PTMcode v2: a resource for functional associations of post-translational modifications within and between proteins

The post-translational regulation of proteins is mainly driven by two molecular events, their modification by several types of moieties and their interaction with other proteins. These two processes are interdependent and together are responsible for the function of the protein in a particular cell state. Several databases focus on the prediction and compilation of protein-protein interactions (PPIs) and no less on the collection and analysis of protein post-translational modifications (PTMs), however, there are no resources that concentrate on describing the regulatory role of PTMs in PPIs. We developed several methods based on residue co-evolution and proximity to predict the functional associations of pairs of PTMs that we apply to modifications in the same protein and between two interacting proteins. In order to make data available for understudied organisms, PTMcode v2 (http://ptmcode.embl.de) includes a new strategy to propagate PTMs from validated modified sites through orthologous proteins. The second release of PTMcode covers 19 eukaryotic species from which we collected more than 300 000 experimentally verified PTMs (>1 300 000 propagated) of 69 types extracting the post-translational regulation of >100 000 proteins and >100 000 interactions. In total, we report 8 million associations of PTMs regulating single proteins and over 9.4 million interplays tuning PPIs

A Study of the Near-Ultraviolet Spectrum of Vega

UV, optical, and near-IR spectra of Vega have been combined to test our understanding of stellar atmospheric opacities, and to examine the possibility of constraining chemical abundances from low-resolution UV fluxes. We have carried out a detailed analysis assuming Local Thermodynamic Equilibrium (LTE) to identify the most important contributors to the UV continuous opacity: H, H$^{-}$, C I, and Si II. Our analysis also assumes that Vega is spherically symmetric and its atmosphere is well described with the plane parallel approximation. Comparing observations and computed fluxes we have been able to discriminate between two different flux scales that have been proposed, the IUE-INES and the HST scales, favoring the latter. The effective temperature and angular diameter derived from the analysis of observed optical and near-UV spectra are in very good agreement with previous determinations based on different techniques. The silicon abundance is poorly constrained by the UV observations of the continuum and strong lines, but the situation is more favorable for carbon and the abundances inferred from the UV continuum and optical absorption lines are in good agreement. Some spectral intervals in the UV spectrum of Vega that the calculations do not reproduce well are likely affected by deviations from LTE, but we conclude that our understanding of UV atmospheric opacities is fairly complete for early A-type stars.Comment: 13 pages, 9 figures, to be published in Ap

Development and validation of a high performance liquid chromatography-tandem mass spectrometry method for the absolute analysis of 17 alpha D-amino acids in cooked meals

In the nutrition field, there is a lack of understanding about the impact that dietary chiral composition may have on health, especially regarding cooked meals. Chiral amino acids (AAs) are naturally present in food and their proportion may vary quite a lot. Besides, the D-amino acids (D-AAs) are present in very low concentration compared to L-AAs, so very sensitive methods are required for their accurate quantitation. Moreover, some of them have been described as indicators of quality and different food processes. In this research, we propose a robust method for the absolute quantitation and enantiomeric ratio of 17 D-AAs in cooked meals. The AAs were extracted from 1 g of the homogenised meal with methanol, derivatised with (S)-N-(4-nitrophenoxycarbonyl) phenylalanine methoxyethyl ester ((S)-NIFE) and analysed by RP-LC-MS/MS. The separation was carried out with an Acquity BEH C18 (100 mm x 2.1 mm, 1.7 µm) column at 70 ºC, with 10 mmol/L ammonium bicarbonate in water as eluent A and acetonitrile as eluent B at a 0.3 mL/min flow rate in gradient elution. The MS operated in positive electrospray ionisation method in multiple reaction monitoring (MRM) mode. Isotopically labelled AAs were used as internal standards for the quantitation. The method was validated for 17 D-AAs in the cooked food samples in terms of specificity, linearity, precision, accuracy, matrix effect and stability. LLOQ are 2.0 ng/mL for most of them. Additionally, linearity was also studied for L-AAs. After optimization and validation, the method was applied to real breakfast, lunch and dinner samples of cooked meals (n = 18) that were part of a diet with a very high concordance with WHO dietary guidelines. Level of concentration of major and minor D-AAs have been described per total daily intake and within each of the three main meals. This method can be used for quality control purposes as well as to investigate the role of chiral composition in food and clinical outcomes

