The ancient CYP716 family is a major contributor to the diversification of eudicot triterpenoid biosynthesis

Triterpenoids are widespread bioactive plant defence compounds with potential use as pharmaceuticals, pesticides and other high-value products. Enzymes belonging to the cytochrome P450 family have an essential role in creating the immense structural diversity of triterpenoids across the plant kingdom. However, for many triterpenoid oxidation reactions, the corresponding enzyme remains unknown. Here we characterize CYP716 enzymes from different medicinal plant species by heterologous expression in engineered yeasts and report ten hitherto unreported triterpenoid oxidation activities, including a cyclization reaction, leading to a triterpenoid lactone. Kingdom-wide phylogenetic analysis of over 400 CYP716s from over 200 plant species reveals details of their evolution and suggests that in eudicots the CYP716s evolved specifically towards triterpenoid biosynthesis. Our findings underscore the great potential of CYP716s as a source for generating triterpenoid structural diversity and expand the toolbox available for synthetic biology programmes for sustainable production of bioactive plant triterpenoids

The RMS Survey: Critical Tests of Accretion Models for the Formation of Massive Stars

There is currently no accepted theoretical framework for the formation of the most massive stars, and the manner in which protostars continue to accrete and grow in mass beyond \sim10Msun is still a controversial topic. In this study we use several prescriptions of stellar accretion and a description of the Galactic gas distribution to simulate the luminosities and spatial distribution of massive protostellar population of the Galaxy. We then compare the observables of each simulation to the results of the Red MSX Source (RMS) survey, a recently compiled database of massive young stellar objects. We find that the observations are best matched by accretion rates which increase as the protostar grows in mass, such as those predicted by the turbulent core and competitive accretion (i.e. Bondi-Hoyle) models. These 'accelerating accretion' models provide very good qualitative and quantitative fits to the data, though we are unable to distinguish between these two models on our simulations alone. We rule out models with accretion rates which are constant with time, and those which are initially very high and which fall away with time, as these produce results which are quantitatively and/or qualitatively incompatible with the observations. To simultaneously match the low- and high-luminosity YSO distribution we require the inclusion of a 'swollen-star' pre-main-sequence phase, the length of which is well-described by the Kelvin-Helmholz timescale. Our results suggest that the lifetime of the YSO phase is \sim 10^5yrs, whereas the compact Hii-region phase lasts between \sim 2 - 4 \times 10^5yrs depending on the final mass of the star. Finally, the absolute numbers of YSOs are best matched by a globally averaged star-formation rate for the Galaxy of 1.5-2Msun/yr.Comment: 22 pages, 24 figures. Accepted for publication in MNRA

The basal epithelial marker P-cadherin associates with breast cancer cell populations harboring a glycolytic and acid-resistant phenotype

