Haplotype differences for copy number variants in the 22q11.23 region among human populations: a pigmentation-based model for selective pressure.

Two gene clusters are tightly linked in a narrow region of chromosome 22q11.23: the macrophage migration inhibitory factor (MIF) gene family and the glutathione S-transferase theta class. Within 120 kb in this region, two 30-kb deletions reach high frequencies in human populations. This gives rise to four haplotypic arrangements, which modulate the number of genes in both families. The variable patterns of linkage disequilibrium (LD) between these copy number variants (CNVs) in diverse human populations remain poorly understood. We analyzed 2469 individuals belonging to 27 human populations with different ethnic origins. Then we correlated the genetic variability of 22q11.23 CNVs with environmental variables. We confirmed an increasing strength of LD from Africa to Asia and to Europe. Further, we highlighted strongly significant correlations between the frequency of one of the haplotypes and pigmentation-related variables: skin color (R2=0.675, P<0.001), distance from the equator (R2=0.454, P<0.001), UVA radiation (R2=0.439, P<0.001), and UVB radiation (R2=0.313, P=0.002). The fact that all MIF-related genes are retained on this haplotype and the evidences gleaned from experimental systems seem to agree with the role of MIF-related genes in melanogenesis. As such, we propose a model that explains the geographic and ethnic distribution of 22q11.23 CNVs among human populations, assuming that MIF-related gene dosage could be associated with adaptation to low UV radiatio

Genome Sequencing of SHH Medulloblastoma Predicts Genotype-Related Response to Smoothened Inhibition

SummarySmoothened (SMO) inhibitors recently entered clinical trials for sonic-hedgehog-driven medulloblastoma (SHH-MB). Clinical response is highly variable. To understand the mechanism(s) of primary resistance and identify pathways cooperating with aberrant SHH signaling, we sequenced and profiled a large cohort of SHH-MBs (n = 133). SHH pathway mutations involved PTCH1 (across all age groups), SUFU (infants, including germline), and SMO (adults). Children >3 years old harbored an excess of downstream MYCN and GLI2 amplifications and frequent TP53 mutations, often in the germline, all of which were rare in infants and adults. Functional assays in different SHH-MB xenograft models demonstrated that SHH-MBs harboring a PTCH1 mutation were responsive to SMO inhibition, whereas tumors harboring an SUFU mutation or MYCN amplification were primarily resistant

Biological Earth observation with animal sensors

Space-based tracking technology using low-cost miniature tags is now delivering data on fine-scale animal movement at near-global scale. Linked with remotely sensed environmental data, this offers a biological lens on habitat integrity and connectivity for conservation and human health; a global network of animal sentinels of environmen-tal change

Mineralogia e gênese de argissolos das Serras do Tabuleiro/Itajaí, Estado de Santa Catarina

As rochas do escudo cristalino, que afloram na porção centro-leste e nordeste do Estado de Santa Catarina, estão dispostas em relevo forte ondulado e montanhoso da unidade geomorfológica Serras do Tabuleiro/Itajaí. A movimentada superfície é resultante dos ciclos tecto magmático metamórficos sofridos pela crosta, responsáveis pelo retrabalhamento de rochas muito antigas formadas do Arqueano ao Proterozoico. Esse compartimento é constituído por rochas metamórficas, e informações sobre pedogênese e composição mineralógica dos solos delas derivados são escassas, fator que motivou a condução deste trabalho. Cinco perfis resultantes da pedogênese desses materiais foram estudados. O primeiro, desenvolvido de hornblendito do Complexo Granulítico de Santa Catarina (P1), foi descrito no topo de elevação em Pomerode, em condições de relevo forte ondulado. O segundo e o quinto perfis (P2 e P5), ambos desenvolvidos de granulitos máficos do mesmo complexo, respectivamente em Massaranduba e Blumenau, foram descritos na base da encosta, em relevo local ondulado. O terceiro perfil (P3), resultante da alteração de xistos do Complexo Metamórfico Brusque, foi descrito em encosta de relevo forte ondulado, em Botuverá. O quarto perfil (P4) foi fruto da pedogênese de granitoides foliados da faixa Granito-Gnáissica Faxinal, sendo descrito no terço inferior da encosta, num relevo ondulado. Foram feitas descrições gerais e morfológicas dos solos e da litologia subjacente, análises físicas e químicas de caracterização e análises mineralógicas da fração argila por difratometria de raios X (DRX), procurando avaliar as transformações sofridas pelos minerais presentes nas rochas durante a evolução dos solos. Todos os solos apresentaram alta relação textural e, ou, grau de desenvolvimento de estrutura em blocos, associada à presença de cerosidade, caracterizando a presença de horizonte diagnóstico B textural, com argila de atividade baixa ou alta e caráter distrófico, alumínico ou alítico, o que permitiu classificá-los como Argissolo Amarelo distrófico típico (P1), Argissolo Amarelo alítico típico (P2, P3 e P5) e Argissolo Vermelho-Amarelo alumínico típico (P4) no Sistema Brasileiro de Classificação de Solos, versão de 2006. Em todos os Argissolos predominou caulinita, secundada por argilominerais do grupo da ilita, interestratificados ilita-vermiculita e, ou, vermiculita com polímeros de hidroxi-Al entrecamadas. Gibbsita, em baixas quantidades, também foi constatada nos perfis P2, P3 e P5. A formação de caulinita é resultante da dissolução de minerais primários, favorecida pelas condições climáticas subtropicais úmidas. Os argilominerais com estrutura 2:1 são provavelmente resultantes da transformação de filossilicatos presentes no material originário. O aumento da atividade da fração argila dos solos relacionou-se com o aumento na quantidade de argilominerais 2:1, cuja proporção foi mais alta no Argissolo desenvolvido de Muscovita-Xisto

