Purification, cloning and regulation of a novel acid-lipase-like protein of hamster expressed in lacrimal glands and tears during lactation ☆

Abstract We report a novel 48-kDa tear acid-lipase-like protein (TALLP), which is markedly induced in lacrimal glands (LG) and secreted in tears of hamster dams during lactation. TALLP is undetectable in LG and tears of normal hamsters, but is also induced after gonadectomy in both sexes and this is prevented by androgen, estrogen or thyroid hormone treatment. These observations and the obliteration of TALLP upon cessation of lactation suggest that endogenous estrogens (in females) and androgens (in males) completely repress TALLP expression. Purified TALLP is monomeric, contains ∼ 18% N-glycosylation and several pI isoforms. TALLP expression was tissue-specific and immunolocalized in LG acinar cells. The cDNA deduced amino-acid sequence of TALLP precursor (398 residue, containing a 19 residues signal-peptide) showed only 43-48% identity with all known mammalian acid-lipases, including even those of other rodents, suggesting that TALLP is a prototype of a new category, within the acid-lipase family. Surprisingly, although the catalytic triad residues and other sequence features important for lipolytic activity are conserved in TALLP, it has no detectable lipase activity. However, TALLP binds the polarity sensitive hydrophobic probe, 1-aminoanthracene (K d = 12 μM). TALLP might have a unique substrate-specificity or a lipid-binding/carrier function in tears of hamster dams. This is the first report of an acid-lipase-like protein secreted in tears of any species. Since TALLP lacks the usual lipase activity, it can be an excellent model to understand better what other structural features in acid-lipases influence their catalytic activity

Nature of singularity formed by the gravitational collapse in Husain space-time with electromagnetic field and scalar field

In this work, we have investigated the outcome of gravitational collapse in Husain space-time in the presence of electro-magnetic and a scalar field with potential. In order to study the nature of the singularity, global behavior of radial null geodesics have been taken into account. The nature of singularities formed has been thoroughly studied for all possible variations of the parameters. These choices of parameters has been presented in tabular form in various dimensions. It is seen that irrespective of whatever values of the parameters chosen, the collapse always results in a naked singularity in all dimensions. There is less possibility of formation of a black hole. Hence this work is a significant counterexample of the cosmic censorship hypothesis.Comment: 9 pages, 19 figure

The Orbiting Carbon Observatory (OCO-2) Tracks 2-3 Peta-Gram Increase in Carbon Release to the Atmosphere During the 2014-2016 El Nino

The powerful El Nio event of 2015-2016 - the third most intense since the 1950s - has exerted a large impact on the Earth's natural climate system. The column-averaged CO2 dry-air mole fraction (XCO2) observations from satellites and ground based networks are analyzed together with in situ observations for the period of September 2014 to October 2016. From the differences between satellite (OCO-2) observations and simulations using an atmospheric chemistry-transport model, we estimate that, relative to the mean annual fluxes for 2014, the most recent El Nio has contributed to an excess CO2 emission from the Earth's surface (land+ocean) to the atmosphere in the range of 2.4+/-0.2 PgC (1 Pg = 10(exp 15) g) over the period of July 2015 to June 2016. The excess CO2 flux is resulted primarily from reduction in vegetation uptake due to drought, and to a lesser degree from increased biomass burning. It is about the half of the CO2 flux anomaly (range: 4.4-6.7 PgC) estimated for the 1997/1998 El Nio. The annual total sink is estimated to be 3.9+/-0.2 PgC for the assumed fossil fuel emission of 10.1 PgC. The major uncertainty in attribution arise from error in anthropogenic emission trends, satellite data and atmospheric transport

Effect of magnetic nanoparticles on the nematic-smectic-A phase transition

Recent experiments on mixed liquid crystals have highlighted the hugely significant role of ferromagnetic nanoparticle impurities in defining the nematic-smectic-A phase transition point. Structured around a Flory-Huggins free energy of isotropic mixing and Landau-de Gennes free energy, this article presents a phenomenological mean-field model that quantifies the role of such impurities in analyzing thermodynamic phases, in a mixture of thermotropic smectic liquid crystal and ferromagnetic nanoparticles. First we discuss the impact of ferromagnetic nanoparticles on the isotropic-ferronematic and ferronematic-ferrosmectic phase transitions and their transition temperatures. This is followed by plotting and discussing various topologies in the phase diagrams. Our model results indicate that there exists a critical concentration of nanoparticle impurities for which the second order N-SmA transition becomes first order at a tricritical point. Calculations based on this model show remarkable agreement with experiment