"BMC Cancer 2014 14:734"BACKGROUND: Cancer stem cells are hypoxia-resistant and present a preponderant glycolytic metabolism. These characteristics are also found in basal-like breast carcinomas (BLBC), which show increased expression of cancer stem cell markers.Recently, we demonstrated that P-cadherin, a biomarker of BLBC and a poor prognostic factor in this disease, mediates stem-like properties and resistance to radiation therapy. Thus, the aim of the present study was to evaluate if P-cadherin expression was associated to breast cancer cell populations with an adapted phenotype to hypoxia. METHODS: Immunohistochemistry was performed to address the expression of P-cadherin, hypoxic, glycolytic and acid-resistance biomarkers in primary human breast carcinomas. In vitro studies were performed using basal-like breast cancer cell lines. qRT-PCR, FACS analysis, western blotting and confocal microscopy were used to assess the expression of P-cadherin after HIF-1a stabilization, achieved by CoCl2 treatment. siRNA-mediated knockdown was used to silence the expression of several targets and qRT-PCR was employed to evaluate the effects of P-cadherin on HIF-1a signaling. P-cadherin high and low breast cancer cell populations were sorted by FACS and levels of GLUT1 and CAIX were assessed by FACS and western blotting. Mammosphere forming efficiency was used to determine the stem cell activity after specific siRNA-mediated knockdown, further confirmed by western blotting. RESULTS: We demonstrated that P-cadherin overexpression was significantly associated with the expression of HIF-1a, GLUT1, CAIX, MCT1 and CD147 in human breast carcinomas. In vitro, we showed that HIF-1a stabilization was accompanied by increased membrane expression of P-cadherin and that P-cadherin silencing led to a decrease of the mRNA levels of GLUT1 and CAIX. We also found that the cell fractions harboring high levels of P-cadherin were the same exhibiting more GLUT1 and CAIX expression. Finally, we showed that P-cadherin silencing significantly decreases the mammosphere forming efficiency in the same range as the silencing of HIF-1a, CAIX or GLUT1, validating that all these markers are being expressed by the same breast cancer stem cell population. CONCLUSIONS: Our results establish a link between aberrant P-cadherin expression and hypoxic, glycolytic and acid-resistant breast cancer cells, suggesting a possible role for this marker in cancer cell metabolismo.This work was funded by FEDER funds through the COMPETE Program (Programa Operacional Factores de Competitividade) and by national funds through FCT (Portuguese Foundation for Science and Technology, Portugal), mainly in the context of the scientific project PTDC/SAU-GMG/120049/2010-FCOMP-01-0124-FEDER-021209, and partially by PTDC/SAU-FCF/104347/2008. FCT funded the research grants of BS (SFRH/BD/69353/2010), ASR (SFRH/BPD/75705/2011), ARN (grant from the project PTDC/SAU-GMG/120049/2010), CP (SFRH/BPD/69479/2010), AV (SFRH/BPD/90303/2012), as well as JP, with Programa Ciencia 2007 (Contratacao de Doutorados para o SCTN - financiamento pelo POPH - QREN - Tipologia 4.2 - Promocao do Emprego Cientifico, comparticipado pelo Fundo Social Europeu e por fundos nacionais do MCTES) and Programa IFCT (FCT Investigator). IPATIMUP is an Associate Laboratory of the Portuguese Ministry of Science, Technology and Higher Education and is partially supported by FCT

Orthopaedic management of Hurler’s disease after hematopoietic stem cell transplantation: a systematic review

The introduction of hematopoietic stem cell transplantation (HSCT) has significantly improved the life-span of Hurler patients (mucopolysaccharidosis type I-H, MPS I-H). Yet, the musculoskeletal manifestations seem largely unresponsive to HSCT. In order to facilitate evidence based management, the aim of the current study was to give a systematic overview of the orthopaedic complications and motor functioning of Hurler's patients after HSCT. A systematic review was conducted of the medical literature published from January 1981 to June 2010. Two reviewers independently assessed all eligible citations, as identified from the Pubmed and Embase databases. A pre-developed data extraction form was used to systematically collect information on the prevalence of radiological and clinical signs, and on the orthopaedic treatments and outcomes. A total of 32 studies, including 399 patient reports were identified. The most frequent musculoskeletal abnormalities were odontoid hypoplasia (72%), thoracolumbar kyphosis (81%), genu valgum (70%), hip dysplasia (90%) and carpal tunnel syndrome (63%), which were often treated surgically during the first decade of life. The overall complication rate of surgical interventions was 13.5%. Motor functioning was further hampered due to reduced joint mobility, hand dexterity, motor development and longitudinal growth. Stem cell transplantation does not halt the progression of a large range of disabling musculoskeletal abnormalities in Hurler's disease. Although prospective data on the quantification, progression and treatment of these deformities were very limited, early surgical intervention is often advocated. Prospective data collection will be mandatory to achieve better evidence on the effect of treatment strategies

The large trans-Neptunian object 2002 TC302 from combined stellar occultation, photometry, and astrometry data