Design of a Collimation Section for the FCC-ee

The design parameters of the FCC-ee foresee operation with a total stored beam energy of about 20 MJ, exceeding those of previous lepton colliders by almost two orders of magnitude. Given the inherent damage potential, a halo collimation system is studied to protect the machine hardware, in particular superconducting equipment such as the final focus quadrupoles, from sudden beam loss. The different constraints that led to dedicating one straight section to collimation will be outlined. In addition, a preliminary layout and optics for a collimation insertion are presented

Development of Collimation Simulations for the FCC-ee

A collimation system is under study for the FCC-ee to protect the machine from the multi-MJ electron and positron beams and limit the backgrounds to the detectors. One of the key aspects of the collimation system design is the setup of simulation studies combining particle tracking and scattering in the collimators. The tracking must include effects important for electron beam single-particle dynamics in the FCC-ee, such as synchrotron radiation. For collimation, an aperture model and particle-matter interactions for electrons are required. There are currently no established simulation frameworks that include all the required features. The latest developments of an integrated framework for multi-turn collimation studies in the FCC-ee are presented. The framework is based on an interface between tracking codes, pyAT and Xtrack, and a particle-matter interaction code, BDSIM, based on Geant4. Promising alternative simulation codes and frameworks are also discussed. The challenges are outlined, and the first results are presented, including preliminary loss maps for the FCC-ee

Influence of B content on microstructure, phase composition and mechanical properties of CVD Ti(B,N) coatings

Within this work the effect of the B content on the microstructure, phase composition and mechanical properties of CVD Ti(B,N) coatings is investigated. Ti(B,N) coatings with B contents from 0 (fcc-TiN) to ∼5, ∼15, ∼30, ∼45 and 66 (h-TiB2) at.% have been deposited by CVD. The elemental composition of the coatings was confirmed by ERDA and their microstructure was investigated using XRD and SEM. With increasing B content, a transition from a fcc to a h-dominated structure via dual-phase fcc/h-Ti(B,N) was observed, which was accompanied by a decreasing grain size from the µm to nm range. Combinatorial use of Raman spectroscopy, XPS and APT measurements indicated B-rich grain boundary segregations and the formation of increasing amounts of h-Ti(B,N)2 clusters embedded within an fcc-Ti(B,N) matrix up to B contents of ∼30 at.%, while for ∼45 at.% B the matrix was predominantly composed of h-Ti(B,N)2. Complementary ab initio calculations predicting the phase formation confirmed the interpretation of the experimental results. In terms of the mechanical properties, nanoindentation measurements and micromechanical testing revealed a rise in hardness from ∼18 to ∼41 GPa and an increasing fracture stress and toughness from ∼7 to ∼13 GPa and ∼4.6 to ∼5.5 MPam1/2, respectively, by increasing the B content up to ∼30 at.%. In contrast, a significant drop in hardness, fracture stress and fracture toughness was observed at ∼45 at.% B. Thus it can be concluded, that both h-TiB2 and dual-phase fcc/h-Ti(B,N) coatings with maximized B content yield superior properties over TiN and consequently improved performance.peerReviewe

Independent and interactive impacts of hypertension and diabetes mellitus on verbal memory: A coordinated analysis of longitudinal data from England, Sweden, and the United States.

The importance of preventing and controlling hypertension (HTN) and diabetes mellitus (DM) to mitigate risks to physical health has long been understood by healthcare professionals. More recently, a growing body of evidence also implicates HTN and DM in age-related cognitive decline and risk for dementia, though consensus has yet to be reached on whether older adults living with comorbid HTN and DM are at heightened risk for cognitive impairment. The present study sought to contribute to this topic through a coordinated analysis of three longitudinal studies of aging from England, Sweden, and the United States (total N=12 513). Identical multilevel linear growth models were fit to each to estimate the impact of baseline disease status on initial level and change in verbal declarative memory performance. Overall, few associations between HTN, DM and cognition were observed. Rate of decline was steeper for Swedish participants with independent HTN but attenuated for their American counterparts. Americans with comorbid HTN and DM showed attenuated decline. Treatment with medication was substantially less prevalent in the earlier-born and lower-educated Swedish sample, which may help to explain our pattern of results. In addition, those living with multiple conditions may be more likely to receive treatment, mitigating cognitive decline. Our results present a nuanced view of the interactions between HTN, DM and cognition and lead us to recommend consideration of treatment status or proxies such as birth cohort and education, in combination with age at assessment and specific measure used, in the interpretation of research in this area