β-lapachone induces growth inhibition and apoptosis in bladder cancer cells by modulation of BCL-2 family and activation of caspases

Aim: To study in vitro the molecular mechanism of apoptosis caused by b-lapachone, a quinone obtained from the bark of the lapacho tree (Tabebuia avellanedae). Materials and Methods: The study was carried out on human bladder carcinoma T24 cell line. Determination of cell viability was done using trypan blue exclusion method, apoptosis quantitative estimation — by DAPI staining and agarose gel electrophoresis for DNA fragmentation. Flow cytometry analysis, RT-PCR and Western blot analysis, colorimetric assay of caspase activity were applied as well. Results: It was found that in micromolar range of concentrations b-lapachone inhibited the viability of T24 cells by inducing apoptosis, which could be proved by formation of apoptotic bodies and DNA fragmentation. Treatment of T24 cells with b-lapachone resulted in a down-regulation of Bcl-2 expression and up-regulation of Bax expression. b-lapachone-induced apoptosis was also associated with activation of caspase-3 and caspase-9, inhibition of IAP expression, and degradation of poly (ADP-ribose) polymerase, phospholipase C-g1 and b-catenin proteins. At the same time Fas and FasL levels were inhibited upon treatment with b-lapachone in a concentration-dependent manner. Conclusion: b-lapachone-induced apoptosis in T24 cells is mediated, at least in part, by the mitochondrial-signaling pathway.Цель: изучить механизмы апоптоза клеток карциномы мочевого пузыря человека Т24 при действии β-лапакона, хинона из коры дерева Tabebuia avellanedae. Материалы и методы: для определения жизнеспособности клеток использовали окраску трипановым синим; окрашивание DAPI и электрофоретический анализ фрагментации ДНК в агарозном геле, метод проточной цитометрии (для количественной оценки апоптоза); полимеразную цепную реакцию в режиме реального времени (РВ-ПЦР) и Вестерн блот-анализ (для оценки уровня экспрессии генов и белков), а также колориметрический анализ активности каспаз. Результаты: выявлено, что в микромолярных концентрациях β-лапакон понижает жизне- способность клеток линии Т24 путем активации апоптоза, что подтверждается формированием апоптотических тел и фрагментацией ДНК. Результаты РВ-ПЦР и иммуноблоттинга указывают на то, что обработка клеток β-лапаконом приводит к снижению экспрессии Bcl-2 и к активации Bax. Апоптоз, индуцированный β-лапаконом, также сопровож- дается активацией каспаз -3­­ и -9, ингибированием экспрессии семейства IAP, а также деградацией поли-(ADP-рибозо) полимеразы, фосфатазы C-γ1 и β-катенина. Тем не менее, уровень экспрессии Fas и FasL снижался при увеличении концентрации β-лапакона. Выводы: апоптоз, индуцированный при действии β-лапакона в клетках Т24, может быть час- тично опосредован митохондриальным сигнальным каскадом

In Situ Observations of the Deformation Behavior and Fracture Mechanisms of Ti-45Al-2Nb-2Mn+0.8 vol pct TiB₂

The deformation and fracture mechanisms of a nearly lamellar Ti-45Al-2Nb-2Mn (at. pct) + 0.8 vol pct TiB₂ intermetallic, processed into an actual low-pressure turbine blade, were examined by means of in situ tensile and tensile-creep experiments performed inside a scanning electron microscope (SEM). Low elongation-to-failure and brittle fracture were observed at room temperature, while the larger elongations-to-failure at high temperature facilitated the observation of the onset and propagation of damage. It was found that the dominant damage mechanisms at high temperature depended on the applied stress level. Interlamellar cracking was observed only above 390 MPa, which suggests that there is a threshold below which this mechanism is inhibited. Failure during creep tests at 250 MPa was controlled by intercolony cracking. The in situ observations demonstrated that the colony boundaries are damage nucleation and propagation sites during tensile creep, and they seem to be the weakest link in the microstructure for the tertiary creep stage. Therefore, it is proposed that interlamellar areas are critical zones for fracture at higher stresses, whereas lower stress, high-temperature creep conditions lead to intercolony cracking and fracture.The authors are grateful to Industria de Turbo Propulsores, S.A. for supplying the intermetallic blades. Funding from the Spanish Ministry of Science and Innovation through projects MAT2009-14547-C02-01 and MAT2009-14547-C02-02 is acknowledged. The Madrid Regional Government supported this project partially through the ESTRUMAT grant P2009/MAT-1585. C.J.B. acknowledges the support from Grant SAB2009-0045 from the Spanish Ministry of Education for his sabbatical stage in Madrid.Publicad

