisms and their interactions in limiting the viabilities of species or populations have stirred much debate and remain difficult to evaluate in the absence of demography-genetics conceptual and technical framework. Here, I computed projected times to metapopulation extinction using (1) a model focusing on the effects of species properties, habitat quality, quantity and temporal variability on the time to demographic extinction; (2) a genetic model focusing on the dynamics of the drift and inbreeding loads under the same species and habitat constraints; (3) a demo-genetic model accounting for demographic-genetic processes and feedbacks.</p> <p>Results</p> <p>Results indicate that a given population may have a high demographic, but low genetic viability or vice versa; and whether genetic or demographic aspects will be the most limiting to overall viability depends on the constraints faced by the species (e.g., reduction of habitat quantity or quality). As a consequence, depending on metapopulation or species characteristics, incorporating genetic considerations to demographically-based viability assessments may either moderately or severely reduce the persistence time. On the other hand, purely genetically-based estimates of species viability may either underestimate (by neglecting demo-genetic interactions) or overestimate (by neglecting the demographic resilience) true viability.</p> <p>Conclusion</p> <p>Unbiased assessments of the viabilities of species may only be obtained by identifying and considering the most limiting processes (i.e., demography or genetics), or, preferentially, by integrating them.</p

Sarcoma classification by DNA methylation profiling

Sarcomas are malignant soft tissue and bone tumours affecting adults, adolescents and children. They represent a morphologically heterogeneous class of tumours and some entities lack defining histopathological features. Therefore, the diagnosis of sarcomas is burdened with a high inter-observer variability and misclassification rate. Here, we demonstrate classification of soft tissue and bone tumours using a machine learning classifier algorithm based on array-generated DNA methylation data. This sarcoma classifier is trained using a dataset of 1077 methylation profiles from comprehensively pre-characterized cases comprising 62 tumour methylation classes constituting a broad range of soft tissue and bone sarcoma subtypes across the entire age spectrum. The performance is validated in a cohort of 428 sarcomatous tumours, of which 322 cases were classified by the sarcoma classifier. Our results demonstrate the potential of the DNA methylation-based sarcoma classification for research and future diagnostic applications