Age of air as a diagnostic for transport timescales in global models

This paper presents the first results of an age-of-air (AoA) inter-comparison of six global transport models. Following a protocol, three global circulation models and three chemistry transport models simulated five tracers with boundary conditions that grow linearly in time. This allows for an evaluation of the AoA and transport times associated with inter-hemispheric transport, vertical mixing in the troposphere, transport to and in the stratosphere, and transport of air masses between land and ocean. Since AoA is not a directly measurable quantity in the atmosphere, simulations of ²²²Rn and SF₆ were also performed. We focus this first analysis on averages over the period 2000–2010, taken from longer simulations covering the period 1988–2014. We find that two models, NIES and TOMCAT, show substantially slower vertical mixing in the troposphere compared to other models (LMDZ, TM5, EMAC, and ACTM). However, while the TOMCAT model, as used here, has slow transport between the hemispheres and between the atmosphere over land and ocean, the NIES model shows efficient horizontal mixing and a smaller latitudinal gradient in SF₆ compared to the other models and observations. We find consistent differences between models concerning vertical mixing of the troposphere, expressed as AoA differences and modelled ²²²Rn gradients between 950 and 500hPa. All models agree, however, on an interesting asymmetry in inter-hemispheric mixing, with faster transport from the Northern Hemisphere surface to the Southern Hemisphere than vice versa. This is attributed to a rectifier effect caused by a stronger seasonal cycle in boundary layer venting over Northern Hemispheric land masses, and possibly to a related asymmetric position of the intertropical convergence zone. The calculated AoA in the mid–upper stratosphere varies considerably among the models (4–7 years). Finally, we find that the inter-model differences are generally larger than differences in AoA that result from using the same model with a different resolution or convective parameterisation. Taken together, the AoA model inter-comparison provides a useful addition to traditional approaches to evaluate transport timescales. Results highlight that inter-model differences associated with resolved transport (advection, reanalysis data, nudging) and parameterised transport (convection, boundary layer mixing) are still large and require further analysis. For this purpose, all model output and analysis software are available

Gridded fossil CO2 emissions and related O2 combustion consistent with national inventories 1959-2018

Quantification of CO2 fluxes at the Earth’s surface is required to evaluate the causes and drivers of observed increases in atmospheric CO2 concentrations. Atmospheric inversion models disaggregate observed variations in atmospheric CO2 concentration to variability in CO2 emissions and sinks. They require prior constraints fossil CO2 emissions. Here we describe GCP-GridFED (version 2019.1), a gridded fossil emissions dataset that is consistent with the national CO2 emissions reported by the Global Carbon Project (GCP). GCP-GridFEDv2019.1 provides monthly fossil CO2 emissions estimates for the period 1959-2018 at a spatial resolution of 0.1°. Estimates are provided separately for oil, coal and natural gas, for mixed international bunker fuels, and for the calcination of limestone during cement production. GCP-GridFED also includes gridded estimates of O2 uptake based on oxidative ratios for oil, coal and natural gas. It will be updated annually and made available for atmospheric inversions contributing to GCP global carbon budget assessments, thus aligning the prior constraints on top-down fossil CO2 emissions with the bottom-up estimates compiled by the GCP

The Orbiting Carbon Observatory (OCO-2) tracks 2–3 peta-gram increase in carbon release to the atmosphere during the 2014–2016 El Niño

The powerful El Niño event of 2015–2016 – the third most intense since the 1950s – has exerted a large impact on the Earth’s natural climate system. The column-averaged CO_2 dry-air mole fraction (XCO_2) observations from satellites and ground-based networks are analyzed together with in situ observations for the period of September 2014 to October 2016. From the differences between satellite (OCO-2) observations and simulations using an atmospheric chemistry-transport model, we estimate that, relative to the mean annual fluxes for 2014, the most recent El Niño has contributed to an excess CO_2 emission from the Earth’s surface (land + ocean) to the atmosphere in the range of 2.4 ± 0.2 PgC (1 Pg = 10^(15) g) over the period of July 2015 to June 2016. The excess CO_2 flux is resulted primarily from reduction in vegetation uptake due to drought, and to a lesser degree from increased biomass burning. It is about the half of the CO_2 flux anomaly (range: 4.4–6.7 PgC) estimated for the 1997/1998 El Niño. The annual total sink is estimated to be 3.9 ± 0.2 PgC for the assumed fossil fuel emission of 10.1 PgC. The major uncertainty in attribution arise from error in anthropogenic emission trends, satellite data and atmospheric transport

Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): Survival results from an adaptive, multiarm, multistage, platform randomised controlled trial