Prediction of major depressive disorder following beta-blocker therapy in patients with cardiovascular diseases

Incident depression has been reported to be associated with poor prognosis in patients with cardiovascular disease (CVD), which might be associated with beta-blocker therapy. Because early detection and intervention can alleviate the severity of depression, we aimed to develop a machine learning (ML) model predicting the onset of major depressive disorder (MDD). A model based on L1 regularized logistic regression was trained against the South Korean nationwide administrative claims database to identify risk factors for the incident MDD after beta-blocker therapy in patients with CVD. We identified 50,397 patients initiating beta-blockers for CVD, with 774 patients developing MDD within 365 days after initiating beta-blocker therapy. An area under the receiver operating characteristic curve (AUC) of 0.74 was achieved. A history of non-selective beta-blockers and factors related to anxiety disorder, sleeping problems, and other chronic diseases were the most strong predictors. AUCs of 0.62–0.71 were achieved in the external validation conducted on six independent electronic health records and claims databases in the USA and South Korea. In conclusion, an ML model that identifies patients at high-risk for incident MDD was developed. Application of ML to identify susceptible patients for adverse events of treatment may serve as an important approach for personalized medicine

Strategies for Controlled Placement of Nanoscale Building Blocks

The capability of placing individual nanoscale building blocks on exact substrate locations in a controlled manner is one of the key requirements to realize future electronic, optical, and magnetic devices and sensors that are composed of such blocks. This article reviews some important advances in the strategies for controlled placement of nanoscale building blocks. In particular, we will overview template assisted placement that utilizes physical, molecular, or electrostatic templates, DNA-programmed assembly, placement using dielectrophoresis, approaches for non-close-packed assembly of spherical particles, and recent development of focused placement schemes including electrostatic funneling, focused placement via molecular gradient patterns, electrodynamic focusing of charged aerosols, and others

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Measurements of Higgs boson production cross sections and couplings in the diphoton decay channel at root s=13 TeV

Measurements of Higgs boson production cross sections and couplings in events where the Higgs boson decays into a pair of photons are reported. Events are selected from a sample of proton-proton collisions at root s = 13TeV collected by the CMS detector at the LHC from 2016 to 2018, corresponding to an integrated luminosity of 137 fb(-1). Analysis categories enriched in Higgs boson events produced via gluon fusion, vector boson fusion, vector boson associated production, and production associated with top quarks are constructed. The total Higgs boson signal strength, relative to the standard model (SM) prediction, is measured to be 1.12 +/- 0.09. Other properties of the Higgs boson are measured, including SM signal strength modifiers, production cross sections, and its couplings to other particles. These include the most precise measurements of gluon fusion and vector boson fusion Higgs boson production in several different kinematic regions, the first measurement of Higgs boson production in association with a top quark pair in five regions of the Higgs boson transverse momentum, and an upper limit on the rate of Higgs boson production in association with a single top quark. All results are found to be in agreement with the SM expectations.Peer reviewe

Measurement of the top quark mass using events with a single reconstructed top quark in pp collisions at root s=13 TeV