Context. Deriving physical properties of trans-Neptunian objects is important for the understanding of our Solar System. This requires observational efforts and the development of techniques suitable for these studies. Aims. Our aim is to characterize the large trans-Neptunian object (TNO) 2002 TC302. Methods. Stellar occultations offer unique opportunities to determine key physical properties of TNOs. On 28 January 2018, 2002 TC302 occulted a mv ~ 15.3 star with designation 593-005847 in the UCAC4 stellar catalog, corresponding to Gaia source 130957813463146112. Twelve positive occultation chords were obtained from Italy, France, Slovenia, and Switzerland. Also, four negative detections were obtained near the north and south limbs. This represents the best observed stellar occultation by a TNO other than Pluto in terms of the number of chords published thus far. From the 12 chords, an accurate elliptical fit to the instantaneous projection of the body can be obtained that is compatible with the near misses. Results. The resulting ellipse has major and minor axes of 543 ± 18 km and 460 ± 11 km, respectively, with a position angle of 3 ± 1 degrees for the minor axis. This information, combined with rotational light curves obtained with the 1.5 m telescope at Sierra Nevada Observatory and the 1.23 m telescope at Calar Alto observatory, allows us to derive possible three-dimensional shapes and density estimations for the body based on hydrostatic equilibrium assumptions. The effective diameter in equivalent area is around 84 km smaller than the radiometrically derived diameter using thermal data from Herschel and Spitzer Space Telescopes. This might indicate the existence of an unresolved satellite of up to ~300 km in diameter, which is required to account for all the thermal flux, although the occultation and thermal diameters are compatible within their error bars given the considerable uncertainty of the thermal results. The existence of a potential satellite also appears to be consistent with other ground-based data presented here. From the effective occultation diameter combined with absolute magnitude measurements we derive a geometric albedo of 0.147 ± 0.005, which would be somewhat smaller if 2002 TC302 has a satellite. The best occultation light curves do not show any signs of ring features or any signatures of a global atmosphere.Funding from Spanish projects AYA2014-56637-C2-1-P, AYA2017-89637-R, from FEDER, and Proyecto de Excelencia de la Junta de Andalucía 2012-FQM1776 is acknowledged. We would like to acknowledge financial support by the Spanish grant AYA-RTI2018-098657-JI00 “LEO-SBNAF” (MCIU/AEI/FEDER, UE) and the financial support from the State Agency for Research of the Spanish MCIU through the “Center of Excellence Severo Ochoa” award for the Instituto de Astrofísica de Andalucía (SEV- 2017-0709). Part of the research received funding from the European Union’s Horizon 2020 Research and Innovation Programme, under grant agreement no. 687378 and from the ERC programme under Grant Agreement no. 669416 Lucky Star. The following authors acknowledge the respective CNPq grants: FB-R 309578/2017-5; RV-M 304544/2017-5, 401903/2016-8; J.I.B.C. 308150/2016-3; MA 427700/2018-3, 310683/2017-3, 473002/2013-2. This study was financed in part by the Coordenação de Aperfeiaçoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance Code 001 and the National Institute of Science and Technology of the e-Universe project (INCT do e-Universo, CNPq grant 465376/2014-2). GBR acknowledges CAPES-FAPERJ/PAPDRJ grant E26/203.173/2016, MA FAPERJ grant E-26/111.488/2013 and ARGJr FAPESP grant 2018/11239-8. E.F.-V. acknowledges support from the 2017 Preeminent Postdoctoral Program (P3) at UCF. C.K., R.S., A.F-T., and G.M. have been supported by the K-125015 and GINOP-2.3.2-15-2016-00003 grants of the Hungarian National Research, Development and Innovation Office (NKFIH), Hungary. G.M. was also supported by the Hungarian National Research, Development and Innovation Office (NKFIH) grant PD-128 360. R.K. and T.P. were supported by the VEGA 2/0031/18 grant

May Measurement Month 2018: a pragmatic global screening campaign to raise awareness of blood pressure by the International Society of Hypertension