Spin and charge ordering in self-doped Mott insulators

We have investigated possible spin and charge ordered states in 3d transition-metal oxides with small or negative charge-transfer energy, which can be regarded as self-doped Mott insulators, using Hartree-Fock calculations on d-p-type lattice models. It was found that an antiferromagnetic state with charge ordering in oxygen 2p orbitals is favored for relatively large charge-transfer energy and may be relevant for PrNiO$_3$ and NdNiO$_3$. On the other hand, an antiferromagnetic state with charge ordering in transition-metal 3$d$ orbitals tends to be stable for highly negative charge-transfer energy and can be stabilized by the breathing-type lattice distortion; this is probably realized in YNiO$_3$.Comment: 4 pages, 4 figure

Durvalumab plus tremelimumab for the treatment of advanced neuroendocrine neoplasms of gastroenteropancreatic and lung origin

Single immune checkpoint blockade has shown limited activity in patients with neuroendocrine neoplasms (NENs). Here the authors report the results of a phase II clinical trial of durvalumab (anti-PD-L1) and tremelimumab (anti CTLA-4) in patients with advanced NENs of gastroenteropancreatic and lung origin. Single immune checkpoint blockade in advanced neuroendocrine neoplasms (NENs) shows limited efficacy; dual checkpoint blockade may improve treatment activity. Dune (NCT03095274) is a non-randomized controlled multicohort phase II clinical trial evaluating durvalumab plus tremelimumab activity and safety in advanced NENs. This study included 123 patients presenting between 2017 and 2019 with typical/atypical lung carcinoids (Cohort 1), G1/2 gastrointestinal (Cohort 2), G1/2 pancreatic (Cohort 3) and G3 gastroenteropancreatic (GEP) (Cohort 4) NENs; who progressed to standard therapies. Patients received 1500 mg durvalumab and 75 mg tremelimumab for up to 13 and 4 cycles (every 4 weeks), respectively. The primary objective was the 9-month clinical benefit rate (CBR) for cohorts 1-3 and 9-month overall survival (OS) rate for Cohort 4. Secondary endpoints included objective response rate, duration of response, progression-free survival according to irRECIST, overall survival, and safety. Correlation of PD-L1 expression with efficacy was exploratory. The 9-month CBR was 25.9%/35.5%/25% for Cohorts 1, 2, and 3 respectively. The 9-month OS rate for Cohort 4 was 36.1%, surpassing the futility threshold. Benefit in Cohort 4 was observed regardless of differentiation and Ki67 levels. PD-L1 combined scores did not correlate with treatment activity. Safety profile was consistent with that of prior studies. In conclusion, durvalumab plus tremelimumab is safe in NENs and shows modest survival benefit in G3 GEP-NENs; with one-third of these patients experiencing a prolonged OS

ALMA resolves the torus of NGC 1068: continuum and molecular line emission

We have used the Atacama Large Millimeter Array (ALMA) to map the emission of the CO(6-5) molecular line and the 432 {\mu}m continuum emission from the 300 pc-sized circumnuclear disk (CND) of the nearby Seyfert 2 galaxy NGC 1068 with a spatial resolution of ~4 pc. These observations spatially resolve the CND and, for the first time, image the dust emission, the molecular gas distribution, and the kinematics from a 7-10 pc-diameter disk that represents the submillimeter counterpart of the putative torus of NGC 1068. We fitted the nuclear spectral energy distribution of the torus using ALMA and near and mid-infrared (NIR/MIR) data with CLUMPY models. The mass and radius of the best-fit solution for the torus are both consistent with the values derived from the ALMA data alone: Mgas_torus=(1+-0.3)x10^5 Msun and Rtorus=3.5+-0.5 pc. The dynamics of the molecular gas in the torus show non-circular motions and enhanced turbulence superposed on the rotating pattern of the disk. The kinematic major axis of the CO torus is tilted relative to its morphological major axis. By contrast with the nearly edge-on orientation of the H2O megamaser disk, we have found evidence suggesting that the molecular torus is less inclined (i=34deg-66deg) at larger radii. The lopsided morphology and complex kinematics of the torus could be the signature of the Papaloizou-Pringle instability, long predicted to likely drive the dynamical evolution of active galactic nuclei (AGN) tori.Comment: Final version accepted by the Astrophysical Journal Letters (ApJLetters) on April 27th 2016, 6 pages, 5 figure