Abstract:A measurement of the top quark mass is performed using a data sample en-riched with single top quark events produced in thetchannel. The study is based on proton-proton collision data, corresponding to an integrated luminosity of 35.9 fb−1, recorded at√s= 13TeV by the CMS experiment at the LHC in 2016. Candidate events are selectedby requiring an isolated high-momentum lepton (muon or electron) and exactly two jets,of which one is identified as originating from a bottom quark. Multivariate discriminantsare designed to separate the signal from the background. Optimized thresholds are placedon the discriminant outputs to obtain an event sample with high signal purity. The topquark mass is found to be172.13+0.76−0.77GeV, where the uncertainty includes both the sta-tistical and systematic components, reaching sub-GeV precision for the first time in thisevent topology. The masses of the top quark and antiquark are also determined separatelyusing the lepton charge in the final state, from which the mass ratio and difference aredetermined to be0.9952+0.0079−0.0104and0.83+1.79−1.35GeV, respectively. The results are consistentwithCPTinvariance

Search for gravitational-wave transients associated with magnetar bursts in advanced LIGO and advanced Virgo data from the third observing run

Gravitational waves are expected to be produced from neutron star oscillations associated with magnetar giant f lares and short bursts. We present the results of a search for short-duration (milliseconds to seconds) and longduration (∼100 s) transient gravitational waves from 13 magnetar short bursts observed during Advanced LIGO, Advanced Virgo, and KAGRA’s third observation run. These 13 bursts come from two magnetars, SGR1935 +2154 and SwiftJ1818.0−1607. We also include three other electromagnetic burst events detected by FermiGBM which were identified as likely coming from one or more magnetars, but they have no association with a known magnetar. No magnetar giant flares were detected during the analysis period. We find no evidence of gravitational waves associated with any of these 16 bursts. We place upper limits on the rms of the integrated incident gravitational-wave strain that reach 3.6 × 10−²³ Hz at 100 Hz for the short-duration search and 1.1 ×10−²² Hz at 450 Hz for the long-duration search. For a ringdown signal at 1590 Hz targeted by the short-duration search the limit is set to 2.3 × 10−²² Hz. Using the estimated distance to each magnetar, we derive upper limits upper limits on the emitted gravitational-wave energy of 1.5 × 1044 erg (1.0 × 1044 erg) for SGR 1935+2154 and 9.4 × 10^43 erg (1.3 × 1044 erg) for Swift J1818.0−1607, for the short-duration (long-duration) search. Assuming isotropic emission of electromagnetic radiation of the burst fluences, we constrain the ratio of gravitational-wave energy to electromagnetic energy for bursts from SGR 1935+2154 with the available fluence information. The lowest of these ratios is 4.5 × 103

Long term creep of TiAl + W + Si with polycrystalline and columnar grain structures

The long term creep properties at 207 MPa and 760°C of TiAl + W + Si with a fully lamellar microstructure and either polycrystalline grains or a columnar grain structure are compared. The results indicate that the columnar grain structure reduces the primary creep strain and delays the onset of tertiary creep, with only 1.2% creep strain after 10,000 h

The effects of heat treatments and tungsten additions on microstructures and tensile properties of powder metallurgy Ti-48Al-2Nb-2Cr

The microstructures and tensile properties of a fully lamellar Ti-48Al-2Cr-2Nb, and two tungsten-modified versions, Ti-48Al-2Cr-2Nb-0.5W and Ti-48Al-2Cr-2Nb-1.0W (atomic percent) are investigated. Gas atomized powders are consolidated by hot isostatic pressing followed by solution treatment and aging. The microstructures are characterized by optical, scanning electron, and transmission electron microscopy and mechanical properties are characterized by room temperature tensile testing. The solution heat treatment, combined with controlled cooling, generates relatively fine, fully lamellar grains. Tungsten reduces the propensity for martensitic gamma formation during cooling, and slows down lamellar coarsening as well as the formation of equiaxed gamma phase during aging. The aging treatment stabilizes the microstructure and, in the tungsten-modified alloys, causes beta phase precipitation at lamellar interfaces and grain boundaries. Both aging and tungsten additions increase the alloy strength and reduce ductility. The fracture morphologies of the alloys are similar and exhibit mixed-mode fracture consisting of inter- and intra-granular cracking, as well as inter-lamellar cracking