BACKGROUND Long-term hormone therapy has been the standard of care for advanced prostate cancer since the 1940s. STAMPEDE is a randomised controlled trial using a multiarm, multistage platform design. It recruits men with high-risk, locally advanced, metastatic or recurrent prostate cancer who are starting first-line long-term hormone therapy. We report primary survival results for three research comparisons testing the addition of zoledronic acid, docetaxel, or their combination to standard of care versus standard of care alone. METHODS Standard of care was hormone therapy for at least 2 years; radiotherapy was encouraged for men with N0M0 disease to November, 2011, then mandated; radiotherapy was optional for men with node-positive non-metastatic (N+M0) disease. Stratified randomisation (via minimisation) allocated men 2:1:1:1 to standard of care only (SOC-only; control), standard of care plus zoledronic acid (SOC + ZA), standard of care plus docetaxel (SOC + Doc), or standard of care with both zoledronic acid and docetaxel (SOC + ZA + Doc). Zoledronic acid (4 mg) was given for six 3-weekly cycles, then 4-weekly until 2 years, and docetaxel (75 mg/m(2)) for six 3-weekly cycles with prednisolone 10 mg daily. There was no blinding to treatment allocation. The primary outcome measure was overall survival. Pairwise comparisons of research versus control had 90% power at 2·5% one-sided α for hazard ratio (HR) 0·75, requiring roughly 400 control arm deaths. Statistical analyses were undertaken with standard log-rank-type methods for time-to-event data, with hazard ratios (HRs) and 95% CIs derived from adjusted Cox models. This trial is registered at ClinicalTrials.gov (NCT00268476) and ControlledTrials.com (ISRCTN78818544). FINDINGS 2962 men were randomly assigned to four groups between Oct 5, 2005, and March 31, 2013. Median age was 65 years (IQR 60-71). 1817 (61%) men had M+ disease, 448 (15%) had N+/X M0, and 697 (24%) had N0M0. 165 (6%) men were previously treated with local therapy, and median prostate-specific antigen was 65 ng/mL (IQR 23-184). Median follow-up was 43 months (IQR 30-60). There were 415 deaths in the control group (347 [84%] prostate cancer). Median overall survival was 71 months (IQR 32 to not reached) for SOC-only, not reached (32 to not reached) for SOC + ZA (HR 0·94, 95% CI 0·79-1·11; p=0·450), 81 months (41 to not reached) for SOC + Doc (0·78, 0·66-0·93; p=0·006), and 76 months (39 to not reached) for SOC + ZA + Doc (0·82, 0·69-0·97; p=0·022). There was no evidence of heterogeneity in treatment effect (for any of the treatments) across prespecified subsets. Grade 3-5 adverse events were reported for 399 (32%) patients receiving SOC, 197 (32%) receiving SOC + ZA, 288 (52%) receiving SOC + Doc, and 269 (52%) receiving SOC + ZA + Doc. INTERPRETATION Zoledronic acid showed no evidence of survival improvement and should not be part of standard of care for this population. Docetaxel chemotherapy, given at the time of long-term hormone therapy initiation, showed evidence of improved survival accompanied by an increase in adverse events. Docetaxel treatment should become part of standard of care for adequately fit men commencing long-term hormone therapy. FUNDING Cancer Research UK, Medical Research Council, Novartis, Sanofi-Aventis, Pfizer, Janssen, Astellas, NIHR Clinical Research Network, Swiss Group for Clinical Cancer Research

Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy

BACKGROUND Abiraterone acetate plus prednisolone improves survival in men with relapsed prostate cancer. We assessed the effect of this combination in men starting long-term androgen-deprivation therapy (ADT), using a multigroup, multistage trial design. METHODS We randomly assigned patients in a 1:1 ratio to receive ADT alone or ADT plus abiraterone acetate (1000 mg daily) and prednisolone (5 mg daily) (combination therapy). Local radiotherapy was mandated for patients with node-negative, nonmetastatic disease and encouraged for those with positive nodes. For patients with nonmetastatic disease with no radiotherapy planned and for patients with metastatic disease, treatment continued until radiologic, clinical, or prostate-specific antigen (PSA) progression; otherwise, treatment was to continue for 2 years or until any type of progression, whichever came first. The primary outcome measure was overall survival. The intermediate primary outcome was failure-free survival (treatment failure was defined as radiologic, clinical, or PSA progression or death from prostate cancer). RESULTS A total of 1917 patients underwent randomization from November 2011 through January 2014. The median age was 67 years, and the median PSA level was 53 ng per milliliter. A total of 52% of the patients had metastatic disease, 20% had node-positive or node-indeterminate nonmetastatic disease, and 28% had node-negative, nonmetastatic disease; 95% had newly diagnosed disease. The median follow-up was 40 months. There were 184 deaths in the combination group as compared with 262 in the ADT-alone group (hazard ratio, 0.63; 95% confidence interval [CI], 0.52 to 0.76; P<0.001); the hazard ratio was 0.75 in patients with nonmetastatic disease and 0.61 in those with metastatic disease. There were 248 treatment-failure events in the combination group as compared with 535 in the ADT-alone group (hazard ratio, 0.29; 95% CI, 0.25 to 0.34; P<0.001); the hazard ratio was 0.21 in patients with nonmetastatic disease and 0.31 in those with metastatic disease. Grade 3 to 5 adverse events occurred in 47% of the patients in the combination group (with nine grade 5 events) and in 33% of the patients in the ADT-alone group (with three grade 5 events). CONCLUSIONS Among men with locally advanced or metastatic prostate cancer, ADT plus abiraterone and prednisolone was associated with significantly higher rates of overall and failure-free survival than ADT alone. (Funded by Cancer Research U.K. and others; STAMPEDE ClinicalTrials.gov number, NCT00268476, and Current Controlled Trials number, ISRCTN78818544.