Aims Raised blood pressure (BP) is the biggest contributor to mortality and disease burden worldwide and fewer than half of those with hypertension are aware of it. May Measurement Month (MMM) is a global campaign set up in 2017, to raise awareness of high BP and as a pragmatic solution to a lack of formal screening worldwide. The 2018 campaign was expanded, aiming to include more participants and countries. Methods and results Eighty-nine countries participated in MMM 2018. Volunteers (≥18 years) were recruited through opportunistic sampling at a variety of screening sites. Each participant had three BP measurements and completed a questionnaire on demographic, lifestyle, and environmental factors. Hypertension was defined as a systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg, or taking antihypertensive medication. In total, 74.9% of screenees provided three BP readings. Multiple imputation using chained equations was used to impute missing readings. 1 504 963 individuals (mean age 45.3 years; 52.4% female) were screened. After multiple imputation, 502 079 (33.4%) individuals had hypertension, of whom 59.5% were aware of their diagnosis and 55.3% were taking antihypertensive medication. Of those on medication, 60.0% were controlled and of all hypertensives, 33.2% were controlled. We detected 224 285 individuals with untreated hypertension and 111 214 individuals with inadequately treated (systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg) hypertension. Conclusion May Measurement Month expanded significantly compared with 2017, including more participants in more countries. The campaign identified over 335 000 adults with untreated or inadequately treated hypertension. In the absence of systematic screening programmes, MMM was effective at raising awareness at least among these individuals at risk

Combined searches for the production of supersymmetric top quark partners in proton-proton collisions at root s=13 TeV

A combination of searches for top squark pair production using proton-proton collision data at a center-of-mass energy of 13 TeV at the CERN LHC, corresponding to an integrated luminosity of 137 fb(-1) collected by the CMS experiment, is presented. Signatures with at least 2 jets and large missing transverse momentum are categorized into events with 0, 1, or 2 leptons. New results for regions of parameter space where the kinematical properties of top squark pair production and top quark pair production are very similar are presented. Depending on themodel, the combined result excludes a top squarkmass up to 1325 GeV for amassless neutralino, and a neutralinomass up to 700 GeV for a top squarkmass of 1150 GeV. Top squarks with masses from 145 to 295 GeV, for neutralino masses from 0 to 100 GeV, with a mass difference between the top squark and the neutralino in a window of 30 GeV around the mass of the top quark, are excluded for the first time with CMS data. The results of theses searches are also interpreted in an alternative signal model of dark matter production via a spin-0 mediator in association with a top quark pair. Upper limits are set on the cross section for mediator particle masses of up to 420 GeV

Measurement of the top quark forward-backward production asymmetry and the anomalous chromoelectric and chromomagnetic moments in pp collisions at √s = 13 TeV

Abstract The parton-level top quark (t) forward-backward asymmetry and the anomalous chromoelectric (d̂ t) and chromomagnetic (μ̂ t) moments have been measured using LHC pp collisions at a center-of-mass energy of 13 TeV, collected in the CMS detector in a data sample corresponding to an integrated luminosity of 35.9 fb−1. The linearized variable AFB(1) is used to approximate the asymmetry. Candidate t t ¯ events decaying to a muon or electron and jets in final states with low and high Lorentz boosts are selected and reconstructed using a fit of the kinematic distributions of the decay products to those expected for t t ¯ final states. The values found for the parameters are AFB(1)=0.048−0.087+0.095(stat)−0.029+0.020(syst),μ̂t=−0.024−0.009+0.013(stat)−0.011+0.016(syst), and a limit is placed on the magnitude of | d̂ t| < 0.03 at 95% confidence level. [Figure not available: see fulltext.

Search for Physics beyond the Standard Model in Events with Overlapping Photons and Jets

Results are reported from a search for new particles that decay into a photon and two gluons, in events with jets. Novel jet substructure techniques are developed that allow photons to be identified in an environment densely populated with hadrons. The analyzed proton-proton collision data were collected by the CMS experiment at the LHC, in 2016 at root s = 13 TeV, and correspond to an integrated luminosity of 35.9 fb(-1). The spectra of total transverse hadronic energy of candidate events are examined for deviations from the standard model predictions. No statistically significant excess is observed over the expected background. The first cross section limits on new physics processes resulting in such events are set. The results are interpreted as upper limits on the rate of gluino pair production, utilizing a simplified stealth supersymmetry model. The excluded gluino masses extend up to 1.7 TeV, for a neutralino mass of 200 GeV and exceed previous mass constraints set by analyses targeting events with isolated photons.Peer reviewe