Regulating in vivo calcification of alginate microbeads

Alginate calcification has been previously reported clinically and during animal implantation; however no study has investigated the mechanism, extensively characterized the mineral, or evaluated multiple methods to regulate or eliminate mineralization. In the present study, alginate calcification was first studied in vitro: calcium-crosslinked alginate beads sequestered surrounding phosphate while forming traces of hydroxyapatite. Calcification in vivo was then examined in nude mice using alginate microbeads with and without adipose stem cells (ASCs). Variables included the delivery method, site of delivery, sex of the animal, time in vivo, crosslinking solution, and method of storage prior to delivery. Calciumcrosslinked alginate microbeads mineralized when injected subcutaneously or implanted intramuscularly after 1e6 months. More extensive analysis with histology, microCT, FTIR, XRD, and EDS showed calcium phosphate deposits throughout the microbeads with surface mineralization that closely matched hydroxyapatite found in bone. Incorporating 25 mM bisphosphonate reduced alginate calcification whereas using barium chloride eliminated mineralization. Buffering the crosslinking solution with HEPES at pH 7.3 while washing and storing samples in basal media prior to implantation also eliminated calcification in vivo. This study shows that alginate processing prior to implantation can significantly influence bulk hydroxyapatite formation and presents a method to regulate alginate calcificationAlginate calcification has been previously reported clinically and during animal implantation; however no study has investigated the mechanism, extensively characterized the mineral, or evaluated multiple methods to regulate or eliminate mineralization. In the present study, alginate calcification was first studied in vitro: calcium-crosslinked alginate beads sequestered surrounding phosphate while forming traces of hydroxyapatite. Calcification in vivo was then examined in nude mice using alginate microbeads with and without adipose stem cells (ASCs). Variables included the delivery method, site of delivery, sex of the animal, time in vivo, crosslinking solution, and method of storage prior to delivery. Calciumcrosslinked alginate microbeads mineralized when injected subcutaneously or implanted intramuscularly after 1e6 months. More extensive analysis with histology, microCT, FTIR, XRD, and EDS showed calcium phosphate deposits throughout the microbeads with surface mineralization that closely matched hydroxyapatite found in bone. Incorporating 25 mM bisphosphonate reduced alginate calcification whereas using barium chloride eliminated mineralization. Buffering the crosslinking solution with HEPES at pH 7.3 while washing and storing samples in basal media prior to implantation also eliminated calcification in vivo. This study shows that alginate processing prior to implantation can significantly influence bulk hydroxyapatite formation and presents a method to regulate alginate calcificatio

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

Mapping subnational HIV mortality in six Latin American countries with incomplete vital registration systems

BackgroundHuman immunodeficiency virus (HIV) remains a public health priority in Latin America. While the burden of HIV is historically concentrated in urban areas and high-risk groups, subnational estimates that cover multiple countries and years are missing. This paucity is partially due to incomplete vital registration (VR) systems and statistical challenges related to estimating mortality rates in areas with low numbers of HIV deaths. In this analysis, we address this gap and provide novel estimates of the HIV mortality rate and the number of HIV deaths by age group, sex, and municipality in Brazil, Colombia, Costa Rica, Ecuador, Guatemala, and Mexico.MethodsWe performed an ecological study using VR data ranging from 2000 to 2017, dependent on individual country data availability. We modeled HIV mortality using a Bayesian spatially explicit mixed-effects regression model that incorporates prior information on VR completeness. We calibrated our results to the Global Burden of Disease Study 2017.ResultsAll countries displayed over a 40-fold difference in HIV mortality between municipalities with the highest and lowest age-standardized HIV mortality rate in the last year of study for men, and over a 20-fold difference for women. Despite decreases in national HIV mortality in all countries-apart from Ecuador-across the period of study, we found broad variation in relative changes in HIV mortality at the municipality level and increasing relative inequality over time in all countries. In all six countries included in this analysis, 50% or more HIV deaths were concentrated in fewer than 10% of municipalities in the latest year of study. In addition, national age patterns reflected shifts in mortality to older age groups-the median age group among decedents ranged from 30 to 45years of age at the municipality level in Brazil, Colombia, and Mexico in 2017.ConclusionsOur subnational estimates of HIV mortality revealed significant spatial variation and diverging local trends in HIV mortality over time and by age. This analysis provides a framework for incorporating data and uncertainty from incomplete VR systems and can help guide more geographically precise public health intervention to support HIV-related care and reduce HIV-related deaths.Peer reviewe

Measurement of the mass difference between top quark and antiquark in pp collisions at root s=8 TeV

Peer reviewe

Search for jet extinction in the inclusive jet-pT spectrum from proton-proton collisions at s=8 TeV

Published by the American Physical Society under the terms of the Creative Commons Attribution 3.0 License. Further distribution of this work must maintain attribution to the author(s) and the published articles title, journal citation, and DOI.The first search at the LHC for the extinction of QCD jet production is presented, using data collected with the CMS detector corresponding to an integrated luminosity of 10.7  fb−1 of proton-proton collisions at a center-of-mass energy of 8 TeV. The extinction model studied in this analysis is motivated by the search for signatures of strong gravity at the TeV scale (terascale gravity) and assumes the existence of string couplings in the strong-coupling limit. In this limit, the string model predicts the suppression of all high-transverse-momentum standard model processes, including jet production, beyond a certain energy scale. To test this prediction, the measured transverse-momentum spectrum is compared to the theoretical prediction of the standard model. No significant deficit of events is found at high transverse momentum. A 95% confidence level lower limit of 3.3 TeV is set on the extinction mass scale

Mapping geographical inequalities in childhood diarrhoeal morbidity and mortality in low-income and middle-income countries, 2000–17 : analysis for the Global Burden of Disease Study 2017

Background Across low-income and middle-income countries (LMICs), one in ten deaths in children younger than 5 years is attributable to diarrhoea. The substantial between-country variation in both diarrhoea incidence and mortality is attributable to interventions that protect children, prevent infection, and treat disease. Identifying subnational regions with the highest burden and mapping associated risk factors can aid in reducing preventable childhood diarrhoea. Methods We used Bayesian model-based geostatistics and a geolocated dataset comprising 15 072 746 children younger than 5 years from 466 surveys in 94 LMICs, in combination with findings of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017, to estimate posterior distributions of diarrhoea prevalence, incidence, and mortality from 2000 to 2017. From these data, we estimated the burden of diarrhoea at varying subnational levels (termed units) by spatially aggregating draws, and we investigated the drivers of subnational patterns by creating aggregated risk factor estimates. Findings The greatest declines in diarrhoeal mortality were seen in south and southeast Asia and South America, where 54·0% (95% uncertainty interval [UI] 38·1–65·8), 17·4% (7·7–28·4), and 59·5% (34·2–86·9) of units, respectively, recorded decreases in deaths from diarrhoea greater than 10%. Although children in much of Africa remain at high risk of death due to diarrhoea, regions with the most deaths were outside Africa, with the highest mortality units located in Pakistan. Indonesia showed the greatest within-country geographical inequality; some regions had mortality rates nearly four times the average country rate. Reductions in mortality were correlated to improvements in water, sanitation, and hygiene (WASH) or reductions in child growth failure (CGF). Similarly, most high-risk areas had poor WASH, high CGF, or low oral rehydration therapy coverage. Interpretation By co-analysing geospatial trends in diarrhoeal burden and its key risk factors, we could assess candidate drivers of subnational death reduction. Further, by doing a counterfactual analysis of the remaining disease burden using key risk factors, we identified potential intervention strategies for vulnerable populations. In view of the demands for limited resources in LMICs, accurately quantifying the burden of diarrhoea and its drivers is important for precision public health

Measurement of the Z boson differential cross section in transverse momentum and rapidity in proton-proton collisions at 8 TeV

We present a measurement of the Z boson differential cross section in rapidity and transverse momentum using a data sample of pp collision events at a centre-of-mass energy s=8 TeV, corresponding to an integrated luminosity of 19.7 fb-1. The Z boson is identified via its decay to a pair of muons. The measurement provides a precision test of quantum chromodynamics over a large region of phase space. In addition, due to the small experimental uncertainties in the measurement the data has the potential to constrain the gluon parton distribution function in the kinematic regime important for Higgs boson production via gluon fusion. The results agree with the next-to-next-to-leading-order predictions computed with the fewz program. The results are also compared to the commonly used leading-order MadGraph and next-to-leading-order powheg generators. © 2015 CERN for the benefit of the CMS Collaboration

Measurement of the ratio B(B-s(0) -> J/psi f(0)(980))/B(B-s(0) -> J/psi phi(1020)) in pp collisions at root s=7 TeV

Peer reviewe

Study of W boson production in pPb collisions at √sNN = 5.02 TeV

The first study of W boson production in pPb collisions is presented, for bosons decaying to a muon or electron, and a neutrino. The measurements are based on a data sample corresponding to an integrated luminosity of 34.6 nb-1 at a nucleon-nucleon centre-of-mass energy of √sNN = 5.02 TeV, collected by the CMS experiment. The W boson differential cross sections, lepton charge asymmetry, and forward-backward asymmetries are measured for leptons of transverse momentum exceeding 25 GeV/c, and as a function of the lepton pseudorapidity in the |ηlab|&lt;2.4 range. Deviations from the expectations based on currently available parton distribution functions are observed, showing the need for including W boson data in nuclear parton distribution global fits. © 2015 CERN for the benefit of the CMS Collaboration

Measurements of the ϒ(1S), ϒ(2S), and ϒ(3S) differential cross sections in pp collisions at s=7TeV

Differential cross sections as a function of transverse momentum pTpT are presented for the production of ϒ(nS)ϒ(nS) (n = 1, 2, 3) states decaying into a pair of muons. Data corresponding to an integrated luminosity of 4.9View the MathML sourcefb−1 in pp collisions at View the MathML sources=7TeV were collected with the CMS detector at the LHC. The analysis selects events with dimuon rapidity |y|<1.2|y|<1.2 and dimuon transverse momentum in the range View the MathML source10<pT<100GeV. The measurements show a transition from an exponential to a power-law behavior at View the MathML sourcepT≈20GeV for the three ϒ states. Above that transition, the ϒ(3S)ϒ(3S) spectrum is significantly harder than that of the ϒ(1S)ϒ(1S). The ratios of the ϒ(3S)ϒ(3S) and ϒ(2S)ϒ(2S) differential cross sections to the ϒ(1S)ϒ(1S) cross section show a rise as pTpT increases at low pTpT, then become flatter at higher pTpT